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-{"docstore/data": {"6dd467cf-1cf2-448b-b9d6-ce147cc7e4c3": {"__data__": {"id_": "6dd467cf-1cf2-448b-b9d6-ce147cc7e4c3", "embedding": null, "metadata": {"page_label": "1", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento titulado \"WHO - Technical Report Series 970\" es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que probablemente aborda temas relacionados con la salud p\u00fablica, investigaciones cient\u00edficas, recomendaciones de pol\u00edticas o directrices sobre pr\u00e1cticas de salud. Sin embargo, el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el informe \"WHO - Technical Report Series 970\"?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe que no se puede encontrar en otros lugares sin acceso al documento completo.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en el informe y c\u00f3mo se relacionan con las tendencias actuales en la salud global?**\n   - Esta pregunta se centra en la relevancia del informe en el contexto de los desaf\u00edos de salud contempor\u00e1neos, lo que podr\u00eda no estar disponible en otras fuentes.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas o enfoques se utilizan en el informe para abordar los problemas de salud discutidos?**\n   - Esta pregunta indaga sobre los m\u00e9todos espec\u00edficos que la OMS podr\u00eda haber utilizado en su investigaci\u00f3n o an\u00e1lisis, lo que podr\u00eda ser \u00fanico para este informe en particular.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que probablemente no se encuentre en otros documentos o fuentes, dado que el contenido del informe no est\u00e1 disponible en el contexto proporcionado.", "excerpt_keywords": "Keywords: salud p\u00fablica, OMS, informe t\u00e9cnico, recomendaciones, investigaci\u00f3n cient\u00edfica"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "856b2a05-511a-4cdd-af5c-b5e4124c8464", "node_type": "4", "metadata": {"page_label": "1", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "6fd8d581b9dab04132735639a4e175cb09211bbedd33080c09365e549063e404", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "acb87d03-d7b5-40e1-be4d-2b8bdbd3469d": {"__data__": {"id_": "acb87d03-d7b5-40e1-be4d-2b8bdbd3469d", "embedding": null, "metadata": {"page_label": "2", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# The World Health Organization\n\nThe World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority for international health matters and public health. One of WHO\u2019s constitutional functions is to provide objective and reliable information and advice in the field of human health, a responsibility that it fulfills in part through its extensive programme of publications. The Organization seeks through its publications to support national health strategies and address the most pressing public health concerns of populations around the world. To respond to the needs of Member States at all levels of development, WHO publishes practical manuals, handbooks and training material for specific categories of health workers; internationally applicable guidelines and standards; reviews and analyses of health policies, programmes and research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision-makers. These books are closely tied to the Organization\u2019s priority activities, encompassing disease prevention and control, the development of equitable health systems based on primary health care, and health promotion for individuals and communities. Progress towards better health for all also demands the global dissemination and exchange of information that draws on the knowledge and experience of all WHO\u2019s Member countries and the collaboration of world leaders in public health and the biomedical sciences. To ensure the widest possible availability of authoritative information and guidance on health matters, WHO secures the broad international distribution of its publications and encourages their translation and adaptation. By helping to promote and protect health and prevent and control disease throughout the world, WHO\u2019s books contribute to achieving the Organization\u2019s principal objective \u2014 the attainment by all people of the highest possible level of health.\n\nThe WHO Technical Report Series makes available the findings of various international groups of experts that provide WHO with the latest scientific and technical advice on a broad range of medical and public health subjects. Members of such expert groups serve without remuneration in their personal capacities rather than as representatives of governments or other bodies; their views do not necessarily reflect the decisions of the stated policy of WHO. An annual subscription to this series, comprising about four to six issues a year, costs CHF 150.00/US$ 180.00 (CHF 105.00/US$ 126.00 in developing countries). For further information, please contact: WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order on line: http://www.who.int/bookorders).\n\n# SELECTED WHO PUBLICATIONS OF RELATED INTEREST\n\n**The International Pharmacopoeia**, fourth edition.  \nVolume 1: general notices; monographs for pharmaceutical substances (A\u2013O)  \nVolume 2: monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents.  \n2006 (1500 pages), also available on CD-ROM and online  \nFirst supplement: general notices; monographs for pharmaceutical substances; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2008 (309 pages), also available on CD-ROM and online  \nSecond supplement: general notices; monographs for pharmaceutical substances and radiopharmaceuticals; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2011 (CD-ROM and online)\n\n**Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms**  \n1998 (94 pages)\n\n**Basic tests for pharmaceutical dosage forms**  \n1991 (134 pages)\n\n**Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials**  \nUpdated, comprehensive edition, 2011 (CD-ROM and online)  \nAlso available on: WHO training modules on GMP. A resource and study pack for trainers, 2007 (CD-ROM).\n\n**WHO Expert Committee on Specifications for Pharmaceutical Preparations**  \nForty-fifth report.  \nWHO Technical Report Series, No. 961, 2011 (428 pages)\n\n**International Nonproprietary Names (INN) for pharmaceutical substances**  \nCumulative List No. 14  \n2011 (available on CD-ROM only)\n\n**The selection and use of essential medicines**  \nReport of the WHO Expert Committee (including the Model List of Essential Medicines for Children).  \nWHO Technical Report Series, No. 965, 2011 (249 pages)\n\n----\n\nFurther information on these and other WHO publications can be obtained from  \nWHO Press, World Health Organization \u2022 1211 Geneva 27, Switzerland \u2022 www.who.int/bookorders  \n**tel.:** +41 22 791 3264; **fax:** +41 22 791 4857; **e-mail:** bookorders@who.int", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento proporciona una visi\u00f3n general sobre la Organizaci\u00f3n Mundial de la Salud (OMS), su establecimiento en 1948, y su funci\u00f3n como autoridad coordinadora en asuntos de salud p\u00fablica a nivel internacional. Se destaca la importancia de las publicaciones de la OMS, que buscan apoyar las estrategias de salud nacionales y abordar preocupaciones de salud p\u00fablica. Adem\u00e1s, se menciona la serie de informes t\u00e9cnicos de la OMS, que incluye hallazgos de grupos de expertos en diversas \u00e1reas de la salud. Tambi\u00e9n se enumeran algunas publicaciones seleccionadas de la OMS relacionadas con la farmacolog\u00eda y la calidad de los medicamentos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las principales \u00e1reas de enfoque de las publicaciones de la OMS y c\u00f3mo contribuyen a la salud global?**\n   - Respuesta: Las publicaciones de la OMS se centran en la prevenci\u00f3n y control de enfermedades, el desarrollo de sistemas de salud equitativos basados en la atenci\u00f3n primaria y la promoci\u00f3n de la salud para individuos y comunidades. Estas publicaciones ayudan a promover y proteger la salud, contribuyendo al objetivo principal de la OMS de alcanzar el m\u00e1s alto nivel de salud posible para todas las personas.\n\n2. **\u00bfQu\u00e9 tipo de expertos contribuyen a la serie de informes t\u00e9cnicos de la OMS y cu\u00e1l es su relaci\u00f3n con las pol\u00edticas de la organizaci\u00f3n?**\n   - Respuesta: Los expertos que contribuyen a la serie de informes t\u00e9cnicos de la OMS sirven sin remuneraci\u00f3n y en sus capacidades personales, no como representantes de gobiernos u otras entidades. Sus opiniones no necesariamente reflejan las decisiones pol\u00edticas de la OMS, lo que subraya la independencia y objetividad de sus recomendaciones.\n\n3. **\u00bfQu\u00e9 costos est\u00e1n asociados con la suscripci\u00f3n a la serie de informes t\u00e9cnicos de la OMS y c\u00f3mo var\u00edan seg\u00fan el nivel de desarrollo de los pa\u00edses?**\n   - Respuesta: La suscripci\u00f3n anual a la serie de informes t\u00e9cnicos de la OMS cuesta CHF 150.00/US$ 180.00, mientras que en los pa\u00edses en desarrollo el costo es de CHF 105.00/US$ 126.00, lo que refleja un esfuerzo por hacer accesible la informaci\u00f3n a diferentes contextos econ\u00f3micos.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\nEl documento \"WHO - Technical Report Series 970\" es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque el contenido espec\u00edfico no est\u00e1 disponible, se puede inferir que el informe aborda temas relevantes en el \u00e1mbito de la salud p\u00fablica, investigaciones cient\u00edficas y recomendaciones de pol\u00edticas de salud. \n\n#### Temas clave:\n- Salud p\u00fablica\n- Investigaciones cient\u00edficas\n- Pol\u00edticas y directrices de salud\n- Tendencias en salud global\n\n#### Entidades:\n- Organizaci\u00f3n Mundial de la Salud (OMS)\n\nEste resumen destaca la naturaleza del informe y su posible enfoque en cuestiones cr\u00edticas de salud, aunque no proporciona detalles espec\u00edficos debido a la falta de contenido disponible.", "excerpt_keywords": "Keywords: World Health Organization, public health, technical report series, pharmaceutical guidelines, health promotion"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8240b5ee-3182-4924-bdd0-b77459465681", "node_type": "4", "metadata": {"page_label": "2", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# The World Health Organization\n\nThe World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority for international health matters and public health. One of WHO\u2019s constitutional functions is to provide objective and reliable information and advice in the field of human health, a responsibility that it fulfills in part through its extensive programme of publications. The Organization seeks through its publications to support national health strategies and address the most pressing public health concerns of populations around the world. To respond to the needs of Member States at all levels of development, WHO publishes practical manuals, handbooks and training material for specific categories of health workers; internationally applicable guidelines and standards; reviews and analyses of health policies, programmes and research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision-makers. These books are closely tied to the Organization\u2019s priority activities, encompassing disease prevention and control, the development of equitable health systems based on primary health care, and health promotion for individuals and communities. Progress towards better health for all also demands the global dissemination and exchange of information that draws on the knowledge and experience of all WHO\u2019s Member countries and the collaboration of world leaders in public health and the biomedical sciences. To ensure the widest possible availability of authoritative information and guidance on health matters, WHO secures the broad international distribution of its publications and encourages their translation and adaptation. By helping to promote and protect health and prevent and control disease throughout the world, WHO\u2019s books contribute to achieving the Organization\u2019s principal objective \u2014 the attainment by all people of the highest possible level of health.\n\nThe WHO Technical Report Series makes available the findings of various international groups of experts that provide WHO with the latest scientific and technical advice on a broad range of medical and public health subjects. Members of such expert groups serve without remuneration in their personal capacities rather than as representatives of governments or other bodies; their views do not necessarily reflect the decisions of the stated policy of WHO. An annual subscription to this series, comprising about four to six issues a year, costs CHF 150.00/US$ 180.00 (CHF 105.00/US$ 126.00 in developing countries). For further information, please contact: WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order on line: http://www.who.int/bookorders).\n\n# SELECTED WHO PUBLICATIONS OF RELATED INTEREST\n\n**The International Pharmacopoeia**, fourth edition.  \nVolume 1: general notices; monographs for pharmaceutical substances (A\u2013O)  \nVolume 2: monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents.  \n2006 (1500 pages), also available on CD-ROM and online  \nFirst supplement: general notices; monographs for pharmaceutical substances; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2008 (309 pages), also available on CD-ROM and online  \nSecond supplement: general notices; monographs for pharmaceutical substances and radiopharmaceuticals; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2011 (CD-ROM and online)\n\n**Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms**  \n1998 (94 pages)\n\n**Basic tests for pharmaceutical dosage forms**  \n1991 (134 pages)\n\n**Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials**  \nUpdated, comprehensive edition, 2011 (CD-ROM and online)  \nAlso available on: WHO training modules on GMP. A resource and study pack for trainers, 2007 (CD-ROM).\n\n**WHO Expert Committee on Specifications for Pharmaceutical Preparations**  \nForty-fifth report.  \nWHO Technical Report Series, No. 961, 2011 (428 pages)\n\n**International Nonproprietary Names (INN) for pharmaceutical substances**  \nCumulative List No. 14  \n2011 (available on CD-ROM only)\n\n**The selection and use of essential medicines**  \nReport of the WHO Expert Committee (including the Model List of Essential Medicines for Children).  \nWHO Technical Report Series, No. 965, 2011 (249 pages)\n\n----\n\nFurther information on these and other WHO publications can be obtained from  \nWHO Press, World Health Organization \u2022 1211 Geneva 27, Switzerland \u2022 www.who.int/bookorders  \n**tel.:** +41 22 791 3264; **fax:** +41 22 791 4857; **e-mail:** bookorders@who.int", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "c831bbc1b04191b0c3c52638cb7cf2ee19127c482bee1214c987db9f602212b4", "class_name": "RelatedNodeInfo"}, "3": {"node_id": "ef48ffb3-43e3-4b4e-861f-8d8be7d02d9f", "node_type": "1", "metadata": {}, "hash": "e0069673dae3643fc340c57d76b6e8ece1b5d398cc3520bd53bec1272454cf97", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# The World Health Organization\n\nThe World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority for international health matters and public health. One of WHO\u2019s constitutional functions is to provide objective and reliable information and advice in the field of human health, a responsibility that it fulfills in part through its extensive programme of publications. The Organization seeks through its publications to support national health strategies and address the most pressing public health concerns of populations around the world. To respond to the needs of Member States at all levels of development, WHO publishes practical manuals, handbooks and training material for specific categories of health workers; internationally applicable guidelines and standards; reviews and analyses of health policies, programmes and research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision-makers. These books are closely tied to the Organization\u2019s priority activities, encompassing disease prevention and control, the development of equitable health systems based on primary health care, and health promotion for individuals and communities. Progress towards better health for all also demands the global dissemination and exchange of information that draws on the knowledge and experience of all WHO\u2019s Member countries and the collaboration of world leaders in public health and the biomedical sciences. To ensure the widest possible availability of authoritative information and guidance on health matters, WHO secures the broad international distribution of its publications and encourages their translation and adaptation. By helping to promote and protect health and prevent and control disease throughout the world, WHO\u2019s books contribute to achieving the Organization\u2019s principal objective \u2014 the attainment by all people of the highest possible level of health.\n\nThe WHO Technical Report Series makes available the findings of various international groups of experts that provide WHO with the latest scientific and technical advice on a broad range of medical and public health subjects. Members of such expert groups serve without remuneration in their personal capacities rather than as representatives of governments or other bodies; their views do not necessarily reflect the decisions of the stated policy of WHO. An annual subscription to this series, comprising about four to six issues a year, costs CHF 150.00/US$ 180.00 (CHF 105.00/US$ 126.00 in developing countries). For further information, please contact: WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order on line: http://www.who.int/bookorders).\n\n# SELECTED WHO PUBLICATIONS OF RELATED INTEREST\n\n**The International Pharmacopoeia**, fourth edition.  \nVolume 1: general notices; monographs for pharmaceutical substances (A\u2013O)  \nVolume 2: monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents.  \n2006 (1500 pages), also available on CD-ROM and online  \nFirst supplement: general notices; monographs for pharmaceutical substances; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2008 (309 pages), also available on CD-ROM and online  \nSecond supplement: general notices; monographs for pharmaceutical substances and radiopharmaceuticals; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2011 (CD-ROM and online)\n\n**Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms**  \n1998 (94 pages)\n\n**Basic tests for pharmaceutical dosage forms**  \n1991 (134 pages)\n\n**Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials**  \nUpdated, comprehensive edition, 2011 (CD-ROM and online)  \nAlso available on: WHO training modules on GMP. A resource and study pack for trainers, 2007 (CD-ROM).\n\n**WHO Expert Committee on Specifications for Pharmaceutical Preparations**  \nForty-fifth report.  \nWHO Technical Report Series, No. 961, 2011 (428 pages)\n\n**International Nonproprietary Names (INN) for pharmaceutical substances**  \nCumulative List No. 14  \n2011 (available on CD-ROM only)", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 4698, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ef48ffb3-43e3-4b4e-861f-8d8be7d02d9f": {"__data__": {"id_": "ef48ffb3-43e3-4b4e-861f-8d8be7d02d9f", "embedding": null, "metadata": {"page_label": "2", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# The World Health Organization\n\nThe World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority for international health matters and public health. One of WHO\u2019s constitutional functions is to provide objective and reliable information and advice in the field of human health, a responsibility that it fulfills in part through its extensive programme of publications. The Organization seeks through its publications to support national health strategies and address the most pressing public health concerns of populations around the world. To respond to the needs of Member States at all levels of development, WHO publishes practical manuals, handbooks and training material for specific categories of health workers; internationally applicable guidelines and standards; reviews and analyses of health policies, programmes and research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision-makers. These books are closely tied to the Organization\u2019s priority activities, encompassing disease prevention and control, the development of equitable health systems based on primary health care, and health promotion for individuals and communities. Progress towards better health for all also demands the global dissemination and exchange of information that draws on the knowledge and experience of all WHO\u2019s Member countries and the collaboration of world leaders in public health and the biomedical sciences. To ensure the widest possible availability of authoritative information and guidance on health matters, WHO secures the broad international distribution of its publications and encourages their translation and adaptation. By helping to promote and protect health and prevent and control disease throughout the world, WHO\u2019s books contribute to achieving the Organization\u2019s principal objective \u2014 the attainment by all people of the highest possible level of health.\n\nThe WHO Technical Report Series makes available the findings of various international groups of experts that provide WHO with the latest scientific and technical advice on a broad range of medical and public health subjects. Members of such expert groups serve without remuneration in their personal capacities rather than as representatives of governments or other bodies; their views do not necessarily reflect the decisions of the stated policy of WHO. An annual subscription to this series, comprising about four to six issues a year, costs CHF 150.00/US$ 180.00 (CHF 105.00/US$ 126.00 in developing countries). For further information, please contact: WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order on line: http://www.who.int/bookorders).\n\n# SELECTED WHO PUBLICATIONS OF RELATED INTEREST\n\n**The International Pharmacopoeia**, fourth edition.  \nVolume 1: general notices; monographs for pharmaceutical substances (A\u2013O)  \nVolume 2: monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents.  \n2006 (1500 pages), also available on CD-ROM and online  \nFirst supplement: general notices; monographs for pharmaceutical substances; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2008 (309 pages), also available on CD-ROM and online  \nSecond supplement: general notices; monographs for pharmaceutical substances and radiopharmaceuticals; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2011 (CD-ROM and online)\n\n**Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms**  \n1998 (94 pages)\n\n**Basic tests for pharmaceutical dosage forms**  \n1991 (134 pages)\n\n**Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials**  \nUpdated, comprehensive edition, 2011 (CD-ROM and online)  \nAlso available on: WHO training modules on GMP. A resource and study pack for trainers, 2007 (CD-ROM).\n\n**WHO Expert Committee on Specifications for Pharmaceutical Preparations**  \nForty-fifth report.  \nWHO Technical Report Series, No. 961, 2011 (428 pages)\n\n**International Nonproprietary Names (INN) for pharmaceutical substances**  \nCumulative List No. 14  \n2011 (available on CD-ROM only)\n\n**The selection and use of essential medicines**  \nReport of the WHO Expert Committee (including the Model List of Essential Medicines for Children).  \nWHO Technical Report Series, No. 965, 2011 (249 pages)\n\n----\n\nFurther information on these and other WHO publications can be obtained from  \nWHO Press, World Health Organization \u2022 1211 Geneva 27, Switzerland \u2022 www.who.int/bookorders  \n**tel.:** +41 22 791 3264; **fax:** +41 22 791 4857; **e-mail:** bookorders@who.int", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl texto proporciona una visi\u00f3n general de la Organizaci\u00f3n Mundial de la Salud (OMS), su funci\u00f3n como autoridad en salud p\u00fablica y su compromiso con la difusi\u00f3n de informaci\u00f3n y publicaciones relacionadas con la salud. Se menciona la serie de informes t\u00e9cnicos de la OMS, que incluye recomendaciones y hallazgos de expertos en diversas \u00e1reas de la salud. Adem\u00e1s, se enumeran varias publicaciones seleccionadas de la OMS que abordan temas como pruebas b\u00e1sicas para medicamentos, aseguramiento de la calidad de productos farmac\u00e9uticos y el uso de medicamentos esenciales.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1l es el costo de una suscripci\u00f3n anual a la serie de informes t\u00e9cnicos de la OMS y c\u00f3mo var\u00eda para los pa\u00edses en desarrollo?**\n   - Respuesta: El costo de una suscripci\u00f3n anual a la serie de informes t\u00e9cnicos de la OMS es de CHF 150.00/US$ 180.00, y de CHF 105.00/US$ 126.00 para los pa\u00edses en desarrollo.\n\n2. **\u00bfQu\u00e9 tipo de materiales y recursos ofrece la OMS para apoyar a los trabajadores de la salud?**\n   - Respuesta: La OMS publica manuales pr\u00e1cticos, gu\u00edas, est\u00e1ndares internacionales, revisiones de pol\u00edticas de salud, y materiales de capacitaci\u00f3n para categor\u00edas espec\u00edficas de trabajadores de la salud.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n se incluye en el informe de la OMS sobre la selecci\u00f3n y uso de medicamentos esenciales?**\n   - Respuesta: El informe incluye recomendaciones de la Comisi\u00f3n de Expertos de la OMS y la Lista Modelo de Medicamentos Esenciales para Ni\u00f1os, y est\u00e1 disponible en la Serie de Informes T\u00e9cnicos de la OMS, No. 965, 2011 (249 p\u00e1ginas).", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Organizaci\u00f3n Mundial de la Salud (OMS)**:\n   - Establecida en 1948 como agencia especializada de la ONU.\n   - Funci\u00f3n principal: autoridad coordinadora en asuntos de salud p\u00fablica a nivel internacional.\n   - Proporciona informaci\u00f3n objetiva y confiable en el campo de la salud humana.\n\n2. **Publicaciones de la OMS**:\n   - Apoyan estrategias de salud nacionales y abordan preocupaciones de salud p\u00fablica.\n   - Incluyen manuales, gu\u00edas, an\u00e1lisis de pol\u00edticas y reportes de consenso.\n   - Enfocadas en prevenci\u00f3n y control de enfermedades, desarrollo de sistemas de salud equitativos y promoci\u00f3n de la salud.\n\n3. **Serie de Informes T\u00e9cnicos de la OMS**:\n   - Presenta hallazgos de grupos de expertos internacionales.\n   - Los expertos sirven sin remuneraci\u00f3n y sus opiniones no reflejan necesariamente las pol\u00edticas de la OMS.\n   - Suscripci\u00f3n anual: CHF 150.00/US$ 180.00 (CHF 105.00/US$ 126.00 en pa\u00edses en desarrollo).\n\n4. **Publicaciones Seleccionadas**:\n   - **Farmacopea Internacional**: Monograf\u00edas y m\u00e9todos de an\u00e1lisis.\n   - **Pruebas B\u00e1sicas para Medicamentos**: Evaluaciones de sustancias farmac\u00e9uticas y formas de dosificaci\u00f3n.\n   - **Aseguramiento de Calidad de Productos Farmac\u00e9uticos**: Compendio de directrices.\n   - **Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas**: Informes t\u00e9cnicos.\n   - **Nombres Comunes Internacionales (INN)**: Listas acumulativas de sustancias farmac\u00e9uticas.\n\n5. **Contacto y Acceso a Publicaciones**:\n   - Informaci\u00f3n adicional disponible a trav\u00e9s de WHO Press, Ginebra, Suiza.\n   - Recursos accesibles en l\u00ednea y en CD-ROM.\n\nEste resumen destaca la misi\u00f3n de la OMS, la importancia de sus publicaciones en la salud global y los recursos espec\u00edficos disponibles para profesionales de la salud y responsables de pol\u00edticas.", "excerpt_keywords": "Keywords: World Health Organization, public health, technical report series, pharmaceutical guidelines, essential medicines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8240b5ee-3182-4924-bdd0-b77459465681", "node_type": "4", "metadata": {"page_label": "2", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# The World Health Organization\n\nThe World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority for international health matters and public health. One of WHO\u2019s constitutional functions is to provide objective and reliable information and advice in the field of human health, a responsibility that it fulfills in part through its extensive programme of publications. The Organization seeks through its publications to support national health strategies and address the most pressing public health concerns of populations around the world. To respond to the needs of Member States at all levels of development, WHO publishes practical manuals, handbooks and training material for specific categories of health workers; internationally applicable guidelines and standards; reviews and analyses of health policies, programmes and research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision-makers. These books are closely tied to the Organization\u2019s priority activities, encompassing disease prevention and control, the development of equitable health systems based on primary health care, and health promotion for individuals and communities. Progress towards better health for all also demands the global dissemination and exchange of information that draws on the knowledge and experience of all WHO\u2019s Member countries and the collaboration of world leaders in public health and the biomedical sciences. To ensure the widest possible availability of authoritative information and guidance on health matters, WHO secures the broad international distribution of its publications and encourages their translation and adaptation. By helping to promote and protect health and prevent and control disease throughout the world, WHO\u2019s books contribute to achieving the Organization\u2019s principal objective \u2014 the attainment by all people of the highest possible level of health.\n\nThe WHO Technical Report Series makes available the findings of various international groups of experts that provide WHO with the latest scientific and technical advice on a broad range of medical and public health subjects. Members of such expert groups serve without remuneration in their personal capacities rather than as representatives of governments or other bodies; their views do not necessarily reflect the decisions of the stated policy of WHO. An annual subscription to this series, comprising about four to six issues a year, costs CHF 150.00/US$ 180.00 (CHF 105.00/US$ 126.00 in developing countries). For further information, please contact: WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order on line: http://www.who.int/bookorders).\n\n# SELECTED WHO PUBLICATIONS OF RELATED INTEREST\n\n**The International Pharmacopoeia**, fourth edition.  \nVolume 1: general notices; monographs for pharmaceutical substances (A\u2013O)  \nVolume 2: monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents.  \n2006 (1500 pages), also available on CD-ROM and online  \nFirst supplement: general notices; monographs for pharmaceutical substances; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2008 (309 pages), also available on CD-ROM and online  \nSecond supplement: general notices; monographs for pharmaceutical substances and radiopharmaceuticals; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2011 (CD-ROM and online)\n\n**Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms**  \n1998 (94 pages)\n\n**Basic tests for pharmaceutical dosage forms**  \n1991 (134 pages)\n\n**Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials**  \nUpdated, comprehensive edition, 2011 (CD-ROM and online)  \nAlso available on: WHO training modules on GMP. A resource and study pack for trainers, 2007 (CD-ROM).\n\n**WHO Expert Committee on Specifications for Pharmaceutical Preparations**  \nForty-fifth report.  \nWHO Technical Report Series, No. 961, 2011 (428 pages)\n\n**International Nonproprietary Names (INN) for pharmaceutical substances**  \nCumulative List No. 14  \n2011 (available on CD-ROM only)\n\n**The selection and use of essential medicines**  \nReport of the WHO Expert Committee (including the Model List of Essential Medicines for Children).  \nWHO Technical Report Series, No. 965, 2011 (249 pages)\n\n----\n\nFurther information on these and other WHO publications can be obtained from  \nWHO Press, World Health Organization \u2022 1211 Geneva 27, Switzerland \u2022 www.who.int/bookorders  \n**tel.:** +41 22 791 3264; **fax:** +41 22 791 4857; **e-mail:** bookorders@who.int", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "c831bbc1b04191b0c3c52638cb7cf2ee19127c482bee1214c987db9f602212b4", "class_name": "RelatedNodeInfo"}, "2": {"node_id": "acb87d03-d7b5-40e1-be4d-2b8bdbd3469d", "node_type": "1", "metadata": {"page_label": "2", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# The World Health Organization\n\nThe World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority for international health matters and public health. One of WHO\u2019s constitutional functions is to provide objective and reliable information and advice in the field of human health, a responsibility that it fulfills in part through its extensive programme of publications. The Organization seeks through its publications to support national health strategies and address the most pressing public health concerns of populations around the world. To respond to the needs of Member States at all levels of development, WHO publishes practical manuals, handbooks and training material for specific categories of health workers; internationally applicable guidelines and standards; reviews and analyses of health policies, programmes and research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision-makers. These books are closely tied to the Organization\u2019s priority activities, encompassing disease prevention and control, the development of equitable health systems based on primary health care, and health promotion for individuals and communities. Progress towards better health for all also demands the global dissemination and exchange of information that draws on the knowledge and experience of all WHO\u2019s Member countries and the collaboration of world leaders in public health and the biomedical sciences. To ensure the widest possible availability of authoritative information and guidance on health matters, WHO secures the broad international distribution of its publications and encourages their translation and adaptation. By helping to promote and protect health and prevent and control disease throughout the world, WHO\u2019s books contribute to achieving the Organization\u2019s principal objective \u2014 the attainment by all people of the highest possible level of health.\n\nThe WHO Technical Report Series makes available the findings of various international groups of experts that provide WHO with the latest scientific and technical advice on a broad range of medical and public health subjects. Members of such expert groups serve without remuneration in their personal capacities rather than as representatives of governments or other bodies; their views do not necessarily reflect the decisions of the stated policy of WHO. An annual subscription to this series, comprising about four to six issues a year, costs CHF 150.00/US$ 180.00 (CHF 105.00/US$ 126.00 in developing countries). For further information, please contact: WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order on line: http://www.who.int/bookorders).\n\n# SELECTED WHO PUBLICATIONS OF RELATED INTEREST\n\n**The International Pharmacopoeia**, fourth edition.  \nVolume 1: general notices; monographs for pharmaceutical substances (A\u2013O)  \nVolume 2: monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents.  \n2006 (1500 pages), also available on CD-ROM and online  \nFirst supplement: general notices; monographs for pharmaceutical substances; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2008 (309 pages), also available on CD-ROM and online  \nSecond supplement: general notices; monographs for pharmaceutical substances and radiopharmaceuticals; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2011 (CD-ROM and online)\n\n**Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms**  \n1998 (94 pages)\n\n**Basic tests for pharmaceutical dosage forms**  \n1991 (134 pages)\n\n**Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials**  \nUpdated, comprehensive edition, 2011 (CD-ROM and online)  \nAlso available on: WHO training modules on GMP. A resource and study pack for trainers, 2007 (CD-ROM).\n\n**WHO Expert Committee on Specifications for Pharmaceutical Preparations**  \nForty-fifth report.  \nWHO Technical Report Series, No. 961, 2011 (428 pages)\n\n**International Nonproprietary Names (INN) for pharmaceutical substances**  \nCumulative List No. 14  \n2011 (available on CD-ROM only)\n\n**The selection and use of essential medicines**  \nReport of the WHO Expert Committee (including the Model List of Essential Medicines for Children).  \nWHO Technical Report Series, No. 965, 2011 (249 pages)\n\n----\n\nFurther information on these and other WHO publications can be obtained from  \nWHO Press, World Health Organization \u2022 1211 Geneva 27, Switzerland \u2022 www.who.int/bookorders  \n**tel.:** +41 22 791 3264; **fax:** +41 22 791 4857; **e-mail:** bookorders@who.int", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "40e8e71611a2c7b40d125f687ba8cf9b319cbe29b2a02fb9f9654ab13ae2aab0", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "**Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms**  \n1998 (94 pages)\n\n**Basic tests for pharmaceutical dosage forms**  \n1991 (134 pages)\n\n**Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials**  \nUpdated, comprehensive edition, 2011 (CD-ROM and online)  \nAlso available on: WHO training modules on GMP. A resource and study pack for trainers, 2007 (CD-ROM).\n\n**WHO Expert Committee on Specifications for Pharmaceutical Preparations**  \nForty-fifth report.  \nWHO Technical Report Series, No. 961, 2011 (428 pages)\n\n**International Nonproprietary Names (INN) for pharmaceutical substances**  \nCumulative List No. 14  \n2011 (available on CD-ROM only)\n\n**The selection and use of essential medicines**  \nReport of the WHO Expert Committee (including the Model List of Essential Medicines for Children).  \nWHO Technical Report Series, No. 965, 2011 (249 pages)\n\n----\n\nFurther information on these and other WHO publications can be obtained from  \nWHO Press, World Health Organization \u2022 1211 Geneva 27, Switzerland \u2022 www.who.int/bookorders  \n**tel.:** +41 22 791 3264; **fax:** +41 22 791 4857; **e-mail:** bookorders@who.int", "mimetype": "text/plain", "start_char_idx": 3970, "end_char_idx": 5170, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f98983b1-0f57-47a9-86ed-a7eb89bb7b18": {"__data__": {"id_": "f98983b1-0f57-47a9-86ed-a7eb89bb7b18", "embedding": null, "metadata": {"page_label": "3", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior:\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que probablemente contiene informaci\u00f3n t\u00e9cnica y recomendaciones de la Organizaci\u00f3n Mundial de la Salud (OMS) sobre un tema espec\u00edfico relacionado con la salud p\u00fablica. Sin embargo, el contenido espec\u00edfico del documento no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el \"WHO - Technical Report Series 970\"?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir recomendaciones de salud p\u00fablica o descubrimientos cient\u00edficos.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en el \"WHO - Technical Report Series 970\"?**\n   - Esta pregunta se centra en identificar los temas espec\u00edficos que el informe cubre, lo que podr\u00eda incluir enfermedades, tratamientos, pol\u00edticas de salud, etc.\n\n3. **\u00bfC\u00f3mo se relaciona el \"WHO - Technical Report Series 970\" con otros informes t\u00e9cnicos de la OMS?**\n   - Esta pregunta busca establecer conexiones entre este informe y otros documentos de la OMS, lo que podr\u00eda ayudar a entender su relevancia y contexto dentro de la serie de informes t\u00e9cnicos de la organizaci\u00f3n.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n que probablemente no se encuentre f\u00e1cilmente en otros lugares, dado que el contenido espec\u00edfico del documento no est\u00e1 disponible en el contexto proporcionado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Organizaci\u00f3n Mundial de la Salud (OMS)**:\n   - Establecida en 1948 como agencia especializada de la ONU.\n   - Funci\u00f3n principal: autoridad en salud p\u00fablica y coordinaci\u00f3n de asuntos de salud internacional.\n   - Publica informaci\u00f3n objetiva y confiable para apoyar estrategias de salud nacionales y abordar preocupaciones de salud p\u00fablica.\n\n2. **Publicaciones de la OMS**:\n   - La OMS produce manuales, gu\u00edas, est\u00e1ndares, revisiones de pol\u00edticas y materiales de capacitaci\u00f3n para trabajadores de la salud.\n   - La serie de informes t\u00e9cnicos de la OMS proporciona hallazgos y recomendaciones de grupos de expertos en diversas \u00e1reas de la salud.\n\n3. **Costo de Suscripci\u00f3n**:\n   - Costo anual de la serie de informes t\u00e9cnicos: CHF 150.00/US$ 180.00.\n   - Precio reducido para pa\u00edses en desarrollo: CHF 105.00/US$ 126.00.\n\n4. **Publicaciones Seleccionadas**:\n   - **Pruebas b\u00e1sicas para medicamentos** (1998, 94 p\u00e1ginas).\n   - **Aseguramiento de la calidad de productos farmac\u00e9uticos** (edici\u00f3n actualizada, 2011, CD-ROM y en l\u00ednea).\n   - **Informe sobre la selecci\u00f3n y uso de medicamentos esenciales** (Informe de la Comisi\u00f3n de Expertos, 2011, 249 p\u00e1ginas).\n\n5. **Contacto y Acceso a Publicaciones**:\n   - Informaci\u00f3n adicional disponible a trav\u00e9s de WHO Press, Ginebra, Suiza.\n   - Contacto: tel. +41 22 791 3264; e-mail: bookorders@who.int; sitio web: www.who.int/bookorders.\n\nEste resumen destaca la misi\u00f3n de la OMS, su enfoque en la publicaci\u00f3n de materiales de salud y el acceso a informaci\u00f3n relevante para la comunidad de salud global.", "excerpt_keywords": "Keywords: OMS, salud p\u00fablica, informes t\u00e9cnicos, recomendaciones, publicaciones"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d0aa6eb7-3f95-44b6-8d83-02973af17394", "node_type": "4", "metadata": {"page_label": "3", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "9934403850c43534212c85d4a197b597475e4ce5f751fd26509184d43361a1bc", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "7138c1f3-148e-4558-81fb-2e26cba2d878": {"__data__": {"id_": "7138c1f3-148e-4558-81fb-2e26cba2d878", "embedding": null, "metadata": {"page_label": "4", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Basado en el contexto proporcionado sobre el documento \"WHO - Technical Report Series 970\", aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el Informe T\u00e9cnico de la OMS 970?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir recomendaciones sobre salud p\u00fablica, pol\u00edticas sanitarias o investigaciones cient\u00edficas.\n\n2. **\u00bfQu\u00e9 temas de salud global se abordan en el documento y c\u00f3mo se relacionan con las tendencias actuales en salud p\u00fablica?**\n   - Esta pregunta se centra en identificar los temas tratados en el informe y su relevancia en el contexto de los desaf\u00edos actuales en salud p\u00fablica, lo que podr\u00eda no estar disponible en otras fuentes.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en la elaboraci\u00f3n del Informe T\u00e9cnico de la OMS 970 y c\u00f3mo se justifican estas elecciones?**\n   - Esta pregunta busca profundizar en el enfoque metodol\u00f3gico del informe, lo que podr\u00eda ofrecer una comprensi\u00f3n m\u00e1s clara de la validez y la aplicabilidad de los hallazgos presentados.\n\n### Resumen de nivel superior del contexto circundante:\nEl \"WHO - Technical Report Series 970\" es un documento publicado por la Organizaci\u00f3n Mundial de la Salud que aborda temas relevantes en el \u00e1mbito de la salud global. Estos informes t\u00e9cnicos suelen incluir investigaciones, recomendaciones y directrices que son fundamentales para la formulaci\u00f3n de pol\u00edticas de salud y la pr\u00e1ctica m\u00e9dica. Aunque el contenido espec\u00edfico del documento no est\u00e1 disponible en el contexto proporcionado, es probable que contenga informaci\u00f3n valiosa sobre la salud p\u00fablica y las estrategias de intervenci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades:\n\nEl documento mencionado, \"WHO - Technical Report Series 970\", es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n1. **Organizaci\u00f3n Mundial de la Salud (OMS)**:\n   - Entidad responsable de la elaboraci\u00f3n del informe, que se enfoca en la salud p\u00fablica a nivel global.\n\n2. **Informe T\u00e9cnico**:\n   - El documento forma parte de la serie de informes t\u00e9cnicos de la OMS, que generalmente abordan temas de salud p\u00fablica, investigaciones cient\u00edficas y recomendaciones para pol\u00edticas de salud.\n\n3. **Salud P\u00fablica**:\n   - Aunque no se especifican los temas tratados, es probable que el informe incluya recomendaciones y hallazgos relacionados con enfermedades, tratamientos, prevenci\u00f3n y pol\u00edticas de salud.\n\n### Temas Potenciales:\n- Recomendaciones de salud p\u00fablica.\n- Hallazgos cient\u00edficos sobre enfermedades o tratamientos.\n- Pol\u00edticas de salud y su implementaci\u00f3n.\n- Comparaciones con otros informes t\u00e9cnicos de la OMS.\n\nEste resumen proporciona una visi\u00f3n general de lo que podr\u00eda abarcar el documento, a pesar de la falta de contenido espec\u00edfico en el contexto proporcionado.", "excerpt_keywords": "Keywords: OMS, salud p\u00fablica, informe t\u00e9cnico, recomendaciones, pol\u00edticas de salud"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c21ebae7-9488-4c5e-b6e3-af4c9f0d03df", "node_type": "4", "metadata": {"page_label": "4", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "65bcf28516a7bd2c0c9f2204340ca0618a0f7da34d1fb62277833c7a3ccfb2d0", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d1f3dc7d-adff-43bb-acf0-892659c3965d": {"__data__": {"id_": "d1f3dc7d-adff-43bb-acf0-892659c3965d", "embedding": null, "metadata": {"page_label": "5", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "\n# Contents\n\n1. **Introduction**  \n   1\n\n2. **General policy**  \n   6  \n   2.1 International collaboration  \n   6  \n   2.1.1 Collaboration with international organizations and agencies  \n   6  \n   2.1.2 Pharmacopoeial Discussion Group  \n   7  \n   2.1.3 International Conference on Harmonisation  \n   7  \n   2.1.4 International Conference of Drug Regulatory Authorities  \n   8  \n   2.2 Cross-cutting pharmaceuticals \u2013 quality assurance issues  \n   8  \n   2.2.1 Biological standardization  \n   8  \n   2.2.2 Essential medicines  \n   9  \n   2.2.3 Herbal and complementary medicines  \n   9  \n   2.2.4 Working group meeting on substandard/spurious/falsely-labelled/falsified/  \n   counterfeit medical products  \n   10\n\n3. **Quality control \u2013 specifications and tests**  \n   10  \n   3.1 *The International Pharmacopoeia*  \n   10  \n   3.1.1 Fourth edition update  \n   10  \n   3.1.2 Outreach with stakeholders  \n   11  \n   3.1.3 Annotated work plan  \n   11  \n   3.1.4 Monograph development  \n   12  \n   3.2 Specifications for medicines, including children\u2019s medicines  \n   12  \n   3.2.1 Medicines for HIV and related conditions  \n   12  \n   3.2.2 Antimalarial medicines  \n   13  \n   3.2.3 Antituberculosis medicines  \n   14  \n   3.2.4 Anti-infectives  \n   14  \n   3.2.5 Other medicines  \n   15  \n   3.2.6 Other paediatrics  \n   16  \n   3.3 General monographs for dosage forms and associated method texts  \n   16  \n   3.3.1 Pharmacopoeial Discussion Group-harmonized general texts  \n   16  \n   3.3.2 Uniformity of content single-dose preparations  \n   21  \n   3.3.3 General monograph on tablets  \n   23  \n   3.4 Preface, general notices and supplementary information sections of  \n   *The International Pharmacopoeia*  \n   24\n\n4. **Quality control \u2013 International Reference Materials (International Chemical Reference Substances and Infrared Reference Spectra)**  \n   25  \n   4.1 Update on International Chemical Reference Substances  \n   25  \n   4.1.1 Report on activities of the host organization related to International  \n   Chemical Reference Substances  \n   25  \n   4.1.2 Frequently asked questions about collaborative trials  \n   26  \n   4.1.3 Annual report on International Chemical Reference Substances 2010  \n   26  \n   4.1.4 Lumefantrine for system suitability testing  \n   27  \n   4.1.5 Bacterial endotoxin  \n   27\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con res\u00famenes de nivel superior que pueden ayudar a entender mejor el contenido:\n\n### Resumen de nivel superior:\nEl documento \"WHO - Technical Report Series 970\" aborda temas relacionados con la pol\u00edtica general de colaboraci\u00f3n internacional en el \u00e1mbito farmac\u00e9utico, el control de calidad de los medicamentos y la estandarizaci\u00f3n de productos farmac\u00e9uticos. Se discuten aspectos como la colaboraci\u00f3n con organizaciones internacionales, la calidad de los medicamentos esenciales, y la importancia de los materiales de referencia internacional en el control de calidad.\n\n### Preguntas:\n\n1. **\u00bfCu\u00e1les son los principales objetivos de la colaboraci\u00f3n internacional mencionados en el informe y c\u00f3mo se implementan en el contexto de la calidad de los medicamentos?**\n   - Esta pregunta busca detalles espec\u00edficos sobre los objetivos y m\u00e9todos de colaboraci\u00f3n internacional que se describen en el documento, lo cual puede no estar disponible en otras fuentes.\n\n2. **\u00bfQu\u00e9 avances se han realizado en la cuarta edici\u00f3n de *The International Pharmacopoeia* seg\u00fan el informe, y cu\u00e1les son las implicaciones para la calidad de los medicamentos?**\n   - Esta pregunta se centra en los cambios y actualizaciones en la cuarta edici\u00f3n de *The International Pharmacopoeia*, proporcionando informaci\u00f3n que puede ser \u00fanica para este documento.\n\n3. **\u00bfQu\u00e9 papel juegan los materiales de referencia internacional en el control de calidad de los productos farmac\u00e9uticos, seg\u00fan el informe?**\n   - Esta pregunta busca profundizar en la importancia y el uso de los materiales de referencia internacional, un tema que puede no ser ampliamente discutido en otras fuentes.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y detallada que se encuentra en el contexto del informe, lo que puede no estar disponible en otros documentos o fuentes.", "prev_section_summary": "El \"WHO - Technical Report Series 970\" es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que aborda temas relevantes en el \u00e1mbito de la salud global. Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relacionadas:\n\n### Temas Clave:\n1. **Hallazgos y Recomendaciones**: El informe probablemente presenta hallazgos significativos y recomendaciones sobre salud p\u00fablica, pol\u00edticas sanitarias y pr\u00e1cticas m\u00e9dicas.\n2. **Salud Global**: Se abordan temas de salud global que son pertinentes a los desaf\u00edos actuales en el \u00e1mbito de la salud p\u00fablica.\n3. **Metodolog\u00edas de Investigaci\u00f3n**: Se discuten las metodolog\u00edas utilizadas en la elaboraci\u00f3n del informe, lo que puede ofrecer una comprensi\u00f3n sobre la validez de los hallazgos.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe, que se centra en mejorar la salud a nivel global.\n- **Salud P\u00fablica**: Un tema central del informe, que incluye estrategias de intervenci\u00f3n y pol\u00edticas de salud.\n\nEste resumen destaca la importancia del informe en la formulaci\u00f3n de pol\u00edticas de salud y su relevancia en el contexto actual de la salud p\u00fablica.", "excerpt_keywords": "Keywords: collaboration, quality assurance, pharmacopoeia, international standards, reference materials"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5e9c97ff-6be9-4b1f-be69-221abbe68dfc", "node_type": "4", "metadata": {"page_label": "5", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "\n# Contents\n\n1. **Introduction**  \n   1\n\n2. **General policy**  \n   6  \n   2.1 International collaboration  \n   6  \n   2.1.1 Collaboration with international organizations and agencies  \n   6  \n   2.1.2 Pharmacopoeial Discussion Group  \n   7  \n   2.1.3 International Conference on Harmonisation  \n   7  \n   2.1.4 International Conference of Drug Regulatory Authorities  \n   8  \n   2.2 Cross-cutting pharmaceuticals \u2013 quality assurance issues  \n   8  \n   2.2.1 Biological standardization  \n   8  \n   2.2.2 Essential medicines  \n   9  \n   2.2.3 Herbal and complementary medicines  \n   9  \n   2.2.4 Working group meeting on substandard/spurious/falsely-labelled/falsified/  \n   counterfeit medical products  \n   10\n\n3. **Quality control \u2013 specifications and tests**  \n   10  \n   3.1 *The International Pharmacopoeia*  \n   10  \n   3.1.1 Fourth edition update  \n   10  \n   3.1.2 Outreach with stakeholders  \n   11  \n   3.1.3 Annotated work plan  \n   11  \n   3.1.4 Monograph development  \n   12  \n   3.2 Specifications for medicines, including children\u2019s medicines  \n   12  \n   3.2.1 Medicines for HIV and related conditions  \n   12  \n   3.2.2 Antimalarial medicines  \n   13  \n   3.2.3 Antituberculosis medicines  \n   14  \n   3.2.4 Anti-infectives  \n   14  \n   3.2.5 Other medicines  \n   15  \n   3.2.6 Other paediatrics  \n   16  \n   3.3 General monographs for dosage forms and associated method texts  \n   16  \n   3.3.1 Pharmacopoeial Discussion Group-harmonized general texts  \n   16  \n   3.3.2 Uniformity of content single-dose preparations  \n   21  \n   3.3.3 General monograph on tablets  \n   23  \n   3.4 Preface, general notices and supplementary information sections of  \n   *The International Pharmacopoeia*  \n   24\n\n4. **Quality control \u2013 International Reference Materials (International Chemical Reference Substances and Infrared Reference Spectra)**  \n   25  \n   4.1 Update on International Chemical Reference Substances  \n   25  \n   4.1.1 Report on activities of the host organization related to International  \n   Chemical Reference Substances  \n   25  \n   4.1.2 Frequently asked questions about collaborative trials  \n   26  \n   4.1.3 Annual report on International Chemical Reference Substances 2010  \n   26  \n   4.1.4 Lumefantrine for system suitability testing  \n   27  \n   4.1.5 Bacterial endotoxin  \n   27\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "6ab4c8e64c2b70dec989d09be4f00a9c90ee573ca85347b91361a2fe101a83f9", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Contents\n\n1. **Introduction**  \n   1\n\n2. **General policy**  \n   6  \n   2.1 International collaboration  \n   6  \n   2.1.1 Collaboration with international organizations and agencies  \n   6  \n   2.1.2 Pharmacopoeial Discussion Group  \n   7  \n   2.1.3 International Conference on Harmonisation  \n   7  \n   2.1.4 International Conference of Drug Regulatory Authorities  \n   8  \n   2.2 Cross-cutting pharmaceuticals \u2013 quality assurance issues  \n   8  \n   2.2.1 Biological standardization  \n   8  \n   2.2.2 Essential medicines  \n   9  \n   2.2.3 Herbal and complementary medicines  \n   9  \n   2.2.4 Working group meeting on substandard/spurious/falsely-labelled/falsified/  \n   counterfeit medical products  \n   10\n\n3. **Quality control \u2013 specifications and tests**  \n   10  \n   3.1 *The International Pharmacopoeia*  \n   10  \n   3.1.1 Fourth edition update  \n   10  \n   3.1.2 Outreach with stakeholders  \n   11  \n   3.1.3 Annotated work plan  \n   11  \n   3.1.4 Monograph development  \n   12  \n   3.2 Specifications for medicines, including children\u2019s medicines  \n   12  \n   3.2.1 Medicines for HIV and related conditions  \n   12  \n   3.2.2 Antimalarial medicines  \n   13  \n   3.2.3 Antituberculosis medicines  \n   14  \n   3.2.4 Anti-infectives  \n   14  \n   3.2.5 Other medicines  \n   15  \n   3.2.6 Other paediatrics  \n   16  \n   3.3 General monographs for dosage forms and associated method texts  \n   16  \n   3.3.1 Pharmacopoeial Discussion Group-harmonized general texts  \n   16  \n   3.3.2 Uniformity of content single-dose preparations  \n   21  \n   3.3.3 General monograph on tablets  \n   23  \n   3.4 Preface, general notices and supplementary information sections of  \n   *The International Pharmacopoeia*  \n   24\n\n4. **Quality control \u2013 International Reference Materials (International Chemical Reference Substances and Infrared Reference Spectra)**  \n   25  \n   4.1 Update on International Chemical Reference Substances  \n   25  \n   4.1.1 Report on activities of the host organization related to International  \n   Chemical Reference Substances  \n   25  \n   4.1.2 Frequently asked questions about collaborative trials  \n   26  \n   4.1.3 Annual report on International Chemical Reference Substances 2010  \n   26  \n   4.1.4 Lumefantrine for system suitability testing  \n   27  \n   4.1.5 Bacterial endotoxin  \n   27", "mimetype": "text/plain", "start_char_idx": 1, "end_char_idx": 2316, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "30f94eef-47f8-4ba0-ac43-1d015f4914e8": {"__data__": {"id_": "30f94eef-47f8-4ba0-ac43-1d015f4914e8", "embedding": null, "metadata": {"page_label": "6", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 5. Quality control \u2013 national laboratories\n5.1 External Quality Assurance Assessment Scheme\n\n## 6. Quality assurance \u2013 good manufacturing practices\n6.1 WHO good manufacturing practices: water for pharmaceutical use\n\n## 7. Quality assurance \u2013 new approaches\n7.1 WHO guidelines on quality risk management\n\n## 8. Quality assurance \u2013 distribution and trade of pharmaceuticals\n8.1 WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce  \n8.2 Update on Joint FIP/WHO guidelines on good pharmacy practice: standards for quality of pharmacy services\n\n## 9. Prequalification of priority essential medicines including active pharmaceutical ingredients\n9.1 Update on the Prequalification of Medicines Programme managed by WHO\n\n## 10. Prequalification of quality control laboratories\n10.1 Update on the prequalification of quality control laboratories  \n10.2 Update on the surveys of the quality of medicines\n\n## 11. Regulatory guidance\n11.1 Policy on oseltamivir and zanamivir  \n11.2 Assessment criteria for blood regulatory systems  \n11.3 Pharmaceutical development for multisource (generic) pharmaceutical products \u2013 points to consider  \n11.4 Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part  \n11.5 Development of paediatric medicines: points to consider in pharmaceutical formulation  \n11.6 Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products: points to consider  \n11.7 Quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients  \n11.8 Update on comparator products\n\n## 12. Nomenclature, terminology and databases\n12.1 Quality assurance terminology  \n12.2 International Nonproprietary Names for pharmaceutical substances\n\n## 13. Miscellaneous\n13.1 Brochures on the Expert Committee and on quality assurance of pharmaceuticals  \n13.2 Sampling procedures for monitoring of market situations  \n13.3 *Index of pharmacopoeias*  \n13.4 Collaboration with pharmacopoeias\n\n## 14. Summary and recommendations\n\nAcknowledgements", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder espec\u00edficamente con el contexto proporcionado, junto con un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de nivel superior:\nEl documento es un informe t\u00e9cnico de la OMS que aborda diversas \u00e1reas relacionadas con la calidad y regulaci\u00f3n de los productos farmac\u00e9uticos. Se centra en la garant\u00eda de calidad, buenas pr\u00e1cticas de manufactura, precalificaci\u00f3n de medicamentos y laboratorios, y proporciona directrices regulatorias. Tambi\u00e9n incluye aspectos sobre nomenclatura y terminolog\u00eda en el \u00e1mbito farmac\u00e9utico, as\u00ed como recomendaciones y procedimientos de muestreo para el monitoreo de la calidad de los medicamentos en el mercado.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son los puntos clave de las directrices de la OMS sobre la gesti\u00f3n de riesgos de calidad en la fabricaci\u00f3n de productos farmac\u00e9uticos?**\n   - Esta pregunta busca detalles espec\u00edficos sobre las nuevas aproximaciones a la garant\u00eda de calidad mencionadas en la secci\u00f3n 7.1.\n\n2. **\u00bfQu\u00e9 criterios se utilizan para la evaluaci\u00f3n de los sistemas regulatorios de sangre seg\u00fan el informe?**\n   - Esta pregunta se enfoca en la secci\u00f3n 11.2, que trata sobre los criterios de evaluaci\u00f3n de los sistemas regulatorios de sangre, un tema que puede no estar ampliamente cubierto en otras fuentes.\n\n3. **\u00bfQu\u00e9 actualizaciones se han realizado en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Esta pregunta se refiere a la secci\u00f3n 9.1, que proporciona informaci\u00f3n sobre el estado actual y las mejoras en el programa de precalificaci\u00f3n, un aspecto crucial para la calidad de los medicamentos esenciales.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" aborda varios temas fundamentales relacionados con la pol\u00edtica farmac\u00e9utica y el control de calidad de los medicamentos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas en la secci\u00f3n:\n\n1. **Colaboraci\u00f3n Internacional**:\n   - **Objetivos**: Fomentar la cooperaci\u00f3n entre organizaciones internacionales y agencias para mejorar la calidad de los medicamentos.\n   - **Entidades Involucradas**:\n     - Organizaciones internacionales (ej. OMS).\n     - **Pharmacopoeial Discussion Group**: Grupo que discute y armoniza est\u00e1ndares farmac\u00e9uticos.\n     - **International Conference on Harmonisation**: Conferencia que busca armonizar regulaciones y est\u00e1ndares en la industria farmac\u00e9utica.\n     - **International Conference of Drug Regulatory Authorities**: Conferencia que re\u00fane a autoridades reguladoras de medicamentos.\n\n2. **Calidad de los Medicamentos**:\n   - **Medicamentos Esenciales**: Enfoque en la calidad y disponibilidad de medicamentos esenciales.\n   - **Medicamentos Herbales y Complementarios**: Consideraciones sobre la calidad y regulaci\u00f3n de estos productos.\n   - **Problemas de Calidad**: Reuniones de grupos de trabajo sobre productos m\u00e9dicos subest\u00e1ndar, falsificados y mal etiquetados.\n\n3. **Control de Calidad**:\n   - **Especificaciones y Pruebas**: Establecimiento de est\u00e1ndares para la calidad de los medicamentos.\n   - **The International Pharmacopoeia**: Documento clave que proporciona est\u00e1ndares y m\u00e9todos para la calidad de los medicamentos.\n     - **Actualizaci\u00f3n de la Cuarta Edici\u00f3n**: Cambios y mejoras en la cuarta edici\u00f3n de este documento.\n     - **Desarrollo de Monograf\u00edas**: Creaci\u00f3n de documentos que describen las especificaciones de diferentes medicamentos.\n\n4. **Materiales de Referencia Internacional**:\n   - **Sustancias Qu\u00edmicas de Referencia Internacional**: Importancia de estos materiales en el control de calidad de productos farmac\u00e9uticos.\n   - **Espectroscop\u00eda Infrarroja**: Uso de espectros de referencia para asegurar la calidad de los productos.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Principal organismo que coordina las pol\u00edticas de salud y calidad de medicamentos a nivel internacional.\n- **Pharmacopoeial Discussion Group**: Grupo que trabaja en la armonizaci\u00f3n de est\u00e1ndares farmac\u00e9uticos.\n- **Autoridades Reguladoras de Medicamentos**: Entidades que supervisan y regulan la calidad de los medicamentos en diferentes pa\u00edses.\n\nEste resumen destaca la importancia de la colaboraci\u00f3n internacional y el establecimiento de est\u00e1ndares para asegurar la calidad y seguridad de los medicamentos a nivel global.", "excerpt_keywords": "Keywords: quality assurance, pharmaceutical preparations, WHO guidelines, prequalification, good manufacturing practices"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6d05f927-6f40-4cb9-9f69-11509e2ade9c", "node_type": "4", "metadata": {"page_label": "6", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 5. Quality control \u2013 national laboratories\n5.1 External Quality Assurance Assessment Scheme\n\n## 6. Quality assurance \u2013 good manufacturing practices\n6.1 WHO good manufacturing practices: water for pharmaceutical use\n\n## 7. Quality assurance \u2013 new approaches\n7.1 WHO guidelines on quality risk management\n\n## 8. Quality assurance \u2013 distribution and trade of pharmaceuticals\n8.1 WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce  \n8.2 Update on Joint FIP/WHO guidelines on good pharmacy practice: standards for quality of pharmacy services\n\n## 9. Prequalification of priority essential medicines including active pharmaceutical ingredients\n9.1 Update on the Prequalification of Medicines Programme managed by WHO\n\n## 10. Prequalification of quality control laboratories\n10.1 Update on the prequalification of quality control laboratories  \n10.2 Update on the surveys of the quality of medicines\n\n## 11. Regulatory guidance\n11.1 Policy on oseltamivir and zanamivir  \n11.2 Assessment criteria for blood regulatory systems  \n11.3 Pharmaceutical development for multisource (generic) pharmaceutical products \u2013 points to consider  \n11.4 Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part  \n11.5 Development of paediatric medicines: points to consider in pharmaceutical formulation  \n11.6 Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products: points to consider  \n11.7 Quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients  \n11.8 Update on comparator products\n\n## 12. Nomenclature, terminology and databases\n12.1 Quality assurance terminology  \n12.2 International Nonproprietary Names for pharmaceutical substances\n\n## 13. Miscellaneous\n13.1 Brochures on the Expert Committee and on quality assurance of pharmaceuticals  \n13.2 Sampling procedures for monitoring of market situations  \n13.3 *Index of pharmacopoeias*  \n13.4 Collaboration with pharmacopoeias\n\n## 14. Summary and recommendations\n\nAcknowledgements", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "23e372e2391152007a6b00ddcc2ed027011cbb06bafae8266a55d7474beb2f2d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 5. Quality control \u2013 national laboratories\n5.1 External Quality Assurance Assessment Scheme\n\n## 6. Quality assurance \u2013 good manufacturing practices\n6.1 WHO good manufacturing practices: water for pharmaceutical use\n\n## 7. Quality assurance \u2013 new approaches\n7.1 WHO guidelines on quality risk management\n\n## 8. Quality assurance \u2013 distribution and trade of pharmaceuticals\n8.1 WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce  \n8.2 Update on Joint FIP/WHO guidelines on good pharmacy practice: standards for quality of pharmacy services\n\n## 9. Prequalification of priority essential medicines including active pharmaceutical ingredients\n9.1 Update on the Prequalification of Medicines Programme managed by WHO\n\n## 10. Prequalification of quality control laboratories\n10.1 Update on the prequalification of quality control laboratories  \n10.2 Update on the surveys of the quality of medicines\n\n## 11. Regulatory guidance\n11.1 Policy on oseltamivir and zanamivir  \n11.2 Assessment criteria for blood regulatory systems  \n11.3 Pharmaceutical development for multisource (generic) pharmaceutical products \u2013 points to consider  \n11.4 Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part  \n11.5 Development of paediatric medicines: points to consider in pharmaceutical formulation  \n11.6 Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products: points to consider  \n11.7 Quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients  \n11.8 Update on comparator products\n\n## 12. Nomenclature, terminology and databases\n12.1 Quality assurance terminology  \n12.2 International Nonproprietary Names for pharmaceutical substances\n\n## 13. Miscellaneous\n13.1 Brochures on the Expert Committee and on quality assurance of pharmaceuticals  \n13.2 Sampling procedures for monitoring of market situations  \n13.3 *Index of pharmacopoeias*  \n13.4 Collaboration with pharmacopoeias\n\n## 14. Summary and recommendations\n\nAcknowledgements", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2245, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c6dae6d1-7c09-4ae5-8fa0-9d9c9536aaae": {"__data__": {"id_": "c6dae6d1-7c09-4ae5-8fa0-9d9c9536aaae", "embedding": null, "metadata": {"page_label": "7", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Annex 1\nDevelopment of monographs for *The International Pharmacopoeia*  \nPage 63\n\n## Annex 2\nWHO good manufacturing practices: water for pharmaceutical use  \nPage 67\n\n## Annex 3\nPharmaceutical development of multisource (generic) pharmaceutical products - points to consider  \nPage 91\n\n## Annex 4\nGuidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part  \nPage 121\n\n## Annex 5\nDevelopment of paediatric medicines: points to consider in formulation  \nPage 197\n\n## Annex 6\nRecommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients  \nPage 227", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que detalla las especificaciones para preparaciones farmac\u00e9uticas. Incluye varios anexos que abordan temas como el desarrollo de monograf\u00edas para la Farmacopea Internacional, buenas pr\u00e1cticas de fabricaci\u00f3n, desarrollo de productos farmac\u00e9uticos multisource (gen\u00e9ricos), y recomendaciones espec\u00edficas para la producci\u00f3n de ingredientes farmac\u00e9uticos activos, entre otros.\n\n### Preguntas:\n\n1. **\u00bfQu\u00e9 temas espec\u00edficos se abordan en el Anexo 3 sobre el desarrollo farmac\u00e9utico de productos multisource?**\n   - Esta pregunta busca detalles sobre los puntos clave que se consideran en el desarrollo de productos farmac\u00e9uticos gen\u00e9ricos, que son esenciales para garantizar su calidad y eficacia.\n\n2. **\u00bfCu\u00e1les son las recomendaciones clave para la calidad del artemisinina seg\u00fan el Anexo 6?**\n   - Esta pregunta se centra en las especificaciones y requisitos de calidad que se deben cumplir para el artemisinina, un ingrediente activo crucial en el tratamiento de la malaria.\n\n3. **\u00bfQu\u00e9 aspectos se consideran en la formulaci\u00f3n de medicamentos pedi\u00e1tricos seg\u00fan el Anexo 5?**\n   - Esta pregunta busca informaci\u00f3n sobre las consideraciones espec\u00edficas que deben tenerse en cuenta al desarrollar medicamentos para la poblaci\u00f3n pedi\u00e1trica, que pueden diferir significativamente de los medicamentos para adultos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS, titulado \"WHO - Technical Report Series 970\", aborda aspectos fundamentales relacionados con la calidad y regulaci\u00f3n de los productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas en la secci\u00f3n:\n\n1. **Control de Calidad en Laboratorios Nacionales**:\n   - **Esquema de Evaluaci\u00f3n de Aseguramiento de Calidad Externa**: Se enfoca en la evaluaci\u00f3n de la calidad en laboratorios nacionales.\n\n2. **Aseguramiento de Calidad y Buenas Pr\u00e1cticas de Manufactura**:\n   - **Buenas Pr\u00e1cticas de Manufactura de la OMS**: Incluye directrices sobre el uso de agua para fines farmac\u00e9uticos.\n\n3. **Nuevas Aproximaciones en Aseguramiento de Calidad**:\n   - **Directrices de la OMS sobre Gesti\u00f3n de Riesgos de Calidad**: Proporciona un marco para la gesti\u00f3n de riesgos en la fabricaci\u00f3n de productos farmac\u00e9uticos.\n\n4. **Distribuci\u00f3n y Comercio de Productos Farmac\u00e9uticos**:\n   - **Esquema de Certificaci\u00f3n de la OMS**: Asegura la calidad de los productos farmac\u00e9uticos en el comercio internacional.\n   - **Actualizaci\u00f3n sobre las Directrices de Buenas Pr\u00e1cticas Farmac\u00e9uticas**: Establece est\u00e1ndares para la calidad de los servicios farmac\u00e9uticos.\n\n5. **Precalificaci\u00f3n de Medicamentos Esenciales**:\n   - **Programa de Precalificaci\u00f3n de Medicamentos**: Actualizaciones sobre la precalificaci\u00f3n de medicamentos y principios activos esenciales.\n\n6. **Precalificaci\u00f3n de Laboratorios de Control de Calidad**:\n   - **Actualizaciones sobre la Precalificaci\u00f3n de Laboratorios**: Informaci\u00f3n sobre la calidad de los laboratorios de control.\n\n7. **Orientaci\u00f3n Regulatoria**:\n   - **Pol\u00edticas sobre Oseltamivir y Zanamivir**: Directrices espec\u00edficas para estos medicamentos.\n   - **Criterios de Evaluaci\u00f3n para Sistemas Regulatorios de Sangre**: Establece criterios para la regulaci\u00f3n de productos sangu\u00edneos.\n   - **Desarrollo de Medicamentos Pedi\u00e1tricos**: Consideraciones para la formulaci\u00f3n de medicamentos para ni\u00f1os.\n\n8. **Nomenclatura y Terminolog\u00eda**:\n   - **Terminolog\u00eda de Aseguramiento de Calidad**: Definiciones y t\u00e9rminos clave en el \u00e1mbito farmac\u00e9utico.\n   - **Nombres Internacionales No Propietarios**: Normas para la nomenclatura de sustancias farmac\u00e9uticas.\n\n9. **Miscellaneous**:\n   - **Procedimientos de Muestreo**: M\u00e9todos para monitorear la calidad de los medicamentos en el mercado.\n   - **Colaboraci\u00f3n con Farmacopeas**: Interacci\u00f3n con diferentes farmacopeas para asegurar est\u00e1ndares de calidad.\n\n10. **Resumen y Recomendaciones**: Conclusiones y sugerencias basadas en los hallazgos del informe.\n\nEste resumen destaca la importancia de la calidad y regulaci\u00f3n en la industria farmac\u00e9utica, as\u00ed como las iniciativas de la OMS para mejorar estos aspectos a nivel global.", "excerpt_keywords": "Keywords: pharmaceutical preparations, WHO guidelines, generic products, quality requirements, pediatric medicines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "19c5ed07-df43-4982-9fbb-0a971c023ded", "node_type": "4", "metadata": {"page_label": "7", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Annex 1\nDevelopment of monographs for *The International Pharmacopoeia*  \nPage 63\n\n## Annex 2\nWHO good manufacturing practices: water for pharmaceutical use  \nPage 67\n\n## Annex 3\nPharmaceutical development of multisource (generic) pharmaceutical products - points to consider  \nPage 91\n\n## Annex 4\nGuidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part  \nPage 121\n\n## Annex 5\nDevelopment of paediatric medicines: points to consider in formulation  \nPage 197\n\n## Annex 6\nRecommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients  \nPage 227", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "c1304dd950c3eb112883045953999ec569622ab5714c424464bb53c0f67a909e", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Annex 1\nDevelopment of monographs for *The International Pharmacopoeia*  \nPage 63\n\n## Annex 2\nWHO good manufacturing practices: water for pharmaceutical use  \nPage 67\n\n## Annex 3\nPharmaceutical development of multisource (generic) pharmaceutical products - points to consider  \nPage 91\n\n## Annex 4\nGuidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part  \nPage 121\n\n## Annex 5\nDevelopment of paediatric medicines: points to consider in formulation  \nPage 197\n\n## Annex 6\nRecommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients  \nPage 227", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 818, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "21dd4fde-9e5d-4b6e-85fe-9fe696229e88": {"__data__": {"id_": "21dd4fde-9e5d-4b6e-85fe-9fe696229e88", "embedding": null, "metadata": {"page_label": "8", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Geneva, 10\u201314 October 2011**\n\n## Members\n\n- **Professor S.A. Bawazir**, Head of Drug Sector and Vice-President, Saudi Food and Drug Authority, Riyadh, Saudi Arabia *(Chairperson)*\n\n- **Mr A.C. da Costa Bezerra**, Senior Pharmacist, Gerente-General de Inspecao e Controle de Medicamentos e Produtos, Agencia Nacional de Vigilancia Sanitaria \u2013 Brazilian Health Surveillance Agency, Brasilia, Brazil\n\n- **Mr E. Wondemagegnehu Biwota**, Addis Ababa, Ethiopia\n\n- **Professor T.G. Dekker**, Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa\n\n- **Professor J. Hoogmartens**, Professor Emeritus, Laboratorium voor Farmaceutische Analyse, Leuven, Belgium\n\n- **Professor S. Jin**, Chief Expert for Pharmaceutical Products, National Institutes for Food and Drug Control, Beijing, People\u2019s Republic of China *(Co-Chairperson)*\n\n- **Dr T. Kawanishi**, Head, Division of Drugs, National Institute of Health Sciences, Tokyo, Japan *(Rapporteur)*\n\n- **Professor H.G. Kristensen**, Vedbaek, Denmark\n\n- **Dr J.A. Molzon**, Associate Director for International Programs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA *(Rapporteur)*\n\n- **Ms C. Munyimba-Yeta**, Director, Inspectorate and Licensing, Pharmaceutical Regulatory Agency, Lusaka, Zambia\n\n- **Ms L. Slamet**, Deputy for Therapeutic Products, Narcotics, Psychotropic and Addictive Substance Control, National Agency of Drug and Food Control, Jakarta Pusat, Indonesia\n\n## Temporary Advisers\n\n- **Mr J.-M. Caudron**, Braine-le-Ch\u00e2teau, Belgium\n\n- **Dr M. Hinds**, Director, Barbados Drug Service, St Michael, Barbados\n\n- **Dr S. Mills**, Ware, Hertfordshire, England\n\n- **Dr L. Paleshnuik**, Val-des-Mont, QC, Canada\n\n- **Ms M.-L. Rabouhans**, Chiswick, London, England\n\n----\n\n\u00b9 Unable to attend.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder espec\u00edficamente con la informaci\u00f3n proporcionada en el contexto:\n\n1. **\u00bfQui\u00e9nes son los miembros del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas y cu\u00e1les son sus roles?**\n   - Esta pregunta se puede responder detallando los nombres, cargos y pa\u00edses de origen de los miembros del comit\u00e9, as\u00ed como sus roles espec\u00edficos, como el de presidente y co-presidente.\n\n2. **\u00bfCu\u00e1les son las fechas y el lugar de la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS en 2011?**\n   - La respuesta a esta pregunta se encuentra en el contexto, que menciona que la reuni\u00f3n tuvo lugar en Ginebra del 10 al 14 de octubre de 2011.\n\n3. **\u00bfQui\u00e9nes son los asesores temporales que participaron en la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS y de d\u00f3nde provienen?**\n   - Esta pregunta puede ser respondida enumerando los nombres y lugares de origen de los asesores temporales mencionados en el documento.\n\n### Resumen de nivel superior:\nEl contexto proporciona informaci\u00f3n sobre la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, celebrada en Ginebra en octubre de 2011. Se enumeran los miembros del comit\u00e9, sus roles y los asesores temporales que participaron. Esta informaci\u00f3n es relevante para entender la composici\u00f3n y el enfoque del comit\u00e9 en la regulaci\u00f3n y control de productos farmac\u00e9uticos a nivel internacional.", "prev_section_summary": "El documento \"WHO - Technical Report Series 970\" de la Organizaci\u00f3n Mundial de la Salud (OMS) se centra en las especificaciones para preparaciones farmac\u00e9uticas y presenta varios anexos que abordan temas cruciales en el \u00e1mbito farmac\u00e9utico. A continuaci\u00f3n se resumen los temas clave y entidades de la secci\u00f3n:\n\n### Temas Clave:\n1. **Desarrollo de Monograf\u00edas**: Se refiere a la creaci\u00f3n de documentos estandarizados para *La Farmacopea Internacional*, que establecen criterios de calidad y especificaciones para medicamentos.\n   \n2. **Buenas Pr\u00e1cticas de Fabricaci\u00f3n**: Incluye directrices sobre el uso de agua en la producci\u00f3n farmac\u00e9utica, asegurando que cumpla con los est\u00e1ndares de calidad necesarios.\n\n3. **Desarrollo de Productos Multisource (Gen\u00e9ricos)**: Se enfoca en los puntos a considerar en el desarrollo de productos farmac\u00e9uticos gen\u00e9ricos, garantizando su calidad y eficacia.\n\n4. **Documentaci\u00f3n para Precalificaci\u00f3n de Medicamentos**: Proporciona pautas sobre la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos gen\u00e9ricos que buscan la precalificaci\u00f3n por parte de la OMS.\n\n5. **Medicamentos Pedi\u00e1tricos**: Aborda consideraciones espec\u00edficas en la formulaci\u00f3n de medicamentos destinados a la poblaci\u00f3n infantil, que requieren un enfoque diferente al de los adultos.\n\n6. **Requisitos de Calidad para Artemisinina**: Establece recomendaciones sobre los est\u00e1ndares de calidad que deben cumplirse para la artemisinina, un ingrediente activo esencial en el tratamiento de la malaria.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable del documento.\n- **Farmacopea Internacional**: Referencia a la colecci\u00f3n de est\u00e1ndares de calidad para medicamentos.\n- **Artemisinina**: Ingrediente activo mencionado en el contexto de la producci\u00f3n de medicamentos antimal\u00e1ricos.\n\nEste resumen proporciona una visi\u00f3n general de los temas tratados en el documento y las entidades relevantes en el contexto de las especificaciones para preparaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, expert committee, specifications, global health"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "be097802-4de1-432f-a2a1-72aaa735b7e7", "node_type": "4", "metadata": {"page_label": "8", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Geneva, 10\u201314 October 2011**\n\n## Members\n\n- **Professor S.A. Bawazir**, Head of Drug Sector and Vice-President, Saudi Food and Drug Authority, Riyadh, Saudi Arabia *(Chairperson)*\n\n- **Mr A.C. da Costa Bezerra**, Senior Pharmacist, Gerente-General de Inspecao e Controle de Medicamentos e Produtos, Agencia Nacional de Vigilancia Sanitaria \u2013 Brazilian Health Surveillance Agency, Brasilia, Brazil\n\n- **Mr E. Wondemagegnehu Biwota**, Addis Ababa, Ethiopia\n\n- **Professor T.G. Dekker**, Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa\n\n- **Professor J. Hoogmartens**, Professor Emeritus, Laboratorium voor Farmaceutische Analyse, Leuven, Belgium\n\n- **Professor S. Jin**, Chief Expert for Pharmaceutical Products, National Institutes for Food and Drug Control, Beijing, People\u2019s Republic of China *(Co-Chairperson)*\n\n- **Dr T. Kawanishi**, Head, Division of Drugs, National Institute of Health Sciences, Tokyo, Japan *(Rapporteur)*\n\n- **Professor H.G. Kristensen**, Vedbaek, Denmark\n\n- **Dr J.A. Molzon**, Associate Director for International Programs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA *(Rapporteur)*\n\n- **Ms C. Munyimba-Yeta**, Director, Inspectorate and Licensing, Pharmaceutical Regulatory Agency, Lusaka, Zambia\n\n- **Ms L. Slamet**, Deputy for Therapeutic Products, Narcotics, Psychotropic and Addictive Substance Control, National Agency of Drug and Food Control, Jakarta Pusat, Indonesia\n\n## Temporary Advisers\n\n- **Mr J.-M. Caudron**, Braine-le-Ch\u00e2teau, Belgium\n\n- **Dr M. Hinds**, Director, Barbados Drug Service, St Michael, Barbados\n\n- **Dr S. Mills**, Ware, Hertfordshire, England\n\n- **Dr L. Paleshnuik**, Val-des-Mont, QC, Canada\n\n- **Ms M.-L. Rabouhans**, Chiswick, London, England\n\n----\n\n\u00b9 Unable to attend.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "54de904ca1cc1b1ce6d4aab5bb714e17d464c0274fee6dcb411a3be0ddecdffb", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Geneva, 10\u201314 October 2011**\n\n## Members\n\n- **Professor S.A. Bawazir**, Head of Drug Sector and Vice-President, Saudi Food and Drug Authority, Riyadh, Saudi Arabia *(Chairperson)*\n\n- **Mr A.C. da Costa Bezerra**, Senior Pharmacist, Gerente-General de Inspecao e Controle de Medicamentos e Produtos, Agencia Nacional de Vigilancia Sanitaria \u2013 Brazilian Health Surveillance Agency, Brasilia, Brazil\n\n- **Mr E. Wondemagegnehu Biwota**, Addis Ababa, Ethiopia\n\n- **Professor T.G. Dekker**, Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa\n\n- **Professor J. Hoogmartens**, Professor Emeritus, Laboratorium voor Farmaceutische Analyse, Leuven, Belgium\n\n- **Professor S. Jin**, Chief Expert for Pharmaceutical Products, National Institutes for Food and Drug Control, Beijing, People\u2019s Republic of China *(Co-Chairperson)*\n\n- **Dr T. Kawanishi**, Head, Division of Drugs, National Institute of Health Sciences, Tokyo, Japan *(Rapporteur)*\n\n- **Professor H.G. Kristensen**, Vedbaek, Denmark\n\n- **Dr J.A. Molzon**, Associate Director for International Programs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA *(Rapporteur)*\n\n- **Ms C. Munyimba-Yeta**, Director, Inspectorate and Licensing, Pharmaceutical Regulatory Agency, Lusaka, Zambia\n\n- **Ms L. Slamet**, Deputy for Therapeutic Products, Narcotics, Psychotropic and Addictive Substance Control, National Agency of Drug and Food Control, Jakarta Pusat, Indonesia\n\n## Temporary Advisers\n\n- **Mr J.-M. Caudron**, Braine-le-Ch\u00e2teau, Belgium\n\n- **Dr M. Hinds**, Director, Barbados Drug Service, St Michael, Barbados\n\n- **Dr S. Mills**, Ware, Hertfordshire, England\n\n- **Dr L. Paleshnuik**, Val-des-Mont, QC, Canada\n\n- **Ms M.-L. Rabouhans**, Chiswick, London, England\n\n----\n\n\u00b9 Unable to attend.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1905, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ba889a8a-24d7-42c4-b86b-7422d63ecef3": {"__data__": {"id_": "ba889a8a-24d7-42c4-b86b-7422d63ecef3", "embedding": null, "metadata": {"page_label": "9", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Dr J.-L. Robert\nService du Contr\u00f4le des M\u00e9dicaments, Laboratoire National de Sant\u00e9, Luxembourg\n\n## Dr S. Singh\nDrug Controller General (India), Ministry of Health & Family Welfare, Government of India, New Delhi, India\n\n## Professor C. Tuleu\nSenior Lecturer in Pharmaceutics, Deputy Director, Centre for Paediatric Pharmacy Research, The School of Pharmacy, University of London, London, England\n\n## Dr A. J. van Zyl\nSea Point, South Africa\n\n## Ms O. del Rosario Villalva Rojas\nExecutive Director of Quality Control Laboratories, National Quality Control Center, National Institute of Health, Lima, Peru\n\n----\n\n## Representation from United Nations offices\n\n### United Nations Children\u2019s Fund (UNICEF)\nDr H.K. Nielsen, Technical Specialist, Essential Medicines, Medicines and Nutrition Centre, UNICEF Supply Division, Copenhagen, Denmark\n\n----\n\n## Representation from specialized agencies and related organizations\n\n### The Global Fund to Fight AIDS, Tuberculosis and Malaria\nMs J. Daviaud, Senior Pharmaceutical QA Technical Officer, Pharmaceutical Procurement Unit, Geneva, Switzerland\n\n### World Intellectual Property Organization (WIPO)\nMs M. Kira, Consultant, Non-Governmental Organizations and Industry Relations Section, Department of External Relations, Geneva, Switzerland\n\n### World Trade Organization (WTO)\nMs X. Wu, Counsellor, Intellectual Property Division, Geneva, Switzerland\n\n----\n\n## Representation from intergovernmental organizations\n\n### Council of Europe\nDr A. Lodi, Head, Laboratory Department, European Directorate for the Quality of Medicines and HealthCare (EDQM), Strasbourg, France\n\n----\n\n*Unable to attend:*\n\n2. United Nations Development Programme (UNDP), New York, NY, USA.\n3. International Atomic Energy Agency (IAEA), Vienna, Austria; United Nations Industrial Development Organization (UNIDO), Vienna, Austria; The World Bank, Washington, DC, USA; World Customs Organization (WCO), Brussels, Belgium.\n5. European Union (EU), Brussels, Belgium.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Composici\u00f3n del Comit\u00e9 de Expertos de la OMS**: El documento presenta a los miembros del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, incluyendo profesionales de diversas organizaciones y pa\u00edses, as\u00ed como sus respectivas funciones y ubicaciones.\n\n2. **Representaci\u00f3n de organizaciones internacionales**: Se detalla la representaci\u00f3n de varias agencias de las Naciones Unidas y organizaciones intergubernamentales, destacando sus roles en la salud p\u00fablica y la farmac\u00e9utica, as\u00ed como la importancia de la colaboraci\u00f3n internacional en estos \u00e1mbitos.\n\n3. **Asistencia y ausencias**: Se menciona a aquellos que no pudieron asistir a la reuni\u00f3n, lo que indica la diversidad de organizaciones involucradas y la relevancia de su participaci\u00f3n en la discusi\u00f3n sobre est\u00e1ndares farmac\u00e9uticos.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 roles desempe\u00f1an los miembros del Comit\u00e9 de Expertos de la OMS en sus respectivas organizaciones y c\u00f3mo contribuyen a la regulaci\u00f3n de las preparaciones farmac\u00e9uticas?**\n   - Esta pregunta busca profundizar en las funciones espec\u00edficas de cada miembro y su impacto en la regulaci\u00f3n farmac\u00e9utica, informaci\u00f3n que no se detalla en el contexto.\n\n2. **\u00bfCu\u00e1les son los objetivos espec\u00edficos de la colaboraci\u00f3n entre la OMS y las organizaciones mencionadas, como UNICEF y el Global Fund, en el \u00e1mbito de las preparaciones farmac\u00e9uticas?**\n   - Esta pregunta se centra en los objetivos y metas de colaboraci\u00f3n que pueden no estar expl\u00edcitamente mencionados en el documento, pero que son cruciales para entender el contexto de la cooperaci\u00f3n internacional.\n\n3. **\u00bfQu\u00e9 criterios se utilizan para seleccionar a los representantes de las organizaciones intergubernamentales y no gubernamentales que asisten a las reuniones del Comit\u00e9 de Expertos de la OMS?**\n   - Esta pregunta busca explorar el proceso de selecci\u00f3n y los criterios que determinan qui\u00e9nes son elegidos para representar a sus organizaciones en estas importantes discusiones, lo cual no se aborda en el texto proporcionado.", "prev_section_summary": "La secci\u00f3n proporciona informaci\u00f3n sobre la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, que tuvo lugar en Ginebra del 10 al 14 de octubre de 2011. Se destacan los siguientes temas y entidades clave:\n\n1. **Composici\u00f3n del Comit\u00e9**: Se enumeran los miembros del comit\u00e9, incluyendo sus nombres, cargos y pa\u00edses de origen. El presidente es el Profesor S.A. Bawazir de Arabia Saudita, y el co-presidente es el Profesor S. Jin de China. Tambi\u00e9n se mencionan dos relatores: el Dr. T. Kawanishi de Jap\u00f3n y el Dr. J.A. Molzon de EE. UU.\n\n2. **Miembros del Comit\u00e9**: Incluye expertos de diversas instituciones y pa\u00edses, como farmac\u00e9uticos, acad\u00e9micos y funcionarios de agencias reguladoras de salud.\n\n3. **Asesores Temporales**: Se mencionan varios asesores temporales que participaron en la reuni\u00f3n, provenientes de diferentes pa\u00edses, como B\u00e9lgica, Barbados, Inglaterra y Canad\u00e1.\n\n4. **Objetivo de la reuni\u00f3n**: Aunque no se detalla en el extracto, el contexto sugiere que el enfoque del comit\u00e9 es la regulaci\u00f3n y control de productos farmac\u00e9uticos a nivel internacional.\n\nEste resumen destaca la diversidad y la experiencia de los miembros y asesores del comit\u00e9, as\u00ed como la importancia de su trabajo en el \u00e1mbito de la salud p\u00fablica global.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, international collaboration, health regulation, expert committee"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "97fa287a-fc10-400c-9d79-b12f727b7930", "node_type": "4", "metadata": {"page_label": "9", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Dr J.-L. Robert\nService du Contr\u00f4le des M\u00e9dicaments, Laboratoire National de Sant\u00e9, Luxembourg\n\n## Dr S. Singh\nDrug Controller General (India), Ministry of Health & Family Welfare, Government of India, New Delhi, India\n\n## Professor C. Tuleu\nSenior Lecturer in Pharmaceutics, Deputy Director, Centre for Paediatric Pharmacy Research, The School of Pharmacy, University of London, London, England\n\n## Dr A. J. van Zyl\nSea Point, South Africa\n\n## Ms O. del Rosario Villalva Rojas\nExecutive Director of Quality Control Laboratories, National Quality Control Center, National Institute of Health, Lima, Peru\n\n----\n\n## Representation from United Nations offices\n\n### United Nations Children\u2019s Fund (UNICEF)\nDr H.K. Nielsen, Technical Specialist, Essential Medicines, Medicines and Nutrition Centre, UNICEF Supply Division, Copenhagen, Denmark\n\n----\n\n## Representation from specialized agencies and related organizations\n\n### The Global Fund to Fight AIDS, Tuberculosis and Malaria\nMs J. Daviaud, Senior Pharmaceutical QA Technical Officer, Pharmaceutical Procurement Unit, Geneva, Switzerland\n\n### World Intellectual Property Organization (WIPO)\nMs M. Kira, Consultant, Non-Governmental Organizations and Industry Relations Section, Department of External Relations, Geneva, Switzerland\n\n### World Trade Organization (WTO)\nMs X. Wu, Counsellor, Intellectual Property Division, Geneva, Switzerland\n\n----\n\n## Representation from intergovernmental organizations\n\n### Council of Europe\nDr A. Lodi, Head, Laboratory Department, European Directorate for the Quality of Medicines and HealthCare (EDQM), Strasbourg, France\n\n----\n\n*Unable to attend:*\n\n2. United Nations Development Programme (UNDP), New York, NY, USA.\n3. International Atomic Energy Agency (IAEA), Vienna, Austria; United Nations Industrial Development Organization (UNIDO), Vienna, Austria; The World Bank, Washington, DC, USA; World Customs Organization (WCO), Brussels, Belgium.\n5. European Union (EU), Brussels, Belgium.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "cf791f45fa6172d0f561ead1f0e41db4d7189bddf485e914c978f54961938d61", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Dr J.-L. Robert\nService du Contr\u00f4le des M\u00e9dicaments, Laboratoire National de Sant\u00e9, Luxembourg\n\n## Dr S. Singh\nDrug Controller General (India), Ministry of Health & Family Welfare, Government of India, New Delhi, India\n\n## Professor C. Tuleu\nSenior Lecturer in Pharmaceutics, Deputy Director, Centre for Paediatric Pharmacy Research, The School of Pharmacy, University of London, London, England\n\n## Dr A. J. van Zyl\nSea Point, South Africa\n\n## Ms O. del Rosario Villalva Rojas\nExecutive Director of Quality Control Laboratories, National Quality Control Center, National Institute of Health, Lima, Peru\n\n----\n\n## Representation from United Nations offices\n\n### United Nations Children\u2019s Fund (UNICEF)\nDr H.K. Nielsen, Technical Specialist, Essential Medicines, Medicines and Nutrition Centre, UNICEF Supply Division, Copenhagen, Denmark\n\n----\n\n## Representation from specialized agencies and related organizations\n\n### The Global Fund to Fight AIDS, Tuberculosis and Malaria\nMs J. Daviaud, Senior Pharmaceutical QA Technical Officer, Pharmaceutical Procurement Unit, Geneva, Switzerland\n\n### World Intellectual Property Organization (WIPO)\nMs M. Kira, Consultant, Non-Governmental Organizations and Industry Relations Section, Department of External Relations, Geneva, Switzerland\n\n### World Trade Organization (WTO)\nMs X. Wu, Counsellor, Intellectual Property Division, Geneva, Switzerland\n\n----\n\n## Representation from intergovernmental organizations\n\n### Council of Europe\nDr A. Lodi, Head, Laboratory Department, European Directorate for the Quality of Medicines and HealthCare (EDQM), Strasbourg, France\n\n----\n\n*Unable to attend:*\n\n2. United Nations Development Programme (UNDP), New York, NY, USA.\n3. International Atomic Energy Agency (IAEA), Vienna, Austria; United Nations Industrial Development Organization (UNIDO), Vienna, Austria; The World Bank, Washington, DC, USA; World Customs Organization (WCO), Brussels, Belgium.\n5. European Union (EU), Brussels, Belgium.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2054, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "310f7f05-2db3-49ae-bade-bdaf8f9b9f26": {"__data__": {"id_": "310f7f05-2db3-49ae-bade-bdaf8f9b9f26", "embedding": null, "metadata": {"page_label": "10", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## European Medicines Agency (EMA)\n\nDr P. Kozarewicz, Scientific Administrator, London, England\n\n## Representation from nongovernmental organizations\n\n### European Chemical Industry Council (CEFIC)/APIC\n\nDr B. Pimentel, Board Member, APIC, and Global Regulatory Affairs Manager, DSM Nutritional Products, Basel, Switzerland\n\n### International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)\n\nDr G. France, Pfizer, United Kingdom; and Dr R. Horder, Abbott, United Kingdom\n\n### International Generic Pharmaceutical Alliance (IGPA)\n\nMr T. Fujino, Director, International Affairs, Japan Generic Medicines Association (JGA), Tokyo, Japan\n\n### International Pharmaceutical Excipients Council (IPEC)\n\nMs L. Vignoli, IPEC Europe, Brussels, Belgium\n\n### World Self-Medication Industry (WSMI)\n\nDr R. Torano, Pharmacopoeial Technical Expert, GlaxoSmithKline, United Kingdom\n\n## Pharmacopoeias\n\n### British Pharmacopoeia Commission\n\nMrs M. Vallender, Acting Group Manager, BP and Laboratory Services, London, England\n\n### Pharmacopoeia of the Republic of Korea\n\nDr Y.H. Choi, Pharmaceutical Standardization Research and Testing Division, Pharmaceuticals and Medical Devices Research Department, National Institute of Food and Drug Safety Evaluation (NIFDS), Korea Food and Drug Administration (KFDA), Cheongwon-gun, Chungbuk, Republic of Korea\n\n### United States Pharmacopeia\n\nDr K.A. Russo, Vice President, Small Molecules, Documentary Standards Division, Rockville, MD, USA\n\n----\n\n6 Unable to attend: Commonwealth Pharmacists Association (CPA), London, England; International Society for Pharmaceutical Engineering (ISPE), Tampa, Florida, USA; International Pharmaceutical Federation (FIP), The Hague, The Netherlands.\n\n7 Unable to attend: Farmacopea Argentina, Buenos Aires, Argentina; Farmacopeia Brasileira, Belo Horizonte MG, Brazil; Pharmacopoeia of the People\u2019s Republic of China, Beijing, People\u2019s Republic of China; Indian Pharmacopoeia, New Delhi, India; Japanese Pharmacopoeia, Tokyo, Japan; State Pharmacopoeia of the Russian Federation, Moscow, Russian Federation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que detalla la reuni\u00f3n del Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas. Se mencionan representantes de diversas organizaciones, incluidos organismos reguladores, asociaciones de la industria farmac\u00e9utica y farmacopoeias de diferentes pa\u00edses. Tambi\u00e9n se indica que algunas organizaciones no pudieron asistir a la reuni\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQui\u00e9nes son los representantes de la Agencia Europea de Medicamentos (EMA) y qu\u00e9 rol desempe\u00f1an en la reuni\u00f3n?**\n   - Respuesta: Dr. P. Kozarewicz es el Administrador Cient\u00edfico de la EMA y representa a esta agencia en la reuni\u00f3n.\n\n2. **\u00bfQu\u00e9 organizaciones no gubernamentales estuvieron representadas en la reuni\u00f3n y qui\u00e9nes fueron sus representantes?**\n   - Respuesta: Las organizaciones no gubernamentales representadas incluyen el Consejo Europeo de la Industria Qu\u00edmica (CEFIC)/APIC con Dr. B. Pimentel, la Federaci\u00f3n Internacional de Asociaciones de Fabricantes de Productos Farmac\u00e9uticos (IFPMA) con Dr. G. France y Dr. R. Horder, la Alianza Internacional de Medicamentos Gen\u00e9ricos (IGPA) con Mr. T. Fujino, el Consejo Internacional de Excipientes Farmac\u00e9uticos (IPEC) con Ms. L. Vignoli, y la Industria Mundial de Autocuidado (WSMI) con Dr. R. Torano.\n\n3. **\u00bfCu\u00e1les son las farmacopoeias representadas en la reuni\u00f3n y qui\u00e9nes son sus respectivos representantes?**\n   - Respuesta: Las farmacopoeias representadas incluyen la Comisi\u00f3n de Farmacopea Brit\u00e1nica con Mrs. M. Vallender, la Farmacopea de la Rep\u00fablica de Corea con Dr. Y.H. Choi, y la Farmacopea de los Estados Unidos con Dr. K.A. Russo.\n\n### Resumen de Nivel Superior\n\nEl informe de la OMS presenta a los miembros del Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas, destacando la participaci\u00f3n de representantes de la Agencia Europea de Medicamentos, diversas organizaciones no gubernamentales y farmacopoeias de varios pa\u00edses. Tambi\u00e9n se menciona que algunas organizaciones no pudieron asistir a la reuni\u00f3n, lo que refleja la diversidad de intereses y la importancia de la colaboraci\u00f3n internacional en la regulaci\u00f3n y estandarizaci\u00f3n de productos farmac\u00e9uticos.", "prev_section_summary": "La secci\u00f3n presenta la composici\u00f3n del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, destacando a sus miembros y sus respectivas organizaciones. Entre los participantes se encuentran profesionales de diversas instituciones, como el Laboratorio Nacional de Salud de Luxemburgo, el Ministerio de Salud y Bienestar Familiar de India, y la Universidad de Londres, entre otros.\n\nAdem\u00e1s, se menciona la representaci\u00f3n de varias agencias de las Naciones Unidas, como UNICEF, as\u00ed como de organizaciones especializadas y relacionadas, como el Global Fund, la Organizaci\u00f3n Mundial de la Propiedad Intelectual (WIPO) y la Organizaci\u00f3n Mundial del Comercio (WTO). Tambi\u00e9n se incluye la representaci\u00f3n de organizaciones intergubernamentales, como el Consejo de Europa.\n\nFinalmente, se se\u00f1ala que algunas organizaciones, como el Programa de las Naciones Unidas para el Desarrollo (UNDP) y la Uni\u00f3n Europea (UE), no pudieron asistir a la reuni\u00f3n, lo que resalta la diversidad y la importancia de la colaboraci\u00f3n internacional en el \u00e1mbito de la regulaci\u00f3n farmac\u00e9utica y la salud p\u00fablica.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, regulatory affairs, pharmacopoeias, international collaboration"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c9b9c6e4-4acb-4260-9241-059b6f5ba980", "node_type": "4", "metadata": {"page_label": "10", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## European Medicines Agency (EMA)\n\nDr P. Kozarewicz, Scientific Administrator, London, England\n\n## Representation from nongovernmental organizations\n\n### European Chemical Industry Council (CEFIC)/APIC\n\nDr B. Pimentel, Board Member, APIC, and Global Regulatory Affairs Manager, DSM Nutritional Products, Basel, Switzerland\n\n### International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)\n\nDr G. France, Pfizer, United Kingdom; and Dr R. Horder, Abbott, United Kingdom\n\n### International Generic Pharmaceutical Alliance (IGPA)\n\nMr T. Fujino, Director, International Affairs, Japan Generic Medicines Association (JGA), Tokyo, Japan\n\n### International Pharmaceutical Excipients Council (IPEC)\n\nMs L. Vignoli, IPEC Europe, Brussels, Belgium\n\n### World Self-Medication Industry (WSMI)\n\nDr R. Torano, Pharmacopoeial Technical Expert, GlaxoSmithKline, United Kingdom\n\n## Pharmacopoeias\n\n### British Pharmacopoeia Commission\n\nMrs M. Vallender, Acting Group Manager, BP and Laboratory Services, London, England\n\n### Pharmacopoeia of the Republic of Korea\n\nDr Y.H. Choi, Pharmaceutical Standardization Research and Testing Division, Pharmaceuticals and Medical Devices Research Department, National Institute of Food and Drug Safety Evaluation (NIFDS), Korea Food and Drug Administration (KFDA), Cheongwon-gun, Chungbuk, Republic of Korea\n\n### United States Pharmacopeia\n\nDr K.A. Russo, Vice President, Small Molecules, Documentary Standards Division, Rockville, MD, USA\n\n----\n\n6 Unable to attend: Commonwealth Pharmacists Association (CPA), London, England; International Society for Pharmaceutical Engineering (ISPE), Tampa, Florida, USA; International Pharmaceutical Federation (FIP), The Hague, The Netherlands.\n\n7 Unable to attend: Farmacopea Argentina, Buenos Aires, Argentina; Farmacopeia Brasileira, Belo Horizonte MG, Brazil; Pharmacopoeia of the People\u2019s Republic of China, Beijing, People\u2019s Republic of China; Indian Pharmacopoeia, New Delhi, India; Japanese Pharmacopoeia, Tokyo, Japan; State Pharmacopoeia of the Russian Federation, Moscow, Russian Federation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "12da08132d823eac8e10222aa37cbcf405b14500a2b6adeab00fea0e92031186", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## European Medicines Agency (EMA)\n\nDr P. Kozarewicz, Scientific Administrator, London, England\n\n## Representation from nongovernmental organizations\n\n### European Chemical Industry Council (CEFIC)/APIC\n\nDr B. Pimentel, Board Member, APIC, and Global Regulatory Affairs Manager, DSM Nutritional Products, Basel, Switzerland\n\n### International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)\n\nDr G. France, Pfizer, United Kingdom; and Dr R. Horder, Abbott, United Kingdom\n\n### International Generic Pharmaceutical Alliance (IGPA)\n\nMr T. Fujino, Director, International Affairs, Japan Generic Medicines Association (JGA), Tokyo, Japan\n\n### International Pharmaceutical Excipients Council (IPEC)\n\nMs L. Vignoli, IPEC Europe, Brussels, Belgium\n\n### World Self-Medication Industry (WSMI)\n\nDr R. Torano, Pharmacopoeial Technical Expert, GlaxoSmithKline, United Kingdom\n\n## Pharmacopoeias\n\n### British Pharmacopoeia Commission\n\nMrs M. Vallender, Acting Group Manager, BP and Laboratory Services, London, England\n\n### Pharmacopoeia of the Republic of Korea\n\nDr Y.H. Choi, Pharmaceutical Standardization Research and Testing Division, Pharmaceuticals and Medical Devices Research Department, National Institute of Food and Drug Safety Evaluation (NIFDS), Korea Food and Drug Administration (KFDA), Cheongwon-gun, Chungbuk, Republic of Korea\n\n### United States Pharmacopeia\n\nDr K.A. Russo, Vice President, Small Molecules, Documentary Standards Division, Rockville, MD, USA\n\n----\n\n6 Unable to attend: Commonwealth Pharmacists Association (CPA), London, England; International Society for Pharmaceutical Engineering (ISPE), Tampa, Florida, USA; International Pharmaceutical Federation (FIP), The Hague, The Netherlands.\n\n7 Unable to attend: Farmacopea Argentina, Buenos Aires, Argentina; Farmacopeia Brasileira, Belo Horizonte MG, Brazil; Pharmacopoeia of the People\u2019s Republic of China, Beijing, People\u2019s Republic of China; Indian Pharmacopoeia, New Delhi, India; Japanese Pharmacopoeia, Tokyo, Japan; State Pharmacopoeia of the Russian Federation, Moscow, Russian Federation.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2160, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "feffce4f-5ead-49f1-a417-289ff4f668fb": {"__data__": {"id_": "feffce4f-5ead-49f1-a417-289ff4f668fb", "embedding": null, "metadata": {"page_label": "11", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Representation from WHO Regional Offices\n\n## WHO Secretariat\n\n- **Dr C.F. Etienne**  \n  Assistant Director-General, Health Systems and Services, WHO, Geneva, Switzerland\n\n- **Dr L. R\u00e4go**  \n  Coordinator, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Kopp**  \n  Manager, Medicines Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland  \n  *(Secretary)*\n\n- **Mr M. Deats**  \n  Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms C. Mendy**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr H. Schmidt**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr Xiaoqiong Zheng**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr A. Padilla**  \n  Manager, Blood Products and Related Biologicals, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr R. Balocco**  \n  Manager, International Nonproprietary Names Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Croft**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr A. Fake**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Mr D. Mubangizi**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms J. Sabartova**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n----\n\n8 Unable to attend: Regional Office for Africa, Brazzaville, Republic of Congo; Regional Office for the Americas, Pan American Health Organization, Washington, DC, United States of America; Regional Office for the Eastern Mediterranean, Cairo, Egypt; Regional Office for Europe, Copenhagen, Denmark; Regional Office for South-East Asia, New Delhi, India; Regional Office for the Western Pacific, Manila, Philippines.\n\n9 Unable to attend.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que incluye una lista de representantes de la Secretar\u00eda de la OMS y sus respectivas funciones. Se menciona que varios representantes de las oficinas regionales de la OMS no pudieron asistir a la reuni\u00f3n, lo que incluye oficinas en \u00c1frica, las Am\u00e9ricas, el Mediterr\u00e1neo Oriental, Europa, el Sudeste Asi\u00e1tico y el Pac\u00edfico Occidental.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQui\u00e9n es el Secretario de la reuni\u00f3n y cu\u00e1l es su funci\u00f3n espec\u00edfica dentro de la OMS?**\n   - Respuesta: El Secretario de la reuni\u00f3n es el Dr. S. Kopp, quien es el Manager del Programa de Aseguramiento de Calidad de Medicamentos en la OMS.\n\n2. **\u00bfQu\u00e9 programas espec\u00edficos est\u00e1n bajo la coordinaci\u00f3n de la Dra. L. R\u00e4go en la OMS?**\n   - Respuesta: La Dra. L. R\u00e4go es la Coordinadora de Calidad y Seguridad: Medicamentos, Medicamentos Esenciales y Productos de Salud en la OMS.\n\n3. **\u00bfCu\u00e1les son las razones por las que las oficinas regionales de la OMS no pudieron asistir a la reuni\u00f3n?**\n   - Respuesta: El documento indica que las oficinas regionales de la OMS en \u00c1frica, las Am\u00e9ricas, el Mediterr\u00e1neo Oriental, Europa, el Sudeste Asi\u00e1tico y el Pac\u00edfico Occidental no pudieron asistir, aunque no se especifican las razones en el texto.", "prev_section_summary": "El documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que presenta la reuni\u00f3n del Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas. A continuaci\u00f3n se resumen los temas clave y las entidades mencionadas:\n\n### Temas Clave:\n1. **Participaci\u00f3n de Organismos Reguladores**: Se destaca la representaci\u00f3n de la Agencia Europea de Medicamentos (EMA) por el Dr. P. Kozarewicz.\n2. **Representaci\u00f3n de Organizaciones No Gubernamentales**: Varias organizaciones de la industria farmac\u00e9utica est\u00e1n representadas, reflejando la colaboraci\u00f3n entre el sector p\u00fablico y privado.\n3. **Farmacopoeias**: Se mencionan las farmacopoeias de diferentes pa\u00edses, lo que subraya la importancia de la estandarizaci\u00f3n en la regulaci\u00f3n de productos farmac\u00e9uticos.\n4. **Asistencia y Ausencias**: Se indica que algunas organizaciones no pudieron asistir a la reuni\u00f3n, lo que resalta la diversidad de intereses en el \u00e1mbito farmac\u00e9utico.\n\n### Entidades Mencionadas:\n- **Agencia Europea de Medicamentos (EMA)**: Dr. P. Kozarewicz.\n- **Consejo Europeo de la Industria Qu\u00edmica (CEFIC)/APIC**: Dr. B. Pimentel.\n- **Federaci\u00f3n Internacional de Asociaciones de Fabricantes de Productos Farmac\u00e9uticos (IFPMA)**: Dr. G. France y Dr. R. Horder.\n- **Alianza Internacional de Medicamentos Gen\u00e9ricos (IGPA)**: Mr. T. Fujino.\n- **Consejo Internacional de Excipientes Farmac\u00e9uticos (IPEC)**: Ms. L. Vignoli.\n- **Industria Mundial de Autocuidado (WSMI)**: Dr. R. Torano.\n- **Comisi\u00f3n de Farmacopea Brit\u00e1nica**: Mrs. M. Vallender.\n- **Farmacopea de la Rep\u00fablica de Corea**: Dr. Y.H. Choi.\n- **Farmacopea de los Estados Unidos**: Dr. K.A. Russo.\n\n### Ausencias Notables:\n- **Commonwealth Pharmacists Association (CPA)**\n- **International Society for Pharmaceutical Engineering (ISPE)**\n- **International Pharmaceutical Federation (FIP)**\n- **Farmacopea Argentina**\n- **Farmacopeia Brasileira**\n- **Pharmacopoeia of the People\u2019s Republic of China**\n- **Indian Pharmacopoeia**\n- **Japanese Pharmacopoeia**\n- **State Pharmacopoeia of the Russian Federation**\n\nEste resumen refleja la diversidad de participantes y la importancia de la colaboraci\u00f3n internacional en la regulaci\u00f3n y estandarizaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: WHO, Quality Assurance, Medicines, Regional Offices, Health Products"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a8b9ffeb-5ac4-4202-9f83-d91020ba5559", "node_type": "4", "metadata": {"page_label": "11", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Representation from WHO Regional Offices\n\n## WHO Secretariat\n\n- **Dr C.F. Etienne**  \n  Assistant Director-General, Health Systems and Services, WHO, Geneva, Switzerland\n\n- **Dr L. R\u00e4go**  \n  Coordinator, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Kopp**  \n  Manager, Medicines Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland  \n  *(Secretary)*\n\n- **Mr M. Deats**  \n  Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms C. Mendy**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr H. Schmidt**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr Xiaoqiong Zheng**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr A. Padilla**  \n  Manager, Blood Products and Related Biologicals, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr R. Balocco**  \n  Manager, International Nonproprietary Names Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Croft**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr A. Fake**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Mr D. Mubangizi**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms J. Sabartova**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n----\n\n8 Unable to attend: Regional Office for Africa, Brazzaville, Republic of Congo; Regional Office for the Americas, Pan American Health Organization, Washington, DC, United States of America; Regional Office for the Eastern Mediterranean, Cairo, Egypt; Regional Office for Europe, Copenhagen, Denmark; Regional Office for South-East Asia, New Delhi, India; Regional Office for the Western Pacific, Manila, Philippines.\n\n9 Unable to attend.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "5ec9f2ebad5c386337ab8716e7ea04f2d9dc3569c52c423078c2e76efee075c0", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Representation from WHO Regional Offices\n\n## WHO Secretariat\n\n- **Dr C.F. Etienne**  \n  Assistant Director-General, Health Systems and Services, WHO, Geneva, Switzerland\n\n- **Dr L. R\u00e4go**  \n  Coordinator, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Kopp**  \n  Manager, Medicines Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland  \n  *(Secretary)*\n\n- **Mr M. Deats**  \n  Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms C. Mendy**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr H. Schmidt**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr Xiaoqiong Zheng**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr A. Padilla**  \n  Manager, Blood Products and Related Biologicals, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr R. Balocco**  \n  Manager, International Nonproprietary Names Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Croft**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr A. Fake**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Mr D. Mubangizi**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms J. Sabartova**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n----\n\n8 Unable to attend: Regional Office for Africa, Brazzaville, Republic of Congo; Regional Office for the Americas, Pan American Health Organization, Washington, DC, United States of America; Regional Office for the Eastern Mediterranean, Cairo, Egypt; Regional Office for Europe, Copenhagen, Denmark; Regional Office for South-East Asia, New Delhi, India; Regional Office for the Western Pacific, Manila, Philippines.\n\n9 Unable to attend.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2456, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f1b07dca-2c4e-4cc3-bdb8-7e89e754424a": {"__data__": {"id_": "f1b07dca-2c4e-4cc3-bdb8-7e89e754424a", "embedding": null, "metadata": {"page_label": "12", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Forty-sixth report**\n\n- **Dr M. Stahl,\u00b9\u2070** Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr Hua Yin,\u00b9\u2070** Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Azatyan,** Manager, Medicines Regulatory Support Programme, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr G.B. Forte,\u00b9\u2070** Coordinator, Medicines Programme Coordination, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms L. Hedman,** Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr C. Ondari,\u00b9\u2070** Coordinator, Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr K. Weerasuriya,** Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms Y. Maruyama,** Traditional Medicine, Health Policy, Development and Services, Health Systems and Services, WHO, Geneva, Switzerland\n\n- **Dr I. Knezevic,** Quality, Safety and Standards, Immunization, Vaccines and Biologicals, Family and Community Health, WHO, Geneva, Switzerland\n\n- **Dr J. Shin,** Quality, Safety and Standards, Immunization, Vaccines and Biologicals, Family and Community Health, WHO, Geneva, Switzerland\n\n- **Dr C.R. Penn,** Disease Monitoring, Assessment and Control, Global Influenza Programme, Health Security and the Environment, WHO, Geneva, Switzerland\n\n- **Dr V. Reggi,** Control of Neglected Tropical Diseases, HIV/AIDS, TB, Malaria and Neglected Tropical Diseases, WHO, Geneva, Switzerland\n\n- **Mr D. Bramley** (Former Editor, *World Health Processing*), Prangins, Switzerland\n\n----\n\n\u00b9\u2070 Unable to attend.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento es el \"Cuarenta y sexto informe\" de la \"Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas\". Enumera a varios expertos y sus roles dentro de la Organizaci\u00f3n Mundial de la Salud (OMS) en Ginebra, Suiza, destacando sus contribuciones a programas relacionados con medicamentos, acceso a medicamentos, y control de enfermedades. Algunos de los expertos mencionados no pudieron asistir a la reuni\u00f3n.\n\n### Preguntas espec\u00edficas:\n1. **\u00bfQui\u00e9nes son los expertos que no pudieron asistir a la reuni\u00f3n seg\u00fan el informe?**\n   - Respuesta: Dr. M. Stahl, Dr. Hua Yin, Dr. G.B. Forte y Dr. C. Ondari.\n\n2. **\u00bfCu\u00e1l es el enfoque principal de la Comisi\u00f3n de Expertos de la OMS mencionado en el informe?**\n   - Respuesta: El enfoque principal es la especificaci\u00f3n y regulaci\u00f3n de preparaciones farmac\u00e9uticas, as\u00ed como la calidad y seguridad de los medicamentos.\n\n3. **\u00bfQu\u00e9 programas espec\u00edficos est\u00e1n relacionados con los roles de los expertos mencionados en el informe?**\n   - Respuesta: Los programas incluyen el Programa de Precalificaci\u00f3n, el Programa de Soporte Regulatorio de Medicamentos, y el Control de Enfermedades Tropicales Desatendidas, entre otros.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que presenta la representaci\u00f3n de la Secretar\u00eda de la OMS en una reuni\u00f3n. A continuaci\u00f3n se detallan los temas clave y las entidades mencionadas:\n\n#### Temas Clave:\n1. **Representaci\u00f3n de la OMS**: Se proporciona una lista de representantes de la Secretar\u00eda de la OMS, junto con sus cargos y \u00e1reas de responsabilidad.\n2. **Calidad y Seguridad de Medicamentos**: Se destaca la importancia de los programas relacionados con la calidad y seguridad de los medicamentos y productos de salud.\n3. **Asistencia a la Reuni\u00f3n**: Se menciona que varias oficinas regionales de la OMS no pudieron asistir a la reuni\u00f3n, aunque no se especifican las razones.\n\n#### Entidades Mencionadas:\n- **Dr. C.F. Etienne**: Assistant Director-General, Health Systems and Services.\n- **Dr. L. R\u00e4go**: Coordinadora de Calidad y Seguridad: Medicamentos, Medicamentos Esenciales y Productos de Salud.\n- **Dr. S. Kopp**: Manager del Programa de Aseguramiento de Calidad de Medicamentos (Secretario de la reuni\u00f3n).\n- **Mr. M. Deats**: Miembro del equipo de Calidad y Seguridad.\n- **Ms. C. Mendy**: Programa de Aseguramiento de Calidad.\n- **Dr. H. Schmidt**: Programa de Aseguramiento de Calidad.\n- **Dr. Xiaoqiong Zheng**: Programa de Aseguramiento de Calidad.\n- **Dr. A. Padilla**: Manager de Productos Sangu\u00edneos y Biol\u00f3gicos Relacionados.\n- **Dr. R. Balocco**: Manager del Programa de Nombres No Propietarios Internacionales.\n- **Dr. S. Croft**: Programa de Precalificaci\u00f3n.\n- **Dr. A. Fake**: Programa de Precalificaci\u00f3n.\n- **Mr. D. Mubangizi**: Programa de Precalificaci\u00f3n.\n- **Ms. J. Sabartova**: Programa de Precalificaci\u00f3n.\n\n#### Oficinas Regionales que No Asistieron:\n- Oficina Regional para \u00c1frica, Brazzaville, Rep\u00fablica del Congo.\n- Oficina Regional para las Am\u00e9ricas, Washington, D.C., Estados Unidos.\n- Oficina Regional para el Mediterr\u00e1neo Oriental, El Cairo, Egipto.\n- Oficina Regional para Europa, Copenhague, Dinamarca.\n- Oficina Regional para el Sudeste Asi\u00e1tico, Nueva Delhi, India.\n- Oficina Regional para el Pac\u00edfico Occidental, Manila, Filipinas.\n\nEste resumen destaca la estructura organizativa de la OMS en relaci\u00f3n con la calidad y seguridad de los medicamentos, as\u00ed como la participaci\u00f3n de sus representantes en la reuni\u00f3n.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, quality and safety, expert committee, medicines access"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cc2d711f-ec21-4266-bb0f-2ea49c50c45a", "node_type": "4", "metadata": {"page_label": "12", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Forty-sixth report**\n\n- **Dr M. Stahl,\u00b9\u2070** Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr Hua Yin,\u00b9\u2070** Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Azatyan,** Manager, Medicines Regulatory Support Programme, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr G.B. Forte,\u00b9\u2070** Coordinator, Medicines Programme Coordination, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms L. Hedman,** Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr C. Ondari,\u00b9\u2070** Coordinator, Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr K. Weerasuriya,** Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms Y. Maruyama,** Traditional Medicine, Health Policy, Development and Services, Health Systems and Services, WHO, Geneva, Switzerland\n\n- **Dr I. Knezevic,** Quality, Safety and Standards, Immunization, Vaccines and Biologicals, Family and Community Health, WHO, Geneva, Switzerland\n\n- **Dr J. Shin,** Quality, Safety and Standards, Immunization, Vaccines and Biologicals, Family and Community Health, WHO, Geneva, Switzerland\n\n- **Dr C.R. Penn,** Disease Monitoring, Assessment and Control, Global Influenza Programme, Health Security and the Environment, WHO, Geneva, Switzerland\n\n- **Dr V. Reggi,** Control of Neglected Tropical Diseases, HIV/AIDS, TB, Malaria and Neglected Tropical Diseases, WHO, Geneva, Switzerland\n\n- **Mr D. Bramley** (Former Editor, *World Health Processing*), Prangins, Switzerland\n\n----\n\n\u00b9\u2070 Unable to attend.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "b5be54acdb0545349c18e9863581ceae90988bd741ffdb244bbb2cb3660213fb", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Forty-sixth report**\n\n- **Dr M. Stahl,\u00b9\u2070** Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr Hua Yin,\u00b9\u2070** Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Azatyan,** Manager, Medicines Regulatory Support Programme, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr G.B. Forte,\u00b9\u2070** Coordinator, Medicines Programme Coordination, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms L. Hedman,** Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr C. Ondari,\u00b9\u2070** Coordinator, Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr K. Weerasuriya,** Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms Y. Maruyama,** Traditional Medicine, Health Policy, Development and Services, Health Systems and Services, WHO, Geneva, Switzerland\n\n- **Dr I. Knezevic,** Quality, Safety and Standards, Immunization, Vaccines and Biologicals, Family and Community Health, WHO, Geneva, Switzerland\n\n- **Dr J. Shin,** Quality, Safety and Standards, Immunization, Vaccines and Biologicals, Family and Community Health, WHO, Geneva, Switzerland\n\n- **Dr C.R. Penn,** Disease Monitoring, Assessment and Control, Global Influenza Programme, Health Security and the Environment, WHO, Geneva, Switzerland\n\n- **Dr V. Reggi,** Control of Neglected Tropical Diseases, HIV/AIDS, TB, Malaria and Neglected Tropical Diseases, WHO, Geneva, Switzerland\n\n- **Mr D. Bramley** (Former Editor, *World Health Processing*), Prangins, Switzerland\n\n----\n\n\u00b9\u2070 Unable to attend.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1891, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ef21ebee-7244-4de8-8a42-07eb52b7cf4f": {"__data__": {"id_": "ef21ebee-7244-4de8-8a42-07eb52b7cf4f", "embedding": null, "metadata": {"page_label": "13", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Declarations of interest\n\nMembers and temporary advisers of the WHO Expert Committee on Specifications for Pharmaceutical Preparations reported the following:\n\nProfessor S. Bawazir, Mr A.C. da Costa Bezerra, Mr E. Wondemagegnehu Biwota, Professor T.G. Dekker, Dr M. Karga-Hinds, Professor J. Hoogmartens, Professor S. Jin, Dr T. Kawanishi, Dr J.A. Molzon, Ms C. Munyimba-Yeta, Dr L. Paleshnuik, Ms M.-L. Rabouhans, Dr J.-L. Robert and Ms O. del Rosario Villalva Rojas reported no conflict of interest.\n\nProfessor H. Kristensen: His wife is a former employee of Novo Nordisk and holds approximately US$ 20 000 in stocks in this company. The WHO Expert Committee on Specifications for Pharmaceutical Preparations does not consider any of the products manufactured by Novo Nordisk.\n\nDr S. Mills was an employee of the company GlaxoSmithKline until July 2009. Dr Mills did not participate in any sessions of the Committee during which specific products were considered.\n\nProfessor C. Tuleu: The School of Pharmacy of the University of London (now: UCL School of Pharmacy), where Professor Tuleu works, received educational grants to support research projects on paediatric formulation and drug delivery from UNICEF and the company Vidopharm SPRL. In addition, the School of Pharmacy has received grants from Pfizer, the Medicine for Children Research Network and Global Research in Paediatrics to support research fellows in Professor Tuleu\u2019s team. Professor Tuleu did not participate in any sessions of the Committee during which specific products were considered.\n\nDr A.J. van Zyl has provided an expert opinion on WHO GMP to the United States Pharmacopeia (USP). This work focused on the preparation of a checklist to assess compliance with WHO GMP for the USP Prequalification of Medicines.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Declaraciones de inter\u00e9s de miembros del Comit\u00e9 de la OMS**: El documento detalla las declaraciones de inter\u00e9s de los miembros y asesores temporales del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. La mayor\u00eda de los miembros no reportan conflictos de inter\u00e9s, mientras que algunos tienen v\u00ednculos financieros o laborales con empresas farmac\u00e9uticas.\n\n2. **Conflictos de inter\u00e9s espec\u00edficos**: Se mencionan casos espec\u00edficos de conflictos de inter\u00e9s, como el de un miembro que tiene acciones en Novo Nordisk y otro que fue empleado de GlaxoSmithKline. Sin embargo, se aclara que estos miembros no participaron en discusiones sobre productos espec\u00edficos de estas empresas.\n\n3. **Financiamiento de investigaciones**: Se destaca que la UCL School of Pharmacy ha recibido financiamiento de varias organizaciones y empresas para proyectos de investigaci\u00f3n, lo que podr\u00eda influir en la percepci\u00f3n de imparcialidad en las recomendaciones del Comit\u00e9.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 medidas se han tomado para asegurar que los miembros del Comit\u00e9 no participen en discusiones sobre productos de empresas con las que tienen conflictos de inter\u00e9s?**\n   - Respuesta: Se indica que los miembros que reportaron conflictos de inter\u00e9s no participaron en sesiones del Comit\u00e9 donde se consideraron productos espec\u00edficos de las empresas involucradas.\n\n2. **\u00bfQu\u00e9 tipo de financiamiento ha recibido la UCL School of Pharmacy y c\u00f3mo podr\u00eda esto afectar la investigaci\u00f3n en formulaciones pedi\u00e1tricas?**\n   - Respuesta: La UCL School of Pharmacy ha recibido subvenciones educativas de UNICEF, Vidopharm SPRL, Pfizer, y otros, lo que podr\u00eda influir en la direcci\u00f3n y los resultados de la investigaci\u00f3n en formulaciones pedi\u00e1tricas.\n\n3. **\u00bfCu\u00e1l es la relaci\u00f3n entre el trabajo de Dr. A.J. van Zyl y la preparaci\u00f3n de medicamentos en el contexto de la OMS?**\n   - Respuesta: Dr. A.J. van Zyl ha proporcionado una opini\u00f3n experta sobre las Buenas Pr\u00e1cticas de Manufactura (GMP) de la OMS al USP, enfoc\u00e1ndose en la creaci\u00f3n de una lista de verificaci\u00f3n para evaluar el cumplimiento con las GMP de la OMS para la Precalificaci\u00f3n de Medicamentos del USP.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\nEl documento es el \"Cuarenta y sexto informe\" de la \"Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas\". A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n#### Temas Clave:\n1. **Especificaciones para Preparaciones Farmac\u00e9uticas**: El enfoque principal del informe es la regulaci\u00f3n y especificaci\u00f3n de medicamentos, asegurando su calidad y seguridad.\n2. **Programas de la OMS**: Se mencionan varios programas relacionados con la calidad y acceso a medicamentos, as\u00ed como el control de enfermedades.\n3. **Contribuciones de Expertos**: Se destaca la participaci\u00f3n de expertos en diferentes \u00e1reas de la salud p\u00fablica y farmac\u00e9utica.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Instituci\u00f3n responsable del informe y de los programas mencionados.\n- **Expertos Mencionados**:\n  - Dr. M. Stahl (Prequalification Programme)\n  - Dr. Hua Yin (Prequalification Programme)\n  - Dr. S. Azatyan (Medicines Regulatory Support Programme)\n  - Dr. G.B. Forte (Medicines Programme Coordination)\n  - Ms. L. Hedman (Medicines Access and Rational Use)\n  - Dr. C. Ondari (Medicines Access and Rational Use)\n  - Dr. K. Weerasuriya (Medicines Access and Rational Use)\n  - Ms. Y. Maruyama (Traditional Medicine)\n  - Dr. I. Knezevic (Quality, Safety and Standards)\n  - Dr. J. Shin (Quality, Safety and Standards)\n  - Dr. C.R. Penn (Global Influenza Programme)\n  - Dr. V. Reggi (Control of Neglected Tropical Diseases)\n  - Mr. D. Bramley (Former Editor, *World Health Processing*)\n\n#### Notas Adicionales:\n- Algunos expertos, como el Dr. M. Stahl, Dr. Hua Yin, Dr. G.B. Forte y Dr. C. Ondari, no pudieron asistir a la reuni\u00f3n. \n\nEste resumen proporciona una visi\u00f3n general de los temas tratados en el informe y las entidades involucradas en la regulaci\u00f3n y especificaci\u00f3n de preparaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, conflict of interest, research funding, GMP compliance"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cd30e9c1-971c-46c5-9b64-d5ab03e8ba2b", "node_type": "4", "metadata": {"page_label": "13", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Declarations of interest\n\nMembers and temporary advisers of the WHO Expert Committee on Specifications for Pharmaceutical Preparations reported the following:\n\nProfessor S. Bawazir, Mr A.C. da Costa Bezerra, Mr E. Wondemagegnehu Biwota, Professor T.G. Dekker, Dr M. Karga-Hinds, Professor J. Hoogmartens, Professor S. Jin, Dr T. Kawanishi, Dr J.A. Molzon, Ms C. Munyimba-Yeta, Dr L. Paleshnuik, Ms M.-L. Rabouhans, Dr J.-L. Robert and Ms O. del Rosario Villalva Rojas reported no conflict of interest.\n\nProfessor H. Kristensen: His wife is a former employee of Novo Nordisk and holds approximately US$ 20 000 in stocks in this company. The WHO Expert Committee on Specifications for Pharmaceutical Preparations does not consider any of the products manufactured by Novo Nordisk.\n\nDr S. Mills was an employee of the company GlaxoSmithKline until July 2009. Dr Mills did not participate in any sessions of the Committee during which specific products were considered.\n\nProfessor C. Tuleu: The School of Pharmacy of the University of London (now: UCL School of Pharmacy), where Professor Tuleu works, received educational grants to support research projects on paediatric formulation and drug delivery from UNICEF and the company Vidopharm SPRL. In addition, the School of Pharmacy has received grants from Pfizer, the Medicine for Children Research Network and Global Research in Paediatrics to support research fellows in Professor Tuleu\u2019s team. Professor Tuleu did not participate in any sessions of the Committee during which specific products were considered.\n\nDr A.J. van Zyl has provided an expert opinion on WHO GMP to the United States Pharmacopeia (USP). This work focused on the preparation of a checklist to assess compliance with WHO GMP for the USP Prequalification of Medicines.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "920f70eb44d9556b66aa763b629ad52279280b7eb870022ddc026dad55ecfb03", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Declarations of interest\n\nMembers and temporary advisers of the WHO Expert Committee on Specifications for Pharmaceutical Preparations reported the following:\n\nProfessor S. Bawazir, Mr A.C. da Costa Bezerra, Mr E. Wondemagegnehu Biwota, Professor T.G. Dekker, Dr M. Karga-Hinds, Professor J. Hoogmartens, Professor S. Jin, Dr T. Kawanishi, Dr J.A. Molzon, Ms C. Munyimba-Yeta, Dr L. Paleshnuik, Ms M.-L. Rabouhans, Dr J.-L. Robert and Ms O. del Rosario Villalva Rojas reported no conflict of interest.\n\nProfessor H. Kristensen: His wife is a former employee of Novo Nordisk and holds approximately US$ 20 000 in stocks in this company. The WHO Expert Committee on Specifications for Pharmaceutical Preparations does not consider any of the products manufactured by Novo Nordisk.\n\nDr S. Mills was an employee of the company GlaxoSmithKline until July 2009. Dr Mills did not participate in any sessions of the Committee during which specific products were considered.\n\nProfessor C. Tuleu: The School of Pharmacy of the University of London (now: UCL School of Pharmacy), where Professor Tuleu works, received educational grants to support research projects on paediatric formulation and drug delivery from UNICEF and the company Vidopharm SPRL. In addition, the School of Pharmacy has received grants from Pfizer, the Medicine for Children Research Network and Global Research in Paediatrics to support research fellows in Professor Tuleu\u2019s team. Professor Tuleu did not participate in any sessions of the Committee during which specific products were considered.\n\nDr A.J. van Zyl has provided an expert opinion on WHO GMP to the United States Pharmacopeia (USP). This work focused on the preparation of a checklist to assess compliance with WHO GMP for the USP Prequalification of Medicines.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1792, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "dbbc2d54-734a-4bf3-89bf-6e9c053b98fb": {"__data__": {"id_": "dbbc2d54-734a-4bf3-89bf-6e9c053b98fb", "embedding": null, "metadata": {"page_label": "14", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Dado el contexto proporcionado sobre el documento \"WHO - Technical Report Series 970\", aqu\u00ed tienes tres preguntas que podr\u00edan tener respuestas espec\u00edficas en este informe:\n\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS en el Informe T\u00e9cnico 970 sobre la salud p\u00fablica y la prevenci\u00f3n de enfermedades?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre las directrices o recomendaciones que la OMS ha emitido en este informe, que pueden no estar disponibles en otras fuentes.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas se describen en el Informe T\u00e9cnico 970 para la evaluaci\u00f3n de intervenciones en salud?**\n   - Esta pregunta se centra en las t\u00e9cnicas o enfoques que la OMS sugiere para evaluar la efectividad de diferentes intervenciones en el \u00e1mbito de la salud, lo cual puede ser \u00fanico a este documento.\n\n3. **\u00bfQu\u00e9 datos o estad\u00edsticas clave se presentan en el Informe T\u00e9cnico 970 que respaldan las conclusiones sobre la carga de enfermedades a nivel global?**\n   - Esta pregunta busca informaci\u00f3n cuantitativa que pueda ser espec\u00edfica del informe y que no se encuentre f\u00e1cilmente en otras publicaciones o reportes.\n\n### Resumen de nivel superior del contexto circundante:\nEl \"WHO - Technical Report Series 970\" es un documento que forma parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas cr\u00edticos en salud p\u00fablica, proporcionando an\u00e1lisis, recomendaciones y directrices basadas en la evidencia. La serie es conocida por su enfoque en la investigaci\u00f3n y la evaluaci\u00f3n de pol\u00edticas de salud, as\u00ed como por su contribuci\u00f3n a la formulaci\u00f3n de estrategias para mejorar la salud a nivel global.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Declaraciones de Inter\u00e9s**: Se presenta un informe sobre los conflictos de inter\u00e9s de los miembros y asesores del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. La mayor\u00eda de los miembros no reportan conflictos, mientras que algunos tienen v\u00ednculos financieros o laborales con empresas farmac\u00e9uticas.\n\n2. **Miembros sin Conflictos de Inter\u00e9s**: La mayor\u00eda de los miembros, incluyendo a:\n   - Professor S. Bawazir\n   - Mr A.C. da Costa Bezerra\n   - Mr E. Wondemagegnehu Biwota\n   - Professor T.G. Dekker\n   - Dr M. Karga-Hinds\n   - Professor J. Hoogmartens\n   - Professor S. Jin\n   - Dr T. Kawanishi\n   - Dr J.A. Molzon\n   - Ms C. Munyimba-Yeta\n   - Dr L. Paleshnuik\n   - Ms M.-L. Rabouhans\n   - Dr J.-L. Robert\n   - Ms O. del Rosario Villalva Rojas\n   reportan no tener conflictos de inter\u00e9s.\n\n3. **Conflictos de Inter\u00e9s Espec\u00edficos**:\n   - **Professor H. Kristensen**: Su esposa es ex-empleada de Novo Nordisk y posee acciones en la compa\u00f1\u00eda, pero el Comit\u00e9 no considera productos de Novo Nordisk.\n   - **Dr S. Mills**: Fue empleado de GlaxoSmithKline hasta julio de 2009 y no particip\u00f3 en discusiones sobre productos espec\u00edficos.\n   - **Professor C. Tuleu**: La UCL School of Pharmacy recibi\u00f3 subvenciones de UNICEF, Vidopharm SPRL, Pfizer y otros para proyectos de investigaci\u00f3n, pero no particip\u00f3 en discusiones sobre productos espec\u00edficos.\n\n4. **Contribuciones de Dr. A.J. van Zyl**: Proporcion\u00f3 una opini\u00f3n experta sobre las Buenas Pr\u00e1cticas de Manufactura (GMP) de la OMS al USP, enfoc\u00e1ndose en la creaci\u00f3n de una lista de verificaci\u00f3n para evaluar el cumplimiento con las GMP de la OMS.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**\n- **Novo Nordisk**\n- **GlaxoSmithKline**\n- **UCL School of Pharmacy**\n- **UNICEF**\n- **Vidopharm SPRL**\n- **Pfizer**\n- **Medicine for Children Research Network**\n- **Global Research in Paediatrics**\n- **United States Pharmacopeia (USP)**\n\nEste resumen destaca los conflictos de inter\u00e9s y las relaciones financieras de los miembros del Comit\u00e9, as\u00ed como las medidas tomadas para evitar la influencia en las decisiones del Comit\u00e9.", "excerpt_keywords": "Keywords: OMS, salud p\u00fablica, recomendaciones, intervenciones, conflictos de inter\u00e9s"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1ba60660-569f-4c3b-9fbe-9c0d3413ffaa", "node_type": "4", "metadata": {"page_label": "14", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "c98e6d107d135a6961bdbb3458c79a6ea23738724d2c88632b9ec84c3a97c6e6", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "5f862cc1-690c-4db0-b2c2-c6cdf68dbc9b": {"__data__": {"id_": "5f862cc1-690c-4db0-b2c2-c6cdf68dbc9b", "embedding": null, "metadata": {"page_label": "15", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nThe WHO Expert Committee on Specifications for Pharmaceutical Preparations met in Geneva from 10 to 14 October 2011. Dr C.F. Etienne, Assistant Director-General for the Health Systems and Services Cluster opened the meeting and, on behalf of the Director-General of the World Health Organization, welcomed all the participants to the forty-sixth meeting of the Expert Committee. She thanked the members of the Expert Committee for contributing their knowledge and expertise to the work of WHO in the area of quality assurance of medicines as well as with practical laboratory studies.\n\nDr Etienne briefly described the reform process in WHO, adding that the Member States had expressed the view that the work on norms and standards was fundamental to the work of WHO. The work of the Expert Committee had provided considerable support to the Prequalification Programme of the United Nations to the extent that the work of that programme depended on the Expert Committee.\n\nThe Expert Committee may have a role to play in dealing with substandard/spurious/falsely-labelled/falsified/counterfeit (SSFFC) medical products, an area on which discussions had increased considerably and the role of WHO in the group was being reviewed.\n\nDr Etienne acknowledged the elected Chairs, i.e. Professors S.A. Bawazir (Chairperson) and S. Jin (Co-Chairperson), and the Rapporteurs, Dr J.A. Molzon and Dr T. Kawanishi.\n\nShe also welcomed the other members of the Committee and the temporary advisers; representatives of the United Nations Children\u2019s Fund (UNICEF), the Global Fund to Fight AIDS, Tuberculosis and Malaria, World Intellectual Property Organization (WIPO), World Trade Organization (WTO), Council of Europe/European Directorate for the Quality of Medicines and HealthCare (EDQM), European Chemical Industry Council/Active Pharmaceutical Ingredients Committee, International Federation of Pharmaceutical Manufacturers and Associations, International Generic Pharmaceutical Alliance, International Pharmaceutical Excipients Council and the World Self-Medication Industry; and representatives of the Pharmacopoeias of Great Britain, the Republic of Korea and of the United States of America.\n\nThe Coordinator of the Quality Assurance and Safety: Medicines team added his welcome to that of Dr Etienne and said that for the second time the Expert Committee would hold an open session to respond to the interest raised by Member States during the World Health Assembly in the quality of medicines, and especially on prevention and control of SSFFC medical products. The Prequalification Programme was based entirely on the guidelines and standards recommended by the Expert Committee. The work of the Expert Committee was closely linked to other organizations such as United Nations bodies and other international organizations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas se reuni\u00f3 en Ginebra del 10 al 14 de octubre de 2011. Durante la reuni\u00f3n, se discutieron temas relacionados con la calidad de los medicamentos y la lucha contra productos m\u00e9dicos subest\u00e1ndar, falsificados y etiquetados incorrectamente (SSFFC). La reuni\u00f3n fue inaugurada por la Dra. C.F. Etienne, quien destac\u00f3 la importancia de las normas y est\u00e1ndares en el trabajo de la OMS y su relaci\u00f3n con el Programa de Precalificaci\u00f3n de las Naciones Unidas. Tambi\u00e9n se reconoci\u00f3 la participaci\u00f3n de varios representantes de organizaciones internacionales y se anunci\u00f3 la celebraci\u00f3n de una sesi\u00f3n abierta para abordar las preocupaciones de los Estados Miembros sobre la calidad de los medicamentos.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1l fue el enfoque principal de la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS en octubre de 2011?**\n   - La reuni\u00f3n se centr\u00f3 en la calidad de los medicamentos y en la prevenci\u00f3n y control de productos m\u00e9dicos subest\u00e1ndar, falsificados y etiquetados incorrectamente (SSFFC).\n\n2. **\u00bfQu\u00e9 papel desempe\u00f1a el Comit\u00e9 de Expertos en relaci\u00f3n con el Programa de Precalificaci\u00f3n de las Naciones Unidas?**\n   - El trabajo del Comit\u00e9 de Expertos proporciona un apoyo considerable al Programa de Precalificaci\u00f3n, ya que este \u00faltimo depende de las directrices y est\u00e1ndares recomendados por el Comit\u00e9.\n\n3. **\u00bfQu\u00e9 organizaciones internacionales estuvieron representadas en la reuni\u00f3n del Comit\u00e9 de Expertos?**\n   - Estuvieron presentes representantes de UNICEF, el Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria, la Organizaci\u00f3n Mundial de la Propiedad Intelectual (WIPO), la Organizaci\u00f3n Mundial del Comercio (WTO), entre otros.", "prev_section_summary": "El contenido proporcionado se refiere al \"WHO - Technical Report Series 970\", un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS). A continuaci\u00f3n se resumen los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Recomendaciones de Salud P\u00fablica**: El informe incluye directrices y recomendaciones de la OMS sobre la salud p\u00fablica y la prevenci\u00f3n de enfermedades.\n2. **Metodolog\u00edas de Evaluaci\u00f3n**: Se describen t\u00e9cnicas y enfoques para evaluar la efectividad de intervenciones en salud.\n3. **Datos y Estad\u00edsticas**: Presenta informaci\u00f3n cuantitativa que respalda las conclusiones sobre la carga de enfermedades a nivel global.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe y de la formulaci\u00f3n de recomendaciones en salud p\u00fablica.\n- **Informe T\u00e9cnico 970**: El documento espec\u00edfico que se analiza, que forma parte de una serie de informes t\u00e9cnicos de la OMS.\n\n### Contexto General:\nEl informe es parte de una serie que aborda temas cr\u00edticos en salud p\u00fablica, proporcionando an\u00e1lisis basados en evidencia y contribuyendo a la formulaci\u00f3n de estrategias para mejorar la salud a nivel global.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, quality assurance, SSFFC, international organizations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "43ca5fb2-5960-45ca-8006-1ac2effce097", "node_type": "4", "metadata": {"page_label": "15", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nThe WHO Expert Committee on Specifications for Pharmaceutical Preparations met in Geneva from 10 to 14 October 2011. Dr C.F. Etienne, Assistant Director-General for the Health Systems and Services Cluster opened the meeting and, on behalf of the Director-General of the World Health Organization, welcomed all the participants to the forty-sixth meeting of the Expert Committee. She thanked the members of the Expert Committee for contributing their knowledge and expertise to the work of WHO in the area of quality assurance of medicines as well as with practical laboratory studies.\n\nDr Etienne briefly described the reform process in WHO, adding that the Member States had expressed the view that the work on norms and standards was fundamental to the work of WHO. The work of the Expert Committee had provided considerable support to the Prequalification Programme of the United Nations to the extent that the work of that programme depended on the Expert Committee.\n\nThe Expert Committee may have a role to play in dealing with substandard/spurious/falsely-labelled/falsified/counterfeit (SSFFC) medical products, an area on which discussions had increased considerably and the role of WHO in the group was being reviewed.\n\nDr Etienne acknowledged the elected Chairs, i.e. Professors S.A. Bawazir (Chairperson) and S. Jin (Co-Chairperson), and the Rapporteurs, Dr J.A. Molzon and Dr T. Kawanishi.\n\nShe also welcomed the other members of the Committee and the temporary advisers; representatives of the United Nations Children\u2019s Fund (UNICEF), the Global Fund to Fight AIDS, Tuberculosis and Malaria, World Intellectual Property Organization (WIPO), World Trade Organization (WTO), Council of Europe/European Directorate for the Quality of Medicines and HealthCare (EDQM), European Chemical Industry Council/Active Pharmaceutical Ingredients Committee, International Federation of Pharmaceutical Manufacturers and Associations, International Generic Pharmaceutical Alliance, International Pharmaceutical Excipients Council and the World Self-Medication Industry; and representatives of the Pharmacopoeias of Great Britain, the Republic of Korea and of the United States of America.\n\nThe Coordinator of the Quality Assurance and Safety: Medicines team added his welcome to that of Dr Etienne and said that for the second time the Expert Committee would hold an open session to respond to the interest raised by Member States during the World Health Assembly in the quality of medicines, and especially on prevention and control of SSFFC medical products. The Prequalification Programme was based entirely on the guidelines and standards recommended by the Expert Committee. The work of the Expert Committee was closely linked to other organizations such as United Nations bodies and other international organizations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "eac35e1b0efd3fc40e665e602c80c00a0fedb9562c84b965c0105e1e2d571892", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 1. Introduction\n\nThe WHO Expert Committee on Specifications for Pharmaceutical Preparations met in Geneva from 10 to 14 October 2011. Dr C.F. Etienne, Assistant Director-General for the Health Systems and Services Cluster opened the meeting and, on behalf of the Director-General of the World Health Organization, welcomed all the participants to the forty-sixth meeting of the Expert Committee. She thanked the members of the Expert Committee for contributing their knowledge and expertise to the work of WHO in the area of quality assurance of medicines as well as with practical laboratory studies.\n\nDr Etienne briefly described the reform process in WHO, adding that the Member States had expressed the view that the work on norms and standards was fundamental to the work of WHO. The work of the Expert Committee had provided considerable support to the Prequalification Programme of the United Nations to the extent that the work of that programme depended on the Expert Committee.\n\nThe Expert Committee may have a role to play in dealing with substandard/spurious/falsely-labelled/falsified/counterfeit (SSFFC) medical products, an area on which discussions had increased considerably and the role of WHO in the group was being reviewed.\n\nDr Etienne acknowledged the elected Chairs, i.e. Professors S.A. Bawazir (Chairperson) and S. Jin (Co-Chairperson), and the Rapporteurs, Dr J.A. Molzon and Dr T. Kawanishi.\n\nShe also welcomed the other members of the Committee and the temporary advisers; representatives of the United Nations Children\u2019s Fund (UNICEF), the Global Fund to Fight AIDS, Tuberculosis and Malaria, World Intellectual Property Organization (WIPO), World Trade Organization (WTO), Council of Europe/European Directorate for the Quality of Medicines and HealthCare (EDQM), European Chemical Industry Council/Active Pharmaceutical Ingredients Committee, International Federation of Pharmaceutical Manufacturers and Associations, International Generic Pharmaceutical Alliance, International Pharmaceutical Excipients Council and the World Self-Medication Industry; and representatives of the Pharmacopoeias of Great Britain, the Republic of Korea and of the United States of America.\n\nThe Coordinator of the Quality Assurance and Safety: Medicines team added his welcome to that of Dr Etienne and said that for the second time the Expert Committee would hold an open session to respond to the interest raised by Member States during the World Health Assembly in the quality of medicines, and especially on prevention and control of SSFFC medical products. The Prequalification Programme was based entirely on the guidelines and standards recommended by the Expert Committee. The work of the Expert Committee was closely linked to other organizations such as United Nations bodies and other international organizations.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2839, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c607e83b-bc04-4774-9b99-9fc1d5c74d08": {"__data__": {"id_": "c607e83b-bc04-4774-9b99-9fc1d5c74d08", "embedding": null, "metadata": {"page_label": "16", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nintergovernmental organizations, other international and regional bodies, the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria, UNICEF, WIPO, the World Bank, manufacturers\u2019 associations, national and regional pharmacopoeias, other institutions, and other WHO Expert Committees. He said that the Expert Committee structure had been and will in the future be the \u201cbackbone\u201d of the Organization\u2019s standard-setting process.\n\nHe stated that the international donor community was becoming increasingly aware of the problem of poor quality medicines. Countries with this problem were more open to recognizing it but there was still a long way to go before poor people would have access to good quality medicines. There was a continuing need for a comprehensive set of guidelines and standards in the area of quality assurance as part of the process of strengthening health systems to prevent the occurrence of, and to detect, medicines of compromised quality, including SFFC and substandard medicines.\n\n## Open session\n\nThe open session, held during the morning of Monday, 10 October 2011, was opened by Dr Etienne, who welcomed representation from permanent representatives to the United Nations Offices, international organizations based in Geneva, and specialized agencies in Switzerland.\n\nShe stated that the aim of the open session of the forty-sixth WHO Expert Committee on Specifications for Pharmaceutical Preparations was to provide more information on the Expert Committee, particularly to WHO Member States, in an open and transparent manner.\n\nPoor quality of medicines and SFFC medicines were unfortunately a major threat to public health, putting the health of numerous patients and the trust of these patients in their health systems at risk; thus this issue was of critical importance for WHO. In the medicines area, standard-setting work continued to be a pillar of WHO\u2019s activities and priorities in support of WHO Member States.\n\nWHO had been involved in medicines\u2019 quality assurance and quality control since 1948. The Expert Committee was created in the very first World Health Assembly. Its work had already begun in 1947, during the transition of health issues previously dealt with under the League of Nations. Thus medicines\u2019 quality assurance was one of WHO\u2019s oldest programmes.\n\nStrong links existed with other WHO activities, such as support of national medicines regulatory authorities (NMRAs), the Prequalification Programme, the Expert Committee on Biological Standardization, the Expert Committee on Selection and Use of Essential Medicines, Traditional Medicine and specific disease programmes.\n\nThe normative activities covered by this Expert Committee not only directly served WHO Member States, but also through implementation by", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en la labor del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, que se ocupa de la calidad de los medicamentos a nivel internacional. Se destaca la creciente preocupaci\u00f3n de la comunidad internacional sobre los medicamentos de mala calidad y la necesidad de establecer directrices y est\u00e1ndares para asegurar la calidad de los medicamentos. La sesi\u00f3n abierta del Comit\u00e9, celebrada el 10 de octubre de 2011, ten\u00eda como objetivo informar a los Estados Miembros de la OMS sobre las actividades del Comit\u00e9 y la importancia de la calidad de los medicamentos para la salud p\u00fablica. La OMS ha estado involucrada en la garant\u00eda y control de calidad de los medicamentos desde 1948, y el trabajo del Comit\u00e9 es fundamental para fortalecer los sistemas de salud y proteger la confianza de los pacientes.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las principales amenazas a la salud p\u00fablica relacionadas con los medicamentos de mala calidad mencionadas en el contexto?**\n   - Respuesta: Las principales amenazas incluyen el riesgo para la salud de numerosos pacientes y la erosi\u00f3n de la confianza de estos pacientes en sus sistemas de salud, lo que puede llevar a un deterioro general de la salud p\u00fablica.\n\n2. **\u00bfQu\u00e9 papel ha desempe\u00f1ado la OMS en la garant\u00eda de calidad de los medicamentos desde su creaci\u00f3n?**\n   - Respuesta: La OMS ha estado involucrada en la garant\u00eda y control de calidad de los medicamentos desde 1948, siendo uno de sus programas m\u00e1s antiguos, y ha establecido un marco normativo que apoya a los Estados Miembros en la regulaci\u00f3n y control de la calidad de los medicamentos.\n\n3. **\u00bfQu\u00e9 iniciativas o programas espec\u00edficos de la OMS est\u00e1n relacionados con la calidad de los medicamentos, seg\u00fan el contexto?**\n   - Respuesta: Las iniciativas incluyen el apoyo a las autoridades nacionales de regulaci\u00f3n de medicamentos (NMRAs), el Programa de Precalificaci\u00f3n, y la colaboraci\u00f3n con otros comit\u00e9s de expertos en \u00e1reas como la estandarizaci\u00f3n biol\u00f3gica y el uso de medicamentos esenciales.\n\n### Resumen de Nivel Superior\n\nEl Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas es crucial para abordar la calidad de los medicamentos a nivel global. La OMS ha estado trabajando en este \u00e1mbito desde su fundaci\u00f3n, y su labor es esencial para fortalecer los sistemas de salud y garantizar que los pacientes tengan acceso a medicamentos de calidad. La creciente preocupaci\u00f3n por los medicamentos de mala calidad resalta la necesidad de establecer directrices y est\u00e1ndares claros para proteger la salud p\u00fablica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Reuni\u00f3n del Comit\u00e9 de Expertos de la OMS:** El Comit\u00e9 se reuni\u00f3 en Ginebra del 10 al 14 de octubre de 2011 para discutir la calidad de los medicamentos.\n2. **Calidad de Medicamentos:** Se abordaron temas relacionados con la prevenci\u00f3n y control de productos m\u00e9dicos subest\u00e1ndar, falsificados y etiquetados incorrectamente (SSFFC).\n3. **Normas y Est\u00e1ndares:** Se destac\u00f3 la importancia de las normas y est\u00e1ndares en el trabajo de la OMS, considerados fundamentales por los Estados Miembros.\n4. **Programa de Precalificaci\u00f3n:** El trabajo del Comit\u00e9 proporciona apoyo significativo al Programa de Precalificaci\u00f3n de las Naciones Unidas, que depende de las directrices y est\u00e1ndares recomendados por el Comit\u00e9.\n5. **Sesi\u00f3n Abierta:** Se anunci\u00f3 la celebraci\u00f3n de una sesi\u00f3n abierta para abordar las preocupaciones de los Estados Miembros sobre la calidad de los medicamentos.\n\n**Entidades Representadas:**\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**\n- **UNICEF (Fondo de las Naciones Unidas para la Infancia)**\n- **Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria**\n- **Organizaci\u00f3n Mundial de la Propiedad Intelectual (WIPO)**\n- **Organizaci\u00f3n Mundial del Comercio (WTO)**\n- **Consejo de Europa/Directorio Europeo para la Calidad de Medicamentos y Atenci\u00f3n Sanitaria (EDQM)**\n- **Consejo Europeo de la Industria Qu\u00edmica/Comit\u00e9 de Ingredientes Farmac\u00e9uticos Activos**\n- **Federaci\u00f3n Internacional de Fabricantes y Asociaciones Farmac\u00e9uticas**\n- **Alianza Internacional de Medicamentos Gen\u00e9ricos**\n- **Consejo Internacional de Excipientes Farmac\u00e9uticos**\n- **Industria Mundial de la Automedicaci\u00f3n**\n- **Representantes de las Farmacopeas de Gran Breta\u00f1a, Corea del Sur y Estados Unidos.**\n\nEste resumen destaca los aspectos m\u00e1s relevantes de la reuni\u00f3n y las entidades involucradas en la discusi\u00f3n sobre la calidad de los medicamentos y la lucha contra productos m\u00e9dicos de calidad inferior.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, quality assurance, public health, standard-setting"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "61cab5a4-b158-4254-bde8-7296f1ce3f80", "node_type": "4", "metadata": {"page_label": "16", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nintergovernmental organizations, other international and regional bodies, the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria, UNICEF, WIPO, the World Bank, manufacturers\u2019 associations, national and regional pharmacopoeias, other institutions, and other WHO Expert Committees. He said that the Expert Committee structure had been and will in the future be the \u201cbackbone\u201d of the Organization\u2019s standard-setting process.\n\nHe stated that the international donor community was becoming increasingly aware of the problem of poor quality medicines. Countries with this problem were more open to recognizing it but there was still a long way to go before poor people would have access to good quality medicines. There was a continuing need for a comprehensive set of guidelines and standards in the area of quality assurance as part of the process of strengthening health systems to prevent the occurrence of, and to detect, medicines of compromised quality, including SFFC and substandard medicines.\n\n## Open session\n\nThe open session, held during the morning of Monday, 10 October 2011, was opened by Dr Etienne, who welcomed representation from permanent representatives to the United Nations Offices, international organizations based in Geneva, and specialized agencies in Switzerland.\n\nShe stated that the aim of the open session of the forty-sixth WHO Expert Committee on Specifications for Pharmaceutical Preparations was to provide more information on the Expert Committee, particularly to WHO Member States, in an open and transparent manner.\n\nPoor quality of medicines and SFFC medicines were unfortunately a major threat to public health, putting the health of numerous patients and the trust of these patients in their health systems at risk; thus this issue was of critical importance for WHO. In the medicines area, standard-setting work continued to be a pillar of WHO\u2019s activities and priorities in support of WHO Member States.\n\nWHO had been involved in medicines\u2019 quality assurance and quality control since 1948. The Expert Committee was created in the very first World Health Assembly. Its work had already begun in 1947, during the transition of health issues previously dealt with under the League of Nations. Thus medicines\u2019 quality assurance was one of WHO\u2019s oldest programmes.\n\nStrong links existed with other WHO activities, such as support of national medicines regulatory authorities (NMRAs), the Prequalification Programme, the Expert Committee on Biological Standardization, the Expert Committee on Selection and Use of Essential Medicines, Traditional Medicine and specific disease programmes.\n\nThe normative activities covered by this Expert Committee not only directly served WHO Member States, but also through implementation by", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "e4d62d5125dbe7f9ad770379a05df5d46cea49ae784fc3a280e196689a647ad3", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nintergovernmental organizations, other international and regional bodies, the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria, UNICEF, WIPO, the World Bank, manufacturers\u2019 associations, national and regional pharmacopoeias, other institutions, and other WHO Expert Committees. He said that the Expert Committee structure had been and will in the future be the \u201cbackbone\u201d of the Organization\u2019s standard-setting process.\n\nHe stated that the international donor community was becoming increasingly aware of the problem of poor quality medicines. Countries with this problem were more open to recognizing it but there was still a long way to go before poor people would have access to good quality medicines. There was a continuing need for a comprehensive set of guidelines and standards in the area of quality assurance as part of the process of strengthening health systems to prevent the occurrence of, and to detect, medicines of compromised quality, including SFFC and substandard medicines.\n\n## Open session\n\nThe open session, held during the morning of Monday, 10 October 2011, was opened by Dr Etienne, who welcomed representation from permanent representatives to the United Nations Offices, international organizations based in Geneva, and specialized agencies in Switzerland.\n\nShe stated that the aim of the open session of the forty-sixth WHO Expert Committee on Specifications for Pharmaceutical Preparations was to provide more information on the Expert Committee, particularly to WHO Member States, in an open and transparent manner.\n\nPoor quality of medicines and SFFC medicines were unfortunately a major threat to public health, putting the health of numerous patients and the trust of these patients in their health systems at risk; thus this issue was of critical importance for WHO. In the medicines area, standard-setting work continued to be a pillar of WHO\u2019s activities and priorities in support of WHO Member States.\n\nWHO had been involved in medicines\u2019 quality assurance and quality control since 1948. The Expert Committee was created in the very first World Health Assembly. Its work had already begun in 1947, during the transition of health issues previously dealt with under the League of Nations. Thus medicines\u2019 quality assurance was one of WHO\u2019s oldest programmes.\n\nStrong links existed with other WHO activities, such as support of national medicines regulatory authorities (NMRAs), the Prequalification Programme, the Expert Committee on Biological Standardization, the Expert Committee on Selection and Use of Essential Medicines, Traditional Medicine and specific disease programmes.\n\nThe normative activities covered by this Expert Committee not only directly served WHO Member States, but also through implementation by", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2838, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "eacc2d5e-810b-45dd-aa5b-60581a151852": {"__data__": {"id_": "eacc2d5e-810b-45dd-aa5b-60581a151852", "embedding": null, "metadata": {"page_label": "17", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nProgrammes within WHO and international organizations such as UNICEF and the Global Fund to Fight AIDS, Tuberculosis and Malaria.\n\nMost of the secretariat\u2019s activities had in the past been funded from WHO\u2019s regular budget. Nowadays more than 80% of the finance was secured through extrabudgetary funding by donors. The Organization took great care to ensure that money did not come from the pharmaceutical industry.\n\nDr Etienne stated that the work of the Expert Committee was becoming a focus of interest. Its meetings were held annually in response to the increased need for normative work. The work of this Expert Committee was of the highest level of normative work at WHO and the outcome of each meeting was published in the WHO Technical Report Series, and was then presented to the WHO Executive Board. Committee members were invited in a personal capacity and did not represent their respective governments.\n\nThe Coordinator of the Quality Assurance and Safety: Medicines team explained that many issues regarding quality assurance would be discussed during the meeting. He suggested that some highlights would be capacity-building, the development and interchangeability of generic pharmaceuticals, paediatric formulations, water for pharmaceutical use, an update on the Prequalification Programme, an update on International Nonproprietary Names (INNs) and a new text on quality risk management. He strongly encouraged members of the Committee to guide WHO on future activities in quality assurance with regard to these and other issues.\n\nThe Secretary of the Expert Committee on Specifications for Pharmaceutical Preparations gave an overview of the governance and operational structure of WHO. She said that the main technical work of the Organization was based on the contributions of experts from around the world. In the area of pharmaceuticals WHO works with a range of national quality control laboratories worldwide, with regulatory bodies, international organizations, nongovernmental organizations (NGOs) and international industry associations.\n\nThe Secretary described the process for selecting experts, the requirements to be fulfilled, the areas of work in WHO covered by expert committees, and the relationship of the expert committees to the WHO Executive Board and the World Health Assembly. She further explained the wide consultation process used by the Expert Committee and the strict clearance process to be followed before issuing any guidelines or specifications. She also summarized the work of the Secretariat during the past year.\n\nThe forty-fifth report of the Expert Committee, which had met in October 2010, had been published and distributed, and its main contents were outlined to members of this Committee.\n\nThere was discussion of the relationship between the International Conference of Drug Regulatory Authorities (ICDRA) and the Expert Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Financiamiento de la OMS**: La mayor\u00eda de las actividades de la secretar\u00eda de la OMS se financiaban anteriormente con el presupuesto regular de la organizaci\u00f3n, pero actualmente m\u00e1s del 80% de los fondos provienen de donaciones extrabudgetarias, asegurando que no provengan de la industria farmac\u00e9utica.\n\n2. **Funci\u00f3n del Comit\u00e9 de Expertos**: El Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas se re\u00fane anualmente para abordar la creciente necesidad de trabajo normativo en el \u00e1mbito farmac\u00e9utico. Sus resultados se publican en la Serie de Informes T\u00e9cnicos de la OMS y se presentan a la Junta Ejecutiva de la OMS.\n\n3. **Colaboraci\u00f3n y Estructura**: La OMS colabora con laboratorios de control de calidad nacionales, organismos reguladores, ONG y asociaciones de la industria para asegurar la calidad y seguridad de los medicamentos. El proceso de selecci\u00f3n de expertos y la consulta amplia son fundamentales para la emisi\u00f3n de directrices y especificaciones.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los temas destacados que se discutir\u00e1n en la reuni\u00f3n del Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas?**\n   - Se discutir\u00e1n temas como la capacidad de construcci\u00f3n, el desarrollo e intercambiabilidad de productos farmac\u00e9uticos gen\u00e9ricos, formulaciones pedi\u00e1tricas, agua para uso farmac\u00e9utico, actualizaciones sobre el Programa de Precalificaci\u00f3n, nombres no propietarios internacionales (INNs) y un nuevo texto sobre gesti\u00f3n de riesgos de calidad.\n\n2. **\u00bfC\u00f3mo se asegura la OMS de que los fondos que recibe no provengan de la industria farmac\u00e9utica?**\n   - La OMS toma gran cuidado para garantizar que m\u00e1s del 80% de su financiamiento, que proviene de donaciones extrabudgetarias, no tenga origen en la industria farmac\u00e9utica, lo que refuerza su independencia y objetividad en el trabajo normativo.\n\n3. **\u00bfQu\u00e9 proceso sigue la OMS para seleccionar a los expertos que participan en el Comit\u00e9 de Expertos?**\n   - La Secretaria del Comit\u00e9 explic\u00f3 que hay un proceso riguroso para seleccionar expertos, que incluye cumplir con ciertos requisitos y seguir un proceso de consulta amplia y un estricto proceso de aprobaci\u00f3n antes de emitir cualquier directriz o especificaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: El Comit\u00e9 se centra en las especificaciones para preparaciones farmac\u00e9uticas y es fundamental para el establecimiento de normas sobre la calidad de los medicamentos a nivel internacional.\n\n2. **Problemas de Calidad de Medicamentos**: Se destaca la creciente preocupaci\u00f3n de la comunidad internacional sobre los medicamentos de mala calidad, incluyendo los medicamentos falsificados, subest\u00e1ndar y de calidad comprometida (SFFC). Esto representa una amenaza significativa para la salud p\u00fablica y la confianza de los pacientes en los sistemas de salud.\n\n3. **Necesidad de Directrices y Est\u00e1ndares**: Existe una necesidad continua de un conjunto integral de directrices y est\u00e1ndares en el \u00e1rea de aseguramiento de la calidad para fortalecer los sistemas de salud y prevenir la aparici\u00f3n de medicamentos de mala calidad.\n\n4. **Historia y Rol de la OMS**: La OMS ha estado involucrada en la garant\u00eda y control de calidad de los medicamentos desde 1948, siendo uno de sus programas m\u00e1s antiguos. El Comit\u00e9 fue creado en la primera Asamblea Mundial de la Salud y ha mantenido un papel crucial en la regulaci\u00f3n de la calidad de los medicamentos.\n\n5. **Colaboraciones y Programas Relacionados**: La OMS colabora con diversas entidades, incluyendo:\n   - **Organizaciones Intergubernamentales**: Como el Fondo Global para la Lucha contra el VIH/SIDA, la Tuberculosis y la Malaria, UNICEF, WIPO, y el Banco Mundial.\n   - **Autoridades Nacionales de Regulaci\u00f3n de Medicamentos (NMRAs)**: Apoyo a las autoridades que regulan la calidad de los medicamentos en los pa\u00edses.\n   - **Programas de Precalificaci\u00f3n**: Para asegurar que los medicamentos cumplan con est\u00e1ndares de calidad antes de ser utilizados en programas de salud p\u00fablica.\n\n6. **Importancia de la Transparencia**: La sesi\u00f3n abierta del Comit\u00e9, celebrada el 10 de octubre de 2011, ten\u00eda como objetivo informar a los Estados Miembros de la OMS sobre las actividades del Comit\u00e9 de manera abierta y transparente, subrayando la importancia de la calidad de los medicamentos para la salud p\u00fablica.\n\n### Conclusi\u00f3n\nEl trabajo del Comit\u00e9 de Expertos de la OMS es esencial para abordar los desaf\u00edos relacionados con la calidad de los medicamentos, garantizando que los pacientes tengan acceso a productos farmac\u00e9uticos seguros y efectivos, y fortaleciendo la confianza en los sistemas de salud a nivel global.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, quality assurance, expert committee, extrabudgetary funding"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e367d65a-a684-4f2a-940e-5b711ebd5473", "node_type": "4", "metadata": {"page_label": "17", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nProgrammes within WHO and international organizations such as UNICEF and the Global Fund to Fight AIDS, Tuberculosis and Malaria.\n\nMost of the secretariat\u2019s activities had in the past been funded from WHO\u2019s regular budget. Nowadays more than 80% of the finance was secured through extrabudgetary funding by donors. The Organization took great care to ensure that money did not come from the pharmaceutical industry.\n\nDr Etienne stated that the work of the Expert Committee was becoming a focus of interest. Its meetings were held annually in response to the increased need for normative work. The work of this Expert Committee was of the highest level of normative work at WHO and the outcome of each meeting was published in the WHO Technical Report Series, and was then presented to the WHO Executive Board. Committee members were invited in a personal capacity and did not represent their respective governments.\n\nThe Coordinator of the Quality Assurance and Safety: Medicines team explained that many issues regarding quality assurance would be discussed during the meeting. He suggested that some highlights would be capacity-building, the development and interchangeability of generic pharmaceuticals, paediatric formulations, water for pharmaceutical use, an update on the Prequalification Programme, an update on International Nonproprietary Names (INNs) and a new text on quality risk management. He strongly encouraged members of the Committee to guide WHO on future activities in quality assurance with regard to these and other issues.\n\nThe Secretary of the Expert Committee on Specifications for Pharmaceutical Preparations gave an overview of the governance and operational structure of WHO. She said that the main technical work of the Organization was based on the contributions of experts from around the world. In the area of pharmaceuticals WHO works with a range of national quality control laboratories worldwide, with regulatory bodies, international organizations, nongovernmental organizations (NGOs) and international industry associations.\n\nThe Secretary described the process for selecting experts, the requirements to be fulfilled, the areas of work in WHO covered by expert committees, and the relationship of the expert committees to the WHO Executive Board and the World Health Assembly. She further explained the wide consultation process used by the Expert Committee and the strict clearance process to be followed before issuing any guidelines or specifications. She also summarized the work of the Secretariat during the past year.\n\nThe forty-fifth report of the Expert Committee, which had met in October 2010, had been published and distributed, and its main contents were outlined to members of this Committee.\n\nThere was discussion of the relationship between the International Conference of Drug Regulatory Authorities (ICDRA) and the Expert Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "31d259f9b8b08ea06d92c10bbfa11d85bf3b1df87b82f942323e48ca816bbb06", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nProgrammes within WHO and international organizations such as UNICEF and the Global Fund to Fight AIDS, Tuberculosis and Malaria.\n\nMost of the secretariat\u2019s activities had in the past been funded from WHO\u2019s regular budget. Nowadays more than 80% of the finance was secured through extrabudgetary funding by donors. The Organization took great care to ensure that money did not come from the pharmaceutical industry.\n\nDr Etienne stated that the work of the Expert Committee was becoming a focus of interest. Its meetings were held annually in response to the increased need for normative work. The work of this Expert Committee was of the highest level of normative work at WHO and the outcome of each meeting was published in the WHO Technical Report Series, and was then presented to the WHO Executive Board. Committee members were invited in a personal capacity and did not represent their respective governments.\n\nThe Coordinator of the Quality Assurance and Safety: Medicines team explained that many issues regarding quality assurance would be discussed during the meeting. He suggested that some highlights would be capacity-building, the development and interchangeability of generic pharmaceuticals, paediatric formulations, water for pharmaceutical use, an update on the Prequalification Programme, an update on International Nonproprietary Names (INNs) and a new text on quality risk management. He strongly encouraged members of the Committee to guide WHO on future activities in quality assurance with regard to these and other issues.\n\nThe Secretary of the Expert Committee on Specifications for Pharmaceutical Preparations gave an overview of the governance and operational structure of WHO. She said that the main technical work of the Organization was based on the contributions of experts from around the world. In the area of pharmaceuticals WHO works with a range of national quality control laboratories worldwide, with regulatory bodies, international organizations, nongovernmental organizations (NGOs) and international industry associations.\n\nThe Secretary described the process for selecting experts, the requirements to be fulfilled, the areas of work in WHO covered by expert committees, and the relationship of the expert committees to the WHO Executive Board and the World Health Assembly. She further explained the wide consultation process used by the Expert Committee and the strict clearance process to be followed before issuing any guidelines or specifications. She also summarized the work of the Secretariat during the past year.\n\nThe forty-fifth report of the Expert Committee, which had met in October 2010, had been published and distributed, and its main contents were outlined to members of this Committee.\n\nThere was discussion of the relationship between the International Conference of Drug Regulatory Authorities (ICDRA) and the Expert Committee.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2966, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "6bfdf2f7-b462-4125-af41-d5ee3d611662": {"__data__": {"id_": "6bfdf2f7-b462-4125-af41-d5ee3d611662", "embedding": null, "metadata": {"page_label": "18", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# The International Pharmacopoeia\n\nThe World Health Assembly approved **The International Pharmacopoeia** in 1948. Since 1975, it has focused on the WHO Model list of essential medicines. New medicines to be included were proposed by WHO disease control programmes to ensure they met the needs of Member States. **The International Pharmacopoeia**, based on the work and decisions of the Expert Committee, gained legal status once a Member State recognized it as official. The consultation procedure for a specification to be entered into **The International Pharmacopoeia** was particularly thorough. Recently, it has held briefing sessions for interested parties, with two sessions conducted so far.\n\nThe current edition is the fourth, issued in 2006, with the first supplement in 2008 and the second in 2011. The second supplement includes a new section on monographs for radiopharmaceuticals. Future texts will be accessible online and widely distributed. New trends impacting **The International Pharmacopoeia** include a shift towards more sophisticated methods for better quality control. Earlier inadequate methods are being reviewed in light of common analytical practices worldwide.\n\nThe advantages of **The International Pharmacopoeia** include internationally validated specifications through an independent process, input from WHO collaborating centres, collaboration with manufacturers worldwide, cost analysis consideration, collaboration with standard-setting organizations, links to other WHO activities, and free use by WHO Member States.\n\n# Other Developments\n\nArtemisinin, widely used in antimalarial medicines, is derived from the plant *Artemisia annua*, a herb in Chinese traditional medicine. A guidance document on artemisinin starting material was proposed.\n\nThe WHO External Quality Assurance Assessment Scheme, advising laboratories on procedure and performance review, was described. In April 2010, EDQM took over responsibility for the preparation and storage of WHO International Chemical Reference Substances (ICRS).\n\nParticipants in the open session suggested that **The International Pharmacopoeia** should include an explanation of how the pharmacopoeia should...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl contexto se centra en **La Farmacopea Internacional**, aprobada por la Asamblea Mundial de la Salud en 1948, que se ha enfocado en la lista de medicamentos esenciales de la OMS desde 1975. La farmacopea ha ganado estatus legal al ser reconocida oficialmente por los Estados Miembros y ha implementado un proceso de consulta exhaustivo para la inclusi\u00f3n de nuevas especificaciones. La cuarta edici\u00f3n fue publicada en 2006, con suplementos en 2008 y 2011, y se est\u00e1n adoptando m\u00e9todos m\u00e1s sofisticados para el control de calidad. Adem\u00e1s, se menciona el uso de artemisinina en medicamentos antipal\u00fadicos y el esquema de evaluaci\u00f3n de calidad externa de la OMS.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los beneficios espec\u00edficos que ofrece La Farmacopea Internacional a los Estados Miembros de la OMS?**\n   - Respuesta: La Farmacopea Internacional proporciona especificaciones validadas internacionalmente a trav\u00e9s de un proceso independiente, colaboraci\u00f3n con centros de referencia de la OMS, interacci\u00f3n con fabricantes a nivel mundial, consideraci\u00f3n de an\u00e1lisis de costos, colaboraci\u00f3n con organizaciones de normalizaci\u00f3n, v\u00ednculos con otras actividades de la OMS y uso gratuito por parte de los Estados Miembros.\n\n2. **\u00bfQu\u00e9 cambios recientes se han implementado en La Farmacopea Internacional en relaci\u00f3n con los m\u00e9todos de control de calidad?**\n   - Respuesta: Se ha observado un cambio hacia m\u00e9todos m\u00e1s sofisticados para un mejor control de calidad, y se est\u00e1n revisando m\u00e9todos anteriores que eran considerados inadecuados, en funci\u00f3n de las pr\u00e1cticas anal\u00edticas comunes a nivel mundial.\n\n3. **\u00bfQu\u00e9 papel juega la planta *Artemisia annua* en el contexto de La Farmacopea Internacional y qu\u00e9 documento se propuso relacionado con ella?**\n   - Respuesta: La planta *Artemisia annua* es la fuente de artemisinina, ampliamente utilizada en medicamentos antipal\u00fadicos. Se propuso un documento de orientaci\u00f3n sobre el material de partida de artemisinina para su inclusi\u00f3n en la farmacopea.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que puede no ser f\u00e1cilmente accesible en otras fuentes, bas\u00e1ndose en los detalles proporcionados en el contexto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Financiamiento de la OMS**:\n   - La mayor\u00eda de las actividades de la secretar\u00eda de la OMS se financiaban anteriormente con el presupuesto regular, pero actualmente m\u00e1s del 80% proviene de donaciones extrabudgetarias, asegurando que no provengan de la industria farmac\u00e9utica.\n\n2. **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**:\n   - Se re\u00fane anualmente para abordar la creciente necesidad de trabajo normativo en el \u00e1mbito farmac\u00e9utico. Los resultados de sus reuniones se publican en la Serie de Informes T\u00e9cnicos de la OMS y se presentan a la Junta Ejecutiva de la OMS.\n\n3. **Temas a Discutir en la Reuni\u00f3n**:\n   - Se abordar\u00e1n temas como:\n     - Capacitaci\u00f3n y desarrollo de capacidades.\n     - Intercambiabilidad de productos farmac\u00e9uticos gen\u00e9ricos.\n     - Formulaciones pedi\u00e1tricas.\n     - Agua para uso farmac\u00e9utico.\n     - Actualizaciones sobre el Programa de Precalificaci\u00f3n.\n     - Nombres no propietarios internacionales (INNs).\n     - Gesti\u00f3n de riesgos de calidad.\n\n4. **Colaboraci\u00f3n y Estructura de la OMS**:\n   - La OMS colabora con laboratorios de control de calidad nacionales, organismos reguladores, ONG y asociaciones de la industria para asegurar la calidad y seguridad de los medicamentos.\n\n5. **Proceso de Selecci\u00f3n de Expertos**:\n   - La selecci\u00f3n de expertos implica cumplir con requisitos espec\u00edficos y seguir un proceso de consulta amplia y un estricto proceso de aprobaci\u00f3n antes de emitir directrices o especificaciones.\n\n6. **Relaci\u00f3n con la Conferencia Internacional de Autoridades Reguladoras de Medicamentos (ICDRA)**:\n   - Se discuti\u00f3 la relaci\u00f3n entre el ICDRA y el Comit\u00e9 de Expertos.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Principal organismo responsable de la salud p\u00fablica a nivel internacional.\n- **UNICEF**: Fondo de las Naciones Unidas para la Infancia, que colabora en programas de salud.\n- **Global Fund**: Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria.\n- **Expert Committee on Specifications for Pharmaceutical Preparations**: Comit\u00e9 que se enfoca en la normativa de preparaciones farmac\u00e9uticas.\n- **ICDRA (International Conference of Drug Regulatory Authorities)**: Conferencia que re\u00fane a autoridades reguladoras de medicamentos.", "excerpt_keywords": "Keywords: International Pharmacopoeia, WHO, artemisinin, quality control, essential medicines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "91441d9c-80a0-4f95-b15f-12d9d52ff18a", "node_type": "4", "metadata": {"page_label": "18", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# The International Pharmacopoeia\n\nThe World Health Assembly approved **The International Pharmacopoeia** in 1948. Since 1975, it has focused on the WHO Model list of essential medicines. New medicines to be included were proposed by WHO disease control programmes to ensure they met the needs of Member States. **The International Pharmacopoeia**, based on the work and decisions of the Expert Committee, gained legal status once a Member State recognized it as official. The consultation procedure for a specification to be entered into **The International Pharmacopoeia** was particularly thorough. Recently, it has held briefing sessions for interested parties, with two sessions conducted so far.\n\nThe current edition is the fourth, issued in 2006, with the first supplement in 2008 and the second in 2011. The second supplement includes a new section on monographs for radiopharmaceuticals. Future texts will be accessible online and widely distributed. New trends impacting **The International Pharmacopoeia** include a shift towards more sophisticated methods for better quality control. Earlier inadequate methods are being reviewed in light of common analytical practices worldwide.\n\nThe advantages of **The International Pharmacopoeia** include internationally validated specifications through an independent process, input from WHO collaborating centres, collaboration with manufacturers worldwide, cost analysis consideration, collaboration with standard-setting organizations, links to other WHO activities, and free use by WHO Member States.\n\n# Other Developments\n\nArtemisinin, widely used in antimalarial medicines, is derived from the plant *Artemisia annua*, a herb in Chinese traditional medicine. A guidance document on artemisinin starting material was proposed.\n\nThe WHO External Quality Assurance Assessment Scheme, advising laboratories on procedure and performance review, was described. In April 2010, EDQM took over responsibility for the preparation and storage of WHO International Chemical Reference Substances (ICRS).\n\nParticipants in the open session suggested that **The International Pharmacopoeia** should include an explanation of how the pharmacopoeia should...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "87b183a3cfe08756d94a0e607a34fa38a5feed63f423795b5e2defbde3cba20c", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# The International Pharmacopoeia\n\nThe World Health Assembly approved **The International Pharmacopoeia** in 1948. Since 1975, it has focused on the WHO Model list of essential medicines. New medicines to be included were proposed by WHO disease control programmes to ensure they met the needs of Member States. **The International Pharmacopoeia**, based on the work and decisions of the Expert Committee, gained legal status once a Member State recognized it as official. The consultation procedure for a specification to be entered into **The International Pharmacopoeia** was particularly thorough. Recently, it has held briefing sessions for interested parties, with two sessions conducted so far.\n\nThe current edition is the fourth, issued in 2006, with the first supplement in 2008 and the second in 2011. The second supplement includes a new section on monographs for radiopharmaceuticals. Future texts will be accessible online and widely distributed. New trends impacting **The International Pharmacopoeia** include a shift towards more sophisticated methods for better quality control. Earlier inadequate methods are being reviewed in light of common analytical practices worldwide.\n\nThe advantages of **The International Pharmacopoeia** include internationally validated specifications through an independent process, input from WHO collaborating centres, collaboration with manufacturers worldwide, cost analysis consideration, collaboration with standard-setting organizations, links to other WHO activities, and free use by WHO Member States.\n\n# Other Developments\n\nArtemisinin, widely used in antimalarial medicines, is derived from the plant *Artemisia annua*, a herb in Chinese traditional medicine. A guidance document on artemisinin starting material was proposed.\n\nThe WHO External Quality Assurance Assessment Scheme, advising laboratories on procedure and performance review, was described. In April 2010, EDQM took over responsibility for the preparation and storage of WHO International Chemical Reference Substances (ICRS).\n\nParticipants in the open session suggested that **The International Pharmacopoeia** should include an explanation of how the pharmacopoeia should...", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2198, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "653b65f0-1c6d-492f-bb37-59b92c19e8d1": {"__data__": {"id_": "653b65f0-1c6d-492f-bb37-59b92c19e8d1", "embedding": null, "metadata": {"page_label": "19", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nbe used, including advice on impurities. It was felt that a distinct and clearly defined section of *The International Pharmacopoeia* containing supplementary information would be very helpful to users.\n\nIn response to a question from a participant regarding the future of the International Medical Products Anti-Counterfeit Taskforce (IMPACT), it was stated that in 2010 the World Health Assembly had set up a working group of Member States to review WHO\u2019s future activities in the area of SSFFC medicines, including the Organization\u2019s involvement in IMPACT. WHO\u2019s function as the secretariat of IMPACT had been put on hold pending the outcome of the working group and the subsequent decision by the World Health Assembly.\n\nThe Committee members responded to questions raised by the audience. The Chair thanked the Member States\u2019 representatives for their attendance and the open session was closed.\n\nThe Expert Committee reconvened and was held in accordance with established procedures.\n\n## Major publications since October 2010\n\nThe forty-fifth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations (WHO Technical Report Series, No. 961) was presented to the meeting of the WHO Executive Board in May 2011 and had since been made available in both print and electronic formats. Published copies were distributed to the participants at the forty-sixth meeting of the Expert Committee.\n\nThe fourth edition of *The International Pharmacopoeia*, including the second supplement, had been issued both on CD-ROM and online.\n\nTwo information brochures about the Expert Committee, its procedure and functioning, and one on the technical areas covered, had been prepared and printed. One was translated into all six official languages of WHO.\n\nAn updated version of the CD-ROM, including all current WHO quality assurance guidelines adopted by the Expert Committee on Specifications for Pharmaceutical Preparations, would be available in a comprehensive and structured form by the end of 2011.\n\nThe Committee wished to thank the secretariat for its efforts in finalizing these publications as they would help to promote the outcome of the work and increase transparency.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Se discuten temas como la necesidad de una secci\u00f3n claramente definida en *La Farmacopea Internacional* que contenga informaci\u00f3n suplementaria, as\u00ed como el futuro del Grupo de Trabajo sobre Productos M\u00e9dicos Falsificados y de Calidad Subest\u00e1ndar (IMPACT). Tambi\u00e9n se mencionan las publicaciones importantes desde octubre de 2010, incluyendo el informe del Comit\u00e9 y la cuarta edici\u00f3n de *La Farmacopea Internacional*. Se destaca el agradecimiento del Comit\u00e9 al secretariado por sus esfuerzos en la finalizaci\u00f3n de estas publicaciones.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 se propuso en relaci\u00f3n con *La Farmacopea Internacional* para ayudar a los usuarios en la identificaci\u00f3n de impurezas?**\n   - Se propuso la creaci\u00f3n de una secci\u00f3n claramente definida en *La Farmacopea Internacional* que contenga informaci\u00f3n suplementaria sobre impurezas, lo cual ser\u00eda de gran ayuda para los usuarios.\n\n2. **\u00bfCu\u00e1l fue la decisi\u00f3n tomada por la Asamblea Mundial de la Salud en 2010 respecto a IMPACT y su funci\u00f3n?**\n   - En 2010, la Asamblea Mundial de la Salud estableci\u00f3 un grupo de trabajo de Estados Miembros para revisar las futuras actividades de la OMS en el \u00e1rea de medicamentos falsificados y de calidad subest\u00e1ndar (SSFFC), lo que llev\u00f3 a que la funci\u00f3n de la OMS como secretar\u00eda de IMPACT se pusiera en espera hasta que se tomara una decisi\u00f3n posterior.\n\n3. **\u00bfQu\u00e9 tipo de materiales informativos se prepararon y distribuyeron en la reuni\u00f3n del Comit\u00e9?**\n   - Se prepararon y distribuyeron dos folletos informativos sobre el Comit\u00e9 de Expertos, su procedimiento y funcionamiento, as\u00ed como uno sobre las \u00e1reas t\u00e9cnicas cubiertas. Uno de estos folletos fue traducido a los seis idiomas oficiales de la OMS.\n\n### Resumen de Nivel Superior\n\nEl Comit\u00e9 de Expertos de la OMS se reuni\u00f3 para discutir la mejora de las especificaciones para preparaciones farmac\u00e9uticas, la necesidad de informaci\u00f3n adicional en *La Farmacopea Internacional*, y el futuro de la lucha contra los medicamentos falsificados a trav\u00e9s de IMPACT. Se presentaron informes y se distribuyeron materiales informativos, destacando la importancia de la transparencia y la calidad en la farmacolog\u00eda.\n\n### Preguntas Adicionales\n\n1. **\u00bfQu\u00e9 impacto se espera que tengan las publicaciones recientes del Comit\u00e9 en la transparencia y la calidad de los medicamentos?**\n   - Las publicaciones recientes, incluyendo el informe del Comit\u00e9 y la actualizaci\u00f3n de la CD-ROM con directrices de calidad, se espera que promuevan la transparencia y mejoren la calidad de los medicamentos al proporcionar informaci\u00f3n clara y accesible.\n\n2. **\u00bfC\u00f3mo se distribuyeron las copias del informe del Comit\u00e9 a los participantes de la reuni\u00f3n?**\n   - Las copias publicadas del informe del Comit\u00e9 fueron distribuidas a los participantes durante la cuarenta y sexta reuni\u00f3n del Comit\u00e9, asegurando que todos tuvieran acceso a la informaci\u00f3n m\u00e1s reciente.\n\n3. **\u00bfQu\u00e9 se incluy\u00f3 en la cuarta edici\u00f3n de *La Farmacopea Internacional* y c\u00f3mo se present\u00f3?**\n   - La cuarta edici\u00f3n de *La Farmacopea Internacional*, que incluye un segundo suplemento, fue emitida tanto en formato CD-ROM como en l\u00ednea, facilitando el acceso a la informaci\u00f3n actualizada sobre est\u00e1ndares farmac\u00e9uticos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **La Farmacopea Internacional**:\n   - Aprobada por la Asamblea Mundial de la Salud en 1948.\n   - Enfoque en la lista de medicamentos esenciales de la OMS desde 1975.\n   - Gana estatus legal al ser reconocida oficialmente por los Estados Miembros.\n   - Proceso de consulta exhaustivo para la inclusi\u00f3n de nuevas especificaciones.\n\n2. **Ediciones y Suplementos**:\n   - Cuarta edici\u00f3n publicada en 2006.\n   - Primer suplemento en 2008 y segundo en 2011, que incluye monograf\u00edas para radiopharmaceuticals.\n   - Acceso futuro a textos en l\u00ednea y distribuci\u00f3n amplia.\n\n3. **Control de Calidad**:\n   - Cambio hacia m\u00e9todos m\u00e1s sofisticados para mejorar el control de calidad.\n   - Revisi\u00f3n de m\u00e9todos anteriores considerados inadecuados.\n\n4. **Beneficios para los Estados Miembros**:\n   - Especificaciones validadas internacionalmente.\n   - Colaboraci\u00f3n con centros de referencia de la OMS y fabricantes globales.\n   - Consideraci\u00f3n de an\u00e1lisis de costos y colaboraci\u00f3n con organizaciones de normalizaci\u00f3n.\n   - Uso gratuito por parte de los Estados Miembros.\n\n5. **Desarrollos Adicionales**:\n   - **Artemisinina**: Derivada de la planta *Artemisia annua*, utilizada en medicamentos antipal\u00fadicos.\n   - Propuesta de un documento de orientaci\u00f3n sobre el material de partida de artemisinina.\n   - Descripci\u00f3n del esquema de evaluaci\u00f3n de calidad externa de la OMS.\n   - Transferencia de responsabilidad a EDQM para la preparaci\u00f3n y almacenamiento de sustancias qu\u00edmicas de referencia internacional de la OMS (ICRS).\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la aprobaci\u00f3n y desarrollo de la Farmacopea Internacional.\n- **Artemisia annua**: Planta de la cual se extrae la artemisinina, utilizada en tratamientos antipal\u00fadicos.\n- **EDQM**: Organizaci\u00f3n que asumi\u00f3 la responsabilidad de las sustancias qu\u00edmicas de referencia de la OMS.", "excerpt_keywords": "Keywords: WHO, International Pharmacopoeia, SSFFC medicines, IMPACT, pharmaceutical preparations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "931a8253-1f7b-4543-8cee-3104592ade0c", "node_type": "4", "metadata": {"page_label": "19", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nbe used, including advice on impurities. It was felt that a distinct and clearly defined section of *The International Pharmacopoeia* containing supplementary information would be very helpful to users.\n\nIn response to a question from a participant regarding the future of the International Medical Products Anti-Counterfeit Taskforce (IMPACT), it was stated that in 2010 the World Health Assembly had set up a working group of Member States to review WHO\u2019s future activities in the area of SSFFC medicines, including the Organization\u2019s involvement in IMPACT. WHO\u2019s function as the secretariat of IMPACT had been put on hold pending the outcome of the working group and the subsequent decision by the World Health Assembly.\n\nThe Committee members responded to questions raised by the audience. The Chair thanked the Member States\u2019 representatives for their attendance and the open session was closed.\n\nThe Expert Committee reconvened and was held in accordance with established procedures.\n\n## Major publications since October 2010\n\nThe forty-fifth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations (WHO Technical Report Series, No. 961) was presented to the meeting of the WHO Executive Board in May 2011 and had since been made available in both print and electronic formats. Published copies were distributed to the participants at the forty-sixth meeting of the Expert Committee.\n\nThe fourth edition of *The International Pharmacopoeia*, including the second supplement, had been issued both on CD-ROM and online.\n\nTwo information brochures about the Expert Committee, its procedure and functioning, and one on the technical areas covered, had been prepared and printed. One was translated into all six official languages of WHO.\n\nAn updated version of the CD-ROM, including all current WHO quality assurance guidelines adopted by the Expert Committee on Specifications for Pharmaceutical Preparations, would be available in a comprehensive and structured form by the end of 2011.\n\nThe Committee wished to thank the secretariat for its efforts in finalizing these publications as they would help to promote the outcome of the work and increase transparency.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "82dc2877a12b79272823dec2b479eada5bb9ab46624dff4a1cd4f84530ac621c", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nbe used, including advice on impurities. It was felt that a distinct and clearly defined section of *The International Pharmacopoeia* containing supplementary information would be very helpful to users.\n\nIn response to a question from a participant regarding the future of the International Medical Products Anti-Counterfeit Taskforce (IMPACT), it was stated that in 2010 the World Health Assembly had set up a working group of Member States to review WHO\u2019s future activities in the area of SSFFC medicines, including the Organization\u2019s involvement in IMPACT. WHO\u2019s function as the secretariat of IMPACT had been put on hold pending the outcome of the working group and the subsequent decision by the World Health Assembly.\n\nThe Committee members responded to questions raised by the audience. The Chair thanked the Member States\u2019 representatives for their attendance and the open session was closed.\n\nThe Expert Committee reconvened and was held in accordance with established procedures.\n\n## Major publications since October 2010\n\nThe forty-fifth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations (WHO Technical Report Series, No. 961) was presented to the meeting of the WHO Executive Board in May 2011 and had since been made available in both print and electronic formats. Published copies were distributed to the participants at the forty-sixth meeting of the Expert Committee.\n\nThe fourth edition of *The International Pharmacopoeia*, including the second supplement, had been issued both on CD-ROM and online.\n\nTwo information brochures about the Expert Committee, its procedure and functioning, and one on the technical areas covered, had been prepared and printed. One was translated into all six official languages of WHO.\n\nAn updated version of the CD-ROM, including all current WHO quality assurance guidelines adopted by the Expert Committee on Specifications for Pharmaceutical Preparations, would be available in a comprehensive and structured form by the end of 2011.\n\nThe Committee wished to thank the secretariat for its efforts in finalizing these publications as they would help to promote the outcome of the work and increase transparency.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2270, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "54aae74b-fce9-4fb4-b008-8ef59a901a4d": {"__data__": {"id_": "54aae74b-fce9-4fb4-b008-8ef59a901a4d", "embedding": null, "metadata": {"page_label": "20", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. General policy\n\n## 2.1 International collaboration\n\n### 2.1.1 Collaboration with international organizations and agencies\n\n**The Global Fund to Fight AIDS, Tuberculosis and Malaria**\n\nThe procurement principles of the Global Fund to Fight AIDS, Tuberculosis and Malaria were outlined for the Expert Committee. The general principles are: best value for money, fairness, integrity and transparency. The Global Fund has procurement guidelines (as published by WHO in 2010) and a quality assurance policy on pharmaceuticals that includes clinical and quality criteria, plus the monitoring of quality. Products are monitored throughout the supply chain; there is systematic random testing and recipients report their test results to the Global Fund. Testing is carried out using the methods of the *British Pharmacopoeia, United States Pharmacopeia* or *International Pharmacopoeia*. Quality control is most difficult at country level.\n\nThe challenges of limited access to additional qualified laboratories were described. Difficulty and delay in achieving methods transfer from manufacturers and in obtaining access to reference substances were also noted. However, it was hoped that in the future it would be possible to access additional monographs so as to be able to avoid transfer of manufacturers\u2019 methods. The need for clear guidance on how to interpret monographs was raised.\n\nIn August 2011 the Global Fund and WHO held a joint meeting on quality assurance of essential medicines which recommended that WHO should continue its work towards common quality requirements for medicines that are not antiviral, antituberculosis and antimalarial (non-ATM) medicines, and should develop a risk categorization of essential medicines. The Global Fund explained its approach to quality assurance of grant-funded medicines, which is particularly thorough for antiretroviral medicines.\n\nThe Committee noted the report and expressed its appreciation to the Global Fund.\n\nThe Expert Committee recommended that the experience of the Global Fund in this area should be shared with the WHO regions to facilitate future collaboration. It was noted that the proposal for revision of the WHO guidance for national procurement agencies (WHO Technical Report Series, No. 937, Annex 6) may be presented in the future to the Expert Committee.\n\n**United Nations Children\u2019s Fund**\n\nThe United Nations Children\u2019s Fund (UNICEF) Supply Division procures supplies such as medicines for itself and for partners, including governments, agencies and NGOs. For pharmaceuticals, UNICEF uses several means to assess", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento aborda la colaboraci\u00f3n internacional en la adquisici\u00f3n y aseguramiento de la calidad de medicamentos, centr\u00e1ndose en dos organizaciones clave: el Global Fund to Fight AIDS, Tuberculosis and Malaria y el United Nations Children\u2019s Fund (UNICEF). Se destacan los principios de adquisici\u00f3n del Global Fund, que incluyen la b\u00fasqueda del mejor valor por dinero, la equidad, la integridad y la transparencia. Tambi\u00e9n se discuten los desaf\u00edos en el control de calidad a nivel nacional y la necesidad de una gu\u00eda clara para interpretar los monogr\u00e1ficos. Adem\u00e1s, se menciona una reuni\u00f3n conjunta entre el Global Fund y la OMS sobre la calidad de los medicamentos esenciales y la recomendaci\u00f3n de compartir experiencias para mejorar la colaboraci\u00f3n futura.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los principios generales de adquisici\u00f3n del Global Fund y c\u00f3mo se implementan en la pr\u00e1ctica?**\n   - Respuesta: Los principios generales de adquisici\u00f3n del Global Fund son el mejor valor por dinero, la equidad, la integridad y la transparencia. Se implementan a trav\u00e9s de directrices de adquisici\u00f3n y una pol\u00edtica de aseguramiento de calidad que incluye criterios cl\u00ednicos y de calidad, as\u00ed como el monitoreo de productos a lo largo de la cadena de suministro.\n\n2. **\u00bfQu\u00e9 desaf\u00edos enfrenta el Global Fund en el control de calidad de los medicamentos a nivel nacional?**\n   - Respuesta: Los desaf\u00edos incluyen el acceso limitado a laboratorios calificados, dificultades y retrasos en la transferencia de m\u00e9todos de los fabricantes, y la obtenci\u00f3n de sustancias de referencia. Adem\u00e1s, se menciona la necesidad de acceso a monogr\u00e1ficos adicionales y una gu\u00eda clara para su interpretaci\u00f3n.\n\n3. **\u00bfQu\u00e9 recomendaciones se hicieron en la reuni\u00f3n conjunta entre el Global Fund y la OMS en agosto de 2011?**\n   - Respuesta: Se recomend\u00f3 que la OMS contin\u00fae trabajando hacia requisitos comunes de calidad para medicamentos no antivirales, antituberculosos y antimal\u00e1ricos, y que desarrolle una categorizaci\u00f3n de riesgo para medicamentos esenciales. Tambi\u00e9n se sugiri\u00f3 compartir la experiencia del Global Fund con las regiones de la OMS para facilitar la colaboraci\u00f3n futura.", "prev_section_summary": "### Temas Clave\n\n1. **Especificaciones para Preparaciones Farmac\u00e9uticas**: Se discuti\u00f3 la necesidad de una secci\u00f3n claramente definida en *La Farmacopea Internacional* que incluya informaci\u00f3n suplementaria sobre impurezas, lo que ser\u00eda \u00fatil para los usuarios.\n\n2. **Futuro de IMPACT**: Se mencion\u00f3 que en 2010, la Asamblea Mundial de la Salud estableci\u00f3 un grupo de trabajo para revisar las actividades futuras de la OMS en relaci\u00f3n con los medicamentos falsificados y de calidad subest\u00e1ndar (SSFFC), lo que llev\u00f3 a que la funci\u00f3n de la OMS como secretar\u00eda de IMPACT se pusiera en espera.\n\n3. **Publicaciones Importantes**: Se presentaron varias publicaciones desde octubre de 2010, incluyendo el informe del Comit\u00e9 (No. 961) y la cuarta edici\u00f3n de *La Farmacopea Internacional*, que ahora est\u00e1 disponible en formato CD-ROM y en l\u00ednea.\n\n4. **Materiales Informativos**: Se prepararon y distribuyeron folletos informativos sobre el Comit\u00e9 y sus procedimientos, as\u00ed como sobre las \u00e1reas t\u00e9cnicas cubiertas, con traducciones a los seis idiomas oficiales de la OMS.\n\n5. **Transparencia y Calidad**: Se destac\u00f3 la importancia de las publicaciones recientes para promover la transparencia y mejorar la calidad de los medicamentos.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la reuni\u00f3n y de las publicaciones discutidas.\n- **IMPACT (International Medical Products Anti-Counterfeit Taskforce)**: Grupo de trabajo relacionado con la lucha contra los medicamentos falsificados.\n- **La Farmacopea Internacional**: Documento clave que se est\u00e1 actualizando para incluir informaci\u00f3n sobre impurezas y est\u00e1ndares farmac\u00e9uticos.\n- **Comit\u00e9 de Expertos de la OMS**: Grupo que se reuni\u00f3 para discutir las especificaciones y publicaciones relacionadas con preparaciones farmac\u00e9uticas. \n\nEste resumen abarca los puntos principales discutidos en la secci\u00f3n, as\u00ed como las entidades involucradas en el contexto de la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS.", "excerpt_keywords": "Keywords: Global Fund, quality assurance, procurement principles, international collaboration, UNICEF"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4392d2bb-1ed5-4c0b-99fe-44007a025dc8", "node_type": "4", "metadata": {"page_label": "20", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. General policy\n\n## 2.1 International collaboration\n\n### 2.1.1 Collaboration with international organizations and agencies\n\n**The Global Fund to Fight AIDS, Tuberculosis and Malaria**\n\nThe procurement principles of the Global Fund to Fight AIDS, Tuberculosis and Malaria were outlined for the Expert Committee. The general principles are: best value for money, fairness, integrity and transparency. The Global Fund has procurement guidelines (as published by WHO in 2010) and a quality assurance policy on pharmaceuticals that includes clinical and quality criteria, plus the monitoring of quality. Products are monitored throughout the supply chain; there is systematic random testing and recipients report their test results to the Global Fund. Testing is carried out using the methods of the *British Pharmacopoeia, United States Pharmacopeia* or *International Pharmacopoeia*. Quality control is most difficult at country level.\n\nThe challenges of limited access to additional qualified laboratories were described. Difficulty and delay in achieving methods transfer from manufacturers and in obtaining access to reference substances were also noted. However, it was hoped that in the future it would be possible to access additional monographs so as to be able to avoid transfer of manufacturers\u2019 methods. The need for clear guidance on how to interpret monographs was raised.\n\nIn August 2011 the Global Fund and WHO held a joint meeting on quality assurance of essential medicines which recommended that WHO should continue its work towards common quality requirements for medicines that are not antiviral, antituberculosis and antimalarial (non-ATM) medicines, and should develop a risk categorization of essential medicines. The Global Fund explained its approach to quality assurance of grant-funded medicines, which is particularly thorough for antiretroviral medicines.\n\nThe Committee noted the report and expressed its appreciation to the Global Fund.\n\nThe Expert Committee recommended that the experience of the Global Fund in this area should be shared with the WHO regions to facilitate future collaboration. It was noted that the proposal for revision of the WHO guidance for national procurement agencies (WHO Technical Report Series, No. 937, Annex 6) may be presented in the future to the Expert Committee.\n\n**United Nations Children\u2019s Fund**\n\nThe United Nations Children\u2019s Fund (UNICEF) Supply Division procures supplies such as medicines for itself and for partners, including governments, agencies and NGOs. For pharmaceuticals, UNICEF uses several means to assess", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "6e633afaad8a1af3cea266d55edec0b4809224b83bda0e339793b44170ac9564", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 2. General policy\n\n## 2.1 International collaboration\n\n### 2.1.1 Collaboration with international organizations and agencies\n\n**The Global Fund to Fight AIDS, Tuberculosis and Malaria**\n\nThe procurement principles of the Global Fund to Fight AIDS, Tuberculosis and Malaria were outlined for the Expert Committee. The general principles are: best value for money, fairness, integrity and transparency. The Global Fund has procurement guidelines (as published by WHO in 2010) and a quality assurance policy on pharmaceuticals that includes clinical and quality criteria, plus the monitoring of quality. Products are monitored throughout the supply chain; there is systematic random testing and recipients report their test results to the Global Fund. Testing is carried out using the methods of the *British Pharmacopoeia, United States Pharmacopeia* or *International Pharmacopoeia*. Quality control is most difficult at country level.\n\nThe challenges of limited access to additional qualified laboratories were described. Difficulty and delay in achieving methods transfer from manufacturers and in obtaining access to reference substances were also noted. However, it was hoped that in the future it would be possible to access additional monographs so as to be able to avoid transfer of manufacturers\u2019 methods. The need for clear guidance on how to interpret monographs was raised.\n\nIn August 2011 the Global Fund and WHO held a joint meeting on quality assurance of essential medicines which recommended that WHO should continue its work towards common quality requirements for medicines that are not antiviral, antituberculosis and antimalarial (non-ATM) medicines, and should develop a risk categorization of essential medicines. The Global Fund explained its approach to quality assurance of grant-funded medicines, which is particularly thorough for antiretroviral medicines.\n\nThe Committee noted the report and expressed its appreciation to the Global Fund.\n\nThe Expert Committee recommended that the experience of the Global Fund in this area should be shared with the WHO regions to facilitate future collaboration. It was noted that the proposal for revision of the WHO guidance for national procurement agencies (WHO Technical Report Series, No. 937, Annex 6) may be presented in the future to the Expert Committee.\n\n**United Nations Children\u2019s Fund**\n\nThe United Nations Children\u2019s Fund (UNICEF) Supply Division procures supplies such as medicines for itself and for partners, including governments, agencies and NGOs. For pharmaceuticals, UNICEF uses several means to assess", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2590, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "a1b39fec-eccb-4660-8d28-f3c09bb6ed97": {"__data__": {"id_": "a1b39fec-eccb-4660-8d28-f3c09bb6ed97", "embedding": null, "metadata": {"page_label": "21", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\npotential manufacturers, including the WHO guidance for procurement agencies and a technical questionnaire. The medicines have to be identical to those prequalified by WHO. For those not prequalified by WHO (i.e. non-ATM) other criteria are used, including the United Nations Agency Product Questionnaire and the requirement that the medicines are on the receiving country\u2019s national essential medicines list. UNICEF also carries out good manufacturing practices (GMP) inspections and 103 inspections were carried out between 2006 and 2010. Products kept in the UNICEF warehouse are visually inspected with tests on randomly selected samples. The prequalification of medical products is always done in connection with a tendering process.\n\nThe Committee noted the report and expressed its appreciation to UNICEF.\n\n## 2.1.2 Pharmacopoeial Discussion Group\n\nThe Pharmacopoeial Discussion Group (PDG), which consists of the *European Pharmacopoeia, Japanese Pharmacopoeia* and *United States Pharmacopeia*, met in June 2011. At present 28 of the 35 General chapters and 41 of the 62 excipient monographs of the current work programme have been harmonized. The General chapter for Microcalorimetry is newly harmonized. Revised General chapters include Bacterial endotoxins and Bulk and tapped density. Excipient sign-offs include revisions to monographs on Benzyl alcohol, Potato starch, Wheat starch, Calcium phosphate dibasic and Calcium phosphate dibasic anhydrous. The last four revisions are the outcome of PDG\u2019s review of previously harmonized excipient monographs.\n\nA press release from the PDG was distributed, which stated that the PDG would no longer meet at the same time and place as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Thus, the PDG will strengthen its independence, but the intention nevertheless is to strengthen harmonization activities among the three pharmacopoeias. WHO is an observer to this group.\n\nThe Expert Committee noted the report.\n\n## 2.1.3 International Conference on Harmonisation\n\nAn update on quality issues was provided to the Expert Committee by the European Union (EU) Quality Lead of the ICH. The concept of \u201cquality by design\u201d was explained and the procedure for developing a product according to this process was outlined. The relationship between risk management, development and a suitable quality management system was highlighted. The ICH quality group carried out six training courses for industry and regulatory staff. A \u201cquestion and answer\u201d document is available on the ICH web site and a series of \u201cpoints to consider\u201d documents were produced.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las actividades y discusiones del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Se abordan temas como la precalificaci\u00f3n de medicamentos por parte de la OMS y UNICEF, la armonizaci\u00f3n de cap\u00edtulos generales y monograf\u00edas de excipientes por parte del Grupo de Discusi\u00f3n Farmacopea (PDG), y la actualizaci\u00f3n sobre cuestiones de calidad proporcionada por la Conferencia Internacional sobre Armonizaci\u00f3n (ICH). Se destaca la importancia de las buenas pr\u00e1cticas de manufactura (GMP) y la necesidad de que los medicamentos cumplan con criterios espec\u00edficos para ser considerados en procesos de licitaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios espec\u00edficos que deben cumplir los medicamentos no precalificados por la OMS para ser considerados en el proceso de licitaci\u00f3n de UNICEF?**\n   - Respuesta: Los medicamentos no precalificados por la OMS deben cumplir con criterios como el cuestionario de productos de la Agencia de las Naciones Unidas y la exigencia de que est\u00e9n en la lista nacional de medicamentos esenciales del pa\u00eds receptor.\n\n2. **\u00bfQu\u00e9 cambios se han realizado en las monograf\u00edas de excipientes por parte del Grupo de Discusi\u00f3n Farmacopea (PDG) desde su \u00faltima reuni\u00f3n?**\n   - Respuesta: Se han revisado las monograf\u00edas de excipientes para Benzyl alcohol, Potato starch, Wheat starch, Calcium phosphate dibasic y Calcium phosphate dibasic anhydrous, como resultado de la revisi\u00f3n de monograf\u00edas de excipientes previamente armonizadas.\n\n3. **\u00bfQu\u00e9 es el concepto de \"calidad por dise\u00f1o\" y c\u00f3mo se relaciona con la gesti\u00f3n de riesgos en el desarrollo de productos farmac\u00e9uticos seg\u00fan la ICH?**\n   - Respuesta: El concepto de \"calidad por dise\u00f1o\" implica desarrollar un producto teniendo en cuenta la calidad desde el inicio del proceso, lo que se relaciona con la gesti\u00f3n de riesgos y el establecimiento de un sistema de gesti\u00f3n de calidad adecuado para asegurar que el producto final cumpla con los est\u00e1ndares requeridos.", "prev_section_summary": "La secci\u00f3n aborda la colaboraci\u00f3n internacional en la adquisici\u00f3n y aseguramiento de la calidad de medicamentos, centr\u00e1ndose en dos organizaciones clave: el Global Fund to Fight AIDS, Tuberculosis and Malaria y el United Nations Children\u2019s Fund (UNICEF).\n\n### Temas clave:\n\n1. **Principios de adquisici\u00f3n del Global Fund**:\n   - Mejor valor por dinero.\n   - Equidad.\n   - Integridad.\n   - Transparencia.\n   - Directrices de adquisici\u00f3n y pol\u00edtica de aseguramiento de calidad que incluye criterios cl\u00ednicos y de calidad.\n\n2. **Control de calidad**:\n   - Monitoreo de productos a lo largo de la cadena de suministro.\n   - Pruebas sistem\u00e1ticas y aleatorias.\n   - Dificultades en el control de calidad a nivel nacional, incluyendo acceso limitado a laboratorios calificados y retrasos en la transferencia de m\u00e9todos de los fabricantes.\n\n3. **Recomendaciones de la reuni\u00f3n conjunta (agosto de 2011)**:\n   - Continuar el trabajo hacia requisitos comunes de calidad para medicamentos no antivirales, antituberculosos y antimal\u00e1ricos.\n   - Desarrollar una categorizaci\u00f3n de riesgo para medicamentos esenciales.\n   - Compartir la experiencia del Global Fund con las regiones de la OMS para facilitar la colaboraci\u00f3n futura.\n\n### Entidades mencionadas:\n\n- **Global Fund to Fight AIDS, Tuberculosis and Malaria**: Enfocado en la adquisici\u00f3n y aseguramiento de la calidad de medicamentos, especialmente antirretrovirales.\n- **United Nations Children\u2019s Fund (UNICEF)**: Encargado de la adquisici\u00f3n de suministros, incluyendo medicamentos, para s\u00ed mismo y para socios como gobiernos y ONGs. \n\nEste resumen destaca la importancia de la colaboraci\u00f3n internacional y los desaf\u00edos en la calidad de los medicamentos, as\u00ed como las recomendaciones para mejorar los procesos de adquisici\u00f3n y control de calidad.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, prequalification, Pharmacopoeial Discussion Group, quality by design"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3b17cd96-7914-4462-8bfc-00da9b3c50cc", "node_type": "4", "metadata": {"page_label": "21", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\npotential manufacturers, including the WHO guidance for procurement agencies and a technical questionnaire. The medicines have to be identical to those prequalified by WHO. For those not prequalified by WHO (i.e. non-ATM) other criteria are used, including the United Nations Agency Product Questionnaire and the requirement that the medicines are on the receiving country\u2019s national essential medicines list. UNICEF also carries out good manufacturing practices (GMP) inspections and 103 inspections were carried out between 2006 and 2010. Products kept in the UNICEF warehouse are visually inspected with tests on randomly selected samples. The prequalification of medical products is always done in connection with a tendering process.\n\nThe Committee noted the report and expressed its appreciation to UNICEF.\n\n## 2.1.2 Pharmacopoeial Discussion Group\n\nThe Pharmacopoeial Discussion Group (PDG), which consists of the *European Pharmacopoeia, Japanese Pharmacopoeia* and *United States Pharmacopeia*, met in June 2011. At present 28 of the 35 General chapters and 41 of the 62 excipient monographs of the current work programme have been harmonized. The General chapter for Microcalorimetry is newly harmonized. Revised General chapters include Bacterial endotoxins and Bulk and tapped density. Excipient sign-offs include revisions to monographs on Benzyl alcohol, Potato starch, Wheat starch, Calcium phosphate dibasic and Calcium phosphate dibasic anhydrous. The last four revisions are the outcome of PDG\u2019s review of previously harmonized excipient monographs.\n\nA press release from the PDG was distributed, which stated that the PDG would no longer meet at the same time and place as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Thus, the PDG will strengthen its independence, but the intention nevertheless is to strengthen harmonization activities among the three pharmacopoeias. WHO is an observer to this group.\n\nThe Expert Committee noted the report.\n\n## 2.1.3 International Conference on Harmonisation\n\nAn update on quality issues was provided to the Expert Committee by the European Union (EU) Quality Lead of the ICH. The concept of \u201cquality by design\u201d was explained and the procedure for developing a product according to this process was outlined. The relationship between risk management, development and a suitable quality management system was highlighted. The ICH quality group carried out six training courses for industry and regulatory staff. A \u201cquestion and answer\u201d document is available on the ICH web site and a series of \u201cpoints to consider\u201d documents were produced.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "31f973a37b3d9c761439b1603af65b5c721ca81b19632681e3a190e03fe46557", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\npotential manufacturers, including the WHO guidance for procurement agencies and a technical questionnaire. The medicines have to be identical to those prequalified by WHO. For those not prequalified by WHO (i.e. non-ATM) other criteria are used, including the United Nations Agency Product Questionnaire and the requirement that the medicines are on the receiving country\u2019s national essential medicines list. UNICEF also carries out good manufacturing practices (GMP) inspections and 103 inspections were carried out between 2006 and 2010. Products kept in the UNICEF warehouse are visually inspected with tests on randomly selected samples. The prequalification of medical products is always done in connection with a tendering process.\n\nThe Committee noted the report and expressed its appreciation to UNICEF.\n\n## 2.1.2 Pharmacopoeial Discussion Group\n\nThe Pharmacopoeial Discussion Group (PDG), which consists of the *European Pharmacopoeia, Japanese Pharmacopoeia* and *United States Pharmacopeia*, met in June 2011. At present 28 of the 35 General chapters and 41 of the 62 excipient monographs of the current work programme have been harmonized. The General chapter for Microcalorimetry is newly harmonized. Revised General chapters include Bacterial endotoxins and Bulk and tapped density. Excipient sign-offs include revisions to monographs on Benzyl alcohol, Potato starch, Wheat starch, Calcium phosphate dibasic and Calcium phosphate dibasic anhydrous. The last four revisions are the outcome of PDG\u2019s review of previously harmonized excipient monographs.\n\nA press release from the PDG was distributed, which stated that the PDG would no longer meet at the same time and place as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Thus, the PDG will strengthen its independence, but the intention nevertheless is to strengthen harmonization activities among the three pharmacopoeias. WHO is an observer to this group.\n\nThe Expert Committee noted the report.\n\n## 2.1.3 International Conference on Harmonisation\n\nAn update on quality issues was provided to the Expert Committee by the European Union (EU) Quality Lead of the ICH. The concept of \u201cquality by design\u201d was explained and the procedure for developing a product according to this process was outlined. The relationship between risk management, development and a suitable quality management system was highlighted. The ICH quality group carried out six training courses for industry and regulatory staff. A \u201cquestion and answer\u201d document is available on the ICH web site and a series of \u201cpoints to consider\u201d documents were produced.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2753, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "982456b4-6978-4779-9a9b-373251aee9ee": {"__data__": {"id_": "982456b4-6978-4779-9a9b-373251aee9ee", "embedding": null, "metadata": {"page_label": "22", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nA new draft guideline will address the development and manufacturing of active pharmaceutical ingredients (APIs) including chemical, biotechnological and biological entities.\n\nA further ICH guideline is being drawn up for metal residues, with the aim of providing a global policy for limiting metal impurities in medicines and ingredients.\n\nFollowing wide consultation, it was decided that the guideline on genotoxic testing and data interpretation for medicines will be revised.\n\nThe Expert Committee noted the report.\n\n## 2.1.4 International Conference of Drug Regulatory Authorities\n\nThe 14th International Conference of Drug Regulatory Authorities (ICDRA) was held in Singapore from 30 November to 3 December 2010 and was attended by 345 participants from over 90 agencies in both developing and developed countries. The conference was hosted by the Health Sciences Authority of Singapore in collaboration with the World Health Organization.\n\nThe ICDRA conferences have been held since the early 1980s and are intended as a platform for achieving consensus on regulatory matters. Issues discussed at the 2010 conference included quality and safety, with a workshop on this topic which presented experience in implementation of WHO guidelines. The conference also issued recommendations to national authorities for updating requirements for stability studies in line with the recommendations of WHO. Recommendations to WHO included updating its annex on national requirements for stability guidelines for medicines and to encourage further developments in the area of stability testing for vaccines and providing additional tools for thermal testing for vaccines.\n\nThe Expert Committee recognized the importance of ICDRA meetings because they bring together regulators from the majority of Member States and recommended the WHO secretariat to pursue its efforts to ensure that the next meeting takes place.\n\n## 2.2 Cross-cutting pharmaceuticals \u2013 quality assurance issues\n\n### 2.2.1 Biological standardization\n\nThe secretary of the Expert Committee on Biological Standardization summarized four cross-cutting issues on that Expert Committee\u2019s agenda. One was an assessment tool for regulatory authorities on the quality of blood products, and a second was a proposal to set up a replacement for the international standard on endotoxin, both of which were proposed for discussion by the Expert Committee on Specifications for Pharmaceutical Preparations.\n\nA third cross-cutting issue related to the labelling of vaccines. This issue had originally been raised by the Immunization Practices Advisory Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento trata sobre las actividades y decisiones de la Comisi\u00f3n de Expertos de la OMS en relaci\u00f3n con la preparaci\u00f3n farmac\u00e9utica. Se discuten nuevas directrices para el desarrollo y fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (APIs), as\u00ed como la revisi\u00f3n de directrices sobre pruebas genot\u00f3xicas. Tambi\u00e9n se menciona la 14\u00aa Conferencia Internacional de Autoridades Reguladoras de Medicamentos (ICDRA) celebrada en Singapur, donde se abordaron temas de calidad y seguridad, y se hicieron recomendaciones para actualizar los requisitos de estudios de estabilidad. Adem\u00e1s, se presentan cuestiones transversales sobre la estandarizaci\u00f3n biol\u00f3gica y la calidad de productos sangu\u00edneos.\n\n### Preguntas espec\u00edficas:\n1. **\u00bfCu\u00e1les son los objetivos de la nueva directriz propuesta para el desarrollo y fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (APIs)?**\n   - La nueva directriz tiene como objetivo abordar el desarrollo y la fabricaci\u00f3n de APIs, incluyendo entidades qu\u00edmicas, biotecnol\u00f3gicas y biol\u00f3gicas, para mejorar la calidad y seguridad de los medicamentos.\n\n2. **\u00bfQu\u00e9 recomendaciones se hicieron a las autoridades nacionales durante la 14\u00aa ICDRA en relaci\u00f3n con los estudios de estabilidad?**\n   - Se recomendaron actualizaciones a los requisitos para los estudios de estabilidad en l\u00ednea con las recomendaciones de la OMS, as\u00ed como la actualizaci\u00f3n del anexo sobre requisitos nacionales para las directrices de estabilidad de medicamentos y el fomento de desarrollos adicionales en pruebas de estabilidad para vacunas.\n\n3. **\u00bfQu\u00e9 cuestiones transversales sobre la estandarizaci\u00f3n biol\u00f3gica se discutieron en la reuni\u00f3n de la Comisi\u00f3n de Expertos?**\n   - Se discutieron cuatro cuestiones transversales, incluyendo la creaci\u00f3n de una herramienta de evaluaci\u00f3n para las autoridades regulatorias sobre la calidad de los productos sangu\u00edneos, la propuesta de un nuevo est\u00e1ndar internacional para endotoxinas, y la cuesti\u00f3n del etiquetado de vacunas, que fue planteada originalmente por el Comit\u00e9 Asesor de Pr\u00e1cticas de Inmunizaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**:\n   - Se centra en las especificaciones para preparaciones farmac\u00e9uticas.\n   - Aprecia el trabajo de UNICEF en la precalificaci\u00f3n de medicamentos.\n\n2. **Precalificaci\u00f3n de Medicamentos**:\n   - Los medicamentos deben ser id\u00e9nticos a los precalificados por la OMS.\n   - Medicamentos no precalificados deben cumplir con el cuestionario de productos de la ONU y estar en la lista nacional de medicamentos esenciales del pa\u00eds receptor.\n   - UNICEF realiza inspecciones de buenas pr\u00e1cticas de manufactura (GMP).\n\n3. **Grupo de Discusi\u00f3n Farmacopea (PDG)**:\n   - Compuesto por la *Farmacopea Europea*, *Farmacopea Japonesa* y *Farmacopea de los Estados Unidos*.\n   - Se han armonizado 28 de 35 cap\u00edtulos generales y 41 de 62 monograf\u00edas de excipientes.\n   - Nuevas armonizaciones incluyen el cap\u00edtulo general de Microcalorimetr\u00eda y revisiones de monograf\u00edas de excipientes como Benzyl alcohol y almidones.\n\n4. **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**:\n   - Se actualizan cuestiones de calidad, destacando el concepto de \"calidad por dise\u00f1o\".\n   - Se enfatiza la relaci\u00f3n entre gesti\u00f3n de riesgos, desarrollo y sistemas de gesti\u00f3n de calidad.\n   - Se han realizado cursos de capacitaci\u00f3n para la industria y el personal regulador.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo que establece est\u00e1ndares para la precalificaci\u00f3n de medicamentos.\n- **UNICEF**: Realiza inspecciones y gestiona la precalificaci\u00f3n de productos m\u00e9dicos.\n- **PDG (Pharmacopoeial Discussion Group)**: Grupo que trabaja en la armonizaci\u00f3n de est\u00e1ndares farmac\u00e9uticos.\n- **ICH (International Conference on Harmonisation)**: Organismo que promueve la armonizaci\u00f3n de requisitos t\u00e9cnicos para la regulaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: pharmaceutical preparations, active pharmaceutical ingredients, regulatory authorities, stability studies, biological standardization"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0852ac1a-2060-4d42-9bdf-3a442f137ac9", "node_type": "4", "metadata": {"page_label": "22", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nA new draft guideline will address the development and manufacturing of active pharmaceutical ingredients (APIs) including chemical, biotechnological and biological entities.\n\nA further ICH guideline is being drawn up for metal residues, with the aim of providing a global policy for limiting metal impurities in medicines and ingredients.\n\nFollowing wide consultation, it was decided that the guideline on genotoxic testing and data interpretation for medicines will be revised.\n\nThe Expert Committee noted the report.\n\n## 2.1.4 International Conference of Drug Regulatory Authorities\n\nThe 14th International Conference of Drug Regulatory Authorities (ICDRA) was held in Singapore from 30 November to 3 December 2010 and was attended by 345 participants from over 90 agencies in both developing and developed countries. The conference was hosted by the Health Sciences Authority of Singapore in collaboration with the World Health Organization.\n\nThe ICDRA conferences have been held since the early 1980s and are intended as a platform for achieving consensus on regulatory matters. Issues discussed at the 2010 conference included quality and safety, with a workshop on this topic which presented experience in implementation of WHO guidelines. The conference also issued recommendations to national authorities for updating requirements for stability studies in line with the recommendations of WHO. Recommendations to WHO included updating its annex on national requirements for stability guidelines for medicines and to encourage further developments in the area of stability testing for vaccines and providing additional tools for thermal testing for vaccines.\n\nThe Expert Committee recognized the importance of ICDRA meetings because they bring together regulators from the majority of Member States and recommended the WHO secretariat to pursue its efforts to ensure that the next meeting takes place.\n\n## 2.2 Cross-cutting pharmaceuticals \u2013 quality assurance issues\n\n### 2.2.1 Biological standardization\n\nThe secretary of the Expert Committee on Biological Standardization summarized four cross-cutting issues on that Expert Committee\u2019s agenda. One was an assessment tool for regulatory authorities on the quality of blood products, and a second was a proposal to set up a replacement for the international standard on endotoxin, both of which were proposed for discussion by the Expert Committee on Specifications for Pharmaceutical Preparations.\n\nA third cross-cutting issue related to the labelling of vaccines. This issue had originally been raised by the Immunization Practices Advisory Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "e414dbfc2308bbbdf84721a048f0ecb10a71a866daef81d5734b483ed2a63697", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nA new draft guideline will address the development and manufacturing of active pharmaceutical ingredients (APIs) including chemical, biotechnological and biological entities.\n\nA further ICH guideline is being drawn up for metal residues, with the aim of providing a global policy for limiting metal impurities in medicines and ingredients.\n\nFollowing wide consultation, it was decided that the guideline on genotoxic testing and data interpretation for medicines will be revised.\n\nThe Expert Committee noted the report.\n\n## 2.1.4 International Conference of Drug Regulatory Authorities\n\nThe 14th International Conference of Drug Regulatory Authorities (ICDRA) was held in Singapore from 30 November to 3 December 2010 and was attended by 345 participants from over 90 agencies in both developing and developed countries. The conference was hosted by the Health Sciences Authority of Singapore in collaboration with the World Health Organization.\n\nThe ICDRA conferences have been held since the early 1980s and are intended as a platform for achieving consensus on regulatory matters. Issues discussed at the 2010 conference included quality and safety, with a workshop on this topic which presented experience in implementation of WHO guidelines. The conference also issued recommendations to national authorities for updating requirements for stability studies in line with the recommendations of WHO. Recommendations to WHO included updating its annex on national requirements for stability guidelines for medicines and to encourage further developments in the area of stability testing for vaccines and providing additional tools for thermal testing for vaccines.\n\nThe Expert Committee recognized the importance of ICDRA meetings because they bring together regulators from the majority of Member States and recommended the WHO secretariat to pursue its efforts to ensure that the next meeting takes place.\n\n## 2.2 Cross-cutting pharmaceuticals \u2013 quality assurance issues\n\n### 2.2.1 Biological standardization\n\nThe secretary of the Expert Committee on Biological Standardization summarized four cross-cutting issues on that Expert Committee\u2019s agenda. One was an assessment tool for regulatory authorities on the quality of blood products, and a second was a proposal to set up a replacement for the international standard on endotoxin, both of which were proposed for discussion by the Expert Committee on Specifications for Pharmaceutical Preparations.\n\nA third cross-cutting issue related to the labelling of vaccines. This issue had originally been raised by the Immunization Practices Advisory Committee.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2685, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "673f60da-1474-491c-825f-363517757bac": {"__data__": {"id_": "673f60da-1474-491c-825f-363517757bac", "embedding": null, "metadata": {"page_label": "23", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n(IPAC) and derived from a concern that the labels attached to vaccines varied enormously. IPAC had requested WHO to devise a standardized format for labels for vaccines. This request would go to the Expert Committee on Biological Standardization. Issues raised related to the format and content of labels, their size, the languages used, the date format, and whether there should be bar coding or another machine-readable system. Also mentioned was the need to improve the readability of labelling.\n\nThe fourth cross-cutting issue was a proposed, legally-binding treaty on mercury that was currently being negotiated by the Member States of the United Nations. The United Nations Environment Programme has coordinated the negotiation process. One issue that has arisen is whether the use of mercury in vaccines should be prohibited completely. The substance thiomersal is used as a preservative in the manufacture of vaccines and WHO has evidence of its safety.\n\nThe Expert Committee noted that some regulators are already involved in this discussion and encouraged giving further emphasis to the use of these mercury derivatives for medicines.\n\n## 2.2.2 Essential medicines\n\nIt was reported to the Expert Committee that the March 2011 meeting of the Expert Committee on the Selection and Use of Essential Medicines had revised the WHO Model list of essential medicines, and especially the list for children. Although there were some divergent opinions within the Committee regarding guidance about extemporaneous preparations, it had been noted that age-appropriate formulations for children were not available for most medicines. The Expert Committee on Essential Medicines had raised the issue of whether WHO could consider drafting guidelines for the compounding of paediatric medicines.\n\n## 2.2.3 Herbal and complementary medicines\n\nWHO\u2019s work on traditional medicine has been expanding, in part because of the growing interest in herbal and complementary medicine worldwide. Among recently issued guidelines relating to traditional medicine was the updated edition of *Quality control methods for herbal materials* which was discussed by this Expert Committee in 2008. Other guidelines describing different aspects of herbal and traditional medicines had been published, as had three documents aimed at expanding the evidence base on quality, safety and efficacy of herbal medicines. An update was currently under way of guidelines on the conservation of medicinal plants, which is being developed jointly with the International Union for the Conservation of Nature and the World Wildlife Fund, to provide a framework for the conservation and sustainable use of herbal medicines. Furthermore, a second WHO global survey on national policy regarding herbal medicines was under way.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS aborda varios temas relacionados con la estandarizaci\u00f3n de etiquetas para vacunas, la revisi\u00f3n de la lista de medicamentos esenciales, y el trabajo en medicina tradicional y complementaria. Se destaca la necesidad de un formato uniforme para las etiquetas de vacunas, la discusi\u00f3n sobre el uso de mercurio en vacunas, la falta de formulaciones adecuadas para ni\u00f1os en medicamentos esenciales, y el creciente inter\u00e9s en las medicinas herbales y complementarias, junto con la conservaci\u00f3n de plantas medicinales.\n\n### Preguntas:\n\n1. **\u00bfCu\u00e1les son los principales problemas identificados en la estandarizaci\u00f3n de etiquetas para vacunas seg\u00fan el IPAC y la OMS?**\n   - Respuesta: Los problemas incluyen la variabilidad en el formato y contenido de las etiquetas, su tama\u00f1o, los idiomas utilizados, el formato de la fecha, la posible inclusi\u00f3n de c\u00f3digos de barras o sistemas legibles por m\u00e1quina, y la necesidad de mejorar la legibilidad de las etiquetas.\n\n2. **\u00bfQu\u00e9 posici\u00f3n tiene la OMS respecto al uso de thiomersal como preservativo en vacunas en el contexto de la negociaci\u00f3n de un tratado sobre mercurio?**\n   - Respuesta: La OMS tiene evidencia de la seguridad del thiomersal y ha alentado a los reguladores a considerar el uso de derivados de mercurio en medicamentos, a pesar de las discusiones sobre la prohibici\u00f3n del uso de mercurio en vacunas.\n\n3. **\u00bfQu\u00e9 iniciativas est\u00e1 llevando a cabo la OMS para abordar la falta de formulaciones adecuadas para medicamentos pedi\u00e1tricos?**\n   - Respuesta: La OMS est\u00e1 considerando la posibilidad de redactar directrices para la preparaci\u00f3n de medicamentos pedi\u00e1tricos, dado que se ha observado que no hay formulaciones adecuadas para la mayor\u00eda de los medicamentos en ni\u00f1os, seg\u00fan lo discutido en la reuni\u00f3n de marzo de 2011 del Comit\u00e9 de Expertos en Medicamentos Esenciales.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Directrices para Ingredientes Farmac\u00e9uticos Activos (APIs)**:\n   - Se est\u00e1 desarrollando una nueva directriz que aborda la fabricaci\u00f3n y desarrollo de APIs, incluyendo entidades qu\u00edmicas, biotecnol\u00f3gicas y biol\u00f3gicas.\n\n2. **Gu\u00eda sobre Residuos Met\u00e1licos**:\n   - Se est\u00e1 elaborando una directriz del ICH para establecer una pol\u00edtica global que limite las impurezas met\u00e1licas en medicamentos e ingredientes.\n\n3. **Revisi\u00f3n de Pruebas Genot\u00f3xicas**:\n   - Se decidi\u00f3 revisar la directriz sobre pruebas genot\u00f3xicas y la interpretaci\u00f3n de datos para medicamentos tras una amplia consulta.\n\n4. **14\u00aa Conferencia Internacional de Autoridades Reguladoras de Medicamentos (ICDRA)**:\n   - Celebrada en Singapur en diciembre de 2010, con la participaci\u00f3n de 345 representantes de m\u00e1s de 90 agencias. Se discutieron temas de calidad y seguridad, y se hicieron recomendaciones para actualizar los requisitos de estudios de estabilidad de acuerdo con las directrices de la OMS.\n\n5. **Recomendaciones a Autoridades Nacionales**:\n   - Se sugiri\u00f3 actualizar los requisitos para estudios de estabilidad y fomentar el desarrollo de pruebas de estabilidad para vacunas.\n\n6. **Estandarizaci\u00f3n Biol\u00f3gica**:\n   - Se abordaron cuatro cuestiones transversales, incluyendo la creaci\u00f3n de una herramienta de evaluaci\u00f3n para la calidad de productos sangu\u00edneos y la propuesta de un nuevo est\u00e1ndar internacional para endotoxinas.\n\n7. **Etiquetado de Vacunas**:\n   - Se discuti\u00f3 la cuesti\u00f3n del etiquetado de vacunas, planteada por el Comit\u00e9 Asesor de Pr\u00e1cticas de Inmunizaci\u00f3n.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo que coordina las directrices y conferencias.\n- **ICDRA (Conferencia Internacional de Autoridades Reguladoras de Medicamentos)**: Plataforma para el consenso en asuntos regulatorios.\n- **Comit\u00e9 de Expertos en Estandarizaci\u00f3n Biol\u00f3gica**: Grupo que aborda cuestiones relacionadas con la calidad y estandarizaci\u00f3n de productos biol\u00f3gicos.", "excerpt_keywords": "Keywords: vaccines, labeling, essential medicines, herbal medicine, thiomersal"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9f1a79c0-dbc3-4a1b-84cb-6ca958c1c3e7", "node_type": "4", "metadata": {"page_label": "23", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n(IPAC) and derived from a concern that the labels attached to vaccines varied enormously. IPAC had requested WHO to devise a standardized format for labels for vaccines. This request would go to the Expert Committee on Biological Standardization. Issues raised related to the format and content of labels, their size, the languages used, the date format, and whether there should be bar coding or another machine-readable system. Also mentioned was the need to improve the readability of labelling.\n\nThe fourth cross-cutting issue was a proposed, legally-binding treaty on mercury that was currently being negotiated by the Member States of the United Nations. The United Nations Environment Programme has coordinated the negotiation process. One issue that has arisen is whether the use of mercury in vaccines should be prohibited completely. The substance thiomersal is used as a preservative in the manufacture of vaccines and WHO has evidence of its safety.\n\nThe Expert Committee noted that some regulators are already involved in this discussion and encouraged giving further emphasis to the use of these mercury derivatives for medicines.\n\n## 2.2.2 Essential medicines\n\nIt was reported to the Expert Committee that the March 2011 meeting of the Expert Committee on the Selection and Use of Essential Medicines had revised the WHO Model list of essential medicines, and especially the list for children. Although there were some divergent opinions within the Committee regarding guidance about extemporaneous preparations, it had been noted that age-appropriate formulations for children were not available for most medicines. The Expert Committee on Essential Medicines had raised the issue of whether WHO could consider drafting guidelines for the compounding of paediatric medicines.\n\n## 2.2.3 Herbal and complementary medicines\n\nWHO\u2019s work on traditional medicine has been expanding, in part because of the growing interest in herbal and complementary medicine worldwide. Among recently issued guidelines relating to traditional medicine was the updated edition of *Quality control methods for herbal materials* which was discussed by this Expert Committee in 2008. Other guidelines describing different aspects of herbal and traditional medicines had been published, as had three documents aimed at expanding the evidence base on quality, safety and efficacy of herbal medicines. An update was currently under way of guidelines on the conservation of medicinal plants, which is being developed jointly with the International Union for the Conservation of Nature and the World Wildlife Fund, to provide a framework for the conservation and sustainable use of herbal medicines. Furthermore, a second WHO global survey on national policy regarding herbal medicines was under way.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "fa5f2c54d35964b86c5bc922cc3be889ca8de34a2824851371510513d64104e5", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n(IPAC) and derived from a concern that the labels attached to vaccines varied enormously. IPAC had requested WHO to devise a standardized format for labels for vaccines. This request would go to the Expert Committee on Biological Standardization. Issues raised related to the format and content of labels, their size, the languages used, the date format, and whether there should be bar coding or another machine-readable system. Also mentioned was the need to improve the readability of labelling.\n\nThe fourth cross-cutting issue was a proposed, legally-binding treaty on mercury that was currently being negotiated by the Member States of the United Nations. The United Nations Environment Programme has coordinated the negotiation process. One issue that has arisen is whether the use of mercury in vaccines should be prohibited completely. The substance thiomersal is used as a preservative in the manufacture of vaccines and WHO has evidence of its safety.\n\nThe Expert Committee noted that some regulators are already involved in this discussion and encouraged giving further emphasis to the use of these mercury derivatives for medicines.\n\n## 2.2.2 Essential medicines\n\nIt was reported to the Expert Committee that the March 2011 meeting of the Expert Committee on the Selection and Use of Essential Medicines had revised the WHO Model list of essential medicines, and especially the list for children. Although there were some divergent opinions within the Committee regarding guidance about extemporaneous preparations, it had been noted that age-appropriate formulations for children were not available for most medicines. The Expert Committee on Essential Medicines had raised the issue of whether WHO could consider drafting guidelines for the compounding of paediatric medicines.\n\n## 2.2.3 Herbal and complementary medicines\n\nWHO\u2019s work on traditional medicine has been expanding, in part because of the growing interest in herbal and complementary medicine worldwide. Among recently issued guidelines relating to traditional medicine was the updated edition of *Quality control methods for herbal materials* which was discussed by this Expert Committee in 2008. Other guidelines describing different aspects of herbal and traditional medicines had been published, as had three documents aimed at expanding the evidence base on quality, safety and efficacy of herbal medicines. An update was currently under way of guidelines on the conservation of medicinal plants, which is being developed jointly with the International Union for the Conservation of Nature and the World Wildlife Fund, to provide a framework for the conservation and sustainable use of herbal medicines. Furthermore, a second WHO global survey on national policy regarding herbal medicines was under way.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2860, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "49974359-ce7e-420a-99a2-99771dfd6d4c": {"__data__": {"id_": "49974359-ce7e-420a-99a2-99771dfd6d4c", "embedding": null, "metadata": {"page_label": "24", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 2.2.4 Working group meeting on substandard/spurious/falsely-labelled/falsified/counterfeit medical products\n\nThere had been much discussion of the issue of SSFFC medical products at recent meetings of WHO\u2019s governing bodies, including the nomenclature and focus for WHO activity. In 2010 the Expert Committee also discussed the issue and decided to leave the terminology for the time being until the concerns of the Member States had been resolved. A working group on SSFFC medical products was set up in 2010 and its meetings are organized by a board composed of Member States, with WHO providing secretarial assistance. The first meeting of the SSFFC working group took place at the beginning of 2011 and the second meeting was due to be held in October 2011. The governing body documents on the working group are available in different languages on the WHO governing bodies\u2019 web site.\n\n## 3. Quality control \u2013 specifications and tests\n\n### 3.1 The International Pharmacopoeia\n\n#### 3.1.1 Fourth edition update\n\nThe second supplement to the fourth edition of *The International Pharmacopoeia* was issued in July 2011. The fourth edition thus comprised the two main volumes published in 2006, the first supplement published in 2008 and the second supplement. *The International Pharmacopoeia* was now available as a cumulative CD-ROM and freely accessible on the WHO medicines web site (http://www.who.int/phint).\n\nThe second supplement includes more than 60 new texts as well as about 20 texts that have been revised.\n\nThe second supplement comprises the monographs adopted by the Expert Committee at its forty-second, forty-third and forty-fourth meetings in October 2007, 2008 and 2009, respectively, with the addition of two texts adopted in October 2010 (artesunate and oseltamivir phosphate) which were also included in this supplement. Two further texts (amikacin injection and kanamycin injection) were erroneously omitted from the compilation of texts in the second supplement and will be published on the WHO medicines web site as errata to the supplement.\n\nTexts adopted as of October 2010 will be posted on the WHO medicines web site according to the usual procedure, before they are compiled into a forthcoming supplement of *The International Pharmacopoeia*. Finalization work before publication was ongoing for a few remaining texts and it was expected that they would soon be made available.\n\nWhile most of the texts have been posted on the WHO medicines web site, some of them, such as that for levonorgestrel tablets, required significant changes.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda dos temas principales: la reuni\u00f3n del grupo de trabajo sobre productos m\u00e9dicos subest\u00e1ndar, espurios, falsamente etiquetados, falsificados y de contrabando (SSFFC) y la actualizaci\u00f3n de la cuarta edici\u00f3n de *The International Pharmacopoeia*. En la primera secci\u00f3n, se discute la creaci\u00f3n de un grupo de trabajo en 2010 para abordar las preocupaciones sobre los productos SSFFC, con reuniones organizadas por un consejo de Estados Miembros y asistencia de la OMS. En la segunda secci\u00f3n, se detalla la publicaci\u00f3n del segundo suplemento de la cuarta edici\u00f3n de *The International Pharmacopoeia* en julio de 2011, que incluye nuevos textos y revisiones de monograf\u00edas adoptadas en reuniones anteriores del Comit\u00e9 de Expertos.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les fueron las decisiones tomadas por el Comit\u00e9 de Expertos de la OMS respecto a la terminolog\u00eda de los productos SSFFC en 2010?**\n   - Respuesta: En 2010, el Comit\u00e9 de Expertos decidi\u00f3 no cambiar la terminolog\u00eda relacionada con los productos SSFFC hasta que se resolvieran las preocupaciones de los Estados Miembros.\n\n2. **\u00bfQu\u00e9 novedades se incluyeron en el segundo suplemento de la cuarta edici\u00f3n de *The International Pharmacopoeia* publicado en julio de 2011?**\n   - Respuesta: El segundo suplemento incluy\u00f3 m\u00e1s de 60 nuevos textos y alrededor de 20 textos revisados, adem\u00e1s de monograf\u00edas adoptadas en reuniones anteriores del Comit\u00e9 de Expertos, incluyendo dos textos adicionales sobre artesunate y oseltamivir fosfato.\n\n3. **\u00bfQu\u00e9 errores se identificaron en la compilaci\u00f3n del segundo suplemento de *The International Pharmacopoeia* y c\u00f3mo se abordar\u00e1n?**\n   - Respuesta: Se identificaron errores en la omisi\u00f3n de los textos sobre inyecci\u00f3n de amikacina y kanamicina, que se publicar\u00e1n como erratas en el sitio web de medicamentos de la OMS.\n\n### Resumen de nivel superior\n\nEl documento de la OMS destaca la importancia de abordar los problemas relacionados con los productos m\u00e9dicos SSFFC y la necesidad de establecer una terminolog\u00eda clara y consensuada entre los Estados Miembros. Adem\u00e1s, se enfatiza la actualizaci\u00f3n de *The International Pharmacopoeia*, que es crucial para garantizar la calidad y la seguridad de los medicamentos a nivel internacional. La publicaci\u00f3n de suplementos y la correcci\u00f3n de errores en los textos son pasos importantes para mantener la integridad de esta referencia farmac\u00e9utica.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Estandarizaci\u00f3n de Etiquetas para Vacunas**:\n   - **Entidad**: IPAC (Comit\u00e9 de Expertos de la OMS).\n   - **Problemas Identificados**: Variabilidad en el formato y contenido de las etiquetas, tama\u00f1o, idiomas, formato de fecha, inclusi\u00f3n de c\u00f3digos de barras y legibilidad.\n\n2. **Uso de Mercurio en Vacunas**:\n   - **Entidad**: Organizaci\u00f3n Mundial de la Salud (OMS).\n   - **Tema**: Negociaci\u00f3n de un tratado sobre mercurio; discusi\u00f3n sobre la prohibici\u00f3n del uso de mercurio en vacunas.\n   - **Sustancia**: Thiomersal, utilizado como preservativo en vacunas, con evidencia de seguridad por parte de la OMS.\n\n3. **Medicamentos Esenciales**:\n   - **Entidad**: Comit\u00e9 de Expertos en Medicamentos Esenciales de la OMS.\n   - **Tema**: Revisi\u00f3n de la lista de medicamentos esenciales, especialmente para ni\u00f1os.\n   - **Problema**: Falta de formulaciones adecuadas para medicamentos pedi\u00e1tricos y consideraci\u00f3n de directrices para su preparaci\u00f3n.\n\n4. **Medicinas Herbales y Complementarias**:\n   - **Entidad**: OMS.\n   - **Tema**: Expansi\u00f3n del trabajo en medicina tradicional y complementaria.\n   - **Iniciativas**: Publicaci\u00f3n de gu\u00edas sobre control de calidad de materiales herbales, conservaci\u00f3n de plantas medicinales, y una encuesta global sobre pol\u00edticas nacionales respecto a las medicinas herbales.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**\n- **IPAC (Comit\u00e9 de Expertos de la OMS)**\n- **Uni\u00f3n Internacional para la Conservaci\u00f3n de la Naturaleza**\n- **Fondo Mundial para la Naturaleza** \n\nEste resumen destaca los principales temas tratados en la secci\u00f3n, as\u00ed como las entidades involucradas en cada uno de ellos.", "excerpt_keywords": "SSFFC, International Pharmacopoeia, quality control, WHO, medical products"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "906d3430-5932-44b9-b239-c005669fd97f", "node_type": "4", "metadata": {"page_label": "24", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 2.2.4 Working group meeting on substandard/spurious/falsely-labelled/falsified/counterfeit medical products\n\nThere had been much discussion of the issue of SSFFC medical products at recent meetings of WHO\u2019s governing bodies, including the nomenclature and focus for WHO activity. In 2010 the Expert Committee also discussed the issue and decided to leave the terminology for the time being until the concerns of the Member States had been resolved. A working group on SSFFC medical products was set up in 2010 and its meetings are organized by a board composed of Member States, with WHO providing secretarial assistance. The first meeting of the SSFFC working group took place at the beginning of 2011 and the second meeting was due to be held in October 2011. The governing body documents on the working group are available in different languages on the WHO governing bodies\u2019 web site.\n\n## 3. Quality control \u2013 specifications and tests\n\n### 3.1 The International Pharmacopoeia\n\n#### 3.1.1 Fourth edition update\n\nThe second supplement to the fourth edition of *The International Pharmacopoeia* was issued in July 2011. The fourth edition thus comprised the two main volumes published in 2006, the first supplement published in 2008 and the second supplement. *The International Pharmacopoeia* was now available as a cumulative CD-ROM and freely accessible on the WHO medicines web site (http://www.who.int/phint).\n\nThe second supplement includes more than 60 new texts as well as about 20 texts that have been revised.\n\nThe second supplement comprises the monographs adopted by the Expert Committee at its forty-second, forty-third and forty-fourth meetings in October 2007, 2008 and 2009, respectively, with the addition of two texts adopted in October 2010 (artesunate and oseltamivir phosphate) which were also included in this supplement. Two further texts (amikacin injection and kanamycin injection) were erroneously omitted from the compilation of texts in the second supplement and will be published on the WHO medicines web site as errata to the supplement.\n\nTexts adopted as of October 2010 will be posted on the WHO medicines web site according to the usual procedure, before they are compiled into a forthcoming supplement of *The International Pharmacopoeia*. Finalization work before publication was ongoing for a few remaining texts and it was expected that they would soon be made available.\n\nWhile most of the texts have been posted on the WHO medicines web site, some of them, such as that for levonorgestrel tablets, required significant changes.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "463f60a179775571c1319c71472b00557e6464c8c7ae63f3f539514b4857631e", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "## 2.2.4 Working group meeting on substandard/spurious/falsely-labelled/falsified/counterfeit medical products\n\nThere had been much discussion of the issue of SSFFC medical products at recent meetings of WHO\u2019s governing bodies, including the nomenclature and focus for WHO activity. In 2010 the Expert Committee also discussed the issue and decided to leave the terminology for the time being until the concerns of the Member States had been resolved. A working group on SSFFC medical products was set up in 2010 and its meetings are organized by a board composed of Member States, with WHO providing secretarial assistance. The first meeting of the SSFFC working group took place at the beginning of 2011 and the second meeting was due to be held in October 2011. The governing body documents on the working group are available in different languages on the WHO governing bodies\u2019 web site.\n\n## 3. Quality control \u2013 specifications and tests\n\n### 3.1 The International Pharmacopoeia\n\n#### 3.1.1 Fourth edition update\n\nThe second supplement to the fourth edition of *The International Pharmacopoeia* was issued in July 2011. The fourth edition thus comprised the two main volumes published in 2006, the first supplement published in 2008 and the second supplement. *The International Pharmacopoeia* was now available as a cumulative CD-ROM and freely accessible on the WHO medicines web site (http://www.who.int/phint).\n\nThe second supplement includes more than 60 new texts as well as about 20 texts that have been revised.\n\nThe second supplement comprises the monographs adopted by the Expert Committee at its forty-second, forty-third and forty-fourth meetings in October 2007, 2008 and 2009, respectively, with the addition of two texts adopted in October 2010 (artesunate and oseltamivir phosphate) which were also included in this supplement. Two further texts (amikacin injection and kanamycin injection) were erroneously omitted from the compilation of texts in the second supplement and will be published on the WHO medicines web site as errata to the supplement.\n\nTexts adopted as of October 2010 will be posted on the WHO medicines web site according to the usual procedure, before they are compiled into a forthcoming supplement of *The International Pharmacopoeia*. Finalization work before publication was ongoing for a few remaining texts and it was expected that they would soon be made available.\n\nWhile most of the texts have been posted on the WHO medicines web site, some of them, such as that for levonorgestrel tablets, required significant changes.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2569, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "eb662ee7-5b25-48dc-b61a-10272d88c509": {"__data__": {"id_": "eb662ee7-5b25-48dc-b61a-10272d88c509", "embedding": null, "metadata": {"page_label": "25", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.1.2 Outreach with stakeholders\n\nA summary was presented to the Expert Committee on the briefing for stakeholders held in July 2011 to obtain their feedback on *The International Pharmacopoeia*. An earlier briefing had been organized for industry in 2009. The intention of the meetings was to have an informal discussion with manufacturers and to obtain their feedback on *The International Pharmacopoeia*. The July 2011 session was open not only to industry but to all interested parties as a response to many requests from NGOs, Member States and others. Thirty participants attended. The participants were asked to send questions in advance so that detailed responses could be prepared. WHO learned of the interest in having more information available on the web site, such as the draft monographs.\n\nThe briefing was also an opportunity for WHO to request samples from manufacturers to support the development of monographs for *The International Pharmacopoeia*. The stakeholders emphasized the importance of these briefings and hoped that they would continue to be held in the future.\n\n# 3.1.3 Annotated work plan\n\nIn October 2010, the Expert Committee had adopted a work plan for monographs to be included in future editions of *The International Pharmacopoeia*. A list of these monographs, updated with their current status (i.e. whether already adopted by the Expert Committee), and with new proposals for developing specifications for active substances and dosage forms, including those for paediatric use, was presented to the Committee. The work plan was updated on the basis of the second supplement of *The International Pharmacopoeia* and the current WHO Model list of essential medicines and with reference to the invitations for expressions of interest of the Prequalification Programme.\n\nThe work plan included medicines used in treatment of HIV/AIDS, malaria and tuberculosis treatment, anti-infectives, oral rehydration therapy, and other medicines. The work plan was discussed during the consultation on specifications for medicines and quality control laboratory issues held in July 2011 and, on the advice of the consultation, the work plan had been amended to include not only the individual monographs for products, but also the important general texts or sections intended to be either developed or revised.\n\nThe different categories of medicines in the work plan were reviewed. There are monographs on the APIs of most antiretroviral medicines already, and monographs on the new ones are in preparation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de nivel superior:\nEl documento detalla las actividades de la Organizaci\u00f3n Mundial de la Salud (OMS) en relaci\u00f3n con *La Farmacopea Internacional*, incluyendo reuniones con partes interesadas para obtener retroalimentaci\u00f3n y un plan de trabajo para el desarrollo de monograf\u00edas. Se menciona la importancia de la colaboraci\u00f3n con fabricantes y la inclusi\u00f3n de medicamentos esenciales en el plan de trabajo, que abarca tratamientos para enfermedades como el VIH/SIDA, malaria y tuberculosis.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 tipo de retroalimentaci\u00f3n se busc\u00f3 de los participantes en la reuni\u00f3n de julio de 2011 sobre *La Farmacopea Internacional* y c\u00f3mo se prepar\u00f3 la OMS para abordar sus preguntas?**\n   - Esta pregunta se centra en el proceso de recopilaci\u00f3n de retroalimentaci\u00f3n y la preparaci\u00f3n de la OMS para la reuni\u00f3n, aspectos que no se encuentran f\u00e1cilmente en otros documentos.\n\n2. **\u00bfCu\u00e1les son algunos de los medicamentos espec\u00edficos que se incluyeron en el plan de trabajo adoptado por el Comit\u00e9 de Expertos en octubre de 2010 y qu\u00e9 importancia tienen para la salud p\u00fablica?**\n   - Esta pregunta busca detalles sobre los medicamentos espec\u00edficos mencionados en el plan de trabajo y su relevancia, lo cual puede no estar ampliamente documentado en otras fuentes.\n\n3. **\u00bfC\u00f3mo se ha adaptado el plan de trabajo para incluir no solo monograf\u00edas individuales, sino tambi\u00e9n textos generales o secciones importantes?**\n   - Esta pregunta se enfoca en la evoluci\u00f3n del plan de trabajo y las razones detr\u00e1s de la inclusi\u00f3n de textos generales, un aspecto que puede no ser evidente en otros documentos relacionados.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Productos M\u00e9dicos SSFFC**:\n   - **Terminolog\u00eda**: En 2010, el Comit\u00e9 de Expertos de la OMS decidi\u00f3 no modificar la terminolog\u00eda relacionada con los productos subest\u00e1ndar, espurios, falsamente etiquetados, falsificados y de contrabando (SSFFC) hasta que se resolvieran las preocupaciones de los Estados Miembros.\n   - **Grupo de Trabajo**: Se estableci\u00f3 un grupo de trabajo sobre productos SSFFC en 2010, con reuniones organizadas por un consejo de Estados Miembros y asistencia de la OMS. La primera reuni\u00f3n se llev\u00f3 a cabo a principios de 2011.\n\n2. **La Internacional Pharmacopoeia**:\n   - **Actualizaci\u00f3n de la Cuarta Edici\u00f3n**: En julio de 2011 se public\u00f3 el segundo suplemento de la cuarta edici\u00f3n de *The International Pharmacopoeia*, que incluye m\u00e1s de 60 nuevos textos y alrededor de 20 textos revisados.\n   - **Monograf\u00edas**: El suplemento incluye monograf\u00edas adoptadas en reuniones anteriores del Comit\u00e9 de Expertos, as\u00ed como dos textos adicionales sobre artesunate y oseltamivir fosfato.\n   - **Errores en la Compilaci\u00f3n**: Se identificaron errores en la omisi\u00f3n de textos sobre inyecci\u00f3n de amikacina y kanamicina, que se publicar\u00e1n como erratas en el sitio web de medicamentos de la OMS.\n\n3. **Accesibilidad**: *The International Pharmacopoeia* est\u00e1 disponible como un CD-ROM acumulativo y de forma gratuita en el sitio web de la OMS.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la salud p\u00fablica internacional que facilita la discusi\u00f3n y regulaci\u00f3n de productos m\u00e9dicos.\n- **Estados Miembros**: Pa\u00edses que forman parte de la OMS y que participan en la toma de decisiones sobre la terminolog\u00eda y regulaci\u00f3n de productos m\u00e9dicos.\n- **Comit\u00e9 de Expertos**: Grupo que asesora a la OMS sobre cuestiones relacionadas con la calidad y seguridad de los medicamentos.\n- ***The International Pharmacopoeia***: Referencia internacional que establece est\u00e1ndares de calidad para medicamentos.", "excerpt_keywords": "Keywords: International Pharmacopoeia, WHO, stakeholder engagement, monographs, essential medicines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "81c67c78-35d8-47cf-a38a-45c4cabec174", "node_type": "4", "metadata": {"page_label": "25", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.1.2 Outreach with stakeholders\n\nA summary was presented to the Expert Committee on the briefing for stakeholders held in July 2011 to obtain their feedback on *The International Pharmacopoeia*. An earlier briefing had been organized for industry in 2009. The intention of the meetings was to have an informal discussion with manufacturers and to obtain their feedback on *The International Pharmacopoeia*. The July 2011 session was open not only to industry but to all interested parties as a response to many requests from NGOs, Member States and others. Thirty participants attended. The participants were asked to send questions in advance so that detailed responses could be prepared. WHO learned of the interest in having more information available on the web site, such as the draft monographs.\n\nThe briefing was also an opportunity for WHO to request samples from manufacturers to support the development of monographs for *The International Pharmacopoeia*. The stakeholders emphasized the importance of these briefings and hoped that they would continue to be held in the future.\n\n# 3.1.3 Annotated work plan\n\nIn October 2010, the Expert Committee had adopted a work plan for monographs to be included in future editions of *The International Pharmacopoeia*. A list of these monographs, updated with their current status (i.e. whether already adopted by the Expert Committee), and with new proposals for developing specifications for active substances and dosage forms, including those for paediatric use, was presented to the Committee. The work plan was updated on the basis of the second supplement of *The International Pharmacopoeia* and the current WHO Model list of essential medicines and with reference to the invitations for expressions of interest of the Prequalification Programme.\n\nThe work plan included medicines used in treatment of HIV/AIDS, malaria and tuberculosis treatment, anti-infectives, oral rehydration therapy, and other medicines. The work plan was discussed during the consultation on specifications for medicines and quality control laboratory issues held in July 2011 and, on the advice of the consultation, the work plan had been amended to include not only the individual monographs for products, but also the important general texts or sections intended to be either developed or revised.\n\nThe different categories of medicines in the work plan were reviewed. There are monographs on the APIs of most antiretroviral medicines already, and monographs on the new ones are in preparation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "5087206bcd744f9cd8912c88db66632bfc458abae8fc56d488cd76fe44d27cd2", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.1.2 Outreach with stakeholders\n\nA summary was presented to the Expert Committee on the briefing for stakeholders held in July 2011 to obtain their feedback on *The International Pharmacopoeia*. An earlier briefing had been organized for industry in 2009. The intention of the meetings was to have an informal discussion with manufacturers and to obtain their feedback on *The International Pharmacopoeia*. The July 2011 session was open not only to industry but to all interested parties as a response to many requests from NGOs, Member States and others. Thirty participants attended. The participants were asked to send questions in advance so that detailed responses could be prepared. WHO learned of the interest in having more information available on the web site, such as the draft monographs.\n\nThe briefing was also an opportunity for WHO to request samples from manufacturers to support the development of monographs for *The International Pharmacopoeia*. The stakeholders emphasized the importance of these briefings and hoped that they would continue to be held in the future.\n\n# 3.1.3 Annotated work plan\n\nIn October 2010, the Expert Committee had adopted a work plan for monographs to be included in future editions of *The International Pharmacopoeia*. A list of these monographs, updated with their current status (i.e. whether already adopted by the Expert Committee), and with new proposals for developing specifications for active substances and dosage forms, including those for paediatric use, was presented to the Committee. The work plan was updated on the basis of the second supplement of *The International Pharmacopoeia* and the current WHO Model list of essential medicines and with reference to the invitations for expressions of interest of the Prequalification Programme.\n\nThe work plan included medicines used in treatment of HIV/AIDS, malaria and tuberculosis treatment, anti-infectives, oral rehydration therapy, and other medicines. The work plan was discussed during the consultation on specifications for medicines and quality control laboratory issues held in July 2011 and, on the advice of the consultation, the work plan had been amended to include not only the individual monographs for products, but also the important general texts or sections intended to be either developed or revised.\n\nThe different categories of medicines in the work plan were reviewed. There are monographs on the APIs of most antiretroviral medicines already, and monographs on the new ones are in preparation.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2531, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "3abaaa6a-ddaf-411e-9ca8-200fbe15b05d": {"__data__": {"id_": "3abaaa6a-ddaf-411e-9ca8-200fbe15b05d", "embedding": null, "metadata": {"page_label": "26", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Monograph development\n\nThe monographs in *The International Pharmacopoeia* provide the quality aspects for the medicines in the WHO lists of essential medicines and in WHO treatment guidelines. Therefore, major WHO programmes, such as that on Prequalification of Medicines, and international organizations such as UNICEF and the Global Fund to Fight AIDS, Tuberculosis and Malaria, rely heavily upon the quality specifications of *The International Pharmacopoeia*. A \u201cschedule for the adoption process\u201d outlining the development history of a draft monograph is included in each working document that is circulated for comment. The phases involved in the development of new monographs were discussed by the Expert Committee and the comments already received were outlined.\n\nThe process was revised by the Expert Committee in order to appropriately reflect each of the phases involved in developing new monographs.\n\nThe Expert Committee adopted the phases which are involved in the development of monographs for *The International Pharmacopoeia* (Annex 1).\n\n## Specifications for medicines, including children\u2019s medicines\n\n### 3.2.1 Medicines for HIV and related conditions\n\n**Antiretrovirals**\n\n**Ritonavir tablets**\n\nThe monograph on the ritonavir API had been adopted by the Expert Committee and was included in the second supplement of *The International Pharmacopoeia*. A draft monograph on ritonavir tablets was then proposed. The present draft monograph on tablets had been sent for comments and these had been consolidated by the secretariat. The Expert Committee reviewed the draft monograph and the comments received.\n\nThe Expert Committee adopted the monograph on ritonavir tablets subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.\n\n**Tenofovir disoproxil fumarate**\n\nWork by the collaborating laboratory on the test for optical rotation was ongoing. The investigation was in progress, but the necessity to obtain additional samples had delayed completion of the proposal for discussion.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en el desarrollo de monograf\u00edas en *The International Pharmacopoeia*, que establece especificaciones de calidad para medicamentos esenciales seg\u00fan la OMS. Se menciona la importancia de estas monograf\u00edas para programas de la OMS y organizaciones internacionales como UNICEF y el Global Fund. El proceso de adopci\u00f3n de nuevas monograf\u00edas fue revisado por un Comit\u00e9 de Expertos, que tambi\u00e9n discuti\u00f3 y adopt\u00f3 monograf\u00edas espec\u00edficas, como la de los comprimidos de ritonavir y el trabajo en curso sobre tenofovir disoproxil fumarato.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 importancia tienen las monograf\u00edas de *The International Pharmacopoeia* para programas de la OMS y organizaciones internacionales?**\n   - Las monograf\u00edas proporcionan especificaciones de calidad que son fundamentales para la precalificaci\u00f3n de medicamentos y gu\u00edas de tratamiento, lo que asegura que los medicamentos esenciales cumplan con est\u00e1ndares de calidad.\n\n2. **\u00bfQu\u00e9 cambios se acordaron en la monograf\u00eda de los comprimidos de ritonavir durante la revisi\u00f3n del Comit\u00e9 de Expertos?**\n   - La monograf\u00eda fue adoptada por el Comit\u00e9 de Expertos, sujeto a la inclusi\u00f3n de cambios acordados basados en los comentarios recibidos y las discusiones mantenidas.\n\n3. **\u00bfCu\u00e1l es el estado actual del trabajo sobre el tenofovir disoproxil fumarato seg\u00fan el documento?**\n   - El trabajo en el laboratorio colaborador sobre la prueba de rotaci\u00f3n \u00f3ptica est\u00e1 en curso, pero la necesidad de obtener muestras adicionales ha retrasado la finalizaci\u00f3n de la propuesta para discusi\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Interacci\u00f3n con Partes Interesadas**:\n   - Se llevaron a cabo reuniones con partes interesadas, incluyendo una sesi\u00f3n en julio de 2011, para obtener retroalimentaci\u00f3n sobre *La Farmacopea Internacional*.\n   - La reuni\u00f3n de julio fue abierta a todos los interesados, no solo a la industria, y se solicit\u00f3 a los participantes que enviaran preguntas con anticipaci\u00f3n para preparar respuestas detalladas.\n   - Se destac\u00f3 la importancia de estas reuniones y el inter\u00e9s en tener m\u00e1s informaci\u00f3n disponible en el sitio web de la OMS.\n\n2. **Plan de Trabajo Anotado**:\n   - En octubre de 2010, el Comit\u00e9 de Expertos adopt\u00f3 un plan de trabajo para las monograf\u00edas que se incluir\u00edan en futuras ediciones de *La Farmacopea Internacional*.\n   - El plan de trabajo abarca medicamentos utilizados en el tratamiento de enfermedades como VIH/SIDA, malaria y tuberculosis, as\u00ed como anti-infectivos y terapia de rehidrataci\u00f3n oral.\n   - Se revisaron las categor\u00edas de medicamentos y se mencion\u00f3 que ya existen monograf\u00edas para la mayor\u00eda de los medicamentos antirretrovirales, mientras que se est\u00e1n preparando monograf\u00edas para nuevos medicamentos.\n\n3. **Desarrollo de Monograf\u00edas**:\n   - El plan de trabajo fue actualizado en base a la segunda suplementaci\u00f3n de *La Farmacopea Internacional* y la lista modelo de medicamentos esenciales de la OMS.\n   - Se incluyeron no solo monograf\u00edas individuales, sino tambi\u00e9n textos generales o secciones importantes que se desarrollar\u00e1n o revisar\u00e1n.\n\n### Entidades Clave:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la coordinaci\u00f3n de las reuniones y el desarrollo de *La Farmacopea Internacional*.\n- **Expert Committee**: Comit\u00e9 que adopta el plan de trabajo y revisa las monograf\u00edas.\n- **Partes Interesadas**: Incluyen fabricantes, ONG, Estados Miembros y otros interesados que participan en las reuniones y proporcionan retroalimentaci\u00f3n.\n- **Medicamentos Esenciales**: Incluyen tratamientos para VIH/SIDA, malaria, tuberculosis y otros medicamentos relevantes para la salud p\u00fablica.", "excerpt_keywords": "Keywords: monographs, International Pharmacopoeia, WHO, antiretrovirals, quality specifications"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1231e3e5-3e8e-45f5-93b6-134a3b17d0eb", "node_type": "4", "metadata": {"page_label": "26", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Monograph development\n\nThe monographs in *The International Pharmacopoeia* provide the quality aspects for the medicines in the WHO lists of essential medicines and in WHO treatment guidelines. Therefore, major WHO programmes, such as that on Prequalification of Medicines, and international organizations such as UNICEF and the Global Fund to Fight AIDS, Tuberculosis and Malaria, rely heavily upon the quality specifications of *The International Pharmacopoeia*. A \u201cschedule for the adoption process\u201d outlining the development history of a draft monograph is included in each working document that is circulated for comment. The phases involved in the development of new monographs were discussed by the Expert Committee and the comments already received were outlined.\n\nThe process was revised by the Expert Committee in order to appropriately reflect each of the phases involved in developing new monographs.\n\nThe Expert Committee adopted the phases which are involved in the development of monographs for *The International Pharmacopoeia* (Annex 1).\n\n## Specifications for medicines, including children\u2019s medicines\n\n### 3.2.1 Medicines for HIV and related conditions\n\n**Antiretrovirals**\n\n**Ritonavir tablets**\n\nThe monograph on the ritonavir API had been adopted by the Expert Committee and was included in the second supplement of *The International Pharmacopoeia*. A draft monograph on ritonavir tablets was then proposed. The present draft monograph on tablets had been sent for comments and these had been consolidated by the secretariat. The Expert Committee reviewed the draft monograph and the comments received.\n\nThe Expert Committee adopted the monograph on ritonavir tablets subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.\n\n**Tenofovir disoproxil fumarate**\n\nWork by the collaborating laboratory on the test for optical rotation was ongoing. The investigation was in progress, but the necessity to obtain additional samples had delayed completion of the proposal for discussion.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "2c12c0e29b5b937ac94ce2c522060e9b76be4216bc851fc5ced216e8d842a745", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Monograph development\n\nThe monographs in *The International Pharmacopoeia* provide the quality aspects for the medicines in the WHO lists of essential medicines and in WHO treatment guidelines. Therefore, major WHO programmes, such as that on Prequalification of Medicines, and international organizations such as UNICEF and the Global Fund to Fight AIDS, Tuberculosis and Malaria, rely heavily upon the quality specifications of *The International Pharmacopoeia*. A \u201cschedule for the adoption process\u201d outlining the development history of a draft monograph is included in each working document that is circulated for comment. The phases involved in the development of new monographs were discussed by the Expert Committee and the comments already received were outlined.\n\nThe process was revised by the Expert Committee in order to appropriately reflect each of the phases involved in developing new monographs.\n\nThe Expert Committee adopted the phases which are involved in the development of monographs for *The International Pharmacopoeia* (Annex 1).\n\n## Specifications for medicines, including children\u2019s medicines\n\n### 3.2.1 Medicines for HIV and related conditions\n\n**Antiretrovirals**\n\n**Ritonavir tablets**\n\nThe monograph on the ritonavir API had been adopted by the Expert Committee and was included in the second supplement of *The International Pharmacopoeia*. A draft monograph on ritonavir tablets was then proposed. The present draft monograph on tablets had been sent for comments and these had been consolidated by the secretariat. The Expert Committee reviewed the draft monograph and the comments received.\n\nThe Expert Committee adopted the monograph on ritonavir tablets subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.\n\n**Tenofovir disoproxil fumarate**\n\nWork by the collaborating laboratory on the test for optical rotation was ongoing. The investigation was in progress, but the necessity to obtain additional samples had delayed completion of the proposal for discussion.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2061, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "9a3a9f4c-7956-48d7-8225-3d3a2d7e1cea": {"__data__": {"id_": "9a3a9f4c-7956-48d7-8225-3d3a2d7e1cea", "embedding": null, "metadata": {"page_label": "27", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.2 Antimalarial medicines\n\n## Update on artemisinin derivatives\n\nDuring review of the monograph on artesunate for inclusion in the second supplement, several corrections regarding nomenclature were identified. In consequence, an in-depth review of related WHO publications was carried out and ambiguity regarding the nomenclature was resolved. It was, therefore, proposed to implement the necessary corrections in the relevant texts of *The International Pharmacopoeia*.\n\nIn June 2011 a teleconference was organized with the experts involved in the revision of the artemisinin derivatives monographs in order to discuss the approach that should be followed for implementing the corrections identified. Proposals made concerning the different aspects of the monographs to be modified were discussed at the consultation on specifications for medicines and quality control laboratory issues held in July 2011. The monographs concerning artesunate and arteminol were, therefore, presented for discussion by the Expert Committee.\n\nIt was noted that both these substances were widely used in artemisinin-based combination therapy and that arteminol was also present as a related substance in the APIs of other artemisinin-derivatives. The Committee emphasized, therefore, that any change made to the monographs for these two substances would need to be implemented in other related monographs.\n\n### Artesunate\n\nThis monograph on artesunate was initially revised by the Expert Committee in 2009 and again in 2010. Following the correction of the ambiguity regarding the nomenclature, the monograph was presented once more to the Expert Committee for further review.\n\nThe Expert Committee adopted the monograph on artesunate subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.\n\n### Arteminol\n\nThe current monograph was still under review in the context of the general revision of monographs on artemisinin derivatives. Although the revised draft presented to the Expert Committee for review took account of the changes proposed to the monograph with regard to the correction of information related to nomenclature, it was considered that other changes might be required.\n\nThe Expert Committee adopted the monograph on arteminol subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en la revisi\u00f3n de las monograf\u00edas de los derivados de artemisinina, espec\u00edficamente artesunato y arteminol, por parte de un Comit\u00e9 de Expertos de la OMS. Se identificaron correcciones en la nomenclatura durante la revisi\u00f3n del artesunato, lo que llev\u00f3 a una revisi\u00f3n m\u00e1s profunda de las publicaciones relacionadas de la OMS. Se organiz\u00f3 una teleconferencia en 2011 para discutir las correcciones necesarias y se presentaron las monograf\u00edas para su discusi\u00f3n. Ambas sustancias son ampliamente utilizadas en la terapia combinada basada en artemisinina, y cualquier cambio en sus monograf\u00edas debe reflejarse en otras monograf\u00edas relacionadas.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 acciones se tomaron para resolver la ambig\u00fcedad en la nomenclatura de los derivados de artemisinina?**\n   - Se llev\u00f3 a cabo una revisi\u00f3n en profundidad de las publicaciones relacionadas de la OMS y se organiz\u00f3 una teleconferencia con expertos para discutir las correcciones necesarias.\n\n2. **\u00bfCu\u00e1les son las implicaciones de los cambios en las monograf\u00edas de artesunato y arteminol para otras monograf\u00edas relacionadas?**\n   - Cualquier cambio realizado en las monograf\u00edas de artesunato y arteminol debe ser implementado en otras monograf\u00edas relacionadas, dado que ambas sustancias son utilizadas en artemisinin-based combination therapy.\n\n3. **\u00bfQu\u00e9 revisiones se realizaron en las monograf\u00edas de artesunato y arteminol antes de su adopci\u00f3n por el Comit\u00e9 de Expertos?**\n   - La monograf\u00eda de artesunato fue revisada en 2009 y 2010, y se present\u00f3 nuevamente despu\u00e9s de corregir la ambig\u00fcedad en la nomenclatura. La monograf\u00eda de arteminol estaba en revisi\u00f3n general, y aunque se consideraron cambios en la nomenclatura, se pens\u00f3 que podr\u00edan ser necesarios otros ajustes.", "prev_section_summary": "### Temas clave\n\n1. **Desarrollo de Monograf\u00edas**: Las monograf\u00edas en *The International Pharmacopoeia* establecen especificaciones de calidad para medicamentos esenciales seg\u00fan la OMS.\n  \n2. **Importancia para Programas de la OMS**: Estas monograf\u00edas son fundamentales para la precalificaci\u00f3n de medicamentos y gu\u00edas de tratamiento, siendo utilizadas por programas de la OMS y organizaciones internacionales como UNICEF y el Global Fund.\n\n3. **Proceso de Adopci\u00f3n**: El proceso de adopci\u00f3n de nuevas monograf\u00edas fue revisado por un Comit\u00e9 de Expertos, que discuti\u00f3 y adopt\u00f3 las fases involucradas en el desarrollo de monograf\u00edas.\n\n4. **Medicamentos Espec\u00edficos**: Se mencionan monograf\u00edas espec\u00edficas, como la de los comprimidos de ritonavir, que fue adoptada con cambios acordados, y el estado del trabajo en curso sobre el tenofovir disoproxil fumarato.\n\n### Entidades\n\n- **Organizaciones**: \n  - OMS (Organizaci\u00f3n Mundial de la Salud)\n  - UNICEF (Fondo de las Naciones Unidas para la Infancia)\n  - Global Fund to Fight AIDS, Tuberculosis and Malaria\n\n- **Medicamentos**:\n  - Ritonavir (API y comprimidos)\n  - Tenofovir disoproxil fumarato\n\n- **Comit\u00e9**: Comit\u00e9 de Expertos de la OMS\n\nEste resumen destaca la relevancia de las monograf\u00edas en la regulaci\u00f3n y calidad de los medicamentos esenciales, as\u00ed como el proceso colaborativo involucrado en su desarrollo y revisi\u00f3n.", "excerpt_keywords": "Keywords: artesunate, arteminol, WHO, antimalarial medicines, nomenclature corrections"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5ed5d1ae-63e8-4f6d-80e7-4182f761c365", "node_type": "4", "metadata": {"page_label": "27", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.2 Antimalarial medicines\n\n## Update on artemisinin derivatives\n\nDuring review of the monograph on artesunate for inclusion in the second supplement, several corrections regarding nomenclature were identified. In consequence, an in-depth review of related WHO publications was carried out and ambiguity regarding the nomenclature was resolved. It was, therefore, proposed to implement the necessary corrections in the relevant texts of *The International Pharmacopoeia*.\n\nIn June 2011 a teleconference was organized with the experts involved in the revision of the artemisinin derivatives monographs in order to discuss the approach that should be followed for implementing the corrections identified. Proposals made concerning the different aspects of the monographs to be modified were discussed at the consultation on specifications for medicines and quality control laboratory issues held in July 2011. The monographs concerning artesunate and arteminol were, therefore, presented for discussion by the Expert Committee.\n\nIt was noted that both these substances were widely used in artemisinin-based combination therapy and that arteminol was also present as a related substance in the APIs of other artemisinin-derivatives. The Committee emphasized, therefore, that any change made to the monographs for these two substances would need to be implemented in other related monographs.\n\n### Artesunate\n\nThis monograph on artesunate was initially revised by the Expert Committee in 2009 and again in 2010. Following the correction of the ambiguity regarding the nomenclature, the monograph was presented once more to the Expert Committee for further review.\n\nThe Expert Committee adopted the monograph on artesunate subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.\n\n### Arteminol\n\nThe current monograph was still under review in the context of the general revision of monographs on artemisinin derivatives. Although the revised draft presented to the Expert Committee for review took account of the changes proposed to the monograph with regard to the correction of information related to nomenclature, it was considered that other changes might be required.\n\nThe Expert Committee adopted the monograph on arteminol subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "c4733404d3c900148dc606761fd1fc9ffd52ce0a231b0c54c8e853a1b4a9e6e9", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.2 Antimalarial medicines\n\n## Update on artemisinin derivatives\n\nDuring review of the monograph on artesunate for inclusion in the second supplement, several corrections regarding nomenclature were identified. In consequence, an in-depth review of related WHO publications was carried out and ambiguity regarding the nomenclature was resolved. It was, therefore, proposed to implement the necessary corrections in the relevant texts of *The International Pharmacopoeia*.\n\nIn June 2011 a teleconference was organized with the experts involved in the revision of the artemisinin derivatives monographs in order to discuss the approach that should be followed for implementing the corrections identified. Proposals made concerning the different aspects of the monographs to be modified were discussed at the consultation on specifications for medicines and quality control laboratory issues held in July 2011. The monographs concerning artesunate and arteminol were, therefore, presented for discussion by the Expert Committee.\n\nIt was noted that both these substances were widely used in artemisinin-based combination therapy and that arteminol was also present as a related substance in the APIs of other artemisinin-derivatives. The Committee emphasized, therefore, that any change made to the monographs for these two substances would need to be implemented in other related monographs.\n\n### Artesunate\n\nThis monograph on artesunate was initially revised by the Expert Committee in 2009 and again in 2010. Following the correction of the ambiguity regarding the nomenclature, the monograph was presented once more to the Expert Committee for further review.\n\nThe Expert Committee adopted the monograph on artesunate subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.\n\n### Arteminol\n\nThe current monograph was still under review in the context of the general revision of monographs on artemisinin derivatives. Although the revised draft presented to the Expert Committee for review took account of the changes proposed to the monograph with regard to the correction of information related to nomenclature, it was considered that other changes might be required.\n\nThe Expert Committee adopted the monograph on arteminol subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2398, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "1eaab0c7-75cf-4461-be2e-44a8c1459177": {"__data__": {"id_": "1eaab0c7-75cf-4461-be2e-44a8c1459177", "embedding": null, "metadata": {"page_label": "28", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Mefloquine hydrochloride\n\nFollowing the adoption of the monograph for mefloquine tablets in October 2010, it was pointed out that the published monograph on mefloquine hydrochloride would need to be reviewed in order to replace the current thin-layer chromatography (TLC) method used for Related substances by a high-performance liquid chromatography (HPLC) method and to revise the limits for impurities.\n\nA first draft of the proposed revision was discussed at the consultation on specifications for medicines and quality control issues held in July 2011 and, in response to the comments made, further analytical work and verifications had been carried out by the collaborating laboratory to which the project was assigned.\n\nThe Expert Committee reviewed a revised version of the tests reflecting the changes and approved the text, subject to comments made during the discussion, for submission for wide consultation in line with the usual procedure.\n\n## New basic tests for antimalarials\n\nThe Expert Committee was informed about the progress made with the basic tests series for antimalarials. These would soon be made available on the web site.\n\n### 3.2.3 Antituberculosis medicines\n\n#### Rifampicin\n\nRifampicin exhibits polymorphism. The polymorph forms I and II, and mixtures of forms I and II, are available on the market. The infrared reference spectrum of Rifampicin RS, published in the first supplement to *The International Pharmacopoeia*, is concordant with form II. It is not intended to place a restriction on the polymorphic form. To this effect the monograph was revised and presented to the Expert Committee with the proposal to add a recrystallization step to the existing infrared (IR) identification method for both the test substance and the reference substance, in case their IR spectra are not concordant. Comments received on the document were reviewed.\n\nThe Expert Committee adopted the monograph on rifampicin subject to inclusion of the agreed changes, based on the comments received and those made during the discussion. Moreover, it recommended proceeding with a similar revision of the monographs for tablets and capsules.\n\n### 3.2.4 Anti-infectives\n\n#### Pyrantel oral suspension\n\nThe Expert Committee reviewed the draft monograph on pyrantel oral suspension and the major comments received. The Expert Committee agreed that the discussion of the monograph should be deferred until a number of issues could be clarified.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Preguntas\n\n1. **\u00bfQu\u00e9 cambios se propusieron para la monograf\u00eda de mefloquina hidrocloruro y por qu\u00e9 fueron necesarios?**\n   - Se propuso reemplazar el m\u00e9todo actual de cromatograf\u00eda en capa fina (TLC) utilizado para las sustancias relacionadas por un m\u00e9todo de cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n (HPLC) y revisar los l\u00edmites para impurezas, debido a la necesidad de mejorar la calidad y precisi\u00f3n en el an\u00e1lisis de este medicamento.\n\n2. **\u00bfCu\u00e1l fue la decisi\u00f3n del Comit\u00e9 de Expertos respecto a la monograf\u00eda de rifampicina y qu\u00e9 cambios se incluyeron?**\n   - El Comit\u00e9 de Expertos adopt\u00f3 la monograf\u00eda de rifampicina con la inclusi\u00f3n de un paso de recristalizaci\u00f3n en el m\u00e9todo de identificaci\u00f3n por espectroscop\u00eda infrarroja (IR) para asegurar la concordancia de los espectros IR entre la sustancia de prueba y la sustancia de referencia, dado que rifampicina exhibe polimorfismo.\n\n3. **\u00bfQu\u00e9 se decidi\u00f3 sobre la monograf\u00eda de la suspensi\u00f3n oral de pirantel y cu\u00e1les fueron las razones para esta decisi\u00f3n?**\n   - El Comit\u00e9 de Expertos decidi\u00f3 posponer la discusi\u00f3n de la monograf\u00eda de la suspensi\u00f3n oral de pirantel hasta que se pudieran aclarar varios problemas importantes que hab\u00edan surgido durante la revisi\u00f3n del borrador.\n\n### Resumen de nivel superior\n\nEl contexto aborda la revisi\u00f3n de varias monograf\u00edas de medicamentos, incluyendo mefloquina hidrocloruro y rifampicina, por parte de un Comit\u00e9 de Expertos. Se destaca la necesidad de actualizar m\u00e9todos anal\u00edticos, como el cambio de TLC a HPLC para mefloquina, y la consideraci\u00f3n del polimorfismo en rifampicina, lo que llev\u00f3 a la adopci\u00f3n de cambios en su monograf\u00eda. Adem\u00e1s, se menciona que la discusi\u00f3n sobre la monograf\u00eda de pirantel se pospuso debido a la necesidad de aclarar ciertos problemas. Estos procesos reflejan un esfuerzo continuo por mejorar la calidad y la especificaci\u00f3n de los medicamentos antimal\u00e1ricos y antituberculosos.", "prev_section_summary": "### Temas Clave\n\n1. **Revisi\u00f3n de Monograf\u00edas**: Se llev\u00f3 a cabo una revisi\u00f3n de las monograf\u00edas de los derivados de artemisinina, espec\u00edficamente artesunato y arteminol, por parte de un Comit\u00e9 de Expertos de la OMS.\n\n2. **Correcciones en Nomenclatura**: Durante la revisi\u00f3n del artesunato, se identificaron varias correcciones necesarias en la nomenclatura, lo que llev\u00f3 a una revisi\u00f3n m\u00e1s profunda de las publicaciones relacionadas de la OMS.\n\n3. **Teleconferencia y Consulta**: En junio de 2011, se organiz\u00f3 una teleconferencia con expertos para discutir las correcciones necesarias, y se llevaron a cabo consultas sobre especificaciones para medicamentos y cuestiones de control de calidad en julio de 2011.\n\n4. **Uso en Terapia Combinada**: Tanto el artesunato como el arteminol son ampliamente utilizados en la terapia combinada basada en artemisinina, lo que implica que cualquier cambio en sus monograf\u00edas debe reflejarse en otras monograf\u00edas relacionadas.\n\n5. **Adopci\u00f3n de Monograf\u00edas**: La monograf\u00eda de artesunato fue adoptada por el Comit\u00e9 de Expertos despu\u00e9s de realizar las correcciones acordadas, mientras que la monograf\u00eda de arteminol a\u00fan estaba bajo revisi\u00f3n, aunque se adopt\u00f3 su versi\u00f3n revisada sujeta a cambios adicionales.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la revisi\u00f3n y adopci\u00f3n de las monograf\u00edas.\n- **Artesunato**: Derivado de artemisinina que fue revisado y adoptado por el Comit\u00e9 de Expertos.\n- **Arteminol**: Otro derivado de artemisinina que estaba en revisi\u00f3n y fue adoptado con cambios acordados.\n- **Comit\u00e9 de Expertos**: Grupo encargado de revisar y adoptar las monograf\u00edas de los medicamentos antimal\u00e1ricos.\n- **Terapia Combinada Basada en Artemisinina**: Tratamiento que utiliza artesunato y arteminol como componentes clave.", "excerpt_keywords": "Mefloquine, Rifampicin, Polymorphism, High-performance liquid chromatography, Antimalarials"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dbe47d98-cb04-4ae8-8598-a0ad58f41fe9", "node_type": "4", "metadata": {"page_label": "28", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Mefloquine hydrochloride\n\nFollowing the adoption of the monograph for mefloquine tablets in October 2010, it was pointed out that the published monograph on mefloquine hydrochloride would need to be reviewed in order to replace the current thin-layer chromatography (TLC) method used for Related substances by a high-performance liquid chromatography (HPLC) method and to revise the limits for impurities.\n\nA first draft of the proposed revision was discussed at the consultation on specifications for medicines and quality control issues held in July 2011 and, in response to the comments made, further analytical work and verifications had been carried out by the collaborating laboratory to which the project was assigned.\n\nThe Expert Committee reviewed a revised version of the tests reflecting the changes and approved the text, subject to comments made during the discussion, for submission for wide consultation in line with the usual procedure.\n\n## New basic tests for antimalarials\n\nThe Expert Committee was informed about the progress made with the basic tests series for antimalarials. These would soon be made available on the web site.\n\n### 3.2.3 Antituberculosis medicines\n\n#### Rifampicin\n\nRifampicin exhibits polymorphism. The polymorph forms I and II, and mixtures of forms I and II, are available on the market. The infrared reference spectrum of Rifampicin RS, published in the first supplement to *The International Pharmacopoeia*, is concordant with form II. It is not intended to place a restriction on the polymorphic form. To this effect the monograph was revised and presented to the Expert Committee with the proposal to add a recrystallization step to the existing infrared (IR) identification method for both the test substance and the reference substance, in case their IR spectra are not concordant. Comments received on the document were reviewed.\n\nThe Expert Committee adopted the monograph on rifampicin subject to inclusion of the agreed changes, based on the comments received and those made during the discussion. Moreover, it recommended proceeding with a similar revision of the monographs for tablets and capsules.\n\n### 3.2.4 Anti-infectives\n\n#### Pyrantel oral suspension\n\nThe Expert Committee reviewed the draft monograph on pyrantel oral suspension and the major comments received. The Expert Committee agreed that the discussion of the monograph should be deferred until a number of issues could be clarified.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "bb5268e28409b4272d13fdef784753ca29ed9d9dfbe3c828aba910ffbe93a72c", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Mefloquine hydrochloride\n\nFollowing the adoption of the monograph for mefloquine tablets in October 2010, it was pointed out that the published monograph on mefloquine hydrochloride would need to be reviewed in order to replace the current thin-layer chromatography (TLC) method used for Related substances by a high-performance liquid chromatography (HPLC) method and to revise the limits for impurities.\n\nA first draft of the proposed revision was discussed at the consultation on specifications for medicines and quality control issues held in July 2011 and, in response to the comments made, further analytical work and verifications had been carried out by the collaborating laboratory to which the project was assigned.\n\nThe Expert Committee reviewed a revised version of the tests reflecting the changes and approved the text, subject to comments made during the discussion, for submission for wide consultation in line with the usual procedure.\n\n## New basic tests for antimalarials\n\nThe Expert Committee was informed about the progress made with the basic tests series for antimalarials. These would soon be made available on the web site.\n\n### 3.2.3 Antituberculosis medicines\n\n#### Rifampicin\n\nRifampicin exhibits polymorphism. The polymorph forms I and II, and mixtures of forms I and II, are available on the market. The infrared reference spectrum of Rifampicin RS, published in the first supplement to *The International Pharmacopoeia*, is concordant with form II. It is not intended to place a restriction on the polymorphic form. To this effect the monograph was revised and presented to the Expert Committee with the proposal to add a recrystallization step to the existing infrared (IR) identification method for both the test substance and the reference substance, in case their IR spectra are not concordant. Comments received on the document were reviewed.\n\nThe Expert Committee adopted the monograph on rifampicin subject to inclusion of the agreed changes, based on the comments received and those made during the discussion. Moreover, it recommended proceeding with a similar revision of the monographs for tablets and capsules.\n\n### 3.2.4 Anti-infectives\n\n#### Pyrantel oral suspension\n\nThe Expert Committee reviewed the draft monograph on pyrantel oral suspension and the major comments received. The Expert Committee agreed that the discussion of the monograph should be deferred until a number of issues could be clarified.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2454, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "89694800-3724-4b32-8bd6-dc0e87c52b92": {"__data__": {"id_": "89694800-3724-4b32-8bd6-dc0e87c52b92", "embedding": null, "metadata": {"page_label": "29", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Pyrantel chewable tablets\n\nThe Expert Committee reviewed the draft monograph on pyrantel chewable tablets and the major comments received. The Expert Committee adopted the monograph on pyrantel chewable tablets subject to inclusion of the agreed changes based on the comments received and those made during the discussion.\n\n# Albendazole chewable tablets\n\nThe Expert Committee reviewed the draft monograph on albendazole chewable tablets. A first draft of the monograph was received from the collaborating laboratory, subsequently amended by the secretariat and sent for wide consultation in September 2011 according to the usual consultative procedure. The monograph remained open for public comment.\n\nThe Expert Committee recommended that further consultation be sought. Furthermore, it was proposed that the API monograph be considered for revision.\n\n## 3.2.5 Other medicines\n\n### Heparins\n\nFollowing alerts regarding some contaminated heparin injections, discussions were held on detection of impurities in the product, with a view to revising the monographs published in a number of pharmacopoeias. The issue of the revision of the heparins monographs in *The International Pharmacopoeia* had been discussed on several occasions during Expert Committee meetings and consultations, notably in 2008 and 2009.\n\nA new method for the determination of dermatan sulfate and other glycosaminoglycans in heparin was presented to the Expert Committee for possible inclusion in *The International Pharmacopoeia*.\n\nThe Expert Committee reviewed this method and approved its inclusion in the monograph, subject to inclusion of the agreed changes. The monograph will be submitted for wide consultation in line with the usual procedure.\n\n### Medroxyprogesterone injection\n\nA new monograph on the contraceptive medroxyprogesterone injection was presented to the Expert Committee for review. The monograph had recently been received by the secretariat and had been sent out for comments. The monograph is still open for public comment.\n\nThe Expert Committee adopted the monograph on medroxyprogesterone injection subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, and also allowing for further comments by members of the Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento revisa varias monograf\u00edas de medicamentos, incluyendo tabletas masticables de pirantel y albendazol, as\u00ed como inyecciones de medroxiprogesterona. La Comisi\u00f3n de Expertos adopt\u00f3 la monograf\u00eda de pirantel con cambios acordados y recomend\u00f3 m\u00e1s consultas para la de albendazol. Tambi\u00e9n se discutieron las heparinas, especialmente en relaci\u00f3n con la detecci\u00f3n de impurezas tras alertas sobre inyecciones contaminadas. Se present\u00f3 un nuevo m\u00e9todo para determinar sulfato de dermatan y otros glicosaminoglicanos en heparina, que fue aprobado para su inclusi\u00f3n en la monograf\u00eda. La monograf\u00eda de medroxiprogesterona fue adoptada con cambios acordados y se mantuvo abierta para comentarios adicionales.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 cambios se acordaron para la monograf\u00eda de las tabletas masticables de pirantel y c\u00f3mo se determinaron?**\n   - La monograf\u00eda fue adoptada por la Comisi\u00f3n de Expertos, sujeta a la inclusi\u00f3n de cambios acordados basados en los comentarios recibidos durante la discusi\u00f3n.\n\n2. **\u00bfCu\u00e1l fue el motivo de la revisi\u00f3n de las monograf\u00edas de heparinas y qu\u00e9 m\u00e9todo nuevo se propuso?**\n   - La revisi\u00f3n se debi\u00f3 a alertas sobre inyecciones de heparina contaminadas. Se present\u00f3 un nuevo m\u00e9todo para la determinaci\u00f3n de sulfato de dermatan y otros glicosaminoglicanos en heparina, que fue aprobado para su inclusi\u00f3n en la monograf\u00eda.\n\n3. **\u00bfQu\u00e9 pasos se est\u00e1n tomando para la monograf\u00eda de albendazol y cu\u00e1l es su estado actual?**\n   - La monograf\u00eda de albendazol fue revisada y se recomend\u00f3 buscar m\u00e1s consultas. Actualmente, la monograf\u00eda permanece abierta para comentarios p\u00fablicos.\n\n### Resumen de nivel superior\n\nEl documento aborda la revisi\u00f3n y adopci\u00f3n de varias monograf\u00edas de medicamentos por parte de un Comit\u00e9 de Expertos, destacando la importancia de la consulta p\u00fablica y la revisi\u00f3n de m\u00e9todos para garantizar la calidad y seguridad de los medicamentos. Se enfatiza la necesidad de abordar problemas de contaminaci\u00f3n en productos farmac\u00e9uticos y la continua evoluci\u00f3n de las monograf\u00edas para reflejar los est\u00e1ndares actuales.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Mefloquina Hidrocloruro**:\n   - **Revisi\u00f3n de Monograf\u00eda**: Se propuso actualizar la monograf\u00eda de mefloquina hidrocloruro para reemplazar el m\u00e9todo de cromatograf\u00eda en capa fina (TLC) por cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n (HPLC) y revisar los l\u00edmites de impurezas.\n   - **Consulta y Aprobaci\u00f3n**: Un primer borrador fue discutido en una consulta en julio de 2011, y se realizaron trabajos anal\u00edticos adicionales. El Comit\u00e9 de Expertos aprob\u00f3 la versi\u00f3n revisada para su consulta amplia.\n\n2. **Medicamentos Antituberculosos**:\n   - **Rifampicina**: \n     - **Polimorfismo**: Rifampicina presenta polimorfismo con formas I y II disponibles en el mercado.\n     - **Revisi\u00f3n de Monograf\u00eda**: Se propuso a\u00f1adir un paso de recristalizaci\u00f3n al m\u00e9todo de identificaci\u00f3n por espectroscop\u00eda infrarroja (IR) para asegurar la concordancia de los espectros entre la sustancia de prueba y la sustancia de referencia.\n     - **Aprobaci\u00f3n**: El Comit\u00e9 de Expertos adopt\u00f3 la monograf\u00eda con los cambios acordados y recomend\u00f3 revisiones similares para las monograf\u00edas de tabletas y c\u00e1psulas.\n\n3. **Medicamentos Anti-infecciosos**:\n   - **Suspensi\u00f3n Oral de Pirantel**: \n     - **Posposici\u00f3n de Discusi\u00f3n**: El Comit\u00e9 de Expertos decidi\u00f3 posponer la discusi\u00f3n de la monograf\u00eda de la suspensi\u00f3n oral de pirantel hasta que se aclararan varios problemas importantes.\n\n### Entidades Clave\n- **Comit\u00e9 de Expertos**: Grupo responsable de revisar y aprobar las monograf\u00edas de medicamentos.\n- **Mefloquina**: Medicamento antimal\u00e1rico cuya monograf\u00eda fue revisada.\n- **Rifampicina**: Medicamento antituberculoso con caracter\u00edsticas de polimorfismo.\n- **Pirantel**: Medicamento anti-infeccioso cuya monograf\u00eda fue pospuesta para discusi\u00f3n.\n\nEste resumen refleja un esfuerzo continuo por mejorar la calidad y especificaci\u00f3n de medicamentos antimal\u00e1ricos y antituberculosos a trav\u00e9s de la revisi\u00f3n de sus monograf\u00edas.", "excerpt_keywords": "Pyrantel, Albendazole, Heparins, Medroxyprogesterone, Monograph"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eb7dced0-5bd9-4c14-9766-51c7c34ac194", "node_type": "4", "metadata": {"page_label": "29", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Pyrantel chewable tablets\n\nThe Expert Committee reviewed the draft monograph on pyrantel chewable tablets and the major comments received. The Expert Committee adopted the monograph on pyrantel chewable tablets subject to inclusion of the agreed changes based on the comments received and those made during the discussion.\n\n# Albendazole chewable tablets\n\nThe Expert Committee reviewed the draft monograph on albendazole chewable tablets. A first draft of the monograph was received from the collaborating laboratory, subsequently amended by the secretariat and sent for wide consultation in September 2011 according to the usual consultative procedure. The monograph remained open for public comment.\n\nThe Expert Committee recommended that further consultation be sought. Furthermore, it was proposed that the API monograph be considered for revision.\n\n## 3.2.5 Other medicines\n\n### Heparins\n\nFollowing alerts regarding some contaminated heparin injections, discussions were held on detection of impurities in the product, with a view to revising the monographs published in a number of pharmacopoeias. The issue of the revision of the heparins monographs in *The International Pharmacopoeia* had been discussed on several occasions during Expert Committee meetings and consultations, notably in 2008 and 2009.\n\nA new method for the determination of dermatan sulfate and other glycosaminoglycans in heparin was presented to the Expert Committee for possible inclusion in *The International Pharmacopoeia*.\n\nThe Expert Committee reviewed this method and approved its inclusion in the monograph, subject to inclusion of the agreed changes. The monograph will be submitted for wide consultation in line with the usual procedure.\n\n### Medroxyprogesterone injection\n\nA new monograph on the contraceptive medroxyprogesterone injection was presented to the Expert Committee for review. The monograph had recently been received by the secretariat and had been sent out for comments. The monograph is still open for public comment.\n\nThe Expert Committee adopted the monograph on medroxyprogesterone injection subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, and also allowing for further comments by members of the Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "516647aeec7768a215fc0b398aa28029c859037313bb823fee90c5929eed7866", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Pyrantel chewable tablets\n\nThe Expert Committee reviewed the draft monograph on pyrantel chewable tablets and the major comments received. The Expert Committee adopted the monograph on pyrantel chewable tablets subject to inclusion of the agreed changes based on the comments received and those made during the discussion.\n\n# Albendazole chewable tablets\n\nThe Expert Committee reviewed the draft monograph on albendazole chewable tablets. A first draft of the monograph was received from the collaborating laboratory, subsequently amended by the secretariat and sent for wide consultation in September 2011 according to the usual consultative procedure. The monograph remained open for public comment.\n\nThe Expert Committee recommended that further consultation be sought. Furthermore, it was proposed that the API monograph be considered for revision.\n\n## 3.2.5 Other medicines\n\n### Heparins\n\nFollowing alerts regarding some contaminated heparin injections, discussions were held on detection of impurities in the product, with a view to revising the monographs published in a number of pharmacopoeias. The issue of the revision of the heparins monographs in *The International Pharmacopoeia* had been discussed on several occasions during Expert Committee meetings and consultations, notably in 2008 and 2009.\n\nA new method for the determination of dermatan sulfate and other glycosaminoglycans in heparin was presented to the Expert Committee for possible inclusion in *The International Pharmacopoeia*.\n\nThe Expert Committee reviewed this method and approved its inclusion in the monograph, subject to inclusion of the agreed changes. The monograph will be submitted for wide consultation in line with the usual procedure.\n\n### Medroxyprogesterone injection\n\nA new monograph on the contraceptive medroxyprogesterone injection was presented to the Expert Committee for review. The monograph had recently been received by the secretariat and had been sent out for comments. The monograph is still open for public comment.\n\nThe Expert Committee adopted the monograph on medroxyprogesterone injection subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, and also allowing for further comments by members of the Committee.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2283, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "54a96d7d-d376-408e-902a-4f9f02183db5": {"__data__": {"id_": "54a96d7d-d376-408e-902a-4f9f02183db5", "embedding": null, "metadata": {"page_label": "30", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Levonorgestrel tablets\n\nThe text on levonorgestrel tablets was adopted in 2010, and following the recommendation made by the Expert Committee, specific requirements for the 30 \u00b5g tablets had been added with regard to the preparation of test solutions and the dissolution test conditions. As these agreed changes were important, the final text was re-presented to the Expert Committee for final endorsement (see also section 3.3.2).\n\nThe proposed modifications were adopted by the Expert Committee.\n\n## 3.2.6 Other paediatrics\n\n### Paediatric retinol oral solution\n\nDraft versions of the monographs on retinol concentrate (oily form), paediatric retinol capsules and paediatric retinol oral solution were discussed at the forty-fifth meeting of the Expert Committee in October 2010. The monograph on retinol concentrate, oily form, was adopted.\n\nThe Committee decided to incorporate the dosage form paediatric retinol soft-gel capsules into the monograph on retinol oral solution, considering the soft gelatin shell as a single-unit container and the liquid content as the actual dosage form. Following the meeting held in 2010, the Expert Committee recommended that the monograph on paediatric retinol oral solution should be modified so that its specifications could also be applied to these single-dose units and that the capsule monograph should be withdrawn.\n\nFollowing the 2010 meeting, revised versions of the monograph on paediatric retinol oral solution were circulated twice according to the usual consultative procedure. The monograph was also discussed at the consultation on specifications for medicines and quality control issues held in July 2011.\n\nThe Expert Committee adopted the monograph on paediatric retinol oral solution subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, and subject to the requirement that the monograph on retinol concentrate (oily form) be adapted in line with the changes to that on retinol oral solution.\n\n## 3.3 General monographs for dosage forms and associated method texts\n\n### 3.3.1 Pharmacopoeial Discussion Group-harmonized general texts\n\nFollowing discussion by the Expert Committee on Specifications for Pharmaceutical Preparations at its forty-fifth meeting in 2010, a number of internationally harmonized, PDG-texts had been adapted to the editorial style of *The International Pharmacopoeia* and sent out for wide consultation as per the usual consultative procedure.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en las modificaciones y adopciones de monograf\u00edas relacionadas con medicamentos, espec\u00edficamente sobre tabletas de levonorgestrel y soluciones orales de retinol pedi\u00e1trico. En 2010, se adoptaron cambios importantes en la monograf\u00eda de tabletas de levonorgestrel, incluyendo requisitos espec\u00edficos para tabletas de 30 \u00b5g. Tambi\u00e9n se discuten las decisiones tomadas por el Comit\u00e9 de Expertos sobre la incorporaci\u00f3n de c\u00e1psulas de gelatina blanda de retinol pedi\u00e1trico en la monograf\u00eda de soluci\u00f3n oral de retinol, as\u00ed como la adaptaci\u00f3n de las especificaciones de la monograf\u00eda de retinol concentrado en forma oleosa. Se menciona el proceso de consulta y revisi\u00f3n que sigui\u00f3 a estas decisiones.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les fueron los cambios espec\u00edficos adoptados para las tabletas de levonorgestrel de 30 \u00b5g en 2010?**\n   - Respuesta: Se a\u00f1adieron requisitos espec\u00edficos con respecto a la preparaci\u00f3n de soluciones de prueba y las condiciones de la prueba de disoluci\u00f3n.\n\n2. **\u00bfQu\u00e9 decisi\u00f3n tom\u00f3 el Comit\u00e9 de Expertos respecto a las c\u00e1psulas de gelatina blanda de retinol pedi\u00e1trico y su relaci\u00f3n con la monograf\u00eda de soluci\u00f3n oral de retinol?**\n   - Respuesta: El Comit\u00e9 decidi\u00f3 incorporar las c\u00e1psulas de gelatina blanda en la monograf\u00eda de soluci\u00f3n oral de retinol, considerando la c\u00e1psula como un contenedor de unidad \u00fanica y el contenido l\u00edquido como la forma de dosificaci\u00f3n real.\n\n3. **\u00bfQu\u00e9 procedimiento se sigui\u00f3 para la revisi\u00f3n de la monograf\u00eda de soluci\u00f3n oral de retinol pedi\u00e1trico despu\u00e9s de la reuni\u00f3n de 2010?**\n   - Respuesta: Se circularon versiones revisadas de la monograf\u00eda dos veces seg\u00fan el procedimiento consultivo habitual y se discuti\u00f3 en una consulta sobre especificaciones para medicamentos y cuestiones de control de calidad en julio de 2011.", "prev_section_summary": "### Temas clave\n\n1. **Revisi\u00f3n de Monograf\u00edas de Medicamentos**:\n   - Se revisaron las monograf\u00edas de tabletas masticables de **pirantel** y **albendazol**.\n   - La monograf\u00eda de pirantel fue adoptada con cambios acordados, mientras que la de albendazol permanece abierta para comentarios p\u00fablicos y se recomienda m\u00e1s consultas.\n\n2. **Heparinas**:\n   - Se discutieron las heparinas en el contexto de alertas sobre inyecciones contaminadas.\n   - Se propuso un nuevo m\u00e9todo para la determinaci\u00f3n de **sulfato de dermatan** y otros **glicosaminoglicanos** en heparina, que fue aprobado para su inclusi\u00f3n en la monograf\u00eda.\n\n3. **Inyecci\u00f3n de Medroxiprogesterona**:\n   - Se present\u00f3 una nueva monograf\u00eda sobre la inyecci\u00f3n contraceptiva de **medroxiprogesterona**, que fue adoptada con cambios acordados y se mantiene abierta para comentarios adicionales.\n\n### Entidades\n\n- **Medicamentos**:\n  - Pirantel (tabletas masticables)\n  - Albendazol (tabletas masticables)\n  - Heparinas\n  - Medroxiprogesterona (inyecci\u00f3n)\n\n- **Comit\u00e9**:\n  - Comit\u00e9 de Expertos de la OMS\n\n- **M\u00e9todos**:\n  - M\u00e9todo para la determinaci\u00f3n de sulfato de dermatan y glicosaminoglicanos en heparina\n\n- **Documentos**:\n  - Monograf\u00edas en *The International Pharmacopoeia*\n\n### Resumen\n\nLa secci\u00f3n aborda la revisi\u00f3n y adopci\u00f3n de monograf\u00edas de medicamentos por parte de un Comit\u00e9 de Expertos, destacando la importancia de la consulta p\u00fablica y la revisi\u00f3n de m\u00e9todos para garantizar la calidad y seguridad de los medicamentos. Se enfatiza la necesidad de abordar problemas de contaminaci\u00f3n en productos farmac\u00e9uticos y la continua evoluci\u00f3n de las monograf\u00edas para reflejar los est\u00e1ndares actuales.", "excerpt_keywords": "Levonorgestrel, paediatric retinol, monographs, Expert Committee, pharmaceutical preparations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "489c27ba-7a24-4e92-9ec5-77b4ea2a7429", "node_type": "4", "metadata": {"page_label": "30", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Levonorgestrel tablets\n\nThe text on levonorgestrel tablets was adopted in 2010, and following the recommendation made by the Expert Committee, specific requirements for the 30 \u00b5g tablets had been added with regard to the preparation of test solutions and the dissolution test conditions. As these agreed changes were important, the final text was re-presented to the Expert Committee for final endorsement (see also section 3.3.2).\n\nThe proposed modifications were adopted by the Expert Committee.\n\n## 3.2.6 Other paediatrics\n\n### Paediatric retinol oral solution\n\nDraft versions of the monographs on retinol concentrate (oily form), paediatric retinol capsules and paediatric retinol oral solution were discussed at the forty-fifth meeting of the Expert Committee in October 2010. The monograph on retinol concentrate, oily form, was adopted.\n\nThe Committee decided to incorporate the dosage form paediatric retinol soft-gel capsules into the monograph on retinol oral solution, considering the soft gelatin shell as a single-unit container and the liquid content as the actual dosage form. Following the meeting held in 2010, the Expert Committee recommended that the monograph on paediatric retinol oral solution should be modified so that its specifications could also be applied to these single-dose units and that the capsule monograph should be withdrawn.\n\nFollowing the 2010 meeting, revised versions of the monograph on paediatric retinol oral solution were circulated twice according to the usual consultative procedure. The monograph was also discussed at the consultation on specifications for medicines and quality control issues held in July 2011.\n\nThe Expert Committee adopted the monograph on paediatric retinol oral solution subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, and subject to the requirement that the monograph on retinol concentrate (oily form) be adapted in line with the changes to that on retinol oral solution.\n\n## 3.3 General monographs for dosage forms and associated method texts\n\n### 3.3.1 Pharmacopoeial Discussion Group-harmonized general texts\n\nFollowing discussion by the Expert Committee on Specifications for Pharmaceutical Preparations at its forty-fifth meeting in 2010, a number of internationally harmonized, PDG-texts had been adapted to the editorial style of *The International Pharmacopoeia* and sent out for wide consultation as per the usual consultative procedure.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f644b58bd9df047677596852c93d280abad5f0df0d3c7e005bfa71baf3fa3832", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Levonorgestrel tablets\n\nThe text on levonorgestrel tablets was adopted in 2010, and following the recommendation made by the Expert Committee, specific requirements for the 30 \u00b5g tablets had been added with regard to the preparation of test solutions and the dissolution test conditions. As these agreed changes were important, the final text was re-presented to the Expert Committee for final endorsement (see also section 3.3.2).\n\nThe proposed modifications were adopted by the Expert Committee.\n\n## 3.2.6 Other paediatrics\n\n### Paediatric retinol oral solution\n\nDraft versions of the monographs on retinol concentrate (oily form), paediatric retinol capsules and paediatric retinol oral solution were discussed at the forty-fifth meeting of the Expert Committee in October 2010. The monograph on retinol concentrate, oily form, was adopted.\n\nThe Committee decided to incorporate the dosage form paediatric retinol soft-gel capsules into the monograph on retinol oral solution, considering the soft gelatin shell as a single-unit container and the liquid content as the actual dosage form. Following the meeting held in 2010, the Expert Committee recommended that the monograph on paediatric retinol oral solution should be modified so that its specifications could also be applied to these single-dose units and that the capsule monograph should be withdrawn.\n\nFollowing the 2010 meeting, revised versions of the monograph on paediatric retinol oral solution were circulated twice according to the usual consultative procedure. The monograph was also discussed at the consultation on specifications for medicines and quality control issues held in July 2011.\n\nThe Expert Committee adopted the monograph on paediatric retinol oral solution subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, and subject to the requirement that the monograph on retinol concentrate (oily form) be adapted in line with the changes to that on retinol oral solution.\n\n## 3.3 General monographs for dosage forms and associated method texts\n\n### 3.3.1 Pharmacopoeial Discussion Group-harmonized general texts\n\nFollowing discussion by the Expert Committee on Specifications for Pharmaceutical Preparations at its forty-fifth meeting in 2010, a number of internationally harmonized, PDG-texts had been adapted to the editorial style of *The International Pharmacopoeia* and sent out for wide consultation as per the usual consultative procedure.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2486, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "b8d2e10f-b387-4b17-98ce-0df352e88f0c": {"__data__": {"id_": "b8d2e10f-b387-4b17-98ce-0df352e88f0c", "embedding": null, "metadata": {"page_label": "31", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nA first set of texts with the comments received were initially reviewed at the consultation on specifications for medicines and quality control issues held in July 2011. These texts covered:\n\n- sulfated ash\n- test for extractable volume of parenteral preparations\n- disintegration test\n- test for particulate contamination: subvisible particles\n- microbial examination of non-sterile products: acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use\n- microbial examination of non-sterile products: tests for specified microorganisms\n- microbial examination of non-sterile products: microbial enumeration tests.\n\nA set of additional texts was then prepared in the same way and sent out for wide consultation in August and September 2011:\n\n- sterility test\n- tablet friability\n- bulk and tapped density of powders\n- bacterial endotoxins test.\n\nAs a consequence of the inclusion of these internationally harmonized monographs it was pointed out that certain texts in *The International Pharmacopoeia* would also require adaptation, for example, the monograph on parenteral preparations.\n\nThe Expert Committee proposed the following maintenance procedure for these texts: when the methods concerned are revised by the PDG and where this will have repercussions for the texts above included in *The International Pharmacopoeia*, the secretariat should consult with selected members of the Expert Committee and then make the required changes to *The International Pharmacopoeia* without the necessity for consulting the full Expert Committee.\n\nFor all following general texts, the Expert Committee acknowledged that they were sent out for wide consultation and duly revised, taking into account the comments received. All the texts described and listed were adopted, subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, unless stated otherwise.\n\n## Test for sulfated ash\n\nDuring its meeting in October 2010, the Expert Committee recommended that the current method described in *The International Pharmacopoeia* for the test", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las actividades de un Comit\u00e9 de Expertos de la OMS sobre especificaciones para preparaciones farmac\u00e9uticas. En 2011, se revisaron y consultaron varios textos relacionados con m\u00e9todos de control de calidad de medicamentos, incluyendo pruebas para cenizas sulfatadas, volumen extra\u00edble de preparaciones parenterales, y pruebas microbiol\u00f3gicas. Se propuso un procedimiento de mantenimiento para adaptar los textos de *La Farmacopea Internacional* en funci\u00f3n de las revisiones realizadas por el Grupo de Trabajo de Farmacopeas (PDG). Adem\u00e1s, se menciona que ciertos textos requerir\u00edan adaptaci\u00f3n debido a la inclusi\u00f3n de monograf\u00edas armonizadas internacionalmente.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 procedimiento se propuso para la adaptaci\u00f3n de los textos de *La Farmacopea Internacional* cuando se revisan los m\u00e9todos por el PDG?**\n   - El procedimiento propuesto establece que, cuando los m\u00e9todos son revisados por el PDG y esto afecta a los textos incluidos en *La Farmacopea Internacional*, la secretar\u00eda debe consultar a miembros seleccionados del Comit\u00e9 de Expertos y realizar los cambios necesarios sin necesidad de consultar al Comit\u00e9 completo.\n\n2. **\u00bfCu\u00e1les son algunos de los textos que se revisaron y enviaron para consulta en agosto y septiembre de 2011?**\n   - Los textos revisados y enviados para consulta incluyen: prueba de esterilidad, friabilidad de tabletas, densidad a granel y densidad apilada de polvos, y prueba de endotoxinas bacterianas.\n\n3. **\u00bfQu\u00e9 se destac\u00f3 sobre la necesidad de adaptar ciertos textos en *La Farmacopea Internacional*?**\n   - Se destac\u00f3 que, debido a la inclusi\u00f3n de monograf\u00edas armonizadas internacionalmente, ciertos textos en *La Farmacopea Internacional* requerir\u00edan adaptaci\u00f3n, como la monograf\u00eda sobre preparaciones parenterales.\n\nEstas preguntas y respuestas est\u00e1n dise\u00f1adas para proporcionar informaci\u00f3n espec\u00edfica que no se puede encontrar f\u00e1cilmente en otros documentos, centr\u00e1ndose en los procedimientos y decisiones del Comit\u00e9 de Expertos de la OMS.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Levonorgestrel Tablets**:\n   - **A\u00f1o de adopci\u00f3n**: 2010.\n   - **Cambios adoptados**: Se a\u00f1adieron requisitos espec\u00edficos para la preparaci\u00f3n de soluciones de prueba y las condiciones de la prueba de disoluci\u00f3n para tabletas de 30 \u00b5g.\n   - **Proceso**: El texto final fue re-presentado al Comit\u00e9 de Expertos para su aprobaci\u00f3n final.\n\n2. **Paediatric Retinol Oral Solution**:\n   - **Monograf\u00edas discutidas**: Incluyen retinol concentrado (forma oleosa), c\u00e1psulas de gelatina blanda pedi\u00e1tricas y soluci\u00f3n oral de retinol pedi\u00e1trico.\n   - **Decisi\u00f3n del Comit\u00e9**: Incorporar las c\u00e1psulas de gelatina blanda en la monograf\u00eda de soluci\u00f3n oral de retinol, considerando la c\u00e1psula como un contenedor de unidad \u00fanica.\n   - **Modificaciones**: Se recomend\u00f3 modificar la monograf\u00eda de soluci\u00f3n oral para que sus especificaciones se aplicaran tambi\u00e9n a las unidades de dosis \u00fanica y se retir\u00f3 la monograf\u00eda de c\u00e1psulas.\n\n3. **Proceso de revisi\u00f3n**:\n   - **Circulaci\u00f3n de versiones revisadas**: Se realizaron dos circulaciones de versiones revisadas de la monograf\u00eda de soluci\u00f3n oral de retinol pedi\u00e1trico.\n   - **Consulta adicional**: Se discuti\u00f3 en una consulta sobre especificaciones para medicamentos y control de calidad en julio de 2011.\n\n4. **General Monographs for Dosage Forms**:\n   - **Grupo de discusi\u00f3n**: Se adaptaron textos armonizados internacionalmente al estilo editorial de *The International Pharmacopoeia* y se enviaron para consulta.\n\n### Entidades Clave:\n- **Levonorgestrel**: Compuesto farmac\u00e9utico.\n- **Retinol**: Vitamina A en forma de soluci\u00f3n y c\u00e1psulas.\n- **Comit\u00e9 de Expertos**: Grupo responsable de la revisi\u00f3n y adopci\u00f3n de monograf\u00edas.\n- **Monograf\u00edas**: Documentos que especifican los est\u00e1ndares para medicamentos.", "excerpt_keywords": "Keywords: pharmaceutical preparations, quality control, International Pharmacopoeia, Expert Committee, microbial examination"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b4f9d5ae-bf0d-4211-8ec2-fed0aeecbead", "node_type": "4", "metadata": {"page_label": "31", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nA first set of texts with the comments received were initially reviewed at the consultation on specifications for medicines and quality control issues held in July 2011. These texts covered:\n\n- sulfated ash\n- test for extractable volume of parenteral preparations\n- disintegration test\n- test for particulate contamination: subvisible particles\n- microbial examination of non-sterile products: acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use\n- microbial examination of non-sterile products: tests for specified microorganisms\n- microbial examination of non-sterile products: microbial enumeration tests.\n\nA set of additional texts was then prepared in the same way and sent out for wide consultation in August and September 2011:\n\n- sterility test\n- tablet friability\n- bulk and tapped density of powders\n- bacterial endotoxins test.\n\nAs a consequence of the inclusion of these internationally harmonized monographs it was pointed out that certain texts in *The International Pharmacopoeia* would also require adaptation, for example, the monograph on parenteral preparations.\n\nThe Expert Committee proposed the following maintenance procedure for these texts: when the methods concerned are revised by the PDG and where this will have repercussions for the texts above included in *The International Pharmacopoeia*, the secretariat should consult with selected members of the Expert Committee and then make the required changes to *The International Pharmacopoeia* without the necessity for consulting the full Expert Committee.\n\nFor all following general texts, the Expert Committee acknowledged that they were sent out for wide consultation and duly revised, taking into account the comments received. All the texts described and listed were adopted, subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, unless stated otherwise.\n\n## Test for sulfated ash\n\nDuring its meeting in October 2010, the Expert Committee recommended that the current method described in *The International Pharmacopoeia* for the test", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "0d6dbefed5d2f5c0a92754b6435a2454bb80d988b1d6c63632b7ad22fbd8050f", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nA first set of texts with the comments received were initially reviewed at the consultation on specifications for medicines and quality control issues held in July 2011. These texts covered:\n\n- sulfated ash\n- test for extractable volume of parenteral preparations\n- disintegration test\n- test for particulate contamination: subvisible particles\n- microbial examination of non-sterile products: acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use\n- microbial examination of non-sterile products: tests for specified microorganisms\n- microbial examination of non-sterile products: microbial enumeration tests.\n\nA set of additional texts was then prepared in the same way and sent out for wide consultation in August and September 2011:\n\n- sterility test\n- tablet friability\n- bulk and tapped density of powders\n- bacterial endotoxins test.\n\nAs a consequence of the inclusion of these internationally harmonized monographs it was pointed out that certain texts in *The International Pharmacopoeia* would also require adaptation, for example, the monograph on parenteral preparations.\n\nThe Expert Committee proposed the following maintenance procedure for these texts: when the methods concerned are revised by the PDG and where this will have repercussions for the texts above included in *The International Pharmacopoeia*, the secretariat should consult with selected members of the Expert Committee and then make the required changes to *The International Pharmacopoeia* without the necessity for consulting the full Expert Committee.\n\nFor all following general texts, the Expert Committee acknowledged that they were sent out for wide consultation and duly revised, taking into account the comments received. All the texts described and listed were adopted, subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, unless stated otherwise.\n\n## Test for sulfated ash\n\nDuring its meeting in October 2010, the Expert Committee recommended that the current method described in *The International Pharmacopoeia* for the test", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2187, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "71efd5b3-5fb5-4c36-b696-304ffbdc13c0": {"__data__": {"id_": "71efd5b3-5fb5-4c36-b696-304ffbdc13c0", "embedding": null, "metadata": {"page_label": "32", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nof sulfated ash be replaced progressively by the internationally harmonized general test on residue on ignition/sulfated ash test. To this effect the method \u201c2.3 Sulfated ash\u201d was revised and sent for wide consultation in April and August 2011. Both methods would be included in *The International Pharmacopoeia* for an interim period. The internationally harmonized test would be specified in new monographs while, for existing monographs, the current test would be specified until it is replaced during the revision of the monographs in question.\n\n## Bulk density and tapped density of powders\n\nThis new general method text was proposed for inclusion in the Supplementary information section of *The International Pharmacopoeia*. The text was based on the internationally harmonized test on bulk density and tapped density of powders.\n\nIt was intended to revise the Supplementary information section of *The International Pharmacopoeia* (structure and contents). In the proposal being reviewed, a new section on test methods used during pharmaceutical development and/or manufacture of dosage forms was included. The general method for bulk density and tapped density of powders would, therefore, be included in this section and a specific number would be assigned to this method once the proposed format and the methods considered for this section have been adopted.\n\n## Tablet friability\n\nIn October 2009 the Expert Committee on Specifications for Pharmaceutical Preparations adopted a revision of the general monograph on Tablets where a reference was made under the Manufacture section to a method of friability testing. Based on the internationally harmonized tablet friability test, a general method text was, therefore, proposed for inclusion in the Supplementary information section of *The International Pharmacopoeia*.\n\n## Disintegration test\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the disintegration test for tablets and capsules should be replaced by the internationally harmonized general test.\n\nThe revision implies both changes to and additions to dimensions and tolerances in the description of the disintegration apparatus. The possibility for retesting when one or two units fail in the first step of the procedure is introduced, as is the possibility to use automatic detection employing modified discs in cases where the use of discs is prescribed.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Revisi\u00f3n de M\u00e9todos de Prueba**: El Comit\u00e9 de Expertos de la OMS en Especificaciones para Preparaciones Farmac\u00e9uticas ha revisado varios m\u00e9todos de prueba, incluyendo el de cenizas sulfatadas, densidad a granel y densidad compactada de polvos, friabilidad de tabletas y pruebas de desintegraci\u00f3n. Estas revisiones buscan armonizar los m\u00e9todos a nivel internacional y mejorar la calidad de las monograf\u00edas en *La Farmacopea Internacional*.\n\n2. **Implementaci\u00f3n de Nuevos M\u00e9todos**: Se est\u00e1n introduciendo nuevos m\u00e9todos de prueba en la secci\u00f3n de informaci\u00f3n suplementaria de *La Farmacopea Internacional*, con un enfoque en la estandarizaci\u00f3n y la mejora de los procedimientos utilizados en el desarrollo y fabricaci\u00f3n de formas de dosificaci\u00f3n.\n\n3. **Cambios en la Prueba de Desintegraci\u00f3n**: Se recomienda reemplazar el m\u00e9todo actual de prueba de desintegraci\u00f3n para tabletas y c\u00e1psulas por un m\u00e9todo armonizado internacionalmente, que incluye cambios en las dimensiones y tolerancias del aparato de desintegraci\u00f3n, as\u00ed como nuevas posibilidades de retesting y detecci\u00f3n autom\u00e1tica.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las implicaciones de la revisi\u00f3n del m\u00e9todo de cenizas sulfatadas en las monograf\u00edas existentes de *La Farmacopea Internacional*?**\n   - La revisi\u00f3n implica que el m\u00e9todo de cenizas sulfatadas ser\u00e1 reemplazado progresivamente por un test armonizado internacionalmente, lo que significa que las monograf\u00edas existentes seguir\u00e1n utilizando el m\u00e9todo actual hasta que sean revisadas y actualizadas.\n\n2. **\u00bfQu\u00e9 cambios se proponen en el m\u00e9todo de prueba de friabilidad de tabletas y c\u00f3mo se relacionan con la armonizaci\u00f3n internacional?**\n   - Se propone un texto de m\u00e9todo general basado en la prueba de friabilidad de tabletas armonizada internacionalmente, que se incluir\u00e1 en la secci\u00f3n de informaci\u00f3n suplementaria de *La Farmacopea Internacional*, lo que busca estandarizar el proceso de prueba y asegurar la calidad de las tabletas.\n\n3. **\u00bfQu\u00e9 nuevas caracter\u00edsticas se introducen en la prueba de desintegraci\u00f3n para tabletas y c\u00e1psulas seg\u00fan las recomendaciones del Comit\u00e9 de Expertos?**\n   - Las nuevas caracter\u00edsticas incluyen cambios en las dimensiones y tolerancias del aparato de desintegraci\u00f3n, la posibilidad de retesting si una o dos unidades fallan en la primera prueba, y la opci\u00f3n de utilizar detecci\u00f3n autom\u00e1tica con discos modificados cuando se requiera el uso de discos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: Se centra en las especificaciones para preparaciones farmac\u00e9uticas y en el control de calidad de medicamentos.\n\n2. **Consultas y Revisi\u00f3n de Textos**: En 2011, se revisaron textos relacionados con m\u00e9todos de control de calidad, incluyendo:\n   - Cenizas sulfatadas\n   - Volumen extra\u00edble de preparaciones parenterales\n   - Prueba de desintegraci\u00f3n\n   - Contaminaci\u00f3n por part\u00edculas subvisibles\n   - Ex\u00e1menes microbiol\u00f3gicos de productos no est\u00e9riles (criterios de aceptaci\u00f3n, microorganismos espec\u00edficos, y pruebas de enumeraci\u00f3n microbiana).\n\n3. **Textos Adicionales**: En agosto y septiembre de 2011, se enviaron para consulta textos adicionales, que incluyen:\n   - Prueba de esterilidad\n   - Friabilidad de tabletas\n   - Densidad a granel y apilada de polvos\n   - Prueba de endotoxinas bacterianas.\n\n4. **Adaptaci\u00f3n de Textos**: Se destac\u00f3 la necesidad de adaptar ciertos textos en *La Farmacopea Internacional* debido a la inclusi\u00f3n de monograf\u00edas armonizadas internacionalmente, como la monograf\u00eda sobre preparaciones parenterales.\n\n5. **Procedimiento de Mantenimiento**: Se propuso un procedimiento donde, si los m\u00e9todos son revisados por el Grupo de Trabajo de Farmacopeas (PDG) y afectan a los textos de *La Farmacopea Internacional*, la secretar\u00eda consultar\u00e1 a miembros seleccionados del Comit\u00e9 de Expertos para realizar los cambios necesarios sin consultar al Comit\u00e9 completo.\n\n6. **Adopci\u00f3n de Textos**: Todos los textos revisados fueron adoptados, considerando los cambios acordados basados en los comentarios recibidos.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**\n- **La Farmacopea Internacional**\n- **Grupo de Trabajo de Farmacopeas (PDG)**\n\nEste resumen proporciona una visi\u00f3n general de los temas tratados en la secci\u00f3n, destacando la importancia de la revisi\u00f3n y adaptaci\u00f3n de los m\u00e9todos de control de calidad en la farmacolog\u00eda.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, international harmonization, testing methods, disintegration test"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7c09f339-8b10-4c50-ac9c-5b3e52099451", "node_type": "4", "metadata": {"page_label": "32", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nof sulfated ash be replaced progressively by the internationally harmonized general test on residue on ignition/sulfated ash test. To this effect the method \u201c2.3 Sulfated ash\u201d was revised and sent for wide consultation in April and August 2011. Both methods would be included in *The International Pharmacopoeia* for an interim period. The internationally harmonized test would be specified in new monographs while, for existing monographs, the current test would be specified until it is replaced during the revision of the monographs in question.\n\n## Bulk density and tapped density of powders\n\nThis new general method text was proposed for inclusion in the Supplementary information section of *The International Pharmacopoeia*. The text was based on the internationally harmonized test on bulk density and tapped density of powders.\n\nIt was intended to revise the Supplementary information section of *The International Pharmacopoeia* (structure and contents). In the proposal being reviewed, a new section on test methods used during pharmaceutical development and/or manufacture of dosage forms was included. The general method for bulk density and tapped density of powders would, therefore, be included in this section and a specific number would be assigned to this method once the proposed format and the methods considered for this section have been adopted.\n\n## Tablet friability\n\nIn October 2009 the Expert Committee on Specifications for Pharmaceutical Preparations adopted a revision of the general monograph on Tablets where a reference was made under the Manufacture section to a method of friability testing. Based on the internationally harmonized tablet friability test, a general method text was, therefore, proposed for inclusion in the Supplementary information section of *The International Pharmacopoeia*.\n\n## Disintegration test\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the disintegration test for tablets and capsules should be replaced by the internationally harmonized general test.\n\nThe revision implies both changes to and additions to dimensions and tolerances in the description of the disintegration apparatus. The possibility for retesting when one or two units fail in the first step of the procedure is introduced, as is the possibility to use automatic detection employing modified discs in cases where the use of discs is prescribed.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "3a49f741997be66db49f04bd3fa462fe4225c8bdeed7f4e7ecd154c0e0e9df20", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nof sulfated ash be replaced progressively by the internationally harmonized general test on residue on ignition/sulfated ash test. To this effect the method \u201c2.3 Sulfated ash\u201d was revised and sent for wide consultation in April and August 2011. Both methods would be included in *The International Pharmacopoeia* for an interim period. The internationally harmonized test would be specified in new monographs while, for existing monographs, the current test would be specified until it is replaced during the revision of the monographs in question.\n\n## Bulk density and tapped density of powders\n\nThis new general method text was proposed for inclusion in the Supplementary information section of *The International Pharmacopoeia*. The text was based on the internationally harmonized test on bulk density and tapped density of powders.\n\nIt was intended to revise the Supplementary information section of *The International Pharmacopoeia* (structure and contents). In the proposal being reviewed, a new section on test methods used during pharmaceutical development and/or manufacture of dosage forms was included. The general method for bulk density and tapped density of powders would, therefore, be included in this section and a specific number would be assigned to this method once the proposed format and the methods considered for this section have been adopted.\n\n## Tablet friability\n\nIn October 2009 the Expert Committee on Specifications for Pharmaceutical Preparations adopted a revision of the general monograph on Tablets where a reference was made under the Manufacture section to a method of friability testing. Based on the internationally harmonized tablet friability test, a general method text was, therefore, proposed for inclusion in the Supplementary information section of *The International Pharmacopoeia*.\n\n## Disintegration test\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the disintegration test for tablets and capsules should be replaced by the internationally harmonized general test.\n\nThe revision implies both changes to and additions to dimensions and tolerances in the description of the disintegration apparatus. The possibility for retesting when one or two units fail in the first step of the procedure is introduced, as is the possibility to use automatic detection employing modified discs in cases where the use of discs is prescribed.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2600, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "b69f4437-bf76-469d-971f-e9b502e41ba0": {"__data__": {"id_": "b69f4437-bf76-469d-971f-e9b502e41ba0", "embedding": null, "metadata": {"page_label": "33", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Dissolution test\n\nThe dissolution test had been reviewed for adaptation for inclusion in *The International Pharmacopoeia*. The Expert Committee judged that the test should be subjected to a thorough review and should be considered by a future Expert Committee.\n\n# Test for extractable volume for parenteral preparations\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the test for extractable volume for parenteral preparations be replaced by the internationally harmonized general test.\n\n# Tests for particulate contamination\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the tests for particulate contamination should be replaced by the internationally harmonized general test, as a revision of method \u201c5.7 Tests for particulate contamination\u201d. The revision includes a distinction between small volume parenterals and large volume parenterals with a limit at 100 ml. The 100 ml preparation is exempted from the pharmacopoeial harmonization and it was proposed to include the 100 ml preparation among the small volume parenterals. As a consequence of the revision of this method, other changes would be made to the headings in chapter 5.7.\n\n# Microbial quality of pharmaceutical preparations\n\nThis relates to the following headings:\n\n- Microbiological examination of non-sterile products;\n- Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use;\n- Microbial enumeration tests;\n- Tests for specified microorganisms.\n\nMicrobiological examination of non-sterile products had been a subject for harmonization, which has resulted in three texts:\n\n- Microbial enumeration tests;\n- Tests for specified microorganisms;\n- Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS, *Technical Report Series 970*, aborda varios aspectos relacionados con la farmacopoeia internacional, incluyendo la revisi\u00f3n de pruebas de disoluci\u00f3n, el volumen extra\u00edble en preparaciones parenterales, la contaminaci\u00f3n particulada y la calidad microbiana de las preparaciones farmac\u00e9uticas. Se destaca que el Comit\u00e9 de Expertos ha recomendado la adaptaci\u00f3n de m\u00e9todos existentes a pruebas armonizadas internacionalmente, as\u00ed como la distinci\u00f3n entre parenterales de peque\u00f1o y gran volumen. Tambi\u00e9n se menciona la armonizaci\u00f3n de criterios de calidad microbiol\u00f3gica para productos no est\u00e9riles.\n\n### Preguntas\n\n1. **\u00bfQu\u00e9 cambios espec\u00edficos se proponen para la prueba de volumen extra\u00edble en preparaciones parenterales seg\u00fan el Comit\u00e9 de Expertos?**\n   - Respuesta: Se recomienda que el m\u00e9todo actual para la prueba de volumen extra\u00edble en preparaciones parenterales sea reemplazado por un test general armonizado internacionalmente.\n\n2. **\u00bfC\u00f3mo se distingue entre parenterales de peque\u00f1o y gran volumen en la revisi\u00f3n de la prueba de contaminaci\u00f3n particulada?**\n   - Respuesta: La revisi\u00f3n incluye una distinci\u00f3n entre parenterales de peque\u00f1o volumen y de gran volumen, estableciendo un l\u00edmite de 100 ml, donde las preparaciones de 100 ml est\u00e1n exentas de la armonizaci\u00f3n farmacopoeial y se propone incluirlas entre las de peque\u00f1o volumen.\n\n3. **\u00bfCu\u00e1les son los cuatro aspectos clave relacionados con la calidad microbiana de las preparaciones farmac\u00e9uticas que se mencionan en el documento?**\n   - Respuesta: Los cuatro aspectos clave son: la microbiolog\u00eda de productos no est\u00e9riles, los criterios de aceptaci\u00f3n para preparaciones farmac\u00e9uticas y sustancias para uso farmac\u00e9utico, las pruebas de enumeraci\u00f3n microbiana y las pruebas para microorganismos espec\u00edficos.", "prev_section_summary": "### Temas Clave\n\n1. **Revisi\u00f3n de M\u00e9todos de Prueba**: Se han revisado varios m\u00e9todos de prueba en el \u00e1mbito farmac\u00e9utico, incluyendo el m\u00e9todo de cenizas sulfatadas, densidad a granel y densidad compactada de polvos, friabilidad de tabletas y pruebas de desintegraci\u00f3n, con el objetivo de armonizar y mejorar la calidad de las monograf\u00edas en *La Farmacopea Internacional*.\n\n2. **Armonizaci\u00f3n Internacional**: Se est\u00e1n implementando m\u00e9todos de prueba armonizados internacionalmente, lo que implica la inclusi\u00f3n de nuevos textos en la secci\u00f3n de informaci\u00f3n suplementaria de *La Farmacopea Internacional*.\n\n3. **Cambios en la Prueba de Desintegraci\u00f3n**: Se recomienda reemplazar el m\u00e9todo actual de prueba de desintegraci\u00f3n para tabletas y c\u00e1psulas por un m\u00e9todo armonizado, que incluye modificaciones en el aparato de desintegraci\u00f3n y nuevas opciones para retesting y detecci\u00f3n autom\u00e1tica.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la revisi\u00f3n y armonizaci\u00f3n de los m\u00e9todos de prueba.\n- **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**: Grupo que adopta y revisa los m\u00e9todos de prueba.\n- **La Farmacopea Internacional**: Publicaci\u00f3n que contiene los m\u00e9todos de prueba y monograf\u00edas para productos farmac\u00e9uticos.\n- **M\u00e9todos de Prueba**: Incluyen cenizas sulfatadas, densidad a granel, densidad compactada, friabilidad de tabletas y pruebas de desintegraci\u00f3n. \n\n### Resumen\n\nEl Comit\u00e9 de Expertos de la OMS ha revisado y propuesto la armonizaci\u00f3n de varios m\u00e9todos de prueba utilizados en la industria farmac\u00e9utica, con el fin de mejorar la calidad y estandarizaci\u00f3n de los procedimientos en *La Farmacopea Internacional*. Se est\u00e1n introduciendo nuevos m\u00e9todos, como el de cenizas sulfatadas y la prueba de friabilidad de tabletas, y se recomienda la adopci\u00f3n de un m\u00e9todo armonizado para la prueba de desintegraci\u00f3n, que incluye cambios significativos en el equipo y el procedimiento.", "excerpt_keywords": "Keywords: dissolution test, extractable volume, particulate contamination, microbial quality, International Pharmacopoeia"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "96bea8da-c8b0-47b4-8501-703eccd238b5", "node_type": "4", "metadata": {"page_label": "33", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Dissolution test\n\nThe dissolution test had been reviewed for adaptation for inclusion in *The International Pharmacopoeia*. The Expert Committee judged that the test should be subjected to a thorough review and should be considered by a future Expert Committee.\n\n# Test for extractable volume for parenteral preparations\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the test for extractable volume for parenteral preparations be replaced by the internationally harmonized general test.\n\n# Tests for particulate contamination\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the tests for particulate contamination should be replaced by the internationally harmonized general test, as a revision of method \u201c5.7 Tests for particulate contamination\u201d. The revision includes a distinction between small volume parenterals and large volume parenterals with a limit at 100 ml. The 100 ml preparation is exempted from the pharmacopoeial harmonization and it was proposed to include the 100 ml preparation among the small volume parenterals. As a consequence of the revision of this method, other changes would be made to the headings in chapter 5.7.\n\n# Microbial quality of pharmaceutical preparations\n\nThis relates to the following headings:\n\n- Microbiological examination of non-sterile products;\n- Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use;\n- Microbial enumeration tests;\n- Tests for specified microorganisms.\n\nMicrobiological examination of non-sterile products had been a subject for harmonization, which has resulted in three texts:\n\n- Microbial enumeration tests;\n- Tests for specified microorganisms;\n- Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "2796a267b9166a6fa909b64edf162ce56fc8d2f36a4db3c7f542a3b32f79bf16", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Dissolution test\n\nThe dissolution test had been reviewed for adaptation for inclusion in *The International Pharmacopoeia*. The Expert Committee judged that the test should be subjected to a thorough review and should be considered by a future Expert Committee.\n\n# Test for extractable volume for parenteral preparations\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the test for extractable volume for parenteral preparations be replaced by the internationally harmonized general test.\n\n# Tests for particulate contamination\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the tests for particulate contamination should be replaced by the internationally harmonized general test, as a revision of method \u201c5.7 Tests for particulate contamination\u201d. The revision includes a distinction between small volume parenterals and large volume parenterals with a limit at 100 ml. The 100 ml preparation is exempted from the pharmacopoeial harmonization and it was proposed to include the 100 ml preparation among the small volume parenterals. As a consequence of the revision of this method, other changes would be made to the headings in chapter 5.7.\n\n# Microbial quality of pharmaceutical preparations\n\nThis relates to the following headings:\n\n- Microbiological examination of non-sterile products;\n- Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use;\n- Microbial enumeration tests;\n- Tests for specified microorganisms.\n\nMicrobiological examination of non-sterile products had been a subject for harmonization, which has resulted in three texts:\n\n- Microbial enumeration tests;\n- Tests for specified microorganisms;\n- Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2039, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "83fbff23-011a-4b0a-92fb-c9c604eaba83": {"__data__": {"id_": "83fbff23-011a-4b0a-92fb-c9c604eaba83", "embedding": null, "metadata": {"page_label": "34", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIt was agreed that the texts on microbial enumeration tests and tests for specified microorganisms would be new (3.3.1 and 3.3.2) in the Methods of analysis section. Furthermore, it was agreed to replace the current text on microbial quality (3.3) with the internationally harmonized text on Microbiological examination of non-sterile products: acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use. This text would be provided for information and would, therefore, be moved to the Supplementary information section and renamed as follows: Microbiological quality of non-sterile products: recommended acceptance criteria for pharmaceutical preparations.\n\nFollowing adoption, the inclusion of methods 3.3.1 and 3.3.2 in *The International Pharmacopoeia* would be reviewed in terms of their applicability within the existing texts of *The International Pharmacopoeia*. Such a review would include excipients and would consider in which monographs of *The International Pharmacopoeia* the methods would be invoked, and would propose limits.\n\n## Test for Sterility\n\nFollowing adoption, the current methods \u201c3.2 test for sterility of non-injectable preparations\u201d and that for \u201c3.2.2 sterility testing of antibiotics\u201d will be replaced with the internationally harmonized test for sterility. Testing of surgical materials was not included in the revision.\n\nThe revision would result in the need for additional advice concerning the testing of antibiotics within the Supplementary information section of *The International Pharmacopoeia*. Further, it would be necessary to change all references to these monographs.\n\nThe clause \u201cunless otherwise prescribed, justified and authorized\u201d is included in the harmonized text. It was felt that the meaning of \u201cjustified and authorized\u201d in the context of *The International Pharmacopoeia* needed explanation. It was, therefore, agreed to include the following wording in the General notices of *The International Pharmacopoeia*:\n\n> \u201cThe expression \u2018unless otherwise justified and authorized\u2019 means that the requirements have to be met or instructions to be followed, unless the relevant national or regional authority authorizes an exemption or modification, where justified in a particular case.\u201d\n\n## Test for Bacterial Endotoxins\n\nThe proposed revision for inclusion in *The International Pharmacopoeia* contained three method texts in contrast to the current text.\n\nThe Expert Committee, therefore, agreed that selected experts would continue to work on the implementation of this new text for existing monographs in *The International Pharmacopoeia*.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las decisiones tomadas por el Comit\u00e9 de Expertos de la OMS sobre las especificaciones para preparaciones farmac\u00e9uticas. Se acord\u00f3 introducir nuevos textos sobre pruebas de enumeraci\u00f3n microbiana y pruebas para microorganismos espec\u00edficos en la secci\u00f3n de M\u00e9todos de an\u00e1lisis. Adem\u00e1s, se reemplazar\u00e1 el texto actual sobre calidad microbiana con uno armonizado internacionalmente. Tambi\u00e9n se revisar\u00e1n los m\u00e9todos de prueba de esterilidad y endotoxinas bacterianas para su inclusi\u00f3n en la Farmacopea Internacional. Se enfatiza la necesidad de aclarar el significado de \"justificado y autorizado\" en el contexto de la Farmacopea.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 cambios se realizar\u00e1n en la secci\u00f3n de M\u00e9todos de an\u00e1lisis de la Farmacopea Internacional respecto a las pruebas de calidad microbiana?**\n   - Se introducir\u00e1n nuevos textos sobre pruebas de enumeraci\u00f3n microbiana (3.3.1 y 3.3.2) y se reemplazar\u00e1 el texto actual sobre calidad microbiana con uno armonizado internacionalmente, que se mover\u00e1 a la secci\u00f3n de informaci\u00f3n suplementaria y se renombrar\u00e1.\n\n2. **\u00bfC\u00f3mo se abordar\u00e1 la necesidad de asesoramiento adicional sobre las pruebas de antibi\u00f3ticos en la Farmacopea Internacional?**\n   - Se requerir\u00e1 asesoramiento adicional en la secci\u00f3n de informaci\u00f3n suplementaria sobre las pruebas de antibi\u00f3ticos, y ser\u00e1 necesario cambiar todas las referencias a los monogr\u00e1ficos relacionados.\n\n3. **\u00bfQu\u00e9 implica la cl\u00e1usula \u201ca menos que se prescriba, justifique y autorice de otra manera\u201d en el contexto de la Farmacopea Internacional?**\n   - Esta cl\u00e1usula significa que los requisitos deben cumplirse o las instrucciones deben seguirse, a menos que una autoridad nacional o regional relevante autorice una exenci\u00f3n o modificaci\u00f3n, donde est\u00e9 justificada en un caso particular.\n\n### Resumen de Nivel Superior\n\nEl Comit\u00e9 de Expertos de la OMS ha acordado realizar varias revisiones importantes en la Farmacopea Internacional, incluyendo la introducci\u00f3n de nuevos m\u00e9todos de an\u00e1lisis para pruebas microbianas y la actualizaci\u00f3n de los m\u00e9todos de prueba de esterilidad y endotoxinas. Estas revisiones buscan armonizar los est\u00e1ndares internacionales y proporcionar claridad sobre la aplicaci\u00f3n de requisitos espec\u00edficos en el contexto de la regulaci\u00f3n farmac\u00e9utica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Prueba de Disoluci\u00f3n**:\n   - Se revis\u00f3 la prueba de disoluci\u00f3n para su posible inclusi\u00f3n en *La Farmacopea Internacional*.\n   - El Comit\u00e9 de Expertos considera que debe ser sometida a una revisi\u00f3n exhaustiva y discutida por un futuro Comit\u00e9 de Expertos.\n\n2. **Volumen Extra\u00edble en Preparaciones Parenterales**:\n   - Se recomienda reemplazar el m\u00e9todo actual para la prueba de volumen extra\u00edble en preparaciones parenterales por un test general armonizado internacionalmente.\n\n3. **Contaminaci\u00f3n Particulada**:\n   - Se sugiere reemplazar el m\u00e9todo actual para las pruebas de contaminaci\u00f3n particulada por un test armonizado internacionalmente.\n   - Se establece una distinci\u00f3n entre parenterales de peque\u00f1o y gran volumen, con un l\u00edmite de 100 ml. Las preparaciones de 100 ml se proponen incluirlas entre las de peque\u00f1o volumen.\n\n4. **Calidad Microbiana de Preparaciones Farmac\u00e9uticas**:\n   - Se abordan cuatro aspectos clave:\n     - Examen microbiol\u00f3gico de productos no est\u00e9riles.\n     - Criterios de aceptaci\u00f3n para preparaciones farmac\u00e9uticas y sustancias para uso farmac\u00e9utico.\n     - Pruebas de enumeraci\u00f3n microbiana.\n     - Pruebas para microorganismos espec\u00edficos.\n   - La armonizaci\u00f3n de la microbiolog\u00eda de productos no est\u00e9riles ha dado lugar a tres textos relacionados.\n\n### Entidades Clave\n- **Comit\u00e9 de Expertos**: Grupo responsable de las recomendaciones sobre las pruebas y m\u00e9todos.\n- **La Farmacopea Internacional**: Referencia para los est\u00e1ndares farmac\u00e9uticos.\n- **Preparaciones Parenterales**: Formas farmac\u00e9uticas que se administran por inyecci\u00f3n.\n- **Contaminaci\u00f3n Particulada**: Problema relacionado con la calidad de las preparaciones inyectables.\n- **Calidad Microbiana**: Aspecto cr\u00edtico en la evaluaci\u00f3n de productos farmac\u00e9uticos, especialmente en productos no est\u00e9riles.", "excerpt_keywords": "Keywords: microbial enumeration, sterility testing, bacterial endotoxins, International Pharmacopoeia, pharmaceutical preparations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b12d1c22-c55c-4e3b-905f-17ab7e95a52f", "node_type": "4", "metadata": {"page_label": "34", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIt was agreed that the texts on microbial enumeration tests and tests for specified microorganisms would be new (3.3.1 and 3.3.2) in the Methods of analysis section. Furthermore, it was agreed to replace the current text on microbial quality (3.3) with the internationally harmonized text on Microbiological examination of non-sterile products: acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use. This text would be provided for information and would, therefore, be moved to the Supplementary information section and renamed as follows: Microbiological quality of non-sterile products: recommended acceptance criteria for pharmaceutical preparations.\n\nFollowing adoption, the inclusion of methods 3.3.1 and 3.3.2 in *The International Pharmacopoeia* would be reviewed in terms of their applicability within the existing texts of *The International Pharmacopoeia*. Such a review would include excipients and would consider in which monographs of *The International Pharmacopoeia* the methods would be invoked, and would propose limits.\n\n## Test for Sterility\n\nFollowing adoption, the current methods \u201c3.2 test for sterility of non-injectable preparations\u201d and that for \u201c3.2.2 sterility testing of antibiotics\u201d will be replaced with the internationally harmonized test for sterility. Testing of surgical materials was not included in the revision.\n\nThe revision would result in the need for additional advice concerning the testing of antibiotics within the Supplementary information section of *The International Pharmacopoeia*. Further, it would be necessary to change all references to these monographs.\n\nThe clause \u201cunless otherwise prescribed, justified and authorized\u201d is included in the harmonized text. It was felt that the meaning of \u201cjustified and authorized\u201d in the context of *The International Pharmacopoeia* needed explanation. It was, therefore, agreed to include the following wording in the General notices of *The International Pharmacopoeia*:\n\n> \u201cThe expression \u2018unless otherwise justified and authorized\u2019 means that the requirements have to be met or instructions to be followed, unless the relevant national or regional authority authorizes an exemption or modification, where justified in a particular case.\u201d\n\n## Test for Bacterial Endotoxins\n\nThe proposed revision for inclusion in *The International Pharmacopoeia* contained three method texts in contrast to the current text.\n\nThe Expert Committee, therefore, agreed that selected experts would continue to work on the implementation of this new text for existing monographs in *The International Pharmacopoeia*.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "1cd0576b6caf42c6c0699a30416010102910e9556e2303f2c59c48d91ff65a80", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIt was agreed that the texts on microbial enumeration tests and tests for specified microorganisms would be new (3.3.1 and 3.3.2) in the Methods of analysis section. Furthermore, it was agreed to replace the current text on microbial quality (3.3) with the internationally harmonized text on Microbiological examination of non-sterile products: acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use. This text would be provided for information and would, therefore, be moved to the Supplementary information section and renamed as follows: Microbiological quality of non-sterile products: recommended acceptance criteria for pharmaceutical preparations.\n\nFollowing adoption, the inclusion of methods 3.3.1 and 3.3.2 in *The International Pharmacopoeia* would be reviewed in terms of their applicability within the existing texts of *The International Pharmacopoeia*. Such a review would include excipients and would consider in which monographs of *The International Pharmacopoeia* the methods would be invoked, and would propose limits.\n\n## Test for Sterility\n\nFollowing adoption, the current methods \u201c3.2 test for sterility of non-injectable preparations\u201d and that for \u201c3.2.2 sterility testing of antibiotics\u201d will be replaced with the internationally harmonized test for sterility. Testing of surgical materials was not included in the revision.\n\nThe revision would result in the need for additional advice concerning the testing of antibiotics within the Supplementary information section of *The International Pharmacopoeia*. Further, it would be necessary to change all references to these monographs.\n\nThe clause \u201cunless otherwise prescribed, justified and authorized\u201d is included in the harmonized text. It was felt that the meaning of \u201cjustified and authorized\u201d in the context of *The International Pharmacopoeia* needed explanation. It was, therefore, agreed to include the following wording in the General notices of *The International Pharmacopoeia*:\n\n> \u201cThe expression \u2018unless otherwise justified and authorized\u2019 means that the requirements have to be met or instructions to be followed, unless the relevant national or regional authority authorizes an exemption or modification, where justified in a particular case.\u201d\n\n## Test for Bacterial Endotoxins\n\nThe proposed revision for inclusion in *The International Pharmacopoeia* contained three method texts in contrast to the current text.\n\nThe Expert Committee, therefore, agreed that selected experts would continue to work on the implementation of this new text for existing monographs in *The International Pharmacopoeia*.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2698, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "839d123a-18ad-49f1-b57c-ba71c2ef2934": {"__data__": {"id_": "839d123a-18ad-49f1-b57c-ba71c2ef2934", "embedding": null, "metadata": {"page_label": "35", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.3.2 Uniformity of content single-dose preparations\n\nA review and explanation of the current pharmacopoeial approach as well as a review of application to published monographs for the general method \u201c5.1 Uniformity of content of single-dose preparations\u201d, was presented to the Expert Committee for consideration.\n\nThe Committee discussed the background document, endorsed the explanatory text as summarized below and adopted the proposed revisions of the relevant monographs. It further agreed that, as a basis for a future policy, this background document and explanatory text would be helpful to assist those involved in the development of new and revised monographs. In this respect, the document might also be made available more widely to provide explanatory information to users of *The International Pharmacopoeia* by its inclusion in the Supplementary information section of the pharmacopoeia.\n\n## Rationale of the review of method 5.1 and its application to tablets and capsules monographs\n\nAt its meeting in October 2010, the Committee discussed the application of uniformity of content testing to monographs in *The International Pharmacopoeia* especially those for tablets and capsules containing two or more APIs, commonly known as fixed-dose combinations (FDCs).\n\nQuestions had arisen with respect to the different testing thresholds applied in the WHO Guidelines for registration of fixed-dose combination medicinal products<sup>1</sup> and in the method of analysis 5.1 of *The International Pharmacopoeia*; the threshold in the WHO guidelines being 25 mg/25% whereas that applied in *The International Pharmacopoeia* was 5 mg/5% (see the agreed correction as regards this threshold under Method of analysis 5.1 Uniformity of content of single-dose preparations below).\n\nIn light of the discussion by the Committee, a review had been carried out of the test and of its application to all tablets and capsules that were the subject of an individual monograph in *The International Pharmacopoeia*, i.e. both those containing a single API and those that were FDCs.\n\nA review document was discussed at the informal consultation on specifications for medicines and quality control laboratory issues in July 2011. A revised version of this document, reflecting the points raised and the recommendations made during the consultation was presented to the Committee for further discussion.\n\n----\n\n<sup>1</sup> In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento presenta una revisi\u00f3n del enfoque farmacopoeial sobre la uniformidad de contenido en preparaciones de dosis \u00fanica, espec\u00edficamente en tabletas y c\u00e1psulas. Se discuten las diferencias en los umbrales de prueba entre las directrices de la OMS para combinaciones de dosis fijas (FDCs) y el m\u00e9todo de an\u00e1lisis de la Farmacopea Internacional. La revisi\u00f3n se llev\u00f3 a cabo en respuesta a preguntas sobre estos umbrales y se discuti\u00f3 en una consulta informal sobre especificaciones para medicamentos y cuestiones de control de calidad en 2011. El Comit\u00e9 de Expertos de la OMS aprob\u00f3 revisiones a las monograf\u00edas relevantes y acord\u00f3 que el documento de fondo ser\u00eda \u00fatil para el desarrollo de nuevas monograf\u00edas.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los umbrales de prueba para la uniformidad de contenido en las combinaciones de dosis fijas seg\u00fan las directrices de la OMS y la Farmacopea Internacional?**\n   - Respuesta: Seg\u00fan las directrices de la OMS, el umbral es de 25 mg/25%, mientras que en la Farmacopea Internacional es de 5 mg/5%.\n\n2. **\u00bfQu\u00e9 se discuti\u00f3 en la reuni\u00f3n del Comit\u00e9 en octubre de 2010 respecto a las monograf\u00edas de tabletas y c\u00e1psulas?**\n   - Respuesta: Se discuti\u00f3 la aplicaci\u00f3n de las pruebas de uniformidad de contenido a las monograf\u00edas de tabletas y c\u00e1psulas, especialmente aquellas que contienen dos o m\u00e1s principios activos (FDCs), y se abordaron las diferencias en los umbrales de prueba.\n\n3. **\u00bfQu\u00e9 se acord\u00f3 en la consulta informal sobre especificaciones para medicamentos en julio de 2011?**\n   - Respuesta: Se discuti\u00f3 un documento de revisi\u00f3n que reflejaba los puntos y recomendaciones planteados durante la consulta, y se present\u00f3 una versi\u00f3n revisada del documento al Comit\u00e9 para su discusi\u00f3n adicional.\n\n### Resumen de nivel superior\n\nEl documento aborda la uniformidad de contenido en preparaciones de dosis \u00fanica, destacando la necesidad de revisar y armonizar los umbrales de prueba entre las directrices de la OMS y la Farmacopea Internacional. Se enfatiza la importancia de esta revisi\u00f3n para el desarrollo de nuevas monograf\u00edas y la mejora de la calidad de los medicamentos, especialmente en el contexto de combinaciones de dosis fijas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: Se centra en las especificaciones para preparaciones farmac\u00e9uticas y la armonizaci\u00f3n de m\u00e9todos de an\u00e1lisis.\n\n2. **M\u00e9todos de An\u00e1lisis**:\n   - **Nuevos Textos**: Se introducir\u00e1n nuevos textos sobre pruebas de enumeraci\u00f3n microbiana (3.3.1 y 3.3.2).\n   - **Reemplazo de Texto**: El texto actual sobre calidad microbiana (3.3) ser\u00e1 reemplazado por uno armonizado internacionalmente y se mover\u00e1 a la secci\u00f3n de informaci\u00f3n suplementaria, renombr\u00e1ndose como \"Calidad microbiol\u00f3gica de productos no est\u00e9riles: criterios de aceptaci\u00f3n recomendados para preparaciones farmac\u00e9uticas\".\n\n3. **Pruebas de Esterilidad**:\n   - Se reemplazar\u00e1n los m\u00e9todos actuales de prueba de esterilidad para preparaciones no inyectables y para antibi\u00f3ticos con un m\u00e9todo armonizado internacionalmente.\n   - Se requerir\u00e1 asesoramiento adicional sobre las pruebas de antibi\u00f3ticos en la secci\u00f3n de informaci\u00f3n suplementaria.\n\n4. **Cl\u00e1usula de Justificaci\u00f3n y Autorizaci\u00f3n**:\n   - Se aclarar\u00e1 el significado de \"a menos que se prescriba, justifique y autorice de otra manera\", indicando que los requisitos deben cumplirse a menos que una autoridad relevante autorice una exenci\u00f3n o modificaci\u00f3n.\n\n5. **Pruebas de Endotoxinas Bacterianas**:\n   - Se propondr\u00e1n tres textos de m\u00e9todos para su inclusi\u00f3n en la Farmacopea Internacional, en contraste con el texto actual.\n\n6. **Revisi\u00f3n de Aplicabilidad**: Se revisar\u00e1 la aplicabilidad de los nuevos m\u00e9todos en los textos existentes de la Farmacopea Internacional, incluyendo excipientes y monograf\u00edas relevantes.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la regulaci\u00f3n y est\u00e1ndares en salud p\u00fablica.\n- **Farmacopea Internacional**: Compendio que establece est\u00e1ndares para la calidad de medicamentos y preparaciones farmac\u00e9uticas.\n- **M\u00e9todos de An\u00e1lisis**: Incluyen pruebas de enumeraci\u00f3n microbiana, pruebas de esterilidad y pruebas de endotoxinas bacterianas. \n\nEste resumen destaca los cambios propuestos y la importancia de la armonizaci\u00f3n en los est\u00e1ndares de calidad farmac\u00e9utica a nivel internacional.", "excerpt_keywords": "Keywords: uniformity of content, single-dose preparations, fixed-dose combinations, pharmacopoeial approach, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "39de5418-1783-4815-a065-de6f82340e7f", "node_type": "4", "metadata": {"page_label": "35", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.3.2 Uniformity of content single-dose preparations\n\nA review and explanation of the current pharmacopoeial approach as well as a review of application to published monographs for the general method \u201c5.1 Uniformity of content of single-dose preparations\u201d, was presented to the Expert Committee for consideration.\n\nThe Committee discussed the background document, endorsed the explanatory text as summarized below and adopted the proposed revisions of the relevant monographs. It further agreed that, as a basis for a future policy, this background document and explanatory text would be helpful to assist those involved in the development of new and revised monographs. In this respect, the document might also be made available more widely to provide explanatory information to users of *The International Pharmacopoeia* by its inclusion in the Supplementary information section of the pharmacopoeia.\n\n## Rationale of the review of method 5.1 and its application to tablets and capsules monographs\n\nAt its meeting in October 2010, the Committee discussed the application of uniformity of content testing to monographs in *The International Pharmacopoeia* especially those for tablets and capsules containing two or more APIs, commonly known as fixed-dose combinations (FDCs).\n\nQuestions had arisen with respect to the different testing thresholds applied in the WHO Guidelines for registration of fixed-dose combination medicinal products<sup>1</sup> and in the method of analysis 5.1 of *The International Pharmacopoeia*; the threshold in the WHO guidelines being 25 mg/25% whereas that applied in *The International Pharmacopoeia* was 5 mg/5% (see the agreed correction as regards this threshold under Method of analysis 5.1 Uniformity of content of single-dose preparations below).\n\nIn light of the discussion by the Committee, a review had been carried out of the test and of its application to all tablets and capsules that were the subject of an individual monograph in *The International Pharmacopoeia*, i.e. both those containing a single API and those that were FDCs.\n\nA review document was discussed at the informal consultation on specifications for medicines and quality control laboratory issues in July 2011. A revised version of this document, reflecting the points raised and the recommendations made during the consultation was presented to the Committee for further discussion.\n\n----\n\n<sup>1</sup> In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "b44e8840fe983330feefe68b24c77799d75d2d3210595fa3b677fb811ae5392f", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.3.2 Uniformity of content single-dose preparations\n\nA review and explanation of the current pharmacopoeial approach as well as a review of application to published monographs for the general method \u201c5.1 Uniformity of content of single-dose preparations\u201d, was presented to the Expert Committee for consideration.\n\nThe Committee discussed the background document, endorsed the explanatory text as summarized below and adopted the proposed revisions of the relevant monographs. It further agreed that, as a basis for a future policy, this background document and explanatory text would be helpful to assist those involved in the development of new and revised monographs. In this respect, the document might also be made available more widely to provide explanatory information to users of *The International Pharmacopoeia* by its inclusion in the Supplementary information section of the pharmacopoeia.\n\n## Rationale of the review of method 5.1 and its application to tablets and capsules monographs\n\nAt its meeting in October 2010, the Committee discussed the application of uniformity of content testing to monographs in *The International Pharmacopoeia* especially those for tablets and capsules containing two or more APIs, commonly known as fixed-dose combinations (FDCs).\n\nQuestions had arisen with respect to the different testing thresholds applied in the WHO Guidelines for registration of fixed-dose combination medicinal products<sup>1</sup> and in the method of analysis 5.1 of *The International Pharmacopoeia*; the threshold in the WHO guidelines being 25 mg/25% whereas that applied in *The International Pharmacopoeia* was 5 mg/5% (see the agreed correction as regards this threshold under Method of analysis 5.1 Uniformity of content of single-dose preparations below).\n\nIn light of the discussion by the Committee, a review had been carried out of the test and of its application to all tablets and capsules that were the subject of an individual monograph in *The International Pharmacopoeia*, i.e. both those containing a single API and those that were FDCs.\n\nA review document was discussed at the informal consultation on specifications for medicines and quality control laboratory issues in July 2011. A revised version of this document, reflecting the points raised and the recommendations made during the consultation was presented to the Committee for further discussion.\n\n----\n\n<sup>1</sup> In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2605, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "6bcf847d-af2d-4a5e-ba1a-a444efc8058f": {"__data__": {"id_": "6bcf847d-af2d-4a5e-ba1a-a444efc8058f", "embedding": null, "metadata": {"page_label": "36", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Method of Analysis\n\nWhile it had been confirmed by the Expert Committee in 2010 that the technical basis of test 5.1 should not be modified, it was, however, recommended at the informal consultation in July 2011 that the text of the method would benefit from editorial improvement. Notably, an important omission in the method was corrected by including a reference to 5 mg or less in the statement concerning the application threshold. The current text referred only to 5% or less and it was recognized that a threshold expressed in terms of the declared weight of API per tablet was more transparent with respect to individual monographs than one expressed in terms of the percentage of the tablet weight represented by the API. A threshold of 5 mg was actually already stated in the relevant specific monographs.\n\nThe Committee adopted and endorsed the edited text of method 5.1.\n\n## Application to Tablets and Capsules Monographs\n\nThe Committee adopted and endorsed the general approach of adding, where appropriate:\n\n- \u201cThe use of the average of the uniformity of content results as an option under Assay (Method B) while retaining the current Assay applicable to a mixed sample of 20 tablets/capsules as Method A.\u201d\n\nIt further agreed to the revision proposals for the following individual monographs for tablets and capsules containing either a single or several APIs; these revisions would be made in accordance with normal procedures:\n\n- **a single API**\n  - atropine (sulfate) tablets\n  - chlorphenamine hydrogen maleate tablets\n  - colchicine tablets\n  - dexamethasone tablets\n  - ergometrine hydrogen maleate tablets\n  - glyceryl trinitrate tablets\n  - levonorgestrel tablets\n  - prednisolone tablets\n\n- **two or more APIs (FDCs)**\n  - rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride tablets\n  - sulfadoxine and pyrimethamine tablets.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder espec\u00edficamente con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento se centra en las recomendaciones y decisiones tomadas por el Comit\u00e9 de Expertos de la OMS sobre las Especificaciones para Preparaciones Farmac\u00e9uticas. En particular, se discuten las mejoras editoriales en el m\u00e9todo de an\u00e1lisis 5.1, la inclusi\u00f3n de un umbral de 5 mg para la aplicaci\u00f3n de pruebas, y la adopci\u00f3n de un enfoque general para la uniformidad de contenido en tabletas y c\u00e1psulas. Adem\u00e1s, se enumeran las monograf\u00edas espec\u00edficas que ser\u00e1n revisadas, tanto para productos con un solo API como para combinaciones de m\u00faltiples APIs.\n\n### Preguntas\n1. **\u00bfCu\u00e1l fue la raz\u00f3n principal para modificar el texto del m\u00e9todo 5.1 en el an\u00e1lisis de tabletas y c\u00e1psulas?**\n   - La modificaci\u00f3n se realiz\u00f3 para corregir una omisi\u00f3n importante al incluir una referencia a un umbral de 5 mg o menos, lo que proporciona una mayor transparencia en comparaci\u00f3n con el umbral anterior expresado en t\u00e9rminos de porcentaje del peso de la tableta.\n\n2. **\u00bfQu\u00e9 enfoque general se adopt\u00f3 respecto a la uniformidad de contenido en los ensayos de tabletas y c\u00e1psulas?**\n   - Se adopt\u00f3 el enfoque de permitir el uso del promedio de los resultados de uniformidad de contenido como una opci\u00f3n bajo el Ensayo (M\u00e9todo B), mientras se mantiene el Ensayo actual aplicable a una muestra mixta de 20 tabletas/c\u00e1psulas como M\u00e9todo A.\n\n3. **\u00bfCu\u00e1les son algunos ejemplos de monograf\u00edas que se revisar\u00e1n seg\u00fan las decisiones del Comit\u00e9?**\n   - Se revisar\u00e1n monograf\u00edas para tabletas que contienen un solo API, como las tabletas de atropina (sulfato) y prednisolona, as\u00ed como combinaciones de m\u00faltiples APIs, como las tabletas de rifampicina, isoniazida, pirazinamida y etambutol hidrocloruro.", "prev_section_summary": "### Temas Clave\n\n1. **Uniformidad de Contenido**: Se revisa el enfoque farmacopoeial sobre la uniformidad de contenido en preparaciones de dosis \u00fanica, espec\u00edficamente en tabletas y c\u00e1psulas.\n\n2. **Combinaciones de Dosis Fijas (FDCs)**: Se discute la aplicaci\u00f3n de pruebas de uniformidad de contenido a monograf\u00edas que contienen dos o m\u00e1s principios activos.\n\n3. **Umbrales de Prueba**: Se identifican diferencias en los umbrales de prueba entre las directrices de la OMS (25 mg/25%) y la Farmacopea Internacional (5 mg/5%).\n\n4. **Revisi\u00f3n y Aprobaci\u00f3n**: El Comit\u00e9 de Expertos de la OMS aprob\u00f3 revisiones a las monograf\u00edas relevantes y consider\u00f3 \u00fatil el documento de fondo para el desarrollo de nuevas monograf\u00edas.\n\n5. **Consulta Informal**: Se llev\u00f3 a cabo una consulta informal en julio de 2011 sobre especificaciones para medicamentos y control de calidad, donde se discuti\u00f3 un documento de revisi\u00f3n.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de las directrices y recomendaciones discutidas.\n- **Farmacopea Internacional**: Referencia para los m\u00e9todos de an\u00e1lisis y monograf\u00edas de medicamentos.\n- **Comit\u00e9 de Expertos**: Grupo que revisa y aprueba las monograf\u00edas y m\u00e9todos de an\u00e1lisis.\n- **Preparaciones de Dosis \u00danica**: Tipo de medicamentos que se analizan en el contexto de uniformidad de contenido.\n- **Principios Activos (APIs)**: Sustancias que se analizan en las tabletas y c\u00e1psulas, tanto en monograf\u00edas individuales como en combinaciones.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, method of analysis, uniformity of content, monographs"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c7daf445-be7d-4aae-9b6c-3fa1e5d7d0e6", "node_type": "4", "metadata": {"page_label": "36", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Method of Analysis\n\nWhile it had been confirmed by the Expert Committee in 2010 that the technical basis of test 5.1 should not be modified, it was, however, recommended at the informal consultation in July 2011 that the text of the method would benefit from editorial improvement. Notably, an important omission in the method was corrected by including a reference to 5 mg or less in the statement concerning the application threshold. The current text referred only to 5% or less and it was recognized that a threshold expressed in terms of the declared weight of API per tablet was more transparent with respect to individual monographs than one expressed in terms of the percentage of the tablet weight represented by the API. A threshold of 5 mg was actually already stated in the relevant specific monographs.\n\nThe Committee adopted and endorsed the edited text of method 5.1.\n\n## Application to Tablets and Capsules Monographs\n\nThe Committee adopted and endorsed the general approach of adding, where appropriate:\n\n- \u201cThe use of the average of the uniformity of content results as an option under Assay (Method B) while retaining the current Assay applicable to a mixed sample of 20 tablets/capsules as Method A.\u201d\n\nIt further agreed to the revision proposals for the following individual monographs for tablets and capsules containing either a single or several APIs; these revisions would be made in accordance with normal procedures:\n\n- **a single API**\n  - atropine (sulfate) tablets\n  - chlorphenamine hydrogen maleate tablets\n  - colchicine tablets\n  - dexamethasone tablets\n  - ergometrine hydrogen maleate tablets\n  - glyceryl trinitrate tablets\n  - levonorgestrel tablets\n  - prednisolone tablets\n\n- **two or more APIs (FDCs)**\n  - rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride tablets\n  - sulfadoxine and pyrimethamine tablets.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "761368308aa4f1d1bc9ac7a8e62b5063a3a89deba7159449d1d6921c671627ff", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Method of Analysis\n\nWhile it had been confirmed by the Expert Committee in 2010 that the technical basis of test 5.1 should not be modified, it was, however, recommended at the informal consultation in July 2011 that the text of the method would benefit from editorial improvement. Notably, an important omission in the method was corrected by including a reference to 5 mg or less in the statement concerning the application threshold. The current text referred only to 5% or less and it was recognized that a threshold expressed in terms of the declared weight of API per tablet was more transparent with respect to individual monographs than one expressed in terms of the percentage of the tablet weight represented by the API. A threshold of 5 mg was actually already stated in the relevant specific monographs.\n\nThe Committee adopted and endorsed the edited text of method 5.1.\n\n## Application to Tablets and Capsules Monographs\n\nThe Committee adopted and endorsed the general approach of adding, where appropriate:\n\n- \u201cThe use of the average of the uniformity of content results as an option under Assay (Method B) while retaining the current Assay applicable to a mixed sample of 20 tablets/capsules as Method A.\u201d\n\nIt further agreed to the revision proposals for the following individual monographs for tablets and capsules containing either a single or several APIs; these revisions would be made in accordance with normal procedures:\n\n- **a single API**\n  - atropine (sulfate) tablets\n  - chlorphenamine hydrogen maleate tablets\n  - colchicine tablets\n  - dexamethasone tablets\n  - ergometrine hydrogen maleate tablets\n  - glyceryl trinitrate tablets\n  - levonorgestrel tablets\n  - prednisolone tablets\n\n- **two or more APIs (FDCs)**\n  - rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride tablets\n  - sulfadoxine and pyrimethamine tablets.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1939, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "05f678f1-ace1-4366-91c0-c958aadbc00f": {"__data__": {"id_": "05f678f1-ace1-4366-91c0-c958aadbc00f", "embedding": null, "metadata": {"page_label": "37", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations - Forty-sixth Report\n\n**Note:** It was noted that for the monograph on levonorgestrel tablets and that for sulfadoxine and pyrimethamine tablets adopted in October 2010, this approach had already been implemented and endorsed during the finalization of the monographs, prior to their publication on the WHO Medicines web site.\n\n## Related WHO Quality Assurance Guidelines\n\nAs noted during the review, an important issue was the existence of different thresholds applied in the WHO guidelines on FDCs and in *The International Pharmacopoeia*. After careful consideration of the possible options, the Expert Committee recommended that the WHO guidelines on FDCs, or any other WHO guidelines concerned, should be revised to bring them into line with *The International Pharmacopoeia*.\n\nThe Committee, therefore, endorsed the need for revising the following WHO guidelines referring to uniformity of content as a quality control test for finished pharmaceutical products:\n\n- **WHO Guidelines for registration of fixed-dose combination medicinal products**\n- **WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part.**\n\n### 3.3.3 General Monograph on Tablets\n\nThe general monograph on tablets was adopted by the Expert Committee in 2009 but was not included in the second supplement of *The International Pharmacopoeia* owing to the absence of some texts to be included in the Supplementary information.\n\nFollowing comments from the WHO Department of Neglected Tropical Diseases (NTD) and from assessors from the WHO Prequalification of Medicines Programme, changes to the general monograph on tablets were proposed. A survey on solid oral forms of albendazole, azithromycin, mebendazole, diethylcarbamazine, ivermectin and praziquantel, which was conducted in six WHO Member States showed that 41 samples out of 72 did not conform with *United States Pharmacopoeia* requirements for dissolution. In the majority of the cases of non-conformity the product was in chewable tablet form. The fact that such a high proportion of samples failed to meet dissolution rate requirements raised concerns about the efficacy of these NTD medicines.\n\nThe Expert Committee considered this issue and discussed possibilities for reviewing the existing monograph with a view to making appropriate changes. Several small changes to the document were made and it was agreed to include references in the monograph to the relevant sections of the Supplementary information. With regard to the monograph\u2019s definition of chewable tablets, it...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de Nivel Superior del Contexto\n\nEl documento es el informe de la 46\u00aa reuni\u00f3n del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Se discuten las directrices de calidad de la OMS, especialmente en relaci\u00f3n con las combinaciones de dosis fijas (FDC) y la monograf\u00eda general sobre tabletas. Se menciona la necesidad de alinear las directrices de la OMS con *The International Pharmacopoeia* y se abordan preocupaciones sobre la eficacia de ciertos medicamentos para enfermedades tropicales desatendidas, basadas en un estudio que mostr\u00f3 que una alta proporci\u00f3n de muestras de tabletas masticables no cumpl\u00eda con los requisitos de disoluci\u00f3n establecidos por la Farmacopea de los Estados Unidos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 cambios se propusieron para la monograf\u00eda general sobre tabletas y por qu\u00e9?**\n   - Se propusieron cambios a la monograf\u00eda general sobre tabletas debido a comentarios de la OMS sobre Enfermedades Tropicales Desatendidas y a los resultados de un estudio que mostr\u00f3 que 41 de 72 muestras de tabletas s\u00f3lidas no cumpl\u00edan con los requisitos de disoluci\u00f3n de la Farmacopea de los Estados Unidos, lo que gener\u00f3 preocupaciones sobre la eficacia de estos medicamentos.\n\n2. **\u00bfCu\u00e1les son las directrices de la OMS que se recomendaron para ser revisadas en relaci\u00f3n con la uniformidad de contenido?**\n   - Se recomend\u00f3 revisar las siguientes directrices de la OMS: las **Directrices para el registro de productos medicinales de combinaci\u00f3n de dosis fijas** y las **Directrices sobre la presentaci\u00f3n de documentaci\u00f3n para un producto farmac\u00e9utico terminado de m\u00faltiples fuentes (gen\u00e9rico): parte de calidad**.\n\n3. **\u00bfQu\u00e9 porcentaje de muestras de tabletas masticables no cumpli\u00f3 con los requisitos de disoluci\u00f3n y qu\u00e9 implicaciones tiene esto?**\n   - El 57% de las muestras (41 de 72) de tabletas s\u00f3lidas no cumpli\u00f3 con los requisitos de disoluci\u00f3n de la Farmacopea de los Estados Unidos, lo que plantea serias preocupaciones sobre la eficacia de los medicamentos utilizados para tratar enfermedades tropicales desatendidas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Revisi\u00f3n del M\u00e9todo de An\u00e1lisis 5.1:** Se realizaron mejoras editoriales en el m\u00e9todo de an\u00e1lisis 5.1, incluyendo la correcci\u00f3n de una omisi\u00f3n importante al establecer un umbral de 5 mg o menos para la aplicaci\u00f3n de pruebas, en lugar de solo referirse a un porcentaje del peso de la tableta.\n   \n2. **Uniformidad de Contenido en Tabletas y C\u00e1psulas:** Se adopt\u00f3 un enfoque que permite el uso del promedio de los resultados de uniformidad de contenido como opci\u00f3n bajo el Ensayo (M\u00e9todo B), manteniendo el Ensayo actual para una muestra mixta de 20 tabletas/c\u00e1psulas como M\u00e9todo A.\n\n3. **Revisiones de Monograf\u00edas:** Se acordaron revisiones para varias monograf\u00edas de tabletas y c\u00e1psulas, tanto para aquellas que contienen un solo API como para combinaciones de m\u00faltiples APIs.\n\n**Entidades:**\n- **Comit\u00e9 de Expertos de la OMS:** Organismo responsable de las recomendaciones sobre especificaciones para preparaciones farmac\u00e9uticas.\n- **M\u00e9todo de An\u00e1lisis 5.1:** M\u00e9todo espec\u00edfico que fue objeto de revisi\u00f3n y mejora.\n- **API (Ingrediente Activo):** Sustancia activa en las tabletas y c\u00e1psulas que se menciona en las monograf\u00edas.\n- **Monograf\u00edas Espec\u00edficas:** Documentos que describen las especificaciones de productos farmac\u00e9uticos, incluyendo:\n  - **Monograf\u00edas de un solo API:** Ejemplos incluyen tabletas de atropina (sulfato), prednisolona, y dexametasona.\n  - **Monograf\u00edas de m\u00faltiples APIs (FDCs):** Ejemplos incluyen tabletas de rifampicina, isoniazida, pirazinamida y etambutol hidrocloruro, as\u00ed como tabletas de sulfadoxina y pirimetamina. \n\nEste resumen destaca los cambios en los m\u00e9todos de an\u00e1lisis y las revisiones de las monograf\u00edas, reflejando el enfoque del Comit\u00e9 de Expertos de la OMS en mejorar la transparencia y la precisi\u00f3n en las especificaciones farmac\u00e9uticas.", "excerpt_keywords": "WHO, pharmaceutical preparations, fixed-dose combinations, quality assurance, dissolution requirements"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bbc13e56-caf7-45c2-8fcd-d094d562260b", "node_type": "4", "metadata": {"page_label": "37", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations - Forty-sixth Report\n\n**Note:** It was noted that for the monograph on levonorgestrel tablets and that for sulfadoxine and pyrimethamine tablets adopted in October 2010, this approach had already been implemented and endorsed during the finalization of the monographs, prior to their publication on the WHO Medicines web site.\n\n## Related WHO Quality Assurance Guidelines\n\nAs noted during the review, an important issue was the existence of different thresholds applied in the WHO guidelines on FDCs and in *The International Pharmacopoeia*. After careful consideration of the possible options, the Expert Committee recommended that the WHO guidelines on FDCs, or any other WHO guidelines concerned, should be revised to bring them into line with *The International Pharmacopoeia*.\n\nThe Committee, therefore, endorsed the need for revising the following WHO guidelines referring to uniformity of content as a quality control test for finished pharmaceutical products:\n\n- **WHO Guidelines for registration of fixed-dose combination medicinal products**\n- **WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part.**\n\n### 3.3.3 General Monograph on Tablets\n\nThe general monograph on tablets was adopted by the Expert Committee in 2009 but was not included in the second supplement of *The International Pharmacopoeia* owing to the absence of some texts to be included in the Supplementary information.\n\nFollowing comments from the WHO Department of Neglected Tropical Diseases (NTD) and from assessors from the WHO Prequalification of Medicines Programme, changes to the general monograph on tablets were proposed. A survey on solid oral forms of albendazole, azithromycin, mebendazole, diethylcarbamazine, ivermectin and praziquantel, which was conducted in six WHO Member States showed that 41 samples out of 72 did not conform with *United States Pharmacopoeia* requirements for dissolution. In the majority of the cases of non-conformity the product was in chewable tablet form. The fact that such a high proportion of samples failed to meet dissolution rate requirements raised concerns about the efficacy of these NTD medicines.\n\nThe Expert Committee considered this issue and discussed possibilities for reviewing the existing monograph with a view to making appropriate changes. Several small changes to the document were made and it was agreed to include references in the monograph to the relevant sections of the Supplementary information. With regard to the monograph\u2019s definition of chewable tablets, it...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "b04ab4f0c6b65a9247b8bf6cb2db51cf48a1d7ae2e60fd2523fecc04524f8836", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations - Forty-sixth Report\n\n**Note:** It was noted that for the monograph on levonorgestrel tablets and that for sulfadoxine and pyrimethamine tablets adopted in October 2010, this approach had already been implemented and endorsed during the finalization of the monographs, prior to their publication on the WHO Medicines web site.\n\n## Related WHO Quality Assurance Guidelines\n\nAs noted during the review, an important issue was the existence of different thresholds applied in the WHO guidelines on FDCs and in *The International Pharmacopoeia*. After careful consideration of the possible options, the Expert Committee recommended that the WHO guidelines on FDCs, or any other WHO guidelines concerned, should be revised to bring them into line with *The International Pharmacopoeia*.\n\nThe Committee, therefore, endorsed the need for revising the following WHO guidelines referring to uniformity of content as a quality control test for finished pharmaceutical products:\n\n- **WHO Guidelines for registration of fixed-dose combination medicinal products**\n- **WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part.**\n\n### 3.3.3 General Monograph on Tablets\n\nThe general monograph on tablets was adopted by the Expert Committee in 2009 but was not included in the second supplement of *The International Pharmacopoeia* owing to the absence of some texts to be included in the Supplementary information.\n\nFollowing comments from the WHO Department of Neglected Tropical Diseases (NTD) and from assessors from the WHO Prequalification of Medicines Programme, changes to the general monograph on tablets were proposed. A survey on solid oral forms of albendazole, azithromycin, mebendazole, diethylcarbamazine, ivermectin and praziquantel, which was conducted in six WHO Member States showed that 41 samples out of 72 did not conform with *United States Pharmacopoeia* requirements for dissolution. In the majority of the cases of non-conformity the product was in chewable tablet form. The fact that such a high proportion of samples failed to meet dissolution rate requirements raised concerns about the efficacy of these NTD medicines.\n\nThe Expert Committee considered this issue and discussed possibilities for reviewing the existing monograph with a view to making appropriate changes. Several small changes to the document were made and it was agreed to include references in the monograph to the relevant sections of the Supplementary information. With regard to the monograph\u2019s definition of chewable tablets, it...", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2654, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "9d4c1dfc-36af-4032-8d5f-97068360188d": {"__data__": {"id_": "9d4c1dfc-36af-4032-8d5f-97068360188d", "embedding": null, "metadata": {"page_label": "38", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Preface, General Notices and Supplementary Information Sections of *The International Pharmacopoeia*\n\n## Supplementary Information Section\n\nIt was appreciated that the reason for including the Supplementary information section in *The International Pharmacopoeia* was to inform and guide users so as to facilitate the proper use and interpretation of the specifications. It was considered important that users could easily find the relevant guidance. It was agreed that, as this section of *The International Pharmacopoeia* was expanding (for example, guidance on Polymorphism and identity tests had been approved in October 2009), it would be advisable to provide a more structured approach to the contents.\n\nIt was recommended that the present texts, together with others agreed or proposed for inclusion under Supplementary information, be presented in a structured format with related texts being grouped together. Adoption of a numbering system similar to that used for Methods of analysis would provide a flexible structure that could accommodate new texts being added to the appropriate section. It was agreed that the structured format preliminarily discussed and presented to the Expert Committee was suitable and it was recommended that it be adopted for the next publication.\n\nIt was noted that the document included both existing texts and a number of suggestions as to possible future components of the different subsections of a restructured Supplementary information section. Existing texts could be incorporated into the structured format from the start and new components added as and when they were approved.\n\nIt was recognized that providing guidance on certain aspects of pharmacopoeial control, such as impurity control and dissolution testing, would be very helpful to users of *The International Pharmacopoeia*, especially in the context of the Prequalification Programme. It was also recognized that providing details of certain test methods used during pharmaceutical development and manufacture of dosage forms was necessary to support the revised general monograph for Tablets.\n\nIt was agreed that Supplementary information for those policy topics considered appropriate should be developed in a similar manner to that for the text.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl contexto se centra en la secci\u00f3n de Informaci\u00f3n Suplementaria de *The International Pharmacopoeia*, destacando la importancia de estructurar esta secci\u00f3n para facilitar la b\u00fasqueda y comprensi\u00f3n de las especificaciones. Se menciona la necesidad de agrupar textos relacionados y adoptar un sistema de numeraci\u00f3n similar al de los M\u00e9todos de an\u00e1lisis. Tambi\u00e9n se reconoce la utilidad de proporcionar orientaci\u00f3n sobre el control de impurezas y pruebas de disoluci\u00f3n, as\u00ed como detalles sobre m\u00e9todos de prueba utilizados en el desarrollo y fabricaci\u00f3n de formas de dosificaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1l es el prop\u00f3sito principal de incluir la secci\u00f3n de Informaci\u00f3n Suplementaria en *The International Pharmacopoeia*?**\n   - Respuesta: El prop\u00f3sito principal es informar y guiar a los usuarios para facilitar el uso y la interpretaci\u00f3n adecuada de las especificaciones.\n\n2. **\u00bfQu\u00e9 se recomend\u00f3 para mejorar la estructura de la secci\u00f3n de Informaci\u00f3n Suplementaria?**\n   - Respuesta: Se recomend\u00f3 presentar los textos en un formato estructurado, agrupando textos relacionados y adoptando un sistema de numeraci\u00f3n similar al de los M\u00e9todos de an\u00e1lisis para acomodar nuevos textos.\n\n3. **\u00bfQu\u00e9 aspectos espec\u00edficos del control farmacopoeico se consideraron \u00fatiles para los usuarios en el contexto del Programa de Precalificaci\u00f3n?**\n   - Respuesta: Se consider\u00f3 \u00fatil proporcionar orientaci\u00f3n sobre el control de impurezas y las pruebas de disoluci\u00f3n, as\u00ed como detalles sobre m\u00e9todos de prueba utilizados en el desarrollo y fabricaci\u00f3n de formas de dosificaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: Se trata de la 46\u00aa reuni\u00f3n del Comit\u00e9 de Expertos sobre Especificaciones para Preparaciones Farmac\u00e9uticas de la OMS.\n\n2. **Directrices de Calidad de la OMS**: Se discuten las directrices relacionadas con las combinaciones de dosis fijas (FDC) y la necesidad de alinearlas con *The International Pharmacopoeia*.\n\n3. **Revisi\u00f3n de Directrices**: Se recomienda la revisi\u00f3n de las siguientes directrices de la OMS:\n   - **Directrices para el registro de productos medicinales de combinaci\u00f3n de dosis fijas**.\n   - **Directrices sobre la presentaci\u00f3n de documentaci\u00f3n para un producto farmac\u00e9utico terminado de m\u00faltiples fuentes (gen\u00e9rico): parte de calidad**.\n\n4. **Monograf\u00eda General sobre Tabletas**: Adoptada en 2009, pero no incluida en el segundo suplemento de *The International Pharmacopoeia* debido a la falta de textos necesarios. Se proponen cambios tras comentarios de la OMS sobre Enfermedades Tropicales Desatendidas.\n\n5. **Estudio de Conformidad**: Un estudio realizado en seis Estados Miembros de la OMS revel\u00f3 que el 57% de las muestras de tabletas s\u00f3lidas (41 de 72) no cumpl\u00edan con los requisitos de disoluci\u00f3n de la Farmacopea de los Estados Unidos, lo que plantea preocupaciones sobre la eficacia de los medicamentos para enfermedades tropicales desatendidas.\n\n6. **Preocupaciones sobre Eficacia**: La alta tasa de no conformidad en las tabletas masticables genera inquietudes sobre la eficacia de los medicamentos utilizados para tratar enfermedades tropicales desatendidas.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organizaci\u00f3n responsable de la salud p\u00fablica internacional.\n- **FDC (Combinaciones de Dosis Fijas)**: Medicamentos que combinan dos o m\u00e1s principios activos en una sola forma de dosificaci\u00f3n.\n- **Farmacopea de los Estados Unidos**: Est\u00e1ndar de calidad para medicamentos en los Estados Unidos.\n- **Enfermedades Tropicales Desatendidas (NTD)**: Grupo de enfermedades que afectan a las poblaciones m\u00e1s vulnerables y que a menudo reciben poca atenci\u00f3n.", "excerpt_keywords": "Keywords: International Pharmacopoeia, Supplementary Information, pharmacopoeial control, impurity control, dissolution testing"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "08574bc6-2f93-456f-9dbd-0f63453993a1", "node_type": "4", "metadata": {"page_label": "38", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Preface, General Notices and Supplementary Information Sections of *The International Pharmacopoeia*\n\n## Supplementary Information Section\n\nIt was appreciated that the reason for including the Supplementary information section in *The International Pharmacopoeia* was to inform and guide users so as to facilitate the proper use and interpretation of the specifications. It was considered important that users could easily find the relevant guidance. It was agreed that, as this section of *The International Pharmacopoeia* was expanding (for example, guidance on Polymorphism and identity tests had been approved in October 2009), it would be advisable to provide a more structured approach to the contents.\n\nIt was recommended that the present texts, together with others agreed or proposed for inclusion under Supplementary information, be presented in a structured format with related texts being grouped together. Adoption of a numbering system similar to that used for Methods of analysis would provide a flexible structure that could accommodate new texts being added to the appropriate section. It was agreed that the structured format preliminarily discussed and presented to the Expert Committee was suitable and it was recommended that it be adopted for the next publication.\n\nIt was noted that the document included both existing texts and a number of suggestions as to possible future components of the different subsections of a restructured Supplementary information section. Existing texts could be incorporated into the structured format from the start and new components added as and when they were approved.\n\nIt was recognized that providing guidance on certain aspects of pharmacopoeial control, such as impurity control and dissolution testing, would be very helpful to users of *The International Pharmacopoeia*, especially in the context of the Prequalification Programme. It was also recognized that providing details of certain test methods used during pharmaceutical development and manufacture of dosage forms was necessary to support the revised general monograph for Tablets.\n\nIt was agreed that Supplementary information for those policy topics considered appropriate should be developed in a similar manner to that for the text.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "185ccd16947c22541e540e5b84192ef857968649f70cbb1d5ec1f6f7b438b009", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Preface, General Notices and Supplementary Information Sections of *The International Pharmacopoeia*\n\n## Supplementary Information Section\n\nIt was appreciated that the reason for including the Supplementary information section in *The International Pharmacopoeia* was to inform and guide users so as to facilitate the proper use and interpretation of the specifications. It was considered important that users could easily find the relevant guidance. It was agreed that, as this section of *The International Pharmacopoeia* was expanding (for example, guidance on Polymorphism and identity tests had been approved in October 2009), it would be advisable to provide a more structured approach to the contents.\n\nIt was recommended that the present texts, together with others agreed or proposed for inclusion under Supplementary information, be presented in a structured format with related texts being grouped together. Adoption of a numbering system similar to that used for Methods of analysis would provide a flexible structure that could accommodate new texts being added to the appropriate section. It was agreed that the structured format preliminarily discussed and presented to the Expert Committee was suitable and it was recommended that it be adopted for the next publication.\n\nIt was noted that the document included both existing texts and a number of suggestions as to possible future components of the different subsections of a restructured Supplementary information section. Existing texts could be incorporated into the structured format from the start and new components added as and when they were approved.\n\nIt was recognized that providing guidance on certain aspects of pharmacopoeial control, such as impurity control and dissolution testing, would be very helpful to users of *The International Pharmacopoeia*, especially in the context of the Prequalification Programme. It was also recognized that providing details of certain test methods used during pharmaceutical development and manufacture of dosage forms was necessary to support the revised general monograph for Tablets.\n\nIt was agreed that Supplementary information for those policy topics considered appropriate should be developed in a similar manner to that for the text.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2261, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "01e7a72b-f8b0-437a-a2c4-388fe92d62df": {"__data__": {"id_": "01e7a72b-f8b0-437a-a2c4-388fe92d62df", "embedding": null, "metadata": {"page_label": "39", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\non Polymorphism and identity tests adopted in 2009. Whenever a specific draft text was prepared, it would be circulated for comment to members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations, notably those involved in monograph development, discussed at an informal consultation and presented to the Expert Committee. It was noted that some supplementary information on monograph development could be compiled from material already available, notably on the WHO Medicines website and/or in reports of the Expert Committee.\n\nThe Expert Committee endorsed the recommendations and encouraged the secretariat to further develop relevant texts for consideration.\n\n## 4. Quality control \u2013 International Reference Materials (International Chemical Reference Substances and Infrared Reference Spectra)\n\n### 4.1 Update on International Chemical Reference Substances\n\nInternational Chemical Reference Substances (ICRS) are reference substances for use as primary standards in physical and chemical tests described in *The International Pharmacopoeia*. The standards are suitable for their intended use and officially adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations. In April 2010 the European Directorate for the Quality of Medicines and HealthCare (EDQM) of the Council of Europe, Strasbourg, France, took over the responsibility for the establishment, preparation, storage and distribution of WHO ICRS from Apoteket AB, previously the WHO Collaborating Centre for Chemical Reference Substances.\n\nSince the meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2010 the secretariat had invited national control laboratories to participate in collaborative studies to characterize ICRS. The invitation had received a positive response. In addition, the secretariat had established a database with information on all reference substances described in *The International Pharmacopoeia*. Furthermore, a document on frequently asked questions about collaborative trials to characterize ICRS had been prepared and circulated for comments.\n\nThe Expert Committee noted the report.\n\n#### 4.1.1 Report on activities of the host organization related to International Chemical Reference Substances\n\nThe Expert Committee received a report from EDQM on progress with regard to the ICRS. A new ICRS, alpha-artemether, would be established in October 2011, and the establishment of beclometasone dipropionate, replacement", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las actividades del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, con un enfoque en la adopci\u00f3n de pruebas de polimorfismo e identidad en 2009. Se menciona la importancia de los Sustancias de Referencia Qu\u00edmica Internacional (ICRS) como est\u00e1ndares primarios en pruebas f\u00edsicas y qu\u00edmicas, y se detalla la transici\u00f3n de la responsabilidad de la preparaci\u00f3n y distribuci\u00f3n de estos est\u00e1ndares al EDQM en 2010. Adem\u00e1s, se destaca la colaboraci\u00f3n con laboratorios de control nacionales para caracterizar los ICRS y la creaci\u00f3n de una base de datos sobre estas sustancias.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1l es el papel del EDQM en la gesti\u00f3n de los ICRS desde 2010?**\n   - El EDQM asumi\u00f3 la responsabilidad de la establecimiento, preparaci\u00f3n, almacenamiento y distribuci\u00f3n de los ICRS de la OMS, que anteriormente estaba a cargo de Apoteket AB.\n\n2. **\u00bfQu\u00e9 tipo de estudios se han invitado a participar a los laboratorios de control nacionales en relaci\u00f3n con los ICRS?**\n   - Se invit\u00f3 a los laboratorios de control nacionales a participar en estudios colaborativos para caracterizar los ICRS, lo cual recibi\u00f3 una respuesta positiva.\n\n3. **\u00bfQu\u00e9 nuevo ICRS se establecer\u00e1 en octubre de 2011 y qu\u00e9 otro ICRS se menciona en el contexto?**\n   - Se establecer\u00e1 un nuevo ICRS, alpha-artemether, en octubre de 2011, y se menciona la creaci\u00f3n de beclometasone dipropionate como un ICRS en desarrollo.\n\n### Resumen de Nivel Superior\n\nEl Comit\u00e9 de Expertos de la OMS se encarga de establecer y revisar est\u00e1ndares para preparaciones farmac\u00e9uticas, incluyendo pruebas de polimorfismo e identidad. Desde 2010, el EDQM gestiona los ICRS, colaborando con laboratorios nacionales para su caracterizaci\u00f3n y manteniendo una base de datos sobre estos est\u00e1ndares. Se est\u00e1n desarrollando nuevos ICRS para mejorar la calidad y la precisi\u00f3n en las pruebas farmac\u00e9uticas.", "prev_section_summary": "### Temas Clave\n\n1. **Prop\u00f3sito de la Informaci\u00f3n Suplementaria**: La secci\u00f3n de Informaci\u00f3n Suplementaria en *The International Pharmacopoeia* tiene como objetivo informar y guiar a los usuarios para facilitar la correcta utilizaci\u00f3n e interpretaci\u00f3n de las especificaciones.\n\n2. **Estructuraci\u00f3n de Contenidos**: Se recomienda adoptar un enfoque m\u00e1s estructurado para la secci\u00f3n, agrupando textos relacionados y utilizando un sistema de numeraci\u00f3n similar al de los M\u00e9todos de an\u00e1lisis, lo que permitir\u00eda una mejor organizaci\u00f3n y la incorporaci\u00f3n de nuevos textos.\n\n3. **Expansi\u00f3n de la Secci\u00f3n**: La secci\u00f3n est\u00e1 en expansi\u00f3n, con la inclusi\u00f3n de nuevos temas como la polimorf\u00eda y pruebas de identidad, lo que subraya la necesidad de un formato que pueda adaptarse a futuros contenidos.\n\n4. **Orientaci\u00f3n sobre Control Farmac\u00e9utico**: Se destaca la importancia de proporcionar orientaci\u00f3n sobre el control de impurezas y pruebas de disoluci\u00f3n, as\u00ed como detalles sobre m\u00e9todos de prueba utilizados en el desarrollo y fabricaci\u00f3n de formas de dosificaci\u00f3n, especialmente en el contexto del Programa de Precalificaci\u00f3n.\n\n5. **Desarrollo de Informaci\u00f3n Suplementaria**: Se acuerda que la informaci\u00f3n suplementaria sobre temas de pol\u00edtica debe desarrollarse de manera similar a la del texto principal.\n\n### Entidades\n\n- ***The International Pharmacopoeia***: Documento que contiene especificaciones y gu\u00edas para el uso de productos farmac\u00e9uticos.\n- **Secci\u00f3n de Informaci\u00f3n Suplementaria**: Parte del documento dedicada a proporcionar orientaci\u00f3n adicional a los usuarios.\n- **M\u00e9todos de an\u00e1lisis**: Sistema de numeraci\u00f3n y organizaci\u00f3n que se propone adoptar para la secci\u00f3n de Informaci\u00f3n Suplementaria.\n- **Programa de Precalificaci\u00f3n**: Iniciativa que busca asegurar la calidad de los productos farmac\u00e9uticos en el contexto de la salud p\u00fablica.\n- **Polimorfismo y pruebas de identidad**: Ejemplos de temas que se han incluido en la secci\u00f3n de Informaci\u00f3n Suplementaria. \n\nEste resumen destaca la importancia de la estructura y la orientaci\u00f3n en el uso de *The International Pharmacopoeia*, as\u00ed como la necesidad de adaptarse a las nuevas demandas y temas relevantes en el campo farmac\u00e9utico.", "excerpt_keywords": "WHO, International Chemical Reference Substances, quality control, pharmacopoeia, EDQM"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cfb0675c-ea9a-4ecf-9cb6-0c956ce60dcb", "node_type": "4", "metadata": {"page_label": "39", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\non Polymorphism and identity tests adopted in 2009. Whenever a specific draft text was prepared, it would be circulated for comment to members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations, notably those involved in monograph development, discussed at an informal consultation and presented to the Expert Committee. It was noted that some supplementary information on monograph development could be compiled from material already available, notably on the WHO Medicines website and/or in reports of the Expert Committee.\n\nThe Expert Committee endorsed the recommendations and encouraged the secretariat to further develop relevant texts for consideration.\n\n## 4. Quality control \u2013 International Reference Materials (International Chemical Reference Substances and Infrared Reference Spectra)\n\n### 4.1 Update on International Chemical Reference Substances\n\nInternational Chemical Reference Substances (ICRS) are reference substances for use as primary standards in physical and chemical tests described in *The International Pharmacopoeia*. The standards are suitable for their intended use and officially adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations. In April 2010 the European Directorate for the Quality of Medicines and HealthCare (EDQM) of the Council of Europe, Strasbourg, France, took over the responsibility for the establishment, preparation, storage and distribution of WHO ICRS from Apoteket AB, previously the WHO Collaborating Centre for Chemical Reference Substances.\n\nSince the meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2010 the secretariat had invited national control laboratories to participate in collaborative studies to characterize ICRS. The invitation had received a positive response. In addition, the secretariat had established a database with information on all reference substances described in *The International Pharmacopoeia*. Furthermore, a document on frequently asked questions about collaborative trials to characterize ICRS had been prepared and circulated for comments.\n\nThe Expert Committee noted the report.\n\n#### 4.1.1 Report on activities of the host organization related to International Chemical Reference Substances\n\nThe Expert Committee received a report from EDQM on progress with regard to the ICRS. A new ICRS, alpha-artemether, would be established in October 2011, and the establishment of beclometasone dipropionate, replacement", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "58f4f04430a38d43442d9c114bf7930190d0cb5e4c8fc41aecc43b1457fff6a1", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\non Polymorphism and identity tests adopted in 2009. Whenever a specific draft text was prepared, it would be circulated for comment to members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations, notably those involved in monograph development, discussed at an informal consultation and presented to the Expert Committee. It was noted that some supplementary information on monograph development could be compiled from material already available, notably on the WHO Medicines website and/or in reports of the Expert Committee.\n\nThe Expert Committee endorsed the recommendations and encouraged the secretariat to further develop relevant texts for consideration.\n\n## 4. Quality control \u2013 International Reference Materials (International Chemical Reference Substances and Infrared Reference Spectra)\n\n### 4.1 Update on International Chemical Reference Substances\n\nInternational Chemical Reference Substances (ICRS) are reference substances for use as primary standards in physical and chemical tests described in *The International Pharmacopoeia*. The standards are suitable for their intended use and officially adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations. In April 2010 the European Directorate for the Quality of Medicines and HealthCare (EDQM) of the Council of Europe, Strasbourg, France, took over the responsibility for the establishment, preparation, storage and distribution of WHO ICRS from Apoteket AB, previously the WHO Collaborating Centre for Chemical Reference Substances.\n\nSince the meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2010 the secretariat had invited national control laboratories to participate in collaborative studies to characterize ICRS. The invitation had received a positive response. In addition, the secretariat had established a database with information on all reference substances described in *The International Pharmacopoeia*. Furthermore, a document on frequently asked questions about collaborative trials to characterize ICRS had been prepared and circulated for comments.\n\nThe Expert Committee noted the report.\n\n#### 4.1.1 Report on activities of the host organization related to International Chemical Reference Substances\n\nThe Expert Committee received a report from EDQM on progress with regard to the ICRS. A new ICRS, alpha-artemether, would be established in October 2011, and the establishment of beclometasone dipropionate, replacement", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2603, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "e5768383-922d-40a6-8c02-906d1be338b6": {"__data__": {"id_": "e5768383-922d-40a6-8c02-906d1be338b6", "embedding": null, "metadata": {"page_label": "40", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nbatch, was under way. The internal study for a further ICRS, azobenzene, replacement batch, had been completed and a collaborative study was due to begin in October 2011.\n\nWhile not within the scope of the WHO\u2013EDQM cooperation agreement, the EDQM laboratory had exceptionally performed a study to support the development of *The International Pharmacopoeia* monograph for artemisinin. The study subjects were the correction/response factor artemisinin and the verification of a liquid chromatography (LC) method.\n\nIt was reported that the ICRS database included 215 ICRS. They had been ranked according to their demand and this ranking was being used to assign priority in monitoring. A monitoring programme had been established and was currently monitoring 23 ICRS. Of the 15 monitored to date, no deficiencies had been detected. In terms of quality control, eight batches have been subjected to quality control for identification.\n\nThe Expert Committee noted the report.\n\n## 4.1.2 Frequently asked questions about collaborative trials\n\nReference standards to be used for assay determinations are examined in collaborative trials. The results obtained are used to assign a content or other analytical values to the standards. WHO had invited national quality control laboratories to join in trials to characterize ICRS, and a document that had been prepared to inform candidates about these studies was presented to the Expert Committee for information.\n\nThe overall goal of this project was to establish a worldwide distribution of ICRS to assist low- and middle-income countries to test for the quality of essential medicines described in *The International Pharmacopoeia* and used, for example, in the treatment of HIV/AIDS, tuberculosis and malaria. The Expert Committee noted the document.\n\n## 4.1.3 Annual report on International Chemical Reference Substances 2010\n\nBased on an umbrella agreement signed between WHO and EDQM in March 2010, and after having received the physical stock of existing ICRS from Apoteket, EDQM restarted the distribution of ICRS in May 2010.\n\nCoordination meetings between WHO and EDQM took place in April and September 2010 to agree upon the details of the ICRS establishment workflow and to prioritize the work for the establishment of new ICRS.\n\nIn 2010 the total number of ICRS distributed by EDQM was 957. The five most frequently requested substances were, in order of demand: artesunate, vanillin, arteminol, artemether and lumefantrine.\n\nThe Expert Committee noted the report and thanked EDQM for its contribution and work in support of WHO Member States.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las actividades del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, destacando el trabajo relacionado con las Sustancias de Referencia Qu\u00edmica Internacional (ICRS). Se menciona la colaboraci\u00f3n entre la OMS y el EDQM, la distribuci\u00f3n de ICRS, y la importancia de estas sustancias para garantizar la calidad de medicamentos esenciales en pa\u00edses de ingresos bajos y medios. Tambi\u00e9n se discuten los ensayos colaborativos para caracterizar ICRS y se presenta un informe anual sobre la distribuci\u00f3n de estas sustancias.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1l fue el objetivo principal del proyecto mencionado en el contexto sobre la distribuci\u00f3n de ICRS?**\n   - El objetivo principal del proyecto fue establecer una distribuci\u00f3n mundial de ICRS para ayudar a los pa\u00edses de ingresos bajos y medios a evaluar la calidad de los medicamentos esenciales descritos en *The International Pharmacopoeia*, utilizados en el tratamiento de enfermedades como el VIH/SIDA, la tuberculosis y la malaria.\n\n2. **\u00bfCu\u00e1ntas ICRS fueron distribuidas por el EDQM en 2010 y cu\u00e1les fueron las cinco sustancias m\u00e1s solicitadas?**\n   - En 2010, el EDQM distribuy\u00f3 un total de 957 ICRS. Las cinco sustancias m\u00e1s solicitadas, en orden de demanda, fueron: artesunate, vanillin, arteminol, artemether y lumefantrine.\n\n3. **\u00bfQu\u00e9 se inform\u00f3 sobre el estado de las ICRS monitoreadas hasta la fecha del informe?**\n   - Se inform\u00f3 que de las 15 ICRS monitoreadas hasta la fecha, no se hab\u00edan detectado deficiencias. Adem\u00e1s, se hab\u00eda establecido un programa de monitoreo que actualmente supervisa 23 ICRS, y ocho lotes hab\u00edan sido sometidos a control de calidad para identificaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: Se encarga de establecer y revisar est\u00e1ndares para preparaciones farmac\u00e9uticas, incluyendo pruebas de polimorfismo e identidad adoptadas en 2009.\n\n2. **Sustancias de Referencia Qu\u00edmica Internacional (ICRS)**: Son sustancias de referencia utilizadas como est\u00e1ndares primarios en pruebas f\u00edsicas y qu\u00edmicas, oficialmente adoptadas por el Comit\u00e9 de Expertos de la OMS.\n\n3. **European Directorate for the Quality of Medicines and HealthCare (EDQM)**: Desde abril de 2010, el EDQM asumi\u00f3 la responsabilidad de la establecimiento, preparaci\u00f3n, almacenamiento y distribuci\u00f3n de los ICRS, anteriormente gestionados por Apoteket AB.\n\n4. **Colaboraci\u00f3n con Laboratorios Nacionales**: Se han invitado a laboratorios de control nacionales a participar en estudios colaborativos para caracterizar los ICRS, lo que ha recibido una respuesta positiva.\n\n5. **Base de Datos de ICRS**: Se ha establecido una base de datos con informaci\u00f3n sobre todas las sustancias de referencia descritas en *The International Pharmacopoeia*.\n\n6. **Nuevos ICRS**: Se anunci\u00f3 la creaci\u00f3n de un nuevo ICRS, alpha-artemether, en octubre de 2011, y se menciona el desarrollo de beclometasone dipropionate como otro ICRS en proceso.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**\n- **EDQM (Direcci\u00f3n Europea de Calidad de Medicamentos y Atenci\u00f3n Sanitaria)**\n- **Apoteket AB** (anteriormente colaborador de la OMS en sustancias de referencia qu\u00edmica) \n\nEste resumen destaca la importancia de los ICRS en el control de calidad de las preparaciones farmac\u00e9uticas y la colaboraci\u00f3n internacional para su desarrollo y caracterizaci\u00f3n.", "excerpt_keywords": "Keywords: ICRS, WHO, EDQM, pharmaceutical preparations, quality control"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "06b7d832-e90d-4a77-a0e3-ffd134b4649b", "node_type": "4", "metadata": {"page_label": "40", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nbatch, was under way. The internal study for a further ICRS, azobenzene, replacement batch, had been completed and a collaborative study was due to begin in October 2011.\n\nWhile not within the scope of the WHO\u2013EDQM cooperation agreement, the EDQM laboratory had exceptionally performed a study to support the development of *The International Pharmacopoeia* monograph for artemisinin. The study subjects were the correction/response factor artemisinin and the verification of a liquid chromatography (LC) method.\n\nIt was reported that the ICRS database included 215 ICRS. They had been ranked according to their demand and this ranking was being used to assign priority in monitoring. A monitoring programme had been established and was currently monitoring 23 ICRS. Of the 15 monitored to date, no deficiencies had been detected. In terms of quality control, eight batches have been subjected to quality control for identification.\n\nThe Expert Committee noted the report.\n\n## 4.1.2 Frequently asked questions about collaborative trials\n\nReference standards to be used for assay determinations are examined in collaborative trials. The results obtained are used to assign a content or other analytical values to the standards. WHO had invited national quality control laboratories to join in trials to characterize ICRS, and a document that had been prepared to inform candidates about these studies was presented to the Expert Committee for information.\n\nThe overall goal of this project was to establish a worldwide distribution of ICRS to assist low- and middle-income countries to test for the quality of essential medicines described in *The International Pharmacopoeia* and used, for example, in the treatment of HIV/AIDS, tuberculosis and malaria. The Expert Committee noted the document.\n\n## 4.1.3 Annual report on International Chemical Reference Substances 2010\n\nBased on an umbrella agreement signed between WHO and EDQM in March 2010, and after having received the physical stock of existing ICRS from Apoteket, EDQM restarted the distribution of ICRS in May 2010.\n\nCoordination meetings between WHO and EDQM took place in April and September 2010 to agree upon the details of the ICRS establishment workflow and to prioritize the work for the establishment of new ICRS.\n\nIn 2010 the total number of ICRS distributed by EDQM was 957. The five most frequently requested substances were, in order of demand: artesunate, vanillin, arteminol, artemether and lumefantrine.\n\nThe Expert Committee noted the report and thanked EDQM for its contribution and work in support of WHO Member States.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "6054156e87a48aae521f91579d9834a1dc20e858f28f2cb5e7613c927d3581dc", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nbatch, was under way. The internal study for a further ICRS, azobenzene, replacement batch, had been completed and a collaborative study was due to begin in October 2011.\n\nWhile not within the scope of the WHO\u2013EDQM cooperation agreement, the EDQM laboratory had exceptionally performed a study to support the development of *The International Pharmacopoeia* monograph for artemisinin. The study subjects were the correction/response factor artemisinin and the verification of a liquid chromatography (LC) method.\n\nIt was reported that the ICRS database included 215 ICRS. They had been ranked according to their demand and this ranking was being used to assign priority in monitoring. A monitoring programme had been established and was currently monitoring 23 ICRS. Of the 15 monitored to date, no deficiencies had been detected. In terms of quality control, eight batches have been subjected to quality control for identification.\n\nThe Expert Committee noted the report.\n\n## 4.1.2 Frequently asked questions about collaborative trials\n\nReference standards to be used for assay determinations are examined in collaborative trials. The results obtained are used to assign a content or other analytical values to the standards. WHO had invited national quality control laboratories to join in trials to characterize ICRS, and a document that had been prepared to inform candidates about these studies was presented to the Expert Committee for information.\n\nThe overall goal of this project was to establish a worldwide distribution of ICRS to assist low- and middle-income countries to test for the quality of essential medicines described in *The International Pharmacopoeia* and used, for example, in the treatment of HIV/AIDS, tuberculosis and malaria. The Expert Committee noted the document.\n\n## 4.1.3 Annual report on International Chemical Reference Substances 2010\n\nBased on an umbrella agreement signed between WHO and EDQM in March 2010, and after having received the physical stock of existing ICRS from Apoteket, EDQM restarted the distribution of ICRS in May 2010.\n\nCoordination meetings between WHO and EDQM took place in April and September 2010 to agree upon the details of the ICRS establishment workflow and to prioritize the work for the establishment of new ICRS.\n\nIn 2010 the total number of ICRS distributed by EDQM was 957. The five most frequently requested substances were, in order of demand: artesunate, vanillin, arteminol, artemether and lumefantrine.\n\nThe Expert Committee noted the report and thanked EDQM for its contribution and work in support of WHO Member States.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2672, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d517bbcd-8035-43f5-ac95-1e7ca4c0035b": {"__data__": {"id_": "d517bbcd-8035-43f5-ac95-1e7ca4c0035b", "embedding": null, "metadata": {"page_label": "41", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 4.1.4 Lumefantrine for system suitability testing\n\nThe report of the EDQM on Lumefantrine for system suitability testing, the first ICRS to be developed by EDQM, was submitted to the Expert Committee. This substance was adopted by the Expert Committee as an International Chemical Reference Substance.\n\n# 4.1.5 Bacterial endotoxin\n\nA request to develop a replacement for the existing standard on bacterial endotoxin had been submitted to the Expert Committee by the WHO team for Quality, Safety and Standards.\n\nBased on earlier agreement that the only reliable approach to maintaining harmonization of the endotoxin unit for pyrogen testing is the establishment of a shared, harmonized reference material, the establishment of a new material becomes necessary once one of the regional stocks is nearing depletion. This was the case for the EDQM material, necessitating the establishment of a new joint material. It was, therefore, proposed to establish the 3rd International Standard for bacterial endotoxin through an international collaborative study.\n\nSince *The International Pharmacopoeia* includes the general test using this standard the Expert Committee considered that it would be important to maintain the continuity of the International Standard. The proposal was consequently endorsed by the Expert Committee.\n\n# 5. Quality control \u2013 national laboratories\n\n## 5.1 External Quality Assurance Assessment Scheme\n\nThe External Quality Assurance Assessment Scheme (EQAAS) is a programme for the external evaluation of quality control management systems in chemical control laboratories. It uses inter-laboratory comparisons to determine the performance of participating laboratories in carrying out specific tests or measurements. The Scheme supplements laboratories\u2019 internal quality assurance procedures by providing an external measure for their testing capabilities.\n\nAnalytical laboratories are required by the WHO good practices for pharmaceutical quality control laboratories and by other regulations, such as ISO/IEC 17025, to participate in proficiency tests. WHO regularly organizes proficiency studies using physicochemical methods described in *The International Pharmacopoeia* (including methods used in pharmaceutical technology such as dissolution testing).\n\nUp to 60 quality control laboratories from all six WHO regions usually participate in this Scheme.\n\n----\n\n*ISO/IEC 17025:2005. General requirements for the competence of testing and calibration laboratories. Geneva, International Organization for Standardization, 2005.*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS detalla el desarrollo de sustancias de referencia qu\u00edmica internacional, como la Lumefantrine, y la necesidad de establecer un nuevo est\u00e1ndar internacional para endotoxinas bacterianas debido al agotamiento de materiales existentes. Adem\u00e1s, se describe el esquema de evaluaci\u00f3n externa de calidad (EQAAS) que permite la comparaci\u00f3n interlaboratorios para asegurar la calidad en los laboratorios de control qu\u00edmico, en cumplimiento con las buenas pr\u00e1cticas y regulaciones internacionales.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1l fue la raz\u00f3n para desarrollar un nuevo est\u00e1ndar internacional para endotoxinas bacterianas?**\n   - La raz\u00f3n para desarrollar un nuevo est\u00e1ndar internacional para endotoxinas bacterianas fue el agotamiento de los materiales existentes en los stocks regionales, lo que hizo necesario establecer un nuevo material conjunto para mantener la armonizaci\u00f3n de la unidad de endotoxinas para pruebas de pirogenos.\n\n2. **\u00bfQu\u00e9 papel desempe\u00f1a la Lumefantrine en el contexto de las sustancias de referencia qu\u00edmica internacional?**\n   - La Lumefantrine fue adoptada como una Sustancia de Referencia Qu\u00edmica Internacional (ICRS) por el Comit\u00e9 de Expertos de la OMS, tras la presentaci\u00f3n de un informe del EDQM sobre su uso para pruebas de idoneidad del sistema.\n\n3. **\u00bfC\u00f3mo contribuye el Esquema de Evaluaci\u00f3n Externa de Calidad (EQAAS) a la gesti\u00f3n de calidad en laboratorios de control qu\u00edmico?**\n   - El EQAAS contribuye a la gesti\u00f3n de calidad en laboratorios de control qu\u00edmico mediante la evaluaci\u00f3n externa de los sistemas de gesti\u00f3n de calidad, utilizando comparaciones interlaboratorios para determinar el rendimiento en pruebas espec\u00edficas, lo que complementa los procedimientos internos de aseguramiento de calidad de los laboratorios.", "prev_section_summary": "### Temas Clave\n\n1. **Colaboraci\u00f3n OMS-EDQM**: Se destaca la cooperaci\u00f3n entre la Organizaci\u00f3n Mundial de la Salud (OMS) y el European Directorate for the Quality of Medicines & HealthCare (EDQM) para el desarrollo y distribuci\u00f3n de Sustancias de Referencia Qu\u00edmica Internacional (ICRS).\n\n2. **Distribuci\u00f3n de ICRS**: En 2010, el EDQM distribuy\u00f3 un total de 957 ICRS, con un enfoque en ayudar a pa\u00edses de ingresos bajos y medios a evaluar la calidad de medicamentos esenciales.\n\n3. **Monitoreo y Control de Calidad**: Se estableci\u00f3 un programa de monitoreo para 23 ICRS, y de las 15 ICRS monitoreadas hasta la fecha, no se detectaron deficiencias. Ocho lotes fueron sometidos a control de calidad para identificaci\u00f3n.\n\n4. **Ensayos Colaborativos**: Se llevaron a cabo ensayos colaborativos para caracterizar ICRS, invitando a laboratorios nacionales de control de calidad a participar.\n\n5. **Sustancias M\u00e1s Solicitadas**: Las cinco sustancias m\u00e1s solicitadas en 2010 fueron artesunate, vanillin, arteminol, artemether y lumefantrine.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Agencia de la ONU responsable de la salud p\u00fablica internacional.\n- **European Directorate for the Quality of Medicines & HealthCare (EDQM)**: Organizaci\u00f3n que establece est\u00e1ndares de calidad para medicamentos en Europa.\n- **Sustancias de Referencia Qu\u00edmica Internacional (ICRS)**: Sustancias utilizadas como est\u00e1ndares en ensayos de calidad de medicamentos.\n- **Medicamentos Esenciales**: Medicamentos que satisfacen las necesidades de salud de la poblaci\u00f3n y son de costo accesible.\n- **Enfermedades Tratadas**: VIH/SIDA, tuberculosis y malaria, que son foco de atenci\u00f3n en la distribuci\u00f3n de ICRS.", "excerpt_keywords": "Keywords: Lumefantrine, bacterial endotoxin, International Chemical Reference Substance, quality control, External Quality Assurance Assessment Scheme"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0eb6e449-2c27-4c1b-b3e1-9386f26fc2c7", "node_type": "4", "metadata": {"page_label": "41", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 4.1.4 Lumefantrine for system suitability testing\n\nThe report of the EDQM on Lumefantrine for system suitability testing, the first ICRS to be developed by EDQM, was submitted to the Expert Committee. This substance was adopted by the Expert Committee as an International Chemical Reference Substance.\n\n# 4.1.5 Bacterial endotoxin\n\nA request to develop a replacement for the existing standard on bacterial endotoxin had been submitted to the Expert Committee by the WHO team for Quality, Safety and Standards.\n\nBased on earlier agreement that the only reliable approach to maintaining harmonization of the endotoxin unit for pyrogen testing is the establishment of a shared, harmonized reference material, the establishment of a new material becomes necessary once one of the regional stocks is nearing depletion. This was the case for the EDQM material, necessitating the establishment of a new joint material. It was, therefore, proposed to establish the 3rd International Standard for bacterial endotoxin through an international collaborative study.\n\nSince *The International Pharmacopoeia* includes the general test using this standard the Expert Committee considered that it would be important to maintain the continuity of the International Standard. The proposal was consequently endorsed by the Expert Committee.\n\n# 5. Quality control \u2013 national laboratories\n\n## 5.1 External Quality Assurance Assessment Scheme\n\nThe External Quality Assurance Assessment Scheme (EQAAS) is a programme for the external evaluation of quality control management systems in chemical control laboratories. It uses inter-laboratory comparisons to determine the performance of participating laboratories in carrying out specific tests or measurements. The Scheme supplements laboratories\u2019 internal quality assurance procedures by providing an external measure for their testing capabilities.\n\nAnalytical laboratories are required by the WHO good practices for pharmaceutical quality control laboratories and by other regulations, such as ISO/IEC 17025, to participate in proficiency tests. WHO regularly organizes proficiency studies using physicochemical methods described in *The International Pharmacopoeia* (including methods used in pharmaceutical technology such as dissolution testing).\n\nUp to 60 quality control laboratories from all six WHO regions usually participate in this Scheme.\n\n----\n\n*ISO/IEC 17025:2005. General requirements for the competence of testing and calibration laboratories. Geneva, International Organization for Standardization, 2005.*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "fee50d2cdecc3b7fa5ff320153643d9ba8130c006c58324fb3729defd6bf6a7a", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 4.1.4 Lumefantrine for system suitability testing\n\nThe report of the EDQM on Lumefantrine for system suitability testing, the first ICRS to be developed by EDQM, was submitted to the Expert Committee. This substance was adopted by the Expert Committee as an International Chemical Reference Substance.\n\n# 4.1.5 Bacterial endotoxin\n\nA request to develop a replacement for the existing standard on bacterial endotoxin had been submitted to the Expert Committee by the WHO team for Quality, Safety and Standards.\n\nBased on earlier agreement that the only reliable approach to maintaining harmonization of the endotoxin unit for pyrogen testing is the establishment of a shared, harmonized reference material, the establishment of a new material becomes necessary once one of the regional stocks is nearing depletion. This was the case for the EDQM material, necessitating the establishment of a new joint material. It was, therefore, proposed to establish the 3rd International Standard for bacterial endotoxin through an international collaborative study.\n\nSince *The International Pharmacopoeia* includes the general test using this standard the Expert Committee considered that it would be important to maintain the continuity of the International Standard. The proposal was consequently endorsed by the Expert Committee.\n\n# 5. Quality control \u2013 national laboratories\n\n## 5.1 External Quality Assurance Assessment Scheme\n\nThe External Quality Assurance Assessment Scheme (EQAAS) is a programme for the external evaluation of quality control management systems in chemical control laboratories. It uses inter-laboratory comparisons to determine the performance of participating laboratories in carrying out specific tests or measurements. The Scheme supplements laboratories\u2019 internal quality assurance procedures by providing an external measure for their testing capabilities.\n\nAnalytical laboratories are required by the WHO good practices for pharmaceutical quality control laboratories and by other regulations, such as ISO/IEC 17025, to participate in proficiency tests. WHO regularly organizes proficiency studies using physicochemical methods described in *The International Pharmacopoeia* (including methods used in pharmaceutical technology such as dissolution testing).\n\nUp to 60 quality control laboratories from all six WHO regions usually participate in this Scheme.\n\n----\n\n*ISO/IEC 17025:2005. General requirements for the competence of testing and calibration laboratories. Geneva, International Organization for Standardization, 2005.*", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2553, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "e9ded452-e4ce-43ab-8f20-ae76617576cc": {"__data__": {"id_": "e9ded452-e4ce-43ab-8f20-ae76617576cc", "embedding": null, "metadata": {"page_label": "42", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nSo far, EQAAS offers proficiency tests which enable participating laboratories to demonstrate their competence by analysing a common test sample. Results are evaluated and participants are judged according to their individual deviation from the true value.\n\nExamples of three tests were described \u2013 namely on the water content of amodiaquine hydrochloride by Karl Fischer titration, dissolution tests of artemether and lumefantrine tablets, and assessment of the density and pH measurement of abacavir oral solution (still in progress at the time of the meeting). Three further tests are scheduled to take place in 2012 including an assay by HPLC of amodiaquine and artesunate tablets, a dissolution test of rifampicin capsules, and assay by titration of chloroquine sulfate oral suspension.\n\nThe Expert Committee raised concerns about the results of some studies which showed considerable variability between laboratories and indicated the need for training in some laboratories.\n\nIt was proposed to extend EQAAS in the future and to encourage participants not only to analyse a common test sample but also, if appropriate, to include commercial medicines drawn from their regional or national markets in the study. Participating laboratories would be given the necessary information to enable them to perform a proficiency test and a market surveillance study concurrently. The plan would be for study participants to receive in advance the protocols and all other details so that they would also be able to collect medicines with a similar composition from their local or regional markets. All samples \u2013 the market surveillance samples as well as the proficiency sample(s) \u2013 would be analysed in one series under repeatable conditions.\n\nDuring the consultation on specifications for medicines and quality control laboratory issues in July 2011, national control laboratories expressed appreciation of the proposal to extend the programme.\n\nMembers of the Expert Committee noted that the extension of the Scheme could bring certain advantages, namely that:\n\n- WHO could assist national authorities to identify and monitor products of low quality;\n- WHO would learn more about the global applicability of methods of *The International Pharmacopoeia* and study results might support revision of relevant monographs and/or general chapters and methods;\n- participants could more easily and confidently verify that the performance of the method applied is suitable by referring to their test result for the common sample (provided that it is satisfactory).\n\nThe Expert Committee approved the proposed extension of the scheme. It was pointed out that the studies for the extended scheme should be selected with care.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en el programa de Evaluaci\u00f3n de la Calidad de los Laboratorios (EQAAS) de la OMS, que ofrece pruebas de competencia para laboratorios mediante el an\u00e1lisis de muestras de prueba comunes. Se describen ejemplos de pruebas realizadas y se expresan preocupaciones sobre la variabilidad de los resultados entre laboratorios, lo que indica la necesidad de capacitaci\u00f3n. Se propone extender el programa para incluir medicamentos comerciales de mercados regionales o nacionales, lo que permitir\u00eda a los laboratorios realizar pruebas de competencia y estudios de vigilancia del mercado simult\u00e1neamente. La extensi\u00f3n del programa podr\u00eda ayudar a identificar productos de baja calidad y mejorar la aplicabilidad de los m\u00e9todos de la Farmacopea Internacional.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los beneficios espec\u00edficos que se esperan al incluir medicamentos comerciales en el programa EQAAS?**\n   - Se espera que la inclusi\u00f3n de medicamentos comerciales permita a los laboratorios realizar pruebas de competencia y estudios de vigilancia del mercado simult\u00e1neamente, lo que facilitar\u00eda la identificaci\u00f3n de productos de baja calidad y mejorar\u00eda la confianza en los m\u00e9todos de an\u00e1lisis aplicados.\n\n2. **\u00bfQu\u00e9 tipo de pruebas se llevaron a cabo en el marco del programa EQAAS y cu\u00e1les est\u00e1n programadas para el futuro?**\n   - Se realizaron pruebas sobre el contenido de agua de la amodiaquina clorhidrato, pruebas de disoluci\u00f3n de tabletas de artemeter y lumefantrina, y mediciones de densidad y pH de la soluci\u00f3n oral de abacavir. Para el futuro, se programaron pruebas de HPLC de tabletas de amodiaquina y artesunato, una prueba de disoluci\u00f3n de c\u00e1psulas de rifampicina y un ensayo por titulaci\u00f3n de suspensi\u00f3n oral de cloroquina.\n\n3. **\u00bfQu\u00e9 preocupaciones se expresaron sobre la variabilidad de los resultados entre laboratorios y c\u00f3mo se planea abordar este problema?**\n   - Se expresaron preocupaciones sobre la considerable variabilidad de los resultados entre laboratorios, lo que indica la necesidad de capacitaci\u00f3n en algunos de ellos. Se planea abordar este problema mediante la extensi\u00f3n del programa EQAAS y la provisi\u00f3n de informaci\u00f3n y protocolos adecuados a los laboratorios participantes para mejorar su competencia y resultados.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Lumefantrine**:\n   - Adoptada como Sustancia de Referencia Qu\u00edmica Internacional (ICRS) por el Comit\u00e9 de Expertos de la OMS.\n   - Utilizada para pruebas de idoneidad del sistema.\n\n2. **Endotoxinas Bacterianas**:\n   - Se solicit\u00f3 el desarrollo de un nuevo est\u00e1ndar internacional debido al agotamiento de los materiales existentes.\n   - Se propuso establecer el 3er Est\u00e1ndar Internacional para endotoxinas bacterianas a trav\u00e9s de un estudio colaborativo internacional.\n   - Importancia de mantener la continuidad del Est\u00e1ndar Internacional en *The International Pharmacopoeia*.\n\n3. **Esquema de Evaluaci\u00f3n Externa de Calidad (EQAAS)**:\n   - Programa para la evaluaci\u00f3n externa de sistemas de gesti\u00f3n de calidad en laboratorios de control qu\u00edmico.\n   - Utiliza comparaciones interlaboratorios para evaluar el rendimiento en pruebas espec\u00edficas.\n   - Complementa los procedimientos internos de aseguramiento de calidad.\n   - Participaci\u00f3n de hasta 60 laboratorios de control de calidad de todas las regiones de la OMS.\n\n4. **Regulaciones y Normativas**:\n   - Cumplimiento con las buenas pr\u00e1cticas de la OMS para laboratorios de control de calidad farmac\u00e9utica.\n   - Referencia a la norma ISO/IEC 17025:2005, que establece requisitos generales para la competencia de laboratorios de ensayo y calibraci\u00f3n.\n\n### Entidades:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo que supervisa y regula los est\u00e1ndares de calidad y seguridad.\n- **EDQM (European Directorate for the Quality of Medicines)**: Entidad que report\u00f3 sobre Lumefantrine y cuyo material de endotoxinas estaba cerca de agotarse.\n- **Comit\u00e9 de Expertos**: Grupo que adopta y respalda las propuestas relacionadas con sustancias de referencia y est\u00e1ndares internacionales.", "excerpt_keywords": "Keywords: EQAAS, pharmaceutical quality, proficiency tests, WHO, laboratory training"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "843766f4-943b-4205-b43e-438b1bf94d63", "node_type": "4", "metadata": {"page_label": "42", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nSo far, EQAAS offers proficiency tests which enable participating laboratories to demonstrate their competence by analysing a common test sample. Results are evaluated and participants are judged according to their individual deviation from the true value.\n\nExamples of three tests were described \u2013 namely on the water content of amodiaquine hydrochloride by Karl Fischer titration, dissolution tests of artemether and lumefantrine tablets, and assessment of the density and pH measurement of abacavir oral solution (still in progress at the time of the meeting). Three further tests are scheduled to take place in 2012 including an assay by HPLC of amodiaquine and artesunate tablets, a dissolution test of rifampicin capsules, and assay by titration of chloroquine sulfate oral suspension.\n\nThe Expert Committee raised concerns about the results of some studies which showed considerable variability between laboratories and indicated the need for training in some laboratories.\n\nIt was proposed to extend EQAAS in the future and to encourage participants not only to analyse a common test sample but also, if appropriate, to include commercial medicines drawn from their regional or national markets in the study. Participating laboratories would be given the necessary information to enable them to perform a proficiency test and a market surveillance study concurrently. The plan would be for study participants to receive in advance the protocols and all other details so that they would also be able to collect medicines with a similar composition from their local or regional markets. All samples \u2013 the market surveillance samples as well as the proficiency sample(s) \u2013 would be analysed in one series under repeatable conditions.\n\nDuring the consultation on specifications for medicines and quality control laboratory issues in July 2011, national control laboratories expressed appreciation of the proposal to extend the programme.\n\nMembers of the Expert Committee noted that the extension of the Scheme could bring certain advantages, namely that:\n\n- WHO could assist national authorities to identify and monitor products of low quality;\n- WHO would learn more about the global applicability of methods of *The International Pharmacopoeia* and study results might support revision of relevant monographs and/or general chapters and methods;\n- participants could more easily and confidently verify that the performance of the method applied is suitable by referring to their test result for the common sample (provided that it is satisfactory).\n\nThe Expert Committee approved the proposed extension of the scheme. It was pointed out that the studies for the extended scheme should be selected with care.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "db3aeda648f829d1c8fb0e2f19d6b77c34ff2a851f0a5bf23b14aa0c371d298d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nSo far, EQAAS offers proficiency tests which enable participating laboratories to demonstrate their competence by analysing a common test sample. Results are evaluated and participants are judged according to their individual deviation from the true value.\n\nExamples of three tests were described \u2013 namely on the water content of amodiaquine hydrochloride by Karl Fischer titration, dissolution tests of artemether and lumefantrine tablets, and assessment of the density and pH measurement of abacavir oral solution (still in progress at the time of the meeting). Three further tests are scheduled to take place in 2012 including an assay by HPLC of amodiaquine and artesunate tablets, a dissolution test of rifampicin capsules, and assay by titration of chloroquine sulfate oral suspension.\n\nThe Expert Committee raised concerns about the results of some studies which showed considerable variability between laboratories and indicated the need for training in some laboratories.\n\nIt was proposed to extend EQAAS in the future and to encourage participants not only to analyse a common test sample but also, if appropriate, to include commercial medicines drawn from their regional or national markets in the study. Participating laboratories would be given the necessary information to enable them to perform a proficiency test and a market surveillance study concurrently. The plan would be for study participants to receive in advance the protocols and all other details so that they would also be able to collect medicines with a similar composition from their local or regional markets. All samples \u2013 the market surveillance samples as well as the proficiency sample(s) \u2013 would be analysed in one series under repeatable conditions.\n\nDuring the consultation on specifications for medicines and quality control laboratory issues in July 2011, national control laboratories expressed appreciation of the proposal to extend the programme.\n\nMembers of the Expert Committee noted that the extension of the Scheme could bring certain advantages, namely that:\n\n- WHO could assist national authorities to identify and monitor products of low quality;\n- WHO would learn more about the global applicability of methods of *The International Pharmacopoeia* and study results might support revision of relevant monographs and/or general chapters and methods;\n- participants could more easily and confidently verify that the performance of the method applied is suitable by referring to their test result for the common sample (provided that it is satisfactory).\n\nThe Expert Committee approved the proposed extension of the scheme. It was pointed out that the studies for the extended scheme should be selected with care.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2787, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "af3e0057-2f17-4d76-a591-3ddf77b5d92a": {"__data__": {"id_": "af3e0057-2f17-4d76-a591-3ddf77b5d92a", "embedding": null, "metadata": {"page_label": "43", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 6. Quality assurance \u2013 good manufacturing practices\n\n## 6.1 WHO good manufacturing practices: water for pharmaceutical use\n\nA draft document on water for pharmaceutical use was presented to the Expert Committee for discussion. The document was intended to supplement the general guidelines on good manufacturing practices (GMP) for pharmaceutical products published by WHO in 2003. The text of the document presented was discussed by the Expert Committee in 2009 when the Committee was requested to bring the document into line with pharmaceutical water systems. The revision had been under way since and all comments received had been discussed at informal consultations. The Expert Committee reviewed the document together with the major comments received during the latest circulation phase.\n\nThe Expert Committee adopted the document subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 2).\n\n# 7. Quality assurance \u2013 new approaches\n\n## 7.1 WHO guidelines on quality risk management\n\nIt was reported that a restructured text of the quality risk management document, incorporating all changes proposed during consultations and discussions to date, was in preparation and would be sent to members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations, and would go through the usual wide circulation process in due course. This new guidance is intended to replace the current WHO guidelines on hazard analysis and critical control points to cover new trends. The Expert Committee agreed to defer its discussion of this topic until the most recent version of the document was available.\n\n# 8. Quality assurance \u2013 distribution and trade of pharmaceuticals\n\n## 8.1 WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce\n\nThe WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce is a voluntary agreement between WHO Member States. Dating from 1969 the Scheme has attracted both controversy and support and there have been many discussions about its value. In 2008 the Expert Committee asked for the Scheme to be reviewed in light of the changing situation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Pr\u00e1cticas de fabricaci\u00f3n y agua farmac\u00e9utica**: Se present\u00f3 un documento en borrador sobre el uso de agua en la fabricaci\u00f3n farmac\u00e9utica, destinado a complementar las directrices generales de buenas pr\u00e1cticas de fabricaci\u00f3n (GMP) publicadas por la OMS en 2003. Este documento fue revisado por el Comit\u00e9 de Expertos, que adopt\u00f3 el texto con cambios acordados tras discusiones y comentarios.\n\n2. **Gesti\u00f3n de riesgos de calidad**: Se est\u00e1 preparando un texto reestructurado sobre gesti\u00f3n de riesgos de calidad que reemplazar\u00e1 las directrices actuales de la OMS sobre an\u00e1lisis de peligros y puntos cr\u00edticos de control. Este nuevo enfoque busca adaptarse a las tendencias actuales y se discutir\u00e1 una vez que est\u00e9 disponible la versi\u00f3n m\u00e1s reciente.\n\n3. **Esquema de certificaci\u00f3n de productos farmac\u00e9uticos**: El Esquema de Certificaci\u00f3n de la OMS sobre la calidad de productos farmac\u00e9uticos en comercio internacional es un acuerdo voluntario entre los Estados Miembros de la OMS, que ha sido objeto de controversia y apoyo desde su creaci\u00f3n en 1969. En 2008, se solicit\u00f3 una revisi\u00f3n del esquema debido a la evoluci\u00f3n de la situaci\u00f3n.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los principales cambios que se discutieron y se acordaron en el documento sobre el uso de agua para productos farmac\u00e9uticos?**\n   - Esta pregunta busca detalles sobre las modificaciones espec\u00edficas que se realizaron en el documento, que no se encuentran en las directrices generales de GMP.\n\n2. **\u00bfQu\u00e9 tendencias actuales se est\u00e1n considerando en la nueva gu\u00eda de gesti\u00f3n de riesgos de calidad que reemplazar\u00e1 las directrices sobre an\u00e1lisis de peligros?**\n   - Esta pregunta se centra en las nuevas tendencias que est\u00e1n influyendo en la reestructuraci\u00f3n de las directrices de gesti\u00f3n de riesgos, lo que puede no estar documentado en otras fuentes.\n\n3. **\u00bfCu\u00e1les son las principales controversias y apoyos que ha recibido el Esquema de Certificaci\u00f3n de la OMS desde su creaci\u00f3n en 1969?**\n   - Esta pregunta busca informaci\u00f3n sobre las discusiones y debates espec\u00edficos que han rodeado al esquema de certificaci\u00f3n, proporcionando un contexto hist\u00f3rico que puede no estar disponible en otros documentos.", "prev_section_summary": "### Temas Clave\n\n1. **Programa EQAAS**: El programa de Evaluaci\u00f3n de la Calidad de los Laboratorios (EQAAS) de la OMS ofrece pruebas de competencia para laboratorios mediante el an\u00e1lisis de muestras de prueba comunes.\n\n2. **Pruebas Realizadas y Futuras**: Se han realizado pruebas sobre el contenido de agua de amodiaquina clorhidrato, disoluci\u00f3n de tabletas de artemeter y lumefantrina, y mediciones de densidad y pH de la soluci\u00f3n oral de abacavir. Se programaron pruebas adicionales para 2012, incluyendo ensayos de HPLC y disoluci\u00f3n de otros medicamentos.\n\n3. **Variabilidad de Resultados**: Se expresaron preocupaciones sobre la considerable variabilidad de los resultados entre laboratorios, lo que indica la necesidad de capacitaci\u00f3n.\n\n4. **Propuesta de Extensi\u00f3n del Programa**: Se propone extender EQAAS para incluir medicamentos comerciales de mercados regionales o nacionales, permitiendo a los laboratorios realizar pruebas de competencia y estudios de vigilancia del mercado simult\u00e1neamente.\n\n5. **Beneficios de la Extensi\u00f3n**: La extensi\u00f3n del programa podr\u00eda ayudar a identificar productos de baja calidad, mejorar la aplicabilidad de los m\u00e9todos de la Farmacopea Internacional y aumentar la confianza en los resultados de las pruebas.\n\n### Entidades\n\n- **EQAAS**: Evaluaci\u00f3n de la Calidad de los Laboratorios.\n- **OMS**: Organizaci\u00f3n Mundial de la Salud.\n- **Amodiaquina clorhidrato**: Medicamento analizado en las pruebas.\n- **Artemeter y lumefantrina**: Medicamentos cuyas tabletas fueron sometidas a pruebas de disoluci\u00f3n.\n- **Abacavir**: Soluci\u00f3n oral cuya densidad y pH fueron evaluados.\n- **HPLC**: Cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n, m\u00e9todo utilizado en las pruebas programadas.\n- **Chloroquine sulfate**: Suspensi\u00f3n oral que ser\u00e1 analizada por titulaci\u00f3n.\n- **Farmacopea Internacional**: Referencia para los m\u00e9todos de an\u00e1lisis utilizados en el programa.", "excerpt_keywords": "Keywords: quality assurance, good manufacturing practices, pharmaceutical water, risk management, certification scheme"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a9559d59-2d70-48b6-a129-2e0e28c2fd62", "node_type": "4", "metadata": {"page_label": "43", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 6. Quality assurance \u2013 good manufacturing practices\n\n## 6.1 WHO good manufacturing practices: water for pharmaceutical use\n\nA draft document on water for pharmaceutical use was presented to the Expert Committee for discussion. The document was intended to supplement the general guidelines on good manufacturing practices (GMP) for pharmaceutical products published by WHO in 2003. The text of the document presented was discussed by the Expert Committee in 2009 when the Committee was requested to bring the document into line with pharmaceutical water systems. The revision had been under way since and all comments received had been discussed at informal consultations. The Expert Committee reviewed the document together with the major comments received during the latest circulation phase.\n\nThe Expert Committee adopted the document subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 2).\n\n# 7. Quality assurance \u2013 new approaches\n\n## 7.1 WHO guidelines on quality risk management\n\nIt was reported that a restructured text of the quality risk management document, incorporating all changes proposed during consultations and discussions to date, was in preparation and would be sent to members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations, and would go through the usual wide circulation process in due course. This new guidance is intended to replace the current WHO guidelines on hazard analysis and critical control points to cover new trends. The Expert Committee agreed to defer its discussion of this topic until the most recent version of the document was available.\n\n# 8. Quality assurance \u2013 distribution and trade of pharmaceuticals\n\n## 8.1 WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce\n\nThe WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce is a voluntary agreement between WHO Member States. Dating from 1969 the Scheme has attracted both controversy and support and there have been many discussions about its value. In 2008 the Expert Committee asked for the Scheme to be reviewed in light of the changing situation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f303119e7af9597f1e36e8eacfc9a268bcc43fa230c63e559080c18df7864f21", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 6. Quality assurance \u2013 good manufacturing practices\n\n## 6.1 WHO good manufacturing practices: water for pharmaceutical use\n\nA draft document on water for pharmaceutical use was presented to the Expert Committee for discussion. The document was intended to supplement the general guidelines on good manufacturing practices (GMP) for pharmaceutical products published by WHO in 2003. The text of the document presented was discussed by the Expert Committee in 2009 when the Committee was requested to bring the document into line with pharmaceutical water systems. The revision had been under way since and all comments received had been discussed at informal consultations. The Expert Committee reviewed the document together with the major comments received during the latest circulation phase.\n\nThe Expert Committee adopted the document subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 2).\n\n# 7. Quality assurance \u2013 new approaches\n\n## 7.1 WHO guidelines on quality risk management\n\nIt was reported that a restructured text of the quality risk management document, incorporating all changes proposed during consultations and discussions to date, was in preparation and would be sent to members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations, and would go through the usual wide circulation process in due course. This new guidance is intended to replace the current WHO guidelines on hazard analysis and critical control points to cover new trends. The Expert Committee agreed to defer its discussion of this topic until the most recent version of the document was available.\n\n# 8. Quality assurance \u2013 distribution and trade of pharmaceuticals\n\n## 8.1 WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce\n\nThe WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce is a voluntary agreement between WHO Member States. Dating from 1969 the Scheme has attracted both controversy and support and there have been many discussions about its value. In 2008 the Expert Committee asked for the Scheme to be reviewed in light of the changing situation.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2259, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "05e81e71-019d-450d-a698-58d5438572e3": {"__data__": {"id_": "05e81e71-019d-450d-a698-58d5438572e3", "embedding": null, "metadata": {"page_label": "44", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nTwo question and answer documents on the Scheme had been prepared by the secretariat and approved by the Expert Committee for publication on the WHO Medicines web site. Moreover, in 2010, a circular letter was prepared asking Member States to comment on the recommendations included in the report of the previous Expert Committee and to submit comments and suggestions about the Scheme. Only 12 responses out of 194 Member States were received, examples of which were presented to the Committee. The conclusion was drawn that in spite of some limitations, Member States acknowledged the value of the WHO Certification Scheme.\n\nIn 2003 the Expert Committee proposed an extension of the Scheme to include starting materials in addition to finished products, and Poland joined this extended scheme. The WHO Medicines web site will in future have a special section dedicated to the Scheme, anticipating that more countries would join.\n\nThe Expert Committee noted the report and stressed the importance of the WHO Certification Scheme for APIs and requested follow-up to make sure that appropriate staff received the communication.\n\n## 8.2 Update on Joint FIP/WHO guidelines on good pharmacy practice: standards for quality of pharmacy services\n\nThe Expert Committee was informed that the good pharmacy practices (GPP) adopted during its forty-fifth meeting had received much attention and had been translated into several languages. It was an important topic on the agenda of the ninety-ninth International Pharmaceutical Federation (FIP) meeting in 2011. The GPP text was endorsed by the FIP Council meeting for implementation by the national pharmaceutical associations of FIP.\n\nThe Expert Committee took note of this news.\n\n# 9. Prequalification of priority essential medicines including active pharmaceutical ingredients\n\n## 9.1 Update on the Prequalification of Medicines Programme managed by WHO\n\nThe Acting Manager of the WHO Prequalification of Medicines Programme reported that, since the 2010 meeting of the Expert Committee, 35 products had been prequalified. These included the new tenofovir/lamivudine + nevirapine combination; amikacin injection; a generic reproductive health product (ethinylestradiol/levonorgestrel); and an artesunate powder for injection. The Programme had also initiated prequalification of APIs during the year and had already prequalified five APIs. The Prequalification Programme had also begun assisting in an external review for the United Nations Population Fund.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en las actividades y actualizaciones del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Se discuten varios temas, incluyendo la importancia del Esquema de Certificaci\u00f3n de la OMS para Ingredientes Farmac\u00e9uticos Activos (APIs), la actualizaci\u00f3n sobre las Buenas Pr\u00e1cticas Farmac\u00e9uticas (GPP) y el Programa de Precalificaci\u00f3n de Medicamentos de la OMS. Se menciona que, a pesar de recibir solo 12 respuestas de 194 Estados Miembros sobre el Esquema de Certificaci\u00f3n, se reconoce su valor. Adem\u00e1s, se informa sobre la precalificaci\u00f3n de 35 productos y 5 APIs desde la \u00faltima reuni\u00f3n del Comit\u00e9 en 2010.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 acciones se tomaron en 2010 para fomentar la participaci\u00f3n de los Estados Miembros en el Esquema de Certificaci\u00f3n de la OMS?**\n   - En 2010, se prepar\u00f3 una carta circular solicitando a los Estados Miembros que comentaran sobre las recomendaciones del informe del Comit\u00e9 anterior y que enviaran comentarios y sugerencias sobre el Esquema.\n\n2. **\u00bfCu\u00e1ntos productos y APIs fueron precalificados por el Programa de Precalificaci\u00f3n de Medicamentos de la OMS desde la reuni\u00f3n de 2010 del Comit\u00e9 de Expertos?**\n   - Desde la reuni\u00f3n de 2010, se precalificaron 35 productos y 5 APIs.\n\n3. **\u00bfCu\u00e1l fue la respuesta del Comit\u00e9 de Expertos respecto a la importancia del Esquema de Certificaci\u00f3n para los APIs?**\n   - El Comit\u00e9 de Expertos destac\u00f3 la importancia del Esquema de Certificaci\u00f3n de la OMS para los APIs y solicit\u00f3 un seguimiento para asegurar que el personal adecuado recibiera la comunicaci\u00f3n relacionada.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Buenas Pr\u00e1cticas de Fabricaci\u00f3n (GMP)**:\n   - Se present\u00f3 un documento en borrador sobre el uso de agua para productos farmac\u00e9uticos, destinado a complementar las directrices de GMP publicadas por la OMS en 2003.\n   - El Comit\u00e9 de Expertos revis\u00f3 y adopt\u00f3 el documento con cambios acordados tras discusiones y comentarios.\n\n2. **Gesti\u00f3n de Riesgos de Calidad**:\n   - Se est\u00e1 preparando un texto reestructurado sobre gesti\u00f3n de riesgos de calidad que reemplazar\u00e1 las directrices actuales sobre an\u00e1lisis de peligros y puntos cr\u00edticos de control.\n   - Este nuevo enfoque busca adaptarse a tendencias actuales y se discutir\u00e1 una vez que est\u00e9 disponible la versi\u00f3n m\u00e1s reciente.\n\n3. **Esquema de Certificaci\u00f3n de Productos Farmac\u00e9uticos**:\n   - El Esquema de Certificaci\u00f3n de la OMS es un acuerdo voluntario entre Estados Miembros, creado en 1969, que ha generado tanto controversia como apoyo.\n   - En 2008, se solicit\u00f3 una revisi\u00f3n del esquema debido a cambios en el contexto internacional.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la publicaci\u00f3n de las directrices y documentos discutidos.\n- **Comit\u00e9 de Expertos**: Grupo encargado de revisar y adoptar los documentos relacionados con las buenas pr\u00e1cticas de fabricaci\u00f3n y gesti\u00f3n de riesgos.\n- **Estados Miembros de la OMS**: Participantes en el Esquema de Certificaci\u00f3n y sujetos a las directrices de la OMS.", "excerpt_keywords": "Keywords: WHO, Certification Scheme, Prequalification, Active Pharmaceutical Ingredients, Good Pharmacy Practice"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0cfcd139-22f1-468e-9743-d84edc7889c5", "node_type": "4", "metadata": {"page_label": "44", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nTwo question and answer documents on the Scheme had been prepared by the secretariat and approved by the Expert Committee for publication on the WHO Medicines web site. Moreover, in 2010, a circular letter was prepared asking Member States to comment on the recommendations included in the report of the previous Expert Committee and to submit comments and suggestions about the Scheme. Only 12 responses out of 194 Member States were received, examples of which were presented to the Committee. The conclusion was drawn that in spite of some limitations, Member States acknowledged the value of the WHO Certification Scheme.\n\nIn 2003 the Expert Committee proposed an extension of the Scheme to include starting materials in addition to finished products, and Poland joined this extended scheme. The WHO Medicines web site will in future have a special section dedicated to the Scheme, anticipating that more countries would join.\n\nThe Expert Committee noted the report and stressed the importance of the WHO Certification Scheme for APIs and requested follow-up to make sure that appropriate staff received the communication.\n\n## 8.2 Update on Joint FIP/WHO guidelines on good pharmacy practice: standards for quality of pharmacy services\n\nThe Expert Committee was informed that the good pharmacy practices (GPP) adopted during its forty-fifth meeting had received much attention and had been translated into several languages. It was an important topic on the agenda of the ninety-ninth International Pharmaceutical Federation (FIP) meeting in 2011. The GPP text was endorsed by the FIP Council meeting for implementation by the national pharmaceutical associations of FIP.\n\nThe Expert Committee took note of this news.\n\n# 9. Prequalification of priority essential medicines including active pharmaceutical ingredients\n\n## 9.1 Update on the Prequalification of Medicines Programme managed by WHO\n\nThe Acting Manager of the WHO Prequalification of Medicines Programme reported that, since the 2010 meeting of the Expert Committee, 35 products had been prequalified. These included the new tenofovir/lamivudine + nevirapine combination; amikacin injection; a generic reproductive health product (ethinylestradiol/levonorgestrel); and an artesunate powder for injection. The Programme had also initiated prequalification of APIs during the year and had already prequalified five APIs. The Prequalification Programme had also begun assisting in an external review for the United Nations Population Fund.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "95cf3f11c19e28c25da12214909e5a18a71e804801211606f16a328a2e54cc9c", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nTwo question and answer documents on the Scheme had been prepared by the secretariat and approved by the Expert Committee for publication on the WHO Medicines web site. Moreover, in 2010, a circular letter was prepared asking Member States to comment on the recommendations included in the report of the previous Expert Committee and to submit comments and suggestions about the Scheme. Only 12 responses out of 194 Member States were received, examples of which were presented to the Committee. The conclusion was drawn that in spite of some limitations, Member States acknowledged the value of the WHO Certification Scheme.\n\nIn 2003 the Expert Committee proposed an extension of the Scheme to include starting materials in addition to finished products, and Poland joined this extended scheme. The WHO Medicines web site will in future have a special section dedicated to the Scheme, anticipating that more countries would join.\n\nThe Expert Committee noted the report and stressed the importance of the WHO Certification Scheme for APIs and requested follow-up to make sure that appropriate staff received the communication.\n\n## 8.2 Update on Joint FIP/WHO guidelines on good pharmacy practice: standards for quality of pharmacy services\n\nThe Expert Committee was informed that the good pharmacy practices (GPP) adopted during its forty-fifth meeting had received much attention and had been translated into several languages. It was an important topic on the agenda of the ninety-ninth International Pharmaceutical Federation (FIP) meeting in 2011. The GPP text was endorsed by the FIP Council meeting for implementation by the national pharmaceutical associations of FIP.\n\nThe Expert Committee took note of this news.\n\n# 9. Prequalification of priority essential medicines including active pharmaceutical ingredients\n\n## 9.1 Update on the Prequalification of Medicines Programme managed by WHO\n\nThe Acting Manager of the WHO Prequalification of Medicines Programme reported that, since the 2010 meeting of the Expert Committee, 35 products had been prequalified. These included the new tenofovir/lamivudine + nevirapine combination; amikacin injection; a generic reproductive health product (ethinylestradiol/levonorgestrel); and an artesunate powder for injection. The Programme had also initiated prequalification of APIs during the year and had already prequalified five APIs. The Prequalification Programme had also begun assisting in an external review for the United Nations Population Fund.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2575, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "cbd5024c-55c4-4c27-8130-5341087d03b5": {"__data__": {"id_": "cbd5024c-55c4-4c27-8130-5341087d03b5", "embedding": null, "metadata": {"page_label": "45", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nof reproductive health products. The Programme had continued to work closely with the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria.\n\nThe number of applications for products to be prequalified in 2011 was 54 (as at 10 October 2011), and of these 35 had been accepted. Twenty-one applications for APIs had been received, two of which had been prequalified and 19 were under assessment. As for the prequalification of control laboratories, five laboratories had been prequalified since October 2010. There are now six prequalified control laboratories in all WHO regions.\n\nIn addition, a retrospective study of generic product dossiers had been conducted. The results showed a number of deficiencies and indicated the need for capacity building for a number of manufacturers of generic products. An external assessment of the WHO Prequalification of Medicines Programme had been conducted and the results were generally positive.\n\nTraining in capacity building for NMRAs was increasing. In 2010 the WHO Prequalification of Medicines Programme organized 16 workshops and was involved in a further five. In 2011 the Programme organized 10 workshops and was involved in a further seven. However, the challenge was to ensure that training was translated into improved implementation of the best practices.\n\nPrequalification is highly dependent on the support from national regulators who are assisting WHO in this programme.\n\nIt was reported that donor funds were declining and that technical expertise was increasingly difficult to obtain. As in many other areas, the WHO Prequalification of Medicines Programme had been trying to do more with less funds.\n\nThe Expert Committee considered that the presentation had highlighted the importance of the WHO Prequalification of Medicines Programme, which was having an influence in a number of areas, such as strengthening capacity at local level and making medicines accessible to those who need them most.\n\n## 10. Prequalification of quality control laboratories\n\n### 10.1 Update on the prequalification of quality control laboratories\n\nThe prequalification procedure for quality control laboratories was originally established in 2004 for Africa only and has since expanded globally. Any quality control laboratory (whether public or private) may participate in the programme. Participation is voluntary and many laboratories have asked to participate. Most of the interested laboratories have been in the African region (the first to be focused on in the expression of interest), where 22 laboratories have expressed interest and so far six have been prequalified. Six laboratories had also been prequalified in Europe. The programme involves initial inspections and pre-audits to assess capacity, followed by a strong capacity-building component involving training.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Precalificaci\u00f3n de Medicamentos y Laboratorios de Control de Calidad**: El Programa de Precalificaci\u00f3n de Medicamentos de la OMS ha estado trabajando para mejorar la calidad y el acceso a los productos farmac\u00e9uticos, especialmente en el contexto de la salud reproductiva y enfermedades como el VIH/SIDA, la tuberculosis y la malaria. En 2011, se recibieron 54 solicitudes para la precalificaci\u00f3n de productos, de las cuales 35 fueron aceptadas. Adem\u00e1s, se ha observado un aumento en la capacitaci\u00f3n de las Autoridades Nacionales de Regulaci\u00f3n de Medicamentos (NMRAs) y se han precalificado laboratorios de control de calidad en varias regiones.\n\n2. **Desaf\u00edos y Necesidades de Capacitaci\u00f3n**: A pesar de los avances, el Programa enfrenta desaf\u00edos significativos, como la disminuci\u00f3n de fondos de donantes y la dificultad para obtener experiencia t\u00e9cnica. Se ha identificado la necesidad de construir capacidades en los fabricantes de productos gen\u00e9ricos y asegurar que la capacitaci\u00f3n se traduzca en la implementaci\u00f3n de mejores pr\u00e1cticas.\n\n3. **Expansi\u00f3n Global del Programa**: Originalmente establecido en 2004 para \u00c1frica, el procedimiento de precalificaci\u00f3n de laboratorios de control de calidad se ha expandido a nivel global, permitiendo la participaci\u00f3n voluntaria de laboratorios p\u00fablicos y privados. Hasta la fecha, se han precalificado laboratorios en \u00c1frica y Europa, con un enfoque en la capacitaci\u00f3n y la evaluaci\u00f3n de capacidades.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los principales desaf\u00edos que enfrenta el Programa de Precalificaci\u00f3n de Medicamentos de la OMS en t\u00e9rminos de financiamiento y experiencia t\u00e9cnica?**\n   - Respuesta: El Programa ha reportado una disminuci\u00f3n en los fondos de donantes y una creciente dificultad para obtener experiencia t\u00e9cnica, lo que complica su capacidad para operar y expandir sus actividades.\n\n2. **\u00bfQu\u00e9 medidas se est\u00e1n tomando para abordar las deficiencias identificadas en los expedientes de productos gen\u00e9ricos?**\n   - Respuesta: Se ha llevado a cabo un estudio retrospectivo que mostr\u00f3 varias deficiencias, lo que indica la necesidad de construir capacidades en los fabricantes de productos gen\u00e9ricos. Esto se est\u00e1 abordando a trav\u00e9s de talleres y capacitaci\u00f3n organizados por el Programa.\n\n3. **\u00bfC\u00f3mo ha evolucionado la participaci\u00f3n de laboratorios en el programa de precalificaci\u00f3n desde su inicio en 2004?**\n   - Respuesta: El programa comenz\u00f3 en 2004 con un enfoque en \u00c1frica y ha expandido su alcance globalmente. Hasta ahora, 22 laboratorios en \u00c1frica han expresado inter\u00e9s, de los cuales seis han sido precalificados, y se han precalificado seis laboratorios adicionales en Europa.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Esquema de Certificaci\u00f3n de la OMS**:\n   - Se prepararon documentos de preguntas y respuestas sobre el Esquema, aprobados para su publicaci\u00f3n en el sitio web de Medicamentos de la OMS.\n   - En 2010, se envi\u00f3 una carta circular a los Estados Miembros solicitando comentarios sobre las recomendaciones del informe anterior del Comit\u00e9, recibiendo solo 12 respuestas de 194 Estados Miembros.\n   - A pesar de las limitaciones, se reconoci\u00f3 el valor del Esquema de Certificaci\u00f3n.\n\n2. **Extensi\u00f3n del Esquema**:\n   - En 2003, se propuso extender el Esquema para incluir materiales de partida adem\u00e1s de productos terminados, con Polonia uni\u00e9ndose a esta extensi\u00f3n.\n   - Se anticipa que m\u00e1s pa\u00edses se unir\u00e1n al Esquema, con una secci\u00f3n especial dedicada en el sitio web de la OMS.\n\n3. **Buenas Pr\u00e1cticas Farmac\u00e9uticas (GPP)**:\n   - Las GPP adoptadas en la reuni\u00f3n n\u00famero 45 del Comit\u00e9 recibieron atenci\u00f3n y fueron traducidas a varios idiomas.\n   - Se discutieron en la reuni\u00f3n de la Federaci\u00f3n Internacional Farmac\u00e9utica (FIP) en 2011, y el texto fue respaldado para su implementaci\u00f3n por asociaciones farmac\u00e9uticas nacionales.\n\n4. **Programa de Precalificaci\u00f3n de Medicamentos de la OMS**:\n   - Desde la reuni\u00f3n de 2010, se han precalificado 35 productos, incluyendo combinaciones de medicamentos y un producto de salud reproductiva.\n   - Se han precalificado 5 APIs y se ha comenzado a asistir en una revisi\u00f3n externa para el Fondo de Poblaci\u00f3n de las Naciones Unidas.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la salud p\u00fablica internacional y de la implementaci\u00f3n de los esquemas de certificaci\u00f3n y precalificaci\u00f3n.\n- **FIP (Federaci\u00f3n Internacional Farmac\u00e9utica)**: Organizaci\u00f3n que apoya la implementaci\u00f3n de buenas pr\u00e1cticas farmac\u00e9uticas a nivel nacional.\n- **Estados Miembros**: Pa\u00edses que forman parte de la OMS y que participan en el Esquema de Certificaci\u00f3n y otras iniciativas.", "excerpt_keywords": "Keywords: Prequalification, WHO, Pharmaceuticals, Quality Control Laboratories, Capacity Building"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "195ab8b7-4578-46d1-b960-0763bc2c5c9a", "node_type": "4", "metadata": {"page_label": "45", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nof reproductive health products. The Programme had continued to work closely with the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria.\n\nThe number of applications for products to be prequalified in 2011 was 54 (as at 10 October 2011), and of these 35 had been accepted. Twenty-one applications for APIs had been received, two of which had been prequalified and 19 were under assessment. As for the prequalification of control laboratories, five laboratories had been prequalified since October 2010. There are now six prequalified control laboratories in all WHO regions.\n\nIn addition, a retrospective study of generic product dossiers had been conducted. The results showed a number of deficiencies and indicated the need for capacity building for a number of manufacturers of generic products. An external assessment of the WHO Prequalification of Medicines Programme had been conducted and the results were generally positive.\n\nTraining in capacity building for NMRAs was increasing. In 2010 the WHO Prequalification of Medicines Programme organized 16 workshops and was involved in a further five. In 2011 the Programme organized 10 workshops and was involved in a further seven. However, the challenge was to ensure that training was translated into improved implementation of the best practices.\n\nPrequalification is highly dependent on the support from national regulators who are assisting WHO in this programme.\n\nIt was reported that donor funds were declining and that technical expertise was increasingly difficult to obtain. As in many other areas, the WHO Prequalification of Medicines Programme had been trying to do more with less funds.\n\nThe Expert Committee considered that the presentation had highlighted the importance of the WHO Prequalification of Medicines Programme, which was having an influence in a number of areas, such as strengthening capacity at local level and making medicines accessible to those who need them most.\n\n## 10. Prequalification of quality control laboratories\n\n### 10.1 Update on the prequalification of quality control laboratories\n\nThe prequalification procedure for quality control laboratories was originally established in 2004 for Africa only and has since expanded globally. Any quality control laboratory (whether public or private) may participate in the programme. Participation is voluntary and many laboratories have asked to participate. Most of the interested laboratories have been in the African region (the first to be focused on in the expression of interest), where 22 laboratories have expressed interest and so far six have been prequalified. Six laboratories had also been prequalified in Europe. The programme involves initial inspections and pre-audits to assess capacity, followed by a strong capacity-building component involving training.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "76c91d226304f5a221116d15ecbbfb4114854b7ac74eb1b43d6b7c5b9d58e346", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nof reproductive health products. The Programme had continued to work closely with the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria.\n\nThe number of applications for products to be prequalified in 2011 was 54 (as at 10 October 2011), and of these 35 had been accepted. Twenty-one applications for APIs had been received, two of which had been prequalified and 19 were under assessment. As for the prequalification of control laboratories, five laboratories had been prequalified since October 2010. There are now six prequalified control laboratories in all WHO regions.\n\nIn addition, a retrospective study of generic product dossiers had been conducted. The results showed a number of deficiencies and indicated the need for capacity building for a number of manufacturers of generic products. An external assessment of the WHO Prequalification of Medicines Programme had been conducted and the results were generally positive.\n\nTraining in capacity building for NMRAs was increasing. In 2010 the WHO Prequalification of Medicines Programme organized 16 workshops and was involved in a further five. In 2011 the Programme organized 10 workshops and was involved in a further seven. However, the challenge was to ensure that training was translated into improved implementation of the best practices.\n\nPrequalification is highly dependent on the support from national regulators who are assisting WHO in this programme.\n\nIt was reported that donor funds were declining and that technical expertise was increasingly difficult to obtain. As in many other areas, the WHO Prequalification of Medicines Programme had been trying to do more with less funds.\n\nThe Expert Committee considered that the presentation had highlighted the importance of the WHO Prequalification of Medicines Programme, which was having an influence in a number of areas, such as strengthening capacity at local level and making medicines accessible to those who need them most.\n\n## 10. Prequalification of quality control laboratories\n\n### 10.1 Update on the prequalification of quality control laboratories\n\nThe prequalification procedure for quality control laboratories was originally established in 2004 for Africa only and has since expanded globally. Any quality control laboratory (whether public or private) may participate in the programme. Participation is voluntary and many laboratories have asked to participate. Most of the interested laboratories have been in the African region (the first to be focused on in the expression of interest), where 22 laboratories have expressed interest and so far six have been prequalified. Six laboratories had also been prequalified in Europe. The programme involves initial inspections and pre-audits to assess capacity, followed by a strong capacity-building component involving training.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2894, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "77645e93-5106-4199-bce8-637d3cfdcc91": {"__data__": {"id_": "77645e93-5106-4199-bce8-637d3cfdcc91", "embedding": null, "metadata": {"page_label": "46", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 10.2 Update on the surveys of the quality of medicines\n\nA survey on the quality of antimalarials in Africa was carried out in cooperation with NMRAs in Cameroon, Ethiopia, Ghana, Kenya, Nigeria and the United Republic of Tanzania. A total of 935 samples was collected at all distribution levels and screened, with 306 of them being tested in a laboratory according to either *The International Pharmacopoeia* or the *United States Pharmacopeia*. There was a 28.5% failure rate overall; two countries showed a 63% and 58% failure rate, respectively. The failure rate for prequalified products was 4% and that for non-prequalified products was 40%. The survey also revealed that some products tested were not registered in the country concerned and some samples contained no active ingredients.\n\nA further study of TB medicines in the newly independent states showed much less deviation from acceptable standards, and none of the WHO-prequalified products failed. However, the study found that several medicines raised quality concerns. This led to a further study which showed that, for example, rifampicin capsules showed problems in assay, probably as a result of stability problems. An additional study of isoniazid/rifampicin tablets revealed a high rate of failure when tested according to *The International Pharmacopoeia* but samples passed when tested with *British Pharmacopoeia* methods.\n\nThe Expert Committee noted the outcome of the study and recommended that feedback should be provided to the respective pharmacopoeias.\n\n# 11. Regulatory guidance\n\n## 11.1 Policy on oseltamivir and zanamivir\n\nA draft document on the shelf-life expiry of oseltamivir was reviewed by the Expert Committee. The issue had arisen since, during the recent H1N1 pandemic, much of the stock of oseltamivir was assigned a shelf-life of five years; it also had a five-year expiry date on the package label. Recently, however, some regulators had extended the shelf-life from five to seven years and some special measures were put in place to enable this extension. Much of the stockpile was manufactured five or six years ago and questions had now been received from Member States as to what they should do with the material.\n\nThe issue was presented to the Expert Committee with a view to obtaining guidance on the retention or disposal of expired stocks of oseltamivir capsules and zanamivir for finished products for which the shelf-life had been extended from five to seven years by a number of national and regional regulatory authorities.\n\nWHO would not normally recommend use of medicines after their expiration since the manufacturer would have tested the product as being within specifications during that period. However, it was noted that the document acknowledged that countries were reluctant to destroy stockpiled medicines since...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Calidad de Medicamentos Antimal\u00e1ricos en \u00c1frica**: Se realiz\u00f3 una encuesta sobre la calidad de los medicamentos antimal\u00e1ricos en varios pa\u00edses africanos, donde se recolectaron 935 muestras. La tasa de fallos fue del 28.5%, con productos precalificados mostrando una tasa de fallo del 4% en comparaci\u00f3n con el 40% de los productos no precalificados. Adem\u00e1s, se encontraron productos no registrados y algunos sin ingredientes activos.\n\n2. **Estudio de Medicamentos para la Tuberculosis**: Un estudio adicional sobre medicamentos para la tuberculosis en estados reci\u00e9n independientes mostr\u00f3 que, aunque no hubo fallos en productos precalificados por la OMS, se identificaron preocupaciones de calidad en varios medicamentos. Se realizaron pruebas que revelaron problemas de estabilidad en c\u00e1psulas de rifampicina y una alta tasa de fallos en tabletas de isoniazida/rifampicina seg\u00fan la *Farmacopea Internacional*.\n\n3. **Pol\u00edtica sobre Oseltamivir y Zanamivir**: La Comisi\u00f3n de Expertos revis\u00f3 un documento sobre la vida \u00fatil de oseltamivir, que hab\u00eda sido extendida de cinco a siete a\u00f1os por algunos reguladores. Se discuti\u00f3 la retenci\u00f3n o eliminaci\u00f3n de existencias de medicamentos caducados, considerando que la OMS generalmente no recomienda el uso de medicamentos despu\u00e9s de su fecha de caducidad, aunque se reconoci\u00f3 la renuencia de los pa\u00edses a destruir medicamentos almacenados.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1l fue la tasa de fallo de los productos antimal\u00e1ricos en los pa\u00edses que participaron en la encuesta y qu\u00e9 diferencias se observaron entre productos precalificados y no precalificados?**\n   - La tasa de fallo general fue del 28.5%, con productos precalificados mostrando una tasa de fallo del 4% y productos no precalificados del 40%.\n\n2. **\u00bfQu\u00e9 problemas de calidad se identificaron en los medicamentos para la tuberculosis y qu\u00e9 m\u00e9todos de prueba mostraron resultados contradictorios?**\n   - Se identificaron problemas de calidad en las c\u00e1psulas de rifampicina, probablemente debido a problemas de estabilidad. Las tabletas de isoniazida/rifampicina mostraron una alta tasa de fallo seg\u00fan la *Farmacopea Internacional*, pero pasaron las pruebas con m\u00e9todos de la *Farmacopea Brit\u00e1nica*.\n\n3. **\u00bfQu\u00e9 consideraciones se discutieron en relaci\u00f3n con la eliminaci\u00f3n de existencias de oseltamivir y zanamivir que hab\u00edan sido extendidas m\u00e1s all\u00e1 de su fecha de caducidad?**\n   - La OMS generalmente no recomienda el uso de medicamentos despu\u00e9s de su fecha de caducidad, pero se reconoci\u00f3 que los pa\u00edses son reacios a destruir medicamentos almacenados, lo que llev\u00f3 a la necesidad de orientaci\u00f3n sobre la retenci\u00f3n o eliminaci\u00f3n de estos productos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Programa de Precalificaci\u00f3n de Medicamentos de la OMS**:\n   - **Objetivo**: Mejorar la calidad y el acceso a productos farmac\u00e9uticos, especialmente en salud reproductiva y enfermedades como VIH/SIDA, tuberculosis y malaria.\n   - **Resultados de 2011**: Se recibieron 54 solicitudes para precalificaci\u00f3n, de las cuales 35 fueron aceptadas. Se recibieron 21 solicitudes para Ingredientes Farmac\u00e9uticos Activos (APIs), con 2 precalificados y 19 en evaluaci\u00f3n.\n\n2. **Capacitaci\u00f3n y Desarrollo de Capacidades**:\n   - **Aumento de Talleres**: En 2010, se organizaron 16 talleres y en 2011, 10 talleres adicionales, con el objetivo de capacitar a las Autoridades Nacionales de Regulaci\u00f3n de Medicamentos (NMRAs).\n   - **Desaf\u00edos**: Asegurar que la capacitaci\u00f3n se traduzca en la implementaci\u00f3n de mejores pr\u00e1cticas.\n\n3. **Desaf\u00edos Financieros y T\u00e9cnicos**:\n   - **Disminuci\u00f3n de Fondos**: Se report\u00f3 una disminuci\u00f3n en los fondos de donantes y dificultades para obtener experiencia t\u00e9cnica, lo que afecta la operaci\u00f3n del programa.\n\n4. **Precalificaci\u00f3n de Laboratorios de Control de Calidad**:\n   - **Expansi\u00f3n Global**: Originalmente establecido en 2004 para \u00c1frica, el programa se ha expandido globalmente. Hasta la fecha, 22 laboratorios en \u00c1frica han mostrado inter\u00e9s, de los cuales 6 han sido precalificados, y otros 6 en Europa.\n   - **Proceso de Participaci\u00f3n**: La participaci\u00f3n es voluntaria y se basa en inspecciones iniciales y auditor\u00edas previas para evaluar la capacidad, seguidas de un componente de capacitaci\u00f3n.\n\n5. **Entidades Involucradas**:\n   - **OMS (Organizaci\u00f3n Mundial de la Salud)**: Coordinadora del programa de precalificaci\u00f3n.\n   - **NMRAs (Autoridades Nacionales de Regulaci\u00f3n de Medicamentos)**: Colaboradores clave en el proceso de precalificaci\u00f3n.\n   - **Global Fund**: Colaboraci\u00f3n en el contexto de salud reproductiva y enfermedades infecciosas.\n\nEste resumen destaca la importancia del Programa de Precalificaci\u00f3n de Medicamentos de la OMS en la mejora de la calidad y el acceso a medicamentos, as\u00ed como los desaf\u00edos que enfrenta en t\u00e9rminos de financiamiento y capacitaci\u00f3n.", "excerpt_keywords": "Keywords: antimalarials, quality survey, oseltamivir, tuberculosis, pharmacopoeia"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d59777bf-575f-4902-9541-6b451dc23450", "node_type": "4", "metadata": {"page_label": "46", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 10.2 Update on the surveys of the quality of medicines\n\nA survey on the quality of antimalarials in Africa was carried out in cooperation with NMRAs in Cameroon, Ethiopia, Ghana, Kenya, Nigeria and the United Republic of Tanzania. A total of 935 samples was collected at all distribution levels and screened, with 306 of them being tested in a laboratory according to either *The International Pharmacopoeia* or the *United States Pharmacopeia*. There was a 28.5% failure rate overall; two countries showed a 63% and 58% failure rate, respectively. The failure rate for prequalified products was 4% and that for non-prequalified products was 40%. The survey also revealed that some products tested were not registered in the country concerned and some samples contained no active ingredients.\n\nA further study of TB medicines in the newly independent states showed much less deviation from acceptable standards, and none of the WHO-prequalified products failed. However, the study found that several medicines raised quality concerns. This led to a further study which showed that, for example, rifampicin capsules showed problems in assay, probably as a result of stability problems. An additional study of isoniazid/rifampicin tablets revealed a high rate of failure when tested according to *The International Pharmacopoeia* but samples passed when tested with *British Pharmacopoeia* methods.\n\nThe Expert Committee noted the outcome of the study and recommended that feedback should be provided to the respective pharmacopoeias.\n\n# 11. Regulatory guidance\n\n## 11.1 Policy on oseltamivir and zanamivir\n\nA draft document on the shelf-life expiry of oseltamivir was reviewed by the Expert Committee. The issue had arisen since, during the recent H1N1 pandemic, much of the stock of oseltamivir was assigned a shelf-life of five years; it also had a five-year expiry date on the package label. Recently, however, some regulators had extended the shelf-life from five to seven years and some special measures were put in place to enable this extension. Much of the stockpile was manufactured five or six years ago and questions had now been received from Member States as to what they should do with the material.\n\nThe issue was presented to the Expert Committee with a view to obtaining guidance on the retention or disposal of expired stocks of oseltamivir capsules and zanamivir for finished products for which the shelf-life had been extended from five to seven years by a number of national and regional regulatory authorities.\n\nWHO would not normally recommend use of medicines after their expiration since the manufacturer would have tested the product as being within specifications during that period. However, it was noted that the document acknowledged that countries were reluctant to destroy stockpiled medicines since...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4ec988c67b1aaa9301cd969c730e6e802298694d8ae66c7199f5ba7e90194c02", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 10.2 Update on the surveys of the quality of medicines\n\nA survey on the quality of antimalarials in Africa was carried out in cooperation with NMRAs in Cameroon, Ethiopia, Ghana, Kenya, Nigeria and the United Republic of Tanzania. A total of 935 samples was collected at all distribution levels and screened, with 306 of them being tested in a laboratory according to either *The International Pharmacopoeia* or the *United States Pharmacopeia*. There was a 28.5% failure rate overall; two countries showed a 63% and 58% failure rate, respectively. The failure rate for prequalified products was 4% and that for non-prequalified products was 40%. The survey also revealed that some products tested were not registered in the country concerned and some samples contained no active ingredients.\n\nA further study of TB medicines in the newly independent states showed much less deviation from acceptable standards, and none of the WHO-prequalified products failed. However, the study found that several medicines raised quality concerns. This led to a further study which showed that, for example, rifampicin capsules showed problems in assay, probably as a result of stability problems. An additional study of isoniazid/rifampicin tablets revealed a high rate of failure when tested according to *The International Pharmacopoeia* but samples passed when tested with *British Pharmacopoeia* methods.\n\nThe Expert Committee noted the outcome of the study and recommended that feedback should be provided to the respective pharmacopoeias.\n\n# 11. Regulatory guidance\n\n## 11.1 Policy on oseltamivir and zanamivir\n\nA draft document on the shelf-life expiry of oseltamivir was reviewed by the Expert Committee. The issue had arisen since, during the recent H1N1 pandemic, much of the stock of oseltamivir was assigned a shelf-life of five years; it also had a five-year expiry date on the package label. Recently, however, some regulators had extended the shelf-life from five to seven years and some special measures were put in place to enable this extension. Much of the stockpile was manufactured five or six years ago and questions had now been received from Member States as to what they should do with the material.\n\nThe issue was presented to the Expert Committee with a view to obtaining guidance on the retention or disposal of expired stocks of oseltamivir capsules and zanamivir for finished products for which the shelf-life had been extended from five to seven years by a number of national and regional regulatory authorities.\n\nWHO would not normally recommend use of medicines after their expiration since the manufacturer would have tested the product as being within specifications during that period. However, it was noted that the document acknowledged that countries were reluctant to destroy stockpiled medicines since...", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2835, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f2957087-6ef6-4edd-bb35-baf9abfb1e1d": {"__data__": {"id_": "f2957087-6ef6-4edd-bb35-baf9abfb1e1d", "embedding": null, "metadata": {"page_label": "47", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nthe scale and severity of a future pandemic could not be predicted and demand may exceed stockpile and manufacturing capacity. The document drafted for discussion included advice that, where a national authority elected to extend shelf-life, this should be considered only for stocks that had been stored under controlled conditions in accordance with manufacturers\u2019 recommendations, and such stocks should be used only in emergencies and where no alternative stocks or alternative medicines were available.\n\nThe Expert Committee recommended that such action should be under the sole responsibility of each national authority, taking into consideration the following points, to ensure that there was no negative impact on the patients.\n\n- The manufacturer should be consulted for evidence to support extending the shelf-life.\n- The products are maintained under storage conditions which comply with the label requirements.\n- The national regulatory authority may wish to follow up with its own testing.\n\n## 11.2 Assessment criteria for blood regulatory systems\n\nThe inherent risks of blood and the difficulty of providing adequate, timely and equitable access to safe blood products require an organized national or regional blood regulatory system in which a competent blood products regulatory authority ensures that appropriate standards are met for production of such products and that safety is monitored. In 2010 the World Health Assembly urged Member States to update their national regulations on donor assessment and deferral: the collection, testing, processing, storage, transportation and use of blood products, and operation of regulatory authorities in order to \u201censure that regulatory control in the area of quality and safety of blood products across the entire transfusion chain meets internationally recognized standards\u201d.\n\nAt the 13th meeting of ICDRA in 2008 it was recommended that WHO should take steps to further develop and strengthen national and regional blood regulatory authorities, and provide harmonized assessment criteria for blood regulatory systems.\n\nTo achieve the aim of an international best practice national blood regulatory framework, the WHO Blood Regulators Network (BRN) had identified a set of integrated general and specific regulatory functions applicable from the time of the collection of source material through to the quality control of the final product, not only covering blood products but also associated substances and medical devices such as in vitro diagnostics. The secretariat had subsequently developed a document on assessment criteria for national blood regulatory systems which was presented to the Expert Committee for discussion. The set of functions identified by the BRN was used to develop an assessment tool for regulatory authorities.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Extensi\u00f3n de la vida \u00fatil de medicamentos**: El documento discute la posibilidad de que las autoridades nacionales extiendan la vida \u00fatil de los medicamentos almacenados bajo condiciones controladas, enfatizando que esto debe hacerse con precauci\u00f3n y solo en situaciones de emergencia. Se recomienda consultar al fabricante y seguir las condiciones de almacenamiento adecuadas.\n\n2. **Regulaci\u00f3n de productos sangu\u00edneos**: Se aborda la necesidad de un sistema regulatorio organizado para la sangre y los productos sangu\u00edneos, destacando la importancia de que las autoridades competentes aseguren que se cumplan los est\u00e1ndares de producci\u00f3n y seguridad. Se menciona la urgencia de actualizar las regulaciones nacionales sobre la evaluaci\u00f3n y la deferencia de donantes.\n\n3. **Red de Reguladores de Sangre de la OMS**: La OMS ha identificado funciones regulatorias integradas para establecer un marco de mejores pr\u00e1cticas en la regulaci\u00f3n de la sangre, que abarca desde la recolecci\u00f3n del material hasta el control de calidad del producto final. Se ha desarrollado un documento sobre criterios de evaluaci\u00f3n para sistemas regulatorios de sangre.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios que deben considerarse al extender la vida \u00fatil de los medicamentos seg\u00fan el documento de la OMS?**\n   - Respuesta: Los criterios incluyen consultar al fabricante para obtener evidencia que respalde la extensi\u00f3n de la vida \u00fatil, asegurarse de que los productos se mantengan bajo condiciones de almacenamiento que cumplan con los requisitos de la etiqueta, y que la autoridad reguladora nacional pueda realizar pruebas adicionales.\n\n2. **\u00bfQu\u00e9 recomendaciones se hicieron en la 13\u00aa reuni\u00f3n de ICDRA en 2008 respecto a las autoridades regulatorias de sangre?**\n   - Respuesta: Se recomend\u00f3 que la OMS tomara medidas para desarrollar y fortalecer las autoridades regulatorias nacionales y regionales de sangre, as\u00ed como proporcionar criterios de evaluaci\u00f3n armonizados para los sistemas regulatorios de sangre.\n\n3. **\u00bfQu\u00e9 papel juega la Red de Reguladores de Sangre de la OMS en la regulaci\u00f3n de productos sangu\u00edneos?**\n   - Respuesta: La Red de Reguladores de Sangre de la OMS ha identificado un conjunto de funciones regulatorias integradas que se aplican desde la recolecci\u00f3n del material fuente hasta el control de calidad del producto final, abarcando no solo productos sangu\u00edneos, sino tambi\u00e9n sustancias asociadas y dispositivos m\u00e9dicos como diagn\u00f3sticos in vitro.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Encuesta sobre la Calidad de Medicamentos Antimal\u00e1ricos en \u00c1frica**:\n   - **Participantes**: Cooperaci\u00f3n con Autoridades Nacionales de Regulaci\u00f3n de Medicamentos (NMRAs) en pa\u00edses como Camer\u00fan, Etiop\u00eda, Ghana, Kenia, Nigeria y Tanzania.\n   - **Muestras**: Se recolectaron 935 muestras, de las cuales 306 fueron analizadas en laboratorio.\n   - **Tasa de Fallo**: 28.5% en general; 4% para productos precalificados y 40% para no precalificados. Se encontraron productos no registrados y algunos sin ingredientes activos.\n\n2. **Estudio de Medicamentos para la Tuberculosis**:\n   - **Resultados**: Menos desviaciones de los est\u00e1ndares aceptables; ning\u00fan producto precalificado por la OMS fall\u00f3.\n   - **Preocupaciones de Calidad**: Problemas de estabilidad en c\u00e1psulas de rifampicina y alta tasa de fallos en tabletas de isoniazida/rifampicina seg\u00fan la *Farmacopea Internacional*, aunque pasaron pruebas con m\u00e9todos de la *Farmacopea Brit\u00e1nica*.\n\n3. **Pol\u00edtica sobre Oseltamivir y Zanamivir**:\n   - **Revisi\u00f3n de Vida \u00datil**: Se discuti\u00f3 la extensi\u00f3n de la vida \u00fatil de oseltamivir de cinco a siete a\u00f1os por algunos reguladores.\n   - **Orientaci\u00f3n sobre Medicamentos Caducados**: La OMS generalmente no recomienda el uso de medicamentos despu\u00e9s de su fecha de caducidad, pero se reconoci\u00f3 la renuencia de los pa\u00edses a destruir existencias almacenadas.\n\n### Entidades Clave\n- **Medicamentos**: Antimal\u00e1ricos, Rifampicina, Isoniazida, Oseltamivir, Zanamivir.\n- **Organismos**: Organizaci\u00f3n Mundial de la Salud (OMS), Autoridades Nacionales de Regulaci\u00f3n de Medicamentos (NMRAs).\n- **Normativas**: *Farmacopea Internacional*, *Farmacopea Brit\u00e1nica*, *Farmacopea de los Estados Unidos*. \n\nEste resumen destaca los hallazgos sobre la calidad de los medicamentos en \u00c1frica y los estudios relacionados con la tuberculosis, as\u00ed como las consideraciones regulatorias sobre la vida \u00fatil de ciertos medicamentos antivirales.", "excerpt_keywords": "Keywords: shelf-life extension, blood regulatory systems, pharmaceutical preparations, WHO recommendations, emergency stockpiles"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3eed0323-55fb-44b3-b8e5-ebce1e2f7553", "node_type": "4", "metadata": {"page_label": "47", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nthe scale and severity of a future pandemic could not be predicted and demand may exceed stockpile and manufacturing capacity. The document drafted for discussion included advice that, where a national authority elected to extend shelf-life, this should be considered only for stocks that had been stored under controlled conditions in accordance with manufacturers\u2019 recommendations, and such stocks should be used only in emergencies and where no alternative stocks or alternative medicines were available.\n\nThe Expert Committee recommended that such action should be under the sole responsibility of each national authority, taking into consideration the following points, to ensure that there was no negative impact on the patients.\n\n- The manufacturer should be consulted for evidence to support extending the shelf-life.\n- The products are maintained under storage conditions which comply with the label requirements.\n- The national regulatory authority may wish to follow up with its own testing.\n\n## 11.2 Assessment criteria for blood regulatory systems\n\nThe inherent risks of blood and the difficulty of providing adequate, timely and equitable access to safe blood products require an organized national or regional blood regulatory system in which a competent blood products regulatory authority ensures that appropriate standards are met for production of such products and that safety is monitored. In 2010 the World Health Assembly urged Member States to update their national regulations on donor assessment and deferral: the collection, testing, processing, storage, transportation and use of blood products, and operation of regulatory authorities in order to \u201censure that regulatory control in the area of quality and safety of blood products across the entire transfusion chain meets internationally recognized standards\u201d.\n\nAt the 13th meeting of ICDRA in 2008 it was recommended that WHO should take steps to further develop and strengthen national and regional blood regulatory authorities, and provide harmonized assessment criteria for blood regulatory systems.\n\nTo achieve the aim of an international best practice national blood regulatory framework, the WHO Blood Regulators Network (BRN) had identified a set of integrated general and specific regulatory functions applicable from the time of the collection of source material through to the quality control of the final product, not only covering blood products but also associated substances and medical devices such as in vitro diagnostics. The secretariat had subsequently developed a document on assessment criteria for national blood regulatory systems which was presented to the Expert Committee for discussion. The set of functions identified by the BRN was used to develop an assessment tool for regulatory authorities.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "95864c38cd9b3366215e53d6ff6727d3ce3f050cd59fae387937bcbc70421d6d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nthe scale and severity of a future pandemic could not be predicted and demand may exceed stockpile and manufacturing capacity. The document drafted for discussion included advice that, where a national authority elected to extend shelf-life, this should be considered only for stocks that had been stored under controlled conditions in accordance with manufacturers\u2019 recommendations, and such stocks should be used only in emergencies and where no alternative stocks or alternative medicines were available.\n\nThe Expert Committee recommended that such action should be under the sole responsibility of each national authority, taking into consideration the following points, to ensure that there was no negative impact on the patients.\n\n- The manufacturer should be consulted for evidence to support extending the shelf-life.\n- The products are maintained under storage conditions which comply with the label requirements.\n- The national regulatory authority may wish to follow up with its own testing.\n\n## 11.2 Assessment criteria for blood regulatory systems\n\nThe inherent risks of blood and the difficulty of providing adequate, timely and equitable access to safe blood products require an organized national or regional blood regulatory system in which a competent blood products regulatory authority ensures that appropriate standards are met for production of such products and that safety is monitored. In 2010 the World Health Assembly urged Member States to update their national regulations on donor assessment and deferral: the collection, testing, processing, storage, transportation and use of blood products, and operation of regulatory authorities in order to \u201censure that regulatory control in the area of quality and safety of blood products across the entire transfusion chain meets internationally recognized standards\u201d.\n\nAt the 13th meeting of ICDRA in 2008 it was recommended that WHO should take steps to further develop and strengthen national and regional blood regulatory authorities, and provide harmonized assessment criteria for blood regulatory systems.\n\nTo achieve the aim of an international best practice national blood regulatory framework, the WHO Blood Regulators Network (BRN) had identified a set of integrated general and specific regulatory functions applicable from the time of the collection of source material through to the quality control of the final product, not only covering blood products but also associated substances and medical devices such as in vitro diagnostics. The secretariat had subsequently developed a document on assessment criteria for national blood regulatory systems which was presented to the Expert Committee for discussion. The set of functions identified by the BRN was used to develop an assessment tool for regulatory authorities.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2878, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d807e6d0-7085-4c9f-8ba3-96102b8d9cdc": {"__data__": {"id_": "d807e6d0-7085-4c9f-8ba3-96102b8d9cdc", "embedding": null, "metadata": {"page_label": "48", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Pharmaceutical Development for Multisource (Generic) Pharmaceutical Products \u2013 Points to Consider\n\nFollowing drafting of the original document at a BRN meeting in 2008, Health Canada and Swissmedic had carried out self-assessment exercises on the basis of the draft and further self-assessment was carried out in Argentina, Brazil and Indonesia. In 2010 the document was introduced to ICDRA at a BRN workshop.\n\nThe Expert Committee took note of the assessment tool presented.\n\n## 11.3 Pharmaceutical Development for Multisource (Generic) Pharmaceutical Products \u2013 Points to Consider\n\nThe development of the document on pharmaceutical development for multisource (generic) pharmaceutical products had been originally endorsed by the Expert Committee in 2007 and, following the collation of comments, was discussed by a WHO expert working group in 2008. The draft was subsequently revised, taking into account the comments received and those made by the working group, and the revised draft was submitted to the Expert Committee in 2008. All comments were incorporated and the Expert Committee discussed the guidelines again in 2009. The draft was further discussed both at the WHO consultation on paediatrics and generics guidelines in 2010 and by the Expert Committee that same year. During 2011 the draft was discussed once more at the WHO consultation on paediatrics and generics guidelines and mailed globally for comments before being resubmitted to the Expert Committee.\n\nThe document provides guidance on the contents of a pharmaceutical development plan for multisource pharmaceutical products including both pre-development activities and the development period, for both the applicants for marketing authorizations and NMRAs. The guidance focuses on the development of multisource finished pharmaceutical products (FPPs) which are intended to be bioequivalent to the relevant comparator product. Multisource FPPs are usually required to be therapeutically equivalent to the comparator product. It aims to provide a structured approach for industry, following the ICH common technical document format for developing high quality, multisource FPPs.\n\nThe Expert Committee reviewed the document and the comments received and made a number of changes to the text. The Committee adopted the document on pharmaceutical development of multisource (generic) pharmaceutical products \u2013 points to consider subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 3).\n\n## 11.4 Guidelines on Submission of Documentation for a Multisource (Generic) Finished Pharmaceutical Product: Quality Part\n\nThese guidelines, which relate to submission of documentation in an application for the evaluation of a product for prequalification, were drafted in June 2010 and discussed within the WHO Prequalification of Medicines Programme assessment.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS, titulado \"Desarrollo Farmac\u00e9utico para Productos Farmac\u00e9uticos Multifuente (Gen\u00e9ricos) \u2013 Puntos a Considerar\", aborda la evoluci\u00f3n y las pautas para el desarrollo de productos farmac\u00e9uticos gen\u00e9ricos. Se menciona que el documento fue inicialmente respaldado por el Comit\u00e9 de Expertos en 2007 y ha pasado por m\u00faltiples revisiones y discusiones en diferentes a\u00f1os y foros, incluyendo consultas sobre pediatr\u00eda y gu\u00edas de gen\u00e9ricos. El objetivo principal es proporcionar una gu\u00eda estructurada para la industria sobre c\u00f3mo desarrollar productos farmac\u00e9uticos terminados (FPPs) que sean bioequivalentes a productos comparadores relevantes. Tambi\u00e9n se discuten las pautas para la presentaci\u00f3n de documentaci\u00f3n relacionada con la evaluaci\u00f3n de productos para la pre-calificaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los principales objetivos del documento sobre el desarrollo farmac\u00e9utico para productos gen\u00e9ricos, y c\u00f3mo se relacionan con la bioequivalencia?**\n   - El documento tiene como objetivo proporcionar una gu\u00eda sobre el contenido de un plan de desarrollo farmac\u00e9utico para productos farmac\u00e9uticos multifuente, enfoc\u00e1ndose en la necesidad de que los productos terminados sean bioequivalentes y terap\u00e9uticamente equivalentes a los productos comparadores.\n\n2. **\u00bfQu\u00e9 procesos de revisi\u00f3n y consulta se llevaron a cabo antes de la adopci\u00f3n final del documento por parte del Comit\u00e9 de Expertos?**\n   - El documento fue discutido en m\u00faltiples ocasiones desde su redacci\u00f3n inicial en 2008, incluyendo revisiones en 2009, 2010 y 2011, donde se recopilaron comentarios de diversas consultas y se realizaron revisiones basadas en esos comentarios antes de su adopci\u00f3n final.\n\n3. **\u00bfQu\u00e9 importancia tienen las pautas sobre la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos multifuente en el contexto de la pre-calificaci\u00f3n de medicamentos?**\n   - Estas pautas son cruciales para asegurar que la documentaci\u00f3n presentada para la evaluaci\u00f3n de productos para la pre-calificaci\u00f3n cumpla con los est\u00e1ndares de calidad necesarios, facilitando as\u00ed el acceso a medicamentos seguros y efectivos en el mercado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Extensi\u00f3n de la Vida \u00datil de Medicamentos**:\n   - Se discute la posibilidad de que las autoridades nacionales extiendan la vida \u00fatil de medicamentos almacenados bajo condiciones controladas.\n   - Se enfatiza que esta acci\u00f3n debe ser considerada solo en emergencias y tras consultar al fabricante, asegurando que se mantengan las condiciones de almacenamiento adecuadas.\n\n2. **Regulaci\u00f3n de Productos Sangu\u00edneos**:\n   - Se destaca la necesidad de un sistema regulatorio organizado para garantizar la seguridad y calidad de los productos sangu\u00edneos.\n   - La Asamblea Mundial de la Salud inst\u00f3 a los Estados Miembros a actualizar sus regulaciones nacionales sobre la evaluaci\u00f3n de donantes y el manejo de productos sangu\u00edneos.\n\n3. **Red de Reguladores de Sangre de la OMS (BRN)**:\n   - La OMS ha identificado funciones regulatorias integradas para establecer un marco de mejores pr\u00e1cticas en la regulaci\u00f3n de la sangre, abarcando desde la recolecci\u00f3n hasta el control de calidad del producto final.\n   - Se ha desarrollado un documento sobre criterios de evaluaci\u00f3n para sistemas regulatorios de sangre, presentado a la Comisi\u00f3n de Expertos para discusi\u00f3n.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la regulaci\u00f3n y est\u00e1ndares de salud a nivel internacional.\n- **Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas**: Grupo que proporciona recomendaciones sobre la regulaci\u00f3n de medicamentos.\n- **Red de Reguladores de Sangre de la OMS (BRN)**: Iniciativa para mejorar la regulaci\u00f3n de productos sangu\u00edneos a nivel nacional e internacional.", "excerpt_keywords": "Keywords: pharmaceutical development, multisource products, bioequivalence, WHO guidelines, prequalification"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a9744e23-27fe-48db-a6d4-f0ee6f67754e", "node_type": "4", "metadata": {"page_label": "48", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Pharmaceutical Development for Multisource (Generic) Pharmaceutical Products \u2013 Points to Consider\n\nFollowing drafting of the original document at a BRN meeting in 2008, Health Canada and Swissmedic had carried out self-assessment exercises on the basis of the draft and further self-assessment was carried out in Argentina, Brazil and Indonesia. In 2010 the document was introduced to ICDRA at a BRN workshop.\n\nThe Expert Committee took note of the assessment tool presented.\n\n## 11.3 Pharmaceutical Development for Multisource (Generic) Pharmaceutical Products \u2013 Points to Consider\n\nThe development of the document on pharmaceutical development for multisource (generic) pharmaceutical products had been originally endorsed by the Expert Committee in 2007 and, following the collation of comments, was discussed by a WHO expert working group in 2008. The draft was subsequently revised, taking into account the comments received and those made by the working group, and the revised draft was submitted to the Expert Committee in 2008. All comments were incorporated and the Expert Committee discussed the guidelines again in 2009. The draft was further discussed both at the WHO consultation on paediatrics and generics guidelines in 2010 and by the Expert Committee that same year. During 2011 the draft was discussed once more at the WHO consultation on paediatrics and generics guidelines and mailed globally for comments before being resubmitted to the Expert Committee.\n\nThe document provides guidance on the contents of a pharmaceutical development plan for multisource pharmaceutical products including both pre-development activities and the development period, for both the applicants for marketing authorizations and NMRAs. The guidance focuses on the development of multisource finished pharmaceutical products (FPPs) which are intended to be bioequivalent to the relevant comparator product. Multisource FPPs are usually required to be therapeutically equivalent to the comparator product. It aims to provide a structured approach for industry, following the ICH common technical document format for developing high quality, multisource FPPs.\n\nThe Expert Committee reviewed the document and the comments received and made a number of changes to the text. The Committee adopted the document on pharmaceutical development of multisource (generic) pharmaceutical products \u2013 points to consider subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 3).\n\n## 11.4 Guidelines on Submission of Documentation for a Multisource (Generic) Finished Pharmaceutical Product: Quality Part\n\nThese guidelines, which relate to submission of documentation in an application for the evaluation of a product for prequalification, were drafted in June 2010 and discussed within the WHO Prequalification of Medicines Programme assessment.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "0559ee9111270bd52b6c2cd489b7e4c818b19a1ced6d0ab4c4ea10f70dd4ea98", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Pharmaceutical Development for Multisource (Generic) Pharmaceutical Products \u2013 Points to Consider\n\nFollowing drafting of the original document at a BRN meeting in 2008, Health Canada and Swissmedic had carried out self-assessment exercises on the basis of the draft and further self-assessment was carried out in Argentina, Brazil and Indonesia. In 2010 the document was introduced to ICDRA at a BRN workshop.\n\nThe Expert Committee took note of the assessment tool presented.\n\n## 11.3 Pharmaceutical Development for Multisource (Generic) Pharmaceutical Products \u2013 Points to Consider\n\nThe development of the document on pharmaceutical development for multisource (generic) pharmaceutical products had been originally endorsed by the Expert Committee in 2007 and, following the collation of comments, was discussed by a WHO expert working group in 2008. The draft was subsequently revised, taking into account the comments received and those made by the working group, and the revised draft was submitted to the Expert Committee in 2008. All comments were incorporated and the Expert Committee discussed the guidelines again in 2009. The draft was further discussed both at the WHO consultation on paediatrics and generics guidelines in 2010 and by the Expert Committee that same year. During 2011 the draft was discussed once more at the WHO consultation on paediatrics and generics guidelines and mailed globally for comments before being resubmitted to the Expert Committee.\n\nThe document provides guidance on the contents of a pharmaceutical development plan for multisource pharmaceutical products including both pre-development activities and the development period, for both the applicants for marketing authorizations and NMRAs. The guidance focuses on the development of multisource finished pharmaceutical products (FPPs) which are intended to be bioequivalent to the relevant comparator product. Multisource FPPs are usually required to be therapeutically equivalent to the comparator product. It aims to provide a structured approach for industry, following the ICH common technical document format for developing high quality, multisource FPPs.\n\nThe Expert Committee reviewed the document and the comments received and made a number of changes to the text. The Committee adopted the document on pharmaceutical development of multisource (generic) pharmaceutical products \u2013 points to consider subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 3).\n\n## 11.4 Guidelines on Submission of Documentation for a Multisource (Generic) Finished Pharmaceutical Product: Quality Part\n\nThese guidelines, which relate to submission of documentation in an application for the evaluation of a product for prequalification, were drafted in June 2010 and discussed within the WHO Prequalification of Medicines Programme assessment.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2894, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "9007136c-8a64-4bfe-b5f1-bc12b6876612": {"__data__": {"id_": "9007136c-8a64-4bfe-b5f1-bc12b6876612", "embedding": null, "metadata": {"page_label": "49", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\ngroup. Following further comments and review, the draft was first presented to the Expert Committee in October 2010. In early 2011 the text was once more reviewed in connection with the draft working document on *Points to consider for the development of multisource (generic) medicines*. Further discussion took place during the informal consultation on development of paediatric and generic medicines in May 2011. A further round of comments ensued, and the draft was also discussed by a small subgroup in September 2011 before being presented to the Expert Committee in October.\n\nDuring the development of the guidelines, some 26 manufacturers who participate in the WHO Prequalification of Medicines Programme also contributed and were involved in the consultation process which led to the first draft of the document. The document was also open for public comment on the WHO Medicines web site, and was presented at workshops organized by the WHO Prequalification of Medicines Programme. The concept behind the guidelines had been implemented since September 2010 with regard to submission to the prequalification process.\n\nThe Expert Committee reviewed the document and the comments received. There was concern about the title of the document and it was requested that the document be adapted to make it clear that the general principles outlined were also applicable to the general process of application for prequalification.\n\nThe members of the Expert Committee agreed to change the title of the guidelines to read: *Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part*.\n\nThe Expert Committee adopted the guidelines, subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 4). Furthermore, the Expert Committee proposed that a new general document be considered.\n\n## 11.5 Development of paediatric medicines: points to consider in pharmaceutical formulation\n\nSafe and effective pharmacotherapy in paediatric patients requires the timely development of medicines and information on their proper use to suit the age, physiological condition and body size of the child. Formulations developed specifically for children are often needed. The use of unlicensed and off-label medicines in children is widespread. Their effects on children have not been properly studied and age-appropriate formulations are generally not available.\n\nPharmacists, parents or caregivers are often faced with the need to manipulate an adult medicine in a way that is not described in the summary of product characteristics. This manipulation can be simple (e.g. breaking tablets", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Preguntas\n\n1. **\u00bfQu\u00e9 cambios se realizaron en el t\u00edtulo de las directrices propuestas por el Comit\u00e9 de Expertos de la OMS y por qu\u00e9?**\n   - El t\u00edtulo de las directrices se cambi\u00f3 a *Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part* para aclarar que los principios generales tambi\u00e9n eran aplicables al proceso de solicitud de precalificaci\u00f3n.\n\n2. **\u00bfCu\u00e1l fue el papel de los fabricantes en el desarrollo de las directrices sobre medicamentos multisource (gen\u00e9ricos)?**\n   - Durante el desarrollo de las directrices, 26 fabricantes que participan en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS contribuyeron y participaron en el proceso de consulta que llev\u00f3 al primer borrador del documento.\n\n3. **\u00bfCu\u00e1les son los desaf\u00edos asociados con la formulaci\u00f3n de medicamentos para pacientes pedi\u00e1tricos seg\u00fan el documento?**\n   - Los desaf\u00edos incluyen la necesidad de desarrollar formulaciones espec\u00edficas para ni\u00f1os, el uso generalizado de medicamentos no autorizados y fuera de indicaci\u00f3n, y la falta de estudios adecuados sobre los efectos de estos medicamentos en ni\u00f1os, lo que resulta en una disponibilidad limitada de formulaciones apropiadas para su edad.\n\n### Resumen de nivel superior\n\nEl documento de la OMS aborda la necesidad de directrices para la presentaci\u00f3n de documentaci\u00f3n relacionada con medicamentos gen\u00e9ricos en el contexto del Programa de Precalificaci\u00f3n de Medicamentos. Se destaca la importancia de adaptar las formulaciones para pacientes pedi\u00e1tricos, dado que los medicamentos para adultos a menudo no son adecuados para ni\u00f1os. La participaci\u00f3n de fabricantes en el desarrollo de estas directrices y la revisi\u00f3n del documento por parte del Comit\u00e9 de Expertos son aspectos clave del proceso. Adem\u00e1s, se subraya la preocupaci\u00f3n por el uso de medicamentos no autorizados en la poblaci\u00f3n pedi\u00e1trica y la falta de formulaciones adecuadas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Desarrollo Farmac\u00e9utico para Productos Gen\u00e9ricos**:\n   - El documento aborda el desarrollo de productos farmac\u00e9uticos multifuente (gen\u00e9ricos) y proporciona pautas sobre el contenido de un plan de desarrollo farmac\u00e9utico.\n   - Se enfoca en la bioequivalencia y la equivalencia terap\u00e9utica de los productos terminados en relaci\u00f3n con los productos comparadores.\n\n2. **Proceso de Revisi\u00f3n y Consulta**:\n   - El documento fue inicialmente respaldado por el Comit\u00e9 de Expertos en 2007 y ha pasado por m\u00faltiples revisiones y discusiones en 2008, 2009, 2010 y 2011.\n   - Se realizaron autoevaluaciones en varios pa\u00edses (Canad\u00e1, Suiza, Argentina, Brasil e Indonesia) y se recopilaron comentarios de diversas consultas antes de su adopci\u00f3n final.\n\n3. **Estructura y Enfoque**:\n   - Se propone un enfoque estructurado para la industria, siguiendo el formato del documento t\u00e9cnico com\u00fan de ICH, para desarrollar productos farmac\u00e9uticos de alta calidad.\n   - El documento incluye actividades de pre-desarrollo y el per\u00edodo de desarrollo para solicitantes de autorizaciones de comercializaci\u00f3n y autoridades reguladoras nacionales de medicamentos (NMRAs).\n\n4. **Pautas de Presentaci\u00f3n de Documentaci\u00f3n**:\n   - Se mencionan pautas espec\u00edficas para la presentaci\u00f3n de documentaci\u00f3n en aplicaciones para la evaluaci\u00f3n de productos para la pre-calificaci\u00f3n, redactadas en junio de 2010.\n   - Estas pautas son esenciales para asegurar que la documentaci\u00f3n cumpla con los est\u00e1ndares de calidad necesarios para la evaluaci\u00f3n de medicamentos.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la elaboraci\u00f3n del documento.\n- **Comit\u00e9 de Expertos**: Grupo que revis\u00f3 y aprob\u00f3 el documento.\n- **NMRAs (National Medicines Regulatory Authorities)**: Autoridades reguladoras que se ven afectadas por las pautas.\n- **ICH (International Council for Harmonisation)**: Organizaci\u00f3n que proporciona el formato t\u00e9cnico com\u00fan mencionado en el documento.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, generic medicines, paediatric formulations, prequalification"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "42dc5d37-72d3-4d2a-8aeb-c2ff4f7adf67", "node_type": "4", "metadata": {"page_label": "49", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\ngroup. Following further comments and review, the draft was first presented to the Expert Committee in October 2010. In early 2011 the text was once more reviewed in connection with the draft working document on *Points to consider for the development of multisource (generic) medicines*. Further discussion took place during the informal consultation on development of paediatric and generic medicines in May 2011. A further round of comments ensued, and the draft was also discussed by a small subgroup in September 2011 before being presented to the Expert Committee in October.\n\nDuring the development of the guidelines, some 26 manufacturers who participate in the WHO Prequalification of Medicines Programme also contributed and were involved in the consultation process which led to the first draft of the document. The document was also open for public comment on the WHO Medicines web site, and was presented at workshops organized by the WHO Prequalification of Medicines Programme. The concept behind the guidelines had been implemented since September 2010 with regard to submission to the prequalification process.\n\nThe Expert Committee reviewed the document and the comments received. There was concern about the title of the document and it was requested that the document be adapted to make it clear that the general principles outlined were also applicable to the general process of application for prequalification.\n\nThe members of the Expert Committee agreed to change the title of the guidelines to read: *Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part*.\n\nThe Expert Committee adopted the guidelines, subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 4). Furthermore, the Expert Committee proposed that a new general document be considered.\n\n## 11.5 Development of paediatric medicines: points to consider in pharmaceutical formulation\n\nSafe and effective pharmacotherapy in paediatric patients requires the timely development of medicines and information on their proper use to suit the age, physiological condition and body size of the child. Formulations developed specifically for children are often needed. The use of unlicensed and off-label medicines in children is widespread. Their effects on children have not been properly studied and age-appropriate formulations are generally not available.\n\nPharmacists, parents or caregivers are often faced with the need to manipulate an adult medicine in a way that is not described in the summary of product characteristics. This manipulation can be simple (e.g. breaking tablets", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "832b5ccd5c695a6c8ade7b11a2c928387995eb6a5370da67c6ef5a53cf7ab7db", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\ngroup. Following further comments and review, the draft was first presented to the Expert Committee in October 2010. In early 2011 the text was once more reviewed in connection with the draft working document on *Points to consider for the development of multisource (generic) medicines*. Further discussion took place during the informal consultation on development of paediatric and generic medicines in May 2011. A further round of comments ensued, and the draft was also discussed by a small subgroup in September 2011 before being presented to the Expert Committee in October.\n\nDuring the development of the guidelines, some 26 manufacturers who participate in the WHO Prequalification of Medicines Programme also contributed and were involved in the consultation process which led to the first draft of the document. The document was also open for public comment on the WHO Medicines web site, and was presented at workshops organized by the WHO Prequalification of Medicines Programme. The concept behind the guidelines had been implemented since September 2010 with regard to submission to the prequalification process.\n\nThe Expert Committee reviewed the document and the comments received. There was concern about the title of the document and it was requested that the document be adapted to make it clear that the general principles outlined were also applicable to the general process of application for prequalification.\n\nThe members of the Expert Committee agreed to change the title of the guidelines to read: *Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part*.\n\nThe Expert Committee adopted the guidelines, subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 4). Furthermore, the Expert Committee proposed that a new general document be considered.\n\n## 11.5 Development of paediatric medicines: points to consider in pharmaceutical formulation\n\nSafe and effective pharmacotherapy in paediatric patients requires the timely development of medicines and information on their proper use to suit the age, physiological condition and body size of the child. Formulations developed specifically for children are often needed. The use of unlicensed and off-label medicines in children is widespread. Their effects on children have not been properly studied and age-appropriate formulations are generally not available.\n\nPharmacists, parents or caregivers are often faced with the need to manipulate an adult medicine in a way that is not described in the summary of product characteristics. This manipulation can be simple (e.g. breaking tablets", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2814, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "8fe82c9b-e3ef-4fbb-bd2a-b28aa86da32b": {"__data__": {"id_": "8fe82c9b-e3ef-4fbb-bd2a-b28aa86da32b", "embedding": null, "metadata": {"page_label": "50", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nthat do not have a score line with a tablet splitter) or complex (e.g. using tablets as a source for an API to prepare a suspension). Pharmacists may also be faced with the need to compound a medicine on the basis of the API.\n\nThis process itself can increase the potential for errors in dosage accuracy and in general can increase the variability of the product. Such handling may be potentially hazardous for the patient as it may affect the stability, bioavailability and accuracy of dosing of an FPP, in particular for controlled-release preparations. The use of such manipulated medicines may expose children to overdosing and unintended side-effects or underdosing without the expected efficacy. Moreover, excipients that are safe for adults may not necessarily be so for children.\n\nIn December 2007, WHO launched its initiative \u201cMake medicines child size\u201d in order to raise awareness and accelerate action in response to the need for improved availability and access to child-specific medicines. Among actions to support the \u201cMake medicines child size\u201d initiative was the *Development of paediatric medicines: points to consider* guidance on pharmaceutical development of paediatric medicines. The intention is to inform regulatory authorities and manufacturers on issues that require special attention during the pharmaceutical development of paediatric medicines, with a focus on the conditions and needs in developing countries.\n\nAt the meeting of the Expert Committee in October 2007, a draft of *Development of paediatric medicines: points to consider* was discussed with a view to contributing to the pharmaceutical part of the document. An extended revision of the part on pharmaceutical development as a stand-alone text was drafted in February 2008 and, following circulation of this document, a great number of comments were received.\n\nIn April 2010 a consultation on paediatrics and generics draft guidelines discussed the draft together with an outline of the paediatric guidelines. Another version of the working document was prepared, based on the discussions during that meeting, the feedback and comments received on the previous version, and the report of the 2008 WHO Informal Meeting on Dosage Forms of Medicines for Children. Following wide circulation, comments were again received and the feedback was discussed by the Expert Committee in October 2010. A new revision was then prepared, taking into account new developments, such as efforts being undertaken by regulatory authorities. Following further discussion during an informal consultation in May 2011 the document, as revised after that meeting, was once again distributed widely for comments.\n\nIt was noted that, among other things, the points to consider document attempted to take into account convenience, reliability, acceptability, minimum dosing and end-user needs. The issues addressed by the guidelines included paediatric dosage forms, formulation design, different means of administration, inhalation, and packaging and labelling. The Expert Committee adopted the", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en la importancia de desarrollar medicamentos pedi\u00e1tricos adecuados y seguros, destacando los riesgos asociados con la manipulaci\u00f3n de medicamentos que no est\u00e1n dise\u00f1ados espec\u00edficamente para ni\u00f1os. Se menciona la iniciativa de la OMS \"Make medicines child size\", que busca mejorar la disponibilidad y el acceso a medicamentos espec\u00edficos para ni\u00f1os. Adem\u00e1s, se discuten las revisiones y consultas realizadas por el Comit\u00e9 de Expertos de la OMS sobre el desarrollo de medicamentos pedi\u00e1tricos, abordando aspectos como la formulaci\u00f3n, la dosificaci\u00f3n y la administraci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los riesgos asociados con la manipulaci\u00f3n de medicamentos en pediatr\u00eda seg\u00fan el documento?**\n   - El documento menciona que la manipulaci\u00f3n de medicamentos puede aumentar la posibilidad de errores en la precisi\u00f3n de la dosificaci\u00f3n, afectar la estabilidad y la biodisponibilidad del producto, y exponer a los ni\u00f1os a sobredosis o subdosificaci\u00f3n, lo que puede resultar en efectos secundarios no deseados o falta de eficacia.\n\n2. **\u00bfQu\u00e9 acciones espec\u00edficas se han tomado en el marco de la iniciativa \"Make medicines child size\"?**\n   - La iniciativa incluye el desarrollo de la gu\u00eda *Development of paediatric medicines: points to consider*, que tiene como objetivo informar a las autoridades regulatorias y a los fabricantes sobre los aspectos que requieren atenci\u00f3n especial en el desarrollo de medicamentos pedi\u00e1tricos, especialmente en los pa\u00edses en desarrollo.\n\n3. **\u00bfQu\u00e9 aspectos se consideraron en las revisiones del documento sobre medicamentos pedi\u00e1tricos?**\n   - Las revisiones del documento tomaron en cuenta la conveniencia, la fiabilidad, la aceptabilidad, la dosificaci\u00f3n m\u00ednima y las necesidades del usuario final. Tambi\u00e9n se abordaron temas como las formas de dosificaci\u00f3n pedi\u00e1trica, el dise\u00f1o de formulaciones, los diferentes m\u00e9todos de administraci\u00f3n, la inhalaci\u00f3n, y el empaquetado y etiquetado de los medicamentos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Desarrollo de Directrices**:\n   - Se presentaron borradores de directrices al Comit\u00e9 de Expertos de la OMS en varias ocasiones entre 2010 y 2011, con revisiones y comentarios continuos.\n   - La participaci\u00f3n de 26 fabricantes en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS fue fundamental en el proceso de consulta.\n\n2. **Cambio de T\u00edtulo**:\n   - El t\u00edtulo de las directrices se modific\u00f3 a *Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part* para aclarar su aplicabilidad al proceso de precalificaci\u00f3n.\n\n3. **Desarrollo de Medicamentos Pedi\u00e1tricos**:\n   - Se enfatiza la necesidad de desarrollar formulaciones espec\u00edficas para ni\u00f1os, dado que los medicamentos para adultos no son adecuados.\n   - Se menciona el uso generalizado de medicamentos no autorizados y fuera de indicaci\u00f3n en la poblaci\u00f3n pedi\u00e1trica, as\u00ed como la falta de estudios sobre sus efectos.\n\n4. **Desaf\u00edos en la Formulaci\u00f3n**:\n   - La falta de formulaciones adecuadas para la edad de los ni\u00f1os y la necesidad de manipular medicamentos adultos son desaf\u00edos significativos.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Instituci\u00f3n responsable de la elaboraci\u00f3n de las directrices.\n- **Comit\u00e9 de Expertos**: Grupo que revis\u00f3 y adopt\u00f3 las directrices.\n- **Programa de Precalificaci\u00f3n de Medicamentos de la OMS**: Iniciativa que involucra a fabricantes en el desarrollo de medicamentos.\n- **Fabricantes**: 26 empresas que participaron en el proceso de consulta para las directrices.\n- **Pacientes Pedi\u00e1tricos**: Grupo objetivo para el desarrollo de formulaciones adecuadas. \n\nEste resumen destaca la importancia de la colaboraci\u00f3n entre fabricantes y la OMS en la creaci\u00f3n de directrices para medicamentos gen\u00e9ricos y la necesidad urgente de abordar los desaf\u00edos en la formulaci\u00f3n de medicamentos para ni\u00f1os.", "excerpt_keywords": "Keywords: pediatric medicines, dosage accuracy, WHO initiative, pharmaceutical development, formulation design"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eae1add7-6e17-45c5-b0d8-d402f7f21160", "node_type": "4", "metadata": {"page_label": "50", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nthat do not have a score line with a tablet splitter) or complex (e.g. using tablets as a source for an API to prepare a suspension). Pharmacists may also be faced with the need to compound a medicine on the basis of the API.\n\nThis process itself can increase the potential for errors in dosage accuracy and in general can increase the variability of the product. Such handling may be potentially hazardous for the patient as it may affect the stability, bioavailability and accuracy of dosing of an FPP, in particular for controlled-release preparations. The use of such manipulated medicines may expose children to overdosing and unintended side-effects or underdosing without the expected efficacy. Moreover, excipients that are safe for adults may not necessarily be so for children.\n\nIn December 2007, WHO launched its initiative \u201cMake medicines child size\u201d in order to raise awareness and accelerate action in response to the need for improved availability and access to child-specific medicines. Among actions to support the \u201cMake medicines child size\u201d initiative was the *Development of paediatric medicines: points to consider* guidance on pharmaceutical development of paediatric medicines. The intention is to inform regulatory authorities and manufacturers on issues that require special attention during the pharmaceutical development of paediatric medicines, with a focus on the conditions and needs in developing countries.\n\nAt the meeting of the Expert Committee in October 2007, a draft of *Development of paediatric medicines: points to consider* was discussed with a view to contributing to the pharmaceutical part of the document. An extended revision of the part on pharmaceutical development as a stand-alone text was drafted in February 2008 and, following circulation of this document, a great number of comments were received.\n\nIn April 2010 a consultation on paediatrics and generics draft guidelines discussed the draft together with an outline of the paediatric guidelines. Another version of the working document was prepared, based on the discussions during that meeting, the feedback and comments received on the previous version, and the report of the 2008 WHO Informal Meeting on Dosage Forms of Medicines for Children. Following wide circulation, comments were again received and the feedback was discussed by the Expert Committee in October 2010. A new revision was then prepared, taking into account new developments, such as efforts being undertaken by regulatory authorities. Following further discussion during an informal consultation in May 2011 the document, as revised after that meeting, was once again distributed widely for comments.\n\nIt was noted that, among other things, the points to consider document attempted to take into account convenience, reliability, acceptability, minimum dosing and end-user needs. The issues addressed by the guidelines included paediatric dosage forms, formulation design, different means of administration, inhalation, and packaging and labelling. The Expert Committee adopted the", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "15baf98bd98e2a8fb30c5386402d8c87204789d40a2098c22d2c2bea818af710", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nthat do not have a score line with a tablet splitter) or complex (e.g. using tablets as a source for an API to prepare a suspension). Pharmacists may also be faced with the need to compound a medicine on the basis of the API.\n\nThis process itself can increase the potential for errors in dosage accuracy and in general can increase the variability of the product. Such handling may be potentially hazardous for the patient as it may affect the stability, bioavailability and accuracy of dosing of an FPP, in particular for controlled-release preparations. The use of such manipulated medicines may expose children to overdosing and unintended side-effects or underdosing without the expected efficacy. Moreover, excipients that are safe for adults may not necessarily be so for children.\n\nIn December 2007, WHO launched its initiative \u201cMake medicines child size\u201d in order to raise awareness and accelerate action in response to the need for improved availability and access to child-specific medicines. Among actions to support the \u201cMake medicines child size\u201d initiative was the *Development of paediatric medicines: points to consider* guidance on pharmaceutical development of paediatric medicines. The intention is to inform regulatory authorities and manufacturers on issues that require special attention during the pharmaceutical development of paediatric medicines, with a focus on the conditions and needs in developing countries.\n\nAt the meeting of the Expert Committee in October 2007, a draft of *Development of paediatric medicines: points to consider* was discussed with a view to contributing to the pharmaceutical part of the document. An extended revision of the part on pharmaceutical development as a stand-alone text was drafted in February 2008 and, following circulation of this document, a great number of comments were received.\n\nIn April 2010 a consultation on paediatrics and generics draft guidelines discussed the draft together with an outline of the paediatric guidelines. Another version of the working document was prepared, based on the discussions during that meeting, the feedback and comments received on the previous version, and the report of the 2008 WHO Informal Meeting on Dosage Forms of Medicines for Children. Following wide circulation, comments were again received and the feedback was discussed by the Expert Committee in October 2010. A new revision was then prepared, taking into account new developments, such as efforts being undertaken by regulatory authorities. Following further discussion during an informal consultation in May 2011 the document, as revised after that meeting, was once again distributed widely for comments.\n\nIt was noted that, among other things, the points to consider document attempted to take into account convenience, reliability, acceptability, minimum dosing and end-user needs. The issues addressed by the guidelines included paediatric dosage forms, formulation design, different means of administration, inhalation, and packaging and labelling. The Expert Committee adopted the", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3134, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "90460357-fb8e-4818-8d70-6d781b75a5f2": {"__data__": {"id_": "90460357-fb8e-4818-8d70-6d781b75a5f2", "embedding": null, "metadata": {"page_label": "51", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Provision by Health-Care Professionals of Patient-Specific Preparations for Children That Are Not Available as Authorized Products: Points to Consider\n\nIn March 2011, the Expert Committee on the Selection and Use of Essential Medicines reviewed the current development of guidance on the extemporaneous preparation of medicines for children and noted the preliminary draft commissioned by the WHO Department of Essential Medicines and Pharmaceutical Policies (now WHO Department of Essential Medicines and Health Products). The Expert Committee on the Selection and Use of Essential Medicines accepted that there may be situations where extemporaneous preparation of medicines for children was necessary, but members expressed concern about the risks of inappropriate preparations. The Committee also considered the risks of diverting efforts aimed at the development of age-appropriate dosage forms for children and indicated that WHO\u2019s endorsement of extemporaneous use should not be seen in any way as indicating a lack of need for commercially available paediatric dosage forms. The Committee raised concerns about potentially conflicting signals arising from a WHO publication that might appear to endorse wider use of manipulation of adult dosage forms for children. Notwithstanding these concerns, the Committee on the Selection and Use of Essential Medicines agreed that the document should be finalized for publication as a time-limited guidance that addresses the current need for advice, including review by the Expert Committee on Specifications for Pharmaceutical Preparations. It was noted that consideration could be given to publication of this guidance document by an organization other than WHO.\n\nThe document was discussed during the informal consultation on paediatric and generics guidelines in May 2011 under the auspices of the Expert Committee on Specifications for Pharmaceutical Preparations. The participants suggested modifying the title to avoid reference to \u201cextemporaneous\u201d and also suggested aligning the title of this document with other similar guidance texts currently under development as \u201cpoints to consider\u201d.\n\nThe document makes it clear that children should have access to authorized, ready-to-administer, age-appropriate preparations of medicines and nothing in the document should detract from this objective. However, the document recognized that such preparations will not always be available and a safe and effective alternative must be sought. In the context of neonatal and paediatric pharmacy practice, the technique of compounding is used by pharmacists to produce medicines from ingredients when no commercially available, authorized, age-appropriate dosage form exists. Compared to the use of authorized medicines there are significant risks; quality, safety and efficacy can", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de Nivel Superior\n\nEl documento de la OMS aborda la necesidad de preparar medicamentos espec\u00edficos para ni\u00f1os cuando no est\u00e1n disponibles en formas autorizadas y adecuadas para su edad. En marzo de 2011, un comit\u00e9 de expertos revis\u00f3 la gu\u00eda sobre la preparaci\u00f3n extempor\u00e1nea de medicamentos para ni\u00f1os, reconociendo que, aunque puede ser necesaria, existen riesgos asociados con estas pr\u00e1cticas. Se enfatiza que los ni\u00f1os deben tener acceso a medicamentos autorizados y que la preparaci\u00f3n de medicamentos debe ser una alternativa segura y efectiva solo cuando no haya opciones disponibles. Adem\u00e1s, se discute la importancia de no desviar esfuerzos hacia la creaci\u00f3n de formas de dosificaci\u00f3n adecuadas para la pediatr\u00eda.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los riesgos asociados con la preparaci\u00f3n extempor\u00e1nea de medicamentos para ni\u00f1os seg\u00fan el documento de la OMS?**\n   - El documento menciona que existen riesgos significativos en t\u00e9rminos de calidad, seguridad y eficacia al utilizar preparaciones extempor\u00e1neas en comparaci\u00f3n con medicamentos autorizados.\n\n2. **\u00bfQu\u00e9 recomendaciones se hicieron durante la consulta informal sobre las pautas pedi\u00e1tricas y de gen\u00e9ricos en mayo de 2011?**\n   - Durante la consulta, se sugiri\u00f3 modificar el t\u00edtulo del documento para evitar la referencia a \"extempor\u00e1neo\" y alinearlo con otros textos de orientaci\u00f3n similares en desarrollo, denomin\u00e1ndolo \"puntos a considerar\".\n\n3. **\u00bfQu\u00e9 papel juega la t\u00e9cnica de compounding en la pr\u00e1ctica farmac\u00e9utica neonatal y pedi\u00e1trica seg\u00fan el documento?**\n   - La t\u00e9cnica de compounding permite a los farmac\u00e9uticos producir medicamentos a partir de ingredientes cuando no existe una forma de dosificaci\u00f3n autorizada y adecuada para la edad en el mercado, aunque conlleva riesgos adicionales en comparaci\u00f3n con el uso de medicamentos autorizados.", "prev_section_summary": "### Temas Clave\n\n1. **Riesgos de Manipulaci\u00f3n de Medicamentos**: Se destaca que la manipulaci\u00f3n de medicamentos no dise\u00f1ados espec\u00edficamente para ni\u00f1os puede aumentar el riesgo de errores en la dosificaci\u00f3n, afectar la estabilidad y biodisponibilidad del producto, y exponer a los ni\u00f1os a sobredosis o subdosificaci\u00f3n.\n\n2. **Iniciativa \"Make medicines child size\"**: Lanzada por la OMS en diciembre de 2007, esta iniciativa busca mejorar la disponibilidad y el acceso a medicamentos espec\u00edficos para ni\u00f1os. Incluye el desarrollo de gu\u00edas sobre la formulaci\u00f3n de medicamentos pedi\u00e1tricos.\n\n3. **Desarrollo de Medicamentos Pedi\u00e1tricos**: Se discuten las revisiones y consultas realizadas por el Comit\u00e9 de Expertos de la OMS sobre el desarrollo de medicamentos pedi\u00e1tricos, abordando aspectos como la formulaci\u00f3n, dosificaci\u00f3n y administraci\u00f3n.\n\n4. **Consideraciones en la Formulaci\u00f3n**: Las gu\u00edas abordan la conveniencia, fiabilidad, aceptabilidad, dosificaci\u00f3n m\u00ednima y necesidades del usuario final, as\u00ed como las formas de dosificaci\u00f3n pedi\u00e1trica, dise\u00f1o de formulaciones, m\u00e9todos de administraci\u00f3n, y empaquetado y etiquetado.\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo que lidera la iniciativa y desarrolla gu\u00edas para medicamentos pedi\u00e1tricos.\n- **Comit\u00e9 de Expertos de la OMS**: Grupo que revisa y discute las gu\u00edas y documentos relacionados con medicamentos pedi\u00e1tricos.\n- **Medicamentos Pedi\u00e1tricos**: Medicamentos dise\u00f1ados espec\u00edficamente para el uso en ni\u00f1os, considerando sus necesidades y caracter\u00edsticas particulares. \n\nEste resumen encapsula los puntos m\u00e1s relevantes y las entidades involucradas en el desarrollo y la regulaci\u00f3n de medicamentos pedi\u00e1tricos seg\u00fan el documento.", "excerpt_keywords": "Keywords: extemporaneous preparation, pediatric medicines, compounding, authorized dosage forms, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c00e0952-bef5-421a-961e-2802215a3203", "node_type": "4", "metadata": {"page_label": "51", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Provision by Health-Care Professionals of Patient-Specific Preparations for Children That Are Not Available as Authorized Products: Points to Consider\n\nIn March 2011, the Expert Committee on the Selection and Use of Essential Medicines reviewed the current development of guidance on the extemporaneous preparation of medicines for children and noted the preliminary draft commissioned by the WHO Department of Essential Medicines and Pharmaceutical Policies (now WHO Department of Essential Medicines and Health Products). The Expert Committee on the Selection and Use of Essential Medicines accepted that there may be situations where extemporaneous preparation of medicines for children was necessary, but members expressed concern about the risks of inappropriate preparations. The Committee also considered the risks of diverting efforts aimed at the development of age-appropriate dosage forms for children and indicated that WHO\u2019s endorsement of extemporaneous use should not be seen in any way as indicating a lack of need for commercially available paediatric dosage forms. The Committee raised concerns about potentially conflicting signals arising from a WHO publication that might appear to endorse wider use of manipulation of adult dosage forms for children. Notwithstanding these concerns, the Committee on the Selection and Use of Essential Medicines agreed that the document should be finalized for publication as a time-limited guidance that addresses the current need for advice, including review by the Expert Committee on Specifications for Pharmaceutical Preparations. It was noted that consideration could be given to publication of this guidance document by an organization other than WHO.\n\nThe document was discussed during the informal consultation on paediatric and generics guidelines in May 2011 under the auspices of the Expert Committee on Specifications for Pharmaceutical Preparations. The participants suggested modifying the title to avoid reference to \u201cextemporaneous\u201d and also suggested aligning the title of this document with other similar guidance texts currently under development as \u201cpoints to consider\u201d.\n\nThe document makes it clear that children should have access to authorized, ready-to-administer, age-appropriate preparations of medicines and nothing in the document should detract from this objective. However, the document recognized that such preparations will not always be available and a safe and effective alternative must be sought. In the context of neonatal and paediatric pharmacy practice, the technique of compounding is used by pharmacists to produce medicines from ingredients when no commercially available, authorized, age-appropriate dosage form exists. Compared to the use of authorized medicines there are significant risks; quality, safety and efficacy can", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "ee57264e12987b75bac6c769453f89347990b2df0e8f380a1c77745992f83ccd", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Provision by Health-Care Professionals of Patient-Specific Preparations for Children That Are Not Available as Authorized Products: Points to Consider\n\nIn March 2011, the Expert Committee on the Selection and Use of Essential Medicines reviewed the current development of guidance on the extemporaneous preparation of medicines for children and noted the preliminary draft commissioned by the WHO Department of Essential Medicines and Pharmaceutical Policies (now WHO Department of Essential Medicines and Health Products). The Expert Committee on the Selection and Use of Essential Medicines accepted that there may be situations where extemporaneous preparation of medicines for children was necessary, but members expressed concern about the risks of inappropriate preparations. The Committee also considered the risks of diverting efforts aimed at the development of age-appropriate dosage forms for children and indicated that WHO\u2019s endorsement of extemporaneous use should not be seen in any way as indicating a lack of need for commercially available paediatric dosage forms. The Committee raised concerns about potentially conflicting signals arising from a WHO publication that might appear to endorse wider use of manipulation of adult dosage forms for children. Notwithstanding these concerns, the Committee on the Selection and Use of Essential Medicines agreed that the document should be finalized for publication as a time-limited guidance that addresses the current need for advice, including review by the Expert Committee on Specifications for Pharmaceutical Preparations. It was noted that consideration could be given to publication of this guidance document by an organization other than WHO.\n\nThe document was discussed during the informal consultation on paediatric and generics guidelines in May 2011 under the auspices of the Expert Committee on Specifications for Pharmaceutical Preparations. The participants suggested modifying the title to avoid reference to \u201cextemporaneous\u201d and also suggested aligning the title of this document with other similar guidance texts currently under development as \u201cpoints to consider\u201d.\n\nThe document makes it clear that children should have access to authorized, ready-to-administer, age-appropriate preparations of medicines and nothing in the document should detract from this objective. However, the document recognized that such preparations will not always be available and a safe and effective alternative must be sought. In the context of neonatal and paediatric pharmacy practice, the technique of compounding is used by pharmacists to produce medicines from ingredients when no commercially available, authorized, age-appropriate dosage form exists. Compared to the use of authorized medicines there are significant risks; quality, safety and efficacy can", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2827, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "030800a8-66a7-4742-8fff-16fa98f54973": {"__data__": {"id_": "030800a8-66a7-4742-8fff-16fa98f54973", "embedding": null, "metadata": {"page_label": "52", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Quality Requirements for Artemisinin as a Starting Material in the Production of Antimalarial Active Pharmaceutical Ingredients\n\nOn various occasions, including at workshops organized by WHO and the Medicines for Malaria Venture, issues relating to quality control specifications applicable to active substances used not only by themselves, but also as starting materials for other active substances, have been discussed. The main challenge identified was that often, when used as starting materials for derivatives, for example when artemisinin is used in the manufacture of artemisinin-derived APIs, these substances were dealt with by some national authorities applying the same control requirements as when they are used directly for manufacturing of FPPs.\n\nQuality control specifications applicable to APIs are often used not only for the active substance itself but also to control the quality of starting materials for the production of other active substances. An example is artemisinin which is an important API and also serves as a starting material for the production of artemisinin-derived antimalarials.\n\nSome national authorities require the same quality standard (i.e. they apply the same limits) for an API and for a starting material. However, it is sufficient for a starting material to have a quality that guarantees that the final product meets the relevant pharmacopoeial standard. Demanding that a starting material meets a quality standard that is too exacting is likely to increase the price and to reduce access to the related FPPs.\n\nOn the basis of a request from the international community, a guidance document on *Quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients* was prepared to clarify the need for different quality levels for artemisinin. The document includes a specification for artemisinin used as a starting material, which was based on proposals made by the manufacturers.\n\n----\n\n3 Regulatory support: Paediatric Medicines Regulatory Network. *WHO Drug Information*, 2011, 25:240\u2013241.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Importancia de la calidad de artemisinina**: La artemisinina es un ingrediente farmac\u00e9utico activo (API) crucial en la producci\u00f3n de medicamentos antipal\u00fadicos. Su calidad es fundamental no solo para su uso directo, sino tambi\u00e9n como material de partida para la fabricaci\u00f3n de derivados antipal\u00fadicos.\n\n2. **Desaf\u00edos en la regulaci\u00f3n**: Existen desaf\u00edos en la regulaci\u00f3n de la calidad de los materiales de partida, ya que algunas autoridades nacionales aplican los mismos est\u00e1ndares de calidad para los API y los materiales de partida, lo que puede ser excesivo y afectar el acceso a los medicamentos.\n\n3. **Gu\u00eda de calidad**: En respuesta a la necesidad de aclarar los diferentes niveles de calidad requeridos para la artemisinina, se elabor\u00f3 un documento de orientaci\u00f3n que establece especificaciones para su uso como material de partida, basado en propuestas de los fabricantes.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las implicaciones de aplicar los mismos est\u00e1ndares de calidad para artemisinina como API y como material de partida?**\n   - Esta pregunta busca explorar c\u00f3mo la aplicaci\u00f3n de est\u00e1ndares de calidad excesivos puede afectar el costo y la disponibilidad de los medicamentos antipal\u00fadicos.\n\n2. **\u00bfQu\u00e9 criterios se consideran suficientes para garantizar que un material de partida cumpla con los est\u00e1ndares farmacop\u00e9uticos relevantes?**\n   - Esta pregunta se centra en los criterios espec\u00edficos que se deben cumplir para que un material de partida sea considerado adecuado para la producci\u00f3n de medicamentos, sin necesidad de cumplir con est\u00e1ndares excesivos.\n\n3. **\u00bfQu\u00e9 propuestas de los fabricantes se incluyeron en el documento de orientaci\u00f3n sobre los requisitos de calidad para la artemisinina?**\n   - Esta pregunta busca detalles sobre las contribuciones espec\u00edficas de los fabricantes que llevaron a la elaboraci\u00f3n de las especificaciones de calidad para la artemisinina como material de partida.", "prev_section_summary": "### Temas Clave\n\n1. **Preparaci\u00f3n Extempor\u00e1nea de Medicamentos para Ni\u00f1os**: El documento aborda la necesidad de preparar medicamentos espec\u00edficos para ni\u00f1os cuando no est\u00e1n disponibles en formas autorizadas y adecuadas para su edad.\n\n2. **Riesgos Asociados**: Se reconocen los riesgos significativos en t\u00e9rminos de calidad, seguridad y eficacia al utilizar preparaciones extempor\u00e1neas en comparaci\u00f3n con medicamentos autorizados.\n\n3. **Acceso a Medicamentos Autorizados**: Se enfatiza que los ni\u00f1os deben tener acceso a medicamentos autorizados y que la preparaci\u00f3n de medicamentos debe ser una alternativa segura y efectiva solo cuando no haya opciones disponibles.\n\n4. **Desarrollo de Formas de Dosificaci\u00f3n Adecuadas**: Se discute la importancia de no desviar esfuerzos hacia la creaci\u00f3n de formas de dosificaci\u00f3n adecuadas para la pediatr\u00eda.\n\n5. **Consulta Informal y Recomendaciones**: Durante una consulta informal en mayo de 2011, se sugiri\u00f3 modificar el t\u00edtulo del documento para evitar la referencia a \"extempor\u00e1neo\" y alinearlo con otros textos de orientaci\u00f3n similares.\n\n6. **T\u00e9cnica de Compounding**: La t\u00e9cnica de compounding permite a los farmac\u00e9uticos producir medicamentos a partir de ingredientes cuando no existe una forma de dosificaci\u00f3n autorizada y adecuada para la edad en el mercado, aunque conlleva riesgos adicionales.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Instituci\u00f3n que comision\u00f3 el desarrollo de la gu\u00eda sobre la preparaci\u00f3n extempor\u00e1nea de medicamentos.\n- **Comit\u00e9 de Expertos en la Selecci\u00f3n y Uso de Medicamentos Esenciales**: Grupo que revis\u00f3 la gu\u00eda y expres\u00f3 preocupaciones sobre los riesgos de las preparaciones extempor\u00e1neas.\n- **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**: Particip\u00f3 en la discusi\u00f3n del documento y en la consulta informal sobre pautas pedi\u00e1tricas y de gen\u00e9ricos. \n\nEste resumen destaca los puntos clave y las entidades relevantes en el contexto de la preparaci\u00f3n de medicamentos para ni\u00f1os, seg\u00fan el documento de la OMS.", "excerpt_keywords": "Keywords: artemisinin, quality control, active pharmaceutical ingredients, regulatory standards, antimalarial"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7235eb94-381a-4475-92f9-fbc7dc5a06fc", "node_type": "4", "metadata": {"page_label": "52", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Quality Requirements for Artemisinin as a Starting Material in the Production of Antimalarial Active Pharmaceutical Ingredients\n\nOn various occasions, including at workshops organized by WHO and the Medicines for Malaria Venture, issues relating to quality control specifications applicable to active substances used not only by themselves, but also as starting materials for other active substances, have been discussed. The main challenge identified was that often, when used as starting materials for derivatives, for example when artemisinin is used in the manufacture of artemisinin-derived APIs, these substances were dealt with by some national authorities applying the same control requirements as when they are used directly for manufacturing of FPPs.\n\nQuality control specifications applicable to APIs are often used not only for the active substance itself but also to control the quality of starting materials for the production of other active substances. An example is artemisinin which is an important API and also serves as a starting material for the production of artemisinin-derived antimalarials.\n\nSome national authorities require the same quality standard (i.e. they apply the same limits) for an API and for a starting material. However, it is sufficient for a starting material to have a quality that guarantees that the final product meets the relevant pharmacopoeial standard. Demanding that a starting material meets a quality standard that is too exacting is likely to increase the price and to reduce access to the related FPPs.\n\nOn the basis of a request from the international community, a guidance document on *Quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients* was prepared to clarify the need for different quality levels for artemisinin. The document includes a specification for artemisinin used as a starting material, which was based on proposals made by the manufacturers.\n\n----\n\n3 Regulatory support: Paediatric Medicines Regulatory Network. *WHO Drug Information*, 2011, 25:240\u2013241.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "52e44cae0d588d4cfe5d40dca512e1c9ac51f72023d70ae740a652f5196f18b8", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Quality Requirements for Artemisinin as a Starting Material in the Production of Antimalarial Active Pharmaceutical Ingredients\n\nOn various occasions, including at workshops organized by WHO and the Medicines for Malaria Venture, issues relating to quality control specifications applicable to active substances used not only by themselves, but also as starting materials for other active substances, have been discussed. The main challenge identified was that often, when used as starting materials for derivatives, for example when artemisinin is used in the manufacture of artemisinin-derived APIs, these substances were dealt with by some national authorities applying the same control requirements as when they are used directly for manufacturing of FPPs.\n\nQuality control specifications applicable to APIs are often used not only for the active substance itself but also to control the quality of starting materials for the production of other active substances. An example is artemisinin which is an important API and also serves as a starting material for the production of artemisinin-derived antimalarials.\n\nSome national authorities require the same quality standard (i.e. they apply the same limits) for an API and for a starting material. However, it is sufficient for a starting material to have a quality that guarantees that the final product meets the relevant pharmacopoeial standard. Demanding that a starting material meets a quality standard that is too exacting is likely to increase the price and to reduce access to the related FPPs.\n\nOn the basis of a request from the international community, a guidance document on *Quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients* was prepared to clarify the need for different quality levels for artemisinin. The document includes a specification for artemisinin used as a starting material, which was based on proposals made by the manufacturers.\n\n----\n\n3 Regulatory support: Paediatric Medicines Regulatory Network. *WHO Drug Information*, 2011, 25:240\u2013241.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2103, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "1c042233-d725-4cf0-b685-5e86b722927d": {"__data__": {"id_": "1c042233-d725-4cf0-b685-5e86b722927d", "embedding": null, "metadata": {"page_label": "53", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe first working document was circulated in March\u2013April 2010 and comments received were first discussed during an informal consultation. A revised version was circulated and the further comments received were discussed at the meeting of the Expert Committee in October 2010. As the assignment of the impurities in the test for related substances in the first revision was tentative and based on the available scientific publications, the Expert Committee members recognized the need to clarify the impurity profile before the document could be completed.\n\nThe task of elucidating the impurity pattern was carried out by EDQM. The retention times of artemisitene and 9-epi artemisinin were identified and a correction factor for artemisitene was determined. It was revealed that the impurity assignment published in the first revision was incorrect. On the basis of this information, a second revision was prepared and circulated for comments in August 2011.\n\nThe Expert Committee reviewed the second revision of the quality requirements and considered the comments received.\n\nThe Expert Committee adopted the document on *Recommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients* subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 6).\n\n## 11.8 Update on comparator products\n\nIt was reported to the Expert Committee that the secretariat was working on the update of the list of comparator products and the assistance of the members of the Committee was requested in order that the list might be published on the website as soon as possible to replace the version adopted in 2002.\n\n# 12. Nomenclature, terminology and databases\n\n## 12.1 Quality assurance terminology\n\n### Quality assurance database\n\nThe WHO quality assurance terminology database was established in August 2005. The entries in this database are taken from the glossary definitions in WHO guidelines pertaining to quality assurance activities. The objectives of the database are to foster the understanding of quality assurance-related activities, promote harmonization in quality assurance terminology globally, and to avoid misunderstandings that may result from the different terms used in various publications and their interpretations. The publications used as a source of information to create the WHO quality assurance terminology database are the quality assurance guidelines adopted by the Expert Committee on Specifications for Pharmaceutical Preparations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas basadas en el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento se centra en las actividades del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, destacando el proceso de revisi\u00f3n y actualizaci\u00f3n de los requisitos de calidad para la artemisinina, un material de partida en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos. Se menciona la importancia de clarificar el perfil de impurezas y la creaci\u00f3n de una base de datos de terminolog\u00eda de aseguramiento de calidad para promover la armonizaci\u00f3n global en este \u00e1mbito.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 errores se identificaron en la primera revisi\u00f3n del perfil de impurezas de la artemisinina y c\u00f3mo se corrigieron en la segunda revisi\u00f3n?**\n   - La primera revisi\u00f3n conten\u00eda una asignaci\u00f3n incorrecta de impurezas, que fue corregida tras la identificaci\u00f3n de los tiempos de retenci\u00f3n de artemisitene y 9-epi artemisinin, as\u00ed como la determinaci\u00f3n de un factor de correcci\u00f3n para artemisitene.\n\n2. **\u00bfCu\u00e1l es el objetivo principal de la base de datos de terminolog\u00eda de aseguramiento de calidad de la OMS?**\n   - El objetivo principal es fomentar la comprensi\u00f3n de las actividades relacionadas con el aseguramiento de calidad, promover la armonizaci\u00f3n en la terminolog\u00eda de aseguramiento de calidad a nivel global y evitar malentendidos derivados de los diferentes t\u00e9rminos utilizados en diversas publicaciones.\n\n3. **\u00bfQu\u00e9 acciones se est\u00e1n tomando para actualizar la lista de productos comparadores y por qu\u00e9 es importante esta actualizaci\u00f3n?**\n   - Se est\u00e1 trabajando en la actualizaci\u00f3n de la lista de productos comparadores, y se solicit\u00f3 la asistencia de los miembros del Comit\u00e9 para que la lista se publique en el sitio web lo antes posible, reemplazando la versi\u00f3n adoptada en 2002, lo que es crucial para mantener la relevancia y precisi\u00f3n de la informaci\u00f3n disponible.", "prev_section_summary": "### Temas Clave\n\n1. **Calidad de la Artemisinina**: La artemisinina es un ingrediente farmac\u00e9utico activo (API) esencial en la producci\u00f3n de medicamentos antipal\u00fadicos y tambi\u00e9n se utiliza como material de partida para la fabricaci\u00f3n de derivados antipal\u00fadicos.\n\n2. **Desaf\u00edos Regulatorios**: Existen dificultades en la regulaci\u00f3n de los est\u00e1ndares de calidad, ya que algunas autoridades nacionales aplican los mismos requisitos para los API y los materiales de partida, lo que puede ser excesivo y afectar la accesibilidad de los medicamentos.\n\n3. **Gu\u00eda de Calidad**: Se elabor\u00f3 un documento de orientaci\u00f3n para establecer diferentes niveles de calidad requeridos para la artemisinina, basado en propuestas de los fabricantes, con el fin de aclarar las especificaciones necesarias para su uso como material de partida.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Organismo que ha organizado talleres y ha participado en la elaboraci\u00f3n de gu\u00edas sobre la calidad de la artemisinina.\n- **Medicines for Malaria Venture**: Organizaci\u00f3n que ha colaborado con la OMS en la discusi\u00f3n de especificaciones de control de calidad.\n- **Fabricantes de Artemisinina**: Proveedores que han contribuido con propuestas para la elaboraci\u00f3n de especificaciones de calidad en el documento de orientaci\u00f3n.\n\n### Resumen\n\nLa secci\u00f3n aborda la importancia de la calidad de la artemisinina como un API y material de partida en la producci\u00f3n de medicamentos antipal\u00fadicos. Se identifican desaf\u00edos regulatorios relacionados con la aplicaci\u00f3n de est\u00e1ndares de calidad excesivos por parte de algunas autoridades nacionales, lo que puede limitar el acceso a los medicamentos. En respuesta a estas preocupaciones, se ha desarrollado un documento de orientaci\u00f3n que establece especificaciones de calidad diferenciadas para la artemisinina, basado en las propuestas de los fabricantes.", "excerpt_keywords": "Keywords: artemisinin, quality assurance, impurities, pharmaceutical preparations, WHO Expert Committee"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f37dd787-a0ae-4e22-ad33-736fb2312c06", "node_type": "4", "metadata": {"page_label": "53", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe first working document was circulated in March\u2013April 2010 and comments received were first discussed during an informal consultation. A revised version was circulated and the further comments received were discussed at the meeting of the Expert Committee in October 2010. As the assignment of the impurities in the test for related substances in the first revision was tentative and based on the available scientific publications, the Expert Committee members recognized the need to clarify the impurity profile before the document could be completed.\n\nThe task of elucidating the impurity pattern was carried out by EDQM. The retention times of artemisitene and 9-epi artemisinin were identified and a correction factor for artemisitene was determined. It was revealed that the impurity assignment published in the first revision was incorrect. On the basis of this information, a second revision was prepared and circulated for comments in August 2011.\n\nThe Expert Committee reviewed the second revision of the quality requirements and considered the comments received.\n\nThe Expert Committee adopted the document on *Recommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients* subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 6).\n\n## 11.8 Update on comparator products\n\nIt was reported to the Expert Committee that the secretariat was working on the update of the list of comparator products and the assistance of the members of the Committee was requested in order that the list might be published on the website as soon as possible to replace the version adopted in 2002.\n\n# 12. Nomenclature, terminology and databases\n\n## 12.1 Quality assurance terminology\n\n### Quality assurance database\n\nThe WHO quality assurance terminology database was established in August 2005. The entries in this database are taken from the glossary definitions in WHO guidelines pertaining to quality assurance activities. The objectives of the database are to foster the understanding of quality assurance-related activities, promote harmonization in quality assurance terminology globally, and to avoid misunderstandings that may result from the different terms used in various publications and their interpretations. The publications used as a source of information to create the WHO quality assurance terminology database are the quality assurance guidelines adopted by the Expert Committee on Specifications for Pharmaceutical Preparations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "0bf6bdb30c3d51745921d2b83774d74990d60145924d28a52cf4dcdf4043b771", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe first working document was circulated in March\u2013April 2010 and comments received were first discussed during an informal consultation. A revised version was circulated and the further comments received were discussed at the meeting of the Expert Committee in October 2010. As the assignment of the impurities in the test for related substances in the first revision was tentative and based on the available scientific publications, the Expert Committee members recognized the need to clarify the impurity profile before the document could be completed.\n\nThe task of elucidating the impurity pattern was carried out by EDQM. The retention times of artemisitene and 9-epi artemisinin were identified and a correction factor for artemisitene was determined. It was revealed that the impurity assignment published in the first revision was incorrect. On the basis of this information, a second revision was prepared and circulated for comments in August 2011.\n\nThe Expert Committee reviewed the second revision of the quality requirements and considered the comments received.\n\nThe Expert Committee adopted the document on *Recommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients* subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 6).\n\n## 11.8 Update on comparator products\n\nIt was reported to the Expert Committee that the secretariat was working on the update of the list of comparator products and the assistance of the members of the Committee was requested in order that the list might be published on the website as soon as possible to replace the version adopted in 2002.\n\n# 12. Nomenclature, terminology and databases\n\n## 12.1 Quality assurance terminology\n\n### Quality assurance database\n\nThe WHO quality assurance terminology database was established in August 2005. The entries in this database are taken from the glossary definitions in WHO guidelines pertaining to quality assurance activities. The objectives of the database are to foster the understanding of quality assurance-related activities, promote harmonization in quality assurance terminology globally, and to avoid misunderstandings that may result from the different terms used in various publications and their interpretations. The publications used as a source of information to create the WHO quality assurance terminology database are the quality assurance guidelines adopted by the Expert Committee on Specifications for Pharmaceutical Preparations.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2664, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "56e788c1-6606-4f05-ad81-1981de9b5d5a": {"__data__": {"id_": "56e788c1-6606-4f05-ad81-1981de9b5d5a", "embedding": null, "metadata": {"page_label": "54", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe WHO quality assurance terminology database has been updated to include all definitions published in glossaries of guidelines from the Expert Committee meeting reports since the Committee was established in 1947. The database currently includes terms and their definitions from a total of 52 guidelines. The number of terms and their definitions is 528; however, the number of entries of terms is more than 800 because many of the terms have been defined differently in various publications or may have differing definitions according to their context. The database clearly indicates in which publication(s) a particular term was defined.\n\nThe terminology database is intended to be a simple tool for editing and retrieving terminology records and should be updated and enlarged periodically.\n\nThe Expert Committee much appreciated this work carried out by the secretariat and decided to set up a group of experts to continue the work on the preferred terminology.\n\n## Definition of API\n\nIn many WHO guidelines the definition for an active pharmaceutical ingredient (API) (singular) is found in the Glossary (for instance it appears three times in the WHO Technical Report Series, No. 961). The definition currently used is:\n\n*\"active pharmaceutical ingredient (API)  \nAny substance or combination of substances used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.\"*\n\nThis definition may imply that commercially available premixes of APIs (such as the popular amoxicillin + clavulanic acid premix) can be regarded as an API, although this would normally be considered to be incorrect. Once an API is mixed with another API, or with an excipient, it is usually no longer considered an API. Thus the current definition may lead to misinterpretation.\n\nThe Expert Committee decided to defer this matter to the group of experts mentioned above who would continue the work on the quality assurance terminology.\n\n## 12.2 International Nonproprietary Names for pharmaceutical substances\n\nThe International Nonproprietary Names (INN) team presented the current status of the INN list. Some 61 names were currently in preparation. Six new stems and two new pre-stems were published recently.\n\nOf 92 INN requests in the past year, 44 were for biologicals. A revised naming policy for biologicals had been adopted and would be published in Bioreview in 2011. According to this policy, additional Arabic numbers might be used to distinguish subspecies which differ significantly.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en la actualizaci\u00f3n de la base de datos de terminolog\u00eda de aseguramiento de calidad de la OMS, que incluye definiciones de t\u00e9rminos utilizados en gu\u00edas desde 1947. Se menciona la definici\u00f3n de \"ingrediente farmac\u00e9utico activo\" (API) y se discuten las implicaciones de esta definici\u00f3n, especialmente en relaci\u00f3n con las mezclas comerciales de APIs. Adem\u00e1s, se presenta el estado actual de los Nombres Comunes Internacionales (INN) para sustancias farmac\u00e9uticas, destacando la preparaci\u00f3n de nuevos nombres y una pol\u00edtica revisada para los biol\u00f3gicos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1ntas definiciones de t\u00e9rminos est\u00e1n actualmente incluidas en la base de datos de terminolog\u00eda de la OMS y cu\u00e1ntas entradas de t\u00e9rminos hay en total?**\n   - La base de datos incluye 528 definiciones de t\u00e9rminos, pero hay m\u00e1s de 800 entradas de t\u00e9rminos debido a las diferentes definiciones en diversas publicaciones.\n\n2. **\u00bfQu\u00e9 implicaciones tiene la definici\u00f3n actual de \"ingrediente farmac\u00e9utico activo\" (API) en relaci\u00f3n con las mezclas comerciales de APIs?**\n   - La definici\u00f3n actual puede llevar a la interpretaci\u00f3n err\u00f3nea de que las mezclas comerciales de APIs, como el premix de amoxicilina + \u00e1cido clavul\u00e1nico, pueden considerarse como un API, aunque normalmente no se considera correcto. Una vez que un API se mezcla con otro API o con un excipiente, generalmente ya no se considera un API.\n\n3. **\u00bfCu\u00e1l es el estado actual de los Nombres Comunes Internacionales (INN) y qu\u00e9 cambios se han realizado en la pol\u00edtica de nombramiento para biol\u00f3gicos?**\n   - Actualmente, hay 61 nombres en preparaci\u00f3n y se han recibido 92 solicitudes de INN en el \u00faltimo a\u00f1o, de las cuales 44 eran para biol\u00f3gicos. Se ha adoptado una pol\u00edtica de nombramiento revisada para biol\u00f3gicos que se publicar\u00e1 en Bioreview en 2011, permitiendo el uso de n\u00fameros \u00e1rabes adicionales para distinguir subspecies que difieren significativamente.", "prev_section_summary": "### Temas Clave\n\n1. **Revisi\u00f3n de Requisitos de Calidad**: El documento detalla el proceso de revisi\u00f3n y actualizaci\u00f3n de los requisitos de calidad para la artemisinina, un material esencial en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos.\n\n2. **Clarificaci\u00f3n del Perfil de Impurezas**: Se identific\u00f3 que la asignaci\u00f3n de impurezas en la primera revisi\u00f3n era incorrecta, lo que llev\u00f3 a la necesidad de clarificar el perfil de impurezas antes de finalizar el documento.\n\n3. **Colaboraci\u00f3n con EDQM**: La tarea de elucidaci\u00f3n del patr\u00f3n de impurezas fue realizada por la Oficina Europea de Calidad de los Medicamentos (EDQM), que ayud\u00f3 a identificar tiempos de retenci\u00f3n y a establecer un factor de correcci\u00f3n.\n\n4. **Actualizaci\u00f3n de Productos Comparadores**: Se est\u00e1 trabajando en la actualizaci\u00f3n de la lista de productos comparadores, con el objetivo de reemplazar la versi\u00f3n adoptada en 2002, lo que es crucial para mantener la precisi\u00f3n de la informaci\u00f3n.\n\n5. **Base de Datos de Terminolog\u00eda de Aseguramiento de Calidad**: Se estableci\u00f3 una base de datos en 2005 para promover la comprensi\u00f3n y la armonizaci\u00f3n de la terminolog\u00eda relacionada con el aseguramiento de calidad a nivel global.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la elaboraci\u00f3n de directrices y recomendaciones en el \u00e1mbito de la salud p\u00fablica.\n- **EDQM (Oficina Europea de Calidad de los Medicamentos)**: Entidad que colabor\u00f3 en la clarificaci\u00f3n del perfil de impurezas de la artemisinina.\n- **Artemisinina**: Material de partida en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos.\n- **Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas**: Grupo encargado de revisar y adoptar documentos relacionados con los est\u00e1ndares de calidad en farmac\u00e9uticos.\n- **Base de Datos de Terminolog\u00eda de Aseguramiento de Calidad de la OMS**: Recurso creado para estandarizar y clarificar la terminolog\u00eda utilizada en actividades de aseguramiento de calidad.", "excerpt_keywords": "Keywords: WHO, quality assurance, active pharmaceutical ingredient, International Nonproprietary Names, terminology database"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0f9cfec0-3710-475b-98d8-3a7e1b5d3913", "node_type": "4", "metadata": {"page_label": "54", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe WHO quality assurance terminology database has been updated to include all definitions published in glossaries of guidelines from the Expert Committee meeting reports since the Committee was established in 1947. The database currently includes terms and their definitions from a total of 52 guidelines. The number of terms and their definitions is 528; however, the number of entries of terms is more than 800 because many of the terms have been defined differently in various publications or may have differing definitions according to their context. The database clearly indicates in which publication(s) a particular term was defined.\n\nThe terminology database is intended to be a simple tool for editing and retrieving terminology records and should be updated and enlarged periodically.\n\nThe Expert Committee much appreciated this work carried out by the secretariat and decided to set up a group of experts to continue the work on the preferred terminology.\n\n## Definition of API\n\nIn many WHO guidelines the definition for an active pharmaceutical ingredient (API) (singular) is found in the Glossary (for instance it appears three times in the WHO Technical Report Series, No. 961). The definition currently used is:\n\n*\"active pharmaceutical ingredient (API)  \nAny substance or combination of substances used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.\"*\n\nThis definition may imply that commercially available premixes of APIs (such as the popular amoxicillin + clavulanic acid premix) can be regarded as an API, although this would normally be considered to be incorrect. Once an API is mixed with another API, or with an excipient, it is usually no longer considered an API. Thus the current definition may lead to misinterpretation.\n\nThe Expert Committee decided to defer this matter to the group of experts mentioned above who would continue the work on the quality assurance terminology.\n\n## 12.2 International Nonproprietary Names for pharmaceutical substances\n\nThe International Nonproprietary Names (INN) team presented the current status of the INN list. Some 61 names were currently in preparation. Six new stems and two new pre-stems were published recently.\n\nOf 92 INN requests in the past year, 44 were for biologicals. A revised naming policy for biologicals had been adopted and would be published in Bioreview in 2011. According to this policy, additional Arabic numbers might be used to distinguish subspecies which differ significantly.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "223e9f1874d49b4b397ac32409a82efc32a1bdbc1dc6a4358a9ee55b0733bece", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe WHO quality assurance terminology database has been updated to include all definitions published in glossaries of guidelines from the Expert Committee meeting reports since the Committee was established in 1947. The database currently includes terms and their definitions from a total of 52 guidelines. The number of terms and their definitions is 528; however, the number of entries of terms is more than 800 because many of the terms have been defined differently in various publications or may have differing definitions according to their context. The database clearly indicates in which publication(s) a particular term was defined.\n\nThe terminology database is intended to be a simple tool for editing and retrieving terminology records and should be updated and enlarged periodically.\n\nThe Expert Committee much appreciated this work carried out by the secretariat and decided to set up a group of experts to continue the work on the preferred terminology.\n\n## Definition of API\n\nIn many WHO guidelines the definition for an active pharmaceutical ingredient (API) (singular) is found in the Glossary (for instance it appears three times in the WHO Technical Report Series, No. 961). The definition currently used is:\n\n*\"active pharmaceutical ingredient (API)  \nAny substance or combination of substances used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.\"*\n\nThis definition may imply that commercially available premixes of APIs (such as the popular amoxicillin + clavulanic acid premix) can be regarded as an API, although this would normally be considered to be incorrect. Once an API is mixed with another API, or with an excipient, it is usually no longer considered an API. Thus the current definition may lead to misinterpretation.\n\nThe Expert Committee decided to defer this matter to the group of experts mentioned above who would continue the work on the quality assurance terminology.\n\n## 12.2 International Nonproprietary Names for pharmaceutical substances\n\nThe International Nonproprietary Names (INN) team presented the current status of the INN list. Some 61 names were currently in preparation. Six new stems and two new pre-stems were published recently.\n\nOf 92 INN requests in the past year, 44 were for biologicals. A revised naming policy for biologicals had been adopted and would be published in Bioreview in 2011. According to this policy, additional Arabic numbers might be used to distinguish subspecies which differ significantly.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2795, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "69b4525d-bed7-4d07-b0c3-df453f703535": {"__data__": {"id_": "69b4525d-bed7-4d07-b0c3-df453f703535", "embedding": null, "metadata": {"page_label": "55", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe INN team had also worked on establishing definitions of the different INNs. This meant attempting to obtain further information from the companies concerned, but this task had been complicated by the fact that some companies no longer existed or had been incorporated into other companies. An internal document on these definitions had been prepared.\n\nApplications for new INNs could now be made through an online interface, which enables more data to be collected than is possible in print form. There is an online application form which, when filled in, is transferred to the user by a secure transfer (in an encrypted file as used in e-banking). Once stored on the server, the data are also encrypted, and the server is protected by the usual WHO firewall and security systems. The aim was to create a global INN data hub to which access would be very restricted and secure. Any use of the data not in line with the rules of the INN application process would lead to refusal of access. Beta-testing was due to take place later in 2011.\n\nThe Expert Committee took note of the INN report.\n\n## 13. Miscellaneous\n\n### 13.1 Brochures on the Expert Committee and on quality assurance of pharmaceuticals\n\nThe new brochure on the Expert Committee on Specifications for Pharmaceutical Preparations summarizes how the Expert Committee works and provides detailed information on the process of the Committee. The second information brochure on quality assurance of pharmaceuticals summarizes the main areas covered by the Expert Committee in the past three years.\n\nIn addition, a CD-ROM had been prepared, including all current guidelines and guidance texts adopted by the Expert Committee and which are also available on the WHO web site in a structured manner according to their subjects, e.g. production, distribution, and so on. A new updated CD-ROM would be issued in due course with the recommendations from the 2011 meeting.\n\nThe Expert Committee expressed its appreciation to the Secretary for the content and design of the brochures developed and the CD-ROM on medicines quality assurance.\n\n### 13.2 Sampling procedures for monitoring of market situations\n\nThe development of sampling procedures for monitoring of market situations had been initiated in response to multiple requests from colleagues carrying out studies. Following a wide enquiry a great deal of material had been received from many countries. The outcome and draft procedures resulting from the evaluation of the material received would be presented to the next Expert Committee meeting.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento se centra en las actividades del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, destacando el trabajo del equipo de Nombres Comunes Internacionales (INN) en la definici\u00f3n de INNs y la implementaci\u00f3n de un sistema en l\u00ednea para la solicitud de nuevos INNs. Tambi\u00e9n se menciona la creaci\u00f3n de folletos informativos sobre el funcionamiento del Comit\u00e9 y la garant\u00eda de calidad de los productos farmac\u00e9uticos, as\u00ed como el desarrollo de procedimientos de muestreo para el monitoreo de situaciones del mercado.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las medidas de seguridad implementadas para proteger los datos en el nuevo sistema de solicitud de INNs?**\n   - El sistema utiliza transferencia segura de datos en archivos encriptados, almacenamiento en un servidor protegido por un firewall de la OMS y sistemas de seguridad, asegurando que el acceso a los datos sea muy restringido y seguro.\n\n2. **\u00bfQu\u00e9 tipo de materiales se incluyeron en el CD-ROM preparado por el Comit\u00e9 de Expertos?**\n   - El CD-ROM incluye todas las gu\u00edas y textos de orientaci\u00f3n actuales adoptados por el Comit\u00e9 de Expertos, organizados de manera estructurada seg\u00fan sus temas, como producci\u00f3n y distribuci\u00f3n.\n\n3. **\u00bfQu\u00e9 motiv\u00f3 el desarrollo de procedimientos de muestreo para el monitoreo de situaciones del mercado?**\n   - El desarrollo de estos procedimientos fue iniciado en respuesta a m\u00faltiples solicitudes de colegas que llevaban a cabo estudios, lo que llev\u00f3 a una amplia recopilaci\u00f3n de material de muchos pa\u00edses para su evaluaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Actualizaci\u00f3n de la Base de Datos de Terminolog\u00eda de Aseguramiento de Calidad de la OMS**:\n   - La base de datos incluye definiciones de t\u00e9rminos de 52 gu\u00edas desde 1947.\n   - Contiene 528 definiciones de t\u00e9rminos, con m\u00e1s de 800 entradas debido a variaciones en las definiciones.\n\n2. **Definici\u00f3n de Ingrediente Farmac\u00e9utico Activo (API)**:\n   - La definici\u00f3n actual de API implica que cualquier sustancia en un producto farmac\u00e9utico terminado que tenga actividad farmacol\u00f3gica se considera un API.\n   - Se se\u00f1ala que las mezclas comerciales de APIs pueden ser malinterpretadas como APIs, lo cual no es correcto seg\u00fan la definici\u00f3n.\n\n3. **Nombres Comunes Internacionales (INN)**:\n   - Actualmente hay 61 nombres en preparaci\u00f3n y 92 solicitudes de INN en el \u00faltimo a\u00f1o, de las cuales 44 son para biol\u00f3gicos.\n   - Se ha adoptado una pol\u00edtica revisada para el nombramiento de biol\u00f3gicos, que se publicar\u00e1 en Bioreview en 2011, permitiendo el uso de n\u00fameros \u00e1rabes para distinguir subspecies.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la actualizaci\u00f3n de la base de datos y la definici\u00f3n de t\u00e9rminos.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: T\u00e9rmino clave definido en las gu\u00edas de la OMS.\n- **INN (Nombres Comunes Internacionales)**: Sistema de nomenclatura para sustancias farmac\u00e9uticas.\n- **Grupo de Expertos**: Se establece para continuar el trabajo sobre la terminolog\u00eda de aseguramiento de calidad.", "excerpt_keywords": "Keywords: INN, WHO, pharmaceutical preparations, quality assurance, sampling procedures"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a47584cc-401a-483b-80c0-3467e6a1ba9d", "node_type": "4", "metadata": {"page_label": "55", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe INN team had also worked on establishing definitions of the different INNs. This meant attempting to obtain further information from the companies concerned, but this task had been complicated by the fact that some companies no longer existed or had been incorporated into other companies. An internal document on these definitions had been prepared.\n\nApplications for new INNs could now be made through an online interface, which enables more data to be collected than is possible in print form. There is an online application form which, when filled in, is transferred to the user by a secure transfer (in an encrypted file as used in e-banking). Once stored on the server, the data are also encrypted, and the server is protected by the usual WHO firewall and security systems. The aim was to create a global INN data hub to which access would be very restricted and secure. Any use of the data not in line with the rules of the INN application process would lead to refusal of access. Beta-testing was due to take place later in 2011.\n\nThe Expert Committee took note of the INN report.\n\n## 13. Miscellaneous\n\n### 13.1 Brochures on the Expert Committee and on quality assurance of pharmaceuticals\n\nThe new brochure on the Expert Committee on Specifications for Pharmaceutical Preparations summarizes how the Expert Committee works and provides detailed information on the process of the Committee. The second information brochure on quality assurance of pharmaceuticals summarizes the main areas covered by the Expert Committee in the past three years.\n\nIn addition, a CD-ROM had been prepared, including all current guidelines and guidance texts adopted by the Expert Committee and which are also available on the WHO web site in a structured manner according to their subjects, e.g. production, distribution, and so on. A new updated CD-ROM would be issued in due course with the recommendations from the 2011 meeting.\n\nThe Expert Committee expressed its appreciation to the Secretary for the content and design of the brochures developed and the CD-ROM on medicines quality assurance.\n\n### 13.2 Sampling procedures for monitoring of market situations\n\nThe development of sampling procedures for monitoring of market situations had been initiated in response to multiple requests from colleagues carrying out studies. Following a wide enquiry a great deal of material had been received from many countries. The outcome and draft procedures resulting from the evaluation of the material received would be presented to the next Expert Committee meeting.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "b14d30e1a290fcfc6e070d44e2c883ee30b0885eb184a8d07eed844bf057495a", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe INN team had also worked on establishing definitions of the different INNs. This meant attempting to obtain further information from the companies concerned, but this task had been complicated by the fact that some companies no longer existed or had been incorporated into other companies. An internal document on these definitions had been prepared.\n\nApplications for new INNs could now be made through an online interface, which enables more data to be collected than is possible in print form. There is an online application form which, when filled in, is transferred to the user by a secure transfer (in an encrypted file as used in e-banking). Once stored on the server, the data are also encrypted, and the server is protected by the usual WHO firewall and security systems. The aim was to create a global INN data hub to which access would be very restricted and secure. Any use of the data not in line with the rules of the INN application process would lead to refusal of access. Beta-testing was due to take place later in 2011.\n\nThe Expert Committee took note of the INN report.\n\n## 13. Miscellaneous\n\n### 13.1 Brochures on the Expert Committee and on quality assurance of pharmaceuticals\n\nThe new brochure on the Expert Committee on Specifications for Pharmaceutical Preparations summarizes how the Expert Committee works and provides detailed information on the process of the Committee. The second information brochure on quality assurance of pharmaceuticals summarizes the main areas covered by the Expert Committee in the past three years.\n\nIn addition, a CD-ROM had been prepared, including all current guidelines and guidance texts adopted by the Expert Committee and which are also available on the WHO web site in a structured manner according to their subjects, e.g. production, distribution, and so on. A new updated CD-ROM would be issued in due course with the recommendations from the 2011 meeting.\n\nThe Expert Committee expressed its appreciation to the Secretary for the content and design of the brochures developed and the CD-ROM on medicines quality assurance.\n\n### 13.2 Sampling procedures for monitoring of market situations\n\nThe development of sampling procedures for monitoring of market situations had been initiated in response to multiple requests from colleagues carrying out studies. Following a wide enquiry a great deal of material had been received from many countries. The outcome and draft procedures resulting from the evaluation of the material received would be presented to the next Expert Committee meeting.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2634, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "b1c0805c-b0ae-447a-bd24-953d6550461a": {"__data__": {"id_": "b1c0805c-b0ae-447a-bd24-953d6550461a", "embedding": null, "metadata": {"page_label": "56", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThere was also a presentation on a new project within this area of work, particularly focusing on the SSFFC products. There was a deficiency of hard data on this issue and the project aimed to establish a global monitoring and surveillance system and disseminate data, to collate best practice and establish a minimum reporting standard on SSFFC products, to assist regulatory authorities to identify SSFFC products, to establish where the risks were greatest, and to encourage collaboration between regulatory authorities on this issue. This is a four-year project in five phases and is being carried out by the team for Quality Assurance and Safety: Medicines in WHO in close collaboration with the regional offices and countries.\n\nThe Expert Committee expressed its appreciation for the project and gave its endorsement. The Committee considered that the idea of having a watch list of products that were frequently falsified would be very helpful to NMRAs.\n\n## 13.3 Index of pharmacopoeias\n\nThis index, including all pharmacopoeias around the world, was first prepared in 2001 and has been regularly updated. In accordance with the recommendations made by the Expert Committee at its forty-fifth meeting, the Index of Pharmacopoeias had been revised. Africa has one pharmacopoeia (this is the African Pharmacopoeia and not a national pharmacopoeia), the Americas four, the Western Pacific has five, and Europe has 30. Of these, five national pharmacopoeias offer free online access, as does The International Pharmacopoeia of WHO. The index contains all contact information for the pharmacopoeias.\n\nThe Expert Committee took note of the report and advised the Secretary to complete and update the missing information in the index as notified by the respective pharmacopoeias.\n\n## 13.4 Collaboration with pharmacopoeias\n\nWHO was working on closer collaboration with a view to exchanging information with other pharmacopoeias and achieving further harmonization. A meeting was held in July 2011 with a number of representatives from secretariats of national pharmacopoeias. FIP would provide an opportunity for a meeting of pharmacopoeia representatives with other stakeholders in 2012, and WHO would offer to organize a private meeting for pharmacopoeia representatives only, to discuss common issues and concerns following up on discussions that had started during a side-meeting held at the 10th ICDRA meeting in Hong Kong Special Administrative Region of the People\u2019s Republic of China in 2002.\n\nThe Expert Committee took note of this initiative and expressed its support for an international meeting of world pharmacopoeias organized by WHO.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Proyecto sobre productos SSFFC**: Se present\u00f3 un nuevo proyecto enfocado en productos farmac\u00e9uticos falsificados y de calidad subest\u00e1ndar (SSFFC). Este proyecto tiene como objetivo establecer un sistema global de monitoreo y vigilancia, recopilar datos y mejores pr\u00e1cticas, y fomentar la colaboraci\u00f3n entre las autoridades regulatorias para identificar y gestionar los riesgos asociados con estos productos.\n\n2. **\u00cdndice de farmacopoeias**: Se ha actualizado el \u00cdndice de Farmacopeas, que incluye informaci\u00f3n sobre todas las farmacopeas del mundo. Este \u00edndice es una herramienta importante para las autoridades regulatorias y proporciona acceso a informaci\u00f3n de contacto y recursos sobre las farmacopeas.\n\n3. **Colaboraci\u00f3n con farmacopeas**: La OMS est\u00e1 trabajando en una colaboraci\u00f3n m\u00e1s estrecha con las farmacopeas nacionales para intercambiar informaci\u00f3n y lograr una mayor armonizaci\u00f3n. Se han planificado reuniones para discutir problemas comunes y fomentar la cooperaci\u00f3n internacional en este \u00e1mbito.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las fases del proyecto de monitoreo y vigilancia de productos SSFFC y qu\u00e9 objetivos espec\u00edficos se buscan alcanzar en cada fase?**\n   - Esta pregunta busca detalles sobre la estructura y los objetivos del proyecto, que no se mencionan expl\u00edcitamente en el texto.\n\n2. **\u00bfQu\u00e9 criterios se est\u00e1n considerando para la creaci\u00f3n de la lista de vigilancia de productos frecuentemente falsificados y c\u00f3mo se determinar\u00e1n los riesgos asociados?**\n   - Esta pregunta se centra en los criterios y metodolog\u00edas que se utilizar\u00e1n para identificar los productos en riesgo, lo cual no se detalla en el contexto.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n espec\u00edfica se est\u00e1 recopilando para completar y actualizar el \u00cdndice de Farmacopeas y cu\u00e1les son los desaf\u00edos que enfrenta la OMS en este proceso?**\n   - Esta pregunta busca informaci\u00f3n sobre el proceso de actualizaci\u00f3n del \u00edndice y los posibles obst\u00e1culos que la OMS podr\u00eda encontrar, que no se abordan en el texto proporcionado.", "prev_section_summary": "### Temas Clave\n\n1. **Nombres Comunes Internacionales (INN)**: El equipo de INN trabaj\u00f3 en la definici\u00f3n de diferentes INNs, enfrentando desaf\u00edos debido a la desaparici\u00f3n o fusi\u00f3n de algunas empresas.\n\n2. **Sistema de Solicitud en L\u00ednea**: Se implement\u00f3 un sistema en l\u00ednea para la solicitud de nuevos INNs, que permite la recolecci\u00f3n de datos de manera m\u00e1s eficiente y segura, utilizando transferencias encriptadas y almacenamiento protegido.\n\n3. **Folletos Informativos**: Se desarrollaron folletos que resumen el funcionamiento del Comit\u00e9 de Expertos y la garant\u00eda de calidad de los productos farmac\u00e9uticos.\n\n4. **CD-ROM de Directrices**: Se prepar\u00f3 un CD-ROM que incluye todas las gu\u00edas y textos de orientaci\u00f3n adoptados por el Comit\u00e9, organizados por temas.\n\n5. **Procedimientos de Muestreo**: Se iniciaron procedimientos de muestreo para monitorear situaciones del mercado en respuesta a solicitudes de colegas, con la evaluaci\u00f3n de material recibido de varios pa\u00edses.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Instituci\u00f3n responsable del Comit\u00e9 de Expertos y de la implementaci\u00f3n de los sistemas de INN.\n- **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**: Grupo que trabaja en la regulaci\u00f3n y calidad de los productos farmac\u00e9uticos.\n- **INN (Nombres Comunes Internacionales)**: Sistema de nomenclatura para medicamentos que busca estandarizar los nombres de los f\u00e1rmacos a nivel global.\n- **Empresas farmac\u00e9uticas**: Entidades involucradas en la provisi\u00f3n de informaci\u00f3n para la definici\u00f3n de INNs.\n\nEste resumen destaca los aspectos m\u00e1s relevantes y las entidades involucradas en la secci\u00f3n del documento.", "excerpt_keywords": "SSFFC, pharmacopoeias, global monitoring, regulatory authorities, collaboration"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ddae9636-e1bb-4092-b751-008b1668c704", "node_type": "4", "metadata": {"page_label": "56", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThere was also a presentation on a new project within this area of work, particularly focusing on the SSFFC products. There was a deficiency of hard data on this issue and the project aimed to establish a global monitoring and surveillance system and disseminate data, to collate best practice and establish a minimum reporting standard on SSFFC products, to assist regulatory authorities to identify SSFFC products, to establish where the risks were greatest, and to encourage collaboration between regulatory authorities on this issue. This is a four-year project in five phases and is being carried out by the team for Quality Assurance and Safety: Medicines in WHO in close collaboration with the regional offices and countries.\n\nThe Expert Committee expressed its appreciation for the project and gave its endorsement. The Committee considered that the idea of having a watch list of products that were frequently falsified would be very helpful to NMRAs.\n\n## 13.3 Index of pharmacopoeias\n\nThis index, including all pharmacopoeias around the world, was first prepared in 2001 and has been regularly updated. In accordance with the recommendations made by the Expert Committee at its forty-fifth meeting, the Index of Pharmacopoeias had been revised. Africa has one pharmacopoeia (this is the African Pharmacopoeia and not a national pharmacopoeia), the Americas four, the Western Pacific has five, and Europe has 30. Of these, five national pharmacopoeias offer free online access, as does The International Pharmacopoeia of WHO. The index contains all contact information for the pharmacopoeias.\n\nThe Expert Committee took note of the report and advised the Secretary to complete and update the missing information in the index as notified by the respective pharmacopoeias.\n\n## 13.4 Collaboration with pharmacopoeias\n\nWHO was working on closer collaboration with a view to exchanging information with other pharmacopoeias and achieving further harmonization. A meeting was held in July 2011 with a number of representatives from secretariats of national pharmacopoeias. FIP would provide an opportunity for a meeting of pharmacopoeia representatives with other stakeholders in 2012, and WHO would offer to organize a private meeting for pharmacopoeia representatives only, to discuss common issues and concerns following up on discussions that had started during a side-meeting held at the 10th ICDRA meeting in Hong Kong Special Administrative Region of the People\u2019s Republic of China in 2002.\n\nThe Expert Committee took note of this initiative and expressed its support for an international meeting of world pharmacopoeias organized by WHO.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "0d489b3734e0909e44903fd79b093e0ab86afc3ac8f04d71f8a9372aa9de3e6f", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThere was also a presentation on a new project within this area of work, particularly focusing on the SSFFC products. There was a deficiency of hard data on this issue and the project aimed to establish a global monitoring and surveillance system and disseminate data, to collate best practice and establish a minimum reporting standard on SSFFC products, to assist regulatory authorities to identify SSFFC products, to establish where the risks were greatest, and to encourage collaboration between regulatory authorities on this issue. This is a four-year project in five phases and is being carried out by the team for Quality Assurance and Safety: Medicines in WHO in close collaboration with the regional offices and countries.\n\nThe Expert Committee expressed its appreciation for the project and gave its endorsement. The Committee considered that the idea of having a watch list of products that were frequently falsified would be very helpful to NMRAs.\n\n## 13.3 Index of pharmacopoeias\n\nThis index, including all pharmacopoeias around the world, was first prepared in 2001 and has been regularly updated. In accordance with the recommendations made by the Expert Committee at its forty-fifth meeting, the Index of Pharmacopoeias had been revised. Africa has one pharmacopoeia (this is the African Pharmacopoeia and not a national pharmacopoeia), the Americas four, the Western Pacific has five, and Europe has 30. Of these, five national pharmacopoeias offer free online access, as does The International Pharmacopoeia of WHO. The index contains all contact information for the pharmacopoeias.\n\nThe Expert Committee took note of the report and advised the Secretary to complete and update the missing information in the index as notified by the respective pharmacopoeias.\n\n## 13.4 Collaboration with pharmacopoeias\n\nWHO was working on closer collaboration with a view to exchanging information with other pharmacopoeias and achieving further harmonization. A meeting was held in July 2011 with a number of representatives from secretariats of national pharmacopoeias. FIP would provide an opportunity for a meeting of pharmacopoeia representatives with other stakeholders in 2012, and WHO would offer to organize a private meeting for pharmacopoeia representatives only, to discuss common issues and concerns following up on discussions that had started during a side-meeting held at the 10th ICDRA meeting in Hong Kong Special Administrative Region of the People\u2019s Republic of China in 2002.\n\nThe Expert Committee took note of this initiative and expressed its support for an international meeting of world pharmacopoeias organized by WHO.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2722, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f14f2f8a-bffa-4a5e-a747-fbb4633f2f62": {"__data__": {"id_": "f14f2f8a-bffa-4a5e-a747-fbb4633f2f62", "embedding": null, "metadata": {"page_label": "57", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 14. Summary and Recommendations\n\nThe Expert Committee on Specifications for Pharmaceutical Preparations provides recommendations and tools to assure the quality of medicines from their development phase to their final distribution to the patients. It advises the Director-General of the World Health Organization in the area of quality assurance of medicines.\n\nThe international guidelines, specifications and nomenclature developed under the aegis of this Committee serve all Member States, international organizations, United Nations agencies, regional and interregional harmonization efforts, and underpin important initiatives, including the prequalification of medicines, the Roll Back Malaria Programme, Stop TB, essential medicines and medicines for children.\n\nThe advice and recommendations provided by this Expert Committee are intended to help national and regional authorities and procurement agencies, as well as major international bodies and institutions, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria, and international organizations such as the United Nations Children\u2019s Fund (UNICEF) to combat circulation of substandard medicines and to work towards access to good-quality medicines.\n\nSince the inception of this WHO Expert Committee in 1948, its members have worked towards making available clear, independent and practical recommendations, written and physical standards, as well as international guidelines for good-quality medicines. Standards in the area of quality assurance for medicines are developed by the Committee through a wide global consultation process building on consensus to reach internationally recognized and up-to-date standards. Detailed recommendations can be found under each relevant section in the report.\n\nThe topics are related to various programmes and activities within WHO. There are joint activities, specifically in collaboration with the WHO Expert Committees on Biological Standardization, and on the Selection and Use of Essential Medicines and its Subcommittee on Medicines for Children. In addition, the Committee serves to develop specific additional guidance and specifications as needed for the various medicines recommended by WHO programmes.\n\nThis Committee also serves the United Nations Prequalification of Medicines Programme managed and operated by WHO, as the Programme could not function without the guidelines, standards and specifications adopted by this Committee after passage through its rigorous, international and wide consultative process. The advantage for the Committee is that, as a result of implementing these guidelines and specifications, practical suggestions for potential revision or on the need for additional guidance are communicated to the Expert Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de Nivel Superior\n\nEl Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas de la OMS proporciona recomendaciones y herramientas para asegurar la calidad de los medicamentos desde su desarrollo hasta su distribuci\u00f3n final. Este Comit\u00e9 asesora al Director General de la OMS en materia de garant\u00eda de calidad de los medicamentos y desarrolla directrices, especificaciones y nomenclatura que benefician a todos los Estados miembros y organizaciones internacionales. Desde su creaci\u00f3n en 1948, ha trabajado en la elaboraci\u00f3n de est\u00e1ndares internacionales a trav\u00e9s de un proceso de consulta global. Adem\u00e1s, colabora con otros comit\u00e9s de la OMS y apoya el Programa de Precalificaci\u00f3n de Medicamentos de la ONU.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los principales programas e iniciativas que se benefician de las directrices y est\u00e1ndares desarrollados por el Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas?**\n   - Esta pregunta busca identificar los programas espec\u00edficos, como el Programa de Precalificaci\u00f3n de Medicamentos y otros, que dependen de las recomendaciones del Comit\u00e9.\n\n2. **\u00bfC\u00f3mo se asegura el Comit\u00e9 que sus recomendaciones y est\u00e1ndares sean actualizados y reconocidos internacionalmente?**\n   - Esta pregunta se centra en el proceso de consulta global y consenso que utiliza el Comit\u00e9 para desarrollar sus est\u00e1ndares, lo que puede no estar documentado en otros lugares.\n\n3. **\u00bfQu\u00e9 papel juega el Comit\u00e9 en la lucha contra la circulaci\u00f3n de medicamentos subest\u00e1ndar y c\u00f3mo colabora con otras organizaciones internacionales?**\n   - Esta pregunta busca explorar la funci\u00f3n espec\u00edfica del Comit\u00e9 en la mejora del acceso a medicamentos de buena calidad y su colaboraci\u00f3n con entidades como UNICEF y el Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Proyecto sobre Productos SSFFC**:\n   - **Objetivo**: Establecer un sistema global de monitoreo y vigilancia para productos farmac\u00e9uticos falsificados y de calidad subest\u00e1ndar (SSFFC).\n   - **Componentes**: Recopilaci\u00f3n de datos, establecimiento de est\u00e1ndares de reporte, identificaci\u00f3n de riesgos y fomento de la colaboraci\u00f3n entre autoridades regulatorias.\n   - **Duraci\u00f3n**: Proyecto de cuatro a\u00f1os dividido en cinco fases.\n   - **Entidades Involucradas**: Equipo de Aseguramiento de Calidad y Seguridad de Medicamentos de la OMS, oficinas regionales y pa\u00edses.\n\n2. **\u00cdndice de Farmacopeas**:\n   - **Descripci\u00f3n**: Compilaci\u00f3n de todas las farmacopeas del mundo, actualizada regularmente desde 2001.\n   - **Acceso**: Incluye informaci\u00f3n de contacto y recursos, con algunas farmacopeas nacionales ofreciendo acceso gratuito en l\u00ednea.\n   - **Distribuci\u00f3n Geogr\u00e1fica**: \u00c1frica (1), Am\u00e9ricas (4), Pac\u00edfico Occidental (5), Europa (30).\n   - **Recomendaciones**: La OMS debe completar y actualizar la informaci\u00f3n faltante en el \u00edndice.\n\n3. **Colaboraci\u00f3n con Farmacopeas**:\n   - **Iniciativa**: Fomentar la colaboraci\u00f3n y el intercambio de informaci\u00f3n entre farmacopeas nacionales para lograr una mayor armonizaci\u00f3n.\n   - **Reuniones**: Se han planificado encuentros para discutir problemas comunes y promover la cooperaci\u00f3n internacional.\n   - **Apoyo**: La Comisi\u00f3n de Expertos de la OMS respalda la organizaci\u00f3n de una reuni\u00f3n internacional de farmacopeas.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Coordinadora del proyecto y de las iniciativas de colaboraci\u00f3n.\n- **NMRAs (Autoridades Nacionales Reguladoras de Medicamentos)**: Beneficiarias de la lista de vigilancia de productos falsificados.\n- **FIP (Federaci\u00f3n Internacional Farmac\u00e9utica)**: Participante en la organizaci\u00f3n de reuniones de farmacopeas.\n\nEste resumen destaca los esfuerzos de la OMS para abordar la falsificaci\u00f3n de medicamentos y mejorar la colaboraci\u00f3n entre farmacopeas a nivel global.", "excerpt_keywords": "Keywords: quality assurance, pharmaceutical preparations, WHO guidelines, substandard medicines, international collaboration"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dc9219bc-3b73-47b7-bab5-523ceaf7cbc5", "node_type": "4", "metadata": {"page_label": "57", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 14. Summary and Recommendations\n\nThe Expert Committee on Specifications for Pharmaceutical Preparations provides recommendations and tools to assure the quality of medicines from their development phase to their final distribution to the patients. It advises the Director-General of the World Health Organization in the area of quality assurance of medicines.\n\nThe international guidelines, specifications and nomenclature developed under the aegis of this Committee serve all Member States, international organizations, United Nations agencies, regional and interregional harmonization efforts, and underpin important initiatives, including the prequalification of medicines, the Roll Back Malaria Programme, Stop TB, essential medicines and medicines for children.\n\nThe advice and recommendations provided by this Expert Committee are intended to help national and regional authorities and procurement agencies, as well as major international bodies and institutions, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria, and international organizations such as the United Nations Children\u2019s Fund (UNICEF) to combat circulation of substandard medicines and to work towards access to good-quality medicines.\n\nSince the inception of this WHO Expert Committee in 1948, its members have worked towards making available clear, independent and practical recommendations, written and physical standards, as well as international guidelines for good-quality medicines. Standards in the area of quality assurance for medicines are developed by the Committee through a wide global consultation process building on consensus to reach internationally recognized and up-to-date standards. Detailed recommendations can be found under each relevant section in the report.\n\nThe topics are related to various programmes and activities within WHO. There are joint activities, specifically in collaboration with the WHO Expert Committees on Biological Standardization, and on the Selection and Use of Essential Medicines and its Subcommittee on Medicines for Children. In addition, the Committee serves to develop specific additional guidance and specifications as needed for the various medicines recommended by WHO programmes.\n\nThis Committee also serves the United Nations Prequalification of Medicines Programme managed and operated by WHO, as the Programme could not function without the guidelines, standards and specifications adopted by this Committee after passage through its rigorous, international and wide consultative process. The advantage for the Committee is that, as a result of implementing these guidelines and specifications, practical suggestions for potential revision or on the need for additional guidance are communicated to the Expert Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "0bece343536a8cd8ace3f78cbffa2f0497e75b1bf4f9c6b7ae9c214db3ff1e20", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 14. Summary and Recommendations\n\nThe Expert Committee on Specifications for Pharmaceutical Preparations provides recommendations and tools to assure the quality of medicines from their development phase to their final distribution to the patients. It advises the Director-General of the World Health Organization in the area of quality assurance of medicines.\n\nThe international guidelines, specifications and nomenclature developed under the aegis of this Committee serve all Member States, international organizations, United Nations agencies, regional and interregional harmonization efforts, and underpin important initiatives, including the prequalification of medicines, the Roll Back Malaria Programme, Stop TB, essential medicines and medicines for children.\n\nThe advice and recommendations provided by this Expert Committee are intended to help national and regional authorities and procurement agencies, as well as major international bodies and institutions, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria, and international organizations such as the United Nations Children\u2019s Fund (UNICEF) to combat circulation of substandard medicines and to work towards access to good-quality medicines.\n\nSince the inception of this WHO Expert Committee in 1948, its members have worked towards making available clear, independent and practical recommendations, written and physical standards, as well as international guidelines for good-quality medicines. Standards in the area of quality assurance for medicines are developed by the Committee through a wide global consultation process building on consensus to reach internationally recognized and up-to-date standards. Detailed recommendations can be found under each relevant section in the report.\n\nThe topics are related to various programmes and activities within WHO. There are joint activities, specifically in collaboration with the WHO Expert Committees on Biological Standardization, and on the Selection and Use of Essential Medicines and its Subcommittee on Medicines for Children. In addition, the Committee serves to develop specific additional guidance and specifications as needed for the various medicines recommended by WHO programmes.\n\nThis Committee also serves the United Nations Prequalification of Medicines Programme managed and operated by WHO, as the Programme could not function without the guidelines, standards and specifications adopted by this Committee after passage through its rigorous, international and wide consultative process. The advantage for the Committee is that, as a result of implementing these guidelines and specifications, practical suggestions for potential revision or on the need for additional guidance are communicated to the Expert Committee.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2768, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "7986a624-f104-4916-98a2-ca844c458894": {"__data__": {"id_": "7986a624-f104-4916-98a2-ca844c458894", "embedding": null, "metadata": {"page_label": "58", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIn conclusion, the Expert Committee on Specifications for Pharmaceutical Preparations gives recommendations and provides independent international standards and guidelines in the area of quality assurance for implementation by WHO Member States, international organizations, United Nations agencies, regional and interregional harmonization efforts, as well as WHO\u2019s medicines-related programmes and initiatives. Making resources available for these activities is, therefore, very cost-effective.\n\n## The following new guidelines were adopted and recommended for use:\n\n- Development of monographs for *The International Pharmacopoeia* (Annex 1)\n- WHO good manufacturing practices: water for pharmaceutical use (Annex 2)\n- Pharmaceutical development of multisource (generic) pharmaceutical products \u2013 points to consider (Annex 3)\n- Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (Annex 4)\n- Development of paediatric medicines: points to consider in formulation (Annex 5)\n- Recommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients (Annex 6)\n\n## For inclusion in *The International Pharmacopoeia*\n\nThe following monographs were adopted:\n\n- **For antiretroviral medicines**\n  - ritonavir tablets\n- **For antimalarial medicines**\n  - artesunate\n  - artenimol\n- **For antituberculosis medicines**\n  - rifampicin (API)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento es un informe de la Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. En \u00e9l se presentan recomendaciones y est\u00e1ndares internacionales en el \u00e1mbito de la garant\u00eda de calidad para su implementaci\u00f3n por parte de los Estados Miembros de la OMS y otras organizaciones. Se adoptaron nuevas directrices y monograf\u00edas para la *Farmacopea Internacional*, incluyendo pautas sobre buenas pr\u00e1cticas de fabricaci\u00f3n y el desarrollo de medicamentos pedi\u00e1tricos, as\u00ed como monograf\u00edas espec\u00edficas para medicamentos antirretrovirales, antimal\u00e1ricos y antituberculosos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las nuevas directrices adoptadas por la Comisi\u00f3n de Expertos de la OMS y qu\u00e9 \u00e1reas espec\u00edficas abordan?**\n   - Esta pregunta busca detalles sobre las directrices espec\u00edficas que se han adoptado, que no se encuentran f\u00e1cilmente en otros documentos.\n\n2. **\u00bfQu\u00e9 monograf\u00edas espec\u00edficas fueron adoptadas para la inclusi\u00f3n en la *Farmacopea Internacional* y para qu\u00e9 tipos de medicamentos?**\n   - Esta pregunta se centra en las monograf\u00edas adoptadas, proporcionando informaci\u00f3n espec\u00edfica sobre los medicamentos que se est\u00e1n regulando.\n\n3. **\u00bfPor qu\u00e9 se considera que hacer disponibles recursos para las actividades de la OMS es una medida costo-efectiva?**\n   - Esta pregunta busca una explicaci\u00f3n sobre la relaci\u00f3n costo-beneficio de las actividades de la OMS en el contexto de la calidad de los medicamentos, un aspecto que puede no estar ampliamente discutido en otros documentos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**: Este comit\u00e9 de la OMS proporciona recomendaciones y herramientas para asegurar la calidad de los medicamentos desde su desarrollo hasta su distribuci\u00f3n final.\n\n2. **Asesoramiento al Director General de la OMS**: El comit\u00e9 asesora en materia de garant\u00eda de calidad de los medicamentos.\n\n3. **Directrices y Especificaciones Internacionales**: Desarrolla normas y nomenclatura que benefician a todos los Estados miembros, organizaciones internacionales y agencias de la ONU, apoyando iniciativas como:\n   - Programa de Precalificaci\u00f3n de Medicamentos\n   - Programa Roll Back Malaria\n   - Stop TB\n   - Medicamentos esenciales y medicamentos para ni\u00f1os\n\n4. **Colaboraci\u00f3n con Otras Entidades**: Trabaja con autoridades nacionales y regionales, agencias de adquisici\u00f3n y organizaciones internacionales como:\n   - Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria\n   - UNICEF\n\n5. **Proceso de Consulta Global**: Los est\u00e1ndares se desarrollan a trav\u00e9s de un proceso de consulta amplia y consenso, asegurando que sean reconocidos y actualizados internacionalmente.\n\n6. **Actividades Conjuntas**: Colabora con otros comit\u00e9s de la OMS, como el de Estandarizaci\u00f3n Biol\u00f3gica y el de Selecci\u00f3n y Uso de Medicamentos Esenciales.\n\n7. **Programa de Precalificaci\u00f3n de Medicamentos de la ONU**: El comit\u00e9 proporciona las directrices y est\u00e1ndares necesarios para el funcionamiento de este programa.\n\nEste resumen destaca la importancia del Comit\u00e9 en la mejora de la calidad de los medicamentos y su papel en la colaboraci\u00f3n internacional para combatir medicamentos subest\u00e1ndar y mejorar el acceso a medicamentos de calidad.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, quality assurance, International Pharmacopoeia, guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce329c44-b0da-402a-ab47-7055dd4d09c4", "node_type": "4", "metadata": {"page_label": "58", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIn conclusion, the Expert Committee on Specifications for Pharmaceutical Preparations gives recommendations and provides independent international standards and guidelines in the area of quality assurance for implementation by WHO Member States, international organizations, United Nations agencies, regional and interregional harmonization efforts, as well as WHO\u2019s medicines-related programmes and initiatives. Making resources available for these activities is, therefore, very cost-effective.\n\n## The following new guidelines were adopted and recommended for use:\n\n- Development of monographs for *The International Pharmacopoeia* (Annex 1)\n- WHO good manufacturing practices: water for pharmaceutical use (Annex 2)\n- Pharmaceutical development of multisource (generic) pharmaceutical products \u2013 points to consider (Annex 3)\n- Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (Annex 4)\n- Development of paediatric medicines: points to consider in formulation (Annex 5)\n- Recommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients (Annex 6)\n\n## For inclusion in *The International Pharmacopoeia*\n\nThe following monographs were adopted:\n\n- **For antiretroviral medicines**\n  - ritonavir tablets\n- **For antimalarial medicines**\n  - artesunate\n  - artenimol\n- **For antituberculosis medicines**\n  - rifampicin (API)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "3a0b1577ede5daed5819eae1ae2cad0b2fe1fcf6b21c8d4225fb6b467ddfcbd6", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIn conclusion, the Expert Committee on Specifications for Pharmaceutical Preparations gives recommendations and provides independent international standards and guidelines in the area of quality assurance for implementation by WHO Member States, international organizations, United Nations agencies, regional and interregional harmonization efforts, as well as WHO\u2019s medicines-related programmes and initiatives. Making resources available for these activities is, therefore, very cost-effective.\n\n## The following new guidelines were adopted and recommended for use:\n\n- Development of monographs for *The International Pharmacopoeia* (Annex 1)\n- WHO good manufacturing practices: water for pharmaceutical use (Annex 2)\n- Pharmaceutical development of multisource (generic) pharmaceutical products \u2013 points to consider (Annex 3)\n- Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (Annex 4)\n- Development of paediatric medicines: points to consider in formulation (Annex 5)\n- Recommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients (Annex 6)\n\n## For inclusion in *The International Pharmacopoeia*\n\nThe following monographs were adopted:\n\n- **For antiretroviral medicines**\n  - ritonavir tablets\n- **For antimalarial medicines**\n  - artesunate\n  - artenimol\n- **For antituberculosis medicines**\n  - rifampicin (API)", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1598, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "8beb214c-52a8-4ed5-9bf7-a3917b88a815": {"__data__": {"id_": "8beb214c-52a8-4ed5-9bf7-a3917b88a815", "embedding": null, "metadata": {"page_label": "59", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- **rifampicin tablets**\n- **rifampicin capsules**\n\n## For anti-infectives\n- pyrantel chewable tablets\n\n## For other medicines\n- levonorgestrel tablets\n- medroxyprogesterone injection\n- paediatric retinol oral solution\n- retinol concentrate (oily form)\n\n## For harmonized general texts (based on PDG texts)\n- test for sulfated ash\n- test for bacterial endotoxins\n- test for sterility\n- tablet friability\n- disintegration test for tablets and capsules\n- bulk density and tapped density of powders\n- test for extractable volume for parenteral preparations\n- microbiological examination of non-sterile products: microbial enumeration tests\n- microbiological examination of non-sterile products: tests for specified microorganisms\n- microbial quality of pharmaceutical preparations\n- test for particulate contamination\n\n## General policy topics and general revision issues for:\n- uniformity of content for single-dose preparations\n- supplementary information section\n\n## The Committee adopted the following new ICRS:\n- Lumefantrine for system suitability\n\n## The following monograph was released for the wide consultation process:\n\n### For antimalarial medicines\n- mefloquine hydrochloride", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 tipos de medicamentos se mencionan en el informe de la OMS y cu\u00e1les son sus formas farmac\u00e9uticas?**\n   - El informe menciona varios medicamentos, incluyendo:\n     - **Rifampicina** en tabletas y c\u00e1psulas.\n     - **Pyrantel** en tabletas masticables (para anti-infectivos).\n     - **Levonorgestrel** en tabletas.\n     - **Medroxiprogesterona** en inyecci\u00f3n.\n     - **Soluci\u00f3n oral de retinol pedi\u00e1trica**.\n     - **Concentrado de retinol** (forma oleosa).\n\n2. **\u00bfCu\u00e1les son algunos de los m\u00e9todos de prueba estandarizados que se adoptaron para los textos generales armonizados?**\n   - Los m\u00e9todos de prueba estandarizados adoptados incluyen:\n     - Prueba de cenizas sulfatadas.\n     - Prueba de endotoxinas bacterianas.\n     - Prueba de esterilidad.\n     - Friabilidad de tabletas.\n     - Prueba de desintegraci\u00f3n para tabletas y c\u00e1psulas.\n     - Densidad a granel y densidad apilada de polvos.\n     - Prueba de volumen extra\u00edble para preparaciones parenterales.\n     - Examen microbiol\u00f3gico de productos no est\u00e9riles: pruebas de enumeraci\u00f3n microbiana y pruebas para microorganismos especificados.\n     - Calidad microbiana de preparaciones farmac\u00e9uticas.\n     - Prueba de contaminaci\u00f3n particulada.\n\n3. **\u00bfQu\u00e9 nuevo ICRS fue adoptado por el Comit\u00e9 y para qu\u00e9 se utiliza?**\n   - El Comit\u00e9 adopt\u00f3 un nuevo ICRS para **Lumefantrina**, que se utiliza para la idoneidad del sistema. Esto sugiere que se est\u00e1 estableciendo un est\u00e1ndar para asegurar que los sistemas de prueba sean adecuados para evaluar la calidad de este medicamento.\n\n### Resumen de nivel superior:\nEl informe de la OMS detalla las especificaciones para varios medicamentos, incluyendo rifampicina, pyrantel, levonorgestrel, y otros, as\u00ed como m\u00e9todos de prueba estandarizados para asegurar la calidad de las preparaciones farmac\u00e9uticas. Tambi\u00e9n se discuten temas de pol\u00edtica general y se adopta un nuevo ICRS para Lumefantrina, que se somete a un proceso de consulta amplia para la monograf\u00eda de mefloquina.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comisi\u00f3n de Expertos de la OMS**: Se centra en la elaboraci\u00f3n de recomendaciones y est\u00e1ndares internacionales para la garant\u00eda de calidad en preparaciones farmac\u00e9uticas.\n\n2. **Recomendaciones y Directrices**:\n   - Desarrollo de monograf\u00edas para *La Farmacopea Internacional*.\n   - Buenas pr\u00e1cticas de fabricaci\u00f3n de la OMS, espec\u00edficamente sobre agua para uso farmac\u00e9utico.\n   - Desarrollo farmac\u00e9utico de productos farmac\u00e9uticos multisource (gen\u00e9ricos).\n   - Pautas para la documentaci\u00f3n de productos farmac\u00e9uticos multisource para el Programa de Precalificaci\u00f3n de Medicamentos de la OMS.\n   - Consideraciones para el desarrollo de medicamentos pedi\u00e1tricos.\n   - Requisitos de calidad para la artemisinina como materia prima en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos.\n\n3. **Monograf\u00edas Adoptadas para la *Farmacopea Internacional***:\n   - **Medicamentos Antirretrovirales**: Ritonavir (tabletas).\n   - **Medicamentos Antimal\u00e1ricos**: Artesunato, artenimol.\n   - **Medicamentos Antituberculosos**: Rifampicina (API).\n\n4. **Costo-efectividad**: Se menciona que hacer disponibles recursos para las actividades de la OMS es una medida costo-efectiva, lo que implica un enfoque en la eficiencia y el impacto positivo de estas iniciativas en la calidad de los medicamentos a nivel global.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, rifampicin, ICRS, antimalarial medicines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6658c379-d7e9-4694-822c-a280d86a3eb8", "node_type": "4", "metadata": {"page_label": "59", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- **rifampicin tablets**\n- **rifampicin capsules**\n\n## For anti-infectives\n- pyrantel chewable tablets\n\n## For other medicines\n- levonorgestrel tablets\n- medroxyprogesterone injection\n- paediatric retinol oral solution\n- retinol concentrate (oily form)\n\n## For harmonized general texts (based on PDG texts)\n- test for sulfated ash\n- test for bacterial endotoxins\n- test for sterility\n- tablet friability\n- disintegration test for tablets and capsules\n- bulk density and tapped density of powders\n- test for extractable volume for parenteral preparations\n- microbiological examination of non-sterile products: microbial enumeration tests\n- microbiological examination of non-sterile products: tests for specified microorganisms\n- microbial quality of pharmaceutical preparations\n- test for particulate contamination\n\n## General policy topics and general revision issues for:\n- uniformity of content for single-dose preparations\n- supplementary information section\n\n## The Committee adopted the following new ICRS:\n- Lumefantrine for system suitability\n\n## The following monograph was released for the wide consultation process:\n\n### For antimalarial medicines\n- mefloquine hydrochloride", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "70409600a4821ad0c9664d0724fb55b7d27d1404b2b4810903185c015de5be6c", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- **rifampicin tablets**\n- **rifampicin capsules**\n\n## For anti-infectives\n- pyrantel chewable tablets\n\n## For other medicines\n- levonorgestrel tablets\n- medroxyprogesterone injection\n- paediatric retinol oral solution\n- retinol concentrate (oily form)\n\n## For harmonized general texts (based on PDG texts)\n- test for sulfated ash\n- test for bacterial endotoxins\n- test for sterility\n- tablet friability\n- disintegration test for tablets and capsules\n- bulk density and tapped density of powders\n- test for extractable volume for parenteral preparations\n- microbiological examination of non-sterile products: microbial enumeration tests\n- microbiological examination of non-sterile products: tests for specified microorganisms\n- microbial quality of pharmaceutical preparations\n- test for particulate contamination\n\n## General policy topics and general revision issues for:\n- uniformity of content for single-dose preparations\n- supplementary information section\n\n## The Committee adopted the following new ICRS:\n- Lumefantrine for system suitability\n\n## The following monograph was released for the wide consultation process:\n\n### For antimalarial medicines\n- mefloquine hydrochloride", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1259, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "a26d3d50-863c-461b-aef6-8af8bc793082": {"__data__": {"id_": "a26d3d50-863c-461b-aef6-8af8bc793082", "embedding": null, "metadata": {"page_label": "60", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Regulatory guidance\n\n## Extension of shelf-life\n\nThe Expert Committee recommended that each national authority, if opting to extend the shelf-life of oseltamivir and zanamivir, should take into consideration the following points to ensure that there was no negative impact on the patients:\n\n- The manufacturer should be consulted for evidence in support of extended shelf-life.\n- The products are maintained under storage conditions in compliance with the label requirements.\n- The national regulatory authority may wish to follow up with its own testing.\n\n# Recommendations in the quality assurance-related areas\n\nThe following recommendations were made in the various quality assurance-related areas. Progress on the suggested actions should be reported to the Expert Committee on Specifications for Pharmaceutical Preparations at its next meeting.\n\n## Collaboration with and among pharmacopoeias\n\n- The Expert Committee expressed support for WHO\u2019s initiative to work more closely with other pharmacopoeias. It also endorsed the proposed international meeting bringing together representatives of all the world\u2019s pharmacopoeias to enable them to discuss common issues and concerns.\n\n## The International Pharmacopoeia\n\n- Continue development of specifications for medicines, general methods and texts and general supplementary information in accordance with the work plan and as decided at the forty-sixth meeting.\n- Continue the efforts at international collaboration in relation to the revision and inclusion of specific monographs and general methods.\n- Continue the preparatory work for a subsequent supplement to *The International Pharmacopoeia*, or towards a fifth edition, especially in electronic form (CD-ROM and online).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda la extensi\u00f3n de la vida \u00fatil de los medicamentos oseltamivir y zanamivir, recomendando que las autoridades nacionales consideren ciertos puntos para garantizar la seguridad de los pacientes. Adem\u00e1s, se discuten recomendaciones en \u00e1reas relacionadas con la garant\u00eda de calidad, destacando la colaboraci\u00f3n entre farmacopoeias y el desarrollo continuo de especificaciones para medicamentos en *The International Pharmacopoeia*.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 pasos deben seguir las autoridades nacionales antes de extender la vida \u00fatil de oseltamivir y zanamivir?**\n   - Las autoridades nacionales deben consultar al fabricante para obtener evidencia que respalde la extensi\u00f3n de la vida \u00fatil, asegurarse de que los productos se mantengan bajo condiciones de almacenamiento adecuadas y considerar realizar pruebas adicionales.\n\n2. **\u00bfCu\u00e1l es el prop\u00f3sito de la reuni\u00f3n internacional propuesta por la OMS entre representantes de las farmacopoeias del mundo?**\n   - El prop\u00f3sito de la reuni\u00f3n es permitir que los representantes de las farmacopoeias discutan problemas y preocupaciones comunes, fomentando as\u00ed una colaboraci\u00f3n m\u00e1s estrecha entre ellas.\n\n3. **\u00bfQu\u00e9 acciones se espera que reporten las autoridades nacionales al Comit\u00e9 de Expertos en su pr\u00f3xima reuni\u00f3n?**\n   - Se espera que las autoridades nacionales informen sobre el progreso de las acciones sugeridas en las \u00e1reas de garant\u00eda de calidad, as\u00ed como sobre la colaboraci\u00f3n con otras farmacopoeias y el desarrollo de especificaciones para medicamentos.", "prev_section_summary": "El contenido de la secci\u00f3n del informe de la OMS se centra en las especificaciones para preparaciones farmac\u00e9uticas y abarca varios temas clave:\n\n1. **Medicamentos Mencionados**:\n   - **Rifampicina**: disponible en tabletas y c\u00e1psulas.\n   - **Pyrantel**: en tabletas masticables, utilizado como anti-infectivo.\n   - **Levonorgestrel**: en tabletas.\n   - **Medroxiprogesterona**: en forma de inyecci\u00f3n.\n   - **Retinol**: en soluci\u00f3n oral pedi\u00e1trica y en forma oleosa concentrada.\n\n2. **M\u00e9todos de Prueba Estandarizados**:\n   - Pruebas para cenizas sulfatadas, endotoxinas bacterianas, esterilidad, friabilidad de tabletas, desintegraci\u00f3n de tabletas y c\u00e1psulas, densidad de polvos, volumen extra\u00edble para preparaciones parenterales, y ex\u00e1menes microbiol\u00f3gicos de productos no est\u00e9riles.\n\n3. **Temas de Pol\u00edtica General**:\n   - Uniformidad del contenido para preparaciones de dosis \u00fanica y secci\u00f3n de informaci\u00f3n suplementaria.\n\n4. **Nuevos ICRS Adoptados**:\n   - Se adopt\u00f3 un nuevo ICRS para **Lumefantrina**, relacionado con la idoneidad del sistema.\n\n5. **Monograf\u00eda en Consulta**:\n   - Se lanz\u00f3 una monograf\u00eda para **Mefloquina** como parte del proceso de consulta amplia.\n\nEste resumen destaca la importancia de asegurar la calidad y la uniformidad en las preparaciones farmac\u00e9uticas, as\u00ed como la adopci\u00f3n de nuevos est\u00e1ndares y la consulta sobre medicamentos antimal\u00e1ricos.", "excerpt_keywords": "Keywords: shelf-life extension, oseltamivir, zanamivir, quality assurance, International Pharmacopoeia"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "649c3c29-abf1-4df6-99b3-8d65d2f0e119", "node_type": "4", "metadata": {"page_label": "60", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Regulatory guidance\n\n## Extension of shelf-life\n\nThe Expert Committee recommended that each national authority, if opting to extend the shelf-life of oseltamivir and zanamivir, should take into consideration the following points to ensure that there was no negative impact on the patients:\n\n- The manufacturer should be consulted for evidence in support of extended shelf-life.\n- The products are maintained under storage conditions in compliance with the label requirements.\n- The national regulatory authority may wish to follow up with its own testing.\n\n# Recommendations in the quality assurance-related areas\n\nThe following recommendations were made in the various quality assurance-related areas. Progress on the suggested actions should be reported to the Expert Committee on Specifications for Pharmaceutical Preparations at its next meeting.\n\n## Collaboration with and among pharmacopoeias\n\n- The Expert Committee expressed support for WHO\u2019s initiative to work more closely with other pharmacopoeias. It also endorsed the proposed international meeting bringing together representatives of all the world\u2019s pharmacopoeias to enable them to discuss common issues and concerns.\n\n## The International Pharmacopoeia\n\n- Continue development of specifications for medicines, general methods and texts and general supplementary information in accordance with the work plan and as decided at the forty-sixth meeting.\n- Continue the efforts at international collaboration in relation to the revision and inclusion of specific monographs and general methods.\n- Continue the preparatory work for a subsequent supplement to *The International Pharmacopoeia*, or towards a fifth edition, especially in electronic form (CD-ROM and online).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "d9fc2098488fb475d2051a17b3461109d91cc8c4109a77921385c7f6501015b8", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Regulatory guidance\n\n## Extension of shelf-life\n\nThe Expert Committee recommended that each national authority, if opting to extend the shelf-life of oseltamivir and zanamivir, should take into consideration the following points to ensure that there was no negative impact on the patients:\n\n- The manufacturer should be consulted for evidence in support of extended shelf-life.\n- The products are maintained under storage conditions in compliance with the label requirements.\n- The national regulatory authority may wish to follow up with its own testing.\n\n# Recommendations in the quality assurance-related areas\n\nThe following recommendations were made in the various quality assurance-related areas. Progress on the suggested actions should be reported to the Expert Committee on Specifications for Pharmaceutical Preparations at its next meeting.\n\n## Collaboration with and among pharmacopoeias\n\n- The Expert Committee expressed support for WHO\u2019s initiative to work more closely with other pharmacopoeias. It also endorsed the proposed international meeting bringing together representatives of all the world\u2019s pharmacopoeias to enable them to discuss common issues and concerns.\n\n## The International Pharmacopoeia\n\n- Continue development of specifications for medicines, general methods and texts and general supplementary information in accordance with the work plan and as decided at the forty-sixth meeting.\n- Continue the efforts at international collaboration in relation to the revision and inclusion of specific monographs and general methods.\n- Continue the preparatory work for a subsequent supplement to *The International Pharmacopoeia*, or towards a fifth edition, especially in electronic form (CD-ROM and online).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1735, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d439ab49-8299-4696-9dfc-070b0589dcba": {"__data__": {"id_": "d439ab49-8299-4696-9dfc-070b0589dcba", "embedding": null, "metadata": {"page_label": "61", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## International Chemical Reference Substances (ICRS)\n\n- Continue to promote the use of ICRS through various activities, including a promotional offer to national authorities.\n- Continue the efforts to further enhance the development of new ICRS.\n\n## External Quality Assurance Assessment Scheme (EQAAS)\n\n- Continue the EQAAS for pharmaceutical quality control laboratories, Phase 5, test series 4 onwards.\n- Further prepare the extension of the Scheme starting with Phase 6 to encourage participants to include commercial medicines drawn from their local and regional markets in the studies, when the test protocol allows doing so.\n\n## Good manufacturing practices (GMP) and manufacture\n\n- Follow up on the revision process for GMP for biologicals undertaken under the aegis of the Expert Committee on Biological Standardization.\n- Continue the consultation process on the quality risk management principles with a view to updating the WHO guidelines on hazard analysis and critical control points to cover new trends.\n\n## WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce\n\n- Continue efforts towards a possible review of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce.\n- Develop a special WHO web site for the WHO Certification Scheme for APIs.\n\n## Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part\n\n- A new general document is to be prepared based on the specific guidance developed for the WHO Prequalification Programme (see Annex 4).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las actividades y directrices del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Se abordan varios temas clave, incluyendo el uso de Sustancias Qu\u00edmicas de Referencia Internacional (ICRS), el Esquema de Evaluaci\u00f3n de Aseguramiento de Calidad Externa (EQAAS), las Buenas Pr\u00e1cticas de Manufactura (GMP), el Esquema de Certificaci\u00f3n de la OMS para productos farmac\u00e9uticos en comercio internacional, y las directrices para la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos gen\u00e9ricos. Se enfatiza la promoci\u00f3n de ICRS, la mejora de GMP, y la revisi\u00f3n del esquema de certificaci\u00f3n, entre otros.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las nuevas iniciativas propuestas para el desarrollo de Sustancias Qu\u00edmicas de Referencia Internacional (ICRS) y c\u00f3mo se espera que impacten en la calidad de los productos farmac\u00e9uticos?**\n   - Esta pregunta busca informaci\u00f3n sobre las actividades espec\u00edficas y los objetivos relacionados con el desarrollo de ICRS que no se detallen en otros documentos.\n\n2. **\u00bfQu\u00e9 cambios se est\u00e1n considerando en el Esquema de Certificaci\u00f3n de la OMS para productos farmac\u00e9uticos en comercio internacional y qu\u00e9 implicaciones podr\u00edan tener para los fabricantes?**\n   - Esta pregunta se centra en los posibles cambios en el esquema de certificaci\u00f3n y c\u00f3mo estos podr\u00edan afectar a la industria farmac\u00e9utica, algo que podr\u00eda no estar ampliamente discutido en otros contextos.\n\n3. **\u00bfC\u00f3mo se planea integrar los principios de gesti\u00f3n de riesgos de calidad en las directrices de la OMS sobre an\u00e1lisis de peligros y puntos cr\u00edticos de control (HACCP) en el contexto de las Buenas Pr\u00e1cticas de Manufactura (GMP)?**\n   - Esta pregunta busca detalles sobre la integraci\u00f3n de nuevos enfoques en la gesti\u00f3n de riesgos de calidad, que podr\u00edan no estar disponibles en otras fuentes.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y detallada que se encuentra en el contexto proporcionado, y que puede no estar disponible en otros documentos o fuentes.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Extensi\u00f3n de la vida \u00fatil de medicamentos**:\n   - Se recomienda que las autoridades nacionales consideren ciertos puntos antes de extender la vida \u00fatil de oseltamivir y zanamivir para garantizar la seguridad de los pacientes.\n   - Pasos a seguir:\n     - Consultar al fabricante para obtener evidencia que respalde la extensi\u00f3n.\n     - Asegurarse de que los productos se mantengan bajo condiciones de almacenamiento adecuadas.\n     - Realizar pruebas adicionales si es necesario.\n\n2. **Recomendaciones en garant\u00eda de calidad**:\n   - Se insta a las autoridades nacionales a informar sobre el progreso de las acciones sugeridas en \u00e1reas de garant\u00eda de calidad en la pr\u00f3xima reuni\u00f3n del Comit\u00e9 de Expertos.\n\n3. **Colaboraci\u00f3n entre farmacopoeias**:\n   - Apoyo a la iniciativa de la OMS para fomentar una colaboraci\u00f3n m\u00e1s estrecha entre farmacopoeias a nivel mundial.\n   - Propuesta de una reuni\u00f3n internacional para discutir problemas y preocupaciones comunes.\n\n4. **Desarrollo de *The International Pharmacopoeia***:\n   - Continuar el desarrollo de especificaciones para medicamentos y m\u00e9todos generales.\n   - Fomentar la colaboraci\u00f3n internacional en la revisi\u00f3n e inclusi\u00f3n de monograf\u00edas espec\u00edficas.\n   - Preparar un suplemento o una quinta edici\u00f3n de *The International Pharmacopoeia*, especialmente en formato electr\u00f3nico.\n\n### Entidades mencionadas:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo que emite las recomendaciones.\n- **Oseltamivir y Zanamivir**: Medicamentos cuyo shelf-life se est\u00e1 considerando extender.\n- **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**: Entidad que supervisa el progreso de las acciones recomendadas.\n- **Farmacopoeias**: Colecciones de est\u00e1ndares de medicamentos que se busca integrar y colaborar.", "excerpt_keywords": "Keywords: ICRS, EQAAS, GMP, WHO Certification Scheme, pharmaceutical quality"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "99815b42-2756-47d1-8ad4-0882c099bc0d", "node_type": "4", "metadata": {"page_label": "61", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## International Chemical Reference Substances (ICRS)\n\n- Continue to promote the use of ICRS through various activities, including a promotional offer to national authorities.\n- Continue the efforts to further enhance the development of new ICRS.\n\n## External Quality Assurance Assessment Scheme (EQAAS)\n\n- Continue the EQAAS for pharmaceutical quality control laboratories, Phase 5, test series 4 onwards.\n- Further prepare the extension of the Scheme starting with Phase 6 to encourage participants to include commercial medicines drawn from their local and regional markets in the studies, when the test protocol allows doing so.\n\n## Good manufacturing practices (GMP) and manufacture\n\n- Follow up on the revision process for GMP for biologicals undertaken under the aegis of the Expert Committee on Biological Standardization.\n- Continue the consultation process on the quality risk management principles with a view to updating the WHO guidelines on hazard analysis and critical control points to cover new trends.\n\n## WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce\n\n- Continue efforts towards a possible review of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce.\n- Develop a special WHO web site for the WHO Certification Scheme for APIs.\n\n## Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part\n\n- A new general document is to be prepared based on the specific guidance developed for the WHO Prequalification Programme (see Annex 4).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "ee2e0a9797d1c9c913fcf2ff9c49a72ec31dcabe15498bb62d8da062692b04b3", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## International Chemical Reference Substances (ICRS)\n\n- Continue to promote the use of ICRS through various activities, including a promotional offer to national authorities.\n- Continue the efforts to further enhance the development of new ICRS.\n\n## External Quality Assurance Assessment Scheme (EQAAS)\n\n- Continue the EQAAS for pharmaceutical quality control laboratories, Phase 5, test series 4 onwards.\n- Further prepare the extension of the Scheme starting with Phase 6 to encourage participants to include commercial medicines drawn from their local and regional markets in the studies, when the test protocol allows doing so.\n\n## Good manufacturing practices (GMP) and manufacture\n\n- Follow up on the revision process for GMP for biologicals undertaken under the aegis of the Expert Committee on Biological Standardization.\n- Continue the consultation process on the quality risk management principles with a view to updating the WHO guidelines on hazard analysis and critical control points to cover new trends.\n\n## WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce\n\n- Continue efforts towards a possible review of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce.\n- Develop a special WHO web site for the WHO Certification Scheme for APIs.\n\n## Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part\n\n- A new general document is to be prepared based on the specific guidance developed for the WHO Prequalification Programme (see Annex 4).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1686, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c3ecfc9a-2d45-4223-8c29-3bc42d255dff": {"__data__": {"id_": "c3ecfc9a-2d45-4223-8c29-3bc42d255dff", "embedding": null, "metadata": {"page_label": "62", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products: points to consider\n\n- Further explore development of these \u201cpoints to consider\u201d jointly with the International Pharmaceutical Federation (FIP) as practice guidance for compounding.\n\n## Update on comparator products\n\n- Provide an update of the list of comparator products on the web site, following review by the members of the Expert Committee, to replace the version from 2002.\n\n## Sampling procedures for monitoring of market situations\n\n- Continue development of sampling procedures based on the numerous examples obtained from many countries as feedback to the secretariat\u2019s communications.\n\n## Quality assurance terminology\n\n- Continue the work on the preferred terms included in the current quality assurance terminology database based on the analysis prepared by the secretariat, with a group of experts, including the definition for an API, on which consultation had already started.\n\n## Index of pharmacopoeias\n\n- Consult with the secretariat representatives of the individual world pharmacopoeias included in the *Index of pharmacopoeias* in order to complete and validate the information therein and update the current version on the web site accordingly.\n\n## WHO databases\n\n- Maintain the International Nonproprietary Names (INN) database and continue to make it available on the web site.\n- Maintain the Quality Assurance database and continue to make it available on the web site.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfCu\u00e1les son los pasos propuestos para el desarrollo de puntos de consideraci\u00f3n para la preparaci\u00f3n de medicamentos espec\u00edficos para ni\u00f1os?**\n   - Respuesta: Se sugiere explorar el desarrollo de estos \"puntos a considerar\" en colaboraci\u00f3n con la Federaci\u00f3n Internacional Farmac\u00e9utica (FIP) como gu\u00eda de pr\u00e1ctica para la preparaci\u00f3n de medicamentos.\n\n2. **\u00bfQu\u00e9 acciones se est\u00e1n tomando para actualizar la lista de productos comparadores en el sitio web de la OMS?**\n   - Respuesta: Se planea proporcionar una actualizaci\u00f3n de la lista de productos comparadores en el sitio web, tras la revisi\u00f3n por parte de los miembros del Comit\u00e9 de Expertos, para reemplazar la versi\u00f3n de 2002.\n\n3. **\u00bfQu\u00e9 bases de datos de la OMS se est\u00e1n manteniendo y actualizando, y cu\u00e1l es su prop\u00f3sito?**\n   - Respuesta: Se est\u00e1n manteniendo la base de datos de Nombres No Propietarios Internacionales (INN) y la base de datos de Aseguramiento de Calidad, ambas disponibles en el sitio web de la OMS, con el prop\u00f3sito de facilitar el acceso a informaci\u00f3n relevante sobre medicamentos y su calidad.\n\n### Resumen de nivel superior del contexto:\nEl documento aborda varios puntos clave relacionados con la preparaci\u00f3n y regulaci\u00f3n de productos farmac\u00e9uticos, especialmente en el contexto de la atenci\u00f3n pedi\u00e1trica. Se enfatiza la necesidad de colaboraci\u00f3n con organizaciones como la FIP para desarrollar gu\u00edas de pr\u00e1ctica, la actualizaci\u00f3n de listas de productos comparadores, el desarrollo de procedimientos de muestreo para monitorear el mercado, y la mejora de la terminolog\u00eda de aseguramiento de calidad. Adem\u00e1s, se menciona la importancia de mantener y actualizar bases de datos cr\u00edticas de la OMS para asegurar la disponibilidad de informaci\u00f3n sobre medicamentos.", "prev_section_summary": "La secci\u00f3n del documento de la OMS se centra en varias iniciativas y directrices relacionadas con la calidad de los productos farmac\u00e9uticos. A continuaci\u00f3n se resumen los temas clave y las entidades mencionadas:\n\n1. **Sustancias Qu\u00edmicas de Referencia Internacional (ICRS)**:\n   - Promoci\u00f3n del uso de ICRS a trav\u00e9s de diversas actividades, incluyendo ofertas promocionales a autoridades nacionales.\n   - Esfuerzos continuos para el desarrollo de nuevas ICRS.\n\n2. **Esquema de Evaluaci\u00f3n de Aseguramiento de Calidad Externa (EQAAS)**:\n   - Continuaci\u00f3n del EQAAS para laboratorios de control de calidad farmac\u00e9utica, avanzando hacia la Fase 5 y m\u00e1s all\u00e1.\n   - Preparaci\u00f3n para la extensi\u00f3n del esquema a la Fase 6, incentivando la inclusi\u00f3n de medicamentos comerciales de mercados locales y regionales en los estudios.\n\n3. **Buenas Pr\u00e1cticas de Manufactura (GMP)**:\n   - Seguimiento del proceso de revisi\u00f3n de GMP para productos biol\u00f3gicos bajo el Comit\u00e9 de Expertos en Estandarizaci\u00f3n Biol\u00f3gica.\n   - Consulta sobre principios de gesti\u00f3n de riesgos de calidad para actualizar las directrices de la OMS sobre an\u00e1lisis de peligros y puntos cr\u00edticos de control (HACCP).\n\n4. **Esquema de Certificaci\u00f3n de la OMS**:\n   - Revisi\u00f3n posible del Esquema de Certificaci\u00f3n de la OMS para productos farmac\u00e9uticos en comercio internacional.\n   - Desarrollo de un sitio web especial de la OMS para el Esquema de Certificaci\u00f3n de Ingredientes Farmac\u00e9uticos Activos (APIs).\n\n5. **Directrices para la presentaci\u00f3n de documentaci\u00f3n de productos farmac\u00e9uticos gen\u00e9ricos**:\n   - Preparaci\u00f3n de un nuevo documento general basado en la orientaci\u00f3n espec\u00edfica desarrollada para el Programa de Precalificaci\u00f3n de la OMS.\n\nEstos temas reflejan el compromiso de la OMS con la mejora continua de la calidad y la seguridad de los productos farmac\u00e9uticos a nivel internacional.", "excerpt_keywords": "Keywords: pharmaceutical preparations, quality assurance, pediatric compounding, comparator products, WHO databases"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fcc73d72-acd3-4cbe-b658-c2ac5c380af3", "node_type": "4", "metadata": {"page_label": "62", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products: points to consider\n\n- Further explore development of these \u201cpoints to consider\u201d jointly with the International Pharmaceutical Federation (FIP) as practice guidance for compounding.\n\n## Update on comparator products\n\n- Provide an update of the list of comparator products on the web site, following review by the members of the Expert Committee, to replace the version from 2002.\n\n## Sampling procedures for monitoring of market situations\n\n- Continue development of sampling procedures based on the numerous examples obtained from many countries as feedback to the secretariat\u2019s communications.\n\n## Quality assurance terminology\n\n- Continue the work on the preferred terms included in the current quality assurance terminology database based on the analysis prepared by the secretariat, with a group of experts, including the definition for an API, on which consultation had already started.\n\n## Index of pharmacopoeias\n\n- Consult with the secretariat representatives of the individual world pharmacopoeias included in the *Index of pharmacopoeias* in order to complete and validate the information therein and update the current version on the web site accordingly.\n\n## WHO databases\n\n- Maintain the International Nonproprietary Names (INN) database and continue to make it available on the web site.\n- Maintain the Quality Assurance database and continue to make it available on the web site.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "7e81eb60ddc6dd6c76733a7f827b9a16b439fd9e303d9da2419c991df73ffa5f", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products: points to consider\n\n- Further explore development of these \u201cpoints to consider\u201d jointly with the International Pharmaceutical Federation (FIP) as practice guidance for compounding.\n\n## Update on comparator products\n\n- Provide an update of the list of comparator products on the web site, following review by the members of the Expert Committee, to replace the version from 2002.\n\n## Sampling procedures for monitoring of market situations\n\n- Continue development of sampling procedures based on the numerous examples obtained from many countries as feedback to the secretariat\u2019s communications.\n\n## Quality assurance terminology\n\n- Continue the work on the preferred terms included in the current quality assurance terminology database based on the analysis prepared by the secretariat, with a group of experts, including the definition for an API, on which consultation had already started.\n\n## Index of pharmacopoeias\n\n- Consult with the secretariat representatives of the individual world pharmacopoeias included in the *Index of pharmacopoeias* in order to complete and validate the information therein and update the current version on the web site accordingly.\n\n## WHO databases\n\n- Maintain the International Nonproprietary Names (INN) database and continue to make it available on the web site.\n- Maintain the Quality Assurance database and continue to make it available on the web site.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1603, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "556db45a-d248-4f43-9f2f-4f9f7c6a2afe": {"__data__": {"id_": "556db45a-d248-4f43-9f2f-4f9f7c6a2afe", "embedding": null, "metadata": {"page_label": "63", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Summary of additional recommendations from the closed session of the Expert Committee\n\n1. **Drafting of the Expert Committee report**\n\n   The Expert Committee appreciated the additional assistance, provided to the rapporteurs by a professional editor during this meeting to speed up and facilitate the report-writing process. Additional practical advice on the future drafting process was given, for example, to enable a review of the draft report by the Expert Committee members each day.\n\n2. **New proceeding**\n\n   The Expert Committee suggested providing e-links to the various documents on the agenda to replace the paper versions of these documents at future meetings. It was also suggested that all presentations be given on the first day to assist in the smooth running of the meeting agenda and to discuss related topics later during the Committee meeting under each agenda item. Moreover, the Expert Committee members suggested providing time slots every day to facilitate the creation of specific subgroups to discuss pending issues during each day of the meeting.\n\n3. **Financial situation analysis**\n\n   The Expert Committee noted that, from the presentations of the various related programmes during the meeting, it had become apparent that some WHO programmes seemed to have considerably more staff and financial resources than the Quality Assurance of Medicines Programme in QSM. This would result in a certain imbalance in comparison with the work of the Quality Assurance of Medicines Programme. As WHO resources seemed to be decreasing within the Organization and affecting this programme and its related activities even more, the Expert Committee wished the following to appear as a note in the report concerning current achievements:", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas basadas en el contexto proporcionado, junto con sus respuestas:\n\n1. **\u00bfQu\u00e9 tipo de asistencia se proporcion\u00f3 a los rapporteurs durante la reuni\u00f3n del Comit\u00e9 de Expertos?**\n   - Se proporcion\u00f3 asistencia adicional a los rapporteurs por parte de un editor profesional, lo que facilit\u00f3 y aceler\u00f3 el proceso de redacci\u00f3n del informe del Comit\u00e9 de Expertos.\n\n2. **\u00bfQu\u00e9 recomendaciones hizo el Comit\u00e9 de Expertos para mejorar la organizaci\u00f3n de futuras reuniones?**\n   - El Comit\u00e9 de Expertos recomend\u00f3 el uso de enlaces electr\u00f3nicos para los documentos de la agenda en lugar de versiones impresas, que todas las presentaciones se realicen el primer d\u00eda, y que se asignen franjas horarias diarias para la creaci\u00f3n de subgrupos espec\u00edficos que discutan temas pendientes.\n\n3. **\u00bfCu\u00e1l fue la preocupaci\u00f3n principal del Comit\u00e9 de Expertos respecto a la situaci\u00f3n financiera de los programas de la OMS?**\n   - El Comit\u00e9 de Expertos expres\u00f3 su preocupaci\u00f3n por el desequilibrio en los recursos y personal entre los diferentes programas de la OMS, se\u00f1alando que algunos programas ten\u00edan considerablemente m\u00e1s recursos que el Programa de Aseguramiento de la Calidad de Medicamentos, lo que podr\u00eda afectar negativamente a este \u00faltimo, especialmente dado que los recursos de la OMS estaban disminuyendo.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento es un resumen de las recomendaciones adicionales del Comit\u00e9 de Expertos de la OMS, que se centr\u00f3 en la mejora del proceso de redacci\u00f3n de informes, la organizaci\u00f3n de futuras reuniones y la evaluaci\u00f3n de la situaci\u00f3n financiera de los programas de la OMS. Se destaca la necesidad de un enfoque m\u00e1s equilibrado en la asignaci\u00f3n de recursos y la importancia de la colaboraci\u00f3n y la comunicaci\u00f3n efectiva durante las reuniones.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Preparaciones Espec\u00edficas para Ni\u00f1os**:\n   - Se propone desarrollar \"puntos a considerar\" en colaboraci\u00f3n con la **Federaci\u00f3n Internacional Farmac\u00e9utica (FIP)** para guiar la pr\u00e1ctica de la preparaci\u00f3n de medicamentos pedi\u00e1tricos que no est\u00e1n disponibles como productos autorizados.\n\n2. **Actualizaci\u00f3n de Productos Comparadores**:\n   - Se planea actualizar la lista de productos comparadores en el sitio web de la **OMS**, reemplazando la versi\u00f3n de 2002, tras la revisi\u00f3n por parte del Comit\u00e9 de Expertos.\n\n3. **Procedimientos de Muestreo**:\n   - Se continuar\u00e1 el desarrollo de procedimientos de muestreo para monitorear situaciones del mercado, bas\u00e1ndose en ejemplos obtenidos de varios pa\u00edses.\n\n4. **Terminolog\u00eda de Aseguramiento de Calidad**:\n   - Se seguir\u00e1 trabajando en los t\u00e9rminos preferidos de la base de datos de terminolog\u00eda de aseguramiento de calidad, incluyendo la definici\u00f3n de un **API (Ingrediente Farmac\u00e9utico Activo)**, con la participaci\u00f3n de un grupo de expertos.\n\n5. **\u00cdndice de Farmacopeas**:\n   - Se consultar\u00e1 con representantes de las farmacopeas mundiales para completar y validar la informaci\u00f3n en el *\u00cdndice de farmacopeas* y actualizar la versi\u00f3n actual en el sitio web.\n\n6. **Bases de Datos de la OMS**:\n   - Se mantendr\u00e1n y actualizar\u00e1n las bases de datos de **Nombres No Propietarios Internacionales (INN)** y de **Aseguramiento de Calidad**, asegurando su disponibilidad en el sitio web de la OMS.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**\n- **FIP (Federaci\u00f3n Internacional Farmac\u00e9utica)**\n- **API (Ingrediente Farmac\u00e9utico Activo)**\n\nEste resumen destaca los esfuerzos de la OMS en la regulaci\u00f3n y mejora de la calidad de los productos farmac\u00e9uticos, especialmente en el contexto de la atenci\u00f3n pedi\u00e1trica y la colaboraci\u00f3n con otras organizaciones.", "excerpt_keywords": "Keywords: Expert Committee, WHO, report drafting, financial analysis, meeting recommendations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "624c8607-e97f-49d2-a581-72abbf7ad270", "node_type": "4", "metadata": {"page_label": "63", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Summary of additional recommendations from the closed session of the Expert Committee\n\n1. **Drafting of the Expert Committee report**\n\n   The Expert Committee appreciated the additional assistance, provided to the rapporteurs by a professional editor during this meeting to speed up and facilitate the report-writing process. Additional practical advice on the future drafting process was given, for example, to enable a review of the draft report by the Expert Committee members each day.\n\n2. **New proceeding**\n\n   The Expert Committee suggested providing e-links to the various documents on the agenda to replace the paper versions of these documents at future meetings. It was also suggested that all presentations be given on the first day to assist in the smooth running of the meeting agenda and to discuss related topics later during the Committee meeting under each agenda item. Moreover, the Expert Committee members suggested providing time slots every day to facilitate the creation of specific subgroups to discuss pending issues during each day of the meeting.\n\n3. **Financial situation analysis**\n\n   The Expert Committee noted that, from the presentations of the various related programmes during the meeting, it had become apparent that some WHO programmes seemed to have considerably more staff and financial resources than the Quality Assurance of Medicines Programme in QSM. This would result in a certain imbalance in comparison with the work of the Quality Assurance of Medicines Programme. As WHO resources seemed to be decreasing within the Organization and affecting this programme and its related activities even more, the Expert Committee wished the following to appear as a note in the report concerning current achievements:", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f92a14d0e3c2bf83a1cba10830a931247f8330be865098d97cce015883580bfb", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Summary of additional recommendations from the closed session of the Expert Committee\n\n1. **Drafting of the Expert Committee report**\n\n   The Expert Committee appreciated the additional assistance, provided to the rapporteurs by a professional editor during this meeting to speed up and facilitate the report-writing process. Additional practical advice on the future drafting process was given, for example, to enable a review of the draft report by the Expert Committee members each day.\n\n2. **New proceeding**\n\n   The Expert Committee suggested providing e-links to the various documents on the agenda to replace the paper versions of these documents at future meetings. It was also suggested that all presentations be given on the first day to assist in the smooth running of the meeting agenda and to discuss related topics later during the Committee meeting under each agenda item. Moreover, the Expert Committee members suggested providing time slots every day to facilitate the creation of specific subgroups to discuss pending issues during each day of the meeting.\n\n3. **Financial situation analysis**\n\n   The Expert Committee noted that, from the presentations of the various related programmes during the meeting, it had become apparent that some WHO programmes seemed to have considerably more staff and financial resources than the Quality Assurance of Medicines Programme in QSM. This would result in a certain imbalance in comparison with the work of the Quality Assurance of Medicines Programme. As WHO resources seemed to be decreasing within the Organization and affecting this programme and its related activities even more, the Expert Committee wished the following to appear as a note in the report concerning current achievements:", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1755, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "e848e92d-708d-4ce8-aae1-94846c178e8c": {"__data__": {"id_": "e848e92d-708d-4ce8-aae1-94846c178e8c", "embedding": null, "metadata": {"page_label": "64", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- Since 2003 the meetings of the WHO Expert Committee on Specifications for Pharmaceutical Preparations have been held on an annual basis;\n- The total number of guidelines which have been produced is 70;\n- The staff currently working in the Quality Assurance of Medicines Programme is two-and-a-half professionals, one secondment and two general-service assistants.\n\nThe Expert Committee wishes to express its recognition of the hard work undertaken and the increasing workload faced by the secretariat, which aims to cope with the frequency of meetings and new trends, in order to respond to the international demands and those of the WHO-associated programmes to provide timely advice and guidance as an up-to-date service to WHO Member States and United Nations programmes. The Expert Committee members strongly recommend the Director-General to provide this programme with adequate resources in the future to carry out this important function of providing independent international standards and guidelines in the area of quality assurance of medicines.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Frecuencia y Producci\u00f3n de Directrices**: Desde 2003, la Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas se re\u00fane anualmente y ha producido un total de 70 directrices.\n\n2. **Recursos y Carga de Trabajo**: La carga de trabajo del secretariado ha aumentado, lo que ha llevado a la Comisi\u00f3n a reconocer la necesidad de m\u00e1s recursos para poder cumplir con las demandas internacionales y proporcionar asesoramiento oportuno a los Estados Miembros de la OMS y programas de las Naciones Unidas.\n\n3. **Composici\u00f3n del Personal**: Actualmente, el programa de Aseguramiento de Calidad de Medicamentos cuenta con un equipo limitado de personal, compuesto por dos profesionales a tiempo completo, un segundo y dos asistentes de servicio general.\n\n### Preguntas espec\u00edficas que este contexto puede responder:\n\n1. **\u00bfCu\u00e1ntas directrices ha producido la Comisi\u00f3n de Expertos de la OMS desde su establecimiento en 2003 y cu\u00e1l es la frecuencia de sus reuniones?**\n   - Respuesta: La Comisi\u00f3n ha producido un total de 70 directrices y se re\u00fane anualmente desde 2003.\n\n2. **\u00bfQu\u00e9 desaf\u00edos enfrenta actualmente el secretariado de la Comisi\u00f3n de Expertos en relaci\u00f3n con su carga de trabajo y recursos?**\n   - Respuesta: El secretariado enfrenta una carga de trabajo creciente debido a la frecuencia de las reuniones y las nuevas tendencias, lo que requiere m\u00e1s recursos para poder responder adecuadamente a las demandas internacionales y proporcionar asesoramiento oportuno.\n\n3. **\u00bfCu\u00e1l es la composici\u00f3n actual del personal que trabaja en el Programa de Aseguramiento de Calidad de Medicamentos de la OMS?**\n   - Respuesta: El programa cuenta con dos profesionales a tiempo completo, un segundo y dos asistentes de servicio general, lo que suma un total de dos y medio profesionales.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Asistencia en la redacci\u00f3n del informe**:\n   - Se destac\u00f3 la ayuda de un editor profesional para los rapporteurs, lo que facilit\u00f3 y aceler\u00f3 el proceso de redacci\u00f3n del informe del Comit\u00e9 de Expertos.\n\n2. **Recomendaciones para futuras reuniones**:\n   - Uso de enlaces electr\u00f3nicos en lugar de documentos impresos.\n   - Realizaci\u00f3n de todas las presentaciones el primer d\u00eda.\n   - Asignaci\u00f3n de franjas horarias diarias para la creaci\u00f3n de subgrupos que discutan temas pendientes.\n\n3. **An\u00e1lisis de la situaci\u00f3n financiera**:\n   - Observaci\u00f3n de un desequilibrio en recursos y personal entre los programas de la OMS, con algunos programas teniendo m\u00e1s recursos que el Programa de Aseguramiento de la Calidad de Medicamentos.\n   - Preocupaci\u00f3n por la disminuci\u00f3n de recursos de la OMS que afecta negativamente al Programa de Aseguramiento de la Calidad de Medicamentos.\n\n### Entidades mencionadas:\n- **Comit\u00e9 de Expertos de la OMS**: Grupo encargado de realizar recomendaciones y an\u00e1lisis sobre programas de la OMS.\n- **Programa de Aseguramiento de la Calidad de Medicamentos**: Programa espec\u00edfico mencionado que enfrenta desaf\u00edos en comparaci\u00f3n con otros programas de la OMS.\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad que se ocupa de la salud p\u00fablica a nivel global y que est\u00e1 experimentando una disminuci\u00f3n en sus recursos.", "excerpt_keywords": "Keywords: WHO, Pharmaceutical Preparations, Quality Assurance, Guidelines, Resources"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "56d8d206-3f86-41fd-918e-af8b270d0ec6", "node_type": "4", "metadata": {"page_label": "64", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- Since 2003 the meetings of the WHO Expert Committee on Specifications for Pharmaceutical Preparations have been held on an annual basis;\n- The total number of guidelines which have been produced is 70;\n- The staff currently working in the Quality Assurance of Medicines Programme is two-and-a-half professionals, one secondment and two general-service assistants.\n\nThe Expert Committee wishes to express its recognition of the hard work undertaken and the increasing workload faced by the secretariat, which aims to cope with the frequency of meetings and new trends, in order to respond to the international demands and those of the WHO-associated programmes to provide timely advice and guidance as an up-to-date service to WHO Member States and United Nations programmes. The Expert Committee members strongly recommend the Director-General to provide this programme with adequate resources in the future to carry out this important function of providing independent international standards and guidelines in the area of quality assurance of medicines.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4ce1b1bee4b47e14bae5bb7b64cea4a6ca3479eba337f4e70be2bf36ffec3717", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- Since 2003 the meetings of the WHO Expert Committee on Specifications for Pharmaceutical Preparations have been held on an annual basis;\n- The total number of guidelines which have been produced is 70;\n- The staff currently working in the Quality Assurance of Medicines Programme is two-and-a-half professionals, one secondment and two general-service assistants.\n\nThe Expert Committee wishes to express its recognition of the hard work undertaken and the increasing workload faced by the secretariat, which aims to cope with the frequency of meetings and new trends, in order to respond to the international demands and those of the WHO-associated programmes to provide timely advice and guidance as an up-to-date service to WHO Member States and United Nations programmes. The Expert Committee members strongly recommend the Director-General to provide this programme with adequate resources in the future to carry out this important function of providing independent international standards and guidelines in the area of quality assurance of medicines.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1131, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f628fed5-5e3e-4ea1-80cf-3445627c802c": {"__data__": {"id_": "f628fed5-5e3e-4ea1-80cf-3445627c802c", "embedding": null, "metadata": {"page_label": "65", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Acknowledgements\n\nSpecial acknowledgement was made by the Committee to Mrs W. Bonny, Ms M. Gaspard, Dr S. Kopp, Ms C. Mendy, Dr H. Schmidt, Dr X. Zheng and to Dr L. R\u00e4go, Quality Assurance and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland, and to Mr D. Bramley, Prangins, Switzerland, who were instrumental in the preparation and proceedings of the meeting.\n\nTechnical guidance included in this report has been produced with the financial assistance of the European Union, the Bill & Melinda Gates Foundation and UNITAID.\n\nThe Committee also acknowledged with thanks the valuable contributions made to its work by the following agencies, institutions, organizations, WHO collaborating centres, WHO programmes and persons:\n\nActive Pharmaceutical Ingredients Committee, European Chemical Industry Council, Brussels, Belgium; Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Danish Medicines Agency, Copenhagen, Denmark; European Commission, Brussels, Belgium; European Directorate for the Quality of Medicines and HealthCare, Council of Europe, Strasbourg, France; European Federation of Pharmaceutical Industries and Associations, Brussels, Belgium; European Medicines Agency, London, England; Fedefarma, Ciudad, Guatemala; Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland; Healthcare Distribution Management Association, Arlington, VA, USA; Indian Drug Manufacturers\u2019 Association, Worli, Mumbai, India; International Federation of Pharmaceutical Manufacturers and Associations, Geneva, Switzerland; International Generic Pharmaceutical Alliance, Brussels, Belgium; International Pharmaceutical Excipients Council, Strasbourg, France; International Pharmaceutical Federation, The Hague, Netherlands; International Society for Pharmaceutical Engineering, Tampa, Florida, USA; Medicines and Healthcare products Regulatory Agency, Inspection and Standards Division, London, England; Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland; Pharmaceutical Research and Manufacturers of America, Washington, DC, USA; Swissmedic, Swiss Agency for Therapeutic Products, Berne, Switzerland; Therapeutic Goods Administration, Woden, ACT, Australia; United Nations Children\u2019s Fund, New York, USA; United Nations Development Programme, New York, USA; The World Bank, Washington, DC, USA; United States of America Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA; United States of America Food and Drug Administration, Office of Pediatric Therapeutics, Office of the Commissioner, Rockville, MD, USA; World Intellectual Property", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que incluye un apartado de agradecimientos. En este apartado, se reconoce la contribuci\u00f3n de varias personas y organizaciones que participaron en la preparaci\u00f3n y desarrollo de la reuni\u00f3n. Tambi\u00e9n se menciona el apoyo financiero recibido de la Uni\u00f3n Europea, la Fundaci\u00f3n Bill y Melinda Gates y UNITAID. Adem\u00e1s, se enumeran diversas agencias, instituciones y organizaciones que colaboraron en el trabajo del Comit\u00e9.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 papel desempe\u00f1aron las personas mencionadas en los agradecimientos en la preparaci\u00f3n del informe?**\n   - Esta pregunta busca detalles sobre las funciones espec\u00edficas de los individuos reconocidos, que no se detallan en el texto.\n\n2. **\u00bfCu\u00e1les son las principales \u00e1reas de enfoque de las organizaciones y agencias mencionadas en el apartado de agradecimientos?**\n   - Esta pregunta se centra en entender mejor las especialidades y contribuciones de las diversas entidades listadas, lo que no se aborda directamente en el texto.\n\n3. **\u00bfQu\u00e9 tipo de asistencia financiera se menciona en el informe y c\u00f3mo se relaciona con el contenido t\u00e9cnico del mismo?**\n   - Esta pregunta busca explorar la conexi\u00f3n entre el apoyo financiero recibido y el contenido t\u00e9cnico del informe, algo que no se detalla expl\u00edcitamente en el texto. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n m\u00e1s profunda y espec\u00edfica que no se encuentra directamente en el texto, fomentando una comprensi\u00f3n m\u00e1s completa del contexto y las contribuciones al informe.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comisi\u00f3n de Expertos de la OMS**: Se encarga de establecer especificaciones para preparaciones farmac\u00e9uticas y se re\u00fane anualmente desde 2003.\n\n2. **Producci\u00f3n de Directrices**: Desde su establecimiento, la Comisi\u00f3n ha producido un total de 70 directrices relacionadas con la calidad de los medicamentos.\n\n3. **Carga de Trabajo y Recursos**: El secretariado enfrenta un aumento en la carga de trabajo debido a la frecuencia de las reuniones y nuevas tendencias, lo que ha llevado a la necesidad de m\u00e1s recursos para cumplir con las demandas internacionales y proporcionar asesoramiento oportuno.\n\n4. **Composici\u00f3n del Personal**: El Programa de Aseguramiento de Calidad de Medicamentos cuenta actualmente con un equipo limitado de personal, compuesto por dos profesionales a tiempo completo, un segundo y dos asistentes de servicio general, sumando un total de dos y medio profesionales.\n\n5. **Recomendaciones**: La Comisi\u00f3n recomienda al Director-General de la OMS que se proporcionen recursos adecuados para llevar a cabo su funci\u00f3n de establecer est\u00e1ndares y directrices internacionales en el \u00e1rea de calidad de los medicamentos. \n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organizaci\u00f3n internacional que coordina esfuerzos en salud p\u00fablica.\n- **Comisi\u00f3n de Expertos**: Grupo encargado de desarrollar directrices sobre especificaciones farmac\u00e9uticas.\n- **Programa de Aseguramiento de Calidad de Medicamentos**: Programa espec\u00edfico dentro de la OMS que se ocupa de la calidad de los medicamentos.", "excerpt_keywords": "Keywords: WHO, acknowledgements, pharmaceutical, technical report, quality assurance"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc7db81c-1445-45dd-acba-c18d0da3d36f", "node_type": "4", "metadata": {"page_label": "65", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Acknowledgements\n\nSpecial acknowledgement was made by the Committee to Mrs W. Bonny, Ms M. Gaspard, Dr S. Kopp, Ms C. Mendy, Dr H. Schmidt, Dr X. Zheng and to Dr L. R\u00e4go, Quality Assurance and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland, and to Mr D. Bramley, Prangins, Switzerland, who were instrumental in the preparation and proceedings of the meeting.\n\nTechnical guidance included in this report has been produced with the financial assistance of the European Union, the Bill & Melinda Gates Foundation and UNITAID.\n\nThe Committee also acknowledged with thanks the valuable contributions made to its work by the following agencies, institutions, organizations, WHO collaborating centres, WHO programmes and persons:\n\nActive Pharmaceutical Ingredients Committee, European Chemical Industry Council, Brussels, Belgium; Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Danish Medicines Agency, Copenhagen, Denmark; European Commission, Brussels, Belgium; European Directorate for the Quality of Medicines and HealthCare, Council of Europe, Strasbourg, France; European Federation of Pharmaceutical Industries and Associations, Brussels, Belgium; European Medicines Agency, London, England; Fedefarma, Ciudad, Guatemala; Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland; Healthcare Distribution Management Association, Arlington, VA, USA; Indian Drug Manufacturers\u2019 Association, Worli, Mumbai, India; International Federation of Pharmaceutical Manufacturers and Associations, Geneva, Switzerland; International Generic Pharmaceutical Alliance, Brussels, Belgium; International Pharmaceutical Excipients Council, Strasbourg, France; International Pharmaceutical Federation, The Hague, Netherlands; International Society for Pharmaceutical Engineering, Tampa, Florida, USA; Medicines and Healthcare products Regulatory Agency, Inspection and Standards Division, London, England; Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland; Pharmaceutical Research and Manufacturers of America, Washington, DC, USA; Swissmedic, Swiss Agency for Therapeutic Products, Berne, Switzerland; Therapeutic Goods Administration, Woden, ACT, Australia; United Nations Children\u2019s Fund, New York, USA; United Nations Development Programme, New York, USA; The World Bank, Washington, DC, USA; United States of America Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA; United States of America Food and Drug Administration, Office of Pediatric Therapeutics, Office of the Commissioner, Rockville, MD, USA; World Intellectual Property", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "326a4ee2ac05e784947dcff6935114cc4c3402d4fac3bcef82cf01adcd63b22b", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Acknowledgements\n\nSpecial acknowledgement was made by the Committee to Mrs W. Bonny, Ms M. Gaspard, Dr S. Kopp, Ms C. Mendy, Dr H. Schmidt, Dr X. Zheng and to Dr L. R\u00e4go, Quality Assurance and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland, and to Mr D. Bramley, Prangins, Switzerland, who were instrumental in the preparation and proceedings of the meeting.\n\nTechnical guidance included in this report has been produced with the financial assistance of the European Union, the Bill & Melinda Gates Foundation and UNITAID.\n\nThe Committee also acknowledged with thanks the valuable contributions made to its work by the following agencies, institutions, organizations, WHO collaborating centres, WHO programmes and persons:\n\nActive Pharmaceutical Ingredients Committee, European Chemical Industry Council, Brussels, Belgium; Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Danish Medicines Agency, Copenhagen, Denmark; European Commission, Brussels, Belgium; European Directorate for the Quality of Medicines and HealthCare, Council of Europe, Strasbourg, France; European Federation of Pharmaceutical Industries and Associations, Brussels, Belgium; European Medicines Agency, London, England; Fedefarma, Ciudad, Guatemala; Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland; Healthcare Distribution Management Association, Arlington, VA, USA; Indian Drug Manufacturers\u2019 Association, Worli, Mumbai, India; International Federation of Pharmaceutical Manufacturers and Associations, Geneva, Switzerland; International Generic Pharmaceutical Alliance, Brussels, Belgium; International Pharmaceutical Excipients Council, Strasbourg, France; International Pharmaceutical Federation, The Hague, Netherlands; International Society for Pharmaceutical Engineering, Tampa, Florida, USA; Medicines and Healthcare products Regulatory Agency, Inspection and Standards Division, London, England; Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland; Pharmaceutical Research and Manufacturers of America, Washington, DC, USA; Swissmedic, Swiss Agency for Therapeutic Products, Berne, Switzerland; Therapeutic Goods Administration, Woden, ACT, Australia; United Nations Children\u2019s Fund, New York, USA; United Nations Development Programme, New York, USA; The World Bank, Washington, DC, USA; United States of America Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA; United States of America Food and Drug Administration, Office of Pediatric Therapeutics, Office of the Commissioner, Rockville, MD, USA; World Intellectual Property", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2697, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f408a4b4-f360-43c6-8b14-f12fc11f1baf": {"__data__": {"id_": "f408a4b4-f360-43c6-8b14-f12fc11f1baf", "embedding": null, "metadata": {"page_label": "66", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que forma parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pol\u00edticas de salud. Sin embargo, en este caso espec\u00edfico, no se proporciona contenido detallado en el texto extra\u00eddo.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son los principales temas o hallazgos discutidos en el informe t\u00e9cnico de la OMS en la serie 970?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe, que no se puede deducir solo del t\u00edtulo.\n\n2. **\u00bfQu\u00e9 recomendaciones espec\u00edficas se hacen en el informe de la OMS para abordar problemas de salud p\u00fablica?**\n   - Dado que los informes t\u00e9cnicos de la OMS suelen incluir recomendaciones, esta pregunta se enfoca en obtener detalles sobre las sugerencias pr\u00e1cticas que se derivan del informe.\n\n3. **\u00bfC\u00f3mo se compara el informe 970 con otros informes anteriores de la serie en t\u00e9rminos de enfoque y contenido?**\n   - Esta pregunta busca establecer un contexto comparativo que podr\u00eda revelar tendencias o cambios en las prioridades de la OMS a lo largo del tiempo.\n\nEstas preguntas est\u00e1n dise\u00f1adas para obtener informaci\u00f3n que probablemente no est\u00e9 disponible en otras fuentes, dado que se centran en el contenido espec\u00edfico del informe mencionado.", "prev_section_summary": "### Resumen de la Secci\u00f3n de Agradecimientos\n\nLa secci\u00f3n de agradecimientos del informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) destaca la contribuci\u00f3n de diversas personas y organizaciones en la preparaci\u00f3n y desarrollo de la reuni\u00f3n. Se menciona un reconocimiento especial a individuos clave, incluyendo a:\n\n- **Mrs W. Bonny**\n- **Ms M. Gaspard**\n- **Dr S. Kopp**\n- **Ms C. Mendy**\n- **Dr H. Schmidt**\n- **Dr X. Zheng**\n- **Dr L. R\u00e4go** (OMS, Ginebra, Suiza)\n- **Mr D. Bramley** (Prangins, Suiza)\n\nEstos individuos fueron fundamentales en la organizaci\u00f3n y los procedimientos de la reuni\u00f3n.\n\n### Asistencia Financiera\nEl informe tambi\u00e9n se\u00f1ala que la orientaci\u00f3n t\u00e9cnica incluida fue producida con el apoyo financiero de:\n\n- **Uni\u00f3n Europea**\n- **Fundaci\u00f3n Bill y Melinda Gates**\n- **UNITAID**\n\n### Contribuciones de Agencias y Organizaciones\nAdem\u00e1s, se agradece a una amplia variedad de agencias, instituciones y organizaciones que colaboraron en el trabajo del Comit\u00e9, incluyendo:\n\n- **Active Pharmaceutical Ingredients Committee** (Bruselas, B\u00e9lgica)\n- **Bureau of Drug and Narcotic, Department of Medical Sciences** (Tailandia)\n- **Danish Medicines Agency** (Copenhague, Dinamarca)\n- **European Medicines Agency** (Londres, Inglaterra)\n- **Global Fund to Fight AIDS, Tuberculosis and Malaria** (Ginebra, Suiza)\n- **United Nations Children\u2019s Fund (UNICEF)** (Nueva York, EE. UU.)\n- **World Bank** (Washington, DC, EE. UU.)\n- **United States Food and Drug Administration (FDA)** (Silver Spring, MD, EE. UU.)\n\n### Temas Clave\n- Reconocimiento a contribuciones individuales y colectivas en el \u00e1mbito de la salud y medicamentos.\n- Importancia del apoyo financiero para la producci\u00f3n de orientaci\u00f3n t\u00e9cnica.\n- Colaboraci\u00f3n internacional entre diversas entidades en el sector farmac\u00e9utico y de salud.\n\nEste resumen encapsula los temas clave y las entidades mencionadas en la secci\u00f3n de agradecimientos del informe.", "excerpt_keywords": "Keywords: OMS, informe t\u00e9cnico, salud p\u00fablica, colaboraci\u00f3n internacional, agradecimientos"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f225fb9e-1844-479a-9744-6340271bc56d", "node_type": "4", "metadata": {"page_label": "66", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "db69f6e48090862c9340235371322da47fd81badc5e9106230eea0903617b80d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "8f41e028-54c4-4df0-8653-0698f26fa25f": {"__data__": {"id_": "8f41e028-54c4-4df0-8653-0698f26fa25f", "embedding": null, "metadata": {"page_label": "67", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "North-West University, Potchefstroom, South Africa; Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa; National Drug Quality Assurance Laboratory, Colombo, Sri Lanka; Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Laboratoire National de Contr\u00f4le des M\u00e9dicaments, Tunis, Tunisia; National Drug Quality Control Laboratory, National Drug Authority, Kampala, Uganda; Central Laboratory for Quality Control of Medicines of the Ministry of Health of Ukraine, Kiev, Ukraine; School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, United Republic of Tanzania; Tanzania Food and Drugs Authority, Dar es Salaam, United Republic of Tanzania; Laboratorio Control de Productos MSP, Comisi\u00f3n Para El Control de Calidad de Medicamentos, Montevideo, Uruguay; Instituto Nacional de Higiene \u201cRafael Rangel\u201d, Caracas, Venezuela; National Institute of Drug Quality Control, Hanoi, Viet Nam; Medicines Control Authority, Control Laboratory of Zimbabwe, Harare, Zimbabwe.\n\nWHO Centre Collaborateur pour la Conformit\u00e9 des M\u00e9dicaments, Laboratoire national de Contr\u00f4le des Produits Pharmaceutiques, Alger, Algeria; WHO Collaborating Centre for Drug Quality Assurance, Therapeutic Goods Administration Laboratories, Woden, ACT, Australia; WHO Collaborating Centre for Drug Quality Assurance, National Institute for the Control of Pharmaceutical and Biological Products, Beijing, People\u2019s Republic of China; WHO Collaborating Centre for Research on Bioequivalence Testing of Medicines, Frankfurt am Main, Germany; WHO Collaborating Centre for Drug Information and Quality Assurance, National Institute of Pharmacy, Budapest, Hungary; WHO Collaborating Centre for Quality Assurance of Essential Drugs, Central Drugs Laboratory, Calcutta, India; WHO Collaborating Centre for Regulatory Control of Pharmaceuticals, National Pharmaceutical Control Bureau, Jalan University, Ministry of Health, Petaling Jaya, Malaysia; WHO Collaborating Centre for Drug Quality Assurance, Pharmaceutical Laboratory, Centre for Analytical Science, Health Sciences Authority, Singapore; WHO Collaborating Centre for Quality Assurance of Medicines, North-West University, Potchefstroom, South Africa; WHO Collaborating Centre for Quality Assurance of Essential Drugs, Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.\n\nAnti-Counterfeiting Medicines Programme, WHO, Geneva, Switzerland; Blood Products and Related Biologicals Programme, WHO, Geneva, Switzerland; Global Malaria Programme, WHO, Geneva, Switzerland; HIV/AIDS Programme, WHO, Geneva, Switzerland; International Medical Products Anti-Counterfeiting Taskforce (IMPACT), WHO, Geneva, Switzerland; Medicine Access and Rational Use Team, WHO, Geneva, Switzerland; Medicines Regulatory Support Programme, WHO, Geneva, Switzerland; Office of the Legal Counsel, WHO, Geneva, Switzerland.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que detalla diversas instituciones y programas relacionados con la calidad y regulaci\u00f3n de medicamentos a nivel mundial. Se mencionan m\u00faltiples centros colaboradores de la OMS en diferentes pa\u00edses, as\u00ed como programas espec\u00edficos de la OMS que abordan temas como la lucha contra medicamentos falsificados, productos biol\u00f3gicos, malaria y VIH/SIDA. La informaci\u00f3n destaca la importancia de la colaboraci\u00f3n internacional en la garant\u00eda de la calidad de los medicamentos y la regulaci\u00f3n de productos farmac\u00e9uticos.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfCu\u00e1les son los principales objetivos del Programa de Medicamentos Anti-Falsificaci\u00f3n de la OMS mencionado en el informe?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las metas y estrategias del programa, que no se detalla en el contexto.\n\n2. **\u00bfQu\u00e9 papel desempe\u00f1a el Laboratorio Nacional de Control de Medicamentos en T\u00fanez dentro de la red de colaboraci\u00f3n de la OMS?**\n   - Esta pregunta se centra en el rol particular de una de las instituciones mencionadas, lo que puede no estar claramente definido en el documento.\n\n3. **\u00bfC\u00f3mo se coordinan las actividades entre los diferentes centros colaboradores de la OMS para asegurar la calidad de los medicamentos a nivel global?**\n   - Esta pregunta busca entender el mecanismo de colaboraci\u00f3n y coordinaci\u00f3n entre las diversas instituciones, un aspecto que puede no estar expl\u00edcitamente abordado en el texto.\n\n### Resumen de Nivel Superior\nEl informe de la OMS destaca la colaboraci\u00f3n internacional en la regulaci\u00f3n y control de la calidad de medicamentos. Se enumeran m\u00faltiples centros de calidad y programas de la OMS que trabajan en la prevenci\u00f3n de medicamentos falsificados y en la mejora del acceso a medicamentos esenciales. La diversidad geogr\u00e1fica de los centros colaboradores subraya la importancia de un enfoque global para abordar los desaf\u00edos en la calidad de los productos farmac\u00e9uticos.", "prev_section_summary": "### Resumen de la Secci\u00f3n\n\nEl contenido extra\u00eddo del documento \"WHO - Technical Report Series 970\" no proporciona informaci\u00f3n espec\u00edfica, ya que se indica \"NO_CONTENT_HERE\". Sin embargo, se puede inferir que el informe forma parte de una serie de publicaciones de la Organizaci\u00f3n Mundial de la Salud (OMS) que abordan temas relevantes en el \u00e1mbito de la salud p\u00fablica y la investigaci\u00f3n m\u00e9dica.\n\n### Temas Clave\n- **Salud P\u00fablica**: El informe probablemente discute cuestiones relacionadas con la salud p\u00fablica, aunque no se especifican detalles.\n- **Investigaci\u00f3n M\u00e9dica**: Es probable que el documento incluya hallazgos o recomendaciones basadas en investigaciones recientes.\n- **Pol\u00edticas de Salud**: Se espera que el informe ofrezca recomendaciones para la formulaci\u00f3n de pol\u00edticas en el sector salud.\n\n### Entidades\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe.\n- **Informe T\u00e9cnico**: Tipo de documento que se espera contenga an\u00e1lisis y recomendaciones sobre temas de salud.\n\nDado que no hay contenido espec\u00edfico disponible, el resumen se basa en la naturaleza general de los informes de la OMS y su prop\u00f3sito en el \u00e1mbito de la salud.", "excerpt_keywords": "Keywords: WHO, drug quality assurance, anti-counterfeiting, international collaboration, pharmaceutical regulation"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9690fa98-3bb8-4870-989b-9d1cd9112d53", "node_type": "4", "metadata": {"page_label": "67", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "North-West University, Potchefstroom, South Africa; Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa; National Drug Quality Assurance Laboratory, Colombo, Sri Lanka; Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Laboratoire National de Contr\u00f4le des M\u00e9dicaments, Tunis, Tunisia; National Drug Quality Control Laboratory, National Drug Authority, Kampala, Uganda; Central Laboratory for Quality Control of Medicines of the Ministry of Health of Ukraine, Kiev, Ukraine; School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, United Republic of Tanzania; Tanzania Food and Drugs Authority, Dar es Salaam, United Republic of Tanzania; Laboratorio Control de Productos MSP, Comisi\u00f3n Para El Control de Calidad de Medicamentos, Montevideo, Uruguay; Instituto Nacional de Higiene \u201cRafael Rangel\u201d, Caracas, Venezuela; National Institute of Drug Quality Control, Hanoi, Viet Nam; Medicines Control Authority, Control Laboratory of Zimbabwe, Harare, Zimbabwe.\n\nWHO Centre Collaborateur pour la Conformit\u00e9 des M\u00e9dicaments, Laboratoire national de Contr\u00f4le des Produits Pharmaceutiques, Alger, Algeria; WHO Collaborating Centre for Drug Quality Assurance, Therapeutic Goods Administration Laboratories, Woden, ACT, Australia; WHO Collaborating Centre for Drug Quality Assurance, National Institute for the Control of Pharmaceutical and Biological Products, Beijing, People\u2019s Republic of China; WHO Collaborating Centre for Research on Bioequivalence Testing of Medicines, Frankfurt am Main, Germany; WHO Collaborating Centre for Drug Information and Quality Assurance, National Institute of Pharmacy, Budapest, Hungary; WHO Collaborating Centre for Quality Assurance of Essential Drugs, Central Drugs Laboratory, Calcutta, India; WHO Collaborating Centre for Regulatory Control of Pharmaceuticals, National Pharmaceutical Control Bureau, Jalan University, Ministry of Health, Petaling Jaya, Malaysia; WHO Collaborating Centre for Drug Quality Assurance, Pharmaceutical Laboratory, Centre for Analytical Science, Health Sciences Authority, Singapore; WHO Collaborating Centre for Quality Assurance of Medicines, North-West University, Potchefstroom, South Africa; WHO Collaborating Centre for Quality Assurance of Essential Drugs, Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.\n\nAnti-Counterfeiting Medicines Programme, WHO, Geneva, Switzerland; Blood Products and Related Biologicals Programme, WHO, Geneva, Switzerland; Global Malaria Programme, WHO, Geneva, Switzerland; HIV/AIDS Programme, WHO, Geneva, Switzerland; International Medical Products Anti-Counterfeiting Taskforce (IMPACT), WHO, Geneva, Switzerland; Medicine Access and Rational Use Team, WHO, Geneva, Switzerland; Medicines Regulatory Support Programme, WHO, Geneva, Switzerland; Office of the Legal Counsel, WHO, Geneva, Switzerland.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "c84fa9f7daa20ba5b7d1d31bb8e975873ad92a3ac4e0f234421c20659f019661", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "North-West University, Potchefstroom, South Africa; Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa; National Drug Quality Assurance Laboratory, Colombo, Sri Lanka; Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Laboratoire National de Contr\u00f4le des M\u00e9dicaments, Tunis, Tunisia; National Drug Quality Control Laboratory, National Drug Authority, Kampala, Uganda; Central Laboratory for Quality Control of Medicines of the Ministry of Health of Ukraine, Kiev, Ukraine; School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, United Republic of Tanzania; Tanzania Food and Drugs Authority, Dar es Salaam, United Republic of Tanzania; Laboratorio Control de Productos MSP, Comisi\u00f3n Para El Control de Calidad de Medicamentos, Montevideo, Uruguay; Instituto Nacional de Higiene \u201cRafael Rangel\u201d, Caracas, Venezuela; National Institute of Drug Quality Control, Hanoi, Viet Nam; Medicines Control Authority, Control Laboratory of Zimbabwe, Harare, Zimbabwe.\n\nWHO Centre Collaborateur pour la Conformit\u00e9 des M\u00e9dicaments, Laboratoire national de Contr\u00f4le des Produits Pharmaceutiques, Alger, Algeria; WHO Collaborating Centre for Drug Quality Assurance, Therapeutic Goods Administration Laboratories, Woden, ACT, Australia; WHO Collaborating Centre for Drug Quality Assurance, National Institute for the Control of Pharmaceutical and Biological Products, Beijing, People\u2019s Republic of China; WHO Collaborating Centre for Research on Bioequivalence Testing of Medicines, Frankfurt am Main, Germany; WHO Collaborating Centre for Drug Information and Quality Assurance, National Institute of Pharmacy, Budapest, Hungary; WHO Collaborating Centre for Quality Assurance of Essential Drugs, Central Drugs Laboratory, Calcutta, India; WHO Collaborating Centre for Regulatory Control of Pharmaceuticals, National Pharmaceutical Control Bureau, Jalan University, Ministry of Health, Petaling Jaya, Malaysia; WHO Collaborating Centre for Drug Quality Assurance, Pharmaceutical Laboratory, Centre for Analytical Science, Health Sciences Authority, Singapore; WHO Collaborating Centre for Quality Assurance of Medicines, North-West University, Potchefstroom, South Africa; WHO Collaborating Centre for Quality Assurance of Essential Drugs, Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.\n\nAnti-Counterfeiting Medicines Programme, WHO, Geneva, Switzerland; Blood Products and Related Biologicals Programme, WHO, Geneva, Switzerland; Global Malaria Programme, WHO, Geneva, Switzerland; HIV/AIDS Programme, WHO, Geneva, Switzerland; International Medical Products Anti-Counterfeiting Taskforce (IMPACT), WHO, Geneva, Switzerland; Medicine Access and Rational Use Team, WHO, Geneva, Switzerland; Medicines Regulatory Support Programme, WHO, Geneva, Switzerland; Office of the Legal Counsel, WHO, Geneva, Switzerland.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2993, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "67b93b5b-8b93-4225-b9fd-59a00313f38b": {"__data__": {"id_": "67b93b5b-8b93-4225-b9fd-59a00313f38b", "embedding": null, "metadata": {"page_label": "68", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pr\u00e1cticas de salud a nivel global. Sin embargo, el contenido espec\u00edfico de la p\u00e1gina 68 no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS en el informe t\u00e9cnico 970 sobre el manejo de enfermedades espec\u00edficas?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las directrices o recomendaciones que la OMS podr\u00eda haber proporcionado en este informe, que podr\u00eda no estar disponible en otros documentos.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas de investigaci\u00f3n se discuten en la p\u00e1gina 68 del informe t\u00e9cnico 970?**\n   - Esta pregunta se centra en las t\u00e9cnicas o enfoques de investigaci\u00f3n que la OMS podr\u00eda haber descrito, lo cual es crucial para entender c\u00f3mo se desarrollaron las conclusiones del informe.\n\n3. **\u00bfQu\u00e9 datos o estad\u00edsticas relevantes se presentan en el informe t\u00e9cnico 970 que podr\u00edan influir en pol\u00edticas de salud p\u00fablica?**\n   - Esta pregunta busca informaci\u00f3n sobre datos espec\u00edficos que podr\u00edan ser utilizados para fundamentar decisiones en pol\u00edticas de salud, lo cual es un aspecto clave en los informes de la OMS.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que podr\u00eda ser \u00fanica para el documento mencionado y que no se podr\u00eda encontrar f\u00e1cilmente en otras fuentes.", "prev_section_summary": "La secci\u00f3n del informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) se centra en la colaboraci\u00f3n internacional para garantizar la calidad y regulaci\u00f3n de medicamentos. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Colaboraci\u00f3n Internacional**: Se destaca la importancia de la cooperaci\u00f3n entre diferentes instituciones y pa\u00edses para asegurar la calidad de los medicamentos.\n2. **Centros Colaboradores de la OMS**: Se enumeran m\u00faltiples centros en diversos pa\u00edses que trabajan en la regulaci\u00f3n y control de la calidad de los productos farmac\u00e9uticos.\n3. **Programas de la OMS**: Se mencionan varios programas espec\u00edficos de la OMS que abordan temas cr\u00edticos como la lucha contra medicamentos falsificados, productos biol\u00f3gicos, malaria y VIH/SIDA.\n\n### Entidades Mencionadas:\n- **Centros de Calidad y Control de Medicamentos**:\n  - North-West University, Potchefstroom, Sud\u00e1frica\n  - Laboratoire National de Contr\u00f4le des M\u00e9dicaments, T\u00fanez\n  - National Drug Quality Assurance Laboratory, Sri Lanka\n  - Bureau of Drug and Narcotic, Tailandia\n  - National Drug Quality Control Laboratory, Uganda\n  - Central Laboratory for Quality Control of Medicines, Ucrania\n  - Muhimbili University of Health and Allied Sciences, Tanzania\n  - Instituto Nacional de Higiene \u201cRafael Rangel\u201d, Venezuela\n  - National Institute of Drug Quality Control, Vietnam\n  - Medicines Control Authority, Zimbabue\n\n- **Programas de la OMS**:\n  - Programa de Medicamentos Anti-Falsificaci\u00f3n\n  - Programa de Productos Biol\u00f3gicos y Relacionados\n  - Programa Global de Malaria\n  - Programa de VIH/SIDA\n  - International Medical Products Anti-Counterfeiting Taskforce (IMPACT)\n  - Medicines Regulatory Support Programme\n\nEste resumen resalta la red de colaboraci\u00f3n y los esfuerzos globales para mejorar la calidad y el acceso a medicamentos esenciales, as\u00ed como la lucha contra la falsificaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: OMS, medicamentos, calidad, regulaci\u00f3n, colaboraci\u00f3n"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "861fec67-942f-4ea1-8c78-52a087ea1c80", "node_type": "4", "metadata": {"page_label": "68", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "601cace64734e07f2dbc273505ea710ed23592ce8e6fc8a162dd2deb1a31f354", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "9e721ec9-fc23-461a-bf7c-06f31fd60a0b": {"__data__": {"id_": "9e721ec9-fc23-461a-bf7c-06f31fd60a0b", "embedding": null, "metadata": {"page_label": "69", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que forma parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pr\u00e1cticas de salud a nivel global. Sin embargo, el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el informe WHO TRS 970?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir datos sobre salud p\u00fablica, pol\u00edticas recomendadas o resultados de investigaciones.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en la serie de informes t\u00e9cnicos de la OMS, y c\u00f3mo se relaciona el informe 970 con esos temas?**\n   - Esta pregunta se centra en el contexto m\u00e1s amplio de la serie de informes, permitiendo entender c\u00f3mo el informe 970 se integra en la discusi\u00f3n general sobre salud p\u00fablica.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizan en el informe WHO TRS 970 para evaluar los problemas de salud discutidos?**\n   - Esta pregunta indaga sobre los enfoques y m\u00e9todos de investigaci\u00f3n que podr\u00edan haber sido utilizados en el informe, lo cual es crucial para entender la validez y aplicabilidad de los hallazgos.\n\nEstas preguntas est\u00e1n dise\u00f1adas para obtener informaci\u00f3n espec\u00edfica que probablemente no se encuentre f\u00e1cilmente en otras fuentes, dado que se centran en el contenido particular del informe y su contexto en la serie de la OMS.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS) que aborda temas relevantes en salud p\u00fablica y medicina. Aunque el contenido espec\u00edfico de la p\u00e1gina 68 no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes basados en el contexto general de la serie:\n\n#### Temas Clave:\n1. **Salud P\u00fablica**: El informe probablemente discute estrategias y recomendaciones para mejorar la salud p\u00fablica a nivel global.\n2. **Investigaci\u00f3n M\u00e9dica**: Es posible que se aborden metodolog\u00edas de investigaci\u00f3n y su aplicaci\u00f3n en el contexto de la salud.\n3. **Pol\u00edticas de Salud**: El informe puede incluir datos y estad\u00edsticas que influyan en la formulaci\u00f3n de pol\u00edticas de salud p\u00fablica.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe y de proporcionar directrices y recomendaciones en el \u00e1mbito de la salud.\n- **Enfermedades Espec\u00edficas**: Aunque no se mencionan en el contenido proporcionado, es probable que el informe trate sobre enfermedades relevantes y su manejo.\n\nEste resumen destaca la importancia del informe en el contexto de la salud global y su potencial impacto en pol\u00edticas y pr\u00e1cticas de salud.", "excerpt_keywords": "Keywords: salud p\u00fablica, investigaci\u00f3n m\u00e9dica, pol\u00edticas de salud, Organizaci\u00f3n Mundial de la Salud, recomendaciones"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3049056f-f021-4c09-809d-188606bae6e8", "node_type": "4", "metadata": {"page_label": "69", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f82ab040345bc898bc6eba476184a37c5dceabba8194198373d1ee5f1cf87b18", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "0e690dd3-4dcc-4405-9d44-d4483e155d84": {"__data__": {"id_": "0e690dd3-4dcc-4405-9d44-d4483e155d84", "embedding": null, "metadata": {"page_label": "70", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Forty-sixth report**\n\nAssociation Training and Research Institute, Parenteral Drug Association, Bethesda, MD, USA; Mr M.M. Das, Kolkata, India; Dr J. Daviaud, Senior Pharmaceutical QA Officer, Pharmaceutical Procurement Unit, Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland; Dr V. Davoust, Quality & Regulatory Policy, Global CMC, WW Pharmaceutical Sciences, Pfizer Global Research & Development, Paris, France; Professor T. Dekker, Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa; Dr L. De-Moor, GlaxoSmithKline, Belgium; Dr J. DiLoreto, Executive Director, Bulk Pharmaceuticals Task Force, Washington, DC, USA; Dr V. Divecha, Cipla, India; Professor J.B. Dressman, Professor of Pharmaceutical Technology, Institut f\u00fcr Pharmazeutische Technologie, Biozentrum, Johann Wolfgang Goethe-Universit\u00e4t, Frankfurt am Main, Germany; Dr A.T. Ducca, Senior Director, Regulatory Affairs, Healthcare Distribution Management Association, Arlington, VA, USA; Dr S. Durand-Stamatidas, Director, Information and Communication, World Self-Medication Industry, Ferney-Voltaire, France; Dr P. Ellis, Director, External Advocacy, Quality Centre of Excellence, GlaxoSmithKline, Brentford, Middlesex, England; Dr A. Falodun, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Benin, Benin City, Nigeria; Dr E. Fefer, Member, United States Pharmacopeia International Health Expert Committee, Rockville, MD, USA; Dr R. Fendt, Head, Global Regulatory & GMP Compliance Pharma, Care Chemicals Division, BASF, Limburgerhof, Germany; Mr A. Ferreira do Nascimento, Ag\u00eancia Nacional de Vigil\u00e2ncia, Bras\u00edlia, Brazil; Dr A. Fleuckiger, Head, Corporate Health Protection, Corporate Safety, Health and Environmental Protection, F. Hoffmann-La Roche, Basel, Switzerland; Dr G.L. France, Vice-President, Quality Strategy, Pfizer Limited and Vice-Chair, IFPMA/RPTS, Maidenhead, England; Dr N.C. Franklin, Wuppertal, Germany; Mr T. Fujino, Director, International Affairs, Japan Generic Medicines Association, Tokyo, Japan; Dr M. Garvin, Senior Director, Scientific and Regulatory Affairs, Pharmaceutical Research and Manufacturers of America, Washington, DC, USA; Dr F. Giorgi, Research and Development, Analytical Development Manager, Sigma-tau Industrie Farmaceutiche Riunite, Pomezia, Italy; Dr L. Girard, Head, Global Pharmacopoeial Affairs, Novartis Group Quality, Quality Systems and Standards, Basel, Switzerland; Dr N. Goldschmidt, USA; Dr E. Gomez, Ridgefield Park, New Jersey, USA; Ms J. Gouws, Department of Health, Medicines Control Council, Pretoria, South Africa; Dr M. Goverde, QC Expert Microbiology, Novartis Pharma, Basel, Switzerland; Ms R.Govithavatangaphong, Director, Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Dr J. Grande, Manager, Regulatory Affairs, McNeil Consumer Healthcare, Markham, England; Dr A. Gray, Senior Lecturer, Department of Therapeutics and Medicines Management and Consultant Pharmacist, Centre for the AIDS Programme of Research in South Africa.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es el \"Cuarenta y sexto informe\" del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Incluye una lista de expertos y sus afiliaciones, que abarcan diversas organizaciones y pa\u00edses, destacando la colaboraci\u00f3n internacional en el \u00e1mbito de la calidad y regulaci\u00f3n de productos farmac\u00e9uticos.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfCu\u00e1les son las principales \u00e1reas de especializaci\u00f3n de los miembros del Comit\u00e9 de Expertos mencionados en el informe?**\n   - Esta pregunta busca identificar las diversas disciplinas y campos de experiencia que aportan los miembros del comit\u00e9, lo que puede no estar claramente delineado en otros documentos.\n\n2. **\u00bfQu\u00e9 papel desempe\u00f1a el Global Fund to Fight AIDS, Tuberculosis and Malaria en la regulaci\u00f3n de productos farmac\u00e9uticos seg\u00fan el informe?**\n   - Esta pregunta se centra en el impacto y la funci\u00f3n espec\u00edfica de esta organizaci\u00f3n en el contexto de la regulaci\u00f3n farmac\u00e9utica, un aspecto que podr\u00eda no estar ampliamente discutido en otras fuentes.\n\n3. **\u00bfC\u00f3mo se refleja la diversidad geogr\u00e1fica en la composici\u00f3n del Comit\u00e9 de Expertos y qu\u00e9 implicaciones podr\u00eda tener esto para la regulaci\u00f3n farmac\u00e9utica global?**\n   - Esta pregunta busca explorar la representaci\u00f3n internacional en el comit\u00e9 y c\u00f3mo esto podr\u00eda influir en las decisiones y recomendaciones sobre est\u00e1ndares farmac\u00e9uticos a nivel global.\n\n### Resumen de Nivel Superior\nEl informe destaca la importancia de la colaboraci\u00f3n internacional en la regulaci\u00f3n y calidad de los productos farmac\u00e9uticos, reflejada en la diversidad de expertos de diferentes pa\u00edses y organizaciones. Esto sugiere un enfoque global para abordar los desaf\u00edos en la industria farmac\u00e9utica, especialmente en el contexto de enfermedades como el VIH/SIDA, la tuberculosis y la malaria.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n#### Temas Clave:\n1. **Salud P\u00fablica**: El informe probablemente aborda cuestiones relacionadas con la salud p\u00fablica, incluyendo pol\u00edticas, pr\u00e1cticas y recomendaciones para mejorar la salud a nivel global.\n2. **Investigaci\u00f3n M\u00e9dica**: Es posible que se presenten hallazgos de investigaciones recientes en el campo de la medicina y la salud.\n3. **Recomendaciones de Pol\u00edticas**: El informe podr\u00eda incluir recomendaciones para gobiernos y organizaciones de salud sobre c\u00f3mo abordar problemas de salud espec\u00edficos.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe, que se dedica a coordinar esfuerzos internacionales en salud p\u00fablica.\n- **Informe T\u00e9cnico**: El tipo de documento que se presenta, que suele contener an\u00e1lisis detallados y recomendaciones basadas en evidencia.\n\nEste resumen proporciona una visi\u00f3n general de los posibles temas y entidades que podr\u00edan estar presentes en el informe, a pesar de la falta de contenido espec\u00edfico en el contexto proporcionado.", "excerpt_keywords": "Keywords: pharmaceutical preparations, WHO Expert Committee, global health, regulatory affairs, international collaboration"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c8a7699c-25ef-4005-8221-8054837ecd26", "node_type": "4", "metadata": {"page_label": "70", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Forty-sixth report**\n\nAssociation Training and Research Institute, Parenteral Drug Association, Bethesda, MD, USA; Mr M.M. Das, Kolkata, India; Dr J. Daviaud, Senior Pharmaceutical QA Officer, Pharmaceutical Procurement Unit, Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland; Dr V. Davoust, Quality & Regulatory Policy, Global CMC, WW Pharmaceutical Sciences, Pfizer Global Research & Development, Paris, France; Professor T. Dekker, Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa; Dr L. De-Moor, GlaxoSmithKline, Belgium; Dr J. DiLoreto, Executive Director, Bulk Pharmaceuticals Task Force, Washington, DC, USA; Dr V. Divecha, Cipla, India; Professor J.B. Dressman, Professor of Pharmaceutical Technology, Institut f\u00fcr Pharmazeutische Technologie, Biozentrum, Johann Wolfgang Goethe-Universit\u00e4t, Frankfurt am Main, Germany; Dr A.T. Ducca, Senior Director, Regulatory Affairs, Healthcare Distribution Management Association, Arlington, VA, USA; Dr S. Durand-Stamatidas, Director, Information and Communication, World Self-Medication Industry, Ferney-Voltaire, France; Dr P. Ellis, Director, External Advocacy, Quality Centre of Excellence, GlaxoSmithKline, Brentford, Middlesex, England; Dr A. Falodun, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Benin, Benin City, Nigeria; Dr E. Fefer, Member, United States Pharmacopeia International Health Expert Committee, Rockville, MD, USA; Dr R. Fendt, Head, Global Regulatory & GMP Compliance Pharma, Care Chemicals Division, BASF, Limburgerhof, Germany; Mr A. Ferreira do Nascimento, Ag\u00eancia Nacional de Vigil\u00e2ncia, Bras\u00edlia, Brazil; Dr A. Fleuckiger, Head, Corporate Health Protection, Corporate Safety, Health and Environmental Protection, F. Hoffmann-La Roche, Basel, Switzerland; Dr G.L. France, Vice-President, Quality Strategy, Pfizer Limited and Vice-Chair, IFPMA/RPTS, Maidenhead, England; Dr N.C. Franklin, Wuppertal, Germany; Mr T. Fujino, Director, International Affairs, Japan Generic Medicines Association, Tokyo, Japan; Dr M. Garvin, Senior Director, Scientific and Regulatory Affairs, Pharmaceutical Research and Manufacturers of America, Washington, DC, USA; Dr F. Giorgi, Research and Development, Analytical Development Manager, Sigma-tau Industrie Farmaceutiche Riunite, Pomezia, Italy; Dr L. Girard, Head, Global Pharmacopoeial Affairs, Novartis Group Quality, Quality Systems and Standards, Basel, Switzerland; Dr N. Goldschmidt, USA; Dr E. Gomez, Ridgefield Park, New Jersey, USA; Ms J. Gouws, Department of Health, Medicines Control Council, Pretoria, South Africa; Dr M. Goverde, QC Expert Microbiology, Novartis Pharma, Basel, Switzerland; Ms R.Govithavatangaphong, Director, Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Dr J. Grande, Manager, Regulatory Affairs, McNeil Consumer Healthcare, Markham, England; Dr A. Gray, Senior Lecturer, Department of Therapeutics and Medicines Management and Consultant Pharmacist, Centre for the AIDS Programme of Research in South Africa.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "a5f5fdab551e1b6296aa205b9fefd726f839e6666863c8b86a5de0faf8413946", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Forty-sixth report**\n\nAssociation Training and Research Institute, Parenteral Drug Association, Bethesda, MD, USA; Mr M.M. Das, Kolkata, India; Dr J. Daviaud, Senior Pharmaceutical QA Officer, Pharmaceutical Procurement Unit, Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland; Dr V. Davoust, Quality & Regulatory Policy, Global CMC, WW Pharmaceutical Sciences, Pfizer Global Research & Development, Paris, France; Professor T. Dekker, Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa; Dr L. De-Moor, GlaxoSmithKline, Belgium; Dr J. DiLoreto, Executive Director, Bulk Pharmaceuticals Task Force, Washington, DC, USA; Dr V. Divecha, Cipla, India; Professor J.B. Dressman, Professor of Pharmaceutical Technology, Institut f\u00fcr Pharmazeutische Technologie, Biozentrum, Johann Wolfgang Goethe-Universit\u00e4t, Frankfurt am Main, Germany; Dr A.T. Ducca, Senior Director, Regulatory Affairs, Healthcare Distribution Management Association, Arlington, VA, USA; Dr S. Durand-Stamatidas, Director, Information and Communication, World Self-Medication Industry, Ferney-Voltaire, France; Dr P. Ellis, Director, External Advocacy, Quality Centre of Excellence, GlaxoSmithKline, Brentford, Middlesex, England; Dr A. Falodun, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Benin, Benin City, Nigeria; Dr E. Fefer, Member, United States Pharmacopeia International Health Expert Committee, Rockville, MD, USA; Dr R. Fendt, Head, Global Regulatory & GMP Compliance Pharma, Care Chemicals Division, BASF, Limburgerhof, Germany; Mr A. Ferreira do Nascimento, Ag\u00eancia Nacional de Vigil\u00e2ncia, Bras\u00edlia, Brazil; Dr A. Fleuckiger, Head, Corporate Health Protection, Corporate Safety, Health and Environmental Protection, F. Hoffmann-La Roche, Basel, Switzerland; Dr G.L. France, Vice-President, Quality Strategy, Pfizer Limited and Vice-Chair, IFPMA/RPTS, Maidenhead, England; Dr N.C. Franklin, Wuppertal, Germany; Mr T. Fujino, Director, International Affairs, Japan Generic Medicines Association, Tokyo, Japan; Dr M. Garvin, Senior Director, Scientific and Regulatory Affairs, Pharmaceutical Research and Manufacturers of America, Washington, DC, USA; Dr F. Giorgi, Research and Development, Analytical Development Manager, Sigma-tau Industrie Farmaceutiche Riunite, Pomezia, Italy; Dr L. Girard, Head, Global Pharmacopoeial Affairs, Novartis Group Quality, Quality Systems and Standards, Basel, Switzerland; Dr N. Goldschmidt, USA; Dr E. Gomez, Ridgefield Park, New Jersey, USA; Ms J. Gouws, Department of Health, Medicines Control Council, Pretoria, South Africa; Dr M. Goverde, QC Expert Microbiology, Novartis Pharma, Basel, Switzerland; Ms R.Govithavatangaphong, Director, Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Dr J. Grande, Manager, Regulatory Affairs, McNeil Consumer Healthcare, Markham, England; Dr A. Gray, Senior Lecturer, Department of Therapeutics and Medicines Management and Consultant Pharmacist, Centre for the AIDS Programme of Research in South Africa.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3189, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "98fb631e-07c4-4dbc-ba69-2b3bd56f1207": {"__data__": {"id_": "98fb631e-07c4-4dbc-ba69-2b3bd56f1207", "embedding": null, "metadata": {"page_label": "71", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\n(CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Congella, South Africa; Dr M. Guazzaroni Jacobs, Director, Quality and Regulatory Policy, Pfizer, New York, NY, USA; Ms N.M. Guerrero-Rivas, Head, Quality Assurance Section, Instituto Especializado de An\u00e1lisis, Estafeta Universitaria, Panam\u00e1, Panama; Guilin Pharmaceutical Company Ltd, Guilin, People\u2019s Republic of China; Dr R. Guinet, Agence fran\u00e7aise de s\u00e9curit\u00e9 sanitaire des produits de sant\u00e9, Saint-Denis, France; Dr G.T. Gunnarsson, Iceland; Professor R. Guy, Professor of Pharmaceutical Sciences, Department of Pharmacy and Pharmacology, University of Bath, Bath, England; Dr N. Habib, Director General of Medical Supplies, Ministry of Health, Oman; Dr N. Hamilton, Industrial Quality and Compliance, Industrial Affairs, Sanofi Aventis, West Malling, Kent, England; Dr A. Hawwa, Lecturer in Pharmacy (Medicines in Children), Medical Biology Centre, Queen\u2019s University Belfast, Belfast, Northern Ireland; Dr M. Hayes-Bachmeyer, TRIS Management, Technical Regulatory Affairs, Pharmaceuticals Division, F. Hoffmann-la Roche, Basel, Switzerland; Dr G.W. Heddell, Director, Inspection Enforcement and Standards Division, Medicines and Healthcare products Regulatory Agency, London, England; Dr D. Hege-Voelksen, Swissmedic, Berne, Switzerland; Dr M. Helling-Borda, Commugny, Switzerland; Ms J. Hiep, QA Pharmacist and Auditor, Adcock Ingram, Bryanston, South Africa; Ms M. Hirschhorn, Chief, Quality Assurance and Analytical Chemistry, Comisi\u00f3n para el Control de Calidad de Medicamentos, Montevideo, Uruguay; Professor J. Hoogmartens, Professor Emeritus, Laboratorium voor Farmaceutische Analyse, Leuven, Belgium; Dr K. Hoppu, Director, Poison Information Centre, Helsinki University Central Hospital, Helsinki, Finland; Dr R. Horder, Consultant, Abbott, Maidencombe, England; Dr H. Hoseh, Head of Registration Unit, Drug Directorate, Jordan Food and Drug Administration, Jordan; Dr Hou Xinping, T\u00dcV S\u00dcD PSB Chemical & Materials, Singapore; Dr N. Ibrahim, National Pharmaceutical Control Bureau, Ministry of Health, Jalan University, Petaling Jaya, Indonesia; Professor R. Jachowicz, Head, Department of Pharmaceutical Technology and Biopharmaceutics, Jagiellonian University Medical College, Faculty of Pharmacy, Krak\u00f3w, Poland; Dr R. J\u00e4hnke, Global Pharma Health Fund e.V., Frankfurt, Germany; Dr M. James, GlaxoSmithKline, Brentford, Middlesex, England; Dr A. Janssen, Manager, Regulatory Affairs, DMV Fonterra Excipients, Friesland Campina Ingredients Innovation, Goch, Germany; Professor Jin Shaohong, Chief Expert for Pharmaceutical Products, National Institutes for Food and Drug Control, Beijing, People\u2019s Republic of China; Dr P. Jones, Director, Analytical Control, Pharmaceutical Sciences, Pfizer Global R&D, Sandwich, England; Dr Y. Juillet, France; Mr D. J\u00fcnemann, Teaching Assistant; Institut f\u00fcr Pharmazeutische Technologie, Biozentrum, Johann Wolfgang Goethe-Universit\u00e4t, Frankfurt and Main, Germany; Ms A. Junttonen, Senior Pharmaceutical Inspector, National\n```\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl texto proviene del \"WHO - Technical Report Series 970\" y presenta una lista de profesionales y acad\u00e9micos de diversas instituciones y empresas relacionadas con la salud y la farmac\u00e9utica. Incluye nombres, t\u00edtulos y afiliaciones de personas de diferentes pa\u00edses, lo que sugiere un enfoque en la colaboraci\u00f3n internacional en el \u00e1mbito de la regulaci\u00f3n y calidad de productos farmac\u00e9uticos.\n\n### Preguntas Generadas\n\n1. **\u00bfQu\u00e9 tipo de instituciones est\u00e1n representadas por los profesionales mencionados en el documento?**\n   - Respuesta: Las instituciones incluyen universidades, agencias reguladoras de salud, empresas farmac\u00e9uticas y centros de investigaci\u00f3n, como la Universidad de KwaZulu-Natal, Pfizer, y la Agencia Francesa de Seguridad Sanitaria de Productos de Salud.\n\n2. **\u00bfCu\u00e1l es el enfoque principal de los profesionales listados en el documento?**\n   - Respuesta: El enfoque principal de los profesionales es la calidad y regulaci\u00f3n de productos farmac\u00e9uticos, as\u00ed como la investigaci\u00f3n y desarrollo en el \u00e1mbito de la farmacolog\u00eda y la salud p\u00fablica.\n\n3. **\u00bfQu\u00e9 regiones del mundo est\u00e1n representadas en la lista de profesionales y sus respectivas instituciones?**\n   - Respuesta: La lista incluye representantes de diversas regiones, como Am\u00e9rica del Norte (EE. UU.), Europa (Reino Unido, Francia, Alemania, Polonia, entre otros), Asia (China, Indonesia, Singapur), y \u00c1frica (Sud\u00e1frica, Om\u00e1n), lo que indica una colaboraci\u00f3n global en el campo de la salud y la farmac\u00e9utica.", "prev_section_summary": "El contenido de la secci\u00f3n se centra en el \"Cuarenta y sexto informe\" del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Colaboraci\u00f3n Internacional**: El informe destaca la importancia de la cooperaci\u00f3n entre expertos de diversas organizaciones y pa\u00edses en el \u00e1mbito de la regulaci\u00f3n y calidad de productos farmac\u00e9uticos.\n2. **Diversidad de Expertos**: Se menciona la amplia gama de especializaciones y experiencias de los miembros del comit\u00e9, lo que refleja un enfoque multidisciplinario en la regulaci\u00f3n farmac\u00e9utica.\n3. **Enfoque en Enfermedades Globales**: El informe subraya la relevancia de la regulaci\u00f3n farmac\u00e9utica en el contexto de enfermedades como el VIH/SIDA, la tuberculosis y la malaria.\n\n### Entidades Mencionadas:\n- **Organizaciones**:\n  - Organizaci\u00f3n Mundial de la Salud (OMS)\n  - Global Fund to Fight AIDS, Tuberculosis and Malaria\n  - Parenteral Drug Association\n  - GlaxoSmithKline\n  - Pfizer Global Research & Development\n  - Novartis Group Quality\n  - Pharmaceutical Research and Manufacturers of America\n\n- **Expertos y sus Afiliaciones**:\n  - Dr. J. Daviaud (Global Fund to Fight AIDS, Tuberculosis and Malaria, Suiza)\n  - Dr. V. Davoust (Pfizer, Francia)\n  - Dr. A. Fleuckiger (F. Hoffmann-La Roche, Suiza)\n  - Dr. M. Garvin (Pharmaceutical Research and Manufacturers of America, EE. UU.)\n  - Dr. A. Gray (Centro para el Programa de Investigaci\u00f3n del SIDA en Sud\u00e1frica)\n\n### Implicaciones:\nLa diversidad geogr\u00e1fica y de especializaci\u00f3n en el comit\u00e9 sugiere que las decisiones y recomendaciones sobre est\u00e1ndares farmac\u00e9uticos se ven influenciadas por una amplia gama de perspectivas, lo que es crucial para abordar los desaf\u00edos globales en la industria farmac\u00e9utica.", "excerpt_keywords": "Keywords: regulaci\u00f3n farmac\u00e9utica, calidad, colaboraci\u00f3n internacional, expertos, salud p\u00fablica"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc39baf5-1ee6-4a1e-9235-af38d3fb89af", "node_type": "4", "metadata": {"page_label": "71", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\n(CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Congella, South Africa; Dr M. Guazzaroni Jacobs, Director, Quality and Regulatory Policy, Pfizer, New York, NY, USA; Ms N.M. Guerrero-Rivas, Head, Quality Assurance Section, Instituto Especializado de An\u00e1lisis, Estafeta Universitaria, Panam\u00e1, Panama; Guilin Pharmaceutical Company Ltd, Guilin, People\u2019s Republic of China; Dr R. Guinet, Agence fran\u00e7aise de s\u00e9curit\u00e9 sanitaire des produits de sant\u00e9, Saint-Denis, France; Dr G.T. Gunnarsson, Iceland; Professor R. Guy, Professor of Pharmaceutical Sciences, Department of Pharmacy and Pharmacology, University of Bath, Bath, England; Dr N. Habib, Director General of Medical Supplies, Ministry of Health, Oman; Dr N. Hamilton, Industrial Quality and Compliance, Industrial Affairs, Sanofi Aventis, West Malling, Kent, England; Dr A. Hawwa, Lecturer in Pharmacy (Medicines in Children), Medical Biology Centre, Queen\u2019s University Belfast, Belfast, Northern Ireland; Dr M. Hayes-Bachmeyer, TRIS Management, Technical Regulatory Affairs, Pharmaceuticals Division, F. Hoffmann-la Roche, Basel, Switzerland; Dr G.W. Heddell, Director, Inspection Enforcement and Standards Division, Medicines and Healthcare products Regulatory Agency, London, England; Dr D. Hege-Voelksen, Swissmedic, Berne, Switzerland; Dr M. Helling-Borda, Commugny, Switzerland; Ms J. Hiep, QA Pharmacist and Auditor, Adcock Ingram, Bryanston, South Africa; Ms M. Hirschhorn, Chief, Quality Assurance and Analytical Chemistry, Comisi\u00f3n para el Control de Calidad de Medicamentos, Montevideo, Uruguay; Professor J. Hoogmartens, Professor Emeritus, Laboratorium voor Farmaceutische Analyse, Leuven, Belgium; Dr K. Hoppu, Director, Poison Information Centre, Helsinki University Central Hospital, Helsinki, Finland; Dr R. Horder, Consultant, Abbott, Maidencombe, England; Dr H. Hoseh, Head of Registration Unit, Drug Directorate, Jordan Food and Drug Administration, Jordan; Dr Hou Xinping, T\u00dcV S\u00dcD PSB Chemical & Materials, Singapore; Dr N. Ibrahim, National Pharmaceutical Control Bureau, Ministry of Health, Jalan University, Petaling Jaya, Indonesia; Professor R. Jachowicz, Head, Department of Pharmaceutical Technology and Biopharmaceutics, Jagiellonian University Medical College, Faculty of Pharmacy, Krak\u00f3w, Poland; Dr R. J\u00e4hnke, Global Pharma Health Fund e.V., Frankfurt, Germany; Dr M. James, GlaxoSmithKline, Brentford, Middlesex, England; Dr A. Janssen, Manager, Regulatory Affairs, DMV Fonterra Excipients, Friesland Campina Ingredients Innovation, Goch, Germany; Professor Jin Shaohong, Chief Expert for Pharmaceutical Products, National Institutes for Food and Drug Control, Beijing, People\u2019s Republic of China; Dr P. Jones, Director, Analytical Control, Pharmaceutical Sciences, Pfizer Global R&D, Sandwich, England; Dr Y. Juillet, France; Mr D. J\u00fcnemann, Teaching Assistant; Institut f\u00fcr Pharmazeutische Technologie, Biozentrum, Johann Wolfgang Goethe-Universit\u00e4t, Frankfurt and Main, Germany; Ms A. Junttonen, Senior Pharmaceutical Inspector, National\n```\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "59939fc24de9bcf314aaa5eea87e7e3f7ba17247443dac089980eaa9f33a493a", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "```\n(CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Congella, South Africa; Dr M. Guazzaroni Jacobs, Director, Quality and Regulatory Policy, Pfizer, New York, NY, USA; Ms N.M. Guerrero-Rivas, Head, Quality Assurance Section, Instituto Especializado de An\u00e1lisis, Estafeta Universitaria, Panam\u00e1, Panama; Guilin Pharmaceutical Company Ltd, Guilin, People\u2019s Republic of China; Dr R. Guinet, Agence fran\u00e7aise de s\u00e9curit\u00e9 sanitaire des produits de sant\u00e9, Saint-Denis, France; Dr G.T. Gunnarsson, Iceland; Professor R. Guy, Professor of Pharmaceutical Sciences, Department of Pharmacy and Pharmacology, University of Bath, Bath, England; Dr N. Habib, Director General of Medical Supplies, Ministry of Health, Oman; Dr N. Hamilton, Industrial Quality and Compliance, Industrial Affairs, Sanofi Aventis, West Malling, Kent, England; Dr A. Hawwa, Lecturer in Pharmacy (Medicines in Children), Medical Biology Centre, Queen\u2019s University Belfast, Belfast, Northern Ireland; Dr M. Hayes-Bachmeyer, TRIS Management, Technical Regulatory Affairs, Pharmaceuticals Division, F. Hoffmann-la Roche, Basel, Switzerland; Dr G.W. Heddell, Director, Inspection Enforcement and Standards Division, Medicines and Healthcare products Regulatory Agency, London, England; Dr D. Hege-Voelksen, Swissmedic, Berne, Switzerland; Dr M. Helling-Borda, Commugny, Switzerland; Ms J. Hiep, QA Pharmacist and Auditor, Adcock Ingram, Bryanston, South Africa; Ms M. Hirschhorn, Chief, Quality Assurance and Analytical Chemistry, Comisi\u00f3n para el Control de Calidad de Medicamentos, Montevideo, Uruguay; Professor J. Hoogmartens, Professor Emeritus, Laboratorium voor Farmaceutische Analyse, Leuven, Belgium; Dr K. Hoppu, Director, Poison Information Centre, Helsinki University Central Hospital, Helsinki, Finland; Dr R. Horder, Consultant, Abbott, Maidencombe, England; Dr H. Hoseh, Head of Registration Unit, Drug Directorate, Jordan Food and Drug Administration, Jordan; Dr Hou Xinping, T\u00dcV S\u00dcD PSB Chemical & Materials, Singapore; Dr N. Ibrahim, National Pharmaceutical Control Bureau, Ministry of Health, Jalan University, Petaling Jaya, Indonesia; Professor R. Jachowicz, Head, Department of Pharmaceutical Technology and Biopharmaceutics, Jagiellonian University Medical College, Faculty of Pharmacy, Krak\u00f3w, Poland; Dr R. J\u00e4hnke, Global Pharma Health Fund e.V., Frankfurt, Germany; Dr M. James, GlaxoSmithKline, Brentford, Middlesex, England; Dr A. Janssen, Manager, Regulatory Affairs, DMV Fonterra Excipients, Friesland Campina Ingredients Innovation, Goch, Germany; Professor Jin Shaohong, Chief Expert for Pharmaceutical Products, National Institutes for Food and Drug Control, Beijing, People\u2019s Republic of China; Dr P. Jones, Director, Analytical Control, Pharmaceutical Sciences, Pfizer Global R&D, Sandwich, England; Dr Y. Juillet, France; Mr D. J\u00fcnemann, Teaching Assistant; Institut f\u00fcr Pharmazeutische Technologie, Biozentrum, Johann Wolfgang Goethe-Universit\u00e4t, Frankfurt and Main, Germany; Ms A. Junttonen, Senior Pharmaceutical Inspector, National\n```", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3063, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c6bfddb8-8940-447c-bb9b-4a02603c98f4": {"__data__": {"id_": "c6bfddb8-8940-447c-bb9b-4a02603c98f4", "embedding": null, "metadata": {"page_label": "72", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAgency for Medicines, Helsinki, Finland; Dr M. Kaplan, Director, Institute for Standardization and Control of Pharmaceuticals, Jerusalem, Israel; Dr M. Karga-Hinds, Director, Barbados Drug Service, Christchurch, Barbados; Dr A.M. Kaukonen, National Agency for Medicines, Helsinki, Finland; Dr T. Kawanishi, Deputy Director General, National Institute of Health Sciences, Tokyo, Japan; Ms H. Kavale, Cipla, Mumbai, India; Dr S. Keitel, Director, European Directorate for the Quality of Medicines and HealthCare, Strasbourg, France; Dr K. Keller, Director and Professor, Federal Ministry of Health, Bonn, Germany; Dr M. Keller, Inspector, Division of Certificates and Licencing, Swissmedic, Berne, Switzerland; Dr L. Kerr, Scientific Operations Adviser, Office of Laboratories and Scientific Services, Therapeutic Goods Administration, Woden, ACT, Australia; Dr M. Khan, Director, Federal Research Center Life Sciences, US Food and Drug Administration, Silver Spring, MD, USA; Professor Kazuko Kimura, Institute of Medicine, Pharmacy and Health Sciences, Kanazawa University, Kanazawa-city, Japan; Ms M. Kira, Consultant, Non-Governmental Organizations and Industry Relations Section, Department of External Relations, World Intellectual Property Organization, Geneva, Switzerland; Dr H. K\u0151szegi-Szalai, Head, Department for Quality Assessment and Control, National Institute of Pharmacy, Budapest, Hungary; Dr A. Kovacs, Secretariat, Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland; Ms S. Kox, Senior Director, Scientific Affairs, European Generic Medicines Association, Brussels, Belgium; Dr P. Kozarewicz, Scientific Administrator, Quality of Medicines Sector, Human Unit Pre-Authorization, European Medicines Agency, London, England; Dr A. Krauss, Principal Scientist, Chemist Laboratory, Therapeutic Goods Administration Laboratories, Woden, ACT, Australia; Professor H.G. Kristensen, Vedbaek, Denmark; Mr A. Kupferman, Industry Pharmacist, Strasbourg, France; Professor S. L\u00e4er, Institut f\u00fcr Klinische Pharmazie und Pharmakotherapie, Heinrich-Heine-Universit\u00e4t, D\u00fcsseldorf, Germany; Dr J.-M. Legrand, GlaxoSmithKline Biologicals, Wavre, Belgium; Dr A. Lodi, Head, Laboratory Department, European Directorate for the Quality of Medicines and HealthCare, Strasbourg, France; Mr M. Lok, Head of Office, Office of Manufacturing Quality, Therapeutic Goods Administration, Woden, ACT, Australia; Ms Low Min Yong, Director, Pharmaceutical Division, Applied Sciences Group, Health Sciences Authority, Singapore; Dr J.C. Lyda, Senior Director, Regulatory Affairs, Parenteral Drug Association Europe, Glienicke, Berlin, Germany; Mr D. Mader, Compliance Auditor, GlaxoSmithKline, Cape Town, South Africa; Dr F. Malik, Pakistan; Reverend J.Y. Martey, Head, Laboratory Services, Quality Control Laboratory, Food and Drugs Board, Accra, Ghana; Dr T. Massa, Vice President, Global Regulatory Sciences \u2013 Chemistry, Manufacturing and Control, Bristol-Myers Squibb, USA; Dr B. Matthews, Alcon, Hemel Hempstead, Herts, England; Dr Y. Matthews, Regulatory Operations Executive, GE Healthcare, Amersham, Bucks.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) titulado \"WHO - Technical Report Series 970\", que presenta las contribuciones de un comit\u00e9 de expertos sobre especificaciones para preparaciones farmac\u00e9uticas. Incluye una lista de participantes de diversas organizaciones y pa\u00edses, destacando sus roles y afiliaciones. Este comit\u00e9 est\u00e1 compuesto por profesionales de la salud, reguladores y expertos en farmacolog\u00eda, que colaboran para establecer est\u00e1ndares y directrices en la calidad de los medicamentos.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQui\u00e9nes son algunos de los miembros clave del comit\u00e9 y cu\u00e1les son sus roles espec\u00edficos en sus respectivas organizaciones?**\n   - Esta pregunta busca detalles sobre la composici\u00f3n del comit\u00e9 y las funciones de sus miembros, que no se encuentran f\u00e1cilmente en otros documentos.\n\n2. **\u00bfQu\u00e9 organizaciones est\u00e1n representadas en el comit\u00e9 y c\u00f3mo contribuyen a la regulaci\u00f3n de los medicamentos a nivel internacional?**\n   - Esta pregunta se centra en las organizaciones mencionadas y su impacto en la regulaci\u00f3n farmac\u00e9utica global, proporcionando un contexto sobre la colaboraci\u00f3n internacional en este \u00e1mbito.\n\n3. **\u00bfCu\u00e1les son los objetivos principales del comit\u00e9 de expertos de la OMS en relaci\u00f3n con las especificaciones para preparaciones farmac\u00e9uticas?**\n   - Esta pregunta busca entender los prop\u00f3sitos y metas del comit\u00e9, lo que puede no estar expl\u00edcitamente detallado en otros informes o documentos relacionados.\n\n### Resumen de Nivel Superior\nEl informe de la OMS presenta un grupo diverso de expertos en farmacolog\u00eda y regulaci\u00f3n de medicamentos, que se re\u00fanen para discutir y establecer est\u00e1ndares para la calidad de las preparaciones farmac\u00e9uticas. Este comit\u00e9 incluye representantes de diferentes pa\u00edses y organizaciones, lo que refleja un esfuerzo colaborativo para mejorar la seguridad y eficacia de los medicamentos a nivel mundial.", "prev_section_summary": "La secci\u00f3n del documento \"WHO - Technical Report Series 970\" presenta una lista de profesionales y acad\u00e9micos de diversas instituciones y empresas relacionadas con la salud y la farmac\u00e9utica. Los temas clave incluyen:\n\n1. **Colaboraci\u00f3n Internacional**: La lista refleja un enfoque global en la regulaci\u00f3n y calidad de productos farmac\u00e9uticos, con representantes de m\u00faltiples pa\u00edses y organizaciones.\n\n2. **Diversidad de Instituciones**: Se mencionan diversas entidades, incluyendo universidades (como la Universidad de KwaZulu-Natal y la Universidad de Bath), agencias reguladoras (como la Agencia Francesa de Seguridad Sanitaria de Productos de Salud y Swissmedic), y empresas farmac\u00e9uticas (como Pfizer y GlaxoSmithKline).\n\n3. **\u00c1reas de Especializaci\u00f3n**: Los profesionales tienen experiencia en \u00e1reas como calidad y regulaci\u00f3n de productos farmac\u00e9uticos, farmacolog\u00eda, an\u00e1lisis qu\u00edmico, y medicina pedi\u00e1trica, lo que indica un enfoque multidisciplinario.\n\n4. **Representaci\u00f3n Geogr\u00e1fica**: La lista incluye profesionales de regiones como Am\u00e9rica del Norte, Europa, Asia y \u00c1frica, lo que subraya la importancia de la cooperaci\u00f3n internacional en el \u00e1mbito de la salud.\n\nEn resumen, la secci\u00f3n destaca la colaboraci\u00f3n entre expertos de diferentes disciplinas y pa\u00edses en la mejora de la calidad y regulaci\u00f3n de productos farmac\u00e9uticos a nivel global.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, regulatory affairs, international collaboration, quality standards"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d82ea119-ba17-487c-8f51-2e61ac949ccf", "node_type": "4", "metadata": {"page_label": "72", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAgency for Medicines, Helsinki, Finland; Dr M. Kaplan, Director, Institute for Standardization and Control of Pharmaceuticals, Jerusalem, Israel; Dr M. Karga-Hinds, Director, Barbados Drug Service, Christchurch, Barbados; Dr A.M. Kaukonen, National Agency for Medicines, Helsinki, Finland; Dr T. Kawanishi, Deputy Director General, National Institute of Health Sciences, Tokyo, Japan; Ms H. Kavale, Cipla, Mumbai, India; Dr S. Keitel, Director, European Directorate for the Quality of Medicines and HealthCare, Strasbourg, France; Dr K. Keller, Director and Professor, Federal Ministry of Health, Bonn, Germany; Dr M. Keller, Inspector, Division of Certificates and Licencing, Swissmedic, Berne, Switzerland; Dr L. Kerr, Scientific Operations Adviser, Office of Laboratories and Scientific Services, Therapeutic Goods Administration, Woden, ACT, Australia; Dr M. Khan, Director, Federal Research Center Life Sciences, US Food and Drug Administration, Silver Spring, MD, USA; Professor Kazuko Kimura, Institute of Medicine, Pharmacy and Health Sciences, Kanazawa University, Kanazawa-city, Japan; Ms M. Kira, Consultant, Non-Governmental Organizations and Industry Relations Section, Department of External Relations, World Intellectual Property Organization, Geneva, Switzerland; Dr H. K\u0151szegi-Szalai, Head, Department for Quality Assessment and Control, National Institute of Pharmacy, Budapest, Hungary; Dr A. Kovacs, Secretariat, Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland; Ms S. Kox, Senior Director, Scientific Affairs, European Generic Medicines Association, Brussels, Belgium; Dr P. Kozarewicz, Scientific Administrator, Quality of Medicines Sector, Human Unit Pre-Authorization, European Medicines Agency, London, England; Dr A. Krauss, Principal Scientist, Chemist Laboratory, Therapeutic Goods Administration Laboratories, Woden, ACT, Australia; Professor H.G. Kristensen, Vedbaek, Denmark; Mr A. Kupferman, Industry Pharmacist, Strasbourg, France; Professor S. L\u00e4er, Institut f\u00fcr Klinische Pharmazie und Pharmakotherapie, Heinrich-Heine-Universit\u00e4t, D\u00fcsseldorf, Germany; Dr J.-M. Legrand, GlaxoSmithKline Biologicals, Wavre, Belgium; Dr A. Lodi, Head, Laboratory Department, European Directorate for the Quality of Medicines and HealthCare, Strasbourg, France; Mr M. Lok, Head of Office, Office of Manufacturing Quality, Therapeutic Goods Administration, Woden, ACT, Australia; Ms Low Min Yong, Director, Pharmaceutical Division, Applied Sciences Group, Health Sciences Authority, Singapore; Dr J.C. Lyda, Senior Director, Regulatory Affairs, Parenteral Drug Association Europe, Glienicke, Berlin, Germany; Mr D. Mader, Compliance Auditor, GlaxoSmithKline, Cape Town, South Africa; Dr F. Malik, Pakistan; Reverend J.Y. Martey, Head, Laboratory Services, Quality Control Laboratory, Food and Drugs Board, Accra, Ghana; Dr T. Massa, Vice President, Global Regulatory Sciences \u2013 Chemistry, Manufacturing and Control, Bristol-Myers Squibb, USA; Dr B. Matthews, Alcon, Hemel Hempstead, Herts, England; Dr Y. Matthews, Regulatory Operations Executive, GE Healthcare, Amersham, Bucks.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "c97bf4eb4ce9ee21b0cc70c5e65ab3dde7172f9d96e9ef510e1eecf849afa024", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAgency for Medicines, Helsinki, Finland; Dr M. Kaplan, Director, Institute for Standardization and Control of Pharmaceuticals, Jerusalem, Israel; Dr M. Karga-Hinds, Director, Barbados Drug Service, Christchurch, Barbados; Dr A.M. Kaukonen, National Agency for Medicines, Helsinki, Finland; Dr T. Kawanishi, Deputy Director General, National Institute of Health Sciences, Tokyo, Japan; Ms H. Kavale, Cipla, Mumbai, India; Dr S. Keitel, Director, European Directorate for the Quality of Medicines and HealthCare, Strasbourg, France; Dr K. Keller, Director and Professor, Federal Ministry of Health, Bonn, Germany; Dr M. Keller, Inspector, Division of Certificates and Licencing, Swissmedic, Berne, Switzerland; Dr L. Kerr, Scientific Operations Adviser, Office of Laboratories and Scientific Services, Therapeutic Goods Administration, Woden, ACT, Australia; Dr M. Khan, Director, Federal Research Center Life Sciences, US Food and Drug Administration, Silver Spring, MD, USA; Professor Kazuko Kimura, Institute of Medicine, Pharmacy and Health Sciences, Kanazawa University, Kanazawa-city, Japan; Ms M. Kira, Consultant, Non-Governmental Organizations and Industry Relations Section, Department of External Relations, World Intellectual Property Organization, Geneva, Switzerland; Dr H. K\u0151szegi-Szalai, Head, Department for Quality Assessment and Control, National Institute of Pharmacy, Budapest, Hungary; Dr A. Kovacs, Secretariat, Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland; Ms S. Kox, Senior Director, Scientific Affairs, European Generic Medicines Association, Brussels, Belgium; Dr P. Kozarewicz, Scientific Administrator, Quality of Medicines Sector, Human Unit Pre-Authorization, European Medicines Agency, London, England; Dr A. Krauss, Principal Scientist, Chemist Laboratory, Therapeutic Goods Administration Laboratories, Woden, ACT, Australia; Professor H.G. Kristensen, Vedbaek, Denmark; Mr A. Kupferman, Industry Pharmacist, Strasbourg, France; Professor S. L\u00e4er, Institut f\u00fcr Klinische Pharmazie und Pharmakotherapie, Heinrich-Heine-Universit\u00e4t, D\u00fcsseldorf, Germany; Dr J.-M. Legrand, GlaxoSmithKline Biologicals, Wavre, Belgium; Dr A. Lodi, Head, Laboratory Department, European Directorate for the Quality of Medicines and HealthCare, Strasbourg, France; Mr M. Lok, Head of Office, Office of Manufacturing Quality, Therapeutic Goods Administration, Woden, ACT, Australia; Ms Low Min Yong, Director, Pharmaceutical Division, Applied Sciences Group, Health Sciences Authority, Singapore; Dr J.C. Lyda, Senior Director, Regulatory Affairs, Parenteral Drug Association Europe, Glienicke, Berlin, Germany; Mr D. Mader, Compliance Auditor, GlaxoSmithKline, Cape Town, South Africa; Dr F. Malik, Pakistan; Reverend J.Y. Martey, Head, Laboratory Services, Quality Control Laboratory, Food and Drugs Board, Accra, Ghana; Dr T. Massa, Vice President, Global Regulatory Sciences \u2013 Chemistry, Manufacturing and Control, Bristol-Myers Squibb, USA; Dr B. Matthews, Alcon, Hemel Hempstead, Herts, England; Dr Y. Matthews, Regulatory Operations Executive, GE Healthcare, Amersham, Bucks.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3186, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "7b454f18-aaac-4c39-9eb8-b58fa09aa93c": {"__data__": {"id_": "7b454f18-aaac-4c39-9eb8-b58fa09aa93c", "embedding": null, "metadata": {"page_label": "73", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior:\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pr\u00e1cticas de salud a nivel global. Aunque el contenido espec\u00edfico de la p\u00e1gina 73 no est\u00e1 disponible, el informe en su conjunto puede contener informaci\u00f3n relevante sobre pol\u00edticas de salud, directrices de tratamiento, o datos epidemiol\u00f3gicos.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las principales recomendaciones de salud p\u00fablica presentadas en el informe WHO - Technical Report Series 970?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre las directrices o recomendaciones que la OMS ha emitido en este informe, que podr\u00edan no estar disponibles en otros documentos.\n\n2. **\u00bfQu\u00e9 temas de investigaci\u00f3n m\u00e9dica se abordan en el informe y c\u00f3mo se relacionan con las tendencias actuales en salud global?**\n   - Esta pregunta se centra en identificar los temas tratados en el informe y su relevancia en el contexto de la salud global contempor\u00e1nea, lo que podr\u00eda no estar claramente documentado en otras fuentes.\n\n3. **\u00bfQu\u00e9 datos epidemiol\u00f3gicos espec\u00edficos se presentan en el informe y c\u00f3mo pueden influir en la formulaci\u00f3n de pol\u00edticas de salud?**\n   - Esta pregunta busca detalles sobre los datos espec\u00edficos que se incluyen en el informe y su posible impacto en la toma de decisiones en el \u00e1mbito de la salud p\u00fablica, lo que podr\u00eda no estar disponible en otros lugares.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y relevante que podr\u00eda ser \u00fanica para el documento mencionado.", "prev_section_summary": "La secci\u00f3n del documento \"WHO - Technical Report Series 970\" presenta un informe del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. A continuaci\u00f3n se resumen los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Composici\u00f3n del Comit\u00e9**: El comit\u00e9 est\u00e1 formado por expertos de diversas organizaciones y pa\u00edses, incluyendo reguladores, cient\u00edficos y profesionales de la salud, que colaboran para establecer est\u00e1ndares de calidad en medicamentos.\n  \n2. **Colaboraci\u00f3n Internacional**: La diversidad de miembros refleja un esfuerzo global para mejorar la regulaci\u00f3n y la calidad de los medicamentos, destacando la importancia de la cooperaci\u00f3n entre diferentes entidades y pa\u00edses.\n\n3. **Objetivos del Comit\u00e9**: Aunque no se detallan expl\u00edcitamente en el texto, se infiere que el comit\u00e9 busca establecer directrices y est\u00e1ndares que aseguren la seguridad y eficacia de las preparaciones farmac\u00e9uticas a nivel mundial.\n\n### Entidades Mencionadas:\n- **Organizaciones**: \n  - Agencia para Medicamentos (Finlandia)\n  - Instituto de Estandarizaci\u00f3n y Control de Medicamentos (Israel)\n  - Servicio de Medicamentos de Barbados\n  - Administraci\u00f3n de Alimentos y Medicamentos de EE. UU.\n  - Agencia Europea de Medicamentos\n  - Autoridad de Salud de Singapur\n  - Organizaci\u00f3n Mundial de la Propiedad Intelectual\n\n- **Profesionales Clave**: \n  - Dr. M. Kaplan (Israel)\n  - Dr. S. Keitel (Francia)\n  - Dr. M. Khan (EE. UU.)\n  - Dr. T. Massa (EE. UU.)\n  - Reverend J.Y. Martey (Ghana)\n\nEste resumen destaca la importancia del comit\u00e9 en la regulaci\u00f3n farmac\u00e9utica internacional y la colaboraci\u00f3n entre diversas entidades para mejorar la calidad de los medicamentos.", "excerpt_keywords": "Keywords: OMS, medicamentos, regulaci\u00f3n, est\u00e1ndares, salud p\u00fablica"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a95a1b3b-9314-4732-a61c-8ef433a20fdb", "node_type": "4", "metadata": {"page_label": "73", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4f10ed4ea88b1d378bbeefda901db70bf3a87349bac3e07924e337af9d134eb1", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "bd77a95f-d125-46a9-9a77-9e13ce291a5a": {"__data__": {"id_": "bd77a95f-d125-46a9-9a77-9e13ce291a5a", "embedding": null, "metadata": {"page_label": "74", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto del documento \"WHO - Technical Report Series 970\":\n\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir recomendaciones sobre salud p\u00fablica, pol\u00edticas sanitarias o investigaciones cient\u00edficas.\n\n2. **\u00bfQu\u00e9 temas de salud global se abordan en el documento y c\u00f3mo se relacionan con las tendencias actuales en la salud p\u00fablica?**\n   - Esta pregunta se enfoca en identificar los temas tratados en el informe y su relevancia en el contexto de los desaf\u00edos actuales en salud p\u00fablica, lo que podr\u00eda no estar disponible en otras fuentes.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron para recopilar datos y elaborar las conclusiones en el Informe 46 de la OMS?**\n   - Esta pregunta busca detalles sobre los m\u00e9todos de investigaci\u00f3n y an\u00e1lisis utilizados en el informe, lo que puede proporcionar una comprensi\u00f3n m\u00e1s profunda de la validez y aplicabilidad de los hallazgos.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS) que abordan diversos temas relacionados con la salud global. Estos informes suelen incluir investigaciones, recomendaciones y directrices sobre pr\u00e1cticas de salud, pol\u00edticas y estrategias para mejorar la salud p\u00fablica a nivel mundial. El Informe 46 en particular podr\u00eda contener informaci\u00f3n relevante sobre un tema espec\u00edfico de salud, as\u00ed como datos y an\u00e1lisis que respaldan sus conclusiones.", "prev_section_summary": "### Resumen de Temas Clave y Entidades:\n\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS) que abordan cuestiones de salud p\u00fablica y recomendaciones para pr\u00e1cticas de salud a nivel global. Aunque el contenido espec\u00edfico de la p\u00e1gina 73 no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n#### Temas Clave:\n1. **Salud P\u00fablica**: El informe probablemente incluye recomendaciones y directrices sobre pr\u00e1cticas de salud p\u00fablica.\n2. **Investigaci\u00f3n M\u00e9dica**: Es posible que se aborden temas de investigaci\u00f3n que son relevantes para la salud global.\n3. **Pol\u00edticas de Salud**: El informe puede contener datos y an\u00e1lisis que influyan en la formulaci\u00f3n de pol\u00edticas de salud.\n4. **Epidemiolog\u00eda**: Se espera que se presenten datos epidemiol\u00f3gicos que ayuden a entender tendencias y problemas de salud.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe y de la formulaci\u00f3n de recomendaciones de salud.\n- **Informe T\u00e9cnico**: El documento en s\u00ed, que forma parte de una serie m\u00e1s amplia de informes t\u00e9cnicos sobre salud.\n\nEste resumen proporciona una visi\u00f3n general de los temas y entidades que podr\u00edan estar presentes en el informe, a pesar de la falta de contenido espec\u00edfico en la secci\u00f3n mencionada.", "excerpt_keywords": "Keywords: salud p\u00fablica, OMS, recomendaciones, investigaci\u00f3n m\u00e9dica, pol\u00edticas de salud"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7b6dd1ed-dbd1-48bd-a558-97e81cc86270", "node_type": "4", "metadata": {"page_label": "74", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "1aca05148d927f8aff929dc074226a79c725ef1cdbf4dcad3beb7e1739d43391", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c8bcdff2-acde-4392-87b5-ec18539b5ec2": {"__data__": {"id_": "c8bcdff2-acde-4392-87b5-ec18539b5ec2", "embedding": null, "metadata": {"page_label": "75", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto del documento \"WHO - Technical Report Series 970\":\n\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir recomendaciones sobre salud p\u00fablica, pol\u00edticas sanitarias o investigaciones cient\u00edficas.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en el estudio o an\u00e1lisis presentado en el documento de la OMS?**\n   - Esta pregunta se centra en las t\u00e9cnicas y enfoques utilizados en la investigaci\u00f3n, lo que puede ser crucial para entender la validez y aplicabilidad de los resultados.\n\n3. **\u00bfC\u00f3mo se relaciona el contenido del Informe 46 con otros informes previos de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta busca establecer conexiones entre diferentes informes, lo que puede ayudar a contextualizar los hallazgos y recomendaciones en un marco m\u00e1s amplio de investigaci\u00f3n y pol\u00edticas de salud.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS), que abordan diversos temas relacionados con la salud p\u00fablica, la investigaci\u00f3n m\u00e9dica y las pol\u00edticas sanitarias. Estos informes son fundamentales para la formulaci\u00f3n de directrices y recomendaciones a nivel global, y suelen incluir an\u00e1lisis de datos, revisiones de literatura y propuestas para futuras investigaciones.", "prev_section_summary": "El documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS) que abordan temas de salud global. El Informe 46, en particular, se centra en hallazgos y recomendaciones relevantes para la salud p\u00fablica, as\u00ed como en metodolog\u00edas de investigaci\u00f3n utilizadas para recopilar datos y elaborar conclusiones. \n\n### Temas clave:\n1. **Hallazgos y recomendaciones**: Informaci\u00f3n espec\u00edfica sobre pol\u00edticas de salud y pr\u00e1cticas recomendadas.\n2. **Temas de salud global**: Identificaci\u00f3n de problemas de salud actuales y su relaci\u00f3n con tendencias en salud p\u00fablica.\n3. **Metodolog\u00edas de investigaci\u00f3n**: M\u00e9todos utilizados para la recopilaci\u00f3n de datos y an\u00e1lisis en el informe.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la publicaci\u00f3n del informe.\n- **Informe 46**: Espec\u00edfico dentro de la serie de informes t\u00e9cnicos que aborda un tema particular de salud.\n\nEste resumen proporciona una visi\u00f3n general de los aspectos m\u00e1s relevantes del documento y su contexto en el \u00e1mbito de la salud p\u00fablica.", "excerpt_keywords": "Keywords: salud p\u00fablica, recomendaciones, metodolog\u00edas, investigaci\u00f3n, Organizaci\u00f3n Mundial de la Salud"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9b2c4f3e-783e-47e2-8495-cb812d7ea3e5", "node_type": "4", "metadata": {"page_label": "75", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f0415e13248dd6232f45d347e5f1adcc81cbe6f547bd32cdfe55a5bb0643d107", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d799eac2-7d35-48c5-9797-b5ae36f3ac74": {"__data__": {"id_": "d799eac2-7d35-48c5-9797-b5ae36f3ac74", "embedding": null, "metadata": {"page_label": "76", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfCu\u00e1l es el enfoque principal del Informe T\u00e9cnico de la OMS en la Serie 970?**\n   - Esta pregunta busca obtener informaci\u00f3n sobre el tema central o los objetivos del informe, que podr\u00eda no estar disponible en otras fuentes.\n\n2. **\u00bfQu\u00e9 recomendaciones espec\u00edficas se presentan en el Informe T\u00e9cnico de la OMS, seg\u00fan la p\u00e1gina 76?**\n   - Esta pregunta se centra en las recomendaciones o conclusiones que se pueden encontrar en la p\u00e1gina espec\u00edfica del documento, lo que podr\u00eda ofrecer informaci\u00f3n detallada y \u00fatil.\n\n3. **\u00bfQu\u00e9 metodolog\u00eda se utiliz\u00f3 para recopilar los datos presentados en el Informe T\u00e9cnico de la OMS?**\n   - Esta pregunta indaga sobre el enfoque metodol\u00f3gico del informe, lo que podr\u00eda proporcionar una comprensi\u00f3n m\u00e1s profunda de la validez y la fiabilidad de los hallazgos presentados.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento mencionado es un Informe T\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) en la Serie 970, que probablemente aborda temas relacionados con la salud p\u00fablica, investigaciones cient\u00edficas o recomendaciones para pol\u00edticas de salud. La falta de contenido espec\u00edfico en la p\u00e1gina 76 sugiere que podr\u00eda haber informaci\u00f3n relevante en otras secciones del informe que no se ha incluido en el contexto proporcionado.", "prev_section_summary": "El contenido de la secci\u00f3n se refiere al documento titulado \"WHO - Technical Report Series 970\", espec\u00edficamente al Informe 46 de esta serie publicada por la Organizaci\u00f3n Mundial de la Salud (OMS). A continuaci\u00f3n se presentan los temas clave y entidades relevantes:\n\n### Temas Clave:\n1. **Hallazgos y Recomendaciones**: Se busca informaci\u00f3n sobre los principales hallazgos y recomendaciones del informe, que pueden incluir aspectos de salud p\u00fablica y pol\u00edticas sanitarias.\n2. **Metodolog\u00edas de Investigaci\u00f3n**: Se indaga sobre las metodolog\u00edas utilizadas en el estudio o an\u00e1lisis presentado, lo que es esencial para evaluar la validez de los resultados.\n3. **Relaci\u00f3n con Informes Previos**: Se explora c\u00f3mo el contenido del Informe 46 se relaciona con otros informes de la misma serie, proporcionando un contexto m\u00e1s amplio.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la publicaci\u00f3n del informe.\n- **Serie de Informes T\u00e9cnicos de la OMS**: Conjunto de documentos que abordan temas de salud p\u00fablica y pol\u00edticas sanitarias.\n\n### Contexto General:\nEl documento es parte de una serie que tiene como objetivo proporcionar directrices y recomendaciones basadas en investigaciones y an\u00e1lisis de datos en el \u00e1mbito de la salud global. Estos informes son cruciales para la formulaci\u00f3n de pol\u00edticas y la promoci\u00f3n de la salud p\u00fablica a nivel internacional.", "excerpt_keywords": "Keywords: OMS, Informe T\u00e9cnico, salud p\u00fablica, recomendaciones, metodolog\u00eda"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f0958b35-f6ae-4803-94d5-10b24520a433", "node_type": "4", "metadata": {"page_label": "76", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "1911e7fff1506d70eee69787f9cdd22af334262532538b9bf0a04b0f67a0b80c", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ba896e1d-ab87-4a75-bf2f-5ee224f2ee56": {"__data__": {"id_": "ba896e1d-ab87-4a75-bf2f-5ee224f2ee56", "embedding": null, "metadata": {"page_label": "77", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 1\n\n## Development of monographs for *The International Pharmacopoeia*\n\nThe process described below is designed to ensure wide consultation and transparency during monograph development and that the adopted texts are made available in a timely manner.\n\nProvision of monographs in *The International Pharmacopoeia* provides the quality dimension for the medicines (included on the basis of their efficacy and safety) in the World Health Organization (WHO) Model lists of essential medicines and in WHO treatment guidelines.\n\nMajor WHO programmes such as the Prequalification of Medicines Programme (funded by the Bill & Melinda Gates Foundation and UNITAID) and others funded or managed by partner organizations such as the United Nations Children\u2019s Fund and the Global Fund to Fight AIDS, Tuberculosis and Malaria, rely heavily upon the quality specifications of *The International Pharmacopoeia*.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en el desarrollo de monograf\u00edas para *La Farmacopea Internacional*, un recurso clave de la Organizaci\u00f3n Mundial de la Salud (OMS) que establece especificaciones de calidad para medicamentos. Este proceso busca asegurar la consulta amplia y la transparencia en el desarrollo de las monograf\u00edas, garantizando que los textos adoptados est\u00e9n disponibles de manera oportuna. Las monograf\u00edas son fundamentales para la calidad de los medicamentos incluidos en las listas de medicamentos esenciales de la OMS y en sus gu\u00edas de tratamiento. Programas importantes de la OMS, como el Programa de Precalificaci\u00f3n de Medicamentos, dependen de estas especificaciones de calidad.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1l es el objetivo principal del desarrollo de monograf\u00edas para *La Farmacopea Internacional* seg\u00fan el documento?**\n   - Respuesta: El objetivo principal es asegurar una consulta amplia y transparencia durante el desarrollo de las monograf\u00edas, garantizando que los textos adoptados est\u00e9n disponibles de manera oportuna.\n\n2. **\u00bfQu\u00e9 papel juegan las monograf\u00edas de *La Farmacopea Internacional* en los programas de la OMS, como el Programa de Precalificaci\u00f3n de Medicamentos?**\n   - Respuesta: Las monograf\u00edas proporcionan las especificaciones de calidad necesarias para los medicamentos, que son fundamentales para la eficacia y seguridad de los tratamientos en programas como el de Precalificaci\u00f3n de Medicamentos, as\u00ed como en otras iniciativas gestionadas por organizaciones asociadas.\n\n3. **\u00bfQu\u00e9 organizaciones financian o gestionan programas que dependen de las especificaciones de calidad de *La Farmacopea Internacional*?**\n   - Respuesta: Programas como el de Precalificaci\u00f3n de Medicamentos son financiados por la Fundaci\u00f3n Bill y Melinda Gates y UNITAID, y tambi\u00e9n dependen de la colaboraci\u00f3n con organizaciones como el Fondo de las Naciones Unidas para la Infancia (UNICEF) y el Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria.", "prev_section_summary": "El contenido proporcionado se refiere a un Informe T\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) en la Serie 970, aunque no se incluye informaci\u00f3n espec\u00edfica de la p\u00e1gina 76. A continuaci\u00f3n se presenta un resumen de los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Informe T\u00e9cnico de la OMS**: El documento es parte de una serie que aborda temas relevantes para la salud p\u00fablica y pol\u00edticas de salud.\n2. **Recomendaciones y Conclusiones**: Se espera que el informe contenga recomendaciones espec\u00edficas que podr\u00edan ser \u00fatiles para la implementaci\u00f3n de pol\u00edticas de salud.\n3. **Metodolog\u00eda de Investigaci\u00f3n**: Se indaga sobre los m\u00e9todos utilizados para recopilar datos, lo que es crucial para evaluar la validez de los hallazgos.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la elaboraci\u00f3n del informe.\n- **Serie 970**: Parte de la colecci\u00f3n de informes t\u00e9cnicos de la OMS que abordan diversos temas de salud.\n\n### Contexto General:\nEl informe probablemente se centra en la investigaci\u00f3n cient\u00edfica y las recomendaciones para mejorar la salud p\u00fablica, aunque la falta de contenido espec\u00edfico en la p\u00e1gina 76 limita la informaci\u00f3n disponible sobre los detalles concretos del documento.", "excerpt_keywords": "Keywords: monographs, International Pharmacopoeia, WHO, quality specifications, essential medicines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2a70502c-e3e6-4cc9-9502-33cc9904b57d", "node_type": "4", "metadata": {"page_label": "77", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 1\n\n## Development of monographs for *The International Pharmacopoeia*\n\nThe process described below is designed to ensure wide consultation and transparency during monograph development and that the adopted texts are made available in a timely manner.\n\nProvision of monographs in *The International Pharmacopoeia* provides the quality dimension for the medicines (included on the basis of their efficacy and safety) in the World Health Organization (WHO) Model lists of essential medicines and in WHO treatment guidelines.\n\nMajor WHO programmes such as the Prequalification of Medicines Programme (funded by the Bill & Melinda Gates Foundation and UNITAID) and others funded or managed by partner organizations such as the United Nations Children\u2019s Fund and the Global Fund to Fight AIDS, Tuberculosis and Malaria, rely heavily upon the quality specifications of *The International Pharmacopoeia*.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4baa4054a8b7dd5379b0017cdaa40b5dcc17b7aa6cefe23dd8a41e9c9f3f51da", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 1\n\n## Development of monographs for *The International Pharmacopoeia*\n\nThe process described below is designed to ensure wide consultation and transparency during monograph development and that the adopted texts are made available in a timely manner.\n\nProvision of monographs in *The International Pharmacopoeia* provides the quality dimension for the medicines (included on the basis of their efficacy and safety) in the World Health Organization (WHO) Model lists of essential medicines and in WHO treatment guidelines.\n\nMajor WHO programmes such as the Prequalification of Medicines Programme (funded by the Bill & Melinda Gates Foundation and UNITAID) and others funded or managed by partner organizations such as the United Nations Children\u2019s Fund and the Global Fund to Fight AIDS, Tuberculosis and Malaria, rely heavily upon the quality specifications of *The International Pharmacopoeia*.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 904, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "3c9f397b-a190-4b65-a646-e35703602319": {"__data__": {"id_": "3c9f397b-a190-4b65-a646-e35703602319", "embedding": null, "metadata": {"page_label": "78", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Process: phases in the development of new monographs\n\n*Note:* A \u201cschedule for the adoption process\u201d outlining the development history of a draft monograph is included in each working document that is circulated for comment.\n\n- **Phase 1:** Identify specific pharmaceutical products for which quality control (QC) specifications need to be developed, following confirmation by all WHO parties concerned (including the Department of Essential Medicines and Health Products, specific disease programmes and the Prequalification of Medicines Programme). Establish whether monographs also need to be developed for the active pharmaceutical ingredients (APIs) contained in the pharmaceutical products identified. Update the current work plan on *The International Pharmacopoeia* web site.\n\n- **Phase 2:** Obtain the contact details for the manufacturers of the selected APIs and pharmaceutical products, as applicable, in collaboration with all parties concerned.\n\n- **Phase 3:** Contact manufacturers for provision of QC specifications and samples.\n\n- **Phase 4:** Identify and contact QC laboratories for collaboration in the project (the number of laboratories will depend on how many APIs and pharmaceutical products have been identified in Phase 1).\n\n- **Phase 5:** Make arrangements with the collaborating laboratories for drafting the specifications and undertaking the necessary laboratory work.\n\n- **Phase 6:** Search for information on QC specifications available in the public domain.\n\n- **Phase 7:** Perform laboratory testing, development and validation, if needed, of QC specifications.\n\n- **Phase 8:** Follow the WHO Expert Committee consultative process: mail draft specifications to the Expert Advisory Panel and specialists, provide drafts on the web site.\n\n- **Phase 9:** Contact collaborating manufacturers to ascertain the availability of the respective substances to establish International Chemical Reference Substances (ICRS), as necessary.\n\n- **Phase 10:** Support the WHO host organization (European Directorate for the Quality of Medicines and HealthCare, Council of Europe) responsible for the establishment of ICRS.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento detalla un proceso estructurado en diez fases para el desarrollo de nuevas monograf\u00edas de productos farmac\u00e9uticos, que incluye la identificaci\u00f3n de productos, la colaboraci\u00f3n con fabricantes y laboratorios, la obtenci\u00f3n de especificaciones de control de calidad (QC), y la validaci\u00f3n de estas especificaciones. Este proceso es parte de un esfuerzo m\u00e1s amplio de la OMS para asegurar la calidad de los medicamentos a nivel internacional.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 criterios se utilizan para identificar los productos farmac\u00e9uticos que necesitan especificaciones de control de calidad en la Fase 1?**\n   - Esta pregunta busca entender los factores espec\u00edficos que gu\u00edan la selecci\u00f3n de productos farmac\u00e9uticos para el desarrollo de monograf\u00edas.\n\n2. **\u00bfCu\u00e1l es el papel de los laboratorios de control de calidad en las fases posteriores del proceso de desarrollo de monograf\u00edas?**\n   - Esta pregunta se centra en la colaboraci\u00f3n con laboratorios y c\u00f3mo contribuyen a la elaboraci\u00f3n y validaci\u00f3n de las especificaciones de QC.\n\n3. **\u00bfQu\u00e9 pasos se siguen para asegurar la disponibilidad de sustancias necesarias para establecer Sustancias de Referencia Qu\u00edmica Internacional (ICRS) en la Fase 9?**\n   - Esta pregunta indaga sobre el proceso espec\u00edfico que se lleva a cabo para garantizar que las sustancias requeridas est\u00e9n disponibles para la creaci\u00f3n de ICRS, lo cual es crucial para la estandarizaci\u00f3n y control de calidad.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Desarrollo de Monograf\u00edas:** El proceso de creaci\u00f3n de monograf\u00edas para *La Farmacopea Internacional* busca asegurar una consulta amplia y transparencia, garantizando la disponibilidad oportuna de los textos adoptados.\n2. **Especificaciones de Calidad:** Las monograf\u00edas establecen las especificaciones de calidad para los medicamentos, que son fundamentales para su eficacia y seguridad.\n3. **Medicamentos Esenciales:** Las monograf\u00edas son cruciales para los medicamentos incluidos en las listas de medicamentos esenciales de la OMS y en sus gu\u00edas de tratamiento.\n4. **Programas de la OMS:** Programas importantes, como el Programa de Precalificaci\u00f3n de Medicamentos, dependen de estas especificaciones de calidad.\n\n**Entidades:**\n1. **Organizaci\u00f3n Mundial de la Salud (OMS):** Responsable del desarrollo de las monograf\u00edas y de la provisi\u00f3n de est\u00e1ndares de calidad para medicamentos.\n2. **Fundaci\u00f3n Bill y Melinda Gates:** Financia el Programa de Precalificaci\u00f3n de Medicamentos.\n3. **UNITAID:** Tambi\u00e9n financia el Programa de Precalificaci\u00f3n de Medicamentos.\n4. **Fondo de las Naciones Unidas para la Infancia (UNICEF):** Colabora en programas que dependen de las especificaciones de calidad.\n5. **Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria:** Otro socio que gestiona programas basados en las especificaciones de *La Farmacopea Internacional*.", "excerpt_keywords": "Keywords: monographs, quality control, pharmaceutical products, WHO, International Chemical Reference Substances"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "458e5489-d3fb-42b0-ad91-b1c8d49d50dd", "node_type": "4", "metadata": {"page_label": "78", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Process: phases in the development of new monographs\n\n*Note:* A \u201cschedule for the adoption process\u201d outlining the development history of a draft monograph is included in each working document that is circulated for comment.\n\n- **Phase 1:** Identify specific pharmaceutical products for which quality control (QC) specifications need to be developed, following confirmation by all WHO parties concerned (including the Department of Essential Medicines and Health Products, specific disease programmes and the Prequalification of Medicines Programme). Establish whether monographs also need to be developed for the active pharmaceutical ingredients (APIs) contained in the pharmaceutical products identified. Update the current work plan on *The International Pharmacopoeia* web site.\n\n- **Phase 2:** Obtain the contact details for the manufacturers of the selected APIs and pharmaceutical products, as applicable, in collaboration with all parties concerned.\n\n- **Phase 3:** Contact manufacturers for provision of QC specifications and samples.\n\n- **Phase 4:** Identify and contact QC laboratories for collaboration in the project (the number of laboratories will depend on how many APIs and pharmaceutical products have been identified in Phase 1).\n\n- **Phase 5:** Make arrangements with the collaborating laboratories for drafting the specifications and undertaking the necessary laboratory work.\n\n- **Phase 6:** Search for information on QC specifications available in the public domain.\n\n- **Phase 7:** Perform laboratory testing, development and validation, if needed, of QC specifications.\n\n- **Phase 8:** Follow the WHO Expert Committee consultative process: mail draft specifications to the Expert Advisory Panel and specialists, provide drafts on the web site.\n\n- **Phase 9:** Contact collaborating manufacturers to ascertain the availability of the respective substances to establish International Chemical Reference Substances (ICRS), as necessary.\n\n- **Phase 10:** Support the WHO host organization (European Directorate for the Quality of Medicines and HealthCare, Council of Europe) responsible for the establishment of ICRS.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "d354e21fd646172dd86fd6af16e16e4dd6d6c8f0d91c4c763832a678c26877e9", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Process: phases in the development of new monographs\n\n*Note:* A \u201cschedule for the adoption process\u201d outlining the development history of a draft monograph is included in each working document that is circulated for comment.\n\n- **Phase 1:** Identify specific pharmaceutical products for which quality control (QC) specifications need to be developed, following confirmation by all WHO parties concerned (including the Department of Essential Medicines and Health Products, specific disease programmes and the Prequalification of Medicines Programme). Establish whether monographs also need to be developed for the active pharmaceutical ingredients (APIs) contained in the pharmaceutical products identified. Update the current work plan on *The International Pharmacopoeia* web site.\n\n- **Phase 2:** Obtain the contact details for the manufacturers of the selected APIs and pharmaceutical products, as applicable, in collaboration with all parties concerned.\n\n- **Phase 3:** Contact manufacturers for provision of QC specifications and samples.\n\n- **Phase 4:** Identify and contact QC laboratories for collaboration in the project (the number of laboratories will depend on how many APIs and pharmaceutical products have been identified in Phase 1).\n\n- **Phase 5:** Make arrangements with the collaborating laboratories for drafting the specifications and undertaking the necessary laboratory work.\n\n- **Phase 6:** Search for information on QC specifications available in the public domain.\n\n- **Phase 7:** Perform laboratory testing, development and validation, if needed, of QC specifications.\n\n- **Phase 8:** Follow the WHO Expert Committee consultative process: mail draft specifications to the Expert Advisory Panel and specialists, provide drafts on the web site.\n\n- **Phase 9:** Contact collaborating manufacturers to ascertain the availability of the respective substances to establish International Chemical Reference Substances (ICRS), as necessary.\n\n- **Phase 10:** Support the WHO host organization (European Directorate for the Quality of Medicines and HealthCare, Council of Europe) responsible for the establishment of ICRS.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2140, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d79c1417-8b57-4088-8e6d-682978e07b40": {"__data__": {"id_": "d79c1417-8b57-4088-8e6d-682978e07b40", "embedding": null, "metadata": {"page_label": "79", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "- **Phase 11**: Collect and collate the comments received during the global consultative process.\n- **Phase 12**: Discuss comments received during the consultation process with contract laboratories, WHO collaborating centres, and if relevant with the ICRS host organization; conduct additional laboratory testing to add, verify and/or validate specifications.\n- **Phase 13**: Discuss the comments received during the consultation process and test results received as feedback from the collaborating laboratories in an informal consultation with experts and specialists.\n- **Phase 14**: Recirculate draft monograph extensively for comments.\n- **Phase 15**: Repeat Phases 8\u201315, until the agreed draft is suitable for adoption.\n- **Phase 16**: Present the drafts to the WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) for possible formal adoption. If not adopted repeat Phases 8\u201314 as often as necessary. If the draft is adopted, proceed to Phase 17.\n- **Phase 17**: Incorporate all changes agreed during the discussion leading to adoption together with any editorial corrections.\n- **Phase 18**: Where necessary, also take account of any further comments that may be received due to comment deadlines for recirculated texts (Phase 12 and subsequent) falling shortly after the relevant consultation or ECSPP meeting.\n- **Phase 19**: In all cases, confirm the amended text by correspondence with the relevant experts and/or contract laboratory before making it available on *The International Pharmacopoeia* web site.\n- **Phase 20**: Make \u201cfinal texts\u201d available on *The International Pharmacopoeia* web site to provide users, such as prequalification assessors and manufacturers, with the approved specifications in advance of the next publication date.\n- **Phase 21**: Include in *The International Pharmacopoeia*.\n\nThe \u201cfinal texts\u201d on *The International Pharmacopoeia* web site for the monographs adopted at the October 2011 meeting, for example, are prefaced with the following wording: \u201cThis monograph was adopted at the Forty-sixth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2011 for inclusion in *The International Pharmacopoeia*\u201d.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento describe un proceso estructurado en varias fases para la elaboraci\u00f3n y adopci\u00f3n de monograf\u00edas en *The International Pharmacopoeia* por parte de la OMS. Este proceso incluye la recopilaci\u00f3n de comentarios, discusiones con laboratorios y expertos, pruebas de laboratorio, y la recirculaci\u00f3n de borradores para obtener m\u00e1s comentarios. Finalmente, se presentan los borradores al Comit\u00e9 de Expertos de la OMS para su adopci\u00f3n formal, y se realizan correcciones editoriales antes de hacer disponibles los textos finales en el sitio web de la farmacopoeia.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 criterios se utilizan para determinar si un borrador de monograf\u00eda es adecuado para su adopci\u00f3n en el Comit\u00e9 de Expertos de la OMS?**\n   - Esta pregunta busca entender los est\u00e1ndares y criterios espec\u00edficos que se aplican durante la evaluaci\u00f3n de los borradores, lo cual no se detalla en el contexto.\n\n2. **\u00bfQu\u00e9 tipo de comentarios se consideran durante el proceso de consulta global y c\u00f3mo se priorizan estos comentarios en las fases posteriores?**\n   - Esta pregunta se centra en la naturaleza de los comentarios recibidos y el proceso de priorizaci\u00f3n, lo que podr\u00eda no estar expl\u00edcitamente mencionado en el texto.\n\n3. **\u00bfC\u00f3mo se asegura la transparencia y la trazabilidad de los cambios realizados en las monograf\u00edas a lo largo de las fases del proceso?**\n   - Esta pregunta indaga sobre los mecanismos implementados para documentar y comunicar los cambios en las monograf\u00edas, un aspecto que podr\u00eda no estar claramente abordado en el contexto proporcionado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento describe un proceso detallado en diez fases para el desarrollo de nuevas monograf\u00edas de productos farmac\u00e9uticos, con el objetivo de establecer especificaciones de control de calidad (QC) que aseguren la calidad de los medicamentos a nivel internacional. A continuaci\u00f3n se presentan los temas clave y las entidades involucradas:\n\n#### Temas Clave:\n1. **Identificaci\u00f3n de Productos:** La primera fase implica la selecci\u00f3n de productos farmac\u00e9uticos que requieren especificaciones de QC, en colaboraci\u00f3n con diversas partes interesadas de la OMS.\n2. **Colaboraci\u00f3n con Fabricantes:** Se establece un proceso para obtener informaci\u00f3n y muestras de los fabricantes de los productos y principios activos seleccionados.\n3. **Laboratorios de Control de Calidad:** Se identifican y contactan laboratorios para colaborar en la elaboraci\u00f3n y validaci\u00f3n de las especificaciones de QC.\n4. **Desarrollo y Validaci\u00f3n de Especificaciones:** Se realizan pruebas de laboratorio y se desarrollan especificaciones, que pueden requerir validaci\u00f3n adicional.\n5. **Proceso Consultivo de la OMS:** Se sigue un proceso consultivo que incluye la revisi\u00f3n de borradores por parte de paneles de expertos y la publicaci\u00f3n de documentos en l\u00ednea.\n6. **Establecimiento de Sustancias de Referencia:** Se asegura la disponibilidad de sustancias necesarias para crear Sustancias de Referencia Qu\u00edmica Internacional (ICRS).\n\n#### Entidades Involucradas:\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Coordinadora del proceso y responsable de la calidad de los medicamentos.\n- **Departamento de Medicamentos Esenciales y Productos de Salud de la OMS:** Participa en la identificaci\u00f3n de productos.\n- **Programas de Enfermedades Espec\u00edficas y Programa de Precalificaci\u00f3n de Medicamentos:** Colaboran en la confirmaci\u00f3n de productos.\n- **Fabricantes de Productos Farmac\u00e9uticos y APIs:** Proporcionan informaci\u00f3n y muestras necesarias para el desarrollo de especificaciones.\n- **Laboratorios de Control de Calidad:** Colaboran en la elaboraci\u00f3n y validaci\u00f3n de especificaciones de QC.\n- **Comit\u00e9 de Expertos de la OMS:** Revisa y proporciona retroalimentaci\u00f3n sobre las especificaciones propuestas.\n\nEste proceso es fundamental para garantizar que los medicamentos cumplan con est\u00e1ndares de calidad internacionales, contribuyendo as\u00ed a la seguridad y eficacia de los tratamientos farmacol\u00f3gicos.", "excerpt_keywords": "Keywords: WHO, International Pharmacopoeia, monographs, pharmaceutical preparations, quality control"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73f84789-0869-46f4-988c-7d5c04dbe2db", "node_type": "4", "metadata": {"page_label": "79", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "- **Phase 11**: Collect and collate the comments received during the global consultative process.\n- **Phase 12**: Discuss comments received during the consultation process with contract laboratories, WHO collaborating centres, and if relevant with the ICRS host organization; conduct additional laboratory testing to add, verify and/or validate specifications.\n- **Phase 13**: Discuss the comments received during the consultation process and test results received as feedback from the collaborating laboratories in an informal consultation with experts and specialists.\n- **Phase 14**: Recirculate draft monograph extensively for comments.\n- **Phase 15**: Repeat Phases 8\u201315, until the agreed draft is suitable for adoption.\n- **Phase 16**: Present the drafts to the WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) for possible formal adoption. If not adopted repeat Phases 8\u201314 as often as necessary. If the draft is adopted, proceed to Phase 17.\n- **Phase 17**: Incorporate all changes agreed during the discussion leading to adoption together with any editorial corrections.\n- **Phase 18**: Where necessary, also take account of any further comments that may be received due to comment deadlines for recirculated texts (Phase 12 and subsequent) falling shortly after the relevant consultation or ECSPP meeting.\n- **Phase 19**: In all cases, confirm the amended text by correspondence with the relevant experts and/or contract laboratory before making it available on *The International Pharmacopoeia* web site.\n- **Phase 20**: Make \u201cfinal texts\u201d available on *The International Pharmacopoeia* web site to provide users, such as prequalification assessors and manufacturers, with the approved specifications in advance of the next publication date.\n- **Phase 21**: Include in *The International Pharmacopoeia*.\n\nThe \u201cfinal texts\u201d on *The International Pharmacopoeia* web site for the monographs adopted at the October 2011 meeting, for example, are prefaced with the following wording: \u201cThis monograph was adopted at the Forty-sixth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2011 for inclusion in *The International Pharmacopoeia*\u201d.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "263ad1f3b8c9f7a1b84557d69338d3ad562e42abf058fa731324077488ae5df5", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "- **Phase 11**: Collect and collate the comments received during the global consultative process.\n- **Phase 12**: Discuss comments received during the consultation process with contract laboratories, WHO collaborating centres, and if relevant with the ICRS host organization; conduct additional laboratory testing to add, verify and/or validate specifications.\n- **Phase 13**: Discuss the comments received during the consultation process and test results received as feedback from the collaborating laboratories in an informal consultation with experts and specialists.\n- **Phase 14**: Recirculate draft monograph extensively for comments.\n- **Phase 15**: Repeat Phases 8\u201315, until the agreed draft is suitable for adoption.\n- **Phase 16**: Present the drafts to the WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) for possible formal adoption. If not adopted repeat Phases 8\u201314 as often as necessary. If the draft is adopted, proceed to Phase 17.\n- **Phase 17**: Incorporate all changes agreed during the discussion leading to adoption together with any editorial corrections.\n- **Phase 18**: Where necessary, also take account of any further comments that may be received due to comment deadlines for recirculated texts (Phase 12 and subsequent) falling shortly after the relevant consultation or ECSPP meeting.\n- **Phase 19**: In all cases, confirm the amended text by correspondence with the relevant experts and/or contract laboratory before making it available on *The International Pharmacopoeia* web site.\n- **Phase 20**: Make \u201cfinal texts\u201d available on *The International Pharmacopoeia* web site to provide users, such as prequalification assessors and manufacturers, with the approved specifications in advance of the next publication date.\n- **Phase 21**: Include in *The International Pharmacopoeia*.\n\nThe \u201cfinal texts\u201d on *The International Pharmacopoeia* web site for the monographs adopted at the October 2011 meeting, for example, are prefaced with the following wording: \u201cThis monograph was adopted at the Forty-sixth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2011 for inclusion in *The International Pharmacopoeia*\u201d.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2221, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "0f05b645-e441-4785-9662-72a0b9e59f26": {"__data__": {"id_": "0f05b645-e441-4785-9662-72a0b9e59f26", "embedding": null, "metadata": {"page_label": "80", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones sobre pr\u00e1cticas de salud. Sin embargo, el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentadas en el informe WHO - Technical Report Series 970?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir recomendaciones sobre pol\u00edticas de salud, resultados de investigaciones o gu\u00edas para la pr\u00e1ctica cl\u00ednica.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en el informe y c\u00f3mo se relacionan con las tendencias actuales en salud global?**\n   - Esta pregunta se centra en la relevancia del informe en el contexto de los desaf\u00edos actuales en salud p\u00fablica, como enfermedades infecciosas, salud mental, o sistemas de salud.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en la investigaci\u00f3n presentada en el informe y c\u00f3mo se validaron los resultados?**\n   - Esta pregunta indaga sobre la rigurosidad cient\u00edfica del informe, buscando detalles sobre los m\u00e9todos de investigaci\u00f3n y la validez de los datos presentados.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que podr\u00eda no estar disponible en otras fuentes, dado que el contenido del informe no se ha proporcionado.", "prev_section_summary": "### Temas Clave\n\n1. **Proceso de Elaboraci\u00f3n de Monograf\u00edas**: Se describe un proceso estructurado en varias fases para la creaci\u00f3n y adopci\u00f3n de monograf\u00edas en *The International Pharmacopoeia* por parte de la OMS.\n\n2. **Recopilaci\u00f3n de Comentarios**: La fase inicial implica la recolecci\u00f3n y organizaci\u00f3n de comentarios recibidos durante un proceso de consulta global.\n\n3. **Discusi\u00f3n y Validaci\u00f3n**: Se llevan a cabo discusiones sobre los comentarios y resultados de pruebas de laboratorio con laboratorios contratados y centros colaboradores de la OMS.\n\n4. **Recirculaci\u00f3n de Borradores**: Los borradores de las monograf\u00edas se recirculan para obtener m\u00e1s comentarios, y este proceso se repite hasta que se considera que el borrador es adecuado para su adopci\u00f3n.\n\n5. **Adopci\u00f3n Formal**: Los borradores se presentan al Comit\u00e9 de Expertos de la OMS para su posible adopci\u00f3n formal, y si no son adoptados, se repiten ciertas fases del proceso.\n\n6. **Incorporaci\u00f3n de Cambios**: Se incorporan todos los cambios acordados y correcciones editoriales antes de hacer disponibles los textos finales.\n\n7. **Disponibilidad de Textos Finales**: Los textos finales se publican en el sitio web de *The International Pharmacopoeia* para su acceso por parte de usuarios como evaluadores de precalificaci\u00f3n y fabricantes.\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la elaboraci\u00f3n y adopci\u00f3n de las monograf\u00edas.\n- **ECSPP (Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas)**: Comit\u00e9 que eval\u00faa y adopta formalmente las monograf\u00edas.\n- **ICRS (Sistema Internacional de Referencia de Sustancias)**: Organizaci\u00f3n que puede estar involucrada en el proceso de consulta.\n- **Laboratorios Contratados y Centros Colaboradores**: Entidades que participan en la discusi\u00f3n y validaci\u00f3n de las especificaciones.\n\nEste resumen destaca la estructura y los pasos del proceso de elaboraci\u00f3n de monograf\u00edas, as\u00ed como las entidades involucradas en el mismo.", "excerpt_keywords": "Keywords: OMS, monograf\u00edas, salud p\u00fablica, farmacopoeia, validaci\u00f3n"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "11af49c1-7fd9-4420-9edb-29564c85e0f9", "node_type": "4", "metadata": {"page_label": "80", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "d492a6eaa41d0de67a60bb0fef0ef2df15e34b224b2c41873ceac66411b17088", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "448f1cf9-0007-4839-9a5a-2d597db9a610": {"__data__": {"id_": "448f1cf9-0007-4839-9a5a-2d597db9a610", "embedding": null, "metadata": {"page_label": "81", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 2\n\n## WHO good manufacturing practices: water for pharmaceutical use\n\n1. **Introduction**  \n   1.1 Scope of the document - 68  \n   1.2 Background to water requirements and uses - 68  \n   1.3 Applicable guides - 69  \n\n2. **General principles for pharmaceutical water systems** - 69  \n\n3. **Water quality specifications**  \n   3.1 General - 70  \n   3.2 Drinking-water - 70  \n   3.3 Bulk purified water - 71  \n   3.4 Bulk highly purified water - 71  \n   3.5 Bulk water for injections - 72  \n   3.6 Other grades of water - 72  \n\n4. **Application of specific types of water to processes and dosage forms** - 72  \n\n5. **Water purification systems**  \n   5.1 General considerations - 73  \n   5.2 Production of drinking-water - 74  \n   5.3 Production of purified water - 76  \n   5.4 Production of highly purified water - 77  \n   5.5 Production of water for injection(s) - 77  \n\n6. **Water storage and distribution systems**  \n   6.1 General - 78  \n   6.2 Materials that come into contact with systems for water for pharmaceutical use - 78  \n   6.3 System sanitization and bioburden control - 80  \n   6.4 Storage vessel requirements - 80  \n   6.5 Requirements for water distribution pipework - 81  \n\n7. **Operational considerations**  \n   7.1 Start-up and commissioning of water systems - 83  \n   7.2 Qualification - 83  \n   7.3 Continuous system monitoring - 85  \n   7.4 Maintenance of water systems - 86  \n   7.5 System reviews - 86  \n\n8. **Inspection of water systems** - 87  \n\n**Further reading** - 88  \n\n----\n\n1 The current document is a revision of WHO good manufacturing practices: water for pharmaceutical use, previously published in WHO Technical Report Series, No. 929, Annex 3, 2005.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento es una revisi\u00f3n de las buenas pr\u00e1cticas de fabricaci\u00f3n de la OMS relacionadas con el agua para uso farmac\u00e9utico. Se detalla la importancia del agua en la producci\u00f3n farmac\u00e9utica, especificando diferentes tipos de agua y sus aplicaciones, as\u00ed como los sistemas de purificaci\u00f3n, almacenamiento y distribuci\u00f3n. Tambi\u00e9n se abordan consideraciones operativas y de inspecci\u00f3n para garantizar la calidad y seguridad del agua utilizada en la industria farmac\u00e9utica.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son las especificaciones de calidad del agua para inyecciones seg\u00fan el documento?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre los est\u00e1ndares y requisitos que debe cumplir el agua destinada a inyecciones, que es crucial para la seguridad de los productos farmac\u00e9uticos.\n\n2. **\u00bfQu\u00e9 materiales se recomiendan para los sistemas de almacenamiento y distribuci\u00f3n de agua para uso farmac\u00e9utico?**\n   - Esta pregunta se centra en los materiales que deben utilizarse en los sistemas que entran en contacto con el agua, lo cual es fundamental para evitar la contaminaci\u00f3n y asegurar la calidad del agua.\n\n3. **\u00bfCu\u00e1les son las consideraciones operativas clave para el inicio y la puesta en marcha de sistemas de agua en la industria farmac\u00e9utica?**\n   - Esta pregunta busca detalles sobre los pasos y procedimientos necesarios para garantizar que los sistemas de agua est\u00e9n correctamente configurados y operativos desde el principio, lo que es esencial para el cumplimiento de las buenas pr\u00e1cticas de fabricaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n#### Temas Clave:\n1. **Salud P\u00fablica**: El informe probablemente aborda cuestiones relacionadas con la salud p\u00fablica, incluyendo pol\u00edticas, pr\u00e1cticas y recomendaciones para mejorar la salud global.\n2. **Investigaci\u00f3n M\u00e9dica**: Es probable que se presenten hallazgos de investigaciones recientes en el campo de la medicina y la salud.\n3. **Recomendaciones de Salud**: El informe podr\u00eda incluir gu\u00edas y recomendaciones para profesionales de la salud y responsables de pol\u00edticas.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe, que se enfoca en la salud global y la promoci\u00f3n de pr\u00e1cticas de salud efectivas.\n- **Investigadores y Expertos en Salud**: Posiblemente, el informe incluye contribuciones de expertos en diversas \u00e1reas de la salud y la medicina.\n\nEste resumen proporciona una visi\u00f3n general de los temas y entidades que podr\u00edan estar presentes en el informe, a pesar de la falta de contenido espec\u00edfico en el extracto proporcionado.", "excerpt_keywords": "Keywords: pharmaceutical water, good manufacturing practices, water quality specifications, water purification systems, operational considerations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54ef2f10-2c38-4b1e-a624-4aa7effec6aa", "node_type": "4", "metadata": {"page_label": "81", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 2\n\n## WHO good manufacturing practices: water for pharmaceutical use\n\n1. **Introduction**  \n   1.1 Scope of the document - 68  \n   1.2 Background to water requirements and uses - 68  \n   1.3 Applicable guides - 69  \n\n2. **General principles for pharmaceutical water systems** - 69  \n\n3. **Water quality specifications**  \n   3.1 General - 70  \n   3.2 Drinking-water - 70  \n   3.3 Bulk purified water - 71  \n   3.4 Bulk highly purified water - 71  \n   3.5 Bulk water for injections - 72  \n   3.6 Other grades of water - 72  \n\n4. **Application of specific types of water to processes and dosage forms** - 72  \n\n5. **Water purification systems**  \n   5.1 General considerations - 73  \n   5.2 Production of drinking-water - 74  \n   5.3 Production of purified water - 76  \n   5.4 Production of highly purified water - 77  \n   5.5 Production of water for injection(s) - 77  \n\n6. **Water storage and distribution systems**  \n   6.1 General - 78  \n   6.2 Materials that come into contact with systems for water for pharmaceutical use - 78  \n   6.3 System sanitization and bioburden control - 80  \n   6.4 Storage vessel requirements - 80  \n   6.5 Requirements for water distribution pipework - 81  \n\n7. **Operational considerations**  \n   7.1 Start-up and commissioning of water systems - 83  \n   7.2 Qualification - 83  \n   7.3 Continuous system monitoring - 85  \n   7.4 Maintenance of water systems - 86  \n   7.5 System reviews - 86  \n\n8. **Inspection of water systems** - 87  \n\n**Further reading** - 88  \n\n----\n\n1 The current document is a revision of WHO good manufacturing practices: water for pharmaceutical use, previously published in WHO Technical Report Series, No. 929, Annex 3, 2005.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "9398c5f53e524a8898bad536c4b784e35781fea3e3c66406fbabb677a0a61283", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 2\n\n## WHO good manufacturing practices: water for pharmaceutical use\n\n1. **Introduction**  \n   1.1 Scope of the document - 68  \n   1.2 Background to water requirements and uses - 68  \n   1.3 Applicable guides - 69  \n\n2. **General principles for pharmaceutical water systems** - 69  \n\n3. **Water quality specifications**  \n   3.1 General - 70  \n   3.2 Drinking-water - 70  \n   3.3 Bulk purified water - 71  \n   3.4 Bulk highly purified water - 71  \n   3.5 Bulk water for injections - 72  \n   3.6 Other grades of water - 72  \n\n4. **Application of specific types of water to processes and dosage forms** - 72  \n\n5. **Water purification systems**  \n   5.1 General considerations - 73  \n   5.2 Production of drinking-water - 74  \n   5.3 Production of purified water - 76  \n   5.4 Production of highly purified water - 77  \n   5.5 Production of water for injection(s) - 77  \n\n6. **Water storage and distribution systems**  \n   6.1 General - 78  \n   6.2 Materials that come into contact with systems for water for pharmaceutical use - 78  \n   6.3 System sanitization and bioburden control - 80  \n   6.4 Storage vessel requirements - 80  \n   6.5 Requirements for water distribution pipework - 81  \n\n7. **Operational considerations**  \n   7.1 Start-up and commissioning of water systems - 83  \n   7.2 Qualification - 83  \n   7.3 Continuous system monitoring - 85  \n   7.4 Maintenance of water systems - 86  \n   7.5 System reviews - 86  \n\n8. **Inspection of water systems** - 87  \n\n**Further reading** - 88  \n\n----\n\n1 The current document is a revision of WHO good manufacturing practices: water for pharmaceutical use, previously published in WHO Technical Report Series, No. 929, Annex 3, 2005.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1694, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "cccf2d91-ae6c-4b40-83b9-1a2998333833": {"__data__": {"id_": "cccf2d91-ae6c-4b40-83b9-1a2998333833", "embedding": null, "metadata": {"page_label": "82", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\n## 1.1 Scope of the document\n\n1.1.1 The guidance contained in this document is intended to provide information about the available specifications for water for pharmaceutical use (WPU), guidance about which quality of water to use for specific applications, such as the manufacture of active pharmaceutical ingredients (APIs) and dosage forms, and to provide guidance on good manufacturing practices (GMP) regarding the design, installation and operation of pharmaceutical water systems. Although the focus of this document is on water for pharmaceutical applications, the guidelines may also be relevant to other industrial or specific uses where the specifications and practices can be applied.\n\n*Note:* This document does not cover water for administration to patients in the formulated state or the use of small quantities of water in pharmacies to compound individually prescribed medicines.\n\n1.1.2 The GMP guidance for WPU contained in this document is intended to be supplementary to the general GMP guidelines for pharmaceutical products published by WHO (*WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report.* Geneva, World Health Organization, 2003 (WHO Technical Report Series, No. 908), Annex 4).\n\n1.1.3 This document refers to available specifications, such as the pharmacopoeias and industry guidance for the use, production, storage and distribution of water in bulk form. In order to avoid confusion it does not attempt to duplicate such material.\n\n1.1.4 The guidance provided in this document can be used in whole or in part as appropriate to the application under consideration.\n\n1.1.5 Where subtle points of difference exist between pharmacopoeial specifications, the manufacturer will be expected to decide which option to choose in accordance with the related marketing authorization submitted to the national medicines regulatory authority.\n\n## 1.2 Background to water requirements and uses\n\n1.2.1 Water is the most widely used substance, raw material or starting material in the production, processing and formulation of pharmaceutical products. It has unique chemical properties due to its polarity and hydrogen bonds. This means it is able to dissolve, absorb, adsorb or suspend many different compounds. These include contaminants that may represent hazards in themselves or that may be able to react with intended product substances, resulting in hazards to health.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Alcance del documento**: Este documento proporciona directrices sobre las especificaciones del agua para uso farmac\u00e9utico (WPU), incluyendo la calidad del agua necesaria para la fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (APIs) y formas de dosificaci\u00f3n. Tambi\u00e9n aborda las buenas pr\u00e1cticas de manufactura (GMP) relacionadas con el dise\u00f1o, instalaci\u00f3n y operaci\u00f3n de sistemas de agua farmac\u00e9utica.\n\n2. **Relevancia del agua en la industria farmac\u00e9utica**: El agua es un componente esencial en la producci\u00f3n y formulaci\u00f3n de productos farmac\u00e9uticos debido a sus propiedades qu\u00edmicas \u00fanicas. Su capacidad para disolver y suspender compuestos la convierte en un material cr\u00edtico, aunque tambi\u00e9n puede ser un veh\u00edculo para contaminantes que representan riesgos para la salud.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de aplicaciones farmac\u00e9uticas requieren diferentes calidades de agua seg\u00fan el documento?**\n   - El documento proporciona orientaci\u00f3n sobre qu\u00e9 calidad de agua utilizar para aplicaciones espec\u00edficas, como la fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (APIs) y formas de dosificaci\u00f3n, aunque no detalla cada aplicaci\u00f3n espec\u00edfica.\n\n2. **\u00bfC\u00f3mo se espera que los fabricantes manejen las diferencias sutiles entre las especificaciones farmacop\u00e9uticas?**\n   - Se espera que los fabricantes decidan qu\u00e9 opci\u00f3n elegir en funci\u00f3n de las diferencias sutiles entre las especificaciones farmacop\u00e9uticas, de acuerdo con la autorizaci\u00f3n de comercializaci\u00f3n relacionada presentada a la autoridad reguladora nacional de medicamentos.\n\n3. **\u00bfQu\u00e9 aspectos de las buenas pr\u00e1cticas de manufactura (GMP) se abordan en relaci\u00f3n con el agua para uso farmac\u00e9utico?**\n   - El documento ofrece directrices sobre las buenas pr\u00e1cticas de manufactura (GMP) espec\u00edficamente para el agua para uso farmac\u00e9utico, que son complementarias a las directrices generales de GMP para productos farmac\u00e9uticos publicadas por la OMS. Esto incluye aspectos del dise\u00f1o, instalaci\u00f3n y operaci\u00f3n de sistemas de agua farmac\u00e9utica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO good manufacturing practices: water for pharmaceutical use\" aborda las buenas pr\u00e1cticas de fabricaci\u00f3n relacionadas con el agua utilizada en la industria farmac\u00e9utica. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n#### Temas Clave:\n1. **Introducci\u00f3n**: Se establece el alcance del documento y se proporciona un contexto sobre los requisitos y usos del agua en la producci\u00f3n farmac\u00e9utica.\n2. **Principios Generales**: Se describen los principios fundamentales que deben seguirse en los sistemas de agua farmac\u00e9utica.\n3. **Especificaciones de Calidad del Agua**: Se detallan las diferentes categor\u00edas de agua (agua potable, agua purificada, agua altamente purificada, agua para inyecciones, entre otros) y sus respectivas especificaciones de calidad.\n4. **Aplicaciones de Agua**: Se discuten las aplicaciones espec\u00edficas de los diferentes tipos de agua en procesos y formas de dosificaci\u00f3n.\n5. **Sistemas de Purificaci\u00f3n de Agua**: Se abordan las consideraciones generales y los m\u00e9todos para la producci\u00f3n de los distintos tipos de agua.\n6. **Almacenamiento y Distribuci\u00f3n**: Se analizan los sistemas de almacenamiento y distribuci\u00f3n, incluyendo los materiales recomendados y los requisitos para evitar la contaminaci\u00f3n.\n7. **Consideraciones Operativas**: Se describen los procedimientos para la puesta en marcha, calificaci\u00f3n, monitoreo continuo, mantenimiento y revisi\u00f3n de los sistemas de agua.\n8. **Inspecci\u00f3n de Sistemas de Agua**: Se menciona la importancia de la inspecci\u00f3n para garantizar la calidad y seguridad del agua utilizada.\n\n#### Entidades:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que establece las buenas pr\u00e1cticas de fabricaci\u00f3n.\n- **Agua para Uso Farmac\u00e9utico**: Categor\u00eda principal del documento, que incluye diferentes tipos de agua y sus especificaciones.\n- **Sistemas de Purificaci\u00f3n**: Infraestructura necesaria para garantizar la calidad del agua.\n- **Materiales de Contacto**: Materiales que deben ser utilizados en los sistemas de almacenamiento y distribuci\u00f3n para evitar la contaminaci\u00f3n.\n\nEste resumen proporciona una visi\u00f3n general de los aspectos m\u00e1s importantes del documento, destacando su enfoque en la calidad y seguridad del agua en la producci\u00f3n farmac\u00e9utica.", "excerpt_keywords": "Keywords: water for pharmaceutical use, good manufacturing practices, active pharmaceutical ingredients, quality specifications, contamination hazards"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6e773651-0dd8-4438-8f09-dc5e0be2aa18", "node_type": "4", "metadata": {"page_label": "82", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\n## 1.1 Scope of the document\n\n1.1.1 The guidance contained in this document is intended to provide information about the available specifications for water for pharmaceutical use (WPU), guidance about which quality of water to use for specific applications, such as the manufacture of active pharmaceutical ingredients (APIs) and dosage forms, and to provide guidance on good manufacturing practices (GMP) regarding the design, installation and operation of pharmaceutical water systems. Although the focus of this document is on water for pharmaceutical applications, the guidelines may also be relevant to other industrial or specific uses where the specifications and practices can be applied.\n\n*Note:* This document does not cover water for administration to patients in the formulated state or the use of small quantities of water in pharmacies to compound individually prescribed medicines.\n\n1.1.2 The GMP guidance for WPU contained in this document is intended to be supplementary to the general GMP guidelines for pharmaceutical products published by WHO (*WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report.* Geneva, World Health Organization, 2003 (WHO Technical Report Series, No. 908), Annex 4).\n\n1.1.3 This document refers to available specifications, such as the pharmacopoeias and industry guidance for the use, production, storage and distribution of water in bulk form. In order to avoid confusion it does not attempt to duplicate such material.\n\n1.1.4 The guidance provided in this document can be used in whole or in part as appropriate to the application under consideration.\n\n1.1.5 Where subtle points of difference exist between pharmacopoeial specifications, the manufacturer will be expected to decide which option to choose in accordance with the related marketing authorization submitted to the national medicines regulatory authority.\n\n## 1.2 Background to water requirements and uses\n\n1.2.1 Water is the most widely used substance, raw material or starting material in the production, processing and formulation of pharmaceutical products. It has unique chemical properties due to its polarity and hydrogen bonds. This means it is able to dissolve, absorb, adsorb or suspend many different compounds. These include contaminants that may represent hazards in themselves or that may be able to react with intended product substances, resulting in hazards to health.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "58ac3dd310e8133ca877c38d7fbb416988ff2d2c53a8ff822160298cc3ee19a4", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 1. Introduction\n\n## 1.1 Scope of the document\n\n1.1.1 The guidance contained in this document is intended to provide information about the available specifications for water for pharmaceutical use (WPU), guidance about which quality of water to use for specific applications, such as the manufacture of active pharmaceutical ingredients (APIs) and dosage forms, and to provide guidance on good manufacturing practices (GMP) regarding the design, installation and operation of pharmaceutical water systems. Although the focus of this document is on water for pharmaceutical applications, the guidelines may also be relevant to other industrial or specific uses where the specifications and practices can be applied.\n\n*Note:* This document does not cover water for administration to patients in the formulated state or the use of small quantities of water in pharmacies to compound individually prescribed medicines.\n\n1.1.2 The GMP guidance for WPU contained in this document is intended to be supplementary to the general GMP guidelines for pharmaceutical products published by WHO (*WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report.* Geneva, World Health Organization, 2003 (WHO Technical Report Series, No. 908), Annex 4).\n\n1.1.3 This document refers to available specifications, such as the pharmacopoeias and industry guidance for the use, production, storage and distribution of water in bulk form. In order to avoid confusion it does not attempt to duplicate such material.\n\n1.1.4 The guidance provided in this document can be used in whole or in part as appropriate to the application under consideration.\n\n1.1.5 Where subtle points of difference exist between pharmacopoeial specifications, the manufacturer will be expected to decide which option to choose in accordance with the related marketing authorization submitted to the national medicines regulatory authority.\n\n## 1.2 Background to water requirements and uses\n\n1.2.1 Water is the most widely used substance, raw material or starting material in the production, processing and formulation of pharmaceutical products. It has unique chemical properties due to its polarity and hydrogen bonds. This means it is able to dissolve, absorb, adsorb or suspend many different compounds. These include contaminants that may represent hazards in themselves or that may be able to react with intended product substances, resulting in hazards to health.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2453, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "3f078a28-a949-44fb-9963-569912012378": {"__data__": {"id_": "3f078a28-a949-44fb-9963-569912012378", "embedding": null, "metadata": {"page_label": "83", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 1.2.2\n\nControl of the quality of water throughout the production, storage and distribution processes, including microbiological and chemical quality, is a major concern. Unlike other product and process ingredients, water is usually drawn from a system on demand, and is not subject to testing and batch or lot release before use. Assurance of quality to meet the on-demand expectation is, therefore, essential. Additionally, certain microbiological tests may require periods of incubation and, therefore, the results are likely to lag behind the water use.\n\n## 1.2.3\n\nControl of the microbiological quality of WPU is a high priority. Some types of microorganism may proliferate in water treatment components and in the storage and distribution systems. It is crucial to minimize microbial contamination by proper design of the system, periodic sanitization and by taking appropriate measures to prevent microbial proliferation.\n\n## 1.2.4\n\nDifferent grades of water quality are required depending on the route of administration of the pharmaceutical products. Other sources of guidance about different grades of water can be found in pharmacopoeias and related documents.\n\n## 1.3 Applicable guides\n\n### 1.3.1\n\nIn addition to the specific guidance provided in this document, the Further reading section includes some relevant publications that can serve as additional background material when planning, installing and using systems intended to provide WPU.\n\n# 2. General principles for pharmaceutical water systems\n\n## 2.1\n\nPharmaceutical water production, storage and distribution systems should be designed, installed, commissioned, qualified and maintained to ensure the reliable production of water of an appropriate quality. It is necessary to validate the water production process to ensure the water generated, stored and distributed is not beyond the designed capacity and meets its specifications.\n\n## 2.2\n\nThe capacity of the system should be designed to meet the average and the peak flow demand of the current operation. If necessary, depending on planned future demands, the system should be designed to permit increases in the capacity or designed to permit modification. All systems, regardless of their size and capacity, should have appropriate recirculation and turnover to assure the system is well controlled chemically and microbiologically.\n\n## 2.3\n\nThe use of the systems following initial validation (installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ)) and after any planned and unplanned maintenance or modification work should be approved by the quality assurance (QA) department using change control documentation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Control de la calidad del agua**: El control de la calidad del agua en los procesos de producci\u00f3n, almacenamiento y distribuci\u00f3n es fundamental, ya que el agua se utiliza bajo demanda y no se somete a pruebas de lotes antes de su uso. Esto implica que se deben implementar medidas para asegurar la calidad microbiol\u00f3gica y qu\u00edmica del agua.\n\n2. **Importancia de la calidad microbiol\u00f3gica**: La calidad microbiol\u00f3gica del agua para uso farmac\u00e9utico (WPU) es una prioridad alta, ya que ciertos microorganismos pueden proliferar en los sistemas de tratamiento y distribuci\u00f3n. Se deben tomar medidas adecuadas para minimizar la contaminaci\u00f3n microbiana.\n\n3. **Dise\u00f1o y mantenimiento de sistemas de agua farmac\u00e9utica**: Los sistemas de producci\u00f3n, almacenamiento y distribuci\u00f3n de agua farmac\u00e9utica deben ser dise\u00f1ados y mantenidos para garantizar la producci\u00f3n confiable de agua de calidad adecuada. Esto incluye la validaci\u00f3n del proceso de producci\u00f3n de agua y la capacidad del sistema para satisfacer la demanda.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las medidas espec\u00edficas que se deben implementar para minimizar la contaminaci\u00f3n microbiana en los sistemas de tratamiento de agua?**\n   - Esta pregunta busca detalles sobre las pr\u00e1cticas de dise\u00f1o y sanitizaci\u00f3n que no se mencionan expl\u00edcitamente en el texto.\n\n2. **\u00bfQu\u00e9 criterios se utilizan para determinar las diferentes calidades de agua requeridas seg\u00fan la ruta de administraci\u00f3n de los productos farmac\u00e9uticos?**\n   - La respuesta a esta pregunta podr\u00eda incluir informaci\u00f3n sobre normativas espec\u00edficas o gu\u00edas que no se detallan en el documento.\n\n3. **\u00bfQu\u00e9 tipo de documentaci\u00f3n de control de cambios es necesaria para la aprobaci\u00f3n del uso de sistemas de agua despu\u00e9s de modificaciones o mantenimiento?**\n   - Esta pregunta se centra en los procedimientos espec\u00edficos de documentaci\u00f3n y aprobaci\u00f3n que son cruciales para el cumplimiento de las normativas, pero que no se explican en profundidad en el texto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Alcance del Documento**:\n   - Proporciona directrices sobre las especificaciones del agua para uso farmac\u00e9utico (WPU).\n   - Incluye orientaci\u00f3n sobre la calidad del agua necesaria para la fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (APIs) y formas de dosificaci\u00f3n.\n   - Aborda las buenas pr\u00e1cticas de manufactura (GMP) relacionadas con el dise\u00f1o, instalaci\u00f3n y operaci\u00f3n de sistemas de agua farmac\u00e9utica.\n   - No cubre el agua para administraci\u00f3n a pacientes ni el uso de peque\u00f1as cantidades en farmacias.\n\n2. **Buenas Pr\u00e1cticas de Manufactura (GMP)**:\n   - La gu\u00eda sobre GMP para WPU es complementaria a las directrices generales de GMP publicadas por la OMS.\n\n3. **Especificaciones y Normativas**:\n   - Hace referencia a especificaciones disponibles, como farmacopoeias y gu\u00edas de la industria sobre el uso, producci\u00f3n, almacenamiento y distribuci\u00f3n de agua en forma a granel.\n   - Los fabricantes deben decidir entre opciones de especificaciones farmacop\u00e9uticas bas\u00e1ndose en la autorizaci\u00f3n de comercializaci\u00f3n presentada a la autoridad reguladora nacional.\n\n4. **Importancia del Agua en la Industria Farmac\u00e9utica**:\n   - El agua es el material m\u00e1s utilizado en la producci\u00f3n y formulaci\u00f3n de productos farmac\u00e9uticos.\n   - Sus propiedades qu\u00edmicas \u00fanicas permiten disolver y suspender diversos compuestos, aunque tambi\u00e9n puede ser un veh\u00edculo para contaminantes que representan riesgos para la salud.\n\n### Entidades Clave:\n- **Agua para Uso Farmac\u00e9utico (WPU)**: Especificaciones y calidad del agua en la industria farmac\u00e9utica.\n- **Ingredientes Farmac\u00e9uticos Activos (APIs)**: Productos cuya fabricaci\u00f3n requiere agua de calidad espec\u00edfica.\n- **Buenas Pr\u00e1cticas de Manufactura (GMP)**: Normativas que gu\u00edan el dise\u00f1o y operaci\u00f3n de sistemas de agua farmac\u00e9utica.\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Publica directrices generales de GMP para productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: water quality, pharmaceutical water systems, microbiological control, good manufacturing practices, validation processes"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5fc28e43-694e-4589-a202-ba39a5eb920b", "node_type": "4", "metadata": {"page_label": "83", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 1.2.2\n\nControl of the quality of water throughout the production, storage and distribution processes, including microbiological and chemical quality, is a major concern. Unlike other product and process ingredients, water is usually drawn from a system on demand, and is not subject to testing and batch or lot release before use. Assurance of quality to meet the on-demand expectation is, therefore, essential. Additionally, certain microbiological tests may require periods of incubation and, therefore, the results are likely to lag behind the water use.\n\n## 1.2.3\n\nControl of the microbiological quality of WPU is a high priority. Some types of microorganism may proliferate in water treatment components and in the storage and distribution systems. It is crucial to minimize microbial contamination by proper design of the system, periodic sanitization and by taking appropriate measures to prevent microbial proliferation.\n\n## 1.2.4\n\nDifferent grades of water quality are required depending on the route of administration of the pharmaceutical products. Other sources of guidance about different grades of water can be found in pharmacopoeias and related documents.\n\n## 1.3 Applicable guides\n\n### 1.3.1\n\nIn addition to the specific guidance provided in this document, the Further reading section includes some relevant publications that can serve as additional background material when planning, installing and using systems intended to provide WPU.\n\n# 2. General principles for pharmaceutical water systems\n\n## 2.1\n\nPharmaceutical water production, storage and distribution systems should be designed, installed, commissioned, qualified and maintained to ensure the reliable production of water of an appropriate quality. It is necessary to validate the water production process to ensure the water generated, stored and distributed is not beyond the designed capacity and meets its specifications.\n\n## 2.2\n\nThe capacity of the system should be designed to meet the average and the peak flow demand of the current operation. If necessary, depending on planned future demands, the system should be designed to permit increases in the capacity or designed to permit modification. All systems, regardless of their size and capacity, should have appropriate recirculation and turnover to assure the system is well controlled chemically and microbiologically.\n\n## 2.3\n\nThe use of the systems following initial validation (installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ)) and after any planned and unplanned maintenance or modification work should be approved by the quality assurance (QA) department using change control documentation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "b56d88a940befaa4396f591ad0b24b5ce05c697016e0a40d11add84178aded47", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "## 1.2.2\n\nControl of the quality of water throughout the production, storage and distribution processes, including microbiological and chemical quality, is a major concern. Unlike other product and process ingredients, water is usually drawn from a system on demand, and is not subject to testing and batch or lot release before use. Assurance of quality to meet the on-demand expectation is, therefore, essential. Additionally, certain microbiological tests may require periods of incubation and, therefore, the results are likely to lag behind the water use.\n\n## 1.2.3\n\nControl of the microbiological quality of WPU is a high priority. Some types of microorganism may proliferate in water treatment components and in the storage and distribution systems. It is crucial to minimize microbial contamination by proper design of the system, periodic sanitization and by taking appropriate measures to prevent microbial proliferation.\n\n## 1.2.4\n\nDifferent grades of water quality are required depending on the route of administration of the pharmaceutical products. Other sources of guidance about different grades of water can be found in pharmacopoeias and related documents.\n\n## 1.3 Applicable guides\n\n### 1.3.1\n\nIn addition to the specific guidance provided in this document, the Further reading section includes some relevant publications that can serve as additional background material when planning, installing and using systems intended to provide WPU.\n\n# 2. General principles for pharmaceutical water systems\n\n## 2.1\n\nPharmaceutical water production, storage and distribution systems should be designed, installed, commissioned, qualified and maintained to ensure the reliable production of water of an appropriate quality. It is necessary to validate the water production process to ensure the water generated, stored and distributed is not beyond the designed capacity and meets its specifications.\n\n## 2.2\n\nThe capacity of the system should be designed to meet the average and the peak flow demand of the current operation. If necessary, depending on planned future demands, the system should be designed to permit increases in the capacity or designed to permit modification. All systems, regardless of their size and capacity, should have appropriate recirculation and turnover to assure the system is well controlled chemically and microbiologically.\n\n## 2.3\n\nThe use of the systems following initial validation (installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ)) and after any planned and unplanned maintenance or modification work should be approved by the quality assurance (QA) department using change control documentation.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2691, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "fc813c6b-9932-4ab0-8bfd-d0eddfe0f0b7": {"__data__": {"id_": "fc813c6b-9932-4ab0-8bfd-d0eddfe0f0b7", "embedding": null, "metadata": {"page_label": "84", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2.4 \nWater sources and treated water should be monitored regularly for chemical, microbiological and, as appropriate, endotoxin contamination. The performance of water purification, storage and distribution systems should also be monitored. Records of the monitoring results, trend analysis and any actions taken should be maintained.\n\n2.5 \nWhere chemical sanitization of the water systems is part of the biocontamination control programme a validated procedure should be followed to ensure that the sanitizing process has been effective and that the sanitizing agent has been effectively removed.\n\n# 3. Water quality specifications\n\n## 3.1 General\n\n3.1.1 \nThe following requirements concern water processed, stored and distributed in bulk form. They do not cover the specification of water formulated for patient administration. Pharmacopoeias include specifications for both bulk and dosage-form types of water.\n\n3.1.2 \nPharmacopoeial requirements or guidance for WPU are described in national, regional and international pharmacopoeias and limits for various impurities or classes of impurities are either specified or recommended. Companies wishing to supply multiple markets should set specifications that meet the strictest requirements from each of the relevant pharmacopoeias.\n\nSimilarly, requirements or guidance are given in pharmacopoeias on the microbiological quality of water.\n\n## 3.2 Drinking-water\n\n3.2.1 \nDrinking-water should be supplied under continuous positive pressure in a plumbing system free of any defects that could lead to contamination of any product.\n\n3.2.2 \nDrinking-water is unmodified except for limited treatment of the water derived from a natural or stored source. Examples of natural sources include springs, wells, rivers, lakes and the sea. The condition of the source water will dictate the treatment required to render it safe for human consumption (drinking). Typical treatment includes desalinization, softening, removal of specific ions, particle reduction and antimicrobial treatment.\n\n3.2.3 \nIt is common for drinking-water to be derived from a public water supply that may be a combination of more than one of the natural sources listed above. It may also be supplied either from an offsite source, e.g. a municipality, or appropriate quality may be achieved onsite through appropriate processing.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de nivel superior del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda la importancia de la calidad del agua, espec\u00edficamente en relaci\u00f3n con su monitoreo y tratamiento. Se enfatiza la necesidad de supervisar regularmente las fuentes de agua y el agua tratada para detectar contaminantes qu\u00edmicos, microbiol\u00f3gicos y endotoxinas. Adem\u00e1s, se establecen especificaciones para el agua potable, que debe ser suministrada bajo presi\u00f3n positiva y libre de defectos que puedan causar contaminaci\u00f3n. Se discuten los tratamientos necesarios para asegurar que el agua derivada de fuentes naturales sea segura para el consumo humano.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 procedimientos deben seguirse para validar la efectividad de la sanitizaci\u00f3n qu\u00edmica en los sistemas de agua?**\n   - El contexto menciona que se debe seguir un procedimiento validado para asegurar que el proceso de sanitizaci\u00f3n ha sido efectivo y que el agente sanitizante ha sido eliminado de manera efectiva.\n\n2. **\u00bfCu\u00e1les son los tratamientos t\u00edpicos que se aplican al agua derivada de fuentes naturales para hacerla segura para el consumo humano?**\n   - Se indican tratamientos como desalinizaci\u00f3n, ablandamiento, eliminaci\u00f3n de iones espec\u00edficos, reducci\u00f3n de part\u00edculas y tratamiento antimicrobiano.\n\n3. **\u00bfQu\u00e9 requisitos deben cumplir las empresas que desean suministrar agua a m\u00faltiples mercados en relaci\u00f3n con las especificaciones de calidad del agua?**\n   - Las empresas deben establecer especificaciones que cumplan con los requisitos m\u00e1s estrictos de cada una de las farmacopoeias relevantes para los mercados en los que desean operar.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Control de la calidad del agua**:\n   - La calidad del agua en los procesos de producci\u00f3n, almacenamiento y distribuci\u00f3n es cr\u00edtica, abarcando tanto la calidad microbiol\u00f3gica como qu\u00edmica.\n   - El agua se utiliza bajo demanda y no se somete a pruebas de lotes antes de su uso, lo que hace esencial asegurar su calidad.\n\n2. **Calidad microbiol\u00f3gica**:\n   - La calidad microbiol\u00f3gica del agua para uso farmac\u00e9utico (WPU) es una alta prioridad.\n   - Se deben implementar medidas para minimizar la contaminaci\u00f3n microbiana, incluyendo un dise\u00f1o adecuado del sistema y sanitizaci\u00f3n peri\u00f3dica.\n\n3. **Grados de calidad del agua**:\n   - Se requieren diferentes grados de calidad del agua seg\u00fan la ruta de administraci\u00f3n de los productos farmac\u00e9uticos.\n   - Se sugiere consultar farmacopoeias y documentos relacionados para obtener m\u00e1s orientaci\u00f3n sobre los diferentes grados de agua.\n\n4. **Principios generales para sistemas de agua farmac\u00e9utica**:\n   - Los sistemas de producci\u00f3n, almacenamiento y distribuci\u00f3n de agua farmac\u00e9utica deben ser dise\u00f1ados, instalados y mantenidos para garantizar la producci\u00f3n confiable de agua de calidad adecuada.\n   - Es necesario validar el proceso de producci\u00f3n de agua para asegurar que cumple con las especificaciones y capacidades dise\u00f1adas.\n\n5. **Capacidad del sistema**:\n   - El sistema debe estar dise\u00f1ado para satisfacer tanto la demanda promedio como la demanda m\u00e1xima de operaci\u00f3n.\n   - Debe permitir modificaciones futuras y contar con recirculaci\u00f3n adecuada para el control qu\u00edmico y microbiol\u00f3gico.\n\n6. **Documentaci\u00f3n de control de cambios**:\n   - Cualquier uso del sistema despu\u00e9s de la validaci\u00f3n inicial y tras mantenimiento o modificaciones debe ser aprobado por el departamento de aseguramiento de calidad (QA) mediante documentaci\u00f3n de control de cambios.\n\n### Entidades clave\n- **Agua para uso farmac\u00e9utico (WPU)**: Agua utilizado en la producci\u00f3n de productos farmac\u00e9uticos.\n- **Microorganismos**: Organismos que pueden proliferar en sistemas de tratamiento y distribuci\u00f3n de agua.\n- **Farmacopeas**: Documentos que proporcionan gu\u00edas sobre los est\u00e1ndares de calidad del agua.\n- **Aseguramiento de calidad (QA)**: Departamento responsable de la aprobaci\u00f3n de cambios y validaciones en los sistemas de agua.", "excerpt_keywords": "Keywords: water quality, microbiological contamination, chemical sanitization, pharmacopoeias, drinking-water treatment"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "19bbe2bd-1687-4345-9ebe-85661becb0ce", "node_type": "4", "metadata": {"page_label": "84", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2.4 \nWater sources and treated water should be monitored regularly for chemical, microbiological and, as appropriate, endotoxin contamination. The performance of water purification, storage and distribution systems should also be monitored. Records of the monitoring results, trend analysis and any actions taken should be maintained.\n\n2.5 \nWhere chemical sanitization of the water systems is part of the biocontamination control programme a validated procedure should be followed to ensure that the sanitizing process has been effective and that the sanitizing agent has been effectively removed.\n\n# 3. Water quality specifications\n\n## 3.1 General\n\n3.1.1 \nThe following requirements concern water processed, stored and distributed in bulk form. They do not cover the specification of water formulated for patient administration. Pharmacopoeias include specifications for both bulk and dosage-form types of water.\n\n3.1.2 \nPharmacopoeial requirements or guidance for WPU are described in national, regional and international pharmacopoeias and limits for various impurities or classes of impurities are either specified or recommended. Companies wishing to supply multiple markets should set specifications that meet the strictest requirements from each of the relevant pharmacopoeias.\n\nSimilarly, requirements or guidance are given in pharmacopoeias on the microbiological quality of water.\n\n## 3.2 Drinking-water\n\n3.2.1 \nDrinking-water should be supplied under continuous positive pressure in a plumbing system free of any defects that could lead to contamination of any product.\n\n3.2.2 \nDrinking-water is unmodified except for limited treatment of the water derived from a natural or stored source. Examples of natural sources include springs, wells, rivers, lakes and the sea. The condition of the source water will dictate the treatment required to render it safe for human consumption (drinking). Typical treatment includes desalinization, softening, removal of specific ions, particle reduction and antimicrobial treatment.\n\n3.2.3 \nIt is common for drinking-water to be derived from a public water supply that may be a combination of more than one of the natural sources listed above. It may also be supplied either from an offsite source, e.g. a municipality, or appropriate quality may be achieved onsite through appropriate processing.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "670669f568be90c84a00dc77b9b36c31a25e8fe50af863af016d2f4a1c96ee07", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 2.4 \nWater sources and treated water should be monitored regularly for chemical, microbiological and, as appropriate, endotoxin contamination. The performance of water purification, storage and distribution systems should also be monitored. Records of the monitoring results, trend analysis and any actions taken should be maintained.\n\n2.5 \nWhere chemical sanitization of the water systems is part of the biocontamination control programme a validated procedure should be followed to ensure that the sanitizing process has been effective and that the sanitizing agent has been effectively removed.\n\n# 3. Water quality specifications\n\n## 3.1 General\n\n3.1.1 \nThe following requirements concern water processed, stored and distributed in bulk form. They do not cover the specification of water formulated for patient administration. Pharmacopoeias include specifications for both bulk and dosage-form types of water.\n\n3.1.2 \nPharmacopoeial requirements or guidance for WPU are described in national, regional and international pharmacopoeias and limits for various impurities or classes of impurities are either specified or recommended. Companies wishing to supply multiple markets should set specifications that meet the strictest requirements from each of the relevant pharmacopoeias.\n\nSimilarly, requirements or guidance are given in pharmacopoeias on the microbiological quality of water.\n\n## 3.2 Drinking-water\n\n3.2.1 \nDrinking-water should be supplied under continuous positive pressure in a plumbing system free of any defects that could lead to contamination of any product.\n\n3.2.2 \nDrinking-water is unmodified except for limited treatment of the water derived from a natural or stored source. Examples of natural sources include springs, wells, rivers, lakes and the sea. The condition of the source water will dictate the treatment required to render it safe for human consumption (drinking). Typical treatment includes desalinization, softening, removal of specific ions, particle reduction and antimicrobial treatment.\n\n3.2.3 \nIt is common for drinking-water to be derived from a public water supply that may be a combination of more than one of the natural sources listed above. It may also be supplied either from an offsite source, e.g. a municipality, or appropriate quality may be achieved onsite through appropriate processing.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2346, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "40e5379f-32ba-4b8c-a8e3-22d17c1da1f3": {"__data__": {"id_": "40e5379f-32ba-4b8c-a8e3-22d17c1da1f3", "embedding": null, "metadata": {"page_label": "85", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.4\nIt is also common for public water supply organizations to conduct tests and guarantee that the drinking-water delivered is of drinking quality. This testing is typically performed on water from the water source.\n\n# 3.2.5\nIt is the responsibility of the pharmaceutical manufacturer to assure that the source water supplying the purified water (PW) treatment system meets the appropriate drinking-water requirements. There may be situations where the water treatment system is used first to achieve drinking-water quality and subsequently purified water. In these situations the point at which drinking-water quality is achieved should be identified and tested.\n\n# 3.2.6\nDrinking-water quality is covered by the WHO drinking-water guidelines, standards from the International Organization for Standardization (ISO) and other regional and national agencies. Drinking-water should comply with the relevant regulations laid down by the competent authority.\n\n# 3.2.7\nIf drinking-water is used directly in certain stages of pharmaceutical manufacture or is the feed-water for the production of higher qualities of WPU, then testing should be carried out periodically by the water user\u2019s site to confirm that the quality meets the standards required for drinking-water.\n\n# 3.3 Bulk purified water\n\n## 3.3.1\nBulk purified water (BPW) should be prepared from a drinking-water source as a minimum-quality feed-water. It should meet the relevant pharmacopoeial specifications for chemical and microbiological purity with appropriate action and alert limits. It should also be protected from recontamination and microbial proliferation. BPW may be prepared by a combination of reverse osmosis (RO) RO/electro-deionization (EDI) and vapour compression (VC). Alert levels for the water system should be determined from knowledge of the system and are not specified in the pharmacopoeias.\n\n# 3.4 Bulk highly purified water\n\n## 3.4.1\nBulk highly purified water (BHPW) should be prepared from drinking-water as a minimum-quality feed-water. BHPW is a unique specification for water found only in the *European Pharmacopoeia*. This grade of water must meet the same quality standard as water for injections (WFI), including the limit for endotoxins, but the water-treatment process used may be different. Current production methods include, for example, double-pass RO coupled with other suitable techniques such as ultrafiltration and deionization.\n\nBHPW may be prepared by a combination of different methods such as RO, ultrafiltration and deionization.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda la calidad del agua potable y su importancia en la fabricaci\u00f3n farmac\u00e9utica. Se menciona que las organizaciones de suministro de agua p\u00fablica realizan pruebas para garantizar que el agua entregada cumpla con los est\u00e1ndares de calidad. Los fabricantes farmac\u00e9uticos son responsables de asegurar que el agua de origen utilizada en sus sistemas de tratamiento cumpla con los requisitos de calidad del agua potable. Se describen diferentes tipos de agua, como el agua purificada a granel (BPW) y el agua altamente purificada a granel (BHPW), y se especifican los m\u00e9todos de tratamiento y las normas que deben cumplirse para cada tipo.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 m\u00e9todos de tratamiento se pueden utilizar para preparar el agua purificada a granel (BPW) y cu\u00e1les son las especificaciones que debe cumplir?**\n   - La BPW debe ser preparada a partir de una fuente de agua potable y cumplir con las especificaciones farmacop\u00e9icas para pureza qu\u00edmica y microbiol\u00f3gica. Los m\u00e9todos de tratamiento incluyen la \u00f3smosis inversa (RO), la electrodi\u00e1lisis (EDI) y la compresi\u00f3n de vapor (VC).\n\n2. **\u00bfCu\u00e1l es la diferencia entre el agua altamente purificada a granel (BHPW) y el agua para inyecciones (WFI) en t\u00e9rminos de est\u00e1ndares de calidad?**\n   - El BHPW debe cumplir con los mismos est\u00e1ndares de calidad que el WFI, incluyendo l\u00edmites para endotoxinas, pero el proceso de tratamiento del agua puede ser diferente. El BHPW es una especificaci\u00f3n \u00fanica que se encuentra solo en la *Farmacopea Europea*.\n\n3. **\u00bfQu\u00e9 responsabilidad tienen los fabricantes farmac\u00e9uticos en relaci\u00f3n con la calidad del agua utilizada en sus procesos de producci\u00f3n?**\n   - Los fabricantes farmac\u00e9uticos son responsables de asegurar que el agua de origen que alimenta su sistema de tratamiento de agua purificada cumpla con los requisitos de calidad del agua potable. Adem\u00e1s, deben realizar pruebas peri\u00f3dicas para confirmar que el agua utilizada en la fabricaci\u00f3n cumple con los est\u00e1ndares requeridos.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Monitoreo de Agua**:\n   - Se requiere un monitoreo regular de las fuentes de agua y del agua tratada para detectar contaminantes qu\u00edmicos, microbiol\u00f3gicos y endotoxinas.\n   - Es esencial mantener registros de los resultados del monitoreo, an\u00e1lisis de tendencias y acciones tomadas.\n\n2. **Sanitizaci\u00f3n Qu\u00edmica**:\n   - Cuando se utiliza la sanitizaci\u00f3n qu\u00edmica en los sistemas de agua, debe seguirse un procedimiento validado para asegurar la efectividad del proceso y la eliminaci\u00f3n del agente sanitizante.\n\n3. **Especificaciones de Calidad del Agua**:\n   - Las especificaciones se aplican al agua procesada, almacenada y distribuida en forma a granel, excluyendo el agua formulada para administraci\u00f3n a pacientes.\n   - Las empresas que deseen operar en m\u00faltiples mercados deben cumplir con los requisitos m\u00e1s estrictos de las farmacopoeias relevantes.\n\n4. **Agua Potable**:\n   - El agua potable debe suministrarse bajo presi\u00f3n positiva continua y en sistemas de plomer\u00eda sin defectos que puedan causar contaminaci\u00f3n.\n   - El agua potable puede derivarse de fuentes naturales (manantiales, pozos, r\u00edos, lagos, mar) y requiere tratamientos espec\u00edficos para ser segura para el consumo humano, como desalinizaci\u00f3n, ablandamiento, eliminaci\u00f3n de iones espec\u00edficos, reducci\u00f3n de part\u00edculas y tratamiento antimicrobiano.\n\n5. **Fuentes de Agua**:\n   - Es com\u00fan que el agua potable provenga de un suministro p\u00fablico que puede combinar varias fuentes naturales, o que se procese en el lugar para alcanzar la calidad adecuada.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las directrices sobre la calidad del agua.\n- **Farmacopeas**: Documentos que establecen especificaciones y requisitos para la calidad del agua.\n- **Contaminantes**: Incluyen qu\u00edmicos, microorganismos y endotoxinas que deben ser monitoreados.\n- **Sistemas de Agua**: Incluyen purificaci\u00f3n, almacenamiento y distribuci\u00f3n que deben ser monitoreados para asegurar su efectividad y seguridad.", "excerpt_keywords": "Keywords: water quality, pharmaceutical manufacturing, purified water, WHO guidelines, water treatment methods"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fe21ea0f-0a31-483d-aeea-8762f821fa86", "node_type": "4", "metadata": {"page_label": "85", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.4\nIt is also common for public water supply organizations to conduct tests and guarantee that the drinking-water delivered is of drinking quality. This testing is typically performed on water from the water source.\n\n# 3.2.5\nIt is the responsibility of the pharmaceutical manufacturer to assure that the source water supplying the purified water (PW) treatment system meets the appropriate drinking-water requirements. There may be situations where the water treatment system is used first to achieve drinking-water quality and subsequently purified water. In these situations the point at which drinking-water quality is achieved should be identified and tested.\n\n# 3.2.6\nDrinking-water quality is covered by the WHO drinking-water guidelines, standards from the International Organization for Standardization (ISO) and other regional and national agencies. Drinking-water should comply with the relevant regulations laid down by the competent authority.\n\n# 3.2.7\nIf drinking-water is used directly in certain stages of pharmaceutical manufacture or is the feed-water for the production of higher qualities of WPU, then testing should be carried out periodically by the water user\u2019s site to confirm that the quality meets the standards required for drinking-water.\n\n# 3.3 Bulk purified water\n\n## 3.3.1\nBulk purified water (BPW) should be prepared from a drinking-water source as a minimum-quality feed-water. It should meet the relevant pharmacopoeial specifications for chemical and microbiological purity with appropriate action and alert limits. It should also be protected from recontamination and microbial proliferation. BPW may be prepared by a combination of reverse osmosis (RO) RO/electro-deionization (EDI) and vapour compression (VC). Alert levels for the water system should be determined from knowledge of the system and are not specified in the pharmacopoeias.\n\n# 3.4 Bulk highly purified water\n\n## 3.4.1\nBulk highly purified water (BHPW) should be prepared from drinking-water as a minimum-quality feed-water. BHPW is a unique specification for water found only in the *European Pharmacopoeia*. This grade of water must meet the same quality standard as water for injections (WFI), including the limit for endotoxins, but the water-treatment process used may be different. Current production methods include, for example, double-pass RO coupled with other suitable techniques such as ultrafiltration and deionization.\n\nBHPW may be prepared by a combination of different methods such as RO, ultrafiltration and deionization.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "05fbcdef312eeae24c5aa247f54e0f013677f2daffc5bf128c5e08baf799bc61", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.4\nIt is also common for public water supply organizations to conduct tests and guarantee that the drinking-water delivered is of drinking quality. This testing is typically performed on water from the water source.\n\n# 3.2.5\nIt is the responsibility of the pharmaceutical manufacturer to assure that the source water supplying the purified water (PW) treatment system meets the appropriate drinking-water requirements. There may be situations where the water treatment system is used first to achieve drinking-water quality and subsequently purified water. In these situations the point at which drinking-water quality is achieved should be identified and tested.\n\n# 3.2.6\nDrinking-water quality is covered by the WHO drinking-water guidelines, standards from the International Organization for Standardization (ISO) and other regional and national agencies. Drinking-water should comply with the relevant regulations laid down by the competent authority.\n\n# 3.2.7\nIf drinking-water is used directly in certain stages of pharmaceutical manufacture or is the feed-water for the production of higher qualities of WPU, then testing should be carried out periodically by the water user\u2019s site to confirm that the quality meets the standards required for drinking-water.\n\n# 3.3 Bulk purified water\n\n## 3.3.1\nBulk purified water (BPW) should be prepared from a drinking-water source as a minimum-quality feed-water. It should meet the relevant pharmacopoeial specifications for chemical and microbiological purity with appropriate action and alert limits. It should also be protected from recontamination and microbial proliferation. BPW may be prepared by a combination of reverse osmosis (RO) RO/electro-deionization (EDI) and vapour compression (VC). Alert levels for the water system should be determined from knowledge of the system and are not specified in the pharmacopoeias.\n\n# 3.4 Bulk highly purified water\n\n## 3.4.1\nBulk highly purified water (BHPW) should be prepared from drinking-water as a minimum-quality feed-water. BHPW is a unique specification for water found only in the *European Pharmacopoeia*. This grade of water must meet the same quality standard as water for injections (WFI), including the limit for endotoxins, but the water-treatment process used may be different. Current production methods include, for example, double-pass RO coupled with other suitable techniques such as ultrafiltration and deionization.\n\nBHPW may be prepared by a combination of different methods such as RO, ultrafiltration and deionization.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2545, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "92aecebc-69be-496e-901c-b4a44c9341e9": {"__data__": {"id_": "92aecebc-69be-496e-901c-b4a44c9341e9", "embedding": null, "metadata": {"page_label": "86", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 3.4.2\nBHPW should also be protected from recontamination and microbial proliferation.\n\n## 3.4.3\nBHPW and WFI have identical microbiological requirements.\n\n## 3.5 Bulk water for injections\n\n### 3.5.1\nBulk water for injections (BWFI) should be prepared from drinking-water (usually with further treatment) or purified water as a minimum-quality feed-water. BWFI is not sterile water and is not a final dosage form. It is an intermediate bulk product and suitable to be used as an ingredient during formulation. BWFI is the highest quality of pharmacopoeial WPU.\n\n### 3.5.2\nCertain pharmacopoeias place constraints upon the permitted purification techniques as part of the specification of the BWFI. *The International Pharmacopoeia* and the *European Pharmacopoeia*, for example, allow only distillation as the final purification step.\n\n### 3.5.3\nBWFI should meet the relevant pharmacopoeial specifications for chemical and microbiological purity (including endotoxin) with appropriate action and alert limits.\n\n### 3.5.4\nBWFI should also be protected from recontamination and microbial proliferation.\n\n## 3.6 Other grades of water\n\n### 3.6.1\nWhen a specific process requires a special non-pharmacopoeial grade of water, its specification must be documented within the company quality system. As a minimum it must meet the pharmacopoeial requirements relating to the grade of WPU required for the type of dosage form or process step.\n\n# 4. Application of specific types of water to processes and dosage forms\n\n## 4.1\nProduct licensing authorities specify the minimum grade of WPU that must be used during the manufacture of the different dosage forms or for different stages in washing, preparation, synthesis, manufacturing or formulation.\n\n## 4.2\nThe grade of water used should take into account the nature and intended use of the intermediate or finished product and the stage in the manufacturing process at which the water is used.\n\n## 4.3\nBHPW can be used in the preparation of products when water of high quality (i.e. very low in microorganisms and endotoxins) is needed, but the", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS detalla las especificaciones para diferentes tipos de agua utilizados en la preparaci\u00f3n farmac\u00e9utica. Se enfatiza la importancia de la calidad del agua, especialmente en la producci\u00f3n de productos inyectables, como el agua para inyecciones en bloque (BWFI) y el agua purificada de alta calidad (BHPW). Se establecen requisitos microbiol\u00f3gicos y qu\u00edmicos, as\u00ed como las t\u00e9cnicas de purificaci\u00f3n permitidas. Adem\u00e1s, se menciona que las autoridades de licencias de productos especifican el grado m\u00ednimo de agua que debe utilizarse en diferentes etapas del proceso de fabricaci\u00f3n.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las diferencias clave entre el agua purificada de alta calidad (BHPW) y el agua para inyecciones en bloque (BWFI) en t\u00e9rminos de su uso y requisitos de calidad?**\n   - Respuesta: BHPW y BWFI tienen requisitos microbiol\u00f3gicos id\u00e9nticos, pero BWFI es un producto intermedio que no es est\u00e9ril y se utiliza como ingrediente en la formulaci\u00f3n, mientras que BHPW se utiliza cuando se necesita agua de alta calidad con muy bajos niveles de microorganismos y endotoxinas.\n\n2. **\u00bfQu\u00e9 t\u00e9cnicas de purificaci\u00f3n son aceptables para la producci\u00f3n de BWFI seg\u00fan las farmacopoeias internacionales?**\n   - Respuesta: Seg\u00fan *The International Pharmacopoeia* y la *European Pharmacopoeia*, la \u00fanica t\u00e9cnica de purificaci\u00f3n permitida como paso final para la producci\u00f3n de BWFI es la destilaci\u00f3n.\n\n3. **\u00bfQu\u00e9 medidas deben tomarse para proteger BWFI de la recontaminaci\u00f3n y la proliferaci\u00f3n microbiana?**\n   - Respuesta: BWFI debe ser protegido de la recontaminaci\u00f3n y la proliferaci\u00f3n microbiana mediante pr\u00e1cticas adecuadas de manejo y almacenamiento, aunque el documento no detalla las medidas espec\u00edficas, se infiere que deben seguirse protocolos de calidad y control en su manipulaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Calidad del Agua Potable**:\n   - Las organizaciones de suministro de agua p\u00fablica realizan pruebas para garantizar que el agua entregada cumpla con los est\u00e1ndares de calidad de agua potable.\n\n2. **Responsabilidad de los Fabricantes Farmac\u00e9uticos**:\n   - Los fabricantes son responsables de asegurar que el agua de origen utilizada en sus sistemas de tratamiento cumpla con los requisitos de calidad del agua potable.\n   - Deben identificar y probar el punto en el que se logra la calidad de agua potable en el proceso de tratamiento.\n\n3. **Normativas y Est\u00e1ndares**:\n   - La calidad del agua potable est\u00e1 regulada por las directrices de la OMS, normas de la ISO y otras agencias regionales y nacionales.\n   - El agua debe cumplir con las regulaciones establecidas por la autoridad competente.\n\n4. **Pruebas Peri\u00f3dicas**:\n   - Si el agua potable se utiliza en la fabricaci\u00f3n farmac\u00e9utica, se deben realizar pruebas peri\u00f3dicas para confirmar que cumple con los est\u00e1ndares requeridos.\n\n5. **Agua Purificada a Granel (BPW)**:\n   - Debe ser preparada a partir de una fuente de agua potable y cumplir con especificaciones farmacop\u00e9icas para pureza qu\u00edmica y microbiol\u00f3gica.\n   - M\u00e9todos de tratamiento incluyen \u00f3smosis inversa (RO), electrodi\u00e1lisis (EDI) y compresi\u00f3n de vapor (VC).\n\n6. **Agua Altamente Purificada a Granel (BHPW)**:\n   - Debe ser preparada a partir de agua potable y cumplir con los mismos est\u00e1ndares de calidad que el agua para inyecciones (WFI), incluyendo l\u00edmites para endotoxinas.\n   - M\u00e9todos de producci\u00f3n incluyen RO de doble paso, ultrafiltraci\u00f3n y desionizaci\u00f3n.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Establece directrices sobre la calidad del agua potable.\n- **ISO (Organizaci\u00f3n Internacional de Normalizaci\u00f3n)**: Proporciona est\u00e1ndares para la calidad del agua.\n- **Agua Purificada a Granel (BPW)**: Tipo de agua que debe cumplir con especificaciones farmac\u00e9uticas.\n- **Agua Altamente Purificada a Granel (BHPW)**: Especificaci\u00f3n \u00fanica en la *Farmacopea Europea* que debe cumplir con est\u00e1ndares de calidad espec\u00edficos.", "excerpt_keywords": "Keywords: BHPW, BWFI, microbiological requirements, purification techniques, pharmaceutical preparations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c810956a-8a6f-4e58-b734-e8627455b54d", "node_type": "4", "metadata": {"page_label": "86", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 3.4.2\nBHPW should also be protected from recontamination and microbial proliferation.\n\n## 3.4.3\nBHPW and WFI have identical microbiological requirements.\n\n## 3.5 Bulk water for injections\n\n### 3.5.1\nBulk water for injections (BWFI) should be prepared from drinking-water (usually with further treatment) or purified water as a minimum-quality feed-water. BWFI is not sterile water and is not a final dosage form. It is an intermediate bulk product and suitable to be used as an ingredient during formulation. BWFI is the highest quality of pharmacopoeial WPU.\n\n### 3.5.2\nCertain pharmacopoeias place constraints upon the permitted purification techniques as part of the specification of the BWFI. *The International Pharmacopoeia* and the *European Pharmacopoeia*, for example, allow only distillation as the final purification step.\n\n### 3.5.3\nBWFI should meet the relevant pharmacopoeial specifications for chemical and microbiological purity (including endotoxin) with appropriate action and alert limits.\n\n### 3.5.4\nBWFI should also be protected from recontamination and microbial proliferation.\n\n## 3.6 Other grades of water\n\n### 3.6.1\nWhen a specific process requires a special non-pharmacopoeial grade of water, its specification must be documented within the company quality system. As a minimum it must meet the pharmacopoeial requirements relating to the grade of WPU required for the type of dosage form or process step.\n\n# 4. Application of specific types of water to processes and dosage forms\n\n## 4.1\nProduct licensing authorities specify the minimum grade of WPU that must be used during the manufacture of the different dosage forms or for different stages in washing, preparation, synthesis, manufacturing or formulation.\n\n## 4.2\nThe grade of water used should take into account the nature and intended use of the intermediate or finished product and the stage in the manufacturing process at which the water is used.\n\n## 4.3\nBHPW can be used in the preparation of products when water of high quality (i.e. very low in microorganisms and endotoxins) is needed, but the", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "ac02449dce86dcf655d4f98e71480c650d445f2ede690651f332a354d8904cae", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 3.4.2\nBHPW should also be protected from recontamination and microbial proliferation.\n\n## 3.4.3\nBHPW and WFI have identical microbiological requirements.\n\n## 3.5 Bulk water for injections\n\n### 3.5.1\nBulk water for injections (BWFI) should be prepared from drinking-water (usually with further treatment) or purified water as a minimum-quality feed-water. BWFI is not sterile water and is not a final dosage form. It is an intermediate bulk product and suitable to be used as an ingredient during formulation. BWFI is the highest quality of pharmacopoeial WPU.\n\n### 3.5.2\nCertain pharmacopoeias place constraints upon the permitted purification techniques as part of the specification of the BWFI. *The International Pharmacopoeia* and the *European Pharmacopoeia*, for example, allow only distillation as the final purification step.\n\n### 3.5.3\nBWFI should meet the relevant pharmacopoeial specifications for chemical and microbiological purity (including endotoxin) with appropriate action and alert limits.\n\n### 3.5.4\nBWFI should also be protected from recontamination and microbial proliferation.\n\n## 3.6 Other grades of water\n\n### 3.6.1\nWhen a specific process requires a special non-pharmacopoeial grade of water, its specification must be documented within the company quality system. As a minimum it must meet the pharmacopoeial requirements relating to the grade of WPU required for the type of dosage form or process step.\n\n# 4. Application of specific types of water to processes and dosage forms\n\n## 4.1\nProduct licensing authorities specify the minimum grade of WPU that must be used during the manufacture of the different dosage forms or for different stages in washing, preparation, synthesis, manufacturing or formulation.\n\n## 4.2\nThe grade of water used should take into account the nature and intended use of the intermediate or finished product and the stage in the manufacturing process at which the water is used.\n\n## 4.3\nBHPW can be used in the preparation of products when water of high quality (i.e. very low in microorganisms and endotoxins) is needed, but the", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2162, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "da85478b-1be1-49ba-a964-76bda3eeb2b0": {"__data__": {"id_": "da85478b-1be1-49ba-a964-76bda3eeb2b0", "embedding": null, "metadata": {"page_label": "87", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 4.4\n\nBWFI should be used in the manufacture of injectable products for dissolving or diluting substances or preparations during the manufacturing of parenterals, and for manufacture of sterile water for preparation of injections. BWFI should also be used for the final rinse after cleaning of equipment and components that come into contact with injectable products as well as for the final rinse in a washing process in which no subsequent thermal or chemical depyrogenization process is applied.\n\n4.5 When steam comes into contact with an injectable product in its final container or with equipment for preparing injectable products, it should conform to the specification for BWFI when condensed.\n\n# 5. Water purification systems\n\n## 5.1 General considerations\n\n5.1.1 The specifications for WPU found in compendia (e.g. pharmacopoeias) do not define the permissible water purification methods apart from for BWFI (refer to section 3.5).\n\n5.1.2 The chosen water purification method or sequence of purification steps must be appropriate to the application in question. The following should be considered when selecting the water treatment method:\n\n- the final water quality specification;\n- the quantity of water required by the user;\n- the available feed-water quality and the variation over time (seasonal changes);\n- the availability of suitable support facilities for system connection (raw water, electricity, heating steam, chilled water, compressed air, sewage system, exhaust air);\n- the sanitization strategy;\n- the availability of water-treatment equipment on the market;\n- the reliability and robustness of the water-treatment equipment in operation;\n- the yield or efficiency of the purification system;\n- the ability to adequately support and maintain the water purification equipment;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda la importancia del agua para inyecci\u00f3n (BWFI) en la fabricaci\u00f3n de productos inyectables y en la purificaci\u00f3n del agua. Se especifica que el BWFI debe ser utilizado para disolver o diluir sustancias durante la fabricaci\u00f3n de parenterales y para el enjuague final de equipos que entran en contacto con productos inyectables. Adem\u00e1s, se discuten consideraciones generales sobre los sistemas de purificaci\u00f3n de agua, enfatizando que el m\u00e9todo de purificaci\u00f3n debe ser adecuado para la aplicaci\u00f3n espec\u00edfica y que se deben tener en cuenta varios factores, como la calidad del agua, la cantidad requerida y la disponibilidad de equipos.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las condiciones bajo las cuales el BWFI debe ser utilizado para el enjuague final de equipos en contacto con productos inyectables?**\n   - Esta pregunta se centra en las especificaciones del uso de BWFI en el proceso de fabricaci\u00f3n y limpieza, que no se detalla en otras fuentes.\n\n2. **\u00bfQu\u00e9 factores deben considerarse al seleccionar un m\u00e9todo de tratamiento de agua para aplicaciones espec\u00edficas en la industria farmac\u00e9utica?**\n   - Esta pregunta aborda los criterios espec\u00edficos que deben evaluarse al elegir un sistema de purificaci\u00f3n de agua, lo cual es crucial para garantizar la calidad del producto final.\n\n3. **\u00bfQu\u00e9 especificaciones debe cumplir el vapor que entra en contacto con productos inyectables en su envase final?**\n   - Esta pregunta se refiere a las normas que deben seguirse para asegurar que el vapor no comprometa la calidad del producto, un aspecto que puede no estar ampliamente cubierto en otras fuentes.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n detallada y espec\u00edfica que se encuentra en el contexto proporcionado, lo que puede no estar disponible en otras partes de la literatura o documentos relacionados.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Tipos de Agua en Preparaci\u00f3n Farmac\u00e9utica**:\n   - **Agua Purificada de Alta Calidad (BHPW)**: Debe ser protegida de la recontaminaci\u00f3n y la proliferaci\u00f3n microbiana. Tiene requisitos microbiol\u00f3gicos id\u00e9nticos a los del agua para inyecciones (WFI).\n   - **Agua para Inyecciones en Bloque (BWFI)**: Preparada a partir de agua potable o agua purificada, no es est\u00e9ril y se utiliza como ingrediente en formulaciones. Es el m\u00e1s alto est\u00e1ndar de agua farmacopoeial.\n\n2. **Requisitos de Calidad**:\n   - Tanto BHPW como BWFI deben cumplir con especificaciones farmacopoeiales para pureza qu\u00edmica y microbiol\u00f3gica, incluyendo l\u00edmites de endotoxinas.\n   - BWFI debe ser protegido de la recontaminaci\u00f3n y la proliferaci\u00f3n microbiana.\n\n3. **T\u00e9cnicas de Purificaci\u00f3n**:\n   - Las farmacopoeias internacionales, como *The International Pharmacopoeia* y la *European Pharmacopoeia*, permiten solo la destilaci\u00f3n como paso final de purificaci\u00f3n para BWFI.\n\n4. **Documentaci\u00f3n y Especificaciones**:\n   - Cualquier grado de agua no farmacopoeial utilizado en un proceso espec\u00edfico debe ser documentado en el sistema de calidad de la empresa, cumpliendo al menos con los requisitos farmacopoeiales para el tipo de forma de dosificaci\u00f3n o etapa del proceso.\n\n5. **Aplicaci\u00f3n en Procesos de Fabricaci\u00f3n**:\n   - Las autoridades de licencias de productos establecen el grado m\u00ednimo de agua que debe utilizarse en la fabricaci\u00f3n de diferentes formas de dosificaci\u00f3n y en diversas etapas del proceso de producci\u00f3n.\n\n### Entidades Clave:\n- **BHPW** (Agua Purificada de Alta Calidad)\n- **BWFI** (Agua para Inyecciones en Bloque)\n- **The International Pharmacopoeia**\n- **European Pharmacopoeia**\n- **Autoridades de Licencias de Productos** \n\nEste resumen destaca la importancia de la calidad del agua en la producci\u00f3n farmac\u00e9utica y las regulaciones que rigen su uso.", "excerpt_keywords": "Keywords: BWFI, water purification, injectable products, pharmaceutical standards, sanitization strategy"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d5f01d8b-e0a7-4f6d-bb4f-1b447da46e6d", "node_type": "4", "metadata": {"page_label": "87", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 4.4\n\nBWFI should be used in the manufacture of injectable products for dissolving or diluting substances or preparations during the manufacturing of parenterals, and for manufacture of sterile water for preparation of injections. BWFI should also be used for the final rinse after cleaning of equipment and components that come into contact with injectable products as well as for the final rinse in a washing process in which no subsequent thermal or chemical depyrogenization process is applied.\n\n4.5 When steam comes into contact with an injectable product in its final container or with equipment for preparing injectable products, it should conform to the specification for BWFI when condensed.\n\n# 5. Water purification systems\n\n## 5.1 General considerations\n\n5.1.1 The specifications for WPU found in compendia (e.g. pharmacopoeias) do not define the permissible water purification methods apart from for BWFI (refer to section 3.5).\n\n5.1.2 The chosen water purification method or sequence of purification steps must be appropriate to the application in question. The following should be considered when selecting the water treatment method:\n\n- the final water quality specification;\n- the quantity of water required by the user;\n- the available feed-water quality and the variation over time (seasonal changes);\n- the availability of suitable support facilities for system connection (raw water, electricity, heating steam, chilled water, compressed air, sewage system, exhaust air);\n- the sanitization strategy;\n- the availability of water-treatment equipment on the market;\n- the reliability and robustness of the water-treatment equipment in operation;\n- the yield or efficiency of the purification system;\n- the ability to adequately support and maintain the water purification equipment;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4684e47371f8a507eafbda062daf2d32db19d11f118cc8f041e78072ed134204", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 4.4\n\nBWFI should be used in the manufacture of injectable products for dissolving or diluting substances or preparations during the manufacturing of parenterals, and for manufacture of sterile water for preparation of injections. BWFI should also be used for the final rinse after cleaning of equipment and components that come into contact with injectable products as well as for the final rinse in a washing process in which no subsequent thermal or chemical depyrogenization process is applied.\n\n4.5 When steam comes into contact with an injectable product in its final container or with equipment for preparing injectable products, it should conform to the specification for BWFI when condensed.\n\n# 5. Water purification systems\n\n## 5.1 General considerations\n\n5.1.1 The specifications for WPU found in compendia (e.g. pharmacopoeias) do not define the permissible water purification methods apart from for BWFI (refer to section 3.5).\n\n5.1.2 The chosen water purification method or sequence of purification steps must be appropriate to the application in question. The following should be considered when selecting the water treatment method:\n\n- the final water quality specification;\n- the quantity of water required by the user;\n- the available feed-water quality and the variation over time (seasonal changes);\n- the availability of suitable support facilities for system connection (raw water, electricity, heating steam, chilled water, compressed air, sewage system, exhaust air);\n- the sanitization strategy;\n- the availability of water-treatment equipment on the market;\n- the reliability and robustness of the water-treatment equipment in operation;\n- the yield or efficiency of the purification system;\n- the ability to adequately support and maintain the water purification equipment;", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1801, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "410cac17-4089-4d58-a2ce-41696af05fbf": {"__data__": {"id_": "410cac17-4089-4d58-a2ce-41696af05fbf", "embedding": null, "metadata": {"page_label": "88", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- the continuity of operational usage considering hours/days, days/years and planned downtime;\n- the total life-cycle costs (capital and operational including maintenance).\n\n## 5.1.3\n\nThe specifications for water purification equipment, storage and distribution systems should take into account the following:\n\n- the location of the plant room;\n- extremes in temperature that the system will encounter;\n- the risk of contamination from leachates from contact materials;\n- the adverse impact of adsorptive contact materials;\n- hygienic or sanitary design, where required;\n- corrosion resistance;\n- freedom from leakage;\n- a system configuration to avoid proliferation of microbiological organisms;\n- tolerance to cleaning and sanitizing agents (thermal and/or chemical);\n- the sanitization strategy;\n- the system capacity and output requirements;\n- the provision of all necessary instruments, test and sampling points to allow all the relevant critical quality parameters of the complete system to be monitored.\n\n## 5.1.4\n\nThe design, configuration and layout of the water purification equipment, storage and distribution systems should also take into account the following physical considerations:\n\n- ability to collect samples;\n- the space available for the installation;\n- structural loadings on buildings;\n- the provision of adequate access for maintenance;\n- the ability to safely handle regeneration and sanitization chemicals.\n\n## 5.2 Production of drinking-water\n\n### 5.2.1\n\nDrinking-water is derived from a raw water source such as a well, river or reservoir. There are no prescribed methods for the treatment of raw water to produce drinking-water from a specific raw water source.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS aborda las especificaciones para equipos de purificaci\u00f3n de agua, sistemas de almacenamiento y distribuci\u00f3n, as\u00ed como la producci\u00f3n de agua potable. Se destacan consideraciones clave para el dise\u00f1o y la operaci\u00f3n de estos sistemas, incluyendo la ubicaci\u00f3n, resistencia a la corrosi\u00f3n, dise\u00f1o higi\u00e9nico, y la capacidad de monitorear par\u00e1metros de calidad. Adem\u00e1s, se menciona que no existen m\u00e9todos prescritos para el tratamiento de agua cruda para producir agua potable, lo que sugiere una flexibilidad en los enfoques utilizados.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las consideraciones clave que deben tenerse en cuenta al dise\u00f1ar sistemas de purificaci\u00f3n de agua seg\u00fan la OMS?**\n   - Respuesta: Las consideraciones incluyen la ubicaci\u00f3n de la planta, las temperaturas extremas, el riesgo de contaminaci\u00f3n, el dise\u00f1o higi\u00e9nico, la resistencia a la corrosi\u00f3n, la libertad de fugas, la configuraci\u00f3n del sistema para evitar la proliferaci\u00f3n de microorganismos, y la capacidad de monitorear par\u00e1metros de calidad.\n\n2. **\u00bfQu\u00e9 aspectos f\u00edsicos deben considerarse en la configuraci\u00f3n de los sistemas de purificaci\u00f3n de agua?**\n   - Respuesta: Los aspectos f\u00edsicos incluyen la capacidad de recolectar muestras, el espacio disponible para la instalaci\u00f3n, las cargas estructurales en los edificios, el acceso adecuado para el mantenimiento, y la capacidad de manejar de manera segura los productos qu\u00edmicos de regeneraci\u00f3n y sanitizaci\u00f3n.\n\n3. **\u00bfQu\u00e9 se menciona sobre la producci\u00f3n de agua potable a partir de fuentes de agua cruda?**\n   - Respuesta: Se indica que el agua potable se deriva de fuentes de agua cruda como pozos, r\u00edos o embalses, y que no existen m\u00e9todos prescritos para el tratamiento de esta agua cruda, lo que permite una variedad de enfoques en su tratamiento.", "prev_section_summary": "### Temas Clave\n\n1. **Uso de BWFI (Agua para Inyecci\u00f3n)**\n   - BWFI es esencial en la fabricaci\u00f3n de productos inyectables, utilizado para disolver o diluir sustancias y para la fabricaci\u00f3n de agua est\u00e9ril para inyecciones.\n   - Debe emplearse para el enjuague final de equipos que entran en contacto con productos inyectables, as\u00ed como en procesos de lavado sin depirogenizaci\u00f3n posterior.\n\n2. **Especificaciones del Vapor**\n   - El vapor que entra en contacto con productos inyectables debe cumplir con las especificaciones de BWFI cuando se condensa.\n\n3. **Sistemas de Purificaci\u00f3n de Agua**\n   - No se definen m\u00e9todos de purificaci\u00f3n de agua en las farmacopeas, excepto para BWFI.\n   - La selecci\u00f3n del m\u00e9todo de purificaci\u00f3n debe ser adecuada para la aplicaci\u00f3n espec\u00edfica, considerando factores como calidad del agua, cantidad requerida, calidad del agua de alimentaci\u00f3n, y disponibilidad de instalaciones de soporte.\n\n### Entidades\n\n- **BWFI (Agua para Inyecci\u00f3n)**\n- **Productos Inyectables**\n- **Equipos de Fabricaci\u00f3n**\n- **Sistemas de Purificaci\u00f3n de Agua**\n- **Farmacopeas**\n- **Estrategia de Sanitizaci\u00f3n**\n- **Equipos de Tratamiento de Agua**\n\nEste resumen destaca la importancia del BWFI en la industria farmac\u00e9utica y los criterios necesarios para la selecci\u00f3n de m\u00e9todos de purificaci\u00f3n de agua, asegurando la calidad y seguridad de los productos inyectables.", "excerpt_keywords": "Keywords: water purification, drinking-water production, sanitary design, contamination risk, system specifications"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "86804cc6-b330-4558-87fe-9b3270a80325", "node_type": "4", "metadata": {"page_label": "88", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- the continuity of operational usage considering hours/days, days/years and planned downtime;\n- the total life-cycle costs (capital and operational including maintenance).\n\n## 5.1.3\n\nThe specifications for water purification equipment, storage and distribution systems should take into account the following:\n\n- the location of the plant room;\n- extremes in temperature that the system will encounter;\n- the risk of contamination from leachates from contact materials;\n- the adverse impact of adsorptive contact materials;\n- hygienic or sanitary design, where required;\n- corrosion resistance;\n- freedom from leakage;\n- a system configuration to avoid proliferation of microbiological organisms;\n- tolerance to cleaning and sanitizing agents (thermal and/or chemical);\n- the sanitization strategy;\n- the system capacity and output requirements;\n- the provision of all necessary instruments, test and sampling points to allow all the relevant critical quality parameters of the complete system to be monitored.\n\n## 5.1.4\n\nThe design, configuration and layout of the water purification equipment, storage and distribution systems should also take into account the following physical considerations:\n\n- ability to collect samples;\n- the space available for the installation;\n- structural loadings on buildings;\n- the provision of adequate access for maintenance;\n- the ability to safely handle regeneration and sanitization chemicals.\n\n## 5.2 Production of drinking-water\n\n### 5.2.1\n\nDrinking-water is derived from a raw water source such as a well, river or reservoir. There are no prescribed methods for the treatment of raw water to produce drinking-water from a specific raw water source.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "869e49916df7aaa5c6bc13adfe1c86e933b7258b0ad99fc508c5868c9f42cfa2", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- the continuity of operational usage considering hours/days, days/years and planned downtime;\n- the total life-cycle costs (capital and operational including maintenance).\n\n## 5.1.3\n\nThe specifications for water purification equipment, storage and distribution systems should take into account the following:\n\n- the location of the plant room;\n- extremes in temperature that the system will encounter;\n- the risk of contamination from leachates from contact materials;\n- the adverse impact of adsorptive contact materials;\n- hygienic or sanitary design, where required;\n- corrosion resistance;\n- freedom from leakage;\n- a system configuration to avoid proliferation of microbiological organisms;\n- tolerance to cleaning and sanitizing agents (thermal and/or chemical);\n- the sanitization strategy;\n- the system capacity and output requirements;\n- the provision of all necessary instruments, test and sampling points to allow all the relevant critical quality parameters of the complete system to be monitored.\n\n## 5.1.4\n\nThe design, configuration and layout of the water purification equipment, storage and distribution systems should also take into account the following physical considerations:\n\n- ability to collect samples;\n- the space available for the installation;\n- structural loadings on buildings;\n- the provision of adequate access for maintenance;\n- the ability to safely handle regeneration and sanitization chemicals.\n\n## 5.2 Production of drinking-water\n\n### 5.2.1\n\nDrinking-water is derived from a raw water source such as a well, river or reservoir. There are no prescribed methods for the treatment of raw water to produce drinking-water from a specific raw water source.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1764, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "4b02c493-43ad-47a1-a349-960214a17dc5": {"__data__": {"id_": "4b02c493-43ad-47a1-a349-960214a17dc5", "embedding": null, "metadata": {"page_label": "89", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 5.2.2\n\nTypical processes employed at a user plant or by a water supply authority include:\n\n- desalinization;\n- filtration;\n- softening;\n- disinfection or sanitization (e.g. by sodium hypochlorite (chlorine) injection);\n- iron (ferrous) removal;\n- precipitation;\n- reduction of concentration of specific inorganic and/or organic materials.\n\n## 5.2.3\n\nThe drinking-water quality should be monitored routinely to account for environmental, seasonal or supply changes which have an impact on the source water quality.\n\n## 5.2.4\n\nAdditional testing should be considered if there is any change in the raw-water source, treatment techniques or system configuration.\n\n## 5.2.5\n\nTrend review may be used to identify changes. If the drinking-water quality changes significantly, but is still within specification, the direct use of this water as a WPU, or as the feed-water to downstream treatment stages, should be reviewed and the result of the review documented.\n\n## 5.2.6\n\nWhere drinking-water is derived from an \u201cin-house\u201d system for the treatment of raw water, the water-treatment steps used and the system configuration should be documented. Changes to the system or to its operation should not be made until a review has been completed and the change approved by the QA department in accordance with change control procedures.\n\n## 5.2.7\n\nWhere drinking-water is stored and distributed by the user, the storage systems must not allow degradation of the water quality before use. After any such storage, testing should be carried out routinely in accordance with a defined method. Where water is stored, the system design and operation should ensure a turnover or recirculation of the stored water sufficient to prevent stagnation.\n\n## 5.2.8\n\nThe drinking-water system is usually considered to be an \u201cindirect impact system\u201d and does not need to be qualified.\n\n## 5.2.9\n\nDrinking-water purchased in bulk and transported to the user by tanker has additional problems and risks not associated with drinking-water delivered by pipeline. Vendor assessment and authorized certification activities, including confirmation of the acceptability of the delivery vehicle, should be undertaken in a similar way to that used for any other starting material.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Procesos de Tratamiento de Agua**: El documento describe los procesos t\u00edpicos utilizados en plantas de tratamiento de agua y por autoridades de suministro de agua, que incluyen desalinizaci\u00f3n, filtraci\u00f3n, desinfecci\u00f3n y eliminaci\u00f3n de hierro, entre otros.\n\n2. **Monitoreo de Calidad del Agua**: Se enfatiza la importancia del monitoreo rutinario de la calidad del agua potable para adaptarse a cambios ambientales, estacionales o en el suministro, as\u00ed como la necesidad de pruebas adicionales ante cambios en la fuente de agua cruda o en las t\u00e9cnicas de tratamiento.\n\n3. **Almacenamiento y Distribuci\u00f3n del Agua**: Se aborda la necesidad de que los sistemas de almacenamiento y distribuci\u00f3n de agua potable mantengan la calidad del agua y se realicen pruebas rutinarias para evitar la degradaci\u00f3n del agua antes de su uso.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 procedimientos deben seguirse antes de realizar cambios en un sistema de tratamiento de agua \"in-house\"?**\n   - El documento establece que cualquier cambio en el sistema o en su operaci\u00f3n debe ser revisado y aprobado por el departamento de aseguramiento de calidad (QA) de acuerdo con los procedimientos de control de cambios.\n\n2. **\u00bfCu\u00e1les son las implicaciones de utilizar agua potable comprada en bulk y transportada por cami\u00f3n?**\n   - El texto menciona que el agua potable comprada en bulk y transportada por cami\u00f3n presenta problemas y riesgos adicionales que no est\u00e1n asociados con el agua entregada por tuber\u00eda, lo que requiere una evaluaci\u00f3n del proveedor y actividades de certificaci\u00f3n autorizadas.\n\n3. **\u00bfQu\u00e9 medidas se deben tomar para asegurar que el agua almacenada no degrade su calidad?**\n   - Se indica que los sistemas de almacenamiento deben estar dise\u00f1ados y operados de tal manera que se garantice un recambio o recirculaci\u00f3n suficiente del agua almacenada para prevenir la estancaci\u00f3n, y que se deben realizar pruebas rutinarias de calidad del agua despu\u00e9s de cualquier almacenamiento.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS se centra en las especificaciones y consideraciones para los sistemas de purificaci\u00f3n de agua, almacenamiento y distribuci\u00f3n, as\u00ed como en la producci\u00f3n de agua potable. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n#### Temas Clave:\n1. **Especificaciones para Equipos de Purificaci\u00f3n de Agua**:\n   - Ubicaci\u00f3n de la planta.\n   - Temperaturas extremas.\n   - Riesgo de contaminaci\u00f3n.\n   - Dise\u00f1o higi\u00e9nico y resistencia a la corrosi\u00f3n.\n   - Prevenci\u00f3n de fugas y proliferaci\u00f3n de microorganismos.\n   - Estrategias de sanitizaci\u00f3n y monitoreo de calidad.\n\n2. **Consideraciones F\u00edsicas en el Dise\u00f1o**:\n   - Capacidad de recolecci\u00f3n de muestras.\n   - Espacio disponible para la instalaci\u00f3n.\n   - Cargas estructurales en edificios.\n   - Acceso para mantenimiento.\n   - Manejo seguro de productos qu\u00edmicos.\n\n3. **Producci\u00f3n de Agua Potable**:\n   - Fuentes de agua cruda (pozos, r\u00edos, embalses).\n   - Flexibilidad en los m\u00e9todos de tratamiento de agua cruda.\n\n#### Entidades:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que establece las directrices y especificaciones.\n- **Equipos de Purificaci\u00f3n de Agua**: Sistemas dise\u00f1ados para tratar agua cruda.\n- **Agua Potable**: Producto final derivado de fuentes de agua cruda.\n\nEste resumen destaca la importancia de un dise\u00f1o cuidadoso y la consideraci\u00f3n de m\u00faltiples factores para garantizar la calidad y seguridad del agua potable.", "excerpt_keywords": "Keywords: water treatment, drinking-water quality, monitoring, storage systems, vendor assessment"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "50c34126-af66-4385-b6f9-d83ac2fd748b", "node_type": "4", "metadata": {"page_label": "89", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 5.2.2\n\nTypical processes employed at a user plant or by a water supply authority include:\n\n- desalinization;\n- filtration;\n- softening;\n- disinfection or sanitization (e.g. by sodium hypochlorite (chlorine) injection);\n- iron (ferrous) removal;\n- precipitation;\n- reduction of concentration of specific inorganic and/or organic materials.\n\n## 5.2.3\n\nThe drinking-water quality should be monitored routinely to account for environmental, seasonal or supply changes which have an impact on the source water quality.\n\n## 5.2.4\n\nAdditional testing should be considered if there is any change in the raw-water source, treatment techniques or system configuration.\n\n## 5.2.5\n\nTrend review may be used to identify changes. If the drinking-water quality changes significantly, but is still within specification, the direct use of this water as a WPU, or as the feed-water to downstream treatment stages, should be reviewed and the result of the review documented.\n\n## 5.2.6\n\nWhere drinking-water is derived from an \u201cin-house\u201d system for the treatment of raw water, the water-treatment steps used and the system configuration should be documented. Changes to the system or to its operation should not be made until a review has been completed and the change approved by the QA department in accordance with change control procedures.\n\n## 5.2.7\n\nWhere drinking-water is stored and distributed by the user, the storage systems must not allow degradation of the water quality before use. After any such storage, testing should be carried out routinely in accordance with a defined method. Where water is stored, the system design and operation should ensure a turnover or recirculation of the stored water sufficient to prevent stagnation.\n\n## 5.2.8\n\nThe drinking-water system is usually considered to be an \u201cindirect impact system\u201d and does not need to be qualified.\n\n## 5.2.9\n\nDrinking-water purchased in bulk and transported to the user by tanker has additional problems and risks not associated with drinking-water delivered by pipeline. Vendor assessment and authorized certification activities, including confirmation of the acceptability of the delivery vehicle, should be undertaken in a similar way to that used for any other starting material.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "2908fcda45c9dff0b1dc1a18b3ee37d195ab7f8ac932d3b8af81dd37d1c518d2", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "## 5.2.2\n\nTypical processes employed at a user plant or by a water supply authority include:\n\n- desalinization;\n- filtration;\n- softening;\n- disinfection or sanitization (e.g. by sodium hypochlorite (chlorine) injection);\n- iron (ferrous) removal;\n- precipitation;\n- reduction of concentration of specific inorganic and/or organic materials.\n\n## 5.2.3\n\nThe drinking-water quality should be monitored routinely to account for environmental, seasonal or supply changes which have an impact on the source water quality.\n\n## 5.2.4\n\nAdditional testing should be considered if there is any change in the raw-water source, treatment techniques or system configuration.\n\n## 5.2.5\n\nTrend review may be used to identify changes. If the drinking-water quality changes significantly, but is still within specification, the direct use of this water as a WPU, or as the feed-water to downstream treatment stages, should be reviewed and the result of the review documented.\n\n## 5.2.6\n\nWhere drinking-water is derived from an \u201cin-house\u201d system for the treatment of raw water, the water-treatment steps used and the system configuration should be documented. Changes to the system or to its operation should not be made until a review has been completed and the change approved by the QA department in accordance with change control procedures.\n\n## 5.2.7\n\nWhere drinking-water is stored and distributed by the user, the storage systems must not allow degradation of the water quality before use. After any such storage, testing should be carried out routinely in accordance with a defined method. Where water is stored, the system design and operation should ensure a turnover or recirculation of the stored water sufficient to prevent stagnation.\n\n## 5.2.8\n\nThe drinking-water system is usually considered to be an \u201cindirect impact system\u201d and does not need to be qualified.\n\n## 5.2.9\n\nDrinking-water purchased in bulk and transported to the user by tanker has additional problems and risks not associated with drinking-water delivered by pipeline. Vendor assessment and authorized certification activities, including confirmation of the acceptability of the delivery vehicle, should be undertaken in a similar way to that used for any other starting material.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2244, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c02a74fa-176a-48d3-9c85-6a9aea8ae409": {"__data__": {"id_": "c02a74fa-176a-48d3-9c85-6a9aea8ae409", "embedding": null, "metadata": {"page_label": "90", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 5.2.10\n\nEquipment and systems used to produce drinking-water should be able to be drained and sanitized. Storage tanks should be closed with appropriately protected vents, and should allow for visual inspection and for being drained and sanitized. Distribution pipework should be able to be drained or flushed and sanitized.\n\n## 5.2.11\n\nSpecial care should be taken to control microbiological contamination of sand filters, carbon beds and water softeners. Once microorganisms have infected a system, the contamination can rapidly form biofilms and spread throughout the system. Techniques for controlling contamination such as back-flushing, chemical and/or thermal sanitization and frequent regeneration should be considered as appropriate.\n\n# 5.3 Production of purified water\n\n## 5.3.1\n\nAny appropriate qualified purification technique or sequence of techniques may be used to prepare purified water (PW). PW is commonly produced by ion exchange, RO, ultrafiltration and/or electro-deionization processes and distillation.\n\n## 5.3.2\n\nThe following should be considered when configuring a water purification system or defining user requirement specifications (URS):\n\n- the feed-water quality and its variation over seasons;\n- the quantity of water required by the user;\n- the required water-quality specification;\n- the sequence of purification stages required;\n- the energy consumption;\n- the extent of pretreatment required to protect the final purification steps;\n- performance optimization, including yield and efficiency of unit treatment-process steps;\n- appropriately located sampling points designed in such a way as to avoid potential contamination;\n- unit process steps should be provided with appropriate instrumentation to measure parameters such as flow, pressure, temperature, conductivity, pH and total organic carbon.\n\n## 5.3.3\n\nAmbient-temperature systems such as ion exchange, RO and ultrafiltration are especially susceptible to microbiological contamination, particularly when equipment is static during periods of no or low demand for water. It is essential to consider the mechanisms for microbiological control and sanitization.\n\nThe method for sanitizing each stage of purification needs to be defined and must include verification of the removal of any agents used. There should be documented evidence of its efficacy.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Mantenimiento y Sanitizaci\u00f3n de Equipos de Agua**: Los equipos y sistemas utilizados para la producci\u00f3n de agua potable deben ser capaces de drenarse y desinfectarse adecuadamente. Esto incluye tanques de almacenamiento que deben estar cerrados con ventilaciones protegidas y permitir inspecciones visuales, as\u00ed como tuber\u00edas de distribuci\u00f3n que deben poder drenarse o enjuagarse.\n\n2. **Control de Contaminaci\u00f3n Microbiol\u00f3gica**: Es crucial controlar la contaminaci\u00f3n microbiol\u00f3gica en sistemas como filtros de arena, lechos de carbono y suavizadores de agua. La contaminaci\u00f3n puede formar biofilms r\u00e1pidamente, por lo que se deben considerar t\u00e9cnicas de control como el retro-lavado y la desinfecci\u00f3n qu\u00edmica o t\u00e9rmica.\n\n3. **Producci\u00f3n de Agua Purificada**: Se pueden utilizar diversas t\u00e9cnicas de purificaci\u00f3n para preparar agua purificada (PW), como intercambio i\u00f3nico, \u00f3smosis inversa (RO), ultrafiltraci\u00f3n y destilaci\u00f3n. Al configurar un sistema de purificaci\u00f3n, se deben considerar factores como la calidad del agua de entrada, la cantidad requerida, las especificaciones de calidad del agua y la optimizaci\u00f3n del rendimiento.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones clave al definir las especificaciones de requisitos del usuario (URS) para un sistema de purificaci\u00f3n de agua?**\n   - Esta pregunta se centra en los factores que deben tenerse en cuenta al configurar un sistema de purificaci\u00f3n, como la calidad del agua de entrada y la cantidad requerida.\n\n2. **\u00bfQu\u00e9 t\u00e9cnicas se pueden implementar para controlar la contaminaci\u00f3n microbiol\u00f3gica en filtros de agua y suavizadores?**\n   - Esta pregunta busca profundizar en las t\u00e9cnicas espec\u00edficas que se pueden utilizar para prevenir la contaminaci\u00f3n microbiol\u00f3gica en sistemas de tratamiento de agua.\n\n3. **\u00bfQu\u00e9 m\u00e9todos de sanitizaci\u00f3n son necesarios para cada etapa del proceso de purificaci\u00f3n de agua y c\u00f3mo se verifica su eficacia?**\n   - Esta pregunta aborda la importancia de definir m\u00e9todos de sanitizaci\u00f3n y la necesidad de documentaci\u00f3n que respalde su efectividad en el proceso de purificaci\u00f3n.", "prev_section_summary": "### Temas Clave\n\n1. **Procesos de Tratamiento de Agua**: Se describen los m\u00e9todos t\u00edpicos utilizados en plantas de tratamiento y por autoridades de suministro de agua, que incluyen:\n   - Desalinizaci\u00f3n\n   - Filtraci\u00f3n\n   - Ablandamiento\n   - Desinfecci\u00f3n (por ejemplo, inyecci\u00f3n de hipoclorito de sodio)\n   - Eliminaci\u00f3n de hierro\n   - Precipitaci\u00f3n\n   - Reducci\u00f3n de la concentraci\u00f3n de materiales inorg\u00e1nicos y/o org\u00e1nicos espec\u00edficos\n\n2. **Monitoreo de Calidad del Agua**: Se destaca la necesidad de monitorear rutinariamente la calidad del agua potable para adaptarse a cambios ambientales, estacionales o en el suministro.\n\n3. **Pruebas Adicionales**: Se sugiere realizar pruebas adicionales si hay cambios en la fuente de agua cruda, t\u00e9cnicas de tratamiento o configuraci\u00f3n del sistema.\n\n4. **Revisi\u00f3n de Tendencias**: Se puede utilizar la revisi\u00f3n de tendencias para identificar cambios en la calidad del agua potable y documentar los resultados de la revisi\u00f3n si hay cambios significativos.\n\n5. **Documentaci\u00f3n de Sistemas \"In-House\"**: Los pasos de tratamiento y la configuraci\u00f3n del sistema deben ser documentados, y cualquier cambio debe ser revisado y aprobado por el departamento de aseguramiento de calidad (QA).\n\n6. **Almacenamiento y Distribuci\u00f3n**: Los sistemas de almacenamiento deben prevenir la degradaci\u00f3n de la calidad del agua y asegurar un recambio suficiente para evitar la estancaci\u00f3n. Se deben realizar pruebas rutinarias despu\u00e9s del almacenamiento.\n\n7. **Agua Comprada en Bulk**: El agua potable comprada en bulk y transportada por cami\u00f3n presenta riesgos adicionales, lo que requiere evaluaci\u00f3n del proveedor y certificaci\u00f3n de la aceptabilidad del veh\u00edculo de entrega.\n\n### Entidades\n\n- **Agua Potable**: El foco principal del documento.\n- **Plantas de Tratamiento de Agua**: Entidades que realizan los procesos de tratamiento.\n- **Autoridades de Suministro de Agua**: Organismos responsables de la calidad del agua potable.\n- **Departamento de Aseguramiento de Calidad (QA)**: Entidad que aprueba cambios en los sistemas de tratamiento.\n- **Proveedores de Agua**: Entidades que suministran agua, especialmente en el contexto de agua comprada en bulk. \n\nEste resumen encapsula los aspectos esenciales de la secci\u00f3n, destacando tanto los procesos como las consideraciones de calidad y gesti\u00f3n del agua potable.", "excerpt_keywords": "Keywords: drinking-water, purification, microbiological contamination, sanitization, water quality"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ba4a0582-994b-47b0-87d8-a8fb8d256b79", "node_type": "4", "metadata": {"page_label": "90", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 5.2.10\n\nEquipment and systems used to produce drinking-water should be able to be drained and sanitized. Storage tanks should be closed with appropriately protected vents, and should allow for visual inspection and for being drained and sanitized. Distribution pipework should be able to be drained or flushed and sanitized.\n\n## 5.2.11\n\nSpecial care should be taken to control microbiological contamination of sand filters, carbon beds and water softeners. Once microorganisms have infected a system, the contamination can rapidly form biofilms and spread throughout the system. Techniques for controlling contamination such as back-flushing, chemical and/or thermal sanitization and frequent regeneration should be considered as appropriate.\n\n# 5.3 Production of purified water\n\n## 5.3.1\n\nAny appropriate qualified purification technique or sequence of techniques may be used to prepare purified water (PW). PW is commonly produced by ion exchange, RO, ultrafiltration and/or electro-deionization processes and distillation.\n\n## 5.3.2\n\nThe following should be considered when configuring a water purification system or defining user requirement specifications (URS):\n\n- the feed-water quality and its variation over seasons;\n- the quantity of water required by the user;\n- the required water-quality specification;\n- the sequence of purification stages required;\n- the energy consumption;\n- the extent of pretreatment required to protect the final purification steps;\n- performance optimization, including yield and efficiency of unit treatment-process steps;\n- appropriately located sampling points designed in such a way as to avoid potential contamination;\n- unit process steps should be provided with appropriate instrumentation to measure parameters such as flow, pressure, temperature, conductivity, pH and total organic carbon.\n\n## 5.3.3\n\nAmbient-temperature systems such as ion exchange, RO and ultrafiltration are especially susceptible to microbiological contamination, particularly when equipment is static during periods of no or low demand for water. It is essential to consider the mechanisms for microbiological control and sanitization.\n\nThe method for sanitizing each stage of purification needs to be defined and must include verification of the removal of any agents used. There should be documented evidence of its efficacy.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "d5facbd29775be2bdfd04c99e902be19ec39fda367c3b8cca03313af8b37c177", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 5.2.10\n\nEquipment and systems used to produce drinking-water should be able to be drained and sanitized. Storage tanks should be closed with appropriately protected vents, and should allow for visual inspection and for being drained and sanitized. Distribution pipework should be able to be drained or flushed and sanitized.\n\n## 5.2.11\n\nSpecial care should be taken to control microbiological contamination of sand filters, carbon beds and water softeners. Once microorganisms have infected a system, the contamination can rapidly form biofilms and spread throughout the system. Techniques for controlling contamination such as back-flushing, chemical and/or thermal sanitization and frequent regeneration should be considered as appropriate.\n\n# 5.3 Production of purified water\n\n## 5.3.1\n\nAny appropriate qualified purification technique or sequence of techniques may be used to prepare purified water (PW). PW is commonly produced by ion exchange, RO, ultrafiltration and/or electro-deionization processes and distillation.\n\n## 5.3.2\n\nThe following should be considered when configuring a water purification system or defining user requirement specifications (URS):\n\n- the feed-water quality and its variation over seasons;\n- the quantity of water required by the user;\n- the required water-quality specification;\n- the sequence of purification stages required;\n- the energy consumption;\n- the extent of pretreatment required to protect the final purification steps;\n- performance optimization, including yield and efficiency of unit treatment-process steps;\n- appropriately located sampling points designed in such a way as to avoid potential contamination;\n- unit process steps should be provided with appropriate instrumentation to measure parameters such as flow, pressure, temperature, conductivity, pH and total organic carbon.\n\n## 5.3.3\n\nAmbient-temperature systems such as ion exchange, RO and ultrafiltration are especially susceptible to microbiological contamination, particularly when equipment is static during periods of no or low demand for water. It is essential to consider the mechanisms for microbiological control and sanitization.\n\nThe method for sanitizing each stage of purification needs to be defined and must include verification of the removal of any agents used. There should be documented evidence of its efficacy.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2347, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "6c0dc010-6c1b-450b-95b9-9567e4777bf4": {"__data__": {"id_": "6c0dc010-6c1b-450b-95b9-9567e4777bf4", "embedding": null, "metadata": {"page_label": "91", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 5.3.4\n\nThe following should be considered:\n\n- Maintenance of minimum flow through the water generation system is recommended at all times;\n- Control of temperature in the system by heat exchanger or plant-room cooling to reduce the risk of microbial growth (guidance value < 25 \u00b0C);\n- Provision of ultraviolet disinfection;\n- Selection of water-treatment components that can periodically be thermally sanitized;\n- Application of chemical sanitization (including agents such as ozone, hydrogen peroxide and/or peracetic acid);\n- Thermal sanitization at > 65 \u00b0C.\n\n## 5.4 Production of highly purified water\n\n5.4.1 Highly purified water (HPW) can be produced by double-pass reverse osmosis coupled with ultrafiltration or by any other appropriate qualified purification technique or sequence of techniques.\n\n5.4.2 The guidance provided in section 5.3 for PW is equally applicable to HPW.\n\n## 5.5 Production of water for injection(s)\n\n5.5.1 Some pharmacopoeias prescribe or limit the permitted final water purification stage in the production of BWFI. Distillation is the preferred technique; it is considered a more robust technique based on phase change, and in some cases, high-temperature operation of the process equipment.\n\n5.5.2 The following should be considered when designing a water purification system and defining URS:\n\n- The feed-water quality;\n- The required water quality specification;\n- The quantity of water;\n- The optimum generator size or generators with variable control to avoid over-frequent start/stop cycling;\n- Blow-down and dump functions;\n- Cool-down venting to avoid contamination ingress.\n\n5.5.3 The system configuration guidance provided in section 5.3 for PW is equally applicable to water for injection.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda la producci\u00f3n y tratamiento de agua para diferentes usos, incluyendo agua purificada (PW), agua altamente purificada (HPW) y agua para inyecciones (BWFI). Se destacan las mejores pr\u00e1cticas para el mantenimiento de sistemas de generaci\u00f3n de agua, el control de temperatura, la desinfecci\u00f3n y la selecci\u00f3n de componentes de tratamiento. Tambi\u00e9n se discuten las t\u00e9cnicas de purificaci\u00f3n recomendadas, como la \u00f3smosis inversa y la destilaci\u00f3n, as\u00ed como consideraciones importantes al dise\u00f1ar sistemas de purificaci\u00f3n de agua.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las recomendaciones espec\u00edficas para el control de temperatura en los sistemas de generaci\u00f3n de agua para minimizar el crecimiento microbiano?**\n   - Respuesta: Se recomienda mantener la temperatura del sistema por debajo de 25 \u00b0C mediante el uso de intercambiadores de calor o enfriamiento en la sala de planta.\n\n2. **\u00bfQu\u00e9 t\u00e9cnicas de desinfecci\u00f3n se sugieren para asegurar la calidad del agua purificada y c\u00f3mo se pueden aplicar?**\n   - Respuesta: Se sugiere la provisi\u00f3n de desinfecci\u00f3n ultravioleta, la selecci\u00f3n de componentes que puedan ser termalmente desinfectados peri\u00f3dicamente, y la aplicaci\u00f3n de sanitizaci\u00f3n qu\u00edmica utilizando agentes como ozono, per\u00f3xido de hidr\u00f3geno y/o \u00e1cido perac\u00e9tico.\n\n3. **Al dise\u00f1ar un sistema de purificaci\u00f3n de agua para inyecciones, \u00bfqu\u00e9 factores deben considerarse en la especificaci\u00f3n de requisitos del usuario (URS)?**\n   - Respuesta: Se deben considerar la calidad del agua de alimentaci\u00f3n, la especificaci\u00f3n de calidad del agua requerida, la cantidad de agua necesaria, el tama\u00f1o \u00f3ptimo del generador, las funciones de blow-down y dump, y el venting de enfriamiento para evitar la entrada de contaminantes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Mantenimiento y Sanitizaci\u00f3n de Equipos de Agua**:\n   - Los equipos y sistemas para la producci\u00f3n de agua potable deben ser drenables y desinfectables.\n   - Los tanques de almacenamiento deben tener ventilaciones protegidas y permitir inspecciones visuales.\n   - Las tuber\u00edas de distribuci\u00f3n deben poder drenarse o enjuagarse.\n\n2. **Control de Contaminaci\u00f3n Microbiol\u00f3gica**:\n   - Es esencial controlar la contaminaci\u00f3n en filtros de arena, lechos de carbono y suavizadores de agua.\n   - La contaminaci\u00f3n puede formar biofilms r\u00e1pidamente, lo que requiere t\u00e9cnicas de control como retro-lavado y desinfecci\u00f3n qu\u00edmica o t\u00e9rmica.\n\n3. **Producci\u00f3n de Agua Purificada (PW)**:\n   - Se pueden utilizar diversas t\u00e9cnicas de purificaci\u00f3n, incluyendo intercambio i\u00f3nico, \u00f3smosis inversa (RO), ultrafiltraci\u00f3n, electro-deionizaci\u00f3n y destilaci\u00f3n.\n   - Al configurar un sistema de purificaci\u00f3n, se deben considerar:\n     - Calidad del agua de entrada y su variaci\u00f3n estacional.\n     - Cantidad de agua requerida.\n     - Especificaciones de calidad del agua.\n     - Secuencia de etapas de purificaci\u00f3n.\n     - Consumo energ\u00e9tico.\n     - Necesidades de pretreatment para proteger etapas finales de purificaci\u00f3n.\n     - Optimizaci\u00f3n del rendimiento, incluyendo rendimiento y eficiencia de los procesos.\n     - Puntos de muestreo ubicados adecuadamente para evitar contaminaci\u00f3n.\n     - Instrumentaci\u00f3n adecuada para medir par\u00e1metros como flujo, presi\u00f3n, temperatura, conductividad, pH y carbono org\u00e1nico total.\n\n4. **Contaminaci\u00f3n Microbiol\u00f3gica en Sistemas de Temperatura Ambiente**:\n   - Sistemas como intercambio i\u00f3nico, RO y ultrafiltraci\u00f3n son susceptibles a contaminaci\u00f3n microbiol\u00f3gica, especialmente cuando est\u00e1n inactivos.\n   - Es crucial definir m\u00e9todos de sanitizaci\u00f3n para cada etapa de purificaci\u00f3n y verificar la eficacia de los agentes utilizados.\n\n### Entidades Clave\n- **Equipos y Sistemas**: Equipos de producci\u00f3n de agua potable, tanques de almacenamiento, tuber\u00edas de distribuci\u00f3n.\n- **Contaminaci\u00f3n Microbiol\u00f3gica**: Filtros de arena, lechos de carbono, suavizadores de agua, biofilms.\n- **T\u00e9cnicas de Purificaci\u00f3n**: Intercambio i\u00f3nico, \u00f3smosis inversa (RO), ultrafiltraci\u00f3n, electro-deionizaci\u00f3n, destilaci\u00f3n.\n- **Par\u00e1metros de Medici\u00f3n**: Flujo, presi\u00f3n, temperatura, conductividad, pH, carbono org\u00e1nico total. \n\nEste resumen destaca la importancia del mantenimiento, control de contaminaci\u00f3n y t\u00e9cnicas de purificaci\u00f3n en la producci\u00f3n de agua potable y purificada.", "excerpt_keywords": "Keywords: water purification, microbial control, highly purified water, water for injection, sanitization techniques"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "259e8698-ea01-4173-a0d0-d04aed835eb6", "node_type": "4", "metadata": {"page_label": "91", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 5.3.4\n\nThe following should be considered:\n\n- Maintenance of minimum flow through the water generation system is recommended at all times;\n- Control of temperature in the system by heat exchanger or plant-room cooling to reduce the risk of microbial growth (guidance value < 25 \u00b0C);\n- Provision of ultraviolet disinfection;\n- Selection of water-treatment components that can periodically be thermally sanitized;\n- Application of chemical sanitization (including agents such as ozone, hydrogen peroxide and/or peracetic acid);\n- Thermal sanitization at > 65 \u00b0C.\n\n## 5.4 Production of highly purified water\n\n5.4.1 Highly purified water (HPW) can be produced by double-pass reverse osmosis coupled with ultrafiltration or by any other appropriate qualified purification technique or sequence of techniques.\n\n5.4.2 The guidance provided in section 5.3 for PW is equally applicable to HPW.\n\n## 5.5 Production of water for injection(s)\n\n5.5.1 Some pharmacopoeias prescribe or limit the permitted final water purification stage in the production of BWFI. Distillation is the preferred technique; it is considered a more robust technique based on phase change, and in some cases, high-temperature operation of the process equipment.\n\n5.5.2 The following should be considered when designing a water purification system and defining URS:\n\n- The feed-water quality;\n- The required water quality specification;\n- The quantity of water;\n- The optimum generator size or generators with variable control to avoid over-frequent start/stop cycling;\n- Blow-down and dump functions;\n- Cool-down venting to avoid contamination ingress.\n\n5.5.3 The system configuration guidance provided in section 5.3 for PW is equally applicable to water for injection.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "fef8b0adb3b875388762f592aae68039cc5495c8f6f3e9d6d18529378af5cb0a", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "## 5.3.4\n\nThe following should be considered:\n\n- Maintenance of minimum flow through the water generation system is recommended at all times;\n- Control of temperature in the system by heat exchanger or plant-room cooling to reduce the risk of microbial growth (guidance value < 25 \u00b0C);\n- Provision of ultraviolet disinfection;\n- Selection of water-treatment components that can periodically be thermally sanitized;\n- Application of chemical sanitization (including agents such as ozone, hydrogen peroxide and/or peracetic acid);\n- Thermal sanitization at > 65 \u00b0C.\n\n## 5.4 Production of highly purified water\n\n5.4.1 Highly purified water (HPW) can be produced by double-pass reverse osmosis coupled with ultrafiltration or by any other appropriate qualified purification technique or sequence of techniques.\n\n5.4.2 The guidance provided in section 5.3 for PW is equally applicable to HPW.\n\n## 5.5 Production of water for injection(s)\n\n5.5.1 Some pharmacopoeias prescribe or limit the permitted final water purification stage in the production of BWFI. Distillation is the preferred technique; it is considered a more robust technique based on phase change, and in some cases, high-temperature operation of the process equipment.\n\n5.5.2 The following should be considered when designing a water purification system and defining URS:\n\n- The feed-water quality;\n- The required water quality specification;\n- The quantity of water;\n- The optimum generator size or generators with variable control to avoid over-frequent start/stop cycling;\n- Blow-down and dump functions;\n- Cool-down venting to avoid contamination ingress.\n\n5.5.3 The system configuration guidance provided in section 5.3 for PW is equally applicable to water for injection.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1736, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ae95e94f-d395-4dd8-8434-54230be7bb5c": {"__data__": {"id_": "ae95e94f-d395-4dd8-8434-54230be7bb5c", "embedding": null, "metadata": {"page_label": "92", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 6. Water storage and distribution systems\n\n6.1 This section applies to WPU systems for PW, BHPW and BWFI. The water storage and distribution should work in conjunction with the purification plant to ensure delivery of water of consistent quality to the user points, and to ensure optimum operation of the water purification equipment.\n\n## 6.1 General\n\n6.1.1 The storage and distribution system should be considered as a key part of the whole system and should be designed to be fully integrated with the water purification components of the system.\n\n6.1.2 Once water has been purified using an appropriate method it can either be used directly or, more frequently, it will be fed into a storage vessel for subsequent distribution to points of use. The following text describes the requirements for storage and distribution systems and point of use (POU).\n\n6.1.3 The storage and distribution system should be configured to prevent microbial proliferation and recontamination of the water (PW, BHPW, BWFI) after treatment. It should be subjected to a combination of online and offline monitoring to ensure that the appropriate water specification is maintained.\n\n## 6.2 Materials that come into contact with systems for water for pharmaceutical use\n\n6.2.1 This section applies to generation equipment for PW, BHPW and BWFI and the associated storage and distribution systems.\n\n6.2.2 The materials that come into contact with WPU, including pipework, valves and fittings, seals, diaphragms and instruments, should be selected to satisfy the following objectives.\n\n- **Compatibility.** The compatibility and suitability of the materials should encompass the full range of its working temperature and potential chemicals that will come into contact with the system at rest, in operation and during sanitization.\n\n- **Prevention of leaching.** All materials that come into contact with WPU should be non-leaching at the range of working and sanitization temperatures of the system.\n\n- **Corrosion resistance.** PW, BHPW and BWFI are highly corrosive.\n\nTo prevent failure of the system and contamination of the water, the materials selected must be appropriate, the method of jointing must be carefully controlled and all fittings and components must be compatible with the pipework.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Importancia de los sistemas de almacenamiento y distribuci\u00f3n de agua**: Los sistemas de almacenamiento y distribuci\u00f3n de agua son componentes cr\u00edticos en la infraestructura de agua para uso farmac\u00e9utico (PW, BHPW y BWFI). Deben integrarse completamente con las plantas de purificaci\u00f3n para garantizar la entrega de agua de calidad constante y el funcionamiento \u00f3ptimo del equipo de purificaci\u00f3n.\n\n2. **Requisitos de dise\u00f1o y materiales**: Los sistemas de almacenamiento y distribuci\u00f3n deben estar dise\u00f1ados para prevenir la proliferaci\u00f3n microbiana y la recontaminaci\u00f3n del agua. Adem\u00e1s, los materiales que entran en contacto con el agua deben ser compatibles, no permitir la lixiviaci\u00f3n y ser resistentes a la corrosi\u00f3n.\n\n3. **Monitoreo y control**: Es esencial implementar un monitoreo tanto en l\u00ednea como fuera de l\u00ednea para asegurar que se mantengan las especificaciones adecuadas del agua despu\u00e9s del tratamiento.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las caracter\u00edsticas clave que deben tener los materiales utilizados en los sistemas de almacenamiento y distribuci\u00f3n de agua para uso farmac\u00e9utico?**\n   - Respuesta: Los materiales deben ser compatibles con el rango de temperatura de trabajo y los qu\u00edmicos en contacto, no deben permitir la lixiviaci\u00f3n a las temperaturas de trabajo y sanitizaci\u00f3n, y deben ser resistentes a la corrosi\u00f3n.\n\n2. **\u00bfQu\u00e9 medidas se deben tomar para prevenir la recontaminaci\u00f3n del agua en los sistemas de almacenamiento y distribuci\u00f3n?**\n   - Respuesta: Los sistemas deben estar configurados para prevenir la proliferaci\u00f3n microbiana y la recontaminaci\u00f3n, y deben ser sometidos a un monitoreo combinado en l\u00ednea y fuera de l\u00ednea para asegurar que se mantengan las especificaciones del agua.\n\n3. **\u00bfPor qu\u00e9 es importante la integraci\u00f3n de los sistemas de almacenamiento y distribuci\u00f3n con las plantas de purificaci\u00f3n de agua?**\n   - Respuesta: La integraci\u00f3n es crucial para asegurar la entrega de agua de calidad constante a los puntos de uso y para garantizar el funcionamiento \u00f3ptimo del equipo de purificaci\u00f3n, lo que es esencial en aplicaciones farmac\u00e9uticas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Mantenimiento de Sistemas de Generaci\u00f3n de Agua**:\n   - Se recomienda mantener un flujo m\u00ednimo en todo momento.\n   - Control de temperatura para minimizar el crecimiento microbiano, con un valor gu\u00eda de < 25 \u00b0C.\n\n2. **Desinfecci\u00f3n**:\n   - Provisi\u00f3n de desinfecci\u00f3n ultravioleta.\n   - Selecci\u00f3n de componentes de tratamiento que puedan ser desinfectados t\u00e9rmicamente.\n   - Aplicaci\u00f3n de sanitizaci\u00f3n qu\u00edmica (ozono, per\u00f3xido de hidr\u00f3geno, \u00e1cido perac\u00e9tico).\n   - Sanitizaci\u00f3n t\u00e9rmica a temperaturas superiores a 65 \u00b0C.\n\n3. **Producci\u00f3n de Agua Altamente Purificada (HPW)**:\n   - Producci\u00f3n mediante \u00f3smosis inversa de doble paso y ultrafiltraci\u00f3n o t\u00e9cnicas de purificaci\u00f3n calificadas.\n   - Las recomendaciones para agua purificada (PW) son aplicables a HPW.\n\n4. **Producci\u00f3n de Agua para Inyecciones (BWFI)**:\n   - La destilaci\u00f3n es la t\u00e9cnica preferida para la purificaci\u00f3n final.\n   - Consideraciones al dise\u00f1ar un sistema de purificaci\u00f3n:\n     - Calidad del agua de alimentaci\u00f3n.\n     - Especificaciones de calidad del agua requerida.\n     - Cantidad de agua necesaria.\n     - Tama\u00f1o \u00f3ptimo del generador y control variable para evitar ciclos de inicio/parada frecuentes.\n     - Funciones de blow-down y dump.\n     - Ventilaci\u00f3n de enfriamiento para evitar la entrada de contaminantes.\n\n5. **Relevancia de las Normas Farmacopeas**:\n   - Algunas farmacopeas prescriben o limitan las etapas de purificaci\u00f3n permitidas para BWFI.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad del documento.\n- **Agentes Qu\u00edmicos**: Ozono, per\u00f3xido de hidr\u00f3geno, \u00e1cido perac\u00e9tico.\n- **T\u00e9cnicas de Purificaci\u00f3n**: \u00d3smosis inversa, ultrafiltraci\u00f3n, destilaci\u00f3n.\n- **Tipos de Agua**: Agua Purificada (PW), Agua Altamente Purificada (HPW), Agua para Inyecciones (BWFI).", "excerpt_keywords": "Keywords: water storage, distribution systems, pharmaceutical use, microbial prevention, material compatibility"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c43262cd-2e2c-48f0-b267-deb394deda79", "node_type": "4", "metadata": {"page_label": "92", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 6. Water storage and distribution systems\n\n6.1 This section applies to WPU systems for PW, BHPW and BWFI. The water storage and distribution should work in conjunction with the purification plant to ensure delivery of water of consistent quality to the user points, and to ensure optimum operation of the water purification equipment.\n\n## 6.1 General\n\n6.1.1 The storage and distribution system should be considered as a key part of the whole system and should be designed to be fully integrated with the water purification components of the system.\n\n6.1.2 Once water has been purified using an appropriate method it can either be used directly or, more frequently, it will be fed into a storage vessel for subsequent distribution to points of use. The following text describes the requirements for storage and distribution systems and point of use (POU).\n\n6.1.3 The storage and distribution system should be configured to prevent microbial proliferation and recontamination of the water (PW, BHPW, BWFI) after treatment. It should be subjected to a combination of online and offline monitoring to ensure that the appropriate water specification is maintained.\n\n## 6.2 Materials that come into contact with systems for water for pharmaceutical use\n\n6.2.1 This section applies to generation equipment for PW, BHPW and BWFI and the associated storage and distribution systems.\n\n6.2.2 The materials that come into contact with WPU, including pipework, valves and fittings, seals, diaphragms and instruments, should be selected to satisfy the following objectives.\n\n- **Compatibility.** The compatibility and suitability of the materials should encompass the full range of its working temperature and potential chemicals that will come into contact with the system at rest, in operation and during sanitization.\n\n- **Prevention of leaching.** All materials that come into contact with WPU should be non-leaching at the range of working and sanitization temperatures of the system.\n\n- **Corrosion resistance.** PW, BHPW and BWFI are highly corrosive.\n\nTo prevent failure of the system and contamination of the water, the materials selected must be appropriate, the method of jointing must be carefully controlled and all fittings and components must be compatible with the pipework.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "d0511d8f4e2c4cc10c0cca36a42444a6f6d6ce4baab627aedbe80093d52a8527", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 6. Water storage and distribution systems\n\n6.1 This section applies to WPU systems for PW, BHPW and BWFI. The water storage and distribution should work in conjunction with the purification plant to ensure delivery of water of consistent quality to the user points, and to ensure optimum operation of the water purification equipment.\n\n## 6.1 General\n\n6.1.1 The storage and distribution system should be considered as a key part of the whole system and should be designed to be fully integrated with the water purification components of the system.\n\n6.1.2 Once water has been purified using an appropriate method it can either be used directly or, more frequently, it will be fed into a storage vessel for subsequent distribution to points of use. The following text describes the requirements for storage and distribution systems and point of use (POU).\n\n6.1.3 The storage and distribution system should be configured to prevent microbial proliferation and recontamination of the water (PW, BHPW, BWFI) after treatment. It should be subjected to a combination of online and offline monitoring to ensure that the appropriate water specification is maintained.\n\n## 6.2 Materials that come into contact with systems for water for pharmaceutical use\n\n6.2.1 This section applies to generation equipment for PW, BHPW and BWFI and the associated storage and distribution systems.\n\n6.2.2 The materials that come into contact with WPU, including pipework, valves and fittings, seals, diaphragms and instruments, should be selected to satisfy the following objectives.\n\n- **Compatibility.** The compatibility and suitability of the materials should encompass the full range of its working temperature and potential chemicals that will come into contact with the system at rest, in operation and during sanitization.\n\n- **Prevention of leaching.** All materials that come into contact with WPU should be non-leaching at the range of working and sanitization temperatures of the system.\n\n- **Corrosion resistance.** PW, BHPW and BWFI are highly corrosive.\n\nTo prevent failure of the system and contamination of the water, the materials selected must be appropriate, the method of jointing must be carefully controlled and all fittings and components must be compatible with the pipework.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2278, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "59c7a740-ed8a-44f1-8ee1-e724aaef4765": {"__data__": {"id_": "59c7a740-ed8a-44f1-8ee1-e724aaef4765", "embedding": null, "metadata": {"page_label": "93", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The system should be passivated after initial installation or after significant modification. When accelerated passivation is undertaken the system should be thoroughly cleaned first and the passivation process should be undertaken in accordance with a clearly defined documented procedure.\n\n- **Smooth internal finish.** Once water has been purified it is susceptible to microbiological contamination and the system is subject to the formation of biofilms when cold storage and distribution are employed. Smooth internal surfaces help to avoid roughness and crevices within the WPU system. Crevices can be the source of contamination because of possible accumulation of microorganisms and formation of biofilms. Crevices are also frequently sites where corrosion can commence. The internal material finish should have an arithmetical average surface roughness of not greater than 0.8 micrometre (Ra). When stainless steel is used, mechanical and electro-polishing techniques may be employed. Electro-polishing improves the resistance of the stainless-steel material to surface corrosion.\n\n- **Jointing.** The selected system materials should be easily joined by welding in a controlled manner. The control of the process should include, as a minimum, qualification of the operator, documentation of the welder set-up, work session test pieces (coupons), logs of all welds and visual inspection of a defined proportion of welds, e.g. 100% hand welds, 10% automatic welds.\n\n- **Design of flanges, unions and valves.** Where flanges, unions or valves are used they should be of a hygienic or sanitary design. Appropriate checks should be carried out to ensure that the correct seals and diaphragms are used and that they are fitted and tightened correctly. Threaded connections should be avoided.\n\n- **Documentation.** All system components should be fully documented and be supported by original or certified copies of material certificates.\n\n- **Materials.** Suitable materials that may be considered for sanitary elements of the system include 316L (low carbon) stainless steel, polypropylene, polyvinylidene-difluoride and perfluoroalkoxy. The choice of material should take into account the intended sanitization method. Other materials such as unplasticized polyvinyl-chloride (uPVC) may be used for treatment equipment designed for less pure water such as ion exchangers and softeners.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS (Informe T\u00e9cnico 970) aborda las mejores pr\u00e1cticas para el dise\u00f1o y mantenimiento de sistemas de purificaci\u00f3n de agua (WPU). Se enfatiza la importancia de la pasivaci\u00f3n del sistema, la necesidad de superficies internas lisas para prevenir la contaminaci\u00f3n microbiol\u00f3gica, y la correcta uni\u00f3n de materiales mediante soldadura controlada. Tambi\u00e9n se discuten los dise\u00f1os higi\u00e9nicos de componentes como bridas y v\u00e1lvulas, la documentaci\u00f3n necesaria para los componentes del sistema, y los materiales adecuados para su construcci\u00f3n.\n\n### Preguntas Espec\u00edficas:\n\n1. **\u00bfCu\u00e1l es la importancia de la pasivaci\u00f3n en un sistema de purificaci\u00f3n de agua y qu\u00e9 pasos deben seguirse antes de realizarla?**\n   - La pasivaci\u00f3n es crucial para prevenir la corrosi\u00f3n y asegurar la integridad del sistema despu\u00e9s de la instalaci\u00f3n o modificaciones significativas. Antes de realizar la pasivaci\u00f3n, el sistema debe ser limpiado a fondo y el proceso debe seguir un procedimiento documentado claramente definido.\n\n2. **\u00bfQu\u00e9 caracter\u00edsticas deben tener las superficies internas de un sistema de purificaci\u00f3n de agua para minimizar el riesgo de contaminaci\u00f3n?**\n   - Las superficies internas deben ser lisas, con una rugosidad superficial aritm\u00e9tica promedio no mayor a 0.8 micr\u00f3metros (Ra). Esto ayuda a evitar la acumulaci\u00f3n de microorganismos y la formaci\u00f3n de biofilms, que pueden ser fuentes de contaminaci\u00f3n.\n\n3. **\u00bfQu\u00e9 materiales son recomendados para los elementos sanitarios de un sistema de purificaci\u00f3n de agua y qu\u00e9 factores deben considerarse al elegirlos?**\n   - Se recomiendan materiales como acero inoxidable 316L (bajo carbono), polipropileno, polivinilideno difluoruro y perfluoroalcoxi. La elecci\u00f3n del material debe tener en cuenta el m\u00e9todo de sanitizaci\u00f3n previsto, as\u00ed como la pureza del agua que se va a tratar.", "prev_section_summary": "### Temas Clave\n\n1. **Importancia de los Sistemas de Almacenamiento y Distribuci\u00f3n**: Estos sistemas son esenciales para el suministro de agua de calidad en aplicaciones farmac\u00e9uticas (PW, BHPW y BWFI) y deben integrarse con las plantas de purificaci\u00f3n para asegurar un funcionamiento \u00f3ptimo.\n\n2. **Dise\u00f1o y Requisitos de Materiales**: Los sistemas deben ser dise\u00f1ados para prevenir la proliferaci\u00f3n microbiana y la recontaminaci\u00f3n del agua. Los materiales en contacto con el agua deben ser compatibles, no permitir la lixiviaci\u00f3n y ser resistentes a la corrosi\u00f3n.\n\n3. **Monitoreo y Control de Calidad**: Es fundamental implementar un monitoreo tanto en l\u00ednea como fuera de l\u00ednea para mantener las especificaciones del agua despu\u00e9s del tratamiento.\n\n### Entidades\n\n- **Sistemas de Almacenamiento y Distribuci\u00f3n de Agua**: PW (agua purificada), BHPW (agua para inyecci\u00f3n de alta calidad) y BWFI (agua para inyecci\u00f3n).\n- **Componentes del Sistema**: Plantas de purificaci\u00f3n, tanques de almacenamiento, tuber\u00edas, v\u00e1lvulas, accesorios, sellos, diafragmas e instrumentos.\n- **Propiedades de Materiales**:\n  - **Compatibilidad**: Deben soportar temperaturas de trabajo y qu\u00edmicos.\n  - **Prevenci\u00f3n de Lixiviaci\u00f3n**: No deben liberar sustancias en el agua.\n  - **Resistencia a la Corrosi\u00f3n**: Deben ser capaces de resistir la corrosi\u00f3n causada por el agua purificada.\n\n### Conclusi\u00f3n\n\nLa secci\u00f3n enfatiza la necesidad de un dise\u00f1o cuidadoso y la selecci\u00f3n de materiales adecuados en los sistemas de almacenamiento y distribuci\u00f3n de agua para uso farmac\u00e9utico, as\u00ed como la importancia del monitoreo para garantizar la calidad del agua.", "excerpt_keywords": "Keywords: passivation, microbiological contamination, sanitary design, welding, materials selection"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "20f17999-4fc6-4de6-a275-e9d79a741b88", "node_type": "4", "metadata": {"page_label": "93", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The system should be passivated after initial installation or after significant modification. When accelerated passivation is undertaken the system should be thoroughly cleaned first and the passivation process should be undertaken in accordance with a clearly defined documented procedure.\n\n- **Smooth internal finish.** Once water has been purified it is susceptible to microbiological contamination and the system is subject to the formation of biofilms when cold storage and distribution are employed. Smooth internal surfaces help to avoid roughness and crevices within the WPU system. Crevices can be the source of contamination because of possible accumulation of microorganisms and formation of biofilms. Crevices are also frequently sites where corrosion can commence. The internal material finish should have an arithmetical average surface roughness of not greater than 0.8 micrometre (Ra). When stainless steel is used, mechanical and electro-polishing techniques may be employed. Electro-polishing improves the resistance of the stainless-steel material to surface corrosion.\n\n- **Jointing.** The selected system materials should be easily joined by welding in a controlled manner. The control of the process should include, as a minimum, qualification of the operator, documentation of the welder set-up, work session test pieces (coupons), logs of all welds and visual inspection of a defined proportion of welds, e.g. 100% hand welds, 10% automatic welds.\n\n- **Design of flanges, unions and valves.** Where flanges, unions or valves are used they should be of a hygienic or sanitary design. Appropriate checks should be carried out to ensure that the correct seals and diaphragms are used and that they are fitted and tightened correctly. Threaded connections should be avoided.\n\n- **Documentation.** All system components should be fully documented and be supported by original or certified copies of material certificates.\n\n- **Materials.** Suitable materials that may be considered for sanitary elements of the system include 316L (low carbon) stainless steel, polypropylene, polyvinylidene-difluoride and perfluoroalkoxy. The choice of material should take into account the intended sanitization method. Other materials such as unplasticized polyvinyl-chloride (uPVC) may be used for treatment equipment designed for less pure water such as ion exchangers and softeners.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "9cc119dadd289b4c75e8ab4f497922eddd3d475da70777b50d0204d1aeee9836", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "The system should be passivated after initial installation or after significant modification. When accelerated passivation is undertaken the system should be thoroughly cleaned first and the passivation process should be undertaken in accordance with a clearly defined documented procedure.\n\n- **Smooth internal finish.** Once water has been purified it is susceptible to microbiological contamination and the system is subject to the formation of biofilms when cold storage and distribution are employed. Smooth internal surfaces help to avoid roughness and crevices within the WPU system. Crevices can be the source of contamination because of possible accumulation of microorganisms and formation of biofilms. Crevices are also frequently sites where corrosion can commence. The internal material finish should have an arithmetical average surface roughness of not greater than 0.8 micrometre (Ra). When stainless steel is used, mechanical and electro-polishing techniques may be employed. Electro-polishing improves the resistance of the stainless-steel material to surface corrosion.\n\n- **Jointing.** The selected system materials should be easily joined by welding in a controlled manner. The control of the process should include, as a minimum, qualification of the operator, documentation of the welder set-up, work session test pieces (coupons), logs of all welds and visual inspection of a defined proportion of welds, e.g. 100% hand welds, 10% automatic welds.\n\n- **Design of flanges, unions and valves.** Where flanges, unions or valves are used they should be of a hygienic or sanitary design. Appropriate checks should be carried out to ensure that the correct seals and diaphragms are used and that they are fitted and tightened correctly. Threaded connections should be avoided.\n\n- **Documentation.** All system components should be fully documented and be supported by original or certified copies of material certificates.\n\n- **Materials.** Suitable materials that may be considered for sanitary elements of the system include 316L (low carbon) stainless steel, polypropylene, polyvinylidene-difluoride and perfluoroalkoxy. The choice of material should take into account the intended sanitization method. Other materials such as unplasticized polyvinyl-chloride (uPVC) may be used for treatment equipment designed for less pure water such as ion exchangers and softeners.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2390, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "a6ed1492-6f65-4cdd-93a0-64c82f54845a": {"__data__": {"id_": "a6ed1492-6f65-4cdd-93a0-64c82f54845a", "embedding": null, "metadata": {"page_label": "94", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nNone of the materials that come into contact with WPU should contain chemicals that will be extracted by the water. Plastics should be non-toxic and should be compatible with all chemicals used. They should be manufactured from materials that should at least meet minimum food grade standards. Their chemical and biological characteristics should meet any relevant pharmacopoeia specifications or recommendations.\n\nPrecautions should be taken to define operational limits for areas where water circulation is reduced and turbulent flow cannot be achieved. Minimum flow rate and change volumes should be defined.\n\n## 6.3 System sanitization and bioburden control\n\n### 6.3.1\nWater treatment equipment, storage and distribution systems used for BPW, BHPW and BWFI should be provided with features to control the proliferation of microbiological organisms during normal use, as well as techniques for sanitizing the system after intervention for maintenance or modification. The techniques employed should be considered during the design of the system and should take into account the interdependency between the materials and the sanitization techniques.\n\n### 6.3.2\nSystems that operate and are maintained at elevated temperatures (e.g. > 65) are generally less susceptible to microbiological contamination than systems that are maintained at lower temperatures. When lower temperatures are required due to the water treatment processes employed or the temperature requirements for the water in use, special precautions should be taken to prevent the ingress and proliferation of microbiological contaminants (see section 6.4.3 for guidance).\n\n## 6.4 Storage vessel requirements\n\n### 6.4.1 General\n\n#### 6.4.1.1\nThe water storage vessel used in a system serves a number of important functions. The design and size of the vessel should take into consideration the following.\n\n### 6.4.2 Capacity\n\n#### 6.4.2.1\nThe capacity of the storage vessel should be determined on the basis of the following requirements:\n\n- It is necessary to provide a buffer capacity between the steady-state generation rate of the water-treatment equipment and the potentially variable simultaneous demand from user points.\n- The water-treatment equipment should be able to operate continuously for significant periods to avoid the inefficiencies and", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS se centra en las especificaciones para los preparativos farmac\u00e9uticos, haciendo hincapi\u00e9 en la importancia de los materiales que entran en contacto con el agua purificada (WPU). Se establece que estos materiales no deben liberar sustancias qu\u00edmicas en el agua y deben cumplir con est\u00e1ndares de calidad alimentaria. Adem\u00e1s, se discuten las medidas de control de biocarga y sanitizaci\u00f3n de los sistemas de tratamiento de agua, as\u00ed como los requisitos para los recipientes de almacenamiento, que deben tener en cuenta la capacidad y la demanda variable.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las caracter\u00edsticas m\u00ednimas que deben cumplir los materiales en contacto con el agua purificada seg\u00fan el documento de la OMS?**\n   - Respuesta: Los materiales deben ser no t\u00f3xicos, compatibles con todos los qu\u00edmicos utilizados, fabricados de acuerdo con est\u00e1ndares m\u00ednimos de calidad alimentaria y cumplir con las especificaciones o recomendaciones de la farmacopoeia relevante.\n\n2. **\u00bfQu\u00e9 precauciones se deben tomar para prevenir la proliferaci\u00f3n de organismos microbiol\u00f3gicos en sistemas de tratamiento de agua que operan a temperaturas m\u00e1s bajas?**\n   - Respuesta: Se deben tomar precauciones especiales para prevenir la entrada y proliferaci\u00f3n de contaminantes microbiol\u00f3gicos, especialmente si se requieren temperaturas m\u00e1s bajas debido a los procesos de tratamiento de agua o a los requisitos de temperatura del agua en uso.\n\n3. **\u00bfC\u00f3mo se determina la capacidad de un recipiente de almacenamiento de agua en un sistema de tratamiento seg\u00fan el informe?**\n   - Respuesta: La capacidad del recipiente debe determinarse considerando la necesidad de proporcionar una capacidad de amortiguamiento entre la tasa de generaci\u00f3n constante del equipo de tratamiento de agua y la demanda variable potencial de los puntos de uso. Adem\u00e1s, el equipo de tratamiento de agua debe poder operar de manera continua durante per\u00edodos significativos para evitar ineficiencias.", "prev_section_summary": "### Temas Clave:\n\n1. **Pasivaci\u00f3n del Sistema:**\n   - Importancia de la pasivaci\u00f3n despu\u00e9s de la instalaci\u00f3n inicial o modificaciones significativas.\n   - Necesidad de limpieza exhaustiva antes de la pasivaci\u00f3n.\n   - Proceso de pasivaci\u00f3n debe seguir un procedimiento documentado.\n\n2. **Acabado Interno Liso:**\n   - Prevenci\u00f3n de contaminaci\u00f3n microbiol\u00f3gica y formaci\u00f3n de biofilms.\n   - Superficies internas deben tener una rugosidad promedio no mayor a 0.8 micr\u00f3metros (Ra).\n   - Uso de t\u00e9cnicas de pulido mec\u00e1nico y electro-pulido para acero inoxidable.\n\n3. **Uni\u00f3n de Materiales:**\n   - Importancia de la soldadura controlada para unir materiales del sistema.\n   - Requisitos de calificaci\u00f3n del operador y documentaci\u00f3n del proceso de soldadura.\n\n4. **Dise\u00f1o Higi\u00e9nico de Componentes:**\n   - Bridas, uniones y v\u00e1lvulas deben tener un dise\u00f1o sanitario.\n   - Verificaci\u00f3n de sellos y diafragmas, evitando conexiones roscadas.\n\n5. **Documentaci\u00f3n:**\n   - Necesidad de documentaci\u00f3n completa de todos los componentes del sistema.\n   - Soporte con copias originales o certificadas de certificados de materiales.\n\n6. **Materiales Adecuados:**\n   - Materiales recomendados incluyen acero inoxidable 316L, polipropileno, polivinilideno difluoruro y perfluoroalcoxi.\n   - Consideraci\u00f3n del m\u00e9todo de sanitizaci\u00f3n y pureza del agua al elegir materiales.\n\n### Entidades:\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**\n- **Acero Inoxidable 316L**\n- **Polipropileno**\n- **Polivinilideno Difluoruro**\n- **Perfluoroalcoxi**\n- **Unplasticized Polyvinyl Chloride (uPVC)**\n- **WPU (Water Purification System)**\n\nEste resumen destaca los aspectos fundamentales y las entidades relevantes en el contexto del dise\u00f1o y mantenimiento de sistemas de purificaci\u00f3n de agua seg\u00fan el informe t\u00e9cnico de la OMS.", "excerpt_keywords": "Keywords: water purification, microbiological control, storage vessel requirements, pharmaceutical preparations, sanitization techniques"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "07555395-8bc5-4ac6-a4a0-02e817753654", "node_type": "4", "metadata": {"page_label": "94", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nNone of the materials that come into contact with WPU should contain chemicals that will be extracted by the water. Plastics should be non-toxic and should be compatible with all chemicals used. They should be manufactured from materials that should at least meet minimum food grade standards. Their chemical and biological characteristics should meet any relevant pharmacopoeia specifications or recommendations.\n\nPrecautions should be taken to define operational limits for areas where water circulation is reduced and turbulent flow cannot be achieved. Minimum flow rate and change volumes should be defined.\n\n## 6.3 System sanitization and bioburden control\n\n### 6.3.1\nWater treatment equipment, storage and distribution systems used for BPW, BHPW and BWFI should be provided with features to control the proliferation of microbiological organisms during normal use, as well as techniques for sanitizing the system after intervention for maintenance or modification. The techniques employed should be considered during the design of the system and should take into account the interdependency between the materials and the sanitization techniques.\n\n### 6.3.2\nSystems that operate and are maintained at elevated temperatures (e.g. > 65) are generally less susceptible to microbiological contamination than systems that are maintained at lower temperatures. When lower temperatures are required due to the water treatment processes employed or the temperature requirements for the water in use, special precautions should be taken to prevent the ingress and proliferation of microbiological contaminants (see section 6.4.3 for guidance).\n\n## 6.4 Storage vessel requirements\n\n### 6.4.1 General\n\n#### 6.4.1.1\nThe water storage vessel used in a system serves a number of important functions. The design and size of the vessel should take into consideration the following.\n\n### 6.4.2 Capacity\n\n#### 6.4.2.1\nThe capacity of the storage vessel should be determined on the basis of the following requirements:\n\n- It is necessary to provide a buffer capacity between the steady-state generation rate of the water-treatment equipment and the potentially variable simultaneous demand from user points.\n- The water-treatment equipment should be able to operate continuously for significant periods to avoid the inefficiencies and", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "277bbca20ff5641b67ae0cdd9776052630c5393e253ae8e25f9cb4e651553cda", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nNone of the materials that come into contact with WPU should contain chemicals that will be extracted by the water. Plastics should be non-toxic and should be compatible with all chemicals used. They should be manufactured from materials that should at least meet minimum food grade standards. Their chemical and biological characteristics should meet any relevant pharmacopoeia specifications or recommendations.\n\nPrecautions should be taken to define operational limits for areas where water circulation is reduced and turbulent flow cannot be achieved. Minimum flow rate and change volumes should be defined.\n\n## 6.3 System sanitization and bioburden control\n\n### 6.3.1\nWater treatment equipment, storage and distribution systems used for BPW, BHPW and BWFI should be provided with features to control the proliferation of microbiological organisms during normal use, as well as techniques for sanitizing the system after intervention for maintenance or modification. The techniques employed should be considered during the design of the system and should take into account the interdependency between the materials and the sanitization techniques.\n\n### 6.3.2\nSystems that operate and are maintained at elevated temperatures (e.g. > 65) are generally less susceptible to microbiological contamination than systems that are maintained at lower temperatures. When lower temperatures are required due to the water treatment processes employed or the temperature requirements for the water in use, special precautions should be taken to prevent the ingress and proliferation of microbiological contaminants (see section 6.4.3 for guidance).\n\n## 6.4 Storage vessel requirements\n\n### 6.4.1 General\n\n#### 6.4.1.1\nThe water storage vessel used in a system serves a number of important functions. The design and size of the vessel should take into consideration the following.\n\n### 6.4.2 Capacity\n\n#### 6.4.2.1\nThe capacity of the storage vessel should be determined on the basis of the following requirements:\n\n- It is necessary to provide a buffer capacity between the steady-state generation rate of the water-treatment equipment and the potentially variable simultaneous demand from user points.\n- The water-treatment equipment should be able to operate continuously for significant periods to avoid the inefficiencies and", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2394, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "17e9fd90-2780-4d17-b626-a2d8de5e4ab8": {"__data__": {"id_": "17e9fd90-2780-4d17-b626-a2d8de5e4ab8", "embedding": null, "metadata": {"page_label": "95", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Contamination control considerations\n\n## 6.4.3\n\n### 6.4.3.1\n\nThe following should be taken into account for the efficient control of contamination:\n\n- The headspace in the storage vessel is an area of risk where water droplets and air can come into contact at temperatures that encourage the proliferation of microbiological organisms. The use of spray-ball or distributor devices should be considered in these systems to wet the surfaces during normal operation, chemical and/or thermal sanitization.\n\n- Nozzles within the storage vessels should be configured to avoid dead zones where microbiological contamination might be harboured.\n\n- Vent filters are fitted to storage vessels to allow the internal level of liquid to fluctuate. The filters should be bacteria-retentive, hydrophobic and should ideally be configured to allow in situ testing of integrity. Offline testing is also acceptable. The use of heated vent filters should be considered for continuous hot storage or systems using periodic heat sanitization to prevent condensation within the filter matrix that might lead to filter blockage and to microbial growth that could contaminate the storage vessels.\n\n- Where pressure-relief valves and bursting discs are provided on storage vessels to protect them from under- and over-pressurization, these devices should be of a sanitary design. Bursting discs should be provided with external rupture indicators to ensure that loss of system integrity is detected.\n\n# Requirements for water distribution pipework\n\n## 6.5\n\n### 6.5.1 General\n\n#### 6.5.1.1\n\nThe distribution of BPW, BHPW and BWFI should be accomplished using a continuously circulating pipework loop. Proliferation of contaminants within", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda consideraciones sobre el control de la contaminaci\u00f3n en sistemas de almacenamiento y distribuci\u00f3n de agua. Se enfatiza la importancia de gestionar el espacio de cabeza en los recipientes de almacenamiento, la configuraci\u00f3n de boquillas para evitar zonas muertas, el uso de filtros de ventilaci\u00f3n adecuados y el dise\u00f1o sanitario de v\u00e1lvulas de alivio de presi\u00f3n y discos de ruptura. Adem\u00e1s, se menciona que la distribuci\u00f3n de agua purificada debe realizarse mediante un sistema de tuber\u00edas de circulaci\u00f3n continua para prevenir la proliferaci\u00f3n de contaminantes.\n\n### Preguntas espec\u00edficas:\n1. **\u00bfQu\u00e9 caracter\u00edsticas deben tener los filtros de ventilaci\u00f3n en los recipientes de almacenamiento para garantizar la seguridad microbiol\u00f3gica?**\n   - Respuesta: Los filtros de ventilaci\u00f3n deben ser retentivos de bacterias, hidrof\u00f3bicos y, idealmente, deben estar configurados para permitir pruebas de integridad in situ. Tambi\u00e9n se acepta la realizaci\u00f3n de pruebas fuera de l\u00ednea.\n\n2. **\u00bfPor qu\u00e9 es importante evitar zonas muertas en las boquillas dentro de los recipientes de almacenamiento?**\n   - Respuesta: Es importante evitar zonas muertas porque son \u00e1reas donde puede acumularse contaminaci\u00f3n microbiol\u00f3gica, lo que representa un riesgo para la calidad del agua almacenada.\n\n3. **\u00bfQu\u00e9 medidas se deben tomar en relaci\u00f3n con los dispositivos de alivio de presi\u00f3n en los recipientes de almacenamiento?**\n   - Respuesta: Los dispositivos de alivio de presi\u00f3n y los discos de ruptura deben ser de dise\u00f1o sanitario y deben estar equipados con indicadores de ruptura externos para detectar la p\u00e9rdida de integridad del sistema.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Materiales en contacto con agua purificada (WPU)**:\n   - Los materiales no deben liberar sustancias qu\u00edmicas en el agua.\n   - Deben ser no t\u00f3xicos y compatibles con todos los qu\u00edmicos utilizados.\n   - Deben cumplir con est\u00e1ndares m\u00ednimos de calidad alimentaria y especificaciones de farmacopoeia.\n\n2. **Control de biocarga y sanitizaci\u00f3n**:\n   - Los sistemas de tratamiento de agua deben incluir caracter\u00edsticas para controlar la proliferaci\u00f3n de organismos microbiol\u00f3gicos.\n   - Se deben implementar t\u00e9cnicas de sanitizaci\u00f3n despu\u00e9s de mantenimiento o modificaciones.\n   - Los sistemas a temperaturas elevadas son menos susceptibles a la contaminaci\u00f3n microbiol\u00f3gica.\n\n3. **Requisitos de recipientes de almacenamiento**:\n   - La capacidad del recipiente debe proporcionar un buffer entre la generaci\u00f3n constante de agua y la demanda variable.\n   - El equipo de tratamiento debe operar de manera continua para evitar ineficiencias.\n\n### Entidades:\n- **WPU**: Agua purificada.\n- **BPW, BHPW, BWFI**: Tipos de agua utilizados en farmac\u00e9utica.\n- **Farmacopoeia**: Referencia para est\u00e1ndares de calidad en productos farmac\u00e9uticos.\n- **Temperaturas**: Se menciona un umbral de 65 grados Celsius para el control de contaminaci\u00f3n microbiol\u00f3gica. \n\nEste resumen destaca la importancia de la calidad de los materiales, el control microbiol\u00f3gico y la adecuada capacidad de almacenamiento en los sistemas de tratamiento de agua para aplicaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: contamination control, storage vessels, vent filters, pressure-relief valves, water distribution"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b49d29fd-640d-4a12-af03-f7adf3ed712a", "node_type": "4", "metadata": {"page_label": "95", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Contamination control considerations\n\n## 6.4.3\n\n### 6.4.3.1\n\nThe following should be taken into account for the efficient control of contamination:\n\n- The headspace in the storage vessel is an area of risk where water droplets and air can come into contact at temperatures that encourage the proliferation of microbiological organisms. The use of spray-ball or distributor devices should be considered in these systems to wet the surfaces during normal operation, chemical and/or thermal sanitization.\n\n- Nozzles within the storage vessels should be configured to avoid dead zones where microbiological contamination might be harboured.\n\n- Vent filters are fitted to storage vessels to allow the internal level of liquid to fluctuate. The filters should be bacteria-retentive, hydrophobic and should ideally be configured to allow in situ testing of integrity. Offline testing is also acceptable. The use of heated vent filters should be considered for continuous hot storage or systems using periodic heat sanitization to prevent condensation within the filter matrix that might lead to filter blockage and to microbial growth that could contaminate the storage vessels.\n\n- Where pressure-relief valves and bursting discs are provided on storage vessels to protect them from under- and over-pressurization, these devices should be of a sanitary design. Bursting discs should be provided with external rupture indicators to ensure that loss of system integrity is detected.\n\n# Requirements for water distribution pipework\n\n## 6.5\n\n### 6.5.1 General\n\n#### 6.5.1.1\n\nThe distribution of BPW, BHPW and BWFI should be accomplished using a continuously circulating pipework loop. Proliferation of contaminants within", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "971a337417ff1e515ae16ad9cd273e11d8e7d730f3453fd5d4a9c5016ad6e297", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Contamination control considerations\n\n## 6.4.3\n\n### 6.4.3.1\n\nThe following should be taken into account for the efficient control of contamination:\n\n- The headspace in the storage vessel is an area of risk where water droplets and air can come into contact at temperatures that encourage the proliferation of microbiological organisms. The use of spray-ball or distributor devices should be considered in these systems to wet the surfaces during normal operation, chemical and/or thermal sanitization.\n\n- Nozzles within the storage vessels should be configured to avoid dead zones where microbiological contamination might be harboured.\n\n- Vent filters are fitted to storage vessels to allow the internal level of liquid to fluctuate. The filters should be bacteria-retentive, hydrophobic and should ideally be configured to allow in situ testing of integrity. Offline testing is also acceptable. The use of heated vent filters should be considered for continuous hot storage or systems using periodic heat sanitization to prevent condensation within the filter matrix that might lead to filter blockage and to microbial growth that could contaminate the storage vessels.\n\n- Where pressure-relief valves and bursting discs are provided on storage vessels to protect them from under- and over-pressurization, these devices should be of a sanitary design. Bursting discs should be provided with external rupture indicators to ensure that loss of system integrity is detected.\n\n# Requirements for water distribution pipework\n\n## 6.5\n\n### 6.5.1 General\n\n#### 6.5.1.1\n\nThe distribution of BPW, BHPW and BWFI should be accomplished using a continuously circulating pipework loop. Proliferation of contaminants within", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1712, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "0ce27bd2-cdd2-4176-a2d9-a7777c24096d": {"__data__": {"id_": "0ce27bd2-cdd2-4176-a2d9-a7777c24096d", "embedding": null, "metadata": {"page_label": "96", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 6.5.1.2\nFiltration should not usually be used in distribution loops or at take off-user points to control biocontamination. Such filters are likely to conceal system contamination.\n\n## 6.5.2 Temperature control and heat exchangers\n\n### 6.5.2.1\nWhere heat exchangers are employed to heat or cool WPU within a system, precautions should be taken to prevent the heating or cooling utility from contaminating the water. The more secure types of heat exchangers of the double tube plate or double plate and frame or tube and shell configuration should be considered. Where these types are not used, an alternative approach whereby the utility is maintained and monitored at a lower pressure than the WPU may be considered. The latter approach is not usually adopted in BWFI systems.\n\n### 6.5.2.2\nWhere heat exchangers are used they should be arranged in continually circulating loops or subloops of the system to avoid unacceptable static water in systems.\n\n### 6.5.2.3\nWhen the temperature is reduced for processing purposes the reduction should occur for the minimum necessary time. The cooling cycles and their duration should be proven satisfactory during the qualification of the system.\n\n## 6.5.3 Circulation pumps\n\n### 6.5.3.1\nCirculation pumps should be of a sanitary design with appropriate seals that prevent contamination of the system. Where stand-by pumps are provided, they should be configured or managed to avoid dead zones trapped within the system.\n\nConsideration should be given to preventing contamination in systems where parallel pump systems are used, especially if there is stagnant water when one of the pumps is not being used.\n\n## 6.5.4 Biocontamination control techniques\n\n### 6.5.4.1\nWater purification systems should be sanitized using chemical or thermal sanitization procedures as appropriate (production and distribution). The procedure and conditions used (such as times and temperatures) should be suitable.\n\n### 6.5.4.2\nThe following control techniques may be used alone or more commonly in combination:\n\n- Maintenance of continuous turbulent flow circulation within water distribution systems reduces the propensity for the formation of biofilms;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Control de Biocontaminaci\u00f3n en Sistemas de Distribuci\u00f3n de Agua**: El documento aborda las mejores pr\u00e1cticas para el control de biocontaminaci\u00f3n en sistemas de distribuci\u00f3n de agua purificada, enfatizando la importancia de evitar la filtraci\u00f3n en puntos cr\u00edticos y la necesidad de mantener un flujo turbulento continuo para prevenir la formaci\u00f3n de biofilmes.\n\n2. **Dise\u00f1o y Mantenimiento de Intercambiadores de Calor**: Se discuten las precauciones necesarias al utilizar intercambiadores de calor en sistemas de agua purificada, incluyendo la selecci\u00f3n de configuraciones seguras y la importancia de evitar el agua est\u00e1tica en el sistema.\n\n3. **Requisitos para Bombas de Circulaci\u00f3n**: Se especifican las caracter\u00edsticas que deben tener las bombas de circulaci\u00f3n, incluyendo un dise\u00f1o sanitario y la gesti\u00f3n adecuada de bombas de reserva para evitar zonas muertas que puedan acumular contaminantes.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfPor qu\u00e9 no se recomienda el uso de filtros en los bucles de distribuci\u00f3n o en los puntos de toma de agua purificada?**\n   - La filtraci\u00f3n no se recomienda en estos puntos porque puede ocultar la contaminaci\u00f3n del sistema, lo que podr\u00eda llevar a un riesgo mayor de biocontaminaci\u00f3n.\n\n2. **\u00bfCu\u00e1les son las configuraciones de intercambiadores de calor m\u00e1s seguras recomendadas para evitar la contaminaci\u00f3n del agua purificada?**\n   - Se recomiendan intercambiadores de calor de doble tubo, de doble placa y marco, o de tubo y carcasa, ya que son considerados m\u00e1s seguros para evitar la contaminaci\u00f3n del agua purificada.\n\n3. **\u00bfQu\u00e9 t\u00e9cnicas de control de biocontaminaci\u00f3n se pueden implementar en sistemas de purificaci\u00f3n de agua?**\n   - Las t\u00e9cnicas incluyen la sanitizaci\u00f3n qu\u00edmica o t\u00e9rmica de los sistemas de purificaci\u00f3n de agua y el mantenimiento de un flujo turbulento continuo en los sistemas de distribuci\u00f3n para reducir la formaci\u00f3n de biofilmes.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Control de Contaminaci\u00f3n**: Se enfatiza la importancia de gestionar adecuadamente el espacio de cabeza en los recipientes de almacenamiento para prevenir la proliferaci\u00f3n de organismos microbiol\u00f3gicos.\n\n2. **Configuraci\u00f3n de Boquillas**: Las boquillas dentro de los recipientes deben estar dise\u00f1adas para evitar zonas muertas, donde la contaminaci\u00f3n microbiol\u00f3gica puede acumularse.\n\n3. **Filtros de Ventilaci\u00f3n**: Los filtros deben ser:\n   - Retentivos de bacterias.\n   - Hidrof\u00f3bicos.\n   - Configurados para permitir pruebas de integridad in situ y pruebas fuera de l\u00ednea.\n   - Se sugiere el uso de filtros de ventilaci\u00f3n calentados para almacenamiento continuo a altas temperaturas.\n\n4. **Dispositivos de Alivio de Presi\u00f3n**: \n   - Deben ser de dise\u00f1o sanitario.\n   - Los discos de ruptura deben contar con indicadores externos para detectar la p\u00e9rdida de integridad del sistema.\n\n5. **Distribuci\u00f3n de Agua**: La distribuci\u00f3n de agua purificada (BPW, BHPW y BWFI) debe realizarse mediante un sistema de tuber\u00edas de circulaci\u00f3n continua para evitar la proliferaci\u00f3n de contaminantes.\n\n### Entidades:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las recomendaciones.\n- **BPW (Agua Purificada)**, **BHPW (Agua Purificada para Uso Farmac\u00e9utico)**, **BWFI (Agua para Inyecciones)**: Tipos de agua mencionados en el contexto de distribuci\u00f3n.\n- **Dispositivos de Alivio de Presi\u00f3n** y **Discos de Ruptura**: Equipos de seguridad en los recipientes de almacenamiento.", "excerpt_keywords": "Keywords: biocontamination, water purification, heat exchangers, circulation pumps, sanitary design"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0e574a20-f5af-40a4-897d-57c9b23b8a3d", "node_type": "4", "metadata": {"page_label": "96", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 6.5.1.2\nFiltration should not usually be used in distribution loops or at take off-user points to control biocontamination. Such filters are likely to conceal system contamination.\n\n## 6.5.2 Temperature control and heat exchangers\n\n### 6.5.2.1\nWhere heat exchangers are employed to heat or cool WPU within a system, precautions should be taken to prevent the heating or cooling utility from contaminating the water. The more secure types of heat exchangers of the double tube plate or double plate and frame or tube and shell configuration should be considered. Where these types are not used, an alternative approach whereby the utility is maintained and monitored at a lower pressure than the WPU may be considered. The latter approach is not usually adopted in BWFI systems.\n\n### 6.5.2.2\nWhere heat exchangers are used they should be arranged in continually circulating loops or subloops of the system to avoid unacceptable static water in systems.\n\n### 6.5.2.3\nWhen the temperature is reduced for processing purposes the reduction should occur for the minimum necessary time. The cooling cycles and their duration should be proven satisfactory during the qualification of the system.\n\n## 6.5.3 Circulation pumps\n\n### 6.5.3.1\nCirculation pumps should be of a sanitary design with appropriate seals that prevent contamination of the system. Where stand-by pumps are provided, they should be configured or managed to avoid dead zones trapped within the system.\n\nConsideration should be given to preventing contamination in systems where parallel pump systems are used, especially if there is stagnant water when one of the pumps is not being used.\n\n## 6.5.4 Biocontamination control techniques\n\n### 6.5.4.1\nWater purification systems should be sanitized using chemical or thermal sanitization procedures as appropriate (production and distribution). The procedure and conditions used (such as times and temperatures) should be suitable.\n\n### 6.5.4.2\nThe following control techniques may be used alone or more commonly in combination:\n\n- Maintenance of continuous turbulent flow circulation within water distribution systems reduces the propensity for the formation of biofilms;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "742f7b39631a3cdf0ec0af77bc97cf4a13d1aa80c849dd75433df033ffea9024", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 6.5.1.2\nFiltration should not usually be used in distribution loops or at take off-user points to control biocontamination. Such filters are likely to conceal system contamination.\n\n## 6.5.2 Temperature control and heat exchangers\n\n### 6.5.2.1\nWhere heat exchangers are employed to heat or cool WPU within a system, precautions should be taken to prevent the heating or cooling utility from contaminating the water. The more secure types of heat exchangers of the double tube plate or double plate and frame or tube and shell configuration should be considered. Where these types are not used, an alternative approach whereby the utility is maintained and monitored at a lower pressure than the WPU may be considered. The latter approach is not usually adopted in BWFI systems.\n\n### 6.5.2.2\nWhere heat exchangers are used they should be arranged in continually circulating loops or subloops of the system to avoid unacceptable static water in systems.\n\n### 6.5.2.3\nWhen the temperature is reduced for processing purposes the reduction should occur for the minimum necessary time. The cooling cycles and their duration should be proven satisfactory during the qualification of the system.\n\n## 6.5.3 Circulation pumps\n\n### 6.5.3.1\nCirculation pumps should be of a sanitary design with appropriate seals that prevent contamination of the system. Where stand-by pumps are provided, they should be configured or managed to avoid dead zones trapped within the system.\n\nConsideration should be given to preventing contamination in systems where parallel pump systems are used, especially if there is stagnant water when one of the pumps is not being used.\n\n## 6.5.4 Biocontamination control techniques\n\n### 6.5.4.1\nWater purification systems should be sanitized using chemical or thermal sanitization procedures as appropriate (production and distribution). The procedure and conditions used (such as times and temperatures) should be suitable.\n\n### 6.5.4.2\nThe following control techniques may be used alone or more commonly in combination:\n\n- Maintenance of continuous turbulent flow circulation within water distribution systems reduces the propensity for the formation of biofilms;", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2255, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "63a370a6-fda6-4da3-ad86-1cc258841a03": {"__data__": {"id_": "63a370a6-fda6-4da3-ad86-1cc258841a03", "embedding": null, "metadata": {"page_label": "97", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "- the system design should ensure the shortest possible length of pipework;\n- for ambient temperature systems, pipework should be isolated from adjacent hot pipes;\n- deadlegs in the pipework should be minimized through appropriate design, and as a guide should not significantly exceed three times the branch diameter as measured from the ID pipe wall to centre line of the point-of-use valve where significant stagnation potential exists;\n- pressure gauges should be separated from the system by membranes;\n- hygienic pattern diaphragm valves should be used;\n- pipework for steam-sanitized systems should be sloped and fully drainable;\n- the growth of microorganisms can be inhibited by:\n  - ultraviolet radiation sources in pipework;\n  - maintaining the system heated (greater than 65 \u00b0C);\n  - sanitizing the system periodically using hot water (guidance temperature > 70 \u00b0C);\n  - sanitizing the system periodically using superheated hot water or clean steam;\n  - routine chemical sanitization using ozone or other suitable chemical agents. When chemical sanitization is used, it is essential to prove that the agent has been removed prior to using the water. Ozone can be effectively removed by using ultraviolet radiation.\n\n# 7. Operational considerations\n\n## 7.1 Start-up and commissioning of water systems\n\n7.1.1 Planned, well-defined, successful and well-documented commissioning and qualification is an essential precursor to successful validation of water systems.\n\n7.1.2 The commissioning work should include setting to work, system set-up, controls, loop tuning and recording of all system performance parameters. If it is intended to use or to refer to commissioning data within the validation work then the quality of the commissioning work and associated data and documentation must be commensurate with the validation plan requirements.\n\n## 7.2 Qualification\n\n7.2.1 WPU, BPW, BHPW and BWFI systems are all considered to be direct impact, quality critical systems that should be qualified. The qualification", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Informe T\u00e9cnico 970 aborda el dise\u00f1o y la operaci\u00f3n de sistemas de agua, enfatizando la importancia de minimizar la longitud de las tuber\u00edas, el aislamiento de tuber\u00edas calientes, y la reducci\u00f3n de \"deadlegs\" en el sistema. Tambi\u00e9n se discuten m\u00e9todos para inhibir el crecimiento de microorganismos, como el uso de radiaci\u00f3n ultravioleta y la sanitizaci\u00f3n peri\u00f3dica. Adem\u00e1s, se subraya la necesidad de una correcta puesta en marcha y calificaci\u00f3n de los sistemas de agua, asegurando que la documentaci\u00f3n y los datos sean adecuados para la validaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfCu\u00e1les son las recomendaciones para el dise\u00f1o de tuber\u00edas en sistemas de agua para minimizar el crecimiento de microorganismos?**\n   - El dise\u00f1o debe asegurar la menor longitud posible de tuber\u00edas, aislar las tuber\u00edas de temperatura ambiente de las tuber\u00edas calientes, y minimizar los \"deadlegs\" para evitar la estancaci\u00f3n, siguiendo la gu\u00eda de no exceder tres veces el di\u00e1metro de la rama.\n\n2. **\u00bfQu\u00e9 m\u00e9todos se sugieren para la sanitizaci\u00f3n de sistemas de agua y c\u00f3mo se debe manejar el uso de agentes qu\u00edmicos?**\n   - Se sugiere la sanitizaci\u00f3n peri\u00f3dica utilizando agua caliente (temperatura > 70 \u00b0C), agua caliente sobrecalentada o vapor limpio, y la sanitizaci\u00f3n qu\u00edmica con ozono u otros agentes. Es crucial demostrar que el agente qu\u00edmico ha sido eliminado antes de usar el agua, y el ozono puede ser eliminado eficazmente mediante radiaci\u00f3n ultravioleta.\n\n3. **\u00bfQu\u00e9 aspectos deben considerarse durante la puesta en marcha y calificaci\u00f3n de sistemas de agua seg\u00fan el documento?**\n   - La puesta en marcha debe ser planificada, bien definida y documentada, incluyendo la configuraci\u00f3n del sistema, controles, ajuste de bucles y registro de par\u00e1metros de rendimiento. La calidad de los datos de la puesta en marcha debe ser adecuada para los requisitos del plan de validaci\u00f3n si se van a utilizar en el trabajo de validaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Control de Biocontaminaci\u00f3n**:\n   - Se enfatiza que la filtraci\u00f3n no debe utilizarse en bucles de distribuci\u00f3n o puntos de toma de agua purificada, ya que puede ocultar la contaminaci\u00f3n del sistema.\n\n2. **Intercambiadores de Calor**:\n   - Se recomienda el uso de intercambiadores de calor de configuraciones seguras (doble tubo, doble placa y marco, tubo y carcasa) para evitar la contaminaci\u00f3n del agua purificada.\n   - Los intercambiadores deben estar dispuestos en bucles de circulaci\u00f3n continua para evitar agua est\u00e1tica.\n\n3. **Bombas de Circulaci\u00f3n**:\n   - Las bombas deben tener un dise\u00f1o sanitario y sellos adecuados para prevenir la contaminaci\u00f3n.\n   - Se debe evitar la formaci\u00f3n de zonas muertas, especialmente en sistemas con bombas en paralelo.\n\n4. **T\u00e9cnicas de Control de Biocontaminaci\u00f3n**:\n   - Se deben aplicar procedimientos de sanitizaci\u00f3n qu\u00edmica o t\u00e9rmica en los sistemas de purificaci\u00f3n de agua.\n   - Mantener un flujo turbulento continuo en los sistemas de distribuci\u00f3n es crucial para reducir la formaci\u00f3n de biofilmes.\n\n### Entidades Clave\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las recomendaciones.\n- **WPU (Water for Pharmaceutical Use)**: Agua purificada para uso farmac\u00e9utico.\n- **BWFI (Bacteriostatic Water for Injection)**: Agua bacteriost\u00e1tica para inyecci\u00f3n.\n- **Intercambiadores de Calor**: Equipos utilizados para calentar o enfriar el agua purificada.\n- **Bombas de Circulaci\u00f3n**: Dispositivos que mantienen el flujo del agua purificada en el sistema. \n\nEste resumen destaca las mejores pr\u00e1cticas y consideraciones cr\u00edticas para el manejo y control de biocontaminaci\u00f3n en sistemas de agua purificada, as\u00ed como los requisitos de dise\u00f1o y operaci\u00f3n de los equipos involucrados.", "excerpt_keywords": "Keywords: water systems, microorganism control, sanitization, commissioning, qualification"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0f5aab5f-f66d-4512-aedc-eff952bf3e01", "node_type": "4", "metadata": {"page_label": "97", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "- the system design should ensure the shortest possible length of pipework;\n- for ambient temperature systems, pipework should be isolated from adjacent hot pipes;\n- deadlegs in the pipework should be minimized through appropriate design, and as a guide should not significantly exceed three times the branch diameter as measured from the ID pipe wall to centre line of the point-of-use valve where significant stagnation potential exists;\n- pressure gauges should be separated from the system by membranes;\n- hygienic pattern diaphragm valves should be used;\n- pipework for steam-sanitized systems should be sloped and fully drainable;\n- the growth of microorganisms can be inhibited by:\n  - ultraviolet radiation sources in pipework;\n  - maintaining the system heated (greater than 65 \u00b0C);\n  - sanitizing the system periodically using hot water (guidance temperature > 70 \u00b0C);\n  - sanitizing the system periodically using superheated hot water or clean steam;\n  - routine chemical sanitization using ozone or other suitable chemical agents. When chemical sanitization is used, it is essential to prove that the agent has been removed prior to using the water. Ozone can be effectively removed by using ultraviolet radiation.\n\n# 7. Operational considerations\n\n## 7.1 Start-up and commissioning of water systems\n\n7.1.1 Planned, well-defined, successful and well-documented commissioning and qualification is an essential precursor to successful validation of water systems.\n\n7.1.2 The commissioning work should include setting to work, system set-up, controls, loop tuning and recording of all system performance parameters. If it is intended to use or to refer to commissioning data within the validation work then the quality of the commissioning work and associated data and documentation must be commensurate with the validation plan requirements.\n\n## 7.2 Qualification\n\n7.2.1 WPU, BPW, BHPW and BWFI systems are all considered to be direct impact, quality critical systems that should be qualified. The qualification", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "7d37322da3a98270666b387763d86dbe0d19c029e306bcb764ea0047f0aea29d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "- the system design should ensure the shortest possible length of pipework;\n- for ambient temperature systems, pipework should be isolated from adjacent hot pipes;\n- deadlegs in the pipework should be minimized through appropriate design, and as a guide should not significantly exceed three times the branch diameter as measured from the ID pipe wall to centre line of the point-of-use valve where significant stagnation potential exists;\n- pressure gauges should be separated from the system by membranes;\n- hygienic pattern diaphragm valves should be used;\n- pipework for steam-sanitized systems should be sloped and fully drainable;\n- the growth of microorganisms can be inhibited by:\n  - ultraviolet radiation sources in pipework;\n  - maintaining the system heated (greater than 65 \u00b0C);\n  - sanitizing the system periodically using hot water (guidance temperature > 70 \u00b0C);\n  - sanitizing the system periodically using superheated hot water or clean steam;\n  - routine chemical sanitization using ozone or other suitable chemical agents. When chemical sanitization is used, it is essential to prove that the agent has been removed prior to using the water. Ozone can be effectively removed by using ultraviolet radiation.\n\n# 7. Operational considerations\n\n## 7.1 Start-up and commissioning of water systems\n\n7.1.1 Planned, well-defined, successful and well-documented commissioning and qualification is an essential precursor to successful validation of water systems.\n\n7.1.2 The commissioning work should include setting to work, system set-up, controls, loop tuning and recording of all system performance parameters. If it is intended to use or to refer to commissioning data within the validation work then the quality of the commissioning work and associated data and documentation must be commensurate with the validation plan requirements.\n\n## 7.2 Qualification\n\n7.2.1 WPU, BPW, BHPW and BWFI systems are all considered to be direct impact, quality critical systems that should be qualified. The qualification", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2021, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "75cb7679-b5d7-4b9d-9662-c0bc3ec05210": {"__data__": {"id_": "75cb7679-b5d7-4b9d-9662-c0bc3ec05210", "embedding": null, "metadata": {"page_label": "98", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nshould follow the validation convention of design review or design qualification (DQ), IQ, OQ, and PQ.\n\n## 7.2.2\n\nThis guidance does not define the standard requirements for the conventional qualification stages DQ, IQ and OQ, but concentrates on the particular PQ approach that should be used for WPU systems to demonstrate their consistent and reliable performance. A three-phase approach should be used to satisfy the objective of proving the reliability and robustness of the system in service over an extended period.\n\nTests on the source water must be included within the validation programme and continued as part of the routine monitoring. The source water should meet the requirements for drinking-water and any internal specification.\n\n**Phase 1.** Sample daily or continuously monitor the incoming feed-water to verify its quality.\n\nA test period of two weeks should be spent monitoring the system intensively. During this period, the system should operate continuously without failure or performance deviation. Usually water is not used for finished pharmaceutical product (FPP) manufacturing during this period. The following activities should be included in the testing approach.\n\n- Undertake chemical and microbiological testing in accordance with a defined plan.\n- Sample or continuously monitor the incoming feed-water daily to verify its quality.\n- Sample or continuously monitor after each step in the purification process.\n- Sample or continuously monitor at each point of use and at other defined sample points.\n- Develop appropriate operating ranges.\n- Develop and finalize operating, cleaning, sanitizing and maintenance procedures.\n- Demonstrate production and delivery of product water of the required quality and quantity.\n- Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting.\n- Verify provisional alert levels.\n- Develop and refine test-failure procedure.\n\n**Phase 2.** A further test period of two weeks should be spent carrying out further intensive monitoring while deploying all the refined SOPs after the satisfactory completion of phase 1. The sampling scheme should be generally the same.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS se centra en las especificaciones para los sistemas de agua purificada (WPU) utilizados en la fabricaci\u00f3n de productos farmac\u00e9uticos. Se describe un enfoque de validaci\u00f3n en tres fases que incluye la revisi\u00f3n del dise\u00f1o (DQ), la calificaci\u00f3n de instalaci\u00f3n (IQ), la calificaci\u00f3n operativa (OQ) y la calificaci\u00f3n de rendimiento (PQ). La gu\u00eda enfatiza la importancia de monitorear la calidad del agua de entrada y realizar pruebas qu\u00edmicas y microbiol\u00f3gicas para asegurar que el sistema funcione de manera confiable y consistente a lo largo del tiempo.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfCu\u00e1les son las actividades espec\u00edficas que deben llevarse a cabo durante la Fase 1 del programa de validaci\u00f3n para los sistemas de agua purificada?**\n   - La Fase 1 incluye actividades como la realizaci\u00f3n de pruebas qu\u00edmicas y microbiol\u00f3gicas, el monitoreo diario de la calidad del agua de entrada, el desarrollo de procedimientos operativos est\u00e1ndar (SOPs), y la verificaci\u00f3n de los niveles de alerta provisionales, entre otros.\n\n2. **\u00bfQu\u00e9 requisitos debe cumplir el agua de origen seg\u00fan el documento de la OMS?**\n   - El agua de origen debe cumplir con los requisitos para el agua potable y cualquier especificaci\u00f3n interna establecida por la organizaci\u00f3n que utiliza el sistema de agua purificada.\n\n3. **\u00bfQu\u00e9 se espera lograr al finalizar la Fase 2 del programa de validaci\u00f3n?**\n   - Al finalizar la Fase 2, se espera que el sistema haya sido monitoreado intensivamente utilizando los SOPs refinados, y que se haya demostrado la producci\u00f3n y entrega de agua de calidad y cantidad requeridas, asegurando as\u00ed la confiabilidad y robustez del sistema en servicio.", "prev_section_summary": "### Temas Clave\n\n1. **Dise\u00f1o de Sistemas de Agua**:\n   - Importancia de minimizar la longitud de las tuber\u00edas.\n   - Aislamiento de tuber\u00edas de temperatura ambiente de tuber\u00edas calientes.\n   - Minimizaci\u00f3n de \"deadlegs\" en el sistema para evitar estancamiento.\n\n2. **Inhibici\u00f3n del Crecimiento de Microorganismos**:\n   - Uso de radiaci\u00f3n ultravioleta en las tuber\u00edas.\n   - Mantenimiento de temperaturas superiores a 65 \u00b0C.\n   - Sanitizaci\u00f3n peri\u00f3dica con agua caliente (> 70 \u00b0C), agua sobrecalentada o vapor limpio.\n   - Sanitizaci\u00f3n qu\u00edmica con ozono y otros agentes, asegurando la eliminaci\u00f3n del agente antes de usar el agua.\n\n3. **Puesta en Marcha y Calificaci\u00f3n de Sistemas**:\n   - Necesidad de una puesta en marcha planificada, bien definida y documentada.\n   - Inclusi\u00f3n de configuraci\u00f3n del sistema, controles, ajuste de bucles y registro de par\u00e1metros de rendimiento.\n   - Calidad de los datos de la puesta en marcha debe ser adecuada para los requisitos del plan de validaci\u00f3n.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad del documento.\n- **Sistemas de Agua**: Incluye WPU (Water Purified Unit), BPW (Bacteriologically Pure Water), BHPW (Bacteriologically High Purity Water) y BWFI (Bacteriologically Water for Injection).\n- **Microorganismos**: Organismos cuyo crecimiento se busca inhibir en los sistemas de agua.\n- **Radiaci\u00f3n Ultravioleta**: M\u00e9todo propuesto para la inhibici\u00f3n del crecimiento microbiano.\n- **Agentes Qu\u00edmicos**: Incluye ozono y otros agentes utilizados para la sanitizaci\u00f3n.\n\n### Resumen General\nEl documento de la OMS en su Informe T\u00e9cnico 970 proporciona directrices sobre el dise\u00f1o y operaci\u00f3n de sistemas de agua, enfatizando la minimizaci\u00f3n de la longitud de las tuber\u00edas y el aislamiento de tuber\u00edas calientes para prevenir el crecimiento de microorganismos. Se sugieren m\u00e9todos de sanitizaci\u00f3n, tanto t\u00e9rmicos como qu\u00edmicos, y se destaca la importancia de una puesta en marcha y calificaci\u00f3n adecuadas para asegurar la calidad y validaci\u00f3n de los sistemas de agua.", "excerpt_keywords": "Keywords: validation, pharmaceutical preparations, water purification, quality monitoring, standard operating procedures"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "113bffda-6339-49b1-a394-176bff5f6844", "node_type": "4", "metadata": {"page_label": "98", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nshould follow the validation convention of design review or design qualification (DQ), IQ, OQ, and PQ.\n\n## 7.2.2\n\nThis guidance does not define the standard requirements for the conventional qualification stages DQ, IQ and OQ, but concentrates on the particular PQ approach that should be used for WPU systems to demonstrate their consistent and reliable performance. A three-phase approach should be used to satisfy the objective of proving the reliability and robustness of the system in service over an extended period.\n\nTests on the source water must be included within the validation programme and continued as part of the routine monitoring. The source water should meet the requirements for drinking-water and any internal specification.\n\n**Phase 1.** Sample daily or continuously monitor the incoming feed-water to verify its quality.\n\nA test period of two weeks should be spent monitoring the system intensively. During this period, the system should operate continuously without failure or performance deviation. Usually water is not used for finished pharmaceutical product (FPP) manufacturing during this period. The following activities should be included in the testing approach.\n\n- Undertake chemical and microbiological testing in accordance with a defined plan.\n- Sample or continuously monitor the incoming feed-water daily to verify its quality.\n- Sample or continuously monitor after each step in the purification process.\n- Sample or continuously monitor at each point of use and at other defined sample points.\n- Develop appropriate operating ranges.\n- Develop and finalize operating, cleaning, sanitizing and maintenance procedures.\n- Demonstrate production and delivery of product water of the required quality and quantity.\n- Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting.\n- Verify provisional alert levels.\n- Develop and refine test-failure procedure.\n\n**Phase 2.** A further test period of two weeks should be spent carrying out further intensive monitoring while deploying all the refined SOPs after the satisfactory completion of phase 1. The sampling scheme should be generally the same.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "2a7d1d57730fb9d2d7ebd7592ffad7f364acbbbe38c91f73f8e88403da6b5456", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nshould follow the validation convention of design review or design qualification (DQ), IQ, OQ, and PQ.\n\n## 7.2.2\n\nThis guidance does not define the standard requirements for the conventional qualification stages DQ, IQ and OQ, but concentrates on the particular PQ approach that should be used for WPU systems to demonstrate their consistent and reliable performance. A three-phase approach should be used to satisfy the objective of proving the reliability and robustness of the system in service over an extended period.\n\nTests on the source water must be included within the validation programme and continued as part of the routine monitoring. The source water should meet the requirements for drinking-water and any internal specification.\n\n**Phase 1.** Sample daily or continuously monitor the incoming feed-water to verify its quality.\n\nA test period of two weeks should be spent monitoring the system intensively. During this period, the system should operate continuously without failure or performance deviation. Usually water is not used for finished pharmaceutical product (FPP) manufacturing during this period. The following activities should be included in the testing approach.\n\n- Undertake chemical and microbiological testing in accordance with a defined plan.\n- Sample or continuously monitor the incoming feed-water daily to verify its quality.\n- Sample or continuously monitor after each step in the purification process.\n- Sample or continuously monitor at each point of use and at other defined sample points.\n- Develop appropriate operating ranges.\n- Develop and finalize operating, cleaning, sanitizing and maintenance procedures.\n- Demonstrate production and delivery of product water of the required quality and quantity.\n- Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting.\n- Verify provisional alert levels.\n- Develop and refine test-failure procedure.\n\n**Phase 2.** A further test period of two weeks should be spent carrying out further intensive monitoring while deploying all the refined SOPs after the satisfactory completion of phase 1. The sampling scheme should be generally the same.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2262, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c9fb4783-d0bb-4268-ad25-32aa37ff1b38": {"__data__": {"id_": "c9fb4783-d0bb-4268-ad25-32aa37ff1b38", "embedding": null, "metadata": {"page_label": "99", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Phase 3\n\nPhase 3 typically runs for one year after the satisfactory completion of phase 2. Water can be used for FPP manufacturing purposes during this phase which has the following objectives:\n\n- to demonstrate reliable performance over an extended period;\n- to ensure that seasonal variations are evaluated.\n\nThe sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2.\n\n## 7.3 Continuous system monitoring\n\n### 7.3.1\n\nAfter completion of phase 3 of the qualification programme for the WPU system, a system review should be undertaken. Following this review a routine monitoring plan should be established based on the results of phase 3.\n\nMonitoring should include a combination of monitoring with online instruments (with appropriately qualified alarm systems) of parameters such as flow, pressure, temperature, conductivity and total organic carbon, and offline sample testing for physical, chemical and microbiological attributes. Offline samples should be taken from points of use or dedicated sample points where points of use cannot be sampled. All water samples should be taken using the same methodology as detailed in production procedures. There should be a suitable flushing and drainage procedure in place.\n\n### 7.3.2\n\nTests should be carried out to ensure that the approved pharmacopoeial and company specification has been met.\n\nThis may include the microbiological quality of water as appropriate.\n\nMonitoring data should be subject to trend analysis (trending should typically be within 2 sigma). Suitable alert and action levels should be established based on historical reported data.\n\n### 7.3.3\n\nAny trend towards frequently exceeding alert limits should trigger a thorough investigation of the root cause, followed by appropriate corrective actions.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto circundante\n\n1. **Objetivos de la Fase 3**: La Fase 3 del programa de calificaci\u00f3n para sistemas de agua purificada (WPU) se centra en demostrar un rendimiento confiable a lo largo del tiempo y evaluar las variaciones estacionales. Esta fase se lleva a cabo durante un a\u00f1o despu\u00e9s de la finalizaci\u00f3n satisfactoria de la Fase 2.\n\n2. **Monitoreo continuo del sistema**: Despu\u00e9s de completar la Fase 3, se debe realizar una revisi\u00f3n del sistema y establecer un plan de monitoreo rutinario. Este monitoreo incluye el uso de instrumentos en l\u00ednea para medir par\u00e1metros cr\u00edticos y pruebas de muestras fuera de l\u00ednea para evaluar atributos f\u00edsicos, qu\u00edmicos y microbiol\u00f3gicos.\n\n3. **An\u00e1lisis de tendencias y acciones correctivas**: Los datos de monitoreo deben ser analizados para identificar tendencias, y cualquier tendencia que indique un exceso frecuente de los l\u00edmites de alerta debe ser investigada a fondo para determinar la causa ra\u00edz y aplicar acciones correctivas adecuadas.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los par\u00e1metros espec\u00edficos que deben ser monitoreados durante la Fase 3 y c\u00f3mo se deben tomar las muestras?**\n   - Respuesta: Durante la Fase 3, se deben monitorear par\u00e1metros como flujo, presi\u00f3n, temperatura, conductividad y carbono org\u00e1nico total. Las muestras deben tomarse de puntos de uso o puntos de muestreo dedicados, utilizando la misma metodolog\u00eda que se detalla en los procedimientos de producci\u00f3n.\n\n2. **\u00bfQu\u00e9 acciones deben tomarse si se detecta una tendencia que excede frecuentemente los l\u00edmites de alerta durante el monitoreo?**\n   - Respuesta: Si se detecta una tendencia que excede frecuentemente los l\u00edmites de alerta, se debe llevar a cabo una investigaci\u00f3n exhaustiva de la causa ra\u00edz y aplicar las acciones correctivas apropiadas.\n\n3. **\u00bfQu\u00e9 tipo de pruebas se deben realizar para asegurar que se cumplen las especificaciones aprobadas durante la Fase 3?**\n   - Respuesta: Se deben realizar pruebas para garantizar que se cumplan las especificaciones farmacop\u00e9icas y de la empresa, lo que puede incluir la evaluaci\u00f3n de la calidad microbiol\u00f3gica del agua, seg\u00fan sea apropiado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Validaci\u00f3n de Sistemas de Agua Purificada (WPU):** El documento establece un enfoque de validaci\u00f3n en tres fases para asegurar el rendimiento consistente y confiable de los sistemas de agua purificada utilizados en la fabricaci\u00f3n de productos farmac\u00e9uticos.\n  \n2. **Fases de Validaci\u00f3n:**\n   - **Fase 1:** Monitoreo intensivo del agua de entrada durante un per\u00edodo de dos semanas, incluyendo pruebas qu\u00edmicas y microbiol\u00f3gicas, desarrollo de procedimientos operativos est\u00e1ndar (SOPs), y verificaci\u00f3n de la calidad del agua.\n   - **Fase 2:** Continuaci\u00f3n del monitoreo intensivo utilizando SOPs refinados, tambi\u00e9n durante un per\u00edodo de dos semanas.\n\n3. **Requisitos del Agua de Origen:** El agua de origen debe cumplir con los est\u00e1ndares de agua potable y cualquier especificaci\u00f3n interna relevante.\n\n4. **Importancia del Monitoreo:** Se enfatiza la necesidad de realizar pruebas continuas y monitoreo para garantizar la calidad del agua a lo largo del tiempo.\n\n**Entidades:**\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Autoridad que emite las directrices sobre las especificaciones para los sistemas de agua purificada.\n- **Sistemas de Agua Purificada (WPU):** Sistemas utilizados en la fabricaci\u00f3n de productos farmac\u00e9uticos que requieren validaci\u00f3n rigurosa.\n- **Procedimientos Operativos Est\u00e1ndar (SOPs):** Documentos que describen los procedimientos para la operaci\u00f3n, mantenimiento, sanitizaci\u00f3n y resoluci\u00f3n de problemas de los sistemas de agua purificada.\n\nEste resumen destaca la estructura y los requisitos de validaci\u00f3n para los sistemas de agua purificada, as\u00ed como la importancia del monitoreo continuo para asegurar su rendimiento en la producci\u00f3n farmac\u00e9utica.", "excerpt_keywords": "Keywords: Phase 3, water purification, continuous monitoring, trend analysis, corrective actions"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "53f0535e-26e5-4aa6-b534-c90b59b1a0bd", "node_type": "4", "metadata": {"page_label": "99", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Phase 3\n\nPhase 3 typically runs for one year after the satisfactory completion of phase 2. Water can be used for FPP manufacturing purposes during this phase which has the following objectives:\n\n- to demonstrate reliable performance over an extended period;\n- to ensure that seasonal variations are evaluated.\n\nThe sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2.\n\n## 7.3 Continuous system monitoring\n\n### 7.3.1\n\nAfter completion of phase 3 of the qualification programme for the WPU system, a system review should be undertaken. Following this review a routine monitoring plan should be established based on the results of phase 3.\n\nMonitoring should include a combination of monitoring with online instruments (with appropriately qualified alarm systems) of parameters such as flow, pressure, temperature, conductivity and total organic carbon, and offline sample testing for physical, chemical and microbiological attributes. Offline samples should be taken from points of use or dedicated sample points where points of use cannot be sampled. All water samples should be taken using the same methodology as detailed in production procedures. There should be a suitable flushing and drainage procedure in place.\n\n### 7.3.2\n\nTests should be carried out to ensure that the approved pharmacopoeial and company specification has been met.\n\nThis may include the microbiological quality of water as appropriate.\n\nMonitoring data should be subject to trend analysis (trending should typically be within 2 sigma). Suitable alert and action levels should be established based on historical reported data.\n\n### 7.3.3\n\nAny trend towards frequently exceeding alert limits should trigger a thorough investigation of the root cause, followed by appropriate corrective actions.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "e1a505c1fe325ea40a7817c4d704894b67ba4f2964cf189fe2e1003bf2957161", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Phase 3\n\nPhase 3 typically runs for one year after the satisfactory completion of phase 2. Water can be used for FPP manufacturing purposes during this phase which has the following objectives:\n\n- to demonstrate reliable performance over an extended period;\n- to ensure that seasonal variations are evaluated.\n\nThe sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2.\n\n## 7.3 Continuous system monitoring\n\n### 7.3.1\n\nAfter completion of phase 3 of the qualification programme for the WPU system, a system review should be undertaken. Following this review a routine monitoring plan should be established based on the results of phase 3.\n\nMonitoring should include a combination of monitoring with online instruments (with appropriately qualified alarm systems) of parameters such as flow, pressure, temperature, conductivity and total organic carbon, and offline sample testing for physical, chemical and microbiological attributes. Offline samples should be taken from points of use or dedicated sample points where points of use cannot be sampled. All water samples should be taken using the same methodology as detailed in production procedures. There should be a suitable flushing and drainage procedure in place.\n\n### 7.3.2\n\nTests should be carried out to ensure that the approved pharmacopoeial and company specification has been met.\n\nThis may include the microbiological quality of water as appropriate.\n\nMonitoring data should be subject to trend analysis (trending should typically be within 2 sigma). Suitable alert and action levels should be established based on historical reported data.\n\n### 7.3.3\n\nAny trend towards frequently exceeding alert limits should trigger a thorough investigation of the root cause, followed by appropriate corrective actions.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1876, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "0c0ee7ff-947c-4ffa-b713-841296e7a9d8": {"__data__": {"id_": "0c0ee7ff-947c-4ffa-b713-841296e7a9d8", "embedding": null, "metadata": {"page_label": "100", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Maintenance of water systems\n\n7.4.1 WPU systems should be maintained in accordance with a controlled, documented maintenance programme that takes into account the following:\n\n- defined frequency for system elements;\n- the calibration programme;\n- SOPs for specific tasks;\n- control of approved spares;\n- issue of a clear maintenance plan and instructions;\n- review and approval of systems for use upon completion of work;\n- record and review of problems and faults during maintenance.\n\n# System reviews\n\n7.5.1 WPU (BPW, BHPW and BWFI) systems should be reviewed at appropriate regular intervals. The review team should comprise representatives from engineering, QA, microbiology, operations and maintenance. The review should consider matters such as:\n\n- changes made since the last review;\n- system performance;\n- reliability;\n- quality trends;\n- failure events;\n- investigations;\n- out-of-specifications results from monitoring;\n- changes to the installation;\n- updated installation documentation;\n- log books;\n- the status of the current SOP list.\n\n7.5.2 For new systems, or systems that display instability or unreliability, the following should also be reviewed:\n\n- need for investigation;\n- corrective actions and preventative actions (CAPA);", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Informe T\u00e9cnico 970) aborda la importancia del mantenimiento y revisi\u00f3n de los sistemas de agua (WPU) en entornos de calidad controlada. Se establece que los sistemas deben seguir un programa de mantenimiento documentado que incluya la frecuencia de mantenimiento, calibraciones, procedimientos operativos est\u00e1ndar (SOPs), y un plan claro de mantenimiento. Adem\u00e1s, se enfatiza la necesidad de revisiones regulares por un equipo multidisciplinario para evaluar el rendimiento, la fiabilidad y cualquier cambio en el sistema.\n\n### Preguntas:\n\n1. **\u00bfCu\u00e1les son los elementos clave que deben incluirse en un programa de mantenimiento documentado para los sistemas WPU?**\n   - Respuesta: Un programa de mantenimiento documentado debe incluir la frecuencia definida para los elementos del sistema, un programa de calibraci\u00f3n, SOPs para tareas espec\u00edficas, control de repuestos aprobados, un plan de mantenimiento claro, revisi\u00f3n y aprobaci\u00f3n de sistemas tras el trabajo, y un registro de problemas y fallos durante el mantenimiento.\n\n2. **\u00bfQu\u00e9 aspectos deben considerarse durante la revisi\u00f3n de los sistemas WPU en intervalos regulares?**\n   - Respuesta: La revisi\u00f3n debe considerar cambios desde la \u00faltima revisi\u00f3n, rendimiento del sistema, fiabilidad, tendencias de calidad, eventos de fallo, investigaciones, resultados fuera de especificaciones, cambios en la instalaci\u00f3n, documentaci\u00f3n actualizada, libros de registro y el estado de la lista actual de SOPs.\n\n3. **\u00bfQu\u00e9 acciones deben tomarse para sistemas nuevos o inestables durante la revisi\u00f3n?**\n   - Respuesta: Para sistemas nuevos o aquellos que muestran inestabilidad o falta de fiabilidad, se debe revisar la necesidad de investigaci\u00f3n y las acciones correctivas y preventivas (CAPA).", "prev_section_summary": "### Resumen de Temas Clave y Entidades de la Secci\u00f3n\n\n1. **Fase 3 del Programa de Calificaci\u00f3n**:\n   - **Duraci\u00f3n**: Se extiende por un a\u00f1o tras la finalizaci\u00f3n satisfactoria de la Fase 2.\n   - **Objetivos**:\n     - Demostrar un rendimiento confiable a lo largo del tiempo.\n     - Evaluar las variaciones estacionales.\n\n2. **Monitoreo Continuo del Sistema**:\n   - **Revisi\u00f3n del Sistema**: Se debe realizar una revisi\u00f3n del sistema al finalizar la Fase 3 y establecer un plan de monitoreo rutinario.\n   - **Par\u00e1metros a Monitorear**:\n     - Flujo\n     - Presi\u00f3n\n     - Temperatura\n     - Conductividad\n     - Carbono Org\u00e1nico Total\n   - **M\u00e9todo de Muestreo**: Las muestras deben tomarse de puntos de uso o puntos de muestreo dedicados, siguiendo la metodolog\u00eda de los procedimientos de producci\u00f3n.\n\n3. **Pruebas y Cumplimiento de Especificaciones**:\n   - Se deben realizar pruebas para asegurar que se cumplen las especificaciones farmacop\u00e9icas y de la empresa, incluyendo la calidad microbiol\u00f3gica del agua.\n\n4. **An\u00e1lisis de Tendencias**:\n   - Los datos de monitoreo deben ser analizados para identificar tendencias, con un enfoque en mantener las tendencias dentro de 2 sigma.\n   - Se deben establecer niveles de alerta y acci\u00f3n basados en datos hist\u00f3ricos.\n\n5. **Acciones Correctivas**:\n   - Si se detecta una tendencia que excede frecuentemente los l\u00edmites de alerta, se debe realizar una investigaci\u00f3n exhaustiva de la causa ra\u00edz y aplicar acciones correctivas adecuadas.\n\n### Entidades Clave:\n- **Fase 3**: Parte del programa de calificaci\u00f3n para sistemas de agua purificada (WPU).\n- **Par\u00e1metros de Monitoreo**: Flujo, presi\u00f3n, temperatura, conductividad, carbono org\u00e1nico total.\n- **Especificaciones**: Farmacop\u00e9icas y de la empresa.\n- **M\u00e9todos de Muestreo**: Puntos de uso y puntos de muestreo dedicados.", "excerpt_keywords": "Keywords: maintenance, water systems, quality assurance, system reviews, corrective actions"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f003df69-4da6-4bc0-a4d0-de46fe501090", "node_type": "4", "metadata": {"page_label": "100", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Maintenance of water systems\n\n7.4.1 WPU systems should be maintained in accordance with a controlled, documented maintenance programme that takes into account the following:\n\n- defined frequency for system elements;\n- the calibration programme;\n- SOPs for specific tasks;\n- control of approved spares;\n- issue of a clear maintenance plan and instructions;\n- review and approval of systems for use upon completion of work;\n- record and review of problems and faults during maintenance.\n\n# System reviews\n\n7.5.1 WPU (BPW, BHPW and BWFI) systems should be reviewed at appropriate regular intervals. The review team should comprise representatives from engineering, QA, microbiology, operations and maintenance. The review should consider matters such as:\n\n- changes made since the last review;\n- system performance;\n- reliability;\n- quality trends;\n- failure events;\n- investigations;\n- out-of-specifications results from monitoring;\n- changes to the installation;\n- updated installation documentation;\n- log books;\n- the status of the current SOP list.\n\n7.5.2 For new systems, or systems that display instability or unreliability, the following should also be reviewed:\n\n- need for investigation;\n- corrective actions and preventative actions (CAPA);", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "d596147792a64d104f887faf32be9d6a3605e2774a9aafcbe2797d864bbfddf6", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Maintenance of water systems\n\n7.4.1 WPU systems should be maintained in accordance with a controlled, documented maintenance programme that takes into account the following:\n\n- defined frequency for system elements;\n- the calibration programme;\n- SOPs for specific tasks;\n- control of approved spares;\n- issue of a clear maintenance plan and instructions;\n- review and approval of systems for use upon completion of work;\n- record and review of problems and faults during maintenance.\n\n# System reviews\n\n7.5.1 WPU (BPW, BHPW and BWFI) systems should be reviewed at appropriate regular intervals. The review team should comprise representatives from engineering, QA, microbiology, operations and maintenance. The review should consider matters such as:\n\n- changes made since the last review;\n- system performance;\n- reliability;\n- quality trends;\n- failure events;\n- investigations;\n- out-of-specifications results from monitoring;\n- changes to the installation;\n- updated installation documentation;\n- log books;\n- the status of the current SOP list.\n\n7.5.2 For new systems, or systems that display instability or unreliability, the following should also be reviewed:\n\n- need for investigation;\n- corrective actions and preventative actions (CAPA);", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1250, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "318dbfc8-07bb-4b8f-beee-a7d380bce559": {"__data__": {"id_": "318dbfc8-07bb-4b8f-beee-a7d380bce559", "embedding": null, "metadata": {"page_label": "101", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 8. Inspection of water systems\n\n8.1 WPU (BPW, BHPW and BWFI) systems are likely to be the subject of regulatory inspection from time to time. Users should consider conducting routine audit and self-inspection of established water systems.\n\n8.2 This GMP guidance can be used as the basis of inspection. A tour of the water generation plant and visible pipework (including user points) should be performed to ensure that the system is appropriately designed, installed and maintained (e.g. that there are no leaks and that the system matches the piping and instrumentation diagram or drawing (P&ID)).\n\nThe following list identifies items and a logical sequence for a WPU system inspection or audit:\n\n- a current drawing of the water system showing all equipment in the system from the inlet to the points of use along with sampling points and their designations;\n- approved piping drawings (e.g. orthographic and/or isometric);\n- a sampling and monitoring plan with a drawing of all sample points;\n- training programme for sample collection and testing;\n- the setting of monitoring alert and action levels;\n- monitoring results and evaluation of trends;\n- inspection of the last annual system review;\n- review of any changes made to the system since the last audit and a check that the change control has been implemented;\n- review of deviations recorded and their investigation;\n- general inspection of system for status and condition;\n- review of maintenance, failure and repair logs;\n- checking calibration and standardization of critical instruments.\n\n8.3 For an established system that is demonstrably under control this scope of review should prove adequate.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Informe T\u00e9cnico 970) aborda la inspecci\u00f3n de sistemas de agua, espec\u00edficamente los sistemas de agua purificada (WPU), que incluyen BPW, BHPW y BWFI. Se enfatiza la importancia de las auditor\u00edas y autoinspecciones rutinarias para garantizar que estos sistemas est\u00e9n dise\u00f1ados, instalados y mantenidos adecuadamente. Se proporciona una lista detallada de elementos a considerar durante una inspecci\u00f3n o auditor\u00eda, que incluye la revisi\u00f3n de dibujos actuales, planes de muestreo, programas de capacitaci\u00f3n y registros de mantenimiento.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 elementos espec\u00edficos deben incluirse en un dibujo actual del sistema de agua para cumplir con los requisitos de inspecci\u00f3n?**\n   - La respuesta se encuentra en la lista de elementos que se deben considerar durante la inspecci\u00f3n, que incluye la representaci\u00f3n de todo el equipo desde la entrada hasta los puntos de uso, as\u00ed como los puntos de muestreo y sus designaciones.\n\n2. **\u00bfCu\u00e1les son los pasos recomendados para llevar a cabo una auditor\u00eda o autoinspecci\u00f3n de un sistema de agua purificada?**\n   - El contexto proporciona una secuencia l\u00f3gica de inspecci\u00f3n que incluye la revisi\u00f3n de dibujos aprobados, planes de muestreo, resultados de monitoreo, y la evaluaci\u00f3n de tendencias, entre otros.\n\n3. **\u00bfQu\u00e9 condiciones se deben cumplir para que un sistema de agua establecido sea considerado \"demostrablemente bajo control\"?**\n   - Seg\u00fan el documento, un sistema que cumple con los requisitos de revisi\u00f3n y que ha sido inspeccionado adecuadamente, con registros de mantenimiento y calibraci\u00f3n, puede ser considerado bajo control.", "prev_section_summary": "### Temas Clave:\n\n1. **Mantenimiento de Sistemas de Agua (WPU)**:\n   - Importancia de un programa de mantenimiento controlado y documentado.\n   - Elementos esenciales del programa de mantenimiento, como frecuencia, calibraci\u00f3n, SOPs, control de repuestos, y planificaci\u00f3n clara.\n\n2. **Revisiones de Sistemas**:\n   - Necesidad de revisiones regulares por un equipo multidisciplinario.\n   - Aspectos a considerar durante la revisi\u00f3n, incluyendo cambios, rendimiento, fiabilidad, tendencias de calidad, y eventos de fallo.\n\n3. **Sistemas Nuevos o Inestables**:\n   - Evaluaci\u00f3n de la necesidad de investigaci\u00f3n y acciones correctivas y preventivas (CAPA) para sistemas que muestran inestabilidad o falta de fiabilidad.\n\n### Entidades:\n\n- **WPU**: Sistemas de agua (Water Purification Units).\n- **BPW, BHPW, BWFI**: Tipos espec\u00edficos de sistemas de agua.\n- **Equipo de Revisi\u00f3n**: Representantes de ingenier\u00eda, aseguramiento de calidad (QA), microbiolog\u00eda, operaciones y mantenimiento.\n- **SOPs**: Procedimientos Operativos Est\u00e1ndar.\n- **CAPA**: Acciones Correctivas y Preventivas.\n\n### Resumen:\nEl documento de la OMS enfatiza la necesidad de un mantenimiento riguroso y revisiones peri\u00f3dicas de los sistemas de agua para asegurar su eficacia y fiabilidad. Se establece un marco claro para el mantenimiento, que incluye la documentaci\u00f3n y el control de procesos, as\u00ed como la importancia de un equipo multidisciplinario para las revisiones, que deben abordar tanto el rendimiento del sistema como cualquier problema que pueda surgir. Para sistemas nuevos o inestables, se requiere un enfoque adicional en la investigaci\u00f3n y la implementaci\u00f3n de acciones correctivas.", "excerpt_keywords": "Keywords: water systems, inspection, WPU, GMP guidance, maintenance"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d2fb1903-c63d-4042-9caa-f761d725f4e4", "node_type": "4", "metadata": {"page_label": "101", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 8. Inspection of water systems\n\n8.1 WPU (BPW, BHPW and BWFI) systems are likely to be the subject of regulatory inspection from time to time. Users should consider conducting routine audit and self-inspection of established water systems.\n\n8.2 This GMP guidance can be used as the basis of inspection. A tour of the water generation plant and visible pipework (including user points) should be performed to ensure that the system is appropriately designed, installed and maintained (e.g. that there are no leaks and that the system matches the piping and instrumentation diagram or drawing (P&ID)).\n\nThe following list identifies items and a logical sequence for a WPU system inspection or audit:\n\n- a current drawing of the water system showing all equipment in the system from the inlet to the points of use along with sampling points and their designations;\n- approved piping drawings (e.g. orthographic and/or isometric);\n- a sampling and monitoring plan with a drawing of all sample points;\n- training programme for sample collection and testing;\n- the setting of monitoring alert and action levels;\n- monitoring results and evaluation of trends;\n- inspection of the last annual system review;\n- review of any changes made to the system since the last audit and a check that the change control has been implemented;\n- review of deviations recorded and their investigation;\n- general inspection of system for status and condition;\n- review of maintenance, failure and repair logs;\n- checking calibration and standardization of critical instruments.\n\n8.3 For an established system that is demonstrably under control this scope of review should prove adequate.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "0aadc4696ef775ec90907f93d777682f13e152418c1b3cd3bb1b51fcd3d6ab31", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 8. Inspection of water systems\n\n8.1 WPU (BPW, BHPW and BWFI) systems are likely to be the subject of regulatory inspection from time to time. Users should consider conducting routine audit and self-inspection of established water systems.\n\n8.2 This GMP guidance can be used as the basis of inspection. A tour of the water generation plant and visible pipework (including user points) should be performed to ensure that the system is appropriately designed, installed and maintained (e.g. that there are no leaks and that the system matches the piping and instrumentation diagram or drawing (P&ID)).\n\nThe following list identifies items and a logical sequence for a WPU system inspection or audit:\n\n- a current drawing of the water system showing all equipment in the system from the inlet to the points of use along with sampling points and their designations;\n- approved piping drawings (e.g. orthographic and/or isometric);\n- a sampling and monitoring plan with a drawing of all sample points;\n- training programme for sample collection and testing;\n- the setting of monitoring alert and action levels;\n- monitoring results and evaluation of trends;\n- inspection of the last annual system review;\n- review of any changes made to the system since the last audit and a check that the change control has been implemented;\n- review of deviations recorded and their investigation;\n- general inspection of system for status and condition;\n- review of maintenance, failure and repair logs;\n- checking calibration and standardization of critical instruments.\n\n8.3 For an established system that is demonstrably under control this scope of review should prove adequate.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1664, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f7fcc978-4133-46b0-b2eb-a38b93d12d73": {"__data__": {"id_": "f7fcc978-4133-46b0-b2eb-a38b93d12d73", "embedding": null, "metadata": {"page_label": "102", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Further reading\n\n**The International Pharmacopoeia.** Geneva, World Health Organization; http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html.\n\n**WHO guidelines on good manufacturing practices: validation.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 4 (WHO Technical Report Series, No. 937); http://www.who.int/medicines/publications/pharmprep/TRS_937.pdf#page=119.\n\n**WHO Guidelines for drinking-water quality, 3rd edition.** Geneva, World Health Organization, 2008; http://www.who.int/water_sanitation_health/dwq/gdwq3rev/en/index.html.\n\n**American Society of Mechanical Engineers.** Bioprocessing Equipment Standard. ASME \u2014 BPE 2000.\n\n**Banes PH.** Passivation; understanding and performing procedures on austenitic stainless steel systems. *Pharmaceutical Engineering*, 1990: 41.\n\n**Guide to inspections of high purity water systems.** Maryland, US Food and Drug Administration, 1993; http://www.fda.gov/ICECI/InspectionGuides.\n\n**Biotechnology. Equipment. Guidance on testing procedures for cleanability.** British Standards Publishing. BS EN 12296, 1998.\n\n**European Medicines Agency.** Note for guidance on the quality of water for pharmaceutical use. London, 2002 (CPMP/QWP/158-01); http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003394.pdf.\n\n**European Pharmacopoeia:** see web site for the publishers of the European Pharmacopoeia and supplements; http://www.pheur.org/.\n\n**Harfst WH.** Selecting piping materials for high-purity water systems. *Ultra Pure Water*, May/June 1994.\n\n**ISPE Good practice guide: commissioning and qualification of pharmaceutical water and steam systems.** ISPE Baseline TM Pharmaceutical Engineering Guide, Vol. 4. International Society for Pharmaceutical Engineering, 2007.\n\n**ISPE Baseline Guide Volume 4: Water and Steam Systems.** International Society for Pharmaceutical Engineering, 2001.\n\n**Noble PT.** Transport considerations for microbial control in piping. *Journal of Pharmaceutical Science and Technology*, 1994, 48: 76\u201385.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que forma parte de la Serie de Informes T\u00e9cnicos (Technical Report Series) y se centra en temas relacionados con la calidad del agua y las buenas pr\u00e1cticas de fabricaci\u00f3n en la industria farmac\u00e9utica. Incluye referencias a diversas gu\u00edas, est\u00e1ndares y publicaciones relevantes que abordan la calidad del agua para uso farmac\u00e9utico, la validaci\u00f3n de procesos de fabricaci\u00f3n y la selecci\u00f3n de materiales para sistemas de agua de alta pureza.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS sobre la calidad del agua para uso farmac\u00e9utico seg\u00fan el documento mencionado?**\n   - Esta pregunta busca respuestas espec\u00edficas sobre las pautas y est\u00e1ndares que la OMS establece para garantizar la calidad del agua en la industria farmac\u00e9utica, que pueden no estar disponibles en otras fuentes.\n\n2. **\u00bfQu\u00e9 aspectos se consideran en la validaci\u00f3n de buenas pr\u00e1cticas de fabricaci\u00f3n seg\u00fan las directrices de la OMS?**\n   - Esta pregunta se enfoca en los criterios y procedimientos que la OMS sugiere para validar las pr\u00e1cticas de fabricaci\u00f3n, lo que puede proporcionar informaci\u00f3n detallada que no se encuentra f\u00e1cilmente en otros documentos.\n\n3. **\u00bfQu\u00e9 materiales se recomiendan para sistemas de agua de alta pureza y cu\u00e1les son las consideraciones para su selecci\u00f3n?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre los materiales adecuados para sistemas de agua de alta pureza, as\u00ed como las razones detr\u00e1s de su selecci\u00f3n, que pueden no estar ampliamente discutidas en otras publicaciones.", "prev_section_summary": "### Temas Clave\n\n1. **Inspecci\u00f3n de Sistemas de Agua**: Se enfatiza la importancia de las inspecciones regulatorias y la necesidad de auditor\u00edas y autoinspecciones rutinarias para los sistemas de agua purificada (WPU), que incluyen BPW, BHPW y BWFI.\n\n2. **Gu\u00eda de Buenas Pr\u00e1cticas de Manufactura (GMP)**: Se menciona que la gu\u00eda GMP puede servir como base para las inspecciones, asegurando que los sistemas est\u00e9n dise\u00f1ados, instalados y mantenidos adecuadamente.\n\n3. **Elementos de Inspecci\u00f3n**: Se proporciona una lista detallada de elementos a considerar durante una auditor\u00eda, que incluye:\n   - Dibujos actuales del sistema de agua.\n   - Planes de muestreo y monitoreo.\n   - Programas de capacitaci\u00f3n.\n   - Resultados de monitoreo y evaluaci\u00f3n de tendencias.\n   - Registros de mantenimiento y calibraci\u00f3n.\n\n4. **Condiciones de Control**: Se establece que un sistema de agua que ha sido revisado adecuadamente y cumple con los requisitos de mantenimiento puede considerarse \"demostrablemente bajo control\".\n\n### Entidades\n\n- **WPU**: Sistemas de Agua Purificada (incluyendo BPW, BHPW y BWFI).\n- **GMP**: Buenas Pr\u00e1cticas de Manufactura.\n- **P&ID**: Diagramas de Tuber\u00edas e Instrumentaci\u00f3n.\n- **Elementos de Inspecci\u00f3n**: Dibujos, planes de muestreo, programas de capacitaci\u00f3n, registros de mantenimiento, etc.\n\nEste resumen destaca la importancia de la inspecci\u00f3n y el mantenimiento de los sistemas de agua purificada, as\u00ed como los elementos clave que deben ser revisados para garantizar su correcto funcionamiento.", "excerpt_keywords": "Keywords: water quality, pharmaceutical manufacturing, good manufacturing practices, high-purity water systems, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4e240693-3668-44c0-acb2-fd42c9a2ab45", "node_type": "4", "metadata": {"page_label": "102", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Further reading\n\n**The International Pharmacopoeia.** Geneva, World Health Organization; http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html.\n\n**WHO guidelines on good manufacturing practices: validation.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 4 (WHO Technical Report Series, No. 937); http://www.who.int/medicines/publications/pharmprep/TRS_937.pdf#page=119.\n\n**WHO Guidelines for drinking-water quality, 3rd edition.** Geneva, World Health Organization, 2008; http://www.who.int/water_sanitation_health/dwq/gdwq3rev/en/index.html.\n\n**American Society of Mechanical Engineers.** Bioprocessing Equipment Standard. ASME \u2014 BPE 2000.\n\n**Banes PH.** Passivation; understanding and performing procedures on austenitic stainless steel systems. *Pharmaceutical Engineering*, 1990: 41.\n\n**Guide to inspections of high purity water systems.** Maryland, US Food and Drug Administration, 1993; http://www.fda.gov/ICECI/InspectionGuides.\n\n**Biotechnology. Equipment. Guidance on testing procedures for cleanability.** British Standards Publishing. BS EN 12296, 1998.\n\n**European Medicines Agency.** Note for guidance on the quality of water for pharmaceutical use. London, 2002 (CPMP/QWP/158-01); http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003394.pdf.\n\n**European Pharmacopoeia:** see web site for the publishers of the European Pharmacopoeia and supplements; http://www.pheur.org/.\n\n**Harfst WH.** Selecting piping materials for high-purity water systems. *Ultra Pure Water*, May/June 1994.\n\n**ISPE Good practice guide: commissioning and qualification of pharmaceutical water and steam systems.** ISPE Baseline TM Pharmaceutical Engineering Guide, Vol. 4. International Society for Pharmaceutical Engineering, 2007.\n\n**ISPE Baseline Guide Volume 4: Water and Steam Systems.** International Society for Pharmaceutical Engineering, 2001.\n\n**Noble PT.** Transport considerations for microbial control in piping. *Journal of Pharmaceutical Science and Technology*, 1994, 48: 76\u201385.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "91f2e8c600653725a0080a2a64a65df1b321ee2eba5e423a75d632b8d5bb9de9", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Further reading\n\n**The International Pharmacopoeia.** Geneva, World Health Organization; http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html.\n\n**WHO guidelines on good manufacturing practices: validation.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 4 (WHO Technical Report Series, No. 937); http://www.who.int/medicines/publications/pharmprep/TRS_937.pdf#page=119.\n\n**WHO Guidelines for drinking-water quality, 3rd edition.** Geneva, World Health Organization, 2008; http://www.who.int/water_sanitation_health/dwq/gdwq3rev/en/index.html.\n\n**American Society of Mechanical Engineers.** Bioprocessing Equipment Standard. ASME \u2014 BPE 2000.\n\n**Banes PH.** Passivation; understanding and performing procedures on austenitic stainless steel systems. *Pharmaceutical Engineering*, 1990: 41.\n\n**Guide to inspections of high purity water systems.** Maryland, US Food and Drug Administration, 1993; http://www.fda.gov/ICECI/InspectionGuides.\n\n**Biotechnology. Equipment. Guidance on testing procedures for cleanability.** British Standards Publishing. BS EN 12296, 1998.\n\n**European Medicines Agency.** Note for guidance on the quality of water for pharmaceutical use. London, 2002 (CPMP/QWP/158-01); http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003394.pdf.\n\n**European Pharmacopoeia:** see web site for the publishers of the European Pharmacopoeia and supplements; http://www.pheur.org/.\n\n**Harfst WH.** Selecting piping materials for high-purity water systems. *Ultra Pure Water*, May/June 1994.\n\n**ISPE Good practice guide: commissioning and qualification of pharmaceutical water and steam systems.** ISPE Baseline TM Pharmaceutical Engineering Guide, Vol. 4. International Society for Pharmaceutical Engineering, 2007.\n\n**ISPE Baseline Guide Volume 4: Water and Steam Systems.** International Society for Pharmaceutical Engineering, 2001.\n\n**Noble PT.** Transport considerations for microbial control in piping. *Journal of Pharmaceutical Science and Technology*, 1994, 48: 76\u201385.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2143, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "da1932ce-1c9d-49f2-b1e0-faa5f273affc": {"__data__": {"id_": "da1932ce-1c9d-49f2-b1e0-faa5f273affc", "embedding": null, "metadata": {"page_label": "103", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "Pharmaceutical Inspection Co-operation Scheme. *PIC/S; Inspection of utilities; P1 009-1*. Geneva, Pharmaceutical Inspection Co-operation Scheme, 2002.\n\nTverberg JC, Kerber SJ. Effect of nitric acid passivation on the surface composition of mechanically polished type 316 L sanitary tube. *European Journal of Parenteral Sciences*, 1998, 3: 117\u2013124.\n\nUS Food and Drug Administration. *Guide to inspections of high purity water systems, high purity water systems* (7/93), 2009; http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074905.htm.\n\n*US Pharmacopeia*: Published annually; see http://www.usp.org/.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Normativas y gu\u00edas de inspecci\u00f3n**: El contexto menciona documentos y gu\u00edas relevantes para la inspecci\u00f3n de sistemas de agua de alta pureza, as\u00ed como normativas de la Pharmaceutical Inspection Co-operation Scheme (PIC/S) y la US Food and Drug Administration (FDA).\n\n2. **Investigaci\u00f3n sobre materiales sanitarios**: Se incluye un estudio espec\u00edfico sobre el efecto de la pasivaci\u00f3n con \u00e1cido n\u00edtrico en la composici\u00f3n superficial de tubos sanitarios de acero inoxidable tipo 316 L, lo que puede ser relevante para la industria farmac\u00e9utica y de dispositivos m\u00e9dicos.\n\n3. **Referencias a publicaciones**: Se hace referencia a la US Pharmacopeia, que es una fuente importante de est\u00e1ndares de calidad para medicamentos y productos farmac\u00e9uticos.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1l es el prop\u00f3sito del documento \"PIC/S; Inspection of utilities; P1 009-1\" y qu\u00e9 aspectos cubre en relaci\u00f3n con la inspecci\u00f3n de utilidades?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido y la finalidad del documento de la PIC/S mencionado en el contexto.\n\n2. **\u00bfQu\u00e9 conclusiones se pueden extraer del estudio de Tverberg y Kerber sobre la pasivaci\u00f3n con \u00e1cido n\u00edtrico en tubos sanitarios de acero inoxidable tipo 316 L?**\n   - Esta pregunta se centra en los hallazgos del estudio mencionado, que podr\u00eda no estar ampliamente disponible en otras fuentes.\n\n3. **\u00bfQu\u00e9 aspectos clave se abordan en la \"Gu\u00eda para inspecciones de sistemas de agua de alta pureza\" de la FDA y c\u00f3mo se relacionan con las pr\u00e1cticas actuales en la industria farmac\u00e9utica?**\n   - Esta pregunta busca detalles sobre las recomendaciones y pr\u00e1cticas que la FDA establece en su gu\u00eda, lo que puede ser crucial para la conformidad en la industria.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nLa secci\u00f3n \"Further reading\" del documento de la Organizaci\u00f3n Mundial de la Salud (OMS) proporciona una lista de referencias y recursos relevantes sobre la calidad del agua y las buenas pr\u00e1cticas de fabricaci\u00f3n en la industria farmac\u00e9utica. Los temas clave incluyen:\n\n1. **Calidad del Agua**:\n   - Directrices de la OMS sobre la calidad del agua para uso farmac\u00e9utico.\n   - Normativas y est\u00e1ndares relacionados con sistemas de agua de alta pureza.\n\n2. **Buenas Pr\u00e1cticas de Fabricaci\u00f3n (BPF)**:\n   - Recomendaciones sobre la validaci\u00f3n de procesos de fabricaci\u00f3n.\n   - Gu\u00edas para la inspecci\u00f3n de sistemas de agua de alta pureza.\n\n3. **Materiales y Equipos**:\n   - Selecci\u00f3n de materiales para sistemas de agua de alta pureza.\n   - Est\u00e1ndares de la American Society of Mechanical Engineers (ASME) para equipos de bioprocesamiento.\n\n4. **Publicaciones y Normativas**:\n   - Referencias a la Farmacopea Internacional y la Farmacopea Europea.\n   - Documentos de la FDA y la Agencia Europea de Medicamentos sobre calidad del agua y procedimientos de limpieza.\n\n### Entidades Mencionadas\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Publica directrices y est\u00e1ndares sobre la calidad del agua y BPF.\n- **American Society of Mechanical Engineers (ASME)**: Establece est\u00e1ndares para equipos de bioprocesamiento.\n- **US Food and Drug Administration (FDA)**: Proporciona gu\u00edas para la inspecci\u00f3n de sistemas de agua de alta pureza.\n- **European Medicines Agency**: Ofrece notas de orientaci\u00f3n sobre la calidad del agua para uso farmac\u00e9utico.\n- **International Society for Pharmaceutical Engineering (ISPE)**: Publica gu\u00edas sobre la calificaci\u00f3n y puesta en marcha de sistemas de agua y vapor farmac\u00e9uticos.\n\nEste resumen destaca la importancia de la calidad del agua y las buenas pr\u00e1cticas en la fabricaci\u00f3n farmac\u00e9utica, as\u00ed como las entidades que establecen y regulan estos est\u00e1ndares.", "excerpt_keywords": "Keywords: Pharmaceutical Inspection, high purity water systems, nitric acid passivation, US Pharmacopeia, good manufacturing practices"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0b79dacd-f069-4bc1-a10c-be60467b0d6d", "node_type": "4", "metadata": {"page_label": "103", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "Pharmaceutical Inspection Co-operation Scheme. *PIC/S; Inspection of utilities; P1 009-1*. Geneva, Pharmaceutical Inspection Co-operation Scheme, 2002.\n\nTverberg JC, Kerber SJ. Effect of nitric acid passivation on the surface composition of mechanically polished type 316 L sanitary tube. *European Journal of Parenteral Sciences*, 1998, 3: 117\u2013124.\n\nUS Food and Drug Administration. *Guide to inspections of high purity water systems, high purity water systems* (7/93), 2009; http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074905.htm.\n\n*US Pharmacopeia*: Published annually; see http://www.usp.org/.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "27f6ac40241f6c7794e64dfd6408e74ec1b7e1bb9ea369fc788e1ba23a3614da", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "Pharmaceutical Inspection Co-operation Scheme. *PIC/S; Inspection of utilities; P1 009-1*. Geneva, Pharmaceutical Inspection Co-operation Scheme, 2002.\n\nTverberg JC, Kerber SJ. Effect of nitric acid passivation on the surface composition of mechanically polished type 316 L sanitary tube. *European Journal of Parenteral Sciences*, 1998, 3: 117\u2013124.\n\nUS Food and Drug Administration. *Guide to inspections of high purity water systems, high purity water systems* (7/93), 2009; http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074905.htm.\n\n*US Pharmacopeia*: Published annually; see http://www.usp.org/.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 610, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "bd484162-c11c-4cae-a30a-9e83517f4cea": {"__data__": {"id_": "bd484162-c11c-4cae-a30a-9e83517f4cea", "embedding": null, "metadata": {"page_label": "104", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que forma parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pol\u00edticas de salud. Sin embargo, el contenido espec\u00edfico del informe en la p\u00e1gina 104 no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las principales recomendaciones de salud p\u00fablica que se presentan en la p\u00e1gina 104 del informe \"WHO - Technical Report Series 970\"?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las recomendaciones que podr\u00edan estar incluidas en esa secci\u00f3n del informe.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas de investigaci\u00f3n se discuten en el informe y c\u00f3mo se aplican a los temas tratados en la p\u00e1gina 104?**\n   - Esta pregunta se centra en las metodolog\u00edas que podr\u00edan ser relevantes para entender los hallazgos o recomendaciones presentadas en esa parte del documento.\n\n3. **\u00bfQu\u00e9 datos o estad\u00edsticas relevantes se presentan en la p\u00e1gina 104 que podr\u00edan influir en la formulaci\u00f3n de pol\u00edticas de salud p\u00fablica?**\n   - Esta pregunta busca informaci\u00f3n sobre datos espec\u00edficos que podr\u00edan ser cruciales para la toma de decisiones en el \u00e1mbito de la salud p\u00fablica, que podr\u00edan estar documentados en esa p\u00e1gina. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n que probablemente no se encuentre f\u00e1cilmente en otros lugares, dado que se centran en el contenido espec\u00edfico de un informe t\u00e9cnico de la OMS.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Normativas y Gu\u00edas de Inspecci\u00f3n**:\n   - **Pharmaceutical Inspection Co-operation Scheme (PIC/S)**: Se menciona el documento *PIC/S; Inspection of utilities; P1 009-1*, que aborda aspectos relacionados con la inspecci\u00f3n de utilidades en la industria farmac\u00e9utica.\n   - **US Food and Drug Administration (FDA)**: Se hace referencia a la *Gu\u00eda para inspecciones de sistemas de agua de alta pureza*, que proporciona directrices sobre la conformidad y las mejores pr\u00e1cticas en la industria.\n\n2. **Investigaci\u00f3n sobre Materiales Sanitarios**:\n   - **Estudio de Tverberg y Kerber**: Se presenta un estudio que investiga el efecto de la pasivaci\u00f3n con \u00e1cido n\u00edtrico en la composici\u00f3n superficial de tubos sanitarios de acero inoxidable tipo 316 L, relevante para la fabricaci\u00f3n de dispositivos m\u00e9dicos y productos farmac\u00e9uticos.\n\n3. **Referencias a Publicaciones Importantes**:\n   - **US Pharmacopeia**: Se menciona como una fuente anual de est\u00e1ndares de calidad para medicamentos y productos farmac\u00e9uticos, esencial para la regulaci\u00f3n y control de calidad en la industria.\n\n### Entidades Clave:\n- **PIC/S**: Pharmaceutical Inspection Co-operation Scheme\n- **FDA**: US Food and Drug Administration\n- **Tverberg JC y Kerber SJ**: Autores del estudio sobre pasivaci\u00f3n de tubos sanitarios\n- **US Pharmacopeia**: Publicaci\u00f3n de est\u00e1ndares farmac\u00e9uticos\n\nEste resumen destaca la importancia de las normativas y gu\u00edas de inspecci\u00f3n, la investigaci\u00f3n sobre materiales utilizados en la industria y las publicaciones que establecen est\u00e1ndares de calidad.", "excerpt_keywords": "Keywords: salud p\u00fablica, investigaci\u00f3n m\u00e9dica, normativas, calidad farmac\u00e9utica, OMS"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "74136141-b915-46d1-a1ce-c85e9c1011a2", "node_type": "4", "metadata": {"page_label": "104", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "1cfec4df41b18a2be8aaffe2a0b4e3bb49dc8ba7176a55689dd86d52cf53ede0", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d9b454c1-7c1a-4181-9747-725d87293c5f": {"__data__": {"id_": "d9b454c1-7c1a-4181-9747-725d87293c5f", "embedding": null, "metadata": {"page_label": "105", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 3\n\n**Pharmaceutical development of multisource (generic) finished pharmaceutical products \u2013 points to consider**\n\n## 1. Introduction\n1.1 General principles  \n1.2 Scope  \n\n## 2. Predevelopment activities\n2.1 Desk research  \n    2.1.1 Quality risk management  \n2.2 Additional considerations  \n    2.2.1 Selection and characterization of comparator finished pharmaceutical product(s)  \n    2.2.2 Benchmarking for formulation experiments and stability studies  \n    2.2.3 Formulation selection experiments  \n    2.2.4 Bioequivalence and dissolution studies  \n\n## 3. Pharmaceutical development\n3.1 Components of the finished pharmaceutical product  \n    3.1.1 Active pharmaceutical ingredient  \n    3.1.2 Excipients  \n3.2 Finished pharmaceutical product  \n    3.2.1 Formulation development  \n    3.2.2 Overages  \n    3.2.3 Physicochemical and biological properties  \n3.3 Manufacturing process development  \n3.4 Container-closure system  \n3.5 Microbiological attributes  \n3.6 Compatibility  \n\n## 4. Glossary\n\n**References**\n\n**Appendix 1**  \nExamples of presenting quality attributes of active pharmaceutical ingredients\n\n**Appendix 2**  \nInformation on development batches\n\n| Section | Page |\n|---------|------|\n| 1. Introduction | 92 |\n| 1.1 General principles | 92 |\n| 1.2 Scope | 92 |\n| 2. Predevelopment activities | 93 |\n| 2.1 Desk research | 93 |\n| 2.1.1 Quality risk management | 93 |\n| 2.2 Additional considerations | 94 |\n| 2.2.1 Selection and characterization of comparator finished pharmaceutical product(s) | 94 |\n| 2.2.2 Benchmarking for formulation experiments and stability studies | 95 |\n| 2.2.3 Formulation selection experiments | 95 |\n| 2.2.4 Bioequivalence and dissolution studies | 96 |\n| 3. Pharmaceutical development | 96 |\n| 3.1 Components of the finished pharmaceutical product | 98 |\n| 3.1.1 Active pharmaceutical ingredient | 98 |\n| 3.1.2 Excipients | 99 |\n| 3.2 Finished pharmaceutical product | 100 |\n| 3.2.1 Formulation development | 100 |\n| 3.2.2 Overages | 102 |\n| 3.2.3 Physicochemical and biological properties | 103 |\n| 3.3 Manufacturing process development | 103 |\n| 3.4 Container-closure system | 104 |\n| 3.5 Microbiological attributes | 107 |\n| 3.6 Compatibility | 108 |\n| 4. Glossary | 109 |\n| References | 113 |\n| Appendix 1 | 115 |\n| Appendix 2 | 118 |", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n### Preguntas y Respuestas\n\n1. **\u00bfCu\u00e1les son los componentes clave que se deben considerar en el desarrollo farmac\u00e9utico de productos farmac\u00e9uticos terminados multisource (gen\u00e9ricos)?**\n   - **Respuesta:** Los componentes clave incluyen el ingrediente farmac\u00e9utico activo (API), los excipientes, el desarrollo de la formulaci\u00f3n, las propiedades fisicoqu\u00edmicas y biol\u00f3gicas, el desarrollo del proceso de fabricaci\u00f3n, el sistema de cierre del envase, los atributos microbiol\u00f3gicos y la compatibilidad.\n\n2. **\u00bfQu\u00e9 actividades se incluyen en la fase de predesarrollo para productos farmac\u00e9uticos gen\u00e9ricos?**\n   - **Respuesta:** Las actividades de predesarrollo incluyen la investigaci\u00f3n de escritorio, la gesti\u00f3n de riesgos de calidad, la selecci\u00f3n y caracterizaci\u00f3n de productos farmac\u00e9uticos terminados comparadores, el benchmarking para experimentos de formulaci\u00f3n y estudios de estabilidad, experimentos de selecci\u00f3n de formulaci\u00f3n, y estudios de bioequivalencia y disoluci\u00f3n.\n\n3. **\u00bfQu\u00e9 se entiende por \"overages\" en el contexto del desarrollo de productos farmac\u00e9uticos?**\n   - **Respuesta:** \"Overages\" se refiere a la cantidad adicional de ingrediente activo o excipientes que se a\u00f1ade a la formulaci\u00f3n para compensar las p\u00e9rdidas que pueden ocurrir durante el proceso de fabricaci\u00f3n, asegurando as\u00ed que el producto final cumpla con las especificaciones de calidad y potencia.\n\n### Resumen de Nivel Superior\n\nEl documento se centra en el desarrollo farmac\u00e9utico de productos farmac\u00e9uticos terminados multisource (gen\u00e9ricos), proporcionando directrices sobre los principios generales, las actividades de predesarrollo y los componentes esenciales del producto. Se abordan aspectos como la investigaci\u00f3n de escritorio, la gesti\u00f3n de riesgos, la formulaci\u00f3n y el proceso de fabricaci\u00f3n, as\u00ed como la importancia de la bioequivalencia y la estabilidad del producto. Adem\u00e1s, se incluyen glosarios y ap\u00e9ndices que ofrecen ejemplos y detalles sobre atributos de calidad y lotes de desarrollo.\n\n### Preguntas Generadas a Partir del Resumen\n\n1. **\u00bfQu\u00e9 importancia tiene la bioequivalencia en el desarrollo de productos farmac\u00e9uticos gen\u00e9ricos?**\n2. **\u00bfC\u00f3mo se lleva a cabo la gesti\u00f3n de riesgos de calidad en el desarrollo farmac\u00e9utico?**\n3. **\u00bfQu\u00e9 ejemplos se proporcionan en el ap\u00e9ndice sobre atributos de calidad de los ingredientes farmac\u00e9uticos activos?**", "prev_section_summary": "### Resumen de temas clave y entidades:\n\nEl contenido proporcionado se refiere al \"WHO - Technical Report Series 970\", un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque no se presenta informaci\u00f3n espec\u00edfica de la p\u00e1gina 104, se pueden inferir algunos temas clave y entidades relevantes:\n\n1. **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la publicaci\u00f3n del informe, que se centra en la salud p\u00fablica y la investigaci\u00f3n m\u00e9dica.\n\n2. **Informe T\u00e9cnico**: Parte de una serie que aborda diversas cuestiones relacionadas con la salud, incluyendo recomendaciones y pol\u00edticas.\n\n3. **Salud P\u00fablica**: Tema central del informe, que probablemente incluye recomendaciones y estrategias para mejorar la salud a nivel global.\n\n4. **Metodolog\u00edas de Investigaci\u00f3n**: Es probable que el informe discuta diferentes enfoques y m\u00e9todos utilizados en la investigaci\u00f3n de salud p\u00fablica.\n\n5. **Datos y Estad\u00edsticas**: Aunque no se especifican, es com\u00fan que tales informes incluyan datos relevantes que apoyen las recomendaciones y conclusiones presentadas.\n\n### Conclusi\u00f3n:\nEl informe \"WHO - Technical Report Series 970\" es un documento t\u00e9cnico que aborda temas de salud p\u00fablica, aunque el contenido espec\u00edfico de la p\u00e1gina 104 no est\u00e1 disponible. Las preguntas formuladas buscan profundizar en las recomendaciones, metodolog\u00edas y datos que podr\u00edan estar presentes en esa secci\u00f3n del informe.", "excerpt_keywords": "Keywords: pharmaceutical development, generic products, bioequivalence, quality risk management, formulation experiments"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "28ac18dd-db95-4102-a63e-72c59e956554", "node_type": "4", "metadata": {"page_label": "105", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 3\n\n**Pharmaceutical development of multisource (generic) finished pharmaceutical products \u2013 points to consider**\n\n## 1. Introduction\n1.1 General principles  \n1.2 Scope  \n\n## 2. Predevelopment activities\n2.1 Desk research  \n    2.1.1 Quality risk management  \n2.2 Additional considerations  \n    2.2.1 Selection and characterization of comparator finished pharmaceutical product(s)  \n    2.2.2 Benchmarking for formulation experiments and stability studies  \n    2.2.3 Formulation selection experiments  \n    2.2.4 Bioequivalence and dissolution studies  \n\n## 3. Pharmaceutical development\n3.1 Components of the finished pharmaceutical product  \n    3.1.1 Active pharmaceutical ingredient  \n    3.1.2 Excipients  \n3.2 Finished pharmaceutical product  \n    3.2.1 Formulation development  \n    3.2.2 Overages  \n    3.2.3 Physicochemical and biological properties  \n3.3 Manufacturing process development  \n3.4 Container-closure system  \n3.5 Microbiological attributes  \n3.6 Compatibility  \n\n## 4. Glossary\n\n**References**\n\n**Appendix 1**  \nExamples of presenting quality attributes of active pharmaceutical ingredients\n\n**Appendix 2**  \nInformation on development batches\n\n| Section | Page |\n|---------|------|\n| 1. Introduction | 92 |\n| 1.1 General principles | 92 |\n| 1.2 Scope | 92 |\n| 2. Predevelopment activities | 93 |\n| 2.1 Desk research | 93 |\n| 2.1.1 Quality risk management | 93 |\n| 2.2 Additional considerations | 94 |\n| 2.2.1 Selection and characterization of comparator finished pharmaceutical product(s) | 94 |\n| 2.2.2 Benchmarking for formulation experiments and stability studies | 95 |\n| 2.2.3 Formulation selection experiments | 95 |\n| 2.2.4 Bioequivalence and dissolution studies | 96 |\n| 3. Pharmaceutical development | 96 |\n| 3.1 Components of the finished pharmaceutical product | 98 |\n| 3.1.1 Active pharmaceutical ingredient | 98 |\n| 3.1.2 Excipients | 99 |\n| 3.2 Finished pharmaceutical product | 100 |\n| 3.2.1 Formulation development | 100 |\n| 3.2.2 Overages | 102 |\n| 3.2.3 Physicochemical and biological properties | 103 |\n| 3.3 Manufacturing process development | 103 |\n| 3.4 Container-closure system | 104 |\n| 3.5 Microbiological attributes | 107 |\n| 3.6 Compatibility | 108 |\n| 4. Glossary | 109 |\n| References | 113 |\n| Appendix 1 | 115 |\n| Appendix 2 | 118 |", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "39169b7e831a74090d136fae5124f435e54415be8e0a182f561a686f52d9a6f4", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 3\n\n**Pharmaceutical development of multisource (generic) finished pharmaceutical products \u2013 points to consider**\n\n## 1. Introduction\n1.1 General principles  \n1.2 Scope  \n\n## 2. Predevelopment activities\n2.1 Desk research  \n    2.1.1 Quality risk management  \n2.2 Additional considerations  \n    2.2.1 Selection and characterization of comparator finished pharmaceutical product(s)  \n    2.2.2 Benchmarking for formulation experiments and stability studies  \n    2.2.3 Formulation selection experiments  \n    2.2.4 Bioequivalence and dissolution studies  \n\n## 3. Pharmaceutical development\n3.1 Components of the finished pharmaceutical product  \n    3.1.1 Active pharmaceutical ingredient  \n    3.1.2 Excipients  \n3.2 Finished pharmaceutical product  \n    3.2.1 Formulation development  \n    3.2.2 Overages  \n    3.2.3 Physicochemical and biological properties  \n3.3 Manufacturing process development  \n3.4 Container-closure system  \n3.5 Microbiological attributes  \n3.6 Compatibility  \n\n## 4. Glossary\n\n**References**\n\n**Appendix 1**  \nExamples of presenting quality attributes of active pharmaceutical ingredients\n\n**Appendix 2**  \nInformation on development batches\n\n| Section | Page |\n|---------|------|\n| 1. Introduction | 92 |\n| 1.1 General principles | 92 |\n| 1.2 Scope | 92 |\n| 2. Predevelopment activities | 93 |\n| 2.1 Desk research | 93 |\n| 2.1.1 Quality risk management | 93 |\n| 2.2 Additional considerations | 94 |\n| 2.2.1 Selection and characterization of comparator finished pharmaceutical product(s) | 94 |\n| 2.2.2 Benchmarking for formulation experiments and stability studies | 95 |\n| 2.2.3 Formulation selection experiments | 95 |\n| 2.2.4 Bioequivalence and dissolution studies | 96 |\n| 3. Pharmaceutical development | 96 |\n| 3.1 Components of the finished pharmaceutical product | 98 |\n| 3.1.1 Active pharmaceutical ingredient | 98 |\n| 3.1.2 Excipients | 99 |\n| 3.2 Finished pharmaceutical product | 100 |\n| 3.2.1 Formulation development | 100 |\n| 3.2.2 Overages | 102 |\n| 3.2.3 Physicochemical and biological properties | 103 |\n| 3.3 Manufacturing process development | 103 |\n| 3.4 Container-closure system | 104 |\n| 3.5 Microbiological attributes | 107 |\n| 3.6 Compatibility | 108 |\n| 4. Glossary | 109 |\n| References | 113 |\n| Appendix 1 | 115 |\n| Appendix 2 | 118 |", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2295, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "9664255d-3845-4c5b-b7e9-69d114d7c410": {"__data__": {"id_": "9664255d-3845-4c5b-b7e9-69d114d7c410", "embedding": null, "metadata": {"page_label": "106", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nThe aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies provide scientific understanding to support the establishment of specifications and manufacturing controls.\n\nThis document focuses on the development of multisource finished pharmaceutical products (FPPs) which are intended to be bioequivalent to the relevant comparator product. Multisource FPPs should<sup>1</sup> accordingly be therapeutically equivalent to the comparator product.\n\nThis document provides a structured approach for industry following the International Conference on Harmonisation (ICH) common technical document (CTD) format, for developing high-quality, multisource FPPs. The ICH-CTD structure for pharmaceutical development information allows for a logical, progressive description of the development process.\n\nThe document is also intended to provide assessors and inspectors with a good understanding of best practices in the development of multisource FPPs and their manufacturing processes.\n\nManufacturers who have chosen a more systematic approach to product development would follow the development within the broader context of quality assurance principles, including the use of quality risk management and pharmaceutical quality systems.\n\nThis document is designed to be used in conjunction with other WHO guidelines and guidance documents (1).\n\n## 1.1 General principles\n\nThe pharmaceutical development studies and the manufacture of primary batches are essential elements for the science and risk-based approach to establish the critical quality attributes (CQAs) of the FPP and the critical process parameters (CPPs) of the manufacturing process.\n\n## 1.2 Scope\n\nThis document addresses the pharmaceutical development of multisource FPPs containing existing active pharmaceutical ingredients (APIs) of synthetic or semi-synthetic origin. For the purposes of this document an existing API is one that has been previously authorized through a finished product by a stringent regulatory authority (SRA) or, for the purposes of a national medicines regulatory authority\n\n----\n\n<sup>1</sup> For the purpose of this document the term \u201cshould\u201d is generally to be interpreted as \u201cis recommended\u201d or \u201cis usually required\u201d.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Objetivo del desarrollo farmac\u00e9utico**: El desarrollo farmac\u00e9utico busca dise\u00f1ar productos de calidad y procesos de fabricaci\u00f3n que aseguren un rendimiento consistente del producto. Esto implica la creaci\u00f3n de especificaciones y controles de fabricaci\u00f3n basados en estudios cient\u00edficos.\n\n2. **Multisource Finished Pharmaceutical Products (FPPs)**: El documento se centra en el desarrollo de productos farmac\u00e9uticos terminados multisource que son bioequivalentes a un producto comparador. Estos productos deben ser terap\u00e9uticamente equivalentes y seguir un enfoque estructurado basado en el formato del Documento T\u00e9cnico Com\u00fan (CTD) de la ICH.\n\n3. **Principios generales y alcance**: Se enfatiza la importancia de los estudios de desarrollo farmac\u00e9utico y la fabricaci\u00f3n de lotes primarios para establecer atributos de calidad cr\u00edticos (CQAs) y par\u00e1metros de proceso cr\u00edticos (CPPs). El documento se aplica a FPPs que contienen ingredientes farmac\u00e9uticos activos (APIs) existentes de origen sint\u00e9tico o semisint\u00e9tico.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 papel juegan los estudios de desarrollo farmac\u00e9utico en la determinaci\u00f3n de los atributos de calidad cr\u00edticos (CQAs) y los par\u00e1metros de proceso cr\u00edticos (CPPs) en la fabricaci\u00f3n de productos farmac\u00e9uticos multisource?**\n   - Esta pregunta se centra en la relaci\u00f3n entre los estudios de desarrollo y la calidad del producto, un aspecto que puede no estar claramente definido en otros documentos.\n\n2. **\u00bfC\u00f3mo se define un ingrediente farmac\u00e9utico activo (API) existente seg\u00fan el contexto de este documento y qu\u00e9 implicaciones tiene esto para el desarrollo de productos farmac\u00e9uticos?**\n   - Esta pregunta busca aclarar la definici\u00f3n espec\u00edfica de un API existente y su relevancia en el contexto del desarrollo de FPPs, lo cual puede no ser evidente en otras fuentes.\n\n3. **\u00bfCu\u00e1les son las mejores pr\u00e1cticas recomendadas para la fabricaci\u00f3n de productos farmac\u00e9uticos multisource seg\u00fan las directrices de la OMS y c\u00f3mo se relacionan con los principios de aseguramiento de la calidad?**\n   - Esta pregunta se enfoca en las mejores pr\u00e1cticas y su alineaci\u00f3n con los principios de calidad, un tema que puede no ser abordado de manera exhaustiva en otros documentos relacionados.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nLa secci\u00f3n del documento se centra en el desarrollo farmac\u00e9utico de productos farmac\u00e9uticos terminados multisource (gen\u00e9ricos) y abarca varios aspectos fundamentales:\n\n1. **Introducci\u00f3n**:\n   - Principios generales y alcance del desarrollo farmac\u00e9utico.\n\n2. **Actividades de Predesarrollo**:\n   - **Investigaci\u00f3n de escritorio**: Incluye la gesti\u00f3n de riesgos de calidad.\n   - **Consideraciones adicionales**: Selecci\u00f3n y caracterizaci\u00f3n de productos farmac\u00e9uticos comparadores, benchmarking para experimentos de formulaci\u00f3n y estabilidad, experimentos de selecci\u00f3n de formulaci\u00f3n, y estudios de bioequivalencia y disoluci\u00f3n.\n\n3. **Desarrollo Farmac\u00e9utico**:\n   - **Componentes del producto farmac\u00e9utico terminado**:\n     - Ingrediente farmac\u00e9utico activo (API).\n     - Excipientes.\n   - **Desarrollo de la formulaci\u00f3n**: Incluye la consideraci\u00f3n de \"overages\", propiedades fisicoqu\u00edmicas y biol\u00f3gicas.\n   - **Desarrollo del proceso de fabricaci\u00f3n**.\n   - **Sistema de cierre del envase**.\n   - **Atributos microbiol\u00f3gicos**.\n   - **Compatibilidad**.\n\n4. **Glosario**: Definiciones de t\u00e9rminos clave utilizados en el documento.\n\n5. **Referencias**: Fuentes citadas en el documento.\n\n6. **Ap\u00e9ndices**:\n   - **Ap\u00e9ndice 1**: Ejemplos de atributos de calidad de ingredientes farmac\u00e9uticos activos.\n   - **Ap\u00e9ndice 2**: Informaci\u00f3n sobre lotes de desarrollo.\n\n### Entidades Clave\n- **Productos farmac\u00e9uticos terminados multisource (gen\u00e9ricos)**.\n- **Ingredientes farmac\u00e9uticos activos (API)**.\n- **Excipientes**.\n- **Bioequivalencia**.\n- **Gesti\u00f3n de riesgos de calidad**.\n- **Formulaci\u00f3n y desarrollo de procesos**.\n- **Atributos microbiol\u00f3gicos y de compatibilidad**.\n\nEste resumen destaca los temas y entidades m\u00e1s relevantes en el contexto del desarrollo farmac\u00e9utico de productos gen\u00e9ricos, proporcionando una visi\u00f3n general de las consideraciones y procesos involucrados.", "excerpt_keywords": "Keywords: pharmaceutical development, multisource FPPs, bioequivalence, quality assurance, active pharmaceutical ingredients"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dd988d37-6248-4055-822e-339f587c09a9", "node_type": "4", "metadata": {"page_label": "106", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nThe aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies provide scientific understanding to support the establishment of specifications and manufacturing controls.\n\nThis document focuses on the development of multisource finished pharmaceutical products (FPPs) which are intended to be bioequivalent to the relevant comparator product. Multisource FPPs should<sup>1</sup> accordingly be therapeutically equivalent to the comparator product.\n\nThis document provides a structured approach for industry following the International Conference on Harmonisation (ICH) common technical document (CTD) format, for developing high-quality, multisource FPPs. The ICH-CTD structure for pharmaceutical development information allows for a logical, progressive description of the development process.\n\nThe document is also intended to provide assessors and inspectors with a good understanding of best practices in the development of multisource FPPs and their manufacturing processes.\n\nManufacturers who have chosen a more systematic approach to product development would follow the development within the broader context of quality assurance principles, including the use of quality risk management and pharmaceutical quality systems.\n\nThis document is designed to be used in conjunction with other WHO guidelines and guidance documents (1).\n\n## 1.1 General principles\n\nThe pharmaceutical development studies and the manufacture of primary batches are essential elements for the science and risk-based approach to establish the critical quality attributes (CQAs) of the FPP and the critical process parameters (CPPs) of the manufacturing process.\n\n## 1.2 Scope\n\nThis document addresses the pharmaceutical development of multisource FPPs containing existing active pharmaceutical ingredients (APIs) of synthetic or semi-synthetic origin. For the purposes of this document an existing API is one that has been previously authorized through a finished product by a stringent regulatory authority (SRA) or, for the purposes of a national medicines regulatory authority\n\n----\n\n<sup>1</sup> For the purpose of this document the term \u201cshould\u201d is generally to be interpreted as \u201cis recommended\u201d or \u201cis usually required\u201d.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "de25ade65974ff1a9b2155f4414029d58ed8ad56fa8d9421b76c5b9b44559db4", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 1. Introduction\n\nThe aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies provide scientific understanding to support the establishment of specifications and manufacturing controls.\n\nThis document focuses on the development of multisource finished pharmaceutical products (FPPs) which are intended to be bioequivalent to the relevant comparator product. Multisource FPPs should<sup>1</sup> accordingly be therapeutically equivalent to the comparator product.\n\nThis document provides a structured approach for industry following the International Conference on Harmonisation (ICH) common technical document (CTD) format, for developing high-quality, multisource FPPs. The ICH-CTD structure for pharmaceutical development information allows for a logical, progressive description of the development process.\n\nThe document is also intended to provide assessors and inspectors with a good understanding of best practices in the development of multisource FPPs and their manufacturing processes.\n\nManufacturers who have chosen a more systematic approach to product development would follow the development within the broader context of quality assurance principles, including the use of quality risk management and pharmaceutical quality systems.\n\nThis document is designed to be used in conjunction with other WHO guidelines and guidance documents (1).\n\n## 1.1 General principles\n\nThe pharmaceutical development studies and the manufacture of primary batches are essential elements for the science and risk-based approach to establish the critical quality attributes (CQAs) of the FPP and the critical process parameters (CPPs) of the manufacturing process.\n\n## 1.2 Scope\n\nThis document addresses the pharmaceutical development of multisource FPPs containing existing active pharmaceutical ingredients (APIs) of synthetic or semi-synthetic origin. For the purposes of this document an existing API is one that has been previously authorized through a finished product by a stringent regulatory authority (SRA) or, for the purposes of a national medicines regulatory authority\n\n----\n\n<sup>1</sup> For the purpose of this document the term \u201cshould\u201d is generally to be interpreted as \u201cis recommended\u201d or \u201cis usually required\u201d.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2405, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f5fb77e8-fee0-4817-8053-3b5816997d1a": {"__data__": {"id_": "f5fb77e8-fee0-4817-8053-3b5816997d1a", "embedding": null, "metadata": {"page_label": "107", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Predevelopment activities\n\n## 2.1 Desk research\n\nDesk research includes all relevant documentation being collected and evaluated prior to initiation of any laboratory activities. This documentation may include information such as is found in:\n\n- WHO, European Medicines Agency (EMA) and United States Food and Drug Administration (US-FDA) web sites that contain regulatory information, for example, the qualitative composition, mode of administration and the primary packing materials of the innovator and multisource FPPs;\n- compendial monographs, scientific literature, patents, technical information typically found in the applicant\u2019s (open) part of the API master file (APIMF), technical information on excipients and prior company knowledge.\n\n### 2.1.1 Quality risk management\n\nAn essential part of desk research entails the identification of possible risks prior to the development of a multisource product.\n\nAn important consideration when selecting the API manufacturer is the fact that the FPP manufacturer is responsible for the control of the API and as such must have a comprehensive understanding of the API. Analysis of the applicant\u2019s part of the APIMF (or drug master file) is, therefore, important.\n\nPoor solubility in aqueous medium is an important quality risk factor for APIs administered in the solid state as there is a high risk that inter-batch variability in physical properties may translate into significant differences in the in vivo performance.\n\nIt is recommended that polymorphism, pseudo-polymorphism and the implications of variability in particle size be routinely considered. Variability in any of these key physical properties is likely to be of particular significance for APIs that have low solubility according to the biopharmaceutics classification.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda las actividades de predesarrollo en la investigaci\u00f3n de productos farmac\u00e9uticos multisource. Se enfatiza la importancia de la investigaci\u00f3n de escritorio, que implica la recopilaci\u00f3n y evaluaci\u00f3n de documentaci\u00f3n relevante antes de iniciar actividades de laboratorio. Esta documentaci\u00f3n incluye informaci\u00f3n de agencias reguladoras, literatura cient\u00edfica y detalles t\u00e9cnicos sobre los ingredientes activos (API) y excipientes. Adem\u00e1s, se destaca la gesti\u00f3n de riesgos de calidad, donde se identifican posibles riesgos asociados con la solubilidad de los API y la variabilidad en sus propiedades f\u00edsicas, lo que puede afectar el rendimiento in vivo del producto.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los principales factores de riesgo de calidad que deben considerarse al desarrollar un producto farmac\u00e9utico multisource?**\n   - Esta pregunta se centra en los riesgos espec\u00edficos mencionados en el contexto, como la solubilidad y la variabilidad de las propiedades f\u00edsicas de los API.\n\n2. **\u00bfPor qu\u00e9 es crucial que el fabricante del producto farmac\u00e9utico terminado (FPP) tenga un entendimiento completo del API?**\n   - Esta pregunta aborda la responsabilidad del fabricante del FPP en el control del API y la importancia de la comprensi\u00f3n t\u00e9cnica para garantizar la calidad del producto final.\n\n3. **\u00bfQu\u00e9 aspectos de la variabilidad en las propiedades f\u00edsicas de los API se deben considerar rutinariamente durante la investigaci\u00f3n de escritorio?**\n   - Esta pregunta se enfoca en los aspectos espec\u00edficos de la variabilidad, como el polimorfismo y el tama\u00f1o de part\u00edcula, que son relevantes para la formulaci\u00f3n de productos con baja solubilidad.\n\n### Resumen de nivel superior\n\nEl documento de la OMS proporciona directrices sobre las actividades de predesarrollo en la investigaci\u00f3n de productos farmac\u00e9uticos, destacando la importancia de la investigaci\u00f3n de escritorio y la gesti\u00f3n de riesgos de calidad. Se enfatiza la necesidad de recopilar informaci\u00f3n de diversas fuentes y de evaluar los riesgos asociados con las propiedades f\u00edsicas de los ingredientes activos, lo que es crucial para el \u00e9xito del desarrollo de productos multisource.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Objetivo del Desarrollo Farmac\u00e9utico**:\n   - Dise\u00f1ar productos farmac\u00e9uticos de calidad y procesos de fabricaci\u00f3n que aseguren un rendimiento consistente.\n   - Establecimiento de especificaciones y controles de fabricaci\u00f3n basados en estudios cient\u00edficos.\n\n2. **Productos Farmac\u00e9uticos Terminados Multisource (FPPs)**:\n   - Enfoque en el desarrollo de FPPs que sean bioequivalentes a un producto comparador.\n   - Los FPPs deben ser terap\u00e9uticamente equivalentes al producto comparador.\n\n3. **Estructura del Documento**:\n   - Proporciona un enfoque estructurado siguiendo el formato del Documento T\u00e9cnico Com\u00fan (CTD) de la ICH.\n   - Facilita una descripci\u00f3n l\u00f3gica y progresiva del proceso de desarrollo.\n\n4. **Mejores Pr\u00e1cticas**:\n   - Orientaci\u00f3n para evaluadores e inspectores sobre las mejores pr\u00e1cticas en el desarrollo y fabricaci\u00f3n de FPPs multisource.\n   - Importancia de un enfoque sistem\u00e1tico en el desarrollo del producto, alineado con principios de aseguramiento de la calidad.\n\n5. **Principios Generales**:\n   - Los estudios de desarrollo farmac\u00e9utico y la fabricaci\u00f3n de lotes primarios son esenciales para establecer atributos de calidad cr\u00edticos (CQAs) y par\u00e1metros de proceso cr\u00edticos (CPPs).\n\n6. **Alcance del Documento**:\n   - Se centra en el desarrollo de FPPs que contienen ingredientes farmac\u00e9uticos activos (APIs) existentes de origen sint\u00e9tico o semisint\u00e9tico.\n   - Definici\u00f3n de un API existente como aquel autorizado previamente por una autoridad reguladora estricta (SRA).\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Emisora del documento.\n- **International Conference on Harmonisation (ICH)**: Referencia para el formato del documento.\n- **Ingredientes Farmac\u00e9uticos Activos (APIs)**: Elementos centrales en el desarrollo de FPPs.\n- **Atributos de Calidad Cr\u00edticos (CQAs)**: Elementos que definen la calidad del producto.\n- **Par\u00e1metros de Proceso Cr\u00edticos (CPPs)**: Elementos que definen el proceso de fabricaci\u00f3n.\n\nEste resumen destaca los aspectos fundamentales del desarrollo farmac\u00e9utico y la importancia de seguir directrices espec\u00edficas para asegurar la calidad y eficacia de los productos farmac\u00e9uticos multisource.", "excerpt_keywords": "Keywords: predevelopment activities, desk research, quality risk management, active pharmaceutical ingredients, solubility variability"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c3c64c67-34e4-4d6d-a450-5b443c705a5a", "node_type": "4", "metadata": {"page_label": "107", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Predevelopment activities\n\n## 2.1 Desk research\n\nDesk research includes all relevant documentation being collected and evaluated prior to initiation of any laboratory activities. This documentation may include information such as is found in:\n\n- WHO, European Medicines Agency (EMA) and United States Food and Drug Administration (US-FDA) web sites that contain regulatory information, for example, the qualitative composition, mode of administration and the primary packing materials of the innovator and multisource FPPs;\n- compendial monographs, scientific literature, patents, technical information typically found in the applicant\u2019s (open) part of the API master file (APIMF), technical information on excipients and prior company knowledge.\n\n### 2.1.1 Quality risk management\n\nAn essential part of desk research entails the identification of possible risks prior to the development of a multisource product.\n\nAn important consideration when selecting the API manufacturer is the fact that the FPP manufacturer is responsible for the control of the API and as such must have a comprehensive understanding of the API. Analysis of the applicant\u2019s part of the APIMF (or drug master file) is, therefore, important.\n\nPoor solubility in aqueous medium is an important quality risk factor for APIs administered in the solid state as there is a high risk that inter-batch variability in physical properties may translate into significant differences in the in vivo performance.\n\nIt is recommended that polymorphism, pseudo-polymorphism and the implications of variability in particle size be routinely considered. Variability in any of these key physical properties is likely to be of particular significance for APIs that have low solubility according to the biopharmaceutics classification.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "2977ec2c6e8a4c7605f9924ae6b7e2437caf6758882bd6e6f79a35b6c1d9df45", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 2. Predevelopment activities\n\n## 2.1 Desk research\n\nDesk research includes all relevant documentation being collected and evaluated prior to initiation of any laboratory activities. This documentation may include information such as is found in:\n\n- WHO, European Medicines Agency (EMA) and United States Food and Drug Administration (US-FDA) web sites that contain regulatory information, for example, the qualitative composition, mode of administration and the primary packing materials of the innovator and multisource FPPs;\n- compendial monographs, scientific literature, patents, technical information typically found in the applicant\u2019s (open) part of the API master file (APIMF), technical information on excipients and prior company knowledge.\n\n### 2.1.1 Quality risk management\n\nAn essential part of desk research entails the identification of possible risks prior to the development of a multisource product.\n\nAn important consideration when selecting the API manufacturer is the fact that the FPP manufacturer is responsible for the control of the API and as such must have a comprehensive understanding of the API. Analysis of the applicant\u2019s part of the APIMF (or drug master file) is, therefore, important.\n\nPoor solubility in aqueous medium is an important quality risk factor for APIs administered in the solid state as there is a high risk that inter-batch variability in physical properties may translate into significant differences in the in vivo performance.\n\nIt is recommended that polymorphism, pseudo-polymorphism and the implications of variability in particle size be routinely considered. Variability in any of these key physical properties is likely to be of particular significance for APIs that have low solubility according to the biopharmaceutics classification.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1794, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "a7a0a66c-0a63-40d9-a9ca-9f95244abead": {"__data__": {"id_": "a7a0a66c-0a63-40d9-a9ca-9f95244abead", "embedding": null, "metadata": {"page_label": "108", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsystem (BCS). The requirement for routine control of polymorphic form and particle size should be considered in accordance with advice in Decision Trees 3 and 4 of ICH Q6A (2). When controls are necessary they should be established based on the results obtained for the API lot(s) used in the biostudies.\n\nFor example, *The International Pharmacopoeia* (Ph. Int.) (3) restricts the polymorphic form of mebendazole API to form C and furthermore states that the formulation, manufacturing process and product packaging of chewable mebendazole tablets are designed and controlled so as to minimize the conversion of the polymorphic form of mebendazole from C to A.\n\nThe initial risk assessment of potential CQAs and CPPs of a multisource product should be based on desk research and the applicant\u2019s own experience with the manufacture of the dosage form.\n\nLiterature, preferably peer-reviewed, may contain risk information essential for predevelopment. For example, the presence of meso-ethambutol hydrochloride in commercial ethambutol hydrochloride API material has been demonstrated in the literature (4), although some pharmacopoeial monographs do not clearly reveal the presence of this impurity. Recently a specific test was included in the *European Pharmacopoeia* (Ph. Eur.) (5) for control of this impurity.\n\nThe least risky strategy for multisource product development is to use the same qualitative and, where possible, quantitative formula as that of the comparator FPP \u2013 so long as this does not lead to the possibility of patent infringement \u2013 in order to minimize the risks related to compatibility, stability and bioequivalence.\n\nAccompanying reconstitution diluents should also be included in the development strategy where appropriate. This topic is discussed further in section 3.\n\n## 2.2 Additional considerations\n\n### 2.2.1 Selection and characterization of comparator finished pharmaceutical product(s)\n\nIn many countries the NMRA provides a list of comparator products. Alternatively, references are available from WHO (Prequalification of Medicines Programme), and in international lists of comparator products. Note that for a dossier to be submitted to the Prequalification of Medicines Programme the comparator must be selected from the published lists. Guidance regarding Prequalification of Medicines Programme comparator products is available under Guidance on bioequivalence studies on the Prequalification of Medicines Programme web site (apps.who.int/prequal/).\n\nIn the case of fixed-dose combination (FDC) FPPs, there will be instances when a combination of APIs is recommended for clinical use but an innovator FDC FPP containing these APIs, whose approval was based on clinical trial data, will not be available as a comparator product. FDCs approved based on data.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con respuestas espec\u00edficas que probablemente no se encuentren en otro lugar:\n\n### Preguntas y Respuestas\n\n1. **\u00bfCu\u00e1l es la importancia del control de la forma polim\u00f3rfica y el tama\u00f1o de part\u00edcula en el desarrollo de productos farmac\u00e9uticos multisource?**\n   - La importancia radica en que el control de la forma polim\u00f3rfica y el tama\u00f1o de part\u00edcula es crucial para garantizar la calidad, eficacia y seguridad del producto farmac\u00e9utico. Seg\u00fan el contexto, se deben establecer controles basados en los resultados obtenidos de los lotes de API utilizados en los estudios de bioequivalencia, lo que ayuda a minimizar riesgos relacionados con la estabilidad y la bioequivalencia del producto.\n\n2. **\u00bfQu\u00e9 estrategia se sugiere para minimizar los riesgos en el desarrollo de productos farmac\u00e9uticos multisource?**\n   - La estrategia menos arriesgada es utilizar la misma f\u00f3rmula cualitativa y, cuando sea posible, cuantitativa que la del producto farmac\u00e9utico de referencia (FPP), siempre que esto no infrinja patentes. Esto ayuda a reducir los riesgos asociados con la compatibilidad, estabilidad y bioequivalencia del producto.\n\n3. **\u00bfQu\u00e9 recursos est\u00e1n disponibles para la selecci\u00f3n de productos farmac\u00e9uticos de referencia en el contexto de la Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - En muchos pa\u00edses, la Autoridad Nacional Reguladora de Medicamentos (NMRA) proporciona listas de productos de referencia. Adem\u00e1s, la OMS ofrece referencias a trav\u00e9s de su Programa de Precalificaci\u00f3n de Medicamentos y en listas internacionales de productos de referencia. Para que un expediente sea presentado al Programa de Precalificaci\u00f3n, el producto de referencia debe seleccionarse de estas listas publicadas.\n\n### Resumen de Nivel Superior\n\nEl contexto aborda la importancia del control de la forma polim\u00f3rfica y el tama\u00f1o de part\u00edcula en el desarrollo de productos farmac\u00e9uticos multisource, destacando la necesidad de establecer controles basados en estudios de bioequivalencia. Se sugiere que la estrategia menos arriesgada para el desarrollo de estos productos es replicar la f\u00f3rmula del producto de referencia, evitando infracciones de patentes. Adem\u00e1s, se mencionan recursos disponibles para la selecci\u00f3n de productos de referencia, incluyendo listas proporcionadas por la NMRA y la OMS, que son esenciales para el proceso de precalificaci\u00f3n de medicamentos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Investigaci\u00f3n de Escritorio:**\n   - Importancia de recopilar y evaluar documentaci\u00f3n relevante antes de iniciar actividades de laboratorio.\n   - Fuentes de informaci\u00f3n incluyen sitios web de agencias reguladoras (OMS, EMA, US-FDA), literatura cient\u00edfica, monograf\u00edas, patentes y archivos maestros de ingredientes activos (API).\n\n2. **Gesti\u00f3n de Riesgos de Calidad:**\n   - Identificaci\u00f3n de riesgos potenciales antes del desarrollo de productos multisource.\n   - La comprensi\u00f3n del API por parte del fabricante del producto farmac\u00e9utico terminado (FPP) es crucial para el control de calidad.\n\n3. **Factores de Riesgo:**\n   - La solubilidad deficiente en medios acuosos es un factor de riesgo importante para los API en estado s\u00f3lido.\n   - Variabilidad en propiedades f\u00edsicas (polimorfismo, pseudo-polimorfismo, tama\u00f1o de part\u00edcula) puede afectar el rendimiento in vivo del producto.\n\n**Entidades:**\n\n- **Organizaciones Reguladoras:**\n  - Organizaci\u00f3n Mundial de la Salud (OMS)\n  - Agencia Europea de Medicamentos (EMA)\n  - Administraci\u00f3n de Alimentos y Medicamentos de EE. UU. (US-FDA)\n\n- **Documentaci\u00f3n:**\n  - Archivos maestros de ingredientes activos (APIMF)\n  - Monograf\u00edas compendiales\n  - Literatura cient\u00edfica y patentes\n\n- **Conceptos T\u00e9cnicos:**\n  - API (Ingrediente Activo)\n  - FPP (Producto Farmac\u00e9utico Terminado)\n  - Clasificaci\u00f3n biofarmac\u00e9utica\n\nEste resumen destaca la importancia de la investigaci\u00f3n de escritorio y la gesti\u00f3n de riesgos en el desarrollo de productos farmac\u00e9uticos multisource, enfatizando la necesidad de un entendimiento profundo de los ingredientes activos y sus propiedades f\u00edsicas.", "excerpt_keywords": "Keywords: pharmaceutical preparations, polymorphic form, risk assessment, bioequivalence, comparator products"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9adcc032-2e8a-4735-8b05-fbaef4df10bb", "node_type": "4", "metadata": {"page_label": "108", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsystem (BCS). The requirement for routine control of polymorphic form and particle size should be considered in accordance with advice in Decision Trees 3 and 4 of ICH Q6A (2). When controls are necessary they should be established based on the results obtained for the API lot(s) used in the biostudies.\n\nFor example, *The International Pharmacopoeia* (Ph. Int.) (3) restricts the polymorphic form of mebendazole API to form C and furthermore states that the formulation, manufacturing process and product packaging of chewable mebendazole tablets are designed and controlled so as to minimize the conversion of the polymorphic form of mebendazole from C to A.\n\nThe initial risk assessment of potential CQAs and CPPs of a multisource product should be based on desk research and the applicant\u2019s own experience with the manufacture of the dosage form.\n\nLiterature, preferably peer-reviewed, may contain risk information essential for predevelopment. For example, the presence of meso-ethambutol hydrochloride in commercial ethambutol hydrochloride API material has been demonstrated in the literature (4), although some pharmacopoeial monographs do not clearly reveal the presence of this impurity. Recently a specific test was included in the *European Pharmacopoeia* (Ph. Eur.) (5) for control of this impurity.\n\nThe least risky strategy for multisource product development is to use the same qualitative and, where possible, quantitative formula as that of the comparator FPP \u2013 so long as this does not lead to the possibility of patent infringement \u2013 in order to minimize the risks related to compatibility, stability and bioequivalence.\n\nAccompanying reconstitution diluents should also be included in the development strategy where appropriate. This topic is discussed further in section 3.\n\n## 2.2 Additional considerations\n\n### 2.2.1 Selection and characterization of comparator finished pharmaceutical product(s)\n\nIn many countries the NMRA provides a list of comparator products. Alternatively, references are available from WHO (Prequalification of Medicines Programme), and in international lists of comparator products. Note that for a dossier to be submitted to the Prequalification of Medicines Programme the comparator must be selected from the published lists. Guidance regarding Prequalification of Medicines Programme comparator products is available under Guidance on bioequivalence studies on the Prequalification of Medicines Programme web site (apps.who.int/prequal/).\n\nIn the case of fixed-dose combination (FDC) FPPs, there will be instances when a combination of APIs is recommended for clinical use but an innovator FDC FPP containing these APIs, whose approval was based on clinical trial data, will not be available as a comparator product. FDCs approved based on data.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "de1d305608b56bf96a89dfccc0c807876c56433f024b8fcdd486030d065aa70b", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsystem (BCS). The requirement for routine control of polymorphic form and particle size should be considered in accordance with advice in Decision Trees 3 and 4 of ICH Q6A (2). When controls are necessary they should be established based on the results obtained for the API lot(s) used in the biostudies.\n\nFor example, *The International Pharmacopoeia* (Ph. Int.) (3) restricts the polymorphic form of mebendazole API to form C and furthermore states that the formulation, manufacturing process and product packaging of chewable mebendazole tablets are designed and controlled so as to minimize the conversion of the polymorphic form of mebendazole from C to A.\n\nThe initial risk assessment of potential CQAs and CPPs of a multisource product should be based on desk research and the applicant\u2019s own experience with the manufacture of the dosage form.\n\nLiterature, preferably peer-reviewed, may contain risk information essential for predevelopment. For example, the presence of meso-ethambutol hydrochloride in commercial ethambutol hydrochloride API material has been demonstrated in the literature (4), although some pharmacopoeial monographs do not clearly reveal the presence of this impurity. Recently a specific test was included in the *European Pharmacopoeia* (Ph. Eur.) (5) for control of this impurity.\n\nThe least risky strategy for multisource product development is to use the same qualitative and, where possible, quantitative formula as that of the comparator FPP \u2013 so long as this does not lead to the possibility of patent infringement \u2013 in order to minimize the risks related to compatibility, stability and bioequivalence.\n\nAccompanying reconstitution diluents should also be included in the development strategy where appropriate. This topic is discussed further in section 3.\n\n## 2.2 Additional considerations\n\n### 2.2.1 Selection and characterization of comparator finished pharmaceutical product(s)\n\nIn many countries the NMRA provides a list of comparator products. Alternatively, references are available from WHO (Prequalification of Medicines Programme), and in international lists of comparator products. Note that for a dossier to be submitted to the Prequalification of Medicines Programme the comparator must be selected from the published lists. Guidance regarding Prequalification of Medicines Programme comparator products is available under Guidance on bioequivalence studies on the Prequalification of Medicines Programme web site (apps.who.int/prequal/).\n\nIn the case of fixed-dose combination (FDC) FPPs, there will be instances when a combination of APIs is recommended for clinical use but an innovator FDC FPP containing these APIs, whose approval was based on clinical trial data, will not be available as a comparator product. FDCs approved based on data.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2872, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c90df2eb-941b-440f-84a4-0a6f6c3d05db": {"__data__": {"id_": "c90df2eb-941b-440f-84a4-0a6f6c3d05db", "embedding": null, "metadata": {"page_label": "109", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pol\u00edticas de salud. Sin embargo, el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el informe WHO - Technical Report Series 970?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe que podr\u00eda no estar disponible en otras fuentes.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en el documento y c\u00f3mo se relacionan con las pol\u00edticas actuales de la OMS?**\n   - Esta pregunta se centra en la conexi\u00f3n entre el informe y las pol\u00edticas de salud p\u00fablica, lo que podr\u00eda ofrecer una perspectiva \u00fanica sobre la direcci\u00f3n de la OMS.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en la investigaci\u00f3n presentada en el WHO - Technical Report Series 970?**\n   - Esta pregunta indaga sobre los m\u00e9todos de investigaci\u00f3n que podr\u00edan haber sido utilizados en el informe, lo que podr\u00eda ser relevante para investigadores y profesionales de la salud.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que podr\u00eda no estar f\u00e1cilmente disponible en otras fuentes, bas\u00e1ndose en el contexto del informe t\u00e9cnico de la OMS.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Control de Forma Polim\u00f3rfica y Tama\u00f1o de Part\u00edcula:**\n   - Importancia en el desarrollo de productos farmac\u00e9uticos multisource.\n   - Necesidad de establecer controles basados en los resultados de los lotes de API utilizados en estudios de bioequivalencia.\n\n2. **Estrategia de Desarrollo:**\n   - Uso de la misma f\u00f3rmula cualitativa y cuantitativa que el producto farmac\u00e9utico de referencia (FPP) para minimizar riesgos de compatibilidad, estabilidad y bioequivalencia, evitando infracciones de patentes.\n\n3. **Evaluaci\u00f3n de Riesgos:**\n   - La evaluaci\u00f3n inicial de riesgos debe basarse en investigaci\u00f3n de escritorio y experiencia del solicitante en la fabricaci\u00f3n del formulario de dosificaci\u00f3n.\n\n4. **Recursos para Selecci\u00f3n de Productos de Referencia:**\n   - Listas proporcionadas por la Autoridad Nacional Reguladora de Medicamentos (NMRA) y la OMS para la selecci\u00f3n de productos de referencia en el contexto de la Precalificaci\u00f3n de Medicamentos.\n\n5. **Consideraciones sobre Combinaciones de Dosis Fijas (FDC):**\n   - Desaf\u00edos en la selecci\u00f3n de productos de referencia cuando no hay un FPP innovador disponible que contenga las combinaciones de API recomendadas.\n\n**Entidades:**\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Proporciona directrices y listas de productos de referencia.\n- **NMRA (Autoridad Nacional Reguladora de Medicamentos):** Ofrece listas de productos de referencia en varios pa\u00edses.\n- **Ph. Int. (Farmacopea Internacional):** Regula la forma polim\u00f3rfica del API de mebendazol.\n- **Ph. Eur. (Farmacopea Europea):** Incluye pruebas espec\u00edficas para el control de impurezas en el API de etambutol.\n- **FPP (Producto Farmac\u00e9utico Terminado):** Referido en el contexto de productos de comparaci\u00f3n y desarrollo de multisource.\n\nEste resumen destaca la importancia del control de calidad en el desarrollo de productos farmac\u00e9uticos, as\u00ed como los recursos y estrategias recomendadas para asegurar la bioequivalencia y la seguridad del producto.", "excerpt_keywords": "Keywords: salud p\u00fablica, bioequivalencia, productos farmac\u00e9uticos, OMS, evaluaci\u00f3n de riesgos"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a11a13ec-fda5-4e30-8174-20c1ac545181", "node_type": "4", "metadata": {"page_label": "109", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f8c494e47476ec39efe66ff6c7ac4a3e8eb958c06de951de2dcc9064b1c8a09b", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "5843445d-758c-4b89-a761-c65dd1f83bdf": {"__data__": {"id_": "5843445d-758c-4b89-a761-c65dd1f83bdf", "embedding": null, "metadata": {"page_label": "110", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Bioequivalence and dissolution studies\n\nBioequivalence and comparative dissolution studies should be conducted with samples from a batch of the FPP of at least pilot size. The dissolution conditions and acceptance criteria should be derived from the dissolution profiles obtained for the biobatch.\n\nWhere an in vivo bioequivalence study could be waived, similarity of the formulations may be required, in particular with respect to excipients that may have an influence on the extent and rate of absorption, e.g. sorbitol in liquid formulations or mannitol in solid dosage forms. For instance, when considering a biowaiver for an immediate-release solid oral dosage form containing a BCS class 3 API, the risk of reaching an inappropriate biowaiver decision needs to be critically evaluated, especially when the extent of absorption (f_abs) is less than 50%. As part of the risk assessment the excipients used will also need to be scrutinized carefully in terms of both qualitative and quantitative composition \u2013 the greater the deviation from the comparator composition, the greater the risk of an inappropriate biowaiver decision.\n\nInclusion of summaries of all bioequivalence studies (passed and failed) on the final formulation in the PD may be required.\n\n# 3. Pharmaceutical development\n\nIt is recommended to use an internationally harmonized structure when submitting a dossier for obtaining a marketing authorization. This section therefore follows the ICH-CTD structure according to ICH M4 (8).\n\n> The text of the M4Q (CTD-Q) guideline (9) is reproduced verbatim in this document in *italic text*, with minor modifications to accommodate WHO terminology and to include certain changes to the text that would be appropriate for multisource pharmaceutical products, notably:\n> \n> - drug substance is replaced with active pharmaceutical ingredient or API;\n> - drug product is replaced with finished pharmaceutical product or FPP;\n> - application is replaced with product dossier or PD;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (WHO - Technical Report Series 970) aborda la importancia de realizar estudios de bioequivalencia y disoluci\u00f3n comparativa para productos farmac\u00e9uticos terminados (FPP). Se enfatiza que estos estudios deben llevarse a cabo con muestras de al menos tama\u00f1o piloto y que las condiciones de disoluci\u00f3n y criterios de aceptaci\u00f3n deben derivarse de los perfiles de disoluci\u00f3n obtenidos de un biobatch. Adem\u00e1s, se discute la posibilidad de renunciar a un estudio de bioequivalencia in vivo bajo ciertas condiciones, especialmente en relaci\u00f3n con los excipientes que pueden afectar la absorci\u00f3n. Tambi\u00e9n se menciona la necesidad de incluir res\u00famenes de todos los estudios de bioequivalencia en el expediente del producto (PD).\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son los criterios que deben considerarse al evaluar la similitud de formulaciones para renunciar a un estudio de bioequivalencia in vivo?**\n   - El contexto menciona que se debe prestar especial atenci\u00f3n a los excipientes que pueden influir en la absorci\u00f3n, como el sorbitol en formulaciones l\u00edquidas o el manitol en formas de dosificaci\u00f3n s\u00f3lidas. La evaluaci\u00f3n de la similitud tambi\u00e9n debe considerar la composici\u00f3n cualitativa y cuantitativa de los excipientes.\n\n2. **\u00bfQu\u00e9 riesgos se deben evaluar al considerar un biowaiver para un API de clase 3 del BCS?**\n   - Se debe evaluar el riesgo de tomar una decisi\u00f3n inapropiada sobre el biowaiver, especialmente si la extensi\u00f3n de la absorci\u00f3n (f_abs) es inferior al 50%. Cuanto mayor sea la desviaci\u00f3n de la composici\u00f3n del comparador, mayor ser\u00e1 el riesgo de una decisi\u00f3n inapropiada.\n\n3. **\u00bfQu\u00e9 modificaciones se han realizado en el texto del M4Q (CTD-Q) para adaptarlo a la terminolog\u00eda de la OMS?**\n   - Las modificaciones incluyen el reemplazo de \"drug substance\" por \"active pharmaceutical ingredient\" (API), \"drug product\" por \"finished pharmaceutical product\" (FPP) y \"application\" por \"product dossier\" (PD). Estas adaptaciones son relevantes para productos farmac\u00e9uticos multisource.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n#### Temas Clave\n1. **Salud P\u00fablica**: El informe probablemente aborda cuestiones relacionadas con la salud p\u00fablica, incluyendo enfermedades, prevenci\u00f3n y promoci\u00f3n de la salud.\n2. **Investigaci\u00f3n M\u00e9dica**: Es posible que se presenten hallazgos de investigaciones recientes en el campo de la medicina y la salud.\n3. **Pol\u00edticas de Salud**: El documento puede incluir recomendaciones para la formulaci\u00f3n de pol\u00edticas de salud basadas en la evidencia presentada.\n4. **Metodolog\u00edas de Investigaci\u00f3n**: Se podr\u00eda discutir sobre los m\u00e9todos utilizados para llevar a cabo la investigaci\u00f3n, lo que es crucial para la validez de los hallazgos.\n\n#### Entidades\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe, que se centra en mejorar la salud a nivel global.\n- **Investigadores y Profesionales de la Salud**: Los posibles destinatarios del informe, quienes podr\u00edan beneficiarse de los hallazgos y recomendaciones presentados.\n\nEste resumen proporciona una visi\u00f3n general de los temas y entidades que podr\u00edan estar presentes en el informe, a pesar de la falta de contenido espec\u00edfico en el contexto proporcionado.", "excerpt_keywords": "Keywords: bioequivalence, dissolution studies, pharmaceutical development, excipients, biowaiver"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9f94aa06-cba1-489d-8d44-4bbb66a563d6", "node_type": "4", "metadata": {"page_label": "110", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Bioequivalence and dissolution studies\n\nBioequivalence and comparative dissolution studies should be conducted with samples from a batch of the FPP of at least pilot size. The dissolution conditions and acceptance criteria should be derived from the dissolution profiles obtained for the biobatch.\n\nWhere an in vivo bioequivalence study could be waived, similarity of the formulations may be required, in particular with respect to excipients that may have an influence on the extent and rate of absorption, e.g. sorbitol in liquid formulations or mannitol in solid dosage forms. For instance, when considering a biowaiver for an immediate-release solid oral dosage form containing a BCS class 3 API, the risk of reaching an inappropriate biowaiver decision needs to be critically evaluated, especially when the extent of absorption (f_abs) is less than 50%. As part of the risk assessment the excipients used will also need to be scrutinized carefully in terms of both qualitative and quantitative composition \u2013 the greater the deviation from the comparator composition, the greater the risk of an inappropriate biowaiver decision.\n\nInclusion of summaries of all bioequivalence studies (passed and failed) on the final formulation in the PD may be required.\n\n# 3. Pharmaceutical development\n\nIt is recommended to use an internationally harmonized structure when submitting a dossier for obtaining a marketing authorization. This section therefore follows the ICH-CTD structure according to ICH M4 (8).\n\n> The text of the M4Q (CTD-Q) guideline (9) is reproduced verbatim in this document in *italic text*, with minor modifications to accommodate WHO terminology and to include certain changes to the text that would be appropriate for multisource pharmaceutical products, notably:\n> \n> - drug substance is replaced with active pharmaceutical ingredient or API;\n> - drug product is replaced with finished pharmaceutical product or FPP;\n> - application is replaced with product dossier or PD;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "6981f7c3f0cff77cc93755a9cf7026e0c808a7b522c334f2c7bce2df0baa2611", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Bioequivalence and dissolution studies\n\nBioequivalence and comparative dissolution studies should be conducted with samples from a batch of the FPP of at least pilot size. The dissolution conditions and acceptance criteria should be derived from the dissolution profiles obtained for the biobatch.\n\nWhere an in vivo bioequivalence study could be waived, similarity of the formulations may be required, in particular with respect to excipients that may have an influence on the extent and rate of absorption, e.g. sorbitol in liquid formulations or mannitol in solid dosage forms. For instance, when considering a biowaiver for an immediate-release solid oral dosage form containing a BCS class 3 API, the risk of reaching an inappropriate biowaiver decision needs to be critically evaluated, especially when the extent of absorption (f_abs) is less than 50%. As part of the risk assessment the excipients used will also need to be scrutinized carefully in terms of both qualitative and quantitative composition \u2013 the greater the deviation from the comparator composition, the greater the risk of an inappropriate biowaiver decision.\n\nInclusion of summaries of all bioequivalence studies (passed and failed) on the final formulation in the PD may be required.\n\n# 3. Pharmaceutical development\n\nIt is recommended to use an internationally harmonized structure when submitting a dossier for obtaining a marketing authorization. This section therefore follows the ICH-CTD structure according to ICH M4 (8).\n\n> The text of the M4Q (CTD-Q) guideline (9) is reproduced verbatim in this document in *italic text*, with minor modifications to accommodate WHO terminology and to include certain changes to the text that would be appropriate for multisource pharmaceutical products, notably:\n> \n> - drug substance is replaced with active pharmaceutical ingredient or API;\n> - drug product is replaced with finished pharmaceutical product or FPP;\n> - application is replaced with product dossier or PD;", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1992, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ea60fd28-f36f-41c0-a8d2-97535a840a2d": {"__data__": {"id_": "ea60fd28-f36f-41c0-a8d2-97535a840a2d", "embedding": null, "metadata": {"page_label": "111", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\n- combination product is replaced with fixed-dose combination or FDC;\n- clinical batches is replaced with comparative bioavailability or biowaiver batches.\n\nFollowing the *italic* text of the M4Q (CTD-Q) guideline (9), additional guidance by WHO is added in normal type to enable it to be easily distinguishable from the ICH text. This additional text is included to further clarify WHO\u2019s expectations and requirements. This approach is intended to facilitate the identification and origin of the text in the document (i.e. whether from ICH or WHO).\n\nIn section 3.2.P.2 below, reference may be made to CTD sections that are not discussed in this document. This is done to guide the manufacturer in completing the PD according to national or regional requirements.\n\n### 3.2.P.2\n\n*The Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this section should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier.*\n\nPharmaceutical development information usually includes, at a minimum:\n\n- the definition of the QTPP as it relates to quality, safety and efficacy, considering, for example, the route of administration, dosage form, bioavailability, strength and stability;\n- identification of the potential CQAs of the FPP so as to adequately control product characteristics that could have an impact on quality;\n- discussion of the potential CQAs of the API(s), excipients and container-closure system(s) including the selection of the type, grade and amount necessary to deliver the product of the desired quality;\n- discussion of the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner.\n```", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS, parte de la Serie de Informes T\u00e9cnicos 970, proporciona directrices sobre el desarrollo farmac\u00e9utico, espec\u00edficamente en la secci\u00f3n 3.2.P.2. Se enfatiza la importancia de realizar estudios de desarrollo para garantizar que la forma de dosificaci\u00f3n, la formulaci\u00f3n, el proceso de fabricaci\u00f3n y otros atributos sean adecuados para el prop\u00f3sito del dossier del producto. Tambi\u00e9n se discuten los par\u00e1metros cr\u00edticos que pueden influir en la reproducibilidad del lote, el rendimiento del producto y la calidad del producto farmac\u00e9utico terminado (FPP). Se menciona la necesidad de identificar y controlar atributos cr\u00edticos de calidad (CQA) tanto del producto terminado como de los ingredientes activos (API) y excipientes.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la secci\u00f3n de desarrollo farmac\u00e9utico seg\u00fan las directrices de la OMS?**\n   - La secci\u00f3n de desarrollo farmac\u00e9utico debe contener informaci\u00f3n sobre los estudios de desarrollo realizados, que establecen la adecuaci\u00f3n de la forma de dosificaci\u00f3n, la formulaci\u00f3n, el proceso de fabricaci\u00f3n, el sistema de cierre del envase, los atributos microbiol\u00f3gicos y las instrucciones de uso. Tambi\u00e9n debe identificar y describir los atributos de formulaci\u00f3n y proceso que pueden influir en la reproducibilidad del lote y la calidad del FPP.\n\n2. **\u00bfCu\u00e1les son los atributos cr\u00edticos de calidad (CQA) que deben considerarse en el desarrollo de un producto farmac\u00e9utico?**\n   - Los atributos cr\u00edticos de calidad (CQA) del producto farmac\u00e9utico terminado (FPP) deben ser identificados para controlar adecuadamente las caracter\u00edsticas del producto que podr\u00edan impactar en la calidad. Esto incluye discutir los CQAs de los ingredientes activos (API), excipientes y sistemas de cierre del envase, as\u00ed como los criterios de selecci\u00f3n para el proceso de fabricaci\u00f3n.\n\n3. **\u00bfC\u00f3mo se diferencia la informaci\u00f3n de desarrollo farmac\u00e9utico de las pruebas de control rutinarias seg\u00fan el documento?**\n   - La informaci\u00f3n de desarrollo farmac\u00e9utico se distingue de las pruebas de control rutinarias en que se centra en los estudios de desarrollo realizados para establecer la adecuaci\u00f3n de varios aspectos del producto, mientras que las pruebas de control rutinarias se llevan a cabo de acuerdo con especificaciones predefinidas y no est\u00e1n orientadas a la investigaci\u00f3n y el desarrollo del producto.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Bioequivalencia y estudios de disoluci\u00f3n**:\n   - Se deben realizar estudios de bioequivalencia y disoluci\u00f3n comparativa con muestras de al menos tama\u00f1o piloto del producto farmac\u00e9utico terminado (FPP).\n   - Las condiciones de disoluci\u00f3n y los criterios de aceptaci\u00f3n deben basarse en los perfiles de disoluci\u00f3n obtenidos de un biobatch.\n\n2. **Renuncia a estudios in vivo**:\n   - En ciertos casos, se puede renunciar a un estudio de bioequivalencia in vivo, pero se requiere evaluar la similitud de las formulaciones, especialmente en relaci\u00f3n con excipientes que afectan la absorci\u00f3n (ej. sorbitol y manitol).\n   - Se debe evaluar el riesgo de decisiones inapropiadas sobre biowaivers, especialmente si la extensi\u00f3n de absorci\u00f3n (f_abs) es menor al 50%.\n\n3. **Evaluaci\u00f3n de excipientes**:\n   - La composici\u00f3n cualitativa y cuantitativa de los excipientes debe ser analizada; mayores desviaciones de la composici\u00f3n del comparador incrementan el riesgo de decisiones inapropiadas.\n\n4. **Inclusi\u00f3n de estudios de bioequivalencia**:\n   - Es posible que se requiera incluir res\u00famenes de todos los estudios de bioequivalencia (tanto aprobados como fallidos) en el expediente del producto (PD).\n\n5. **Desarrollo farmac\u00e9utico**:\n   - Se recomienda seguir una estructura armonizada internacionalmente al presentar un expediente para la autorizaci\u00f3n de comercializaci\u00f3n, siguiendo la estructura ICH-CTD seg\u00fan ICH M4.\n\n6. **Modificaciones terminol\u00f3gicas**:\n   - Se han realizado adaptaciones en el texto del M4Q (CTD-Q) para alinearlo con la terminolog\u00eda de la OMS, como el uso de \"active pharmaceutical ingredient\" (API) en lugar de \"drug substance\", \"finished pharmaceutical product\" (FPP) en lugar de \"drug product\", y \"product dossier\" (PD) en lugar de \"application\".\n\n### Entidades clave:\n- **FPP**: Producto farmac\u00e9utico terminado.\n- **API**: Ingrediente farmac\u00e9utico activo.\n- **Biowaiver**: Renuncia a estudios de bioequivalencia in vivo.\n- **BCS**: Sistema de clasificaci\u00f3n biol\u00f3gica.\n- **ICH**: Consejo Internacional de Armonizaci\u00f3n.", "excerpt_keywords": "Keywords: pharmaceutical development, quality attributes, fixed-dose combination, bioavailability, product dossier"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1405dce6-3f38-4b97-95ae-7f02f2b153e5", "node_type": "4", "metadata": {"page_label": "111", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\n- combination product is replaced with fixed-dose combination or FDC;\n- clinical batches is replaced with comparative bioavailability or biowaiver batches.\n\nFollowing the *italic* text of the M4Q (CTD-Q) guideline (9), additional guidance by WHO is added in normal type to enable it to be easily distinguishable from the ICH text. This additional text is included to further clarify WHO\u2019s expectations and requirements. This approach is intended to facilitate the identification and origin of the text in the document (i.e. whether from ICH or WHO).\n\nIn section 3.2.P.2 below, reference may be made to CTD sections that are not discussed in this document. This is done to guide the manufacturer in completing the PD according to national or regional requirements.\n\n### 3.2.P.2\n\n*The Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this section should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier.*\n\nPharmaceutical development information usually includes, at a minimum:\n\n- the definition of the QTPP as it relates to quality, safety and efficacy, considering, for example, the route of administration, dosage form, bioavailability, strength and stability;\n- identification of the potential CQAs of the FPP so as to adequately control product characteristics that could have an impact on quality;\n- discussion of the potential CQAs of the API(s), excipients and container-closure system(s) including the selection of the type, grade and amount necessary to deliver the product of the desired quality;\n- discussion of the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner.\n```", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "b14d0ffc011e178ccf6164a324adf6b541fae9a53deb7ea907e3a90cc267c076", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "```\n- combination product is replaced with fixed-dose combination or FDC;\n- clinical batches is replaced with comparative bioavailability or biowaiver batches.\n\nFollowing the *italic* text of the M4Q (CTD-Q) guideline (9), additional guidance by WHO is added in normal type to enable it to be easily distinguishable from the ICH text. This additional text is included to further clarify WHO\u2019s expectations and requirements. This approach is intended to facilitate the identification and origin of the text in the document (i.e. whether from ICH or WHO).\n\nIn section 3.2.P.2 below, reference may be made to CTD sections that are not discussed in this document. This is done to guide the manufacturer in completing the PD according to national or regional requirements.\n\n### 3.2.P.2\n\n*The Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this section should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier.*\n\nPharmaceutical development information usually includes, at a minimum:\n\n- the definition of the QTPP as it relates to quality, safety and efficacy, considering, for example, the route of administration, dosage form, bioavailability, strength and stability;\n- identification of the potential CQAs of the FPP so as to adequately control product characteristics that could have an impact on quality;\n- discussion of the potential CQAs of the API(s), excipients and container-closure system(s) including the selection of the type, grade and amount necessary to deliver the product of the desired quality;\n- discussion of the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner.\n```", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2461, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c5621bc9-59f6-4f16-a74a-4d09f63c0999": {"__data__": {"id_": "c5621bc9-59f6-4f16-a74a-4d09f63c0999", "embedding": null, "metadata": {"page_label": "112", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Components of the Finished Pharmaceutical Product\n\nThese features should be discussed as part of the product development, using the principles of risk management over the entire life-cycle of the product (ICH Q8 (10)). The information gained through the predevelopment activities may already have disclosed some of these features and could form an integral part of pharmaceutical development.\n\nFor a discussion of additional pharmaceutical development issues specific to the development of FDCs, reference can be made to WHO Technical Report Series, No. 929, Annex 5, section 6.3.2 (6).\n\nReference documents for pharmaceutical development include ICH guidelines Q6A, Q8, Q9 and Q10 (2, 10\u201312).\n\n## 3.1 Components of the Finished Pharmaceutical Product\n\n### 3.2.P.2.1\n\nThe components of the FPP are the ingredients listed under section 3.2.1.P.1 (Description and composition of the FPP in the PD). The components thus include the API(s) and all the excipients, as well as those excipients that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. water for granulation) and any others (e.g. nitrogen or silicone for stoppers).\n\n### 3.1.1 Active Pharmaceutical Ingredient\n\n#### 3.2.P.2.1.1\n\nThe compatibility of the API with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (e.g. water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For FDCs, the compatibility of APIs with each other should be discussed.\n\nPhysicochemical characteristics of the API may influence both the manufacturing capability and the performance of the FPP.\n\nInformation on the intrinsic physicochemical properties of the molecule, e.g. solubility, solid-state properties, including polymorphism and habit, melting range, pK\u2090 and hygroscopicity, is needed for the development of the product to allow the manufacturer of the FPP to take full responsibility for the quality and quality control (QC) of the API and the FPP.\n\nAdditionally, the manufacturer will need information (either from the API manufacturer, or gathered by another party, or by itself) on potentially critical properties of the API, together with specifications, as applicable, e.g. solubility at 37 \u00b0C at relevant physiological pH values to permit BCS classification of the API, partition coefficient (octanol/water) at 37 \u00b0C and particle size distribution, which may affect dissolution rate and bioavailability, as well as density, bulk and tapped density, flowability, compressibility, and other factors which may influence processibility. The above-mentioned properties of the API should usually be supported by experimental data (or by information from peer-reviewed literature) and discussed with respect to CQAs and CPPs.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado, as\u00ed como un resumen de nivel superior del contenido:\n\n### Resumen de Nivel Superior\nEl documento de la OMS discute los componentes del Producto Farmac\u00e9utico Terminado (FPP) y la importancia de la gesti\u00f3n de riesgos en el desarrollo de productos farmac\u00e9uticos. Se enfatiza la necesidad de evaluar la compatibilidad del Ingrediente Farmac\u00e9utico Activo (API) con excipientes y otros factores fisicoqu\u00edmicos que pueden influir en la calidad y el rendimiento del FPP. Adem\u00e1s, se menciona la importancia de la informaci\u00f3n sobre las propiedades intr\u00ednsecas del API para garantizar la calidad y el control de calidad del producto final.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n sobre las propiedades fisicoqu\u00edmicas del API es crucial para el desarrollo del FPP y por qu\u00e9?**\n   - Esta pregunta busca respuestas sobre las propiedades espec\u00edficas del API que son necesarias para garantizar la calidad y el rendimiento del FPP, as\u00ed como su impacto en el proceso de fabricaci\u00f3n.\n\n2. **\u00bfC\u00f3mo se debe abordar la compatibilidad de los APIs en formulaciones de Combinaciones de F\u00e1rmacos (FDCs) seg\u00fan el documento?**\n   - Esta pregunta se centra en la discusi\u00f3n sobre la compatibilidad entre diferentes APIs en FDCs, un aspecto que puede no estar ampliamente cubierto en otras fuentes.\n\n3. **\u00bfQu\u00e9 documentos de referencia se mencionan en el contexto del desarrollo farmac\u00e9utico y cu\u00e1l es su relevancia?**\n   - Esta pregunta busca identificar y explicar la importancia de los documentos de referencia, como las gu\u00edas ICH, en el proceso de desarrollo farmac\u00e9utico, lo que puede no ser evidente en otros textos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS, parte de la Serie de Informes T\u00e9cnicos 970, se centra en las directrices para el desarrollo farmac\u00e9utico, espec\u00edficamente en la secci\u00f3n 3.2.P.2. A continuaci\u00f3n se presentan los temas clave y entidades relevantes:\n\n#### Temas Clave\n\n1. **Desarrollo Farmac\u00e9utico**: La secci\u00f3n debe incluir informaci\u00f3n sobre estudios de desarrollo que validen la adecuaci\u00f3n de la forma de dosificaci\u00f3n, formulaci\u00f3n, proceso de fabricaci\u00f3n, sistema de cierre del envase, atributos microbiol\u00f3gicos e instrucciones de uso.\n\n2. **Atributos Cr\u00edticos de Calidad (CQA)**: Se enfatiza la identificaci\u00f3n y control de los CQAs del producto farmac\u00e9utico terminado (FPP), as\u00ed como de los ingredientes activos (API) y excipientes.\n\n3. **Par\u00e1metros Cr\u00edticos**: Se deben identificar y describir los atributos de formulaci\u00f3n y proceso que pueden influir en la reproducibilidad del lote y la calidad del FPP.\n\n4. **Diferenciaci\u00f3n de Pruebas**: La informaci\u00f3n de desarrollo farmac\u00e9utico se distingue de las pruebas de control rutinarias, ya que se centra en estudios de desarrollo en lugar de pruebas de conformidad con especificaciones.\n\n5. **QTPP (Quality Target Product Profile)**: Se debe definir el QTPP en relaci\u00f3n con la calidad, seguridad y eficacia, considerando aspectos como la v\u00eda de administraci\u00f3n, forma de dosificaci\u00f3n, biodisponibilidad, potencia y estabilidad.\n\n6. **Estrategia de Control de Proceso**: Se discuten los criterios de selecci\u00f3n para el proceso de fabricaci\u00f3n y la estrategia de control necesaria para producir lotes comerciales que cumplan consistentemente con el QTPP.\n\n#### Entidades Relevantes\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que proporciona las directrices.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que se eval\u00faa en t\u00e9rminos de calidad.\n- **API (Ingrediente Activo)**: Sustancia que proporciona la acci\u00f3n farmacol\u00f3gica.\n- **Excipientes**: Sustancias inactivas que se utilizan en la formulaci\u00f3n del producto.\n- **Sistema de Cierre del Envase**: Elemento cr\u00edtico para la preservaci\u00f3n y calidad del producto.\n\nEste resumen destaca la importancia de un enfoque sistem\u00e1tico en el desarrollo farmac\u00e9utico, asegurando que todos los aspectos del producto sean cuidadosamente considerados y validados para cumplir con los est\u00e1ndares de calidad y eficacia.", "excerpt_keywords": "Keywords: pharmaceutical development, active pharmaceutical ingredient, excipients, risk management, quality control"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "abd80673-3b60-4f1c-b9ec-3e95fa27fd57", "node_type": "4", "metadata": {"page_label": "112", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Components of the Finished Pharmaceutical Product\n\nThese features should be discussed as part of the product development, using the principles of risk management over the entire life-cycle of the product (ICH Q8 (10)). The information gained through the predevelopment activities may already have disclosed some of these features and could form an integral part of pharmaceutical development.\n\nFor a discussion of additional pharmaceutical development issues specific to the development of FDCs, reference can be made to WHO Technical Report Series, No. 929, Annex 5, section 6.3.2 (6).\n\nReference documents for pharmaceutical development include ICH guidelines Q6A, Q8, Q9 and Q10 (2, 10\u201312).\n\n## 3.1 Components of the Finished Pharmaceutical Product\n\n### 3.2.P.2.1\n\nThe components of the FPP are the ingredients listed under section 3.2.1.P.1 (Description and composition of the FPP in the PD). The components thus include the API(s) and all the excipients, as well as those excipients that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. water for granulation) and any others (e.g. nitrogen or silicone for stoppers).\n\n### 3.1.1 Active Pharmaceutical Ingredient\n\n#### 3.2.P.2.1.1\n\nThe compatibility of the API with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (e.g. water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For FDCs, the compatibility of APIs with each other should be discussed.\n\nPhysicochemical characteristics of the API may influence both the manufacturing capability and the performance of the FPP.\n\nInformation on the intrinsic physicochemical properties of the molecule, e.g. solubility, solid-state properties, including polymorphism and habit, melting range, pK\u2090 and hygroscopicity, is needed for the development of the product to allow the manufacturer of the FPP to take full responsibility for the quality and quality control (QC) of the API and the FPP.\n\nAdditionally, the manufacturer will need information (either from the API manufacturer, or gathered by another party, or by itself) on potentially critical properties of the API, together with specifications, as applicable, e.g. solubility at 37 \u00b0C at relevant physiological pH values to permit BCS classification of the API, partition coefficient (octanol/water) at 37 \u00b0C and particle size distribution, which may affect dissolution rate and bioavailability, as well as density, bulk and tapped density, flowability, compressibility, and other factors which may influence processibility. The above-mentioned properties of the API should usually be supported by experimental data (or by information from peer-reviewed literature) and discussed with respect to CQAs and CPPs.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f4cea47ec3836a4e4cf59afc11026a7f83e82859f6cece8a39cd309939948d12", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Components of the Finished Pharmaceutical Product\n\nThese features should be discussed as part of the product development, using the principles of risk management over the entire life-cycle of the product (ICH Q8 (10)). The information gained through the predevelopment activities may already have disclosed some of these features and could form an integral part of pharmaceutical development.\n\nFor a discussion of additional pharmaceutical development issues specific to the development of FDCs, reference can be made to WHO Technical Report Series, No. 929, Annex 5, section 6.3.2 (6).\n\nReference documents for pharmaceutical development include ICH guidelines Q6A, Q8, Q9 and Q10 (2, 10\u201312).\n\n## 3.1 Components of the Finished Pharmaceutical Product\n\n### 3.2.P.2.1\n\nThe components of the FPP are the ingredients listed under section 3.2.1.P.1 (Description and composition of the FPP in the PD). The components thus include the API(s) and all the excipients, as well as those excipients that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. water for granulation) and any others (e.g. nitrogen or silicone for stoppers).\n\n### 3.1.1 Active Pharmaceutical Ingredient\n\n#### 3.2.P.2.1.1\n\nThe compatibility of the API with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (e.g. water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For FDCs, the compatibility of APIs with each other should be discussed.\n\nPhysicochemical characteristics of the API may influence both the manufacturing capability and the performance of the FPP.\n\nInformation on the intrinsic physicochemical properties of the molecule, e.g. solubility, solid-state properties, including polymorphism and habit, melting range, pK\u2090 and hygroscopicity, is needed for the development of the product to allow the manufacturer of the FPP to take full responsibility for the quality and quality control (QC) of the API and the FPP.\n\nAdditionally, the manufacturer will need information (either from the API manufacturer, or gathered by another party, or by itself) on potentially critical properties of the API, together with specifications, as applicable, e.g. solubility at 37 \u00b0C at relevant physiological pH values to permit BCS classification of the API, partition coefficient (octanol/water) at 37 \u00b0C and particle size distribution, which may affect dissolution rate and bioavailability, as well as density, bulk and tapped density, flowability, compressibility, and other factors which may influence processibility. The above-mentioned properties of the API should usually be supported by experimental data (or by information from peer-reviewed literature) and discussed with respect to CQAs and CPPs.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2885, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f433dedc-f74a-4482-ad62-531e3bf3d065": {"__data__": {"id_": "f433dedc-f74a-4482-ad62-531e3bf3d065", "embedding": null, "metadata": {"page_label": "113", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The specifications of the API manufacturer and the retest period or expiry date derived from formal regulatory stability studies should also be available to the manufacturer of the FPP.\n\nGuidance on compatibility studies is provided in Appendix 3 of the WHO *Guidelines for registration of fixed-dose combination medicinal products* (6). In addition to visual examination, chromatography results (assay, purity) are required to demonstrate API\u2013API and API\u2013excipient compatibility. In general, API\u2013excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product.\n\nStress testing of the API should be designed to include simulation, as far as possible, of the conditions that may be encountered during the manufacturing process of the FPP. An example is provided in Appendix 1.\n\n### 3.1.2 Excipients\n\n\u201c3.2.P.2.1.2 *The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions.*\u201d\n\nWhen choosing excipients, those with a compendial monograph are generally preferred and may be required in certain jurisdictions. Other resources are available for information on acceptable excipients and their concentrations such as the US-FDA IIG (13) list and the *Handbook of pharmaceutical excipients* (14). Use of excipients at concentrations outside the established ranges is discouraged and generally requires justification. In addition, available guidelines which address particular excipients to be avoided should usually be consulted, for example, azo colourants as listed in EMA guideline CPMP/463/00 (15). Other guidelines such as WHO\u2019s *Development of paediatric medicines: points to consider in pharmaceutical development* (16) may provide useful general guidance in this regard.\n\nThe characteristics and amounts of excipients that can influence the performance of the pharmaceutical product or its manufacturing capability should usually be discussed relative to the respective function. The ability of functional excipients, e.g. pH-adjusting agents, buffers, stabilizers (such as antioxidants and chelating agents), preservatives and dissolution modifiers (such as surface active agents), to perform throughout the intended shelf-life of the FPP should usually be demonstrated.\n\nAntimicrobial preservatives are discussed in 3.2.P.2.5.\n\nMany excipients such as povidone, microcrystalline cellulose and lactose are by nature multifunctional. The chemically identical excipients may have different grades (physical properties) with different functional characteristics; therefore, conformance to pharmacopoeial specifications does not always...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl texto proporciona directrices sobre la elecci\u00f3n y uso de excipientes en la formulaci\u00f3n de productos farmac\u00e9uticos, as\u00ed como la importancia de la compatibilidad entre el principio activo (API) y los excipientes. Se menciona que los excipientes deben ser seleccionados cuidadosamente, preferiblemente aquellos que tienen una monograf\u00eda en una farmacopea, y que su concentraci\u00f3n y caracter\u00edsticas deben discutirse en relaci\u00f3n con su funci\u00f3n en el producto final. Tambi\u00e9n se aborda la necesidad de realizar estudios de compatibilidad y pruebas de estr\u00e9s para asegurar que los excipientes mantengan su funcionalidad a lo largo de la vida \u00fatil del producto.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de estudios son necesarios para demostrar la compatibilidad entre el API y los excipientes, y qu\u00e9 resultados se requieren?**\n   - El texto menciona que se requieren resultados de cromatograf\u00eda (an\u00e1lisis y pureza) adem\u00e1s de una evaluaci\u00f3n visual para demostrar la compatibilidad entre el API y los excipientes.\n\n2. **\u00bfCu\u00e1les son las consideraciones clave al seleccionar excipientes para un producto farmac\u00e9utico?**\n   - Al seleccionar excipientes, se deben considerar aquellos que tienen una monograf\u00eda en una farmacopea, su concentraci\u00f3n, caracter\u00edsticas que influyen en el rendimiento del producto, y se debe evitar el uso de excipientes en concentraciones fuera de los rangos establecidos sin justificaci\u00f3n.\n\n3. **\u00bfQu\u00e9 papel juegan los excipientes multifuncionales en la formulaci\u00f3n de productos farmac\u00e9uticos y c\u00f3mo se deben evaluar?**\n   - Los excipientes multifuncionales, como la povidona y la celulosa microcristalina, pueden tener diferentes grados con propiedades f\u00edsicas y caracter\u00edsticas funcionales distintas. Por lo tanto, es importante evaluar su conformidad con las especificaciones farmacop\u00e9icas y su capacidad para desempe\u00f1ar su funci\u00f3n a lo largo de la vida \u00fatil del producto.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS proporciona directrices sobre la selecci\u00f3n y evaluaci\u00f3n de excipientes en la formulaci\u00f3n de productos farmac\u00e9uticos, enfatizando la importancia de la compatibilidad entre el principio activo y los excipientes, as\u00ed como la necesidad de realizar estudios de estabilidad y pruebas de estr\u00e9s. Se destaca que la elecci\u00f3n de excipientes debe basarse en su funci\u00f3n, caracter\u00edsticas, y cumplimiento con las normativas establecidas, y se deben evitar excipientes que no cumplan con los est\u00e1ndares de seguridad y eficacia.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Desarrollo del Producto Farmac\u00e9utico:**\n   - Importancia de discutir las caracter\u00edsticas del Producto Farmac\u00e9utico Terminado (FPP) en el contexto del desarrollo del producto, aplicando principios de gesti\u00f3n de riesgos a lo largo de su ciclo de vida.\n\n2. **Componentes del FPP:**\n   - El FPP incluye el Ingrediente Farmac\u00e9utico Activo (API) y excipientes, as\u00ed como excipientes que pueden no estar presentes en cada lote o que se eliminan durante el procesamiento.\n\n3. **Compatibilidad del API:**\n   - Necesidad de evaluar la compatibilidad del API con los excipientes y entre diferentes APIs en formulaciones de Combinaciones de F\u00e1rmacos (FDCs).\n\n4. **Propiedades Fisicoqu\u00edmicas del API:**\n   - Discusi\u00f3n sobre caracter\u00edsticas como contenido de agua, solubilidad, distribuci\u00f3n del tama\u00f1o de part\u00edculas, forma polim\u00f3rfica y otras propiedades que pueden influir en el rendimiento del FPP.\n\n5. **Documentos de Referencia:**\n   - Menci\u00f3n de las gu\u00edas ICH (Q6A, Q8, Q9 y Q10) como documentos clave para el desarrollo farmac\u00e9utico.\n\n**Entidades:**\n\n- **FPP (Producto Farmac\u00e9utico Terminado):** Compuesto por el API y excipientes.\n- **API (Ingrediente Farmac\u00e9utico Activo):** Sustancia que proporciona la acci\u00f3n farmacol\u00f3gica.\n- **Excipientes:** Sustancias inactivas que acompa\u00f1an al API en la formulaci\u00f3n.\n- **FDC (Combinaciones de F\u00e1rmacos):** Formulaciones que contienen m\u00e1s de un API.\n- **ICH (International Council for Harmonisation):** Organizaci\u00f3n que proporciona directrices para el desarrollo farmac\u00e9utico.\n\nEste resumen destaca la importancia de la evaluaci\u00f3n de la compatibilidad y las propiedades fisicoqu\u00edmicas del API en el desarrollo de productos farmac\u00e9uticos, as\u00ed como la referencia a documentos normativos que gu\u00edan este proceso.", "excerpt_keywords": "Keywords: excipients, API compatibility, pharmaceutical formulation, stability studies, regulatory guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d2d8d1b-3daf-4121-9e94-94377f07cc0d", "node_type": "4", "metadata": {"page_label": "113", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The specifications of the API manufacturer and the retest period or expiry date derived from formal regulatory stability studies should also be available to the manufacturer of the FPP.\n\nGuidance on compatibility studies is provided in Appendix 3 of the WHO *Guidelines for registration of fixed-dose combination medicinal products* (6). In addition to visual examination, chromatography results (assay, purity) are required to demonstrate API\u2013API and API\u2013excipient compatibility. In general, API\u2013excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product.\n\nStress testing of the API should be designed to include simulation, as far as possible, of the conditions that may be encountered during the manufacturing process of the FPP. An example is provided in Appendix 1.\n\n### 3.1.2 Excipients\n\n\u201c3.2.P.2.1.2 *The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions.*\u201d\n\nWhen choosing excipients, those with a compendial monograph are generally preferred and may be required in certain jurisdictions. Other resources are available for information on acceptable excipients and their concentrations such as the US-FDA IIG (13) list and the *Handbook of pharmaceutical excipients* (14). Use of excipients at concentrations outside the established ranges is discouraged and generally requires justification. In addition, available guidelines which address particular excipients to be avoided should usually be consulted, for example, azo colourants as listed in EMA guideline CPMP/463/00 (15). Other guidelines such as WHO\u2019s *Development of paediatric medicines: points to consider in pharmaceutical development* (16) may provide useful general guidance in this regard.\n\nThe characteristics and amounts of excipients that can influence the performance of the pharmaceutical product or its manufacturing capability should usually be discussed relative to the respective function. The ability of functional excipients, e.g. pH-adjusting agents, buffers, stabilizers (such as antioxidants and chelating agents), preservatives and dissolution modifiers (such as surface active agents), to perform throughout the intended shelf-life of the FPP should usually be demonstrated.\n\nAntimicrobial preservatives are discussed in 3.2.P.2.5.\n\nMany excipients such as povidone, microcrystalline cellulose and lactose are by nature multifunctional. The chemically identical excipients may have different grades (physical properties) with different functional characteristics; therefore, conformance to pharmacopoeial specifications does not always...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "c9c35dc4b1a55e20c8aa2757303fa43154448685c3b93dac34bba5420afbd740", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "The specifications of the API manufacturer and the retest period or expiry date derived from formal regulatory stability studies should also be available to the manufacturer of the FPP.\n\nGuidance on compatibility studies is provided in Appendix 3 of the WHO *Guidelines for registration of fixed-dose combination medicinal products* (6). In addition to visual examination, chromatography results (assay, purity) are required to demonstrate API\u2013API and API\u2013excipient compatibility. In general, API\u2013excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product.\n\nStress testing of the API should be designed to include simulation, as far as possible, of the conditions that may be encountered during the manufacturing process of the FPP. An example is provided in Appendix 1.\n\n### 3.1.2 Excipients\n\n\u201c3.2.P.2.1.2 *The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions.*\u201d\n\nWhen choosing excipients, those with a compendial monograph are generally preferred and may be required in certain jurisdictions. Other resources are available for information on acceptable excipients and their concentrations such as the US-FDA IIG (13) list and the *Handbook of pharmaceutical excipients* (14). Use of excipients at concentrations outside the established ranges is discouraged and generally requires justification. In addition, available guidelines which address particular excipients to be avoided should usually be consulted, for example, azo colourants as listed in EMA guideline CPMP/463/00 (15). Other guidelines such as WHO\u2019s *Development of paediatric medicines: points to consider in pharmaceutical development* (16) may provide useful general guidance in this regard.\n\nThe characteristics and amounts of excipients that can influence the performance of the pharmaceutical product or its manufacturing capability should usually be discussed relative to the respective function. The ability of functional excipients, e.g. pH-adjusting agents, buffers, stabilizers (such as antioxidants and chelating agents), preservatives and dissolution modifiers (such as surface active agents), to perform throughout the intended shelf-life of the FPP should usually be demonstrated.\n\nAntimicrobial preservatives are discussed in 3.2.P.2.5.\n\nMany excipients such as povidone, microcrystalline cellulose and lactose are by nature multifunctional. The chemically identical excipients may have different grades (physical properties) with different functional characteristics; therefore, conformance to pharmacopoeial specifications does not always...", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2804, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "bf64bd9c-b5dd-444f-9d09-630a977ae9a6": {"__data__": {"id_": "bf64bd9c-b5dd-444f-9d09-630a977ae9a6", "embedding": null, "metadata": {"page_label": "114", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Finished Pharmaceutical Product \"3.2.P.2.2\"\n\n## 3.2.1 Formulation Development\n\n### 3.2.P.2.2.1\n\nA brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed when appropriate.\n\nWhen preparing the PD for submission, the data requirements of the NMRA regarding formulation development may depend on whether the multisource product has been newly developed by the applicant or manufacturer or whether it is an established multisource product.\n\nThe WHO Prequalification of Medicines Programme defines an established multisource product as one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier should usually be completed with the exception of P.2.2.1 (a). In addition, a product quality review should usually be provided in the PD as outlined in Appendix 2 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1).\n\nThe requirements for bioequivalence studies should be taken into consideration, for example, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (e.g.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los requisitos para el desarrollo de productos farmac\u00e9uticos terminados (FPP) en el contexto de la precalificaci\u00f3n de medicamentos. Se enfatiza la importancia de proporcionar un resumen del desarrollo de la formulaci\u00f3n, considerando la ruta de administraci\u00f3n y el uso propuesto. Se discuten las diferencias entre formulaciones de bioequivalencia y biowaiver, as\u00ed como los requisitos de datos para productos multisource, diferenciando entre productos reci\u00e9n desarrollados y aquellos establecidos. Se establece que un producto multisource se considera establecido si ha estado en el mercado durante al menos cinco a\u00f1os y cumple con ciertos criterios de producci\u00f3n.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfCu\u00e1les son los criterios que definen un producto multisource establecido seg\u00fan el Programa de Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Un producto multisource se considera establecido si ha sido comercializado por el solicitante o fabricante asociado con el dossier durante al menos cinco a\u00f1os y ha producido al menos 10 lotes de producci\u00f3n en el \u00faltimo a\u00f1o, o si ha producido menos de 10 lotes en el \u00faltimo a\u00f1o, debe haber producido no menos de 25 lotes en los \u00faltimos tres a\u00f1os.\n\n2. **\u00bfQu\u00e9 se debe incluir en el resumen del desarrollo de la formulaci\u00f3n de un FPP?**\n   - El resumen debe incluir consideraciones sobre la ruta de administraci\u00f3n y el uso propuesto, as\u00ed como discutir las diferencias entre las formulaciones de bioequivalencia o biowaiver y la formulaci\u00f3n descrita en 3.2.P.1. Tambi\u00e9n se deben discutir los resultados de estudios comparativos in vitro (como la disoluci\u00f3n) o in vivo (como la bioequivalencia) cuando sea apropiado.\n\n3. **\u00bfQu\u00e9 se requiere en la preparaci\u00f3n del dossier (PD) para productos multisource reci\u00e9n desarrollados en comparaci\u00f3n con los establecidos?**\n   - Para productos multisource reci\u00e9n desarrollados, los requisitos de datos del NMRA sobre el desarrollo de la formulaci\u00f3n pueden variar, mientras que para productos establecidos, generalmente se deben completar todas las secciones de P.2.2.1 del dossier, excepto P.2.2.1 (a), y se debe proporcionar una revisi\u00f3n de calidad del producto seg\u00fan lo indicado en las directrices de la OMS.", "prev_section_summary": "### Temas Clave\n\n1. **Compatibilidad de Excipientes y Principios Activos (API)**:\n   - Se requiere realizar estudios de compatibilidad, incluyendo an\u00e1lisis cromatogr\u00e1ficos y evaluaciones visuales, para demostrar la compatibilidad entre el API y los excipientes.\n   - La compatibilidad no es necesaria para excipientes espec\u00edficos si hay evidencia de su presencia en productos comparadores.\n\n2. **Selecci\u00f3n de Excipientes**:\n   - Se prefieren excipientes con monograf\u00edas en farmacopeas y se deben discutir sus concentraciones y caracter\u00edsticas en relaci\u00f3n con su funci\u00f3n en el producto final.\n   - El uso de excipientes fuera de los rangos establecidos requiere justificaci\u00f3n.\n\n3. **Pruebas de Estr\u00e9s**:\n   - Las pruebas de estr\u00e9s del API deben simular las condiciones del proceso de fabricaci\u00f3n del producto farmac\u00e9utico terminado (FPP).\n\n4. **Excipientes Multifuncionales**:\n   - Excipientes como la povidona y la celulosa microcristalina pueden tener diferentes grados y propiedades, lo que requiere una evaluaci\u00f3n cuidadosa de su conformidad con las especificaciones farmacop\u00e9icas.\n\n5. **Gu\u00edas y Recursos**:\n   - Se mencionan varias gu\u00edas y recursos, como la lista de excipientes aceptables de la FDA y el *Handbook of pharmaceutical excipients*, que pueden ser consultados para la selecci\u00f3n de excipientes.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Proporciona directrices sobre la formulaci\u00f3n de productos farmac\u00e9uticos.\n- **API (Active Pharmaceutical Ingredient)**: Ingrediente activo en productos farmac\u00e9uticos.\n- **FPP (Finished Pharmaceutical Product)**: Producto farmac\u00e9utico terminado.\n- **Excipientes**: Sustancias inactivas que se utilizan en la formulaci\u00f3n de medicamentos.\n- **Farmacopeas**: Compendios que contienen est\u00e1ndares para la calidad de medicamentos y excipientes.\n- **Gu\u00edas de la FDA y EMA**: Documentos que ofrecen directrices sobre la selecci\u00f3n y uso de excipientes.\n\nEste resumen destaca la importancia de la compatibilidad, la selecci\u00f3n adecuada de excipientes y la necesidad de realizar pruebas de estr\u00e9s para asegurar la calidad y eficacia de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: formulation development, multisource product, bioequivalence, WHO Prequalification, pharmaceutical guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e35e2f64-5674-4687-8d0d-78db08777150", "node_type": "4", "metadata": {"page_label": "114", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Finished Pharmaceutical Product \"3.2.P.2.2\"\n\n## 3.2.1 Formulation Development\n\n### 3.2.P.2.2.1\n\nA brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed when appropriate.\n\nWhen preparing the PD for submission, the data requirements of the NMRA regarding formulation development may depend on whether the multisource product has been newly developed by the applicant or manufacturer or whether it is an established multisource product.\n\nThe WHO Prequalification of Medicines Programme defines an established multisource product as one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier should usually be completed with the exception of P.2.2.1 (a). In addition, a product quality review should usually be provided in the PD as outlined in Appendix 2 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1).\n\nThe requirements for bioequivalence studies should be taken into consideration, for example, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (e.g.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "c2aecb21567c959f91a71732321bd64939b2f751f5250271b2ba1e08be8f27fe", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Finished Pharmaceutical Product \"3.2.P.2.2\"\n\n## 3.2.1 Formulation Development\n\n### 3.2.P.2.2.1\n\nA brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed when appropriate.\n\nWhen preparing the PD for submission, the data requirements of the NMRA regarding formulation development may depend on whether the multisource product has been newly developed by the applicant or manufacturer or whether it is an established multisource product.\n\nThe WHO Prequalification of Medicines Programme defines an established multisource product as one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier should usually be completed with the exception of P.2.2.1 (a). In addition, a product quality review should usually be provided in the PD as outlined in Appendix 2 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1).\n\nThe requirements for bioequivalence studies should be taken into consideration, for example, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (e.g.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1927, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "84189e88-1910-4d54-94a0-aa08d830e255": {"__data__": {"id_": "84189e88-1910-4d54-94a0-aa08d830e255", "embedding": null, "metadata": {"page_label": "115", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Guidelines on Registration Requirements\n\n**WHO guidelines on registration requirements to establish interchangeability for multisource (generic) pharmaceutical products (7)** can be consulted.\n\nTablet scoring may be recommended or required in certain jurisdictions or, for example, when scoring is indicated in the WHO invitation for expression of interest, or is specified for an invited FPP in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology.\n\nIf the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should usually include a description of the test method, individual values, mean and relative standard deviation of the results. Uniformity testing (i.e. content uniformity or mass variation, depending on the requirement for the whole tablet) should be performed on each split portion from a minimum of 10 randomly selected whole tablets. As an example the number of units (i.e. the splits) would be 10 halves for bisected tablets (one half of each tablet is retained for the test) or 10 quarters for quadrisected tablets (one quarter of each tablet is retained for the test). At least one batch of each strength should be tested. Ideally the study should cover a range of the hardness values. The splitting of the tablets should be performed in a manner that would be representative of that used by the consumer (e.g. manually split by hand). The uniformity test on split portions only needs to be demonstrated once and does not need to be added to the FPP specification(s). The tablet description in the FPP specification and in the product information (e.g. SmPC, labelling or package leaflet) should reflect the presence of a score line.\n\nIf a paediatric dose is to be obtained by splitting a tablet, a demonstration of content uniformity of tablet fragments may be required.\n\nFor modified-release tablets designed to be divided into equal halves, demonstration of dissolution profile similarity of the tablet halves against the whole tablet may be required.\n\nWhere relevant, labelling should state that the score line is only intended to facilitate breaking for ease of swallowing and not to divide the tablet into equal doses. In this case a demonstration of uniformity is unlikely to be required.\n\n## In Vitro Dissolution or Drug Release\n\nA discussion should usually be included as to how the development of the formulation relates to development of the dissolution method(s) and the generation of the dissolution profile.\n\nThe results of studies justifying the choice of in vitro dissolution or drug release conditions (e.g. apparatus, rotation speed and medium) are usually required in the PD. Data should also usually demonstrate whether the method is sensitive to changes in manufacturing processes and/or changes in grades and/or...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento proporciona directrices de la OMS sobre los requisitos de registro para establecer la intercambiabilidad de productos farmac\u00e9uticos multisource (gen\u00e9ricos). Se discuten aspectos relacionados con el dise\u00f1o y la evaluaci\u00f3n de tabletas, incluyendo la importancia de las l\u00edneas de puntuaci\u00f3n para facilitar la divisi\u00f3n de las tabletas, la uniformidad de dosis en fragmentos de tabletas, y la necesidad de estudios de disoluci\u00f3n para tabletas modificadas. Tambi\u00e9n se menciona que la informaci\u00f3n en el etiquetado debe aclarar el prop\u00f3sito de la l\u00ednea de puntuaci\u00f3n y que se deben realizar pruebas de uniformidad en tabletas divididas.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de pruebas de uniformidad se requieren para tabletas que se pueden dividir y c\u00f3mo se deben llevar a cabo?**\n   - Se requiere realizar pruebas de uniformidad (ya sea de contenido o de variaci\u00f3n de masa) en cada porci\u00f3n dividida de un m\u00ednimo de 10 tabletas enteras seleccionadas al azar. Por ejemplo, para tabletas bisecadas, se retendr\u00eda una mitad de cada tableta para la prueba.\n\n2. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al etiquetar tabletas con l\u00edneas de puntuaci\u00f3n?**\n   - El etiquetado debe indicar que la l\u00ednea de puntuaci\u00f3n est\u00e1 destinada a facilitar la ruptura para facilitar la degluci\u00f3n y no para dividir la tableta en dosis iguales. En este caso, es poco probable que se requiera una demostraci\u00f3n de uniformidad.\n\n3. **\u00bfQu\u00e9 requisitos se establecen para las tabletas modificadas que est\u00e1n dise\u00f1adas para ser divididas en mitades iguales?**\n   - Para tabletas modificadas que se pueden dividir en mitades, se puede requerir una demostraci\u00f3n de similitud del perfil de disoluci\u00f3n entre las mitades de la tableta y la tableta entera.\n\n### Resumen de Nivel Superior\n\nLas directrices de la OMS sobre los requisitos de registro para productos farmac\u00e9uticos gen\u00e9ricos abordan la importancia de la puntuaci\u00f3n en tabletas, la necesidad de pruebas de uniformidad en tabletas divididas, y los requisitos de disoluci\u00f3n para tabletas modificadas. Se enfatiza que la informaci\u00f3n en el etiquetado debe ser clara respecto al uso de las l\u00edneas de puntuaci\u00f3n y que las pruebas de uniformidad son esenciales para garantizar la dosificaci\u00f3n adecuada en tabletas que se pueden dividir.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Desarrollo de Formulaci\u00f3n de Productos Farmac\u00e9uticos Terminados (FPP)**:\n   - Se requiere un resumen que describa el desarrollo del FPP, considerando la ruta de administraci\u00f3n y el uso propuesto.\n   - Es importante discutir las diferencias entre formulaciones de bioequivalencia y biowaiver, as\u00ed como los resultados de estudios comparativos in vitro e in vivo.\n\n2. **Productos Multisource**:\n   - Un producto multisource se considera \"establecido\" si ha estado en el mercado durante al menos cinco a\u00f1os y ha producido al menos 10 lotes en el \u00faltimo a\u00f1o, o 25 lotes en los \u00faltimos tres a\u00f1os si ha producido menos de 10 en el \u00faltimo a\u00f1o.\n   - Para productos establecidos, se deben completar todas las secciones del dossier, excepto P.2.2.1 (a), y se debe incluir una revisi\u00f3n de calidad del producto.\n\n3. **Requisitos de Datos para el Dossier (PD)**:\n   - Los requisitos de datos del NMRA pueden variar seg\u00fan si el producto multisource es nuevo o establecido.\n   - Se deben considerar los requisitos para estudios de bioequivalencia, especialmente al formular m\u00faltiples concentraciones o cuando el producto puede ser elegible para un biowaiver.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad que establece directrices para la precalificaci\u00f3n de medicamentos.\n- **NMRA (Autoridad Nacional Reguladora de Medicamentos)**: Entidad que regula los requisitos de datos para el desarrollo de formulaciones.\n- **Productos Multisource**: Medicamentos gen\u00e9ricos que cumplen con criterios espec\u00edficos de comercializaci\u00f3n y producci\u00f3n.\n- **Bioequivalencia y Biowaiver**: Conceptos relacionados con la comparaci\u00f3n de formulaciones y la elegibilidad para exenciones en estudios de bioequivalencia.", "excerpt_keywords": "Keywords: WHO guidelines, registration requirements, multisource pharmaceuticals, tablet scoring, content uniformity"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ebd7dd76-9f68-4dc0-8bfc-4e60e4c5c408", "node_type": "4", "metadata": {"page_label": "115", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Guidelines on Registration Requirements\n\n**WHO guidelines on registration requirements to establish interchangeability for multisource (generic) pharmaceutical products (7)** can be consulted.\n\nTablet scoring may be recommended or required in certain jurisdictions or, for example, when scoring is indicated in the WHO invitation for expression of interest, or is specified for an invited FPP in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology.\n\nIf the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should usually include a description of the test method, individual values, mean and relative standard deviation of the results. Uniformity testing (i.e. content uniformity or mass variation, depending on the requirement for the whole tablet) should be performed on each split portion from a minimum of 10 randomly selected whole tablets. As an example the number of units (i.e. the splits) would be 10 halves for bisected tablets (one half of each tablet is retained for the test) or 10 quarters for quadrisected tablets (one quarter of each tablet is retained for the test). At least one batch of each strength should be tested. Ideally the study should cover a range of the hardness values. The splitting of the tablets should be performed in a manner that would be representative of that used by the consumer (e.g. manually split by hand). The uniformity test on split portions only needs to be demonstrated once and does not need to be added to the FPP specification(s). The tablet description in the FPP specification and in the product information (e.g. SmPC, labelling or package leaflet) should reflect the presence of a score line.\n\nIf a paediatric dose is to be obtained by splitting a tablet, a demonstration of content uniformity of tablet fragments may be required.\n\nFor modified-release tablets designed to be divided into equal halves, demonstration of dissolution profile similarity of the tablet halves against the whole tablet may be required.\n\nWhere relevant, labelling should state that the score line is only intended to facilitate breaking for ease of swallowing and not to divide the tablet into equal doses. In this case a demonstration of uniformity is unlikely to be required.\n\n## In Vitro Dissolution or Drug Release\n\nA discussion should usually be included as to how the development of the formulation relates to development of the dissolution method(s) and the generation of the dissolution profile.\n\nThe results of studies justifying the choice of in vitro dissolution or drug release conditions (e.g. apparatus, rotation speed and medium) are usually required in the PD. Data should also usually demonstrate whether the method is sensitive to changes in manufacturing processes and/or changes in grades and/or...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "e3ea5da2a9b5075c06ed3f3c7b65b58b6fb953550c146d331e9b99c24fc36383", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Guidelines on Registration Requirements\n\n**WHO guidelines on registration requirements to establish interchangeability for multisource (generic) pharmaceutical products (7)** can be consulted.\n\nTablet scoring may be recommended or required in certain jurisdictions or, for example, when scoring is indicated in the WHO invitation for expression of interest, or is specified for an invited FPP in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology.\n\nIf the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should usually include a description of the test method, individual values, mean and relative standard deviation of the results. Uniformity testing (i.e. content uniformity or mass variation, depending on the requirement for the whole tablet) should be performed on each split portion from a minimum of 10 randomly selected whole tablets. As an example the number of units (i.e. the splits) would be 10 halves for bisected tablets (one half of each tablet is retained for the test) or 10 quarters for quadrisected tablets (one quarter of each tablet is retained for the test). At least one batch of each strength should be tested. Ideally the study should cover a range of the hardness values. The splitting of the tablets should be performed in a manner that would be representative of that used by the consumer (e.g. manually split by hand). The uniformity test on split portions only needs to be demonstrated once and does not need to be added to the FPP specification(s). The tablet description in the FPP specification and in the product information (e.g. SmPC, labelling or package leaflet) should reflect the presence of a score line.\n\nIf a paediatric dose is to be obtained by splitting a tablet, a demonstration of content uniformity of tablet fragments may be required.\n\nFor modified-release tablets designed to be divided into equal halves, demonstration of dissolution profile similarity of the tablet halves against the whole tablet may be required.\n\nWhere relevant, labelling should state that the score line is only intended to facilitate breaking for ease of swallowing and not to divide the tablet into equal doses. In this case a demonstration of uniformity is unlikely to be required.\n\n## In Vitro Dissolution or Drug Release\n\nA discussion should usually be included as to how the development of the formulation relates to development of the dissolution method(s) and the generation of the dissolution profile.\n\nThe results of studies justifying the choice of in vitro dissolution or drug release conditions (e.g. apparatus, rotation speed and medium) are usually required in the PD. Data should also usually demonstrate whether the method is sensitive to changes in manufacturing processes and/or changes in grades and/or...", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2950, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "4d12be5d-fdff-4aa2-b4ba-92f0122faa62": {"__data__": {"id_": "4d12be5d-fdff-4aa2-b4ba-92f0122faa62", "embedding": null, "metadata": {"page_label": "116", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nor amounts of critical excipients and particle size where relevant. The dissolution method should be sensitive to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters.\n\nRecommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1).\n\nIn the case of rapidly dissolving FPPs containing highly soluble APIs (BCS classes 1 and 3), a single-point dissolution test limit of 80% in 30 minutes or less is considered sufficient as a routine QC test for batch-to-batch uniformity. For slowly dissolving or poorly water-soluble APIs (BCS classes 2 and 4) in immediate-release products, a two-point dissolution range (a dissolution window), one at an early time-point (e.g. Q = 60% in 45 minutes) and the other at a later point (e.g. Q = 80% in 90 minutes), is recommended to characterize the quality of the product. Note that in some cases the later point may be lower than 80% if a plateau is reached.\n\nModified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine QC. Preferably, this test should possess in vitro\u2013in vivo correlation. Results demonstrating the effect of pH on the dissolution profile are usually required, if appropriate for the type of dosage form.\n\nFor extended-release FPPs the testing conditions should be set to cover the entire period of expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test period, upper and lower limits should be set for individual units. Generally the acceptance range at each intermediate test point should not exceed 25% or \u00b1 12.5% of the targeted value. Dissolution results are usually required for several lots including those used for pharmacokinetic and bioavailability or biowaiver studies.\n\nThe dissolution acceptance limit(s) should also be incorporated into the stability programmes.\n\nWhere there are scientific grounds that the defined release characteristics of oral pharmaceutical products may be adversely affected by the presence of alcohol, e.g. for modified-release products containing opiates, 5%, 10% and 20% ethanol should be added to the dissolution medium proposed for routine testing in order to demonstrate that no dose dumping will occur through intake with alcoholic beverages.\n\n## 3.2.2 Overages\n\n### 3.2.P.2.2.2 Any overages in the formulation(s) described in 3.2.P.1 should be justified.\n\nJustification of an overage to compensate for loss during manufacture", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Dissoluci\u00f3n y Control de Calidad**: El documento establece directrices sobre los m\u00e9todos de disoluci\u00f3n para productos farmac\u00e9uticos terminados (FPPs), diferenciando entre productos de liberaci\u00f3n r\u00e1pida y lenta, y enfatiza la importancia de la correlaci\u00f3n in vitro-in vivo. Se especifican l\u00edmites de aceptaci\u00f3n para pruebas de disoluci\u00f3n y se discuten las condiciones de prueba para productos de liberaci\u00f3n modificada y extendida.\n\n2. **Impacto del Alcohol en la Liberaci\u00f3n de Medicamentos**: Se menciona que la presencia de alcohol puede afectar negativamente las caracter\u00edsticas de liberaci\u00f3n de ciertos productos farmac\u00e9uticos, especialmente aquellos de liberaci\u00f3n modificada que contienen opi\u00e1ceos. Se recomienda incluir etanol en el medio de disoluci\u00f3n para evaluar el riesgo de liberaci\u00f3n excesiva (dose dumping).\n\n3. **Justificaci\u00f3n de Overages en Formulaciones**: Se requiere que cualquier exceso en la formulaci\u00f3n de un producto farmac\u00e9utico sea justificado, especialmente para compensar las p\u00e9rdidas durante el proceso de fabricaci\u00f3n.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios espec\u00edficos para establecer l\u00edmites de aceptaci\u00f3n en las pruebas de disoluci\u00f3n para productos de liberaci\u00f3n extendida?**\n   - Esta pregunta busca detalles sobre los criterios y rangos de aceptaci\u00f3n que deben cumplirse durante las pruebas de disoluci\u00f3n para productos de liberaci\u00f3n extendida, que no se encuentran f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfQu\u00e9 justificaciones son aceptables para los overages en las formulaciones de productos farmac\u00e9uticos?**\n   - Esta pregunta se centra en las razones que pueden ser consideradas v\u00e1lidas para incluir overages en las formulaciones, lo que puede no estar claramente definido en otras gu\u00edas o documentos.\n\n3. **\u00bfC\u00f3mo se debe evaluar el efecto del pH en el perfil de disoluci\u00f3n de un producto farmac\u00e9utico?**\n   - Esta pregunta busca informaci\u00f3n sobre los m\u00e9todos y consideraciones espec\u00edficas para evaluar c\u00f3mo el pH afecta la disoluci\u00f3n de un producto, un aspecto que puede ser crucial para la formulaci\u00f3n y que no siempre se aborda en otras fuentes.", "prev_section_summary": "### Temas Clave\n\n1. **Requisitos de Registro de la OMS**: Directrices sobre la intercambiabilidad de productos farmac\u00e9uticos multisource (gen\u00e9ricos).\n  \n2. **Puntuaci\u00f3n de Tabletas**: La puntuaci\u00f3n puede ser recomendada o requerida en ciertas jurisdicciones y es importante para facilitar la divisi\u00f3n en dosis fraccionadas.\n\n3. **Uniformidad de Dosis**: Se requiere un estudio para asegurar la uniformidad de dosis en fragmentos de tabletas, incluyendo pruebas de uniformidad de contenido o variaci\u00f3n de masa en tabletas divididas.\n\n4. **Pruebas de Uniformidad**: Deben realizarse en al menos 10 tabletas enteras seleccionadas al azar, con ejemplos espec\u00edficos para tabletas bisecadas y cuadrisecadas.\n\n5. **Dosis Pedi\u00e1trica**: Puede ser necesaria una demostraci\u00f3n de uniformidad de contenido en fragmentos de tabletas si se obtiene una dosis pedi\u00e1trica al dividir una tableta.\n\n6. **Tabletas de Liberaci\u00f3n Modificada**: Se puede requerir una demostraci\u00f3n de similitud del perfil de disoluci\u00f3n entre las mitades de la tableta y la tableta entera.\n\n7. **Etiquetado**: Debe aclarar que la l\u00ednea de puntuaci\u00f3n es para facilitar la ruptura y no para dividir en dosis iguales, lo que puede eximir de la necesidad de demostrar uniformidad.\n\n8. **Disoluci\u00f3n In Vitro**: Se debe discutir c\u00f3mo el desarrollo de la formulaci\u00f3n se relaciona con el m\u00e9todo de disoluci\u00f3n y la generaci\u00f3n del perfil de disoluci\u00f3n.\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad que proporciona las directrices.\n- **FPP (Forma Farmac\u00e9utica de Producto)**: Referencia a los productos farmac\u00e9uticos en cuesti\u00f3n.\n- **Tabletas**: Forma farmac\u00e9utica que se discute en t\u00e9rminos de puntuaci\u00f3n y divisi\u00f3n.\n- **Dosis Pedi\u00e1trica**: Consideraci\u00f3n especial para la administraci\u00f3n de medicamentos a ni\u00f1os.\n- **Pruebas de Uniformidad**: M\u00e9todos de evaluaci\u00f3n de la consistencia en la dosificaci\u00f3n de tabletas.\n- **Liberaci\u00f3n Modificada**: Tipo de formulaci\u00f3n de tabletas que requiere consideraciones especiales en su evaluaci\u00f3n.\n\nEste resumen destaca los aspectos esenciales de las directrices de la OMS sobre la puntuaci\u00f3n y la uniformidad de las tabletas, as\u00ed como los requisitos de etiquetado y pruebas de disoluci\u00f3n.", "excerpt_keywords": "Keywords: dissolution, pharmaceutical preparations, overages, quality control, modified-release"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "24226fc8-3443-47eb-bcd9-ca845f16edb7", "node_type": "4", "metadata": {"page_label": "116", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nor amounts of critical excipients and particle size where relevant. The dissolution method should be sensitive to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters.\n\nRecommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1).\n\nIn the case of rapidly dissolving FPPs containing highly soluble APIs (BCS classes 1 and 3), a single-point dissolution test limit of 80% in 30 minutes or less is considered sufficient as a routine QC test for batch-to-batch uniformity. For slowly dissolving or poorly water-soluble APIs (BCS classes 2 and 4) in immediate-release products, a two-point dissolution range (a dissolution window), one at an early time-point (e.g. Q = 60% in 45 minutes) and the other at a later point (e.g. Q = 80% in 90 minutes), is recommended to characterize the quality of the product. Note that in some cases the later point may be lower than 80% if a plateau is reached.\n\nModified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine QC. Preferably, this test should possess in vitro\u2013in vivo correlation. Results demonstrating the effect of pH on the dissolution profile are usually required, if appropriate for the type of dosage form.\n\nFor extended-release FPPs the testing conditions should be set to cover the entire period of expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test period, upper and lower limits should be set for individual units. Generally the acceptance range at each intermediate test point should not exceed 25% or \u00b1 12.5% of the targeted value. Dissolution results are usually required for several lots including those used for pharmacokinetic and bioavailability or biowaiver studies.\n\nThe dissolution acceptance limit(s) should also be incorporated into the stability programmes.\n\nWhere there are scientific grounds that the defined release characteristics of oral pharmaceutical products may be adversely affected by the presence of alcohol, e.g. for modified-release products containing opiates, 5%, 10% and 20% ethanol should be added to the dissolution medium proposed for routine testing in order to demonstrate that no dose dumping will occur through intake with alcoholic beverages.\n\n## 3.2.2 Overages\n\n### 3.2.P.2.2.2 Any overages in the formulation(s) described in 3.2.P.1 should be justified.\n\nJustification of an overage to compensate for loss during manufacture", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "18ac7324a396d77e1a50232bd3570fe1e7b36917b9a24ea062cc48437bb4d6cc", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nor amounts of critical excipients and particle size where relevant. The dissolution method should be sensitive to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters.\n\nRecommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1).\n\nIn the case of rapidly dissolving FPPs containing highly soluble APIs (BCS classes 1 and 3), a single-point dissolution test limit of 80% in 30 minutes or less is considered sufficient as a routine QC test for batch-to-batch uniformity. For slowly dissolving or poorly water-soluble APIs (BCS classes 2 and 4) in immediate-release products, a two-point dissolution range (a dissolution window), one at an early time-point (e.g. Q = 60% in 45 minutes) and the other at a later point (e.g. Q = 80% in 90 minutes), is recommended to characterize the quality of the product. Note that in some cases the later point may be lower than 80% if a plateau is reached.\n\nModified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine QC. Preferably, this test should possess in vitro\u2013in vivo correlation. Results demonstrating the effect of pH on the dissolution profile are usually required, if appropriate for the type of dosage form.\n\nFor extended-release FPPs the testing conditions should be set to cover the entire period of expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test period, upper and lower limits should be set for individual units. Generally the acceptance range at each intermediate test point should not exceed 25% or \u00b1 12.5% of the targeted value. Dissolution results are usually required for several lots including those used for pharmacokinetic and bioavailability or biowaiver studies.\n\nThe dissolution acceptance limit(s) should also be incorporated into the stability programmes.\n\nWhere there are scientific grounds that the defined release characteristics of oral pharmaceutical products may be adversely affected by the presence of alcohol, e.g. for modified-release products containing opiates, 5%, 10% and 20% ethanol should be added to the dissolution medium proposed for routine testing in order to demonstrate that no dose dumping will occur through intake with alcoholic beverages.\n\n## 3.2.2 Overages\n\n### 3.2.P.2.2.2 Any overages in the formulation(s) described in 3.2.P.1 should be justified.\n\nJustification of an overage to compensate for loss during manufacture", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2966, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "9d04f46c-e82e-48a6-b451-22e7ca2f5b35": {"__data__": {"id_": "9d04f46c-e82e-48a6-b451-22e7ca2f5b35", "embedding": null, "metadata": {"page_label": "117", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.3 Physicochemical and biological properties\n\n3.2.P.2.2.3 Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency and/or immunological activity, should be addressed.\n\n# 3.3 Manufacturing process development\n\n3.2.P.2.3 The selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.\n\nFor products that meet the criteria of an established multisource product, in order to fulfil the requirements of section P.2.3, section P.2.3 (b) of the dossier should be completed and a product quality review should usually be submitted as outlined in Appendix 2 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1). The guidance below applies to all other products, for which section P.2.3 should be completed in its entirety.\n\nThe rationale for choosing the particular pharmaceutical product (e.g. dosage form, delivery system) should be provided in the PD. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence quality and performance of the FPP should usually be explained (e.g. wet granulation using high-shear granulator). The results of an API stress study may be included in the rationale. Any developmental work undertaken on protecting the FPP from deterioration (e.g. protection from light or moisture) should also be included.\n\nThe manufacturing process of the multisource FPP should be appropriate for the product that is in development. It does not need to be the same as that of the comparator FPP.\n\nEfforts should be primarily directed towards reducing variability in process and product quality. In order to achieve this, all critical sources of variability should be identified and explained and the sources of variability should be minimized and controlled.\n\nProcess development studies should provide the basis for process improvement, process validation and any process control requirements. All CPPs should usually be identified, monitored or controlled to ensure that the product is of the desired quality.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda las propiedades fisicoqu\u00edmicas y biol\u00f3gicas de los productos farmac\u00e9uticos terminados (FPP) y el desarrollo del proceso de fabricaci\u00f3n. Se enfatiza la importancia de par\u00e1metros como pH, fuerza i\u00f3nica, disoluci\u00f3n y actividad biol\u00f3gica, as\u00ed como la necesidad de justificar la selecci\u00f3n y optimizaci\u00f3n del proceso de fabricaci\u00f3n. Se menciona que para productos que cumplen con los criterios de un producto multisource establecido, se deben completar secciones espec\u00edficas del dossier y realizar revisiones de calidad del producto. Adem\u00e1s, se destaca la importancia de reducir la variabilidad en la calidad del proceso y del producto, y se requiere que todos los par\u00e1metros cr\u00edticos del proceso (CPP) sean identificados y controlados.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los par\u00e1metros fisicoqu\u00edmicos y biol\u00f3gicos que deben ser considerados para evaluar el rendimiento de un FPP, y por qu\u00e9 son importantes?**\n   - Esta pregunta busca respuestas sobre la relevancia de par\u00e1metros como pH, fuerza i\u00f3nica y actividad biol\u00f3gica, que son fundamentales para la eficacia y seguridad del producto.\n\n2. **\u00bfQu\u00e9 justificaciones se deben proporcionar al seleccionar un proceso de fabricaci\u00f3n espec\u00edfico para un FPP, y c\u00f3mo se relacionan con la calidad del producto final?**\n   - Esta pregunta se centra en la necesidad de una justificaci\u00f3n cient\u00edfica para las decisiones de fabricaci\u00f3n, lo que puede incluir la elecci\u00f3n de m\u00e9todos de llenado y envasado.\n\n3. **\u00bfCu\u00e1les son las estrategias recomendadas para minimizar la variabilidad en el proceso de fabricaci\u00f3n de un FPP, y qu\u00e9 impacto tiene esto en la calidad del producto?**\n   - Esta pregunta busca explorar las pr\u00e1cticas espec\u00edficas que se deben implementar para controlar la variabilidad y asegurar que el producto cumpla con los est\u00e1ndares de calidad deseados.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **M\u00e9todos de Disoluci\u00f3n y Control de Calidad**:\n   - Se establecen directrices para la realizaci\u00f3n de pruebas de disoluci\u00f3n en productos farmac\u00e9uticos terminados (FPPs).\n   - Se diferencian los m\u00e9todos para FPPs de liberaci\u00f3n r\u00e1pida (BCS clases 1 y 3) y de liberaci\u00f3n lenta o poco soluble (BCS clases 2 y 4).\n   - Se recomienda un l\u00edmite de disoluci\u00f3n del 80% en 30 minutos para FPPs de liberaci\u00f3n r\u00e1pida y un rango de dos puntos para FPPs de liberaci\u00f3n lenta.\n\n2. **Pruebas para Productos de Liberaci\u00f3n Modificada y Extendida**:\n   - Se requiere una prueba de disoluci\u00f3n significativa para FPPs de liberaci\u00f3n modificada, preferiblemente con correlaci\u00f3n in vitro-in vivo.\n   - Para FPPs de liberaci\u00f3n extendida, se deben establecer condiciones de prueba que cubran todo el periodo de liberaci\u00f3n esperado, con l\u00edmites de aceptaci\u00f3n espec\u00edficos.\n\n3. **Impacto del Alcohol en la Liberaci\u00f3n de Medicamentos**:\n   - Se menciona que el alcohol puede afectar negativamente la liberaci\u00f3n de ciertos productos, especialmente los que contienen opi\u00e1ceos.\n   - Se recomienda a\u00f1adir etanol al medio de disoluci\u00f3n para evaluar el riesgo de liberaci\u00f3n excesiva (dose dumping).\n\n4. **Justificaci\u00f3n de Overages en Formulaciones**:\n   - Cualquier exceso en la formulaci\u00f3n debe ser justificado, especialmente para compensar p\u00e9rdidas durante la fabricaci\u00f3n.\n\n### Entidades Clave\n- **FPP (Finished Pharmaceutical Products)**: Productos farmac\u00e9uticos terminados.\n- **API (Active Pharmaceutical Ingredients)**: Ingredientes farmac\u00e9uticos activos.\n- **BCS (Biopharmaceutics Classification System)**: Sistema de clasificaci\u00f3n biofarmac\u00e9utica que categoriza los f\u00e1rmacos seg\u00fan su solubilidad y permeabilidad.\n- **WHO (World Health Organization)**: Organizaci\u00f3n Mundial de la Salud, responsable de establecer directrices y est\u00e1ndares en salud p\u00fablica y farmac\u00e9utica. \n\nEste resumen abarca los aspectos fundamentales de la secci\u00f3n, incluyendo las recomendaciones sobre disoluci\u00f3n, el impacto del alcohol y la justificaci\u00f3n de overages en formulaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: physicochemical properties, manufacturing process, product quality, variability control, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "297f027c-390c-4d80-a0f2-8a468881a433", "node_type": "4", "metadata": {"page_label": "117", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.3 Physicochemical and biological properties\n\n3.2.P.2.2.3 Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency and/or immunological activity, should be addressed.\n\n# 3.3 Manufacturing process development\n\n3.2.P.2.3 The selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.\n\nFor products that meet the criteria of an established multisource product, in order to fulfil the requirements of section P.2.3, section P.2.3 (b) of the dossier should be completed and a product quality review should usually be submitted as outlined in Appendix 2 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1). The guidance below applies to all other products, for which section P.2.3 should be completed in its entirety.\n\nThe rationale for choosing the particular pharmaceutical product (e.g. dosage form, delivery system) should be provided in the PD. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence quality and performance of the FPP should usually be explained (e.g. wet granulation using high-shear granulator). The results of an API stress study may be included in the rationale. Any developmental work undertaken on protecting the FPP from deterioration (e.g. protection from light or moisture) should also be included.\n\nThe manufacturing process of the multisource FPP should be appropriate for the product that is in development. It does not need to be the same as that of the comparator FPP.\n\nEfforts should be primarily directed towards reducing variability in process and product quality. In order to achieve this, all critical sources of variability should be identified and explained and the sources of variability should be minimized and controlled.\n\nProcess development studies should provide the basis for process improvement, process validation and any process control requirements. All CPPs should usually be identified, monitored or controlled to ensure that the product is of the desired quality.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "20540f9b87d0b986a52dedc6b2c68f47e0ff8f93b7be6655f9bb29f5fe1fcc9f", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.3 Physicochemical and biological properties\n\n3.2.P.2.2.3 Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency and/or immunological activity, should be addressed.\n\n# 3.3 Manufacturing process development\n\n3.2.P.2.3 The selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.\n\nFor products that meet the criteria of an established multisource product, in order to fulfil the requirements of section P.2.3, section P.2.3 (b) of the dossier should be completed and a product quality review should usually be submitted as outlined in Appendix 2 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1). The guidance below applies to all other products, for which section P.2.3 should be completed in its entirety.\n\nThe rationale for choosing the particular pharmaceutical product (e.g. dosage form, delivery system) should be provided in the PD. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence quality and performance of the FPP should usually be explained (e.g. wet granulation using high-shear granulator). The results of an API stress study may be included in the rationale. Any developmental work undertaken on protecting the FPP from deterioration (e.g. protection from light or moisture) should also be included.\n\nThe manufacturing process of the multisource FPP should be appropriate for the product that is in development. It does not need to be the same as that of the comparator FPP.\n\nEfforts should be primarily directed towards reducing variability in process and product quality. In order to achieve this, all critical sources of variability should be identified and explained and the sources of variability should be minimized and controlled.\n\nProcess development studies should provide the basis for process improvement, process validation and any process control requirements. All CPPs should usually be identified, monitored or controlled to ensure that the product is of the desired quality.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2440, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "0c5dd78b-ff61-45fb-83d3-cc319dc3ebe5": {"__data__": {"id_": "0c5dd78b-ff61-45fb-83d3-cc319dc3ebe5", "embedding": null, "metadata": {"page_label": "118", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nFor sterile products, an appropriate method of sterilization for the pharmaceutical product and primary packaging material should be chosen. Where relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided in the PD.\n\n*Differences between the manufacturing process(es) used to produce comparative bioavailability or biowaiver batches and the process described in 3.2.P.3.3 that can influence the performance of the product should be discussed.*\n\nThe scientific rationale for the selection, optimization, and scale-up of the manufacturing process described in 3.2.P.3.3 should usually be explained, in particular the CPPs (e.g. rate of addition of granulating fluid, massing time, and granulation end-point). A discussion of the CPPs, controls, and process robustness with respect to the QTPP and CQA of the product should usually be included (10).\n\nBased on close monitoring of the manufacturing process in the pilot batches, provisional acceptance ranges should be proposed for the CQAs of intermediates and CPPs that impact on downstream processing. Interim acceptance criteria may be approved until enough knowledge is available to finalize CQAs of intermediates and CPPs for production batches.\n\nThe manufacturing process used for pilot batches should be the same as the one proposed to be applied to production batches and should provide product of the same quality and meeting the same specifications as that intended for marketing.\n\n## 3.4 Container-closure system\n\n### 3.2.P.2.4\n\n*The suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider, e.g. choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP).*\n\nThe properties of the container-closure systems should be defined by the characteristics of the FPP and the conditions prevailing in the intended market (e.g. climatic zone IVb).\n\nStability testing of primary batches of the FPP is conducted on samples packaged in the container-closure system selected for marketing in order to confirm compatibility and product stability to support PDs for marketing authorization.\n\nWhen the container-closure system is a critical factor for FPP stability, batch or supplier variations need to be minimized through tight specifications and extended sampling plans for QC testing.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS se centra en las especificaciones para la preparaci\u00f3n farmac\u00e9utica, especialmente en la producci\u00f3n de productos est\u00e9riles. Se discuten aspectos cr\u00edticos como la elecci\u00f3n del m\u00e9todo de esterilizaci\u00f3n, la justificaci\u00f3n de procesos de fabricaci\u00f3n, la importancia de los par\u00e1metros cr\u00edticos de proceso (CPP) y la robustez del proceso en relaci\u00f3n con la calidad del producto. Tambi\u00e9n se aborda la idoneidad del sistema de cierre del envase, considerando factores como la compatibilidad de materiales, la protecci\u00f3n contra la humedad y la luz, y la estabilidad del producto.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 justificaciones se deben proporcionar al elegir m\u00e9todos de procesamiento as\u00e9ptico sobre la esterilizaci\u00f3n terminal para productos farmac\u00e9uticos est\u00e9riles?**\n   - El contexto menciona que se debe proporcionar una justificaci\u00f3n en el expediente de producto (PD) para la selecci\u00f3n de m\u00e9todos de procesamiento as\u00e9ptico o de otros m\u00e9todos de esterilizaci\u00f3n en lugar de la esterilizaci\u00f3n terminal.\n\n2. **\u00bfCu\u00e1les son los par\u00e1metros cr\u00edticos de proceso (CPP) que deben ser discutidos en relaci\u00f3n con la optimizaci\u00f3n y escalado del proceso de fabricaci\u00f3n?**\n   - Se debe explicar la selecci\u00f3n, optimizaci\u00f3n y escalado del proceso de fabricaci\u00f3n, incluyendo CPPs como la tasa de adici\u00f3n del l\u00edquido aglutinante, el tiempo de masificaci\u00f3n y el punto final de granulaci\u00f3n.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al evaluar la idoneidad del sistema de cierre del envase para un producto farmac\u00e9utico?**\n   - La discusi\u00f3n sobre la idoneidad del sistema de cierre debe incluir la elecci\u00f3n de materiales, la protecci\u00f3n contra la humedad y la luz, la compatibilidad de los materiales de construcci\u00f3n con la forma de dosificaci\u00f3n, y la seguridad y rendimiento de estos materiales en la entrega de dosis.", "prev_section_summary": "### Temas Clave\n\n1. **Propiedades Fisicoqu\u00edmicas y Biol\u00f3gicas**:\n   - Importancia de par\u00e1metros como pH, fuerza i\u00f3nica, disoluci\u00f3n, redispersi\u00f3n, reconstituci\u00f3n, distribuci\u00f3n del tama\u00f1o de part\u00edculas, agregaci\u00f3n, polimorfismo, propiedades reol\u00f3gicas, y actividad biol\u00f3gica o inmunol\u00f3gica en el rendimiento de los productos farmac\u00e9uticos terminados (FPP).\n\n2. **Desarrollo del Proceso de Fabricaci\u00f3n**:\n   - Selecci\u00f3n y optimizaci\u00f3n del proceso de fabricaci\u00f3n, incluyendo aspectos cr\u00edticos y justificaci\u00f3n del m\u00e9todo de esterilizaci\u00f3n.\n   - Para productos multisource, se requiere completar secciones espec\u00edficas del dossier y realizar revisiones de calidad del producto.\n\n3. **Justificaci\u00f3n Cient\u00edfica**:\n   - Necesidad de proporcionar una justificaci\u00f3n cient\u00edfica para la elecci\u00f3n del producto farmac\u00e9utico, as\u00ed como de los procesos de fabricaci\u00f3n, llenado y envasado que afectan la calidad y el rendimiento del FPP.\n\n4. **Minimizaci\u00f3n de Variabilidad**:\n   - Estrategias para identificar, minimizar y controlar las fuentes de variabilidad en el proceso y la calidad del producto.\n   - Importancia de los estudios de desarrollo del proceso para la mejora, validaci\u00f3n y control de procesos.\n\n### Entidades\n\n- **FPP (Finished Pharmaceutical Product)**: Producto farmac\u00e9utico terminado.\n- **CPP (Critical Process Parameters)**: Par\u00e1metros cr\u00edticos del proceso que deben ser identificados y controlados.\n- **API (Active Pharmaceutical Ingredient)**: Ingrediente farmac\u00e9utico activo.\n- **Multisource Product**: Producto farmac\u00e9utico que cumple con criterios establecidos para ser considerado equivalente a un producto de referencia.\n- **WHO (World Health Organization)**: Organizaci\u00f3n Mundial de la Salud, que proporciona directrices y est\u00e1ndares para la calidad de los medicamentos.\n\nEste resumen destaca la importancia de los par\u00e1metros fisicoqu\u00edmicos y biol\u00f3gicos en el desarrollo y fabricaci\u00f3n de productos farmac\u00e9uticos, as\u00ed como la necesidad de un enfoque riguroso para garantizar la calidad y eficacia del producto final.", "excerpt_keywords": "Keywords: sterilization, pharmaceutical preparations, critical process parameters, container-closure system, product stability"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f5562bb0-66ea-4dea-a888-eff8fa330095", "node_type": "4", "metadata": {"page_label": "118", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nFor sterile products, an appropriate method of sterilization for the pharmaceutical product and primary packaging material should be chosen. Where relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided in the PD.\n\n*Differences between the manufacturing process(es) used to produce comparative bioavailability or biowaiver batches and the process described in 3.2.P.3.3 that can influence the performance of the product should be discussed.*\n\nThe scientific rationale for the selection, optimization, and scale-up of the manufacturing process described in 3.2.P.3.3 should usually be explained, in particular the CPPs (e.g. rate of addition of granulating fluid, massing time, and granulation end-point). A discussion of the CPPs, controls, and process robustness with respect to the QTPP and CQA of the product should usually be included (10).\n\nBased on close monitoring of the manufacturing process in the pilot batches, provisional acceptance ranges should be proposed for the CQAs of intermediates and CPPs that impact on downstream processing. Interim acceptance criteria may be approved until enough knowledge is available to finalize CQAs of intermediates and CPPs for production batches.\n\nThe manufacturing process used for pilot batches should be the same as the one proposed to be applied to production batches and should provide product of the same quality and meeting the same specifications as that intended for marketing.\n\n## 3.4 Container-closure system\n\n### 3.2.P.2.4\n\n*The suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider, e.g. choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP).*\n\nThe properties of the container-closure systems should be defined by the characteristics of the FPP and the conditions prevailing in the intended market (e.g. climatic zone IVb).\n\nStability testing of primary batches of the FPP is conducted on samples packaged in the container-closure system selected for marketing in order to confirm compatibility and product stability to support PDs for marketing authorization.\n\nWhen the container-closure system is a critical factor for FPP stability, batch or supplier variations need to be minimized through tight specifications and extended sampling plans for QC testing.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "faee577468d7079090d54572d970381d69e2f34a5240308ddd8ed35648987ddb", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nFor sterile products, an appropriate method of sterilization for the pharmaceutical product and primary packaging material should be chosen. Where relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided in the PD.\n\n*Differences between the manufacturing process(es) used to produce comparative bioavailability or biowaiver batches and the process described in 3.2.P.3.3 that can influence the performance of the product should be discussed.*\n\nThe scientific rationale for the selection, optimization, and scale-up of the manufacturing process described in 3.2.P.3.3 should usually be explained, in particular the CPPs (e.g. rate of addition of granulating fluid, massing time, and granulation end-point). A discussion of the CPPs, controls, and process robustness with respect to the QTPP and CQA of the product should usually be included (10).\n\nBased on close monitoring of the manufacturing process in the pilot batches, provisional acceptance ranges should be proposed for the CQAs of intermediates and CPPs that impact on downstream processing. Interim acceptance criteria may be approved until enough knowledge is available to finalize CQAs of intermediates and CPPs for production batches.\n\nThe manufacturing process used for pilot batches should be the same as the one proposed to be applied to production batches and should provide product of the same quality and meeting the same specifications as that intended for marketing.\n\n## 3.4 Container-closure system\n\n### 3.2.P.2.4\n\n*The suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider, e.g. choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP).*\n\nThe properties of the container-closure systems should be defined by the characteristics of the FPP and the conditions prevailing in the intended market (e.g. climatic zone IVb).\n\nStability testing of primary batches of the FPP is conducted on samples packaged in the container-closure system selected for marketing in order to confirm compatibility and product stability to support PDs for marketing authorization.\n\nWhen the container-closure system is a critical factor for FPP stability, batch or supplier variations need to be minimized through tight specifications and extended sampling plans for QC testing.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2780, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "2dcde4b8-bd33-4e5a-b832-725da0d4cb74": {"__data__": {"id_": "2dcde4b8-bd33-4e5a-b832-725da0d4cb74", "embedding": null, "metadata": {"page_label": "119", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "To facilitate the visual identification of spuriously or falsely-labelled, falsified or counterfeit (SFFC) medicines (including by the public) the description needs to be completely detailed in the product information. Details may include information on the container-closure system, such as \u201cround, white opaque, high-density polyethylene (HDPE) bottles fitted with white opaque, polypropylene continuous thread closures with induction sealing liner\u201d, or \u201ca blister package comprising clear transparent polyvinyl chloride (PVC) film with a backing of aluminium foil coated with heat-seal lacquer\u201d.\n\nPrimary packing materials, particularly plastics, should comply with relevant pharmacopoeial and food contact regulations.\n\nTesting requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration and possibly, the manufacturing process. The pharmacopoeias provide standards that are required for packaging materials; examples include the following:\n\n- glass containers (17, 18);\n- plastic containers (19, 20);\n- rubber/elastomeric closures (21, 22).\n\nTable 1 outlines the general recommendations for the various dosage forms for once-only studies to establish the suitability of the container-closure system contact materials.\n\n### Table 1\n**Studies to establish the suitability of the container-closure system contact materials**\n\n|                                  | Solid oral products | Oral liquid and topical products | Sterile products (including ophthalmic preparations) |\n|----------------------------------|---------------------|----------------------------------|------------------------------------------------------|\n| Description of any additional treatments<sup>a</sup> | \u00d7                   | \u00d7                                | \u00d7 (sterilization and depyrogenation of the components) |\n| Extraction studies               | \u2013                   | \u00d7                                | \u00d7                                                    |\n| Interaction studies (migration/sorption) | \u2013                   | \u00d7                                | \u00d7                                                    |\n| Moisture permeability            | \u00d7 (uptake)          | \u00d7 (usually loss)                 | \u00d7 (usually loss)                                     |\n| Light transmission               | \u00d7<sup>b</sup>       | \u00d7                                |                                                      |\n\n<sup>\u00d7</sup> Information should usually be submitted.  \n<sup>\u2013</sup> Information does not need to be submitted.  \n<sup>a</sup> E.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials.  \n<sup>b</sup> Not required if product has been shown to be photostable.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con res\u00famenes de nivel superior que pueden ayudar a formularlas:\n\n### Resumen de nivel superior:\nEl documento de la OMS detalla la importancia de una descripci\u00f3n precisa de los medicamentos para identificar aquellos que son falsificados o mal etiquetados. Se enfatiza la necesidad de cumplir con regulaciones pertinentes para los materiales de embalaje y se presentan recomendaciones sobre estudios necesarios para verificar la idoneidad de los sistemas de cierre de envases seg\u00fan el tipo de producto.\n\n### Preguntas:\n\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n se debe incluir en la descripci\u00f3n del sistema de cierre del envase para facilitar la identificaci\u00f3n de medicamentos falsificados?**\n   - Respuesta: La descripci\u00f3n debe ser completamente detallada e incluir informaci\u00f3n sobre el sistema de cierre del envase, como el tipo de material (por ejemplo, \"botellas de polietileno de alta densidad (HDPE) opacas y blancas\") y el dise\u00f1o del envase (por ejemplo, \"un paquete de bl\u00edster que comprende una pel\u00edcula de cloruro de polivinilo (PVC) transparente con un respaldo de papel de aluminio\").\n\n2. **\u00bfCu\u00e1les son los requisitos de prueba para los materiales de contacto del sistema de cierre del envase seg\u00fan el tipo de producto?**\n   - Respuesta: Los requisitos de prueba dependen del tipo de forma de dosificaci\u00f3n y la v\u00eda de administraci\u00f3n. Por ejemplo, para productos orales s\u00f3lidos, se recomienda realizar estudios de permeabilidad a la humedad y transmisi\u00f3n de luz, mientras que para productos est\u00e9riles, se requieren estudios de extracci\u00f3n e interacci\u00f3n.\n\n3. **\u00bfQu\u00e9 regulaciones deben cumplir los materiales de embalaje primarios, especialmente los pl\u00e1sticos?**\n   - Respuesta: Los materiales de embalaje primarios, particularmente los pl\u00e1sticos, deben cumplir con las regulaciones farmacop\u00e9icas y de contacto alimentario pertinentes, asegurando que sean seguros para su uso en productos farmac\u00e9uticos.", "prev_section_summary": "### Temas Clave\n\n1. **M\u00e9todos de Esterilizaci\u00f3n**: Se enfatiza la importancia de elegir un m\u00e9todo adecuado de esterilizaci\u00f3n para productos farmac\u00e9uticos est\u00e9riles y la necesidad de justificar la elecci\u00f3n de procesamiento as\u00e9ptico o m\u00e9todos alternativos en lugar de la esterilizaci\u00f3n terminal.\n\n2. **Par\u00e1metros Cr\u00edticos de Proceso (CPP)**: Se requiere una explicaci\u00f3n detallada sobre la selecci\u00f3n, optimizaci\u00f3n y escalado del proceso de fabricaci\u00f3n, incluyendo la discusi\u00f3n de CPPs como la tasa de adici\u00f3n de l\u00edquido aglutinante, el tiempo de masificaci\u00f3n y el punto final de granulaci\u00f3n.\n\n3. **Robustez del Proceso**: Se debe discutir la robustez del proceso en relaci\u00f3n con la calidad del producto (CQA) y el perfil de calidad del producto (QTPP).\n\n4. **Sistema de Cierre del Envase**: Se aborda la idoneidad del sistema de cierre del envase, considerando la elecci\u00f3n de materiales, protecci\u00f3n contra humedad y luz, compatibilidad de materiales con la forma de dosificaci\u00f3n, y la seguridad y rendimiento en la entrega de dosis.\n\n5. **Pruebas de Estabilidad**: Se menciona la importancia de realizar pruebas de estabilidad en lotes primarios del producto farmac\u00e9utico empaquetados en el sistema de cierre seleccionado para confirmar la compatibilidad y estabilidad del producto.\n\n6. **Variaciones en Lotes o Proveedores**: Se destaca la necesidad de minimizar variaciones en lotes o proveedores cuando el sistema de cierre es un factor cr\u00edtico para la estabilidad del producto.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite directrices sobre especificaciones para preparaciones farmac\u00e9uticas.\n- **FPP (Forma Farmac\u00e9utica Final)**: Producto farmac\u00e9utico que se est\u00e1 evaluando.\n- **CPP (Par\u00e1metro Cr\u00edtico de Proceso)**: Factores que afectan el proceso de fabricaci\u00f3n y la calidad del producto.\n- **CQA (Atributo Cr\u00edtico de Calidad)**: Caracter\u00edsticas del producto que deben ser controladas para asegurar la calidad.\n- **QTPP (Perfil de Calidad del Producto)**: Especificaciones que definen la calidad del producto final.\n- **Sistema de Cierre del Envase**: Componentes utilizados para sellar y proteger el producto farmac\u00e9utico durante su almacenamiento y transporte.", "excerpt_keywords": "Keywords: medicines, falsified, container-closure system, testing requirements, pharmacopoeial regulations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a9080536-b406-41d9-82f9-24902fb6b68a", "node_type": "4", "metadata": {"page_label": "119", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "To facilitate the visual identification of spuriously or falsely-labelled, falsified or counterfeit (SFFC) medicines (including by the public) the description needs to be completely detailed in the product information. Details may include information on the container-closure system, such as \u201cround, white opaque, high-density polyethylene (HDPE) bottles fitted with white opaque, polypropylene continuous thread closures with induction sealing liner\u201d, or \u201ca blister package comprising clear transparent polyvinyl chloride (PVC) film with a backing of aluminium foil coated with heat-seal lacquer\u201d.\n\nPrimary packing materials, particularly plastics, should comply with relevant pharmacopoeial and food contact regulations.\n\nTesting requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration and possibly, the manufacturing process. The pharmacopoeias provide standards that are required for packaging materials; examples include the following:\n\n- glass containers (17, 18);\n- plastic containers (19, 20);\n- rubber/elastomeric closures (21, 22).\n\nTable 1 outlines the general recommendations for the various dosage forms for once-only studies to establish the suitability of the container-closure system contact materials.\n\n### Table 1\n**Studies to establish the suitability of the container-closure system contact materials**\n\n|                                  | Solid oral products | Oral liquid and topical products | Sterile products (including ophthalmic preparations) |\n|----------------------------------|---------------------|----------------------------------|------------------------------------------------------|\n| Description of any additional treatments<sup>a</sup> | \u00d7                   | \u00d7                                | \u00d7 (sterilization and depyrogenation of the components) |\n| Extraction studies               | \u2013                   | \u00d7                                | \u00d7                                                    |\n| Interaction studies (migration/sorption) | \u2013                   | \u00d7                                | \u00d7                                                    |\n| Moisture permeability            | \u00d7 (uptake)          | \u00d7 (usually loss)                 | \u00d7 (usually loss)                                     |\n| Light transmission               | \u00d7<sup>b</sup>       | \u00d7                                |                                                      |\n\n<sup>\u00d7</sup> Information should usually be submitted.  \n<sup>\u2013</sup> Information does not need to be submitted.  \n<sup>a</sup> E.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials.  \n<sup>b</sup> Not required if product has been shown to be photostable.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "cd04c259c98b59fa6ca34d14e71ed0a949973c834618fd502710e8f72f50fbba", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "To facilitate the visual identification of spuriously or falsely-labelled, falsified or counterfeit (SFFC) medicines (including by the public) the description needs to be completely detailed in the product information. Details may include information on the container-closure system, such as \u201cround, white opaque, high-density polyethylene (HDPE) bottles fitted with white opaque, polypropylene continuous thread closures with induction sealing liner\u201d, or \u201ca blister package comprising clear transparent polyvinyl chloride (PVC) film with a backing of aluminium foil coated with heat-seal lacquer\u201d.\n\nPrimary packing materials, particularly plastics, should comply with relevant pharmacopoeial and food contact regulations.\n\nTesting requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration and possibly, the manufacturing process. The pharmacopoeias provide standards that are required for packaging materials; examples include the following:\n\n- glass containers (17, 18);\n- plastic containers (19, 20);\n- rubber/elastomeric closures (21, 22).\n\nTable 1 outlines the general recommendations for the various dosage forms for once-only studies to establish the suitability of the container-closure system contact materials.\n\n### Table 1\n**Studies to establish the suitability of the container-closure system contact materials**\n\n|                                  | Solid oral products | Oral liquid and topical products | Sterile products (including ophthalmic preparations) |\n|----------------------------------|---------------------|----------------------------------|------------------------------------------------------|\n| Description of any additional treatments<sup>a</sup> | \u00d7                   | \u00d7                                | \u00d7 (sterilization and depyrogenation of the components) |\n| Extraction studies               | \u2013                   | \u00d7                                | \u00d7                                                    |\n| Interaction studies (migration/sorption) | \u2013                   | \u00d7                                | \u00d7                                                    |\n| Moisture permeability            | \u00d7 (uptake)          | \u00d7 (usually loss)                 | \u00d7 (usually loss)                                     |\n| Light transmission               | \u00d7<sup>b</sup>       | \u00d7                                |                                                      |\n\n<sup>\u00d7</sup> Information should usually be submitted.  \n<sup>\u2013</sup> Information does not need to be submitted.  \n<sup>a</sup> E.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials.  \n<sup>b</sup> Not required if product has been shown to be photostable.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2783, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d77ede86-c56a-4a03-9b4a-6fd8d3a5c4b6": {"__data__": {"id_": "d77ede86-c56a-4a03-9b4a-6fd8d3a5c4b6", "embedding": null, "metadata": {"page_label": "120", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe suitability of the container-closure system used for the storage, transportation (shipping) and use of any intermediate or in-process products (e.g. premixes, bulk FPP) should also be discussed.\n\n## Devices\n\nThere are certain situations in which pharmaceutical dosage forms are developed in association with specific devices. The device might be critical to enabling delivery of the medicine or it might be included in order to facilitate administration.\n\nWhere the device is critical to drug delivery and fully integrated with the product formulation, this product formulation\u2013device combination should be considered as the primary product for the purposes of regulatory submission. Examples of such products include metered dose inhalers (MDIs), dry powder inhalers, intranasal sprays and ready-made intravenous infusions. For these products the data necessary to support a regulatory submission would include:\n\n- Physical and chemical stability data for the product formulation\u2013device combination in its primary pack in order to support the claimed shelf-life and storage conditions;\n- Relevant data on extractables and leachables;\n- For multidose products, demonstration of accurate dose delivery over the shelf-life of the product under the registered storage conditions;\n- For multidose products with a dose-counting mechanism, stability data to demonstrate reliable performance of that mechanism over the shelf-life of the product under the registered storage conditions;\n- Specification control and secure sourcing of all device components;\n- Relevant information on any secondary device associated with the FPP, such as a spacer device sometimes associated with inhaled products such as MDIs and nebulizers. This device enables dose delivery in situations where the patient cannot easily use the primary product to inhale the dose, particularly where administration to children is involved. The device acts as a temporary reservoir for the dose which can then be inhaled more easily by the patient. There will be some variability inherent to a spacer device but, nevertheless, an acceptable accuracy of dose delivery when using this device needs to be demonstrated.\n\nAlternatively, the co-developed device may be intended to facilitate measurement of the prescribed dose prior to administration; this is particularly important for paediatric products where flexibility of dose may also be a requirement. Examples include spoons, cups, syringes or droppers for oral administration.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder espec\u00edficamente con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS aborda la importancia de los sistemas de contenedores y cierres para el almacenamiento y transporte de productos farmac\u00e9uticos intermedios y en proceso. Tambi\u00e9n se discute la relaci\u00f3n entre formas de dosificaci\u00f3n farmac\u00e9utica y dispositivos espec\u00edficos que facilitan la entrega del medicamento. Se enfatiza que cuando un dispositivo es cr\u00edtico para la entrega del f\u00e1rmaco, debe considerarse como parte integral del producto para fines de presentaci\u00f3n regulatoria. Se enumeran los datos necesarios para respaldar la presentaci\u00f3n regulatoria de combinaciones de formulaciones de productos y dispositivos, as\u00ed como la importancia de la precisi\u00f3n en la entrega de dosis, especialmente en productos multidose y en aplicaciones pedi\u00e1tricas.\n\n### Preguntas\n1. **\u00bfQu\u00e9 tipo de datos son necesarios para respaldar la presentaci\u00f3n regulatoria de un producto que combina una formulaci\u00f3n farmac\u00e9utica y un dispositivo cr\u00edtico para la entrega del medicamento?**\n   - Esta pregunta se centra en los requisitos espec\u00edficos de datos mencionados en el contexto, que incluyen estabilidad f\u00edsica y qu\u00edmica, datos sobre extractables y leachables, y demostraciones de entrega precisa de dosis.\n\n2. **\u00bfC\u00f3mo se debe abordar la variabilidad inherente a los dispositivos secundarios, como los espaciadores, en la entrega de dosis de productos farmac\u00e9uticos?**\n   - Esta pregunta explora la necesidad de demostrar la precisi\u00f3n en la entrega de dosis al utilizar dispositivos secundarios, lo cual es crucial para la administraci\u00f3n efectiva, especialmente en poblaciones vulnerables como los ni\u00f1os.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al desarrollar dispositivos co-dise\u00f1ados para la medici\u00f3n de dosis en productos pedi\u00e1tricos?**\n   - Esta pregunta se enfoca en las caracter\u00edsticas espec\u00edficas que deben considerarse al dise\u00f1ar dispositivos que faciliten la medici\u00f3n de dosis, destacando la flexibilidad de dosis como un requisito importante para los productos dirigidos a ni\u00f1os.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Identificaci\u00f3n de Medicamentos Falsificados**: Se enfatiza la necesidad de descripciones detalladas en la informaci\u00f3n del producto para facilitar la identificaci\u00f3n visual de medicamentos falsificados o mal etiquetados (SFFC).\n\n2. **Descripci\u00f3n del Sistema de Cierre del Envase**: Se requiere que la descripci\u00f3n incluya detalles espec\u00edficos sobre el sistema de cierre del envase, como el tipo de material y el dise\u00f1o del envase (ejemplos: botellas de HDPE, paquetes de bl\u00edster de PVC).\n\n3. **Regulaciones de Materiales de Embalaje**: Los materiales de embalaje primarios, especialmente los pl\u00e1sticos, deben cumplir con regulaciones farmacop\u00e9icas y de contacto alimentario.\n\n4. **Requisitos de Prueba**: Los requisitos de prueba para verificar la idoneidad de los materiales de contacto del sistema de cierre dependen de la forma de dosificaci\u00f3n y la v\u00eda de administraci\u00f3n. Se presentan recomendaciones espec\u00edficas para diferentes tipos de productos (s\u00f3lidos orales, l\u00edquidos orales y productos est\u00e9riles).\n\n5. **Tabla de Estudios Recomendados**: Se incluye una tabla que detalla los estudios necesarios para establecer la idoneidad de los materiales de contacto del sistema de cierre, como estudios de extracci\u00f3n, interacci\u00f3n, permeabilidad a la humedad y transmisi\u00f3n de luz.\n\n### Entidades Clave\n\n- **Medicamentos SFFC**: Medicamentos falsificados o mal etiquetados.\n- **Materiales de Embalaje**: Incluyen pl\u00e1sticos, vidrio y cierres de goma/elast\u00f3meros.\n- **Regulaciones**: Normativas farmacop\u00e9icas y de contacto alimentario.\n- **Tipos de Productos**: Productos orales s\u00f3lidos, l\u00edquidos orales, productos t\u00f3picos y productos est\u00e9riles (incluyendo preparaciones oft\u00e1lmicas).\n- **Estudios de Prueba**: Estudios de extracci\u00f3n, interacci\u00f3n, permeabilidad a la humedad y transmisi\u00f3n de luz. \n\nEste resumen destaca la importancia de la informaci\u00f3n detallada y el cumplimiento normativo en la identificaci\u00f3n y seguridad de los medicamentos.", "excerpt_keywords": "Keywords: pharmaceutical preparations, container-closure system, drug delivery devices, regulatory submission, dose measurement"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c0d9f3cb-162a-466e-b5cd-2f82a3fa1cca", "node_type": "4", "metadata": {"page_label": "120", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe suitability of the container-closure system used for the storage, transportation (shipping) and use of any intermediate or in-process products (e.g. premixes, bulk FPP) should also be discussed.\n\n## Devices\n\nThere are certain situations in which pharmaceutical dosage forms are developed in association with specific devices. The device might be critical to enabling delivery of the medicine or it might be included in order to facilitate administration.\n\nWhere the device is critical to drug delivery and fully integrated with the product formulation, this product formulation\u2013device combination should be considered as the primary product for the purposes of regulatory submission. Examples of such products include metered dose inhalers (MDIs), dry powder inhalers, intranasal sprays and ready-made intravenous infusions. For these products the data necessary to support a regulatory submission would include:\n\n- Physical and chemical stability data for the product formulation\u2013device combination in its primary pack in order to support the claimed shelf-life and storage conditions;\n- Relevant data on extractables and leachables;\n- For multidose products, demonstration of accurate dose delivery over the shelf-life of the product under the registered storage conditions;\n- For multidose products with a dose-counting mechanism, stability data to demonstrate reliable performance of that mechanism over the shelf-life of the product under the registered storage conditions;\n- Specification control and secure sourcing of all device components;\n- Relevant information on any secondary device associated with the FPP, such as a spacer device sometimes associated with inhaled products such as MDIs and nebulizers. This device enables dose delivery in situations where the patient cannot easily use the primary product to inhale the dose, particularly where administration to children is involved. The device acts as a temporary reservoir for the dose which can then be inhaled more easily by the patient. There will be some variability inherent to a spacer device but, nevertheless, an acceptable accuracy of dose delivery when using this device needs to be demonstrated.\n\nAlternatively, the co-developed device may be intended to facilitate measurement of the prescribed dose prior to administration; this is particularly important for paediatric products where flexibility of dose may also be a requirement. Examples include spoons, cups, syringes or droppers for oral administration.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "39543cd23e70cff95c9f2c26585f78d4098b28fc8e042b068334e45baa6133a9", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe suitability of the container-closure system used for the storage, transportation (shipping) and use of any intermediate or in-process products (e.g. premixes, bulk FPP) should also be discussed.\n\n## Devices\n\nThere are certain situations in which pharmaceutical dosage forms are developed in association with specific devices. The device might be critical to enabling delivery of the medicine or it might be included in order to facilitate administration.\n\nWhere the device is critical to drug delivery and fully integrated with the product formulation, this product formulation\u2013device combination should be considered as the primary product for the purposes of regulatory submission. Examples of such products include metered dose inhalers (MDIs), dry powder inhalers, intranasal sprays and ready-made intravenous infusions. For these products the data necessary to support a regulatory submission would include:\n\n- Physical and chemical stability data for the product formulation\u2013device combination in its primary pack in order to support the claimed shelf-life and storage conditions;\n- Relevant data on extractables and leachables;\n- For multidose products, demonstration of accurate dose delivery over the shelf-life of the product under the registered storage conditions;\n- For multidose products with a dose-counting mechanism, stability data to demonstrate reliable performance of that mechanism over the shelf-life of the product under the registered storage conditions;\n- Specification control and secure sourcing of all device components;\n- Relevant information on any secondary device associated with the FPP, such as a spacer device sometimes associated with inhaled products such as MDIs and nebulizers. This device enables dose delivery in situations where the patient cannot easily use the primary product to inhale the dose, particularly where administration to children is involved. The device acts as a temporary reservoir for the dose which can then be inhaled more easily by the patient. There will be some variability inherent to a spacer device but, nevertheless, an acceptable accuracy of dose delivery when using this device needs to be demonstrated.\n\nAlternatively, the co-developed device may be intended to facilitate measurement of the prescribed dose prior to administration; this is particularly important for paediatric products where flexibility of dose may also be a requirement. Examples include spoons, cups, syringes or droppers for oral administration.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2567, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "753f1a10-5a3b-46b0-9a39-8a1116b19b96": {"__data__": {"id_": "753f1a10-5a3b-46b0-9a39-8a1116b19b96", "embedding": null, "metadata": {"page_label": "121", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\ndelivery and droppers for nasal or aural delivery. A device is required to be \nincluded with the container-closure system for oral liquids or solids (e.g. \nsolutions, emulsions, suspensions and powders or granules), whenever the \npackage provides for multiple doses. \n\nIn accordance with the Ph. Int. (3) general chapter Liquid preparations \nfor oral use: \n\"Each dose from a multidose container is administered by means of a \ndevice suitable for measuring the prescribed volume. The device is usually a \nspoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for \nother volumes or, for oral drops, a suitable dropper.\" \n\nIn these cases the following data would be required to support a \nregulatory submission: \n\n- for a device accompanying a multidose container, the results \n  of a study demonstrating the reproducibility of the device (e.g. \n  consistent delivery of the intended volume), generally at the lowest \n  intended dose; \n- specifications for the device materials, including specific identification \n  testing of the material which will be in contact with the FPP. \n\nWhen the intention is to submit a PD in CTD format a sample of the \ndevice should usually be provided with Module 1 of the PD. \n\n### 3.5 Microbiological attributes\n\n#### 3.2.P.2.5 Where appropriate the microbiological attributes of the dosage form \nshould be discussed, including, for example, the rationale for not performing \nmicrobial limits testing for non-sterile products and the selection and effectiveness \nof preservative systems in products containing antimicrobial preservatives. For \nsterile products the integrity of the container-closure system to prevent microbial \ncontamination should be addressed. \n\nWhere an antimicrobial preservative is included in the formulation the \namount used needs to be justified by submission of results of studies of the product \nformulated with different concentrations of the preservative(s) to demonstrate the \nlowest necessary but still effective concentration. The effectiveness of the agent \nneeds to be justified and verified by appropriate studies (e.g. national, regional or \ninternational pharmacopoeial general chapters on antimicrobial preservatives) \nusing a batch of the FPP. If the lower limit for the proposed acceptance criterion for \nthe assay of the preservative is less than 90.0%, the effectiveness of the agent has to be \nestablished with a batch of the FPP containing a concentration of the antimicrobial \npreservative corresponding to the lower proposed acceptance criteria. \n\nAs outlined in the WHO guidelines on Stability testing of active \npharmaceutical ingredients and finished pharmaceutical products (23), a single \n```\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los requisitos para la presentaci\u00f3n de dispositivos de dosificaci\u00f3n que acompa\u00f1an a envases de medicamentos orales de m\u00faltiples dosis. Se enfatiza la necesidad de incluir un dispositivo adecuado para medir la dosis, as\u00ed como la importancia de demostrar la reproducibilidad del dispositivo y la calidad de los materiales utilizados. Adem\u00e1s, se abordan los atributos microbiol\u00f3gicos de las formas de dosificaci\u00f3n, incluyendo la justificaci\u00f3n del uso de conservantes antimicrobianos y la necesidad de estudios que respalden su efectividad.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de estudios son necesarios para demostrar la reproducibilidad de un dispositivo de dosificaci\u00f3n que acompa\u00f1a a un envase multidose?**\n   - Respuesta: Se requiere la presentaci\u00f3n de resultados de un estudio que demuestre la consistencia en la entrega del volumen destinado, generalmente en la dosis m\u00e1s baja prevista.\n\n2. **\u00bfCu\u00e1les son las especificaciones que deben cumplirse para los materiales del dispositivo de dosificaci\u00f3n en contacto con el producto farmac\u00e9utico terminado (FPP)?**\n   - Respuesta: Se deben proporcionar especificaciones para los materiales del dispositivo, incluyendo pruebas de identificaci\u00f3n espec\u00edficas del material que estar\u00e1 en contacto con el FPP.\n\n3. **\u00bfQu\u00e9 justificaciones son necesarias para el uso de conservantes antimicrobianos en productos farmac\u00e9uticos no est\u00e9riles?**\n   - Respuesta: Se debe discutir la selecci\u00f3n y efectividad de los sistemas de preservaci\u00f3n, as\u00ed como la raz\u00f3n para no realizar pruebas de l\u00edmites microbianos en productos no est\u00e9riles, y se deben presentar estudios que demuestren la concentraci\u00f3n m\u00e1s baja necesaria pero a\u00fan efectiva del conservante.", "prev_section_summary": "### Temas Clave\n\n1. **Sistemas de Contenedores y Cierres**: Se discute la importancia de los sistemas de contenedores y cierres para el almacenamiento, transporte y uso de productos farmac\u00e9uticos intermedios y en proceso.\n\n2. **Dispositivos Asociados a Formas de Dosificaci\u00f3n**: Se aborda la relaci\u00f3n entre las formas de dosificaci\u00f3n farmac\u00e9utica y dispositivos espec\u00edficos que facilitan la entrega del medicamento.\n\n3. **Combinaciones de Formulaciones y Dispositivos**: Cuando un dispositivo es cr\u00edtico para la entrega del f\u00e1rmaco, se considera parte integral del producto para fines de presentaci\u00f3n regulatoria.\n\n4. **Datos Necesarios para Presentaci\u00f3n Regulatoria**: Se enumeran los datos necesarios para respaldar la presentaci\u00f3n regulatoria de combinaciones de formulaciones de productos y dispositivos, incluyendo estabilidad, extractables y leachables, y precisi\u00f3n en la entrega de dosis.\n\n5. **Variabilidad en Dispositivos Secundarios**: Se menciona la necesidad de demostrar la precisi\u00f3n en la entrega de dosis al utilizar dispositivos secundarios, como espaciadores, especialmente en la administraci\u00f3n pedi\u00e1trica.\n\n6. **Dispositivos para Medici\u00f3n de Dosis**: Se discuten consideraciones para el desarrollo de dispositivos co-dise\u00f1ados que faciliten la medici\u00f3n de dosis, destacando la flexibilidad de dosis como un requisito importante para productos pedi\u00e1tricos.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite el documento.\n- **Comit\u00e9 de Expertos de la OMS**: Grupo responsable de las especificaciones para preparaciones farmac\u00e9uticas.\n- **Formas de Dosificaci\u00f3n**: Incluye inhaladores de dosis medida (MDIs), inhaladores de polvo seco, aerosoles intranasales y soluciones intravenosas listas para usar.\n- **Dispositivos**: Incluyen espaciadores, cucharas, tazas, jeringas y goteros para la administraci\u00f3n oral.\n- **Productos Multidose**: Productos que permiten m\u00faltiples dosis, donde se requiere demostrar la entrega precisa de dosis a lo largo de su vida \u00fatil.\n\nEste resumen destaca los aspectos fundamentales y las entidades relevantes en la secci\u00f3n proporcionada del documento de la OMS.", "excerpt_keywords": "Keywords: dosage forms, antimicrobial preservatives, regulatory submission, device reproducibility, microbiological attributes"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e7092195-8be5-4e16-9d25-72de8e816ef5", "node_type": "4", "metadata": {"page_label": "121", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\ndelivery and droppers for nasal or aural delivery. A device is required to be \nincluded with the container-closure system for oral liquids or solids (e.g. \nsolutions, emulsions, suspensions and powders or granules), whenever the \npackage provides for multiple doses. \n\nIn accordance with the Ph. Int. (3) general chapter Liquid preparations \nfor oral use: \n\"Each dose from a multidose container is administered by means of a \ndevice suitable for measuring the prescribed volume. The device is usually a \nspoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for \nother volumes or, for oral drops, a suitable dropper.\" \n\nIn these cases the following data would be required to support a \nregulatory submission: \n\n- for a device accompanying a multidose container, the results \n  of a study demonstrating the reproducibility of the device (e.g. \n  consistent delivery of the intended volume), generally at the lowest \n  intended dose; \n- specifications for the device materials, including specific identification \n  testing of the material which will be in contact with the FPP. \n\nWhen the intention is to submit a PD in CTD format a sample of the \ndevice should usually be provided with Module 1 of the PD. \n\n### 3.5 Microbiological attributes\n\n#### 3.2.P.2.5 Where appropriate the microbiological attributes of the dosage form \nshould be discussed, including, for example, the rationale for not performing \nmicrobial limits testing for non-sterile products and the selection and effectiveness \nof preservative systems in products containing antimicrobial preservatives. For \nsterile products the integrity of the container-closure system to prevent microbial \ncontamination should be addressed. \n\nWhere an antimicrobial preservative is included in the formulation the \namount used needs to be justified by submission of results of studies of the product \nformulated with different concentrations of the preservative(s) to demonstrate the \nlowest necessary but still effective concentration. The effectiveness of the agent \nneeds to be justified and verified by appropriate studies (e.g. national, regional or \ninternational pharmacopoeial general chapters on antimicrobial preservatives) \nusing a batch of the FPP. If the lower limit for the proposed acceptance criterion for \nthe assay of the preservative is less than 90.0%, the effectiveness of the agent has to be \nestablished with a batch of the FPP containing a concentration of the antimicrobial \npreservative corresponding to the lower proposed acceptance criteria. \n\nAs outlined in the WHO guidelines on Stability testing of active \npharmaceutical ingredients and finished pharmaceutical products (23), a single \n```\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "e82973d81c22d969d720b13c19c85bdee535adf5805824a3f0dce5d7585d1891", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "```\ndelivery and droppers for nasal or aural delivery. A device is required to be \nincluded with the container-closure system for oral liquids or solids (e.g. \nsolutions, emulsions, suspensions and powders or granules), whenever the \npackage provides for multiple doses. \n\nIn accordance with the Ph. Int. (3) general chapter Liquid preparations \nfor oral use: \n\"Each dose from a multidose container is administered by means of a \ndevice suitable for measuring the prescribed volume. The device is usually a \nspoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for \nother volumes or, for oral drops, a suitable dropper.\" \n\nIn these cases the following data would be required to support a \nregulatory submission: \n\n- for a device accompanying a multidose container, the results \n  of a study demonstrating the reproducibility of the device (e.g. \n  consistent delivery of the intended volume), generally at the lowest \n  intended dose; \n- specifications for the device materials, including specific identification \n  testing of the material which will be in contact with the FPP. \n\nWhen the intention is to submit a PD in CTD format a sample of the \ndevice should usually be provided with Module 1 of the PD. \n\n### 3.5 Microbiological attributes\n\n#### 3.2.P.2.5 Where appropriate the microbiological attributes of the dosage form \nshould be discussed, including, for example, the rationale for not performing \nmicrobial limits testing for non-sterile products and the selection and effectiveness \nof preservative systems in products containing antimicrobial preservatives. For \nsterile products the integrity of the container-closure system to prevent microbial \ncontamination should be addressed. \n\nWhere an antimicrobial preservative is included in the formulation the \namount used needs to be justified by submission of results of studies of the product \nformulated with different concentrations of the preservative(s) to demonstrate the \nlowest necessary but still effective concentration. The effectiveness of the agent \nneeds to be justified and verified by appropriate studies (e.g. national, regional or \ninternational pharmacopoeial general chapters on antimicrobial preservatives) \nusing a batch of the FPP. If the lower limit for the proposed acceptance criterion for \nthe assay of the preservative is less than 90.0%, the effectiveness of the agent has to be \nestablished with a batch of the FPP containing a concentration of the antimicrobial \npreservative corresponding to the lower proposed acceptance criteria. \n\nAs outlined in the WHO guidelines on Stability testing of active \npharmaceutical ingredients and finished pharmaceutical products (23), a single \n```", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2700, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "953ec761-5ec7-4190-9c25-17f1d6bc1dd4": {"__data__": {"id_": "953ec761-5ec7-4190-9c25-17f1d6bc1dd4", "embedding": null, "metadata": {"page_label": "122", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Compatibility\n\n## 3.2.P.2.6\n\nThe compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation of API in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labelling.\n\nWhere a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules for reconstitution), which are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required.\n\nWhere sterile, reconstituted products are to be further diluted, compatibility will have to be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of individual and total degradation products, subvisible particulate matter and extractables from the packaging components) should be demonstrated in glass, PVC and polyolefin containers. However, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers.\n\nIn the case of infusion sets where a product formulation is added to an infusion vehicle in an intravenous administration set (giving set) immediately prior to administration, the following data would be required:\n\n- physical and chemical stability data for the prepared infusion to support the claimed in-use shelf-life and storage conditions;\n- compatibility data to support the claimed in-use shelf-life and storage conditions;\n- specification control and secure sourcing of all giving set contact materials.\n\nStudies are usually required to cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies co-administration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the co-administered FPP (i.e. in addition to the other, aforementioned parameters for the mixture, the assay and degradation levels of each co-administered FPP should be reported).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS aborda la compatibilidad de productos farmac\u00e9uticos (FPP) con diluyentes y dispositivos de dosificaci\u00f3n. Se especifica que, en ciertos casos, no se requieren estudios de compatibilidad, especialmente para l\u00edquidos orales que se administran inmediatamente. Sin embargo, para productos reconstituidos que se diluyen posteriormente, se deben realizar estudios de compatibilidad con todos los diluyentes propuestos. Tambi\u00e9n se menciona la necesidad de datos sobre estabilidad f\u00edsica y qu\u00edmica, as\u00ed como la compatibilidad en el caso de conjuntos de infusi\u00f3n. Se enfatiza la importancia de realizar estudios en diferentes tipos de envases y bajo condiciones espec\u00edficas de almacenamiento.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de estudios de compatibilidad son necesarios para productos reconstituidos que se diluyen antes de la administraci\u00f3n?**\n   - Respuesta: Se deben demostrar la compatibilidad con todos los diluyentes sobre el rango de diluci\u00f3n propuesto en el etiquetado, preferiblemente utilizando muestras envejecidas.\n\n2. **\u00bfQu\u00e9 par\u00e1metros deben evaluarse para demostrar la compatibilidad en diferentes tipos de envases?**\n   - Respuesta: Se deben evaluar par\u00e1metros como apariencia, pH, ensayo, niveles de productos de degradaci\u00f3n individuales y totales, materia particulada subvisible y extractables de los componentes del envase en vidrio, PVC y poliolefina.\n\n3. **\u00bfQu\u00e9 datos son necesarios para respaldar la vida \u00fatil en uso y las condiciones de almacenamiento de una infusi\u00f3n preparada?**\n   - Respuesta: Se requieren datos sobre la estabilidad f\u00edsica y qu\u00edmica de la infusi\u00f3n preparada, datos de compatibilidad y control de especificaciones y abastecimiento seguro de todos los materiales de contacto del conjunto de infusi\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Dispositivos de Dosificaci\u00f3n**:\n   - Se requiere un dispositivo adecuado para medir la dosis en envases de medicamentos orales de m\u00faltiples dosis (ej. cucharas, jeringas orales, goteros).\n   - Es necesario demostrar la reproducibilidad del dispositivo, especialmente en la dosis m\u00e1s baja prevista.\n\n2. **Especificaciones de Materiales**:\n   - Se deben proporcionar especificaciones para los materiales del dispositivo, incluyendo pruebas de identificaci\u00f3n de los materiales en contacto con el producto farmac\u00e9utico terminado (FPP).\n\n3. **Presentaci\u00f3n Regulatoria**:\n   - Al presentar un Dossier de Producto (PD) en formato CTD, se debe incluir una muestra del dispositivo en el M\u00f3dulo 1.\n\n4. **Atributos Microbiol\u00f3gicos**:\n   - Se debe discutir la justificaci\u00f3n para no realizar pruebas de l\u00edmites microbianos en productos no est\u00e9riles y la efectividad de los sistemas de preservaci\u00f3n.\n   - Para productos est\u00e9riles, se debe asegurar la integridad del sistema de cierre del envase para prevenir la contaminaci\u00f3n microbiana.\n\n5. **Conservantes Antimicrobianos**:\n   - La cantidad de conservante antimicrobiano debe ser justificada mediante estudios que demuestren la concentraci\u00f3n m\u00e1s baja necesaria pero efectiva.\n   - La efectividad del conservante debe ser verificada por estudios apropiados, y si el l\u00edmite inferior de aceptaci\u00f3n es menor al 90.0%, se debe establecer la efectividad con un lote del FPP que contenga la concentraci\u00f3n correspondiente.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las directrices.\n- **Ph. Int.**: Referencia a la Farmacopea Internacional que establece normas para preparaciones l\u00edquidas orales.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que se presenta para su regulaci\u00f3n.\n- **Conservantes Antimicrobianos**: Sustancias utilizadas para prevenir el crecimiento microbiano en productos farmac\u00e9uticos. \n\nEste resumen abarca los aspectos esenciales relacionados con la presentaci\u00f3n de dispositivos de dosificaci\u00f3n y los atributos microbiol\u00f3gicos de los productos farmac\u00e9uticos, seg\u00fan lo estipulado en el documento de la OMS.", "excerpt_keywords": "compatibility, reconstitution, diluents, infusion sets, stability"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bd65de1e-eb09-452c-ad7e-c905d7e24f79", "node_type": "4", "metadata": {"page_label": "122", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Compatibility\n\n## 3.2.P.2.6\n\nThe compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation of API in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labelling.\n\nWhere a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules for reconstitution), which are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required.\n\nWhere sterile, reconstituted products are to be further diluted, compatibility will have to be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of individual and total degradation products, subvisible particulate matter and extractables from the packaging components) should be demonstrated in glass, PVC and polyolefin containers. However, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers.\n\nIn the case of infusion sets where a product formulation is added to an infusion vehicle in an intravenous administration set (giving set) immediately prior to administration, the following data would be required:\n\n- physical and chemical stability data for the prepared infusion to support the claimed in-use shelf-life and storage conditions;\n- compatibility data to support the claimed in-use shelf-life and storage conditions;\n- specification control and secure sourcing of all giving set contact materials.\n\nStudies are usually required to cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies co-administration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the co-administered FPP (i.e. in addition to the other, aforementioned parameters for the mixture, the assay and degradation levels of each co-administered FPP should be reported).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "dde33cb7c59b8f38315318ee31e00e5cddd89d79fd061df8c56948f2f3b9c456", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Compatibility\n\n## 3.2.P.2.6\n\nThe compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation of API in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labelling.\n\nWhere a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules for reconstitution), which are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required.\n\nWhere sterile, reconstituted products are to be further diluted, compatibility will have to be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of individual and total degradation products, subvisible particulate matter and extractables from the packaging components) should be demonstrated in glass, PVC and polyolefin containers. However, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers.\n\nIn the case of infusion sets where a product formulation is added to an infusion vehicle in an intravenous administration set (giving set) immediately prior to administration, the following data would be required:\n\n- physical and chemical stability data for the prepared infusion to support the claimed in-use shelf-life and storage conditions;\n- compatibility data to support the claimed in-use shelf-life and storage conditions;\n- specification control and secure sourcing of all giving set contact materials.\n\nStudies are usually required to cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies co-administration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the co-administered FPP (i.e. in addition to the other, aforementioned parameters for the mixture, the assay and degradation levels of each co-administered FPP should be reported).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2325, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "6d8bbf84-7fe8-4636-b2ad-0b4fb5bdc171": {"__data__": {"id_": "6d8bbf84-7fe8-4636-b2ad-0b4fb5bdc171", "embedding": null, "metadata": {"page_label": "123", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 4. Glossary\n\nThe definitions given below apply to the terms as used in these guidelines. They may have different meanings in other contexts.\n\n**active pharmaceutical ingredient**\n\nAny substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.\n\n**comparator product**\n\nThe comparator product is a pharmaceutical product with which the multisource product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality have been established. The selection of the comparator product is usually made at the national level by the medicines regulatory authority. (For the WHO Prequalification of Medicines Programme, the selection of the comparator product is based on the information presented under Guidance on bioequivalence studies available on the Prequalification web site.)\n\n**control strategy**\n\nA planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to active pharmaceutical ingredient and finished pharmaceutical product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.\n\n**critical process parameter (CPP)**\n\nA process parameter whose variability has an impact on a critical quality attribute and, therefore, should be monitored or controlled to ensure the process produces the desired quality.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento \"WHO - Technical Report Series 970\" incluye un glosario que define t\u00e9rminos clave relacionados con la fabricaci\u00f3n de productos farmac\u00e9uticos. Se abordan conceptos como el \"ingrediente farmac\u00e9utico activo\", el \"producto comparador\", la \"estrategia de control\" y el \"par\u00e1metro cr\u00edtico del proceso\". Estas definiciones son esenciales para entender las directrices sobre la calidad y la regulaci\u00f3n de los medicamentos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1l es la diferencia entre un ingrediente farmac\u00e9utico activo y un producto comparador seg\u00fan el documento?**\n   - Esta pregunta busca aclarar las definiciones y roles de estos dos t\u00e9rminos en el contexto de la fabricaci\u00f3n y regulaci\u00f3n de medicamentos.\n\n2. **\u00bfQu\u00e9 elementos se consideran en una estrategia de control para asegurar la calidad del producto farmac\u00e9utico?**\n   - Esta pregunta se enfoca en los componentes espec\u00edficos que forman parte de una estrategia de control, lo que puede ser crucial para la calidad del proceso de fabricaci\u00f3n.\n\n3. **\u00bfPor qu\u00e9 es importante monitorear los par\u00e1metros cr\u00edticos del proceso (CPP) en la producci\u00f3n farmac\u00e9utica?**\n   - Esta pregunta indaga sobre la relevancia de los CPP y su impacto en la calidad del producto final, lo que es fundamental para garantizar la eficacia y seguridad de los medicamentos.", "prev_section_summary": "### Temas Clave\n\n1. **Compatibilidad de Productos Farmac\u00e9uticos (FPP)**: Se aborda la necesidad de evaluar la compatibilidad de los FPP con diluyentes y dispositivos de dosificaci\u00f3n, considerando factores como la estabilidad y la interacci\u00f3n con los materiales de los envases.\n\n2. **Estudios de Compatibilidad**: Se especifica que no se requieren estudios de compatibilidad para l\u00edquidos orales que se administran inmediatamente. Sin embargo, para productos reconstituidos que se diluyen posteriormente, se deben realizar estudios de compatibilidad con todos los diluyentes propuestos.\n\n3. **Par\u00e1metros de Evaluaci\u00f3n**: Se deben evaluar varios par\u00e1metros para demostrar la compatibilidad, incluyendo apariencia, pH, niveles de productos de degradaci\u00f3n, materia particulada subvisible y extractables de los envases.\n\n4. **Conjuntos de Infusi\u00f3n**: Se requiere informaci\u00f3n sobre la estabilidad f\u00edsica y qu\u00edmica de las infusiones preparadas, as\u00ed como datos de compatibilidad y control de especificaciones para los materiales de contacto en conjuntos de infusi\u00f3n.\n\n5. **Condiciones de Almacenamiento**: Los estudios de compatibilidad deben cubrir la duraci\u00f3n de almacenamiento especificada en el etiquetado, con ejemplos de 24 horas a temperatura ambiente y 72 horas en refrigeraci\u00f3n.\n\n### Entidades\n\n- **FPP (Formulaciones Farmac\u00e9uticas)**: Productos que requieren evaluaci\u00f3n de compatibilidad.\n- **Diluyentes**: Sustancias con las que se eval\u00faa la compatibilidad de los FPP.\n- **Dispositivos de Dosificaci\u00f3n**: Equipos utilizados para administrar los FPP.\n- **Envases**: Materiales en los que se almacenan los FPP, como vidrio, PVC y poliolefina.\n- **Conjuntos de Infusi\u00f3n**: Sistemas utilizados para la administraci\u00f3n intravenosa de FPP.\n- **Estudios de Estabilidad**: Evaluaciones necesarias para respaldar la vida \u00fatil y las condiciones de almacenamiento de los FPP.\n\nEste resumen destaca la importancia de la compatibilidad en la formulaci\u00f3n y administraci\u00f3n de productos farmac\u00e9uticos, as\u00ed como los requisitos espec\u00edficos para garantizar su seguridad y eficacia.", "excerpt_keywords": "Keywords: pharmaceutical, active ingredient, comparator product, control strategy, critical process parameter"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c68bbc49-bf45-42f2-b4ca-69a24edab1bd", "node_type": "4", "metadata": {"page_label": "123", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 4. Glossary\n\nThe definitions given below apply to the terms as used in these guidelines. They may have different meanings in other contexts.\n\n**active pharmaceutical ingredient**\n\nAny substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.\n\n**comparator product**\n\nThe comparator product is a pharmaceutical product with which the multisource product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality have been established. The selection of the comparator product is usually made at the national level by the medicines regulatory authority. (For the WHO Prequalification of Medicines Programme, the selection of the comparator product is based on the information presented under Guidance on bioequivalence studies available on the Prequalification web site.)\n\n**control strategy**\n\nA planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to active pharmaceutical ingredient and finished pharmaceutical product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.\n\n**critical process parameter (CPP)**\n\nA process parameter whose variability has an impact on a critical quality attribute and, therefore, should be monitored or controlled to ensure the process produces the desired quality.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "6b28f09d4f7920383c16c92ff8a76c1a73d5e96cd12b709f2553920d458d1a07", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 4. Glossary\n\nThe definitions given below apply to the terms as used in these guidelines. They may have different meanings in other contexts.\n\n**active pharmaceutical ingredient**\n\nAny substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.\n\n**comparator product**\n\nThe comparator product is a pharmaceutical product with which the multisource product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality have been established. The selection of the comparator product is usually made at the national level by the medicines regulatory authority. (For the WHO Prequalification of Medicines Programme, the selection of the comparator product is based on the information presented under Guidance on bioequivalence studies available on the Prequalification web site.)\n\n**control strategy**\n\nA planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to active pharmaceutical ingredient and finished pharmaceutical product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.\n\n**critical process parameter (CPP)**\n\nA process parameter whose variability has an impact on a critical quality attribute and, therefore, should be monitored or controlled to ensure the process produces the desired quality.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1927, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "cf94848a-9e25-454b-99fc-a20a34583b09": {"__data__": {"id_": "cf94848a-9e25-454b-99fc-a20a34583b09", "embedding": null, "metadata": {"page_label": "124", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## critical quality attribute (CQA)\n\nA physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality.\n\n## finished pharmaceutical product (FPP)\n\nA finished dosage form of a pharmaceutical product, which has undergone all stages of manufacture, including packaging in its final container and labelling.\n\n## fixed-dose combination finished pharmaceutical product (FDC-FPP)\n\nA finished pharmaceutical product that contains two or more active pharmaceutical ingredients.\n\n## formal experimental design\n\nA structured, organized method for determining the relationship between factors affecting a process and the output of that process. Also known as \u201cdesign of experiments\u201d.\n\n## generic product\n\nSee multisource (generic) pharmaceutical products.\n\n## life-cycle\n\nAll phases in the life of a product from the initial development through marketing until the product\u2019s discontinuation.\n\n## multisource (generic) pharmaceutical products\n\nMultisource pharmaceutical products are pharmaceutically equivalent or pharmaceutically alternative products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable.\n\n## pharmaceutical alternatives\n\nProducts are pharmaceutical alternative(s) if they contain the same molar amount of the same active pharmaceutical moiety(s) but differ in dosage form (e.g. tablets versus capsules), and/or chemical form (e.g. different salts, different esters). Pharmaceutical alternatives deliver the same active moiety by the same route of administration but are otherwise not pharmaceutically equivalent. They may or may not be bioequivalent or therapeutically equivalent to the comparator product.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder con la informaci\u00f3n proporcionada en el contexto, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) se centra en las especificaciones para preparaciones farmac\u00e9uticas. Define varios t\u00e9rminos clave relacionados con la calidad y la fabricaci\u00f3n de productos farmac\u00e9uticos, incluyendo atributos cr\u00edticos de calidad, productos farmac\u00e9uticos terminados, combinaciones de dosis fijas, y alternativas farmac\u00e9uticas. Tambi\u00e9n se menciona el ciclo de vida de un producto y la equivalencia de productos gen\u00e9ricos.\n\n### Preguntas\n\n1. **\u00bfQu\u00e9 se entiende por \"atributo cr\u00edtico de calidad\" (CQA) y por qu\u00e9 es importante en la fabricaci\u00f3n de productos farmac\u00e9uticos?**\n   - Respuesta: Un CQA es una propiedad f\u00edsica, qu\u00edmica, biol\u00f3gica o microbiol\u00f3gica que debe estar dentro de un l\u00edmite, rango o distribuci\u00f3n apropiados para asegurar la calidad deseada del producto. Es importante porque garantiza que el producto final cumpla con los est\u00e1ndares de calidad necesarios para su eficacia y seguridad.\n\n2. **\u00bfCu\u00e1l es la diferencia entre un producto farmac\u00e9utico terminado (FPP) y un producto farmac\u00e9utico de combinaci\u00f3n de dosis fija (FDC-FPP)?**\n   - Respuesta: Un FPP es una forma de dosificaci\u00f3n final que ha pasado por todas las etapas de fabricaci\u00f3n, incluyendo el envasado y etiquetado. En cambio, un FDC-FPP es un tipo espec\u00edfico de FPP que contiene dos o m\u00e1s ingredientes farmac\u00e9uticos activos en una sola formulaci\u00f3n.\n\n3. **\u00bfQu\u00e9 son los productos farmac\u00e9uticos multisource y c\u00f3mo se relacionan con la equivalencia terap\u00e9utica?**\n   - Respuesta: Los productos farmac\u00e9uticos multisource son productos que son farmac\u00e9uticamente equivalentes o alternativos, y pueden o no ser terap\u00e9uticamente equivalentes. Aquellos que son terap\u00e9uticamente equivalentes son intercambiables, lo que significa que pueden ser utilizados de manera similar en el tratamiento de una condici\u00f3n m\u00e9dica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Ingredientes Farmac\u00e9uticos Activos (API)**:\n   - Definici\u00f3n: Sustancias o mezclas utilizadas en la fabricaci\u00f3n de formas farmac\u00e9uticas que tienen actividad farmacol\u00f3gica o efectos directos en la salud.\n\n2. **Producto Comparador**:\n   - Definici\u00f3n: Producto farmac\u00e9utico con el que se espera que un producto multisource sea intercambiable en la pr\u00e1ctica cl\u00ednica. Generalmente, es el producto innovador con eficacia, seguridad y calidad establecidas.\n\n3. **Estrategia de Control**:\n   - Definici\u00f3n: Conjunto planificado de controles que asegura el rendimiento del proceso y la calidad del producto. Incluye par\u00e1metros relacionados con los ingredientes activos, condiciones de operaci\u00f3n, controles en proceso y especificaciones del producto terminado.\n\n4. **Par\u00e1metro Cr\u00edtico del Proceso (CPP)**:\n   - Definici\u00f3n: Par\u00e1metro del proceso cuya variabilidad afecta a un atributo cr\u00edtico de calidad y que debe ser monitoreado o controlado para garantizar la calidad del producto final.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que establece directrices sobre la calidad y regulaci\u00f3n de medicamentos.\n- **Reguladores de Medicamentos**: Autoridades nacionales responsables de la selecci\u00f3n de productos comparadores y la regulaci\u00f3n de medicamentos.\n- **Productos Farmac\u00e9uticos**: Incluyen tanto ingredientes activos como productos terminados que se utilizan en el diagn\u00f3stico y tratamiento de enfermedades. \n\nEste resumen proporciona una visi\u00f3n general de los t\u00e9rminos y conceptos esenciales relacionados con la fabricaci\u00f3n y regulaci\u00f3n de productos farmac\u00e9uticos seg\u00fan el documento de la OMS.", "excerpt_keywords": "Keywords: pharmaceutical preparations, critical quality attribute, finished pharmaceutical product, fixed-dose combination, multisource products"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9dd249be-54a1-4ad2-806b-e254f70eba29", "node_type": "4", "metadata": {"page_label": "124", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## critical quality attribute (CQA)\n\nA physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality.\n\n## finished pharmaceutical product (FPP)\n\nA finished dosage form of a pharmaceutical product, which has undergone all stages of manufacture, including packaging in its final container and labelling.\n\n## fixed-dose combination finished pharmaceutical product (FDC-FPP)\n\nA finished pharmaceutical product that contains two or more active pharmaceutical ingredients.\n\n## formal experimental design\n\nA structured, organized method for determining the relationship between factors affecting a process and the output of that process. Also known as \u201cdesign of experiments\u201d.\n\n## generic product\n\nSee multisource (generic) pharmaceutical products.\n\n## life-cycle\n\nAll phases in the life of a product from the initial development through marketing until the product\u2019s discontinuation.\n\n## multisource (generic) pharmaceutical products\n\nMultisource pharmaceutical products are pharmaceutically equivalent or pharmaceutically alternative products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable.\n\n## pharmaceutical alternatives\n\nProducts are pharmaceutical alternative(s) if they contain the same molar amount of the same active pharmaceutical moiety(s) but differ in dosage form (e.g. tablets versus capsules), and/or chemical form (e.g. different salts, different esters). Pharmaceutical alternatives deliver the same active moiety by the same route of administration but are otherwise not pharmaceutically equivalent. They may or may not be bioequivalent or therapeutically equivalent to the comparator product.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f0e467300828e57d9df0cd4dfa4be8da00274d2fccada703647131252d7761b5", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## critical quality attribute (CQA)\n\nA physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality.\n\n## finished pharmaceutical product (FPP)\n\nA finished dosage form of a pharmaceutical product, which has undergone all stages of manufacture, including packaging in its final container and labelling.\n\n## fixed-dose combination finished pharmaceutical product (FDC-FPP)\n\nA finished pharmaceutical product that contains two or more active pharmaceutical ingredients.\n\n## formal experimental design\n\nA structured, organized method for determining the relationship between factors affecting a process and the output of that process. Also known as \u201cdesign of experiments\u201d.\n\n## generic product\n\nSee multisource (generic) pharmaceutical products.\n\n## life-cycle\n\nAll phases in the life of a product from the initial development through marketing until the product\u2019s discontinuation.\n\n## multisource (generic) pharmaceutical products\n\nMultisource pharmaceutical products are pharmaceutically equivalent or pharmaceutically alternative products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable.\n\n## pharmaceutical alternatives\n\nProducts are pharmaceutical alternative(s) if they contain the same molar amount of the same active pharmaceutical moiety(s) but differ in dosage form (e.g. tablets versus capsules), and/or chemical form (e.g. different salts, different esters). Pharmaceutical alternatives deliver the same active moiety by the same route of administration but are otherwise not pharmaceutically equivalent. They may or may not be bioequivalent or therapeutically equivalent to the comparator product.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1893, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "7691c42e-9737-4bbc-9c10-bf924ab02f8c": {"__data__": {"id_": "7691c42e-9737-4bbc-9c10-bf924ab02f8c", "embedding": null, "metadata": {"page_label": "125", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 3\n\n**pharmaceutical equivalence**  \nProducts are pharmaceutical equivalents if they contain the same molar amount of the same active pharmaceutical ingredient(s) in the same dosage form, if they meet comparable standards, and if they are intended to be administered by the same route. Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, as differences in the excipients and/or the manufacturing process and some other variables can lead to differences in product performance.\n\n**pharmaceutical product**  \nAny preparation for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient.\n\n**pilot-scale batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For example, for solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger; unless otherwise adequately justified.\n\n**primary batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product used in a stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf-life, as the case may be.\n\n**process robustness**  \nAbility of a process to tolerate variability of materials and changes of the process and equipment without negative impact on quality.\n\n**production batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product manufactured at production scale by using production equipment in a production facility as specified in the application.\n\n**quality**  \nThe suitability of either an active pharmaceutical ingredient or a pharmaceutical product for its intended use. This term includes such attributes as the identity, strength and purity.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Anexo 3 aborda definiciones clave relacionadas con la equivalencia farmac\u00e9utica, los productos farmac\u00e9uticos, y los procesos de fabricaci\u00f3n. Se definen t\u00e9rminos como \"equivalencia farmac\u00e9utica\", \"producto farmac\u00e9utico\", \"lote a escala piloto\", \"lote primario\", \"robustez del proceso\", \"lote de producci\u00f3n\" y \"calidad\". Estas definiciones son fundamentales para entender la regulaci\u00f3n y el desarrollo de productos farmac\u00e9uticos, as\u00ed como su evaluaci\u00f3n en t\u00e9rminos de seguridad y eficacia.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 criterios deben cumplirse para que dos productos sean considerados equivalentes farmac\u00e9uticos?**\n   - Respuesta: Dos productos son considerados equivalentes farmac\u00e9uticos si contienen la misma cantidad molar del mismo(s) ingrediente(s) farmac\u00e9utico(s) activo(s) en la misma forma de dosificaci\u00f3n, cumplen con est\u00e1ndares comparables y est\u00e1n destinados a ser administrados por la misma v\u00eda.\n\n2. **\u00bfCu\u00e1l es la diferencia entre un lote a escala piloto y un lote de producci\u00f3n en la fabricaci\u00f3n de productos farmac\u00e9uticos?**\n   - Respuesta: Un lote a escala piloto es fabricado mediante un procedimiento que simula el proceso de un lote a escala de producci\u00f3n, generalmente siendo al menos una d\u00e9cima parte del tama\u00f1o de un lote de producci\u00f3n completo. En cambio, un lote de producci\u00f3n es fabricado a escala de producci\u00f3n utilizando equipos de producci\u00f3n en una instalaci\u00f3n especificada en la solicitud.\n\n3. **\u00bfQu\u00e9 se entiende por \"robustez del proceso\" en el contexto de la fabricaci\u00f3n farmac\u00e9utica?**\n   - Respuesta: La robustez del proceso se refiere a la capacidad de un proceso para tolerar variaciones en los materiales y cambios en el proceso y el equipo sin que esto afecte negativamente la calidad del producto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS aborda las especificaciones para preparaciones farmac\u00e9uticas y define varios t\u00e9rminos esenciales relacionados con la calidad y la fabricaci\u00f3n de productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n1. **Atributo Cr\u00edtico de Calidad (CQA)**: Propiedades f\u00edsicas, qu\u00edmicas, biol\u00f3gicas o microbiol\u00f3gicas que deben estar dentro de l\u00edmites apropiados para asegurar la calidad del producto.\n\n2. **Producto Farmac\u00e9utico Terminado (FPP)**: Forma de dosificaci\u00f3n final que ha completado todas las etapas de fabricaci\u00f3n, incluyendo el envasado y etiquetado.\n\n3. **Producto Farmac\u00e9utico de Combinaci\u00f3n de Dosis Fija (FDC-FPP)**: FPP que contiene dos o m\u00e1s ingredientes farmac\u00e9uticos activos en una sola formulaci\u00f3n.\n\n4. **Dise\u00f1o Experimental Formal**: M\u00e9todo estructurado para determinar la relaci\u00f3n entre factores que afectan un proceso y su resultado, tambi\u00e9n conocido como \"dise\u00f1o de experimentos\".\n\n5. **Producto Gen\u00e9rico**: Se refiere a productos farmac\u00e9uticos multisource.\n\n6. **Ciclo de Vida**: Todas las fases en la vida de un producto, desde su desarrollo inicial hasta su discontinuaci\u00f3n.\n\n7. **Productos Farmac\u00e9uticos Multisource**: Productos que son farmac\u00e9uticamente equivalentes o alternativos, que pueden o no ser terap\u00e9uticamente equivalentes. Los que son terap\u00e9uticamente equivalentes son intercambiables.\n\n8. **Alternativas Farmac\u00e9uticas**: Productos que contienen la misma cantidad molar del mismo principio activo, pero que difieren en forma de dosificaci\u00f3n o forma qu\u00edmica. Pueden no ser equivalentes farmac\u00e9uticamente, y su bioequivalencia o equivalencia terap\u00e9utica puede variar.\n\nEste resumen destaca la importancia de la calidad y la equivalencia en la fabricaci\u00f3n y regulaci\u00f3n de productos farmac\u00e9uticos, as\u00ed como los t\u00e9rminos clave que son fundamentales para entender el contexto de las especificaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: pharmaceutical equivalence, production batch, process robustness, quality, pilot-scale batch"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a005cb34-0c8b-4e7a-9348-5d001a0a4ab6", "node_type": "4", "metadata": {"page_label": "125", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 3\n\n**pharmaceutical equivalence**  \nProducts are pharmaceutical equivalents if they contain the same molar amount of the same active pharmaceutical ingredient(s) in the same dosage form, if they meet comparable standards, and if they are intended to be administered by the same route. Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, as differences in the excipients and/or the manufacturing process and some other variables can lead to differences in product performance.\n\n**pharmaceutical product**  \nAny preparation for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient.\n\n**pilot-scale batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For example, for solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger; unless otherwise adequately justified.\n\n**primary batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product used in a stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf-life, as the case may be.\n\n**process robustness**  \nAbility of a process to tolerate variability of materials and changes of the process and equipment without negative impact on quality.\n\n**production batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product manufactured at production scale by using production equipment in a production facility as specified in the application.\n\n**quality**  \nThe suitability of either an active pharmaceutical ingredient or a pharmaceutical product for its intended use. This term includes such attributes as the identity, strength and purity.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "57023a2076392d531ddf1f77add9c3f5f6aa912fb48d6701e5f843f0b727e0d4", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 3\n\n**pharmaceutical equivalence**  \nProducts are pharmaceutical equivalents if they contain the same molar amount of the same active pharmaceutical ingredient(s) in the same dosage form, if they meet comparable standards, and if they are intended to be administered by the same route. Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, as differences in the excipients and/or the manufacturing process and some other variables can lead to differences in product performance.\n\n**pharmaceutical product**  \nAny preparation for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient.\n\n**pilot-scale batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For example, for solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger; unless otherwise adequately justified.\n\n**primary batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product used in a stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf-life, as the case may be.\n\n**process robustness**  \nAbility of a process to tolerate variability of materials and changes of the process and equipment without negative impact on quality.\n\n**production batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product manufactured at production scale by using production equipment in a production facility as specified in the application.\n\n**quality**  \nThe suitability of either an active pharmaceutical ingredient or a pharmaceutical product for its intended use. This term includes such attributes as the identity, strength and purity.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2021, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "1a723ba4-6ce9-427c-8d68-dfb5a3f81bac": {"__data__": {"id_": "1a723ba4-6ce9-427c-8d68-dfb5a3f81bac", "embedding": null, "metadata": {"page_label": "126", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## quality target product profile (QTPP)\n\nA prospective summary of the quality characteristics of a finished pharmaceutical product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the finished pharmaceutical product.\n\n## stringent regulatory authority (SRA)\n\nFor the purpose of this document, a stringent regulatory authority (SRA) is the medicines regulatory authority in a country which is:\n\n- (a) a member of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (European Union, Japan and the United States of America); or (b) an ICH Observer, being the European Free Trade Association as represented by SwissMedic and Health Canada (as may be updated from time to time); or (c) a regulatory authority associated with an ICH member through a legally binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time);\n\n- only in relation to good manufacturing practices inspections: a medicines regulatory authority that is a member of the Pharmaceutical Inspection Co-operation Scheme as specified at http://www.picscheme.org.\n\n## therapeutic equivalence\n\nTwo pharmaceutical products are considered to be therapeutically equivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and after administration in the same molar dose, their effects, with respect to both efficacy and safety, are essentially the same when administered to patients by the same route under the conditions specified in the labelling. This can be demonstrated by appropriate bioequivalence studies, such as pharmacokinetic, pharmacodynamic, clinical or in vitro studies.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que aborda las especificaciones para preparaciones farmac\u00e9uticas. Se definen conceptos clave como el \"perfil de calidad del producto objetivo\" (QTPP), la \"autoridad reguladora estricta\" (SRA) y la \"equivalencia terap\u00e9utica\". El QTPP es un resumen prospectivo de las caracter\u00edsticas de calidad que un producto farmac\u00e9utico terminado debe alcanzar para garantizar su calidad, seguridad y eficacia. La SRA se refiere a las autoridades reguladoras de medicamentos en pa\u00edses que cumplen con ciertos est\u00e1ndares internacionales. La equivalencia terap\u00e9utica se refiere a la comparaci\u00f3n de productos farmac\u00e9uticos en t\u00e9rminos de eficacia y seguridad.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios que definen a una autoridad reguladora estricta (SRA) seg\u00fan el documento?**\n   - Respuesta: Una SRA es una autoridad reguladora de medicamentos en un pa\u00eds que es miembro de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH), un observador de la ICH, o una autoridad asociada a un miembro de la ICH a trav\u00e9s de un acuerdo de reconocimiento mutuo. Adem\u00e1s, en relaci\u00f3n con las inspecciones de buenas pr\u00e1cticas de fabricaci\u00f3n, debe ser miembro del Esquema de Cooperaci\u00f3n de Inspecci\u00f3n Farmac\u00e9utica.\n\n2. **\u00bfQu\u00e9 estudios son necesarios para demostrar la equivalencia terap\u00e9utica entre dos productos farmac\u00e9uticos?**\n   - Respuesta: La equivalencia terap\u00e9utica puede demostrarse mediante estudios de bioequivalencia apropiados, que pueden incluir estudios farmacocin\u00e9ticos, farmacodin\u00e1micos, cl\u00ednicos o in vitro.\n\n3. **\u00bfQu\u00e9 aspectos se consideran al definir el perfil de calidad del producto objetivo (QTPP) de un producto farmac\u00e9utico?**\n   - Respuesta: El QTPP es un resumen prospectivo que incluye las caracter\u00edsticas de calidad que se deben lograr en un producto farmac\u00e9utico terminado, teniendo en cuenta tanto la seguridad como la eficacia del producto.\n\nEstas preguntas y respuestas est\u00e1n dise\u00f1adas para proporcionar informaci\u00f3n espec\u00edfica que puede no estar f\u00e1cilmente disponible en otros documentos o fuentes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl Anexo 3 del documento de la OMS (Organizaci\u00f3n Mundial de la Salud) proporciona definiciones esenciales relacionadas con la equivalencia y calidad de los productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n1. **Equivalencia Farmac\u00e9utica**: Se refiere a productos que contienen la misma cantidad molar del mismo(s) ingrediente(s) activo(s) en la misma forma de dosificaci\u00f3n, cumplen con est\u00e1ndares comparables y est\u00e1n destinados a ser administrados por la misma v\u00eda. Se destaca que la equivalencia farmac\u00e9utica no garantiza equivalencia terap\u00e9utica.\n\n2. **Producto Farmac\u00e9utico**: Cualquier preparaci\u00f3n destinada a modificar o explorar sistemas fisiol\u00f3gicos o estados patol\u00f3gicos en humanos o animales, con el fin de beneficiar al receptor.\n\n3. **Lote a Escala Piloto**: Un lote fabricado que simula el proceso de producci\u00f3n a gran escala, generalmente siendo al menos una d\u00e9cima parte del tama\u00f1o de un lote de producci\u00f3n completo.\n\n4. **Lote Primario**: Lote utilizado en estudios de estabilidad para establecer per\u00edodos de rean\u00e1lisis o vida \u00fatil, cuyos datos se presentan en una solicitud de registro.\n\n5. **Robustez del Proceso**: Capacidad de un proceso para manejar variaciones en los materiales y cambios en el proceso y equipo sin afectar negativamente la calidad del producto.\n\n6. **Lote de Producci\u00f3n**: Lote fabricado a escala de producci\u00f3n utilizando equipos y instalaciones especificadas en la solicitud.\n\n7. **Calidad**: Se refiere a la idoneidad de un ingrediente activo o producto farmac\u00e9utico para su uso previsto, incluyendo atributos como identidad, potencia y pureza.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite el documento.\n- **Ingredientes Farmac\u00e9uticos Activos**: Sustancias que tienen un efecto terap\u00e9utico.\n- **Formas de Dosificaci\u00f3n**: M\u00e9todos en que se administran los medicamentos (tabletas, c\u00e1psulas, etc.).\n- **Estudios de Estabilidad**: Evaluaciones para determinar la duraci\u00f3n y condiciones de almacenamiento de un producto farmac\u00e9utico.\n\nEste resumen proporciona una visi\u00f3n general de los conceptos fundamentales que son cruciales para la regulaci\u00f3n y desarrollo de productos farmac\u00e9uticos, as\u00ed como su evaluaci\u00f3n en t\u00e9rminos de seguridad y eficacia.", "excerpt_keywords": "Keywords: pharmaceutical preparations, quality target product profile, stringent regulatory authority, therapeutic equivalence, bioequivalence studies"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c587bd7-fbc5-49da-b7f0-a9031035e859", "node_type": "4", "metadata": {"page_label": "126", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## quality target product profile (QTPP)\n\nA prospective summary of the quality characteristics of a finished pharmaceutical product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the finished pharmaceutical product.\n\n## stringent regulatory authority (SRA)\n\nFor the purpose of this document, a stringent regulatory authority (SRA) is the medicines regulatory authority in a country which is:\n\n- (a) a member of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (European Union, Japan and the United States of America); or (b) an ICH Observer, being the European Free Trade Association as represented by SwissMedic and Health Canada (as may be updated from time to time); or (c) a regulatory authority associated with an ICH member through a legally binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time);\n\n- only in relation to good manufacturing practices inspections: a medicines regulatory authority that is a member of the Pharmaceutical Inspection Co-operation Scheme as specified at http://www.picscheme.org.\n\n## therapeutic equivalence\n\nTwo pharmaceutical products are considered to be therapeutically equivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and after administration in the same molar dose, their effects, with respect to both efficacy and safety, are essentially the same when administered to patients by the same route under the conditions specified in the labelling. This can be demonstrated by appropriate bioequivalence studies, such as pharmacokinetic, pharmacodynamic, clinical or in vitro studies.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "184b137f7b507076444c8eb47991aa1afdd5863e8c3461771d58eb07b93dcfee", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## quality target product profile (QTPP)\n\nA prospective summary of the quality characteristics of a finished pharmaceutical product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the finished pharmaceutical product.\n\n## stringent regulatory authority (SRA)\n\nFor the purpose of this document, a stringent regulatory authority (SRA) is the medicines regulatory authority in a country which is:\n\n- (a) a member of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (European Union, Japan and the United States of America); or (b) an ICH Observer, being the European Free Trade Association as represented by SwissMedic and Health Canada (as may be updated from time to time); or (c) a regulatory authority associated with an ICH member through a legally binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time);\n\n- only in relation to good manufacturing practices inspections: a medicines regulatory authority that is a member of the Pharmaceutical Inspection Co-operation Scheme as specified at http://www.picscheme.org.\n\n## therapeutic equivalence\n\nTwo pharmaceutical products are considered to be therapeutically equivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and after administration in the same molar dose, their effects, with respect to both efficacy and safety, are essentially the same when administered to patients by the same route under the conditions specified in the labelling. This can be demonstrated by appropriate bioequivalence studies, such as pharmacokinetic, pharmacodynamic, clinical or in vitro studies.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1839, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "6744ab3b-c7cc-4f5c-886a-a49cdd6bf4a7": {"__data__": {"id_": "6744ab3b-c7cc-4f5c-886a-a49cdd6bf4a7", "embedding": null, "metadata": {"page_label": "127", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# References\n\n1. WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012, Annex 4 (WHO Technical Report Series, No. 970).\n\n2. Q6A: Specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999; http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q6A/Step4/Q6Astep4.pdf.\n\n3. The International Pharmacopoeia, 4th ed., Vol. 1. General notices; monographs for pharmaceutical substances (A\u2013O) and Vol. 2: Monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents. Geneva, World Health Organization, 2006, also available in CD-ROM format and online.\n\n   *The International Pharmacopoeia, 4th ed., First supplement.* Geneva, World Health Organization, 2008 (http://apps.who.int/phint/en/p/docf/).\n\n   *The International Pharmacopoeia, 4th ed., Second supplement,* 2011, available on CD-ROM.\n\n4. Prasad B et al. A new validated differential scanning calorimetric procedure for monitoring the less active R,S isomer of ethambutol dihydrochloride in bulk drug samples and anti-tuberculosis formulations. *Pharmacopeial Forum,* 2007, 33: 326-333.\n\n5. European pharmacopoeia, 7th ed. Strasbourg, European Directorate for the Quality of Medicines, 2010.\n\n6. Guidelines for registration of fixed-dose combination medicinal products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n7. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n8. M4: ICH Harmonised Tripartite Guideline \u2013 Organisation of the common technical document for the registration of pharmaceuticals for human use. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2004 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R3_Organisation/M4_R3__organisation.pdf).\n\n9. M4Q: ICH Harmonised Tripartite Guideline \u2013 The common technical document for the registration of pharmaceuticals for human use: quality. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2000.\n\n10. Q8: Pharmaceutical development. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf).\n\n11. Q9: Quality risk management. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2005 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento es el \"WHO Technical Report Series 970\", que incluye referencias sobre directrices y especificaciones para la presentaci\u00f3n de documentaci\u00f3n relacionada con productos farmac\u00e9uticos gen\u00e9ricos y multisource. Se mencionan varias gu\u00edas de la Organizaci\u00f3n Mundial de la Salud (OMS) y de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) que abordan aspectos de calidad, desarrollo farmac\u00e9utico, gesti\u00f3n de riesgos y requisitos de registro para productos farmac\u00e9uticos. Tambi\u00e9n se citan publicaciones relevantes, como la Farmacopea Internacional y la Farmacopea Europea.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las principales diferencias entre las gu\u00edas de la OMS y las de la ICH en relaci\u00f3n con la calidad de los productos farmac\u00e9uticos?**\n   - Esta pregunta busca una comparaci\u00f3n directa que no se aborda expl\u00edcitamente en el documento, pero que puede ser inferida a partir de las referencias.\n\n2. **\u00bfQu\u00e9 procedimientos espec\u00edficos se recomiendan para la validaci\u00f3n de m\u00e9todos anal\u00edticos en la evaluaci\u00f3n de is\u00f3meros de medicamentos, seg\u00fan el art\u00edculo de Prasad et al.?**\n   - Esta pregunta se centra en un estudio espec\u00edfico mencionado en el documento, que podr\u00eda no estar ampliamente disponible en otras fuentes.\n\n3. **\u00bfC\u00f3mo se define la \"intercambiabilidad\" en el contexto de los productos farmac\u00e9uticos multisource seg\u00fan las directrices de la OMS?**\n   - Esta pregunta busca una definici\u00f3n precisa que puede no estar claramente explicada en otras partes del documento o en otras fuentes.\n\n### Resumen de Nivel Superior\n\nEl \"WHO Technical Report Series 970\" proporciona un marco de referencia para la calidad y el registro de productos farmac\u00e9uticos gen\u00e9ricos y multisource. Incluye directrices sobre la presentaci\u00f3n de documentaci\u00f3n, especificaciones de calidad, y m\u00e9todos anal\u00edticos, as\u00ed como referencias a normativas internacionales. Este documento es crucial para asegurar que los productos farmac\u00e9uticos cumplan con los est\u00e1ndares necesarios para su aprobaci\u00f3n y uso en el mercado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Perfil de Calidad del Producto Objetivo (QTPP)**:\n   - Definici\u00f3n: Un resumen prospectivo de las caracter\u00edsticas de calidad que un producto farmac\u00e9utico terminado debe alcanzar para garantizar su calidad, seguridad y eficacia.\n\n2. **Autoridad Reguladora Estricta (SRA)**:\n   - Definici\u00f3n: Autoridad reguladora de medicamentos en un pa\u00eds que cumple con ciertos est\u00e1ndares internacionales.\n   - Criterios:\n     - Miembro de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) (ej. Uni\u00f3n Europea, Jap\u00f3n, EE. UU.).\n     - Observador de la ICH (ej. Asociaci\u00f3n Europea de Libre Comercio).\n     - Autoridad asociada a un miembro de la ICH mediante un acuerdo de reconocimiento mutuo (ej. Australia, Islandia, Liechtenstein, Noruega).\n     - En relaci\u00f3n con las inspecciones de buenas pr\u00e1cticas de fabricaci\u00f3n, debe ser miembro del Esquema de Cooperaci\u00f3n de Inspecci\u00f3n Farmac\u00e9utica.\n\n3. **Equivalencia Terap\u00e9utica**:\n   - Definici\u00f3n: Dos productos farmac\u00e9uticos son considerados equivalentes si son equivalentes farmac\u00e9uticos o alternativas farmac\u00e9uticas y, tras la administraci\u00f3n en la misma dosis molar, sus efectos en eficacia y seguridad son esencialmente los mismos.\n   - Demostraci\u00f3n: A trav\u00e9s de estudios de bioequivalencia, que pueden incluir estudios farmacocin\u00e9ticos, farmacodin\u00e1micos, cl\u00ednicos o in vitro.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable del documento.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Organizaci\u00f3n que establece est\u00e1ndares para la regulaci\u00f3n de productos farmac\u00e9uticos.\n- **Esquema de Cooperaci\u00f3n de Inspecci\u00f3n Farmac\u00e9utica**: Iniciativa que agrupa a autoridades reguladoras para asegurar buenas pr\u00e1cticas de fabricaci\u00f3n.\n\nEste resumen destaca los conceptos fundamentales y las entidades relevantes en el contexto de las especificaciones para preparaciones farmac\u00e9uticas seg\u00fan el informe de la OMS.", "excerpt_keywords": "Keywords: pharmaceutical quality, WHO guidelines, ICH standards, generic medicines, regulatory requirements"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2105e4e1-e23e-4a6d-8f0b-197296e45d91", "node_type": "4", "metadata": {"page_label": "127", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# References\n\n1. WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012, Annex 4 (WHO Technical Report Series, No. 970).\n\n2. Q6A: Specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999; http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q6A/Step4/Q6Astep4.pdf.\n\n3. The International Pharmacopoeia, 4th ed., Vol. 1. General notices; monographs for pharmaceutical substances (A\u2013O) and Vol. 2: Monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents. Geneva, World Health Organization, 2006, also available in CD-ROM format and online.\n\n   *The International Pharmacopoeia, 4th ed., First supplement.* Geneva, World Health Organization, 2008 (http://apps.who.int/phint/en/p/docf/).\n\n   *The International Pharmacopoeia, 4th ed., Second supplement,* 2011, available on CD-ROM.\n\n4. Prasad B et al. A new validated differential scanning calorimetric procedure for monitoring the less active R,S isomer of ethambutol dihydrochloride in bulk drug samples and anti-tuberculosis formulations. *Pharmacopeial Forum,* 2007, 33: 326-333.\n\n5. European pharmacopoeia, 7th ed. Strasbourg, European Directorate for the Quality of Medicines, 2010.\n\n6. Guidelines for registration of fixed-dose combination medicinal products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n7. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n8. M4: ICH Harmonised Tripartite Guideline \u2013 Organisation of the common technical document for the registration of pharmaceuticals for human use. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2004 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R3_Organisation/M4_R3__organisation.pdf).\n\n9. M4Q: ICH Harmonised Tripartite Guideline \u2013 The common technical document for the registration of pharmaceuticals for human use: quality. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2000.\n\n10. Q8: Pharmaceutical development. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf).\n\n11. Q9: Quality risk management. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2005 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "df13a7f71ef510c5beaca1a3feb3defe60c31847ec97d18d9e27ad23bead9d8d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# References\n\n1. WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012, Annex 4 (WHO Technical Report Series, No. 970).\n\n2. Q6A: Specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999; http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q6A/Step4/Q6Astep4.pdf.\n\n3. The International Pharmacopoeia, 4th ed., Vol. 1. General notices; monographs for pharmaceutical substances (A\u2013O) and Vol. 2: Monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents. Geneva, World Health Organization, 2006, also available in CD-ROM format and online.\n\n   *The International Pharmacopoeia, 4th ed., First supplement.* Geneva, World Health Organization, 2008 (http://apps.who.int/phint/en/p/docf/).\n\n   *The International Pharmacopoeia, 4th ed., Second supplement,* 2011, available on CD-ROM.\n\n4. Prasad B et al. A new validated differential scanning calorimetric procedure for monitoring the less active R,S isomer of ethambutol dihydrochloride in bulk drug samples and anti-tuberculosis formulations. *Pharmacopeial Forum,* 2007, 33: 326-333.\n\n5. European pharmacopoeia, 7th ed. Strasbourg, European Directorate for the Quality of Medicines, 2010.\n\n6. Guidelines for registration of fixed-dose combination medicinal products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n7. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n8. M4: ICH Harmonised Tripartite Guideline \u2013 Organisation of the common technical document for the registration of pharmaceuticals for human use. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2004 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R3_Organisation/M4_R3__organisation.pdf).\n\n9. M4Q: ICH Harmonised Tripartite Guideline \u2013 The common technical document for the registration of pharmaceuticals for human use: quality. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2000.\n\n10. Q8: Pharmaceutical development. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf).\n\n11. Q9: Quality risk management. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2005 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3442, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c6344b35-2f14-4950-945c-4987c7a7cac5": {"__data__": {"id_": "c6344b35-2f14-4950-945c-4987c7a7cac5", "embedding": null, "metadata": {"page_label": "128", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Forty-sixth report\n\n12. **Q10: Pharmaceutical quality system.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008 http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf.\n\n13. **Inactive ingredient guide.** US Food and Drug Administration http://www.accessdata.fda.gov/ scripts/cder/iig/index.cfm.\n\n14. Rowe RC, Sheskey PJ, Quinn ME, eds. **Handbook of pharmaceutical excipients, 6th ed.** London, Pharmaceutical Press, 2009.\n\n15. **Excipients in the label and package leaflet of medicinal products for human use.** Committee for Proprietary Medicinal Products, 2003 (CPMP/463/00Final).\n\n16. **Development of paediatric medicines: points to consider in pharmaceutical development.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report.* Geneva, World Health Organization, 2012, Annex 5 (WHO Technical Report Series, No. 970).\n\n17. **Containers \u2013 glass.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n18. **Glass containers for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 303\u2013307\n\n19. **Plastic containers and closures for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 308\u2013309.\n\n20. **Containers \u2013 plastic.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n21. **Elastomeric closures for injections.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007: 144\u2013145.\n\n22. **Rubber closures for containers.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 316\u2013317.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento es el \"Cuarenta y sexto informe\" de la Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Incluye referencias a gu\u00edas y manuales sobre sistemas de calidad farmac\u00e9utica, excipientes, y contenedores para productos farmac\u00e9uticos. Se mencionan normativas y documentos relevantes de la FDA, la Farmacopea de los Estados Unidos y la Farmacopea Europea, as\u00ed como consideraciones para el desarrollo de medicamentos pedi\u00e1tricos.\n\n### Preguntas\n\n1. **\u00bfQu\u00e9 documento de la Conferencia Internacional sobre Armonizaci\u00f3n se menciona en el informe y cu\u00e1l es su enfoque principal?**\n   - Respuesta: Se menciona el documento \"Q10: Pharmaceutical quality system\", que se centra en los requisitos t\u00e9cnicos para el registro de productos farmac\u00e9uticos para uso humano, publicado en 2008.\n\n2. **\u00bfCu\u00e1les son algunas de las consideraciones espec\u00edficas para el desarrollo de medicamentos pedi\u00e1tricos seg\u00fan el informe?**\n   - Respuesta: El informe incluye un anexo titulado \"Development of paediatric medicines: points to consider in pharmaceutical development\", que aborda aspectos clave en el desarrollo de medicamentos destinados a la poblaci\u00f3n pedi\u00e1trica.\n\n3. **\u00bfQu\u00e9 tipos de contenedores para productos farmac\u00e9uticos se discuten en el informe y qu\u00e9 normativas se citan para cada tipo?**\n   - Respuesta: Se discuten contenedores de vidrio y pl\u00e1stico, as\u00ed como cierres elastom\u00e9ricos y de goma. Se citan normativas de la Farmacopea de los Estados Unidos y la Farmacopea Europea para cada tipo de contenedor, especificando las ediciones y secciones relevantes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Directrices de la OMS**:\n   - Se mencionan las \"Gu\u00edas de la OMS sobre la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos gen\u00e9ricos\" y otros informes relevantes que establecen est\u00e1ndares de calidad y requisitos de registro.\n\n2. **Especificaciones de Calidad**:\n   - Referencias a documentos como Q6A, Q8 y Q9 de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) que abordan especificaciones, desarrollo farmac\u00e9utico y gesti\u00f3n de riesgos.\n\n3. **Farmacopeas**:\n   - Se citan la \"Farmacopea Internacional\" y la \"Farmacopea Europea\", que proporcionan monograf\u00edas y m\u00e9todos de an\u00e1lisis para sustancias farmac\u00e9uticas.\n\n4. **Intercambiabilidad de Productos**:\n   - Directrices sobre la intercambiabilidad de productos farmac\u00e9uticos multisource, destacando la importancia de establecer requisitos claros para su registro.\n\n5. **M\u00e9todos Anal\u00edticos**:\n   - Se menciona un estudio espec\u00edfico sobre un procedimiento de calorimetr\u00eda diferencial para monitorear is\u00f3meros de etambutol, lo que resalta la importancia de la validaci\u00f3n de m\u00e9todos anal\u00edticos en la evaluaci\u00f3n de medicamentos.\n\n6. **Publicaciones y Documentos**:\n   - Se listan varios documentos y gu\u00edas relevantes que son fundamentales para la regulaci\u00f3n y calidad de los productos farmac\u00e9uticos, incluyendo enlaces a recursos en l\u00ednea.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad en la regulaci\u00f3n de medicamentos y directrices de calidad.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Organizaci\u00f3n que establece est\u00e1ndares internacionales para la regulaci\u00f3n de productos farmac\u00e9uticos.\n- **Farmacopea Internacional**: Compendio de est\u00e1ndares de calidad para medicamentos.\n- **Farmacopea Europea**: Documento que establece normas para la calidad de medicamentos en Europa.\n- **Prasad B et al.**: Autores de un estudio sobre m\u00e9todos anal\u00edticos para is\u00f3meros de medicamentos.\n\nEste resumen destaca la importancia de las directrices y est\u00e1ndares internacionales en la regulaci\u00f3n y calidad de los productos farmac\u00e9uticos, as\u00ed como la necesidad de m\u00e9todos anal\u00edticos validados para asegurar la eficacia y seguridad de los medicamentos.", "excerpt_keywords": "Keywords: pharmaceutical quality, excipients, pediatric medicines, containers, regulatory guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54f6c785-bd93-4e5d-afa7-c140b98a27e1", "node_type": "4", "metadata": {"page_label": "128", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Forty-sixth report\n\n12. **Q10: Pharmaceutical quality system.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008 http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf.\n\n13. **Inactive ingredient guide.** US Food and Drug Administration http://www.accessdata.fda.gov/ scripts/cder/iig/index.cfm.\n\n14. Rowe RC, Sheskey PJ, Quinn ME, eds. **Handbook of pharmaceutical excipients, 6th ed.** London, Pharmaceutical Press, 2009.\n\n15. **Excipients in the label and package leaflet of medicinal products for human use.** Committee for Proprietary Medicinal Products, 2003 (CPMP/463/00Final).\n\n16. **Development of paediatric medicines: points to consider in pharmaceutical development.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report.* Geneva, World Health Organization, 2012, Annex 5 (WHO Technical Report Series, No. 970).\n\n17. **Containers \u2013 glass.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n18. **Glass containers for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 303\u2013307\n\n19. **Plastic containers and closures for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 308\u2013309.\n\n20. **Containers \u2013 plastic.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n21. **Elastomeric closures for injections.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007: 144\u2013145.\n\n22. **Rubber closures for containers.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 316\u2013317.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "b1748ff948d06f8aa2f440e6c9375a6b75e47f7a9ea27994c30b359b6d597515", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Forty-sixth report\n\n12. **Q10: Pharmaceutical quality system.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008 http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf.\n\n13. **Inactive ingredient guide.** US Food and Drug Administration http://www.accessdata.fda.gov/ scripts/cder/iig/index.cfm.\n\n14. Rowe RC, Sheskey PJ, Quinn ME, eds. **Handbook of pharmaceutical excipients, 6th ed.** London, Pharmaceutical Press, 2009.\n\n15. **Excipients in the label and package leaflet of medicinal products for human use.** Committee for Proprietary Medicinal Products, 2003 (CPMP/463/00Final).\n\n16. **Development of paediatric medicines: points to consider in pharmaceutical development.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report.* Geneva, World Health Organization, 2012, Annex 5 (WHO Technical Report Series, No. 970).\n\n17. **Containers \u2013 glass.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n18. **Glass containers for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 303\u2013307\n\n19. **Plastic containers and closures for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 308\u2013309.\n\n20. **Containers \u2013 plastic.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n21. **Elastomeric closures for injections.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007: 144\u2013145.\n\n22. **Rubber closures for containers.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 316\u2013317.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1862, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "24299a43-9dae-4a0f-accc-ad39c237b7dc": {"__data__": {"id_": "24299a43-9dae-4a0f-accc-ad39c237b7dc", "embedding": null, "metadata": {"page_label": "129", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 1\n\n## Examples of presenting quality attributes of active pharmaceutical ingredients\n\nPhysicochemical characteristics of the active pharmaceutical ingredient (API) that can influence manufacturing capability and the performance of the finished pharmaceutical product (FPP) should be tabulated and discussed, for example, as in the following tables.\n\n| pH (of the buffer) | Solubility (mg/ml) |\n|--------------------|--------------------|\n| 1.2                |                    |\n| 4.5                |                    |\n| 6.8                |                    |\n| pKa of API         |                    |\n\nMethod (compendial):\n\n### Particle size of API used in relevant laboratory and pilot-scale batches\n\n| Measured data (\u00b5m)\\<br/>\\<API batch no.> \\<FPP batch no.> (design) | Batch number (and use)\\<br/>\\<API batch no.> \\<FPP batch no.> (final laboratory) | Batch number (and use)\\<br/>Proposed acceptance range (\u00b5m)\\<br/>\\<API batch no.> \\<FPP batch no.> (stability) | Batch number (and use)\\<br/>\\<API batch no.> \\<FPP batch no.> (bioequivalence) | Batch number (and use) | |\n| - | - | - | - | - | - |\n| D 10 | | | | | |\n| D 50 | | | | | |\n| D 90 | | | | | |\n\n\n*Add rows as needed. Change data range as relevant.*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Informe T\u00e9cnico 970 incluye un ap\u00e9ndice que presenta ejemplos de c\u00f3mo se pueden presentar los atributos de calidad de los ingredientes farmac\u00e9uticos activos (API). Se enfatiza la importancia de las caracter\u00edsticas fisicoqu\u00edmicas del API, que pueden influir en la capacidad de fabricaci\u00f3n y el rendimiento del producto farmac\u00e9utico terminado (FPP). Se proporcionan tablas para registrar datos sobre el pH, la solubilidad y el tama\u00f1o de part\u00edcula del API en diferentes lotes, as\u00ed como su uso en estudios de estabilidad y bioequivalencia.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 atributos fisicoqu\u00edmicos del API se consideran importantes para la fabricaci\u00f3n y el rendimiento del FPP seg\u00fan el documento?**\n   - Respuesta: El documento menciona el pH del buffer, la solubilidad (mg/ml) y el pKa del API como atributos fisicoqu\u00edmicos importantes que pueden influir en la capacidad de fabricaci\u00f3n y el rendimiento del producto farmac\u00e9utico terminado.\n\n2. **\u00bfC\u00f3mo se debe presentar la informaci\u00f3n sobre el tama\u00f1o de part\u00edcula del API en los lotes de laboratorio y piloto seg\u00fan las directrices de la OMS?**\n   - Respuesta: La informaci\u00f3n sobre el tama\u00f1o de part\u00edcula del API debe presentarse en una tabla que incluya datos medidos (D10, D50, D90) junto con los n\u00fameros de lote y su uso en diferentes contextos, como laboratorio final, estabilidad y bioequivalencia.\n\n3. **\u00bfQu\u00e9 se sugiere hacer con las tablas presentadas en el ap\u00e9ndice en t\u00e9rminos de personalizaci\u00f3n y adaptaci\u00f3n?**\n   - Respuesta: Se sugiere que se pueden agregar filas seg\u00fan sea necesario y que se pueden cambiar los rangos de datos para que sean relevantes a las circunstancias espec\u00edficas de cada API y FPP.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl **Cuarenta y sexto informe** de la **Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas** aborda varios temas relevantes en el \u00e1mbito de la calidad farmac\u00e9utica y el desarrollo de medicamentos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n#### Temas Clave:\n1. **Sistema de Calidad Farmac\u00e9utica (Q10)**: Se menciona el documento de la Conferencia Internacional sobre Armonizaci\u00f3n que establece los requisitos t\u00e9cnicos para el registro de productos farmac\u00e9uticos.\n2. **Gu\u00eda de Excipientes Inactivos**: Referencia a la FDA sobre la regulaci\u00f3n de excipientes en productos farmac\u00e9uticos.\n3. **Desarrollo de Medicamentos Pedi\u00e1tricos**: Consideraciones espec\u00edficas para la formulaci\u00f3n y desarrollo de medicamentos dirigidos a la poblaci\u00f3n infantil.\n4. **Contenedores Farmac\u00e9uticos**: Discusi\u00f3n sobre diferentes tipos de contenedores (vidrio y pl\u00e1stico) y sus normativas asociadas, incluyendo cierres elastom\u00e9ricos y de goma.\n\n#### Entidades Mencionadas:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Publicador del informe.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Entidad que proporciona directrices sobre calidad farmac\u00e9utica.\n- **Administraci\u00f3n de Alimentos y Medicamentos de EE. UU. (FDA)**: Referenciada en relaci\u00f3n con la gu\u00eda de excipientes.\n- **Farmacopea de los Estados Unidos**: Cita de normativas sobre contenedores y cierres.\n- **Farmacopea Europea**: Referencias a normativas sobre contenedores y cierres para uso farmac\u00e9utico.\n\nEste informe es fundamental para entender las normativas y consideraciones en la calidad y desarrollo de productos farmac\u00e9uticos, especialmente en el contexto de la pediatr\u00eda y el uso de excipientes.", "excerpt_keywords": "Keywords: active pharmaceutical ingredients, physicochemical characteristics, manufacturing capability, finished pharmaceutical product, particle size"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "69bbb4d5-e909-4839-90eb-28083551b8d5", "node_type": "4", "metadata": {"page_label": "129", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 1\n\n## Examples of presenting quality attributes of active pharmaceutical ingredients\n\nPhysicochemical characteristics of the active pharmaceutical ingredient (API) that can influence manufacturing capability and the performance of the finished pharmaceutical product (FPP) should be tabulated and discussed, for example, as in the following tables.\n\n| pH (of the buffer) | Solubility (mg/ml) |\n|--------------------|--------------------|\n| 1.2                |                    |\n| 4.5                |                    |\n| 6.8                |                    |\n| pKa of API         |                    |\n\nMethod (compendial):\n\n### Particle size of API used in relevant laboratory and pilot-scale batches\n\n| Measured data (\u00b5m)\\<br/>\\<API batch no.> \\<FPP batch no.> (design) | Batch number (and use)\\<br/>\\<API batch no.> \\<FPP batch no.> (final laboratory) | Batch number (and use)\\<br/>Proposed acceptance range (\u00b5m)\\<br/>\\<API batch no.> \\<FPP batch no.> (stability) | Batch number (and use)\\<br/>\\<API batch no.> \\<FPP batch no.> (bioequivalence) | Batch number (and use) | |\n| - | - | - | - | - | - |\n| D 10 | | | | | |\n| D 50 | | | | | |\n| D 90 | | | | | |\n\n\n*Add rows as needed. Change data range as relevant.*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "1fd72b960f07df3a67e1b70dc7c455c210d4f3350b99bfa78eceed3660fd7285", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Appendix 1\n\n## Examples of presenting quality attributes of active pharmaceutical ingredients\n\nPhysicochemical characteristics of the active pharmaceutical ingredient (API) that can influence manufacturing capability and the performance of the finished pharmaceutical product (FPP) should be tabulated and discussed, for example, as in the following tables.\n\n| pH (of the buffer) | Solubility (mg/ml) |\n|--------------------|--------------------|\n| 1.2                |                    |\n| 4.5                |                    |\n| 6.8                |                    |\n| pKa of API         |                    |\n\nMethod (compendial):\n\n### Particle size of API used in relevant laboratory and pilot-scale batches\n\n| Measured data (\u00b5m)\\<br/>\\<API batch no.> \\<FPP batch no.> (design) | Batch number (and use)\\<br/>\\<API batch no.> \\<FPP batch no.> (final laboratory) | Batch number (and use)\\<br/>Proposed acceptance range (\u00b5m)\\<br/>\\<API batch no.> \\<FPP batch no.> (stability) | Batch number (and use)\\<br/>\\<API batch no.> \\<FPP batch no.> (bioequivalence) | Batch number (and use) | |\n| - | - | - | - | - | - |\n| D 10 | | | | | |\n| D 50 | | | | | |\n| D 90 | | | | | |\n\n\n*Add rows as needed. Change data range as relevant.*", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1237, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d0be2c9e-bc73-462c-9081-a083f1e48e3d": {"__data__": {"id_": "d0be2c9e-bc73-462c-9081-a083f1e48e3d", "embedding": null, "metadata": {"page_label": "130", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Method (compendial):\n\n### Apparent density of API used in relevant laboratory and pilot-scale batches\n\n| \\<API batch no.> \\<FPP batch no.> (design) | \\<API batch no.> \\<FPP batch no.> (final laboratory) | \\<API batch no.> \\<FPP batch no.> (stability) | \\<API batch no.> \\<FPP batch no.> (bioequivalence) | Proposed acceptance range (g/ml) |\n| - | - | - | - | - |\n| Bulk | | | | |\n| Tapped | | | | |\n\n\n## Method (compendial):\n\n| Stress Condition | Treatment | Observations |\n| - | - | - |\n| None | Initial values of the API | Assay: S1: *Insert as many rows as necessary* D1: *Insert as many rows as necessary* Total unspecified: Total impurities: |\n| Temperature | A thin layer of the API is kept at 80 \u00b0C for 4 weeks in a Petri dish (open system) with sampling once a week | Assay: S1: D1: Total unspecified: Total impurities: |\n\n\n*continues*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 par\u00e1metros se eval\u00faan en el m\u00e9todo de densidad aparente del API en lotes de laboratorio y escala piloto?**\n   - En el m\u00e9todo de densidad aparente del API, se eval\u00faan dos tipos de densidad: la densidad a granel (Bulk) y la densidad compactada (Tapped). Se registran los n\u00fameros de lote del API y del producto farmac\u00e9utico terminado (FPP) en diferentes etapas: dise\u00f1o, laboratorio final, estabilidad y bioequivalencia, junto con un rango de aceptaci\u00f3n propuesto en gramos por mililitro (g/ml).\n\n2. **\u00bfQu\u00e9 condiciones de estr\u00e9s se consideran en el m\u00e9todo compendial para evaluar la estabilidad del API?**\n   - En el m\u00e9todo compendial, se consideran condiciones de estr\u00e9s como la temperatura. Un tratamiento espec\u00edfico implica mantener una delgada capa del API a 80 \u00b0C durante 4 semanas en un plato de Petri (sistema abierto), con muestreo una vez por semana. Las observaciones incluyen el an\u00e1lisis de la pureza y las impurezas del API a lo largo del tiempo.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n se debe registrar en las observaciones durante el tratamiento del API bajo condiciones de estr\u00e9s?**\n   - Durante el tratamiento del API bajo condiciones de estr\u00e9s, se deben registrar los valores iniciales del API y los resultados del ensayo, que incluyen S1 (primer conjunto de datos) y D1 (segundo conjunto de datos). Tambi\u00e9n se debe documentar el total de impurezas no especificadas y el total de impurezas encontradas.\n\n### Resumen de nivel superior del contexto:\nEl documento se centra en los m\u00e9todos compendiales utilizados para evaluar la densidad aparente y la estabilidad de los ingredientes farmac\u00e9uticos activos (API) en diferentes etapas de producci\u00f3n. Se describen las condiciones de estr\u00e9s que se aplican al API, as\u00ed como los par\u00e1metros que se deben observar y registrar durante las pruebas de estabilidad. Esto es crucial para garantizar la calidad y la eficacia de los productos farmac\u00e9uticos.", "prev_section_summary": "### Resumen de los temas clave y entidades de la secci\u00f3n:\n\n1. **Atributos de Calidad de los Ingredientes Farmac\u00e9uticos Activos (API)**:\n   - Se destacan las caracter\u00edsticas fisicoqu\u00edmicas del API que son cruciales para la fabricaci\u00f3n y el rendimiento del producto farmac\u00e9utico terminado (FPP).\n\n2. **Caracter\u00edsticas Fisicoqu\u00edmicas**:\n   - **pH del buffer**: Se presentan valores espec\u00edficos (1.2, 4.5, 6.8) y el pKa del API.\n   - **Solubilidad**: Se menciona la necesidad de registrar la solubilidad en mg/ml.\n\n3. **Tama\u00f1o de Part\u00edcula**:\n   - Se proporciona un formato tabular para registrar el tama\u00f1o de part\u00edcula del API (D10, D50, D90) en diferentes lotes y contextos, como laboratorio, estabilidad y bioequivalencia.\n\n4. **Personalizaci\u00f3n de Tablas**:\n   - Se sugiere que las tablas pueden ser adaptadas a\u00f1adiendo filas y modificando los rangos de datos seg\u00fan las necesidades espec\u00edficas de cada API y FPP.\n\n5. **M\u00e9todo Compendial**:\n   - Se menciona la importancia de seguir m\u00e9todos estandarizados para la medici\u00f3n y presentaci\u00f3n de datos.\n\n### Entidades Clave:\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que tiene un efecto farmacol\u00f3gico.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que contiene el API.\n- **pH, Solubilidad, pKa**: Atributos fisicoqu\u00edmicos relevantes.\n- **D10, D50, D90**: Medidas del tama\u00f1o de part\u00edcula del API.\n\nEste resumen encapsula los elementos esenciales del ap\u00e9ndice, destacando la importancia de los atributos de calidad en la industria farmac\u00e9utica y la necesidad de una presentaci\u00f3n clara y adaptable de los datos.", "excerpt_keywords": "Keywords: API, FPP, compendial methods, stability testing, apparent density"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3159bb96-360a-4dd3-930d-90d1bd0a30d6", "node_type": "4", "metadata": {"page_label": "130", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Method (compendial):\n\n### Apparent density of API used in relevant laboratory and pilot-scale batches\n\n| \\<API batch no.> \\<FPP batch no.> (design) | \\<API batch no.> \\<FPP batch no.> (final laboratory) | \\<API batch no.> \\<FPP batch no.> (stability) | \\<API batch no.> \\<FPP batch no.> (bioequivalence) | Proposed acceptance range (g/ml) |\n| - | - | - | - | - |\n| Bulk | | | | |\n| Tapped | | | | |\n\n\n## Method (compendial):\n\n| Stress Condition | Treatment | Observations |\n| - | - | - |\n| None | Initial values of the API | Assay: S1: *Insert as many rows as necessary* D1: *Insert as many rows as necessary* Total unspecified: Total impurities: |\n| Temperature | A thin layer of the API is kept at 80 \u00b0C for 4 weeks in a Petri dish (open system) with sampling once a week | Assay: S1: D1: Total unspecified: Total impurities: |\n\n\n*continues*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "301df11f0bbc585358674239131d13687681ffedb3b1f4756af597fd7b4d9425", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Method (compendial):\n\n### Apparent density of API used in relevant laboratory and pilot-scale batches\n\n| \\<API batch no.> \\<FPP batch no.> (design) | \\<API batch no.> \\<FPP batch no.> (final laboratory) | \\<API batch no.> \\<FPP batch no.> (stability) | \\<API batch no.> \\<FPP batch no.> (bioequivalence) | Proposed acceptance range (g/ml) |\n| - | - | - | - | - |\n| Bulk | | | | |\n| Tapped | | | | |\n\n\n## Method (compendial):\n\n| Stress Condition | Treatment | Observations |\n| - | - | - |\n| None | Initial values of the API | Assay: S1: *Insert as many rows as necessary* D1: *Insert as many rows as necessary* Total unspecified: Total impurities: |\n| Temperature | A thin layer of the API is kept at 80 \u00b0C for 4 weeks in a Petri dish (open system) with sampling once a week | Assay: S1: D1: Total unspecified: Total impurities: |\n\n\n*continues*", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 920, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ab278607-253c-4e06-b01a-eea4dbed8d61": {"__data__": {"id_": "ab278607-253c-4e06-b01a-eea4dbed8d61", "embedding": null, "metadata": {"page_label": "131", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "\n| Stress Condition | Treatment | Observations |\n| - | - | - |\n| Humidity | A thin layer of the API is kept at 40 \u00b0C / 100% relative humidity for 4 weeks in a Petri dish (open system) with sampling once a fortnight | Assay: S1: D1: Total unspecified: Total impurities: |\n| Oxidation | Oxygen is bubbled slowly through the oxygen-saturated aqueous solution/suspension (under constant mixing) of the API for 24 hours with sampling every 8 hours | Assay: S1: D1: Total unspecified: Total impurities: |\n\n\nS1, S2, etc., are synthesis impurities (as in API specifications).  \nD1, D2, etc., are degradation products.\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Technical Report Series 970) presenta un estudio sobre la estabilidad de un principio activo (API) bajo diferentes condiciones de estr\u00e9s, como la humedad y la oxidaci\u00f3n. Se describen los tratamientos aplicados, que incluyen mantener el API en condiciones espec\u00edficas de temperatura y humedad, as\u00ed como la exposici\u00f3n a ox\u00edgeno. Se realizan muestreos peri\u00f3dicos para evaluar la presencia de impurezas de s\u00edntesis (S1, S2, etc.) y productos de degradaci\u00f3n (D1, D2, etc.).\n\n### Preguntas\n1. **\u00bfQu\u00e9 condiciones espec\u00edficas de temperatura y humedad se utilizan para evaluar la estabilidad del API en el estudio?**\n   - Respuesta: Se mantiene una capa del API a 40 \u00b0C y 100% de humedad relativa durante 4 semanas en un plato de Petri.\n\n2. **\u00bfCon qu\u00e9 frecuencia se realizan los muestreos durante el tratamiento de oxidaci\u00f3n del API?**\n   - Respuesta: Se realizan muestreos cada 8 horas durante un tratamiento de 24 horas en el que se burbujea ox\u00edgeno a trav\u00e9s de una soluci\u00f3n/suspensi\u00f3n acuosa saturada de ox\u00edgeno del API.\n\n3. **\u00bfQu\u00e9 tipos de impurezas se analizan en el estudio y c\u00f3mo se clasifican?**\n   - Respuesta: Se analizan impurezas de s\u00edntesis (S1, S2, etc.) y productos de degradaci\u00f3n (D1, D2, etc.), que se reportan en los resultados de los ensayos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: El documento es parte de un informe del Comit\u00e9 de Expertos de la Organizaci\u00f3n Mundial de la Salud (OMS) sobre especificaciones para preparaciones farmac\u00e9uticas.\n\n2. **M\u00e9todos Compendiales**: Se describen m\u00e9todos estandarizados para evaluar la densidad aparente y la estabilidad de los ingredientes farmac\u00e9uticos activos (API).\n\n3. **Densidad Aparente del API**:\n   - **Tipos de Densidad**: Se eval\u00faan dos tipos de densidad: \n     - **Densidad a Granel (Bulk)**: Medida de la densidad del API en su estado suelto.\n     - **Densidad Compactada (Tapped)**: Medida de la densidad del API despu\u00e9s de ser compactado.\n   - **Registro de Datos**: Se requiere el registro de n\u00fameros de lote del API y del producto farmac\u00e9utico terminado (FPP) en diferentes etapas (dise\u00f1o, laboratorio final, estabilidad, bioequivalencia) y un rango de aceptaci\u00f3n propuesto en gramos por mililitro (g/ml).\n\n4. **Condiciones de Estr\u00e9s para Evaluaci\u00f3n de Estabilidad**:\n   - **Condiciones Consideradas**: Se menciona el estr\u00e9s t\u00e9rmico como una condici\u00f3n de evaluaci\u00f3n.\n   - **Tratamiento**: Un tratamiento espec\u00edfico implica mantener una delgada capa del API a 80 \u00b0C durante 4 semanas en un plato de Petri, con muestreo semanal.\n   - **Observaciones**: Se deben registrar los valores iniciales del API y los resultados del ensayo, incluyendo datos sobre pureza y total de impurezas.\n\n5. **Importancia de la Evaluaci\u00f3n**: La evaluaci\u00f3n de la densidad y estabilidad del API es crucial para garantizar la calidad y eficacia de los productos farmac\u00e9uticos.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable del documento.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia cuya densidad y estabilidad se eval\u00faan.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que contiene el API.\n- **Condiciones de Estr\u00e9s**: Factores como temperatura que afectan la estabilidad del API. \n\nEste resumen destaca los aspectos fundamentales del documento, centr\u00e1ndose en los m\u00e9todos de evaluaci\u00f3n de la calidad de los ingredientes farmac\u00e9uticos activos.", "excerpt_keywords": "Keywords: API, stability, humidity, oxidation, impurities"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ec6a0bf9-fa5d-49c4-8d80-2e465d447d0e", "node_type": "4", "metadata": {"page_label": "131", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "\n| Stress Condition | Treatment | Observations |\n| - | - | - |\n| Humidity | A thin layer of the API is kept at 40 \u00b0C / 100% relative humidity for 4 weeks in a Petri dish (open system) with sampling once a fortnight | Assay: S1: D1: Total unspecified: Total impurities: |\n| Oxidation | Oxygen is bubbled slowly through the oxygen-saturated aqueous solution/suspension (under constant mixing) of the API for 24 hours with sampling every 8 hours | Assay: S1: D1: Total unspecified: Total impurities: |\n\n\nS1, S2, etc., are synthesis impurities (as in API specifications).  \nD1, D2, etc., are degradation products.\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "a54d2f3811ad315f631257cac7a808ca812aae6d81804243836100ae68684889", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "| Stress Condition | Treatment | Observations |\n| - | - | - |\n| Humidity | A thin layer of the API is kept at 40 \u00b0C / 100% relative humidity for 4 weeks in a Petri dish (open system) with sampling once a fortnight | Assay: S1: D1: Total unspecified: Total impurities: |\n| Oxidation | Oxygen is bubbled slowly through the oxygen-saturated aqueous solution/suspension (under constant mixing) of the API for 24 hours with sampling every 8 hours | Assay: S1: D1: Total unspecified: Total impurities: |\n\n\nS1, S2, etc., are synthesis impurities (as in API specifications).  \nD1, D2, etc., are degradation products.", "mimetype": "text/plain", "start_char_idx": 1, "end_char_idx": 609, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "5550e6d3-2f8d-4930-834f-79ddbf9b1ebe": {"__data__": {"id_": "5550e6d3-2f8d-4930-834f-79ddbf9b1ebe", "embedding": null, "metadata": {"page_label": "132", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 2\n\n## Information on development batches\n\n**Table 1**  \nScreening laboratory batches with different proportions of excipients to match comparator dissolution\n\n| Ingredients\\<br/>Grams | Lab01\\<br/>% | Lab01\\<br/>Lab02\\<br/>Grams | Lab02\\<br/>Lab03\\<br/>% | Lab03\\<br/>Lab04\\<br/>Grams | Lab04\\<br/>% | Grams | % | |\n| - | - | - | - | - | - | - | - | - |\n| active pharmaceutical ingredient (API) 1 | | | | | | | | |\n| API 2 | | | | | | | | |\n| API 3 | | | | | | | | |\n| Excipient 1 | | | | | | | | |\n| Excipient 2 | | | | | | | | |\n| Excipient 3 | | | | | | | | |\n| Excipient 4 | | | | | | | | |\n| Excipient 5 | | | | | | | | |\n| Dissolution, % at pH \u2026 | | | | | | | | |\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento \"WHO - Technical Report Series 970\" incluye un ap\u00e9ndice que proporciona informaci\u00f3n sobre lotes de desarrollo de productos farmac\u00e9uticos. En particular, se presenta una tabla que detalla las proporciones de excipientes utilizados en diferentes lotes de laboratorio para igualar la disoluci\u00f3n de un comparador. La tabla incluye ingredientes activos y excipientes, as\u00ed como datos sobre la disoluci\u00f3n en diferentes condiciones.\n\n### Preguntas\n1. **\u00bfQu\u00e9 ingredientes activos y excipientes se est\u00e1n evaluando en los lotes de laboratorio seg\u00fan la tabla presentada en el ap\u00e9ndice?**\n   - Esta pregunta busca identificar los componentes espec\u00edficos que se est\u00e1n utilizando en el desarrollo de los lotes, lo cual es crucial para entender la formulaci\u00f3n del producto.\n\n2. **\u00bfC\u00f3mo se comparan las proporciones de excipientes entre los diferentes laboratorios seg\u00fan la tabla?**\n   - Esta pregunta se centra en las diferencias en las formulaciones entre los laboratorios, lo que puede ser relevante para evaluar la consistencia y la eficacia de los lotes desarrollados.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n se proporciona sobre la disoluci\u00f3n de los lotes en diferentes pH, y por qu\u00e9 es importante esta informaci\u00f3n en el desarrollo de productos farmac\u00e9uticos?**\n   - Esta pregunta busca profundizar en la importancia de los datos de disoluci\u00f3n en el contexto del desarrollo farmac\u00e9utico, lo que puede influir en la biodisponibilidad y la eficacia del medicamento.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl contenido extra\u00eddo del documento de la OMS (Technical Report Series 970) se centra en la evaluaci\u00f3n de la estabilidad de un principio activo (API) bajo condiciones de estr\u00e9s espec\u00edficas. Los temas clave incluyen:\n\n1. **Condiciones de Estr\u00e9s**:\n   - **Humedad**: Se mantiene el API a 40 \u00b0C y 100% de humedad relativa durante 4 semanas en un sistema abierto (plato de Petri).\n   - **Oxidaci\u00f3n**: Se introduce ox\u00edgeno en una soluci\u00f3n acuosa saturada de ox\u00edgeno del API durante 24 horas, con agitaci\u00f3n constante.\n\n2. **Muestreo**:\n   - En la prueba de humedad, se realiza un muestreo cada dos semanas.\n   - En la prueba de oxidaci\u00f3n, se realizan muestreos cada 8 horas.\n\n3. **An\u00e1lisis de Impurezas**:\n   - Se analizan impurezas de s\u00edntesis (designadas como S1, S2, etc.) y productos de degradaci\u00f3n (designados como D1, D2, etc.).\n   - Los resultados de los ensayos incluyen la evaluaci\u00f3n de impurezas totales y productos no especificados.\n\n### Entidades Clave\n- **API (Principio Activo)**: Sustancia cuyo comportamiento se estudia bajo condiciones de estr\u00e9s.\n- **Condiciones de Estr\u00e9s**: Humedad y oxidaci\u00f3n.\n- **M\u00e9todos de Muestreo**: Muestreo cada 8 horas y cada dos semanas.\n- **Clasificaci\u00f3n de Impurezas**: Impurezas de s\u00edntesis (S1, S2, etc.) y productos de degradaci\u00f3n (D1, D2, etc.).\n\nEste resumen proporciona una visi\u00f3n general de los m\u00e9todos y objetivos del estudio sobre la estabilidad del API, as\u00ed como la clasificaci\u00f3n de los compuestos analizados.", "excerpt_keywords": "Keywords: pharmaceutical development, excipients, dissolution testing, active pharmaceutical ingredients, laboratory batches"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ac100f0d-cbf6-4a98-ab6f-0f592ba87c58", "node_type": "4", "metadata": {"page_label": "132", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 2\n\n## Information on development batches\n\n**Table 1**  \nScreening laboratory batches with different proportions of excipients to match comparator dissolution\n\n| Ingredients\\<br/>Grams | Lab01\\<br/>% | Lab01\\<br/>Lab02\\<br/>Grams | Lab02\\<br/>Lab03\\<br/>% | Lab03\\<br/>Lab04\\<br/>Grams | Lab04\\<br/>% | Grams | % | |\n| - | - | - | - | - | - | - | - | - |\n| active pharmaceutical ingredient (API) 1 | | | | | | | | |\n| API 2 | | | | | | | | |\n| API 3 | | | | | | | | |\n| Excipient 1 | | | | | | | | |\n| Excipient 2 | | | | | | | | |\n| Excipient 3 | | | | | | | | |\n| Excipient 4 | | | | | | | | |\n| Excipient 5 | | | | | | | | |\n| Dissolution, % at pH \u2026 | | | | | | | | |\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "2fc649d1f881b07258883962a8f9a39d27608fb5358f9d324eaa610b12818846", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Appendix 2\n\n## Information on development batches\n\n**Table 1**  \nScreening laboratory batches with different proportions of excipients to match comparator dissolution\n\n| Ingredients\\<br/>Grams | Lab01\\<br/>% | Lab01\\<br/>Lab02\\<br/>Grams | Lab02\\<br/>Lab03\\<br/>% | Lab03\\<br/>Lab04\\<br/>Grams | Lab04\\<br/>% | Grams | % | |\n| - | - | - | - | - | - | - | - | - |\n| active pharmaceutical ingredient (API) 1 | | | | | | | | |\n| API 2 | | | | | | | | |\n| API 3 | | | | | | | | |\n| Excipient 1 | | | | | | | | |\n| Excipient 2 | | | | | | | | |\n| Excipient 3 | | | | | | | | |\n| Excipient 4 | | | | | | | | |\n| Excipient 5 | | | | | | | | |\n| Dissolution, % at pH \u2026 | | | | | | | | |", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 680, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "43875ca6-a304-4b9b-9232-223bf97212d5": {"__data__": {"id_": "43875ca6-a304-4b9b-9232-223bf97212d5", "embedding": null, "metadata": {"page_label": "133", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Table 2\nExample table for developmental multipoint dissolution profiles (hypothetical example \u2013 Ph. Int., paddle, 75 rpm, 900 ml)\n\n| Time (min) | Percentage API dissolved | Percentage API dissolved | Percentage API dissolved |\n|------------|--------------------------|--------------------------|--------------------------|\n|            | pH 1.2 buffer            | pH 4.5 buffer            | pH 6.8 buffer            |\n| 5          |                          |                          |                          |\n| 10         |                          |                          |                          |\n| 15         |                          |                          |                          |\n| 20         |                          |                          |                          |\n| 30         |                          |                          |                          |\n| 45         |                          |                          |                          |\n| 60         |                          |                          |                          |\n| 90         |                          |                          |                          |\n\nRepeat the table as needed, for example, for comparator product and development batch chosen for scale-up.\n\nWhen comparing dissolution profiles of products, for example, comparator and test products or different strengths of the same product, the dissolution conditions and sampling intervals must be the same.\n\n**Graphical presentation and summary evaluation of the results of comparative dissolution studies of the test (samples taken from the bioequivalence batch no. \u2026) and comparator products:**", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) presenta un ejemplo de tabla para perfiles de disoluci\u00f3n multipunto en el desarrollo de productos farmac\u00e9uticos. Se menciona la importancia de mantener condiciones de disoluci\u00f3n y intervalos de muestreo consistentes al comparar perfiles de disoluci\u00f3n de productos, como productos de referencia y productos en desarrollo. La tabla incluye tiempos espec\u00edficos y porcentajes de API (ingrediente farmac\u00e9utico activo) disueltos en diferentes buffers (pH 1.2, 4.5 y 6.8). Tambi\u00e9n se sugiere que se repita la tabla para productos comparadores y lotes de desarrollo seleccionados para escalado.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 condiciones de disoluci\u00f3n se deben mantener al comparar perfiles de disoluci\u00f3n de productos farmac\u00e9uticos?**\n   - Las condiciones de disoluci\u00f3n y los intervalos de muestreo deben ser los mismos al comparar perfiles de disoluci\u00f3n de productos, como productos comparadores y productos de prueba o diferentes concentraciones del mismo producto.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n se debe incluir en la tabla de perfiles de disoluci\u00f3n multipunto seg\u00fan el ejemplo proporcionado?**\n   - La tabla debe incluir el tiempo en minutos y el porcentaje de API disuelto en diferentes buffers (pH 1.2, 4.5 y 6.8) en intervalos de tiempo espec\u00edficos (5, 10, 15, 20, 30, 45, 60 y 90 minutos).\n\n3. **\u00bfCu\u00e1l es el prop\u00f3sito de repetir la tabla de perfiles de disoluci\u00f3n en el contexto del desarrollo farmac\u00e9utico?**\n   - La tabla debe repetirse para incluir datos de productos comparadores y lotes de desarrollo seleccionados para escalado, lo que permite una evaluaci\u00f3n comparativa de la disoluci\u00f3n entre diferentes formulaciones y condiciones de prueba.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl ap\u00e9ndice 2 del documento \"WHO - Technical Report Series 970\" se centra en la informaci\u00f3n sobre lotes de desarrollo de productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n#### Temas Clave:\n1. **Desarrollo de Lotes**: Se discuten los lotes de laboratorio que se est\u00e1n evaluando para determinar la formulaci\u00f3n adecuada de un producto farmac\u00e9utico.\n2. **Proporciones de Excipientes**: La tabla presenta diferentes proporciones de excipientes utilizadas en varios laboratorios para igualar la disoluci\u00f3n de un comparador, lo que es esencial para la formulaci\u00f3n del medicamento.\n3. **Dissoluci\u00f3n**: Se incluye informaci\u00f3n sobre la disoluci\u00f3n de los lotes en diferentes condiciones de pH, lo que es crucial para evaluar la biodisponibilidad y eficacia del producto.\n\n#### Entidades:\n- **Ingredientes Activos**: Se mencionan varios ingredientes activos (API 1, API 2, API 3) que son componentes clave en la formulaci\u00f3n del medicamento.\n- **Excipientes**: Se listan varios excipientes (Excipient 1, Excipient 2, Excipient 3, Excipient 4, Excipient 5) que se utilizan en las formulaciones.\n- **Laboratorios**: Se hace referencia a diferentes laboratorios (Lab01, Lab02, Lab03, Lab04) que est\u00e1n involucrados en el desarrollo y evaluaci\u00f3n de los lotes.\n\nEste resumen destaca la importancia de la formulaci\u00f3n y la evaluaci\u00f3n de la disoluci\u00f3n en el desarrollo de productos farmac\u00e9uticos, as\u00ed como los componentes espec\u00edficos involucrados en este proceso.", "excerpt_keywords": "Keywords: dissolution profiles, pharmaceutical development, bioequivalence, API dissolution, comparative studies"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "42611fbf-9e27-4460-97ab-f140e973c97f", "node_type": "4", "metadata": {"page_label": "133", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Table 2\nExample table for developmental multipoint dissolution profiles (hypothetical example \u2013 Ph. Int., paddle, 75 rpm, 900 ml)\n\n| Time (min) | Percentage API dissolved | Percentage API dissolved | Percentage API dissolved |\n|------------|--------------------------|--------------------------|--------------------------|\n|            | pH 1.2 buffer            | pH 4.5 buffer            | pH 6.8 buffer            |\n| 5          |                          |                          |                          |\n| 10         |                          |                          |                          |\n| 15         |                          |                          |                          |\n| 20         |                          |                          |                          |\n| 30         |                          |                          |                          |\n| 45         |                          |                          |                          |\n| 60         |                          |                          |                          |\n| 90         |                          |                          |                          |\n\nRepeat the table as needed, for example, for comparator product and development batch chosen for scale-up.\n\nWhen comparing dissolution profiles of products, for example, comparator and test products or different strengths of the same product, the dissolution conditions and sampling intervals must be the same.\n\n**Graphical presentation and summary evaluation of the results of comparative dissolution studies of the test (samples taken from the bioequivalence batch no. \u2026) and comparator products:**", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4c12704c2dbc16460d7649179e92ca88f4ec3ad065cd0b534ce5886331126679", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Table 2\nExample table for developmental multipoint dissolution profiles (hypothetical example \u2013 Ph. Int., paddle, 75 rpm, 900 ml)\n\n| Time (min) | Percentage API dissolved | Percentage API dissolved | Percentage API dissolved |\n|------------|--------------------------|--------------------------|--------------------------|\n|            | pH 1.2 buffer            | pH 4.5 buffer            | pH 6.8 buffer            |\n| 5          |                          |                          |                          |\n| 10         |                          |                          |                          |\n| 15         |                          |                          |                          |\n| 20         |                          |                          |                          |\n| 30         |                          |                          |                          |\n| 45         |                          |                          |                          |\n| 60         |                          |                          |                          |\n| 90         |                          |                          |                          |\n\nRepeat the table as needed, for example, for comparator product and development batch chosen for scale-up.\n\nWhen comparing dissolution profiles of products, for example, comparator and test products or different strengths of the same product, the dissolution conditions and sampling intervals must be the same.\n\n**Graphical presentation and summary evaluation of the results of comparative dissolution studies of the test (samples taken from the bioequivalence batch no. \u2026) and comparator products:**", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1690, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "25abcf89-fe4a-4276-8f60-1e1726783f01": {"__data__": {"id_": "25abcf89-fe4a-4276-8f60-1e1726783f01", "embedding": null, "metadata": {"page_label": "134", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto del documento \"WHO - Technical Report Series 970\":\n\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentadas en el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda no estar disponible en otros documentos o res\u00famenes.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en el estudio presentado en el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta se centra en las t\u00e9cnicas y enfoques utilizados en la investigaci\u00f3n, lo que puede ser crucial para entender la validez y aplicabilidad de los resultados.\n\n3. **\u00bfC\u00f3mo se relaciona el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS con otros informes previos en la misma serie?**\n   - Esta pregunta busca establecer conexiones y comparaciones entre diferentes informes, lo que puede proporcionar una visi\u00f3n m\u00e1s amplia del desarrollo de la investigaci\u00f3n en el \u00e1rea tratada.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica y recomendaciones para pol\u00edticas de salud. El Informe 46 en particular podr\u00eda contener hallazgos significativos, metodolog\u00edas de investigaci\u00f3n y recomendaciones que impacten en la pr\u00e1ctica de la salud p\u00fablica a nivel global.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Perfiles de Disoluci\u00f3n Multipunto**: Se presenta un ejemplo de tabla para registrar los perfiles de disoluci\u00f3n multipunto de productos farmac\u00e9uticos, destacando la importancia de evaluar la disoluci\u00f3n en diferentes condiciones de pH (1.2, 4.5 y 6.8).\n\n2. **Condiciones de Disoluci\u00f3n**: Se enfatiza que al comparar perfiles de disoluci\u00f3n de productos (como productos de prueba y productos comparadores), es crucial mantener las mismas condiciones de disoluci\u00f3n y los mismos intervalos de muestreo.\n\n3. **Intervalos de Tiempo**: La tabla incluye intervalos de tiempo espec\u00edficos (5, 10, 15, 20, 30, 45, 60 y 90 minutos) para medir el porcentaje de ingrediente farmac\u00e9utico activo (API) disuelto.\n\n4. **Repetici\u00f3n de la Tabla**: Se sugiere que la tabla se repita para incluir datos de productos comparadores y lotes de desarrollo seleccionados para escalado, lo que permite una evaluaci\u00f3n comparativa m\u00e1s completa.\n\n5. **Evaluaci\u00f3n Gr\u00e1fica**: Se menciona la necesidad de una presentaci\u00f3n gr\u00e1fica y una evaluaci\u00f3n resumida de los resultados de los estudios de disoluci\u00f3n comparativa entre los productos de prueba y los productos comparadores.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad del documento.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Componente clave en la evaluaci\u00f3n de disoluci\u00f3n.\n- **Buffers**: Soluciones utilizadas en las pruebas de disoluci\u00f3n (pH 1.2, 4.5, 6.8).\n- **Productos Comparadores y de Prueba**: Tipos de productos farmac\u00e9uticos en estudio.\n- **Lotes de Desarrollo**: Referencia a las formulaciones en desarrollo que se est\u00e1n evaluando.\n\nEste resumen destaca la estructura y los elementos esenciales del contenido relacionado con los perfiles de disoluci\u00f3n en el contexto del desarrollo farmac\u00e9utico.", "excerpt_keywords": "Keywords: OMS, Informe 46, disoluci\u00f3n, farmac\u00e9uticos, salud p\u00fablica"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a07d034b-4d9d-4cc0-8cd9-217e47bc64ec", "node_type": "4", "metadata": {"page_label": "134", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "a0cfa8042d4e678e02c048f2e05fbb00a1219abc45eab30045c460e24f875f0d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "0ce96b3e-5784-4f06-9825-b55e7ad9e8b2": {"__data__": {"id_": "0ce96b3e-5784-4f06-9825-b55e7ad9e8b2", "embedding": null, "metadata": {"page_label": "135", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n**Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part**\n\n## 1. Introduction\n1.1 Background  \n1.2 Objectives  \n1.3 Scope  \n1.4 General principles  \n1.5 Guidance on format  \n\n## 2. Glossary\n\n## 3. Quality summaries\n3.1 Module 2.3: Quality overall summary \u2013 product dossiers (QOS-PD)  \n3.2 Module 1.4.2: Quality information summary (QIS)  \n\n## 4. Module 3: Quality\n4.1 Table of contents of Module 3  \n4.2 Body of data  \n    3.2.S Drug substance (or active pharmaceutical ingredient (API))  \n    3.2.P Drug product (or finished pharmaceutical product (FPP))  \n    3.2.A Appendices  \n    3.2.R Regional information  \n4.3 Literature references  \n\n## References\n\n## Appendix 1\nRecommendations for conducting and assessing comparative dissolution profiles  \n\n## Appendix 2\nProduct quality review requirements for *established multisource products*  \n\n----\n\n| Section | Page |\n|---------|------|\n| 1. Introduction | 122 |\n| 2. Glossary | 125 |\n| 3. Quality summaries | 128 |\n| 4. Module 3: Quality | 129 |\n| References | 189 |\n| Appendix 1 | 193 |\n| Appendix 2 | 195 |", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder espec\u00edficamente con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento es una gu\u00eda de la Organizaci\u00f3n Mundial de la Salud (OMS) sobre la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos gen\u00e9ricos en el marco del Programa de Precalificaci\u00f3n de Medicamentos. Se centra en la parte de calidad y detalla los m\u00f3dulos y secciones que deben incluirse en la documentaci\u00f3n, as\u00ed como las recomendaciones para la evaluaci\u00f3n de perfiles de disoluci\u00f3n y los requisitos de revisi\u00f3n de calidad para productos multisource establecidos.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son los m\u00f3dulos espec\u00edficos que se deben incluir en la documentaci\u00f3n de calidad para productos farmac\u00e9uticos gen\u00e9ricos seg\u00fan la gu\u00eda de la OMS?**\n   - Respuesta: La gu\u00eda menciona varios m\u00f3dulos, incluyendo el M\u00f3dulo 2.3 (Quality overall summary \u2013 product dossiers) y el M\u00f3dulo 1.4.2 (Quality information summary), as\u00ed como el M\u00f3dulo 3 que abarca el contenido del cuerpo de datos, que incluye informaci\u00f3n sobre la sustancia activa (API) y el producto terminado (FPP).\n\n2. **\u00bfQu\u00e9 secciones se recomiendan para la evaluaci\u00f3n de perfiles de disoluci\u00f3n comparativa en productos farmac\u00e9uticos gen\u00e9ricos?**\n   - Respuesta: El documento incluye un Ap\u00e9ndice 1 que proporciona recomendaciones espec\u00edficas para la realizaci\u00f3n y evaluaci\u00f3n de perfiles de disoluci\u00f3n comparativa, lo cual es crucial para demostrar la equivalencia de calidad entre productos gen\u00e9ricos y sus productos de referencia.\n\n3. **\u00bfQu\u00e9 requisitos se establecen para la revisi\u00f3n de calidad de productos multisource establecidos en el contexto de la precalificaci\u00f3n de medicamentos?**\n   - Respuesta: El Ap\u00e9ndice 2 del documento detalla los requisitos de revisi\u00f3n de calidad para productos multisource establecidos, lo que implica que se deben cumplir ciertos criterios para asegurar que estos productos mantengan est\u00e1ndares de calidad adecuados para su aprobaci\u00f3n en el programa de precalificaci\u00f3n de la OMS.", "prev_section_summary": "El contenido de la secci\u00f3n se refiere al \"WHO - Technical Report Series 970\", espec\u00edficamente al Informe 46 de esta serie. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Hallazgos y Recomendaciones**: Se busca informaci\u00f3n sobre los principales hallazgos y recomendaciones del Informe 46, lo que indica que el documento aborda aspectos relevantes para la salud p\u00fablica.\n2. **Metodolog\u00edas de Investigaci\u00f3n**: Se menciona la importancia de las metodolog\u00edas utilizadas en el estudio, sugiriendo que el informe detalla los enfoques y t\u00e9cnicas aplicadas en la investigaci\u00f3n.\n3. **Relaci\u00f3n con Informes Previos**: Se plantea la necesidad de comparar el Informe 46 con otros informes de la misma serie, lo que sugiere un inter\u00e9s en la evoluci\u00f3n y continuidad de la investigaci\u00f3n en el \u00e1rea de salud p\u00fablica.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la publicaci\u00f3n de la serie de informes t\u00e9cnicos.\n- **Informe 46**: Espec\u00edfico documento dentro de la serie que se est\u00e1 analizando.\n\n### Contexto General:\nEl documento forma parte de una serie de informes t\u00e9cnicos que abordan temas de salud p\u00fablica y recomendaciones para pol\u00edticas de salud, lo que resalta su relevancia en el \u00e1mbito global de la salud.", "excerpt_keywords": "Keywords: WHO, pharmaceutical, quality, guidelines, prequalification"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d0a7e4f7-a1d4-40b2-99f2-cba800ec62b6", "node_type": "4", "metadata": {"page_label": "135", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n**Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part**\n\n## 1. Introduction\n1.1 Background  \n1.2 Objectives  \n1.3 Scope  \n1.4 General principles  \n1.5 Guidance on format  \n\n## 2. Glossary\n\n## 3. Quality summaries\n3.1 Module 2.3: Quality overall summary \u2013 product dossiers (QOS-PD)  \n3.2 Module 1.4.2: Quality information summary (QIS)  \n\n## 4. Module 3: Quality\n4.1 Table of contents of Module 3  \n4.2 Body of data  \n    3.2.S Drug substance (or active pharmaceutical ingredient (API))  \n    3.2.P Drug product (or finished pharmaceutical product (FPP))  \n    3.2.A Appendices  \n    3.2.R Regional information  \n4.3 Literature references  \n\n## References\n\n## Appendix 1\nRecommendations for conducting and assessing comparative dissolution profiles  \n\n## Appendix 2\nProduct quality review requirements for *established multisource products*  \n\n----\n\n| Section | Page |\n|---------|------|\n| 1. Introduction | 122 |\n| 2. Glossary | 125 |\n| 3. Quality summaries | 128 |\n| 4. Module 3: Quality | 129 |\n| References | 189 |\n| Appendix 1 | 193 |\n| Appendix 2 | 195 |", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "6c6978c25670e57de20eb705b38b43f219bc605bd9f385d4ab5fd8d15aa1c535", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 4\n\n**Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part**\n\n## 1. Introduction\n1.1 Background  \n1.2 Objectives  \n1.3 Scope  \n1.4 General principles  \n1.5 Guidance on format  \n\n## 2. Glossary\n\n## 3. Quality summaries\n3.1 Module 2.3: Quality overall summary \u2013 product dossiers (QOS-PD)  \n3.2 Module 1.4.2: Quality information summary (QIS)  \n\n## 4. Module 3: Quality\n4.1 Table of contents of Module 3  \n4.2 Body of data  \n    3.2.S Drug substance (or active pharmaceutical ingredient (API))  \n    3.2.P Drug product (or finished pharmaceutical product (FPP))  \n    3.2.A Appendices  \n    3.2.R Regional information  \n4.3 Literature references  \n\n## References\n\n## Appendix 1\nRecommendations for conducting and assessing comparative dissolution profiles  \n\n## Appendix 2\nProduct quality review requirements for *established multisource products*  \n\n----\n\n| Section | Page |\n|---------|------|\n| 1. Introduction | 122 |\n| 2. Glossary | 125 |\n| 3. Quality summaries | 128 |\n| 4. Module 3: Quality | 129 |\n| References | 189 |\n| Appendix 1 | 193 |\n| Appendix 2 | 195 |", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1186, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "64f5df98-cd81-4d72-b32e-db8b0dfc98ae": {"__data__": {"id_": "64f5df98-cd81-4d72-b32e-db8b0dfc98ae", "embedding": null, "metadata": {"page_label": "136", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\n## 1.1 Background\n\nThe *Procedure for prequalification of pharmaceutical products* (1) outlines the procedure and considerations for the process undertaken by WHO in providing United Nations agencies with advice on the acceptability, in principle, of pharmaceutical products for procurement by such agencies. It states:\n\n> \"This activity of WHO aims to facilitate access to priority essential medicines that meet WHO-recommended norms and standards of acceptable quality.\"\n\nAs mentioned in WHO Technical Report Series, No. 961 (1), in submitting an expression of interest (EOI) for product evaluation, the applicant should send a product dossier (PD) to the WHO focal point (together with the other data required), in the format specified in the WHO guidance documents on submitting product data and information.\n\nThrough the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) process, considerable harmonization has been achieved on the organization for the Quality module of the registration documents with the issuance of the *Common technical document (CTD) - quality (ICH M4Q)* guideline (2). This format, recommended in the M4Q guideline for the quality information of registration applications, has become widely accepted by regulatory authorities both within and beyond the ICH regions.\n\nThe current document provides recommendations on the quality information for active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs) that should be submitted to WHO to support PDs.\n\nAlternative approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. It is also important to note that the WHO Prequalification of Medicines Programme may request information or material, or define conditions not specifically described in this guidance, in order to adequately assess the quality of a pharmaceutical product.\n\n## 1.2 Objectives\n\nThese guidelines are intended to:\n\n- assist applicants in the preparation of the *Quality Module* of PDs for multisource products by providing clear general guidance on the format of these dossiers;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que pueden ser respondidas por el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla el procedimiento para la precalificaci\u00f3n de productos farmac\u00e9uticos, que busca facilitar el acceso a medicamentos esenciales que cumplan con los est\u00e1ndares de calidad recomendados por la OMS. Se menciona la importancia de enviar un expediente de producto (PD) en un formato espec\u00edfico y se hace referencia a la armonizaci\u00f3n lograda a trav\u00e9s de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH). Adem\u00e1s, se establecen recomendaciones sobre la informaci\u00f3n de calidad que debe incluirse en los PDs para ingredientes farmac\u00e9uticos activos (APIs) y productos farmac\u00e9uticos terminados (FPPs).\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 es un expediente de producto (PD) y qu\u00e9 informaci\u00f3n debe incluir para la evaluaci\u00f3n de la OMS?**\n   - El expediente de producto (PD) es un conjunto de documentos que los solicitantes deben enviar a la OMS al presentar una expresi\u00f3n de inter\u00e9s para la evaluaci\u00f3n de un producto. Debe incluir informaci\u00f3n sobre la calidad de los ingredientes farmac\u00e9uticos activos (APIs) y productos farmac\u00e9uticos terminados (FPPs), siguiendo el formato especificado en las gu\u00edas de la OMS.\n\n2. **\u00bfC\u00f3mo ha influido la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) en el proceso de registro de productos farmac\u00e9uticos?**\n   - La ICH ha logrado una considerable armonizaci\u00f3n en la organizaci\u00f3n del m\u00f3dulo de calidad de los documentos de registro mediante la emisi\u00f3n de la gu\u00eda del *Common Technical Document (CTD) - quality (ICH M4Q)*, que ha sido ampliamente aceptada por las autoridades regulatorias tanto dentro como fuera de las regiones de la ICH.\n\n3. **\u00bfQu\u00e9 alternativas pueden ser aceptables en el proceso de precalificaci\u00f3n de medicamentos seg\u00fan la OMS?**\n   - Alternativas a los principios y pr\u00e1cticas descritos en el documento pueden ser aceptables siempre que est\u00e9n respaldadas por una justificaci\u00f3n cient\u00edfica adecuada. Adem\u00e1s, el Programa de Precalificaci\u00f3n de Medicamentos de la OMS puede solicitar informaci\u00f3n o material adicional que no est\u00e9 espec\u00edficamente descrito en la gu\u00eda para evaluar adecuadamente la calidad de un producto farmac\u00e9utico.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento es una gu\u00eda de la Organizaci\u00f3n Mundial de la Salud (OMS) que proporciona directrices sobre la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos gen\u00e9ricos en el contexto del Programa de Precalificaci\u00f3n de Medicamentos, espec\u00edficamente en la parte de calidad. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n#### Temas Clave:\n1. **Introducci\u00f3n**: Contexto, objetivos, alcance, principios generales y formato de la documentaci\u00f3n.\n2. **Glosario**: Definiciones de t\u00e9rminos relevantes utilizados en el documento.\n3. **Res\u00famenes de Calidad**:\n   - M\u00f3dulo 2.3: Resumen general de calidad para dossiers de productos.\n   - M\u00f3dulo 1.4.2: Resumen de informaci\u00f3n de calidad.\n4. **M\u00f3dulo 3: Calidad**:\n   - Contenido del cuerpo de datos, incluyendo informaci\u00f3n sobre la sustancia activa (API) y el producto terminado (FPP).\n   - Informaci\u00f3n regional y ap\u00e9ndices.\n5. **Referencias**: Fuentes citadas en el documento.\n6. **Ap\u00e9ndices**:\n   - Ap\u00e9ndice 1: Recomendaciones para la evaluaci\u00f3n de perfiles de disoluci\u00f3n comparativa.\n   - Ap\u00e9ndice 2: Requisitos de revisi\u00f3n de calidad para productos multisource establecidos.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la gu\u00eda.\n- **Productos farmac\u00e9uticos gen\u00e9ricos**: Tipo de productos a los que se aplica la gu\u00eda.\n- **Sustancia activa (API)**: Componente clave en la formulaci\u00f3n de medicamentos.\n- **Producto farmac\u00e9utico terminado (FPP)**: Producto final que se presenta para la precalificaci\u00f3n.\n- **M\u00f3dulos y Ap\u00e9ndices**: Estructura organizativa del documento que detalla los requisitos y recomendaciones.\n\nEste resumen proporciona una visi\u00f3n general de los elementos esenciales de la secci\u00f3n, destacando la importancia de la calidad en la documentaci\u00f3n para la precalificaci\u00f3n de medicamentos gen\u00e9ricos.", "excerpt_keywords": "Keywords: prequalification, pharmaceutical products, WHO, quality module, active pharmaceutical ingredients"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c3f6b3a9-15f0-4d0d-a2fb-cffc0cfd0688", "node_type": "4", "metadata": {"page_label": "136", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\n## 1.1 Background\n\nThe *Procedure for prequalification of pharmaceutical products* (1) outlines the procedure and considerations for the process undertaken by WHO in providing United Nations agencies with advice on the acceptability, in principle, of pharmaceutical products for procurement by such agencies. It states:\n\n> \"This activity of WHO aims to facilitate access to priority essential medicines that meet WHO-recommended norms and standards of acceptable quality.\"\n\nAs mentioned in WHO Technical Report Series, No. 961 (1), in submitting an expression of interest (EOI) for product evaluation, the applicant should send a product dossier (PD) to the WHO focal point (together with the other data required), in the format specified in the WHO guidance documents on submitting product data and information.\n\nThrough the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) process, considerable harmonization has been achieved on the organization for the Quality module of the registration documents with the issuance of the *Common technical document (CTD) - quality (ICH M4Q)* guideline (2). This format, recommended in the M4Q guideline for the quality information of registration applications, has become widely accepted by regulatory authorities both within and beyond the ICH regions.\n\nThe current document provides recommendations on the quality information for active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs) that should be submitted to WHO to support PDs.\n\nAlternative approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. It is also important to note that the WHO Prequalification of Medicines Programme may request information or material, or define conditions not specifically described in this guidance, in order to adequately assess the quality of a pharmaceutical product.\n\n## 1.2 Objectives\n\nThese guidelines are intended to:\n\n- assist applicants in the preparation of the *Quality Module* of PDs for multisource products by providing clear general guidance on the format of these dossiers;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "1e4ea42149894dfc8cccc8d3de21413c08c84c920767e753d8cc491512099b1f", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 1. Introduction\n\n## 1.1 Background\n\nThe *Procedure for prequalification of pharmaceutical products* (1) outlines the procedure and considerations for the process undertaken by WHO in providing United Nations agencies with advice on the acceptability, in principle, of pharmaceutical products for procurement by such agencies. It states:\n\n> \"This activity of WHO aims to facilitate access to priority essential medicines that meet WHO-recommended norms and standards of acceptable quality.\"\n\nAs mentioned in WHO Technical Report Series, No. 961 (1), in submitting an expression of interest (EOI) for product evaluation, the applicant should send a product dossier (PD) to the WHO focal point (together with the other data required), in the format specified in the WHO guidance documents on submitting product data and information.\n\nThrough the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) process, considerable harmonization has been achieved on the organization for the Quality module of the registration documents with the issuance of the *Common technical document (CTD) - quality (ICH M4Q)* guideline (2). This format, recommended in the M4Q guideline for the quality information of registration applications, has become widely accepted by regulatory authorities both within and beyond the ICH regions.\n\nThe current document provides recommendations on the quality information for active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs) that should be submitted to WHO to support PDs.\n\nAlternative approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. It is also important to note that the WHO Prequalification of Medicines Programme may request information or material, or define conditions not specifically described in this guidance, in order to adequately assess the quality of a pharmaceutical product.\n\n## 1.2 Objectives\n\nThese guidelines are intended to:\n\n- assist applicants in the preparation of the *Quality Module* of PDs for multisource products by providing clear general guidance on the format of these dossiers;", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2239, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f9333025-a1fc-4b2f-a546-8f7031fead66": {"__data__": {"id_": "f9333025-a1fc-4b2f-a546-8f7031fead66", "embedding": null, "metadata": {"page_label": "137", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Scope\n\nThese guidelines apply to PDs for multisource pharmaceutical products containing existing APIs of synthetic or semi-synthetic origin. For the purposes of these guidelines, an existing API is one that has been previously approved through a finished product by a stringent regulatory authority (SRA)<sup>1</sup> or by WHO. Fermentation, biological, biotechnological and herbal APIs are covered by other guidelines.\n\n# General principles\n\nTo facilitate the preparation of the PD, these guidelines are organized in accordance with the structure of the ICH Common technical document \u2013 quality (M4Q) guideline (2).\n\nThe text of the M4Q (CTD-Q) guideline (2) has been restated verbatim in these guidelines in **bold text**, with minor modifications to accommodate WHO terminology and to include certain text that would be appropriate for multisource pharmaceutical products, notably:\n\n- \u201cDrug substance\u201d is replaced with \u201cactive pharmaceutical ingredient\u201d or \u201cAPI\u201d.\n- \u201cDrug product\u201d is replaced with \u201cfinished pharmaceutical product\u201d or \u201cFPP\u201d.\n- \u201cApplication\u201d is replaced with \u201cproduct dossier\u201d or \u201cPD\u201d.\n- \u201cCombination product\u201d is replaced with \u201cfixed-dose combination\u201d or \u201cFDC\u201d.\n- \u201cClinical batches\u201d is replaced with \u201ccomparative bioavailability\u201d or \u201cbiowaiver batches\u201d.\n\n----\n\n<sup>1</sup> A stringent regulatory authority (SRA): a regulatory authority which is:\n- a member of the International Conference on Harmonisation (ICH) (as specified on www.ich.org); or\n- an ICH observer, being the European Free Trade Association (EFTA), as represented by SwissMedic, and Health Canada (as may be updated from time to time); or\n- a regulatory authority associated with an ICH member through a legally-binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento es un conjunto de directrices de la OMS que se aplica a los expedientes de productos (PD) para productos farmac\u00e9uticos multisource que contienen ingredientes farmac\u00e9uticos activos (API) existentes de origen sint\u00e9tico o semisint\u00e9tico. Se establece que un API existente es aquel que ha sido aprobado previamente por una autoridad reguladora estricta (SRA) o por la OMS. Las directrices est\u00e1n organizadas seg\u00fan la estructura del documento t\u00e9cnico com\u00fan de ICH y contienen modificaciones para adaptarse a la terminolog\u00eda de la OMS.\n\n### Preguntas\n1. **\u00bfQu\u00e9 se entiende por un \"API existente\" seg\u00fan las directrices de la OMS?**\n   - Un \"API existente\" es un ingrediente farmac\u00e9utico activo que ha sido previamente aprobado a trav\u00e9s de un producto terminado por una autoridad reguladora estricta (SRA) o por la OMS.\n\n2. **\u00bfC\u00f3mo se han adaptado las terminolog\u00edas del documento t\u00e9cnico com\u00fan de ICH en las directrices de la OMS?**\n   - Las terminolog\u00edas han sido adaptadas de la siguiente manera: \"Drug substance\" se convierte en \"active pharmaceutical ingredient\" (API), \"Drug product\" en \"finished pharmaceutical product\" (FPP), \"Application\" en \"product dossier\" (PD), \"Combination product\" en \"fixed-dose combination\" (FDC), y \"Clinical batches\" en \"comparative bioavailability\" o \"biowaiver batches\".\n\n3. **\u00bfQu\u00e9 tipos de APIs no est\u00e1n cubiertos por estas directrices de la OMS?**\n   - Las directrices no cubren APIs de fermentaci\u00f3n, biol\u00f3gicos, biotecnol\u00f3gicos y herbales, ya que estos est\u00e1n regulados por otras directrices espec\u00edficas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Procedimiento de Precalificaci\u00f3n de Productos Farmac\u00e9uticos**: El documento describe el proceso que sigue la OMS para evaluar la aceptabilidad de productos farmac\u00e9uticos para su adquisici\u00f3n por agencias de las Naciones Unidas, con el objetivo de facilitar el acceso a medicamentos esenciales que cumplan con los est\u00e1ndares de calidad recomendados.\n\n2. **Expediente de Producto (PD)**: Se requiere que los solicitantes env\u00eden un expediente de producto al presentar una expresi\u00f3n de inter\u00e9s para la evaluaci\u00f3n. Este expediente debe incluir informaci\u00f3n sobre la calidad de los ingredientes farmac\u00e9uticos activos (APIs) y productos farmac\u00e9uticos terminados (FPPs), siguiendo un formato espec\u00edfico.\n\n3. **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Se menciona la influencia de la ICH en la armonizaci\u00f3n de los documentos de registro, destacando la gu\u00eda del *Common Technical Document (CTD) - quality (ICH M4Q)*, que ha sido adoptada por diversas autoridades regulatorias.\n\n4. **Recomendaciones sobre Informaci\u00f3n de Calidad**: El documento proporciona directrices sobre la informaci\u00f3n de calidad que debe incluirse en los PDs para APIs y FPPs, y permite enfoques alternativos siempre que est\u00e9n respaldados por justificaci\u00f3n cient\u00edfica.\n\n5. **Programa de Precalificaci\u00f3n de Medicamentos de la OMS**: Este programa puede solicitar informaci\u00f3n adicional o definir condiciones no descritas en la gu\u00eda para evaluar adecuadamente la calidad de un producto farmac\u00e9utico.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la precalificaci\u00f3n de productos farmac\u00e9uticos.\n- **Naciones Unidas**: Agencias que adquieren productos farmac\u00e9uticos basados en la evaluaci\u00f3n de la OMS.\n- **ICH (Conferencia Internacional sobre Armonizaci\u00f3n)**: Organizaci\u00f3n que ha contribuido a la armonizaci\u00f3n de los requisitos de registro de productos farmac\u00e9uticos.\n- **APIs (Ingredientes Farmac\u00e9uticos Activos)**: Componentes activos de los productos farmac\u00e9uticos.\n- **FPPs (Productos Farmac\u00e9uticos Terminados)**: Productos finales que se ofrecen para su uso.", "excerpt_keywords": "Keywords: guidelines, pharmaceutical products, active pharmaceutical ingredient, stringent regulatory authority, product dossier"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8e1aadaa-9fa1-4746-b72c-b81eeec34e8a", "node_type": "4", "metadata": {"page_label": "137", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Scope\n\nThese guidelines apply to PDs for multisource pharmaceutical products containing existing APIs of synthetic or semi-synthetic origin. For the purposes of these guidelines, an existing API is one that has been previously approved through a finished product by a stringent regulatory authority (SRA)<sup>1</sup> or by WHO. Fermentation, biological, biotechnological and herbal APIs are covered by other guidelines.\n\n# General principles\n\nTo facilitate the preparation of the PD, these guidelines are organized in accordance with the structure of the ICH Common technical document \u2013 quality (M4Q) guideline (2).\n\nThe text of the M4Q (CTD-Q) guideline (2) has been restated verbatim in these guidelines in **bold text**, with minor modifications to accommodate WHO terminology and to include certain text that would be appropriate for multisource pharmaceutical products, notably:\n\n- \u201cDrug substance\u201d is replaced with \u201cactive pharmaceutical ingredient\u201d or \u201cAPI\u201d.\n- \u201cDrug product\u201d is replaced with \u201cfinished pharmaceutical product\u201d or \u201cFPP\u201d.\n- \u201cApplication\u201d is replaced with \u201cproduct dossier\u201d or \u201cPD\u201d.\n- \u201cCombination product\u201d is replaced with \u201cfixed-dose combination\u201d or \u201cFDC\u201d.\n- \u201cClinical batches\u201d is replaced with \u201ccomparative bioavailability\u201d or \u201cbiowaiver batches\u201d.\n\n----\n\n<sup>1</sup> A stringent regulatory authority (SRA): a regulatory authority which is:\n- a member of the International Conference on Harmonisation (ICH) (as specified on www.ich.org); or\n- an ICH observer, being the European Free Trade Association (EFTA), as represented by SwissMedic, and Health Canada (as may be updated from time to time); or\n- a regulatory authority associated with an ICH member through a legally-binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "fd16bf04632e0da057ac2c442f23ff42884ccbd8422421ebf5c51e065f138224", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Scope\n\nThese guidelines apply to PDs for multisource pharmaceutical products containing existing APIs of synthetic or semi-synthetic origin. For the purposes of these guidelines, an existing API is one that has been previously approved through a finished product by a stringent regulatory authority (SRA)<sup>1</sup> or by WHO. Fermentation, biological, biotechnological and herbal APIs are covered by other guidelines.\n\n# General principles\n\nTo facilitate the preparation of the PD, these guidelines are organized in accordance with the structure of the ICH Common technical document \u2013 quality (M4Q) guideline (2).\n\nThe text of the M4Q (CTD-Q) guideline (2) has been restated verbatim in these guidelines in **bold text**, with minor modifications to accommodate WHO terminology and to include certain text that would be appropriate for multisource pharmaceutical products, notably:\n\n- \u201cDrug substance\u201d is replaced with \u201cactive pharmaceutical ingredient\u201d or \u201cAPI\u201d.\n- \u201cDrug product\u201d is replaced with \u201cfinished pharmaceutical product\u201d or \u201cFPP\u201d.\n- \u201cApplication\u201d is replaced with \u201cproduct dossier\u201d or \u201cPD\u201d.\n- \u201cCombination product\u201d is replaced with \u201cfixed-dose combination\u201d or \u201cFDC\u201d.\n- \u201cClinical batches\u201d is replaced with \u201ccomparative bioavailability\u201d or \u201cbiowaiver batches\u201d.\n\n----\n\n<sup>1</sup> A stringent regulatory authority (SRA): a regulatory authority which is:\n- a member of the International Conference on Harmonisation (ICH) (as specified on www.ich.org); or\n- an ICH observer, being the European Free Trade Association (EFTA), as represented by SwissMedic, and Health Canada (as may be updated from time to time); or\n- a regulatory authority associated with an ICH member through a legally-binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1830, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "b80d8c2b-cec7-43c7-a79d-81ea60249f06": {"__data__": {"id_": "b80d8c2b-cec7-43c7-a79d-81ea60249f06", "embedding": null, "metadata": {"page_label": "138", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAdditional guidance by WHO, following the **bold** text reproduced from the M4Q (CTD-Q) guideline (2), is printed in plain text to make it easily distinguishable from the ICH text and is included to provide further clarity on WHO\u2019s expectations for the content of PDs. This approach is intended to facilitate the identification and origin of the text in these guidelines (i.e. from ICH or from WHO).\n\nThe content of these guidelines should be read in conjunction with relevant information described in other existing WHO or ICH reference documents and guidelines. The quality of existing APIs and corresponding multisource products should not be inferior to new APIs and innovator (comparator) FPPs. Therefore, the principles of the ICH guidelines that are referenced throughout this document and in other WHO guidelines may equally apply to existing APIs and multisource products.\n\nScientific literature may be appropriate to fulfill the requirements for some of the information or parameters outlined in these guidelines (e.g. qualification of specified identified impurities). Furthermore, the requirements outlined in certain sections may not be applicable to the proposed API or FPP. In these situations, either a summary and the full reference to the scientific literature should be provided, or the non-applicability of the requested information should be clearly indicated with an accompanying explanatory note.\n\n## 1.5 Guidance on format\n\nThe recommendations outlined in the WHO general filing guideline *Guidelines on submission of documentation for a multisource (generic) finished product: general format: preparation of product dossiers in common technical document format* (3) should be followed for the format and presentation of the PD.\n\nThere may be a number of instances where repetition of sections can be considered appropriate. Whenever a section is repeated, it should be made clear what the section refers to by creating a distinguishing title in parentheses following the M4Q (CTD-Q) guideline heading, e.g. 3.2.S Drug substance (or API) (name, Manufacturer A).\n\nThe following are recommendations for the presentation of the information in the Quality module for different scenarios that may be encountered:\n\n- The Open part (non-proprietary information) of each APIMF should always be included in its entirety in the PD, as an annex to 3.2.S.\n- For an FPP containing more than one API, one complete \u201c3.2.S\u201d section should be provided for one API, followed by another complete \u201c3.2.S\u201d section for each of the other APIs.\n- For an API from multiple manufacturers, one complete \u201c3.2.S\u201d section should be provided for the API from one manufacturer, followed by", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con respuestas espec\u00edficas que probablemente no se encuentren en otro lugar:\n\n### Preguntas y Respuestas\n\n1. **\u00bfCu\u00e1l es la importancia de la calidad de los APIs existentes en comparaci\u00f3n con los nuevos APIs y FPPs innovadores seg\u00fan las directrices de la OMS?**\n   - La OMS establece que la calidad de los APIs existentes y los productos multisource no debe ser inferior a la de los nuevos APIs y los productos farmac\u00e9uticos terminados (FPPs) innovadores. Esto implica que los principios de las directrices de ICH aplicables a nuevos productos tambi\u00e9n son relevantes para los productos existentes, asegurando as\u00ed un est\u00e1ndar de calidad uniforme en el mercado.\n\n2. **\u00bfQu\u00e9 se debe hacer si ciertos requisitos de las directrices no son aplicables a un API o FPP propuesto?**\n   - En situaciones donde los requisitos de las directrices no son aplicables, se debe proporcionar un resumen y la referencia completa a la literatura cient\u00edfica que respalde esta decisi\u00f3n. Alternativamente, se debe indicar claramente la no aplicabilidad de la informaci\u00f3n solicitada, acompa\u00f1ada de una nota explicativa que justifique esta exclusi\u00f3n.\n\n3. **\u00bfC\u00f3mo se debe estructurar la presentaci\u00f3n de la informaci\u00f3n en el m\u00f3dulo de Calidad para un FPP que contiene m\u00faltiples APIs?**\n   - Para un FPP que contiene m\u00e1s de un API, se debe proporcionar una secci\u00f3n completa \u201c3.2.S\u201d para cada API. Esto significa que despu\u00e9s de la secci\u00f3n correspondiente a un API, se debe incluir otra secci\u00f3n \u201c3.2.S\u201d completa para cada uno de los otros APIs, asegurando que cada uno est\u00e9 claramente identificado y documentado.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS proporciona directrices sobre la calidad y presentaci\u00f3n de la documentaci\u00f3n para productos farmac\u00e9uticos, enfatizando que la calidad de los APIs existentes debe ser comparable a la de los nuevos productos. Se destaca la importancia de la literatura cient\u00edfica para justificar la no aplicabilidad de ciertos requisitos y se ofrecen recomendaciones espec\u00edficas sobre c\u00f3mo estructurar la informaci\u00f3n en el m\u00f3dulo de Calidad, especialmente en casos de m\u00faltiples APIs en un FPP.", "prev_section_summary": "### Temas Clave\n\n1. **Alcance de las Directrices**: Las directrices se aplican a los expedientes de productos (PD) para productos farmac\u00e9uticos multisource que contienen ingredientes farmac\u00e9uticos activos (API) existentes de origen sint\u00e9tico o semisint\u00e9tico.\n\n2. **Definici\u00f3n de API Existente**: Un API existente es aquel que ha sido aprobado previamente por una autoridad reguladora estricta (SRA) o por la OMS.\n\n3. **Exclusiones**: Las directrices no cubren APIs de fermentaci\u00f3n, biol\u00f3gicos, biotecnol\u00f3gicos y herbales, que est\u00e1n regulados por otras directrices.\n\n4. **Adaptaci\u00f3n de Terminolog\u00eda**: Las directrices han modificado la terminolog\u00eda del documento t\u00e9cnico com\u00fan de ICH para alinearse con la terminolog\u00eda de la OMS, incluyendo cambios en t\u00e9rminos como \"drug substance\" a \"active pharmaceutical ingredient\" (API) y \"drug product\" a \"finished pharmaceutical product\" (FPP).\n\n5. **Estructura de las Directrices**: Las directrices est\u00e1n organizadas de acuerdo con la estructura del documento t\u00e9cnico com\u00fan de ICH \u2013 calidad (M4Q).\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las directrices.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en los productos farmac\u00e9uticos.\n- **SRA (Autoridad Reguladora Estricta)**: Autoridades que han aprobado los APIs existentes.\n- **ICH (Conferencia Internacional sobre Armonizaci\u00f3n)**: Organizaci\u00f3n que establece directrices para la regulaci\u00f3n de productos farmac\u00e9uticos.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que contiene el API.\n- **FDC (Combinaci\u00f3n de Dosis Fija)**: Tipo de producto que combina m\u00faltiples APIs en una sola formulaci\u00f3n.\n- **Biowaiver Batches**: Lotes utilizados para estudios de bioequivalencia comparativa. \n\nEste resumen proporciona una visi\u00f3n general de los temas y entidades clave abordados en la secci\u00f3n del documento.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, APIs, quality guidelines, product dossiers"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fbd651a4-130b-4d0a-9c8c-a1f88756886b", "node_type": "4", "metadata": {"page_label": "138", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAdditional guidance by WHO, following the **bold** text reproduced from the M4Q (CTD-Q) guideline (2), is printed in plain text to make it easily distinguishable from the ICH text and is included to provide further clarity on WHO\u2019s expectations for the content of PDs. This approach is intended to facilitate the identification and origin of the text in these guidelines (i.e. from ICH or from WHO).\n\nThe content of these guidelines should be read in conjunction with relevant information described in other existing WHO or ICH reference documents and guidelines. The quality of existing APIs and corresponding multisource products should not be inferior to new APIs and innovator (comparator) FPPs. Therefore, the principles of the ICH guidelines that are referenced throughout this document and in other WHO guidelines may equally apply to existing APIs and multisource products.\n\nScientific literature may be appropriate to fulfill the requirements for some of the information or parameters outlined in these guidelines (e.g. qualification of specified identified impurities). Furthermore, the requirements outlined in certain sections may not be applicable to the proposed API or FPP. In these situations, either a summary and the full reference to the scientific literature should be provided, or the non-applicability of the requested information should be clearly indicated with an accompanying explanatory note.\n\n## 1.5 Guidance on format\n\nThe recommendations outlined in the WHO general filing guideline *Guidelines on submission of documentation for a multisource (generic) finished product: general format: preparation of product dossiers in common technical document format* (3) should be followed for the format and presentation of the PD.\n\nThere may be a number of instances where repetition of sections can be considered appropriate. Whenever a section is repeated, it should be made clear what the section refers to by creating a distinguishing title in parentheses following the M4Q (CTD-Q) guideline heading, e.g. 3.2.S Drug substance (or API) (name, Manufacturer A).\n\nThe following are recommendations for the presentation of the information in the Quality module for different scenarios that may be encountered:\n\n- The Open part (non-proprietary information) of each APIMF should always be included in its entirety in the PD, as an annex to 3.2.S.\n- For an FPP containing more than one API, one complete \u201c3.2.S\u201d section should be provided for one API, followed by another complete \u201c3.2.S\u201d section for each of the other APIs.\n- For an API from multiple manufacturers, one complete \u201c3.2.S\u201d section should be provided for the API from one manufacturer, followed by", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f5131c489f405f53dea7871cfcc91e2925e8aa4b286b8072f70bb6a011ff88bc", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAdditional guidance by WHO, following the **bold** text reproduced from the M4Q (CTD-Q) guideline (2), is printed in plain text to make it easily distinguishable from the ICH text and is included to provide further clarity on WHO\u2019s expectations for the content of PDs. This approach is intended to facilitate the identification and origin of the text in these guidelines (i.e. from ICH or from WHO).\n\nThe content of these guidelines should be read in conjunction with relevant information described in other existing WHO or ICH reference documents and guidelines. The quality of existing APIs and corresponding multisource products should not be inferior to new APIs and innovator (comparator) FPPs. Therefore, the principles of the ICH guidelines that are referenced throughout this document and in other WHO guidelines may equally apply to existing APIs and multisource products.\n\nScientific literature may be appropriate to fulfill the requirements for some of the information or parameters outlined in these guidelines (e.g. qualification of specified identified impurities). Furthermore, the requirements outlined in certain sections may not be applicable to the proposed API or FPP. In these situations, either a summary and the full reference to the scientific literature should be provided, or the non-applicability of the requested information should be clearly indicated with an accompanying explanatory note.\n\n## 1.5 Guidance on format\n\nThe recommendations outlined in the WHO general filing guideline *Guidelines on submission of documentation for a multisource (generic) finished product: general format: preparation of product dossiers in common technical document format* (3) should be followed for the format and presentation of the PD.\n\nThere may be a number of instances where repetition of sections can be considered appropriate. Whenever a section is repeated, it should be made clear what the section refers to by creating a distinguishing title in parentheses following the M4Q (CTD-Q) guideline heading, e.g. 3.2.S Drug substance (or API) (name, Manufacturer A).\n\nThe following are recommendations for the presentation of the information in the Quality module for different scenarios that may be encountered:\n\n- The Open part (non-proprietary information) of each APIMF should always be included in its entirety in the PD, as an annex to 3.2.S.\n- For an FPP containing more than one API, one complete \u201c3.2.S\u201d section should be provided for one API, followed by another complete \u201c3.2.S\u201d section for each of the other APIs.\n- For an API from multiple manufacturers, one complete \u201c3.2.S\u201d section should be provided for the API from one manufacturer, followed by", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2755, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "bb93380b-8a37-4065-bc66-1f9d7ebf18d9": {"__data__": {"id_": "bb93380b-8a37-4065-bc66-1f9d7ebf18d9", "embedding": null, "metadata": {"page_label": "139", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Glossary\n\nThe definitions provided below apply to the words and phrases used in these guidelines. Although an effort has been made to use standard definitions as far as possible, they may have different meanings in other contexts and documents. The following definitions are provided to facilitate interpretation of the guidelines.\n\n### active pharmaceutical ingredient (API)\n\nAny substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form, and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body.\n\n### active pharmaceutical ingredient (API) starting material\n\nA raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house (ICH Q7). See also starting materials for synthesis.\n\n----\n\n- For an FPP with multiple strengths (e.g. 10, 50, 100 mg) one complete \"3.2.P\" section should be provided with the information for the different strengths provided within the subsections. One complete copy of the PD should be provided for each FPP strength.\n- For an FPP with multiple container-closure systems (e.g. bottles and unit dose blisters) one complete \"3.2.P\" section should be provided with the information for the different presentations provided within the subsections.\n- For multiple FPPs (e.g. tablets and a parenteral product) a separate dossier is required for each FPP.\n- For an FPP supplied with reconstitution diluent(s) one complete \"3.2.P\" section should be provided for the FPP, followed by the information on the diluent(s) in a separate part \"3.2.P\", as appropriate.\n- For a co-blistered FPP one complete \"3.2.P\" section should be provided for each product.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) presenta un glosario de t\u00e9rminos relacionados con los ingredientes farmac\u00e9uticos activos (API) y sus materiales de inicio. Define qu\u00e9 constituye un API y un material de inicio de API, adem\u00e1s de proporcionar directrices sobre la presentaci\u00f3n de informaci\u00f3n para productos farmac\u00e9uticos terminados (FPP) con diferentes caracter\u00edsticas, como m\u00faltiples concentraciones, sistemas de cierre y formulaciones.\n\n### Preguntas:\n\n1. **\u00bfQu\u00e9 se considera un \"material de inicio de API\" y c\u00f3mo se relaciona con la producci\u00f3n de un API?**\n   - Respuesta: Un material de inicio de API es una materia prima, intermedio o un API que se utiliza en la producci\u00f3n de un API y que se incorpora como un fragmento estructural significativo en la estructura del API. Puede ser un art\u00edculo comercial, un material adquirido de proveedores bajo contrato o producido internamente.\n\n2. **\u00bfQu\u00e9 requisitos se establecen para la presentaci\u00f3n de informaci\u00f3n sobre un FPP que tiene m\u00faltiples concentraciones?**\n   - Respuesta: Para un FPP con m\u00faltiples concentraciones (por ejemplo, 10, 50, 100 mg), se debe proporcionar una secci\u00f3n completa \"3.2.P\" que incluya la informaci\u00f3n para las diferentes concentraciones dentro de las subsecciones. Adem\u00e1s, se debe proporcionar una copia completa del documento de presentaci\u00f3n (PD) para cada concentraci\u00f3n del FPP.\n\n3. **\u00bfC\u00f3mo se debe manejar la informaci\u00f3n sobre un FPP que se suministra con diluyentes de reconstituci\u00f3n?**\n   - Respuesta: Para un FPP que se suministra con diluyentes de reconstituci\u00f3n, se debe proporcionar una secci\u00f3n completa \"3.2.P\" para el FPP, seguida de la informaci\u00f3n sobre los diluyentes en una parte separada \"3.2.P\", seg\u00fan sea apropiado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Calidad de APIs y FPPs**:\n   - La OMS establece que la calidad de los APIs existentes y los productos multisource no debe ser inferior a la de los nuevos APIs y FPPs innovadores. Esto asegura un est\u00e1ndar de calidad uniforme en el mercado.\n\n2. **Uso de Literatura Cient\u00edfica**:\n   - Se permite el uso de literatura cient\u00edfica para cumplir con ciertos requisitos de las directrices. Si un requisito no es aplicable, se debe proporcionar un resumen y la referencia completa a la literatura o indicar claramente su no aplicabilidad con una nota explicativa.\n\n3. **Estructura de Documentaci\u00f3n**:\n   - Se recomienda seguir las directrices de la OMS para la presentaci\u00f3n de la documentaci\u00f3n de productos farmac\u00e9uticos. Esto incluye la inclusi\u00f3n de secciones completas \u201c3.2.S\u201d para cada API en un FPP que contenga m\u00faltiples APIs.\n\n4. **Repetici\u00f3n de Secciones**:\n   - Se permite la repetici\u00f3n de secciones en la documentaci\u00f3n, siempre que se indique claramente a qu\u00e9 se refiere cada secci\u00f3n mediante t\u00edtulos distintivos.\n\n### Entidades Clave\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite directrices sobre la calidad de productos farmac\u00e9uticos.\n- **APIs (Ingredientes Activos Farmac\u00e9uticos)**: Sustancias que proporcionan la acci\u00f3n farmacol\u00f3gica en los productos.\n- **FPPs (Productos Farmac\u00e9uticos Terminados)**: Formulaciones finales que contienen uno o m\u00e1s APIs.\n- **ICH (Conferencia Internacional sobre Armonizaci\u00f3n)**: Organizaci\u00f3n que proporciona directrices sobre la calidad y regulaci\u00f3n de productos farmac\u00e9uticos.\n- **APIMF (Maestro de Informaci\u00f3n del Ingrediente Activo)**: Documento que contiene informaci\u00f3n sobre un API.\n\nEste resumen destaca la importancia de la calidad en la industria farmac\u00e9utica y proporciona directrices claras sobre c\u00f3mo estructurar la documentaci\u00f3n necesaria para cumplir con los est\u00e1ndares establecidos por la OMS.", "excerpt_keywords": "Keywords: active pharmaceutical ingredient, API starting material, pharmaceutical dosage form, product information presentation, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ca8015f2-eeeb-4445-be94-d759ed58a52d", "node_type": "4", "metadata": {"page_label": "139", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Glossary\n\nThe definitions provided below apply to the words and phrases used in these guidelines. Although an effort has been made to use standard definitions as far as possible, they may have different meanings in other contexts and documents. The following definitions are provided to facilitate interpretation of the guidelines.\n\n### active pharmaceutical ingredient (API)\n\nAny substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form, and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body.\n\n### active pharmaceutical ingredient (API) starting material\n\nA raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house (ICH Q7). See also starting materials for synthesis.\n\n----\n\n- For an FPP with multiple strengths (e.g. 10, 50, 100 mg) one complete \"3.2.P\" section should be provided with the information for the different strengths provided within the subsections. One complete copy of the PD should be provided for each FPP strength.\n- For an FPP with multiple container-closure systems (e.g. bottles and unit dose blisters) one complete \"3.2.P\" section should be provided with the information for the different presentations provided within the subsections.\n- For multiple FPPs (e.g. tablets and a parenteral product) a separate dossier is required for each FPP.\n- For an FPP supplied with reconstitution diluent(s) one complete \"3.2.P\" section should be provided for the FPP, followed by the information on the diluent(s) in a separate part \"3.2.P\", as appropriate.\n- For a co-blistered FPP one complete \"3.2.P\" section should be provided for each product.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "8b1553c1d904c986485c19e0b644c8e4bc7aaddf34903535550f13d7ed0ea33a", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 2. Glossary\n\nThe definitions provided below apply to the words and phrases used in these guidelines. Although an effort has been made to use standard definitions as far as possible, they may have different meanings in other contexts and documents. The following definitions are provided to facilitate interpretation of the guidelines.\n\n### active pharmaceutical ingredient (API)\n\nAny substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form, and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body.\n\n### active pharmaceutical ingredient (API) starting material\n\nA raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house (ICH Q7). See also starting materials for synthesis.\n\n----\n\n- For an FPP with multiple strengths (e.g. 10, 50, 100 mg) one complete \"3.2.P\" section should be provided with the information for the different strengths provided within the subsections. One complete copy of the PD should be provided for each FPP strength.\n- For an FPP with multiple container-closure systems (e.g. bottles and unit dose blisters) one complete \"3.2.P\" section should be provided with the information for the different presentations provided within the subsections.\n- For multiple FPPs (e.g. tablets and a parenteral product) a separate dossier is required for each FPP.\n- For an FPP supplied with reconstitution diluent(s) one complete \"3.2.P\" section should be provided for the FPP, followed by the information on the diluent(s) in a separate part \"3.2.P\", as appropriate.\n- For a co-blistered FPP one complete \"3.2.P\" section should be provided for each product.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2140, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "523fee71-5347-4a93-a83f-d9dfefc0df0b": {"__data__": {"id_": "523fee71-5347-4a93-a83f-d9dfefc0df0b", "embedding": null, "metadata": {"page_label": "140", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Applicant\n\nThe person or entity who, by the deadline mentioned in the invitation, submits an expression of interest (EOI) to participate in this procedure in respect of the product(s) listed in the invitation, together with the required documentation on such product(s).\n\n## Biopharmaceutics Classification System (BCS) Highly Soluble\n\nAn API for which the highest dose recommended by WHO (if the API appears on the WHO Model list of essential medicines) or highest dose strength available on the market as an oral solid dosage form (if the API does not appear on the WHO Model list of essential medicines) is soluble in 250 ml or less of aqueous media over the pH range of 1.2\u20136.8 at 37 \u00b0C.\n\n## Commitment Batches\n\nProduction batches of an API or FPP for which the stability studies are initiated or completed post-approval through a commitment made in a regulatory application.\n\n## Comparator Product\n\nA pharmaceutical product with which the generic product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality have been established. For the Prequalification of Medicines Programme, the selection of the comparator product is based on the information presented under Guidance on bioequivalence studies available on the Prequalification web site.\n\n## Established Multisource (Generic) Product\n\nA multisource product that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year, or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years.\n\n## Existing API\n\nAn API that is not considered a new active substance, which has been previously approved through a finished product by a stringent regulatory authority or by WHO, but requires the filing of a dossier. This would include, for example, new PDs and variations to multisource products.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento se centra en las especificaciones para preparaciones farmac\u00e9uticas, abordando conceptos clave como el proceso de solicitud para participar en la evaluaci\u00f3n de productos, la clasificaci\u00f3n de sustancias activas seg\u00fan su solubilidad, la definici\u00f3n de lotes de compromiso, productos comparadores, productos multisource establecidos y sustancias activas existentes. Estos t\u00e9rminos son relevantes para la regulaci\u00f3n y evaluaci\u00f3n de medicamentos, especialmente en el contexto de la pre-calificaci\u00f3n de medicamentos por parte de la OMS.\n\n### Preguntas\n\n1. **\u00bfQu\u00e9 criterios debe cumplir un producto para ser considerado un \"Established Multisource (Generic) Product\"?**\n   - Respuesta: Un producto multisource debe haber sido comercializado por el solicitante o fabricante asociado con el expediente durante al menos cinco a\u00f1os y debe haber producido al menos 10 lotes de producci\u00f3n en el a\u00f1o anterior, o si se produjeron menos de 10 lotes en el a\u00f1o anterior, no menos de 25 lotes en los \u00faltimos tres a\u00f1os.\n\n2. **\u00bfC\u00f3mo se define un \"Comparator Product\" en el contexto de la evaluaci\u00f3n de medicamentos?**\n   - Respuesta: Un \"Comparator Product\" es un producto farmac\u00e9utico con el cual se pretende que el producto gen\u00e9rico sea intercambiable en la pr\u00e1ctica cl\u00ednica. Normalmente, este producto es el innovador para el cual se han establecido la eficacia, seguridad y calidad.\n\n3. **\u00bfQu\u00e9 implica la categor\u00eda de \"Existing API\" y qu\u00e9 requisitos se deben cumplir para su presentaci\u00f3n?**\n   - Respuesta: Un \"Existing API\" es una sustancia activa que no se considera una nueva sustancia activa y que ha sido previamente aprobada a trav\u00e9s de un producto terminado por una autoridad reguladora estricta o por la OMS, pero que requiere la presentaci\u00f3n de un expediente. Esto incluye, por ejemplo, nuevos documentos de producto (PDs) y variaciones a productos multisource.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Definiciones de t\u00e9rminos**:\n   - **Ingrediente farmac\u00e9utico activo (API)**: Sustancia o mezcla utilizada en la fabricaci\u00f3n de formas farmac\u00e9uticas que proporciona actividad farmacol\u00f3gica o efecto directo en el diagn\u00f3stico, tratamiento o prevenci\u00f3n de enfermedades.\n   - **Material de inicio de API**: Materia prima, intermedio o API utilizado en la producci\u00f3n de un API, que se incorpora como un fragmento estructural significativo en su estructura. Puede ser adquirido comercialmente, comprado bajo contrato o producido internamente.\n\n2. **Directrices para la presentaci\u00f3n de informaci\u00f3n sobre productos farmac\u00e9uticos terminados (FPP)**:\n   - **M\u00faltiples concentraciones**: Se requiere una secci\u00f3n completa \"3.2.P\" para cada concentraci\u00f3n, junto con una copia del documento de presentaci\u00f3n (PD) para cada una.\n   - **M\u00faltiples sistemas de cierre**: Se debe proporcionar una secci\u00f3n \"3.2.P\" completa para cada presentaci\u00f3n.\n   - **M\u00faltiples FPPs**: Se necesita un expediente separado para cada FPP.\n   - **FPP con diluyentes de reconstituci\u00f3n**: Se debe incluir una secci\u00f3n \"3.2.P\" para el FPP y otra para los diluyentes.\n   - **FPP co-blisterados**: Se requiere una secci\u00f3n \"3.2.P\" completa para cada producto.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las directrices.\n- **API**: Ingrediente clave en la fabricaci\u00f3n de medicamentos.\n- **FPP**: Producto farmac\u00e9utico terminado que se presenta en diversas formas y concentraciones. \n\nEste resumen proporciona una visi\u00f3n general de los conceptos y requisitos establecidos en la secci\u00f3n del glosario y las directrices de presentaci\u00f3n.", "excerpt_keywords": "Keywords: pharmaceutical preparations, biopharmaceutics, comparator product, multisource product, active pharmaceutical ingredient"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "70b50c8c-46fd-4af1-afb4-96d4a26b73e3", "node_type": "4", "metadata": {"page_label": "140", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Applicant\n\nThe person or entity who, by the deadline mentioned in the invitation, submits an expression of interest (EOI) to participate in this procedure in respect of the product(s) listed in the invitation, together with the required documentation on such product(s).\n\n## Biopharmaceutics Classification System (BCS) Highly Soluble\n\nAn API for which the highest dose recommended by WHO (if the API appears on the WHO Model list of essential medicines) or highest dose strength available on the market as an oral solid dosage form (if the API does not appear on the WHO Model list of essential medicines) is soluble in 250 ml or less of aqueous media over the pH range of 1.2\u20136.8 at 37 \u00b0C.\n\n## Commitment Batches\n\nProduction batches of an API or FPP for which the stability studies are initiated or completed post-approval through a commitment made in a regulatory application.\n\n## Comparator Product\n\nA pharmaceutical product with which the generic product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality have been established. For the Prequalification of Medicines Programme, the selection of the comparator product is based on the information presented under Guidance on bioequivalence studies available on the Prequalification web site.\n\n## Established Multisource (Generic) Product\n\nA multisource product that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year, or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years.\n\n## Existing API\n\nAn API that is not considered a new active substance, which has been previously approved through a finished product by a stringent regulatory authority or by WHO, but requires the filing of a dossier. This would include, for example, new PDs and variations to multisource products.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "8efb5607e21b97c83e4ed3972bf2f539dc9f465a540824c433b60db5b304e4b2", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Applicant\n\nThe person or entity who, by the deadline mentioned in the invitation, submits an expression of interest (EOI) to participate in this procedure in respect of the product(s) listed in the invitation, together with the required documentation on such product(s).\n\n## Biopharmaceutics Classification System (BCS) Highly Soluble\n\nAn API for which the highest dose recommended by WHO (if the API appears on the WHO Model list of essential medicines) or highest dose strength available on the market as an oral solid dosage form (if the API does not appear on the WHO Model list of essential medicines) is soluble in 250 ml or less of aqueous media over the pH range of 1.2\u20136.8 at 37 \u00b0C.\n\n## Commitment Batches\n\nProduction batches of an API or FPP for which the stability studies are initiated or completed post-approval through a commitment made in a regulatory application.\n\n## Comparator Product\n\nA pharmaceutical product with which the generic product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality have been established. For the Prequalification of Medicines Programme, the selection of the comparator product is based on the information presented under Guidance on bioequivalence studies available on the Prequalification web site.\n\n## Established Multisource (Generic) Product\n\nA multisource product that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year, or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years.\n\n## Existing API\n\nAn API that is not considered a new active substance, which has been previously approved through a finished product by a stringent regulatory authority or by WHO, but requires the filing of a dossier. This would include, for example, new PDs and variations to multisource products.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2120, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d1fd6a00-0c33-4fb1-bb6e-72556af5aa70": {"__data__": {"id_": "d1fd6a00-0c33-4fb1-bb6e-72556af5aa70", "embedding": null, "metadata": {"page_label": "141", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n**finished pharmaceutical product (FPP)**  \nA finished dosage form of a pharmaceutical product which has undergone all stages of manufacture, including packaging in its final container and labelling.\n\n**innovator pharmaceutical product**  \nGenerally the pharmaceutical product that was first authorized for marketing (normally as a patented product) on the basis of documentation of efficacy, safety and quality.\n\n**manufacturer**  \nA company that carries out operations such as production, packaging, repackaging, labelling and relabelling of pharmaceuticals.\n\n**multisource (generic) pharmaceutical products**  \nPharmaceutically equivalent or pharmaceutically alternative products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable.\n\n**officially recognized pharmacopoeia (or compendium)**  \nThose pharmacopoeias recognized in the WHO Prequalification of Medicines Programme (i.e. *British Pharmacopoeia* (BP), *European Pharmacopoeia* (Ph.Eur.), *The International Pharmacopoeia* (Ph.Int.), *Japanese Pharmacopoeia* (JP) and *United States Pharmacopeia* (USP)).\n\n**ongoing stability study**  \nThe study carried out by the manufacturer on production batches according to a predetermined schedule in order to monitor, confirm and extend the projected retest period (or shelf-life) of the API, or confirm or extend the shelf-life of the FPP.\n\n**pilot-scale batch**  \nA batch of an API or FPP manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For example, for solid oral dosage forms a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger; unless otherwise adequately justified.\n\n**primary batch**  \nA batch of an API or FPP used in a stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf-life. For the WHO Prequalification of Medicines Programme, primary batch requirements are outlined in 3.2.S.7.1 and 3.2.P.8.1 for the API and FPP, respectively.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Informe T\u00e9cnico 970 incluye definiciones clave relacionadas con productos farmac\u00e9uticos. Se abordan conceptos como el producto farmac\u00e9utico terminado (FPP), el producto farmac\u00e9utico innovador, el fabricante, los productos farmac\u00e9uticos multisource (gen\u00e9ricos), las farmacopeas reconocidas oficialmente, estudios de estabilidad en curso, lotes a escala piloto y lotes primarios. Estas definiciones son fundamentales para entender los procesos de fabricaci\u00f3n, regulaci\u00f3n y evaluaci\u00f3n de medicamentos en el contexto de la pre-calificaci\u00f3n de medicamentos por parte de la OMS.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 requisitos espec\u00edficos se establecen para los lotes primarios en el contexto de la pre-calificaci\u00f3n de medicamentos de la OMS?**\n   - Esta pregunta busca informaci\u00f3n sobre los requisitos detallados que se mencionan en las secciones 3.2.S.7.1 y 3.2.P.8.1, que no se encuentran f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfCu\u00e1l es la diferencia entre un producto farmac\u00e9utico innovador y un producto farmac\u00e9utico multisource (gen\u00e9rico) seg\u00fan el documento?**\n   - Esta pregunta se centra en las definiciones y caracter\u00edsticas que distinguen a estos dos tipos de productos farmac\u00e9uticos, proporcionando claridad sobre su clasificaci\u00f3n.\n\n3. **\u00bfQu\u00e9 implica un estudio de estabilidad en curso y c\u00f3mo se relaciona con la vida \u00fatil de un producto farmac\u00e9utico terminado (FPP)?**\n   - Esta pregunta busca una comprensi\u00f3n m\u00e1s profunda del proceso y la importancia de los estudios de estabilidad en la determinaci\u00f3n de la vida \u00fatil de los productos farmac\u00e9uticos, un aspecto cr\u00edtico en la fabricaci\u00f3n y regulaci\u00f3n de medicamentos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS se centra en las especificaciones para las preparaciones farmac\u00e9uticas y define varios t\u00e9rminos importantes relacionados con la regulaci\u00f3n y evaluaci\u00f3n de medicamentos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n1. **Solicitante (Applicant)**: Persona o entidad que presenta una expresi\u00f3n de inter\u00e9s para participar en el procedimiento de evaluaci\u00f3n de productos, junto con la documentaci\u00f3n requerida.\n\n2. **Sistema de Clasificaci\u00f3n Biofarmac\u00e9utica (BCS) - Alta Solubilidad**: Se refiere a un API cuya dosis m\u00e1s alta recomendada es soluble en 250 ml o menos de medio acuoso en un rango de pH de 1.2 a 6.8 a 37 \u00b0C.\n\n3. **Lotes de Compromiso (Commitment Batches)**: Lotes de producci\u00f3n de un API o FPP para los cuales se inician o completan estudios de estabilidad despu\u00e9s de la aprobaci\u00f3n, como parte de un compromiso en una solicitud regulatoria.\n\n4. **Producto Comparador (Comparator Product)**: Producto farmac\u00e9utico con el cual se espera que el producto gen\u00e9rico sea intercambiable en la pr\u00e1ctica cl\u00ednica, normalmente el producto innovador que ha demostrado eficacia, seguridad y calidad.\n\n5. **Producto Multisource Establecido (Established Multisource (Generic) Product)**: Producto multisource que ha estado en el mercado durante al menos cinco a\u00f1os y ha producido al menos 10 lotes en el \u00faltimo a\u00f1o, o al menos 25 lotes en los \u00faltimos tres a\u00f1os si se produjeron menos de 10 en el \u00faltimo a\u00f1o.\n\n6. **API Existente (Existing API)**: Sustancia activa que no se considera nueva y que ha sido aprobada previamente por una autoridad reguladora estricta o por la OMS, pero que requiere la presentaci\u00f3n de un expediente.\n\n### Conclusi\u00f3n\nEstos t\u00e9rminos son fundamentales para entender el proceso de evaluaci\u00f3n y regulaci\u00f3n de medicamentos, especialmente en el contexto de la pre-calificaci\u00f3n de medicamentos por parte de la OMS.", "excerpt_keywords": "Keywords: pharmaceutical product, stability study, innovator product, multisource product, pharmacopoeia"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9671cd89-3633-4761-b8a0-9d1279cd6c94", "node_type": "4", "metadata": {"page_label": "141", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n**finished pharmaceutical product (FPP)**  \nA finished dosage form of a pharmaceutical product which has undergone all stages of manufacture, including packaging in its final container and labelling.\n\n**innovator pharmaceutical product**  \nGenerally the pharmaceutical product that was first authorized for marketing (normally as a patented product) on the basis of documentation of efficacy, safety and quality.\n\n**manufacturer**  \nA company that carries out operations such as production, packaging, repackaging, labelling and relabelling of pharmaceuticals.\n\n**multisource (generic) pharmaceutical products**  \nPharmaceutically equivalent or pharmaceutically alternative products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable.\n\n**officially recognized pharmacopoeia (or compendium)**  \nThose pharmacopoeias recognized in the WHO Prequalification of Medicines Programme (i.e. *British Pharmacopoeia* (BP), *European Pharmacopoeia* (Ph.Eur.), *The International Pharmacopoeia* (Ph.Int.), *Japanese Pharmacopoeia* (JP) and *United States Pharmacopeia* (USP)).\n\n**ongoing stability study**  \nThe study carried out by the manufacturer on production batches according to a predetermined schedule in order to monitor, confirm and extend the projected retest period (or shelf-life) of the API, or confirm or extend the shelf-life of the FPP.\n\n**pilot-scale batch**  \nA batch of an API or FPP manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For example, for solid oral dosage forms a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger; unless otherwise adequately justified.\n\n**primary batch**  \nA batch of an API or FPP used in a stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf-life. For the WHO Prequalification of Medicines Programme, primary batch requirements are outlined in 3.2.S.7.1 and 3.2.P.8.1 for the API and FPP, respectively.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f593e5d95c97668d59a0fe5951a4f5d97bc12d32ec3a4d1f579f5ab5b7a47231", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 4\n\n**finished pharmaceutical product (FPP)**  \nA finished dosage form of a pharmaceutical product which has undergone all stages of manufacture, including packaging in its final container and labelling.\n\n**innovator pharmaceutical product**  \nGenerally the pharmaceutical product that was first authorized for marketing (normally as a patented product) on the basis of documentation of efficacy, safety and quality.\n\n**manufacturer**  \nA company that carries out operations such as production, packaging, repackaging, labelling and relabelling of pharmaceuticals.\n\n**multisource (generic) pharmaceutical products**  \nPharmaceutically equivalent or pharmaceutically alternative products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable.\n\n**officially recognized pharmacopoeia (or compendium)**  \nThose pharmacopoeias recognized in the WHO Prequalification of Medicines Programme (i.e. *British Pharmacopoeia* (BP), *European Pharmacopoeia* (Ph.Eur.), *The International Pharmacopoeia* (Ph.Int.), *Japanese Pharmacopoeia* (JP) and *United States Pharmacopeia* (USP)).\n\n**ongoing stability study**  \nThe study carried out by the manufacturer on production batches according to a predetermined schedule in order to monitor, confirm and extend the projected retest period (or shelf-life) of the API, or confirm or extend the shelf-life of the FPP.\n\n**pilot-scale batch**  \nA batch of an API or FPP manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For example, for solid oral dosage forms a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger; unless otherwise adequately justified.\n\n**primary batch**  \nA batch of an API or FPP used in a stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf-life. For the WHO Prequalification of Medicines Programme, primary batch requirements are outlined in 3.2.S.7.1 and 3.2.P.8.1 for the API and FPP, respectively.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2196, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "5537eedb-e456-447c-8a71-228e367c86a0": {"__data__": {"id_": "5537eedb-e456-447c-8a71-228e367c86a0", "embedding": null, "metadata": {"page_label": "142", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3. Quality summaries\n\n## 3.1 Module 2.3: Quality overall summary \u2013 product dossiers (QOS-PD)\n\nThe Quality overall summary (QOS) is a summary that follows the scope and the outline of the Body of data in Module 3. The QOS should not include information, data or justification that was not already included in Module 3 or in other parts of the CTD.\n\nThe QOS should include sufficient information from each section to provide the Quality assessor with an overview of Module 3. The QOS should also emphasize critical key parameters of the product and provide, for instance, justification in cases where guidelines were not followed. The QOS should include a discussion of key issues that integrates information from sections in the Quality module and supporting information from other Modules (e.g. qualification of impurities via toxicological studies), including cross-referencing to volume and page number in other Modules.\n\nThe WHO *Quality overall summary \u2013 product dossiers (QOS-PD)* template should be completed for multisource pharmaceutical products containing APIs of synthetic or semi-synthetic origin (see 1.3 Scope for further clarification) and their corresponding FPPs.\n\nAll sections and fields in the QOS-PD template that would be applicable should be completed. It is understood that certain sections and fields may not apply and should be indicated as such by reporting \u201cnot applicable\u201d in the appropriate area with an accompanying explanatory note.\n\nThe use of tables to summarize the information is encouraged where possible. The tables included in the template may need to be expanded or duplicated (e.g. for multiple strengths). These tables are included as illustrative examples of how to summarize information. Other approaches can be used to summarize the information if they fulfil the same purpose.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n### Preguntas y Respuestas\n\n1. **\u00bfCu\u00e1l es el prop\u00f3sito principal del Quality overall summary (QOS) en el contexto de los dossiers de productos farmac\u00e9uticos?**\n   - **Respuesta:** El prop\u00f3sito principal del QOS es proporcionar un resumen que siga el alcance y el esquema del Cuerpo de datos en el M\u00f3dulo 3, ofreciendo al evaluador de calidad una visi\u00f3n general de este m\u00f3dulo. Debe incluir informaci\u00f3n cr\u00edtica y justificaciones en caso de que no se sigan las directrices establecidas.\n\n2. **\u00bfQu\u00e9 se debe hacer si hay secciones o campos en el QOS-PD que no son aplicables?**\n   - **Respuesta:** Si hay secciones o campos en el QOS-PD que no son aplicables, se debe indicar como \"no aplicable\" en el \u00e1rea correspondiente, acompa\u00f1\u00e1ndolo con una nota explicativa que justifique la raz\u00f3n de su no aplicaci\u00f3n.\n\n3. **\u00bfC\u00f3mo se recomienda presentar la informaci\u00f3n en el QOS-PD para facilitar su comprensi\u00f3n?**\n   - **Respuesta:** Se recomienda el uso de tablas para resumir la informaci\u00f3n donde sea posible. Las tablas incluidas en el template pueden necesitar ser ampliadas o duplicadas para reflejar m\u00faltiples concentraciones, y se pueden utilizar otros enfoques siempre que cumplan el mismo prop\u00f3sito de resumir la informaci\u00f3n.\n\n### Resumen de Nivel Superior\n\nEl documento se centra en la importancia del Quality overall summary (QOS) dentro de los dossiers de productos farmac\u00e9uticos, espec\u00edficamente para productos multisource que contienen ingredientes activos de origen sint\u00e9tico o semi-sint\u00e9tico. Se enfatiza que el QOS debe ser un resumen conciso que no incluya informaci\u00f3n no presente en el M\u00f3dulo 3 o en otras partes del CTD. Adem\u00e1s, se destaca la necesidad de justificar cualquier desviaci\u00f3n de las directrices y la recomendaci\u00f3n de utilizar tablas para una mejor presentaci\u00f3n de la informaci\u00f3n.\n\n### Preguntas Mejoradas\n\n1. **\u00bfQu\u00e9 tipo de productos farmac\u00e9uticos deben completar el template del QOS-PD seg\u00fan las directrices de la OMS?**\n2. **\u00bfQu\u00e9 tipo de informaci\u00f3n se debe integrar en el QOS para abordar cuestiones clave relacionadas con la calidad del producto?**\n3. **\u00bfQu\u00e9 se sugiere hacer si se requiere resumir informaci\u00f3n de m\u00faltiples fortalezas en el QOS-PD?**", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nLa secci\u00f3n del documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en el Informe T\u00e9cnico 970 aborda definiciones fundamentales relacionadas con la fabricaci\u00f3n y regulaci\u00f3n de productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas:\n\n1. **Productos Farmac\u00e9uticos Terminados (FPP)**: Se define como la forma de dosificaci\u00f3n final de un producto farmac\u00e9utico que ha completado todas las etapas de fabricaci\u00f3n, incluyendo el empaquetado y etiquetado.\n\n2. **Productos Farmac\u00e9uticos Innovadores**: Se refiere a los productos que fueron autorizados por primera vez para su comercializaci\u00f3n, generalmente bajo patente, bas\u00e1ndose en documentaci\u00f3n que demuestra su eficacia, seguridad y calidad.\n\n3. **Fabricantes**: Empresas que realizan operaciones de producci\u00f3n, empaquetado, reempaquetado, etiquetado y reetiquetado de productos farmac\u00e9uticos.\n\n4. **Productos Farmac\u00e9uticos Multisource (Gen\u00e9ricos)**: Productos que son equivalentes farmac\u00e9uticamente o alternativos, que pueden o no ser terap\u00e9uticamente equivalentes. Los que son terap\u00e9uticamente equivalentes son intercambiables.\n\n5. **Farmacopeas Reconocidas Oficialmente**: Incluye farmacopeas que son reconocidas en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS, como la *British Pharmacopoeia*, *European Pharmacopoeia*, *The International Pharmacopoeia*, *Japanese Pharmacopoeia* y *United States Pharmacopeia*.\n\n6. **Estudios de Estabilidad en Curso**: Estudios realizados por el fabricante sobre lotes de producci\u00f3n para monitorear y extender el per\u00edodo de rean\u00e1lisis o la vida \u00fatil del ingrediente activo (API) o del FPP.\n\n7. **Lotes a Escala Piloto**: Lotes de un API o FPP fabricados mediante un procedimiento que simula el que se aplicar\u00e1 a un lote de producci\u00f3n a gran escala, con un tama\u00f1o m\u00ednimo generalmente de una d\u00e9cima parte del lote de producci\u00f3n completo.\n\n8. **Lotes Primarios**: Lotes de un API o FPP utilizados en un estudio de estabilidad, cuyos datos se presentan en una solicitud de registro para establecer un per\u00edodo de rean\u00e1lisis o vida \u00fatil. Los requisitos para los lotes primarios est\u00e1n especificados en secciones espec\u00edficas del documento.\n\nEste resumen proporciona una visi\u00f3n general de los t\u00e9rminos y conceptos clave que son esenciales para entender el contexto de la fabricaci\u00f3n y regulaci\u00f3n de medicamentos en el marco de la OMS.", "excerpt_keywords": "Keywords: Quality overall summary, product dossiers, multisource pharmaceutical products, CTD, regulatory guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73ce251c-79aa-4fd8-a566-ac38d8d60c88", "node_type": "4", "metadata": {"page_label": "142", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3. Quality summaries\n\n## 3.1 Module 2.3: Quality overall summary \u2013 product dossiers (QOS-PD)\n\nThe Quality overall summary (QOS) is a summary that follows the scope and the outline of the Body of data in Module 3. The QOS should not include information, data or justification that was not already included in Module 3 or in other parts of the CTD.\n\nThe QOS should include sufficient information from each section to provide the Quality assessor with an overview of Module 3. The QOS should also emphasize critical key parameters of the product and provide, for instance, justification in cases where guidelines were not followed. The QOS should include a discussion of key issues that integrates information from sections in the Quality module and supporting information from other Modules (e.g. qualification of impurities via toxicological studies), including cross-referencing to volume and page number in other Modules.\n\nThe WHO *Quality overall summary \u2013 product dossiers (QOS-PD)* template should be completed for multisource pharmaceutical products containing APIs of synthetic or semi-synthetic origin (see 1.3 Scope for further clarification) and their corresponding FPPs.\n\nAll sections and fields in the QOS-PD template that would be applicable should be completed. It is understood that certain sections and fields may not apply and should be indicated as such by reporting \u201cnot applicable\u201d in the appropriate area with an accompanying explanatory note.\n\nThe use of tables to summarize the information is encouraged where possible. The tables included in the template may need to be expanded or duplicated (e.g. for multiple strengths). These tables are included as illustrative examples of how to summarize information. Other approaches can be used to summarize the information if they fulfil the same purpose.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f362f699ca5120da98c74d669504b28b5e54c02e7e925d5fb20b3d62b4dfed4d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3. Quality summaries\n\n## 3.1 Module 2.3: Quality overall summary \u2013 product dossiers (QOS-PD)\n\nThe Quality overall summary (QOS) is a summary that follows the scope and the outline of the Body of data in Module 3. The QOS should not include information, data or justification that was not already included in Module 3 or in other parts of the CTD.\n\nThe QOS should include sufficient information from each section to provide the Quality assessor with an overview of Module 3. The QOS should also emphasize critical key parameters of the product and provide, for instance, justification in cases where guidelines were not followed. The QOS should include a discussion of key issues that integrates information from sections in the Quality module and supporting information from other Modules (e.g. qualification of impurities via toxicological studies), including cross-referencing to volume and page number in other Modules.\n\nThe WHO *Quality overall summary \u2013 product dossiers (QOS-PD)* template should be completed for multisource pharmaceutical products containing APIs of synthetic or semi-synthetic origin (see 1.3 Scope for further clarification) and their corresponding FPPs.\n\nAll sections and fields in the QOS-PD template that would be applicable should be completed. It is understood that certain sections and fields may not apply and should be indicated as such by reporting \u201cnot applicable\u201d in the appropriate area with an accompanying explanatory note.\n\nThe use of tables to summarize the information is encouraged where possible. The tables included in the template may need to be expanded or duplicated (e.g. for multiple strengths). These tables are included as illustrative examples of how to summarize information. Other approaches can be used to summarize the information if they fulfil the same purpose.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1823, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "5fdfa9cb-9525-467d-86f0-38c6d40daa46": {"__data__": {"id_": "5fdfa9cb-9525-467d-86f0-38c6d40daa46", "embedding": null, "metadata": {"page_label": "143", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Module 1.4.2: Quality information summary (QIS)\n\nThe QIS template should be completed to provide a condensed summary of the key quality information for the PD and constitutes part of the submission package. The QIS provides an accurate record of technical data in the PD at the time of prequalification. The QIS is a condensed version of the QOS-PD and represents the final agreed-upon key information on the API and FPP from the PD assessment (including, but not limited to, identification of the manufacturer(s), site addresses, API/FPP specifications, stability conclusions and relevant commitments).\n\nThe QIS template is structured according to the numbering and section headings of the ICH M4Q (CTD-Q) guideline to permit the rapid assembly of the QIS by copying the requisite information from the corresponding portions of the QOS-PD filed with the PD. It is acknowledged that the numbering of the sections in the QIS may not be entirely sequential. Those sections not considered necessary for inclusion in the QIS have been removed (e.g. 2.3.S.5 Reference standards or materials) and the remaining sections have retained their original numbering to maintain consistency with the original PD.\n\nThe QIS will serve as an official reference document in the course of good manufacturing practices (GMP) inspections, variation assessments and requalification assessments as performed by WHO.\n\n# 4. Module 3: Quality\n\n## 4.1 Table of contents of Module 3\n\nA Table of contents for the filed product dossier should be provided.\n\n## 4.2 Body of data\n\n### 3.2.S Drug substance (or active pharmaceutical ingredient, API)\n\nThere are four options for submitting the API information to WHO:\n\n- **Option 1:** confirmation of API prequalification document;\n- **Option 2:** Certificate of Suitability of the *European Pharmacopoeia* (Ph.Eur.) (CEP); or\n- **Option 3:** active pharmaceutical ingredient master file (APIMF) procedure; or\n- **Option 4:** full details in the PD.\n\nThe applicant should clearly indicate at the beginning of the API section (in the PD and in the QOS-PD) how the information on the API for each API manufacturer is being submitted. The API information submitted by the applicant or FPP manufacturer should include the following according to the options used.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (WHO - Technical Report Series 970) aborda la importancia del Quality Information Summary (QIS) como parte del paquete de presentaci\u00f3n para la precalificaci\u00f3n de productos farmac\u00e9uticos. El QIS resume la informaci\u00f3n clave sobre la calidad del principio activo (API) y el producto farmac\u00e9utico terminado (FPP), y se estructura de acuerdo con las directrices ICH M4Q. Adem\u00e1s, se describen las cuatro opciones disponibles para presentar la informaci\u00f3n del API a la OMS.\n\n### Preguntas:\n1. **\u00bfCu\u00e1l es la funci\u00f3n principal del Quality Information Summary (QIS) en el proceso de precalificaci\u00f3n de productos farmac\u00e9uticos?**\n   - El QIS proporciona un resumen condensado de la informaci\u00f3n clave sobre la calidad del producto, sirviendo como un documento de referencia oficial durante las inspecciones de buenas pr\u00e1cticas de manufactura (GMP) y evaluaciones de variaciones.\n\n2. **\u00bfQu\u00e9 opciones tiene un solicitante para presentar la informaci\u00f3n del principio activo (API) a la OMS, y qu\u00e9 debe incluir cada opci\u00f3n?**\n   - Las cuatro opciones son: 1) confirmaci\u00f3n del documento de precalificaci\u00f3n del API, 2) Certificado de Idoneidad de la Farmacopea Europea (CEP), 3) procedimiento de archivo maestro del principio activo (APIMF), y 4) detalles completos en el dossier del producto (PD). Cada opci\u00f3n tiene requisitos espec\u00edficos que deben ser indicados claramente al inicio de la secci\u00f3n del API.\n\n3. **\u00bfPor qu\u00e9 se ha estructurado el QIS de acuerdo con las secciones del ICH M4Q (CTD-Q) y qu\u00e9 implicaciones tiene esto para su uso?**\n   - La estructura del QIS seg\u00fan las secciones del ICH M4Q permite una r\u00e1pida recopilaci\u00f3n de informaci\u00f3n al copiar datos relevantes del QOS-PD. Esto asegura consistencia y facilita la revisi\u00f3n durante las evaluaciones de calidad, aunque algunas secciones no necesarias han sido eliminadas para mantener la concisi\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Quality Overall Summary (QOS):** \n   - Es un resumen que sigue el esquema del Cuerpo de datos en el M\u00f3dulo 3 del CTD (Common Technical Document).\n   - No debe incluir informaci\u00f3n que no est\u00e9 presente en el M\u00f3dulo 3 o en otras partes del CTD.\n\n2. **Prop\u00f3sito del QOS:**\n   - Proporcionar al evaluador de calidad una visi\u00f3n general del M\u00f3dulo 3.\n   - Enfatizar par\u00e1metros cr\u00edticos del producto y justificar desviaciones de las directrices.\n\n3. **Integraci\u00f3n de Informaci\u00f3n:**\n   - Debe incluir una discusi\u00f3n de cuestiones clave que integre informaci\u00f3n de diferentes secciones del m\u00f3dulo de calidad y de otros m\u00f3dulos, como estudios toxicol\u00f3gicos.\n\n4. **Template del QOS-PD:**\n   - Debe ser completado para productos farmac\u00e9uticos multisource con APIs de origen sint\u00e9tico o semi-sint\u00e9tico.\n   - Secciones no aplicables deben ser marcadas como \"no aplicable\" con una nota explicativa.\n\n5. **Presentaci\u00f3n de Informaci\u00f3n:**\n   - Se recomienda el uso de tablas para resumir informaci\u00f3n, que pueden ser ampliadas o duplicadas seg\u00fan sea necesario.\n\n**Entidades:**\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Autoridad que proporciona las directrices para la elaboraci\u00f3n del QOS.\n- **QOS-PD (Quality Overall Summary \u2013 Product Dossiers):** Template espec\u00edfico para productos farmac\u00e9uticos.\n- **M\u00f3dulo 3:** Parte del CTD que contiene datos sobre la calidad del producto.\n- **APIs (Active Pharmaceutical Ingredients):** Ingredientes activos de origen sint\u00e9tico o semi-sint\u00e9tico que se analizan en el QOS.\n- **FPPs (Finished Pharmaceutical Products):** Productos farmac\u00e9uticos terminados que corresponden a los APIs analizados.\n\nEste resumen destaca la importancia del QOS en la evaluaci\u00f3n de la calidad de productos farmac\u00e9uticos y las directrices espec\u00edficas que deben seguirse para su elaboraci\u00f3n.", "excerpt_keywords": "Keywords: Quality Information Summary, API, prequalification, WHO, pharmaceutical products"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "27710dcf-7213-4281-9466-a60e34752b54", "node_type": "4", "metadata": {"page_label": "143", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Module 1.4.2: Quality information summary (QIS)\n\nThe QIS template should be completed to provide a condensed summary of the key quality information for the PD and constitutes part of the submission package. The QIS provides an accurate record of technical data in the PD at the time of prequalification. The QIS is a condensed version of the QOS-PD and represents the final agreed-upon key information on the API and FPP from the PD assessment (including, but not limited to, identification of the manufacturer(s), site addresses, API/FPP specifications, stability conclusions and relevant commitments).\n\nThe QIS template is structured according to the numbering and section headings of the ICH M4Q (CTD-Q) guideline to permit the rapid assembly of the QIS by copying the requisite information from the corresponding portions of the QOS-PD filed with the PD. It is acknowledged that the numbering of the sections in the QIS may not be entirely sequential. Those sections not considered necessary for inclusion in the QIS have been removed (e.g. 2.3.S.5 Reference standards or materials) and the remaining sections have retained their original numbering to maintain consistency with the original PD.\n\nThe QIS will serve as an official reference document in the course of good manufacturing practices (GMP) inspections, variation assessments and requalification assessments as performed by WHO.\n\n# 4. Module 3: Quality\n\n## 4.1 Table of contents of Module 3\n\nA Table of contents for the filed product dossier should be provided.\n\n## 4.2 Body of data\n\n### 3.2.S Drug substance (or active pharmaceutical ingredient, API)\n\nThere are four options for submitting the API information to WHO:\n\n- **Option 1:** confirmation of API prequalification document;\n- **Option 2:** Certificate of Suitability of the *European Pharmacopoeia* (Ph.Eur.) (CEP); or\n- **Option 3:** active pharmaceutical ingredient master file (APIMF) procedure; or\n- **Option 4:** full details in the PD.\n\nThe applicant should clearly indicate at the beginning of the API section (in the PD and in the QOS-PD) how the information on the API for each API manufacturer is being submitted. The API information submitted by the applicant or FPP manufacturer should include the following according to the options used.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "b94f8115ae38b3b0d0b35ea30f3737fd22827fce05bfac9a3a5f128866d61ccd", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Module 1.4.2: Quality information summary (QIS)\n\nThe QIS template should be completed to provide a condensed summary of the key quality information for the PD and constitutes part of the submission package. The QIS provides an accurate record of technical data in the PD at the time of prequalification. The QIS is a condensed version of the QOS-PD and represents the final agreed-upon key information on the API and FPP from the PD assessment (including, but not limited to, identification of the manufacturer(s), site addresses, API/FPP specifications, stability conclusions and relevant commitments).\n\nThe QIS template is structured according to the numbering and section headings of the ICH M4Q (CTD-Q) guideline to permit the rapid assembly of the QIS by copying the requisite information from the corresponding portions of the QOS-PD filed with the PD. It is acknowledged that the numbering of the sections in the QIS may not be entirely sequential. Those sections not considered necessary for inclusion in the QIS have been removed (e.g. 2.3.S.5 Reference standards or materials) and the remaining sections have retained their original numbering to maintain consistency with the original PD.\n\nThe QIS will serve as an official reference document in the course of good manufacturing practices (GMP) inspections, variation assessments and requalification assessments as performed by WHO.\n\n# 4. Module 3: Quality\n\n## 4.1 Table of contents of Module 3\n\nA Table of contents for the filed product dossier should be provided.\n\n## 4.2 Body of data\n\n### 3.2.S Drug substance (or active pharmaceutical ingredient, API)\n\nThere are four options for submitting the API information to WHO:\n\n- **Option 1:** confirmation of API prequalification document;\n- **Option 2:** Certificate of Suitability of the *European Pharmacopoeia* (Ph.Eur.) (CEP); or\n- **Option 3:** active pharmaceutical ingredient master file (APIMF) procedure; or\n- **Option 4:** full details in the PD.\n\nThe applicant should clearly indicate at the beginning of the API section (in the PD and in the QOS-PD) how the information on the API for each API manufacturer is being submitted. The API information submitted by the applicant or FPP manufacturer should include the following according to the options used.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2275, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "03755e8c-9597-4f7b-bb45-bd03903bda9b": {"__data__": {"id_": "03755e8c-9597-4f7b-bb45-bd03903bda9b", "embedding": null, "metadata": {"page_label": "144", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Option 1: Confirmation of API prequalification document.\n\nA complete copy of the Confirmation of API prequalification document should be provided in Module 1, together with the duly filled out authorization box in the name of the FPP manufacturer or applicant.\n\nThe applicant should supply the following information in the dossier, with data summarized in the QOS-PD.\n\n- **3.2.S.1.3 General properties** \u2013 discussions on any additional applicable physiochemical and other relevant API properties that are not controlled by the API manufacturer\u2019s specifications, e.g. solubilities and polymorphs according to the guidance in this section.\n- **3.2.S.2** \u2013 if the sterility of the FPP is based upon the sterile manufacture of the API then data on the sterilization process together with full validation data should be provided.\n- **3.2.S.3.1 Elucidation of structure and other characteristics** \u2013 studies to identify polymorphs and particle size distribution, where applicable, according to the guidance in this section.\n- **3.2.S.4.1 Specification** \u2013 the specifications of the FPP manufacturer including all tests and limits of the API manufacturer\u2019s specifications and any additional tests and acceptance criteria that are not controlled by the API manufacturer\u2019s specifications such as polymorphs and/or particle size distribution.\n- **3.2.S.4.2/3.2.S.4.3 Analytical procedures and validation** \u2013 any methods used by the FPP manufacturer in addition to those in the API manufacturer\u2019s specifications.\n- **3.2.S.4.4 Batch analysis** \u2013 results from two batches of at least pilot-scale, demonstrating compliance with the FPP manufacturer\u2019s API specifications.\n- **3.2.S.5 Reference standards or materials** \u2013 information on the FPP manufacturer\u2019s reference standards.\n- **3.2.S.7 Stability** \u2013 data to support the retest period if either the proposed retest period is longer or the proposed storage conditions are at a higher temperature or humidity to that of the prequalified API.\n\n## Option 2: Certificate of Suitability of the European Pharmacopoeia (CEP)\n\nA complete copy of the CEP (including any annexes) should be provided in Module 1. The declaration of access for the CEP should be", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las especificaciones para la preparaci\u00f3n farmac\u00e9utica, espec\u00edficamente en los requisitos para la presentaci\u00f3n de documentos relacionados con la pre-calificaci\u00f3n de ingredientes farmac\u00e9uticos activos (API) y el Certificado de Idoneidad de la Farmacopea Europea (CEP). Se detallan los elementos que deben incluirse en el dossier del solicitante, como propiedades generales, especificaciones, procedimientos anal\u00edticos, an\u00e1lisis de lotes, est\u00e1ndares de referencia y estabilidad.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n adicional sobre las propiedades fisicoqu\u00edmicas del API debe incluirse en la secci\u00f3n 3.2.S.1.3 del dossier?**\n   - Respuesta: Debe incluir discusiones sobre cualquier propiedad fisicoqu\u00edmica y relevante del API que no est\u00e9 controlada por las especificaciones del fabricante del API, como solubilidades y polimorfos.\n\n2. **\u00bfQu\u00e9 datos son necesarios para demostrar la esterilidad del producto farmac\u00e9utico terminado (FPP) si se basa en la fabricaci\u00f3n est\u00e9ril del API?**\n   - Respuesta: Se deben proporcionar datos sobre el proceso de esterilizaci\u00f3n junto con la validaci\u00f3n completa de dicho proceso.\n\n3. **\u00bfCu\u00e1les son los requisitos para la secci\u00f3n de estabilidad (3.2.S.7) en el dossier del solicitante?**\n   - Respuesta: Se debe proporcionar datos que respalden el per\u00edodo de rean\u00e1lisis si el per\u00edodo propuesto es m\u00e1s largo o si las condiciones de almacenamiento propuestas son a una temperatura o humedad m\u00e1s alta que las del API pre-calificado.\n\n### Resumen de Nivel Superior\n\nEl documento establece directrices para la presentaci\u00f3n de informaci\u00f3n relacionada con la pre-calificaci\u00f3n de APIs y la obtenci\u00f3n de un CEP. Se enfatiza la importancia de proporcionar datos completos y espec\u00edficos sobre las propiedades del API, los procesos de esterilizaci\u00f3n, las especificaciones del fabricante y la estabilidad del producto. Estas directrices son cruciales para garantizar la calidad y seguridad de los productos farmac\u00e9uticos.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Quality Information Summary (QIS)**:\n   - El QIS es un resumen condensado de la informaci\u00f3n clave sobre la calidad del producto farmac\u00e9utico (PD) y es parte del paquete de presentaci\u00f3n para la precalificaci\u00f3n.\n   - Proporciona un registro preciso de los datos t\u00e9cnicos en el PD al momento de la precalificaci\u00f3n.\n   - Representa la informaci\u00f3n clave acordada sobre el principio activo (API) y el producto farmac\u00e9utico terminado (FPP) tras la evaluaci\u00f3n del PD.\n\n2. **Estructura del QIS**:\n   - El QIS est\u00e1 estructurado seg\u00fan las secciones y numeraci\u00f3n de las directrices ICH M4Q (CTD-Q) para facilitar la recopilaci\u00f3n de informaci\u00f3n.\n   - Algunas secciones no necesarias han sido eliminadas para mantener la concisi\u00f3n, pero se ha mantenido la numeraci\u00f3n original para asegurar consistencia.\n\n3. **Uso del QIS**:\n   - Servir\u00e1 como documento de referencia oficial durante las inspecciones de buenas pr\u00e1cticas de manufactura (GMP), evaluaciones de variaciones y requalificaciones realizadas por la OMS.\n\n4. **Opciones para presentar informaci\u00f3n del API**:\n   - **Opci\u00f3n 1**: Confirmaci\u00f3n del documento de precalificaci\u00f3n del API.\n   - **Opci\u00f3n 2**: Certificado de Idoneidad de la Farmacopea Europea (CEP).\n   - **Opci\u00f3n 3**: Procedimiento de archivo maestro del principio activo (APIMF).\n   - **Opci\u00f3n 4**: Detalles completos en el dossier del producto (PD).\n   - El solicitante debe indicar claramente c\u00f3mo se est\u00e1 presentando la informaci\u00f3n del API al inicio de la secci\u00f3n correspondiente.\n\n### Entidades clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la evaluaci\u00f3n y precalificaci\u00f3n de productos farmac\u00e9uticos.\n- **API (Active Pharmaceutical Ingredient)**: Principio activo del producto farmac\u00e9utico.\n- **FPP (Finished Pharmaceutical Product)**: Producto farmac\u00e9utico terminado.\n- **ICH M4Q (CTD-Q)**: Directrices que estructuran la presentaci\u00f3n de informaci\u00f3n sobre calidad en los dossiers de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: API prequalification, pharmaceutical specifications, stability data, European Pharmacopoeia, analytical procedures"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "01c293c0-fd29-46ea-8531-be827130344f", "node_type": "4", "metadata": {"page_label": "144", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Option 1: Confirmation of API prequalification document.\n\nA complete copy of the Confirmation of API prequalification document should be provided in Module 1, together with the duly filled out authorization box in the name of the FPP manufacturer or applicant.\n\nThe applicant should supply the following information in the dossier, with data summarized in the QOS-PD.\n\n- **3.2.S.1.3 General properties** \u2013 discussions on any additional applicable physiochemical and other relevant API properties that are not controlled by the API manufacturer\u2019s specifications, e.g. solubilities and polymorphs according to the guidance in this section.\n- **3.2.S.2** \u2013 if the sterility of the FPP is based upon the sterile manufacture of the API then data on the sterilization process together with full validation data should be provided.\n- **3.2.S.3.1 Elucidation of structure and other characteristics** \u2013 studies to identify polymorphs and particle size distribution, where applicable, according to the guidance in this section.\n- **3.2.S.4.1 Specification** \u2013 the specifications of the FPP manufacturer including all tests and limits of the API manufacturer\u2019s specifications and any additional tests and acceptance criteria that are not controlled by the API manufacturer\u2019s specifications such as polymorphs and/or particle size distribution.\n- **3.2.S.4.2/3.2.S.4.3 Analytical procedures and validation** \u2013 any methods used by the FPP manufacturer in addition to those in the API manufacturer\u2019s specifications.\n- **3.2.S.4.4 Batch analysis** \u2013 results from two batches of at least pilot-scale, demonstrating compliance with the FPP manufacturer\u2019s API specifications.\n- **3.2.S.5 Reference standards or materials** \u2013 information on the FPP manufacturer\u2019s reference standards.\n- **3.2.S.7 Stability** \u2013 data to support the retest period if either the proposed retest period is longer or the proposed storage conditions are at a higher temperature or humidity to that of the prequalified API.\n\n## Option 2: Certificate of Suitability of the European Pharmacopoeia (CEP)\n\nA complete copy of the CEP (including any annexes) should be provided in Module 1. The declaration of access for the CEP should be", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "302e998e3f5bb498d7b271504d70ccbe8ba94522775c17e42e4ed793b3673132", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Option 1: Confirmation of API prequalification document.\n\nA complete copy of the Confirmation of API prequalification document should be provided in Module 1, together with the duly filled out authorization box in the name of the FPP manufacturer or applicant.\n\nThe applicant should supply the following information in the dossier, with data summarized in the QOS-PD.\n\n- **3.2.S.1.3 General properties** \u2013 discussions on any additional applicable physiochemical and other relevant API properties that are not controlled by the API manufacturer\u2019s specifications, e.g. solubilities and polymorphs according to the guidance in this section.\n- **3.2.S.2** \u2013 if the sterility of the FPP is based upon the sterile manufacture of the API then data on the sterilization process together with full validation data should be provided.\n- **3.2.S.3.1 Elucidation of structure and other characteristics** \u2013 studies to identify polymorphs and particle size distribution, where applicable, according to the guidance in this section.\n- **3.2.S.4.1 Specification** \u2013 the specifications of the FPP manufacturer including all tests and limits of the API manufacturer\u2019s specifications and any additional tests and acceptance criteria that are not controlled by the API manufacturer\u2019s specifications such as polymorphs and/or particle size distribution.\n- **3.2.S.4.2/3.2.S.4.3 Analytical procedures and validation** \u2013 any methods used by the FPP manufacturer in addition to those in the API manufacturer\u2019s specifications.\n- **3.2.S.4.4 Batch analysis** \u2013 results from two batches of at least pilot-scale, demonstrating compliance with the FPP manufacturer\u2019s API specifications.\n- **3.2.S.5 Reference standards or materials** \u2013 information on the FPP manufacturer\u2019s reference standards.\n- **3.2.S.7 Stability** \u2013 data to support the retest period if either the proposed retest period is longer or the proposed storage conditions are at a higher temperature or humidity to that of the prequalified API.\n\n## Option 2: Certificate of Suitability of the European Pharmacopoeia (CEP)\n\nA complete copy of the CEP (including any annexes) should be provided in Module 1. The declaration of access for the CEP should be", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2266, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d42ca7a8-196c-4454-be53-a88a054ba49c": {"__data__": {"id_": "d42ca7a8-196c-4454-be53-a88a054ba49c", "embedding": null, "metadata": {"page_label": "145", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\nduly filled out by the CEP holder on behalf of the FPP manufacturer or applicant to the WHO Prequalification of Medicines Programme who refers to the CEP.\n\nIn addition, a written commitment should be included that the applicant will inform WHO in the event that the CEP is withdrawn. It should also be acknowledged by the applicant that withdrawal of the CEP will require additional consideration of the API data requirements to support the PD. The written commitment should accompany the copy of the CEP in Module 1.\n\nTogether with the CEP, the applicant should supply the following information in the dossier, with data summarized in the QOS-PD.\n\n- **3.2.S.1.3 General properties** \u2013 discussions on any additional applicable physicochemical and other relevant properties of the API that are not controlled by the CEP and Ph.Eur. monograph, e.g. solubilities and polymorphs according to the guidance in this section.\n\n- **3.2.S.3.1 Elucidation of structure and other characteristics** \u2013 studies to identify polymorphs (except where the CEP specifies a polymorphic form) and particle size distribution, where applicable, according to the guidance in this section.\n\n- **3.2.S.4.1 Specification** \u2013 the specifications of the FPP manufacturer including all tests and limits of the CEP and Ph.Eur. monograph and any additional tests and acceptance criteria that are not controlled in the CEP and Ph.Eur. monograph, such as polymorphs and/or particle size distribution.\n\n- **3.2.S.4.2/3.2.S.4.3 Analytical procedures and validation** \u2013 for any methods used by the FPP manufacturer in addition to those in the CEP and Ph.Eur. monograph.\n\n- **3.2.S.4.4 Batch analysis** \u2013 results from two batches of at least pilot-scale, demonstrating compliance with the FPP manufacturer\u2019s API specifications.\n\n- **3.2.S.5 Reference standards or materials** \u2013 information on the FPP manufacturer\u2019s reference standards.\n\n- **3.2.S.6 Container-closure system** \u2013 specifications including descriptions and identification of primary packaging components except where the CEP specifies a container-closure system and the applicant declares the intent to use the same container-closure system.\n\n- **3.2.S.7 Stability** \u2013 except where the CEP specifies a retest period that is the same as or longer than that proposed by the applicant, and storage conditions are the same or at a higher temperature and humidity than those proposed by the applicant.\n```\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 tipo de compromiso debe incluir el solicitante al presentar la solicitud de precalificaci\u00f3n de medicamentos a la OMS?**\n   - El solicitante debe incluir un compromiso por escrito en el que se compromete a informar a la OMS en caso de que se retire el Certificado de Producto Espec\u00edfico (CEP). Adem\u00e1s, debe reconocer que la retirada del CEP requerir\u00e1 una consideraci\u00f3n adicional de los requisitos de datos del ingrediente farmac\u00e9utico activo (API) para respaldar el expediente de producto (PD).\n\n2. **\u00bfQu\u00e9 informaci\u00f3n adicional debe proporcionar el solicitante junto con el CEP en el expediente?**\n   - Junto con el CEP, el solicitante debe proporcionar informaci\u00f3n resumida en el QOS-PD, que incluye propiedades generales del API, estudios de identificaci\u00f3n de polimorfos y distribuci\u00f3n del tama\u00f1o de part\u00edculas, especificaciones del fabricante del producto farmac\u00e9utico terminado (FPP), procedimientos anal\u00edticos y validaci\u00f3n, an\u00e1lisis de lotes, est\u00e1ndares de referencia, especificaciones del sistema de cierre del contenedor y datos de estabilidad.\n\n3. **\u00bfQu\u00e9 condiciones deben cumplirse en relaci\u00f3n con la estabilidad del API seg\u00fan el CEP?**\n   - La estabilidad del API debe ser evaluada, excepto en los casos en que el CEP especifique un per\u00edodo de rean\u00e1lisis que sea igual o m\u00e1s largo que el propuesto por el solicitante. Adem\u00e1s, las condiciones de almacenamiento deben ser las mismas o de mayor temperatura y humedad que las propuestas por el solicitante.\n\n### Resumen de nivel superior del contexto:\nEl documento detalla los requisitos que deben cumplir los solicitantes al presentar un expediente para la pre-calificaci\u00f3n de medicamentos a la OMS, espec\u00edficamente en relaci\u00f3n con el Certificado de Producto Espec\u00edfico (CEP). Se enfatiza la importancia de proporcionar informaci\u00f3n adicional sobre las propiedades del ingrediente farmac\u00e9utico activo (API), as\u00ed como compromisos relacionados con la retirada del CEP y la estabilidad del producto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Documentaci\u00f3n para la Precalificaci\u00f3n de APIs**:\n   - Se requiere una copia completa del documento de confirmaci\u00f3n de la precalificaci\u00f3n del ingrediente farmac\u00e9utico activo (API) en el M\u00f3dulo 1, junto con una autorizaci\u00f3n debidamente completada a nombre del fabricante o solicitante del producto farmac\u00e9utico terminado (FPP).\n\n2. **Informaci\u00f3n a Incluir en el Dossier**:\n   - **Propiedades Generales (3.2.S.1.3)**: Discusiones sobre propiedades fisicoqu\u00edmicas adicionales del API no controladas por las especificaciones del fabricante, como solubilidades y polimorfos.\n   - **Esterilidad (3.2.S.2)**: Datos sobre el proceso de esterilizaci\u00f3n y validaci\u00f3n si la esterilidad del FPP se basa en la fabricaci\u00f3n est\u00e9ril del API.\n   - **Estructura y Caracter\u00edsticas (3.2.S.3.1)**: Estudios para identificar polimorfos y distribuci\u00f3n del tama\u00f1o de part\u00edculas.\n   - **Especificaciones (3.2.S.4.1)**: Especificaciones del fabricante del FPP, incluyendo pruebas y l\u00edmites de las especificaciones del fabricante del API.\n   - **Procedimientos Anal\u00edticos (3.2.S.4.2/3.2.S.4.3)**: M\u00e9todos utilizados por el fabricante del FPP adem\u00e1s de los especificados por el fabricante del API.\n   - **An\u00e1lisis de Lotes (3.2.S.4.4)**: Resultados de al menos dos lotes a escala piloto que demuestren el cumplimiento con las especificaciones del API del fabricante del FPP.\n   - **Est\u00e1ndares de Referencia (3.2.S.5)**: Informaci\u00f3n sobre los est\u00e1ndares de referencia del fabricante del FPP.\n   - **Estabilidad (3.2.S.7)**: Datos que respalden el per\u00edodo de rean\u00e1lisis si es m\u00e1s largo o si las condiciones de almacenamiento son m\u00e1s exigentes que las del API precalificado.\n\n3. **Certificado de Idoneidad de la Farmacopea Europea (CEP)**:\n   - Se debe proporcionar una copia completa del CEP, incluyendo anexos, en el M\u00f3dulo 1, junto con la declaraci\u00f3n de acceso correspondiente.\n\n### Entidades Clave\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en productos farmac\u00e9uticos.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que contiene el API.\n- **CEP (Certificado de Idoneidad de la Farmacopea Europea)**: Certificaci\u00f3n que garantiza que un API cumple con los est\u00e1ndares de la Farmacopea Europea.\n- **Especificaciones**: Requisitos y pruebas que deben cumplir los productos farmac\u00e9uticos.\n- **Estabilidad**: Capacidad de un producto para mantener su calidad bajo condiciones espec\u00edficas durante un per\u00edodo determinado. \n\nEste resumen destaca la importancia de la documentaci\u00f3n y los requisitos espec\u00edficos para garantizar la calidad y seguridad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: WHO, Prequalification, CEP, API, Stability"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "10703599-ba09-4126-9f2e-8e013ea480c8", "node_type": "4", "metadata": {"page_label": "145", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\nduly filled out by the CEP holder on behalf of the FPP manufacturer or applicant to the WHO Prequalification of Medicines Programme who refers to the CEP.\n\nIn addition, a written commitment should be included that the applicant will inform WHO in the event that the CEP is withdrawn. It should also be acknowledged by the applicant that withdrawal of the CEP will require additional consideration of the API data requirements to support the PD. The written commitment should accompany the copy of the CEP in Module 1.\n\nTogether with the CEP, the applicant should supply the following information in the dossier, with data summarized in the QOS-PD.\n\n- **3.2.S.1.3 General properties** \u2013 discussions on any additional applicable physicochemical and other relevant properties of the API that are not controlled by the CEP and Ph.Eur. monograph, e.g. solubilities and polymorphs according to the guidance in this section.\n\n- **3.2.S.3.1 Elucidation of structure and other characteristics** \u2013 studies to identify polymorphs (except where the CEP specifies a polymorphic form) and particle size distribution, where applicable, according to the guidance in this section.\n\n- **3.2.S.4.1 Specification** \u2013 the specifications of the FPP manufacturer including all tests and limits of the CEP and Ph.Eur. monograph and any additional tests and acceptance criteria that are not controlled in the CEP and Ph.Eur. monograph, such as polymorphs and/or particle size distribution.\n\n- **3.2.S.4.2/3.2.S.4.3 Analytical procedures and validation** \u2013 for any methods used by the FPP manufacturer in addition to those in the CEP and Ph.Eur. monograph.\n\n- **3.2.S.4.4 Batch analysis** \u2013 results from two batches of at least pilot-scale, demonstrating compliance with the FPP manufacturer\u2019s API specifications.\n\n- **3.2.S.5 Reference standards or materials** \u2013 information on the FPP manufacturer\u2019s reference standards.\n\n- **3.2.S.6 Container-closure system** \u2013 specifications including descriptions and identification of primary packaging components except where the CEP specifies a container-closure system and the applicant declares the intent to use the same container-closure system.\n\n- **3.2.S.7 Stability** \u2013 except where the CEP specifies a retest period that is the same as or longer than that proposed by the applicant, and storage conditions are the same or at a higher temperature and humidity than those proposed by the applicant.\n```\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "857d0bf3ff5b3079bab40c474cdd26cf64e66e9c089187333476cadc3074d1b0", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "```\nduly filled out by the CEP holder on behalf of the FPP manufacturer or applicant to the WHO Prequalification of Medicines Programme who refers to the CEP.\n\nIn addition, a written commitment should be included that the applicant will inform WHO in the event that the CEP is withdrawn. It should also be acknowledged by the applicant that withdrawal of the CEP will require additional consideration of the API data requirements to support the PD. The written commitment should accompany the copy of the CEP in Module 1.\n\nTogether with the CEP, the applicant should supply the following information in the dossier, with data summarized in the QOS-PD.\n\n- **3.2.S.1.3 General properties** \u2013 discussions on any additional applicable physicochemical and other relevant properties of the API that are not controlled by the CEP and Ph.Eur. monograph, e.g. solubilities and polymorphs according to the guidance in this section.\n\n- **3.2.S.3.1 Elucidation of structure and other characteristics** \u2013 studies to identify polymorphs (except where the CEP specifies a polymorphic form) and particle size distribution, where applicable, according to the guidance in this section.\n\n- **3.2.S.4.1 Specification** \u2013 the specifications of the FPP manufacturer including all tests and limits of the CEP and Ph.Eur. monograph and any additional tests and acceptance criteria that are not controlled in the CEP and Ph.Eur. monograph, such as polymorphs and/or particle size distribution.\n\n- **3.2.S.4.2/3.2.S.4.3 Analytical procedures and validation** \u2013 for any methods used by the FPP manufacturer in addition to those in the CEP and Ph.Eur. monograph.\n\n- **3.2.S.4.4 Batch analysis** \u2013 results from two batches of at least pilot-scale, demonstrating compliance with the FPP manufacturer\u2019s API specifications.\n\n- **3.2.S.5 Reference standards or materials** \u2013 information on the FPP manufacturer\u2019s reference standards.\n\n- **3.2.S.6 Container-closure system** \u2013 specifications including descriptions and identification of primary packaging components except where the CEP specifies a container-closure system and the applicant declares the intent to use the same container-closure system.\n\n- **3.2.S.7 Stability** \u2013 except where the CEP specifies a retest period that is the same as or longer than that proposed by the applicant, and storage conditions are the same or at a higher temperature and humidity than those proposed by the applicant.\n```", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2428, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "e0449bf8-5b98-4275-b964-431b437d7b04": {"__data__": {"id_": "e0449bf8-5b98-4275-b964-431b437d7b04", "embedding": null, "metadata": {"page_label": "146", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIn the case of sterile APIs, data on the process for sterilization of the API including validation data should be included in the PD.\n\n- **Option 3: Active pharmaceutical ingredient master file (APIMF) procedure**  \n  Full details of the chemistry, manufacturing process, quality controls during manufacturing and process validation for the API may be submitted as an APIMF by the API manufacturer as outlined in WHO\u2019s *Guidelines on active pharmaceutical ingredient master file procedure* (4).  \n  In such cases, the Open part (non-proprietary information) needs to be included in its entirety in the PD as an annex to 3.2.S. In addition, the applicant or FPP manufacturer should complete the following sections in the PD and QOS-PD in full according to the guidance provided unless otherwise indicated in the respective sections:  \n  **General information S.1.1\u2013S.1.3**  \n  **Manufacture S.2**  \n  - **Manufacturer(s) S.2.1**  \n  - **Description of manufacturing process and process controls S.2.2**  \n  - **Controls of critical steps and intermediates S.2.4**  \n  **Elucidation of structure and other characteristics S.3.1**  \n  **Impurities S.3.2**  \n  **Control of the API S.4.1\u2013S.4.5**  \n  **Reference standards or materials S.5**  \n  **Container-closure system S.6**  \n  **Stability S.7.1\u2013S.7.3**  \n\n  It is the responsibility of the applicant to ensure that the complete APIMF (i.e. both the applicant\u2019s Open part and the API manufacturer\u2019s Restricted part) is supplied to WHO directly by the API manufacturer and that the applicant has access to the relevant information in the APIMF concerning the current manufacture of the API.  \n  A copy of the letter of access should be provided in the PD Module 1. APIMF holders can use the guidance provided for the option \u201cFull details in the PD\u201d for preparation of the relevant sections of the Open and Restricted parts of their APIMFs. Reference should also be made to the APIMF guidelines in WHO Technical Report Series, No. 948, Annex 4 (4).\n\n- **Option 4: Full details in the PD**  \n  Information on the 3.2.S *Active pharmaceutical ingredient* sections, including full details of chemistry, manufacturing process, quality controls during manufacturing and process validation for the API,", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las especificaciones para la preparaci\u00f3n de productos farmac\u00e9uticos, espec\u00edficamente en la presentaci\u00f3n de informaci\u00f3n sobre ingredientes farmac\u00e9uticos activos (API) en el contexto de la Organizaci\u00f3n Mundial de la Salud (OMS). Se describen dos opciones para la presentaci\u00f3n de datos sobre el API: la opci\u00f3n de presentar un archivo maestro de ingredientes farmac\u00e9uticos activos (APIMF) y la opci\u00f3n de proporcionar todos los detalles directamente en el expediente de producto (PD). Se enfatiza la importancia de incluir informaci\u00f3n sobre el proceso de esterilizaci\u00f3n, la validaci\u00f3n, y la responsabilidad del solicitante de asegurar que la informaci\u00f3n relevante est\u00e9 disponible y accesible.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en el expediente de producto (PD) si se opta por la opci\u00f3n de archivo maestro de ingredientes farmac\u00e9uticos activos (APIMF)?**\n   - La informaci\u00f3n que debe incluirse en el PD incluye la parte abierta del APIMF, as\u00ed como secciones espec\u00edficas como informaci\u00f3n general, fabricaci\u00f3n, control de impurezas, y estabilidad, entre otras.\n\n2. **\u00bfCu\u00e1l es la responsabilidad del solicitante en relaci\u00f3n con el archivo maestro de ingredientes farmac\u00e9uticos activos (APIMF)?**\n   - El solicitante es responsable de asegurarse de que el APIMF completo, que incluye tanto la parte abierta como la parte restringida, sea suministrado a la OMS directamente por el fabricante del API y de que tenga acceso a la informaci\u00f3n relevante sobre la fabricaci\u00f3n actual del API.\n\n3. **\u00bfQu\u00e9 se debe proporcionar en el m\u00f3dulo 1 del expediente de producto en relaci\u00f3n con el acceso al APIMF?**\n   - Se debe proporcionar una copia de la carta de acceso en el m\u00f3dulo 1 del expediente de producto, que demuestre que el solicitante tiene acceso a la parte restringida del APIMF.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS establece directrices sobre c\u00f3mo presentar informaci\u00f3n sobre ingredientes farmac\u00e9uticos activos en el contexto de la regulaci\u00f3n de productos farmac\u00e9uticos. Se ofrecen dos opciones para la presentaci\u00f3n de datos: a trav\u00e9s de un archivo maestro (APIMF) o directamente en el expediente de producto. Se subraya la importancia de la validaci\u00f3n de procesos, el control de calidad y la responsabilidad del solicitante en la gesti\u00f3n de la informaci\u00f3n relacionada con el API.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Compromiso del Solicitante**:\n   - El solicitante debe incluir un compromiso por escrito para informar a la OMS en caso de que se retire el Certificado de Producto Espec\u00edfico (CEP).\n   - Reconocimiento de que la retirada del CEP requerir\u00e1 una revisi\u00f3n adicional de los requisitos de datos del ingrediente farmac\u00e9utico activo (API).\n\n2. **Informaci\u00f3n a Proporcionar**:\n   - Junto con el CEP, el solicitante debe presentar informaci\u00f3n resumida en el QOS-PD, que incluye:\n     - **Propiedades Generales**: Propiedades fisicoqu\u00edmicas adicionales del API no controladas por el CEP.\n     - **Elucidaci\u00f3n de Estructura**: Estudios sobre polimorfos y distribuci\u00f3n del tama\u00f1o de part\u00edculas.\n     - **Especificaciones**: Especificaciones del fabricante del producto farmac\u00e9utico terminado (FPP) que incluyen pruebas y l\u00edmites del CEP.\n     - **Procedimientos Anal\u00edticos**: M\u00e9todos utilizados por el fabricante que no est\u00e1n en el CEP.\n     - **An\u00e1lisis de Lotes**: Resultados de al menos dos lotes a escala piloto.\n     - **Est\u00e1ndares de Referencia**: Informaci\u00f3n sobre los est\u00e1ndares de referencia del fabricante.\n     - **Sistema de Cierre del Contenedor**: Especificaciones de los componentes de embalaje primario.\n     - **Estabilidad**: Evaluaci\u00f3n de estabilidad del API, considerando condiciones de almacenamiento y per\u00edodos de rean\u00e1lisis.\n\n3. **Requisitos de Estabilidad**:\n   - La estabilidad debe ser evaluada, salvo que el CEP indique un per\u00edodo de rean\u00e1lisis igual o m\u00e1s largo que el propuesto por el solicitante.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad que supervisa la precalificaci\u00f3n de medicamentos.\n- **CEP (Certificado de Producto Espec\u00edfico)**: Documento que certifica la calidad del ingrediente farmac\u00e9utico activo.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en un medicamento.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que contiene el API.\n- **QOS-PD (Quality Overall Summary - Product Dossier)**: Resumen de calidad que acompa\u00f1a la solicitud.\n\nEste resumen destaca los requisitos y compromisos que deben cumplir los solicitantes al presentar su documentaci\u00f3n para la precalificaci\u00f3n de medicamentos ante la OMS, as\u00ed como la informaci\u00f3n espec\u00edfica que debe ser proporcionada.", "excerpt_keywords": "Keywords: pharmaceutical preparations, active pharmaceutical ingredient, APIMF, sterilization process, quality control"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c131b967-dab6-4fe4-8cca-8fb69c0a27e1", "node_type": "4", "metadata": {"page_label": "146", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIn the case of sterile APIs, data on the process for sterilization of the API including validation data should be included in the PD.\n\n- **Option 3: Active pharmaceutical ingredient master file (APIMF) procedure**  \n  Full details of the chemistry, manufacturing process, quality controls during manufacturing and process validation for the API may be submitted as an APIMF by the API manufacturer as outlined in WHO\u2019s *Guidelines on active pharmaceutical ingredient master file procedure* (4).  \n  In such cases, the Open part (non-proprietary information) needs to be included in its entirety in the PD as an annex to 3.2.S. In addition, the applicant or FPP manufacturer should complete the following sections in the PD and QOS-PD in full according to the guidance provided unless otherwise indicated in the respective sections:  \n  **General information S.1.1\u2013S.1.3**  \n  **Manufacture S.2**  \n  - **Manufacturer(s) S.2.1**  \n  - **Description of manufacturing process and process controls S.2.2**  \n  - **Controls of critical steps and intermediates S.2.4**  \n  **Elucidation of structure and other characteristics S.3.1**  \n  **Impurities S.3.2**  \n  **Control of the API S.4.1\u2013S.4.5**  \n  **Reference standards or materials S.5**  \n  **Container-closure system S.6**  \n  **Stability S.7.1\u2013S.7.3**  \n\n  It is the responsibility of the applicant to ensure that the complete APIMF (i.e. both the applicant\u2019s Open part and the API manufacturer\u2019s Restricted part) is supplied to WHO directly by the API manufacturer and that the applicant has access to the relevant information in the APIMF concerning the current manufacture of the API.  \n  A copy of the letter of access should be provided in the PD Module 1. APIMF holders can use the guidance provided for the option \u201cFull details in the PD\u201d for preparation of the relevant sections of the Open and Restricted parts of their APIMFs. Reference should also be made to the APIMF guidelines in WHO Technical Report Series, No. 948, Annex 4 (4).\n\n- **Option 4: Full details in the PD**  \n  Information on the 3.2.S *Active pharmaceutical ingredient* sections, including full details of chemistry, manufacturing process, quality controls during manufacturing and process validation for the API,", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "af86860c1fc4c906ae79dd586ae8bed8fa0e40e4f84b83601d598fa2f367f70d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIn the case of sterile APIs, data on the process for sterilization of the API including validation data should be included in the PD.\n\n- **Option 3: Active pharmaceutical ingredient master file (APIMF) procedure**  \n  Full details of the chemistry, manufacturing process, quality controls during manufacturing and process validation for the API may be submitted as an APIMF by the API manufacturer as outlined in WHO\u2019s *Guidelines on active pharmaceutical ingredient master file procedure* (4).  \n  In such cases, the Open part (non-proprietary information) needs to be included in its entirety in the PD as an annex to 3.2.S. In addition, the applicant or FPP manufacturer should complete the following sections in the PD and QOS-PD in full according to the guidance provided unless otherwise indicated in the respective sections:  \n  **General information S.1.1\u2013S.1.3**  \n  **Manufacture S.2**  \n  - **Manufacturer(s) S.2.1**  \n  - **Description of manufacturing process and process controls S.2.2**  \n  - **Controls of critical steps and intermediates S.2.4**  \n  **Elucidation of structure and other characteristics S.3.1**  \n  **Impurities S.3.2**  \n  **Control of the API S.4.1\u2013S.4.5**  \n  **Reference standards or materials S.5**  \n  **Container-closure system S.6**  \n  **Stability S.7.1\u2013S.7.3**  \n\n  It is the responsibility of the applicant to ensure that the complete APIMF (i.e. both the applicant\u2019s Open part and the API manufacturer\u2019s Restricted part) is supplied to WHO directly by the API manufacturer and that the applicant has access to the relevant information in the APIMF concerning the current manufacture of the API.  \n  A copy of the letter of access should be provided in the PD Module 1. APIMF holders can use the guidance provided for the option \u201cFull details in the PD\u201d for preparation of the relevant sections of the Open and Restricted parts of their APIMFs. Reference should also be made to the APIMF guidelines in WHO Technical Report Series, No. 948, Annex 4 (4).\n\n- **Option 4: Full details in the PD**  \n  Information on the 3.2.S *Active pharmaceutical ingredient* sections, including full details of chemistry, manufacturing process, quality controls during manufacturing and process validation for the API,", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2318, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f754e854-6f3d-49d3-a7d8-7210188c0a9a": {"__data__": {"id_": "f754e854-6f3d-49d3-a7d8-7210188c0a9a", "embedding": null, "metadata": {"page_label": "147", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.S.1 General information (name, manufacturer)\n\n## 3.2.S.1.1 Nomenclature (name, manufacturer)\n\nInformation on the nomenclature of the API should be provided. For example:\n\n- (recommended) International Nonproprietary Name (INN);\n- compendial name, if relevant;\n- chemical name(s);\n- company or laboratory code;\n- other nonproprietary name(s) (e.g. national name, United States Adopted Name (USAN), British Approved Name (BAN));\n- Chemical Abstracts Service (CAS) registry number.\n\nThe chemical names listed should be consistent with those appearing in the scientific literature and those appearing on the product labelling information (e.g. in the summary of product characteristics (SmPC) and package leaflet, also known as the patient information leaflet (PIL)). Where several names exist the preferred name should be indicated.\n\n## 3.2.S.1.2 Structure (name, manufacturer)\n\nThe structural formula, including relative and absolute stereochemistry, the molecular formula, and the relative molecular mass should be provided.\n\nThis information should be consistent with that provided in section 3.2.S.1.1. For APIs existing as salts the molecular mass of the free base or acid should also be provided.\n\n## 3.2.S.1.3 General properties (name, manufacturer)\n\nA list should be provided of physicochemical and other relevant properties of the API.\n\nThis information can be used in developing the specifications, in formulating FPPs and in the testing for release and stability purposes.\n\nThe physical and chemical properties of the API should be discussed, including the physical description, solubilities in common solvents (e.g. water, alcohols, dichloromethane and acetone), quantitative aqueous pH solubility profile (e.g. pH 1.2\u20136.8, dose/solubility volume), polymorphism, pH and pKa values, ultraviolet (UV) absorption maxima and molar absorptivity, melting point, refractive index (for a liquid), hygroscopicity and partition coefficient (see...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n### Preguntas y Respuestas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n se recomienda incluir sobre la nomenclatura del API seg\u00fan el documento?**\n   - Se recomienda incluir el Nombre No Propietario Internacional (INN), el nombre de la farmacopea si es relevante, los nombres qu\u00edmicos, el c\u00f3digo de la empresa o laboratorio, otros nombres no propietarios (como el nombre nacional, el Nombre Adoptado en Estados Unidos (USAN) o el Nombre Aprobado Brit\u00e1nico (BAN)), y el n\u00famero de registro del Servicio de Res\u00famenes Qu\u00edmicos (CAS). Adem\u00e1s, los nombres qu\u00edmicos deben ser consistentes con la literatura cient\u00edfica y la informaci\u00f3n de etiquetado del producto.\n\n2. **\u00bfQu\u00e9 detalles estructurales deben proporcionarse para el API?**\n   - Debe proporcionarse la f\u00f3rmula estructural, incluyendo la estereoqu\u00edmica relativa y absoluta, la f\u00f3rmula molecular y la masa molecular relativa. Para los APIs que existen como sales, tambi\u00e9n se debe incluir la masa molecular de la base libre o del \u00e1cido.\n\n3. **\u00bfCu\u00e1les son algunas propiedades fisicoqu\u00edmicas relevantes que deben listarse para el API?**\n   - Se deben discutir propiedades como la descripci\u00f3n f\u00edsica, solubilidades en disolventes comunes (agua, alcoholes, diclorometano y acetona), el perfil de solubilidad en pH cuantitativo (pH 1.2\u20136.8), polimorfismo, valores de pH y pKa, m\u00e1ximos de absorci\u00f3n ultravioleta (UV) y absorptividad molar, punto de fusi\u00f3n, \u00edndice de refracci\u00f3n (para l\u00edquidos), higroscopicidad y coeficiente de partici\u00f3n.\n\n### Resumen de Nivel Superior\n\nEl documento proporciona directrices sobre la informaci\u00f3n que debe incluirse en la secci\u00f3n 3.2.S.1 sobre la informaci\u00f3n general del API, que abarca la nomenclatura, la estructura y las propiedades generales. Se enfatiza la importancia de la consistencia en la nomenclatura y la presentaci\u00f3n de datos estructurales y fisicoqu\u00edmicos, que son esenciales para el desarrollo de especificaciones, formulaciones de productos farmac\u00e9uticos y pruebas de liberaci\u00f3n y estabilidad.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Organizaci\u00f3n Mundial de la Salud (OMS)**: La secci\u00f3n se centra en las directrices de la OMS para la presentaci\u00f3n de informaci\u00f3n sobre ingredientes farmac\u00e9uticos activos (API) en el contexto de la regulaci\u00f3n de productos farmac\u00e9uticos.\n\n2. **Ingredientes Farmac\u00e9uticos Activos (API)**: Se discuten dos opciones para la presentaci\u00f3n de datos sobre los API: \n   - **Opci\u00f3n 3**: Procedimiento de archivo maestro de ingredientes farmac\u00e9uticos activos (APIMF).\n   - **Opci\u00f3n 4**: Presentaci\u00f3n de todos los detalles directamente en el expediente de producto (PD).\n\n3. **Proceso de Esterilizaci\u00f3n**: Se enfatiza la necesidad de incluir datos sobre el proceso de esterilizaci\u00f3n y la validaci\u00f3n de los API est\u00e9riles en el PD.\n\n4. **Estructura del PD**: Se detallan las secciones espec\u00edficas que deben completarse en el PD y el QOS-PD, incluyendo:\n   - Informaci\u00f3n general (S.1.1\u2013S.1.3)\n   - Fabricaci\u00f3n (S.2)\n   - Control de impurezas (S.3.2)\n   - Control del API (S.4.1\u2013S.4.5)\n   - Estabilidad (S.7.1\u2013S.7.3)\n\n5. **Responsabilidad del Solicitante**: Se establece que el solicitante debe asegurarse de que el APIMF completo sea suministrado a la OMS por el fabricante del API y que tenga acceso a la informaci\u00f3n relevante.\n\n6. **Carta de Acceso**: Se requiere que el solicitante proporcione una copia de la carta de acceso en el m\u00f3dulo 1 del PD, que demuestre el acceso a la parte restringida del APIMF.\n\n7. **Referencias**: Se menciona la necesidad de referirse a las directrices del APIMF en el Informe T\u00e9cnico de la OMS, No. 948, Anexo 4.\n\n### Entidades Clave\n- **OMS**: Organizaci\u00f3n Mundial de la Salud.\n- **APIMF**: Archivo Maestro de Ingredientes Farmac\u00e9uticos Activos.\n- **PD**: Expediente de Producto.\n- **QOS-PD**: Calidad del Expediente de Producto. \n\nEste resumen destaca los aspectos esenciales relacionados con la presentaci\u00f3n de informaci\u00f3n sobre API y las responsabilidades de los solicitantes en el contexto de la regulaci\u00f3n farmac\u00e9utica.", "excerpt_keywords": "Keywords: API, nomenclature, physicochemical properties, structural formula, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d26994a3-e397-48a8-9339-acdba202d583", "node_type": "4", "metadata": {"page_label": "147", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.S.1 General information (name, manufacturer)\n\n## 3.2.S.1.1 Nomenclature (name, manufacturer)\n\nInformation on the nomenclature of the API should be provided. For example:\n\n- (recommended) International Nonproprietary Name (INN);\n- compendial name, if relevant;\n- chemical name(s);\n- company or laboratory code;\n- other nonproprietary name(s) (e.g. national name, United States Adopted Name (USAN), British Approved Name (BAN));\n- Chemical Abstracts Service (CAS) registry number.\n\nThe chemical names listed should be consistent with those appearing in the scientific literature and those appearing on the product labelling information (e.g. in the summary of product characteristics (SmPC) and package leaflet, also known as the patient information leaflet (PIL)). Where several names exist the preferred name should be indicated.\n\n## 3.2.S.1.2 Structure (name, manufacturer)\n\nThe structural formula, including relative and absolute stereochemistry, the molecular formula, and the relative molecular mass should be provided.\n\nThis information should be consistent with that provided in section 3.2.S.1.1. For APIs existing as salts the molecular mass of the free base or acid should also be provided.\n\n## 3.2.S.1.3 General properties (name, manufacturer)\n\nA list should be provided of physicochemical and other relevant properties of the API.\n\nThis information can be used in developing the specifications, in formulating FPPs and in the testing for release and stability purposes.\n\nThe physical and chemical properties of the API should be discussed, including the physical description, solubilities in common solvents (e.g. water, alcohols, dichloromethane and acetone), quantitative aqueous pH solubility profile (e.g. pH 1.2\u20136.8, dose/solubility volume), polymorphism, pH and pKa values, ultraviolet (UV) absorption maxima and molar absorptivity, melting point, refractive index (for a liquid), hygroscopicity and partition coefficient (see...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "ebdf5354f817f1f2dff4504ba5332c306061ae39c42c16af7cb28666825491ee", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.S.1 General information (name, manufacturer)\n\n## 3.2.S.1.1 Nomenclature (name, manufacturer)\n\nInformation on the nomenclature of the API should be provided. For example:\n\n- (recommended) International Nonproprietary Name (INN);\n- compendial name, if relevant;\n- chemical name(s);\n- company or laboratory code;\n- other nonproprietary name(s) (e.g. national name, United States Adopted Name (USAN), British Approved Name (BAN));\n- Chemical Abstracts Service (CAS) registry number.\n\nThe chemical names listed should be consistent with those appearing in the scientific literature and those appearing on the product labelling information (e.g. in the summary of product characteristics (SmPC) and package leaflet, also known as the patient information leaflet (PIL)). Where several names exist the preferred name should be indicated.\n\n## 3.2.S.1.2 Structure (name, manufacturer)\n\nThe structural formula, including relative and absolute stereochemistry, the molecular formula, and the relative molecular mass should be provided.\n\nThis information should be consistent with that provided in section 3.2.S.1.1. For APIs existing as salts the molecular mass of the free base or acid should also be provided.\n\n## 3.2.S.1.3 General properties (name, manufacturer)\n\nA list should be provided of physicochemical and other relevant properties of the API.\n\nThis information can be used in developing the specifications, in formulating FPPs and in the testing for release and stability purposes.\n\nThe physical and chemical properties of the API should be discussed, including the physical description, solubilities in common solvents (e.g. water, alcohols, dichloromethane and acetone), quantitative aqueous pH solubility profile (e.g. pH 1.2\u20136.8, dose/solubility volume), polymorphism, pH and pKa values, ultraviolet (UV) absorption maxima and molar absorptivity, melting point, refractive index (for a liquid), hygroscopicity and partition coefficient (see...", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1952, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c27bb1f2-0b9f-4494-8fb9-25140dcf4c76": {"__data__": {"id_": "c27bb1f2-0b9f-4494-8fb9-25140dcf4c76", "embedding": null, "metadata": {"page_label": "148", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Physical Description\n\nThe physical description should include appearance, colour and physical state. Solid forms should be identified as being crystalline or amorphous (see 3.2.S.3.1 for further information on API solid forms).\n\n# Solubilities and Quantitative Aqueous pH Solubility Profile\n\nThe following should be provided for all options for the submission of API data.\n\n- The solubilities in a number of common solvents should be provided (e.g. in water, alcohols, dichloromethane and acetone).\n- The solubilities over the physiological pH range (pH 1.2\u20136.8) in several buffered media should be provided in mg/ml. If this information is not readily available (e.g. from literature references), it should be generated in-house.\n\nFor solid oral dosage forms, the dose/solubility volume should be provided as determined according to the formula:\n\n\\[\n\\text{dose/solubility volume} = \\frac{\\text{largest dosage strength (mg)}}{\\text{the minimum concentration of the drug (mg/ml)*}}\n\\]\n\n*corresponding to the lowest solubility determined over the physiological pH range (pH 1.2\u20136.8) and temperature (37 \u00b1 0.5 \u00b0C).\n\nAccording to the Biopharmaceutics Classification System (BCS), highly soluble (or highly water soluble) APIs are those with a dose/solubility volume of \u2264 250 ml.\n\nFor example, compound A has as its lowest solubility at 37 \u00b1 0.5\u00b0C, 1.0 mg/ml at pH 6.8 and is available in 100 mg, 200 mg and 400 mg strengths. This API would not be considered a BCS highly soluble API as its dose/solubility volume is greater than 250 ml (400 mg/1.0 mg/ml = 400 ml).\n\n# Polymorphism\n\nAs recommended in ICH\u2019s *CTD-Q Questions and answers/location issues document* (5) the following list explains where specific data should be located in the PD:\n\n- The polymorphic form(s) present in the proposed API should be listed in section 3.2.S.1.3.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfQu\u00e9 informaci\u00f3n se debe incluir en la descripci\u00f3n f\u00edsica de un API seg\u00fan el documento?**\n   - La descripci\u00f3n f\u00edsica debe incluir la apariencia, el color y el estado f\u00edsico del API. Adem\u00e1s, se debe identificar si las formas s\u00f3lidas son cristalinas o amorfas.\n\n2. **\u00bfC\u00f3mo se determina el volumen de dosis/solubilidad para formas de dosificaci\u00f3n oral s\u00f3lida y qu\u00e9 implica un volumen de dosis/solubilidad mayor a 250 ml?**\n   - El volumen de dosis/solubilidad se determina utilizando la f\u00f3rmula: \\(\\text{dose/solubility volume} = \\frac{\\text{largest dosage strength (mg)}}{\\text{the minimum concentration of the drug (mg/ml)*}}\\), donde el denominador corresponde a la menor solubilidad determinada en el rango de pH fisiol\u00f3gico (pH 1.2\u20136.8) y a una temperatura de 37 \u00b1 0.5 \u00b0C. Un volumen de dosis/solubilidad mayor a 250 ml indica que el API no es considerado altamente soluble seg\u00fan el Sistema de Clasificaci\u00f3n Biofarmac\u00e9utica (BCS).\n\n3. **\u00bfD\u00f3nde se debe listar la(s) forma(s) polim\u00f3rfica(s) presente(s) en el API propuesto seg\u00fan las recomendaciones del ICH?**\n   - Las formas polim\u00f3rficas presentes en el API propuesto deben ser listadas en la secci\u00f3n 3.2.S.1.3 del documento.\n\n### Resumen de nivel superior del contexto:\nEl documento proporciona directrices sobre la descripci\u00f3n f\u00edsica de los ingredientes farmac\u00e9uticos activos (API), incluyendo su apariencia, color y estado f\u00edsico, as\u00ed como la identificaci\u00f3n de formas s\u00f3lidas. Tambi\u00e9n se detalla la necesidad de presentar datos sobre la solubilidad del API en varios disolventes y en un rango de pH fisiol\u00f3gico, junto con el c\u00e1lculo del volumen de dosis/solubilidad para formas de dosificaci\u00f3n oral s\u00f3lida. Adem\u00e1s, se menciona la importancia de documentar las formas polim\u00f3rficas del API en una secci\u00f3n espec\u00edfica del informe.", "prev_section_summary": "### Resumen de Temas Clave y Entidades de la Secci\u00f3n 3.2.S.1\n\n1. **Nomenclatura del API**:\n   - Se debe proporcionar informaci\u00f3n sobre el nombre del API, incluyendo:\n     - Nombre No Propietario Internacional (INN).\n     - Nombre de la farmacopea, si es relevante.\n     - Nombres qu\u00edmicos.\n     - C\u00f3digo de la empresa o laboratorio.\n     - Otros nombres no propietarios (nombres nacionales, USAN, BAN).\n     - N\u00famero de registro del Servicio de Res\u00famenes Qu\u00edmicos (CAS).\n   - Consistencia con la literatura cient\u00edfica y etiquetado del producto es esencial.\n\n2. **Estructura del API**:\n   - Se requiere la f\u00f3rmula estructural, que debe incluir:\n     - Estereoqu\u00edmica relativa y absoluta.\n     - F\u00f3rmula molecular.\n     - Masa molecular relativa.\n   - Para APIs en forma de sales, se debe incluir la masa molecular de la base libre o del \u00e1cido.\n\n3. **Propiedades Generales del API**:\n   - Se debe listar propiedades fisicoqu\u00edmicas relevantes, que incluyen:\n     - Descripci\u00f3n f\u00edsica.\n     - Solubilidades en disolventes comunes (agua, alcoholes, diclorometano, acetona).\n     - Perfil de solubilidad en pH cuantitativo (pH 1.2\u20136.8).\n     - Polimorfismo.\n     - Valores de pH y pKa.\n     - M\u00e1ximos de absorci\u00f3n UV y absorptividad molar.\n     - Punto de fusi\u00f3n.\n     - \u00cdndice de refracci\u00f3n (para l\u00edquidos).\n     - Higroscopicidad.\n     - Coeficiente de partici\u00f3n.\n\n### Entidades Clave:\n- **API** (Ingrediente Farmac\u00e9utico Activo)\n- **INN** (Nombre No Propietario Internacional)\n- **USAN** (Nombre Adoptado en Estados Unidos)\n- **BAN** (Nombre Aprobado Brit\u00e1nico)\n- **CAS** (Servicio de Res\u00famenes Qu\u00edmicos)\n- **FPP** (Forma Farmac\u00e9utica del Producto)\n- **SmPC** (Resumen de Caracter\u00edsticas del Producto)\n- **PIL** (Prospecto de Informaci\u00f3n para el Paciente)\n\nEste resumen destaca la importancia de la nomenclatura, la estructura y las propiedades fisicoqu\u00edmicas del API, que son fundamentales para el desarrollo y la regulaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: API, solubility, polymorphism, physical description, Biopharmaceutics Classification System"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "82aef7ce-e536-49d0-a6bd-2527cec16a24", "node_type": "4", "metadata": {"page_label": "148", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Physical Description\n\nThe physical description should include appearance, colour and physical state. Solid forms should be identified as being crystalline or amorphous (see 3.2.S.3.1 for further information on API solid forms).\n\n# Solubilities and Quantitative Aqueous pH Solubility Profile\n\nThe following should be provided for all options for the submission of API data.\n\n- The solubilities in a number of common solvents should be provided (e.g. in water, alcohols, dichloromethane and acetone).\n- The solubilities over the physiological pH range (pH 1.2\u20136.8) in several buffered media should be provided in mg/ml. If this information is not readily available (e.g. from literature references), it should be generated in-house.\n\nFor solid oral dosage forms, the dose/solubility volume should be provided as determined according to the formula:\n\n\\[\n\\text{dose/solubility volume} = \\frac{\\text{largest dosage strength (mg)}}{\\text{the minimum concentration of the drug (mg/ml)*}}\n\\]\n\n*corresponding to the lowest solubility determined over the physiological pH range (pH 1.2\u20136.8) and temperature (37 \u00b1 0.5 \u00b0C).\n\nAccording to the Biopharmaceutics Classification System (BCS), highly soluble (or highly water soluble) APIs are those with a dose/solubility volume of \u2264 250 ml.\n\nFor example, compound A has as its lowest solubility at 37 \u00b1 0.5\u00b0C, 1.0 mg/ml at pH 6.8 and is available in 100 mg, 200 mg and 400 mg strengths. This API would not be considered a BCS highly soluble API as its dose/solubility volume is greater than 250 ml (400 mg/1.0 mg/ml = 400 ml).\n\n# Polymorphism\n\nAs recommended in ICH\u2019s *CTD-Q Questions and answers/location issues document* (5) the following list explains where specific data should be located in the PD:\n\n- The polymorphic form(s) present in the proposed API should be listed in section 3.2.S.1.3.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "dcdccd2c162435a6231e6446374848fc30606f0b5f18cde1c1e1bf7820a5e60a", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Physical Description\n\nThe physical description should include appearance, colour and physical state. Solid forms should be identified as being crystalline or amorphous (see 3.2.S.3.1 for further information on API solid forms).\n\n# Solubilities and Quantitative Aqueous pH Solubility Profile\n\nThe following should be provided for all options for the submission of API data.\n\n- The solubilities in a number of common solvents should be provided (e.g. in water, alcohols, dichloromethane and acetone).\n- The solubilities over the physiological pH range (pH 1.2\u20136.8) in several buffered media should be provided in mg/ml. If this information is not readily available (e.g. from literature references), it should be generated in-house.\n\nFor solid oral dosage forms, the dose/solubility volume should be provided as determined according to the formula:\n\n\\[\n\\text{dose/solubility volume} = \\frac{\\text{largest dosage strength (mg)}}{\\text{the minimum concentration of the drug (mg/ml)*}}\n\\]\n\n*corresponding to the lowest solubility determined over the physiological pH range (pH 1.2\u20136.8) and temperature (37 \u00b1 0.5 \u00b0C).\n\nAccording to the Biopharmaceutics Classification System (BCS), highly soluble (or highly water soluble) APIs are those with a dose/solubility volume of \u2264 250 ml.\n\nFor example, compound A has as its lowest solubility at 37 \u00b1 0.5\u00b0C, 1.0 mg/ml at pH 6.8 and is available in 100 mg, 200 mg and 400 mg strengths. This API would not be considered a BCS highly soluble API as its dose/solubility volume is greater than 250 ml (400 mg/1.0 mg/ml = 400 ml).\n\n# Polymorphism\n\nAs recommended in ICH\u2019s *CTD-Q Questions and answers/location issues document* (5) the following list explains where specific data should be located in the PD:\n\n- The polymorphic form(s) present in the proposed API should be listed in section 3.2.S.1.3.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1833, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "4748c33a-b29f-450d-9457-6384e1374c39": {"__data__": {"id_": "4748c33a-b29f-450d-9457-6384e1374c39", "embedding": null, "metadata": {"page_label": "149", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n- The description of manufacturing process and process controls (3.2.S.2.2) should indicate which polymorphic form is manufactured, where relevant.\n- The literature references or studies performed to identify the potential polymorphic forms of the API, including the study results, should be provided in section 3.2.S.3.1.\n- If a polymorphic form is to be defined or limited (e.g. for APIs that are not BCS highly soluble and/or where polymorphism has been identified as an issue), details should be included in 3.2.S.4.1-3.2.S.4.5.\n\nAdditional information is included in the referenced sections of these guidelines.\n\n## Particle size distribution\n\nAs recommended in ICH\u2019s *CTD-Q Questions and answers/location issues* document (5), the studies performed to determine the particle size distribution of the API should be provided in section 3.2.S.3.1 (refer to this section of these guidelines for additional information).\n\n## Information from the literature\n\nSupportive data and results from specific studies or published literature can be included within or attached to this section.\n\nReference documents: ICH Q6A (6).\n\n### 3.2.S.2 Manufacture (name, manufacturer)\n\n#### 3.2.S.2.1 Manufacturer(s) (name, manufacturer)\n\nThe name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.\n\nThe facilities involved in the manufacturing, packaging, labelling, testing and storage of the API should be listed. If certain companies are responsible only for specific steps (e.g. milling of the API) this should be clearly indicated.\n\nThe list of manufacturers or companies should specify the actual addresses of the production or manufacturing site(s) involved (including block(s) and unit(s)), rather than the administrative offices. Telephone number(s), fax number(s) and e-mail address(es) should be provided.\n\nA valid manufacturing authorization should be provided for the production of APIs. If available, a certificate of compliance with GMP should be provided in the PD in Module 1.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfQu\u00e9 informaci\u00f3n espec\u00edfica debe incluirse en la secci\u00f3n 3.2.S.3.1 sobre los estudios realizados para identificar las formas polim\u00f3rficas del API?**\n   - Respuesta: En la secci\u00f3n 3.2.S.3.1, se deben incluir las referencias literarias o los estudios realizados para identificar las formas polim\u00f3rficas potenciales del API, as\u00ed como los resultados de dichos estudios.\n\n2. **\u00bfCu\u00e1les son los requisitos para la documentaci\u00f3n de los fabricantes involucrados en la producci\u00f3n del API seg\u00fan la secci\u00f3n 3.2.S.2.1?**\n   - Respuesta: La secci\u00f3n 3.2.S.2.1 requiere que se proporcione el nombre, direcci\u00f3n y responsabilidad de cada fabricante, incluidos los contratistas, as\u00ed como los sitios de producci\u00f3n o instalaciones involucradas en la fabricaci\u00f3n y prueba del API. Tambi\u00e9n se deben incluir los n\u00fameros de tel\u00e9fono, fax y direcciones de correo electr\u00f3nico, y se debe presentar una autorizaci\u00f3n de fabricaci\u00f3n v\u00e1lida.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta si se define o limita una forma polim\u00f3rfica del API?**\n   - Respuesta: Si se define o limita una forma polim\u00f3rfica del API, se deben incluir detalles en las secciones 3.2.S.4.1 a 3.2.S.4.5, especialmente si el API no es altamente soluble seg\u00fan el BCS o si se ha identificado el polimorfismo como un problema.\n\n### Resumen de nivel superior del contexto:\nEl documento proporciona directrices sobre la fabricaci\u00f3n y control de procesos de ingredientes farmac\u00e9uticos activos (API), enfatizando la importancia de documentar las formas polim\u00f3rficas y la distribuci\u00f3n del tama\u00f1o de part\u00edculas. Se requiere informaci\u00f3n detallada sobre los fabricantes y las instalaciones involucradas en la producci\u00f3n del API, as\u00ed como la necesidad de cumplir con las normativas de Buenas Pr\u00e1cticas de Manufactura (GMP).", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Descripci\u00f3n F\u00edsica del API**:\n   - **Aspectos a Incluir**: Apariencia, color y estado f\u00edsico.\n   - **Formas S\u00f3lidas**: Identificaci\u00f3n como cristalinas o amorfas.\n\n2. **Solubilidades y Perfil de Solubilidad en pH Aqueoso Cuantitativo**:\n   - **Datos Requeridos**: Solubilidades en disolventes comunes (agua, alcoholes, diclorometano, acetona).\n   - **Rango de pH**: Solubilidades en el rango fisiol\u00f3gico (pH 1.2\u20136.8) en medios tamponados, expresadas en mg/ml.\n   - **C\u00e1lculo de Volumen de Dosis/Solubilidad**: \n     - F\u00f3rmula: \\(\\text{dose/solubility volume} = \\frac{\\text{largest dosage strength (mg)}}{\\text{the minimum concentration of the drug (mg/ml)*}}\\)\n     - **Interpretaci\u00f3n**: Un volumen de dosis/susolubilidad \u2264 250 ml indica que el API es altamente soluble seg\u00fan el Sistema de Clasificaci\u00f3n Biofarmac\u00e9utica (BCS).\n\n3. **Polimorfismo**:\n   - **Recomendaciones del ICH**: Las formas polim\u00f3rficas del API propuesto deben ser listadas en la secci\u00f3n 3.2.S.1.3 del documento.\n\n### Entidades Clave:\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en medicamentos.\n- **BCS (Sistema de Clasificaci\u00f3n Biofarmac\u00e9utica)**: Clasificaci\u00f3n que determina la solubilidad y permeabilidad de los APIs.\n- **pH**: Medida de acidez o alcalinidad, relevante para la solubilidad del API.\n- **Secci\u00f3n 3.2.S.1.3**: Parte del documento donde se debe listar la informaci\u00f3n sobre polimorfismo.\n\nEste resumen destaca los aspectos esenciales relacionados con la descripci\u00f3n f\u00edsica, solubilidad y polimorfismo de los APIs seg\u00fan las directrices del documento.", "excerpt_keywords": "Keywords: manufacturing process, polymorphic forms, API, particle size distribution, GMP compliance"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2378cabc-e59e-4cef-82c7-3fe7d77ac3db", "node_type": "4", "metadata": {"page_label": "149", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n- The description of manufacturing process and process controls (3.2.S.2.2) should indicate which polymorphic form is manufactured, where relevant.\n- The literature references or studies performed to identify the potential polymorphic forms of the API, including the study results, should be provided in section 3.2.S.3.1.\n- If a polymorphic form is to be defined or limited (e.g. for APIs that are not BCS highly soluble and/or where polymorphism has been identified as an issue), details should be included in 3.2.S.4.1-3.2.S.4.5.\n\nAdditional information is included in the referenced sections of these guidelines.\n\n## Particle size distribution\n\nAs recommended in ICH\u2019s *CTD-Q Questions and answers/location issues* document (5), the studies performed to determine the particle size distribution of the API should be provided in section 3.2.S.3.1 (refer to this section of these guidelines for additional information).\n\n## Information from the literature\n\nSupportive data and results from specific studies or published literature can be included within or attached to this section.\n\nReference documents: ICH Q6A (6).\n\n### 3.2.S.2 Manufacture (name, manufacturer)\n\n#### 3.2.S.2.1 Manufacturer(s) (name, manufacturer)\n\nThe name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.\n\nThe facilities involved in the manufacturing, packaging, labelling, testing and storage of the API should be listed. If certain companies are responsible only for specific steps (e.g. milling of the API) this should be clearly indicated.\n\nThe list of manufacturers or companies should specify the actual addresses of the production or manufacturing site(s) involved (including block(s) and unit(s)), rather than the administrative offices. Telephone number(s), fax number(s) and e-mail address(es) should be provided.\n\nA valid manufacturing authorization should be provided for the production of APIs. If available, a certificate of compliance with GMP should be provided in the PD in Module 1.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "7368ae33b67a3979000e001ec2ba6bd83f877af388f5f36b5f9e34e32096bf7a", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 4\n\n- The description of manufacturing process and process controls (3.2.S.2.2) should indicate which polymorphic form is manufactured, where relevant.\n- The literature references or studies performed to identify the potential polymorphic forms of the API, including the study results, should be provided in section 3.2.S.3.1.\n- If a polymorphic form is to be defined or limited (e.g. for APIs that are not BCS highly soluble and/or where polymorphism has been identified as an issue), details should be included in 3.2.S.4.1-3.2.S.4.5.\n\nAdditional information is included in the referenced sections of these guidelines.\n\n## Particle size distribution\n\nAs recommended in ICH\u2019s *CTD-Q Questions and answers/location issues* document (5), the studies performed to determine the particle size distribution of the API should be provided in section 3.2.S.3.1 (refer to this section of these guidelines for additional information).\n\n## Information from the literature\n\nSupportive data and results from specific studies or published literature can be included within or attached to this section.\n\nReference documents: ICH Q6A (6).\n\n### 3.2.S.2 Manufacture (name, manufacturer)\n\n#### 3.2.S.2.1 Manufacturer(s) (name, manufacturer)\n\nThe name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.\n\nThe facilities involved in the manufacturing, packaging, labelling, testing and storage of the API should be listed. If certain companies are responsible only for specific steps (e.g. milling of the API) this should be clearly indicated.\n\nThe list of manufacturers or companies should specify the actual addresses of the production or manufacturing site(s) involved (including block(s) and unit(s)), rather than the administrative offices. Telephone number(s), fax number(s) and e-mail address(es) should be provided.\n\nA valid manufacturing authorization should be provided for the production of APIs. If available, a certificate of compliance with GMP should be provided in the PD in Module 1.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2113, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ceedf2a3-7da6-48b7-95a9-48b135cb8332": {"__data__": {"id_": "ceedf2a3-7da6-48b7-95a9-48b135cb8332", "embedding": null, "metadata": {"page_label": "150", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.S.2.2 Description of manufacturing process and process controls (name, manufacturer)\n\nThe description of the API manufacturing process represents the applicant\u2019s commitment for the manufacture of the API. Information should be provided to adequately describe the manufacturing process and process controls. For example:\n\n- A flow diagram of the synthetic process(es) should be provided that includes molecular formulas, weights, yield ranges, chemical structures of starting materials, intermediates, reagents and API reflecting stereochemistry, and identifies operating conditions and solvents.\n\n- A sequential procedural narrative of the manufacturing process should be submitted. The narrative should include, for example, quantities of raw materials, solvents, catalysts and reagents reflecting the representative batch scale for commercial manufacture, identification of critical steps, process controls, equipment and operating conditions (e.g. temperature, pressure, pH, time).\n\n- Alternative processes should be explained and described with the same level of detail as the primary process. Reprocessing steps should be identified and justified. Any data to support this justification should be either referenced or filed in 3.2.S.2.5.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF may be indicated for confidential information. In this case, if detailed information is presented in the Restricted part, the information to be provided for this section of the PD includes a flow chart (including molecular structures and all reagents and solvents) and a brief outline of the manufacturing process, with special emphasis on the final steps, including purification procedures. However, for sterile APIs, full validation data on the sterilization process should be provided in the Open part (in cases where there is no further sterilization of the final product).\n\nThe following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier.\n\nAs discussed in ICH Q7 (7) and WHO Technical Report Series, No. 957, Annex 2 (8), the point at which the API starting material is introduced into the manufacturing process is the starting point for the application of GMP requirements. The API starting material itself needs to be proposed and its choice justified by the manufacturer and accepted as such by assessors. The API starting material should be proposed taking into account the complexity of the molecule, the proximity of the API starting material to the final API, the availability of the API starting material as a commercial chemical and the quality controls placed upon the API starting material. This justification should be documented in the dossier and be available for review by WHO GMP inspectors.\n\nIn situations where the API starting material is a complex molecule and only a minimal number of synthetic steps from the final API, a further molecule called the starting material for synthesis should be proposed and its choice justified.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n se requiere para describir el proceso de fabricaci\u00f3n del API y los controles de proceso?**\n   - Se requiere un diagrama de flujo del proceso sint\u00e9tico que incluya f\u00f3rmulas moleculares, pesos, rangos de rendimiento, estructuras qu\u00edmicas de los materiales iniciales, intermedios, reactivos y el API, as\u00ed como condiciones operativas y solventes. Adem\u00e1s, se debe presentar una narrativa secuencial del proceso de fabricaci\u00f3n que detalle las cantidades de materias primas, solventes, catalizadores y reactivos, identificando pasos cr\u00edticos y condiciones operativas.\n\n2. **\u00bfC\u00f3mo se debe justificar la elecci\u00f3n del material de partida del API en el proceso de fabricaci\u00f3n?**\n   - La elecci\u00f3n del material de partida del API debe ser propuesta y justificada por el fabricante, teniendo en cuenta la complejidad de la mol\u00e9cula, la proximidad del material de partida al API final, la disponibilidad del material como un qu\u00edmico comercial y los controles de calidad aplicados. Esta justificaci\u00f3n debe estar documentada en el expediente y ser accesible para la revisi\u00f3n de los inspectores de GMP de la OMS.\n\n3. **\u00bfQu\u00e9 requisitos adicionales se aplican cuando se utiliza el procedimiento APIMF para la presentaci\u00f3n de informaci\u00f3n del API?**\n   - Cuando se utiliza el procedimiento APIMF, se puede indicar una referencia cruzada a la parte restringida del APIMF para informaci\u00f3n confidencial. En este caso, se debe proporcionar un diagrama de flujo que incluya estructuras moleculares y todos los reactivos y solventes, as\u00ed como un esquema breve del proceso de fabricaci\u00f3n, enfatizando los pasos finales y los procedimientos de purificaci\u00f3n. Para APIs est\u00e9riles, se deben proporcionar datos completos de validaci\u00f3n del proceso de esterilizaci\u00f3n en la parte abierta.\n\n### Resumen de nivel superior del contexto:\nEl contexto se centra en la descripci\u00f3n del proceso de fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (API) y los controles de proceso necesarios para cumplir con los requisitos de Buenas Pr\u00e1cticas de Manufactura (GMP). Se enfatiza la importancia de proporcionar informaci\u00f3n detallada sobre el proceso, incluyendo diagramas de flujo, narrativas secuenciales y justificaciones para la elecci\u00f3n de materiales de partida. Tambi\u00e9n se menciona el procedimiento APIMF y los requisitos espec\u00edficos para la presentaci\u00f3n de informaci\u00f3n confidencial y est\u00e9ril.", "prev_section_summary": "### Resumen de temas clave y entidades de la secci\u00f3n:\n\n1. **Polimorfismo de API**:\n   - Se requiere que la descripci\u00f3n del proceso de fabricaci\u00f3n y controles (secci\u00f3n 3.2.S.2.2) indique la forma polim\u00f3rfica que se fabrica.\n   - En la secci\u00f3n 3.2.S.3.1, se deben incluir referencias literarias y estudios realizados para identificar las formas polim\u00f3rficas potenciales del API, junto con los resultados de dichos estudios.\n   - Si se define o limita una forma polim\u00f3rfica, se deben proporcionar detalles en las secciones 3.2.S.4.1 a 3.2.S.4.5, especialmente para APIs que no son altamente solubles o donde el polimorfismo es un problema.\n\n2. **Distribuci\u00f3n del tama\u00f1o de part\u00edculas**:\n   - Se recomienda que los estudios sobre la distribuci\u00f3n del tama\u00f1o de part\u00edculas del API se incluyan en la secci\u00f3n 3.2.S.3.1, conforme a las directrices del documento ICH *CTD-Q Questions and answers/location issues*.\n\n3. **Informaci\u00f3n de fabricantes**:\n   - En la secci\u00f3n 3.2.S.2.1, se debe proporcionar el nombre, direcci\u00f3n y responsabilidad de cada fabricante, incluidos los contratistas, as\u00ed como los sitios de producci\u00f3n o instalaciones involucradas en la fabricaci\u00f3n y prueba del API.\n   - Se debe listar las instalaciones de fabricaci\u00f3n, envasado, etiquetado, prueba y almacenamiento del API, especificando direcciones reales y no solo oficinas administrativas.\n   - Se requiere presentar una autorizaci\u00f3n de fabricaci\u00f3n v\u00e1lida y, si est\u00e1 disponible, un certificado de cumplimiento con las Buenas Pr\u00e1cticas de Manufactura (GMP).\n\n### Entidades clave:\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que se fabrica y se controla en el proceso.\n- **Fabricantes**: Entidades responsables de la producci\u00f3n del API, incluyendo contratistas.\n- **Secciones del documento**: 3.2.S.2.2, 3.2.S.3.1, 3.2.S.4.1-3.2.S.4.5.\n- **Documentos de referencia**: ICH Q6A, ICH *CTD-Q Questions and answers/location issues*. \n\nEste resumen destaca la importancia de la documentaci\u00f3n y el cumplimiento normativo en la fabricaci\u00f3n de APIs, as\u00ed como la consideraci\u00f3n del polimorfismo y la distribuci\u00f3n del tama\u00f1o de part\u00edculas.", "excerpt_keywords": "Keywords: API manufacturing, process controls, GMP requirements, flow diagram, starting material"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a528b92f-99f3-42fb-bda4-d558acd6d6fe", "node_type": "4", "metadata": {"page_label": "150", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.S.2.2 Description of manufacturing process and process controls (name, manufacturer)\n\nThe description of the API manufacturing process represents the applicant\u2019s commitment for the manufacture of the API. Information should be provided to adequately describe the manufacturing process and process controls. For example:\n\n- A flow diagram of the synthetic process(es) should be provided that includes molecular formulas, weights, yield ranges, chemical structures of starting materials, intermediates, reagents and API reflecting stereochemistry, and identifies operating conditions and solvents.\n\n- A sequential procedural narrative of the manufacturing process should be submitted. The narrative should include, for example, quantities of raw materials, solvents, catalysts and reagents reflecting the representative batch scale for commercial manufacture, identification of critical steps, process controls, equipment and operating conditions (e.g. temperature, pressure, pH, time).\n\n- Alternative processes should be explained and described with the same level of detail as the primary process. Reprocessing steps should be identified and justified. Any data to support this justification should be either referenced or filed in 3.2.S.2.5.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF may be indicated for confidential information. In this case, if detailed information is presented in the Restricted part, the information to be provided for this section of the PD includes a flow chart (including molecular structures and all reagents and solvents) and a brief outline of the manufacturing process, with special emphasis on the final steps, including purification procedures. However, for sterile APIs, full validation data on the sterilization process should be provided in the Open part (in cases where there is no further sterilization of the final product).\n\nThe following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier.\n\nAs discussed in ICH Q7 (7) and WHO Technical Report Series, No. 957, Annex 2 (8), the point at which the API starting material is introduced into the manufacturing process is the starting point for the application of GMP requirements. The API starting material itself needs to be proposed and its choice justified by the manufacturer and accepted as such by assessors. The API starting material should be proposed taking into account the complexity of the molecule, the proximity of the API starting material to the final API, the availability of the API starting material as a commercial chemical and the quality controls placed upon the API starting material. This justification should be documented in the dossier and be available for review by WHO GMP inspectors.\n\nIn situations where the API starting material is a complex molecule and only a minimal number of synthetic steps from the final API, a further molecule called the starting material for synthesis should be proposed and its choice justified.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "5343752915b980534ac30a2cd2a8cd7386455bc2368763391cc04746f8e45ff7", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.S.2.2 Description of manufacturing process and process controls (name, manufacturer)\n\nThe description of the API manufacturing process represents the applicant\u2019s commitment for the manufacture of the API. Information should be provided to adequately describe the manufacturing process and process controls. For example:\n\n- A flow diagram of the synthetic process(es) should be provided that includes molecular formulas, weights, yield ranges, chemical structures of starting materials, intermediates, reagents and API reflecting stereochemistry, and identifies operating conditions and solvents.\n\n- A sequential procedural narrative of the manufacturing process should be submitted. The narrative should include, for example, quantities of raw materials, solvents, catalysts and reagents reflecting the representative batch scale for commercial manufacture, identification of critical steps, process controls, equipment and operating conditions (e.g. temperature, pressure, pH, time).\n\n- Alternative processes should be explained and described with the same level of detail as the primary process. Reprocessing steps should be identified and justified. Any data to support this justification should be either referenced or filed in 3.2.S.2.5.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF may be indicated for confidential information. In this case, if detailed information is presented in the Restricted part, the information to be provided for this section of the PD includes a flow chart (including molecular structures and all reagents and solvents) and a brief outline of the manufacturing process, with special emphasis on the final steps, including purification procedures. However, for sterile APIs, full validation data on the sterilization process should be provided in the Open part (in cases where there is no further sterilization of the final product).\n\nThe following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier.\n\nAs discussed in ICH Q7 (7) and WHO Technical Report Series, No. 957, Annex 2 (8), the point at which the API starting material is introduced into the manufacturing process is the starting point for the application of GMP requirements. The API starting material itself needs to be proposed and its choice justified by the manufacturer and accepted as such by assessors. The API starting material should be proposed taking into account the complexity of the molecule, the proximity of the API starting material to the final API, the availability of the API starting material as a commercial chemical and the quality controls placed upon the API starting material. This justification should be documented in the dossier and be available for review by WHO GMP inspectors.\n\nIn situations where the API starting material is a complex molecule and only a minimal number of synthetic steps from the final API, a further molecule called the starting material for synthesis should be proposed and its choice justified.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3064, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d2a824d0-9d54-4bc7-ae4c-645d0950c071": {"__data__": {"id_": "d2a824d0-9d54-4bc7-ae4c-645d0950c071", "embedding": null, "metadata": {"page_label": "151", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The starting material for synthesis defines the starting point in the manufacturing process for an API to be described in an application. The applicant should propose and justify which substances should be considered as starting materials for synthesis (see section 3.2.S.2.3 for further guidance). In the case where the precursor to the API is obtained by fermentation, or is of plant or animal origin, such a molecule can be considered the API starting material regardless of complexity.\n\nA one-step synthesis may be accepted in exceptional cases, for example, where the API starting material is covered by a CEP, or where the API starting material is an API accepted through the APIMF or API prequalification procedure within the WHO Prequalification of Medicines Programme, or when the structure of the API is so simple that a one-step synthesis can be justified, e.g. ethambutol or ethionamide.\n\nIn addition to the detailed description of the manufacturing process as per ICH M4Q, the recovery of materials, if any, should be described in detail with the step in which they are introduced into the process. Recovery operations should be adequately controlled such that impurity levels do not increase over time. For recovery of solvents, any processing to improve the quality of the recovered solvent should be described. Regarding recycling of filtrates (mother liquors) to obtain second crops, information should be available on maximum holding times for mother liquors and maximum number of times the material can be recycled. Data on impurity levels should be provided to justify recycling of filtrates.\n\nWhere there are multiple manufacturing sites being used by one API manufacturer, a comprehensive list in tabular form should be provided comparing the processes at each of the sites and highlighting any differences.\n\nAll solvents used in the manufacture (including purification and/or crystallization step(s)) should be clearly identified. Solvents used in the final steps should be of high purity. Use of recovered solvents in the final steps of purification and/or crystallization is not recommended; however their use can be justified on presentation of sufficient data demonstrating that recovered solvents meet appropriate standards as outlined in ICH Q7 (7).\n\nWhere polymorphic or amorphous forms have been identified, the form resulting from the synthesis should be stated.\n\nWhere particle size is considered a critical attribute (see 3.2.S.3.1 for details) the particle size reduction method(s) (e.g. milling or micronization) should be described.\n\nJustification should be provided for use of alternative manufacturing processes. Alternative processes should be explained with the same level of detail as for the primary process. It should be demonstrated that batches obtained by the alternative processes have the same impurity profile as obtained by the principal process. If the impurity profile obtained is different it should be demonstrated to be acceptable according to the requirements described under S.3.2.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS detalla los requisitos para la fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (API), enfoc\u00e1ndose en la definici\u00f3n de materiales de partida, procesos de s\u00edntesis, recuperaci\u00f3n de materiales, uso de disolventes, y justificaci\u00f3n de procesos alternativos. Se enfatiza la necesidad de un control riguroso de impurezas y la documentaci\u00f3n de procesos en m\u00faltiples sitios de fabricaci\u00f3n.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las condiciones excepcionales bajo las cuales se puede aceptar una s\u00edntesis de un solo paso para un API, y qu\u00e9 ejemplos se mencionan en el documento?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las excepciones a la regla general de s\u00edntesis y ejemplos concretos que se mencionan.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n se requiere para justificar el reciclaje de filtrados (madres licuores) en el proceso de fabricaci\u00f3n de un API?**\n   - Esta pregunta se centra en los requisitos espec\u00edficos que deben cumplirse para considerar el reciclaje de ciertos materiales en el proceso de fabricaci\u00f3n.\n\n3. **\u00bfQu\u00e9 criterios se deben cumplir para que los disolventes recuperados sean aceptables en las etapas finales de purificaci\u00f3n y/o cristalizaci\u00f3n?**\n   - Esta pregunta busca detalles sobre los est\u00e1ndares que deben cumplir los disolventes recuperados para ser utilizados en etapas cr\u00edticas del proceso de fabricaci\u00f3n. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n que puede no estar f\u00e1cilmente disponible en otras fuentes, enfoc\u00e1ndose en detalles espec\u00edficos del proceso de fabricaci\u00f3n de APIs seg\u00fan lo descrito en el documento de la OMS.", "prev_section_summary": "### Temas Clave:\n\n1. **Descripci\u00f3n del Proceso de Fabricaci\u00f3n del API**:\n   - Importancia de proporcionar informaci\u00f3n detallada sobre el proceso de fabricaci\u00f3n y los controles de proceso.\n   - Requisitos para incluir diagramas de flujo, narrativas secuenciales y justificaciones para la elecci\u00f3n de materiales.\n\n2. **Diagrama de Flujo**:\n   - Debe incluir f\u00f3rmulas moleculares, pesos, rangos de rendimiento, estructuras qu\u00edmicas de materiales iniciales, intermedios, reactivos y el API, as\u00ed como condiciones operativas y solventes.\n\n3. **Narrativa Secuencial**:\n   - Detalles sobre cantidades de materias primas, solventes, catalizadores y reactivos, identificaci\u00f3n de pasos cr\u00edticos y condiciones operativas (temperatura, presi\u00f3n, pH, tiempo).\n\n4. **Procesos Alternativos**:\n   - Descripci\u00f3n y justificaci\u00f3n de procesos alternativos y pasos de reprocesamiento.\n\n5. **Procedimiento APIMF**:\n   - Referencias cruzadas a la parte restringida para informaci\u00f3n confidencial y requisitos espec\u00edficos para la presentaci\u00f3n de informaci\u00f3n sobre APIs est\u00e9riles.\n\n6. **Material de Partida del API**:\n   - Justificaci\u00f3n de la elecci\u00f3n del material de partida, considerando la complejidad de la mol\u00e9cula y los controles de calidad.\n\n### Entidades:\n\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa utilizada en la fabricaci\u00f3n de medicamentos.\n- **GMP (Buenas Pr\u00e1cticas de Manufactura)**: Normativas que aseguran que los productos se fabrican y controlan de acuerdo con est\u00e1ndares de calidad.\n- **APIMF (Active Pharmaceutical Ingredient Master File)**: Archivo maestro que contiene informaci\u00f3n sobre el API.\n- **ICH Q7**: Directrices sobre las Buenas Pr\u00e1cticas de Manufactura para APIs.\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad que establece est\u00e1ndares y directrices para la salud p\u00fablica y la fabricaci\u00f3n de medicamentos.\n\n### Resumen:\nLa secci\u00f3n aborda la necesidad de una descripci\u00f3n exhaustiva del proceso de fabricaci\u00f3n de APIs, incluyendo diagramas de flujo y narrativas detalladas. Se enfatiza la justificaci\u00f3n de la elecci\u00f3n del material de partida y se mencionan requisitos espec\u00edficos para la presentaci\u00f3n de informaci\u00f3n confidencial bajo el procedimiento APIMF. Adem\u00e1s, se destaca la importancia de cumplir con las Buenas Pr\u00e1cticas de Manufactura (GMP) y la documentaci\u00f3n necesaria para la revisi\u00f3n por parte de inspectores de la OMS.", "excerpt_keywords": "Keywords: API, synthesis, manufacturing process, solvents, impurity profile"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ed50dd58-9570-430c-99b2-094156895bbe", "node_type": "4", "metadata": {"page_label": "151", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The starting material for synthesis defines the starting point in the manufacturing process for an API to be described in an application. The applicant should propose and justify which substances should be considered as starting materials for synthesis (see section 3.2.S.2.3 for further guidance). In the case where the precursor to the API is obtained by fermentation, or is of plant or animal origin, such a molecule can be considered the API starting material regardless of complexity.\n\nA one-step synthesis may be accepted in exceptional cases, for example, where the API starting material is covered by a CEP, or where the API starting material is an API accepted through the APIMF or API prequalification procedure within the WHO Prequalification of Medicines Programme, or when the structure of the API is so simple that a one-step synthesis can be justified, e.g. ethambutol or ethionamide.\n\nIn addition to the detailed description of the manufacturing process as per ICH M4Q, the recovery of materials, if any, should be described in detail with the step in which they are introduced into the process. Recovery operations should be adequately controlled such that impurity levels do not increase over time. For recovery of solvents, any processing to improve the quality of the recovered solvent should be described. Regarding recycling of filtrates (mother liquors) to obtain second crops, information should be available on maximum holding times for mother liquors and maximum number of times the material can be recycled. Data on impurity levels should be provided to justify recycling of filtrates.\n\nWhere there are multiple manufacturing sites being used by one API manufacturer, a comprehensive list in tabular form should be provided comparing the processes at each of the sites and highlighting any differences.\n\nAll solvents used in the manufacture (including purification and/or crystallization step(s)) should be clearly identified. Solvents used in the final steps should be of high purity. Use of recovered solvents in the final steps of purification and/or crystallization is not recommended; however their use can be justified on presentation of sufficient data demonstrating that recovered solvents meet appropriate standards as outlined in ICH Q7 (7).\n\nWhere polymorphic or amorphous forms have been identified, the form resulting from the synthesis should be stated.\n\nWhere particle size is considered a critical attribute (see 3.2.S.3.1 for details) the particle size reduction method(s) (e.g. milling or micronization) should be described.\n\nJustification should be provided for use of alternative manufacturing processes. Alternative processes should be explained with the same level of detail as for the primary process. It should be demonstrated that batches obtained by the alternative processes have the same impurity profile as obtained by the principal process. If the impurity profile obtained is different it should be demonstrated to be acceptable according to the requirements described under S.3.2.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "1b28cee2b3bba57eec420cb53ee518e797aeee3e06abdabb0bf18729e58f4c0b", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "The starting material for synthesis defines the starting point in the manufacturing process for an API to be described in an application. The applicant should propose and justify which substances should be considered as starting materials for synthesis (see section 3.2.S.2.3 for further guidance). In the case where the precursor to the API is obtained by fermentation, or is of plant or animal origin, such a molecule can be considered the API starting material regardless of complexity.\n\nA one-step synthesis may be accepted in exceptional cases, for example, where the API starting material is covered by a CEP, or where the API starting material is an API accepted through the APIMF or API prequalification procedure within the WHO Prequalification of Medicines Programme, or when the structure of the API is so simple that a one-step synthesis can be justified, e.g. ethambutol or ethionamide.\n\nIn addition to the detailed description of the manufacturing process as per ICH M4Q, the recovery of materials, if any, should be described in detail with the step in which they are introduced into the process. Recovery operations should be adequately controlled such that impurity levels do not increase over time. For recovery of solvents, any processing to improve the quality of the recovered solvent should be described. Regarding recycling of filtrates (mother liquors) to obtain second crops, information should be available on maximum holding times for mother liquors and maximum number of times the material can be recycled. Data on impurity levels should be provided to justify recycling of filtrates.\n\nWhere there are multiple manufacturing sites being used by one API manufacturer, a comprehensive list in tabular form should be provided comparing the processes at each of the sites and highlighting any differences.\n\nAll solvents used in the manufacture (including purification and/or crystallization step(s)) should be clearly identified. Solvents used in the final steps should be of high purity. Use of recovered solvents in the final steps of purification and/or crystallization is not recommended; however their use can be justified on presentation of sufficient data demonstrating that recovered solvents meet appropriate standards as outlined in ICH Q7 (7).\n\nWhere polymorphic or amorphous forms have been identified, the form resulting from the synthesis should be stated.\n\nWhere particle size is considered a critical attribute (see 3.2.S.3.1 for details) the particle size reduction method(s) (e.g. milling or micronization) should be described.\n\nJustification should be provided for use of alternative manufacturing processes. Alternative processes should be explained with the same level of detail as for the primary process. It should be demonstrated that batches obtained by the alternative processes have the same impurity profile as obtained by the principal process. If the impurity profile obtained is different it should be demonstrated to be acceptable according to the requirements described under S.3.2.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3039, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "a7934f11-86c3-41fc-a032-cbb5daa9a85c": {"__data__": {"id_": "a7934f11-86c3-41fc-a032-cbb5daa9a85c", "embedding": null, "metadata": {"page_label": "152", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIt is acceptable to provide information on pilot-scale manufacture, provided it is representative of production scale and scale-up is reported immediately to WHO according to the requirements of the WHO variation guidelines (9).\n\n## 3.2.S.2.3 Control of materials (name, manufacturer)\n\nMaterials used in the manufacture of the API (e.g. raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process. Information on the quality and control of these materials should be provided. Information demonstrating that materials meet standards appropriate for their intended use should be provided, as appropriate (details in 3.2.A.2).\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section.\n\nThe following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier.\n\nThe API starting material should be fully characterized and suitable specifications proposed and justified, including, at a minimum, control for identity, assay, impurity content and any other critical attribute of the material. For each API starting material, the name and address of the manufacturing site(s) of the manufacturer(s) should be indicated. A brief description of the preparation of the API starting material should be provided for each manufacturer, including the solvents, catalysts and reagents used. A single set of specifications should be proposed for the starting material that applies to material from all sources. Any future changes to the API starting material manufacturers, mode of preparation or specifications should be notified.\n\nAs indicated in section 3.2.S.2 there are occasions where a starting material for synthesis may also need to be defined. In general, the starting material for synthesis described in the PD should:\n\n- be a synthetic precursor of one or more synthesis steps prior to the final API intermediate. Acids, bases, salts, esters and similar derivatives of the API, as well as the racemate of a single enantiomer API, are not considered final intermediates;\n- be a well characterized, isolated and purified substance with its structure fully elucidated including its stereochemistry (when applicable);\n- have well-defined specifications that include among others one or more specific identity tests and tests and limits for assay and specified, unspecified and total impurities;\n- be incorporated as a significant structural fragment into the structure of the API.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS establece directrices sobre la fabricaci\u00f3n y control de materiales para la producci\u00f3n de ingredientes farmac\u00e9uticos activos (API). Se enfatiza la importancia de caracterizar completamente los materiales de partida, proponer especificaciones adecuadas y notificar cualquier cambio en los fabricantes o en el proceso de preparaci\u00f3n. Tambi\u00e9n se menciona la posibilidad de proporcionar informaci\u00f3n sobre la fabricaci\u00f3n a escala piloto, siempre que sea representativa de la escala de producci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n se debe proporcionar sobre los materiales utilizados en la fabricaci\u00f3n de un API?**\n   - Se debe listar cada material, identificando su uso en el proceso, y proporcionar informaci\u00f3n sobre su calidad y control, asegurando que cumplan con los est\u00e1ndares apropiados para su uso previsto.\n\n2. **\u00bfCu\u00e1les son los requisitos para la caracterizaci\u00f3n de los materiales de partida en la producci\u00f3n de un API?**\n   - Los materiales de partida deben estar completamente caracterizados, con especificaciones adecuadas que incluyan control de identidad, ensayo, contenido de impurezas y otros atributos cr\u00edticos. Adem\u00e1s, se debe indicar el nombre y la direcci\u00f3n del fabricante.\n\n3. **\u00bfQu\u00e9 condiciones deben cumplirse para que un material de partida se considere adecuado para la s\u00edntesis de un API?**\n   - Debe ser un precursor sint\u00e9tico bien caracterizado, aislado y purificado, con su estructura completamente elucidada, y tener especificaciones bien definidas que incluyan pruebas de identidad y l\u00edmites para impurezas. Adem\u00e1s, debe ser un fragmento estructural significativo del API.", "prev_section_summary": "### Temas Clave:\n\n1. **Materiales de Partida para S\u00edntesis**: Se define el material inicial en el proceso de fabricaci\u00f3n de un ingrediente farmac\u00e9utico activo (API) y se requiere que el solicitante proponga y justifique qu\u00e9 sustancias se consideran como tales.\n\n2. **S\u00edntesis de un Solo Paso**: Se aceptan excepciones para la s\u00edntesis de un solo paso en casos espec\u00edficos, como cuando el material de partida est\u00e1 cubierto por un CEP o es aceptado a trav\u00e9s de procedimientos de precalificaci\u00f3n de la OMS.\n\n3. **Recuperaci\u00f3n de Materiales**: Se debe detallar la recuperaci\u00f3n de materiales en el proceso de fabricaci\u00f3n, asegurando que los niveles de impurezas no aumenten con el tiempo. Se requiere informaci\u00f3n sobre el reciclaje de filtrados, incluyendo tiempos de retenci\u00f3n y n\u00famero m\u00e1ximo de reciclajes.\n\n4. **Uso de Disolventes**: Todos los disolventes utilizados deben ser identificados y se recomienda que los disolventes recuperados no se usen en etapas finales, a menos que se justifique su uso con datos que demuestren que cumplen con los est\u00e1ndares adecuados.\n\n5. **Formas Polim\u00f3rficas y Tama\u00f1o de Part\u00edcula**: Se debe indicar la forma resultante de la s\u00edntesis si se han identificado formas polim\u00f3rficas o amorfas, y se deben describir los m\u00e9todos de reducci\u00f3n de tama\u00f1o de part\u00edcula si este es un atributo cr\u00edtico.\n\n6. **Procesos de Fabricaci\u00f3n Alternativos**: Se requiere justificaci\u00f3n para el uso de procesos alternativos, que deben ser explicados con el mismo nivel de detalle que el proceso principal, asegurando que el perfil de impurezas sea comparable.\n\n### Entidades:\n\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que se utiliza en la fabricaci\u00f3n de medicamentos.\n- **CEP (Certificado de Excipiente Farmac\u00e9utico)**: Certificaci\u00f3n que asegura la calidad de un excipiente.\n- **APIMF (Maestro de Ingredientes Farmac\u00e9uticos Activos)**: Documentaci\u00f3n que proporciona informaci\u00f3n sobre un API.\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organizaci\u00f3n que establece directrices y est\u00e1ndares para la salud p\u00fablica.\n- **ICH Q7**: Directrices sobre buenas pr\u00e1cticas de fabricaci\u00f3n para ingredientes farmac\u00e9uticos activos.\n- **Filtrados (Madres Licuores)**: Soluciones que quedan despu\u00e9s de la cristalizaci\u00f3n o filtraci\u00f3n, que pueden ser recicladas.\n\nEste resumen abarca los aspectos esenciales del proceso de fabricaci\u00f3n de APIs seg\u00fan el documento de la OMS, destacando la importancia de la justificaci\u00f3n y el control en cada etapa del proceso.", "excerpt_keywords": "Keywords: pharmaceutical preparations, API manufacturing, quality control, starting materials, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ef45487-dbfa-45bb-8f39-80408f2176a3", "node_type": "4", "metadata": {"page_label": "152", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIt is acceptable to provide information on pilot-scale manufacture, provided it is representative of production scale and scale-up is reported immediately to WHO according to the requirements of the WHO variation guidelines (9).\n\n## 3.2.S.2.3 Control of materials (name, manufacturer)\n\nMaterials used in the manufacture of the API (e.g. raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process. Information on the quality and control of these materials should be provided. Information demonstrating that materials meet standards appropriate for their intended use should be provided, as appropriate (details in 3.2.A.2).\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section.\n\nThe following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier.\n\nThe API starting material should be fully characterized and suitable specifications proposed and justified, including, at a minimum, control for identity, assay, impurity content and any other critical attribute of the material. For each API starting material, the name and address of the manufacturing site(s) of the manufacturer(s) should be indicated. A brief description of the preparation of the API starting material should be provided for each manufacturer, including the solvents, catalysts and reagents used. A single set of specifications should be proposed for the starting material that applies to material from all sources. Any future changes to the API starting material manufacturers, mode of preparation or specifications should be notified.\n\nAs indicated in section 3.2.S.2 there are occasions where a starting material for synthesis may also need to be defined. In general, the starting material for synthesis described in the PD should:\n\n- be a synthetic precursor of one or more synthesis steps prior to the final API intermediate. Acids, bases, salts, esters and similar derivatives of the API, as well as the racemate of a single enantiomer API, are not considered final intermediates;\n- be a well characterized, isolated and purified substance with its structure fully elucidated including its stereochemistry (when applicable);\n- have well-defined specifications that include among others one or more specific identity tests and tests and limits for assay and specified, unspecified and total impurities;\n- be incorporated as a significant structural fragment into the structure of the API.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "1e06b28cad005ccd0b1174f62048457cd16f5b84f315210db858a7a39cab3fdf", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIt is acceptable to provide information on pilot-scale manufacture, provided it is representative of production scale and scale-up is reported immediately to WHO according to the requirements of the WHO variation guidelines (9).\n\n## 3.2.S.2.3 Control of materials (name, manufacturer)\n\nMaterials used in the manufacture of the API (e.g. raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process. Information on the quality and control of these materials should be provided. Information demonstrating that materials meet standards appropriate for their intended use should be provided, as appropriate (details in 3.2.A.2).\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section.\n\nThe following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier.\n\nThe API starting material should be fully characterized and suitable specifications proposed and justified, including, at a minimum, control for identity, assay, impurity content and any other critical attribute of the material. For each API starting material, the name and address of the manufacturing site(s) of the manufacturer(s) should be indicated. A brief description of the preparation of the API starting material should be provided for each manufacturer, including the solvents, catalysts and reagents used. A single set of specifications should be proposed for the starting material that applies to material from all sources. Any future changes to the API starting material manufacturers, mode of preparation or specifications should be notified.\n\nAs indicated in section 3.2.S.2 there are occasions where a starting material for synthesis may also need to be defined. In general, the starting material for synthesis described in the PD should:\n\n- be a synthetic precursor of one or more synthesis steps prior to the final API intermediate. Acids, bases, salts, esters and similar derivatives of the API, as well as the racemate of a single enantiomer API, are not considered final intermediates;\n- be a well characterized, isolated and purified substance with its structure fully elucidated including its stereochemistry (when applicable);\n- have well-defined specifications that include among others one or more specific identity tests and tests and limits for assay and specified, unspecified and total impurities;\n- be incorporated as a significant structural fragment into the structure of the API.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2662, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "9d9af543-5d33-4950-b811-4f18a9c62814": {"__data__": {"id_": "9d9af543-5d33-4950-b811-4f18a9c62814", "embedding": null, "metadata": {"page_label": "153", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\nCopies of the specifications for the materials used in the synthesis, extraction, isolation and purification steps should be provided in the PD, including starting materials, reagents, solvents, catalysts and recovered materials. Confirmation should be provided that the specifications apply to materials used at each manufacturing site. A certificate of analysis of the starting material for synthesis should be provided. A summary of the information on starting materials should be provided in the QOS-PD.\n\nThe carry-over of impurities of the starting materials for synthesis into the final API should be considered and discussed.\n\nA letter of attestation should be provided confirming that the API and the starting materials and reagents used to manufacture the API are without risk of transmitting agents of animal spongiform encephalopathies.\n\nWhen available a CEP demonstrating compliance with recommendations on transmissible spongiform encephalopathy (TSE) should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.2.4 Controls of critical steps and intermediates (name, manufacturer)\n\n**Critical steps:** Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to ensure that the process is controlled should be provided.\n\n**Intermediates:** Information on the quality and control of intermediates isolated during the process should be provided.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD, with the exception of information that is also relevant for the applicant (4).\n\nThe following requirements apply to the fourth option for submission of API information where full details are provided in the dossier.\n\nThe critical steps should be identified. These can include: steps where significant impurities are removed or introduced; steps introducing an essential molecular structural element such as a chiral centre or resulting in a major chemical transformation; steps having an impact on solid-state properties and homogeneity of the API that may be relevant for use in solid dosage forms.\n\nSpecifications for isolated intermediates should be provided and should include tests and acceptance criteria for identity, purity and assay, where applicable.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.2.5 Process validation and/or evaluation (name, manufacturer)\n\nProcess validation and/or evaluation studies for aseptic processing and sterilization should be included.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior del contenido:\n\n### Resumen de Nivel Superior\nEl documento detalla los requisitos para la presentaci\u00f3n de informaci\u00f3n sobre la fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (API), centr\u00e1ndose en las especificaciones de los materiales utilizados en los procesos de s\u00edntesis, extracci\u00f3n, aislamiento y purificaci\u00f3n. Se enfatiza la importancia de la calidad y control de los materiales, as\u00ed como la validaci\u00f3n de procesos cr\u00edticos. Tambi\u00e9n se menciona la necesidad de garantizar que los materiales no transmitan agentes de encefalopat\u00edas espongiformes transmisibles (TSE) y se requiere documentaci\u00f3n espec\u00edfica, como certificados de an\u00e1lisis y cartas de atestaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de documentaci\u00f3n se requiere para asegurar que los materiales utilizados en la fabricaci\u00f3n del API no transmiten agentes de encefalopat\u00edas espongiformes transmisibles?**\n   - Se requiere una carta de atestaci\u00f3n que confirme que el API y los materiales de partida y reactivos utilizados en su fabricaci\u00f3n no presentan riesgo de transmitir agentes de TSE. Adem\u00e1s, cuando est\u00e9 disponible, se debe proporcionar un Certificado de Excepci\u00f3n (CEP) que demuestre el cumplimiento de las recomendaciones sobre TSE.\n\n2. **\u00bfCu\u00e1les son los criterios de aceptaci\u00f3n que deben incluirse para los pasos cr\u00edticos en el proceso de fabricaci\u00f3n del API?**\n   - Los criterios de aceptaci\u00f3n deben incluir pruebas y criterios de aceptaci\u00f3n con justificaci\u00f3n, que incluyan datos experimentales, para los pasos cr\u00edticos identificados en el proceso de fabricaci\u00f3n. Estos pasos pueden incluir aquellos donde se eliminan o introducen impurezas significativas, se introduce un elemento estructural molecular esencial, o se impactan las propiedades del estado s\u00f3lido y la homogeneidad del API.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n se debe proporcionar sobre los intermediarios aislados durante el proceso de fabricaci\u00f3n del API?**\n   - Se debe proporcionar informaci\u00f3n sobre la calidad y control de los intermediarios aislados, incluyendo especificaciones que contengan pruebas y criterios de aceptaci\u00f3n para identidad, pureza y ensayo, cuando sea aplicable. Esto es crucial para asegurar que los intermediarios cumplen con los est\u00e1ndares requeridos antes de avanzar en el proceso de fabricaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Fabricaci\u00f3n a Escala Piloto**: Se permite proporcionar informaci\u00f3n sobre la fabricaci\u00f3n a escala piloto, siempre que sea representativa de la escala de producci\u00f3n y se notifique cualquier escalado a la OMS seg\u00fan las directrices de variaci\u00f3n.\n\n2. **Control de Materiales**: \n   - Se deben listar todos los materiales utilizados en la fabricaci\u00f3n del ingrediente farmac\u00e9utico activo (API), incluyendo materias primas, materiales de partida, disolventes, reactivos y catalizadores.\n   - Es necesario proporcionar informaci\u00f3n sobre la calidad y el control de estos materiales, asegurando que cumplan con los est\u00e1ndares apropiados para su uso.\n\n3. **Materiales de Partida**:\n   - Los materiales de partida deben estar completamente caracterizados y se deben proponer especificaciones adecuadas que incluyan control de identidad, ensayo, contenido de impurezas y otros atributos cr\u00edticos.\n   - Se debe indicar el nombre y la direcci\u00f3n de los fabricantes de los materiales de partida, as\u00ed como una breve descripci\u00f3n de su preparaci\u00f3n.\n\n4. **Especificaciones**: \n   - Se debe proponer un conjunto \u00fanico de especificaciones para los materiales de partida que se aplique a todos los proveedores.\n   - Cualquier cambio futuro en los fabricantes, modo de preparaci\u00f3n o especificaciones debe ser notificado.\n\n5. **Definici\u00f3n de Materiales de Partida para S\u00edntesis**:\n   - Deben ser precursores sint\u00e9ticos bien caracterizados, aislados y purificados, con estructura completamente elucidada.\n   - Deben tener especificaciones bien definidas que incluyan pruebas de identidad y l\u00edmites para impurezas.\n   - Deben ser incorporados como fragmentos estructurales significativos en la estructura del API.\n\n### Entidades Clave\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia utilizada en la fabricaci\u00f3n de medicamentos.\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad que establece directrices y requisitos para la fabricaci\u00f3n y control de materiales farmac\u00e9uticos.\n- **APIMF (Active Pharmaceutical Ingredient Master File)**: Procedimiento que permite la presentaci\u00f3n de informaci\u00f3n sobre el API.\n- **Materiales de Partida**: Sustancias utilizadas en la s\u00edntesis del API que deben cumplir con especificaciones rigurosas.", "excerpt_keywords": "Keywords: API, specifications, process validation, TSE, intermediates"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d16bd0e8-1a48-432c-aa5f-32cc52824bc4", "node_type": "4", "metadata": {"page_label": "153", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\nCopies of the specifications for the materials used in the synthesis, extraction, isolation and purification steps should be provided in the PD, including starting materials, reagents, solvents, catalysts and recovered materials. Confirmation should be provided that the specifications apply to materials used at each manufacturing site. A certificate of analysis of the starting material for synthesis should be provided. A summary of the information on starting materials should be provided in the QOS-PD.\n\nThe carry-over of impurities of the starting materials for synthesis into the final API should be considered and discussed.\n\nA letter of attestation should be provided confirming that the API and the starting materials and reagents used to manufacture the API are without risk of transmitting agents of animal spongiform encephalopathies.\n\nWhen available a CEP demonstrating compliance with recommendations on transmissible spongiform encephalopathy (TSE) should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.2.4 Controls of critical steps and intermediates (name, manufacturer)\n\n**Critical steps:** Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to ensure that the process is controlled should be provided.\n\n**Intermediates:** Information on the quality and control of intermediates isolated during the process should be provided.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD, with the exception of information that is also relevant for the applicant (4).\n\nThe following requirements apply to the fourth option for submission of API information where full details are provided in the dossier.\n\nThe critical steps should be identified. These can include: steps where significant impurities are removed or introduced; steps introducing an essential molecular structural element such as a chiral centre or resulting in a major chemical transformation; steps having an impact on solid-state properties and homogeneity of the API that may be relevant for use in solid dosage forms.\n\nSpecifications for isolated intermediates should be provided and should include tests and acceptance criteria for identity, purity and assay, where applicable.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.2.5 Process validation and/or evaluation (name, manufacturer)\n\nProcess validation and/or evaluation studies for aseptic processing and sterilization should be included.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "8dbb8b31946d1ba8d67900d1460ab9e78ff10c2b8df34207e13c923fd11fa4fa", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 4\n\nCopies of the specifications for the materials used in the synthesis, extraction, isolation and purification steps should be provided in the PD, including starting materials, reagents, solvents, catalysts and recovered materials. Confirmation should be provided that the specifications apply to materials used at each manufacturing site. A certificate of analysis of the starting material for synthesis should be provided. A summary of the information on starting materials should be provided in the QOS-PD.\n\nThe carry-over of impurities of the starting materials for synthesis into the final API should be considered and discussed.\n\nA letter of attestation should be provided confirming that the API and the starting materials and reagents used to manufacture the API are without risk of transmitting agents of animal spongiform encephalopathies.\n\nWhen available a CEP demonstrating compliance with recommendations on transmissible spongiform encephalopathy (TSE) should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.2.4 Controls of critical steps and intermediates (name, manufacturer)\n\n**Critical steps:** Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to ensure that the process is controlled should be provided.\n\n**Intermediates:** Information on the quality and control of intermediates isolated during the process should be provided.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD, with the exception of information that is also relevant for the applicant (4).\n\nThe following requirements apply to the fourth option for submission of API information where full details are provided in the dossier.\n\nThe critical steps should be identified. These can include: steps where significant impurities are removed or introduced; steps introducing an essential molecular structural element such as a chiral centre or resulting in a major chemical transformation; steps having an impact on solid-state properties and homogeneity of the API that may be relevant for use in solid dosage forms.\n\nSpecifications for isolated intermediates should be provided and should include tests and acceptance criteria for identity, purity and assay, where applicable.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.2.5 Process validation and/or evaluation (name, manufacturer)\n\nProcess validation and/or evaluation studies for aseptic processing and sterilization should be included.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2677, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "baa6c284-364b-4ef4-b452-eed7b74497e1": {"__data__": {"id_": "baa6c284-364b-4ef4-b452-eed7b74497e1", "embedding": null, "metadata": {"page_label": "154", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD.\n\nThe following requirements apply to the fourth option for submission of API information where full details are provided in the dossier.\n\nIt is expected that the manufacturing processes for all APIs are properly controlled. If the API is prepared as sterile a complete description should be provided of the aseptic processing and/or sterilization methods. A description of the controls used to maintain the sterility of the API during storage and transportation should also be provided. Alternative processes should be justified and described (see guidance in 3.2.S.2.2 for the level of detail expected).\n\n## 3.2.S.2.6 Manufacturing process development (name, manufacturer)\n\nA description and discussion should be provided of the significant changes made to the manufacturing process and/or manufacturing site of the API used in producing comparative bioavailability or biowaiver, scale-up, pilot, and, if available, production scale batches.\n\nReference should be made to the API data provided in Section 3.2.S.4.4.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD.\n\n## 3.2.S.3 Characterization (name, manufacturer)\n\n### 3.2.S.3.1 Elucidation of structure and other characteristics (name, manufacturer)\n\nConfirmation of structure based on, e.g. synthetic route and spectral analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included.\n\n**Elucidation of structure**\n\nThe PD should include quality assurance (QA) certified copies of the spectra, peak assignments and a detailed interpretation of the data from the studies performed to elucidate and/or confirm the structure of the API. The QOS-PD should include a list of the studies performed and a conclusion from the studies (e.g. whether the results support the proposed structure).\n\nFor APIs that are not described in an officially recognized pharmacopoeia, the studies carried out to elucidate and/or confirm the chemical structure normally include elemental analysis, infrared (IR), ultraviolet (UV), nuclear magnetic resonance (NMR) and mass spectra (MS) studies. Other tests could include X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).\n\nFor APIs that are described in an officially recognized pharmacopoeia it is generally sufficient to provide copies of the IR spectrum of the API from each.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas basadas en el contexto proporcionado, junto con un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los requisitos para la presentaci\u00f3n de informaci\u00f3n sobre ingredientes farmac\u00e9uticos activos (API) en el contexto de la preparaci\u00f3n de medicamentos. Se enfatiza la importancia del control de los procesos de fabricaci\u00f3n, especialmente para APIs est\u00e9riles, y se requiere una descripci\u00f3n exhaustiva de los m\u00e9todos de procesamiento y control de calidad. Adem\u00e1s, se abordan los procedimientos para la caracterizaci\u00f3n de la estructura qu\u00edmica de los APIs, incluyendo la necesidad de estudios espectrosc\u00f3picos y otros an\u00e1lisis para confirmar su identidad y pureza.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n se requiere para justificar los procesos alternativos de fabricaci\u00f3n de un API est\u00e9ril?**\n   - La respuesta a esta pregunta se puede encontrar en la secci\u00f3n que menciona la necesidad de justificar y describir los procesos alternativos, as\u00ed como la referencia a la gu\u00eda en 3.2.S.2.2 sobre el nivel de detalle esperado.\n\n2. **\u00bfCu\u00e1les son los estudios espec\u00edficos que se deben realizar para confirmar la estructura qu\u00edmica de un API que no est\u00e1 descrito en una farmacopea oficialmente reconocida?**\n   - La respuesta se puede extraer de la secci\u00f3n que enumera los estudios necesarios, como an\u00e1lisis elemental, espectroscop\u00eda IR, UV, NMR y MS, as\u00ed como pruebas adicionales como XRPD y DSC.\n\n3. **\u00bfQu\u00e9 documentos de calidad se deben incluir en el dossier para respaldar la elucidaci\u00f3n de la estructura de un API?**\n   - Esta pregunta se relaciona con la parte del texto que menciona que el PD debe incluir copias certificadas por aseguramiento de calidad (QA) de los espectros, asignaciones de picos y una interpretaci\u00f3n detallada de los datos de los estudios realizados para confirmar la estructura del API.", "prev_section_summary": "### Temas Clave\n\n1. **Especificaciones de Materiales**: Se requiere proporcionar copias de las especificaciones para los materiales utilizados en los procesos de s\u00edntesis, extracci\u00f3n, aislamiento y purificaci\u00f3n de ingredientes farmac\u00e9uticos activos (API). Esto incluye materiales de partida, reactivos, disolventes, catalizadores y materiales recuperados.\n\n2. **Control de Impurezas**: Es importante considerar y discutir la transferencia de impurezas de los materiales de partida al API final.\n\n3. **Transmisi\u00f3n de TSE**: Se debe incluir una carta de atestaci\u00f3n que confirme que el API y los materiales utilizados en su fabricaci\u00f3n no presentan riesgo de transmitir agentes de encefalopat\u00edas espongiformes transmisibles (TSE). Tambi\u00e9n se debe proporcionar un Certificado de Excepci\u00f3n (CEP) cuando est\u00e9 disponible.\n\n4. **Controles de Pasos Cr\u00edticos**: Se deben proporcionar pruebas y criterios de aceptaci\u00f3n para los pasos cr\u00edticos en el proceso de fabricaci\u00f3n, as\u00ed como informaci\u00f3n sobre la calidad y control de los intermediarios aislados.\n\n5. **Validaci\u00f3n de Procesos**: Se deben incluir estudios de validaci\u00f3n y/o evaluaci\u00f3n de procesos para el procesamiento as\u00e9ptico y la esterilizaci\u00f3n.\n\n### Entidades\n\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa utilizada en la fabricaci\u00f3n de medicamentos.\n- **TSE (Encefalopat\u00edas Espongiformes Transmisibles)**: Grupo de enfermedades que afectan el sistema nervioso central de los animales y humanos.\n- **CEP (Certificado de Excepci\u00f3n)**: Documento que demuestra el cumplimiento de las recomendaciones sobre TSE.\n- **ICH Q6A**: Documento de referencia que establece directrices sobre la calidad de los productos farmac\u00e9uticos.\n\n### Resumen\n\nLa secci\u00f3n aborda los requisitos para la presentaci\u00f3n de informaci\u00f3n sobre la fabricaci\u00f3n de API, enfatizando la importancia de las especificaciones de materiales, el control de impurezas, la prevenci\u00f3n de la transmisi\u00f3n de TSE, y la validaci\u00f3n de procesos cr\u00edticos. Se requiere documentaci\u00f3n espec\u00edfica para asegurar la calidad y seguridad de los materiales utilizados en la producci\u00f3n de API.", "excerpt_keywords": "Keywords: API, manufacturing process, characterization, quality assurance, pharmacopoeia"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c602926f-4207-4a7a-b67b-799298ac3592", "node_type": "4", "metadata": {"page_label": "154", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD.\n\nThe following requirements apply to the fourth option for submission of API information where full details are provided in the dossier.\n\nIt is expected that the manufacturing processes for all APIs are properly controlled. If the API is prepared as sterile a complete description should be provided of the aseptic processing and/or sterilization methods. A description of the controls used to maintain the sterility of the API during storage and transportation should also be provided. Alternative processes should be justified and described (see guidance in 3.2.S.2.2 for the level of detail expected).\n\n## 3.2.S.2.6 Manufacturing process development (name, manufacturer)\n\nA description and discussion should be provided of the significant changes made to the manufacturing process and/or manufacturing site of the API used in producing comparative bioavailability or biowaiver, scale-up, pilot, and, if available, production scale batches.\n\nReference should be made to the API data provided in Section 3.2.S.4.4.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD.\n\n## 3.2.S.3 Characterization (name, manufacturer)\n\n### 3.2.S.3.1 Elucidation of structure and other characteristics (name, manufacturer)\n\nConfirmation of structure based on, e.g. synthetic route and spectral analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included.\n\n**Elucidation of structure**\n\nThe PD should include quality assurance (QA) certified copies of the spectra, peak assignments and a detailed interpretation of the data from the studies performed to elucidate and/or confirm the structure of the API. The QOS-PD should include a list of the studies performed and a conclusion from the studies (e.g. whether the results support the proposed structure).\n\nFor APIs that are not described in an officially recognized pharmacopoeia, the studies carried out to elucidate and/or confirm the chemical structure normally include elemental analysis, infrared (IR), ultraviolet (UV), nuclear magnetic resonance (NMR) and mass spectra (MS) studies. Other tests could include X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).\n\nFor APIs that are described in an officially recognized pharmacopoeia it is generally sufficient to provide copies of the IR spectrum of the API from each.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "bc4158bfa8c845086bee3e0fbdff83a31b32a68f6a4df59c12463805ef736f8a", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD.\n\nThe following requirements apply to the fourth option for submission of API information where full details are provided in the dossier.\n\nIt is expected that the manufacturing processes for all APIs are properly controlled. If the API is prepared as sterile a complete description should be provided of the aseptic processing and/or sterilization methods. A description of the controls used to maintain the sterility of the API during storage and transportation should also be provided. Alternative processes should be justified and described (see guidance in 3.2.S.2.2 for the level of detail expected).\n\n## 3.2.S.2.6 Manufacturing process development (name, manufacturer)\n\nA description and discussion should be provided of the significant changes made to the manufacturing process and/or manufacturing site of the API used in producing comparative bioavailability or biowaiver, scale-up, pilot, and, if available, production scale batches.\n\nReference should be made to the API data provided in Section 3.2.S.4.4.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD.\n\n## 3.2.S.3 Characterization (name, manufacturer)\n\n### 3.2.S.3.1 Elucidation of structure and other characteristics (name, manufacturer)\n\nConfirmation of structure based on, e.g. synthetic route and spectral analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included.\n\n**Elucidation of structure**\n\nThe PD should include quality assurance (QA) certified copies of the spectra, peak assignments and a detailed interpretation of the data from the studies performed to elucidate and/or confirm the structure of the API. The QOS-PD should include a list of the studies performed and a conclusion from the studies (e.g. whether the results support the proposed structure).\n\nFor APIs that are not described in an officially recognized pharmacopoeia, the studies carried out to elucidate and/or confirm the chemical structure normally include elemental analysis, infrared (IR), ultraviolet (UV), nuclear magnetic resonance (NMR) and mass spectra (MS) studies. Other tests could include X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).\n\nFor APIs that are described in an officially recognized pharmacopoeia it is generally sufficient to provide copies of the IR spectrum of the API from each.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2709, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f439938c-cb88-45ec-995a-5ed80ac8cfdc": {"__data__": {"id_": "f439938c-cb88-45ec-995a-5ed80ac8cfdc", "embedding": null, "metadata": {"page_label": "155", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Isomerism/stereochemistry\n\nWhen an API is chiral, it should be specified whether specific stereoisomers or a mixture of stereoisomers have been used in the comparative biostudies, and information should be given as to the stereoisomer of the API that is to be used in the FPP.\n\nWhere the potential for stereoisomerism exists, a discussion should be included of the possible isomers that can result from the manufacturing process and the steps where chirality was introduced. The identicality of the isomeric composition of the API to that of the API in the comparator product should be established. Information on the physical and chemical properties of the isomeric mixture or single enantiomer should be provided, as appropriate. The API specification should include a test to ensure isomeric identity and purity.\n\nThe potential for interconversion of the isomers in the isomeric mixture, or racemization of the single enantiomer should be discussed.\n\nWhen a single enantiomer of the API is claimed for non-pharmacopoeial APIs, unequivocal proof of absolute configuration of asymmetric centres should be provided, such as determined by X-ray of a single crystal.\n\nIf, based on the structure of the API, there is not a potential for stereoisomerism, it is sufficient to include a statement to this effect.\n\n# Polymorphism\n\nMany APIs can exist in different physical forms in the solid state. Polymorphism is characterized as the ability of an API to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water the solvates are also commonly known as hydrates.\n\nPolymorphic forms of the same chemical compound differ in internal solid-state structure and, therefore, may possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These properties can have a direct impact on API processability, pharmaceutical product manufacturability and product quality and performance, including stability, dissolution and bioavailability. The unexpected appearance or disappearance of a polymorphic form may lead to serious pharmaceutical consequences.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior\nEl documento de la OMS aborda dos conceptos clave en la farmacolog\u00eda: el isomerismo/estereoisomer\u00eda y el polimorfismo de los principios activos (API). Se enfatiza la importancia de especificar la composici\u00f3n estereoisom\u00e9rica de un API, especialmente cuando es quiral, y se requiere informaci\u00f3n sobre su pureza y propiedades. Adem\u00e1s, se discute c\u00f3mo los diferentes formas polim\u00f3rficas de un API pueden afectar sus propiedades qu\u00edmicas y f\u00edsicas, lo que a su vez puede influir en la manufacturabilidad y calidad del producto farmac\u00e9utico.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de pruebas se deben incluir en la especificaci\u00f3n del API para garantizar la identidad y pureza isom\u00e9rica?**\n   - Esta pregunta busca detalles sobre los m\u00e9todos espec\u00edficos que se deben utilizar para verificar la composici\u00f3n isom\u00e9rica de un API.\n\n2. **\u00bfCu\u00e1les son las implicaciones farmac\u00e9uticas de la aparici\u00f3n inesperada de una forma polim\u00f3rfica de un API?**\n   - Esta pregunta se centra en las consecuencias pr\u00e1cticas y potencialmente graves que pueden surgir de cambios en la forma polim\u00f3rfica de un API.\n\n3. **\u00bfQu\u00e9 tipo de evidencia se requiere para demostrar la configuraci\u00f3n absoluta de los centros asim\u00e9tricos en un enanti\u00f3mero \u00fanico de un API no farmacopoeial?**\n   - Esta pregunta busca informaci\u00f3n sobre los est\u00e1ndares de evidencia necesarios para validar la configuraci\u00f3n estereoisom\u00e9rica de un API que no est\u00e1 regulado por una farmacopea.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Procedimiento APIMF**: Se menciona que, cuando se utiliza el procedimiento APIMF, una referencia cruzada a la parte restringida del APIMF es suficiente para la secci\u00f3n del Dossier (PD).\n\n2. **Control de Procesos de Fabricaci\u00f3n**: Se enfatiza la necesidad de que los procesos de fabricaci\u00f3n de todos los Ingredientes Farmac\u00e9uticos Activos (API) est\u00e9n adecuadamente controlados. Para los APIs est\u00e9riles, se requiere una descripci\u00f3n completa de los m\u00e9todos de procesamiento as\u00e9ptico y/o de esterilizaci\u00f3n, as\u00ed como de los controles para mantener la esterilidad durante el almacenamiento y transporte.\n\n3. **Desarrollo del Proceso de Fabricaci\u00f3n**: Se debe proporcionar una descripci\u00f3n y discusi\u00f3n de los cambios significativos en el proceso de fabricaci\u00f3n y/o en el sitio de fabricaci\u00f3n del API, especialmente en relaci\u00f3n con lotes de bioequivalencia comparativa, escalado, piloto y producci\u00f3n.\n\n4. **Caracterizaci\u00f3n de la Estructura**: Se requiere la confirmaci\u00f3n de la estructura del API mediante an\u00e1lisis espectrosc\u00f3picos y otros m\u00e9todos. Se debe incluir informaci\u00f3n sobre isomerismo, estereoqu\u00edmica y formaci\u00f3n de polimorfos.\n\n5. **Documentaci\u00f3n de Calidad**: El Dossier debe incluir copias certificadas por aseguramiento de calidad (QA) de los espectros, asignaciones de picos y una interpretaci\u00f3n detallada de los datos de los estudios realizados para confirmar la estructura del API.\n\n6. **Estudios Espec\u00edficos para APIs No Reconocidos**: Para APIs que no est\u00e1n descritos en una farmacopea oficialmente reconocida, se requieren estudios como an\u00e1lisis elemental, espectroscop\u00eda IR, UV, NMR y MS, as\u00ed como pruebas adicionales como XRPD y DSC.\n\n7. **Farmacopeas Reconocidas**: Para APIs descritos en farmacopeas reconocidas, generalmente es suficiente proporcionar copias del espectro IR del API.\n\n### Entidades Clave\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite el documento.\n- **APIMF (Active Pharmaceutical Ingredient Master File)**: Procedimiento mencionado para la presentaci\u00f3n de informaci\u00f3n sobre APIs.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia cuya fabricaci\u00f3n y caracterizaci\u00f3n se detalla en el documento.\n- **QA (Quality Assurance)**: Aseguramiento de calidad relacionado con la documentaci\u00f3n requerida.\n- **Espectroscop\u00eda**: M\u00e9todos anal\u00edticos mencionados para la caracterizaci\u00f3n de la estructura del API. \n\nEste resumen abarca los aspectos fundamentales y las entidades relevantes del contenido proporcionado, destacando la importancia de la regulaci\u00f3n y el control en la fabricaci\u00f3n y caracterizaci\u00f3n de los APIs.", "excerpt_keywords": "Keywords: isomerism, stereochemistry, polymorphism, active pharmaceutical ingredient, pharmaceutical quality"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f0530cee-c154-448d-a118-7d210549d390", "node_type": "4", "metadata": {"page_label": "155", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Isomerism/stereochemistry\n\nWhen an API is chiral, it should be specified whether specific stereoisomers or a mixture of stereoisomers have been used in the comparative biostudies, and information should be given as to the stereoisomer of the API that is to be used in the FPP.\n\nWhere the potential for stereoisomerism exists, a discussion should be included of the possible isomers that can result from the manufacturing process and the steps where chirality was introduced. The identicality of the isomeric composition of the API to that of the API in the comparator product should be established. Information on the physical and chemical properties of the isomeric mixture or single enantiomer should be provided, as appropriate. The API specification should include a test to ensure isomeric identity and purity.\n\nThe potential for interconversion of the isomers in the isomeric mixture, or racemization of the single enantiomer should be discussed.\n\nWhen a single enantiomer of the API is claimed for non-pharmacopoeial APIs, unequivocal proof of absolute configuration of asymmetric centres should be provided, such as determined by X-ray of a single crystal.\n\nIf, based on the structure of the API, there is not a potential for stereoisomerism, it is sufficient to include a statement to this effect.\n\n# Polymorphism\n\nMany APIs can exist in different physical forms in the solid state. Polymorphism is characterized as the ability of an API to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water the solvates are also commonly known as hydrates.\n\nPolymorphic forms of the same chemical compound differ in internal solid-state structure and, therefore, may possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These properties can have a direct impact on API processability, pharmaceutical product manufacturability and product quality and performance, including stability, dissolution and bioavailability. The unexpected appearance or disappearance of a polymorphic form may lead to serious pharmaceutical consequences.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "7f778b3cf7986fc36ccbc825501efdad1cc7adb9c9cc5344d2ab66b33e43d51b", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Isomerism/stereochemistry\n\nWhen an API is chiral, it should be specified whether specific stereoisomers or a mixture of stereoisomers have been used in the comparative biostudies, and information should be given as to the stereoisomer of the API that is to be used in the FPP.\n\nWhere the potential for stereoisomerism exists, a discussion should be included of the possible isomers that can result from the manufacturing process and the steps where chirality was introduced. The identicality of the isomeric composition of the API to that of the API in the comparator product should be established. Information on the physical and chemical properties of the isomeric mixture or single enantiomer should be provided, as appropriate. The API specification should include a test to ensure isomeric identity and purity.\n\nThe potential for interconversion of the isomers in the isomeric mixture, or racemization of the single enantiomer should be discussed.\n\nWhen a single enantiomer of the API is claimed for non-pharmacopoeial APIs, unequivocal proof of absolute configuration of asymmetric centres should be provided, such as determined by X-ray of a single crystal.\n\nIf, based on the structure of the API, there is not a potential for stereoisomerism, it is sufficient to include a statement to this effect.\n\n# Polymorphism\n\nMany APIs can exist in different physical forms in the solid state. Polymorphism is characterized as the ability of an API to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water the solvates are also commonly known as hydrates.\n\nPolymorphic forms of the same chemical compound differ in internal solid-state structure and, therefore, may possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These properties can have a direct impact on API processability, pharmaceutical product manufacturability and product quality and performance, including stability, dissolution and bioavailability. The unexpected appearance or disappearance of a polymorphic form may lead to serious pharmaceutical consequences.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2465, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "e87de8ed-5afb-4bcb-8331-bc33b99c3681": {"__data__": {"id_": "e87de8ed-5afb-4bcb-8331-bc33b99c3681", "embedding": null, "metadata": {"page_label": "156", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nApplicants to the WHO Prequalification of Medicines Programme and API manufacturers are expected to have adequate knowledge about the polymorphism of the APIs used and/or produced. Information on polymorphism can come from the scientific literature, patents, compendia or other references to determine if polymorphism is a concern, e.g. for APIs that are not BCS highly soluble. In the absence of published data for APIs that are not BSC highly soluble, polymorphic screening will be necessary to determine if the API can exist in more than one crystalline form. Polymorphic screening is generally accomplished via crystallization studies using different solvents and conditions.\n\nA number of methods can be used to characterize the polymorphic forms of an API. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. XRPD can also be used to provide unequivocal proof of polymorphism. Other methods, including microscopy, thermal analysis (e.g. DSC, thermal gravimetric analysis and hot-stage microscopy) and spectroscopy (e.g. IR, Raman, and solid-state nuclear magnetic resonance (ssNMR)) are helpful for further characterization of polymorphic forms. Where polymorphism is a concern, the applicants or manufacturers of APIs should demonstrate that a suitable method, capable of distinguishing different polymorphs, is available to them.\n\nDecision tree 4(1) of ICH Q6A (6) can be used where screening is necessary and 4(2) can be used to investigate if different polymorphic forms have different properties that may affect performance, bioavailability and stability of the FPP and to decide whether a preferred polymorph should be monitored at release and on storage of the API. Where there is a preferred polymorph, acceptance criteria should be incorporated into the API specification to ensure polymorphic equivalence of the commercial material and that of the API batches used in the comparative bioavailability or biowaiver studies. The polymorphic characterization of the API batches used in comparative bioavailability or biowaiver studies by the above-mentioned methods should be provided. The method used to control polymorphic form should be demonstrated to be specific for the preferred form.\n\nPolymorphism can also include solvation or hydration products (also known as pseudopolymorphs). If the API is used in a solvated form, the following information should be provided:\n\n- specifications for the solvent-free API in 3.2.S.2.4, if that compound is a synthetic precursor;\n- specifications for the solvated API including appropriate limits on the weight ratio of API to solvent (with data to support the proposed limits);\n- a description of the method used to prepare the solvate in 3.2.S.2.2.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS aborda la importancia del conocimiento sobre el polimorfismo de los principios activos (API) en el contexto de la precalificaci\u00f3n de medicamentos. Se enfatiza la necesidad de realizar estudios de cribado polim\u00f3rfico para determinar si un API puede existir en m\u00e1s de una forma cristalina, especialmente si no es altamente soluble seg\u00fan el sistema BCS. Se describen m\u00e9todos para caracterizar las formas polim\u00f3rficas, siendo la difracci\u00f3n de rayos X de cristal \u00fanico el est\u00e1ndar de oro. Adem\u00e1s, se menciona la importancia de establecer criterios de aceptaci\u00f3n para asegurar la equivalencia polim\u00f3rfica y se discuten los productos de solvataci\u00f3n o hidrataci\u00f3n como pseudopolimorfos.\n\n### Preguntas Espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los m\u00e9todos m\u00e1s confiables para demostrar la existencia de polimorfismo en un API y cu\u00e1l se considera el est\u00e1ndar de oro?**\n   - Respuesta: La demostraci\u00f3n de una estructura no equivalente mediante difracci\u00f3n de rayos X de cristal \u00fanico es actualmente considerada como la evidencia definitiva de polimorfismo. Adem\u00e1s, la difracci\u00f3n de rayos X en polvo (XRPD) tambi\u00e9n puede proporcionar prueba inequ\u00edvoca de polimorfismo.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n se debe proporcionar si un API se utiliza en forma de solvatado?**\n   - Respuesta: Se debe proporcionar especificaciones para el API libre de solvente, especificaciones para el API solvado que incluyan l\u00edmites apropiados en la relaci\u00f3n peso de API a solvente, y una descripci\u00f3n del m\u00e9todo utilizado para preparar el solvatado.\n\n3. **\u00bfC\u00f3mo se deben manejar las formas polim\u00f3rficas preferidas en los estudios de bioequivalencia o biowaiver?**\n   - Respuesta: Donde hay un polimorfo preferido, se deben incorporar criterios de aceptaci\u00f3n en la especificaci\u00f3n del API para asegurar la equivalencia polim\u00f3rfica del material comercial y de los lotes de API utilizados en los estudios de bioequivalencia o biowaiver. Adem\u00e1s, la caracterizaci\u00f3n polim\u00f3rfica de los lotes de API utilizados en estos estudios debe ser proporcionada, y el m\u00e9todo utilizado para controlar la forma polim\u00f3rfica debe ser espec\u00edfico para la forma preferida.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n#### Temas Clave\n\n1. **Isomerismo y Estereoisomer\u00eda**:\n   - Importancia de especificar si se utilizan estereois\u00f3meros espec\u00edficos o una mezcla en estudios comparativos.\n   - Necesidad de establecer la identidad isom\u00e9rica del API en comparaci\u00f3n con el producto de referencia.\n   - Requerimiento de pruebas para garantizar la pureza y la identidad isom\u00e9rica.\n   - Discusi\u00f3n sobre la posibilidad de interconversi\u00f3n de is\u00f3meros y racemizaci\u00f3n de enanti\u00f3meros.\n   - Para APIs no farmacopoeiales, se requiere prueba inequ\u00edvoca de la configuraci\u00f3n absoluta de los centros asim\u00e9tricos.\n\n2. **Polimorfismo**:\n   - Definici\u00f3n de polimorfismo como la capacidad de un API para existir en diferentes fases cristalinas.\n   - Diferencias en propiedades qu\u00edmicas y f\u00edsicas entre formas polim\u00f3rficas que pueden afectar la manufacturabilidad y calidad del producto.\n   - Consecuencias farmac\u00e9uticas de la aparici\u00f3n o desaparici\u00f3n inesperada de formas polim\u00f3rficas.\n\n#### Entidades\n\n- **API (Active Pharmaceutical Ingredient)**: Componente activo en medicamentos que puede presentar isomerismo y polimorfismo.\n- **Estereois\u00f3meros**: Is\u00f3meros que tienen la misma f\u00f3rmula molecular pero diferente disposici\u00f3n espacial.\n- **Enantiomeros**: Is\u00f3meros \u00f3pticos que son im\u00e1genes especulares no superponibles.\n- **Polimorfismo**: Fen\u00f3meno que permite a un compuesto qu\u00edmico existir en m\u00faltiples formas cristalinas.\n- **Solvatos y Hidrataci\u00f3n**: Formas cristalinas que contienen solventes, siendo los hidratos aquellos que contienen agua.\n\nEste resumen destaca la relevancia de la estereoisomer\u00eda y el polimorfismo en el desarrollo y la calidad de los productos farmac\u00e9uticos, as\u00ed como los requisitos espec\u00edficos para la caracterizaci\u00f3n de APIs.", "excerpt_keywords": "Keywords: polymorphism, active pharmaceutical ingredient, crystallization, bioavailability, solvation"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4d592e77-b313-4a73-b501-480d7634fdcf", "node_type": "4", "metadata": {"page_label": "156", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nApplicants to the WHO Prequalification of Medicines Programme and API manufacturers are expected to have adequate knowledge about the polymorphism of the APIs used and/or produced. Information on polymorphism can come from the scientific literature, patents, compendia or other references to determine if polymorphism is a concern, e.g. for APIs that are not BCS highly soluble. In the absence of published data for APIs that are not BSC highly soluble, polymorphic screening will be necessary to determine if the API can exist in more than one crystalline form. Polymorphic screening is generally accomplished via crystallization studies using different solvents and conditions.\n\nA number of methods can be used to characterize the polymorphic forms of an API. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. XRPD can also be used to provide unequivocal proof of polymorphism. Other methods, including microscopy, thermal analysis (e.g. DSC, thermal gravimetric analysis and hot-stage microscopy) and spectroscopy (e.g. IR, Raman, and solid-state nuclear magnetic resonance (ssNMR)) are helpful for further characterization of polymorphic forms. Where polymorphism is a concern, the applicants or manufacturers of APIs should demonstrate that a suitable method, capable of distinguishing different polymorphs, is available to them.\n\nDecision tree 4(1) of ICH Q6A (6) can be used where screening is necessary and 4(2) can be used to investigate if different polymorphic forms have different properties that may affect performance, bioavailability and stability of the FPP and to decide whether a preferred polymorph should be monitored at release and on storage of the API. Where there is a preferred polymorph, acceptance criteria should be incorporated into the API specification to ensure polymorphic equivalence of the commercial material and that of the API batches used in the comparative bioavailability or biowaiver studies. The polymorphic characterization of the API batches used in comparative bioavailability or biowaiver studies by the above-mentioned methods should be provided. The method used to control polymorphic form should be demonstrated to be specific for the preferred form.\n\nPolymorphism can also include solvation or hydration products (also known as pseudopolymorphs). If the API is used in a solvated form, the following information should be provided:\n\n- specifications for the solvent-free API in 3.2.S.2.4, if that compound is a synthetic precursor;\n- specifications for the solvated API including appropriate limits on the weight ratio of API to solvent (with data to support the proposed limits);\n- a description of the method used to prepare the solvate in 3.2.S.2.2.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "8848aa15553fadafb71eebac4a62fdb846baf472490fa4ccefc42e3c524dd688", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nApplicants to the WHO Prequalification of Medicines Programme and API manufacturers are expected to have adequate knowledge about the polymorphism of the APIs used and/or produced. Information on polymorphism can come from the scientific literature, patents, compendia or other references to determine if polymorphism is a concern, e.g. for APIs that are not BCS highly soluble. In the absence of published data for APIs that are not BSC highly soluble, polymorphic screening will be necessary to determine if the API can exist in more than one crystalline form. Polymorphic screening is generally accomplished via crystallization studies using different solvents and conditions.\n\nA number of methods can be used to characterize the polymorphic forms of an API. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. XRPD can also be used to provide unequivocal proof of polymorphism. Other methods, including microscopy, thermal analysis (e.g. DSC, thermal gravimetric analysis and hot-stage microscopy) and spectroscopy (e.g. IR, Raman, and solid-state nuclear magnetic resonance (ssNMR)) are helpful for further characterization of polymorphic forms. Where polymorphism is a concern, the applicants or manufacturers of APIs should demonstrate that a suitable method, capable of distinguishing different polymorphs, is available to them.\n\nDecision tree 4(1) of ICH Q6A (6) can be used where screening is necessary and 4(2) can be used to investigate if different polymorphic forms have different properties that may affect performance, bioavailability and stability of the FPP and to decide whether a preferred polymorph should be monitored at release and on storage of the API. Where there is a preferred polymorph, acceptance criteria should be incorporated into the API specification to ensure polymorphic equivalence of the commercial material and that of the API batches used in the comparative bioavailability or biowaiver studies. The polymorphic characterization of the API batches used in comparative bioavailability or biowaiver studies by the above-mentioned methods should be provided. The method used to control polymorphic form should be demonstrated to be specific for the preferred form.\n\nPolymorphism can also include solvation or hydration products (also known as pseudopolymorphs). If the API is used in a solvated form, the following information should be provided:\n\n- specifications for the solvent-free API in 3.2.S.2.4, if that compound is a synthetic precursor;\n- specifications for the solvated API including appropriate limits on the weight ratio of API to solvent (with data to support the proposed limits);\n- a description of the method used to prepare the solvate in 3.2.S.2.2.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2873, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "10082ae2-3613-4802-840a-818a641b43da": {"__data__": {"id_": "10082ae2-3613-4802-840a-818a641b43da", "embedding": null, "metadata": {"page_label": "157", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Particle size distribution\n\nFor APIs that are not BCS highly soluble contained in solid FPPs, or liquid FPPs containing undissolved API, the particle size distribution of the material can have an effect on the in vitro and/or in vivo behaviour of the FPP. Particle size distribution can also be important in dosage form performance (e.g., delivery of inhalation products), achieving uniformity of content in low-dose tablets (e.g. 2 mg or less), desired smoothness in ophthalmic preparations and stability of suspensions.\n\nIf particle size distribution is an important parameter (e.g. as in the above cases), results from an investigation of several batches of the API should be provided, including characterization of the batch(es) used in the comparative bioavailability or biowaiver studies. API specifications should include controls on the particle size distribution to ensure consistency with the material in the batch(es) used in the comparative bioavailability and biowaiver studies (e.g. limits for d10, d50 and d90). The criteria should be established statistically, based on the standard deviation of the test results from the previously mentioned studies. The following example is provided for illustrative purposes as possible acceptance criteria for particle size distribution limits:\n\n- d10 not more than (NMT) 10% of total volume less than X \u00b5m;\n- d50 XX \u00b5m\u2013XXX \u00b5m;\n- d90 not less than (NLT) 90% of total volume less than XXXX \u00b5m.\n\nOther controls on particle size distribution can be considered acceptable, if scientifically justified.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.3.2 Impurities (name, manufacturer)\n\n### Information on impurities should be provided.\n\nDetails on the principles for the control of impurities (e.g. reporting, identification and qualification) are outlined in the ICH Q3A, Q3B and Q3C impurity guidelines (10\u201312). Additional information elaborating on some of the elements discussed in the ICH guidelines is outlined below.\n\nRegardless of whether a pharmacopoeial standard is claimed, a discussion should be provided of the potential and actual impurities arising from the synthesis, manufacture or degradation of the API. This should cover starting materials, by-products, intermediates, chiral impurities and degradation products and should include the chemical names, structures and origins of the impurities. The discussion of pharmacopoeial APIs should not be limited to the impurities specified in the API monograph.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl texto aborda la importancia de la distribuci\u00f3n del tama\u00f1o de part\u00edculas en los principios activos (API) que no son altamente solubles seg\u00fan el sistema BCS, especialmente en formas farmac\u00e9uticas s\u00f3lidas y l\u00edquidas. Se destaca c\u00f3mo la distribuci\u00f3n del tama\u00f1o de part\u00edculas puede influir en el comportamiento in vitro e in vivo de los productos farmac\u00e9uticos. Adem\u00e1s, se menciona la necesidad de proporcionar resultados de investigaciones sobre varias lotes de API y establecer especificaciones que incluyan controles sobre la distribuci\u00f3n del tama\u00f1o de part\u00edculas. Tambi\u00e9n se discuten las impurezas en los API, enfatizando la importancia de identificar y controlar las impurezas que pueden surgir durante la s\u00edntesis, fabricaci\u00f3n o degradaci\u00f3n del API.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios estad\u00edsticos sugeridos para establecer los l\u00edmites de distribuci\u00f3n del tama\u00f1o de part\u00edculas en los API?**\n   - El texto menciona que los criterios deben establecerse estad\u00edsticamente, bas\u00e1ndose en la desviaci\u00f3n est\u00e1ndar de los resultados de las pruebas de los estudios de bioequivalencia o biowaiver previos.\n\n2. **\u00bfQu\u00e9 tipos de impurezas deben ser discutidos en relaci\u00f3n con los API, seg\u00fan las pautas ICH?**\n   - Se deben discutir impurezas potenciales y reales que surjan de la s\u00edntesis, fabricaci\u00f3n o degradaci\u00f3n del API, incluyendo materiales de partida, subproductos, intermedios, impurezas quirales y productos de degradaci\u00f3n, junto con sus nombres qu\u00edmicos, estructuras y or\u00edgenes.\n\n3. **\u00bfQu\u00e9 ejemplos de l\u00edmites de aceptaci\u00f3n para la distribuci\u00f3n del tama\u00f1o de part\u00edculas se proporcionan en el texto?**\n   - Se proporcionan ejemplos como: \n     - d10 no m\u00e1s del 10% del volumen total menor que X \u00b5m;\n     - d50 en el rango de XX \u00b5m a XXX \u00b5m;\n     - d90 no menos del 90% del volumen total menor que XXXX \u00b5m.\n\n### Resumen de nivel superior\n\nEl documento enfatiza la relevancia de la distribuci\u00f3n del tama\u00f1o de part\u00edculas en la formulaci\u00f3n y eficacia de los productos farmac\u00e9uticos, especialmente para aquellos que no son altamente solubles. Se requiere un an\u00e1lisis detallado de varios lotes de API para asegurar la consistencia y se establecen criterios espec\u00edficos para el control de la distribuci\u00f3n del tama\u00f1o de part\u00edculas. Adem\u00e1s, se subraya la necesidad de un enfoque exhaustivo para identificar y controlar las impurezas en los API, siguiendo las pautas establecidas por la ICH.", "prev_section_summary": "### Temas Clave:\n\n1. **Polimorfismo de APIs**: La secci\u00f3n destaca la importancia del conocimiento sobre el polimorfismo de los principios activos (APIs) en el contexto de la precalificaci\u00f3n de medicamentos por parte de la OMS.\n\n2. **Cribado Polim\u00f3rfico**: Se enfatiza la necesidad de realizar estudios de cribado polim\u00f3rfico para determinar si un API puede existir en m\u00e1s de una forma cristalina, especialmente si no es altamente soluble seg\u00fan el sistema BCS.\n\n3. **M\u00e9todos de Caracterizaci\u00f3n**: Se describen varios m\u00e9todos para caracterizar las formas polim\u00f3rficas, siendo la difracci\u00f3n de rayos X de cristal \u00fanico el est\u00e1ndar de oro, junto con XRPD y otras t\u00e9cnicas como microscop\u00eda, an\u00e1lisis t\u00e9rmico y espectroscopia.\n\n4. **Criterios de Aceptaci\u00f3n**: Se menciona la importancia de establecer criterios de aceptaci\u00f3n para asegurar la equivalencia polim\u00f3rfica entre el material comercial y los lotes de API utilizados en estudios de bioequivalencia o biowaiver.\n\n5. **Solvataci\u00f3n y Pseudopolimorfos**: Se aborda el tema de los productos de solvataci\u00f3n o hidrataci\u00f3n, conocidos como pseudopolimorfos, y la informaci\u00f3n que debe proporcionarse si un API se utiliza en forma de solvatado.\n\n### Entidades:\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la precalificaci\u00f3n de medicamentos.\n- **APIs (Principios Activos)**: Sustancias utilizadas en la fabricaci\u00f3n de medicamentos.\n- **BCS (Biopharmaceutics Classification System)**: Sistema que clasifica los f\u00e1rmacos seg\u00fan su solubilidad y permeabilidad.\n- **M\u00e9todos de Caracterizaci\u00f3n**: Incluyen difracci\u00f3n de rayos X de cristal \u00fanico, XRPD, microscop\u00eda, an\u00e1lisis t\u00e9rmico (DSC, TGA, microscop\u00eda de etapa caliente) y espectroscopia (IR, Raman, ssNMR).\n- **ICH Q6A**: Directrices que incluyen \u00e1rboles de decisi\u00f3n para evaluar el polimorfismo.\n- **Pseudopolimorfos**: Formas de un API que incluyen productos de solvataci\u00f3n o hidrataci\u00f3n. \n\nEste resumen proporciona una visi\u00f3n general de los aspectos m\u00e1s relevantes del polimorfismo en la fabricaci\u00f3n y evaluaci\u00f3n de APIs, as\u00ed como los m\u00e9todos y criterios necesarios para su caracterizaci\u00f3n y control.", "excerpt_keywords": "Keywords: particle size distribution, APIs, impurities, bioavailability, ICH guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2a64fb6a-e529-470b-b5c9-b8cff93fa8ab", "node_type": "4", "metadata": {"page_label": "157", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Particle size distribution\n\nFor APIs that are not BCS highly soluble contained in solid FPPs, or liquid FPPs containing undissolved API, the particle size distribution of the material can have an effect on the in vitro and/or in vivo behaviour of the FPP. Particle size distribution can also be important in dosage form performance (e.g., delivery of inhalation products), achieving uniformity of content in low-dose tablets (e.g. 2 mg or less), desired smoothness in ophthalmic preparations and stability of suspensions.\n\nIf particle size distribution is an important parameter (e.g. as in the above cases), results from an investigation of several batches of the API should be provided, including characterization of the batch(es) used in the comparative bioavailability or biowaiver studies. API specifications should include controls on the particle size distribution to ensure consistency with the material in the batch(es) used in the comparative bioavailability and biowaiver studies (e.g. limits for d10, d50 and d90). The criteria should be established statistically, based on the standard deviation of the test results from the previously mentioned studies. The following example is provided for illustrative purposes as possible acceptance criteria for particle size distribution limits:\n\n- d10 not more than (NMT) 10% of total volume less than X \u00b5m;\n- d50 XX \u00b5m\u2013XXX \u00b5m;\n- d90 not less than (NLT) 90% of total volume less than XXXX \u00b5m.\n\nOther controls on particle size distribution can be considered acceptable, if scientifically justified.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.3.2 Impurities (name, manufacturer)\n\n### Information on impurities should be provided.\n\nDetails on the principles for the control of impurities (e.g. reporting, identification and qualification) are outlined in the ICH Q3A, Q3B and Q3C impurity guidelines (10\u201312). Additional information elaborating on some of the elements discussed in the ICH guidelines is outlined below.\n\nRegardless of whether a pharmacopoeial standard is claimed, a discussion should be provided of the potential and actual impurities arising from the synthesis, manufacture or degradation of the API. This should cover starting materials, by-products, intermediates, chiral impurities and degradation products and should include the chemical names, structures and origins of the impurities. The discussion of pharmacopoeial APIs should not be limited to the impurities specified in the API monograph.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "5dbc9ecf5065a723481853b1f28971173d98bebf63ce8442f20df640b129717b", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Particle size distribution\n\nFor APIs that are not BCS highly soluble contained in solid FPPs, or liquid FPPs containing undissolved API, the particle size distribution of the material can have an effect on the in vitro and/or in vivo behaviour of the FPP. Particle size distribution can also be important in dosage form performance (e.g., delivery of inhalation products), achieving uniformity of content in low-dose tablets (e.g. 2 mg or less), desired smoothness in ophthalmic preparations and stability of suspensions.\n\nIf particle size distribution is an important parameter (e.g. as in the above cases), results from an investigation of several batches of the API should be provided, including characterization of the batch(es) used in the comparative bioavailability or biowaiver studies. API specifications should include controls on the particle size distribution to ensure consistency with the material in the batch(es) used in the comparative bioavailability and biowaiver studies (e.g. limits for d10, d50 and d90). The criteria should be established statistically, based on the standard deviation of the test results from the previously mentioned studies. The following example is provided for illustrative purposes as possible acceptance criteria for particle size distribution limits:\n\n- d10 not more than (NMT) 10% of total volume less than X \u00b5m;\n- d50 XX \u00b5m\u2013XXX \u00b5m;\n- d90 not less than (NLT) 90% of total volume less than XXXX \u00b5m.\n\nOther controls on particle size distribution can be considered acceptable, if scientifically justified.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.3.2 Impurities (name, manufacturer)\n\n### Information on impurities should be provided.\n\nDetails on the principles for the control of impurities (e.g. reporting, identification and qualification) are outlined in the ICH Q3A, Q3B and Q3C impurity guidelines (10\u201312). Additional information elaborating on some of the elements discussed in the ICH guidelines is outlined below.\n\nRegardless of whether a pharmacopoeial standard is claimed, a discussion should be provided of the potential and actual impurities arising from the synthesis, manufacture or degradation of the API. This should cover starting materials, by-products, intermediates, chiral impurities and degradation products and should include the chemical names, structures and origins of the impurities. The discussion of pharmacopoeial APIs should not be limited to the impurities specified in the API monograph.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2472, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "163ad738-7dd9-4a8a-951d-78d43e5ce287": {"__data__": {"id_": "163ad738-7dd9-4a8a-951d-78d43e5ce287", "embedding": null, "metadata": {"page_label": "158", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe tables in the QOS-PD template should be used to summarize the information on the API-related and process-related impurities. In the QOS-PD, the term \u201corigin\u201d refers to how and where the impurity was introduced (e.g. \u201cSynthetic intermediate from Step 4 of the synthesis\u201d or \u201cPotential by-product due to rearrangement from Step 6 of the synthesis\u201d). It should also be indicated if the impurity is a metabolite of the API.\n\nThe ICH thresholds for reporting, identification (used to set the limit for individual unknown impurities) and qualification are determined on the basis of potential exposure to the impurity, e.g. by the maximum daily dose (MDD) of the API. For APIs available in multiple dosage forms and strengths having different MDD values, it is imperative that the thresholds and corresponding controls for each of the presentations be considered to ensure that the risks posed by impurities have been addressed. This is normally achieved by using the highest potential daily MDD, rather than the maintenance dose. For parenteral products the maximum hourly dose of the API should also be included.\n\nIt is acknowledged that APIs of semi-synthetic origin do not fall within the scope of the ICH impurity guidelines. However, depending on the nature of the API and the extent of the chemical modification steps, the principles regarding the control of impurities (e.g. reporting, identification and qualification) could be extended to apply to APIs of semi-synthetic origin. As an illustrative example, an API whose precursor molecule was derived from a fermentation process or a natural product of plant or animal origin, which has subsequently undergone several chemical modification reactions, would generally fall within the scope of the ICH impurity guidelines, whereas an API whose sole chemical step was the formation of a salt from a fermentation product generally would not. It is understood that there is some latitude for these types of APIs.\n\n## Identification of impurities\n\nIt is recognized by the pharmacopoeias that APIs can be obtained from various sources and thus can contain impurities not considered during the development of the monograph. Furthermore, a change in the production or source may give rise to additional impurities that are not adequately controlled by the official compendial monograph. As a result each PD is assessed independently to consider the potential impurities that may arise from the proposed route(s) of synthesis. For these reasons the ICH limits for unspecified impurities (e.g. NMT 0.10% or 1.0 mg per day intake (whichever is lower) for APIs having an MDD \u2264 2 g/day) are generally recommended, rather than the general limits for unspecified impurities that may appear in the official compendial monograph, which could potentially be higher than the applicable ICH limit.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS aborda las especificaciones para las preparaciones farmac\u00e9uticas, centr\u00e1ndose en la identificaci\u00f3n y control de impurezas en los principios activos (API). Se discuten los umbrales establecidos por la ICH para la notificaci\u00f3n, identificaci\u00f3n y calificaci\u00f3n de impurezas, que dependen de la exposici\u00f3n potencial a estas impurezas, medida a trav\u00e9s de la dosis diaria m\u00e1xima (MDD) del API. Tambi\u00e9n se menciona que los APIs de origen semisint\u00e9tico pueden no estar completamente cubiertos por las directrices de impurezas de la ICH, pero se pueden aplicar principios similares dependiendo de la naturaleza del API. Adem\u00e1s, se enfatiza la importancia de evaluar cada dossier de producto (PD) de manera independiente para identificar impurezas potenciales.\n\n### Preguntas:\n1. **\u00bfC\u00f3mo se determina el l\u00edmite para las impurezas desconocidas en los APIs seg\u00fan las directrices de la ICH?**\n   - La determinaci\u00f3n del l\u00edmite para las impurezas desconocidas se basa en la exposici\u00f3n potencial a la impureza, que se mide a trav\u00e9s de la dosis diaria m\u00e1xima (MDD) del API. Para APIs con m\u00faltiples formas de dosificaci\u00f3n y MDD, se utiliza la MDD m\u00e1s alta para establecer los l\u00edmites y controles correspondientes.\n\n2. **\u00bfQu\u00e9 consideraciones se deben tener en cuenta para los APIs de origen semisint\u00e9tico en relaci\u00f3n con las impurezas?**\n   - Aunque los APIs de origen semisint\u00e9tico no caen estrictamente bajo las directrices de impurezas de la ICH, los principios de control de impurezas pueden extenderse a ellos dependiendo de la naturaleza del API y la extensi\u00f3n de los pasos de modificaci\u00f3n qu\u00edmica. Por ejemplo, un API derivado de un proceso de fermentaci\u00f3n que ha pasado por varias reacciones qu\u00edmicas podr\u00eda estar sujeto a estas directrices.\n\n3. **\u00bfPor qu\u00e9 es importante evaluar cada dossier de producto (PD) de manera independiente en relaci\u00f3n con las impurezas?**\n   - Es crucial evaluar cada PD de manera independiente porque los APIs pueden ser obtenidos de diversas fuentes y pueden contener impurezas no consideradas en la monograf\u00eda oficial. Adem\u00e1s, un cambio en la producci\u00f3n o la fuente puede dar lugar a impurezas adicionales que no est\u00e1n adecuadamente controladas por la monograf\u00eda, lo que requiere una evaluaci\u00f3n espec\u00edfica para cada caso.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Distribuci\u00f3n del Tama\u00f1o de Part\u00edculas**:\n   - La distribuci\u00f3n del tama\u00f1o de part\u00edculas es crucial para los principios activos (API) que no son altamente solubles seg\u00fan el sistema BCS, especialmente en formas farmac\u00e9uticas s\u00f3lidas y l\u00edquidas.\n   - Afecta el comportamiento in vitro e in vivo de los productos farmac\u00e9uticos, as\u00ed como el rendimiento de las formas de dosificaci\u00f3n (por ejemplo, en productos de inhalaci\u00f3n y tabletas de baja dosis).\n\n2. **Investigaci\u00f3n y Especificaciones**:\n   - Se deben proporcionar resultados de investigaciones sobre varios lotes de API, incluyendo la caracterizaci\u00f3n de los lotes utilizados en estudios de bioequivalencia o biowaiver.\n   - Las especificaciones del API deben incluir controles sobre la distribuci\u00f3n del tama\u00f1o de part\u00edculas, con l\u00edmites establecidos para d10, d50 y d90.\n\n3. **Criterios Estad\u00edsticos**:\n   - Los criterios para establecer l\u00edmites de distribuci\u00f3n del tama\u00f1o de part\u00edculas deben basarse en la desviaci\u00f3n est\u00e1ndar de los resultados de pruebas de estudios previos.\n\n4. **Ejemplos de L\u00edmites de Aceptaci\u00f3n**:\n   - d10: no m\u00e1s del 10% del volumen total menor que X \u00b5m.\n   - d50: en el rango de XX \u00b5m a XXX \u00b5m.\n   - d90: no menos del 90% del volumen total menor que XXXX \u00b5m.\n\n5. **Impurezas**:\n   - Se debe proporcionar informaci\u00f3n sobre las impurezas potenciales y reales que pueden surgir de la s\u00edntesis, fabricaci\u00f3n o degradaci\u00f3n del API.\n   - Esto incluye materiales de partida, subproductos, intermedios, impurezas quirales y productos de degradaci\u00f3n, junto con sus nombres qu\u00edmicos, estructuras y or\u00edgenes.\n\n6. **Referencias**:\n   - Se hace referencia a las pautas ICH Q3A, Q3B y Q3C para el control de impurezas y a ICH Q6A para la distribuci\u00f3n del tama\u00f1o de part\u00edculas.\n\n### Entidades Clave:\n- **API (Principios Activos)**: Sustancias que tienen un efecto farmacol\u00f3gico.\n- **FPP (Formas Farmac\u00e9uticas de Producto)**: Formas en las que se presenta el medicamento.\n- **BCS (Biopharmaceutics Classification System)**: Sistema que clasifica los f\u00e1rmacos seg\u00fan su solubilidad y permeabilidad.\n- **ICH (International Council for Harmonisation)**: Consejo que establece pautas para la regulaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: impurities, API, ICH guidelines, maximum daily dose, pharmaceutical preparations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0386e271-02a3-4979-98eb-153e8c51cc26", "node_type": "4", "metadata": {"page_label": "158", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe tables in the QOS-PD template should be used to summarize the information on the API-related and process-related impurities. In the QOS-PD, the term \u201corigin\u201d refers to how and where the impurity was introduced (e.g. \u201cSynthetic intermediate from Step 4 of the synthesis\u201d or \u201cPotential by-product due to rearrangement from Step 6 of the synthesis\u201d). It should also be indicated if the impurity is a metabolite of the API.\n\nThe ICH thresholds for reporting, identification (used to set the limit for individual unknown impurities) and qualification are determined on the basis of potential exposure to the impurity, e.g. by the maximum daily dose (MDD) of the API. For APIs available in multiple dosage forms and strengths having different MDD values, it is imperative that the thresholds and corresponding controls for each of the presentations be considered to ensure that the risks posed by impurities have been addressed. This is normally achieved by using the highest potential daily MDD, rather than the maintenance dose. For parenteral products the maximum hourly dose of the API should also be included.\n\nIt is acknowledged that APIs of semi-synthetic origin do not fall within the scope of the ICH impurity guidelines. However, depending on the nature of the API and the extent of the chemical modification steps, the principles regarding the control of impurities (e.g. reporting, identification and qualification) could be extended to apply to APIs of semi-synthetic origin. As an illustrative example, an API whose precursor molecule was derived from a fermentation process or a natural product of plant or animal origin, which has subsequently undergone several chemical modification reactions, would generally fall within the scope of the ICH impurity guidelines, whereas an API whose sole chemical step was the formation of a salt from a fermentation product generally would not. It is understood that there is some latitude for these types of APIs.\n\n## Identification of impurities\n\nIt is recognized by the pharmacopoeias that APIs can be obtained from various sources and thus can contain impurities not considered during the development of the monograph. Furthermore, a change in the production or source may give rise to additional impurities that are not adequately controlled by the official compendial monograph. As a result each PD is assessed independently to consider the potential impurities that may arise from the proposed route(s) of synthesis. For these reasons the ICH limits for unspecified impurities (e.g. NMT 0.10% or 1.0 mg per day intake (whichever is lower) for APIs having an MDD \u2264 2 g/day) are generally recommended, rather than the general limits for unspecified impurities that may appear in the official compendial monograph, which could potentially be higher than the applicable ICH limit.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "83afe7369805048629181e674b7fd0802eceeb9fbe9790a50f6ed87000f3ebe6", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe tables in the QOS-PD template should be used to summarize the information on the API-related and process-related impurities. In the QOS-PD, the term \u201corigin\u201d refers to how and where the impurity was introduced (e.g. \u201cSynthetic intermediate from Step 4 of the synthesis\u201d or \u201cPotential by-product due to rearrangement from Step 6 of the synthesis\u201d). It should also be indicated if the impurity is a metabolite of the API.\n\nThe ICH thresholds for reporting, identification (used to set the limit for individual unknown impurities) and qualification are determined on the basis of potential exposure to the impurity, e.g. by the maximum daily dose (MDD) of the API. For APIs available in multiple dosage forms and strengths having different MDD values, it is imperative that the thresholds and corresponding controls for each of the presentations be considered to ensure that the risks posed by impurities have been addressed. This is normally achieved by using the highest potential daily MDD, rather than the maintenance dose. For parenteral products the maximum hourly dose of the API should also be included.\n\nIt is acknowledged that APIs of semi-synthetic origin do not fall within the scope of the ICH impurity guidelines. However, depending on the nature of the API and the extent of the chemical modification steps, the principles regarding the control of impurities (e.g. reporting, identification and qualification) could be extended to apply to APIs of semi-synthetic origin. As an illustrative example, an API whose precursor molecule was derived from a fermentation process or a natural product of plant or animal origin, which has subsequently undergone several chemical modification reactions, would generally fall within the scope of the ICH impurity guidelines, whereas an API whose sole chemical step was the formation of a salt from a fermentation product generally would not. It is understood that there is some latitude for these types of APIs.\n\n## Identification of impurities\n\nIt is recognized by the pharmacopoeias that APIs can be obtained from various sources and thus can contain impurities not considered during the development of the monograph. Furthermore, a change in the production or source may give rise to additional impurities that are not adequately controlled by the official compendial monograph. As a result each PD is assessed independently to consider the potential impurities that may arise from the proposed route(s) of synthesis. For these reasons the ICH limits for unspecified impurities (e.g. NMT 0.10% or 1.0 mg per day intake (whichever is lower) for APIs having an MDD \u2264 2 g/day) are generally recommended, rather than the general limits for unspecified impurities that may appear in the official compendial monograph, which could potentially be higher than the applicable ICH limit.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2908, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "73252ccd-1488-4c08-a7fd-356d0bf3b34b": {"__data__": {"id_": "73252ccd-1488-4c08-a7fd-356d0bf3b34b", "embedding": null, "metadata": {"page_label": "159", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Qualification of Impurities\n\nThe ICH impurity guidelines should be consulted for options on the qualification of impurities. The limit specified for an identified impurity in an officially recognized pharmacopoeia is generally considered to be qualified. The following is an additional option for qualification of impurities in existing APIs:\n\nThe limit for an impurity present in an existing API can be accepted by comparing the results of tests for impurities found in the existing API with those observed in an innovator product using the same validated, stability-indicating analytical procedure (e.g. comparative (high-performance liquid chromatography (HPLC) studies). If samples of the innovator product are not available, the impurity profile may also be compared to a different prequalified FPP with the same route of administration and similar characteristics (e.g. tablet versus capsule). It is recommended that the studies be conducted on comparable samples (e.g. samples of a similar age) to obtain a meaningful comparison of the impurity profiles.\n\nLevels of impurities generated from studies under accelerated or stressed storage conditions of the innovator or prequalified FPP are not considered acceptable/qualified.\n\nA specified impurity present in the existing API is considered qualified if the amount of the impurity in the existing API reflects the levels observed in the innovator or prequalified FPP.\n\n# Basis for Setting the Acceptance Criteria\n\nThe basis for setting the acceptance criteria for the impurities should be provided. This is established by considering the identification and qualification thresholds for API-related impurities (e.g. starting materials, by-products, intermediates, chiral impurities or degradation products) and the concentration limits for process-related impurities (e.g. residual solvents) according to the applicable ICH guidelines (e.g. Q3A (10), Q3C (12)).\n\nThe qualified level should be considered as the maximum allowable limit. However, limits which are considerably wider than the actual manufacturing process capability are generally discouraged. For this reason the acceptance criteria are also set taking into consideration the actual levels of impurities found in several batches of the API from each manufacturer, including the levels found in the batches used for the comparative bioavailability or biowaiver studies. When reporting the results of quantitative tests, the actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. In cases where a large number of batches have been tested it is acceptable to summarize the results of all the batches tested with a range of analytical results.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento aborda la calificaci\u00f3n de impurezas en ingredientes farmac\u00e9uticos activos (API) seg\u00fan las directrices del ICH. Se establece que los l\u00edmites de impurezas identificadas en una farmacopoeia reconocida son generalmente considerados calificados. Se sugiere que la calificaci\u00f3n de impurezas en APIs existentes puede realizarse comparando los resultados de pruebas de impurezas con un producto innovador o un producto farmac\u00e9utico precalificado. Adem\u00e1s, se discute c\u00f3mo establecer criterios de aceptaci\u00f3n para impurezas, considerando los niveles observados en lotes de API y las directrices aplicables del ICH.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 procedimiento se recomienda para calificar impurezas en un API existente si no se dispone de muestras del producto innovador?**\n   - Respuesta: Se recomienda comparar el perfil de impurezas del API existente con el de un producto farmac\u00e9utico prequalificado que tenga la misma v\u00eda de administraci\u00f3n y caracter\u00edsticas similares.\n\n2. **\u00bfCu\u00e1les son las consideraciones clave al establecer criterios de aceptaci\u00f3n para impurezas en un API?**\n   - Respuesta: Los criterios de aceptaci\u00f3n deben basarse en los umbrales de identificaci\u00f3n y calificaci\u00f3n para impurezas relacionadas con el API, as\u00ed como en los l\u00edmites de concentraci\u00f3n para impurezas relacionadas con el proceso, de acuerdo con las directrices del ICH.\n\n3. **\u00bfPor qu\u00e9 no se consideran aceptables los niveles de impurezas generados en estudios bajo condiciones de almacenamiento acelerado o estresado?**\n   - Respuesta: Los niveles de impurezas generados en tales estudios no se consideran aceptables o calificados porque no reflejan las condiciones normales de almacenamiento y estabilidad del producto.", "prev_section_summary": "### Temas Clave:\n\n1. **Especificaciones para Impurezas en APIs**: El documento aborda c\u00f3mo se deben resumir las impurezas relacionadas con el principio activo (API) y el proceso en el formato QOS-PD, destacando la importancia de identificar el origen de las impurezas.\n\n2. **Umbrales de la ICH**: Se discuten los umbrales establecidos por la ICH para la notificaci\u00f3n, identificaci\u00f3n y calificaci\u00f3n de impurezas, que dependen de la dosis diaria m\u00e1xima (MDD) del API. Se enfatiza la necesidad de considerar la MDD m\u00e1s alta para establecer l\u00edmites y controles.\n\n3. **APIs de Origen Semisint\u00e9tico**: Aunque no est\u00e1n completamente cubiertos por las directrices de impurezas de la ICH, se menciona que los principios de control de impurezas pueden aplicarse a estos APIs dependiendo de su naturaleza y los pasos de modificaci\u00f3n qu\u00edmica.\n\n4. **Evaluaci\u00f3n Independiente de Dossiers de Producto (PD)**: Se subraya la importancia de evaluar cada PD de manera independiente para identificar impurezas potenciales, dado que los APIs pueden provenir de diversas fuentes y cambios en la producci\u00f3n pueden introducir nuevas impurezas.\n\n### Entidades:\n\n- **API (Principio Activo)**: Sustancia activa en un medicamento.\n- **ICH (International Council for Harmonisation)**: Organizaci\u00f3n que establece directrices para la regulaci\u00f3n de productos farmac\u00e9uticos.\n- **MDD (Dosis Diaria M\u00e1xima)**: Cantidad m\u00e1xima de un API que se puede administrar diariamente.\n- **QOS-PD (Quality Overall Summary - Product Dossier)**: Plantilla utilizada para resumir informaci\u00f3n sobre impurezas en APIs.\n- **Monograf\u00eda Oficial**: Documento que establece est\u00e1ndares para la calidad de un medicamento.\n\nEste resumen destaca los aspectos m\u00e1s relevantes del documento, centr\u00e1ndose en la identificaci\u00f3n y control de impurezas en los APIs, as\u00ed como en la importancia de la evaluaci\u00f3n individual de cada producto farmac\u00e9utico.", "excerpt_keywords": "Keywords: impurities, qualification, ICH guidelines, acceptance criteria, pharmaceutical products"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "80f4c462-d87a-44f5-92d4-34f861740ca3", "node_type": "4", "metadata": {"page_label": "159", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Qualification of Impurities\n\nThe ICH impurity guidelines should be consulted for options on the qualification of impurities. The limit specified for an identified impurity in an officially recognized pharmacopoeia is generally considered to be qualified. The following is an additional option for qualification of impurities in existing APIs:\n\nThe limit for an impurity present in an existing API can be accepted by comparing the results of tests for impurities found in the existing API with those observed in an innovator product using the same validated, stability-indicating analytical procedure (e.g. comparative (high-performance liquid chromatography (HPLC) studies). If samples of the innovator product are not available, the impurity profile may also be compared to a different prequalified FPP with the same route of administration and similar characteristics (e.g. tablet versus capsule). It is recommended that the studies be conducted on comparable samples (e.g. samples of a similar age) to obtain a meaningful comparison of the impurity profiles.\n\nLevels of impurities generated from studies under accelerated or stressed storage conditions of the innovator or prequalified FPP are not considered acceptable/qualified.\n\nA specified impurity present in the existing API is considered qualified if the amount of the impurity in the existing API reflects the levels observed in the innovator or prequalified FPP.\n\n# Basis for Setting the Acceptance Criteria\n\nThe basis for setting the acceptance criteria for the impurities should be provided. This is established by considering the identification and qualification thresholds for API-related impurities (e.g. starting materials, by-products, intermediates, chiral impurities or degradation products) and the concentration limits for process-related impurities (e.g. residual solvents) according to the applicable ICH guidelines (e.g. Q3A (10), Q3C (12)).\n\nThe qualified level should be considered as the maximum allowable limit. However, limits which are considerably wider than the actual manufacturing process capability are generally discouraged. For this reason the acceptance criteria are also set taking into consideration the actual levels of impurities found in several batches of the API from each manufacturer, including the levels found in the batches used for the comparative bioavailability or biowaiver studies. When reporting the results of quantitative tests, the actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. In cases where a large number of batches have been tested it is acceptable to summarize the results of all the batches tested with a range of analytical results.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4871053b1612527d7c54035def6eb5e6c71e78f4df6ad84a67cf9d35e7fde654", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Qualification of Impurities\n\nThe ICH impurity guidelines should be consulted for options on the qualification of impurities. The limit specified for an identified impurity in an officially recognized pharmacopoeia is generally considered to be qualified. The following is an additional option for qualification of impurities in existing APIs:\n\nThe limit for an impurity present in an existing API can be accepted by comparing the results of tests for impurities found in the existing API with those observed in an innovator product using the same validated, stability-indicating analytical procedure (e.g. comparative (high-performance liquid chromatography (HPLC) studies). If samples of the innovator product are not available, the impurity profile may also be compared to a different prequalified FPP with the same route of administration and similar characteristics (e.g. tablet versus capsule). It is recommended that the studies be conducted on comparable samples (e.g. samples of a similar age) to obtain a meaningful comparison of the impurity profiles.\n\nLevels of impurities generated from studies under accelerated or stressed storage conditions of the innovator or prequalified FPP are not considered acceptable/qualified.\n\nA specified impurity present in the existing API is considered qualified if the amount of the impurity in the existing API reflects the levels observed in the innovator or prequalified FPP.\n\n# Basis for Setting the Acceptance Criteria\n\nThe basis for setting the acceptance criteria for the impurities should be provided. This is established by considering the identification and qualification thresholds for API-related impurities (e.g. starting materials, by-products, intermediates, chiral impurities or degradation products) and the concentration limits for process-related impurities (e.g. residual solvents) according to the applicable ICH guidelines (e.g. Q3A (10), Q3C (12)).\n\nThe qualified level should be considered as the maximum allowable limit. However, limits which are considerably wider than the actual manufacturing process capability are generally discouraged. For this reason the acceptance criteria are also set taking into consideration the actual levels of impurities found in several batches of the API from each manufacturer, including the levels found in the batches used for the comparative bioavailability or biowaiver studies. When reporting the results of quantitative tests, the actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. In cases where a large number of batches have been tested it is acceptable to summarize the results of all the batches tested with a range of analytical results.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2718, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "b341402b-49cb-473d-87b6-be46ea8d2ddc": {"__data__": {"id_": "b341402b-49cb-473d-87b6-be46ea8d2ddc", "embedding": null, "metadata": {"page_label": "160", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIf there are identified impurities specified in an official compendial monograph that are not controlled by the proposed routine in-house analytical procedure, a justification for their exclusion from routine analyses should be provided (e.g. \u201cImpurities D, E and F listed in *The International Pharmacopoeia* (Ph.Int.) monograph are not potential impurities from the proposed route of synthesis used by manufacturer X\u201d). If acceptable justification cannot be provided it should be demonstrated that the routine in-house method is capable of separating and detecting the impurities specified in the official compendial monograph at an acceptable level (e.g. 0.10%). If such a demonstration cannot be performed, a one-time study should be conducted applying the pharmacopoeial method to several recent batches to demonstrate the absence of the impurities listed in the pharmacopoeia.\n\nICH class II solvent(s) used prior to the last step of the manufacturing process may be exempted from routine control in API specifications if suitable justification is provided. Submission of results demonstrating less than 10% of the ICH Q3C limit (option 1) of the solvent(s) in three consecutive production-scale batches or six consecutive pilot-scale batches of the API or a suitable intermediate would be considered acceptable justification. The last step solvents used in the process should always be routinely controlled in the final API.\n\nFor guidance on acceptable residual solvent limits refer to ICH Q3C (12). The limit for residues of triethylamine (TEA) is either 320 ppm on the basis of ICH Q3C option 1 or 3.2 mg/day on the basis of permitted daily exposure (PDE).\n\nThe absence of known, established highly toxic impurities (genotoxic) used in the process or formed as a by-product should be discussed and suitable limits should be proposed. The limits should be justified by appropriate reference to available guidance (e.g. EMEA/CHMP/QWP/ 251344/2006 (13) or USFDA Guidance for Industry. *Genotoxic and carcinogenic impurities in drug substances and products, recommended approaches (14)*) or by providing experimental safety data or published data in peer-reviewed journals.\n\nResidues of metal catalysts used in the manufacturing process and determined to be present in batches of API are to be controlled in specifications. This requirement does not apply to metals that are deliberate components of the pharmaceutical substance (such as a counter ion of a salt) or metals that are used as a pharmaceutical excipient in the FPP (e.g. an iron oxide pigment). The guideline on the specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000 (15)) or any equivalent approaches can be used to address this issue. The requirement normally does not apply to extraneous metal contaminants that are more appropriately addressed by GMP, good distribution practices (GDP) or any other relevant quality provision such as the heavy metal test in monographs of recognized pharmacopoeias that cover metal contamination originating from manufacturing equipment and the environment.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS aborda las especificaciones para preparaciones farmac\u00e9uticas, centr\u00e1ndose en el control de impurezas en productos farmac\u00e9uticos. Se discuten las justificaciones necesarias para la exclusi\u00f3n de impurezas identificadas en monograf\u00edas oficiales, el manejo de solventes residuales, la evaluaci\u00f3n de impurezas genot\u00f3xicas y los l\u00edmites para residuos de catalizadores met\u00e1licos. Se enfatiza la importancia de demostrar la ausencia de impurezas y de seguir directrices establecidas para garantizar la seguridad y calidad de los productos farmac\u00e9uticos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 justificaci\u00f3n se requiere para excluir impurezas identificadas en una monograf\u00eda oficial de los an\u00e1lisis rutinarios?**\n   - La justificaci\u00f3n debe demostrar que las impurezas no son potenciales impurezas del proceso de s\u00edntesis utilizado por el fabricante. Si no se puede proporcionar una justificaci\u00f3n aceptable, se debe demostrar que el m\u00e9todo anal\u00edtico rutinario puede separar y detectar las impurezas especificadas en la monograf\u00eda oficial a un nivel aceptable (por ejemplo, 0.10%).\n\n2. **\u00bfCu\u00e1les son los l\u00edmites aceptables para los residuos de triethylamine (TEA) seg\u00fan las directrices de ICH Q3C?**\n   - Los l\u00edmites aceptables para los residuos de triethylamine son 320 ppm seg\u00fan la opci\u00f3n 1 de ICH Q3C o 3.2 mg/d\u00eda basado en la exposici\u00f3n diaria permitida (PDE).\n\n3. **\u00bfQu\u00e9 requisitos se aplican a los residuos de catalizadores met\u00e1licos en las especificaciones de API?**\n   - Los residuos de catalizadores met\u00e1licos utilizados en el proceso de fabricaci\u00f3n y que se determinan presentes en lotes de API deben ser controlados en las especificaciones. Sin embargo, esta exigencia no se aplica a los metales que son componentes deliberados de la sustancia farmac\u00e9utica o que se utilizan como excipientes farmac\u00e9uticos en el producto farmac\u00e9utico terminado (FPP). \n\nEstas preguntas y respuestas est\u00e1n dise\u00f1adas para proporcionar informaci\u00f3n espec\u00edfica que puede no estar f\u00e1cilmente disponible en otras fuentes, centr\u00e1ndose en aspectos t\u00e9cnicos y normativos del control de calidad en la fabricaci\u00f3n de productos farmac\u00e9uticos.", "prev_section_summary": "### Temas Clave\n\n1. **Calificaci\u00f3n de Impurezas**: Se discuten las directrices del ICH para la calificaci\u00f3n de impurezas en ingredientes farmac\u00e9uticos activos (API). Se establece que los l\u00edmites de impurezas identificadas en farmacopoeias reconocidas son generalmente considerados calificados.\n\n2. **Comparaci\u00f3n de Perfiles de Impurezas**: Se sugiere que la calificaci\u00f3n de impurezas en APIs existentes puede realizarse comparando los resultados de pruebas de impurezas con un producto innovador o un producto farmac\u00e9utico precalificado, utilizando procedimientos anal\u00edticos validados.\n\n3. **Condiciones de Almacenamiento**: Se aclara que los niveles de impurezas generados en estudios bajo condiciones de almacenamiento acelerado o estresado no son aceptables para la calificaci\u00f3n.\n\n4. **Criterios de Aceptaci\u00f3n**: Se establece la necesidad de proporcionar una base para los criterios de aceptaci\u00f3n de impurezas, considerando los umbrales de identificaci\u00f3n y calificaci\u00f3n, as\u00ed como los l\u00edmites de concentraci\u00f3n para impurezas relacionadas con el proceso.\n\n5. **Informe de Resultados**: Se enfatiza la importancia de reportar resultados cuantitativos de manera precisa, evitando declaraciones vagas.\n\n### Entidades\n\n- **ICH**: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.\n- **API**: Ingrediente Farmac\u00e9utico Activo.\n- **FPP**: Producto Farmac\u00e9utico Final.\n- **HPLC**: Cromatograf\u00eda L\u00edquida de Alta Eficiencia.\n- **Directrices ICH**: Incluyen Q3A y Q3C, que abordan la identificaci\u00f3n y calificaci\u00f3n de impurezas.\n\nEste resumen proporciona una visi\u00f3n general de los aspectos clave relacionados con la calificaci\u00f3n de impurezas en APIs y los criterios de aceptaci\u00f3n establecidos en el documento.", "excerpt_keywords": "Keywords: impurities, pharmaceutical preparations, ICH guidelines, residual solvents, metal catalysts"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6dad416f-c01e-4274-a8be-573e0dd6ec65", "node_type": "4", "metadata": {"page_label": "160", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIf there are identified impurities specified in an official compendial monograph that are not controlled by the proposed routine in-house analytical procedure, a justification for their exclusion from routine analyses should be provided (e.g. \u201cImpurities D, E and F listed in *The International Pharmacopoeia* (Ph.Int.) monograph are not potential impurities from the proposed route of synthesis used by manufacturer X\u201d). If acceptable justification cannot be provided it should be demonstrated that the routine in-house method is capable of separating and detecting the impurities specified in the official compendial monograph at an acceptable level (e.g. 0.10%). If such a demonstration cannot be performed, a one-time study should be conducted applying the pharmacopoeial method to several recent batches to demonstrate the absence of the impurities listed in the pharmacopoeia.\n\nICH class II solvent(s) used prior to the last step of the manufacturing process may be exempted from routine control in API specifications if suitable justification is provided. Submission of results demonstrating less than 10% of the ICH Q3C limit (option 1) of the solvent(s) in three consecutive production-scale batches or six consecutive pilot-scale batches of the API or a suitable intermediate would be considered acceptable justification. The last step solvents used in the process should always be routinely controlled in the final API.\n\nFor guidance on acceptable residual solvent limits refer to ICH Q3C (12). The limit for residues of triethylamine (TEA) is either 320 ppm on the basis of ICH Q3C option 1 or 3.2 mg/day on the basis of permitted daily exposure (PDE).\n\nThe absence of known, established highly toxic impurities (genotoxic) used in the process or formed as a by-product should be discussed and suitable limits should be proposed. The limits should be justified by appropriate reference to available guidance (e.g. EMEA/CHMP/QWP/ 251344/2006 (13) or USFDA Guidance for Industry. *Genotoxic and carcinogenic impurities in drug substances and products, recommended approaches (14)*) or by providing experimental safety data or published data in peer-reviewed journals.\n\nResidues of metal catalysts used in the manufacturing process and determined to be present in batches of API are to be controlled in specifications. This requirement does not apply to metals that are deliberate components of the pharmaceutical substance (such as a counter ion of a salt) or metals that are used as a pharmaceutical excipient in the FPP (e.g. an iron oxide pigment). The guideline on the specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000 (15)) or any equivalent approaches can be used to address this issue. The requirement normally does not apply to extraneous metal contaminants that are more appropriately addressed by GMP, good distribution practices (GDP) or any other relevant quality provision such as the heavy metal test in monographs of recognized pharmacopoeias that cover metal contamination originating from manufacturing equipment and the environment.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "8848c1f97a2bab1a9f73157210b877b438b9d0a3c938fb0298e99708febf0850", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIf there are identified impurities specified in an official compendial monograph that are not controlled by the proposed routine in-house analytical procedure, a justification for their exclusion from routine analyses should be provided (e.g. \u201cImpurities D, E and F listed in *The International Pharmacopoeia* (Ph.Int.) monograph are not potential impurities from the proposed route of synthesis used by manufacturer X\u201d). If acceptable justification cannot be provided it should be demonstrated that the routine in-house method is capable of separating and detecting the impurities specified in the official compendial monograph at an acceptable level (e.g. 0.10%). If such a demonstration cannot be performed, a one-time study should be conducted applying the pharmacopoeial method to several recent batches to demonstrate the absence of the impurities listed in the pharmacopoeia.\n\nICH class II solvent(s) used prior to the last step of the manufacturing process may be exempted from routine control in API specifications if suitable justification is provided. Submission of results demonstrating less than 10% of the ICH Q3C limit (option 1) of the solvent(s) in three consecutive production-scale batches or six consecutive pilot-scale batches of the API or a suitable intermediate would be considered acceptable justification. The last step solvents used in the process should always be routinely controlled in the final API.\n\nFor guidance on acceptable residual solvent limits refer to ICH Q3C (12). The limit for residues of triethylamine (TEA) is either 320 ppm on the basis of ICH Q3C option 1 or 3.2 mg/day on the basis of permitted daily exposure (PDE).\n\nThe absence of known, established highly toxic impurities (genotoxic) used in the process or formed as a by-product should be discussed and suitable limits should be proposed. The limits should be justified by appropriate reference to available guidance (e.g. EMEA/CHMP/QWP/ 251344/2006 (13) or USFDA Guidance for Industry. *Genotoxic and carcinogenic impurities in drug substances and products, recommended approaches (14)*) or by providing experimental safety data or published data in peer-reviewed journals.\n\nResidues of metal catalysts used in the manufacturing process and determined to be present in batches of API are to be controlled in specifications. This requirement does not apply to metals that are deliberate components of the pharmaceutical substance (such as a counter ion of a salt) or metals that are used as a pharmaceutical excipient in the FPP (e.g. an iron oxide pigment). The guideline on the specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000 (15)) or any equivalent approaches can be used to address this issue. The requirement normally does not apply to extraneous metal contaminants that are more appropriately addressed by GMP, good distribution practices (GDP) or any other relevant quality provision such as the heavy metal test in monographs of recognized pharmacopoeias that cover metal contamination originating from manufacturing equipment and the environment.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3180, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "61c15370-f1b6-4b2f-b372-61916784255b": {"__data__": {"id_": "61c15370-f1b6-4b2f-b372-61916784255b", "embedding": null, "metadata": {"page_label": "161", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Reference documents: ICH Q6A, Q3A, Q3C (6, 10, 12).\n\n## 3.2.S.4 Control of the API (name, manufacturer)\n\n### 3.2.S.4.1 Specification (name, manufacturer)\n\n**The specification for the API should be provided.**\n\nAs defined in ICH\u2019s Q6A guideline (6), a specification is:\n\n> \u201cA list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. \u2018Conformance to specifications\u2019 means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.\u201d\n\nCopies of the API specifications, dated and signed by authorized personnel (e.g. the person in charge of the quality control or quality assurance department) should be provided in the PD, including specifications from each API manufacturer as well as those of the FPP manufacturer.\n\nThe FPP manufacturer\u2019s API specification should be summarized according to the table in the QOS-PD template under the headings: tests, acceptance criteria and analytical procedures (including types, sources and versions for the methods).\n\n- The **standard** declared by the applicant could be an officially recognized compendial standard (e.g. BP, JP, Ph.Eur., Ph.Int., USP) or an in-house (manufacturer\u2019s) standard.\n- The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes.\n- For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV, HPLC or laser diffraction), the source refers to the origin of the analytical procedure (e.g. BP, JP, Ph.Eur., Ph.Int., USP or in-house) and the version (e.g. code number/version/date) should be provided for version control purposes.\n\nIn cases where there is more than one API manufacturer, the FPP manufacturer\u2019s API specifications should be one single compiled set of specifications that is identical for each manufacturer. It is acceptable to lay down in the specification more than one acceptance criterion and/or analytical method.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento se centra en la especificaci\u00f3n del Ingrediente Farmac\u00e9utico Activo (API) seg\u00fan las directrices de ICH Q6A. Se define la especificaci\u00f3n como un conjunto de pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n que deben cumplirse para que un API o un Producto Farmac\u00e9utico Final (FPP) se considere aceptable para su uso. Se enfatiza la importancia de que las especificaciones sean firmadas por personal autorizado y que se mantenga un control de versiones adecuado. Adem\u00e1s, se menciona que en caso de m\u00faltiples fabricantes de API, se debe proporcionar un conjunto de especificaciones compiladas que sean id\u00e9nticas para cada fabricante.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 tipo de personal debe firmar las especificaciones del API y por qu\u00e9 es importante esta firma?**\n   - La firma debe ser de personal autorizado, como el encargado del control de calidad o del departamento de aseguramiento de la calidad. Esta firma es importante porque valida que las especificaciones han sido revisadas y aprobadas, asegurando su conformidad con los est\u00e1ndares de calidad requeridos por las autoridades regulatorias.\n\n2. **\u00bfCu\u00e1les son los elementos clave que deben incluirse en la tabla de especificaciones del API seg\u00fan el formato QOS-PD?**\n   - La tabla debe incluir los encabezados de pruebas, criterios de aceptaci\u00f3n y procedimientos anal\u00edticos. Adem\u00e1s, debe detallar el tipo de procedimiento anal\u00edtico utilizado, la fuente de dicho procedimiento y la versi\u00f3n correspondiente para el control de versiones.\n\n3. **\u00bfQu\u00e9 se debe hacer si hay m\u00e1s de un fabricante de API en relaci\u00f3n con las especificaciones del FPP?**\n   - En caso de que haya m\u00e1s de un fabricante de API, el fabricante del FPP debe proporcionar un \u00fanico conjunto de especificaciones compiladas que sea id\u00e9ntico para cada fabricante. Esto asegura la consistencia y la conformidad en los criterios de calidad establecidos para el API utilizado en el FPP.", "prev_section_summary": "### Temas Clave\n\n1. **Control de Impurezas**: Se requiere justificaci\u00f3n para excluir impurezas identificadas en monograf\u00edas oficiales de los an\u00e1lisis rutinarios. Si no se puede justificar su exclusi\u00f3n, se debe demostrar que el m\u00e9todo anal\u00edtico puede detectar dichas impurezas a un nivel aceptable.\n\n2. **Solventes Residuales**: Los solventes de clase II de ICH utilizados antes del \u00faltimo paso del proceso de fabricaci\u00f3n pueden ser exentos de control rutinario si se proporciona una justificaci\u00f3n adecuada. Se aceptan resultados que demuestren menos del 10% del l\u00edmite de ICH Q3C en lotes consecutivos.\n\n3. **Impurezas Genot\u00f3xicas**: Se debe discutir la ausencia de impurezas altamente t\u00f3xicas y establecer l\u00edmites adecuados, justific\u00e1ndolos con referencias a gu\u00edas disponibles o datos experimentales.\n\n4. **Residuos de Catalizadores Met\u00e1licos**: Los residuos de catalizadores met\u00e1licos presentes en lotes de API deben ser controlados en las especificaciones, excepto aquellos que son componentes deliberados de la sustancia farmac\u00e9utica o excipientes en el producto terminado.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite directrices sobre especificaciones para preparaciones farmac\u00e9uticas.\n- **ICH (International Council for Harmonisation)**: Proporciona directrices sobre l\u00edmites de solventes residuales y otros aspectos de calidad.\n- **EMEA/CHMP**: Referencias a gu\u00edas espec\u00edficas sobre l\u00edmites de impurezas y residuos de catalizadores met\u00e1licos.\n- **USFDA**: Proporciona orientaci\u00f3n sobre impurezas genot\u00f3xicas y carcinog\u00e9nicas en sustancias y productos farmac\u00e9uticos.\n\nEste resumen destaca los aspectos t\u00e9cnicos y normativos relacionados con el control de calidad en la fabricaci\u00f3n de productos farmac\u00e9uticos, enfatizando la importancia de la justificaci\u00f3n y el cumplimiento de las directrices establecidas.", "excerpt_keywords": "Keywords: API specifications, ICH guidelines, quality control, analytical procedures, regulatory compliance"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "75ae3cee-9d58-40e3-9b68-3ce4930426b5", "node_type": "4", "metadata": {"page_label": "161", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Reference documents: ICH Q6A, Q3A, Q3C (6, 10, 12).\n\n## 3.2.S.4 Control of the API (name, manufacturer)\n\n### 3.2.S.4.1 Specification (name, manufacturer)\n\n**The specification for the API should be provided.**\n\nAs defined in ICH\u2019s Q6A guideline (6), a specification is:\n\n> \u201cA list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. \u2018Conformance to specifications\u2019 means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.\u201d\n\nCopies of the API specifications, dated and signed by authorized personnel (e.g. the person in charge of the quality control or quality assurance department) should be provided in the PD, including specifications from each API manufacturer as well as those of the FPP manufacturer.\n\nThe FPP manufacturer\u2019s API specification should be summarized according to the table in the QOS-PD template under the headings: tests, acceptance criteria and analytical procedures (including types, sources and versions for the methods).\n\n- The **standard** declared by the applicant could be an officially recognized compendial standard (e.g. BP, JP, Ph.Eur., Ph.Int., USP) or an in-house (manufacturer\u2019s) standard.\n- The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes.\n- For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV, HPLC or laser diffraction), the source refers to the origin of the analytical procedure (e.g. BP, JP, Ph.Eur., Ph.Int., USP or in-house) and the version (e.g. code number/version/date) should be provided for version control purposes.\n\nIn cases where there is more than one API manufacturer, the FPP manufacturer\u2019s API specifications should be one single compiled set of specifications that is identical for each manufacturer. It is acceptable to lay down in the specification more than one acceptance criterion and/or analytical method.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "04dc10e29960b52033fa480a1b8407b9a6ab047a011facfeeb3c67891db853a1", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Reference documents: ICH Q6A, Q3A, Q3C (6, 10, 12).\n\n## 3.2.S.4 Control of the API (name, manufacturer)\n\n### 3.2.S.4.1 Specification (name, manufacturer)\n\n**The specification for the API should be provided.**\n\nAs defined in ICH\u2019s Q6A guideline (6), a specification is:\n\n> \u201cA list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. \u2018Conformance to specifications\u2019 means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.\u201d\n\nCopies of the API specifications, dated and signed by authorized personnel (e.g. the person in charge of the quality control or quality assurance department) should be provided in the PD, including specifications from each API manufacturer as well as those of the FPP manufacturer.\n\nThe FPP manufacturer\u2019s API specification should be summarized according to the table in the QOS-PD template under the headings: tests, acceptance criteria and analytical procedures (including types, sources and versions for the methods).\n\n- The **standard** declared by the applicant could be an officially recognized compendial standard (e.g. BP, JP, Ph.Eur., Ph.Int., USP) or an in-house (manufacturer\u2019s) standard.\n- The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes.\n- For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV, HPLC or laser diffraction), the source refers to the origin of the analytical procedure (e.g. BP, JP, Ph.Eur., Ph.Int., USP or in-house) and the version (e.g. code number/version/date) should be provided for version control purposes.\n\nIn cases where there is more than one API manufacturer, the FPP manufacturer\u2019s API specifications should be one single compiled set of specifications that is identical for each manufacturer. It is acceptable to lay down in the specification more than one acceptance criterion and/or analytical method.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2358, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "079c0ba0-2385-4b18-94c0-0174b2589b60": {"__data__": {"id_": "079c0ba0-2385-4b18-94c0-0174b2589b60", "embedding": null, "metadata": {"page_label": "162", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nfor a single parameter with the statement \u201cfor API from manufacturer A\u201d (e.g. in the case of residual solvents).\n\nAny non-routine testing should be clearly identified as such and justified together with the proposal on the frequency of non-routine testing.\n\nThe ICH Q6A guideline (6) outlines recommendations for a number of universal and specific tests and criteria for APIs.\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12) and officially recognized pharmacopoeias.\n\n## 3.2.S.4.2 Analytical procedures (name, manufacturer)\n\n**The analytical procedures used for testing the API should be provided.**\n\nCopies of the in-house analytical procedures used to generate testing results provided in the PD, as well as those proposed for routine testing of the API by the FPP manufacturer, should be provided. Unless modified it is not necessary to provide copies of officially recognized compendial analytical procedures.\n\nTables for summarizing a number of the different analytical procedures and validation information (e.g. HPLC assay/impurity methods, gas chromatography (GC) methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the in-house analytical procedures of the FPP manufacturer for determination of the residual solvents, assay and purity of the API, in section 2.3.S.4.2 of the QOS-PD. Other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD. Officially recognized compendial methods need not be summarized unless modifications have been made.\n\nAlthough HPLC is normally considered the method of choice for determining API-related impurities, other chromatographic methods such as GC and thin-layer chromatography (TLC) can also be used if appropriately validated. For determination of related substances, reference standards should normally be available for each of the identified impurities, particularly those known to be toxic and the concentration of the impurities should be quantified against their own reference standards. Impurity standards may be obtained from pharmacopoeias (individual impurities or resolution mixtures), from commercial sources or prepared in-house. It is considered acceptable to use the API as an external standard to estimate the levels of impurities, provided the response factors of those impurities are sufficiently close to that of the API, i.e. between 80 and 120%. In cases where the response factor is outside this range it may still be acceptable to use the API, provided a correction factor is applied. Data to support calculation of the correction factor should be provided for an in-house method. Unspecified impurities may be quantified using a solution of the API as the reference standard at a concentration corresponding to the limit established for individual unspecified impurities.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS detalla las especificaciones para los procedimientos anal\u00edticos de las sustancias farmac\u00e9uticas activas (API). Se enfatiza la importancia de proporcionar procedimientos anal\u00edticos in-house y la necesidad de justificar cualquier prueba no rutinaria. Adem\u00e1s, se mencionan las recomendaciones de la gu\u00eda ICH Q6A sobre pruebas universales y espec\u00edficas, as\u00ed como la utilizaci\u00f3n de m\u00e9todos cromatogr\u00e1ficos validados para la determinaci\u00f3n de impurezas y la cuantificaci\u00f3n de sustancias relacionadas.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n se debe incluir sobre los procedimientos anal\u00edticos utilizados para las pruebas de API?**\n   - Se debe proporcionar copias de los procedimientos anal\u00edticos in-house utilizados para generar resultados de pruebas, as\u00ed como aquellos propuestos para las pruebas rutinarias por el fabricante del producto farmac\u00e9utico terminado (FPP). No es necesario incluir copias de procedimientos compendiales oficialmente reconocidos a menos que se hayan modificado.\n\n2. **\u00bfCu\u00e1les son las condiciones bajo las cuales se puede utilizar el API como est\u00e1ndar externo para la cuantificaci\u00f3n de impurezas?**\n   - El API puede ser utilizado como est\u00e1ndar externo para estimar los niveles de impurezas siempre que los factores de respuesta de esas impurezas est\u00e9n suficientemente cerca del del API, es decir, entre el 80% y el 120%. Si el factor de respuesta est\u00e1 fuera de este rango, a\u00fan puede ser aceptable usar el API, siempre que se aplique un factor de correcci\u00f3n.\n\n3. **\u00bfQu\u00e9 se debe hacer en caso de que se realicen pruebas no rutinarias en el API?**\n   - Cualquier prueba no rutinaria debe ser claramente identificada y justificada, junto con una propuesta sobre la frecuencia de dichas pruebas no rutinarias. Esto asegura que se mantenga la transparencia y la justificaci\u00f3n en el proceso de control de calidad del API.", "prev_section_summary": "### Temas Clave:\n\n1. **Especificaci\u00f3n del API**: Se define como un conjunto de pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n que deben cumplirse para que un API o un Producto Farmac\u00e9utico Final (FPP) sea considerado aceptable para su uso.\n\n2. **Importancia de la Firma**: Las especificaciones deben ser firmadas por personal autorizado, como el encargado del control de calidad o del aseguramiento de la calidad, para validar su revisi\u00f3n y aprobaci\u00f3n.\n\n3. **Control de Versiones**: Es esencial proporcionar el n\u00famero de referencia y la versi\u00f3n de las especificaciones para asegurar un control adecuado de las versiones.\n\n4. **Tabla de Especificaciones**: Debe incluir encabezados como pruebas, criterios de aceptaci\u00f3n y procedimientos anal\u00edticos, detallando el tipo de procedimiento, su fuente y la versi\u00f3n correspondiente.\n\n5. **M\u00faltiples Fabricantes de API**: Si hay m\u00e1s de un fabricante de API, el fabricante del FPP debe proporcionar un conjunto \u00fanico de especificaciones que sea id\u00e9ntico para cada fabricante, garantizando consistencia en los criterios de calidad.\n\n### Entidades:\n\n- **ICH Q6A**: Directriz que define la especificaci\u00f3n del API.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en un medicamento.\n- **FPP (Producto Farmac\u00e9utico Final)**: Producto terminado que contiene el API.\n- **Personal Autorizado**: Individuos responsables de la revisi\u00f3n y aprobaci\u00f3n de las especificaciones.\n- **Est\u00e1ndares Compendiales**: Normas reconocidas oficialmente (ej. BP, JP, Ph.Eur., USP).\n- **Procedimientos Anal\u00edticos**: M\u00e9todos utilizados para evaluar la calidad del API (ej. HPLC, UV, IR).\n\nEste resumen destaca la importancia de las especificaciones del API en el contexto de la calidad y la regulaci\u00f3n farmac\u00e9utica, as\u00ed como los requisitos para su documentaci\u00f3n y control.", "excerpt_keywords": "Keywords: API, analytical procedures, ICH Q6A, impurities, non-routine testing"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4eaab0db-e4b0-434a-a506-b5fa198267a3", "node_type": "4", "metadata": {"page_label": "162", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nfor a single parameter with the statement \u201cfor API from manufacturer A\u201d (e.g. in the case of residual solvents).\n\nAny non-routine testing should be clearly identified as such and justified together with the proposal on the frequency of non-routine testing.\n\nThe ICH Q6A guideline (6) outlines recommendations for a number of universal and specific tests and criteria for APIs.\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12) and officially recognized pharmacopoeias.\n\n## 3.2.S.4.2 Analytical procedures (name, manufacturer)\n\n**The analytical procedures used for testing the API should be provided.**\n\nCopies of the in-house analytical procedures used to generate testing results provided in the PD, as well as those proposed for routine testing of the API by the FPP manufacturer, should be provided. Unless modified it is not necessary to provide copies of officially recognized compendial analytical procedures.\n\nTables for summarizing a number of the different analytical procedures and validation information (e.g. HPLC assay/impurity methods, gas chromatography (GC) methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the in-house analytical procedures of the FPP manufacturer for determination of the residual solvents, assay and purity of the API, in section 2.3.S.4.2 of the QOS-PD. Other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD. Officially recognized compendial methods need not be summarized unless modifications have been made.\n\nAlthough HPLC is normally considered the method of choice for determining API-related impurities, other chromatographic methods such as GC and thin-layer chromatography (TLC) can also be used if appropriately validated. For determination of related substances, reference standards should normally be available for each of the identified impurities, particularly those known to be toxic and the concentration of the impurities should be quantified against their own reference standards. Impurity standards may be obtained from pharmacopoeias (individual impurities or resolution mixtures), from commercial sources or prepared in-house. It is considered acceptable to use the API as an external standard to estimate the levels of impurities, provided the response factors of those impurities are sufficiently close to that of the API, i.e. between 80 and 120%. In cases where the response factor is outside this range it may still be acceptable to use the API, provided a correction factor is applied. Data to support calculation of the correction factor should be provided for an in-house method. Unspecified impurities may be quantified using a solution of the API as the reference standard at a concentration corresponding to the limit established for individual unspecified impurities.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "9298eaa2be5921b525b731f7ecfd2f576bb693970b378800fec7a332d0ea02b0", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nfor a single parameter with the statement \u201cfor API from manufacturer A\u201d (e.g. in the case of residual solvents).\n\nAny non-routine testing should be clearly identified as such and justified together with the proposal on the frequency of non-routine testing.\n\nThe ICH Q6A guideline (6) outlines recommendations for a number of universal and specific tests and criteria for APIs.\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12) and officially recognized pharmacopoeias.\n\n## 3.2.S.4.2 Analytical procedures (name, manufacturer)\n\n**The analytical procedures used for testing the API should be provided.**\n\nCopies of the in-house analytical procedures used to generate testing results provided in the PD, as well as those proposed for routine testing of the API by the FPP manufacturer, should be provided. Unless modified it is not necessary to provide copies of officially recognized compendial analytical procedures.\n\nTables for summarizing a number of the different analytical procedures and validation information (e.g. HPLC assay/impurity methods, gas chromatography (GC) methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the in-house analytical procedures of the FPP manufacturer for determination of the residual solvents, assay and purity of the API, in section 2.3.S.4.2 of the QOS-PD. Other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD. Officially recognized compendial methods need not be summarized unless modifications have been made.\n\nAlthough HPLC is normally considered the method of choice for determining API-related impurities, other chromatographic methods such as GC and thin-layer chromatography (TLC) can also be used if appropriately validated. For determination of related substances, reference standards should normally be available for each of the identified impurities, particularly those known to be toxic and the concentration of the impurities should be quantified against their own reference standards. Impurity standards may be obtained from pharmacopoeias (individual impurities or resolution mixtures), from commercial sources or prepared in-house. It is considered acceptable to use the API as an external standard to estimate the levels of impurities, provided the response factors of those impurities are sufficiently close to that of the API, i.e. between 80 and 120%. In cases where the response factor is outside this range it may still be acceptable to use the API, provided a correction factor is applied. Data to support calculation of the correction factor should be provided for an in-house method. Unspecified impurities may be quantified using a solution of the API as the reference standard at a concentration corresponding to the limit established for individual unspecified impurities.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2972, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "5efb52a4-8346-435a-94e8-389dc0f7b37e": {"__data__": {"id_": "5efb52a4-8346-435a-94e8-389dc0f7b37e", "embedding": null, "metadata": {"page_label": "163", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "(e.g. 0.10%). The test for related substances in the Ph.Int. monograph for lamivudine serves as a typical example.\n\nThe system suitability tests (SSTs) represent an integral part of the method and are used to ensure the satisfactory performance of the chosen chromatographic system. As a minimum, HPLC and GC purity methods should include SSTs for resolution and repeatability. For HPLC methods to control API-related impurities, this is typically done using a solution of the API with a concentration corresponding to the limit for unspecified impurities. Resolution of the two closest eluting peaks is generally recommended. However, the choice of alternative peaks can be used if justified (e.g. choice of a toxic impurity). In accordance with the Ph.Int. section on Methods of analysis the repeatability test should include an acceptable number of replicate injections. HPLC assay methods should include SSTs for repeatability and in addition either peak asymmetry, theoretical plates or resolution. For TLC methods, the SSTs should verify the ability of the system to separate and detect the analyte(s) (e.g. by applying a spot corresponding to the API at a concentration corresponding to the limit of unspecified impurities).\n\nReference documents: ICH Q2 (16), WHO Technical Report Series, No. 943, Annex 3 (17).\n\n### 3.2.S.4.3 Validation of analytical procedures (name, manufacturer)\n\n**Analytical validation information, including experimental data for the analytical procedures used for testing the API, should be provided.**\n\nCopies should be provided of the validation reports for the analytical procedures used to generate testing results provided in the PD, as well as those proposed for routine testing of the API by the FPP manufacturer.\n\nTables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods, GC methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures of the FPP manufacturer for determination of residual solvents, assay and purity of the API, in section 2.3.S.4.3 of the QOS-PD. The validation data for other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD.\n\nAs recognized by regulatory authorities and pharmacopoeias themselves, verification of compendial methods can be necessary. The compendial methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. Different sources of the same API or FPP can contain impurities and/or degradation products that were not considered during the development of the monograph. Therefore, the monograph and compendial", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl texto se centra en la validaci\u00f3n de procedimientos anal\u00edticos para el control de impurezas y la pureza de los ingredientes farmac\u00e9uticos activos (API) en la industria farmac\u00e9utica. Se discuten las pruebas de idoneidad del sistema (SST) que son esenciales para garantizar el rendimiento adecuado de los m\u00e9todos cromatogr\u00e1ficos, como HPLC y GC. Se enfatiza la importancia de proporcionar informaci\u00f3n de validaci\u00f3n anal\u00edtica, incluyendo datos experimentales y copias de informes de validaci\u00f3n, as\u00ed como la necesidad de verificar m\u00e9todos compendiales debido a posibles variaciones en impurezas de diferentes fuentes del mismo API o producto farmac\u00e9utico terminado (FPP).\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 criterios se deben cumplir para las pruebas de idoneidad del sistema (SST) en m\u00e9todos HPLC y GC seg\u00fan el contexto proporcionado?**\n   - Respuesta: Las SST deben incluir pruebas de resoluci\u00f3n y repetibilidad. Para HPLC, se recomienda usar una soluci\u00f3n del API con una concentraci\u00f3n correspondiente al l\u00edmite de impurezas no especificadas, y se debe verificar la resoluci\u00f3n de los dos picos m\u00e1s cercanos que eluyen.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n se requiere en los informes de validaci\u00f3n anal\u00edtica para los procedimientos utilizados en la prueba del API?**\n   - Respuesta: Se deben proporcionar copias de los informes de validaci\u00f3n de los procedimientos anal\u00edticos utilizados para generar los resultados de las pruebas presentadas en el dossier de producto (PD), as\u00ed como aquellos propuestos para las pruebas rutinarias del API por el fabricante del FPP.\n\n3. **\u00bfPor qu\u00e9 es importante la verificaci\u00f3n de los m\u00e9todos compendiales seg\u00fan el texto?**\n   - Respuesta: La verificaci\u00f3n de los m\u00e9todos compendiales es importante porque estos m\u00e9todos suelen estar validados en base a un API o FPP de un fabricante espec\u00edfico. Diferentes fuentes del mismo API o FPP pueden contener impurezas y/o productos de degradaci\u00f3n que no fueron considerados durante el desarrollo de la monograf\u00eda, lo que puede afectar la calidad del producto.", "prev_section_summary": "### Temas Clave:\n1. **Procedimientos Anal\u00edticos para API**: Se requiere que se proporcionen copias de los procedimientos anal\u00edticos in-house utilizados para las pruebas de las sustancias farmac\u00e9uticas activas (API) y aquellos propuestos para pruebas rutinarias por el fabricante del producto farmac\u00e9utico terminado (FPP).\n\n2. **Pruebas No Rutinarias**: Cualquier prueba no rutinaria debe ser claramente identificada y justificada, junto con una propuesta sobre la frecuencia de dichas pruebas.\n\n3. **Gu\u00eda ICH Q6A**: Se mencionan las recomendaciones de la gu\u00eda ICH Q6A, que abarca pruebas universales y espec\u00edficas para APIs.\n\n4. **M\u00e9todos Cromatogr\u00e1ficos**: Se destaca el uso de m\u00e9todos como HPLC, GC y cromatograf\u00eda en capa fina (TLC) para la determinaci\u00f3n de impurezas, siempre que est\u00e9n debidamente validados.\n\n5. **Est\u00e1ndares de Impurezas**: Se requiere que existan est\u00e1ndares de referencia para cada impureza identificada, especialmente aquellas conocidas por ser t\u00f3xicas.\n\n6. **Uso del API como Est\u00e1ndar Externo**: Se permite el uso del API como est\u00e1ndar externo para la cuantificaci\u00f3n de impurezas, siempre que los factores de respuesta est\u00e9n entre el 80% y el 120% del del API.\n\n### Entidades:\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las recomendaciones y especificaciones.\n- **ICH (International Council for Harmonisation)**: Proporciona directrices como la Q6A, Q3A y Q3C.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Fabricante que realiza pruebas rutinarias del API.\n- **API (Sustancia Farmac\u00e9utica Activa)**: Compuesto que se est\u00e1 evaluando y probando.\n- **M\u00e9todos Anal\u00edticos**: HPLC, GC, TLC, entre otros, utilizados para la evaluaci\u00f3n de impurezas y pureza del API.\n\n### Resumen:\nEl documento de la OMS establece directrices sobre los procedimientos anal\u00edticos para las sustancias farmac\u00e9uticas activas, enfatizando la necesidad de proporcionar procedimientos in-house y justificar pruebas no rutinarias. Se mencionan las recomendaciones de la gu\u00eda ICH Q6A y se permite el uso del API como est\u00e1ndar externo para la cuantificaci\u00f3n de impurezas bajo ciertas condiciones. Adem\u00e1s, se requiere la disponibilidad de est\u00e1ndares de referencia para impurezas identificadas.", "excerpt_keywords": "Keywords: validation, analytical procedures, impurities, chromatographic methods, system suitability tests"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8c784ec5-b6d9-4c53-ba1f-ee148b85ce51", "node_type": "4", "metadata": {"page_label": "163", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "(e.g. 0.10%). The test for related substances in the Ph.Int. monograph for lamivudine serves as a typical example.\n\nThe system suitability tests (SSTs) represent an integral part of the method and are used to ensure the satisfactory performance of the chosen chromatographic system. As a minimum, HPLC and GC purity methods should include SSTs for resolution and repeatability. For HPLC methods to control API-related impurities, this is typically done using a solution of the API with a concentration corresponding to the limit for unspecified impurities. Resolution of the two closest eluting peaks is generally recommended. However, the choice of alternative peaks can be used if justified (e.g. choice of a toxic impurity). In accordance with the Ph.Int. section on Methods of analysis the repeatability test should include an acceptable number of replicate injections. HPLC assay methods should include SSTs for repeatability and in addition either peak asymmetry, theoretical plates or resolution. For TLC methods, the SSTs should verify the ability of the system to separate and detect the analyte(s) (e.g. by applying a spot corresponding to the API at a concentration corresponding to the limit of unspecified impurities).\n\nReference documents: ICH Q2 (16), WHO Technical Report Series, No. 943, Annex 3 (17).\n\n### 3.2.S.4.3 Validation of analytical procedures (name, manufacturer)\n\n**Analytical validation information, including experimental data for the analytical procedures used for testing the API, should be provided.**\n\nCopies should be provided of the validation reports for the analytical procedures used to generate testing results provided in the PD, as well as those proposed for routine testing of the API by the FPP manufacturer.\n\nTables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods, GC methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures of the FPP manufacturer for determination of residual solvents, assay and purity of the API, in section 2.3.S.4.3 of the QOS-PD. The validation data for other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD.\n\nAs recognized by regulatory authorities and pharmacopoeias themselves, verification of compendial methods can be necessary. The compendial methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. Different sources of the same API or FPP can contain impurities and/or degradation products that were not considered during the development of the monograph. Therefore, the monograph and compendial", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "93cd34dc63e86f6cab6d307528a817ba92875696c7864ac34d02cfb3dc94d6c2", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "(e.g. 0.10%). The test for related substances in the Ph.Int. monograph for lamivudine serves as a typical example.\n\nThe system suitability tests (SSTs) represent an integral part of the method and are used to ensure the satisfactory performance of the chosen chromatographic system. As a minimum, HPLC and GC purity methods should include SSTs for resolution and repeatability. For HPLC methods to control API-related impurities, this is typically done using a solution of the API with a concentration corresponding to the limit for unspecified impurities. Resolution of the two closest eluting peaks is generally recommended. However, the choice of alternative peaks can be used if justified (e.g. choice of a toxic impurity). In accordance with the Ph.Int. section on Methods of analysis the repeatability test should include an acceptable number of replicate injections. HPLC assay methods should include SSTs for repeatability and in addition either peak asymmetry, theoretical plates or resolution. For TLC methods, the SSTs should verify the ability of the system to separate and detect the analyte(s) (e.g. by applying a spot corresponding to the API at a concentration corresponding to the limit of unspecified impurities).\n\nReference documents: ICH Q2 (16), WHO Technical Report Series, No. 943, Annex 3 (17).\n\n### 3.2.S.4.3 Validation of analytical procedures (name, manufacturer)\n\n**Analytical validation information, including experimental data for the analytical procedures used for testing the API, should be provided.**\n\nCopies should be provided of the validation reports for the analytical procedures used to generate testing results provided in the PD, as well as those proposed for routine testing of the API by the FPP manufacturer.\n\nTables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods, GC methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures of the FPP manufacturer for determination of residual solvents, assay and purity of the API, in section 2.3.S.4.3 of the QOS-PD. The validation data for other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD.\n\nAs recognized by regulatory authorities and pharmacopoeias themselves, verification of compendial methods can be necessary. The compendial methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. Different sources of the same API or FPP can contain impurities and/or degradation products that were not considered during the development of the monograph. Therefore, the monograph and compendial", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2822, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "95efb0a1-5f90-42fe-acec-bf69bfa19db2": {"__data__": {"id_": "95efb0a1-5f90-42fe-acec-bf69bfa19db2", "embedding": null, "metadata": {"page_label": "164", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe method should be demonstrated as suitable to control the impurity profile of the API from the intended source(s).\n\nIn general, verification is not necessary for compendial API assay methods. However, specificity of a specific compendial assay method should be demonstrated if there are any potential impurities that are not specified in the compendial monograph. If an officially recognized compendial method is used to control API-related impurities that are not specified in the monograph, full validation of the method is expected with respect to those impurities.\n\nIf an officially recognized compendial standard is claimed and an in-house method is used in lieu of the compendial method (e.g. for assay or for specified impurities), equivalence of the in-house and compendial methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For impurity methods, the sample analysed should be the API spiked with impurities at concentrations equivalent to their specification limits.\n\nReference documents: ICH Q2 (16).\n\n## 3.2.S.4.4 Batch analyses (name, manufacturer)\n\n**Description of batches and results of batch analyses should be provided.**\n\nThe information provided should include batch number, batch size, date and production site of relevant API batches used in comparative bioavailability or biowaiver studies, preclinical and clinical data (if relevant), stability, pilot, scale-up and, if available, production-scale batches. These data are used to establish the specifications and evaluate consistency in API quality.\n\nAnalytical results should be provided from at least two batches of at least pilot scale from each proposed manufacturing site of the API and should include the batch(es) used in the comparative bioavailability or biowaiver studies. A pilot-scale batch should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nCopies of the certificates of analysis, both from the API manufacturer(s) and the FPP manufacturer, should be provided for the profiled batches and any company responsible for generating the test results should be identified. The FPP manufacturer\u2019s test results should be summarized in the QOS-PD.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.\n\nA discussion and justification should be provided for any incomplete analyses (e.g. results not tested according to the proposed specification).\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS establece directrices sobre la validaci\u00f3n de m\u00e9todos anal\u00edticos para el control de impurezas en ingredientes farmac\u00e9uticos activos (API). Se menciona que, aunque la verificaci\u00f3n no es necesaria para m\u00e9todos de ensayo compendiales, la especificidad debe ser demostrada si hay impurezas no especificadas. Adem\u00e1s, se requiere que se proporcionen an\u00e1lisis de lotes de API, incluyendo resultados anal\u00edticos y certificados de an\u00e1lisis, para evaluar la calidad y consistencia del API en estudios de bioequivalencia o biowaiver.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 se debe demostrar si se utiliza un m\u00e9todo compendial para controlar impurezas no especificadas en la monograf\u00eda?**\n   - Se debe demostrar la especificidad del m\u00e9todo y, si se utiliza un m\u00e9todo compendial reconocido, se espera una validaci\u00f3n completa del mismo con respecto a esas impurezas.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la descripci\u00f3n de los lotes de API utilizados en estudios de bioequivalencia?**\n   - La descripci\u00f3n debe incluir el n\u00famero de lote, tama\u00f1o del lote, fecha y sitio de producci\u00f3n de los lotes relevantes de API, as\u00ed como datos de estabilidad, lotes piloto, escalado y, si est\u00e1n disponibles, lotes a escala de producci\u00f3n.\n\n3. **\u00bfQu\u00e9 tipo de resultados anal\u00edticos se deben proporcionar para los lotes de API y c\u00f3mo deben ser presentados?**\n   - Se deben proporcionar resultados anal\u00edticos de al menos dos lotes de escala piloto de cada sitio de fabricaci\u00f3n propuesto, incluyendo resultados num\u00e9ricos espec\u00edficos en lugar de declaraciones vagas como \"dentro de los l\u00edmites\" o \"conforma\". Adem\u00e1s, se debe discutir cualquier an\u00e1lisis incompleto y justificarlo.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Validaci\u00f3n de Procedimientos Anal\u00edticos**:\n   - Se enfatiza la importancia de la validaci\u00f3n de los procedimientos anal\u00edticos utilizados para el control de impurezas y la pureza de los ingredientes farmac\u00e9uticos activos (API).\n   - Se requiere informaci\u00f3n anal\u00edtica, incluyendo datos experimentales y copias de informes de validaci\u00f3n.\n\n2. **Pruebas de Idoneidad del Sistema (SST)**:\n   - Las SST son esenciales para garantizar el rendimiento adecuado de los m\u00e9todos cromatogr\u00e1ficos, como HPLC (Cromatograf\u00eda L\u00edquida de Alta Eficiencia) y GC (Cromatograf\u00eda de Gases).\n   - Deben incluir pruebas de resoluci\u00f3n y repetibilidad.\n   - Para HPLC, se recomienda usar una soluci\u00f3n del API con una concentraci\u00f3n correspondiente al l\u00edmite de impurezas no especificadas.\n\n3. **Requisitos de Informes de Validaci\u00f3n**:\n   - Se deben proporcionar copias de los informes de validaci\u00f3n de los procedimientos anal\u00edticos utilizados para generar resultados de pruebas en el dossier de producto (PD).\n   - Se deben resumir las diferentes metodolog\u00edas anal\u00edticas y su informaci\u00f3n de validaci\u00f3n en tablas espec\u00edficas del QOS-PD (Quality Overall Summary - Product Dossier).\n\n4. **Verificaci\u00f3n de M\u00e9todos Compendiales**:\n   - La verificaci\u00f3n de m\u00e9todos compendiales es necesaria debido a que estos m\u00e9todos pueden estar validados en base a un API o FPP de un fabricante espec\u00edfico.\n   - Diferentes fuentes del mismo API o FPP pueden contener impurezas y productos de degradaci\u00f3n no considerados en la monograf\u00eda original.\n\n### Entidades Clave\n- **API**: Ingrediente Farmac\u00e9utico Activo.\n- **FPP**: Producto Farmac\u00e9utico Terminado.\n- **HPLC**: Cromatograf\u00eda L\u00edquida de Alta Eficiencia.\n- **GC**: Cromatograf\u00eda de Gases.\n- **SST**: Pruebas de Idoneidad del Sistema.\n- **QOS-PD**: Dossier de Producto - Resumen General de Calidad.\n- **ICH Q2**: Directrices sobre validaci\u00f3n de m\u00e9todos anal\u00edticos.\n- **Ph.Int.**: Farmacopea Internacional. \n\nEste resumen destaca la importancia de la validaci\u00f3n y verificaci\u00f3n en los procedimientos anal\u00edticos dentro de la industria farmac\u00e9utica, asegurando la calidad y seguridad de los productos.", "excerpt_keywords": "Keywords: validation, impurities, pharmaceutical preparations, batch analysis, compendial methods"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ddca21ae-6682-4219-a780-5129c180a003", "node_type": "4", "metadata": {"page_label": "164", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe method should be demonstrated as suitable to control the impurity profile of the API from the intended source(s).\n\nIn general, verification is not necessary for compendial API assay methods. However, specificity of a specific compendial assay method should be demonstrated if there are any potential impurities that are not specified in the compendial monograph. If an officially recognized compendial method is used to control API-related impurities that are not specified in the monograph, full validation of the method is expected with respect to those impurities.\n\nIf an officially recognized compendial standard is claimed and an in-house method is used in lieu of the compendial method (e.g. for assay or for specified impurities), equivalence of the in-house and compendial methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For impurity methods, the sample analysed should be the API spiked with impurities at concentrations equivalent to their specification limits.\n\nReference documents: ICH Q2 (16).\n\n## 3.2.S.4.4 Batch analyses (name, manufacturer)\n\n**Description of batches and results of batch analyses should be provided.**\n\nThe information provided should include batch number, batch size, date and production site of relevant API batches used in comparative bioavailability or biowaiver studies, preclinical and clinical data (if relevant), stability, pilot, scale-up and, if available, production-scale batches. These data are used to establish the specifications and evaluate consistency in API quality.\n\nAnalytical results should be provided from at least two batches of at least pilot scale from each proposed manufacturing site of the API and should include the batch(es) used in the comparative bioavailability or biowaiver studies. A pilot-scale batch should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nCopies of the certificates of analysis, both from the API manufacturer(s) and the FPP manufacturer, should be provided for the profiled batches and any company responsible for generating the test results should be identified. The FPP manufacturer\u2019s test results should be summarized in the QOS-PD.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.\n\nA discussion and justification should be provided for any incomplete analyses (e.g. results not tested according to the proposed specification).\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "6df351583652feca3cb38b1c53493d7da402958214747640f1beb71a1bad779f", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe method should be demonstrated as suitable to control the impurity profile of the API from the intended source(s).\n\nIn general, verification is not necessary for compendial API assay methods. However, specificity of a specific compendial assay method should be demonstrated if there are any potential impurities that are not specified in the compendial monograph. If an officially recognized compendial method is used to control API-related impurities that are not specified in the monograph, full validation of the method is expected with respect to those impurities.\n\nIf an officially recognized compendial standard is claimed and an in-house method is used in lieu of the compendial method (e.g. for assay or for specified impurities), equivalence of the in-house and compendial methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For impurity methods, the sample analysed should be the API spiked with impurities at concentrations equivalent to their specification limits.\n\nReference documents: ICH Q2 (16).\n\n## 3.2.S.4.4 Batch analyses (name, manufacturer)\n\n**Description of batches and results of batch analyses should be provided.**\n\nThe information provided should include batch number, batch size, date and production site of relevant API batches used in comparative bioavailability or biowaiver studies, preclinical and clinical data (if relevant), stability, pilot, scale-up and, if available, production-scale batches. These data are used to establish the specifications and evaluate consistency in API quality.\n\nAnalytical results should be provided from at least two batches of at least pilot scale from each proposed manufacturing site of the API and should include the batch(es) used in the comparative bioavailability or biowaiver studies. A pilot-scale batch should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nCopies of the certificates of analysis, both from the API manufacturer(s) and the FPP manufacturer, should be provided for the profiled batches and any company responsible for generating the test results should be identified. The FPP manufacturer\u2019s test results should be summarized in the QOS-PD.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.\n\nA discussion and justification should be provided for any incomplete analyses (e.g. results not tested according to the proposed specification).\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2965, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "a58a57b5-e983-4d51-aec3-85f5b92f9f87": {"__data__": {"id_": "a58a57b5-e983-4d51-aec3-85f5b92f9f87", "embedding": null, "metadata": {"page_label": "165", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.S.4.5 Justification of specification (name, manufacturer)\n\n**Justification for the API specification should be provided.**\n\nA discussion should be provided on the inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendial standard(s). If the officially recognized compendial methods have been modified or replaced a discussion of the modifications or replacement method(s) should be included.\n\nThe justification for certain tests, analytical procedures and acceptance criteria may have been discussed in other sections of the PD (e.g. for impurities or particle size distribution) and does not need to be repeated here, although a cross-reference should be provided.\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12), and officially recognized pharmacopoeias.\n\n# 3.2.S.5.5 Reference standards or materials (name, manufacturer)\n\n**Information on the reference standards or reference materials used for testing of the API should be provided.**\n\nInformation should be provided on the reference standard(s) used to generate data in the PD, as well as those to be used by the FPP manufacturer in routine API and FPP testing.\n\nThe source(s) of the reference standards or materials used in the testing of the API should be provided (e.g. those used for the identification, purity and assay tests). These could be classified as primary or secondary reference standards.\n\nA suitable primary reference standard should be obtained from an officially recognized pharmacopoeial source (e.g. BP, JP, Ph.Eur., Ph.Int., USP) where one exists, and the lot number should be provided. Where a pharmacopoeial standard is claimed for the API and/or the FPP, the primary reference standard should be obtained from that pharmacopoeia when available. Primary reference standards from officially recognized pharmacopoeial sources do not need further structural elucidation.\n\nOtherwise a primary standard may be a batch of the API that has been fully characterized (e.g. by IR, UV, NMR and mass spectrometry (MS) analyses). Further purification techniques may be needed to render the material acceptable for use as a chemical reference standard. The purity requirements for a chemical reference substance depend upon its intended use. A chemical reference substance proposed for an identification test does not require meticulous purification since the presence of a small percentage of impurities in the substance often has no noticeable effect on the test. On the other hand, chemical reference substances that are to be used in assays should possess a high degree of purity (such as 99.5% on the dried or water/solvent free basis). Absolute content of the primary", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS (WHO - Technical Report Series 970) aborda la justificaci\u00f3n de las especificaciones para los ingredientes farmac\u00e9uticos activos (API) y la informaci\u00f3n sobre los est\u00e1ndares de referencia utilizados en las pruebas de estos API. Se enfatiza la necesidad de discutir la inclusi\u00f3n de pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n, as\u00ed como las diferencias con los est\u00e1ndares compendiales reconocidos. Tambi\u00e9n se detalla la clasificaci\u00f3n de los est\u00e1ndares de referencia en primarios y secundarios, y se especifica la importancia de la pureza de los est\u00e1ndares seg\u00fan su uso previsto.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 criterios se deben considerar al justificar la inclusi\u00f3n de pruebas y procedimientos anal\u00edticos para un API en el documento de presentaci\u00f3n (PD)?**\n   - Esta pregunta se centra en los aspectos espec\u00edficos que deben discutirse al justificar las especificaciones de un API, como la evoluci\u00f3n de las pruebas y las diferencias con los est\u00e1ndares compendiales.\n\n2. **\u00bfCu\u00e1les son las diferencias entre un est\u00e1ndar de referencia primario y uno secundario, y c\u00f3mo se determina la pureza requerida para cada tipo?**\n   - Esta pregunta busca aclarar la clasificaci\u00f3n de los est\u00e1ndares de referencia y los criterios de pureza que se aplican a cada uno, lo que no se detalla en otros documentos.\n\n3. **\u00bfQu\u00e9 pasos deben seguirse para obtener un est\u00e1ndar de referencia primario de una fuente farmacop\u00e9ica reconocida y qu\u00e9 informaci\u00f3n adicional se debe incluir en la documentaci\u00f3n?**\n   - Esta pregunta se enfoca en el proceso de obtenci\u00f3n de est\u00e1ndares de referencia primarios y la informaci\u00f3n necesaria, como el n\u00famero de lote y la necesidad de caracterizaci\u00f3n estructural, que son aspectos cr\u00edticos en la documentaci\u00f3n de un API.", "prev_section_summary": "### Temas Clave\n\n1. **Validaci\u00f3n de M\u00e9todos Anal\u00edticos**: Se establece que los m\u00e9todos anal\u00edticos para el control de impurezas en ingredientes farmac\u00e9uticos activos (API) deben ser adecuados y, en ciertos casos, se requiere demostrar la especificidad del m\u00e9todo si hay impurezas no especificadas en la monograf\u00eda compendial.\n\n2. **M\u00e9todos Compendiales vs. M\u00e9todos In-House**: Si se utiliza un m\u00e9todo in-house en lugar de un m\u00e9todo compendial reconocido, se debe demostrar la equivalencia entre ambos m\u00e9todos mediante an\u00e1lisis duplicados.\n\n3. **An\u00e1lisis de Lotes**: Se requiere proporcionar informaci\u00f3n detallada sobre los lotes de API utilizados en estudios de bioequivalencia, incluyendo n\u00famero de lote, tama\u00f1o, fecha y sitio de producci\u00f3n, as\u00ed como resultados anal\u00edticos de al menos dos lotes de escala piloto.\n\n4. **Resultados Anal\u00edticos**: Los resultados deben ser presentados de manera num\u00e9rica y espec\u00edfica, evitando declaraciones vagas. Adem\u00e1s, se debe discutir cualquier an\u00e1lisis incompleto y justificarlo.\n\n5. **Documentaci\u00f3n de Referencia**: Se mencionan documentos de referencia relevantes, como ICH Q2, Q6A, Q3A y Q3C, que gu\u00edan las pr\u00e1cticas de validaci\u00f3n y an\u00e1lisis.\n\n### Entidades\n\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que se utiliza en la fabricaci\u00f3n de medicamentos.\n- **M\u00e9todos Compendiales**: M\u00e9todos anal\u00edticos oficialmente reconocidos que se utilizan para el control de calidad.\n- **M\u00e9todos In-House**: M\u00e9todos desarrollados internamente por una empresa para el an\u00e1lisis de productos.\n- **Lotes**: Cantidades espec\u00edficas de API producidas en un per\u00edodo determinado.\n- **Bioequivalencia**: Comparaci\u00f3n de la biodisponibilidad de dos formulaciones de un mismo medicamento.\n- **Certificados de An\u00e1lisis**: Documentos que certifican que un lote de producto cumple con las especificaciones establecidas.\n\nEste resumen abarca los aspectos esenciales de la secci\u00f3n, destacando la importancia de la validaci\u00f3n de m\u00e9todos anal\u00edticos y la documentaci\u00f3n necesaria para garantizar la calidad y consistencia de los API.", "excerpt_keywords": "Keywords: API specification, reference standards, analytical procedures, compendial methods, purity requirements"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e7c25dfc-bbeb-42b4-8186-1bae326c47b8", "node_type": "4", "metadata": {"page_label": "165", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.S.4.5 Justification of specification (name, manufacturer)\n\n**Justification for the API specification should be provided.**\n\nA discussion should be provided on the inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendial standard(s). If the officially recognized compendial methods have been modified or replaced a discussion of the modifications or replacement method(s) should be included.\n\nThe justification for certain tests, analytical procedures and acceptance criteria may have been discussed in other sections of the PD (e.g. for impurities or particle size distribution) and does not need to be repeated here, although a cross-reference should be provided.\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12), and officially recognized pharmacopoeias.\n\n# 3.2.S.5.5 Reference standards or materials (name, manufacturer)\n\n**Information on the reference standards or reference materials used for testing of the API should be provided.**\n\nInformation should be provided on the reference standard(s) used to generate data in the PD, as well as those to be used by the FPP manufacturer in routine API and FPP testing.\n\nThe source(s) of the reference standards or materials used in the testing of the API should be provided (e.g. those used for the identification, purity and assay tests). These could be classified as primary or secondary reference standards.\n\nA suitable primary reference standard should be obtained from an officially recognized pharmacopoeial source (e.g. BP, JP, Ph.Eur., Ph.Int., USP) where one exists, and the lot number should be provided. Where a pharmacopoeial standard is claimed for the API and/or the FPP, the primary reference standard should be obtained from that pharmacopoeia when available. Primary reference standards from officially recognized pharmacopoeial sources do not need further structural elucidation.\n\nOtherwise a primary standard may be a batch of the API that has been fully characterized (e.g. by IR, UV, NMR and mass spectrometry (MS) analyses). Further purification techniques may be needed to render the material acceptable for use as a chemical reference standard. The purity requirements for a chemical reference substance depend upon its intended use. A chemical reference substance proposed for an identification test does not require meticulous purification since the presence of a small percentage of impurities in the substance often has no noticeable effect on the test. On the other hand, chemical reference substances that are to be used in assays should possess a high degree of purity (such as 99.5% on the dried or water/solvent free basis). Absolute content of the primary", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "e2e3bf36e01aa6a1db2b4c7a59db4cd26d9aa1f4f954b37d9d86105f355c47a9", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.S.4.5 Justification of specification (name, manufacturer)\n\n**Justification for the API specification should be provided.**\n\nA discussion should be provided on the inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendial standard(s). If the officially recognized compendial methods have been modified or replaced a discussion of the modifications or replacement method(s) should be included.\n\nThe justification for certain tests, analytical procedures and acceptance criteria may have been discussed in other sections of the PD (e.g. for impurities or particle size distribution) and does not need to be repeated here, although a cross-reference should be provided.\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12), and officially recognized pharmacopoeias.\n\n# 3.2.S.5.5 Reference standards or materials (name, manufacturer)\n\n**Information on the reference standards or reference materials used for testing of the API should be provided.**\n\nInformation should be provided on the reference standard(s) used to generate data in the PD, as well as those to be used by the FPP manufacturer in routine API and FPP testing.\n\nThe source(s) of the reference standards or materials used in the testing of the API should be provided (e.g. those used for the identification, purity and assay tests). These could be classified as primary or secondary reference standards.\n\nA suitable primary reference standard should be obtained from an officially recognized pharmacopoeial source (e.g. BP, JP, Ph.Eur., Ph.Int., USP) where one exists, and the lot number should be provided. Where a pharmacopoeial standard is claimed for the API and/or the FPP, the primary reference standard should be obtained from that pharmacopoeia when available. Primary reference standards from officially recognized pharmacopoeial sources do not need further structural elucidation.\n\nOtherwise a primary standard may be a batch of the API that has been fully characterized (e.g. by IR, UV, NMR and mass spectrometry (MS) analyses). Further purification techniques may be needed to render the material acceptable for use as a chemical reference standard. The purity requirements for a chemical reference substance depend upon its intended use. A chemical reference substance proposed for an identification test does not require meticulous purification since the presence of a small percentage of impurities in the substance often has no noticeable effect on the test. On the other hand, chemical reference substances that are to be used in assays should possess a high degree of purity (such as 99.5% on the dried or water/solvent free basis). Absolute content of the primary", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2742, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "b0a9ea4c-7b8b-4bdb-b818-523adc5f15d6": {"__data__": {"id_": "b0a9ea4c-7b8b-4bdb-b818-523adc5f15d6", "embedding": null, "metadata": {"page_label": "166", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nReference standard must be declared and should follow the scheme: 100% minus organic impurities (quantified by an assay procedure, e.g. HPLC or DSC) minus inorganic impurities minus volatile impurities by loss on drying (or water content minus residual solvents).\n\nA secondary (or in-house) reference standard can be used by establishing it against a suitable primary reference standard, e.g. by providing legible copies of the IR of the primary and secondary reference standards run concomitantly and by providing its certificate of analysis, including assay determined against the primary reference standard. A secondary reference standard is often characterized and evaluated for its intended purpose with additional procedures other than those used in routine testing (e.g. if additional solvents are used during the additional purification process that are not used for routine purposes).\n\nReference standards should normally be established for specified impurities. Refer to 3.2.S.4.2 for additional guidance.\n\nReference documents: ICH Q6A (6), *WHO Technical Report Series*, No. 943, Annex 3 (17).\n\n## 3.2.S.6 Container-closure system (name, manufacturer)\n\nA description of the container-closure system(s) should be provided, including the identity of materials of construction of each primary packaging component, and their specifications. The specifications should include description and identification (and critical dimensions with drawings, where appropriate). Non-compendial methods (with validation) should be included, where appropriate.\n\nFor non-functional secondary packaging components (e.g. those that do not provide additional protection), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.\n\nThe suitability should be discussed with respect to, for example, choice of materials, protection from moisture and light, compatibility of the materials of construction with the API, including sorption to container and leaching, and/or safety of materials of construction.\n\nThe WHO *Guidelines on packaging for pharmaceutical products* (18) and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for APIs.\n\nPrimary packaging components are those that are in direct contact with the API or FPP. The specifications for the primary packaging components should be provided and should include a specific test for identification (e.g. IR).\n\nCopies of the labels applied on the secondary packaging of the API should be provided and should include the conditions of storage. In addition, the name and address of the manufacturer of the API should be stated on the label.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS se centra en las especificaciones para preparaciones farmac\u00e9uticas, destacando la importancia de los est\u00e1ndares de referencia y la descripci\u00f3n del sistema de envase y cierre. Se establece un esquema para declarar los est\u00e1ndares de referencia, que incluye la cuantificaci\u00f3n de impurezas org\u00e1nicas, inorg\u00e1nicas y vol\u00e1tiles. Tambi\u00e9n se menciona la posibilidad de utilizar est\u00e1ndares de referencia secundarios, siempre que se establezcan adecuadamente en relaci\u00f3n con un est\u00e1ndar primario. Adem\u00e1s, se requiere una descripci\u00f3n detallada del sistema de envase, incluyendo materiales de construcci\u00f3n, especificaciones y pruebas de identificaci\u00f3n, as\u00ed como informaci\u00f3n sobre el etiquetado y almacenamiento del producto.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 procedimientos adicionales se pueden utilizar para caracterizar y evaluar un est\u00e1ndar de referencia secundario en comparaci\u00f3n con los utilizados en las pruebas rutinarias?**\n   - Esta pregunta busca informaci\u00f3n sobre los m\u00e9todos espec\u00edficos que pueden diferir de los procedimientos est\u00e1ndar, lo cual no se detalla en otros documentos.\n\n2. **\u00bfCu\u00e1les son los criterios espec\u00edficos que deben considerarse al seleccionar materiales para el sistema de envase y cierre en relaci\u00f3n con la protecci\u00f3n del API?**\n   - Esta pregunta se enfoca en los factores cr\u00edticos que afectan la elecci\u00f3n de materiales, que pueden no estar claramente definidos en otras gu\u00edas.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en el certificado de an\u00e1lisis de un est\u00e1ndar de referencia secundario para que sea considerado adecuado?**\n   - Esta pregunta busca detalles sobre los requisitos espec\u00edficos que deben cumplirse en el certificado de an\u00e1lisis, que pueden no estar disponibles en otras fuentes.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS proporciona directrices sobre la declaraci\u00f3n y establecimiento de est\u00e1ndares de referencia para preparaciones farmac\u00e9uticas, as\u00ed como sobre la descripci\u00f3n y especificaciones de los sistemas de envase y cierre. Se enfatiza la importancia de la caracterizaci\u00f3n de impurezas y la necesidad de pruebas de identificaci\u00f3n para los componentes de envase en contacto directo con el API. Adem\u00e1s, se menciona la necesidad de cumplir con las recomendaciones de las gu\u00edas de la OMS y las farmacopeas reconocidas oficialmente.", "prev_section_summary": "### Temas Clave:\n\n1. **Justificaci\u00f3n de Especificaciones para API**:\n   - Se requiere una discusi\u00f3n sobre la inclusi\u00f3n de pruebas, evoluci\u00f3n de pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n.\n   - Es importante se\u00f1alar las diferencias con los est\u00e1ndares compendiales reconocidos y discutir cualquier modificaci\u00f3n o m\u00e9todo de reemplazo.\n\n2. **Est\u00e1ndares de Referencia**:\n   - Se debe proporcionar informaci\u00f3n sobre los est\u00e1ndares de referencia utilizados en las pruebas de los API, incluyendo su clasificaci\u00f3n como primarios o secundarios.\n   - Los est\u00e1ndares primarios deben ser obtenidos de fuentes farmacop\u00e9icas reconocidas y se debe incluir el n\u00famero de lote.\n\n3. **Pureza de los Est\u00e1ndares**:\n   - La pureza de los est\u00e1ndares de referencia var\u00eda seg\u00fan su uso: los est\u00e1ndares para pruebas de identificaci\u00f3n pueden tener un porcentaje de impurezas, mientras que los utilizados en ensayos deben tener una alta pureza (por ejemplo, 99.5%).\n\n### Entidades:\n\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en medicamentos.\n- **FPP (Forma Farmac\u00e9utica del Producto)**: Producto final que contiene el API.\n- **Est\u00e1ndares de Referencia**: Materiales utilizados para asegurar la calidad y consistencia en las pruebas.\n- **Fuentes Farmacop\u00e9icas**: Documentos oficiales que establecen est\u00e1ndares de calidad (ej. BP, JP, Ph.Eur., Ph.Int., USP).\n- **M\u00e9todos Anal\u00edticos**: Procedimientos utilizados para evaluar la calidad del API.\n- **Criterios de Aceptaci\u00f3n**: Normas que determinan si un producto cumple con los requisitos establecidos.\n\nEste resumen destaca la importancia de la justificaci\u00f3n y documentaci\u00f3n adecuada en la evaluaci\u00f3n de ingredientes farmac\u00e9uticos activos y sus est\u00e1ndares de referencia.", "excerpt_keywords": "Keywords: reference standards, pharmaceutical preparations, container-closure system, impurities characterization, packaging specifications"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "951eda41-bf45-4adf-a145-08741c8d55aa", "node_type": "4", "metadata": {"page_label": "166", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nReference standard must be declared and should follow the scheme: 100% minus organic impurities (quantified by an assay procedure, e.g. HPLC or DSC) minus inorganic impurities minus volatile impurities by loss on drying (or water content minus residual solvents).\n\nA secondary (or in-house) reference standard can be used by establishing it against a suitable primary reference standard, e.g. by providing legible copies of the IR of the primary and secondary reference standards run concomitantly and by providing its certificate of analysis, including assay determined against the primary reference standard. A secondary reference standard is often characterized and evaluated for its intended purpose with additional procedures other than those used in routine testing (e.g. if additional solvents are used during the additional purification process that are not used for routine purposes).\n\nReference standards should normally be established for specified impurities. Refer to 3.2.S.4.2 for additional guidance.\n\nReference documents: ICH Q6A (6), *WHO Technical Report Series*, No. 943, Annex 3 (17).\n\n## 3.2.S.6 Container-closure system (name, manufacturer)\n\nA description of the container-closure system(s) should be provided, including the identity of materials of construction of each primary packaging component, and their specifications. The specifications should include description and identification (and critical dimensions with drawings, where appropriate). Non-compendial methods (with validation) should be included, where appropriate.\n\nFor non-functional secondary packaging components (e.g. those that do not provide additional protection), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.\n\nThe suitability should be discussed with respect to, for example, choice of materials, protection from moisture and light, compatibility of the materials of construction with the API, including sorption to container and leaching, and/or safety of materials of construction.\n\nThe WHO *Guidelines on packaging for pharmaceutical products* (18) and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for APIs.\n\nPrimary packaging components are those that are in direct contact with the API or FPP. The specifications for the primary packaging components should be provided and should include a specific test for identification (e.g. IR).\n\nCopies of the labels applied on the secondary packaging of the API should be provided and should include the conditions of storage. In addition, the name and address of the manufacturer of the API should be stated on the label.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "c33ad9d2bc539f6943e2e1fc34bd3af1b5a5526297bc0ceb322eaa954bc5b29b", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nReference standard must be declared and should follow the scheme: 100% minus organic impurities (quantified by an assay procedure, e.g. HPLC or DSC) minus inorganic impurities minus volatile impurities by loss on drying (or water content minus residual solvents).\n\nA secondary (or in-house) reference standard can be used by establishing it against a suitable primary reference standard, e.g. by providing legible copies of the IR of the primary and secondary reference standards run concomitantly and by providing its certificate of analysis, including assay determined against the primary reference standard. A secondary reference standard is often characterized and evaluated for its intended purpose with additional procedures other than those used in routine testing (e.g. if additional solvents are used during the additional purification process that are not used for routine purposes).\n\nReference standards should normally be established for specified impurities. Refer to 3.2.S.4.2 for additional guidance.\n\nReference documents: ICH Q6A (6), *WHO Technical Report Series*, No. 943, Annex 3 (17).\n\n## 3.2.S.6 Container-closure system (name, manufacturer)\n\nA description of the container-closure system(s) should be provided, including the identity of materials of construction of each primary packaging component, and their specifications. The specifications should include description and identification (and critical dimensions with drawings, where appropriate). Non-compendial methods (with validation) should be included, where appropriate.\n\nFor non-functional secondary packaging components (e.g. those that do not provide additional protection), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.\n\nThe suitability should be discussed with respect to, for example, choice of materials, protection from moisture and light, compatibility of the materials of construction with the API, including sorption to container and leaching, and/or safety of materials of construction.\n\nThe WHO *Guidelines on packaging for pharmaceutical products* (18) and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for APIs.\n\nPrimary packaging components are those that are in direct contact with the API or FPP. The specifications for the primary packaging components should be provided and should include a specific test for identification (e.g. IR).\n\nCopies of the labels applied on the secondary packaging of the API should be provided and should include the conditions of storage. In addition, the name and address of the manufacturer of the API should be stated on the label.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2792, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c825f6d6-cb1d-4a7a-be38-c7bc57b6714a": {"__data__": {"id_": "c825f6d6-cb1d-4a7a-be38-c7bc57b6714a", "embedding": null, "metadata": {"page_label": "167", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Stability (name, manufacturer)\n\n## Stability summary and conclusions (name, manufacturer)\n\nThe types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include results, for example, from forced degradation studies and stress conditions, as well as conclusions with respect to storage conditions and retest date or shelf-life, as appropriate.\n\nThe WHO guidelines *Stability testing of active pharmaceutical ingredients and finished pharmaceutical products* (19) should be consulted for recommendations on the core stability data package required for the prequalification of APIs and FPPs.\n\nAs outlined in the WHO stability guidelines, the purpose of stability testing is to: \u201cprovide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light.\u201d\n\nThe tables in the QOS-PD template should be used to summarize the results from the stability studies and related information (e.g. conditions, testing parameters, conclusions and commitments).\n\n### Stress testing\n\nAs outlined in the ICH Q1A guidance document (20), stress testing of the API can help identify the likely degradation products which, in turn, can help to establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual API and the type of FPP involved.\n\nStress testing may be carried out on a single batch of the API. For examples of typical stress conditions refer to section 2.1.2 of *WHO Technical Report Series, No. 953, Annex 2* (19), as well as, \u201cA typical set of studies of the degradation paths of an active pharmaceutical ingredient\u201d, in: *WHO Technical Report Series, No. 929, Annex 5, Table A1* (21).\n\nThe objective of stress testing is not to completely degrade the API but to cause degradation to occur to a small extent, typically 10\u201330% loss of API by assay when compared with non-degraded API. This target is chosen so that some degradation occurs, but not enough to generate secondary products. For this reason the conditions and duration may need to be varied when the API is especially susceptible to a particular stress factor. In the total absence of degradation products after 10 days the API is considered stable under the particular stress condition.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas:\n\n1. **\u00bfCu\u00e1l es el objetivo principal de las pruebas de estabilidad seg\u00fan las directrices de la OMS?**\n   - El objetivo principal de las pruebas de estabilidad, seg\u00fan las directrices de la OMS, es proporcionar evidencia de c\u00f3mo la calidad de un ingrediente farmac\u00e9utico activo (API) o un producto farmac\u00e9utico terminado (FPP) var\u00eda con el tiempo bajo la influencia de diversos factores ambientales, como temperatura, humedad y luz.\n\n2. **\u00bfQu\u00e9 se busca lograr con las pruebas de estr\u00e9s en los ingredientes farmac\u00e9uticos activos (API)?**\n   - Las pruebas de estr\u00e9s buscan identificar los productos de degradaci\u00f3n probables, establecer las v\u00edas de degradaci\u00f3n y validar el poder indicativo de estabilidad de los procedimientos anal\u00edticos utilizados. El objetivo no es degradar completamente el API, sino causar una degradaci\u00f3n leve, t\u00edpicamente del 10 al 30% en comparaci\u00f3n con el API no degradado.\n\n3. **\u00bfQu\u00e9 se debe incluir en el resumen de los estudios de estabilidad seg\u00fan el contexto proporcionado?**\n   - El resumen de los estudios de estabilidad debe incluir los tipos de estudios realizados, los protocolos utilizados, los resultados de los estudios (incluyendo estudios de degradaci\u00f3n forzada y condiciones de estr\u00e9s), as\u00ed como conclusiones sobre las condiciones de almacenamiento y la fecha de rean\u00e1lisis o vida \u00fatil, seg\u00fan sea apropiado.\n\n### Resumen de nivel superior del contexto:\nEl contexto aborda las pruebas de estabilidad de ingredientes farmac\u00e9uticos activos y productos farmac\u00e9uticos terminados, destacando la importancia de estas pruebas para garantizar la calidad a lo largo del tiempo bajo diversas condiciones ambientales. Se menciona la necesidad de realizar pruebas de estr\u00e9s para identificar productos de degradaci\u00f3n y se enfatiza la consulta de las directrices de la OMS para obtener recomendaciones sobre los datos de estabilidad necesarios para la precalificaci\u00f3n de estos productos. Adem\u00e1s, se detalla que el objetivo de las pruebas de estr\u00e9s es provocar una degradaci\u00f3n controlada sin llegar a generar productos secundarios.", "prev_section_summary": "### Temas Clave\n\n1. **Est\u00e1ndares de Referencia**:\n   - Importancia de declarar los est\u00e1ndares de referencia en la evaluaci\u00f3n de impurezas.\n   - Proceso de cuantificaci\u00f3n de impurezas org\u00e1nicas, inorg\u00e1nicas y vol\u00e1tiles.\n   - Uso de est\u00e1ndares de referencia secundarios, que deben establecerse en relaci\u00f3n con un est\u00e1ndar primario y caracterizarse adecuadamente.\n\n2. **Sistema de Envase y Cierre**:\n   - Descripci\u00f3n detallada de los componentes del sistema de envase, incluyendo materiales de construcci\u00f3n y especificaciones.\n   - Consideraciones sobre la protecci\u00f3n del API, compatibilidad de materiales y seguridad.\n   - Requisitos para la identificaci\u00f3n y etiquetado de los componentes de envase, as\u00ed como las condiciones de almacenamiento.\n\n3. **Documentaci\u00f3n y Normativas**:\n   - Referencias a documentos de orientaci\u00f3n como ICH Q6A y las gu\u00edas de la OMS sobre envase para productos farmac\u00e9uticos.\n   - Necesidad de incluir m\u00e9todos no compendiales con validaci\u00f3n en las especificaciones.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite directrices sobre est\u00e1ndares de referencia y envase para productos farmac\u00e9uticos.\n- **Est\u00e1ndares de Referencia Primarios y Secundarios**: Clasificaci\u00f3n de est\u00e1ndares utilizados para la evaluaci\u00f3n de impurezas.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que se encuentra en contacto directo con el envase primario.\n- **FPP (Producto Farmac\u00e9utico Final)**: Producto que contiene el API y est\u00e1 destinado al consumidor.\n- **M\u00e9todos Anal\u00edticos**: T\u00e9cnicas como HPLC (Cromatograf\u00eda L\u00edquida de Alta Resoluci\u00f3n) y DSC (Calorimetr\u00eda Diferencial de Barrido) para la cuantificaci\u00f3n de impurezas.\n- **Farmacopeas Reconocidas**: Documentos oficiales que establecen est\u00e1ndares de calidad y especificaciones para productos farmac\u00e9uticos. \n\nEste resumen destaca la importancia de los est\u00e1ndares de referencia y la adecuada descripci\u00f3n del sistema de envase y cierre en la producci\u00f3n de preparaciones farmac\u00e9uticas, as\u00ed como la necesidad de cumplir con normativas y directrices establecidas.", "excerpt_keywords": "Stability testing, Stress testing, Active pharmaceutical ingredients, WHO guidelines, Degradation products"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0f0dc63d-ff2a-4732-9025-37698ee47597", "node_type": "4", "metadata": {"page_label": "167", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Stability (name, manufacturer)\n\n## Stability summary and conclusions (name, manufacturer)\n\nThe types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include results, for example, from forced degradation studies and stress conditions, as well as conclusions with respect to storage conditions and retest date or shelf-life, as appropriate.\n\nThe WHO guidelines *Stability testing of active pharmaceutical ingredients and finished pharmaceutical products* (19) should be consulted for recommendations on the core stability data package required for the prequalification of APIs and FPPs.\n\nAs outlined in the WHO stability guidelines, the purpose of stability testing is to: \u201cprovide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light.\u201d\n\nThe tables in the QOS-PD template should be used to summarize the results from the stability studies and related information (e.g. conditions, testing parameters, conclusions and commitments).\n\n### Stress testing\n\nAs outlined in the ICH Q1A guidance document (20), stress testing of the API can help identify the likely degradation products which, in turn, can help to establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual API and the type of FPP involved.\n\nStress testing may be carried out on a single batch of the API. For examples of typical stress conditions refer to section 2.1.2 of *WHO Technical Report Series, No. 953, Annex 2* (19), as well as, \u201cA typical set of studies of the degradation paths of an active pharmaceutical ingredient\u201d, in: *WHO Technical Report Series, No. 929, Annex 5, Table A1* (21).\n\nThe objective of stress testing is not to completely degrade the API but to cause degradation to occur to a small extent, typically 10\u201330% loss of API by assay when compared with non-degraded API. This target is chosen so that some degradation occurs, but not enough to generate secondary products. For this reason the conditions and duration may need to be varied when the API is especially susceptible to a particular stress factor. In the total absence of degradation products after 10 days the API is considered stable under the particular stress condition.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "a138d3b2e0ba3171f7dcf956a94f25536cd1bc7f39b4c4ba5be5a5a49e8b1184", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Stability (name, manufacturer)\n\n## Stability summary and conclusions (name, manufacturer)\n\nThe types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include results, for example, from forced degradation studies and stress conditions, as well as conclusions with respect to storage conditions and retest date or shelf-life, as appropriate.\n\nThe WHO guidelines *Stability testing of active pharmaceutical ingredients and finished pharmaceutical products* (19) should be consulted for recommendations on the core stability data package required for the prequalification of APIs and FPPs.\n\nAs outlined in the WHO stability guidelines, the purpose of stability testing is to: \u201cprovide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light.\u201d\n\nThe tables in the QOS-PD template should be used to summarize the results from the stability studies and related information (e.g. conditions, testing parameters, conclusions and commitments).\n\n### Stress testing\n\nAs outlined in the ICH Q1A guidance document (20), stress testing of the API can help identify the likely degradation products which, in turn, can help to establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual API and the type of FPP involved.\n\nStress testing may be carried out on a single batch of the API. For examples of typical stress conditions refer to section 2.1.2 of *WHO Technical Report Series, No. 953, Annex 2* (19), as well as, \u201cA typical set of studies of the degradation paths of an active pharmaceutical ingredient\u201d, in: *WHO Technical Report Series, No. 929, Annex 5, Table A1* (21).\n\nThe objective of stress testing is not to completely degrade the API but to cause degradation to occur to a small extent, typically 10\u201330% loss of API by assay when compared with non-degraded API. This target is chosen so that some degradation occurs, but not enough to generate secondary products. For this reason the conditions and duration may need to be varied when the API is especially susceptible to a particular stress factor. In the total absence of degradation products after 10 days the API is considered stable under the particular stress condition.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2452, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "a3b68da5-ec96-4ffd-8e10-8f275cf56bbf": {"__data__": {"id_": "a3b68da5-ec96-4ffd-8e10-8f275cf56bbf", "embedding": null, "metadata": {"page_label": "168", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe tables in the QOS-PD template should be used to summarize the results of the stress testing and should include the treatment conditions (e.g. temperatures, relative humidities, concentrations of solutions and durations) and the observations for the various test parameters (e.g. assay, degradation products). The discussion of results should highlight whether mass balance was observed.\n\nPhotostability testing should be an integral part of stress testing. The standard conditions are described in ICH Q1B (22). If \u201cprotect from light\u201d is stated in one of the officially recognized pharmacopoeias for the API, it is sufficient to state \u201cprotect from light\u201d on labelling, in lieu of photostability studies when the container-closure system is shown to be light protective.\n\nWhen available it is acceptable to provide the relevant data published in the scientific literature (including, but not limited to, WHO Public Assessment Reports (WHOPARs), European Public Assessment Reports (EPARs)) to support the identified degradation products and pathways.\n\n## Accelerated and long-term testing\n\nAvailable information on the stability of the API under accelerated and long-term storage conditions should be provided, including information in the public domain or obtained from scientific literature. The source of the information should be identified.\n\nThe required long-term storage conditions for APIs in the WHO Prequalification of Medicines Programme are either 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH or 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH. Studies covering the proposed retest period under the above-mentioned long-term storage conditions will provide better assurance of the stability of APIs at the conditions of the supply chain corresponding to the WHO and its Prequalification of Medicines Programme environments. Alternative conditions should be supported with appropriate evidence, which may include literature references or in-house studies, demonstrating that storage at 30 \u00b0C is inappropriate for the API. For APIs intended for storage in a refrigerator and those intended for storage in a freezer, refer to the WHO stability guidelines in the *WHO Technical Report Series*, No. 953, Annex 2 (19). APIs intended for storage below \u201320 \u00b0C should be treated on a case-by-case basis.\n\nTo establish the retest period, data should be provided on not less than three batches of at least pilot scale. The batches should be manufactured by the same synthesis route as production batches and using a method of manufacture and a procedure that simulates the final process to be used for production batches. The stability testing programme should be summarized and the results of stability testing should be summarized in the dossier and in the tables in the QOS-PD.\n\nThe information on the stability studies should include details such as storage conditions, batch number, batch size, container-closure system and completed (and proposed) test intervals. The discussion of results should focus on the stability of the API under the specified conditions.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS proporciona directrices sobre las pruebas de estabilidad de los ingredientes farmac\u00e9uticos activos (API) en el contexto de la precalificaci\u00f3n de medicamentos. Se enfatiza la importancia de realizar pruebas de estr\u00e9s, que incluyen condiciones de temperatura, humedad y fotoprotecci\u00f3n, as\u00ed como la necesidad de documentar los resultados de estas pruebas. Tambi\u00e9n se discuten las condiciones de almacenamiento a largo plazo requeridas y la necesidad de datos de estabilidad de al menos tres lotes para establecer el per\u00edodo de rean\u00e1lisis. Se menciona que la informaci\u00f3n sobre la estabilidad puede provenir de literatura cient\u00edfica y que se deben seguir pautas espec\u00edficas para diferentes condiciones de almacenamiento.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las condiciones de almacenamiento a largo plazo requeridas para los API en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Las condiciones de almacenamiento a largo plazo requeridas son 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH o 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n se debe incluir al establecer el per\u00edodo de rean\u00e1lisis para un API?**\n   - Se debe proporcionar informaci\u00f3n sobre al menos tres lotes de escala piloto, incluyendo condiciones de almacenamiento, n\u00famero de lote, tama\u00f1o del lote, sistema de cierre del contenedor y los intervalos de prueba completados (y propuestos).\n\n3. **\u00bfQu\u00e9 se debe hacer si un API est\u00e1 destinado a ser almacenado a temperaturas inferiores a -20 \u00b0C?**\n   - Los API destinados a almacenamiento por debajo de -20 \u00b0C deben ser tratados caso por caso, lo que implica que se debe proporcionar evidencia adecuada para justificar las condiciones de almacenamiento elegidas.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS establece directrices para la evaluaci\u00f3n de la estabilidad de los ingredientes farmac\u00e9uticos activos, enfatizando la importancia de las pruebas de estr\u00e9s y la documentaci\u00f3n de los resultados. Se especifican las condiciones de almacenamiento a largo plazo y se requiere que los datos de estabilidad provengan de m\u00faltiples lotes para garantizar la validez de los resultados. Adem\u00e1s, se menciona la posibilidad de utilizar datos de literatura cient\u00edfica para respaldar los hallazgos sobre productos de degradaci\u00f3n y v\u00edas.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Pruebas de estabilidad**:\n   - Objetivo: Proporcionar evidencia sobre c\u00f3mo la calidad de un ingrediente farmac\u00e9utico activo (API) o un producto farmac\u00e9utico terminado (FPP) var\u00eda con el tiempo bajo diferentes factores ambientales (temperatura, humedad, luz).\n   - Importancia: Garantizar la calidad y seguridad de los productos farmac\u00e9uticos a lo largo de su vida \u00fatil.\n\n2. **Directrices de la OMS**:\n   - Se deben consultar las directrices de la OMS sobre pruebas de estabilidad para obtener recomendaciones sobre el paquete de datos de estabilidad necesario para la precalificaci\u00f3n de APIs y FPPs.\n\n3. **Resumen de estudios de estabilidad**:\n   - Debe incluir: tipos de estudios realizados, protocolos utilizados, resultados de estudios de degradaci\u00f3n forzada y condiciones de estr\u00e9s, conclusiones sobre condiciones de almacenamiento, y fechas de rean\u00e1lisis o vida \u00fatil.\n\n4. **Pruebas de estr\u00e9s**:\n   - Definici\u00f3n: Ayudan a identificar productos de degradaci\u00f3n, establecer v\u00edas de degradaci\u00f3n y validar la capacidad de los procedimientos anal\u00edticos para indicar estabilidad.\n   - Objetivo: Provocar una degradaci\u00f3n controlada (10-30% de p\u00e9rdida del API) sin generar productos secundarios.\n   - Ejecuci\u00f3n: Puede realizarse en un solo lote de API, y las condiciones de estr\u00e9s pueden variar seg\u00fan la susceptibilidad del API.\n\n5. **Referencias**:\n   - Se mencionan documentos de la OMS y la ICH (International Council for Harmonisation) como fuentes de orientaci\u00f3n sobre las pruebas de estabilidad y estr\u00e9s.\n\n### Entidades clave:\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Proporciona directrices sobre pruebas de estabilidad.\n- **ICH (Consejo Internacional para la Armonizaci\u00f3n)**: Ofrece documentos de orientaci\u00f3n sobre pruebas de estr\u00e9s.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que se somete a pruebas de estabilidad y estr\u00e9s.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que tambi\u00e9n se eval\u00faa en t\u00e9rminos de estabilidad.", "excerpt_keywords": "Keywords: stability testing, pharmaceutical preparations, WHO guidelines, stress testing, active pharmaceutical ingredient"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5bd14002-6873-4259-a6a8-4ae9d152653d", "node_type": "4", "metadata": {"page_label": "168", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe tables in the QOS-PD template should be used to summarize the results of the stress testing and should include the treatment conditions (e.g. temperatures, relative humidities, concentrations of solutions and durations) and the observations for the various test parameters (e.g. assay, degradation products). The discussion of results should highlight whether mass balance was observed.\n\nPhotostability testing should be an integral part of stress testing. The standard conditions are described in ICH Q1B (22). If \u201cprotect from light\u201d is stated in one of the officially recognized pharmacopoeias for the API, it is sufficient to state \u201cprotect from light\u201d on labelling, in lieu of photostability studies when the container-closure system is shown to be light protective.\n\nWhen available it is acceptable to provide the relevant data published in the scientific literature (including, but not limited to, WHO Public Assessment Reports (WHOPARs), European Public Assessment Reports (EPARs)) to support the identified degradation products and pathways.\n\n## Accelerated and long-term testing\n\nAvailable information on the stability of the API under accelerated and long-term storage conditions should be provided, including information in the public domain or obtained from scientific literature. The source of the information should be identified.\n\nThe required long-term storage conditions for APIs in the WHO Prequalification of Medicines Programme are either 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH or 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH. Studies covering the proposed retest period under the above-mentioned long-term storage conditions will provide better assurance of the stability of APIs at the conditions of the supply chain corresponding to the WHO and its Prequalification of Medicines Programme environments. Alternative conditions should be supported with appropriate evidence, which may include literature references or in-house studies, demonstrating that storage at 30 \u00b0C is inappropriate for the API. For APIs intended for storage in a refrigerator and those intended for storage in a freezer, refer to the WHO stability guidelines in the *WHO Technical Report Series*, No. 953, Annex 2 (19). APIs intended for storage below \u201320 \u00b0C should be treated on a case-by-case basis.\n\nTo establish the retest period, data should be provided on not less than three batches of at least pilot scale. The batches should be manufactured by the same synthesis route as production batches and using a method of manufacture and a procedure that simulates the final process to be used for production batches. The stability testing programme should be summarized and the results of stability testing should be summarized in the dossier and in the tables in the QOS-PD.\n\nThe information on the stability studies should include details such as storage conditions, batch number, batch size, container-closure system and completed (and proposed) test intervals. The discussion of results should focus on the stability of the API under the specified conditions.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "915ddfb6089fe0913ab8843868133d23bf89664f196bb82e8603969ebb72a21d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe tables in the QOS-PD template should be used to summarize the results of the stress testing and should include the treatment conditions (e.g. temperatures, relative humidities, concentrations of solutions and durations) and the observations for the various test parameters (e.g. assay, degradation products). The discussion of results should highlight whether mass balance was observed.\n\nPhotostability testing should be an integral part of stress testing. The standard conditions are described in ICH Q1B (22). If \u201cprotect from light\u201d is stated in one of the officially recognized pharmacopoeias for the API, it is sufficient to state \u201cprotect from light\u201d on labelling, in lieu of photostability studies when the container-closure system is shown to be light protective.\n\nWhen available it is acceptable to provide the relevant data published in the scientific literature (including, but not limited to, WHO Public Assessment Reports (WHOPARs), European Public Assessment Reports (EPARs)) to support the identified degradation products and pathways.\n\n## Accelerated and long-term testing\n\nAvailable information on the stability of the API under accelerated and long-term storage conditions should be provided, including information in the public domain or obtained from scientific literature. The source of the information should be identified.\n\nThe required long-term storage conditions for APIs in the WHO Prequalification of Medicines Programme are either 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH or 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH. Studies covering the proposed retest period under the above-mentioned long-term storage conditions will provide better assurance of the stability of APIs at the conditions of the supply chain corresponding to the WHO and its Prequalification of Medicines Programme environments. Alternative conditions should be supported with appropriate evidence, which may include literature references or in-house studies, demonstrating that storage at 30 \u00b0C is inappropriate for the API. For APIs intended for storage in a refrigerator and those intended for storage in a freezer, refer to the WHO stability guidelines in the *WHO Technical Report Series*, No. 953, Annex 2 (19). APIs intended for storage below \u201320 \u00b0C should be treated on a case-by-case basis.\n\nTo establish the retest period, data should be provided on not less than three batches of at least pilot scale. The batches should be manufactured by the same synthesis route as production batches and using a method of manufacture and a procedure that simulates the final process to be used for production batches. The stability testing programme should be summarized and the results of stability testing should be summarized in the dossier and in the tables in the QOS-PD.\n\nThe information on the stability studies should include details such as storage conditions, batch number, batch size, container-closure system and completed (and proposed) test intervals. The discussion of results should focus on the stability of the API under the specified conditions.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3104, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "a8271676-c9de-4261-b9e7-28d9b8477a74": {"__data__": {"id_": "a8271676-c9de-4261-b9e7-28d9b8477a74", "embedding": null, "metadata": {"page_label": "169", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. Ranges of analytical results where relevant and any trends that were observed should be included. For quantitative tests (e.g. individual and total degradation product tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. Where methods are different from those described in S.4.2, descriptions and validation of the methodology used in stability studies should be provided.\n\nThe minimum data required at the time of submitting the dossier (in the general case) are shown in Table 1.\n\n**Table 1**  \nMinimum data required at the time of submitting the dossier\n\n| Storage temperature (\u00b0C) | Relative humidity (%) | Minimum time period (months) |\n| - | - | - |\n| Accelerated 40 \u00b1 2 | 75 \u00b1 5 | 6 |\n| Intermediatea | \u2013a | \u2013a |\n| Long-term 30 \u00b1 2 | 65 \u00b1 5 or 75 \u00b1 5 | 6 |\n\n\n<sup>a</sup>Where long-term conditions are 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH or 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, there is no intermediate condition.\n\nRefer to WHO Technical Report Series, No. 953, Annex 2 (19) for further information regarding the storage conditions, container-closure system, test specifications and testing frequency.\n\n**Proposed storage statement and retest period**\n\nA storage statement should be established for display on the label, based on the stability evaluation of the API. The WHO stability guidelines include a number of recommended storage statements that should be used when supported by the stability studies.\n\nA retest period should be derived from the stability information and should be displayed on the container label.\n\nAfter this retest period a batch of API destined for use in the manufacture of an FPP could be retested and then, if in compliance with the specification, could be used immediately (e.g. within 30 days). If retested and found compliant, the batch does not receive an additional period corresponding to the time established for the retest period. However, an API batch can be retested multiple times and a different portion of the batch used after each retest, as long as it", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los requisitos m\u00ednimos de datos necesarios para la presentaci\u00f3n de un dossier relacionado con la estabilidad de los ingredientes farmac\u00e9uticos activos (API). Se especifican las condiciones de almacenamiento, la humedad relativa y los per\u00edodos de tiempo m\u00ednimos para las pruebas de estabilidad. Adem\u00e1s, se enfatiza la importancia de proporcionar resultados num\u00e9ricos concretos en las pruebas anal\u00edticas y se establece la necesidad de un enunciado de almacenamiento y un per\u00edodo de rean\u00e1lisis que deben ser claramente indicados en las etiquetas de los productos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en los resultados de las pruebas anal\u00edticas para cumplir con las directrices de la OMS?**\n   - Las pruebas anal\u00edticas deben incluir rangos de resultados y tendencias observadas, as\u00ed como resultados num\u00e9ricos concretos en lugar de declaraciones vagas como \"dentro de los l\u00edmites\" o \"conforma\".\n\n2. **\u00bfCu\u00e1les son las condiciones de almacenamiento y los per\u00edodos m\u00ednimos requeridos para las pruebas de estabilidad de un API seg\u00fan la OMS?**\n   - Las condiciones de almacenamiento incluyen: \n     - Acelerado: 40 \u00b1 2 \u00b0C y 75 \u00b1 5% de humedad relativa por un m\u00ednimo de 6 meses.\n     - A largo plazo: 30 \u00b1 2 \u00b0C y 65 \u00b1 5% o 75 \u00b1 5% de humedad relativa, tambi\u00e9n por un m\u00ednimo de 6 meses.\n     - No hay condiciones intermedias si se cumplen las condiciones a largo plazo.\n\n3. **\u00bfQu\u00e9 debe hacerse despu\u00e9s del per\u00edodo de rean\u00e1lisis de un lote de API y c\u00f3mo se puede utilizar el lote despu\u00e9s de ser retestado?**\n   - Despu\u00e9s del per\u00edodo de rean\u00e1lisis, un lote de API puede ser retestado y, si cumple con las especificaciones, puede ser utilizado inmediatamente (dentro de 30 d\u00edas). No se a\u00f1ade un per\u00edodo adicional al lote si se retesta y se encuentra conforme, y se puede retestar m\u00faltiples veces utilizando diferentes porciones del lote.", "prev_section_summary": "### Temas Clave\n\n1. **Pruebas de Estr\u00e9s**: Se enfatiza la importancia de realizar pruebas de estr\u00e9s para evaluar la estabilidad de los ingredientes farmac\u00e9uticos activos (API). Esto incluye condiciones de temperatura, humedad, concentraciones de soluciones y duraci\u00f3n de las pruebas.\n\n2. **Fotostabilidad**: Las pruebas de fotostabilidad deben ser parte integral de las pruebas de estr\u00e9s. Si un API requiere protecci\u00f3n contra la luz, se puede indicar en el etiquetado si el sistema de cierre del contenedor es adecuado.\n\n3. **Datos de Literatura Cient\u00edfica**: Se permite el uso de datos publicados en la literatura cient\u00edfica, como informes de evaluaci\u00f3n p\u00fablica de la OMS y la EMA, para respaldar los productos de degradaci\u00f3n y las v\u00edas identificadas.\n\n4. **Condiciones de Almacenamiento a Largo Plazo**: Las condiciones requeridas para el almacenamiento a largo plazo de los API son 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH o 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH. Se requiere evidencia adecuada para condiciones alternativas.\n\n5. **Establecimiento del Per\u00edodo de Rean\u00e1lisis**: Para establecer el per\u00edodo de rean\u00e1lisis, se deben proporcionar datos de al menos tres lotes de escala piloto, fabricados con el mismo m\u00e9todo que los lotes de producci\u00f3n.\n\n6. **Documentaci\u00f3n de Resultados**: Los resultados de las pruebas de estabilidad deben ser resumidos en el expediente y en las tablas del QOS-PD, incluyendo detalles como condiciones de almacenamiento, n\u00famero de lote, tama\u00f1o del lote y sistema de cierre del contenedor.\n\n### Entidades\n\n- **API (Ingredientes Farmac\u00e9uticos Activos)**: Sustancias que se utilizan en la fabricaci\u00f3n de medicamentos.\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Entidad que proporciona directrices sobre la precalificaci\u00f3n de medicamentos.\n- **ICH Q1B**: Directrices sobre pruebas de fotostabilidad.\n- **QOS-PD**: Plantilla para resumir los resultados de las pruebas de estabilidad.\n- **WHOPARs y EPARs**: Informes de evaluaci\u00f3n p\u00fablica de la OMS y la EMA, respectivamente.\n- **Condiciones de Almacenamiento**: 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH o 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH.\n- **Estudios de Estabilidad**: Evaluaciones necesarias para determinar la estabilidad de los API bajo condiciones espec\u00edficas.", "excerpt_keywords": "Keywords: stability evaluation, active pharmaceutical ingredients, storage conditions, retest period, analytical results"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8283c45b-f991-4c63-a212-97bc08b389ae", "node_type": "4", "metadata": {"page_label": "169", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. Ranges of analytical results where relevant and any trends that were observed should be included. For quantitative tests (e.g. individual and total degradation product tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. Where methods are different from those described in S.4.2, descriptions and validation of the methodology used in stability studies should be provided.\n\nThe minimum data required at the time of submitting the dossier (in the general case) are shown in Table 1.\n\n**Table 1**  \nMinimum data required at the time of submitting the dossier\n\n| Storage temperature (\u00b0C) | Relative humidity (%) | Minimum time period (months) |\n| - | - | - |\n| Accelerated 40 \u00b1 2 | 75 \u00b1 5 | 6 |\n| Intermediatea | \u2013a | \u2013a |\n| Long-term 30 \u00b1 2 | 65 \u00b1 5 or 75 \u00b1 5 | 6 |\n\n\n<sup>a</sup>Where long-term conditions are 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH or 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, there is no intermediate condition.\n\nRefer to WHO Technical Report Series, No. 953, Annex 2 (19) for further information regarding the storage conditions, container-closure system, test specifications and testing frequency.\n\n**Proposed storage statement and retest period**\n\nA storage statement should be established for display on the label, based on the stability evaluation of the API. The WHO stability guidelines include a number of recommended storage statements that should be used when supported by the stability studies.\n\nA retest period should be derived from the stability information and should be displayed on the container label.\n\nAfter this retest period a batch of API destined for use in the manufacture of an FPP could be retested and then, if in compliance with the specification, could be used immediately (e.g. within 30 days). If retested and found compliant, the batch does not receive an additional period corresponding to the time established for the retest period. However, an API batch can be retested multiple times and a different portion of the batch used after each retest, as long as it", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "f2019f2c5648ee5e6c1f8b4044368c1aa99cbf29833840f4ee3a3ad6d80b9f14", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. Ranges of analytical results where relevant and any trends that were observed should be included. For quantitative tests (e.g. individual and total degradation product tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. Where methods are different from those described in S.4.2, descriptions and validation of the methodology used in stability studies should be provided.\n\nThe minimum data required at the time of submitting the dossier (in the general case) are shown in Table 1.\n\n**Table 1**  \nMinimum data required at the time of submitting the dossier\n\n| Storage temperature (\u00b0C) | Relative humidity (%) | Minimum time period (months) |\n| - | - | - |\n| Accelerated 40 \u00b1 2 | 75 \u00b1 5 | 6 |\n| Intermediatea | \u2013a | \u2013a |\n| Long-term 30 \u00b1 2 | 65 \u00b1 5 or 75 \u00b1 5 | 6 |\n\n\n<sup>a</sup>Where long-term conditions are 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH or 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, there is no intermediate condition.\n\nRefer to WHO Technical Report Series, No. 953, Annex 2 (19) for further information regarding the storage conditions, container-closure system, test specifications and testing frequency.\n\n**Proposed storage statement and retest period**\n\nA storage statement should be established for display on the label, based on the stability evaluation of the API. The WHO stability guidelines include a number of recommended storage statements that should be used when supported by the stability studies.\n\nA retest period should be derived from the stability information and should be displayed on the container label.\n\nAfter this retest period a batch of API destined for use in the manufacture of an FPP could be retested and then, if in compliance with the specification, could be used immediately (e.g. within 30 days). If retested and found compliant, the batch does not receive an additional period corresponding to the time established for the retest period. However, an API batch can be retested multiple times and a different portion of the batch used after each retest, as long as it", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2201, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c080c747-fefd-46ef-a159-6e8ba184f7e6": {"__data__": {"id_": "c080c747-fefd-46ef-a159-6e8ba184f7e6", "embedding": null, "metadata": {"page_label": "170", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\ncontinues to comply with the specification. For APIs known to be labile (e.g. certain antibiotics) it is more appropriate to establish a shelf-life than a retest period (20).\n\nLimited extrapolation of the real-time data from the long-term storage condition beyond the observed range to extend the retest period can be done at the time of assessment of the PD, if justified. Applicants should consult the ICH Q1E guideline (23) for further details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated conditions and the data show little or no variability, the proposed retest period could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months).\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), WHO Technical Report Series, No. 953, Annex 2 (19).\n\n## 3.2.S.7.2 Post-approval stability protocol and stability commitment (name, manufacturer)\n\nThe post-approval stability protocol and stability commitment should be provided.\n\n### Primary stability study commitment\n\nWhen the available long-term stability data on primary batches do not cover the proposed retest period granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the retest period. A written commitment (signed and dated) to continue long-term testing over the retest period should be included in the dossier when relevant.\n\n### Commitment stability studies\n\nThe long-term stability studies for the commitment batches should be conducted through the proposed retest period on at least three production batches. Where stability data were not provided for three production batches, a written commitment (signed and dated) should be included in the dossier.\n\nThe stability protocol for the commitment batches should be provided and should include, but not be limited to, the following parameters:\n\n- number of batch(es) and different batch sizes, if applicable;\n- relevant physical, chemical, microbiological and biological test methods;\n- acceptance criteria;\n- reference to test methods;\n- description of the container-closure system(s);", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento se centra en las especificaciones para los estudios de estabilidad de los principios activos (APIs) en la industria farmac\u00e9utica, destacando la importancia de establecer per\u00edodos de rean\u00e1lisis y compromisos de estabilidad post-aprobaci\u00f3n. Se menciona que para ciertos APIs labiles, es m\u00e1s adecuado establecer una vida \u00fatil en lugar de un per\u00edodo de rean\u00e1lisis. Tambi\u00e9n se discuten las condiciones bajo las cuales se puede extrapolar la informaci\u00f3n de estabilidad y se detallan los requisitos para los estudios de estabilidad de compromiso.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las condiciones bajo las cuales se puede extrapolar la informaci\u00f3n de estabilidad para extender el per\u00edodo de rean\u00e1lisis de un API?**\n   - La extrapolaci\u00f3n de datos de estabilidad a largo plazo puede hacerse si no se observan cambios significativos en un per\u00edodo de 6 meses bajo condiciones aceleradas y si los datos muestran poca o ninguna variabilidad. En este caso, el per\u00edodo de rean\u00e1lisis propuesto podr\u00eda ser hasta el doble del per\u00edodo cubierto por los datos a largo plazo, pero no debe exceder los datos a largo plazo por m\u00e1s de 12 meses.\n\n2. **\u00bfQu\u00e9 tipo de compromiso se requiere si los datos de estabilidad a largo plazo no cubren el per\u00edodo de rean\u00e1lisis propuesto?**\n   - Se requiere un compromiso escrito (firmado y fechado) para continuar los estudios de estabilidad a largo plazo durante el per\u00edodo de rean\u00e1lisis. Este compromiso debe incluir la realizaci\u00f3n de estudios de estabilidad en al menos tres lotes de producci\u00f3n.\n\n3. **\u00bfQu\u00e9 par\u00e1metros deben incluirse en el protocolo de estabilidad para los lotes de compromiso?**\n   - El protocolo de estabilidad debe incluir, entre otros, el n\u00famero de lotes y diferentes tama\u00f1os de lote, m\u00e9todos de prueba f\u00edsicos, qu\u00edmicos, microbiol\u00f3gicos y biol\u00f3gicos relevantes, criterios de aceptaci\u00f3n, referencia a m\u00e9todos de prueba y una descripci\u00f3n del sistema de cierre del envase.", "prev_section_summary": "### Temas Clave\n\n1. **Requisitos de Datos para Dossier de Estabilidad**: Se especifican los datos m\u00ednimos necesarios al presentar un dossier relacionado con la estabilidad de los ingredientes farmac\u00e9uticos activos (API), incluyendo condiciones de almacenamiento y per\u00edodos de tiempo.\n\n2. **Condiciones de Almacenamiento**: Se detallan las condiciones de almacenamiento para pruebas de estabilidad, que incluyen:\n   - **Acelerado**: 40 \u00b1 2 \u00b0C y 75 \u00b1 5% de humedad relativa por un m\u00ednimo de 6 meses.\n   - **A Largo Plazo**: 30 \u00b1 2 \u00b0C con 65 \u00b1 5% o 75 \u00b1 5% de humedad relativa, tambi\u00e9n por un m\u00ednimo de 6 meses.\n   - **Condiciones Intermedias**: No aplicables si se cumplen las condiciones a largo plazo.\n\n3. **Resultados de Pruebas Anal\u00edticas**: Se enfatiza la necesidad de proporcionar resultados num\u00e9ricos concretos y no declaraciones vagas en las pruebas anal\u00edticas.\n\n4. **Declaraci\u00f3n de Almacenamiento y Per\u00edodo de Rean\u00e1lisis**: Se requiere establecer una declaraci\u00f3n de almacenamiento basada en la evaluaci\u00f3n de estabilidad del API y un per\u00edodo de rean\u00e1lisis que debe ser indicado en la etiqueta del producto.\n\n5. **Uso de Lotes Retestados**: Un lote de API puede ser retestado despu\u00e9s del per\u00edodo de rean\u00e1lisis y, si cumple con las especificaciones, puede ser utilizado inmediatamente. Se permite el rean\u00e1lisis m\u00faltiple de un lote.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad que proporciona las directrices sobre estabilidad de API.\n- **Ingredientes Farmac\u00e9uticos Activos (API)**: Sustancias que se utilizan en la fabricaci\u00f3n de productos farmac\u00e9uticos.\n- **Condiciones de Almacenamiento**: Incluyen temperatura y humedad relativa.\n- **Pruebas Anal\u00edticas**: M\u00e9todos utilizados para evaluar la estabilidad y calidad de los API.\n- **Dossier**: Documentaci\u00f3n que se presenta para la evaluaci\u00f3n de la estabilidad de los API.\n- **Per\u00edodo de Rean\u00e1lisis**: Tiempo establecido para volver a evaluar un lote de API. \n\nEste resumen abarca los aspectos esenciales y las entidades relevantes en la secci\u00f3n proporcionada del documento de la OMS.", "excerpt_keywords": "Keywords: stability studies, retest period, pharmaceutical preparations, active pharmaceutical ingredients, post-approval commitment"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "750a8c4e-af00-4283-a0c0-fe7ec781bdfa", "node_type": "4", "metadata": {"page_label": "170", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\ncontinues to comply with the specification. For APIs known to be labile (e.g. certain antibiotics) it is more appropriate to establish a shelf-life than a retest period (20).\n\nLimited extrapolation of the real-time data from the long-term storage condition beyond the observed range to extend the retest period can be done at the time of assessment of the PD, if justified. Applicants should consult the ICH Q1E guideline (23) for further details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated conditions and the data show little or no variability, the proposed retest period could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months).\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), WHO Technical Report Series, No. 953, Annex 2 (19).\n\n## 3.2.S.7.2 Post-approval stability protocol and stability commitment (name, manufacturer)\n\nThe post-approval stability protocol and stability commitment should be provided.\n\n### Primary stability study commitment\n\nWhen the available long-term stability data on primary batches do not cover the proposed retest period granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the retest period. A written commitment (signed and dated) to continue long-term testing over the retest period should be included in the dossier when relevant.\n\n### Commitment stability studies\n\nThe long-term stability studies for the commitment batches should be conducted through the proposed retest period on at least three production batches. Where stability data were not provided for three production batches, a written commitment (signed and dated) should be included in the dossier.\n\nThe stability protocol for the commitment batches should be provided and should include, but not be limited to, the following parameters:\n\n- number of batch(es) and different batch sizes, if applicable;\n- relevant physical, chemical, microbiological and biological test methods;\n- acceptance criteria;\n- reference to test methods;\n- description of the container-closure system(s);", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "8c5fae0c5fc515641be15102994e073fe03614ab5ddc626fd3bbacd52f893a32", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\ncontinues to comply with the specification. For APIs known to be labile (e.g. certain antibiotics) it is more appropriate to establish a shelf-life than a retest period (20).\n\nLimited extrapolation of the real-time data from the long-term storage condition beyond the observed range to extend the retest period can be done at the time of assessment of the PD, if justified. Applicants should consult the ICH Q1E guideline (23) for further details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated conditions and the data show little or no variability, the proposed retest period could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months).\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), WHO Technical Report Series, No. 953, Annex 2 (19).\n\n## 3.2.S.7.2 Post-approval stability protocol and stability commitment (name, manufacturer)\n\nThe post-approval stability protocol and stability commitment should be provided.\n\n### Primary stability study commitment\n\nWhen the available long-term stability data on primary batches do not cover the proposed retest period granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the retest period. A written commitment (signed and dated) to continue long-term testing over the retest period should be included in the dossier when relevant.\n\n### Commitment stability studies\n\nThe long-term stability studies for the commitment batches should be conducted through the proposed retest period on at least three production batches. Where stability data were not provided for three production batches, a written commitment (signed and dated) should be included in the dossier.\n\nThe stability protocol for the commitment batches should be provided and should include, but not be limited to, the following parameters:\n\n- number of batch(es) and different batch sizes, if applicable;\n- relevant physical, chemical, microbiological and biological test methods;\n- acceptance criteria;\n- reference to test methods;\n- description of the container-closure system(s);", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2322, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ed1bfa32-9c1b-47b2-a255-92009ccc23f4": {"__data__": {"id_": "ed1bfa32-9c1b-47b2-a255-92009ccc23f4", "embedding": null, "metadata": {"page_label": "171", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "\n- testing frequency;\n- description of the conditions of storage (standardized conditions for long-term testing as described in these guidelines and consistent with the API labelling, should be used);\n- other applicable parameters specific to the API.\n\n### Ongoing stability studies\n\nThe stability of the API should be monitored according to a continuous and appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of degradation products). The purpose of the ongoing stability programme is to monitor the API and to determine that the API remains stable and can be expected to remain stable within the retest period in all future batches.\n\nAt least one production batch per year of API (unless none is produced during that year) should be added to the stability monitoring programme and tested at least annually to confirm the stability. In certain situations, additional batches should be included. A written commitment (signed and dated) to ongoing stability studies should be included in the dossier.\n\nRefer to section 2.1.11 of WHO Technical Report Series, No. 953, Annex 2 (19), for further information on ongoing stability studies.\n\nAny differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), WHO Technical Report Series, No. 953, Annex 2 (19).\n\n#### 3.2.S.7.3 Stability data (name, manufacturer)\n\nResults of the stability studies (e.g. forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included.\n\nThe actual stability results used to support the proposed retest period should be included in the dossier. For quantitative tests (e.g. individual and total degradation product tests and assay tests) it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), Q2 (16) WHO Technical Report Series, No. 953, Annex 2 (19).\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda la estabilidad de los Ingredientes Farmac\u00e9uticos Activos (API) y establece directrices para la realizaci\u00f3n de estudios de estabilidad. Se enfatiza la importancia de un programa continuo de monitoreo de estabilidad que permita detectar problemas de estabilidad, como cambios en los niveles de productos de degradaci\u00f3n. Se requiere que al menos un lote de producci\u00f3n por a\u00f1o se incluya en el programa de monitoreo y se realicen pruebas anuales para confirmar la estabilidad. Adem\u00e1s, se deben presentar los resultados de los estudios de estabilidad en formatos apropiados y proporcionar datos num\u00e9ricos concretos en lugar de declaraciones vagas.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de compromiso se requiere en el dossier para los estudios de estabilidad en los API?**\n   - Se requiere un compromiso escrito, firmado y fechado, que indique la intenci\u00f3n de llevar a cabo estudios de estabilidad continuos.\n\n2. **\u00bfCu\u00e1les son las condiciones de almacenamiento recomendadas para los estudios de estabilidad de los API?**\n   - Se deben utilizar condiciones de almacenamiento estandarizadas para pruebas a largo plazo, tal como se describe en las directrices y que sean consistentes con el etiquetado del API.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en el dossier respecto a los resultados de los estudios de estabilidad?**\n   - El dossier debe incluir los resultados reales de estabilidad que apoyen el per\u00edodo de rean\u00e1lisis propuesto, as\u00ed como informaci\u00f3n sobre los procedimientos anal\u00edticos utilizados y la validaci\u00f3n de estos procedimientos. Adem\u00e1s, se deben proporcionar resultados num\u00e9ricos concretos para pruebas cuantitativas, evitando declaraciones vagas como \"dentro de los l\u00edmites\".", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Estabilidad de Principios Activos (APIs):** Se enfatiza la importancia de establecer per\u00edodos de rean\u00e1lisis y vida \u00fatil para APIs, especialmente aquellos que son labiles, como ciertos antibi\u00f3ticos.\n2. **Extrapolaci\u00f3n de Datos de Estabilidad:** Se permite la extrapolaci\u00f3n de datos de estabilidad a largo plazo para extender el per\u00edodo de rean\u00e1lisis bajo condiciones espec\u00edficas, como la ausencia de cambios significativos en un per\u00edodo de 6 meses bajo condiciones aceleradas.\n3. **Compromiso de Estabilidad Post-Aprobaci\u00f3n:** Se requiere un compromiso escrito para continuar los estudios de estabilidad si los datos disponibles no cubren el per\u00edodo de rean\u00e1lisis propuesto.\n4. **Protocolo de Estabilidad para Lotes de Compromiso:** Se deben incluir par\u00e1metros espec\u00edficos en el protocolo de estabilidad, como m\u00e9todos de prueba, criterios de aceptaci\u00f3n y descripci\u00f3n del sistema de cierre del envase.\n\n**Entidades:**\n- **Organizaci\u00f3n:** WHO (Organizaci\u00f3n Mundial de la Salud)\n- **Documentos de Referencia:** ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series No. 953\n- **Tipos de Estudios:** Estudios de estabilidad a largo plazo, estudios de estabilidad de compromiso\n- **Par\u00e1metros de Estudio:** M\u00e9todos de prueba f\u00edsicos, qu\u00edmicos, microbiol\u00f3gicos y biol\u00f3gicos, criterios de aceptaci\u00f3n, descripci\u00f3n del sistema de cierre del envase.\n\nEste resumen destaca la importancia de la estabilidad en la industria farmac\u00e9utica y los requisitos necesarios para garantizar la calidad y seguridad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: stability studies, active pharmaceutical ingredients, monitoring program, degradation products, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7aa740e2-5d6a-469e-850e-6fc60c1c6e3e", "node_type": "4", "metadata": {"page_label": "171", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "\n- testing frequency;\n- description of the conditions of storage (standardized conditions for long-term testing as described in these guidelines and consistent with the API labelling, should be used);\n- other applicable parameters specific to the API.\n\n### Ongoing stability studies\n\nThe stability of the API should be monitored according to a continuous and appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of degradation products). The purpose of the ongoing stability programme is to monitor the API and to determine that the API remains stable and can be expected to remain stable within the retest period in all future batches.\n\nAt least one production batch per year of API (unless none is produced during that year) should be added to the stability monitoring programme and tested at least annually to confirm the stability. In certain situations, additional batches should be included. A written commitment (signed and dated) to ongoing stability studies should be included in the dossier.\n\nRefer to section 2.1.11 of WHO Technical Report Series, No. 953, Annex 2 (19), for further information on ongoing stability studies.\n\nAny differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), WHO Technical Report Series, No. 953, Annex 2 (19).\n\n#### 3.2.S.7.3 Stability data (name, manufacturer)\n\nResults of the stability studies (e.g. forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included.\n\nThe actual stability results used to support the proposed retest period should be included in the dossier. For quantitative tests (e.g. individual and total degradation product tests and assay tests) it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), Q2 (16) WHO Technical Report Series, No. 953, Annex 2 (19).\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "9d01fbeb7b9c6386847a2093ff321a3d4c66d8e900ba2b9780f27021407de810", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "- testing frequency;\n- description of the conditions of storage (standardized conditions for long-term testing as described in these guidelines and consistent with the API labelling, should be used);\n- other applicable parameters specific to the API.\n\n### Ongoing stability studies\n\nThe stability of the API should be monitored according to a continuous and appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of degradation products). The purpose of the ongoing stability programme is to monitor the API and to determine that the API remains stable and can be expected to remain stable within the retest period in all future batches.\n\nAt least one production batch per year of API (unless none is produced during that year) should be added to the stability monitoring programme and tested at least annually to confirm the stability. In certain situations, additional batches should be included. A written commitment (signed and dated) to ongoing stability studies should be included in the dossier.\n\nRefer to section 2.1.11 of WHO Technical Report Series, No. 953, Annex 2 (19), for further information on ongoing stability studies.\n\nAny differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), WHO Technical Report Series, No. 953, Annex 2 (19).\n\n#### 3.2.S.7.3 Stability data (name, manufacturer)\n\nResults of the stability studies (e.g. forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included.\n\nThe actual stability results used to support the proposed retest period should be included in the dossier. For quantitative tests (e.g. individual and total degradation product tests and assay tests) it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), Q2 (16) WHO Technical Report Series, No. 953, Annex 2 (19).", "mimetype": "text/plain", "start_char_idx": 1, "end_char_idx": 2289, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f99bbfde-dca2-44b2-a202-2cba182ed572": {"__data__": {"id_": "f99bbfde-dca2-44b2-a202-2cba182ed572", "embedding": null, "metadata": {"page_label": "172", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P Drug product (or finished pharmaceutical product (FPP))\n\n## 3.2.P.1 Description and composition of the FPP (name, dosage form)\n\nA description of the FPP and its composition should be provided. The information provided should include, for example:\n\n- **Description of the dosage form**\n\n  The description of the FPP should include the physical description, available strengths, release mechanism (e.g. immediate or modified (delayed or extended)), as well as any other distinguishable characteristics, e.g.\n\n  \u201cThe proposed XYZ 50-mg tablets are available as white, oval, film-coated tablets, debossed with \u201850\u2019 on one side and a break-line on the other side.\n\n  The proposed XYZ 100-mg tablets are available as yellow, round, film-coated tablets, debossed with \u2018100\u2019 on one side and plain on the other side.\u201d\n\n- **Composition, i.e. list of all components of the dosage form, and their amount on a per unit basis (including overages, if any), the function of the components, and a reference to their quality standards (e.g. compendial monographs or manufacturer\u2019s specifications).**\n\n  The tables in the QOS-PD template should be used to summarize the composition of the FPP and express the quantity of each component on a per unit basis (e.g. mg per tablet, mg per ml, mg per vial) and a percentage basis, including a statement of the total weight or measure of the dosage unit. The individual components for mixtures prepared in-house (e.g. coatings) should be included in the tables where applicable.\n\n  All components used in the manufacturing process should be listed, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g. \u201c1 mg of active ingredient base = 1.075 mg active ingredient hydrochloride\u201d). All overages should be clearly indicated (e.g. \u201ccontains 2% overage of the API to compensate for manufacturing losses\u201d).\n\n  The components should be declared by their proper or common names, quality standards (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and, if applicable, their grades (e.g. \u201cmicrocrystalline cellulose NF (PH 102)\u201d) and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Informe T\u00e9cnico 970) detalla los requisitos para la descripci\u00f3n y composici\u00f3n de un producto farmac\u00e9utico terminado (FPP). Se enfatiza la importancia de proporcionar una descripci\u00f3n clara de la forma de dosificaci\u00f3n, incluyendo caracter\u00edsticas f\u00edsicas, mecanismos de liberaci\u00f3n y una lista exhaustiva de todos los componentes, sus cantidades, funciones y est\u00e1ndares de calidad. Tambi\u00e9n se menciona la necesidad de incluir informaci\u00f3n sobre los ingredientes activos y cualquier sobrecarga en la formulaci\u00f3n.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 informaci\u00f3n espec\u00edfica debe incluirse en la descripci\u00f3n de la forma de dosificaci\u00f3n de un FPP seg\u00fan el documento de la OMS?**\n   - Esta pregunta busca detalles sobre los elementos que deben ser descritos, como caracter\u00edsticas f\u00edsicas y mecanismos de liberaci\u00f3n, que no se encuentran f\u00e1cilmente en otros documentos.\n\n2. **\u00bfC\u00f3mo se deben presentar las cantidades de los componentes en la composici\u00f3n de un FPP y qu\u00e9 est\u00e1ndares de calidad se deben referenciar?**\n   - Esta pregunta se centra en la forma de presentar la informaci\u00f3n sobre los componentes y los est\u00e1ndares de calidad, lo cual es crucial para la regulaci\u00f3n y no siempre est\u00e1 claramente definido en otras fuentes.\n\n3. **\u00bfQu\u00e9 tipo de componentes deben ser listados en el proceso de fabricaci\u00f3n de un FPP, incluyendo aquellos que no se a\u00f1aden a cada lote?**\n   - Esta pregunta aborda la exhaustividad en la lista de componentes, incluyendo aquellos que pueden ser eliminados durante el proceso, lo que es un aspecto t\u00e9cnico que puede no estar ampliamente cubierto en otros documentos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Estudios de Estabilidad de API:**\n   - Importancia de un programa continuo de monitoreo de estabilidad para detectar problemas, como cambios en los niveles de productos de degradaci\u00f3n.\n   - Se requiere incluir al menos un lote de producci\u00f3n por a\u00f1o en el programa de monitoreo y realizar pruebas anuales.\n\n2. **Compromiso Escrito:**\n   - Es necesario un compromiso escrito, firmado y fechado en el dossier que indique la intenci\u00f3n de llevar a cabo estudios de estabilidad continuos.\n\n3. **Condiciones de Almacenamiento:**\n   - Deben utilizarse condiciones de almacenamiento estandarizadas para pruebas a largo plazo, alineadas con el etiquetado del API.\n\n4. **Presentaci\u00f3n de Resultados:**\n   - Los resultados de los estudios de estabilidad deben presentarse en formatos apropiados (tabular, gr\u00e1fico, narrativo) y deben incluir informaci\u00f3n sobre los procedimientos anal\u00edticos utilizados y su validaci\u00f3n.\n   - Se deben proporcionar resultados num\u00e9ricos concretos para pruebas cuantitativas, evitando declaraciones vagas.\n\n5. **Justificaci\u00f3n Cient\u00edfica:**\n   - Cualquier diferencia entre los protocolos de estabilidad de los lotes primarios y los lotes de compromiso o en curso debe estar cient\u00edficamente justificada.\n\n**Entidades:**\n\n- **API (Ingrediente Farmac\u00e9utico Activo):** Sustancia cuyo comportamiento de estabilidad se est\u00e1 evaluando.\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Entidad que proporciona las directrices y recomendaciones sobre estudios de estabilidad.\n- **ICH (International Council for Harmonisation):** Referencias documentales que gu\u00edan los estudios de estabilidad (Q1A, Q1B, Q1D, Q1E, Q2).\n- **Dossier:** Documento que debe incluir el compromiso escrito y los resultados de los estudios de estabilidad.\n\nEste resumen destaca la importancia de un enfoque sistem\u00e1tico y documentado para garantizar la estabilidad de los API a lo largo del tiempo, as\u00ed como la necesidad de cumplir con las normativas establecidas por organismos reguladores.", "excerpt_keywords": "Keywords: pharmaceutical product, dosage form, composition, quality standards, active ingredient"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "11f43e55-882d-4fe6-9a4f-7b0d676347a9", "node_type": "4", "metadata": {"page_label": "172", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P Drug product (or finished pharmaceutical product (FPP))\n\n## 3.2.P.1 Description and composition of the FPP (name, dosage form)\n\nA description of the FPP and its composition should be provided. The information provided should include, for example:\n\n- **Description of the dosage form**\n\n  The description of the FPP should include the physical description, available strengths, release mechanism (e.g. immediate or modified (delayed or extended)), as well as any other distinguishable characteristics, e.g.\n\n  \u201cThe proposed XYZ 50-mg tablets are available as white, oval, film-coated tablets, debossed with \u201850\u2019 on one side and a break-line on the other side.\n\n  The proposed XYZ 100-mg tablets are available as yellow, round, film-coated tablets, debossed with \u2018100\u2019 on one side and plain on the other side.\u201d\n\n- **Composition, i.e. list of all components of the dosage form, and their amount on a per unit basis (including overages, if any), the function of the components, and a reference to their quality standards (e.g. compendial monographs or manufacturer\u2019s specifications).**\n\n  The tables in the QOS-PD template should be used to summarize the composition of the FPP and express the quantity of each component on a per unit basis (e.g. mg per tablet, mg per ml, mg per vial) and a percentage basis, including a statement of the total weight or measure of the dosage unit. The individual components for mixtures prepared in-house (e.g. coatings) should be included in the tables where applicable.\n\n  All components used in the manufacturing process should be listed, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g. \u201c1 mg of active ingredient base = 1.075 mg active ingredient hydrochloride\u201d). All overages should be clearly indicated (e.g. \u201ccontains 2% overage of the API to compensate for manufacturing losses\u201d).\n\n  The components should be declared by their proper or common names, quality standards (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and, if applicable, their grades (e.g. \u201cmicrocrystalline cellulose NF (PH 102)\u201d) and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4ecd3f94533270a6e7049787240e9b80a0b7a86e2ada2caa50b3311c530a4b13", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.P Drug product (or finished pharmaceutical product (FPP))\n\n## 3.2.P.1 Description and composition of the FPP (name, dosage form)\n\nA description of the FPP and its composition should be provided. The information provided should include, for example:\n\n- **Description of the dosage form**\n\n  The description of the FPP should include the physical description, available strengths, release mechanism (e.g. immediate or modified (delayed or extended)), as well as any other distinguishable characteristics, e.g.\n\n  \u201cThe proposed XYZ 50-mg tablets are available as white, oval, film-coated tablets, debossed with \u201850\u2019 on one side and a break-line on the other side.\n\n  The proposed XYZ 100-mg tablets are available as yellow, round, film-coated tablets, debossed with \u2018100\u2019 on one side and plain on the other side.\u201d\n\n- **Composition, i.e. list of all components of the dosage form, and their amount on a per unit basis (including overages, if any), the function of the components, and a reference to their quality standards (e.g. compendial monographs or manufacturer\u2019s specifications).**\n\n  The tables in the QOS-PD template should be used to summarize the composition of the FPP and express the quantity of each component on a per unit basis (e.g. mg per tablet, mg per ml, mg per vial) and a percentage basis, including a statement of the total weight or measure of the dosage unit. The individual components for mixtures prepared in-house (e.g. coatings) should be included in the tables where applicable.\n\n  All components used in the manufacturing process should be listed, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g. \u201c1 mg of active ingredient base = 1.075 mg active ingredient hydrochloride\u201d). All overages should be clearly indicated (e.g. \u201ccontains 2% overage of the API to compensate for manufacturing losses\u201d).\n\n  The components should be declared by their proper or common names, quality standards (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and, if applicable, their grades (e.g. \u201cmicrocrystalline cellulose NF (PH 102)\u201d) and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2415, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "14f5a5ba-2770-425a-9b24-2ecce8a8cb44": {"__data__": {"id_": "14f5a5ba-2770-425a-9b24-2ecce8a8cb44", "embedding": null, "metadata": {"page_label": "173", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The function of each component (e.g. diluent or filler, binder, disintegrant, lubricant, glidant, granulating solvent, coating agent or antimicrobial preservative) should be stated. If an excipient performs multiple functions the predominant function should be indicated. The qualitative composition, including solvents, should be provided for all proprietary components or blends (e.g. capsule shells, colouring blends or imprinting inks). This information (excluding the solvents) is to be listed in the product information (e.g. summary of product characteristics, labelling and package leaflet).\n\n- **Description of accompanying reconstitution diluent(s)**  \n  For FPPs supplied with reconstitution diluent(s) that are commercially available or that have been assessed and considered acceptable in connection with another PD with the WHO Prequalification of Medicines Programme, a brief description of the reconstitution diluents(s) should be provided.  \n  For FPPs supplied with reconstitution diluent(s) that are not commercially available or have not been assessed and considered acceptable in connection with another PD with the WHO Prequalification of Medicines Programme, information on the diluent(s) should be provided in a separate FPP portion (\u201c3.2.P\u201d), as appropriate.\n\n- **Type of container and closure used for the dosage form and accompanying reconstitution diluent, if applicable**  \n  The container-closure used for the FPP (and accompanying reconstitution diluent, if applicable) should be briefly described, with further details provided under 3.2.P.7 Container-closure system, e.g.\n\n  > \u201cThe product is available in HDPE bottles with polypropylene caps (in sizes of 100s, 500s and 1000s) and in PVC/aluminium foil unit dose blisters (in packages of 100s) (cards of 5 \u00d7 2, 10 cards per package).\u201d\n\nReference documents: ICH Q6A (6).\n\n### 3.2.P.2 Pharmaceutical development (name, dosage form)\n\nThe Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfQu\u00e9 informaci\u00f3n se debe incluir sobre los excipientes en la documentaci\u00f3n del producto?**\n   - La documentaci\u00f3n del producto debe incluir la funci\u00f3n de cada componente (como diluyentes, aglutinantes, desintegrantes, etc.), indicando la funci\u00f3n predominante si un excipiente cumple m\u00faltiples funciones. Adem\u00e1s, se debe proporcionar la composici\u00f3n cualitativa, incluyendo los disolventes, para todos los componentes o mezclas propietarias, excluyendo los disolventes, que deben ser listados en la informaci\u00f3n del producto.\n\n2. **\u00bfC\u00f3mo se debe abordar la descripci\u00f3n de los diluyentes de reconstituci\u00f3n para los productos farmac\u00e9uticos?**\n   - Para los productos farmac\u00e9uticos que se suministran con diluyentes de reconstituci\u00f3n que son comercialmente disponibles o que han sido evaluados y considerados aceptables por el Programa de Precalificaci\u00f3n de Medicamentos de la OMS, se debe proporcionar una breve descripci\u00f3n de estos diluyentes. Si los diluyentes no son comercialmente disponibles o no han sido evaluados, la informaci\u00f3n debe ser proporcionada en una secci\u00f3n separada del producto farmac\u00e9utico.\n\n3. **\u00bfQu\u00e9 detalles se deben incluir sobre el sistema de envase y cierre del producto farmac\u00e9utico?**\n   - Se debe proporcionar una breve descripci\u00f3n del sistema de envase y cierre utilizado para el producto farmac\u00e9utico y, si es aplicable, para el diluyente de reconstituci\u00f3n. Los detalles adicionales deben ser incluidos en la secci\u00f3n 3.2.P.7 del sistema de envase y cierre, como el tipo de materiales utilizados y las presentaciones disponibles.\n\n### Resumen de nivel superior del contexto:\nEl contexto se centra en los requisitos de documentaci\u00f3n para productos farmac\u00e9uticos, espec\u00edficamente en la secci\u00f3n de desarrollo farmac\u00e9utico. Se enfatiza la necesidad de detallar la funci\u00f3n de los excipientes, la descripci\u00f3n de los diluyentes de reconstituci\u00f3n y la informaci\u00f3n sobre el sistema de envase y cierre. Adem\u00e1s, se menciona que la informaci\u00f3n debe ser clara y diferenciada de las pruebas de control rutinarias.", "prev_section_summary": "### Temas Clave:\n\n1. **Descripci\u00f3n del Producto Farmac\u00e9utico Terminado (FPP)**:\n   - Importancia de proporcionar una descripci\u00f3n clara de la forma de dosificaci\u00f3n.\n   - Caracter\u00edsticas f\u00edsicas, mecanismos de liberaci\u00f3n y distinciones del producto.\n\n2. **Composici\u00f3n del FPP**:\n   - Listado exhaustivo de todos los componentes, sus cantidades y funciones.\n   - Referencias a est\u00e1ndares de calidad (monograf\u00edas compendiales o especificaciones del fabricante).\n\n3. **Presentaci\u00f3n de la Informaci\u00f3n**:\n   - Uso de tablas en el formato QOS-PD para resumir la composici\u00f3n.\n   - Expresi\u00f3n de cantidades en base por unidad y porcentaje, incluyendo el peso total de la unidad de dosificaci\u00f3n.\n\n4. **Componentes en el Proceso de Fabricaci\u00f3n**:\n   - Inclusi\u00f3n de todos los componentes, incluso aquellos que no se a\u00f1aden a cada lote o que pueden ser eliminados durante el proceso.\n   - Declaraci\u00f3n de ingredientes activos y sobrecargas en la formulaci\u00f3n.\n\n5. **Nomenclatura y Est\u00e1ndares**:\n   - Declaraci\u00f3n de componentes por sus nombres comunes o adecuados, est\u00e1ndares de calidad y caracter\u00edsticas t\u00e9cnicas especiales.\n\n### Entidades:\n\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que se presenta al consumidor.\n- **Componentes**: Ingredientes que forman parte de la formulaci\u00f3n del FPP.\n- **Est\u00e1ndares de Calidad**: Referencias como BP (British Pharmacopoeia), JP (Japanese Pharmacopoeia), Ph.Eur. (European Pharmacopoeia), USP (United States Pharmacopeia).\n- **Mecanismos de Liberaci\u00f3n**: M\u00e9todos de liberaci\u00f3n del f\u00e1rmaco (inmediata, modificada).\n- **Sobrecargas**: Cantidades adicionales de ingredientes activos para compensar p\u00e9rdidas durante la fabricaci\u00f3n. \n\nEste resumen destaca la importancia de la claridad y la exhaustividad en la descripci\u00f3n y composici\u00f3n de los productos farmac\u00e9uticos, as\u00ed como la necesidad de adherirse a est\u00e1ndares de calidad reconocidos.", "excerpt_keywords": "Keywords: excipients, reconstitution diluents, container-closure system, pharmaceutical development, product information"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5c57fddf-b693-4e96-8b0f-8315567d8c61", "node_type": "4", "metadata": {"page_label": "173", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The function of each component (e.g. diluent or filler, binder, disintegrant, lubricant, glidant, granulating solvent, coating agent or antimicrobial preservative) should be stated. If an excipient performs multiple functions the predominant function should be indicated. The qualitative composition, including solvents, should be provided for all proprietary components or blends (e.g. capsule shells, colouring blends or imprinting inks). This information (excluding the solvents) is to be listed in the product information (e.g. summary of product characteristics, labelling and package leaflet).\n\n- **Description of accompanying reconstitution diluent(s)**  \n  For FPPs supplied with reconstitution diluent(s) that are commercially available or that have been assessed and considered acceptable in connection with another PD with the WHO Prequalification of Medicines Programme, a brief description of the reconstitution diluents(s) should be provided.  \n  For FPPs supplied with reconstitution diluent(s) that are not commercially available or have not been assessed and considered acceptable in connection with another PD with the WHO Prequalification of Medicines Programme, information on the diluent(s) should be provided in a separate FPP portion (\u201c3.2.P\u201d), as appropriate.\n\n- **Type of container and closure used for the dosage form and accompanying reconstitution diluent, if applicable**  \n  The container-closure used for the FPP (and accompanying reconstitution diluent, if applicable) should be briefly described, with further details provided under 3.2.P.7 Container-closure system, e.g.\n\n  > \u201cThe product is available in HDPE bottles with polypropylene caps (in sizes of 100s, 500s and 1000s) and in PVC/aluminium foil unit dose blisters (in packages of 100s) (cards of 5 \u00d7 2, 10 cards per package).\u201d\n\nReference documents: ICH Q6A (6).\n\n### 3.2.P.2 Pharmaceutical development (name, dosage form)\n\nThe Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "8a7d5956065ffeb00253d959699d68ee2a6e06928c03a2480fa4c1131d03c61e", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "The function of each component (e.g. diluent or filler, binder, disintegrant, lubricant, glidant, granulating solvent, coating agent or antimicrobial preservative) should be stated. If an excipient performs multiple functions the predominant function should be indicated. The qualitative composition, including solvents, should be provided for all proprietary components or blends (e.g. capsule shells, colouring blends or imprinting inks). This information (excluding the solvents) is to be listed in the product information (e.g. summary of product characteristics, labelling and package leaflet).\n\n- **Description of accompanying reconstitution diluent(s)**  \n  For FPPs supplied with reconstitution diluent(s) that are commercially available or that have been assessed and considered acceptable in connection with another PD with the WHO Prequalification of Medicines Programme, a brief description of the reconstitution diluents(s) should be provided.  \n  For FPPs supplied with reconstitution diluent(s) that are not commercially available or have not been assessed and considered acceptable in connection with another PD with the WHO Prequalification of Medicines Programme, information on the diluent(s) should be provided in a separate FPP portion (\u201c3.2.P\u201d), as appropriate.\n\n- **Type of container and closure used for the dosage form and accompanying reconstitution diluent, if applicable**  \n  The container-closure used for the FPP (and accompanying reconstitution diluent, if applicable) should be briefly described, with further details provided under 3.2.P.7 Container-closure system, e.g.\n\n  > \u201cThe product is available in HDPE bottles with polypropylene caps (in sizes of 100s, 500s and 1000s) and in PVC/aluminium foil unit dose blisters (in packages of 100s) (cards of 5 \u00d7 2, 10 cards per package).\u201d\n\nReference documents: ICH Q6A (6).\n\n### 3.2.P.2 Pharmaceutical development (name, dosage form)\n\nThe Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2364, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "f1ecf961-ed33-4226-b8d8-1c7a5a82da7c": {"__data__": {"id_": "f1ecf961-ed33-4226-b8d8-1c7a5a82da7c", "embedding": null, "metadata": {"page_label": "174", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsection should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier.\n\nPharmaceutical development information should include, at a minimum:\n\n- the definition of the quality target product profile (QTPP) as it relates to quality, safety and efficacy, considering, for example, the route of administration, dosage form, bioavailability, strength and stability;\n- identification of the potential critical quality attributes (CQAs) of the FPP so as to adequately control the product characteristics that could have an impact on quality;\n- discussion of the potential CQAs of the API(s), excipients and container-closure system(s) including the selection of the type, grade and amount to deliver drug product of the desired quality;\n- discussion of the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner.\n\nThese features should be discussed as part of the product development using the principles of risk management over the entire life-cycle of the product (ICH Q8) (25).\n\nFor a discussion of additional pharmaceutical development issues specific to the development of FDCs reference should be made to section 6.3.2 of WHO Technical Report Series, No. 929, Annex 5 (21).\n\nReference documents: ICH Q6A (6), Q8 (25), Q9 (26), Q10 (27).\n\n## 3.2.P.2.1 Components of the FPP (name, dosage form)\n\n### 3.2.P.2.1.1 Active pharmaceutical ingredient (name, dosage form)\n\nThe compatibility of the API with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (e.g. water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For FDCs, the compatibility of APIs with each other should be discussed.\n\nPhysicochemical characteristics of the API may influence both the manufacturing capability and the performance of the FPP.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado, junto con res\u00famenes de nivel superior que pueden ayudar a formularlas:\n\n### Resumen de nivel superior:\nEl documento de la OMS aborda la importancia del desarrollo farmac\u00e9utico, centr\u00e1ndose en la identificaci\u00f3n de atributos cr\u00edticos de calidad (CQAs) y la definici\u00f3n del perfil de calidad del producto objetivo (QTPP). Se enfatiza la necesidad de discutir la compatibilidad de los ingredientes activos (API) con excipientes y entre s\u00ed, as\u00ed como las caracter\u00edsticas fisicoqu\u00edmicas que pueden influir en la calidad y el rendimiento del producto farmac\u00e9utico final (FPP).\n\n### Preguntas:\n\n1. **\u00bfCu\u00e1les son los atributos cr\u00edticos de calidad (CQAs) que deben considerarse al desarrollar un producto farmac\u00e9utico final (FPP) y c\u00f3mo se relacionan con el perfil de calidad del producto objetivo (QTPP)?**\n   - Esta pregunta busca una respuesta espec\u00edfica sobre los CQAs y su conexi\u00f3n con el QTPP, que no se detalla en otros documentos.\n\n2. **\u00bfQu\u00e9 criterios se deben tener en cuenta al seleccionar excipientes y sistemas de cierre para asegurar la calidad del producto farmac\u00e9utico final (FPP)?**\n   - Esta pregunta se centra en la selecci\u00f3n de excipientes y sistemas de cierre, un aspecto que puede no estar ampliamente cubierto en otras fuentes.\n\n3. **\u00bfC\u00f3mo influyen las caracter\u00edsticas fisicoqu\u00edmicas del ingrediente activo (API) en la capacidad de fabricaci\u00f3n y el rendimiento del producto farmac\u00e9utico final (FPP)?**\n   - Esta pregunta busca una explicaci\u00f3n detallada sobre la relaci\u00f3n entre las propiedades fisicoqu\u00edmicas del API y su impacto en el proceso de fabricaci\u00f3n y la calidad del FPP, un tema que puede no ser tratado en profundidad en otros documentos. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y detallada que se encuentra en el contexto proporcionado, lo que puede no estar disponible en otras fuentes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Funciones de los Excipientes**:\n   - Se debe especificar la funci\u00f3n de cada componente (ej. diluyentes, aglutinantes, desintegrantes, etc.).\n   - Si un excipiente tiene m\u00faltiples funciones, se debe indicar la funci\u00f3n predominante.\n   - La composici\u00f3n cualitativa, incluyendo disolventes, debe ser proporcionada para todos los componentes o mezclas propietarias, excluyendo los disolventes que se listar\u00e1n en la informaci\u00f3n del producto.\n\n2. **Diluyentes de Reconstituci\u00f3n**:\n   - Para productos farmac\u00e9uticos (FPPs) con diluyentes comercialmente disponibles o aceptados por el Programa de Precalificaci\u00f3n de Medicamentos de la OMS, se debe incluir una breve descripci\u00f3n.\n   - Para diluyentes no disponibles comercialmente o no evaluados, la informaci\u00f3n debe ser presentada en una secci\u00f3n separada del producto.\n\n3. **Sistema de Envase y Cierre**:\n   - Se debe proporcionar una breve descripci\u00f3n del sistema de envase y cierre utilizado para el FPP y, si aplica, para el diluyente de reconstituci\u00f3n.\n   - Detalles adicionales deben ser incluidos en la secci\u00f3n 3.2.P.7, como el tipo de materiales y las presentaciones disponibles.\n\n4. **Desarrollo Farmac\u00e9utico**:\n   - La secci\u00f3n de desarrollo farmac\u00e9utico debe incluir informaci\u00f3n sobre los estudios de desarrollo realizados para establecer la idoneidad de la forma de dosificaci\u00f3n, formulaci\u00f3n, proceso de fabricaci\u00f3n, sistema de envase y cierre, atributos microbiol\u00f3gicos e instrucciones de uso.\n   - Se distingue entre estos estudios y las pruebas de control rutinarias.\n\n### Entidades Clave:\n- **Componentes**: Diluyentes, aglutinantes, desintegrantes, lubricantes, glidantes, disolventes, agentes de recubrimiento, conservantes antimicrobianos.\n- **Documentos de referencia**: ICH Q6A.\n- **Secciones del documento**: 3.2.P (desarrollo farmac\u00e9utico), 3.2.P.7 (sistema de envase y cierre).\n- **Programas**: Programa de Precalificaci\u00f3n de Medicamentos de la OMS. \n\nEste resumen destaca los requisitos de documentaci\u00f3n y desarrollo para productos farmac\u00e9uticos, enfatizando la importancia de la claridad y la especificidad en la informaci\u00f3n presentada.", "excerpt_keywords": "Keywords: pharmaceutical development, quality target product profile, critical quality attributes, active pharmaceutical ingredient, formulation compatibility"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a3d566a4-1a97-4548-8566-a03f0244829c", "node_type": "4", "metadata": {"page_label": "174", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsection should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier.\n\nPharmaceutical development information should include, at a minimum:\n\n- the definition of the quality target product profile (QTPP) as it relates to quality, safety and efficacy, considering, for example, the route of administration, dosage form, bioavailability, strength and stability;\n- identification of the potential critical quality attributes (CQAs) of the FPP so as to adequately control the product characteristics that could have an impact on quality;\n- discussion of the potential CQAs of the API(s), excipients and container-closure system(s) including the selection of the type, grade and amount to deliver drug product of the desired quality;\n- discussion of the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner.\n\nThese features should be discussed as part of the product development using the principles of risk management over the entire life-cycle of the product (ICH Q8) (25).\n\nFor a discussion of additional pharmaceutical development issues specific to the development of FDCs reference should be made to section 6.3.2 of WHO Technical Report Series, No. 929, Annex 5 (21).\n\nReference documents: ICH Q6A (6), Q8 (25), Q9 (26), Q10 (27).\n\n## 3.2.P.2.1 Components of the FPP (name, dosage form)\n\n### 3.2.P.2.1.1 Active pharmaceutical ingredient (name, dosage form)\n\nThe compatibility of the API with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (e.g. water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For FDCs, the compatibility of APIs with each other should be discussed.\n\nPhysicochemical characteristics of the API may influence both the manufacturing capability and the performance of the FPP.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "d64ff381678a821545413846c0c5dbd9897b9e175da7ae41e564b46bf59f6984", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsection should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier.\n\nPharmaceutical development information should include, at a minimum:\n\n- the definition of the quality target product profile (QTPP) as it relates to quality, safety and efficacy, considering, for example, the route of administration, dosage form, bioavailability, strength and stability;\n- identification of the potential critical quality attributes (CQAs) of the FPP so as to adequately control the product characteristics that could have an impact on quality;\n- discussion of the potential CQAs of the API(s), excipients and container-closure system(s) including the selection of the type, grade and amount to deliver drug product of the desired quality;\n- discussion of the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner.\n\nThese features should be discussed as part of the product development using the principles of risk management over the entire life-cycle of the product (ICH Q8) (25).\n\nFor a discussion of additional pharmaceutical development issues specific to the development of FDCs reference should be made to section 6.3.2 of WHO Technical Report Series, No. 929, Annex 5 (21).\n\nReference documents: ICH Q6A (6), Q8 (25), Q9 (26), Q10 (27).\n\n## 3.2.P.2.1 Components of the FPP (name, dosage form)\n\n### 3.2.P.2.1.1 Active pharmaceutical ingredient (name, dosage form)\n\nThe compatibility of the API with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (e.g. water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For FDCs, the compatibility of APIs with each other should be discussed.\n\nPhysicochemical characteristics of the API may influence both the manufacturing capability and the performance of the FPP.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2413, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "30a1926c-d0f0-4d28-9a74-711e500ec560": {"__data__": {"id_": "30a1926c-d0f0-4d28-9a74-711e500ec560", "embedding": null, "metadata": {"page_label": "175", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Guidance on Compatibility Studies\n\nGuidance on compatibility studies is provided in Appendix 3 of the WHO *Guidelines for registration of fixed-dose combination medicinal products* (WHO Technical Report Series, No. 929, Annex 5, 2005) (21). In addition to visual examination, chromatographic results (assay, purity) are required to demonstrate API\u2013API and API\u2013excipient compatibility. In general, API\u2013excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product.\n\n## 3.2.P.2.1.2 Excipients (name, dosage form)\n\n**The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions.**\n\nWhen choosing excipients those with a compendial monograph are generally preferred and may be required in certain jurisdictions. Other resources are available for information on acceptable excipients and their concentrations, such as the US Food and Drug Administration (FDA) inactive ingredient guide (IIG) list (28) and the *Handbook of pharmaceutical excipients* (29). Use of excipients in concentrations outside established ranges is discouraged and generally requires justification (30). In addition, available guidelines should be referenced which discuss particular excipients to be avoided, for example azo-colourants as listed in the EMA Guideline CPMP/463/00 (31). Other guidance such as the WHO *Guidelines on development of paediatric medicines: points to consider in formulation* (32) may provide useful general guidance in this regard.\n\nRanges in concentrations or alternatives for excipients are normally not accepted unless supported by appropriate process validation data. Where relevant, compatibility study results (e.g. on compatibility of a primary or secondary amine API with lactose) should be included to justify the choice of excipients. Specific details should be provided where necessary (e.g. on use of potato or corn starch).\n\nWhere antioxidants are included in the formulation, the effectiveness of the proposed concentration of the antioxidant should be justified and verified by appropriate studies.\n\nAntimicrobial preservatives are discussed in 3.2.P.2.5.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior del contenido:\n\n### Resumen de Nivel Superior\nEl documento de la OMS proporciona directrices sobre estudios de compatibilidad para productos farmac\u00e9uticos de combinaci\u00f3n de dosis fijas. Se enfatiza la importancia de demostrar la compatibilidad entre el principio activo (API) y los excipientes mediante resultados cromatogr\u00e1ficos y estudios de compatibilidad. Se recomienda el uso de excipientes con monograf\u00eda compendial y se desaconseja el uso de concentraciones fuera de los rangos establecidos sin justificaci\u00f3n adecuada. Tambi\u00e9n se menciona la necesidad de justificar la efectividad de antioxidantes y se hace referencia a la discusi\u00f3n sobre conservantes antimicrobianos.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de resultados cromatogr\u00e1ficos son necesarios para demostrar la compatibilidad entre el API y los excipientes?**\n   - El documento menciona que se requieren resultados de cromatograf\u00eda relacionados con el ensayo y la pureza para demostrar la compatibilidad entre el API y los excipientes.\n\n2. **\u00bfCu\u00e1les son las recomendaciones sobre el uso de excipientes que no tienen una monograf\u00eda compendial?**\n   - Se sugiere que se prefieran excipientes con una monograf\u00eda compendial y que se utilicen recursos como la gu\u00eda de ingredientes inactivos de la FDA para obtener informaci\u00f3n sobre excipientes aceptables. El uso de excipientes en concentraciones fuera de los rangos establecidos generalmente requiere justificaci\u00f3n.\n\n3. **\u00bfQu\u00e9 se debe considerar al incluir antioxidantes en la formulaci\u00f3n de un producto farmac\u00e9utico?**\n   - La efectividad de la concentraci\u00f3n propuesta de antioxidante debe ser justificada y verificada mediante estudios apropiados, seg\u00fan lo indicado en las directrices.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS se centra en el desarrollo farmac\u00e9utico, destacando la importancia de identificar y describir los atributos cr\u00edticos de calidad (CQAs) y el perfil de calidad del producto objetivo (QTPP) para asegurar la calidad, seguridad y eficacia de los productos farmac\u00e9uticos finales (FPP). A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n1. **Desarrollo Farmac\u00e9utico**:\n   - Importancia de identificar atributos cr\u00edticos de calidad (CQAs) y definir el perfil de calidad del producto objetivo (QTPP).\n   - Necesidad de datos de apoyo y resultados de estudios espec\u00edficos para respaldar el desarrollo farmac\u00e9utico.\n\n2. **Perfil de Calidad del Producto Objetivo (QTPP)**:\n   - Definici\u00f3n relacionada con la calidad, seguridad y eficacia, considerando factores como la v\u00eda de administraci\u00f3n, forma de dosificaci\u00f3n, biodisponibilidad, potencia y estabilidad.\n\n3. **Atributos Cr\u00edticos de Calidad (CQAs)**:\n   - Identificaci\u00f3n de CQAs del FPP para controlar caracter\u00edsticas del producto que impactan en la calidad.\n   - Discusi\u00f3n sobre los CQAs de los ingredientes activos (API), excipientes y sistemas de cierre.\n\n4. **Selecci\u00f3n de Excipientes y Sistemas de Cierre**:\n   - Criterios para seleccionar el tipo, grado y cantidad de excipientes y sistemas de cierre que aseguren la calidad del FPP.\n\n5. **Proceso de Fabricaci\u00f3n**:\n   - Selecci\u00f3n de criterios para el proceso de fabricaci\u00f3n y la estrategia de control necesaria para producir lotes comerciales que cumplan consistentemente con el QTPP.\n\n6. **Caracter\u00edsticas Fisicoqu\u00edmicas del API**:\n   - Discusi\u00f3n sobre la compatibilidad del API con excipientes y entre s\u00ed, as\u00ed como las caracter\u00edsticas fisicoqu\u00edmicas (contenido de agua, solubilidad, distribuci\u00f3n del tama\u00f1o de part\u00edculas, forma polim\u00f3rfica o estado s\u00f3lido) que pueden influir en el rendimiento del FPP.\n\n7. **Gesti\u00f3n de Riesgos**:\n   - Aplicaci\u00f3n de principios de gesti\u00f3n de riesgos a lo largo del ciclo de vida del producto (referencia a ICH Q8).\n\n8. **Referencias**:\n   - Documentos de referencia relevantes como ICH Q6A, Q8, Q9 y Q10.\n\nEste resumen destaca la estructura y los elementos esenciales que deben considerarse en el desarrollo de productos farmac\u00e9uticos, enfatizando la importancia de la calidad y la consistencia en la fabricaci\u00f3n.", "excerpt_keywords": "Keywords: compatibility studies, excipients, fixed-dose combination, pharmaceutical formulation, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "39e58d01-15a4-40e7-8c1f-ecdd8cfcf2f2", "node_type": "4", "metadata": {"page_label": "175", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Guidance on Compatibility Studies\n\nGuidance on compatibility studies is provided in Appendix 3 of the WHO *Guidelines for registration of fixed-dose combination medicinal products* (WHO Technical Report Series, No. 929, Annex 5, 2005) (21). In addition to visual examination, chromatographic results (assay, purity) are required to demonstrate API\u2013API and API\u2013excipient compatibility. In general, API\u2013excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product.\n\n## 3.2.P.2.1.2 Excipients (name, dosage form)\n\n**The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions.**\n\nWhen choosing excipients those with a compendial monograph are generally preferred and may be required in certain jurisdictions. Other resources are available for information on acceptable excipients and their concentrations, such as the US Food and Drug Administration (FDA) inactive ingredient guide (IIG) list (28) and the *Handbook of pharmaceutical excipients* (29). Use of excipients in concentrations outside established ranges is discouraged and generally requires justification (30). In addition, available guidelines should be referenced which discuss particular excipients to be avoided, for example azo-colourants as listed in the EMA Guideline CPMP/463/00 (31). Other guidance such as the WHO *Guidelines on development of paediatric medicines: points to consider in formulation* (32) may provide useful general guidance in this regard.\n\nRanges in concentrations or alternatives for excipients are normally not accepted unless supported by appropriate process validation data. Where relevant, compatibility study results (e.g. on compatibility of a primary or secondary amine API with lactose) should be included to justify the choice of excipients. Specific details should be provided where necessary (e.g. on use of potato or corn starch).\n\nWhere antioxidants are included in the formulation, the effectiveness of the proposed concentration of the antioxidant should be justified and verified by appropriate studies.\n\nAntimicrobial preservatives are discussed in 3.2.P.2.5.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "e3def01d704a11ab89f34658a44c3b0f04dd905d885eaddb09dbd4289063c30d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Guidance on Compatibility Studies\n\nGuidance on compatibility studies is provided in Appendix 3 of the WHO *Guidelines for registration of fixed-dose combination medicinal products* (WHO Technical Report Series, No. 929, Annex 5, 2005) (21). In addition to visual examination, chromatographic results (assay, purity) are required to demonstrate API\u2013API and API\u2013excipient compatibility. In general, API\u2013excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product.\n\n## 3.2.P.2.1.2 Excipients (name, dosage form)\n\n**The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions.**\n\nWhen choosing excipients those with a compendial monograph are generally preferred and may be required in certain jurisdictions. Other resources are available for information on acceptable excipients and their concentrations, such as the US Food and Drug Administration (FDA) inactive ingredient guide (IIG) list (28) and the *Handbook of pharmaceutical excipients* (29). Use of excipients in concentrations outside established ranges is discouraged and generally requires justification (30). In addition, available guidelines should be referenced which discuss particular excipients to be avoided, for example azo-colourants as listed in the EMA Guideline CPMP/463/00 (31). Other guidance such as the WHO *Guidelines on development of paediatric medicines: points to consider in formulation* (32) may provide useful general guidance in this regard.\n\nRanges in concentrations or alternatives for excipients are normally not accepted unless supported by appropriate process validation data. Where relevant, compatibility study results (e.g. on compatibility of a primary or secondary amine API with lactose) should be included to justify the choice of excipients. Specific details should be provided where necessary (e.g. on use of potato or corn starch).\n\nWhere antioxidants are included in the formulation, the effectiveness of the proposed concentration of the antioxidant should be justified and verified by appropriate studies.\n\nAntimicrobial preservatives are discussed in 3.2.P.2.5.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2338, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "73e449f7-8f25-48f3-9d37-5a22d20e0b91": {"__data__": {"id_": "73e449f7-8f25-48f3-9d37-5a22d20e0b91", "embedding": null, "metadata": {"page_label": "176", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.2.2 Finished pharmaceutical product (name, dosage form)\n\n## 3.2.P.2.2.1 Formulation development (name, dosage form)\n\nA brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed, when appropriate.\n\nThe WHO Prequalification of Medicines Programme defines an established multisource product as one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier and QOS-PD should be completed with the exception of P.2.2.1 (a). In addition, a product quality review should be provided as outlined in Appendix 2.\n\nThe requirements for bioequivalence studies should be taken into consideration, for example, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (e.g. WHO Technical Report Series, No. 937, Annex 7) (33) should be consulted.\n\nProduct scoring may be recommended or required, for example, when scoring is indicated in the WHO Invitation for EOIs, or is specified for an invited FPP in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology.\n\nIf the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should include a description of the test method, individual values, mean and relative standard deviation (RSD) of the results. Uniformity testing (i.e. content uniformity for split portions containing less than 5 mg or less than 5% of the weight of the dosage unit portion, or mass uniformity for", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los requisitos para el desarrollo de productos farmac\u00e9uticos terminados (FPP), centr\u00e1ndose en la formulaci\u00f3n, la bioequivalencia y la calidad del producto. Se menciona la definici\u00f3n de un producto multisource establecido y se discuten las pruebas necesarias para asegurar la uniformidad de dosis en tabletas, especialmente aquellas que est\u00e1n dise\u00f1adas para ser divididas. Tambi\u00e9n se hace hincapi\u00e9 en la importancia de realizar estudios comparativos y en la consulta de documentos de referencia de la OMS.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 criterios debe cumplir un producto para ser considerado un \"producto multisource establecido\" seg\u00fan el Programa de Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Respuesta: Un producto debe haber sido comercializado por el solicitante o fabricante asociado con el dossier durante al menos cinco a\u00f1os y haber producido al menos 10 lotes de producci\u00f3n en el a\u00f1o anterior, o si se produjeron menos de 10 lotes, no menos de 25 lotes en los \u00faltimos tres a\u00f1os.\n\n2. **\u00bfQu\u00e9 tipo de estudios se deben considerar al formular m\u00faltiples fortalezas de un producto farmac\u00e9utico terminado?**\n   - Respuesta: Se deben considerar los requisitos para estudios de bioequivalencia, especialmente si el producto puede ser elegible para una exenci\u00f3n de bioequivalencia (biowaiver).\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en el documento de desarrollo del producto (PD) para un comprimido funcionalmente escoreado?**\n   - Respuesta: El PD debe incluir una descripci\u00f3n del m\u00e9todo de prueba, los valores individuales, la media y la desviaci\u00f3n est\u00e1ndar relativa (RSD) de los resultados, as\u00ed como los resultados de las pruebas de uniformidad de contenido o de masa para las porciones divididas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Estudios de Compatibilidad:** Se proporciona orientaci\u00f3n sobre la realizaci\u00f3n de estudios de compatibilidad entre principios activos (API) y excipientes en productos farmac\u00e9uticos de combinaci\u00f3n de dosis fijas.\n2. **Resultados Cromatogr\u00e1ficos:** Se requieren resultados de cromatograf\u00eda (ensayo y pureza) para demostrar la compatibilidad entre API y excipientes.\n3. **Elecci\u00f3n de Excipientes:** Se recomienda el uso de excipientes con monograf\u00eda compendial y se desaconseja el uso de concentraciones fuera de los rangos establecidos sin justificaci\u00f3n adecuada.\n4. **Justificaci\u00f3n de Antioxidantes:** La efectividad de los antioxidantes en la formulaci\u00f3n debe ser justificada y verificada mediante estudios apropiados.\n5. **Conservantes Antimicrobianos:** Se menciona que los conservantes antimicrobianos son discutidos en una secci\u00f3n espec\u00edfica del documento.\n\n**Entidades:**\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Autoridad que proporciona las directrices.\n- **FDA (Administraci\u00f3n de Alimentos y Medicamentos de EE. UU.):** Fuente de informaci\u00f3n sobre excipientes aceptables.\n- **EMA (Agencia Europea de Medicamentos):** Proporciona directrices sobre excipientes a evitar.\n- **Compendial Monograph:** Referencia para excipientes preferidos.\n- **Antioxidantes y Conservantes Antimicrobianos:** Componentes discutidos en el contexto de formulaciones farmac\u00e9uticas.\n\nEste resumen destaca la importancia de la compatibilidad de los componentes en la formulaci\u00f3n de medicamentos y las directrices que deben seguirse para garantizar la seguridad y eficacia del producto final.", "excerpt_keywords": "Keywords: pharmaceutical formulation, bioequivalence, multisource product, dosage uniformity, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d6f25aa7-ef9b-442f-b5de-71532eb5e3da", "node_type": "4", "metadata": {"page_label": "176", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.2.2 Finished pharmaceutical product (name, dosage form)\n\n## 3.2.P.2.2.1 Formulation development (name, dosage form)\n\nA brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed, when appropriate.\n\nThe WHO Prequalification of Medicines Programme defines an established multisource product as one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier and QOS-PD should be completed with the exception of P.2.2.1 (a). In addition, a product quality review should be provided as outlined in Appendix 2.\n\nThe requirements for bioequivalence studies should be taken into consideration, for example, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (e.g. WHO Technical Report Series, No. 937, Annex 7) (33) should be consulted.\n\nProduct scoring may be recommended or required, for example, when scoring is indicated in the WHO Invitation for EOIs, or is specified for an invited FPP in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology.\n\nIf the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should include a description of the test method, individual values, mean and relative standard deviation (RSD) of the results. Uniformity testing (i.e. content uniformity for split portions containing less than 5 mg or less than 5% of the weight of the dosage unit portion, or mass uniformity for", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "bf51ddd0b1494709784d9e34dd263cfa88dd377196b6d89c8670039c9cf4ed39", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.P.2.2 Finished pharmaceutical product (name, dosage form)\n\n## 3.2.P.2.2.1 Formulation development (name, dosage form)\n\nA brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed, when appropriate.\n\nThe WHO Prequalification of Medicines Programme defines an established multisource product as one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier and QOS-PD should be completed with the exception of P.2.2.1 (a). In addition, a product quality review should be provided as outlined in Appendix 2.\n\nThe requirements for bioequivalence studies should be taken into consideration, for example, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (e.g. WHO Technical Report Series, No. 937, Annex 7) (33) should be consulted.\n\nProduct scoring may be recommended or required, for example, when scoring is indicated in the WHO Invitation for EOIs, or is specified for an invited FPP in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology.\n\nIf the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should include a description of the test method, individual values, mean and relative standard deviation (RSD) of the results. Uniformity testing (i.e. content uniformity for split portions containing less than 5 mg or less than 5% of the weight of the dosage unit portion, or mass uniformity for", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2325, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "cbb12153-c672-4363-bffa-33687f9d6259": {"__data__": {"id_": "cbb12153-c672-4363-bffa-33687f9d6259", "embedding": null, "metadata": {"page_label": "177", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, pol\u00edticas de salud y recomendaciones para la pr\u00e1ctica cl\u00ednica y la investigaci\u00f3n. Sin embargo, el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS en el informe t\u00e9cnico 970 sobre la salud p\u00fablica?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre las directrices o recomendaciones que la OMS ha emitido en este informe, que podr\u00edan ser relevantes para profesionales de la salud y responsables de pol\u00edticas.\n\n2. **\u00bfQu\u00e9 temas de investigaci\u00f3n se abordan en el informe WHO TRS 970 y c\u00f3mo podr\u00edan impactar la pr\u00e1ctica cl\u00ednica?**\n   - Esta pregunta se centra en identificar los temas espec\u00edficos tratados en el informe y su posible aplicaci\u00f3n en el \u00e1mbito cl\u00ednico, lo que podr\u00eda ser \u00fatil para m\u00e9dicos e investigadores.\n\n3. **\u00bfC\u00f3mo se compara el contenido del informe WHO TRS 970 con otros informes t\u00e9cnicos anteriores de la OMS?**\n   - Esta pregunta busca establecer un contexto comparativo que podr\u00eda ayudar a entender la evoluci\u00f3n de las recomendaciones y enfoques de la OMS en temas de salud a lo largo del tiempo.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n que probablemente no se encuentre f\u00e1cilmente en otros lugares, dado que se centran en el contenido espec\u00edfico del informe y su relevancia en el campo de la salud p\u00fablica.", "prev_section_summary": "### Temas Clave\n\n1. **Desarrollo de Formulaci\u00f3n de Productos Farmac\u00e9uticos Terminados (FPP)**: Se requiere un resumen que describa el desarrollo del FPP, considerando la ruta de administraci\u00f3n y el uso propuesto. Es importante discutir las diferencias entre las formulaciones de bioequivalencia comparativa y la formulaci\u00f3n descrita en la secci\u00f3n 3.2.P.1.\n\n2. **Definici\u00f3n de Producto Multisource Establecido**: Seg\u00fan el Programa de Precalificaci\u00f3n de Medicamentos de la OMS, un producto se considera establecido si ha sido comercializado durante al menos cinco a\u00f1os y ha producido un m\u00ednimo de 10 lotes en el \u00faltimo a\u00f1o, o 25 lotes en los \u00faltimos tres a\u00f1os si se produjeron menos de 10 en el \u00faltimo a\u00f1o.\n\n3. **Requisitos para Estudios de Bioequivalencia**: Se deben considerar los requisitos para estudios de bioequivalencia al formular m\u00faltiples fortalezas de un producto, especialmente si el producto puede ser elegible para una exenci\u00f3n de bioequivalencia (biowaiver).\n\n4. **Pruebas de Uniformidad de Dosis**: Para tabletas funcionalmente escoreadas, se debe realizar un estudio para asegurar la uniformidad de dosis en los fragmentos de la tableta. El documento de desarrollo del producto (PD) debe incluir detalles sobre el m\u00e9todo de prueba y los resultados de uniformidad.\n\n5. **Consulta de Documentos de Referencia de la OMS**: Se recomienda consultar documentos de referencia de la OMS para guiar el desarrollo y evaluaci\u00f3n de productos farmac\u00e9uticos.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Entidad que establece directrices y requisitos para productos farmac\u00e9uticos.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que se presenta para su comercializaci\u00f3n.\n- **Bioequivalencia**: Comparaci\u00f3n de la biodisponibilidad entre diferentes formulaciones de un mismo f\u00e1rmaco.\n- **Producto Multisource Establecido**: Producto que cumple con criterios espec\u00edficos de comercializaci\u00f3n y producci\u00f3n.\n- **Documentos de Referencia de la OMS**: Publicaciones que proporcionan directrices y est\u00e1ndares para la industria farmac\u00e9utica. \n\nEste resumen destaca los aspectos esenciales del desarrollo y evaluaci\u00f3n de productos farmac\u00e9uticos terminados seg\u00fan las directrices de la OMS.", "excerpt_keywords": "Keywords: salud p\u00fablica, productos farmac\u00e9uticos, bioequivalencia, OMS, directrices"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cff0eab1-28b5-4f2f-81d2-8460b5807a64", "node_type": "4", "metadata": {"page_label": "177", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "0ad7982307835a390448baee5c436b975a77038ba5b2e93621d18b874a8d7c69", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "7bff25fa-ebdb-45f5-8820-f85527113ec5": {"__data__": {"id_": "7bff25fa-ebdb-45f5-8820-f85527113ec5", "embedding": null, "metadata": {"page_label": "178", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Modified-release FPPs\n\nModified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine quality control. Preferably this test should possess in vitro\u2013in vivo correlation. Results demonstrating the effect of pH on the dissolution profile should be submitted if appropriate for the type of dosage form.\n\nFor extended-release FPPs, the testing conditions should be set to cover the entire time period of expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test point, upper and lower limits should be set for individual units. Generally the acceptance range at each intermediate test point should not exceed 25% or \u00b1 12.5% of the targeted value. Dissolution results should be submitted for several lots, including those lots used for pharmacokinetic and bioavailability or biowaiver studies.\n\nRecommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.\n\n## 3.2.P.2.2.2 Overages (name, dosage form)\n\nAny overages in the formulation(s) described in 3.2.P.1 should be justified.\n\nJustification of an overage to compensate for loss during manufacture should be provided, including information on the step(s) where the loss occurs, the reasons for the loss and batch analysis release data (assay results).\n\nOverages for the sole purpose of extending the shelf-life of the FPP are generally not acceptable.\n\n## 3.2.P.2.2.3 Physicochemical and biological properties (name, dosage form)\n\nParameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS (Informe T\u00e9cnico 970) aborda las pruebas de disoluci\u00f3n y otros par\u00e1metros relevantes para los productos farmac\u00e9uticos de liberaci\u00f3n modificada (FPPs). Se enfatiza la importancia de tener un m\u00e9todo de disoluci\u00f3n significativo para el control de calidad, as\u00ed como la necesidad de correlaci\u00f3n in vitro-in vivo. Para los FPPs de liberaci\u00f3n prolongada, se deben establecer condiciones de prueba que cubran todo el per\u00edodo de liberaci\u00f3n esperado, incluyendo l\u00edmites de aceptaci\u00f3n para los resultados de disoluci\u00f3n. Tambi\u00e9n se discuten las justificaciones para los sobrecargas en las formulaciones y los par\u00e1metros fisicoqu\u00edmicos y biol\u00f3gicos que deben ser considerados.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 criterios se deben cumplir para que un test de disoluci\u00f3n sea considerado significativo en el control de calidad de los FPPs de liberaci\u00f3n modificada?**\n   - Esta pregunta busca detalles sobre los requisitos espec\u00edficos que un test de disoluci\u00f3n debe cumplir, que no se encuentran f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfCu\u00e1les son las implicaciones de no demostrar la ausencia de \"dose dumping\" en los FPPs de liberaci\u00f3n prolongada?**\n   - Esta pregunta se centra en las consecuencias espec\u00edficas que pueden surgir si no se cumplen los criterios de liberaci\u00f3n de dosis, lo cual puede no estar ampliamente discutido en otros documentos.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n se debe proporcionar para justificar la inclusi\u00f3n de sobrecargas en la formulaci\u00f3n de un FPP?**\n   - Esta pregunta busca informaci\u00f3n detallada sobre los requisitos de justificaci\u00f3n para las sobrecargas, que puede no estar claramente especificada en otras normativas o gu\u00edas.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS proporciona directrices sobre la evaluaci\u00f3n y control de calidad de los productos farmac\u00e9uticos de liberaci\u00f3n modificada, enfatizando la importancia de las pruebas de disoluci\u00f3n y la justificaci\u00f3n de sobrecargas en las formulaciones. Se requiere que las pruebas de disoluci\u00f3n sean representativas y que se establezcan l\u00edmites de aceptaci\u00f3n claros. Adem\u00e1s, se deben considerar diversos par\u00e1metros fisicoqu\u00edmicos y biol\u00f3gicos que afectan el rendimiento del FPP.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Documento:** WHO - Technical Report Series 970  \n**Entidad:** Organizaci\u00f3n Mundial de la Salud (OMS)  \n**Tipo de Documento:** Informe t\u00e9cnico sobre salud p\u00fablica  \n\n#### Temas Clave:\n1. **Recomendaciones de Salud P\u00fablica:** El informe probablemente incluye directrices y recomendaciones de la OMS dirigidas a mejorar la salud p\u00fablica y la pr\u00e1ctica cl\u00ednica.\n  \n2. **Investigaci\u00f3n M\u00e9dica:** Se espera que el documento aborde temas de investigaci\u00f3n relevantes que podr\u00edan influir en la pr\u00e1ctica cl\u00ednica y en la formulaci\u00f3n de pol\u00edticas de salud.\n\n3. **Comparaci\u00f3n de Informes:** El contenido del informe puede ser comparado con otros informes t\u00e9cnicos anteriores de la OMS, lo que permite analizar la evoluci\u00f3n de las recomendaciones y enfoques en salud p\u00fablica.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Entidad responsable de la publicaci\u00f3n del informe y de la formulaci\u00f3n de pol\u00edticas y recomendaciones en salud global.\n- **Informe T\u00e9cnico:** Parte de la serie de informes t\u00e9cnicos que la OMS publica regularmente para abordar diversos temas de salud.\n\nEste resumen destaca la importancia del informe en el contexto de la salud p\u00fablica y la investigaci\u00f3n m\u00e9dica, aunque el contenido espec\u00edfico no est\u00e1 disponible en el contexto proporcionado.", "excerpt_keywords": "Keywords: modified-release, dissolution testing, overages, quality control, physicochemical properties"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "58f5509d-eafd-496a-b1a8-d33b1cf28aad", "node_type": "4", "metadata": {"page_label": "178", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Modified-release FPPs\n\nModified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine quality control. Preferably this test should possess in vitro\u2013in vivo correlation. Results demonstrating the effect of pH on the dissolution profile should be submitted if appropriate for the type of dosage form.\n\nFor extended-release FPPs, the testing conditions should be set to cover the entire time period of expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test point, upper and lower limits should be set for individual units. Generally the acceptance range at each intermediate test point should not exceed 25% or \u00b1 12.5% of the targeted value. Dissolution results should be submitted for several lots, including those lots used for pharmacokinetic and bioavailability or biowaiver studies.\n\nRecommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.\n\n## 3.2.P.2.2.2 Overages (name, dosage form)\n\nAny overages in the formulation(s) described in 3.2.P.1 should be justified.\n\nJustification of an overage to compensate for loss during manufacture should be provided, including information on the step(s) where the loss occurs, the reasons for the loss and batch analysis release data (assay results).\n\nOverages for the sole purpose of extending the shelf-life of the FPP are generally not acceptable.\n\n## 3.2.P.2.2.3 Physicochemical and biological properties (name, dosage form)\n\nParameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "a2c07899220a34cdeb58ff4e6079c07635f5e2d334fb09813c787c5838d941c5", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Modified-release FPPs\n\nModified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine quality control. Preferably this test should possess in vitro\u2013in vivo correlation. Results demonstrating the effect of pH on the dissolution profile should be submitted if appropriate for the type of dosage form.\n\nFor extended-release FPPs, the testing conditions should be set to cover the entire time period of expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test point, upper and lower limits should be set for individual units. Generally the acceptance range at each intermediate test point should not exceed 25% or \u00b1 12.5% of the targeted value. Dissolution results should be submitted for several lots, including those lots used for pharmacokinetic and bioavailability or biowaiver studies.\n\nRecommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.\n\n## 3.2.P.2.2.2 Overages (name, dosage form)\n\nAny overages in the formulation(s) described in 3.2.P.1 should be justified.\n\nJustification of an overage to compensate for loss during manufacture should be provided, including information on the step(s) where the loss occurs, the reasons for the loss and batch analysis release data (assay results).\n\nOverages for the sole purpose of extending the shelf-life of the FPP are generally not acceptable.\n\n## 3.2.P.2.2.3 Physicochemical and biological properties (name, dosage form)\n\nParameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1995, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ac944827-6e6e-45f4-b68b-9298463ca94d": {"__data__": {"id_": "ac944827-6e6e-45f4-b68b-9298463ca94d", "embedding": null, "metadata": {"page_label": "179", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.2.3 Manufacturing process development (name, dosage form)\n\nThe selection and optimization of the manufacturing process described in 3.2.P.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.\n\nWhere relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided.\n\nDifferences between the manufacturing process(es) used to produce comparative bioavailability or biowaiver batches and the process described in 3.2.P.3 that can influence the performance of the product should be discussed.\n\nFor products that meet the criteria of an established multisource product, in order to fulfill the requirements of section P.2.3, section P.2.3 (b) of the dossier and QOS-PD should be completed and a product quality review should be submitted as outlined in Appendix 2. The guidance that follows applies to all other products for which section P.2.3 should be completed in its entirety.\n\nThe rationale for choosing the particular pharmaceutical product (e.g. dosage form, delivery system) should be provided. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence FPP quality and performance should be explained (e.g. wet granulation using high shear granulator). API stress study results may be included in the rationale. Any developmental work undertaken to protect the FPP from deterioration should also be included (e.g. protection from light or moisture).\n\nThe scientific rationale for the selection, optimization and scale-up of the manufacturing process described in 3.2.P.3.3 should be explained, in particular the critical aspects (e.g. rate of addition of granulating fluid, massing time and granulation end-point). A discussion of the critical process parameters (CPP), controls and robustness with respect to the QTPP and CQA of the product should be included (ICH Q8 (25)).\n\n# 3.2.P.2.4 Container-closure system (name, dosage form)\n\nThe suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider, e.g. choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP).\n\nTesting requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration. The pharmacopoeias provide standards that are required for packaging materials, including, for example, the following:", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda aspectos cr\u00edticos del desarrollo del proceso de fabricaci\u00f3n de productos farmac\u00e9uticos, incluyendo la selecci\u00f3n y optimizaci\u00f3n de procesos, m\u00e9todos de esterilizaci\u00f3n, y la justificaci\u00f3n de decisiones relacionadas con el envase y el cierre del producto. Se enfatiza la importancia de discutir las diferencias en los procesos de fabricaci\u00f3n que pueden influir en el rendimiento del producto, as\u00ed como la necesidad de cumplir con los requisitos de calidad y seguridad en el dise\u00f1o del sistema de envase.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los aspectos cr\u00edticos que deben considerarse al seleccionar un proceso de fabricaci\u00f3n para un producto farmac\u00e9utico, y c\u00f3mo se justifican las decisiones tomadas en este contexto?**\n   - Esta pregunta busca respuestas sobre los criterios espec\u00edficos que se deben evaluar al elegir un proceso de fabricaci\u00f3n, as\u00ed como ejemplos de justificaciones que podr\u00edan no estar documentadas en otras fuentes.\n\n2. **\u00bfQu\u00e9 factores deben tenerse en cuenta al seleccionar un sistema de envase y cierre para un producto farmac\u00e9utico, y c\u00f3mo se eval\u00faa su idoneidad?**\n   - Esta pregunta se centra en los criterios de selecci\u00f3n del sistema de envase y cierre, incluyendo aspectos como la compatibilidad de materiales y la protecci\u00f3n contra factores ambientales, que pueden no estar claramente definidos en otras gu\u00edas.\n\n3. **\u00bfC\u00f3mo se determina la diferencia en el rendimiento del producto entre los lotes de bioequivalencia comparativa y los lotes producidos seg\u00fan el proceso descrito en 3.2.P.3?**\n   - Esta pregunta busca explorar las diferencias espec\u00edficas en los procesos de fabricaci\u00f3n que pueden afectar el rendimiento del producto, proporcionando detalles que podr\u00edan no estar disponibles en otras partes de la literatura.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS proporciona directrices sobre el desarrollo de procesos de fabricaci\u00f3n para productos farmac\u00e9uticos, enfatizando la importancia de la selecci\u00f3n adecuada de m\u00e9todos de fabricaci\u00f3n y envase. Se requiere una justificaci\u00f3n clara para las decisiones tomadas, especialmente en relaci\u00f3n con la esterilizaci\u00f3n y la protecci\u00f3n del producto. Adem\u00e1s, se destaca la necesidad de cumplir con los est\u00e1ndares de calidad y seguridad, as\u00ed como de discutir las diferencias en los procesos que pueden influir en el rendimiento del producto.", "prev_section_summary": "### Temas Clave\n\n1. **Pruebas de Disoluci\u00f3n para FPPs de Liberaci\u00f3n Modificada**:\n   - Importancia de tener un test de disoluci\u00f3n significativo para el control de calidad.\n   - Preferencia por la correlaci\u00f3n in vitro-in vivo.\n   - Necesidad de presentar resultados sobre el efecto del pH en el perfil de disoluci\u00f3n.\n\n2. **Condiciones de Prueba para FPPs de Liberaci\u00f3n Prolongada**:\n   - Establecimiento de condiciones de prueba que cubran todo el per\u00edodo de liberaci\u00f3n esperado.\n   - Inclusi\u00f3n de puntos de prueba tempranos para demostrar la ausencia de \"dose dumping\".\n   - Definici\u00f3n de l\u00edmites de aceptaci\u00f3n para los resultados de disoluci\u00f3n.\n\n3. **Justificaci\u00f3n de Sobrecargas**:\n   - Necesidad de justificar cualquier sobrecarga en la formulaci\u00f3n para compensar p\u00e9rdidas durante la fabricaci\u00f3n.\n   - Informaci\u00f3n requerida sobre los pasos donde ocurren las p\u00e9rdidas y datos de an\u00e1lisis de lotes.\n\n4. **Propiedades Fisicoqu\u00edmicas y Biol\u00f3gicas**:\n   - Consideraci\u00f3n de par\u00e1metros como pH, fuerza i\u00f3nica, disoluci\u00f3n, distribuci\u00f3n del tama\u00f1o de part\u00edculas, y actividad biol\u00f3gica o inmunol\u00f3gica.\n\n### Entidades\n\n- **FPPs (Formulaciones Farmac\u00e9uticas de Liberaci\u00f3n Modificada)**: Productos farmac\u00e9uticos que liberan el principio activo de manera controlada.\n- **Pruebas de Disoluci\u00f3n**: M\u00e9todos utilizados para evaluar la tasa de liberaci\u00f3n del f\u00e1rmaco en un medio espec\u00edfico.\n- **\"Dose Dumping\"**: Liberaci\u00f3n r\u00e1pida e inesperada de una dosis de medicamento que puede ser peligrosa.\n- **Sobrecargas**: Cantidades adicionales de un ingrediente en la formulaci\u00f3n para compensar p\u00e9rdidas durante la producci\u00f3n.\n- **Par\u00e1metros Fisicoqu\u00edmicos**: Caracter\u00edsticas que afectan el rendimiento del FPP, como pH y distribuci\u00f3n del tama\u00f1o de part\u00edculas.\n\nEste resumen destaca la importancia de las pruebas de disoluci\u00f3n y la justificaci\u00f3n de sobrecargas en la formulaci\u00f3n de productos farmac\u00e9uticos de liberaci\u00f3n modificada, as\u00ed como los par\u00e1metros que deben ser considerados para asegurar su eficacia y seguridad.", "excerpt_keywords": "Keywords: manufacturing process, sterilization methods, container-closure system, pharmaceutical product, critical process parameters"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a7614ad9-5a8b-46a9-ab98-fb579641b6d6", "node_type": "4", "metadata": {"page_label": "179", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.2.3 Manufacturing process development (name, dosage form)\n\nThe selection and optimization of the manufacturing process described in 3.2.P.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.\n\nWhere relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided.\n\nDifferences between the manufacturing process(es) used to produce comparative bioavailability or biowaiver batches and the process described in 3.2.P.3 that can influence the performance of the product should be discussed.\n\nFor products that meet the criteria of an established multisource product, in order to fulfill the requirements of section P.2.3, section P.2.3 (b) of the dossier and QOS-PD should be completed and a product quality review should be submitted as outlined in Appendix 2. The guidance that follows applies to all other products for which section P.2.3 should be completed in its entirety.\n\nThe rationale for choosing the particular pharmaceutical product (e.g. dosage form, delivery system) should be provided. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence FPP quality and performance should be explained (e.g. wet granulation using high shear granulator). API stress study results may be included in the rationale. Any developmental work undertaken to protect the FPP from deterioration should also be included (e.g. protection from light or moisture).\n\nThe scientific rationale for the selection, optimization and scale-up of the manufacturing process described in 3.2.P.3.3 should be explained, in particular the critical aspects (e.g. rate of addition of granulating fluid, massing time and granulation end-point). A discussion of the critical process parameters (CPP), controls and robustness with respect to the QTPP and CQA of the product should be included (ICH Q8 (25)).\n\n# 3.2.P.2.4 Container-closure system (name, dosage form)\n\nThe suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider, e.g. choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP).\n\nTesting requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration. The pharmacopoeias provide standards that are required for packaging materials, including, for example, the following:", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "fbed02d980f7dea22558b68c250a945ff39beba9e1316f56040223710f9c3b39", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.P.2.3 Manufacturing process development (name, dosage form)\n\nThe selection and optimization of the manufacturing process described in 3.2.P.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.\n\nWhere relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided.\n\nDifferences between the manufacturing process(es) used to produce comparative bioavailability or biowaiver batches and the process described in 3.2.P.3 that can influence the performance of the product should be discussed.\n\nFor products that meet the criteria of an established multisource product, in order to fulfill the requirements of section P.2.3, section P.2.3 (b) of the dossier and QOS-PD should be completed and a product quality review should be submitted as outlined in Appendix 2. The guidance that follows applies to all other products for which section P.2.3 should be completed in its entirety.\n\nThe rationale for choosing the particular pharmaceutical product (e.g. dosage form, delivery system) should be provided. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence FPP quality and performance should be explained (e.g. wet granulation using high shear granulator). API stress study results may be included in the rationale. Any developmental work undertaken to protect the FPP from deterioration should also be included (e.g. protection from light or moisture).\n\nThe scientific rationale for the selection, optimization and scale-up of the manufacturing process described in 3.2.P.3.3 should be explained, in particular the critical aspects (e.g. rate of addition of granulating fluid, massing time and granulation end-point). A discussion of the critical process parameters (CPP), controls and robustness with respect to the QTPP and CQA of the product should be included (ICH Q8 (25)).\n\n# 3.2.P.2.4 Container-closure system (name, dosage form)\n\nThe suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider, e.g. choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP).\n\nTesting requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration. The pharmacopoeias provide standards that are required for packaging materials, including, for example, the following:", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2857, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "405b6f74-4c9e-4679-81a0-8c97ef308ff9": {"__data__": {"id_": "405b6f74-4c9e-4679-81a0-8c97ef308ff9", "embedding": null, "metadata": {"page_label": "180", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- glass containers: (34, 35);\n- plastic containers: (36, 37);\n- rubber/elastomeric closures (38, 39).\n\nTable 2 outlines the general recommendations for the various dosage forms for one-time studies to establish the suitability of the container-closure system contact materials.\n\n## Table 2\n### One-time studies to establish the suitability of the container-closure system contact materials\n\n| | Solid oral products | Oral liquid and topical products | Sterile products (including ophthalmics) |\n| - | - | - | - |\n| Description of any additional treatmentsa | \u00d7 | \u00d7 | \u00d7 (sterilization and depyrogenation of the components) |\n| Extraction studies | \u2013 | \u00d7 | \u00d7 |\n| Interaction studies (migration/sorption) | \u2013 | \u00d7 | \u00d7 |\n| Moisture permeability | \u00d7 (uptake) | \u00d7 (usually loss) | \u00d7 (usually loss) |\n| Light transmission | \u00d7b | \u00d7 | \u00d7 |\n\n\n<sup>\u00d7</sup> Information should be submitted.  \n<sup>\u2013</sup> Information does not need to be submitted.  \n<sup>a</sup> E.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials.  \n<sup>b</sup> Not required if product has been shown to be photostable.\n\nFor solid oral dosage forms and solid APIs, compliance with regulations on plastic materials coming into contact with food (for example (EU) No. 10/2011 (40)) can be considered acceptable.\n\nThe suitability of the container-closure system used for the storage, transportation (shipping) and use of any intermediate or in-process products (e.g. premixes or bulk FPP) should also be discussed.\n\nA device is required to be included with the container-closure system for administration of oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules), whenever the package provides for multiple doses.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla las recomendaciones del Comit\u00e9 de Expertos sobre las Especificaciones para Preparaciones Farmac\u00e9uticas, enfoc\u00e1ndose en la idoneidad de los sistemas de cierre y contenedores para diferentes formas de dosificaci\u00f3n. Se presenta una tabla que resume los estudios necesarios para evaluar los materiales de contacto de los sistemas de cierre y contenedores, incluyendo productos orales s\u00f3lidos, l\u00edquidos orales y productos est\u00e9riles. Tambi\u00e9n se menciona la necesidad de cumplir con regulaciones espec\u00edficas y la inclusi\u00f3n de dispositivos para la administraci\u00f3n de productos en dosis m\u00faltiples.\n\n### Preguntas\n1. **\u00bfQu\u00e9 tipo de estudios se requieren para evaluar la idoneidad de los materiales de contacto en productos est\u00e9riles seg\u00fan la tabla presentada?**\n   - Respuesta: Para los productos est\u00e9riles, se requieren estudios de tratamientos adicionales (como esterilizaci\u00f3n y depirogenaci\u00f3n), estudios de extracci\u00f3n, estudios de interacci\u00f3n (migraci\u00f3n/sorci\u00f3n), permeabilidad a la humedad y transmisi\u00f3n de luz.\n\n2. **\u00bfQu\u00e9 regulaciones se consideran aceptables para los materiales pl\u00e1sticos en contacto con productos orales s\u00f3lidos y APIs s\u00f3lidos?**\n   - Respuesta: Se considera aceptable el cumplimiento con regulaciones sobre materiales pl\u00e1sticos en contacto con alimentos, como el (UE) No. 10/2011.\n\n3. **\u00bfQu\u00e9 dispositivos son necesarios para la administraci\u00f3n de l\u00edquidos orales o s\u00f3lidos en envases que permiten m\u00faltiples dosis?**\n   - Respuesta: Se requiere incluir un dispositivo con el sistema de cierre y contenedor para la administraci\u00f3n de l\u00edquidos orales o s\u00f3lidos, como soluciones, emulsiones, suspensiones y polvos o gr\u00e1nulos, siempre que el paquete est\u00e9 dise\u00f1ado para dosis m\u00faltiples.", "prev_section_summary": "### Temas Clave\n\n1. **Desarrollo del Proceso de Fabricaci\u00f3n**:\n   - Selecci\u00f3n y optimizaci\u00f3n del proceso de fabricaci\u00f3n, incluyendo aspectos cr\u00edticos.\n   - Justificaci\u00f3n de m\u00e9todos de esterilizaci\u00f3n, ya sea procesamiento as\u00e9ptico o esterilizaci\u00f3n terminal.\n   - Discusi\u00f3n sobre diferencias en procesos de fabricaci\u00f3n que afectan la bioequivalencia y el rendimiento del producto.\n\n2. **Justificaci\u00f3n del Producto Farmac\u00e9utico**:\n   - Razonamiento cient\u00edfico detr\u00e1s de la elecci\u00f3n de la forma farmac\u00e9utica y el sistema de entrega.\n   - Explicaci\u00f3n de los procesos de fabricaci\u00f3n, llenado y envasado que influyen en la calidad y rendimiento del producto final (FPP).\n   - Inclusi\u00f3n de resultados de estudios de estr\u00e9s del principio activo (API) y trabajos de desarrollo para proteger el FPP de la degradaci\u00f3n.\n\n3. **Par\u00e1metros Cr\u00edticos del Proceso**:\n   - Selecci\u00f3n, optimizaci\u00f3n y escalado del proceso de fabricaci\u00f3n, con \u00e9nfasis en par\u00e1metros cr\u00edticos del proceso (CPP) y su robustez en relaci\u00f3n con el perfil de calidad del producto (QTPP) y atributos de calidad cr\u00edticos (CQA).\n\n4. **Sistema de Envase y Cierre**:\n   - Evaluaci\u00f3n de la idoneidad del sistema de envase y cierre para almacenamiento, transporte y uso del FPP.\n   - Consideraciones sobre materiales, protecci\u00f3n contra humedad y luz, compatibilidad de materiales, y seguridad.\n   - Requisitos de prueba para verificar la idoneidad de los materiales de contacto del sistema de envase y cierre, dependiendo de la forma farmac\u00e9utica y la v\u00eda de administraci\u00f3n.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las directrices.\n- **FPP (Producto Farmac\u00e9utico Final)**: Producto que se est\u00e1 desarrollando.\n- **API (Principio Activo)**: Componente activo del producto farmac\u00e9utico.\n- **CPP (Par\u00e1metros Cr\u00edticos del Proceso)**: Factores que afectan la calidad del proceso de fabricaci\u00f3n.\n- **QTPP (Perfil de Calidad del Producto)**: Expectativas de calidad del producto final.\n- **CQA (Atributos de Calidad Cr\u00edticos)**: Caracter\u00edsticas que deben ser controladas para asegurar la calidad del producto.\n\n### Resumen\n\nLa secci\u00f3n aborda la importancia de la selecci\u00f3n y optimizaci\u00f3n de procesos de fabricaci\u00f3n en el desarrollo de productos farmac\u00e9uticos, enfatizando la necesidad de justificaci\u00f3n clara para decisiones relacionadas con la esterilizaci\u00f3n y el sistema de envase. Se requiere una discusi\u00f3n sobre las diferencias en los procesos que pueden influir en el rendimiento del producto, as\u00ed como el cumplimiento de est\u00e1ndares de calidad y seguridad. Adem\u00e1s, se destaca la evaluaci\u00f3n de la idoneidad del sistema de envase y cierre, considerando aspectos como la compatibilidad de materiales y la protecci\u00f3n del producto.", "excerpt_keywords": "Keywords: container-closure system, pharmaceutical preparations, dosage forms, extraction studies, moisture permeability"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c770e19b-017f-416d-82bf-5ae8435e4351", "node_type": "4", "metadata": {"page_label": "180", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- glass containers: (34, 35);\n- plastic containers: (36, 37);\n- rubber/elastomeric closures (38, 39).\n\nTable 2 outlines the general recommendations for the various dosage forms for one-time studies to establish the suitability of the container-closure system contact materials.\n\n## Table 2\n### One-time studies to establish the suitability of the container-closure system contact materials\n\n| | Solid oral products | Oral liquid and topical products | Sterile products (including ophthalmics) |\n| - | - | - | - |\n| Description of any additional treatmentsa | \u00d7 | \u00d7 | \u00d7 (sterilization and depyrogenation of the components) |\n| Extraction studies | \u2013 | \u00d7 | \u00d7 |\n| Interaction studies (migration/sorption) | \u2013 | \u00d7 | \u00d7 |\n| Moisture permeability | \u00d7 (uptake) | \u00d7 (usually loss) | \u00d7 (usually loss) |\n| Light transmission | \u00d7b | \u00d7 | \u00d7 |\n\n\n<sup>\u00d7</sup> Information should be submitted.  \n<sup>\u2013</sup> Information does not need to be submitted.  \n<sup>a</sup> E.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials.  \n<sup>b</sup> Not required if product has been shown to be photostable.\n\nFor solid oral dosage forms and solid APIs, compliance with regulations on plastic materials coming into contact with food (for example (EU) No. 10/2011 (40)) can be considered acceptable.\n\nThe suitability of the container-closure system used for the storage, transportation (shipping) and use of any intermediate or in-process products (e.g. premixes or bulk FPP) should also be discussed.\n\nA device is required to be included with the container-closure system for administration of oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules), whenever the package provides for multiple doses.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "0dfa530740cf321899889f34d0a2e0167ed2e7cdef145186f07bac84346c2d54", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- glass containers: (34, 35);\n- plastic containers: (36, 37);\n- rubber/elastomeric closures (38, 39).\n\nTable 2 outlines the general recommendations for the various dosage forms for one-time studies to establish the suitability of the container-closure system contact materials.\n\n## Table 2\n### One-time studies to establish the suitability of the container-closure system contact materials\n\n| | Solid oral products | Oral liquid and topical products | Sterile products (including ophthalmics) |\n| - | - | - | - |\n| Description of any additional treatmentsa | \u00d7 | \u00d7 | \u00d7 (sterilization and depyrogenation of the components) |\n| Extraction studies | \u2013 | \u00d7 | \u00d7 |\n| Interaction studies (migration/sorption) | \u2013 | \u00d7 | \u00d7 |\n| Moisture permeability | \u00d7 (uptake) | \u00d7 (usually loss) | \u00d7 (usually loss) |\n| Light transmission | \u00d7b | \u00d7 | \u00d7 |\n\n\n<sup>\u00d7</sup> Information should be submitted.  \n<sup>\u2013</sup> Information does not need to be submitted.  \n<sup>a</sup> E.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials.  \n<sup>b</sup> Not required if product has been shown to be photostable.\n\nFor solid oral dosage forms and solid APIs, compliance with regulations on plastic materials coming into contact with food (for example (EU) No. 10/2011 (40)) can be considered acceptable.\n\nThe suitability of the container-closure system used for the storage, transportation (shipping) and use of any intermediate or in-process products (e.g. premixes or bulk FPP) should also be discussed.\n\nA device is required to be included with the container-closure system for administration of oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules), whenever the package provides for multiple doses.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1817, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "0a002e45-48dc-4d7c-ae75-1aca5095e7ff": {"__data__": {"id_": "0a002e45-48dc-4d7c-ae75-1aca5095e7ff", "embedding": null, "metadata": {"page_label": "181", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# In accordance with the Ph.Int. general chapter *Liquid preparations for oral use*:\n\n\"Each dose from a multidose container is administered by means of a device suitable for measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for other volumes or, for oral drops, a suitable dropper.\"\n\nFor a device accompanying a multidose container, the results of a study should be provided demonstrating the reproducibility of the device (e.g. consistent delivery of the intended volume), generally at the lowest intended dose.\n\nA sample of the device should be provided with Module 1.\n\n## 3.2.P.2.5 Microbiological attributes (name, dosage form)\n\nWhere appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container-closure system to prevent microbial contamination should be addressed.\n\nWhere an antimicrobial preservative is included in the formulation, the amount used should be justified by submission of results of studies on the product formulated with different concentrations of the preservative(s) to demonstrate the least necessary but still effective concentration. The effectiveness of the agent should be justified and verified by appropriate studies (e.g. USP or Ph.Eur. general chapters on antimicrobial preservatives) using a batch of the FPP. If the lower limit for the proposed acceptance criterion for the assay of the preservative is less than 90.0%, the effectiveness of the agent should be established with a batch of the FPP containing a concentration of the antimicrobial preservative corresponding to the lower proposed acceptance criteria.\n\nAs outlined in the WHO stability guidelines (*WHO Technical Report Series, No. 953, Annex 2, 2009 (19)*), a single primary stability batch of the FPP should be tested for effectiveness of the antimicrobial preservative (in addition to preservative content) at the proposed shelf-life for verification purposes, regardless of whether there is a difference between the release and shelf-life acceptance criteria for preservative content.\n\n## 3.2.P.2.6 Compatibility (name, dosage form)\n\nThe compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation of API in solution, sorption on injection vessels, stability)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior del contenido:\n\n### Resumen de Nivel Superior\nEl documento de la OMS aborda las directrices para la preparaci\u00f3n de l\u00edquidos orales, enfatizando la importancia de utilizar dispositivos de medici\u00f3n adecuados para administrar dosis desde envases multidose. Se discuten los atributos microbiol\u00f3gicos de las formas de dosificaci\u00f3n, incluyendo la justificaci\u00f3n del uso de conservantes antimicrobianos y la necesidad de pruebas de efectividad. Tambi\u00e9n se menciona la compatibilidad de la forma farmac\u00e9utica con diluyentes y dispositivos de dosificaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de dispositivos son recomendados para medir las dosis de l\u00edquidos orales desde un envase multidose y cu\u00e1l es la importancia de su reproducibilidad?**\n   - Respuesta: Se recomiendan cucharas, tazas para vol\u00famenes de 5 ml o m\u00faltiplos, o jeringas orales para otros vol\u00famenes, y es importante demostrar la reproducibilidad del dispositivo para asegurar la entrega consistente del volumen prescrito, especialmente en la dosis m\u00e1s baja.\n\n2. **\u00bfQu\u00e9 justificaciones se requieren para el uso de conservantes antimicrobianos en productos farmac\u00e9uticos y c\u00f3mo se debe verificar su efectividad?**\n   - Respuesta: Se requiere justificar la cantidad de conservante utilizado mediante estudios que demuestren la concentraci\u00f3n m\u00ednima necesaria pero efectiva. La efectividad debe ser verificada con estudios apropiados, y si el l\u00edmite inferior de aceptaci\u00f3n es menor al 90.0%, se debe establecer la efectividad con un lote que contenga la concentraci\u00f3n correspondiente.\n\n3. **\u00bfC\u00f3mo se debe abordar la compatibilidad de la forma farmac\u00e9utica con los diluyentes de reconstituci\u00f3n o dispositivos de dosificaci\u00f3n?**\n   - Respuesta: La compatibilidad debe ser evaluada en t\u00e9rminos de posibles problemas como la precipitaci\u00f3n del principio activo en soluci\u00f3n, la adsorci\u00f3n en los recipientes de inyecci\u00f3n y la estabilidad general del producto.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que puede no estar f\u00e1cilmente disponible en otras fuentes, bas\u00e1ndose en el contenido detallado del documento.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS se centra en las especificaciones para preparaciones farmac\u00e9uticas, destacando la importancia de los sistemas de cierre y contenedores en la seguridad y eficacia de los productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n#### Temas Clave:\n1. **Sistemas de Cierre y Contenedores**: Se discuten los diferentes tipos de contenedores (vidrio, pl\u00e1stico) y cierres (goma/elastom\u00e9ricos) utilizados en la industria farmac\u00e9utica.\n2. **Estudios de Idoneidad**: Se presentan recomendaciones para estudios \u00fanicos que eval\u00faan la idoneidad de los materiales de contacto de los sistemas de cierre y contenedores para diversas formas de dosificaci\u00f3n.\n3. **Regulaciones**: Se menciona la importancia de cumplir con regulaciones espec\u00edficas, como la (UE) No. 10/2011, para materiales pl\u00e1sticos en contacto con productos orales s\u00f3lidos.\n4. **Dispositivos de Administraci\u00f3n**: Se requiere la inclusi\u00f3n de dispositivos para la administraci\u00f3n de productos en dosis m\u00faltiples, asegurando la correcta dosificaci\u00f3n de l\u00edquidos orales y s\u00f3lidos.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las recomendaciones.\n- **Comit\u00e9 de Expertos**: Grupo responsable de las especificaciones para preparaciones farmac\u00e9uticas.\n- **Regulaci\u00f3n (UE) No. 10/2011**: Normativa que regula los materiales pl\u00e1sticos en contacto con alimentos, considerada aceptable para productos farmac\u00e9uticos.\n- **Tipos de Productos**: \n  - Productos orales s\u00f3lidos\n  - Productos l\u00edquidos orales y t\u00f3picos\n  - Productos est\u00e9riles (incluyendo oft\u00e1lmicos)\n\nEste resumen proporciona una visi\u00f3n general de los aspectos m\u00e1s relevantes del documento, enfatizando la importancia de la evaluaci\u00f3n de los materiales de contacto y el cumplimiento normativo en la industria farmac\u00e9utica.", "excerpt_keywords": "Keywords: liquid preparations, antimicrobial preservatives, dosage devices, microbiological attributes, compatibility"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b78c7dbf-0718-46da-af1f-02f659ba9b0a", "node_type": "4", "metadata": {"page_label": "181", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# In accordance with the Ph.Int. general chapter *Liquid preparations for oral use*:\n\n\"Each dose from a multidose container is administered by means of a device suitable for measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for other volumes or, for oral drops, a suitable dropper.\"\n\nFor a device accompanying a multidose container, the results of a study should be provided demonstrating the reproducibility of the device (e.g. consistent delivery of the intended volume), generally at the lowest intended dose.\n\nA sample of the device should be provided with Module 1.\n\n## 3.2.P.2.5 Microbiological attributes (name, dosage form)\n\nWhere appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container-closure system to prevent microbial contamination should be addressed.\n\nWhere an antimicrobial preservative is included in the formulation, the amount used should be justified by submission of results of studies on the product formulated with different concentrations of the preservative(s) to demonstrate the least necessary but still effective concentration. The effectiveness of the agent should be justified and verified by appropriate studies (e.g. USP or Ph.Eur. general chapters on antimicrobial preservatives) using a batch of the FPP. If the lower limit for the proposed acceptance criterion for the assay of the preservative is less than 90.0%, the effectiveness of the agent should be established with a batch of the FPP containing a concentration of the antimicrobial preservative corresponding to the lower proposed acceptance criteria.\n\nAs outlined in the WHO stability guidelines (*WHO Technical Report Series, No. 953, Annex 2, 2009 (19)*), a single primary stability batch of the FPP should be tested for effectiveness of the antimicrobial preservative (in addition to preservative content) at the proposed shelf-life for verification purposes, regardless of whether there is a difference between the release and shelf-life acceptance criteria for preservative content.\n\n## 3.2.P.2.6 Compatibility (name, dosage form)\n\nThe compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation of API in solution, sorption on injection vessels, stability)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "23710ffa4a635e2bdabe48c20eff84ba5672a8d4ea5c414747c45648a196877c", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# In accordance with the Ph.Int. general chapter *Liquid preparations for oral use*:\n\n\"Each dose from a multidose container is administered by means of a device suitable for measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for other volumes or, for oral drops, a suitable dropper.\"\n\nFor a device accompanying a multidose container, the results of a study should be provided demonstrating the reproducibility of the device (e.g. consistent delivery of the intended volume), generally at the lowest intended dose.\n\nA sample of the device should be provided with Module 1.\n\n## 3.2.P.2.5 Microbiological attributes (name, dosage form)\n\nWhere appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container-closure system to prevent microbial contamination should be addressed.\n\nWhere an antimicrobial preservative is included in the formulation, the amount used should be justified by submission of results of studies on the product formulated with different concentrations of the preservative(s) to demonstrate the least necessary but still effective concentration. The effectiveness of the agent should be justified and verified by appropriate studies (e.g. USP or Ph.Eur. general chapters on antimicrobial preservatives) using a batch of the FPP. If the lower limit for the proposed acceptance criterion for the assay of the preservative is less than 90.0%, the effectiveness of the agent should be established with a batch of the FPP containing a concentration of the antimicrobial preservative corresponding to the lower proposed acceptance criteria.\n\nAs outlined in the WHO stability guidelines (*WHO Technical Report Series, No. 953, Annex 2, 2009 (19)*), a single primary stability batch of the FPP should be tested for effectiveness of the antimicrobial preservative (in addition to preservative content) at the proposed shelf-life for verification purposes, regardless of whether there is a difference between the release and shelf-life acceptance criteria for preservative content.\n\n## 3.2.P.2.6 Compatibility (name, dosage form)\n\nThe compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation of API in solution, sorption on injection vessels, stability)", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2573, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "971a3b81-ab61-4600-88e6-265fb19ed74e": {"__data__": {"id_": "971a3b81-ab61-4600-88e6-265fb19ed74e", "embedding": null, "metadata": {"page_label": "182", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**should be addressed to provide appropriate and supportive information for the labelling.**\n\nWhere a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules for such reconstitution) that are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required.\n\nWhere sterile, reconstituted products are to be further diluted, compatibility should be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of individual and total degradation products, subvisible particulate matter and extractables from the packaging components) should be demonstrated in glass, PVC and polyolefin containers. However, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers.\n\nStudies should cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies coadministration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the coadministered FPP (i.e. in addition to other aforementioned parameters for the mixture, the assay and degradation levels of each coadministered FPP should be reported).\n\n## 3.2.P.3 Manufacture (name, dosage form)\n\n### 3.2.P.3.1 Manufacturer(s) (name, dosage form)\n\n**The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.**\n\nThe facilities involved in the manufacturing, packaging, labelling and testing should be listed. If certain companies are responsible only for specific steps (e.g. manufacturing of an intermediate), this should be clearly indicated (WHO good distribution practices for pharmaceutical products (41)).\n\nThe list of manufacturers or companies should specify the actual addresses of production or manufacturing site(s) involved (including block(s) and unit(s)), rather than the administrative offices.\n\nFor a mixture of an API with an excipient, the blending of the API with the excipient is considered to be the first step in the manufacture of the final product and, therefore, the mixture does not fall under the definition of an API. The only exceptions are in the cases where the API cannot exist on its own. Similarly, for a mixture of APIs, the blending of the APIs is considered to be the first step in the manufacturing process.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n### Preguntas y Respuestas\n\n1. **\u00bfQu\u00e9 tipo de estudios de compatibilidad son necesarios para productos reconstituidos que se van a diluir?**\n   - **Respuesta:** Para productos reconstituidos que se van a diluir, se debe demostrar la compatibilidad con todos los diluyentes a lo largo del rango de diluci\u00f3n propuesto en el etiquetado. Estos estudios deben preferiblemente realizarse en muestras envejecidas.\n\n2. **\u00bfQu\u00e9 par\u00e1metros deben evaluarse para demostrar la compatibilidad de las mezclas en diferentes tipos de envases?**\n   - **Respuesta:** La compatibilidad debe evaluarse en funci\u00f3n de par\u00e1metros como apariencia, pH, ensayo, niveles de productos de degradaci\u00f3n individuales y totales, materia particulada subvisible y extractables de los componentes del envase. Esto debe hacerse en envases de vidrio, PVC y poliolefina, a menos que se especifiquen otros envases en el etiquetado.\n\n3. **\u00bfC\u00f3mo se debe documentar la responsabilidad de los fabricantes en el proceso de producci\u00f3n de un producto farmac\u00e9utico?**\n   - **Respuesta:** Se debe proporcionar el nombre, direcci\u00f3n y responsabilidad de cada fabricante, incluidos los contratistas, as\u00ed como de cada sitio o instalaci\u00f3n de producci\u00f3n propuesta involucrada en la fabricaci\u00f3n y pruebas. Adem\u00e1s, se debe especificar la direcci\u00f3n real de los sitios de producci\u00f3n, en lugar de las oficinas administrativas.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS establece directrices sobre la compatibilidad y el etiquetado de productos farmac\u00e9uticos, especialmente en relaci\u00f3n con la fabricaci\u00f3n y la responsabilidad de los fabricantes. Se enfatiza la importancia de realizar estudios de compatibilidad para productos reconstituidos y diluidos, as\u00ed como la necesidad de documentar adecuadamente la cadena de producci\u00f3n y los fabricantes involucrados. Esto incluye la evaluaci\u00f3n de la compatibilidad en diferentes tipos de envases y la especificaci\u00f3n de los par\u00e1metros que deben ser considerados durante estos estudios.\n\n### Preguntas Mejoradas\n\n1. **\u00bfCu\u00e1les son las implicaciones de no realizar estudios de compatibilidad en productos reconstituidos que se diluyen?**\n2. **\u00bfQu\u00e9 consideraciones deben tener en cuenta los fabricantes al seleccionar envases para productos farmac\u00e9uticos?**\n3. **\u00bfC\u00f3mo afecta la mezcla de excipientes y APIs a la definici\u00f3n de un API en el contexto de la fabricaci\u00f3n farmac\u00e9utica?**", "prev_section_summary": "### Temas Clave\n\n1. **Dispositivos de Medici\u00f3n para L\u00edquidos Orales**:\n   - Se recomienda el uso de cucharas, tazas o jeringas orales para medir dosis desde envases multidose.\n   - La reproducibilidad del dispositivo es crucial para asegurar la entrega consistente del volumen prescrito.\n\n2. **Atributos Microbiol\u00f3gicos**:\n   - Se debe discutir la justificaci\u00f3n para no realizar pruebas de l\u00edmites microbianos en productos no est\u00e9riles.\n   - La selecci\u00f3n y efectividad de los sistemas de preservantes antimicrobianos deben ser evaluadas.\n   - Para productos est\u00e9riles, se debe garantizar la integridad del sistema de cierre del envase para prevenir contaminaci\u00f3n microbiana.\n\n3. **Uso de Conservantes Antimicrobianos**:\n   - La cantidad de conservante debe ser justificada mediante estudios que demuestren la concentraci\u00f3n m\u00ednima efectiva.\n   - La efectividad del conservante debe ser verificada con estudios apropiados, especialmente si el l\u00edmite de aceptaci\u00f3n es menor al 90.0%.\n\n4. **Compatibilidad de la Forma Farmac\u00e9utica**:\n   - Se debe evaluar la compatibilidad del producto farmac\u00e9utico con diluyentes de reconstituci\u00f3n y dispositivos de dosificaci\u00f3n, considerando aspectos como la precipitaci\u00f3n del principio activo y la estabilidad general del producto.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las directrices.\n- **Ph.Int.**: Referencia a la Farmacopea Internacional.\n- **FPP (Forma Farmac\u00e9utica del Producto)**: T\u00e9rmino utilizado para referirse al producto farmac\u00e9utico final.\n- **Conservantes Antimicrobianos**: Sustancias utilizadas para prevenir el crecimiento microbiano en productos farmac\u00e9uticos.\n- **Estudios de Estabilidad**: Evaluaciones necesarias para verificar la efectividad de los conservantes a lo largo de la vida \u00fatil del producto.\n\nEste resumen destaca los aspectos m\u00e1s relevantes y las entidades mencionadas en la secci\u00f3n, proporcionando una visi\u00f3n clara de los requisitos y consideraciones para la preparaci\u00f3n de l\u00edquidos orales.", "excerpt_keywords": "Keywords: compatibility studies, pharmaceutical preparations, manufacturing process, labeling requirements, excipients"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bfb1aee4-c3eb-4607-a5f3-a9bf38efe903", "node_type": "4", "metadata": {"page_label": "182", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**should be addressed to provide appropriate and supportive information for the labelling.**\n\nWhere a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules for such reconstitution) that are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required.\n\nWhere sterile, reconstituted products are to be further diluted, compatibility should be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of individual and total degradation products, subvisible particulate matter and extractables from the packaging components) should be demonstrated in glass, PVC and polyolefin containers. However, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers.\n\nStudies should cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies coadministration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the coadministered FPP (i.e. in addition to other aforementioned parameters for the mixture, the assay and degradation levels of each coadministered FPP should be reported).\n\n## 3.2.P.3 Manufacture (name, dosage form)\n\n### 3.2.P.3.1 Manufacturer(s) (name, dosage form)\n\n**The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.**\n\nThe facilities involved in the manufacturing, packaging, labelling and testing should be listed. If certain companies are responsible only for specific steps (e.g. manufacturing of an intermediate), this should be clearly indicated (WHO good distribution practices for pharmaceutical products (41)).\n\nThe list of manufacturers or companies should specify the actual addresses of production or manufacturing site(s) involved (including block(s) and unit(s)), rather than the administrative offices.\n\nFor a mixture of an API with an excipient, the blending of the API with the excipient is considered to be the first step in the manufacture of the final product and, therefore, the mixture does not fall under the definition of an API. The only exceptions are in the cases where the API cannot exist on its own. Similarly, for a mixture of APIs, the blending of the APIs is considered to be the first step in the manufacturing process.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "bb2d5127eecd35a4716e54dfcd5c32c0660eab0cbde89e7e684bc06aff3555ce", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**should be addressed to provide appropriate and supportive information for the labelling.**\n\nWhere a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules for such reconstitution) that are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required.\n\nWhere sterile, reconstituted products are to be further diluted, compatibility should be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of individual and total degradation products, subvisible particulate matter and extractables from the packaging components) should be demonstrated in glass, PVC and polyolefin containers. However, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers.\n\nStudies should cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies coadministration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the coadministered FPP (i.e. in addition to other aforementioned parameters for the mixture, the assay and degradation levels of each coadministered FPP should be reported).\n\n## 3.2.P.3 Manufacture (name, dosage form)\n\n### 3.2.P.3.1 Manufacturer(s) (name, dosage form)\n\n**The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.**\n\nThe facilities involved in the manufacturing, packaging, labelling and testing should be listed. If certain companies are responsible only for specific steps (e.g. manufacturing of an intermediate), this should be clearly indicated (WHO good distribution practices for pharmaceutical products (41)).\n\nThe list of manufacturers or companies should specify the actual addresses of production or manufacturing site(s) involved (including block(s) and unit(s)), rather than the administrative offices.\n\nFor a mixture of an API with an excipient, the blending of the API with the excipient is considered to be the first step in the manufacture of the final product and, therefore, the mixture does not fall under the definition of an API. The only exceptions are in the cases where the API cannot exist on its own. Similarly, for a mixture of APIs, the blending of the APIs is considered to be the first step in the manufacturing process.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2893, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "8583dcb6-8e2d-4d0c-aaab-f6aacee04a4f": {"__data__": {"id_": "8583dcb6-8e2d-4d0c-aaab-f6aacee04a4f", "embedding": null, "metadata": {"page_label": "183", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Manufacture of the Final Product\n\nSites for such manufacturing steps should be listed in this section.\n\nA valid manufacturing authorization for pharmaceutical production, as well as a marketing authorization, should be submitted to demonstrate that the product is registered or licensed in accordance with national requirements (Module 1, 1.2.2).\n\nFor each site where the major production step(s) are carried out, when applicable, attach a WHO-type certificate of GMP issued by the competent authority in terms of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce (Module 1, 1.2.2).\n\n## Justification for Any Differences to the Product in the Country or Countries Issuing the WHO-type Certificate(s)\n\nWhen there are differences between the product for which this application is submitted and that marketed in the country or countries which provided the WHO-type certificate(s), it is necessary to provide data to support the applicability of the certificate(s) despite the differences. Depending on the case, it may be necessary to provide validation data for example for differences in site of manufacture, specifications and formulation. Note that only minor differences are likely to be acceptable. Differences in container labelling need not normally be justified.\n\n## Regulatory Situation in Other Countries\n\nA listing should be provided of the countries in which this product has been granted a marketing authorization, this product has been withdrawn from the market and/or this application for marketing has been rejected, deferred or withdrawn (Module 1, 1.2.2).\n\nReference documents: WHO Technical Report Series, No. 961, Annex 3 (42) and No. 957, Annex 5 (41).\n\n### 3.2.P.3.2 Batch Formula (Name, Dosage Form)\n\nA batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards.\n\nThe tables in the QOS-PD template should be used to summarize the batch formula of the FPP for each proposed commercial batch size and to express the quantity of each component on a per batch basis, including a statement of the total weight or measure of the batch.\n\nAll components used in the manufacturing process should be included, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento proporciona directrices sobre la fabricaci\u00f3n del producto farmac\u00e9utico final, incluyendo la necesidad de listar los sitios de fabricaci\u00f3n, presentar autorizaciones de fabricaci\u00f3n y comercializaci\u00f3n, y justificar cualquier diferencia entre el producto presentado y el que tiene un certificado de la OMS. Tambi\u00e9n se requiere una lista de los pa\u00edses donde se ha autorizado el producto y un formato de lote que detalle todos los componentes utilizados en el proceso de fabricaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de certificaci\u00f3n se requiere para los sitios de fabricaci\u00f3n y qu\u00e9 informaci\u00f3n debe incluirse al respecto?**\n   - Se requiere un certificado de Buenas Pr\u00e1cticas de Manufactura (GMP) emitido por la autoridad competente, que debe adjuntarse para cada sitio donde se realicen los pasos de producci\u00f3n principales.\n\n2. **\u00bfQu\u00e9 tipo de diferencias entre el producto presentado y el que tiene el certificado de la OMS son aceptables sin necesidad de justificaci\u00f3n?**\n   - Solo se aceptan diferencias menores, y las diferencias en el etiquetado del envase normalmente no necesitan ser justificadas.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la secci\u00f3n sobre la situaci\u00f3n regulatoria en otros pa\u00edses?**\n   - Debe incluirse una lista de los pa\u00edses donde se ha otorgado autorizaci\u00f3n de comercializaci\u00f3n, as\u00ed como aquellos donde el producto ha sido retirado del mercado o donde la solicitud de comercializaci\u00f3n ha sido rechazada, diferida o retirada.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Compatibilidad de Productos Farmac\u00e9uticos:**\n   - Se requiere demostrar la compatibilidad de productos reconstituidos que se diluyen con todos los diluyentes propuestos en el etiquetado.\n   - Los estudios de compatibilidad deben realizarse preferiblemente en muestras envejecidas y abarcar la duraci\u00f3n de almacenamiento especificada en el etiquetado.\n\n2. **Evaluaci\u00f3n de Envases:**\n   - La compatibilidad debe evaluarse en diferentes tipos de envases (vidrio, PVC, poliolefina) en funci\u00f3n de par\u00e1metros como apariencia, pH, niveles de degradaci\u00f3n y extractables.\n   - Si se especifican envases en el etiquetado, la compatibilidad solo necesita demostrarse en esos envases.\n\n3. **Responsabilidad de los Fabricantes:**\n   - Se debe proporcionar informaci\u00f3n detallada sobre los fabricantes, incluyendo nombre, direcci\u00f3n y responsabilidad de cada uno, as\u00ed como de los sitios de producci\u00f3n.\n   - La mezcla de un principio activo (API) con un excipiente se considera el primer paso en la fabricaci\u00f3n del producto final.\n\n4. **Coadministraci\u00f3n de Productos Farmac\u00e9uticos:**\n   - La compatibilidad debe ser demostrada no solo para el producto principal, sino tambi\u00e9n para los productos coadministrados, incluyendo niveles de ensayo y degradaci\u00f3n.\n\n**Entidades:**\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Entidad responsable de establecer directrices sobre la fabricaci\u00f3n y etiquetado de productos farmac\u00e9uticos.\n- **Fabricantes:** Incluye tanto a los fabricantes principales como a los contratistas y las instalaciones involucradas en la producci\u00f3n y pruebas.\n- **Productos Farmac\u00e9uticos (FPPs):** Incluye soluciones, emulsiones, suspensiones y productos reconstituidos que requieren estudios de compatibilidad.\n- **Envases:** Tipos de envases mencionados incluyen vidrio, PVC y poliolefina, que son relevantes para la evaluaci\u00f3n de compatibilidad.\n\nEste resumen destaca la importancia de la compatibilidad en la fabricaci\u00f3n de productos farmac\u00e9uticos y la necesidad de una documentaci\u00f3n clara sobre los fabricantes y sus responsabilidades.", "excerpt_keywords": "Manufacturing, Authorization, GMP, Regulatory, Batch Formula"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d14fc8f1-b6d1-4029-b5ec-d2aaca865629", "node_type": "4", "metadata": {"page_label": "183", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Manufacture of the Final Product\n\nSites for such manufacturing steps should be listed in this section.\n\nA valid manufacturing authorization for pharmaceutical production, as well as a marketing authorization, should be submitted to demonstrate that the product is registered or licensed in accordance with national requirements (Module 1, 1.2.2).\n\nFor each site where the major production step(s) are carried out, when applicable, attach a WHO-type certificate of GMP issued by the competent authority in terms of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce (Module 1, 1.2.2).\n\n## Justification for Any Differences to the Product in the Country or Countries Issuing the WHO-type Certificate(s)\n\nWhen there are differences between the product for which this application is submitted and that marketed in the country or countries which provided the WHO-type certificate(s), it is necessary to provide data to support the applicability of the certificate(s) despite the differences. Depending on the case, it may be necessary to provide validation data for example for differences in site of manufacture, specifications and formulation. Note that only minor differences are likely to be acceptable. Differences in container labelling need not normally be justified.\n\n## Regulatory Situation in Other Countries\n\nA listing should be provided of the countries in which this product has been granted a marketing authorization, this product has been withdrawn from the market and/or this application for marketing has been rejected, deferred or withdrawn (Module 1, 1.2.2).\n\nReference documents: WHO Technical Report Series, No. 961, Annex 3 (42) and No. 957, Annex 5 (41).\n\n### 3.2.P.3.2 Batch Formula (Name, Dosage Form)\n\nA batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards.\n\nThe tables in the QOS-PD template should be used to summarize the batch formula of the FPP for each proposed commercial batch size and to express the quantity of each component on a per batch basis, including a statement of the total weight or measure of the batch.\n\nAll components used in the manufacturing process should be included, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "3b87eb0a268943250c29f6deb971c11484a178b2ab6c084ee3384e59019a98ab", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Manufacture of the Final Product\n\nSites for such manufacturing steps should be listed in this section.\n\nA valid manufacturing authorization for pharmaceutical production, as well as a marketing authorization, should be submitted to demonstrate that the product is registered or licensed in accordance with national requirements (Module 1, 1.2.2).\n\nFor each site where the major production step(s) are carried out, when applicable, attach a WHO-type certificate of GMP issued by the competent authority in terms of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce (Module 1, 1.2.2).\n\n## Justification for Any Differences to the Product in the Country or Countries Issuing the WHO-type Certificate(s)\n\nWhen there are differences between the product for which this application is submitted and that marketed in the country or countries which provided the WHO-type certificate(s), it is necessary to provide data to support the applicability of the certificate(s) despite the differences. Depending on the case, it may be necessary to provide validation data for example for differences in site of manufacture, specifications and formulation. Note that only minor differences are likely to be acceptable. Differences in container labelling need not normally be justified.\n\n## Regulatory Situation in Other Countries\n\nA listing should be provided of the countries in which this product has been granted a marketing authorization, this product has been withdrawn from the market and/or this application for marketing has been rejected, deferred or withdrawn (Module 1, 1.2.2).\n\nReference documents: WHO Technical Report Series, No. 961, Annex 3 (42) and No. 957, Annex 5 (41).\n\n### 3.2.P.3.2 Batch Formula (Name, Dosage Form)\n\nA batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards.\n\nThe tables in the QOS-PD template should be used to summarize the batch formula of the FPP for each proposed commercial batch size and to express the quantity of each component on a per batch basis, including a statement of the total weight or measure of the batch.\n\nAll components used in the manufacturing process should be included, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2671, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "e556da80-fceb-4c9f-a5a5-95e964b0133b": {"__data__": {"id_": "e556da80-fceb-4c9f-a5a5-95e964b0133b", "embedding": null, "metadata": {"page_label": "184", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n\"1 kg of active ingredient base = 1.075 kg active ingredient hydrochloride\"). All overages should be clearly indicated (e.g. \"Contains 5 kg (corresponding to 2%) overage of the API to compensate for manufacturing losses\").\n\nThe components should be declared by their proper or common names, quality standards (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and, if applicable, their grades (e.g. \"Microcrystalline cellulose NF (PH 102)\") and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified).\n\n## 3.2.P.3.3 Description of manufacturing process and process controls (name, dosage form)\n\nA flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified.\n\nA narrative description of the manufacturing process, including packaging, that represents the sequence of steps undertaken and the scale of production should also be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (e.g. tumble blender, in-line homogenizer) and working capacity, where relevant.\n\nSteps in the process should have the appropriate process parameters identified, such as time, temperature, or pH. Associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section 3.2.P.3.4. In certain cases, environmental conditions (e.g. low humidity for an effervescent product) should be stated.\n\nThe maximum holding time for bulk FPP prior to final packaging should be stated. The holding time should be supported by the submission of stability data if longer than 30 days. For an aseptically processed FPP, sterile filtration of the bulk and filling into final containers should preferably be continuous; any holding time should be justified.\n\nProposals for the reprocessing of materials should be justified. Any data to support this justification should be either referenced or filed in this section (3.2.P.3.3).\n\nThe information above should be summarized in the QOS-PD template and should reflect the production of the proposed commercial batches. See Glossary (section 2) for definitions of pilot-scale and production-scale batches.\n\nFor the manufacture of sterile products the class (e.g. A, B or C) of the areas should be stated for each activity (e.g. compounding, filling and sealing), as well as the sterilization parameters, including for equipment, container-closure system and terminal sterilization.\n\nReference documents: ICH Q8 (25), Q9 (26), Q10 (27).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la declaraci\u00f3n de los componentes de un producto farmac\u00e9utico?**\n   - La declaraci\u00f3n de los componentes debe incluir los nombres propios o comunes de los ingredientes, los est\u00e1ndares de calidad aplicables (como BP, JP, Ph.Eur., Ph.Int., USP, o in-house), sus grados (por ejemplo, \"Microcrystalline cellulose NF (PH 102)\"), y cualquier caracter\u00edstica t\u00e9cnica especial (como si son liofilizados, micronizados, solubilizados o emulsionados).\n\n2. **\u00bfCu\u00e1les son los requisitos para la descripci\u00f3n del proceso de fabricaci\u00f3n y los controles de proceso en la documentaci\u00f3n de un producto farmac\u00e9utico?**\n   - Se debe presentar un diagrama de flujo que muestre los pasos del proceso y la entrada de materiales. Adem\u00e1s, se debe proporcionar una descripci\u00f3n narrativa del proceso de fabricaci\u00f3n, incluyendo el embalaje, identificando el tipo de equipo utilizado y sus capacidades. Tambi\u00e9n se deben identificar los par\u00e1metros del proceso, como tiempo, temperatura o pH, y justificar los rangos num\u00e9ricos para los pasos cr\u00edticos.\n\n3. **\u00bfQu\u00e9 condiciones deben cumplirse para el tiempo de espera de productos farmac\u00e9uticos antes del empaquetado final?**\n   - El tiempo m\u00e1ximo de espera para productos farmac\u00e9uticos en forma de producto terminado (FPP) antes del empaquetado final debe ser declarado. Si este tiempo es superior a 30 d\u00edas, debe estar respaldado por datos de estabilidad. Para productos procesados as\u00e9pticamente, la filtraci\u00f3n est\u00e9ril del producto a granel y el llenado en los envases finales deben ser preferiblemente continuos, y cualquier tiempo de espera debe ser justificado.\n\n### Resumen de nivel superior del contexto:\nEl documento de la OMS establece directrices para la preparaci\u00f3n y control de productos farmac\u00e9uticos, enfatizando la importancia de declarar correctamente los ingredientes, describir detalladamente el proceso de fabricaci\u00f3n y los controles asociados, y justificar los tiempos de espera y reprocesamiento de materiales. Se requiere un enfoque riguroso para asegurar la calidad y la seguridad de los productos farmac\u00e9uticos, incluyendo la identificaci\u00f3n de equipos y condiciones ambientales relevantes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Fabricaci\u00f3n del Producto Final**:\n   - Se requiere listar los sitios de fabricaci\u00f3n.\n   - Es necesario presentar autorizaciones de fabricaci\u00f3n y comercializaci\u00f3n v\u00e1lidas.\n\n2. **Certificaci\u00f3n de Buenas Pr\u00e1cticas de Manufactura (GMP)**:\n   - Para cada sitio de producci\u00f3n, se debe adjuntar un certificado de GMP emitido por la autoridad competente, conforme al esquema de certificaci\u00f3n de la OMS.\n\n3. **Justificaci\u00f3n de Diferencias**:\n   - Si hay diferencias entre el producto presentado y el que tiene el certificado de la OMS, se debe proporcionar datos que respalden la aplicabilidad del certificado.\n   - Solo se aceptan diferencias menores; las diferencias en el etiquetado del envase no requieren justificaci\u00f3n.\n\n4. **Situaci\u00f3n Regulatoria en Otros Pa\u00edses**:\n   - Se debe incluir una lista de pa\u00edses donde se ha otorgado autorizaci\u00f3n de comercializaci\u00f3n, as\u00ed como aquellos donde el producto ha sido retirado o donde la solicitud ha sido rechazada, diferida o retirada.\n\n5. **F\u00f3rmula del Lote**:\n   - Se debe proporcionar una f\u00f3rmula de lote que incluya todos los componentes del producto, sus cantidades por lote y referencias a sus est\u00e1ndares de calidad.\n   - Se deben utilizar tablas del formato QOS-PD para resumir la f\u00f3rmula del lote y expresar la cantidad de cada componente.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Referencia principal para certificaciones y est\u00e1ndares.\n- **Autorizaciones de Fabricaci\u00f3n y Comercializaci\u00f3n**: Documentos necesarios para la legalidad del producto.\n- **Certificado de GMP**: Documento que asegura que los procesos de fabricaci\u00f3n cumplen con los est\u00e1ndares de calidad.\n- **Pa\u00edses**: Entidades donde se eval\u00faa la situaci\u00f3n regulatoria del producto.", "excerpt_keywords": "Keywords: pharmaceutical preparations, manufacturing process, quality standards, process controls, sterile products"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fcd6180e-f73d-497b-8914-bc619adc7ae2", "node_type": "4", "metadata": {"page_label": "184", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n\"1 kg of active ingredient base = 1.075 kg active ingredient hydrochloride\"). All overages should be clearly indicated (e.g. \"Contains 5 kg (corresponding to 2%) overage of the API to compensate for manufacturing losses\").\n\nThe components should be declared by their proper or common names, quality standards (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and, if applicable, their grades (e.g. \"Microcrystalline cellulose NF (PH 102)\") and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified).\n\n## 3.2.P.3.3 Description of manufacturing process and process controls (name, dosage form)\n\nA flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified.\n\nA narrative description of the manufacturing process, including packaging, that represents the sequence of steps undertaken and the scale of production should also be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (e.g. tumble blender, in-line homogenizer) and working capacity, where relevant.\n\nSteps in the process should have the appropriate process parameters identified, such as time, temperature, or pH. Associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section 3.2.P.3.4. In certain cases, environmental conditions (e.g. low humidity for an effervescent product) should be stated.\n\nThe maximum holding time for bulk FPP prior to final packaging should be stated. The holding time should be supported by the submission of stability data if longer than 30 days. For an aseptically processed FPP, sterile filtration of the bulk and filling into final containers should preferably be continuous; any holding time should be justified.\n\nProposals for the reprocessing of materials should be justified. Any data to support this justification should be either referenced or filed in this section (3.2.P.3.3).\n\nThe information above should be summarized in the QOS-PD template and should reflect the production of the proposed commercial batches. See Glossary (section 2) for definitions of pilot-scale and production-scale batches.\n\nFor the manufacture of sterile products the class (e.g. A, B or C) of the areas should be stated for each activity (e.g. compounding, filling and sealing), as well as the sterilization parameters, including for equipment, container-closure system and terminal sterilization.\n\nReference documents: ICH Q8 (25), Q9 (26), Q10 (27).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "82b9f672ab90869f505719d29f520c576132a9ea826d55543d1a26260acb65c7", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n\"1 kg of active ingredient base = 1.075 kg active ingredient hydrochloride\"). All overages should be clearly indicated (e.g. \"Contains 5 kg (corresponding to 2%) overage of the API to compensate for manufacturing losses\").\n\nThe components should be declared by their proper or common names, quality standards (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and, if applicable, their grades (e.g. \"Microcrystalline cellulose NF (PH 102)\") and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified).\n\n## 3.2.P.3.3 Description of manufacturing process and process controls (name, dosage form)\n\nA flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified.\n\nA narrative description of the manufacturing process, including packaging, that represents the sequence of steps undertaken and the scale of production should also be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (e.g. tumble blender, in-line homogenizer) and working capacity, where relevant.\n\nSteps in the process should have the appropriate process parameters identified, such as time, temperature, or pH. Associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section 3.2.P.3.4. In certain cases, environmental conditions (e.g. low humidity for an effervescent product) should be stated.\n\nThe maximum holding time for bulk FPP prior to final packaging should be stated. The holding time should be supported by the submission of stability data if longer than 30 days. For an aseptically processed FPP, sterile filtration of the bulk and filling into final containers should preferably be continuous; any holding time should be justified.\n\nProposals for the reprocessing of materials should be justified. Any data to support this justification should be either referenced or filed in this section (3.2.P.3.3).\n\nThe information above should be summarized in the QOS-PD template and should reflect the production of the proposed commercial batches. See Glossary (section 2) for definitions of pilot-scale and production-scale batches.\n\nFor the manufacture of sterile products the class (e.g. A, B or C) of the areas should be stated for each activity (e.g. compounding, filling and sealing), as well as the sterilization parameters, including for equipment, container-closure system and terminal sterilization.\n\nReference documents: ICH Q8 (25), Q9 (26), Q10 (27).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2845, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ec3dd428-a47a-46b5-ba37-0a65b6972cb2": {"__data__": {"id_": "ec3dd428-a47a-46b5-ba37-0a65b6972cb2", "embedding": null, "metadata": {"page_label": "185", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.3.4 Controls of critical steps and intermediates (name, dosage form)\n\n**Critical steps:** Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is controlled.\n\n**Intermediates:** Information on the quality and control of intermediates isolated during the process should be provided.\n\nExamples of applicable in-process controls include:\n\n- **Granulations:** \n  - Moisture (limits expressed as a range)\n  - Blend uniformity (e.g. low-dose tablets)\n  - Bulk and tapped densities and particle size distribution\n\n- **Solid oral products:** \n  - Average weight\n  - Weight variation\n  - Hardness\n  - Thickness\n  - Friability\n  - Disintegration checked periodically throughout compression\n  - Weight gain during coating\n\n- **Semi-solids:** \n  - Viscosity\n  - Homogeneity\n  - pH\n\n- **Transdermal dosage forms:** \n  - Assay of API\u2013adhesive mixture\n  - Weight per area of coated patch without backing\n\n- **Metered dose inhalers:** \n  - Fill weight or volume\n  - Leak testing\n  - Valve delivery\n\n- **Dry powder inhalers:** \n  - Assay of API\u2013excipient blend\n  - Moisture\n  - Weight variation of individually contained doses such as capsules or blisters\n\n- **Liquids:** \n  - pH\n  - Specific gravity\n  - Clarity of solutions\n\n- **Parenterals:** \n  - Appearance\n  - Clarity\n  - Fill volume or weight\n  - pH\n  - Filter integrity tests\n  - Particulate matter\n  - Leak testing of ampoules\n  - Pre-filtration and/or pre-sterilization bioburden testing\n\nReference documents: ICH Q2 (16), Q6A (6), Q8 (25), Q9 (26), Q10 (27), WHO Technical Report Series, No. 929, Annex 5 (21).\n\n# 3.2.P.3.5 Process validation and/or evaluation (name, dosage form)\n\nDescription, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (e.g. validation of the sterilization process or aseptic processing or filling). Viral safety evaluation should be provided in 3.2A.2, if necessary.\n\nFor products that meet the criteria of an established multisource product, a product quality review as outlined in Appendix 2 may be submitted in lieu of the information below.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS detalla los controles de calidad y validaci\u00f3n en el proceso de fabricaci\u00f3n de productos farmac\u00e9uticos. Se enfatiza la importancia de realizar pruebas y establecer criterios de aceptaci\u00f3n en pasos cr\u00edticos del proceso, as\u00ed como en los intermedios. Se enumeran ejemplos de controles en diferentes formas de dosificaci\u00f3n, incluyendo s\u00f3lidos orales, semis\u00f3lidos, inhaladores y parenterales. Adem\u00e1s, se menciona la necesidad de documentaci\u00f3n y resultados de estudios de validaci\u00f3n para asegurar la calidad y seguridad del producto.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son los criterios de aceptaci\u00f3n espec\u00edficos para la uniformidad de mezcla en tabletas de baja dosis seg\u00fan el contexto?**\n   - Esta pregunta busca informaci\u00f3n detallada sobre un aspecto espec\u00edfico de los controles en el proceso de fabricaci\u00f3n que no se detalla en otras fuentes.\n\n2. **\u00bfQu\u00e9 pruebas de integridad de filtro se requieren para productos parenterales y por qu\u00e9 son importantes?**\n   - Esta pregunta se centra en un aspecto cr\u00edtico de la fabricaci\u00f3n de productos parenterales, que es esencial para garantizar la seguridad del producto.\n\n3. **\u00bfQu\u00e9 documentaci\u00f3n se necesita para la validaci\u00f3n de procesos cr\u00edticos en la fabricaci\u00f3n de productos farmac\u00e9uticos y c\u00f3mo se relaciona con la evaluaci\u00f3n de seguridad viral?**\n   - Esta pregunta aborda la conexi\u00f3n entre la validaci\u00f3n de procesos y la evaluaci\u00f3n de seguridad, un tema que puede no estar claramente definido en otras fuentes. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y relevante que puede no estar disponible en otros documentos o contextos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Declaraci\u00f3n de Componentes**:\n   - **Nombres**: Propios o comunes de los ingredientes activos.\n   - **Est\u00e1ndares de Calidad**: BP, JP, Ph.Eur., Ph.Int., USP, in-house.\n   - **Grados y Caracter\u00edsticas T\u00e9cnicas**: Ejemplos incluyen \"Microcrystalline cellulose NF (PH 102)\", liofilizados, micronizados, solubilizados, o emulsionados.\n\n2. **Descripci\u00f3n del Proceso de Fabricaci\u00f3n**:\n   - **Diagrama de Flujo**: Representaci\u00f3n visual de los pasos del proceso y entrada de materiales.\n   - **Descripci\u00f3n Narrativa**: Secuencia de pasos, escala de producci\u00f3n, y detalles sobre procesos o tecnolog\u00edas novedosas.\n   - **Identificaci\u00f3n de Equipos**: Tipo y capacidad de los equipos utilizados (ej. mezclador de tambor, homogeneizador en l\u00ednea).\n   - **Par\u00e1metros del Proceso**: Identificaci\u00f3n de tiempo, temperatura, pH, y justificaci\u00f3n de rangos num\u00e9ricos.\n\n3. **Tiempo de Espera y Reprocesamiento**:\n   - **Tiempo M\u00e1ximo de Espera**: Declaraci\u00f3n del tiempo para productos farmac\u00e9uticos antes del empaquetado final, con datos de estabilidad si excede 30 d\u00edas.\n   - **Filtraci\u00f3n Est\u00e9ril**: Preferiblemente continua para productos procesados as\u00e9pticamente, con justificaci\u00f3n de cualquier tiempo de espera.\n   - **Reprocesamiento de Materiales**: Justificaci\u00f3n y datos de soporte deben ser referenciados o incluidos.\n\n4. **Fabricaci\u00f3n de Productos Est\u00e9riles**:\n   - **Clasificaci\u00f3n de \u00c1reas**: Clase (A, B o C) para actividades como compounding, llenado y sellado.\n   - **Par\u00e1metros de Esterilizaci\u00f3n**: Incluyendo equipos y sistemas de cierre de envases.\n\n5. **Documentaci\u00f3n de Referencia**:\n   - **ICH Q8, Q9, Q10**: Documentos de referencia que gu\u00edan la calidad y control de procesos en la fabricaci\u00f3n farmac\u00e9utica.\n\n### Entidades Clave:\n- **Organizaci\u00f3n**: OMS (Organizaci\u00f3n Mundial de la Salud).\n- **Documentos de Calidad**: BP (British Pharmacopoeia), JP (Japanese Pharmacopoeia), Ph.Eur. (European Pharmacopoeia), Ph.Int. (International Pharmacopoeia), USP (United States Pharmacopeia).\n- **Tipos de Equipos**: Mezclador de tambor, homogeneizador en l\u00ednea.\n- **Clases de \u00c1reas**: A, B, C (para productos est\u00e9riles).\n- **Secciones del Documento**: 3.2.P.3.3 (Descripci\u00f3n del proceso de fabricaci\u00f3n y controles de proceso). \n\nEste resumen destaca la importancia de la documentaci\u00f3n rigurosa y la justificaci\u00f3n en la fabricaci\u00f3n de productos farmac\u00e9uticos para asegurar su calidad y seguridad.", "excerpt_keywords": "Keywords: quality control, process validation, pharmaceutical manufacturing, critical steps, in-process controls"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "866709ff-3f26-4fb5-9880-c8a6fa9adcad", "node_type": "4", "metadata": {"page_label": "185", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.3.4 Controls of critical steps and intermediates (name, dosage form)\n\n**Critical steps:** Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is controlled.\n\n**Intermediates:** Information on the quality and control of intermediates isolated during the process should be provided.\n\nExamples of applicable in-process controls include:\n\n- **Granulations:** \n  - Moisture (limits expressed as a range)\n  - Blend uniformity (e.g. low-dose tablets)\n  - Bulk and tapped densities and particle size distribution\n\n- **Solid oral products:** \n  - Average weight\n  - Weight variation\n  - Hardness\n  - Thickness\n  - Friability\n  - Disintegration checked periodically throughout compression\n  - Weight gain during coating\n\n- **Semi-solids:** \n  - Viscosity\n  - Homogeneity\n  - pH\n\n- **Transdermal dosage forms:** \n  - Assay of API\u2013adhesive mixture\n  - Weight per area of coated patch without backing\n\n- **Metered dose inhalers:** \n  - Fill weight or volume\n  - Leak testing\n  - Valve delivery\n\n- **Dry powder inhalers:** \n  - Assay of API\u2013excipient blend\n  - Moisture\n  - Weight variation of individually contained doses such as capsules or blisters\n\n- **Liquids:** \n  - pH\n  - Specific gravity\n  - Clarity of solutions\n\n- **Parenterals:** \n  - Appearance\n  - Clarity\n  - Fill volume or weight\n  - pH\n  - Filter integrity tests\n  - Particulate matter\n  - Leak testing of ampoules\n  - Pre-filtration and/or pre-sterilization bioburden testing\n\nReference documents: ICH Q2 (16), Q6A (6), Q8 (25), Q9 (26), Q10 (27), WHO Technical Report Series, No. 929, Annex 5 (21).\n\n# 3.2.P.3.5 Process validation and/or evaluation (name, dosage form)\n\nDescription, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (e.g. validation of the sterilization process or aseptic processing or filling). Viral safety evaluation should be provided in 3.2A.2, if necessary.\n\nFor products that meet the criteria of an established multisource product, a product quality review as outlined in Appendix 2 may be submitted in lieu of the information below.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4c2eaf003ba0599934dc3549175e70f41a2fd6b8762215266ea73e5a2c61b142", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.P.3.4 Controls of critical steps and intermediates (name, dosage form)\n\n**Critical steps:** Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is controlled.\n\n**Intermediates:** Information on the quality and control of intermediates isolated during the process should be provided.\n\nExamples of applicable in-process controls include:\n\n- **Granulations:** \n  - Moisture (limits expressed as a range)\n  - Blend uniformity (e.g. low-dose tablets)\n  - Bulk and tapped densities and particle size distribution\n\n- **Solid oral products:** \n  - Average weight\n  - Weight variation\n  - Hardness\n  - Thickness\n  - Friability\n  - Disintegration checked periodically throughout compression\n  - Weight gain during coating\n\n- **Semi-solids:** \n  - Viscosity\n  - Homogeneity\n  - pH\n\n- **Transdermal dosage forms:** \n  - Assay of API\u2013adhesive mixture\n  - Weight per area of coated patch without backing\n\n- **Metered dose inhalers:** \n  - Fill weight or volume\n  - Leak testing\n  - Valve delivery\n\n- **Dry powder inhalers:** \n  - Assay of API\u2013excipient blend\n  - Moisture\n  - Weight variation of individually contained doses such as capsules or blisters\n\n- **Liquids:** \n  - pH\n  - Specific gravity\n  - Clarity of solutions\n\n- **Parenterals:** \n  - Appearance\n  - Clarity\n  - Fill volume or weight\n  - pH\n  - Filter integrity tests\n  - Particulate matter\n  - Leak testing of ampoules\n  - Pre-filtration and/or pre-sterilization bioburden testing\n\nReference documents: ICH Q2 (16), Q6A (6), Q8 (25), Q9 (26), Q10 (27), WHO Technical Report Series, No. 929, Annex 5 (21).\n\n# 3.2.P.3.5 Process validation and/or evaluation (name, dosage form)\n\nDescription, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (e.g. validation of the sterilization process or aseptic processing or filling). Viral safety evaluation should be provided in 3.2A.2, if necessary.\n\nFor products that meet the criteria of an established multisource product, a product quality review as outlined in Appendix 2 may be submitted in lieu of the information below.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2294, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "90c3b8c2-a54d-4ecc-9f42-51014b6d61ef": {"__data__": {"id_": "90c3b8c2-a54d-4ecc-9f42-51014b6d61ef", "embedding": null, "metadata": {"page_label": "186", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe following information should be provided for all other products:\n\n1. A copy of the process validation protocol, specific to this FPP, described below;\n2. A commitment that three consecutive, production-scale batches of this FPP will be subjected to prospective validation in accordance with the above protocol. The applicant should submit a written commitment that information from these studies will be available for verification after prequalification by the WHO inspection team;\n3. If the process validation studies have already been conducted (e.g. for sterile products), a copy of the process validation report should be provided in the PD in lieu of 1. and 2. above.\n\nOne of the most practical forms of process validation, mainly for non-sterile products, is the final testing of the product to an extent greater than that required in routine quality control. It may involve extensive sampling, far beyond that called for in routine quality control and testing to normal quality control specifications and often for certain parameters only. Thus, for instance, several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then analysed statistically to verify the \u201cnormality\u201d of the distribution and to determine the standard deviation from the average weight. Confidence limits for individual results and for batch homogeneity are also estimated. Strong assurance is provided that samples taken at random will meet regulatory requirements if the confidence limits are well within compendial specifications.\n\nSimilarly, extensive sampling and testing may be performed with regard to any quality requirements. In addition, intermediate stages may be validated in the same way, e.g. dozens of samples may be assayed individually to validate mixing or granulation stages of low-dose tablet production by using the content uniformity test. Certain product characteristics may occasionally be skip-tested. Thus, subvisual particulate matter in parenteral preparations may be determined by means of electronic devices, or tablets or capsules tested for their dissolution profile if such tests are not performed on every batch.\n\nWhere ranges of batch sizes are proposed, it should be shown that variations in batch size would not adversely alter the characteristics of the finished product. It is envisaged that those parameters listed in the following validation scheme would need to be revalidated once further scale-up is proposed after prequalification.\n\nThe process validation protocol should include, but not be limited to, the following:\n\n- A reference to the current master production document;\n- A discussion of the critical equipment;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfQu\u00e9 tipo de compromiso debe presentar el solicitante respecto a la validaci\u00f3n de los lotes de productos farmac\u00e9uticos?**\n   - El solicitante debe presentar un compromiso por escrito de que tres lotes consecutivos a escala de producci\u00f3n del producto farmac\u00e9utico formulado (FPP) ser\u00e1n sometidos a validaci\u00f3n prospectiva de acuerdo con el protocolo de validaci\u00f3n del proceso. Adem\u00e1s, debe asegurar que la informaci\u00f3n de estos estudios estar\u00e1 disponible para verificaci\u00f3n despu\u00e9s de la precalificaci\u00f3n por parte del equipo de inspecci\u00f3n de la OMS.\n\n2. **\u00bfCu\u00e1les son algunos de los m\u00e9todos de validaci\u00f3n del proceso que se pueden utilizar para productos no est\u00e9riles?**\n   - Para productos no est\u00e9riles, una forma pr\u00e1ctica de validaci\u00f3n del proceso es la prueba final del producto, que puede incluir un muestreo extenso m\u00e1s all\u00e1 de lo requerido en el control de calidad rutinario. Esto puede implicar pesar varios cientos de tabletas por lote para determinar la uniformidad de la dosis unitaria y analizar estad\u00edsticamente los resultados para verificar la \"normalidad\" de la distribuci\u00f3n.\n\n3. **\u00bfQu\u00e9 aspectos deben incluirse en el protocolo de validaci\u00f3n del proceso seg\u00fan el documento de la OMS?**\n   - El protocolo de validaci\u00f3n del proceso debe incluir, entre otros aspectos, una referencia al documento maestro de producci\u00f3n actual y una discusi\u00f3n sobre el equipo cr\u00edtico utilizado en el proceso de producci\u00f3n.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento de la OMS establece directrices para la validaci\u00f3n de procesos en la producci\u00f3n de productos farmac\u00e9uticos, enfatizando la importancia de la validaci\u00f3n prospectiva y el compromiso del solicitante para garantizar la calidad del producto. Se describen m\u00e9todos de validaci\u00f3n, especialmente para productos no est\u00e9riles, y se especifican los elementos que deben incluirse en el protocolo de validaci\u00f3n del proceso. Adem\u00e1s, se menciona la necesidad de revalidar ciertos par\u00e1metros si se propone un aumento de escala despu\u00e9s de la precalificaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Controles de Calidad en Pasos Cr\u00edticos:**\n   - Importancia de realizar pruebas y establecer criterios de aceptaci\u00f3n en pasos cr\u00edticos del proceso de fabricaci\u00f3n.\n   - Necesidad de justificaci\u00f3n y datos experimentales para los controles.\n\n2. **Intermedios:**\n   - Informaci\u00f3n sobre la calidad y control de intermedios aislados durante el proceso de fabricaci\u00f3n.\n\n3. **Ejemplos de Controles en Proceso:**\n   - Granulaciones: humedad, uniformidad de mezcla, densidades y distribuci\u00f3n de tama\u00f1o de part\u00edculas.\n   - Productos orales s\u00f3lidos: peso promedio, variaci\u00f3n de peso, dureza, grosor, friabilidad, desintegraci\u00f3n y ganancia de peso durante el recubrimiento.\n   - Semis\u00f3lidos: viscosidad, homogeneidad y pH.\n   - Formas de dosificaci\u00f3n transd\u00e9rmicas: mezcla de API-adhesivo y peso por \u00e1rea del parche.\n   - Inhaladores de dosis medida: peso o volumen de llenado, pruebas de fuga y entrega de v\u00e1lvula.\n   - Inhaladores de polvo seco: mezcla de API-excipiente, humedad y variaci\u00f3n de peso.\n   - L\u00edquidos: pH, gravedad espec\u00edfica y claridad.\n   - Parenterales: apariencia, claridad, volumen o peso de llenado, pH, pruebas de integridad de filtro, materia particulada, pruebas de fuga y biocarga previa a la filtraci\u00f3n/esterilizaci\u00f3n.\n\n4. **Validaci\u00f3n de Procesos:**\n   - Documentaci\u00f3n y resultados de estudios de validaci\u00f3n para pasos cr\u00edticos o ensayos cr\u00edticos en el proceso de fabricaci\u00f3n.\n   - Evaluaci\u00f3n de seguridad viral cuando sea necesario.\n\n**Entidades:**\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Fuente del documento.\n- **ICH (International Council for Harmonisation):** Referencias a documentos de ICH que gu\u00edan los controles de calidad y validaci\u00f3n.\n- **Formas de Dosificaci\u00f3n:** Granulaciones, productos orales s\u00f3lidos, semis\u00f3lidos, transdermales, inhaladores, l\u00edquidos y parenterales.\n- **Criterios de Aceptaci\u00f3n:** Par\u00e1metros espec\u00edficos para asegurar la calidad del producto durante la fabricaci\u00f3n.\n\nEste resumen destaca la importancia de los controles de calidad y la validaci\u00f3n en la fabricaci\u00f3n de productos farmac\u00e9uticos, as\u00ed como los criterios espec\u00edficos que deben cumplirse para garantizar la seguridad y eficacia del producto final.", "excerpt_keywords": "Keywords: process validation, pharmaceutical preparations, quality control, WHO guidelines, batch testing"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d0fce398-4fda-4cfc-92a2-c718049a109b", "node_type": "4", "metadata": {"page_label": "186", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe following information should be provided for all other products:\n\n1. A copy of the process validation protocol, specific to this FPP, described below;\n2. A commitment that three consecutive, production-scale batches of this FPP will be subjected to prospective validation in accordance with the above protocol. The applicant should submit a written commitment that information from these studies will be available for verification after prequalification by the WHO inspection team;\n3. If the process validation studies have already been conducted (e.g. for sterile products), a copy of the process validation report should be provided in the PD in lieu of 1. and 2. above.\n\nOne of the most practical forms of process validation, mainly for non-sterile products, is the final testing of the product to an extent greater than that required in routine quality control. It may involve extensive sampling, far beyond that called for in routine quality control and testing to normal quality control specifications and often for certain parameters only. Thus, for instance, several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then analysed statistically to verify the \u201cnormality\u201d of the distribution and to determine the standard deviation from the average weight. Confidence limits for individual results and for batch homogeneity are also estimated. Strong assurance is provided that samples taken at random will meet regulatory requirements if the confidence limits are well within compendial specifications.\n\nSimilarly, extensive sampling and testing may be performed with regard to any quality requirements. In addition, intermediate stages may be validated in the same way, e.g. dozens of samples may be assayed individually to validate mixing or granulation stages of low-dose tablet production by using the content uniformity test. Certain product characteristics may occasionally be skip-tested. Thus, subvisual particulate matter in parenteral preparations may be determined by means of electronic devices, or tablets or capsules tested for their dissolution profile if such tests are not performed on every batch.\n\nWhere ranges of batch sizes are proposed, it should be shown that variations in batch size would not adversely alter the characteristics of the finished product. It is envisaged that those parameters listed in the following validation scheme would need to be revalidated once further scale-up is proposed after prequalification.\n\nThe process validation protocol should include, but not be limited to, the following:\n\n- A reference to the current master production document;\n- A discussion of the critical equipment;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "5f2a8b8e679f21acd04f07b763f6a560622b9e25a6f5b0b113a5a455b5f51fd2", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe following information should be provided for all other products:\n\n1. A copy of the process validation protocol, specific to this FPP, described below;\n2. A commitment that three consecutive, production-scale batches of this FPP will be subjected to prospective validation in accordance with the above protocol. The applicant should submit a written commitment that information from these studies will be available for verification after prequalification by the WHO inspection team;\n3. If the process validation studies have already been conducted (e.g. for sterile products), a copy of the process validation report should be provided in the PD in lieu of 1. and 2. above.\n\nOne of the most practical forms of process validation, mainly for non-sterile products, is the final testing of the product to an extent greater than that required in routine quality control. It may involve extensive sampling, far beyond that called for in routine quality control and testing to normal quality control specifications and often for certain parameters only. Thus, for instance, several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then analysed statistically to verify the \u201cnormality\u201d of the distribution and to determine the standard deviation from the average weight. Confidence limits for individual results and for batch homogeneity are also estimated. Strong assurance is provided that samples taken at random will meet regulatory requirements if the confidence limits are well within compendial specifications.\n\nSimilarly, extensive sampling and testing may be performed with regard to any quality requirements. In addition, intermediate stages may be validated in the same way, e.g. dozens of samples may be assayed individually to validate mixing or granulation stages of low-dose tablet production by using the content uniformity test. Certain product characteristics may occasionally be skip-tested. Thus, subvisual particulate matter in parenteral preparations may be determined by means of electronic devices, or tablets or capsules tested for their dissolution profile if such tests are not performed on every batch.\n\nWhere ranges of batch sizes are proposed, it should be shown that variations in batch size would not adversely alter the characteristics of the finished product. It is envisaged that those parameters listed in the following validation scheme would need to be revalidated once further scale-up is proposed after prequalification.\n\nThe process validation protocol should include, but not be limited to, the following:\n\n- A reference to the current master production document;\n- A discussion of the critical equipment;", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2760, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "2840050f-b828-4910-afca-bb5f6fe8a1e3": {"__data__": {"id_": "2840050f-b828-4910-afca-bb5f6fe8a1e3", "embedding": null, "metadata": {"page_label": "187", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n- The process parameters that can affect the quality of the FPP (critical process parameters (CPPs)) including challenge experiments and failure mode operation;\n- Details of the sampling: sampling points, stages of sampling, methods of sampling and the sampling plans (including schematics of blender or storage bins for uniformity testing of the final blend);\n- The testing parameters and acceptance criteria including in-process and release specifications and comparative dissolution profiles of validation batches against the batch(es) used in the bioavailability or biowaiver studies;\n- The analytical procedures or a reference to appropriate section(s) of the dossier;\n- The methods for recording and evaluating results;\n- The proposed timeframe for completion of the protocol.\n\nThe manufacture of sterile FPPs needs to take place in a well-controlled manufacturing area (e.g. a strictly controlled environment using highly reliable procedures and with appropriate in-process controls). A detailed description of these conditions, procedures and controls should be provided, together with actual copies of the standard operating procedures for the following:\n\n- Washing, treatment, sterilization and depyrogenation of containers, closures and equipment;\n- Filtration of solutions;\n- Lyophilization process;\n- Leaker test of filled and sealed ampoules;\n- Final inspection of the product;\n- Sterilization cycle.\n\nThe sterilization process used to destroy or remove microorganisms is probably the single most important process in the manufacture of parenteral FPPs. The process can make use of moist heat (e.g. steam), dry heat, filtration, gaseous sterilization (e.g. ethylene oxide) or radiation. It should be noted that terminal steam sterilization, when practical, is considered to be the method of choice to ensure sterility of the final FPP. Therefore, scientific justification for selecting any other method of sterilization should be provided.\n\nThe sterilization process should be described in detail and evidence should be provided to confirm that it will produce a sterile product with a high degree of reliability and that the physical and chemical properties as well as", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con res\u00famenes de nivel superior que pueden ayudar a formularlas:\n\n### Resumen de Nivel Superior\nEl documento se centra en los par\u00e1metros cr\u00edticos del proceso (CPPs) que afectan la calidad de los productos farmac\u00e9uticos terminados (FPPs) est\u00e9riles, as\u00ed como en los procedimientos de fabricaci\u00f3n, control de calidad y esterilizaci\u00f3n necesarios para garantizar la seguridad y eficacia de estos productos. Se enfatiza la importancia de un entorno de fabricaci\u00f3n controlado y la necesidad de justificaci\u00f3n cient\u00edfica para los m\u00e9todos de esterilizaci\u00f3n elegidos.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son los par\u00e1metros cr\u00edticos del proceso (CPPs) que deben considerarse al fabricar productos farmac\u00e9uticos est\u00e9riles?**\n   - Esta pregunta se centra en los aspectos espec\u00edficos mencionados en el contexto, como los experimentos de desaf\u00edo y la operaci\u00f3n en modo de falla, que son esenciales para garantizar la calidad del FPP.\n\n2. **\u00bfQu\u00e9 procedimientos est\u00e1ndar se deben seguir para la esterilizaci\u00f3n y depirogenaci\u00f3n de los envases y equipos utilizados en la fabricaci\u00f3n de FPPs est\u00e9riles?**\n   - Aqu\u00ed se busca informaci\u00f3n detallada sobre los procedimientos espec\u00edficos que deben documentarse y seguirse, como el lavado, tratamiento y esterilizaci\u00f3n, que son cruciales para mantener la integridad del producto.\n\n3. **\u00bfQu\u00e9 justificaci\u00f3n cient\u00edfica se requiere para seleccionar un m\u00e9todo de esterilizaci\u00f3n diferente al de esterilizaci\u00f3n por vapor terminal?**\n   - Esta pregunta aborda la necesidad de proporcionar evidencia y justificaci\u00f3n para el uso de m\u00e9todos alternativos de esterilizaci\u00f3n, lo que es fundamental para asegurar la fiabilidad del proceso de fabricaci\u00f3n de FPPs est\u00e9riles. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y detallada que no se puede encontrar f\u00e1cilmente en otros documentos o fuentes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Validaci\u00f3n del Proceso:**\n   - Importancia de la validaci\u00f3n prospectiva para garantizar la calidad de los productos farmac\u00e9uticos.\n   - Necesidad de un protocolo de validaci\u00f3n espec\u00edfico para cada producto farmac\u00e9utico formulado (FPP).\n\n2. **Compromiso del Solicitante:**\n   - El solicitante debe comprometerse a validar tres lotes consecutivos a escala de producci\u00f3n y proporcionar informaci\u00f3n para verificaci\u00f3n posterior a la precalificaci\u00f3n.\n\n3. **M\u00e9todos de Validaci\u00f3n:**\n   - Para productos no est\u00e9riles, se sugiere realizar pruebas finales del producto que incluyan muestreo extenso y an\u00e1lisis estad\u00edstico para verificar la uniformidad de la dosis.\n   - Validaci\u00f3n de etapas intermedias del proceso, como mezcla y granulaci\u00f3n.\n\n4. **Revalidaci\u00f3n:**\n   - Se requiere revalidar ciertos par\u00e1metros si se propone un aumento de escala despu\u00e9s de la precalificaci\u00f3n.\n\n5. **Elementos del Protocolo de Validaci\u00f3n:**\n   - Debe incluir referencias al documento maestro de producci\u00f3n y discusiones sobre el equipo cr\u00edtico utilizado.\n\n**Entidades:**\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Entidad responsable de establecer directrices para la validaci\u00f3n de procesos en la producci\u00f3n farmac\u00e9utica.\n- **FPP (Producto Farmac\u00e9utico Formulado):** Producto que est\u00e1 sujeto a validaci\u00f3n de procesos.\n- **Protocolo de Validaci\u00f3n del Proceso:** Documento que detalla los procedimientos y m\u00e9todos de validaci\u00f3n a seguir.\n- **Lotes de Producci\u00f3n:** Cantidades de producto fabricadas que deben ser validadas.\n\nEste resumen destaca la importancia de la validaci\u00f3n en la producci\u00f3n farmac\u00e9utica y los requisitos espec\u00edficos que deben cumplirse para asegurar la calidad y conformidad de los productos.", "excerpt_keywords": "Keywords: critical process parameters, sterile FPPs, sterilization methods, quality control, validation protocol"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8d4ecb7e-71ad-460e-8f08-c0e7a1333d96", "node_type": "4", "metadata": {"page_label": "187", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n- The process parameters that can affect the quality of the FPP (critical process parameters (CPPs)) including challenge experiments and failure mode operation;\n- Details of the sampling: sampling points, stages of sampling, methods of sampling and the sampling plans (including schematics of blender or storage bins for uniformity testing of the final blend);\n- The testing parameters and acceptance criteria including in-process and release specifications and comparative dissolution profiles of validation batches against the batch(es) used in the bioavailability or biowaiver studies;\n- The analytical procedures or a reference to appropriate section(s) of the dossier;\n- The methods for recording and evaluating results;\n- The proposed timeframe for completion of the protocol.\n\nThe manufacture of sterile FPPs needs to take place in a well-controlled manufacturing area (e.g. a strictly controlled environment using highly reliable procedures and with appropriate in-process controls). A detailed description of these conditions, procedures and controls should be provided, together with actual copies of the standard operating procedures for the following:\n\n- Washing, treatment, sterilization and depyrogenation of containers, closures and equipment;\n- Filtration of solutions;\n- Lyophilization process;\n- Leaker test of filled and sealed ampoules;\n- Final inspection of the product;\n- Sterilization cycle.\n\nThe sterilization process used to destroy or remove microorganisms is probably the single most important process in the manufacture of parenteral FPPs. The process can make use of moist heat (e.g. steam), dry heat, filtration, gaseous sterilization (e.g. ethylene oxide) or radiation. It should be noted that terminal steam sterilization, when practical, is considered to be the method of choice to ensure sterility of the final FPP. Therefore, scientific justification for selecting any other method of sterilization should be provided.\n\nThe sterilization process should be described in detail and evidence should be provided to confirm that it will produce a sterile product with a high degree of reliability and that the physical and chemical properties as well as", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "e22ffbbc10d830e0b5ee8236527114062d99152f7aa887d2d979e8a3a09e0d8b", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 4\n\n- The process parameters that can affect the quality of the FPP (critical process parameters (CPPs)) including challenge experiments and failure mode operation;\n- Details of the sampling: sampling points, stages of sampling, methods of sampling and the sampling plans (including schematics of blender or storage bins for uniformity testing of the final blend);\n- The testing parameters and acceptance criteria including in-process and release specifications and comparative dissolution profiles of validation batches against the batch(es) used in the bioavailability or biowaiver studies;\n- The analytical procedures or a reference to appropriate section(s) of the dossier;\n- The methods for recording and evaluating results;\n- The proposed timeframe for completion of the protocol.\n\nThe manufacture of sterile FPPs needs to take place in a well-controlled manufacturing area (e.g. a strictly controlled environment using highly reliable procedures and with appropriate in-process controls). A detailed description of these conditions, procedures and controls should be provided, together with actual copies of the standard operating procedures for the following:\n\n- Washing, treatment, sterilization and depyrogenation of containers, closures and equipment;\n- Filtration of solutions;\n- Lyophilization process;\n- Leaker test of filled and sealed ampoules;\n- Final inspection of the product;\n- Sterilization cycle.\n\nThe sterilization process used to destroy or remove microorganisms is probably the single most important process in the manufacture of parenteral FPPs. The process can make use of moist heat (e.g. steam), dry heat, filtration, gaseous sterilization (e.g. ethylene oxide) or radiation. It should be noted that terminal steam sterilization, when practical, is considered to be the method of choice to ensure sterility of the final FPP. Therefore, scientific justification for selecting any other method of sterilization should be provided.\n\nThe sterilization process should be described in detail and evidence should be provided to confirm that it will produce a sterile product with a high degree of reliability and that the physical and chemical properties as well as", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2194, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "fd373cd5-1a36-4370-8685-b2c9adf47b61": {"__data__": {"id_": "fd373cd5-1a36-4370-8685-b2c9adf47b61", "embedding": null, "metadata": {"page_label": "188", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe safety of the FPP will not be affected. Details such as Fo range, temperature range and peak dwell time for an FPP and the container-closure system should be provided. Although standard autoclaving cycles of 121 \u00b0C for 15 minutes or more would not need a detailed rationale, such justifications should be provided for reduced temperature cycles or elevated temperature cycles with shortened exposure times. If ethylene oxide is used, studies and acceptance criteria should control the levels of residual ethylene oxide and related compounds.\n\nAny filters used should be validated with respect to pore size, compatibility with the product, absence of extractables and lack of adsorption of the API or any of the components.\n\nFor the validation of aseptic processing of parenteral products that cannot be terminally sterilized, simulation process trials should be conducted. This involves filling containers with culture media under normal conditions, followed by incubation. Refer to current WHO GMP guidelines for details.\n\nReference documents: ICH Q8 (25), Q9 (26), Q10 (27), WHO Technical Report Series, No. 961, Annex 3 (42).\n\n## 3.2.P.4 Control of excipients (name, dosage form)\n\n### 3.2.P.4.1 Specifications (name, dosage form)\n\n**The specifications for excipients should be provided.**\n\nThe specifications from the applicant or the FPP manufacturer should be provided for all excipients, including those that may not be added to every batch (e.g. acid and alkali), those that do not appear in the final FPP (e.g. solvents) and any others used in the manufacturing process (e.g. nitrogen or silicon for stoppers).\n\nIf the standard claimed for an excipient is an officially recognized compendial standard, it is sufficient to state that the excipient is tested according to the requirements of that standard, rather than reproducing the specifications found in the officially recognized compendial monograph.\n\nIf the standard claimed for an excipient is a non-compendial standard (e.g. in-house standard) or includes tests that are supplementary to those appearing in the officially recognized compendial monograph, a copy of the specification for the excipient should be provided.\n\nFor products submitted to the WHO Prequalification of Medicines Programme, only excipients with an officially recognized pharmacopoeial monograph should be used. Exceptions may be justified.\n\nFor excipients of natural origin, microbial limit testing should be included in the specifications. Skip-testing is acceptable if justified (submission of acceptable results of five production batches).\n\nFor oils of plant origin (e.g. soy bean oil or peanut oil) the absence of aflatoxins or biocides should be demonstrated.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las especificaciones y controles necesarios para la preparaci\u00f3n farmac\u00e9utica final (FPP) y los excipientes utilizados en su fabricaci\u00f3n. Se discuten aspectos de seguridad, validaci\u00f3n de procesos de esterilizaci\u00f3n, especificaciones de excipientes, y requisitos para la pre-calificaci\u00f3n de medicamentos por parte de la OMS. Se enfatiza la importancia de proporcionar detalles sobre los ciclos de esterilizaci\u00f3n, la validaci\u00f3n de filtros, y las pruebas microbiol\u00f3gicas para excipientes de origen natural.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 justificaciones son necesarias para los ciclos de esterilizaci\u00f3n que no cumplen con los est\u00e1ndares de autoclave convencionales?**\n   - Respuesta: Se deben proporcionar justificaciones detalladas para ciclos de temperatura reducida o ciclos de temperatura elevada con tiempos de exposici\u00f3n acortados, aunque los ciclos est\u00e1ndar de autoclave a 121 \u00b0C por 15 minutos o m\u00e1s no requieren una justificaci\u00f3n detallada.\n\n2. **\u00bfCu\u00e1les son los requisitos espec\u00edficos para los excipientes de origen natural en t\u00e9rminos de pruebas microbiol\u00f3gicas?**\n   - Respuesta: Para los excipientes de origen natural, se debe incluir pruebas de l\u00edmite microbiano en las especificaciones. Se permite el \"skip-testing\" si se justifica, lo que implica la presentaci\u00f3n de resultados aceptables de cinco lotes de producci\u00f3n.\n\n3. **\u00bfQu\u00e9 tipo de est\u00e1ndares se deben utilizar para los excipientes en productos que se someten al Programa de Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Respuesta: Solo se deben utilizar excipientes que cuenten con una monograf\u00eda farmacop\u00e9ica oficialmente reconocida. Se pueden justificar excepciones, pero en general, se requiere el cumplimiento de est\u00e1ndares reconocidos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Par\u00e1metros Cr\u00edticos del Proceso (CPPs)**:\n   - Se mencionan los CPPs que afectan la calidad de los productos farmac\u00e9uticos terminados (FPPs) est\u00e9riles, incluyendo experimentos de desaf\u00edo y modos de falla.\n\n2. **Muestreo**:\n   - Detalles sobre los puntos de muestreo, etapas, m\u00e9todos y planes de muestreo, as\u00ed como esquemas para pruebas de uniformidad del producto final.\n\n3. **Especificaciones de Pruebas**:\n   - Par\u00e1metros de prueba y criterios de aceptaci\u00f3n, incluyendo especificaciones en proceso y de liberaci\u00f3n, as\u00ed como perfiles de disoluci\u00f3n comparativa de lotes de validaci\u00f3n.\n\n4. **Procedimientos Anal\u00edticos**:\n   - Referencias a secciones apropiadas del expediente para los procedimientos anal\u00edticos.\n\n5. **Registro y Evaluaci\u00f3n de Resultados**:\n   - M\u00e9todos para registrar y evaluar los resultados obtenidos durante el proceso.\n\n6. **Condiciones de Fabricaci\u00f3n**:\n   - Importancia de un \u00e1rea de fabricaci\u00f3n controlada y procedimientos est\u00e1ndar para el lavado, tratamiento, esterilizaci\u00f3n y depirogenaci\u00f3n de envases y equipos.\n\n7. **Esterilizaci\u00f3n**:\n   - Proceso cr\u00edtico para eliminar microorganismos, con m\u00e9todos como calor h\u00famedo, calor seco, filtraci\u00f3n, esterilizaci\u00f3n gaseosa y radiaci\u00f3n. Se destaca la preferencia por la esterilizaci\u00f3n por vapor terminal y la necesidad de justificaci\u00f3n cient\u00edfica para m\u00e9todos alternativos.\n\n8. **Documentaci\u00f3n**:\n   - Se requiere una descripci\u00f3n detallada de los procedimientos y condiciones de fabricaci\u00f3n, as\u00ed como copias de los procedimientos operativos est\u00e1ndar.\n\n### Entidades Clave\n- **FPP (Productos Farmac\u00e9uticos Terminados)**: Productos que requieren un proceso de fabricaci\u00f3n controlado y esterilizaci\u00f3n.\n- **CPP (Par\u00e1metros Cr\u00edticos del Proceso)**: Factores que afectan la calidad del FPP.\n- **Esterilizaci\u00f3n**: Proceso esencial en la fabricaci\u00f3n de FPPs parenterales.\n- **M\u00e9todos de Esterilizaci\u00f3n**: Incluyen vapor, calor seco, filtraci\u00f3n, gas (\u00f3xido de etileno) y radiaci\u00f3n.\n\nEste resumen abarca los aspectos fundamentales del proceso de fabricaci\u00f3n de FPPs est\u00e9riles, enfatizando la importancia de los controles de calidad y la justificaci\u00f3n cient\u00edfica en los m\u00e9todos de esterilizaci\u00f3n.", "excerpt_keywords": "Keywords: pharmaceutical preparations, sterilization, excipients, WHO guidelines, microbial testing"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d86f7ef1-fe67-48a8-9aaa-16a3d4c6325f", "node_type": "4", "metadata": {"page_label": "188", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe safety of the FPP will not be affected. Details such as Fo range, temperature range and peak dwell time for an FPP and the container-closure system should be provided. Although standard autoclaving cycles of 121 \u00b0C for 15 minutes or more would not need a detailed rationale, such justifications should be provided for reduced temperature cycles or elevated temperature cycles with shortened exposure times. If ethylene oxide is used, studies and acceptance criteria should control the levels of residual ethylene oxide and related compounds.\n\nAny filters used should be validated with respect to pore size, compatibility with the product, absence of extractables and lack of adsorption of the API or any of the components.\n\nFor the validation of aseptic processing of parenteral products that cannot be terminally sterilized, simulation process trials should be conducted. This involves filling containers with culture media under normal conditions, followed by incubation. Refer to current WHO GMP guidelines for details.\n\nReference documents: ICH Q8 (25), Q9 (26), Q10 (27), WHO Technical Report Series, No. 961, Annex 3 (42).\n\n## 3.2.P.4 Control of excipients (name, dosage form)\n\n### 3.2.P.4.1 Specifications (name, dosage form)\n\n**The specifications for excipients should be provided.**\n\nThe specifications from the applicant or the FPP manufacturer should be provided for all excipients, including those that may not be added to every batch (e.g. acid and alkali), those that do not appear in the final FPP (e.g. solvents) and any others used in the manufacturing process (e.g. nitrogen or silicon for stoppers).\n\nIf the standard claimed for an excipient is an officially recognized compendial standard, it is sufficient to state that the excipient is tested according to the requirements of that standard, rather than reproducing the specifications found in the officially recognized compendial monograph.\n\nIf the standard claimed for an excipient is a non-compendial standard (e.g. in-house standard) or includes tests that are supplementary to those appearing in the officially recognized compendial monograph, a copy of the specification for the excipient should be provided.\n\nFor products submitted to the WHO Prequalification of Medicines Programme, only excipients with an officially recognized pharmacopoeial monograph should be used. Exceptions may be justified.\n\nFor excipients of natural origin, microbial limit testing should be included in the specifications. Skip-testing is acceptable if justified (submission of acceptable results of five production batches).\n\nFor oils of plant origin (e.g. soy bean oil or peanut oil) the absence of aflatoxins or biocides should be demonstrated.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "53d8e18ea0eede4b36fb39c3b872f83d242746f9a1039f6eeec2961ca40bb680", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe safety of the FPP will not be affected. Details such as Fo range, temperature range and peak dwell time for an FPP and the container-closure system should be provided. Although standard autoclaving cycles of 121 \u00b0C for 15 minutes or more would not need a detailed rationale, such justifications should be provided for reduced temperature cycles or elevated temperature cycles with shortened exposure times. If ethylene oxide is used, studies and acceptance criteria should control the levels of residual ethylene oxide and related compounds.\n\nAny filters used should be validated with respect to pore size, compatibility with the product, absence of extractables and lack of adsorption of the API or any of the components.\n\nFor the validation of aseptic processing of parenteral products that cannot be terminally sterilized, simulation process trials should be conducted. This involves filling containers with culture media under normal conditions, followed by incubation. Refer to current WHO GMP guidelines for details.\n\nReference documents: ICH Q8 (25), Q9 (26), Q10 (27), WHO Technical Report Series, No. 961, Annex 3 (42).\n\n## 3.2.P.4 Control of excipients (name, dosage form)\n\n### 3.2.P.4.1 Specifications (name, dosage form)\n\n**The specifications for excipients should be provided.**\n\nThe specifications from the applicant or the FPP manufacturer should be provided for all excipients, including those that may not be added to every batch (e.g. acid and alkali), those that do not appear in the final FPP (e.g. solvents) and any others used in the manufacturing process (e.g. nitrogen or silicon for stoppers).\n\nIf the standard claimed for an excipient is an officially recognized compendial standard, it is sufficient to state that the excipient is tested according to the requirements of that standard, rather than reproducing the specifications found in the officially recognized compendial monograph.\n\nIf the standard claimed for an excipient is a non-compendial standard (e.g. in-house standard) or includes tests that are supplementary to those appearing in the officially recognized compendial monograph, a copy of the specification for the excipient should be provided.\n\nFor products submitted to the WHO Prequalification of Medicines Programme, only excipients with an officially recognized pharmacopoeial monograph should be used. Exceptions may be justified.\n\nFor excipients of natural origin, microbial limit testing should be included in the specifications. Skip-testing is acceptable if justified (submission of acceptable results of five production batches).\n\nFor oils of plant origin (e.g. soy bean oil or peanut oil) the absence of aflatoxins or biocides should be demonstrated.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2781, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "42908ea9-c178-4b2d-a3d5-691810703759": {"__data__": {"id_": "42908ea9-c178-4b2d-a3d5-691810703759", "embedding": null, "metadata": {"page_label": "189", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The colours permitted for use are limited to those listed in the \"Japanese pharmaceutical excipients\", the European Union (EU) \"List of permitted food colours\", and the FDA \"Inactive ingredient guide\". For proprietary mixtures, the supplier's product sheet with the qualitative formulation should be submitted, in addition to the FPP manufacturer's specifications for the product, including identification testing.\n\nFor flavours, the qualitative composition should be submitted, as well as a declaration that the excipients comply with foodstuff regulations (e.g. USA or EU regulations).\n\nInformation that is considered confidential may be submitted directly to the WHO Prequalification of Medicines Programme by the supplier who should make reference in the cover letter to the specific related product.\n\nOther certifications of at-risk components may be required on a case-by-case basis.\n\nIf additional purification is undertaken on commercially available excipients, details of the process of purification and modified specifications should be submitted.\n\nReference documents: ICH Q6A (6).\n\n### 3.2.P.4.2 Analytical procedures (name, dosage form)\n\nThe analytical procedures used for testing the excipients should be provided, where appropriate.\n\nCopies of analytical procedures from officially recognized compendial monographs do not need to be submitted.\n\nReference document: ICH Q2 (16).\n\n### 3.2.P.4.3 Validation of analytical procedures (name, dosage form)\n\nAnalytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, where appropriate.\n\nCopies of analytical validation information are generally not submitted for the testing of excipients, with the exception of the validation of in-house methods where appropriate.\n\nReference document: ICH Q2 (16).\n\n### 3.2.P.4.4 Justification of specifications (name, dosage form)\n\nJustification for the proposed excipient specifications should be provided, where appropriate.\n\nA discussion of the tests that are supplementary to those appearing in the officially recognized compendial monograph should be provided.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS establece directrices sobre el uso de excipientes en productos farmac\u00e9uticos, incluyendo colores y sabores permitidos, as\u00ed como los requisitos para la presentaci\u00f3n de informaci\u00f3n anal\u00edtica y validaci\u00f3n de procedimientos. Se menciona que los colores deben estar en listas espec\u00edficas de regulaciones de Jap\u00f3n, la UE y la FDA. Adem\u00e1s, se requiere que los proveedores presenten informaci\u00f3n sobre la composici\u00f3n cualitativa de los excipientes y su conformidad con las regulaciones de alimentos. Tambi\u00e9n se discuten los procedimientos anal\u00edticos y la justificaci\u00f3n de las especificaciones de los excipientes.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son las regulaciones espec\u00edficas que deben seguirse para los colores permitidos en los excipientes seg\u00fan el documento de la OMS?**\n   - Esta pregunta busca una respuesta detallada sobre las listas de colores permitidos y las regulaciones espec\u00edficas mencionadas en el contexto.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la declaraci\u00f3n de conformidad de los excipientes con las regulaciones de alimentos?**\n   - Esta pregunta se centra en los requisitos espec\u00edficos que deben cumplirse para demostrar que los excipientes son conformes a las regulaciones alimentarias, lo cual no se detalla expl\u00edcitamente en el contexto.\n\n3. **\u00bfQu\u00e9 tipo de informaci\u00f3n anal\u00edtica se requiere para la validaci\u00f3n de los procedimientos anal\u00edticos utilizados en la prueba de excipientes?**\n   - Esta pregunta busca aclarar qu\u00e9 datos experimentales o informaci\u00f3n espec\u00edfica se necesita para validar los procedimientos anal\u00edticos, m\u00e1s all\u00e1 de lo que se menciona en el contexto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Seguridad de la Preparaci\u00f3n Farmac\u00e9utica Final (FPP)**:\n   - La seguridad del FPP no se ver\u00e1 afectada por los procesos de esterilizaci\u00f3n si se proporcionan detalles adecuados sobre los ciclos de esterilizaci\u00f3n y el sistema de cierre del contenedor.\n\n2. **Ciclos de Esterilizaci\u00f3n**:\n   - Los ciclos est\u00e1ndar de autoclave (121 \u00b0C por 15 minutos) no requieren justificaci\u00f3n, pero se deben justificar los ciclos de temperatura reducida o elevada con tiempos de exposici\u00f3n acortados.\n   - Si se utiliza \u00f3xido de etileno, se deben controlar los niveles residuales y compuestos relacionados.\n\n3. **Validaci\u00f3n de Filtros**:\n   - Los filtros utilizados deben ser validados en cuanto a tama\u00f1o de poro, compatibilidad con el producto, ausencia de extractables y falta de adsorci\u00f3n del principio activo (API) o componentes.\n\n4. **Procesos Aseptic\u00f3s**:\n   - Para productos parenterales que no pueden ser esterilizados terminalmente, se deben realizar ensayos de simulaci\u00f3n del proceso, llenando contenedores con medios de cultivo y luego incubando.\n\n5. **Control de Excipientes**:\n   - Se deben proporcionar especificaciones para todos los excipientes, incluyendo aquellos que no se a\u00f1aden a cada lote o que no aparecen en el FPP final.\n   - Si un excipiente sigue un est\u00e1ndar compendial reconocido, basta con indicar que se prueba seg\u00fan ese est\u00e1ndar.\n   - Para excipientes de origen natural, se debe incluir pruebas de l\u00edmite microbiano, permitiendo el \"skip-testing\" si se justifica.\n\n6. **Requisitos para la Precalificaci\u00f3n de Medicamentos de la OMS**:\n   - Solo se deben utilizar excipientes con una monograf\u00eda farmacop\u00e9ica oficialmente reconocida, aunque se pueden justificar excepciones.\n\n7. **Pruebas Espec\u00edficas para Excipientes de Origen Vegetal**:\n   - Se debe demostrar la ausencia de aflatoxinas o biocidas en aceites de origen vegetal como el aceite de soya o de cacahuate.\n\n### Entidades Clave\n- **FPP (Preparaci\u00f3n Farmac\u00e9utica Final)**\n- **\u00d3xido de Etileno**\n- **Filtros**\n- **Excipientes**\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**\n- **GMP (Buenas Pr\u00e1cticas de Manufactura)**\n- **ICH (Consejo Internacional de Armonizaci\u00f3n)**\n- **Monograf\u00edas Farmacop\u00e9icas**", "excerpt_keywords": "Keywords: excipients, analytical procedures, validation, food regulations, WHO Prequalification"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c4f2929b-5ae4-49f3-a021-62602769627f", "node_type": "4", "metadata": {"page_label": "189", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The colours permitted for use are limited to those listed in the \"Japanese pharmaceutical excipients\", the European Union (EU) \"List of permitted food colours\", and the FDA \"Inactive ingredient guide\". For proprietary mixtures, the supplier's product sheet with the qualitative formulation should be submitted, in addition to the FPP manufacturer's specifications for the product, including identification testing.\n\nFor flavours, the qualitative composition should be submitted, as well as a declaration that the excipients comply with foodstuff regulations (e.g. USA or EU regulations).\n\nInformation that is considered confidential may be submitted directly to the WHO Prequalification of Medicines Programme by the supplier who should make reference in the cover letter to the specific related product.\n\nOther certifications of at-risk components may be required on a case-by-case basis.\n\nIf additional purification is undertaken on commercially available excipients, details of the process of purification and modified specifications should be submitted.\n\nReference documents: ICH Q6A (6).\n\n### 3.2.P.4.2 Analytical procedures (name, dosage form)\n\nThe analytical procedures used for testing the excipients should be provided, where appropriate.\n\nCopies of analytical procedures from officially recognized compendial monographs do not need to be submitted.\n\nReference document: ICH Q2 (16).\n\n### 3.2.P.4.3 Validation of analytical procedures (name, dosage form)\n\nAnalytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, where appropriate.\n\nCopies of analytical validation information are generally not submitted for the testing of excipients, with the exception of the validation of in-house methods where appropriate.\n\nReference document: ICH Q2 (16).\n\n### 3.2.P.4.4 Justification of specifications (name, dosage form)\n\nJustification for the proposed excipient specifications should be provided, where appropriate.\n\nA discussion of the tests that are supplementary to those appearing in the officially recognized compendial monograph should be provided.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4a3fda1c1f5152d26a0d0375409f00d3497c6ea399ceccc2a0b7a355a0771339", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "The colours permitted for use are limited to those listed in the \"Japanese pharmaceutical excipients\", the European Union (EU) \"List of permitted food colours\", and the FDA \"Inactive ingredient guide\". For proprietary mixtures, the supplier's product sheet with the qualitative formulation should be submitted, in addition to the FPP manufacturer's specifications for the product, including identification testing.\n\nFor flavours, the qualitative composition should be submitted, as well as a declaration that the excipients comply with foodstuff regulations (e.g. USA or EU regulations).\n\nInformation that is considered confidential may be submitted directly to the WHO Prequalification of Medicines Programme by the supplier who should make reference in the cover letter to the specific related product.\n\nOther certifications of at-risk components may be required on a case-by-case basis.\n\nIf additional purification is undertaken on commercially available excipients, details of the process of purification and modified specifications should be submitted.\n\nReference documents: ICH Q6A (6).\n\n### 3.2.P.4.2 Analytical procedures (name, dosage form)\n\nThe analytical procedures used for testing the excipients should be provided, where appropriate.\n\nCopies of analytical procedures from officially recognized compendial monographs do not need to be submitted.\n\nReference document: ICH Q2 (16).\n\n### 3.2.P.4.3 Validation of analytical procedures (name, dosage form)\n\nAnalytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, where appropriate.\n\nCopies of analytical validation information are generally not submitted for the testing of excipients, with the exception of the validation of in-house methods where appropriate.\n\nReference document: ICH Q2 (16).\n\n### 3.2.P.4.4 Justification of specifications (name, dosage form)\n\nJustification for the proposed excipient specifications should be provided, where appropriate.\n\nA discussion of the tests that are supplementary to those appearing in the officially recognized compendial monograph should be provided.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2145, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ad1667aa-abd6-4f1b-921f-0206324fb1cb": {"__data__": {"id_": "ad1667aa-abd6-4f1b-921f-0206324fb1cb", "embedding": null, "metadata": {"page_label": "190", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.4.5 Excipients of human or animal origin (name, dosage form)\n\nFor excipients of human or animal origin, information should be provided regarding adventitious agents (e.g. sources, specifications, description of the testing performed, viral safety data) (details in 3.2.A.2).\n\nThe following excipients should be addressed in this section: gelatin, phosphates, stearic acid, magnesium stearate and other stearates. If the excipients are of plant origin a declaration to this effect will suffice.\n\nFor excipients of animal origin, a letter of attestation should be provided confirming that the excipients used to manufacture the FPP are without risk of transmitting agents of animal spongiform encephalopathies.\n\nMaterials of animal origin should be avoided whenever possible.\n\nWhen available a CEP demonstrating TSE-compliance should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1.\n\nReference documents: ICH Q5A (43), Q5D (44), Q6B (45), WHO Technical Report Series, No. 908, Annex 1 (46).\n\n# 3.2.P.4.6 Novel excipients (name, dosage form)\n\nFor excipient(s) used for the first time in an FPP or by a new route of administration, full details of manufacture, characterization, and controls, with cross-references to supporting safety data (non-clinical and/or clinical) should be provided according to the API and/or FPP format (details in 3.2.A.3).\n\nNovel excipients are not accepted in the WHO Prequalification of Medicines Programme. For the purpose of these guidelines, a novel excipient is one that has not been used (at a similar level and by the same route of administration) in a product approved by an SRA or by WHO.\n\n# 3.2.P.5 Control of FPP (name, dosage form)\n\n## 3.2.P.5.1 Specification(s) (name, dosage form)\n\nThe specification(s) for the FPP should be provided.\n\nAs defined in ICH\u2019s Q6A guideline, a specification is:\n\n> \u201ca list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. \u201cConformance to specifications\u201d means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.\u201d", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS aborda la regulaci\u00f3n de excipientes en productos farmac\u00e9uticos, centr\u00e1ndose en aquellos de origen humano o animal. Se requiere informaci\u00f3n sobre agentes adventicios, especificaciones y seguridad viral para excipientes de origen animal. Se enfatiza la necesidad de evitar materiales de origen animal siempre que sea posible y se establece que los excipientes novedosos no son aceptados en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS. Adem\u00e1s, se definen las especificaciones para los productos farmac\u00e9uticos, que son criterios cr\u00edticos aprobados por las autoridades regulatorias.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de documentaci\u00f3n se requiere para excipientes de origen animal en la fabricaci\u00f3n de productos farmac\u00e9uticos?**\n   - Se requiere una carta de atestaci\u00f3n que confirme que los excipientes utilizados no representan un riesgo de transmisi\u00f3n de agentes de encefalopat\u00edas espongiformes animales. Adem\u00e1s, se debe proporcionar un Certificado de Excipiente (CEP) que demuestre el cumplimiento de TSE, si est\u00e1 disponible.\n\n2. **\u00bfCu\u00e1les son los excipientes espec\u00edficos que deben ser abordados en la secci\u00f3n sobre excipientes de origen humano o animal?**\n   - Los excipientes que deben ser abordados incluyen gelatina, fosfatos, \u00e1cido estearico, estearato de magnesio y otros estearatos. Si los excipientes son de origen vegetal, solo se requiere una declaraci\u00f3n al respecto.\n\n3. **\u00bfQu\u00e9 se entiende por un excipiente novedoso seg\u00fan las directrices de la OMS y cu\u00e1l es su estatus en el Programa de Precalificaci\u00f3n de Medicamentos?**\n   - Un excipiente novedoso es aquel que no ha sido utilizado en un producto aprobado por una Autoridad Reguladora de SRA o por la OMS, a un nivel similar y por la misma v\u00eda de administraci\u00f3n. Estos excipientes no son aceptados en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Colores Permitidos**:\n   - Los colores utilizados en excipientes deben estar en las listas de:\n     - Excipientes farmac\u00e9uticos japoneses.\n     - Lista de colores alimentarios permitidos de la Uni\u00f3n Europea (UE).\n     - Gu\u00eda de ingredientes inactivos de la FDA.\n\n2. **Informaci\u00f3n de Proveedores**:\n   - Para mezclas propietarias, se requiere la hoja de producto del proveedor con la formulaci\u00f3n cualitativa y las especificaciones del fabricante del producto (FPP), incluyendo pruebas de identificaci\u00f3n.\n\n3. **Sabores**:\n   - Se debe presentar la composici\u00f3n cualitativa de los sabores y una declaraci\u00f3n de conformidad con las regulaciones alimentarias (por ejemplo, regulaciones de EE. UU. o UE).\n\n4. **Confidencialidad**:\n   - La informaci\u00f3n confidencial puede ser enviada directamente al Programa de Precalificaci\u00f3n de Medicamentos de la OMS, mencionando el producto relacionado en la carta de presentaci\u00f3n.\n\n5. **Certificaciones Adicionales**:\n   - Pueden ser requeridas certificaciones de componentes en riesgo seg\u00fan el caso.\n\n6. **Purificaci\u00f3n de Excipientes**:\n   - Si se realiza una purificaci\u00f3n adicional en excipientes comercialmente disponibles, se deben presentar detalles del proceso y especificaciones modificadas.\n\n7. **Procedimientos Anal\u00edticos**:\n   - Se deben proporcionar los procedimientos anal\u00edticos utilizados para probar los excipientes, aunque no es necesario enviar copias de procedimientos de monograf\u00edas compendiales reconocidas.\n\n8. **Validaci\u00f3n de Procedimientos Anal\u00edticos**:\n   - Se requiere informaci\u00f3n de validaci\u00f3n anal\u00edtica, incluyendo datos experimentales, para los procedimientos anal\u00edticos utilizados, excepto para m\u00e9todos in-house donde sea apropiado.\n\n9. **Justificaci\u00f3n de Especificaciones**:\n   - Se debe proporcionar una justificaci\u00f3n para las especificaciones propuestas de los excipientes, incluyendo una discusi\u00f3n sobre pruebas adicionales a las de las monograf\u00edas compendiales reconocidas.\n\n### Entidades Clave\n- **Organismos Reguladores**: OMS, FDA, UE.\n- **Documentos de Referencia**: ICH Q6A, ICH Q2.\n- **Tipos de Excipientes**: Colores, sabores, mezclas propietarias.\n- **Requisitos de Presentaci\u00f3n**: Hojas de producto, declaraciones de conformidad, detalles de purificaci\u00f3n.", "excerpt_keywords": "Keywords: excipients, animal origin, viral safety, specifications, WHO Prequalification"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b7185212-2620-47e6-af45-3fc1c9eed859", "node_type": "4", "metadata": {"page_label": "190", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.4.5 Excipients of human or animal origin (name, dosage form)\n\nFor excipients of human or animal origin, information should be provided regarding adventitious agents (e.g. sources, specifications, description of the testing performed, viral safety data) (details in 3.2.A.2).\n\nThe following excipients should be addressed in this section: gelatin, phosphates, stearic acid, magnesium stearate and other stearates. If the excipients are of plant origin a declaration to this effect will suffice.\n\nFor excipients of animal origin, a letter of attestation should be provided confirming that the excipients used to manufacture the FPP are without risk of transmitting agents of animal spongiform encephalopathies.\n\nMaterials of animal origin should be avoided whenever possible.\n\nWhen available a CEP demonstrating TSE-compliance should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1.\n\nReference documents: ICH Q5A (43), Q5D (44), Q6B (45), WHO Technical Report Series, No. 908, Annex 1 (46).\n\n# 3.2.P.4.6 Novel excipients (name, dosage form)\n\nFor excipient(s) used for the first time in an FPP or by a new route of administration, full details of manufacture, characterization, and controls, with cross-references to supporting safety data (non-clinical and/or clinical) should be provided according to the API and/or FPP format (details in 3.2.A.3).\n\nNovel excipients are not accepted in the WHO Prequalification of Medicines Programme. For the purpose of these guidelines, a novel excipient is one that has not been used (at a similar level and by the same route of administration) in a product approved by an SRA or by WHO.\n\n# 3.2.P.5 Control of FPP (name, dosage form)\n\n## 3.2.P.5.1 Specification(s) (name, dosage form)\n\nThe specification(s) for the FPP should be provided.\n\nAs defined in ICH\u2019s Q6A guideline, a specification is:\n\n> \u201ca list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. \u201cConformance to specifications\u201d means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.\u201d", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "862a54c58cef47a60e3617fcd4e77b1821961d4f5cf2d84f90551baf8e87ce37", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.P.4.5 Excipients of human or animal origin (name, dosage form)\n\nFor excipients of human or animal origin, information should be provided regarding adventitious agents (e.g. sources, specifications, description of the testing performed, viral safety data) (details in 3.2.A.2).\n\nThe following excipients should be addressed in this section: gelatin, phosphates, stearic acid, magnesium stearate and other stearates. If the excipients are of plant origin a declaration to this effect will suffice.\n\nFor excipients of animal origin, a letter of attestation should be provided confirming that the excipients used to manufacture the FPP are without risk of transmitting agents of animal spongiform encephalopathies.\n\nMaterials of animal origin should be avoided whenever possible.\n\nWhen available a CEP demonstrating TSE-compliance should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1.\n\nReference documents: ICH Q5A (43), Q5D (44), Q6B (45), WHO Technical Report Series, No. 908, Annex 1 (46).\n\n# 3.2.P.4.6 Novel excipients (name, dosage form)\n\nFor excipient(s) used for the first time in an FPP or by a new route of administration, full details of manufacture, characterization, and controls, with cross-references to supporting safety data (non-clinical and/or clinical) should be provided according to the API and/or FPP format (details in 3.2.A.3).\n\nNovel excipients are not accepted in the WHO Prequalification of Medicines Programme. For the purpose of these guidelines, a novel excipient is one that has not been used (at a similar level and by the same route of administration) in a product approved by an SRA or by WHO.\n\n# 3.2.P.5 Control of FPP (name, dosage form)\n\n## 3.2.P.5.1 Specification(s) (name, dosage form)\n\nThe specification(s) for the FPP should be provided.\n\nAs defined in ICH\u2019s Q6A guideline, a specification is:\n\n> \u201ca list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. \u201cConformance to specifications\u201d means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.\u201d", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2484, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "97d69c8d-d099-43f6-9779-cc9d8efb8beb": {"__data__": {"id_": "97d69c8d-d099-43f6-9779-cc9d8efb8beb", "embedding": null, "metadata": {"page_label": "191", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "A copy of the FPP specification(s) from the applicant (as well as the company responsible for the batch release of the FPP, if different from the applicant), dated and signed by authorized personnel (i.e. the person in charge of the quality control or quality assurance department) should be provided in the PD. Two separate sets of specifications may be set out: after packaging of the FPP (release) and at the end of the shelf-life.\n\nThe specifications should be summarized according to the tables in the QOS-PD template including the tests, acceptance criteria and analytical procedures (listing types, sources and versions for the methods).\n\n- The standard declared by the applicant could be an officially recognized compendial standard (e.g. BP, JP, Ph.Eur., Ph.Int., USP) or an in-house (manufacturer\u2019s) standard.\n- The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes.\n- For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV or HPLC); the source refers to the origin of the analytical procedure (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and the version (e.g. code number/version/date) should be provided for version control purposes.\n\nICH\u2019s Q6A guideline outlines recommendations for a number of universal and specific tests and criteria for FPPs. Specifications should include, at a minimum, tests for appearance, identification, assay, purity, performance tests (e.g. dissolution), physical tests (e.g. loss on drying, hardness, friability and particle size), uniformity of dosage units, and, as applicable, identification and assay of antimicrobial or chemical preservatives (e.g. antioxidants) and microbial limit tests.\n\nThe following information provides guidance on specific tests that are not addressed by ICH\u2019s Q6A guideline:\n\n- fixed-dose combination FPPs (FDC-FPPs):\n  - analytical methods that can distinguish each API in the presence of the other API(s) should be developed and validated,\n  - acceptance criteria for degradation products should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, its acceptance limits should in general be calculated with reference to the worst case (the API with the smaller area under the curve). Alternatively the content of such impurities could be calculated in relation to their reference standards.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas:\n\n1. **\u00bfQu\u00e9 tipo de est\u00e1ndares pueden ser declarados por el solicitante en las especificaciones del FPP?**\n   - El solicitante puede declarar un est\u00e1ndar oficialmente reconocido, como los compendios BP, JP, Ph.Eur., Ph.Int. o un est\u00e1ndar interno (de fabricante).\n\n2. **\u00bfCu\u00e1les son los requisitos m\u00ednimos de pruebas que deben incluirse en las especificaciones de un FPP seg\u00fan la gu\u00eda Q6A de ICH?**\n   - Las especificaciones deben incluir, como m\u00ednimo, pruebas para apariencia, identificaci\u00f3n, ensayo, pureza, pruebas de rendimiento (como disoluci\u00f3n), pruebas f\u00edsicas (como p\u00e9rdida por secado, dureza, friabilidad y tama\u00f1o de part\u00edcula), uniformidad de unidades de dosificaci\u00f3n, y, si corresponde, identificaci\u00f3n y ensayo de conservantes antimicrobianos o qu\u00edmicos y pruebas de l\u00edmite microbiano.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al establecer criterios de aceptaci\u00f3n para productos de degradaci\u00f3n en FDC-FPPs?**\n   - Los criterios de aceptaci\u00f3n para productos de degradaci\u00f3n deben establecerse con referencia al API del cual se derivan. Si una impureza resulta de una reacci\u00f3n qu\u00edmica entre dos o m\u00e1s APIs, sus l\u00edmites de aceptaci\u00f3n generalmente deben calcularse en relaci\u00f3n con el peor caso (el API con el \u00e1rea bajo la curva m\u00e1s peque\u00f1a). Alternativamente, el contenido de tales impurezas podr\u00eda calcularse en relaci\u00f3n con sus est\u00e1ndares de referencia.\n\n### Resumen de nivel superior del contexto:\nEl documento proporciona directrices sobre las especificaciones de productos farmac\u00e9uticos terminados (FPP) que deben ser presentadas por los solicitantes. Se requiere que las especificaciones sean firmadas por personal autorizado y que incluyan dos conjuntos de especificaciones: uno para el momento de la liberaci\u00f3n y otro para el final de la vida \u00fatil. Las especificaciones deben resumirse en tablas que incluyan pruebas, criterios de aceptaci\u00f3n y procedimientos anal\u00edticos, y deben cumplir con las recomendaciones de la gu\u00eda Q6A de ICH, que detalla pruebas m\u00ednimas necesarias y consideraciones espec\u00edficas para combinaciones de dosis fijas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Excipientes de Origen Humano o Animal**:\n   - Se requiere informaci\u00f3n sobre agentes adventicios, especificaciones, pruebas realizadas y datos de seguridad viral.\n   - Excipientes espec\u00edficos a abordar: gelatina, fosfatos, \u00e1cido estearico, estearato de magnesio y otros estearatos.\n   - Para excipientes de origen animal, se necesita una carta de atestaci\u00f3n sobre el riesgo de encefalopat\u00edas espongiformes.\n\n2. **Evitar Materiales de Origen Animal**:\n   - Se recomienda evitar el uso de materiales de origen animal siempre que sea posible.\n\n3. **Certificado de Excipiente (CEP)**:\n   - Se debe proporcionar un CEP que demuestre el cumplimiento de TSE, si est\u00e1 disponible.\n\n4. **Excipientes Novedosos**:\n   - Definici\u00f3n: Excipientes utilizados por primera vez en un FPP o por una nueva v\u00eda de administraci\u00f3n.\n   - No son aceptados en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS.\n   - Se requiere informaci\u00f3n completa sobre fabricaci\u00f3n, caracterizaci\u00f3n y controles, junto con datos de seguridad.\n\n5. **Control de FPP**:\n   - Se deben proporcionar especificaciones para el FPP, que incluyen pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n.\n   - Las especificaciones son est\u00e1ndares de calidad cr\u00edticos aprobados por autoridades regulatorias.\n\n### Entidades Clave\n- **Excipientes**: Gelatina, fosfatos, \u00e1cido estearico, estearato de magnesio.\n- **Documentos de Referencia**: ICH Q5A, Q5D, Q6B, WHO Technical Report Series, No. 908.\n- **Programas**: Programa de Precalificaci\u00f3n de Medicamentos de la OMS.\n- **Certificaci\u00f3n**: Certificado de Excipiente (CEP), carta de atestaci\u00f3n.", "excerpt_keywords": "Keywords: FPP specifications, quality control, ICH Q6A, analytical procedures, fixed-dose combination"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a3b9312e-b4fb-4150-a97c-7e00feeff40f", "node_type": "4", "metadata": {"page_label": "191", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "A copy of the FPP specification(s) from the applicant (as well as the company responsible for the batch release of the FPP, if different from the applicant), dated and signed by authorized personnel (i.e. the person in charge of the quality control or quality assurance department) should be provided in the PD. Two separate sets of specifications may be set out: after packaging of the FPP (release) and at the end of the shelf-life.\n\nThe specifications should be summarized according to the tables in the QOS-PD template including the tests, acceptance criteria and analytical procedures (listing types, sources and versions for the methods).\n\n- The standard declared by the applicant could be an officially recognized compendial standard (e.g. BP, JP, Ph.Eur., Ph.Int., USP) or an in-house (manufacturer\u2019s) standard.\n- The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes.\n- For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV or HPLC); the source refers to the origin of the analytical procedure (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and the version (e.g. code number/version/date) should be provided for version control purposes.\n\nICH\u2019s Q6A guideline outlines recommendations for a number of universal and specific tests and criteria for FPPs. Specifications should include, at a minimum, tests for appearance, identification, assay, purity, performance tests (e.g. dissolution), physical tests (e.g. loss on drying, hardness, friability and particle size), uniformity of dosage units, and, as applicable, identification and assay of antimicrobial or chemical preservatives (e.g. antioxidants) and microbial limit tests.\n\nThe following information provides guidance on specific tests that are not addressed by ICH\u2019s Q6A guideline:\n\n- fixed-dose combination FPPs (FDC-FPPs):\n  - analytical methods that can distinguish each API in the presence of the other API(s) should be developed and validated,\n  - acceptance criteria for degradation products should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, its acceptance limits should in general be calculated with reference to the worst case (the API with the smaller area under the curve). Alternatively the content of such impurities could be calculated in relation to their reference standards.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "38a25c22eb3db8fea4d6d3986bb4b7fab237e18146c155e37b4f55b00770bde5", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "A copy of the FPP specification(s) from the applicant (as well as the company responsible for the batch release of the FPP, if different from the applicant), dated and signed by authorized personnel (i.e. the person in charge of the quality control or quality assurance department) should be provided in the PD. Two separate sets of specifications may be set out: after packaging of the FPP (release) and at the end of the shelf-life.\n\nThe specifications should be summarized according to the tables in the QOS-PD template including the tests, acceptance criteria and analytical procedures (listing types, sources and versions for the methods).\n\n- The standard declared by the applicant could be an officially recognized compendial standard (e.g. BP, JP, Ph.Eur., Ph.Int., USP) or an in-house (manufacturer\u2019s) standard.\n- The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes.\n- For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV or HPLC); the source refers to the origin of the analytical procedure (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and the version (e.g. code number/version/date) should be provided for version control purposes.\n\nICH\u2019s Q6A guideline outlines recommendations for a number of universal and specific tests and criteria for FPPs. Specifications should include, at a minimum, tests for appearance, identification, assay, purity, performance tests (e.g. dissolution), physical tests (e.g. loss on drying, hardness, friability and particle size), uniformity of dosage units, and, as applicable, identification and assay of antimicrobial or chemical preservatives (e.g. antioxidants) and microbial limit tests.\n\nThe following information provides guidance on specific tests that are not addressed by ICH\u2019s Q6A guideline:\n\n- fixed-dose combination FPPs (FDC-FPPs):\n  - analytical methods that can distinguish each API in the presence of the other API(s) should be developed and validated,\n  - acceptance criteria for degradation products should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, its acceptance limits should in general be calculated with reference to the worst case (the API with the smaller area under the curve). Alternatively the content of such impurities could be calculated in relation to their reference standards.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2488, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "8aa6bd23-bceb-48d7-8388-588d0299feaa": {"__data__": {"id_": "8aa6bd23-bceb-48d7-8388-588d0299feaa", "embedding": null, "metadata": {"page_label": "192", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- A test and limit for content uniformity is required for each API present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit.\n- For the API(s) present at \u2265 5 mg and \u2265 5% of the weight of the dosage unit, a test and limit for weight variation may be established in lieu of content uniformity testing.\n\n- **Modified-release products**: A meaningful API release method.\n- **Inhalation and nasal products**: Consistency of delivered dose (throughout the use of the product), particle or droplet size distribution profiles (comparable to the product used in in vivo studies where applicable) and if applicable for the dosage form, moisture content, leak rate, microbial limits, preservative assay, sterility and weight loss.\n- **Suppositories**: Uniformity of dosage units, melting point.\n- **Transdermal dosage forms**: Peel or shear force, mean weight per unit area and dissolution.\n\nUnless there is appropriate justification, the acceptable limit for the API content of the FPP in the release specifications is \u00b1 5% of the label claim (i.e. 95.0\u2013105.0%).\n\nFor products such as tablets, capsules and suppositories where a test for uniformity of single-dose preparations is required, a test and limit for content uniformity is required when the API is present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit. Otherwise, the test for mass uniformity may be applied.\n\nSkip-testing is acceptable for parameters such as identification of colouring materials and microbial limits, when justified by the submission of acceptable supportive results for five production batches. When justification for skip-testing has been accepted the specifications should include a footnote, stating, at a minimum, the following skip-testing requirements: at least every tenth batch and at least one batch annually is tested. In addition, for stability-indicating parameters such as microbial limits, testing will be performed at release and at the end of shelf-life during stability studies.\n\nAny differences between release and shelf-life tests and acceptance criteria should be clearly indicated and justified. Note that such differences for parameters such as dissolution are normally not accepted.\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS establece directrices sobre las especificaciones para preparaciones farmac\u00e9uticas, enfoc\u00e1ndose en la uniformidad del contenido y variaciones de peso de los ingredientes activos (API) en productos farmac\u00e9uticos. Se detallan pruebas espec\u00edficas para diferentes formas de dosificaci\u00f3n, como productos de liberaci\u00f3n modificada, inhalaci\u00f3n, supositorios y formas transd\u00e9rmicas. Tambi\u00e9n se menciona la aceptaci\u00f3n de pruebas de omisi\u00f3n bajo ciertas condiciones y la necesidad de justificar cualquier diferencia entre las pruebas de liberaci\u00f3n y las de vida \u00fatil.\n\n### Preguntas Espec\u00edficas:\n\n1. **\u00bfQu\u00e9 criterios se deben cumplir para establecer un l\u00edmite de variaci\u00f3n de peso en lugar de una prueba de uniformidad de contenido para los API en productos farmac\u00e9uticos?**\n   - Respuesta: Un l\u00edmite de variaci\u00f3n de peso puede establecerse en lugar de una prueba de uniformidad de contenido si el API est\u00e1 presente en cantidades de \u2265 5 mg y \u2265 5% del peso de la unidad de dosificaci\u00f3n.\n\n2. **\u00bfCu\u00e1les son los requisitos de prueba para productos de inhalaci\u00f3n y nasales seg\u00fan el documento?**\n   - Respuesta: Para productos de inhalaci\u00f3n y nasales, se requiere consistencia en la dosis entregada, perfiles de distribuci\u00f3n del tama\u00f1o de part\u00edculas o gotas, y, si es aplicable, contenido de humedad, tasa de fuga, l\u00edmites microbianos, ensayo de conservantes, esterilidad y p\u00e9rdida de peso.\n\n3. **\u00bfQu\u00e9 condiciones justifican la aceptaci\u00f3n de pruebas de omisi\u00f3n para par\u00e1metros como la identificaci\u00f3n de materiales colorantes y l\u00edmites microbianos?**\n   - Respuesta: Las pruebas de omisi\u00f3n son aceptables si se presenta una justificaci\u00f3n mediante resultados de apoyo aceptables de cinco lotes de producci\u00f3n. Adem\u00e1s, las especificaciones deben incluir una nota al pie que indique que al menos cada d\u00e9cimo lote y al menos un lote anualmente ser\u00e1n probados.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Especificaciones de Productos Farmac\u00e9uticos Terminados (FPP)**:\n   - Se requiere una copia de las especificaciones del FPP firmada y fechada por personal autorizado.\n   - Deben presentarse dos conjuntos de especificaciones: uno para el momento de liberaci\u00f3n y otro para el final de la vida \u00fatil.\n\n2. **Est\u00e1ndares**:\n   - Los est\u00e1ndares pueden ser compendiales (BP, JP, Ph.Eur., Ph.Int., USP) o internos (de fabricante).\n   - Se debe proporcionar el n\u00famero de referencia y la versi\u00f3n de las especificaciones para control de versiones.\n\n3. **Procedimientos Anal\u00edticos**:\n   - Los procedimientos deben indicar el tipo (visual, IR, UV, HPLC), la fuente (compendios o internos) y la versi\u00f3n para control de versiones.\n\n4. **Gu\u00eda ICH Q6A**:\n   - Establece recomendaciones para pruebas y criterios m\u00ednimos que deben incluirse en las especificaciones de FPP.\n   - Pruebas m\u00ednimas incluyen: apariencia, identificaci\u00f3n, ensayo, pureza, pruebas de rendimiento (disoluci\u00f3n), pruebas f\u00edsicas (p\u00e9rdida por secado, dureza, friabilidad, tama\u00f1o de part\u00edcula), uniformidad de unidades de dosificaci\u00f3n, y pruebas de conservantes antimicrobianos o qu\u00edmicos.\n\n5. **Combinaciones de Dosis Fijas (FDC-FPPs)**:\n   - Se deben desarrollar y validar m\u00e9todos anal\u00edticos que distingan cada API en presencia de otros APIs.\n   - Los criterios de aceptaci\u00f3n para productos de degradaci\u00f3n deben establecerse en relaci\u00f3n con el API del cual derivan, considerando el peor caso en caso de impurezas resultantes de reacciones entre APIs.\n\n### Entidades Clave\n- **FPP (Producto Farmac\u00e9utico Terminado)**\n- **Est\u00e1ndares Compendiales**: BP, JP, Ph.Eur., Ph.Int., USP\n- **Gu\u00eda ICH Q6A**\n- **API (Ingrediente Activo)**\n- **Personal Autorizado**: Responsable de control de calidad o aseguramiento de calidad. \n\nEste resumen destaca los aspectos esenciales relacionados con la presentaci\u00f3n de especificaciones para productos farmac\u00e9uticos, los est\u00e1ndares aplicables, los procedimientos anal\u00edticos requeridos y las consideraciones espec\u00edficas para combinaciones de dosis fijas.", "excerpt_keywords": "Keywords: pharmaceutical preparations, content uniformity, active pharmaceutical ingredient, testing specifications, skip-testing"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "12a0ec0a-d943-484f-8400-b221d1cc86eb", "node_type": "4", "metadata": {"page_label": "192", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- A test and limit for content uniformity is required for each API present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit.\n- For the API(s) present at \u2265 5 mg and \u2265 5% of the weight of the dosage unit, a test and limit for weight variation may be established in lieu of content uniformity testing.\n\n- **Modified-release products**: A meaningful API release method.\n- **Inhalation and nasal products**: Consistency of delivered dose (throughout the use of the product), particle or droplet size distribution profiles (comparable to the product used in in vivo studies where applicable) and if applicable for the dosage form, moisture content, leak rate, microbial limits, preservative assay, sterility and weight loss.\n- **Suppositories**: Uniformity of dosage units, melting point.\n- **Transdermal dosage forms**: Peel or shear force, mean weight per unit area and dissolution.\n\nUnless there is appropriate justification, the acceptable limit for the API content of the FPP in the release specifications is \u00b1 5% of the label claim (i.e. 95.0\u2013105.0%).\n\nFor products such as tablets, capsules and suppositories where a test for uniformity of single-dose preparations is required, a test and limit for content uniformity is required when the API is present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit. Otherwise, the test for mass uniformity may be applied.\n\nSkip-testing is acceptable for parameters such as identification of colouring materials and microbial limits, when justified by the submission of acceptable supportive results for five production batches. When justification for skip-testing has been accepted the specifications should include a footnote, stating, at a minimum, the following skip-testing requirements: at least every tenth batch and at least one batch annually is tested. In addition, for stability-indicating parameters such as microbial limits, testing will be performed at release and at the end of shelf-life during stability studies.\n\nAny differences between release and shelf-life tests and acceptance criteria should be clearly indicated and justified. Note that such differences for parameters such as dissolution are normally not accepted.\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4e9414e8513b5cf9d69bb3e00e444e4d5224f41395b5717e94e482ed03863251", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- A test and limit for content uniformity is required for each API present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit.\n- For the API(s) present at \u2265 5 mg and \u2265 5% of the weight of the dosage unit, a test and limit for weight variation may be established in lieu of content uniformity testing.\n\n- **Modified-release products**: A meaningful API release method.\n- **Inhalation and nasal products**: Consistency of delivered dose (throughout the use of the product), particle or droplet size distribution profiles (comparable to the product used in in vivo studies where applicable) and if applicable for the dosage form, moisture content, leak rate, microbial limits, preservative assay, sterility and weight loss.\n- **Suppositories**: Uniformity of dosage units, melting point.\n- **Transdermal dosage forms**: Peel or shear force, mean weight per unit area and dissolution.\n\nUnless there is appropriate justification, the acceptable limit for the API content of the FPP in the release specifications is \u00b1 5% of the label claim (i.e. 95.0\u2013105.0%).\n\nFor products such as tablets, capsules and suppositories where a test for uniformity of single-dose preparations is required, a test and limit for content uniformity is required when the API is present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit. Otherwise, the test for mass uniformity may be applied.\n\nSkip-testing is acceptable for parameters such as identification of colouring materials and microbial limits, when justified by the submission of acceptable supportive results for five production batches. When justification for skip-testing has been accepted the specifications should include a footnote, stating, at a minimum, the following skip-testing requirements: at least every tenth batch and at least one batch annually is tested. In addition, for stability-indicating parameters such as microbial limits, testing will be performed at release and at the end of shelf-life during stability studies.\n\nAny differences between release and shelf-life tests and acceptance criteria should be clearly indicated and justified. Note that such differences for parameters such as dissolution are normally not accepted.\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2364, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "5e5c765a-94b3-401f-ab44-47daeba41cbd": {"__data__": {"id_": "5e5c765a-94b3-401f-ab44-47daeba41cbd", "embedding": null, "metadata": {"page_label": "193", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.5.2 Analytical procedures (name, dosage form)\n\n**The analytical procedures used for testing the FPP should be provided.**\n\nCopies of the in-house analytical procedures used during pharmaceutical development (if used to generate testing results provided in the PD) as well as those proposed for routine testing should be provided. Unless modified it is not necessary to provide copies of analytical procedures described in officially recognized compendia.\n\nTables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.\n\nRefer to section 3.2.S.4.2 of these guidelines for additional guidance on analytical procedures.\n\nReference document: ICH Q2 (16).\n\n# 3.2.P.5.3 Validation of analytical procedures (name, dosage form)\n\n**Analytical validation information, including experimental data, for the analytical procedures used for testing the FPP, should be provided.**\n\nCopies of the validation reports for the in-house analytical procedures used during pharmaceutical development (if used to support testing results provided in the PD) as well as those proposed for routine testing should be provided.\n\nTables for summarizing a number of the different analytical procedures and validation information (e.g. HPLC assay and impurity methods, and GC methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.\n\nAs recognized by regulatory authorities and pharmacopoeias themselves, verification of compendial methods can be necessary. The compendial methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. The same API or FPP obtained from different sources can contain impurities and/or degradation products or excipients that were not considered during the development of the monograph. Therefore, the monograph and compendial method(s) should be demonstrated suitable for the control of the proposed FPP.\n\nFor officially recognized compendial FPP assay methods, verification should include a demonstration of specificity, accuracy and repeatability (method precision). If an officially recognized compendial method is used to control related substances that are not specified in the monograph, full validation of the method is expected with respect to those related substances.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los procedimientos anal\u00edticos y la validaci\u00f3n de estos procedimientos para la prueba de productos farmac\u00e9uticos terminados (FPP). Se enfatiza la importancia de proporcionar copias de los procedimientos anal\u00edticos utilizados durante el desarrollo farmac\u00e9utico y aquellos propuestos para pruebas rutinarias. Adem\u00e1s, se menciona que, aunque no es necesario proporcionar procedimientos descritos en compendios reconocidos oficialmente, se deben incluir tablas para resumir la informaci\u00f3n anal\u00edtica y de validaci\u00f3n. Tambi\u00e9n se destaca la necesidad de verificar m\u00e9todos compendiales, especialmente cuando se utilizan para controlar sustancias relacionadas no especificadas en la monograf\u00eda.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n se debe incluir en las tablas para resumir los procedimientos anal\u00edticos y la validaci\u00f3n de estos?**\n   - Las tablas deben resumir los procedimientos anal\u00edticos utilizados para la determinaci\u00f3n del ensayo, sustancias relacionadas y disoluci\u00f3n del FPP, as\u00ed como la informaci\u00f3n de validaci\u00f3n correspondiente, como m\u00e9todos de HPLC y GC.\n\n2. **\u00bfPor qu\u00e9 es importante verificar los m\u00e9todos compendiales utilizados para el control de FPP?**\n   - Es importante porque los m\u00e9todos compendiales pueden estar validados con base en un API o FPP de un fabricante espec\u00edfico, y el mismo API o FPP de diferentes fuentes puede contener impurezas o productos de degradaci\u00f3n no considerados en la monograf\u00eda original.\n\n3. **\u00bfQu\u00e9 aspectos deben demostrarse al verificar m\u00e9todos de ensayo compendiales oficialmente reconocidos?**\n   - Se debe demostrar la especificidad, precisi\u00f3n (repetibilidad) y exactitud del m\u00e9todo. Si se utiliza un m\u00e9todo compendial para controlar sustancias relacionadas no especificadas en la monograf\u00eda, se espera una validaci\u00f3n completa del m\u00e9todo respecto a esas sustancias.", "prev_section_summary": "### Temas Clave:\n\n1. **Uniformidad de Contenido y Variaci\u00f3n de Peso**:\n   - Se requiere una prueba de uniformidad de contenido para cada ingrediente activo (API) presente en la forma farmac\u00e9utica final (FPP) si est\u00e1 en cantidades de menos de 5 mg o menos del 5% del peso de la unidad de dosificaci\u00f3n.\n   - Para API presentes en cantidades de \u2265 5 mg y \u2265 5% del peso de la unidad de dosificaci\u00f3n, se puede establecer un l\u00edmite de variaci\u00f3n de peso en lugar de realizar una prueba de uniformidad de contenido.\n\n2. **Requisitos Espec\u00edficos para Diferentes Formas de Dosificaci\u00f3n**:\n   - **Productos de Liberaci\u00f3n Modificada**: M\u00e9todo significativo de liberaci\u00f3n del API.\n   - **Productos de Inhalaci\u00f3n y Nasales**: Consistencia en la dosis entregada, distribuci\u00f3n del tama\u00f1o de part\u00edculas o gotas, y otros par\u00e1metros como contenido de humedad y l\u00edmites microbianos.\n   - **Supositorios**: Uniformidad de las unidades de dosificaci\u00f3n y punto de fusi\u00f3n.\n   - **Formas Transd\u00e9rmicas**: Fuerza de pelado o corte, peso medio por unidad de \u00e1rea y disoluci\u00f3n.\n\n3. **L\u00edmites de Contenido del API**:\n   - El l\u00edmite aceptable para el contenido del API en las especificaciones de liberaci\u00f3n es \u00b1 5% de la declaraci\u00f3n en la etiqueta (95.0\u2013105.0%).\n\n4. **Pruebas de Omissi\u00f3n**:\n   - Se aceptan pruebas de omisi\u00f3n para ciertos par\u00e1metros si se justifica con resultados de cinco lotes de producci\u00f3n. Las especificaciones deben incluir requisitos claros sobre la frecuencia de las pruebas.\n\n5. **Diferencias entre Pruebas de Liberaci\u00f3n y Vida \u00datil**:\n   - Cualquier diferencia entre las pruebas de liberaci\u00f3n y las de vida \u00fatil debe ser claramente indicada y justificada, especialmente para par\u00e1metros como la disoluci\u00f3n.\n\n### Entidades:\n\n- **Organizaci\u00f3n**: Organizaci\u00f3n Mundial de la Salud (OMS)\n- **Documentos de Referencia**: ICH Q3B, Q3C, Q6A\n- **Formas Farmac\u00e9uticas**: FPP, productos de liberaci\u00f3n modificada, productos de inhalaci\u00f3n, supositorios, formas transd\u00e9rmicas.\n- **Par\u00e1metros de Prueba**: Uniformidad de contenido, variaci\u00f3n de peso, consistencia de dosis, distribuci\u00f3n de tama\u00f1o de part\u00edculas, l\u00edmites microbianos, pruebas de omisi\u00f3n. \n\nEste resumen abarca los aspectos esenciales del documento, destacando las directrices sobre las especificaciones para preparaciones farmac\u00e9uticas y los requisitos de prueba para diferentes formas de dosificaci\u00f3n.", "excerpt_keywords": "Keywords: analytical procedures, validation, pharmaceutical development, compendial methods, FPP testing"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e41b0a82-7760-44a4-9324-9066fd11abec", "node_type": "4", "metadata": {"page_label": "193", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.5.2 Analytical procedures (name, dosage form)\n\n**The analytical procedures used for testing the FPP should be provided.**\n\nCopies of the in-house analytical procedures used during pharmaceutical development (if used to generate testing results provided in the PD) as well as those proposed for routine testing should be provided. Unless modified it is not necessary to provide copies of analytical procedures described in officially recognized compendia.\n\nTables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.\n\nRefer to section 3.2.S.4.2 of these guidelines for additional guidance on analytical procedures.\n\nReference document: ICH Q2 (16).\n\n# 3.2.P.5.3 Validation of analytical procedures (name, dosage form)\n\n**Analytical validation information, including experimental data, for the analytical procedures used for testing the FPP, should be provided.**\n\nCopies of the validation reports for the in-house analytical procedures used during pharmaceutical development (if used to support testing results provided in the PD) as well as those proposed for routine testing should be provided.\n\nTables for summarizing a number of the different analytical procedures and validation information (e.g. HPLC assay and impurity methods, and GC methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.\n\nAs recognized by regulatory authorities and pharmacopoeias themselves, verification of compendial methods can be necessary. The compendial methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. The same API or FPP obtained from different sources can contain impurities and/or degradation products or excipients that were not considered during the development of the monograph. Therefore, the monograph and compendial method(s) should be demonstrated suitable for the control of the proposed FPP.\n\nFor officially recognized compendial FPP assay methods, verification should include a demonstration of specificity, accuracy and repeatability (method precision). If an officially recognized compendial method is used to control related substances that are not specified in the monograph, full validation of the method is expected with respect to those related substances.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "82958d6f4c841abfe3da0656690748b3d0ce5df439c9b999e6e2964215cfe287", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.P.5.2 Analytical procedures (name, dosage form)\n\n**The analytical procedures used for testing the FPP should be provided.**\n\nCopies of the in-house analytical procedures used during pharmaceutical development (if used to generate testing results provided in the PD) as well as those proposed for routine testing should be provided. Unless modified it is not necessary to provide copies of analytical procedures described in officially recognized compendia.\n\nTables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.\n\nRefer to section 3.2.S.4.2 of these guidelines for additional guidance on analytical procedures.\n\nReference document: ICH Q2 (16).\n\n# 3.2.P.5.3 Validation of analytical procedures (name, dosage form)\n\n**Analytical validation information, including experimental data, for the analytical procedures used for testing the FPP, should be provided.**\n\nCopies of the validation reports for the in-house analytical procedures used during pharmaceutical development (if used to support testing results provided in the PD) as well as those proposed for routine testing should be provided.\n\nTables for summarizing a number of the different analytical procedures and validation information (e.g. HPLC assay and impurity methods, and GC methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.\n\nAs recognized by regulatory authorities and pharmacopoeias themselves, verification of compendial methods can be necessary. The compendial methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. The same API or FPP obtained from different sources can contain impurities and/or degradation products or excipients that were not considered during the development of the monograph. Therefore, the monograph and compendial method(s) should be demonstrated suitable for the control of the proposed FPP.\n\nFor officially recognized compendial FPP assay methods, verification should include a demonstration of specificity, accuracy and repeatability (method precision). If an officially recognized compendial method is used to control related substances that are not specified in the monograph, full validation of the method is expected with respect to those related substances.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2768, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "b7c512d7-9408-4eee-8637-818ce85dbf5d": {"__data__": {"id_": "b7c512d7-9408-4eee-8637-818ce85dbf5d", "embedding": null, "metadata": {"page_label": "194", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIf an officially recognized compendial standard is claimed and an in-house method is used in lieu of the compendial method (e.g. for assay or for related compounds), equivalence of the in-house and compendial methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For methods for the determination of related compounds, the sample analysed should be the placebo spiked with related compounds at concentrations equivalent to their specification limits.\n\nReference document: ICH Q2 (16).\n\n## 3.2.P5.4 Batch analyses (name, dosage form)\n\nA description of batches and results of batch analyses should be provided.\n\nInformation on relevant FPP batches used to establish the specifications and evaluate consistency in manufacturing should be provided and should include strength and batch number, batch size, date and site of production and use (e.g. used in comparative bioavailability or biowaiver studies, preclinical and clinical studies (if relevant), stability, pilot, scale-up and, if available, production-scale batches).\n\nAnalytical results generated by the company responsible for the batch release of the FPP (generally the applicant or the FPP manufacturer, if different from the applicant) should be provided for not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions), or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nThe results should include those of tests on the batch(es) used in the comparative bioavailability or biowaiver studies. Copies of the certificates of analysis for these batches should be provided in the PD and the company responsible for generating the testing results should be identified.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. The discussion should include ranges of analytical results, where relevant. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than...\n\n----\n\n*The term \u201ccomplicated FPP\u201d includes sterile products, metered dose inhaler products, dry powder inhaler products and transdermal delivery systems. Other specific products under \u201ccomplicated FPP\u201d include ritonavir/lopinavir FDC tablets and FDCs containing rifampicin or an artemisinin. As the invitations for EOI change over time, the listing of individual \u201ccomplicated FPPs\u201d is not meaningful and applicants should contact the Head of Assessments, WHO Prequalification of Medicines Programme in case of doubt.*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS se centra en las especificaciones para preparaciones farmac\u00e9uticas y establece directrices sobre c\u00f3mo demostrar la equivalencia entre m\u00e9todos anal\u00edticos in-house y compendiales. Tambi\u00e9n detalla los requisitos para el an\u00e1lisis de lotes, incluyendo la informaci\u00f3n necesaria sobre los lotes de productos farmac\u00e9uticos terminados (FPP) y la importancia de proporcionar resultados anal\u00edticos y certificados de an\u00e1lisis. Se menciona la distinci\u00f3n entre FPP sencillos y complicados, as\u00ed como la necesidad de un enfoque detallado en la discusi\u00f3n de resultados anal\u00edticos.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 pasos deben seguirse para demostrar la equivalencia entre un m\u00e9todo anal\u00edtico in-house y un m\u00e9todo compendial?**\n   - El contexto menciona que se debe realizar un an\u00e1lisis duplicado de una muestra utilizando ambos m\u00e9todos y proporcionar los resultados del estudio, as\u00ed como utilizar un placebo spiked con compuestos relacionados en concentraciones equivalentes a sus l\u00edmites de especificaci\u00f3n.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la descripci\u00f3n de los lotes de productos farmac\u00e9uticos terminados (FPP) para cumplir con las especificaciones de la OMS?**\n   - La descripci\u00f3n debe incluir la fuerza y el n\u00famero de lote, el tama\u00f1o del lote, la fecha y el sitio de producci\u00f3n, y el uso del lote en estudios de bioequivalencia, estudios cl\u00ednicos, estabilidad, entre otros.\n\n3. **\u00bfCu\u00e1ntos lotes de FPP deben analizarse y qu\u00e9 criterios deben cumplirse para los an\u00e1lisis de lotes en el caso de FPP sencillos y complicados?**\n   - Para FPP sencillos, se debe proporcionar al menos un lote de escala piloto y un segundo lote que puede ser m\u00e1s peque\u00f1o. Para FPP complicados, se deben proporcionar resultados de al menos dos lotes de escala piloto. Adem\u00e1s, los lotes deben ser representativos del proceso que se aplicar\u00e1 a un lote de producci\u00f3n a gran escala.", "prev_section_summary": "### Temas Clave\n\n1. **Procedimientos Anal\u00edticos**: Se requiere proporcionar copias de los procedimientos anal\u00edticos utilizados para la prueba de productos farmac\u00e9uticos terminados (FPP), tanto los desarrollados internamente como los propuestos para pruebas rutinarias. No es necesario incluir procedimientos de compendios reconocidos, a menos que se hayan modificado.\n\n2. **Tablas de Resumen**: Se deben utilizar tablas para resumir los procedimientos anal\u00edticos y la informaci\u00f3n de validaci\u00f3n, incluyendo m\u00e9todos como HPLC y GC, para la determinaci\u00f3n del ensayo, sustancias relacionadas y disoluci\u00f3n del FPP.\n\n3. **Validaci\u00f3n de Procedimientos Anal\u00edticos**: Es esencial proporcionar informaci\u00f3n de validaci\u00f3n anal\u00edtica, incluyendo datos experimentales y copias de los informes de validaci\u00f3n para los procedimientos anal\u00edticos utilizados.\n\n4. **Verificaci\u00f3n de M\u00e9todos Compendiales**: Se destaca la necesidad de verificar los m\u00e9todos compendiales, ya que pueden no ser adecuados para FPP de diferentes fuentes debido a impurezas o productos de degradaci\u00f3n no considerados en la monograf\u00eda original.\n\n5. **Aspectos de Verificaci\u00f3n**: Para los m\u00e9todos de ensayo compendiales reconocidos oficialmente, se debe demostrar especificidad, precisi\u00f3n y exactitud. Si se utilizan para controlar sustancias no especificadas en la monograf\u00eda, se requiere una validaci\u00f3n completa.\n\n### Entidades\n\n- **FPP (Productos Farmac\u00e9uticos Terminados)**: El objeto de las pruebas y procedimientos anal\u00edticos.\n- **HPLC (Cromatograf\u00eda L\u00edquida de Alta Eficiencia)**: Un m\u00e9todo anal\u00edtico mencionado para la determinaci\u00f3n de ensayos y sustancias relacionadas.\n- **GC (Cromatograf\u00eda de Gases)**: Otro m\u00e9todo anal\u00edtico mencionado para la validaci\u00f3n.\n- **ICH Q2**: Documento de referencia mencionado para guiar los procedimientos anal\u00edticos y su validaci\u00f3n.\n- **Compendios Reconocidos**: Fuentes oficiales que describen m\u00e9todos anal\u00edticos que pueden no requerir validaci\u00f3n adicional si no se modifican.\n\nEste resumen abarca los aspectos fundamentales y las entidades relevantes en la secci\u00f3n proporcionada del documento de la OMS.", "excerpt_keywords": "Keywords: pharmaceutical preparations, compendial methods, batch analyses, bioequivalence, analytical results"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "033a8462-0e8a-496a-9197-3aa5b0140c6a", "node_type": "4", "metadata": {"page_label": "194", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIf an officially recognized compendial standard is claimed and an in-house method is used in lieu of the compendial method (e.g. for assay or for related compounds), equivalence of the in-house and compendial methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For methods for the determination of related compounds, the sample analysed should be the placebo spiked with related compounds at concentrations equivalent to their specification limits.\n\nReference document: ICH Q2 (16).\n\n## 3.2.P5.4 Batch analyses (name, dosage form)\n\nA description of batches and results of batch analyses should be provided.\n\nInformation on relevant FPP batches used to establish the specifications and evaluate consistency in manufacturing should be provided and should include strength and batch number, batch size, date and site of production and use (e.g. used in comparative bioavailability or biowaiver studies, preclinical and clinical studies (if relevant), stability, pilot, scale-up and, if available, production-scale batches).\n\nAnalytical results generated by the company responsible for the batch release of the FPP (generally the applicant or the FPP manufacturer, if different from the applicant) should be provided for not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions), or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nThe results should include those of tests on the batch(es) used in the comparative bioavailability or biowaiver studies. Copies of the certificates of analysis for these batches should be provided in the PD and the company responsible for generating the testing results should be identified.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. The discussion should include ranges of analytical results, where relevant. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than...\n\n----\n\n*The term \u201ccomplicated FPP\u201d includes sterile products, metered dose inhaler products, dry powder inhaler products and transdermal delivery systems. Other specific products under \u201ccomplicated FPP\u201d include ritonavir/lopinavir FDC tablets and FDCs containing rifampicin or an artemisinin. As the invitations for EOI change over time, the listing of individual \u201ccomplicated FPPs\u201d is not meaningful and applicants should contact the Head of Assessments, WHO Prequalification of Medicines Programme in case of doubt.*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "ffc8d83844c03f254ccbc93a3eceec577f655f23c0e2724c47ea554b82b88f5f", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIf an officially recognized compendial standard is claimed and an in-house method is used in lieu of the compendial method (e.g. for assay or for related compounds), equivalence of the in-house and compendial methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For methods for the determination of related compounds, the sample analysed should be the placebo spiked with related compounds at concentrations equivalent to their specification limits.\n\nReference document: ICH Q2 (16).\n\n## 3.2.P5.4 Batch analyses (name, dosage form)\n\nA description of batches and results of batch analyses should be provided.\n\nInformation on relevant FPP batches used to establish the specifications and evaluate consistency in manufacturing should be provided and should include strength and batch number, batch size, date and site of production and use (e.g. used in comparative bioavailability or biowaiver studies, preclinical and clinical studies (if relevant), stability, pilot, scale-up and, if available, production-scale batches).\n\nAnalytical results generated by the company responsible for the batch release of the FPP (generally the applicant or the FPP manufacturer, if different from the applicant) should be provided for not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions), or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nThe results should include those of tests on the batch(es) used in the comparative bioavailability or biowaiver studies. Copies of the certificates of analysis for these batches should be provided in the PD and the company responsible for generating the testing results should be identified.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. The discussion should include ranges of analytical results, where relevant. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than...\n\n----\n\n*The term \u201ccomplicated FPP\u201d includes sterile products, metered dose inhaler products, dry powder inhaler products and transdermal delivery systems. Other specific products under \u201ccomplicated FPP\u201d include ritonavir/lopinavir FDC tablets and FDCs containing rifampicin or an artemisinin. As the invitations for EOI change over time, the listing of individual \u201ccomplicated FPPs\u201d is not meaningful and applicants should contact the Head of Assessments, WHO Prequalification of Medicines Programme in case of doubt.*", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3124, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "8a07a5c3-048e-4dd9-b7fe-b5aca023d606": {"__data__": {"id_": "8a07a5c3-048e-4dd9-b7fe-b5aca023d606", "embedding": null, "metadata": {"page_label": "195", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\nthan vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d (e.g. \u201clevels of degradation product A ranged from 0.2 to 0.4%\u201d). Dissolution results should be expressed, at a minimum, as both the average and the range of individual results. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.\n\nA discussion and justification should be provided for any incomplete analyses (e.g. for any parameters not tested according to the proposed specification).\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).\n\n## 3.2.P.5.5 Characterization of impurities (name, dosage form)\n\n**Information on the characterization of impurities should be provided, if not previously provided in \u201c3.2.S.3.2 Impurities\u201d.**\n\nA discussion should be provided of all impurities that are potential degradation products (including those among the impurities identified in 3.2.S.3.2 as well as potential degradation products resulting from interaction of the API with other APIs (FDCs), excipients or the container-closure system) and FPP process-related impurities (e.g. residual solvents in the manufacturing process for the FPP).\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).\n\n## 3.2.P.5.6 Justification of specification(s) (name, dosage form)\n\n**Justification for the proposed FPP specification(s) should be provided.**\n\nA discussion should be provided on the omission or inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendial standard(s). If the officially recognized compendial methods have been modified or replaced, a discussion should be included.\n\nThe justification for certain tests, analytical procedures and acceptance criteria (e.g. degradation products or dissolution method development) may have been discussed in other sections of the PD and would not need to be repeated here, although a cross-reference should be provided.\n\nICH Q6A (6) should be consulted for the development of specifications for FPPs.\n\n## 3.2.P.6 Reference standards or materials (name, dosage form)\n\n**Information on the reference standards or reference materials used for testing of the FPP should be provided, if not previously provided in \u201c3.2.S.5 Reference standards or materials\u201d.**\n\nSee section 3.2.S.5 for information that should be provided on reference standards or materials. Information should be provided on reference materials of FPP degradation products, where not included in 3.2.S.5.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con respuestas espec\u00edficas que probablemente no se encuentren en otro lugar:\n\n### Preguntas y Respuestas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n se debe incluir en la caracterizaci\u00f3n de impurezas seg\u00fan la secci\u00f3n 3.2.P.5.5?**\n   - La caracterizaci\u00f3n de impurezas debe incluir una discusi\u00f3n sobre todas las impurezas que son productos de degradaci\u00f3n potenciales, incluyendo aquellas identificadas en la secci\u00f3n 3.2.S.3.2 y los productos de degradaci\u00f3n resultantes de la interacci\u00f3n del principio activo (API) con otros APIs, excipientes o el sistema de cierre del envase. Tambi\u00e9n se deben considerar las impurezas relacionadas con el proceso de fabricaci\u00f3n del producto farmac\u00e9utico terminado (FPP), como los solventes residuales.\n\n2. **\u00bfQu\u00e9 justificaci\u00f3n se requiere para las especificaciones propuestas en la secci\u00f3n 3.2.P.5.6?**\n   - Se debe proporcionar una discusi\u00f3n sobre la omisi\u00f3n o inclusi\u00f3n de ciertas pruebas, la evoluci\u00f3n de las pruebas, los procedimientos anal\u00edticos y los criterios de aceptaci\u00f3n, as\u00ed como las diferencias con respecto a los est\u00e1ndares oficialmente reconocidos. Si se han modificado o reemplazado m\u00e9todos compendiales reconocidos, tambi\u00e9n se debe incluir una discusi\u00f3n sobre ello. Adem\u00e1s, se puede hacer referencia a justificaciones discutidas en otras secciones del documento.\n\n3. **\u00bfQu\u00e9 tipo de informaci\u00f3n se debe proporcionar sobre los est\u00e1ndares o materiales de referencia en la secci\u00f3n 3.2.P.6?**\n   - Se debe proporcionar informaci\u00f3n sobre los est\u00e1ndares de referencia o materiales de referencia utilizados para las pruebas del FPP, si no se ha proporcionado previamente en la secci\u00f3n 3.2.S.5. Esto incluye informaci\u00f3n sobre materiales de referencia de los productos de degradaci\u00f3n del FPP que no est\u00e9n incluidos en la secci\u00f3n 3.2.S.5.\n\n### Resumen de Nivel Superior\n\nEl contexto se centra en las directrices de la OMS sobre la caracterizaci\u00f3n de impurezas y la justificaci\u00f3n de especificaciones en productos farmac\u00e9uticos. Se enfatiza la importancia de proporcionar informaci\u00f3n detallada sobre las impurezas, los m\u00e9todos de prueba y los est\u00e1ndares de referencia. Las secciones mencionadas abordan la necesidad de una discusi\u00f3n clara y justificada sobre los an\u00e1lisis realizados, as\u00ed como la inclusi\u00f3n de datos espec\u00edficos sobre productos de degradaci\u00f3n y su impacto en la calidad del producto farmac\u00e9utico terminado.", "prev_section_summary": "### Temas Clave\n\n1. **Equivalencia de M\u00e9todos Anal\u00edticos**: Se establece la necesidad de demostrar la equivalencia entre un m\u00e9todo anal\u00edtico in-house y un m\u00e9todo compendial mediante an\u00e1lisis duplicados de una muestra y el uso de placebos spiked con compuestos relacionados.\n\n2. **An\u00e1lisis de Lotes de Productos Farmac\u00e9uticos Terminados (FPP)**: Se requiere una descripci\u00f3n detallada de los lotes, incluyendo fuerza, n\u00famero de lote, tama\u00f1o, fecha y sitio de producci\u00f3n, as\u00ed como su uso en estudios relevantes.\n\n3. **Requisitos de An\u00e1lisis**: Para FPP sencillos, se debe proporcionar al menos un lote de escala piloto y un segundo lote m\u00e1s peque\u00f1o. Para FPP complicados, se deben analizar al menos dos lotes de escala piloto.\n\n4. **Resultados Anal\u00edticos**: Los resultados de los an\u00e1lisis deben ser presentados de manera detallada, enfoc\u00e1ndose en observaciones y rangos de resultados, en lugar de simplemente afirmar que \"todos los tests cumplen con las especificaciones\".\n\n5. **Clasificaci\u00f3n de FPP**: Se distingue entre FPP sencillos y complicados, con ejemplos espec\u00edficos de productos que caen en cada categor\u00eda.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las directrices.\n- **ICH Q2**: Documento de referencia mencionado para la equivalencia de m\u00e9todos.\n- **FPP (Formulaci\u00f3n Farmac\u00e9utica Terminada)**: T\u00e9rmino utilizado para referirse a los productos farmac\u00e9uticos que se analizan.\n- **Compuestos Relacionados**: Sustancias que se analizan junto con el producto principal para determinar su calidad.\n- **Lotes**: Unidades de producci\u00f3n que deben ser analizadas y documentadas.\n- **Complicados FPP**: Categor\u00eda que incluye productos como inhaladores y sistemas de entrega transd\u00e9rmica.\n\nEste resumen proporciona una visi\u00f3n general de los puntos clave y las entidades relevantes en la secci\u00f3n del documento de la OMS sobre especificaciones para preparaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: impurities, specifications, degradation products, reference standards, dissolution profiles"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6950dd7e-50e1-4a20-a736-b1ec18fc0dc9", "node_type": "4", "metadata": {"page_label": "195", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\nthan vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d (e.g. \u201clevels of degradation product A ranged from 0.2 to 0.4%\u201d). Dissolution results should be expressed, at a minimum, as both the average and the range of individual results. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.\n\nA discussion and justification should be provided for any incomplete analyses (e.g. for any parameters not tested according to the proposed specification).\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).\n\n## 3.2.P.5.5 Characterization of impurities (name, dosage form)\n\n**Information on the characterization of impurities should be provided, if not previously provided in \u201c3.2.S.3.2 Impurities\u201d.**\n\nA discussion should be provided of all impurities that are potential degradation products (including those among the impurities identified in 3.2.S.3.2 as well as potential degradation products resulting from interaction of the API with other APIs (FDCs), excipients or the container-closure system) and FPP process-related impurities (e.g. residual solvents in the manufacturing process for the FPP).\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).\n\n## 3.2.P.5.6 Justification of specification(s) (name, dosage form)\n\n**Justification for the proposed FPP specification(s) should be provided.**\n\nA discussion should be provided on the omission or inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendial standard(s). If the officially recognized compendial methods have been modified or replaced, a discussion should be included.\n\nThe justification for certain tests, analytical procedures and acceptance criteria (e.g. degradation products or dissolution method development) may have been discussed in other sections of the PD and would not need to be repeated here, although a cross-reference should be provided.\n\nICH Q6A (6) should be consulted for the development of specifications for FPPs.\n\n## 3.2.P.6 Reference standards or materials (name, dosage form)\n\n**Information on the reference standards or reference materials used for testing of the FPP should be provided, if not previously provided in \u201c3.2.S.5 Reference standards or materials\u201d.**\n\nSee section 3.2.S.5 for information that should be provided on reference standards or materials. Information should be provided on reference materials of FPP degradation products, where not included in 3.2.S.5.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "bfcf9bc413a7987f7770fe1cdb6cf23750ac250b55d5bed40848f410338eff2e", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 4\n\nthan vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d (e.g. \u201clevels of degradation product A ranged from 0.2 to 0.4%\u201d). Dissolution results should be expressed, at a minimum, as both the average and the range of individual results. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.\n\nA discussion and justification should be provided for any incomplete analyses (e.g. for any parameters not tested according to the proposed specification).\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).\n\n## 3.2.P.5.5 Characterization of impurities (name, dosage form)\n\n**Information on the characterization of impurities should be provided, if not previously provided in \u201c3.2.S.3.2 Impurities\u201d.**\n\nA discussion should be provided of all impurities that are potential degradation products (including those among the impurities identified in 3.2.S.3.2 as well as potential degradation products resulting from interaction of the API with other APIs (FDCs), excipients or the container-closure system) and FPP process-related impurities (e.g. residual solvents in the manufacturing process for the FPP).\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).\n\n## 3.2.P.5.6 Justification of specification(s) (name, dosage form)\n\n**Justification for the proposed FPP specification(s) should be provided.**\n\nA discussion should be provided on the omission or inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendial standard(s). If the officially recognized compendial methods have been modified or replaced, a discussion should be included.\n\nThe justification for certain tests, analytical procedures and acceptance criteria (e.g. degradation products or dissolution method development) may have been discussed in other sections of the PD and would not need to be repeated here, although a cross-reference should be provided.\n\nICH Q6A (6) should be consulted for the development of specifications for FPPs.\n\n## 3.2.P.6 Reference standards or materials (name, dosage form)\n\n**Information on the reference standards or reference materials used for testing of the FPP should be provided, if not previously provided in \u201c3.2.S.5 Reference standards or materials\u201d.**\n\nSee section 3.2.S.5 for information that should be provided on reference standards or materials. Information should be provided on reference materials of FPP degradation products, where not included in 3.2.S.5.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2526, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "b1e011d5-0146-440e-b5ad-7d98819bc7e6": {"__data__": {"id_": "b1e011d5-0146-440e-b5ad-7d98819bc7e6", "embedding": null, "metadata": {"page_label": "196", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Container-closure system (name, dosage form)\n\nA description of the container-closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. The specifications should include description and identification (and critical dimensions, with drawings where appropriate). Non-compendial methods (with validation) should be included, where appropriate.\n\nFor non-functional secondary packaging components (e.g. those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.\n\nSuitability information should be located in 3.2.P.2.\n\nThe WHO *Guidelines on packaging for pharmaceutical products* and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for FPPs.\n\nDescriptions, materials of construction and specifications (of the company responsible for packaging the FPP, generally the FPP manufacturer) should be provided for the packaging components that are:\n\n- in direct contact with the dosage form (e.g. container, closure, liner, desiccant and filler);\n- used for drug delivery (including the device(s) for multidose solutions, emulsions, suspensions and powders or granules for reconstitution into solution, emulsion or suspension);\n- used as a protective barrier to help ensure stability or sterility;\n- necessary to ensure FPP quality during storage and shipping.\n\nPrimary packaging components are those that are in direct contact with the API or FPP.\n\nThe specifications for the primary packaging components should include a specific test for identification (e.g. IR). Specifications for film and foil materials should include limits for thickness or area weight.\n\nInformation to establish the suitability (e.g. qualification) of the container-closure system should be discussed in section 3.2.P.2. Comparative studies may be warranted for certain changes in packaging components (e.g. a comparative delivery study (droplet size) for a change in manufacturer of dropper tips).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS proporciona directrices sobre los sistemas de envase y cierre para productos farmac\u00e9uticos. Se enfatiza la importancia de describir los componentes de envase primario, incluyendo los materiales de construcci\u00f3n y sus especificaciones. Se requiere informaci\u00f3n sobre los componentes que est\u00e1n en contacto directo con el producto, as\u00ed como aquellos que son necesarios para la entrega del medicamento y para garantizar la calidad durante el almacenamiento y el transporte. Tambi\u00e9n se menciona la necesidad de realizar pruebas espec\u00edficas para la identificaci\u00f3n de los materiales y se sugiere consultar las gu\u00edas de la OMS y las farmacopeas reconocidas oficialmente.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de pruebas espec\u00edficas se deben realizar para la identificaci\u00f3n de los componentes de envase primario, y qu\u00e9 m\u00e9todos no compendiales pueden ser utilizados?**\n   - Esta pregunta busca informaci\u00f3n detallada sobre los m\u00e9todos de prueba que no son est\u00e1ndar y que pueden ser aplicados en la identificaci\u00f3n de materiales de envase.\n\n2. **\u00bfCu\u00e1les son las consideraciones clave para la selecci\u00f3n de materiales de construcci\u00f3n de los componentes de envase que est\u00e1n en contacto directo con el producto farmac\u00e9utico?**\n   - Esta pregunta se centra en los criterios que deben tenerse en cuenta al elegir materiales para garantizar la calidad y seguridad del producto.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n adicional se debe proporcionar para los componentes de envase secundarios funcionales en comparaci\u00f3n con los no funcionales?**\n   - Esta pregunta busca aclarar las diferencias en la informaci\u00f3n requerida para distintos tipos de envases secundarios, lo que puede ser crucial para el cumplimiento normativo.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nLa secci\u00f3n del documento se centra en las directrices de la OMS relacionadas con la caracterizaci\u00f3n de impurezas, la justificaci\u00f3n de especificaciones y el uso de est\u00e1ndares de referencia en productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas:\n\n1. **Caracterizaci\u00f3n de Impurezas (3.2.P.5.5)**:\n   - Se requiere una discusi\u00f3n sobre todas las impurezas que son productos de degradaci\u00f3n potenciales.\n   - Impurezas a considerar:\n     - Productos de degradaci\u00f3n identificados en la secci\u00f3n 3.2.S.3.2.\n     - Productos de degradaci\u00f3n resultantes de interacciones del principio activo (API) con otros APIs, excipientes o el sistema de cierre del envase.\n     - Impurezas relacionadas con el proceso de fabricaci\u00f3n del producto farmac\u00e9utico terminado (FPP), como solventes residuales.\n\n2. **Justificaci\u00f3n de Especificaciones (3.2.P.5.6)**:\n   - Se debe proporcionar una discusi\u00f3n sobre la inclusi\u00f3n o exclusi\u00f3n de pruebas, evoluci\u00f3n de pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n.\n   - Se deben se\u00f1alar diferencias con respecto a los est\u00e1ndares compendiales reconocidos.\n   - Si se han modificado o reemplazado m\u00e9todos compendiales, se debe incluir una discusi\u00f3n al respecto.\n   - Se sugiere consultar ICH Q6A para el desarrollo de especificaciones para FPPs.\n\n3. **Est\u00e1ndares o Materiales de Referencia (3.2.P.6)**:\n   - Informaci\u00f3n sobre los est\u00e1ndares de referencia o materiales de referencia utilizados para las pruebas del FPP debe ser proporcionada.\n   - Se debe incluir informaci\u00f3n sobre materiales de referencia de productos de degradaci\u00f3n del FPP que no est\u00e9n en la secci\u00f3n 3.2.S.5.\n\n### Entidades Referenciadas:\n- **ICH Q3B**: Directrices sobre impurezas.\n- **ICH Q3C**: Directrices sobre impurezas relacionadas con solventes residuales.\n- **ICH Q6A**: Directrices sobre especificaciones para productos farmac\u00e9uticos terminados (FPPs).\n\n### Conclusi\u00f3n\nLa secci\u00f3n enfatiza la importancia de proporcionar informaci\u00f3n detallada y justificada sobre las impurezas, las especificaciones y los est\u00e1ndares de referencia en el contexto de la calidad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: container-closure system, primary packaging, pharmaceutical products, specifications, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ac80ab36-2331-4460-8f60-5a6a77d590e6", "node_type": "4", "metadata": {"page_label": "196", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Container-closure system (name, dosage form)\n\nA description of the container-closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. The specifications should include description and identification (and critical dimensions, with drawings where appropriate). Non-compendial methods (with validation) should be included, where appropriate.\n\nFor non-functional secondary packaging components (e.g. those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.\n\nSuitability information should be located in 3.2.P.2.\n\nThe WHO *Guidelines on packaging for pharmaceutical products* and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for FPPs.\n\nDescriptions, materials of construction and specifications (of the company responsible for packaging the FPP, generally the FPP manufacturer) should be provided for the packaging components that are:\n\n- in direct contact with the dosage form (e.g. container, closure, liner, desiccant and filler);\n- used for drug delivery (including the device(s) for multidose solutions, emulsions, suspensions and powders or granules for reconstitution into solution, emulsion or suspension);\n- used as a protective barrier to help ensure stability or sterility;\n- necessary to ensure FPP quality during storage and shipping.\n\nPrimary packaging components are those that are in direct contact with the API or FPP.\n\nThe specifications for the primary packaging components should include a specific test for identification (e.g. IR). Specifications for film and foil materials should include limits for thickness or area weight.\n\nInformation to establish the suitability (e.g. qualification) of the container-closure system should be discussed in section 3.2.P.2. Comparative studies may be warranted for certain changes in packaging components (e.g. a comparative delivery study (droplet size) for a change in manufacturer of dropper tips).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "258eee0463b4cda4900891dd6dfb5c3cbfb6ebea7a24d4ec726591d5bd97d415", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Container-closure system (name, dosage form)\n\nA description of the container-closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. The specifications should include description and identification (and critical dimensions, with drawings where appropriate). Non-compendial methods (with validation) should be included, where appropriate.\n\nFor non-functional secondary packaging components (e.g. those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.\n\nSuitability information should be located in 3.2.P.2.\n\nThe WHO *Guidelines on packaging for pharmaceutical products* and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for FPPs.\n\nDescriptions, materials of construction and specifications (of the company responsible for packaging the FPP, generally the FPP manufacturer) should be provided for the packaging components that are:\n\n- in direct contact with the dosage form (e.g. container, closure, liner, desiccant and filler);\n- used for drug delivery (including the device(s) for multidose solutions, emulsions, suspensions and powders or granules for reconstitution into solution, emulsion or suspension);\n- used as a protective barrier to help ensure stability or sterility;\n- necessary to ensure FPP quality during storage and shipping.\n\nPrimary packaging components are those that are in direct contact with the API or FPP.\n\nThe specifications for the primary packaging components should include a specific test for identification (e.g. IR). Specifications for film and foil materials should include limits for thickness or area weight.\n\nInformation to establish the suitability (e.g. qualification) of the container-closure system should be discussed in section 3.2.P.2. Comparative studies may be warranted for certain changes in packaging components (e.g. a comparative delivery study (droplet size) for a change in manufacturer of dropper tips).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2175, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "0c8f4c45-7d06-425a-a82b-9b3fab32ec90": {"__data__": {"id_": "0c8f4c45-7d06-425a-a82b-9b3fab32ec90", "embedding": null, "metadata": {"page_label": "197", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.8 Stability (name, dosage form)\n\n## 3.2.P.8.1 Stability summary and conclusions (name, dosage form)\n\nThe types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include, for example, conclusions with respect to storage conditions and shelf-life, and, if applicable, in-use storage conditions and shelf-life.\n\nThe WHO stability guidelines *Stability testing of active pharmaceutical ingredients and finished pharmaceutical products* (19) should be consulted for recommendations on the core stability data package required for the prequalification of APIs and FPPs.\n\nAs outlined in the WHO stability guidelines, the purpose of stability testing is to provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. The stability programme also includes the study of product-related factors that influence the quality of the API or FPP, for example, interaction of API with excipients, container-closure systems and packaging materials.\n\n### Stress testing\n\nAs outlined in the WHO stability guidelines, photostability testing should be conducted on at least one primary batch of the FPP if appropriate. If \u201cprotect from light\u201d is stated in one of the officially recognized pharmacopoeias for the API or FPP it is sufficient to state \u201cprotect from light\u201d on labelling, in lieu of photostability studies, when the container-closure system is shown to be light protective. Additional stress testing of specific types of dosage forms may be appropriate (e.g. cyclic studies for semi-solid products or freeze\u2013thaw studies for liquid products).\n\n### Accelerated, intermediate (if necessary) and long-term testing\n\nStability data must demonstrate stability of the medicinal product throughout its intended shelf-life under the climatic conditions prevalent in the target countries. Merely applying the same requirements applicable to other markets could potentially lead to substandard products if stability studies are conducted at the storage conditions for countries in Climatic Zone I/II when the products are supplied in countries in Climatic Zones III and IV. Refer to *WHO Technical Report Series*, No. 953, Annex 2, Appendix 1 (7) for information on climatic zones. Effective as of September 2011, the required long-term storage conditions for the WHO Prequalification of Medicines Programme are 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, and after this date the long-term data submitted in the PD (see Table 3) should be at these conditions. The use of alternative long-term conditions will need to be justified and should be supported with appropriate evidence.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfCu\u00e1les son las condiciones de almacenamiento a largo plazo requeridas por el Programa de Precalificaci\u00f3n de Medicamentos de la OMS desde septiembre de 2011?**\n   - Respuesta: Las condiciones de almacenamiento a largo plazo requeridas son 30 \u00b0C \u00b1 2 \u00b0C y 75% \u00b1 5% de humedad relativa (RH).\n\n2. **\u00bfQu\u00e9 tipo de pruebas de estabilidad se deben realizar para los productos farmac\u00e9uticos y cu\u00e1les son algunos factores que pueden influir en la calidad del API o FPP?**\n   - Respuesta: Se deben realizar pruebas de estabilidad aceleradas, intermedias (si es necesario) y a largo plazo. Los factores que pueden influir en la calidad incluyen la interacci\u00f3n del API con excipientes, sistemas de cierre de envases y materiales de embalaje.\n\n3. **\u00bfQu\u00e9 se debe hacer si un producto farmac\u00e9utico requiere protecci\u00f3n contra la luz seg\u00fan las farmacopeas reconocidas?**\n   - Respuesta: Si se indica \"proteger de la luz\" en una de las farmacopeas reconocidas, es suficiente incluir esta advertencia en el etiquetado, siempre que el sistema de cierre del envase sea demostrado como protector contra la luz, sin necesidad de realizar estudios de fotostabilidad.\n\n### Resumen de nivel superior del contexto:\nEl contexto aborda la estabilidad de ingredientes farmac\u00e9uticos activos (API) y productos farmac\u00e9uticos terminados (FPP), destacando la importancia de las pruebas de estabilidad para garantizar la calidad a lo largo del tiempo bajo diversas condiciones ambientales. Se mencionan las pruebas de estr\u00e9s, la necesidad de realizar estudios de estabilidad en funci\u00f3n de las condiciones clim\u00e1ticas de los pa\u00edses de destino, y se especifican las condiciones de almacenamiento a largo plazo requeridas por la OMS. Adem\u00e1s, se discute la importancia de la interacci\u00f3n entre el API y otros componentes del producto, as\u00ed como la necesidad de cumplir con las normativas de etiquetado en relaci\u00f3n con la protecci\u00f3n contra la luz.", "prev_section_summary": "### Temas Clave\n\n1. **Descripci\u00f3n de Sistemas de Envase y Cierre**: Se requiere una descripci\u00f3n detallada de los sistemas de envase, incluyendo los materiales de construcci\u00f3n y especificaciones de cada componente de envase primario.\n\n2. **Especificaciones de Componentes de Envase Primario**: Las especificaciones deben incluir identificaci\u00f3n, dimensiones cr\u00edticas y m\u00e9todos de prueba, incluyendo m\u00e9todos no compendiales validados.\n\n3. **Componentes de Envase Secundario**: Se debe proporcionar una breve descripci\u00f3n para componentes no funcionales y m\u00e1s informaci\u00f3n para componentes funcionales.\n\n4. **Consulta de Directrices**: Se recomienda consultar las *Gu\u00edas de la OMS sobre envase para productos farmac\u00e9uticos* y farmacopeas reconocidas para obtener recomendaciones sobre la informaci\u00f3n de envase.\n\n5. **Componentes en Contacto Directo**: Se debe proporcionar informaci\u00f3n sobre los componentes que est\u00e1n en contacto directo con el producto, aquellos utilizados para la entrega del medicamento, y los que act\u00faan como barreras protectoras.\n\n6. **Pruebas de Identificaci\u00f3n**: Se requiere realizar pruebas espec\u00edficas para la identificaci\u00f3n de materiales, como espectroscop\u00eda infrarroja (IR), y establecer l\u00edmites para materiales de pel\u00edcula y papel de aluminio.\n\n7. **Estudios Comparativos**: Se pueden requerir estudios comparativos para ciertos cambios en los componentes de envase.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las directrices.\n- **FPP (Forma Farmac\u00e9utica Final)**: Producto farmac\u00e9utico que se envasa.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en contacto con el envase primario.\n- **Componentes de Envase**: Incluyen contenedores, cierres, recubrimientos, deshidratantes y dispositivos de entrega.\n- **M\u00e9todos No Compendiales**: M\u00e9todos de prueba que no est\u00e1n estandarizados pero son validados.\n- **Secci\u00f3n 3.2.P.2**: Parte del documento donde se discute la idoneidad del sistema de envase-cierre. \n\nEste resumen abarca los aspectos esenciales de la secci\u00f3n sobre sistemas de envase y cierre, destacando la importancia de la especificaci\u00f3n y validaci\u00f3n de los materiales utilizados en el empaquetado de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: stability testing, pharmaceutical products, WHO guidelines, storage conditions, climatic zones"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cb70faa1-efcc-47d1-912a-0552301bd829", "node_type": "4", "metadata": {"page_label": "197", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.8 Stability (name, dosage form)\n\n## 3.2.P.8.1 Stability summary and conclusions (name, dosage form)\n\nThe types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include, for example, conclusions with respect to storage conditions and shelf-life, and, if applicable, in-use storage conditions and shelf-life.\n\nThe WHO stability guidelines *Stability testing of active pharmaceutical ingredients and finished pharmaceutical products* (19) should be consulted for recommendations on the core stability data package required for the prequalification of APIs and FPPs.\n\nAs outlined in the WHO stability guidelines, the purpose of stability testing is to provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. The stability programme also includes the study of product-related factors that influence the quality of the API or FPP, for example, interaction of API with excipients, container-closure systems and packaging materials.\n\n### Stress testing\n\nAs outlined in the WHO stability guidelines, photostability testing should be conducted on at least one primary batch of the FPP if appropriate. If \u201cprotect from light\u201d is stated in one of the officially recognized pharmacopoeias for the API or FPP it is sufficient to state \u201cprotect from light\u201d on labelling, in lieu of photostability studies, when the container-closure system is shown to be light protective. Additional stress testing of specific types of dosage forms may be appropriate (e.g. cyclic studies for semi-solid products or freeze\u2013thaw studies for liquid products).\n\n### Accelerated, intermediate (if necessary) and long-term testing\n\nStability data must demonstrate stability of the medicinal product throughout its intended shelf-life under the climatic conditions prevalent in the target countries. Merely applying the same requirements applicable to other markets could potentially lead to substandard products if stability studies are conducted at the storage conditions for countries in Climatic Zone I/II when the products are supplied in countries in Climatic Zones III and IV. Refer to *WHO Technical Report Series*, No. 953, Annex 2, Appendix 1 (7) for information on climatic zones. Effective as of September 2011, the required long-term storage conditions for the WHO Prequalification of Medicines Programme are 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, and after this date the long-term data submitted in the PD (see Table 3) should be at these conditions. The use of alternative long-term conditions will need to be justified and should be supported with appropriate evidence.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "51499ea172e549d668cf69aef53bff08b79e48b71920020eee5e829a5560daf6", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.P.8 Stability (name, dosage form)\n\n## 3.2.P.8.1 Stability summary and conclusions (name, dosage form)\n\nThe types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include, for example, conclusions with respect to storage conditions and shelf-life, and, if applicable, in-use storage conditions and shelf-life.\n\nThe WHO stability guidelines *Stability testing of active pharmaceutical ingredients and finished pharmaceutical products* (19) should be consulted for recommendations on the core stability data package required for the prequalification of APIs and FPPs.\n\nAs outlined in the WHO stability guidelines, the purpose of stability testing is to provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. The stability programme also includes the study of product-related factors that influence the quality of the API or FPP, for example, interaction of API with excipients, container-closure systems and packaging materials.\n\n### Stress testing\n\nAs outlined in the WHO stability guidelines, photostability testing should be conducted on at least one primary batch of the FPP if appropriate. If \u201cprotect from light\u201d is stated in one of the officially recognized pharmacopoeias for the API or FPP it is sufficient to state \u201cprotect from light\u201d on labelling, in lieu of photostability studies, when the container-closure system is shown to be light protective. Additional stress testing of specific types of dosage forms may be appropriate (e.g. cyclic studies for semi-solid products or freeze\u2013thaw studies for liquid products).\n\n### Accelerated, intermediate (if necessary) and long-term testing\n\nStability data must demonstrate stability of the medicinal product throughout its intended shelf-life under the climatic conditions prevalent in the target countries. Merely applying the same requirements applicable to other markets could potentially lead to substandard products if stability studies are conducted at the storage conditions for countries in Climatic Zone I/II when the products are supplied in countries in Climatic Zones III and IV. Refer to *WHO Technical Report Series*, No. 953, Annex 2, Appendix 1 (7) for information on climatic zones. Effective as of September 2011, the required long-term storage conditions for the WHO Prequalification of Medicines Programme are 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, and after this date the long-term data submitted in the PD (see Table 3) should be at these conditions. The use of alternative long-term conditions will need to be justified and should be supported with appropriate evidence.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2717, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "a9f000a9-99c5-4392-b919-ac8bd7f76319": {"__data__": {"id_": "a9f000a9-99c5-4392-b919-ac8bd7f76319", "embedding": null, "metadata": {"page_label": "198", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nOther storage conditions are outlined in the WHO stability guidelines for FPPs packaged in impermeable and semi-permeable containers and those intended for storage in a refrigerator and in a freezer. FPPs intended for storage below \u221220 \u00b0C should be treated on a case-by-case basis.\n\n**Table 3**  \nMinimum data required at the time of submitting the dossier (in the general case)\n\n| Storage temperature (\u00b0C) | Relative humidity (%) | Minimum time period (months) |\n| - | - | - |\n| Accelerated 40 \u00b1 2 | 75 \u00b1 5 | 6 |\n| Intermediatea | N/A | N/A |\n| Long-term 30 \u00b1 2 | 75 \u00b1 5 | 6 |\n\n\n<sup>a</sup>Where long-term conditions are 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, there is no intermediate condition.\n\nRefer to **WHO Technical Report Series**, No. 953, Annex 2 (19) for further information regarding the storage conditions. Reference should also be made to the WHO Prequalification of Medicines Programme web site for any exceptions to the stated requirements.\n\nTo establish the shelf-life, data should be provided on not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nThe stability testing programme should be summarized and the results of stability testing should be reported in the dossier and summarized in the tables in the QOS-PD. Bracketing and matrixing of proportional strengths can be applied if scientifically justified.\n\nFor sterile products, sterility should be reported at the beginning and end of shelf-life. For parenteral products, subvisible particulate matter should be reported frequently, but not necessarily at every test interval. Bacterial endotoxins need only be reported at the initial test point. Weight loss from plastic containers should be reported over the shelf-life.\n\nAny in-use period and associated storage conditions should be justified with experimental data, for example, after opening, reconstitution and/or dilution.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla las condiciones de almacenamiento y los requisitos de estabilidad para los productos farmac\u00e9uticos terminados (FPPs). Se especifican las temperaturas de almacenamiento, la humedad relativa y los per\u00edodos m\u00ednimos de tiempo para las pruebas de estabilidad. Adem\u00e1s, se establece que se deben proporcionar datos de al menos dos lotes para establecer la vida \u00fatil, y se describen las pruebas necesarias para productos est\u00e9riles y no est\u00e9riles.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las condiciones de almacenamiento m\u00ednimas requeridas para los productos farmac\u00e9uticos terminados (FPPs) seg\u00fan la OMS?**\n   - Respuesta: Las condiciones m\u00ednimas de almacenamiento requeridas son: \n     - Temperatura acelerada: 40 \u00b1 2 \u00b0C con 75 \u00b1 5% de humedad relativa durante 6 meses.\n     - Condiciones a largo plazo: 30 \u00b1 2 \u00b0C con 75 \u00b1 5% de humedad relativa durante 6 meses. No hay condiciones intermedias especificadas.\n\n2. **\u00bfQu\u00e9 tipo de datos se requieren para establecer la vida \u00fatil de un FPP y cu\u00e1ntos lotes deben ser evaluados?**\n   - Respuesta: Se requieren datos de al menos dos lotes de al menos escala piloto. Para FPPs no complicados, se puede presentar un lote de escala piloto y un segundo lote m\u00e1s peque\u00f1o (por ejemplo, 25,000 o 50,000 tabletas o c\u00e1psulas) de cada fuerza propuesta del FPP.\n\n3. **\u00bfQu\u00e9 pruebas espec\u00edficas deben realizarse para productos est\u00e9riles y parenterales en relaci\u00f3n con la estabilidad?**\n   - Respuesta: Para productos est\u00e9riles, se debe informar sobre la esterilidad al inicio y al final de la vida \u00fatil. Para productos parenterales, se debe reportar la materia particulada subvisible con frecuencia, pero no necesariamente en cada intervalo de prueba. Los endotoxinas bacterianas solo necesitan ser reportadas en el punto de prueba inicial.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Estabilidad de Productos Farmac\u00e9uticos**:\n   - Se aborda la importancia de las pruebas de estabilidad para los ingredientes farmac\u00e9uticos activos (API) y productos farmac\u00e9uticos terminados (FPP).\n   - Se enfatiza c\u00f3mo la calidad de un API o FPP puede variar con el tiempo debido a factores ambientales como temperatura, humedad y luz.\n\n2. **Pruebas de Estr\u00e9s**:\n   - Se menciona la necesidad de realizar pruebas de fotostabilidad en al menos un lote primario del FPP.\n   - Si se requiere protecci\u00f3n contra la luz seg\u00fan las farmacopeas reconocidas, se puede indicar en el etiquetado si el sistema de cierre del envase es protector.\n\n3. **Pruebas de Estabilidad**:\n   - Se deben realizar pruebas de estabilidad aceleradas, intermedias (si es necesario) y a largo plazo.\n   - Los datos de estabilidad deben demostrar que el producto se mantiene estable durante su vida \u00fatil prevista bajo las condiciones clim\u00e1ticas de los pa\u00edses de destino.\n\n4. **Condiciones de Almacenamiento a Largo Plazo**:\n   - Desde septiembre de 2011, las condiciones requeridas para el almacenamiento a largo plazo son 30 \u00b0C \u00b1 2 \u00b0C y 75% \u00b1 5% de humedad relativa (RH).\n   - Se requiere justificaci\u00f3n y evidencia adecuada si se utilizan condiciones de almacenamiento alternativas.\n\n5. **Interacci\u00f3n de Componentes**:\n   - Se destaca la importancia de estudiar la interacci\u00f3n del API con excipientes, sistemas de cierre de envases y materiales de embalaje, ya que estos pueden influir en la calidad del producto.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Proporciona directrices sobre pruebas de estabilidad.\n- **API (Ingredientes Farmac\u00e9uticos Activos)**: Sustancias que tienen efectos terap\u00e9uticos.\n- **FPP (Productos Farmac\u00e9uticos Terminados)**: Formulaciones finales que se administran a los pacientes.\n- **Climatic Zones (Zonas Clim\u00e1ticas)**: Clasificaci\u00f3n que afecta las condiciones de almacenamiento y estabilidad de los productos farmac\u00e9uticos. \n\nEste resumen encapsula los aspectos fundamentales de la estabilidad de productos farmac\u00e9uticos y las directrices de la OMS relacionadas con su evaluaci\u00f3n y almacenamiento.", "excerpt_keywords": "Keywords: stability testing, pharmaceutical preparations, storage conditions, shelf-life, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "885bc7ad-7f67-4197-a365-d28deedba665", "node_type": "4", "metadata": {"page_label": "198", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nOther storage conditions are outlined in the WHO stability guidelines for FPPs packaged in impermeable and semi-permeable containers and those intended for storage in a refrigerator and in a freezer. FPPs intended for storage below \u221220 \u00b0C should be treated on a case-by-case basis.\n\n**Table 3**  \nMinimum data required at the time of submitting the dossier (in the general case)\n\n| Storage temperature (\u00b0C) | Relative humidity (%) | Minimum time period (months) |\n| - | - | - |\n| Accelerated 40 \u00b1 2 | 75 \u00b1 5 | 6 |\n| Intermediatea | N/A | N/A |\n| Long-term 30 \u00b1 2 | 75 \u00b1 5 | 6 |\n\n\n<sup>a</sup>Where long-term conditions are 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, there is no intermediate condition.\n\nRefer to **WHO Technical Report Series**, No. 953, Annex 2 (19) for further information regarding the storage conditions. Reference should also be made to the WHO Prequalification of Medicines Programme web site for any exceptions to the stated requirements.\n\nTo establish the shelf-life, data should be provided on not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nThe stability testing programme should be summarized and the results of stability testing should be reported in the dossier and summarized in the tables in the QOS-PD. Bracketing and matrixing of proportional strengths can be applied if scientifically justified.\n\nFor sterile products, sterility should be reported at the beginning and end of shelf-life. For parenteral products, subvisible particulate matter should be reported frequently, but not necessarily at every test interval. Bacterial endotoxins need only be reported at the initial test point. Weight loss from plastic containers should be reported over the shelf-life.\n\nAny in-use period and associated storage conditions should be justified with experimental data, for example, after opening, reconstitution and/or dilution.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "9eb4e1c9b2a8c0e5665c5c299273d3c03184fc924606c90af5915ebc8ccee11a", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nOther storage conditions are outlined in the WHO stability guidelines for FPPs packaged in impermeable and semi-permeable containers and those intended for storage in a refrigerator and in a freezer. FPPs intended for storage below \u221220 \u00b0C should be treated on a case-by-case basis.\n\n**Table 3**  \nMinimum data required at the time of submitting the dossier (in the general case)\n\n| Storage temperature (\u00b0C) | Relative humidity (%) | Minimum time period (months) |\n| - | - | - |\n| Accelerated 40 \u00b1 2 | 75 \u00b1 5 | 6 |\n| Intermediatea | N/A | N/A |\n| Long-term 30 \u00b1 2 | 75 \u00b1 5 | 6 |\n\n\n<sup>a</sup>Where long-term conditions are 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, there is no intermediate condition.\n\nRefer to **WHO Technical Report Series**, No. 953, Annex 2 (19) for further information regarding the storage conditions. Reference should also be made to the WHO Prequalification of Medicines Programme web site for any exceptions to the stated requirements.\n\nTo establish the shelf-life, data should be provided on not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nThe stability testing programme should be summarized and the results of stability testing should be reported in the dossier and summarized in the tables in the QOS-PD. Bracketing and matrixing of proportional strengths can be applied if scientifically justified.\n\nFor sterile products, sterility should be reported at the beginning and end of shelf-life. For parenteral products, subvisible particulate matter should be reported frequently, but not necessarily at every test interval. Bacterial endotoxins need only be reported at the initial test point. Weight loss from plastic containers should be reported over the shelf-life.\n\nAny in-use period and associated storage conditions should be justified with experimental data, for example, after opening, reconstitution and/or dilution.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2378, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "32666921-234a-4ca1-a1e1-1f8958ee6334": {"__data__": {"id_": "32666921-234a-4ca1-a1e1-1f8958ee6334", "embedding": null, "metadata": {"page_label": "199", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Stability Studies Information\n\nThe information on the stability studies should include details such as:\n\n- Storage conditions;\n- Strength;\n- Batch number, including the API batch number(s) and manufacturer(s);\n- Batch size;\n- Container-closure system including orientation (e.g. erect, inverted, on-side) where applicable;\n- Completed (and proposed) test intervals.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. The discussion should include ranges of analytical results and any trends that were observed. For quantitative tests (e.g. individual and total degradation product tests and assay tests) actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. Dissolution results should be expressed, at a minimum, as both the average and range of individual results.\n\nApplicants should consult ICH\u2019s Q1E guideline (23) for details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated condition and the data show little or no variability, the proposed shelf-life could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months).\n\n## Proposed Storage Statement and Shelf-life\n\nThe proposed storage statement and shelf-life (and in-use storage conditions and in-use period, if applicable) for the FPP should be provided.\n\nThe recommended labelling statements for use based on the stability studies, are provided in the WHO stability guidelines (19).\n\nReference documents: *WHO Technical Report Series*, No. 953, Annex 2 (19), ICH Q1A (20), Q1B (22), Q1C (47), Q1D (24), Q1E (23), Q3B (11), Q6A (6).\n\n### 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment (name, dosage form)\n\nThe post-approval stability protocol and stability commitment should be provided.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que pueden ser respondidas con la informaci\u00f3n proporcionada en el contexto, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento proporciona directrices sobre los estudios de estabilidad de productos farmac\u00e9uticos, enfatizando la importancia de detallar las condiciones de almacenamiento, los resultados de las pruebas y la interpretaci\u00f3n de los datos. Se menciona la necesidad de un protocolo de estabilidad post-aprobaci\u00f3n y un compromiso de estabilidad, as\u00ed como la consulta de las gu\u00edas del ICH para la evaluaci\u00f3n de los datos de estabilidad y la propuesta de vida \u00fatil.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n espec\u00edfica debe incluirse en los estudios de estabilidad de un producto farmac\u00e9utico?**\n   - Los estudios de estabilidad deben incluir detalles como las condiciones de almacenamiento, la fuerza del producto, el n\u00famero de lote (incluyendo el n\u00famero de lote del API y los fabricantes), el tama\u00f1o del lote, el sistema de cierre del contenedor (incluyendo la orientaci\u00f3n) y los intervalos de prueba completados y propuestos.\n\n2. **\u00bfC\u00f3mo deben presentarse los resultados de las pruebas cuantitativas en los estudios de estabilidad?**\n   - Los resultados de las pruebas cuantitativas deben presentarse con resultados num\u00e9ricos espec\u00edficos en lugar de declaraciones vagas. Por ejemplo, los resultados de disoluci\u00f3n deben expresarse como el promedio y el rango de resultados individuales.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al proponer la vida \u00fatil de un producto farmac\u00e9utico basado en datos de estabilidad?**\n   - Al proponer la vida \u00fatil, se debe considerar la gu\u00eda Q1E del ICH, que indica que si no se observa un cambio significativo en 6 meses bajo condiciones aceleradas y los datos muestran poca o ninguna variabilidad, la vida \u00fatil propuesta podr\u00eda ser hasta el doble del per\u00edodo cubierto por los datos a largo plazo, pero no debe exceder los datos a largo plazo por m\u00e1s de 12 meses.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Condiciones de Almacenamiento**:\n   - Se especifican las condiciones de almacenamiento para productos farmac\u00e9uticos terminados (FPPs) en diferentes temperaturas y niveles de humedad.\n   - Se mencionan condiciones aceleradas (40 \u00b1 2 \u00b0C, 75 \u00b1 5% de humedad relativa) y a largo plazo (30 \u00b1 2 \u00b0C, 75 \u00b1 5% de humedad relativa), con un per\u00edodo m\u00ednimo de 6 meses para ambas.\n\n2. **Requisitos de Datos para la Vida \u00datil**:\n   - Para establecer la vida \u00fatil de un FPP, se requieren datos de al menos dos lotes de escala piloto.\n   - En el caso de FPPs no complicados, se puede presentar un lote de escala piloto y un segundo lote m\u00e1s peque\u00f1o.\n\n3. **Pruebas de Estabilidad**:\n   - Se deben resumir y reportar los resultados de las pruebas de estabilidad en el dossier.\n   - Se permite el uso de bracketing y matrixing para fortalezas proporcionales si est\u00e1 cient\u00edficamente justificado.\n\n4. **Productos Est\u00e9riles y Parenterales**:\n   - Para productos est\u00e9riles, se debe informar sobre la esterilidad al inicio y al final de la vida \u00fatil.\n   - Para productos parenterales, se debe reportar la materia particulada subvisible y los endotoxinas bacterianas solo en el punto de prueba inicial.\n\n5. **Justificaci\u00f3n de Condiciones de Almacenamiento**:\n   - Cualquier per\u00edodo de uso y las condiciones de almacenamiento asociadas deben ser justificadas con datos experimentales, especialmente despu\u00e9s de la apertura, reconstituci\u00f3n o diluci\u00f3n.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que establece las directrices.\n- **FPP (Productos Farmac\u00e9uticos Terminados)**: El objeto de las directrices.\n- **Temperaturas y Humedad**: Par\u00e1metros cr\u00edticos para el almacenamiento.\n- **Lotes de Escala Piloto**: Requisitos para la evaluaci\u00f3n de la vida \u00fatil.\n- **Pruebas de Estabilidad**: Procedimientos necesarios para asegurar la calidad del producto.\n- **Productos Est\u00e9riles y Parenterales**: Categor\u00edas espec\u00edficas de productos que requieren pruebas adicionales. \n\nEste resumen abarca los aspectos esenciales del documento, destacando las condiciones de almacenamiento, los requisitos de datos y las pruebas necesarias para garantizar la estabilidad y seguridad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: stability studies, storage conditions, shelf-life, ICH guidelines, pharmaceutical products"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5fab1dcb-ece5-4d64-9a91-1ab921b52605", "node_type": "4", "metadata": {"page_label": "199", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Stability Studies Information\n\nThe information on the stability studies should include details such as:\n\n- Storage conditions;\n- Strength;\n- Batch number, including the API batch number(s) and manufacturer(s);\n- Batch size;\n- Container-closure system including orientation (e.g. erect, inverted, on-side) where applicable;\n- Completed (and proposed) test intervals.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. The discussion should include ranges of analytical results and any trends that were observed. For quantitative tests (e.g. individual and total degradation product tests and assay tests) actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. Dissolution results should be expressed, at a minimum, as both the average and range of individual results.\n\nApplicants should consult ICH\u2019s Q1E guideline (23) for details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated condition and the data show little or no variability, the proposed shelf-life could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months).\n\n## Proposed Storage Statement and Shelf-life\n\nThe proposed storage statement and shelf-life (and in-use storage conditions and in-use period, if applicable) for the FPP should be provided.\n\nThe recommended labelling statements for use based on the stability studies, are provided in the WHO stability guidelines (19).\n\nReference documents: *WHO Technical Report Series*, No. 953, Annex 2 (19), ICH Q1A (20), Q1B (22), Q1C (47), Q1D (24), Q1E (23), Q3B (11), Q6A (6).\n\n### 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment (name, dosage form)\n\nThe post-approval stability protocol and stability commitment should be provided.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "d005c733c70542276e2612f410af16ae93ce9dbcc16d1e1b950a8c3aadc9eced", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Stability Studies Information\n\nThe information on the stability studies should include details such as:\n\n- Storage conditions;\n- Strength;\n- Batch number, including the API batch number(s) and manufacturer(s);\n- Batch size;\n- Container-closure system including orientation (e.g. erect, inverted, on-side) where applicable;\n- Completed (and proposed) test intervals.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. The discussion should include ranges of analytical results and any trends that were observed. For quantitative tests (e.g. individual and total degradation product tests and assay tests) actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. Dissolution results should be expressed, at a minimum, as both the average and range of individual results.\n\nApplicants should consult ICH\u2019s Q1E guideline (23) for details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated condition and the data show little or no variability, the proposed shelf-life could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months).\n\n## Proposed Storage Statement and Shelf-life\n\nThe proposed storage statement and shelf-life (and in-use storage conditions and in-use period, if applicable) for the FPP should be provided.\n\nThe recommended labelling statements for use based on the stability studies, are provided in the WHO stability guidelines (19).\n\nReference documents: *WHO Technical Report Series*, No. 953, Annex 2 (19), ICH Q1A (20), Q1B (22), Q1C (47), Q1D (24), Q1E (23), Q3B (11), Q6A (6).\n\n### 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment (name, dosage form)\n\nThe post-approval stability protocol and stability commitment should be provided.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1989, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "6bbdbe7c-0ab4-45a4-8107-b0527281029d": {"__data__": {"id_": "6bbdbe7c-0ab4-45a4-8107-b0527281029d", "embedding": null, "metadata": {"page_label": "200", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Primary stability study commitment\n\nWhen the available data on long-term stability of primary batches do not cover the proposed shelf-life granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the shelf-life. A written commitment (signed and dated) to continue long-term testing over the shelf-life period should be included in the dossier.\n\n## Commitment stability studies\n\nThe long-term stability studies for the commitment batches should be conducted throughout the proposed shelf-life on at least three production batches of each strength in each container-closure system. Where stability data were not provided for three production batches of each strength, a written commitment (signed and dated) should be included in the dossier.\n\n## Ongoing stability studies\n\nAs described in the WHO stability guidelines (19), an ongoing stability programme is established to monitor the product over its shelf-life and to determine that the product remains and can be expected to remain within specifications under the storage conditions on the label. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every container-closure system, if relevant, should be included in the stability programme (unless none is produced during that year). Bracketing and matrixing may be applicable. A written commitment (signed and dated) to this effect should be included in the dossier.\n\nAny differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.\n\nReference document: ICH Q1A (20).\n\n## 3.2.P.8.3 Stability data (name, dosage form)\n\nResults of the stability studies should be presented in an appropriate format (e.g. tabular, graphical, narrative). Information on the analytical procedures used to generate the data and validation of these procedures should be included.\n\nInformation on characterization of impurities is located in 3.2.P.5.5.\n\nThe actual stability results and reports used to support the proposed shelf-life should be provided in the PD. For quantitative tests (e.g. individual and total degradation product tests and assay tests), actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda el compromiso de estudios de estabilidad a largo plazo para lotes primarios de productos farmac\u00e9uticos. Se establece que, si los datos disponibles no cubren la vida \u00fatil propuesta, se debe hacer un compromiso por escrito para continuar los estudios de estabilidad. Se requiere que los estudios de estabilidad a largo plazo se realicen en al menos tres lotes de producci\u00f3n de cada fuerza y sistema de cierre de contenedor. Adem\u00e1s, se menciona la importancia de un programa de estabilidad en curso para monitorear el producto durante su vida \u00fatil y se especifica que los resultados de los estudios de estabilidad deben presentarse de manera adecuada y con datos num\u00e9ricos concretos.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 requisitos espec\u00edficos se deben cumplir para los estudios de estabilidad a largo plazo de los lotes de compromiso seg\u00fan el documento de la OMS?**\n   - Respuesta: Los estudios de estabilidad a largo plazo para los lotes de compromiso deben realizarse a lo largo de la vida \u00fatil propuesta en al menos tres lotes de producci\u00f3n de cada fuerza y sistema de cierre de contenedor. Si no se proporcionaron datos de estabilidad para tres lotes de cada fuerza, se debe incluir un compromiso por escrito en el expediente.\n\n2. **\u00bfC\u00f3mo se debe presentar la informaci\u00f3n de los resultados de los estudios de estabilidad seg\u00fan las directrices de la OMS?**\n   - Respuesta: Los resultados de los estudios de estabilidad deben presentarse en un formato apropiado, que puede ser tabular, gr\u00e1fico o narrativo. Adem\u00e1s, se debe incluir informaci\u00f3n sobre los procedimientos anal\u00edticos utilizados para generar los datos y la validaci\u00f3n de estos procedimientos.\n\n3. **\u00bfQu\u00e9 justificaciones son necesarias si hay diferencias entre los protocolos de estabilidad utilizados para los lotes primarios y los lotes de compromiso u otros lotes en curso?**\n   - Respuesta: Cualquier diferencia entre los protocolos de estabilidad utilizados para los lotes primarios y aquellos propuestos para los lotes de compromiso o en curso debe estar cient\u00edficamente justificada.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Estudios de Estabilidad**: Se enfatiza la importancia de realizar estudios de estabilidad para productos farmac\u00e9uticos, que deben incluir informaci\u00f3n detallada sobre:\n   - **Condiciones de Almacenamiento**: Especificar c\u00f3mo y d\u00f3nde se almacenar\u00e1 el producto.\n   - **Fuerza del Producto**: Indicar la concentraci\u00f3n o potencia del f\u00e1rmaco.\n   - **N\u00famero de Lote**: Incluir el n\u00famero de lote del principio activo (API) y del fabricante.\n   - **Tama\u00f1o del Lote**: Detallar la cantidad producida en cada lote.\n   - **Sistema de Cierre del Contenedor**: Describir el tipo de envase y su orientaci\u00f3n (por ejemplo, erguido, invertido).\n   - **Intervalos de Prueba**: Listar los intervalos de prueba completados y propuestos.\n\n2. **Discusi\u00f3n de Resultados**: Los resultados de las pruebas deben ser discutidos en t\u00e9rminos de observaciones y tendencias, proporcionando datos num\u00e9ricos espec\u00edficos en lugar de declaraciones generales. Los resultados de disoluci\u00f3n deben incluir el promedio y el rango de resultados individuales.\n\n3. **Gu\u00eda ICH Q1E**: Se recomienda consultar esta gu\u00eda para la evaluaci\u00f3n y extrapolaci\u00f3n de datos de estabilidad, que sugiere que si no hay cambios significativos en 6 meses bajo condiciones aceleradas, la vida \u00fatil propuesta podr\u00eda ser hasta el doble del per\u00edodo cubierto por los datos a largo plazo, sin excederlos por m\u00e1s de 12 meses.\n\n4. **Declaraci\u00f3n de Almacenamiento Propuesta y Vida \u00datil**: Se debe proporcionar una declaraci\u00f3n de almacenamiento y vida \u00fatil propuesta, as\u00ed como condiciones de almacenamiento en uso y per\u00edodo de uso, si corresponde.\n\n5. **Protocolo de Estabilidad Post-aprobaci\u00f3n**: Se debe presentar un protocolo de estabilidad post-aprobaci\u00f3n y un compromiso de estabilidad para el producto farmac\u00e9utico.\n\n### Entidades Clave\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que proporciona las directrices.\n- **ICH (International Council for Harmonisation)**: Organizaci\u00f3n que establece gu\u00edas para la evaluaci\u00f3n de datos de estabilidad.\n- **FPP (Formulaci\u00f3n Farmac\u00e9utica del Producto)**: Referente al producto farmac\u00e9utico en estudio.\n- **Documentos de Referencia**: Incluyen varios informes y gu\u00edas de la OMS y el ICH que son relevantes para los estudios de estabilidad. \n\nEste resumen destaca la importancia de la rigurosidad en los estudios de estabilidad y la necesidad de seguir directrices espec\u00edficas para garantizar la calidad y seguridad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: stability studies, shelf-life, commitment, pharmaceutical products, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a8bd7205-ef28-4158-b96e-e99a6375ad29", "node_type": "4", "metadata": {"page_label": "200", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Primary stability study commitment\n\nWhen the available data on long-term stability of primary batches do not cover the proposed shelf-life granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the shelf-life. A written commitment (signed and dated) to continue long-term testing over the shelf-life period should be included in the dossier.\n\n## Commitment stability studies\n\nThe long-term stability studies for the commitment batches should be conducted throughout the proposed shelf-life on at least three production batches of each strength in each container-closure system. Where stability data were not provided for three production batches of each strength, a written commitment (signed and dated) should be included in the dossier.\n\n## Ongoing stability studies\n\nAs described in the WHO stability guidelines (19), an ongoing stability programme is established to monitor the product over its shelf-life and to determine that the product remains and can be expected to remain within specifications under the storage conditions on the label. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every container-closure system, if relevant, should be included in the stability programme (unless none is produced during that year). Bracketing and matrixing may be applicable. A written commitment (signed and dated) to this effect should be included in the dossier.\n\nAny differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.\n\nReference document: ICH Q1A (20).\n\n## 3.2.P.8.3 Stability data (name, dosage form)\n\nResults of the stability studies should be presented in an appropriate format (e.g. tabular, graphical, narrative). Information on the analytical procedures used to generate the data and validation of these procedures should be included.\n\nInformation on characterization of impurities is located in 3.2.P.5.5.\n\nThe actual stability results and reports used to support the proposed shelf-life should be provided in the PD. For quantitative tests (e.g. individual and total degradation product tests and assay tests), actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "72f076dba4cb0225a505c39dde60b1713f1338ee7d6507c787a20a6597f15aeb", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Primary stability study commitment\n\nWhen the available data on long-term stability of primary batches do not cover the proposed shelf-life granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the shelf-life. A written commitment (signed and dated) to continue long-term testing over the shelf-life period should be included in the dossier.\n\n## Commitment stability studies\n\nThe long-term stability studies for the commitment batches should be conducted throughout the proposed shelf-life on at least three production batches of each strength in each container-closure system. Where stability data were not provided for three production batches of each strength, a written commitment (signed and dated) should be included in the dossier.\n\n## Ongoing stability studies\n\nAs described in the WHO stability guidelines (19), an ongoing stability programme is established to monitor the product over its shelf-life and to determine that the product remains and can be expected to remain within specifications under the storage conditions on the label. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every container-closure system, if relevant, should be included in the stability programme (unless none is produced during that year). Bracketing and matrixing may be applicable. A written commitment (signed and dated) to this effect should be included in the dossier.\n\nAny differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.\n\nReference document: ICH Q1A (20).\n\n## 3.2.P.8.3 Stability data (name, dosage form)\n\nResults of the stability studies should be presented in an appropriate format (e.g. tabular, graphical, narrative). Information on the analytical procedures used to generate the data and validation of these procedures should be included.\n\nInformation on characterization of impurities is located in 3.2.P.5.5.\n\nThe actual stability results and reports used to support the proposed shelf-life should be provided in the PD. For quantitative tests (e.g. individual and total degradation product tests and assay tests), actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2392, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "daa170ec-d8b3-4e84-8181-16f9a625de3d": {"__data__": {"id_": "daa170ec-d8b3-4e84-8181-16f9a625de3d", "embedding": null, "metadata": {"page_label": "201", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendices\n\n## 3.2.A.1 Facilities and equipment\n\nNot applicable (i.e. not a biotech product).\n\n## 3.2.A.2 Adventitious agents safety evaluation\n\n## 3.2.A.3 Novel excipients\n\nNovel excipients are not accepted in the WHO Prequalification of Medicines Programme.\n\n# Regional information\n\n## 3.2.R.1 Production documentation\n\n### 3.2.R.1.1 Executed production documents\n\nA minimum of two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale (the batch used in comparative bioavailability or biowaiver studies) and a second batch which may be smaller (e.g. for solid oral dosage forms, 25,000 or 50,000 tablets or capsules), should be manufactured for each strength. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nFor solid oral dosage forms, pilot scale is generally, at a minimum, one-tenth that of full production scale or 100,000 tablets or capsules, whichever is the larger.\n\nCopies of the executed production documents should be provided for the batches used in the comparative bioavailability or biowaiver studies. Any notations made by operators on the executed production documents should be clearly legible.\n\nIf not included in the executed batch records through sufficient in-process testing, data should be provided for the batch used in comparative bioavailability or biowaiver studies that demonstrate the uniformity of this batch. The data to establish the uniformity of the biobatch should involve testing to an extent greater than that required in routine quality control.\n\nEnglish translations of executed records should be provided where relevant.\n\n----\n\nDissolution results should be expressed, at a minimum, as both the average and range of individual results.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1C (47), Q1D (24), Q1E (23), Q2 (16).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Serie de Informes T\u00e9cnicos 970 aborda aspectos relacionados con la producci\u00f3n y evaluaci\u00f3n de medicamentos, espec\u00edficamente en el contexto de la Precalificaci\u00f3n de Medicamentos. Se menciona que no se aceptan excipientes novedosos y se establecen requisitos para la documentaci\u00f3n de producci\u00f3n, incluyendo la necesidad de fabricar lotes de escala piloto y proporcionar documentaci\u00f3n ejecutada para estudios de bioequivalencia o biowaiver. Tambi\u00e9n se enfatiza la importancia de demostrar la uniformidad de los lotes y la presentaci\u00f3n de resultados de disoluci\u00f3n.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los requisitos m\u00ednimos para la fabricaci\u00f3n de lotes de medicamentos en el contexto de la Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Respuesta: Se requieren al menos dos lotes de escala piloto para cada fuerza del medicamento, o al menos un lote de escala piloto y un segundo lote m\u00e1s peque\u00f1o en el caso de formas farmac\u00e9uticas s\u00f3lidas de liberaci\u00f3n inmediata o soluciones no est\u00e9riles.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la documentaci\u00f3n ejecutada de producci\u00f3n para los estudios de bioequivalencia?**\n   - Respuesta: Deben proporcionarse copias de los documentos de producci\u00f3n ejecutados para los lotes utilizados en los estudios de bioequivalencia, y cualquier anotaci\u00f3n hecha por los operadores debe ser claramente legible.\n\n3. **\u00bfC\u00f3mo se deben presentar los resultados de disoluci\u00f3n seg\u00fan las directrices de la OMS?**\n   - Respuesta: Los resultados de disoluci\u00f3n deben expresarse, como m\u00ednimo, tanto como el promedio como el rango de los resultados individuales.", "prev_section_summary": "### Temas Clave\n\n1. **Compromiso de Estudios de Estabilidad**: Se requiere un compromiso por escrito para continuar los estudios de estabilidad a largo plazo si los datos disponibles no cubren la vida \u00fatil propuesta.\n\n2. **Estudios de Estabilidad de Lotes de Compromiso**: Los estudios deben realizarse en al menos tres lotes de producci\u00f3n de cada fuerza y sistema de cierre de contenedor a lo largo de la vida \u00fatil propuesta.\n\n3. **Programa de Estabilidad en Curso**: Se establece un programa para monitorear el producto durante su vida \u00fatil, incluyendo al menos un lote por a\u00f1o de cada fuerza y sistema de cierre, a menos que no se produzca ninguno.\n\n4. **Justificaci\u00f3n Cient\u00edfica**: Cualquier diferencia entre los protocolos de estabilidad de los lotes primarios y los lotes de compromiso o en curso debe ser cient\u00edficamente justificada.\n\n5. **Presentaci\u00f3n de Resultados**: Los resultados de los estudios de estabilidad deben presentarse en formatos apropiados (tabular, gr\u00e1fico, narrativo) y deben incluir datos num\u00e9ricos concretos.\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las directrices sobre estudios de estabilidad.\n- **Lotes de Producci\u00f3n**: Referencia a los lotes de productos farmac\u00e9uticos que se est\u00e1n evaluando.\n- **Vida \u00datil**: Per\u00edodo durante el cual se espera que el producto mantenga su calidad y eficacia.\n- **Protocolos de Estabilidad**: M\u00e9todos y procedimientos utilizados para evaluar la estabilidad de los productos.\n- **Compromiso por Escrito**: Documento que debe ser firmado y fechado para formalizar el compromiso de continuar los estudios de estabilidad.\n- **ICH Q1A**: Documento de referencia mencionado que proporciona directrices sobre estabilidad.", "excerpt_keywords": "Keywords: WHO, Prequalification, production documentation, bioequivalence, dissolution results"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5080c859-effc-41f0-b5a7-d4f2572ae844", "node_type": "4", "metadata": {"page_label": "201", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendices\n\n## 3.2.A.1 Facilities and equipment\n\nNot applicable (i.e. not a biotech product).\n\n## 3.2.A.2 Adventitious agents safety evaluation\n\n## 3.2.A.3 Novel excipients\n\nNovel excipients are not accepted in the WHO Prequalification of Medicines Programme.\n\n# Regional information\n\n## 3.2.R.1 Production documentation\n\n### 3.2.R.1.1 Executed production documents\n\nA minimum of two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale (the batch used in comparative bioavailability or biowaiver studies) and a second batch which may be smaller (e.g. for solid oral dosage forms, 25,000 or 50,000 tablets or capsules), should be manufactured for each strength. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nFor solid oral dosage forms, pilot scale is generally, at a minimum, one-tenth that of full production scale or 100,000 tablets or capsules, whichever is the larger.\n\nCopies of the executed production documents should be provided for the batches used in the comparative bioavailability or biowaiver studies. Any notations made by operators on the executed production documents should be clearly legible.\n\nIf not included in the executed batch records through sufficient in-process testing, data should be provided for the batch used in comparative bioavailability or biowaiver studies that demonstrate the uniformity of this batch. The data to establish the uniformity of the biobatch should involve testing to an extent greater than that required in routine quality control.\n\nEnglish translations of executed records should be provided where relevant.\n\n----\n\nDissolution results should be expressed, at a minimum, as both the average and range of individual results.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1C (47), Q1D (24), Q1E (23), Q2 (16).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "5b2b602bab2531060b8ecbe1f2928a61195ffc9bb715dd9d05000c436f43b544", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Appendices\n\n## 3.2.A.1 Facilities and equipment\n\nNot applicable (i.e. not a biotech product).\n\n## 3.2.A.2 Adventitious agents safety evaluation\n\n## 3.2.A.3 Novel excipients\n\nNovel excipients are not accepted in the WHO Prequalification of Medicines Programme.\n\n# Regional information\n\n## 3.2.R.1 Production documentation\n\n### 3.2.R.1.1 Executed production documents\n\nA minimum of two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale (the batch used in comparative bioavailability or biowaiver studies) and a second batch which may be smaller (e.g. for solid oral dosage forms, 25,000 or 50,000 tablets or capsules), should be manufactured for each strength. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nFor solid oral dosage forms, pilot scale is generally, at a minimum, one-tenth that of full production scale or 100,000 tablets or capsules, whichever is the larger.\n\nCopies of the executed production documents should be provided for the batches used in the comparative bioavailability or biowaiver studies. Any notations made by operators on the executed production documents should be clearly legible.\n\nIf not included in the executed batch records through sufficient in-process testing, data should be provided for the batch used in comparative bioavailability or biowaiver studies that demonstrate the uniformity of this batch. The data to establish the uniformity of the biobatch should involve testing to an extent greater than that required in routine quality control.\n\nEnglish translations of executed records should be provided where relevant.\n\n----\n\nDissolution results should be expressed, at a minimum, as both the average and range of individual results.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1C (47), Q1D (24), Q1E (23), Q2 (16).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2009, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "7d263796-6c29-492a-b29e-120e1c7101bc": {"__data__": {"id_": "7d263796-6c29-492a-b29e-120e1c7101bc", "embedding": null, "metadata": {"page_label": "202", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.R.1.2 Master production documents\n\nCopies of the FPP master production documents should be provided for each proposed strength, commercial batch size and manufacturing site.\n\nThe details in the master production documents should include, but not be limited to, the following:\n\n- **master formula;**\n- **dispensing, processing and packaging sections with relevant material and operational details;**\n- **relevant calculations** (e.g. if the amount of API is adjusted based on the assay results or on the anhydrous basis);\n- **identification of all equipment** by, at a minimum, type and working capacity (including make, model and equipment number, where possible);\n- **process parameters** (e.g. mixing time, mixing speed, milling screen size, processing temperature range, granulation end-point and tablet machine speed (expressed as target and range));\n- **list of in-process tests** (e.g. appearance, pH, assay, blend uniformity, viscosity, particle size distribution, loss on drying, weight variation, hardness, disintegration time, weight gain during coating, leaker test, minimum fill, clarity and filter integrity checks) and specifications;\n- **sampling plan** with regard to the:\n  - steps at which sampling should be done (e.g. drying, lubrication and compression),\n  - number of samples that should be tested (e.g. for blend uniformity testing of low-dose FPPs, blend drawn using a sampling thief from x positions in the blender),\n  - frequency of testing (e.g. weight variation every x minutes during compression or capsule filling);\n- **precautions necessary to ensure product quality** (e.g. temperature and humidity control and maximum holding times);\n- for sterile products, reference to **standard operating procedures (SOPs)** in appropriate sections and a list of all relevant SOPs at the end of the document;\n- **theoretical and actual yield;**\n- **compliance with the GMP requirements.**\n\nReference document: WHO Technical Report Series, No. 961 (48).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en los documentos maestros de producci\u00f3n para cada lote comercial propuesto?**\n   - Los documentos maestros de producci\u00f3n deben incluir, entre otros, la f\u00f3rmula maestra, secciones de dispensaci\u00f3n, procesamiento y empaque con detalles operativos, c\u00e1lculos relevantes, identificaci\u00f3n del equipo, par\u00e1metros del proceso, lista de pruebas en proceso, plan de muestreo, precauciones para asegurar la calidad del producto, referencia a procedimientos operativos est\u00e1ndar (SOPs) para productos est\u00e9riles, rendimiento te\u00f3rico y real, y cumplimiento con los requisitos de Buenas Pr\u00e1cticas de Manufactura (GMP).\n\n2. **\u00bfCu\u00e1les son algunos ejemplos de pruebas en proceso que deben ser listadas en los documentos maestros de producci\u00f3n?**\n   - Ejemplos de pruebas en proceso incluyen apariencia, pH, ensayo, uniformidad de mezcla, viscosidad, distribuci\u00f3n del tama\u00f1o de part\u00edculas, p\u00e9rdida por secado, variaci\u00f3n de peso, dureza, tiempo de desintegraci\u00f3n, ganancia de peso durante el recubrimiento, prueba de fugas, llenado m\u00ednimo, claridad y verificaci\u00f3n de integridad de filtros.\n\n3. **\u00bfQu\u00e9 aspectos se deben considerar en el plan de muestreo seg\u00fan los documentos maestros de producci\u00f3n?**\n   - El plan de muestreo debe considerar los pasos en los que se debe realizar el muestreo (como secado, lubricaci\u00f3n y compresi\u00f3n), el n\u00famero de muestras que deben ser probadas (por ejemplo, para la prueba de uniformidad de mezcla de FPPs de baja dosis), y la frecuencia de las pruebas (por ejemplo, variaci\u00f3n de peso cada ciertos minutos durante la compresi\u00f3n o llenado de c\u00e1psulas).\n\n### Resumen de nivel superior:\nLos documentos maestros de producci\u00f3n son esenciales para garantizar la calidad y la consistencia en la fabricaci\u00f3n de productos farmac\u00e9uticos. Deben contener informaci\u00f3n detallada sobre la f\u00f3rmula, el proceso de producci\u00f3n, el equipo utilizado, las pruebas realizadas durante la producci\u00f3n y el cumplimiento de las normativas de calidad. Esto asegura que cada lote producido cumpla con los est\u00e1ndares requeridos y que se mantenga la integridad del producto final.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Precalificaci\u00f3n de Medicamentos de la OMS**:\n   - El documento establece directrices para la producci\u00f3n y evaluaci\u00f3n de medicamentos en el contexto de la precalificaci\u00f3n.\n\n2. **Excipientes Novedosos**:\n   - Se menciona que no se aceptan excipientes novedosos en el programa de precalificaci\u00f3n.\n\n3. **Documentaci\u00f3n de Producci\u00f3n**:\n   - Se requiere la fabricaci\u00f3n de al menos dos lotes de escala piloto para cada fuerza del medicamento.\n   - En el caso de formas farmac\u00e9uticas s\u00f3lidas de liberaci\u00f3n inmediata o soluciones no est\u00e9riles, se acepta un lote de escala piloto y un segundo lote m\u00e1s peque\u00f1o.\n\n4. **Escala Piloto**:\n   - Para formas s\u00f3lidas orales, la escala piloto debe ser, como m\u00ednimo, una d\u00e9cima parte de la escala de producci\u00f3n completa o 100,000 tabletas/c\u00e1psulas, lo que sea mayor.\n\n5. **Documentos Ejecutados**:\n   - Se deben proporcionar copias de los documentos de producci\u00f3n ejecutados para los lotes utilizados en estudios de bioequivalencia o biowaiver.\n   - Las anotaciones de los operadores en los documentos deben ser legibles.\n\n6. **Uniformidad de Lotes**:\n   - Se requiere demostrar la uniformidad del lote utilizado en estudios de bioequivalencia, con pruebas m\u00e1s exhaustivas que las de control de calidad rutinario.\n\n7. **Resultados de Disoluci\u00f3n**:\n   - Los resultados de disoluci\u00f3n deben presentarse como el promedio y el rango de los resultados individuales.\n\n8. **Referencias**:\n   - Se citan documentos de referencia de la ICH (International Council for Harmonisation) que respaldan las directrices.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que establece las directrices.\n- **FPP (Formas Farmac\u00e9uticas Finales)**: Tipos de productos farmac\u00e9uticos a los que se aplican las directrices.\n- **ICH (International Council for Harmonisation)**: Organizaci\u00f3n que proporciona documentos de referencia para la regulaci\u00f3n de medicamentos.", "excerpt_keywords": "Keywords: master production documents, pharmaceutical manufacturing, quality assurance, Good Manufacturing Practices, in-process testing"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9e2d7133-fcc1-443e-b469-aacb906e9083", "node_type": "4", "metadata": {"page_label": "202", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.R.1.2 Master production documents\n\nCopies of the FPP master production documents should be provided for each proposed strength, commercial batch size and manufacturing site.\n\nThe details in the master production documents should include, but not be limited to, the following:\n\n- **master formula;**\n- **dispensing, processing and packaging sections with relevant material and operational details;**\n- **relevant calculations** (e.g. if the amount of API is adjusted based on the assay results or on the anhydrous basis);\n- **identification of all equipment** by, at a minimum, type and working capacity (including make, model and equipment number, where possible);\n- **process parameters** (e.g. mixing time, mixing speed, milling screen size, processing temperature range, granulation end-point and tablet machine speed (expressed as target and range));\n- **list of in-process tests** (e.g. appearance, pH, assay, blend uniformity, viscosity, particle size distribution, loss on drying, weight variation, hardness, disintegration time, weight gain during coating, leaker test, minimum fill, clarity and filter integrity checks) and specifications;\n- **sampling plan** with regard to the:\n  - steps at which sampling should be done (e.g. drying, lubrication and compression),\n  - number of samples that should be tested (e.g. for blend uniformity testing of low-dose FPPs, blend drawn using a sampling thief from x positions in the blender),\n  - frequency of testing (e.g. weight variation every x minutes during compression or capsule filling);\n- **precautions necessary to ensure product quality** (e.g. temperature and humidity control and maximum holding times);\n- for sterile products, reference to **standard operating procedures (SOPs)** in appropriate sections and a list of all relevant SOPs at the end of the document;\n- **theoretical and actual yield;**\n- **compliance with the GMP requirements.**\n\nReference document: WHO Technical Report Series, No. 961 (48).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "707b29f8f1957ea043d83298c1bd8010a82b8ab86bca1b5c1096f18fd00f5b09", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.R.1.2 Master production documents\n\nCopies of the FPP master production documents should be provided for each proposed strength, commercial batch size and manufacturing site.\n\nThe details in the master production documents should include, but not be limited to, the following:\n\n- **master formula;**\n- **dispensing, processing and packaging sections with relevant material and operational details;**\n- **relevant calculations** (e.g. if the amount of API is adjusted based on the assay results or on the anhydrous basis);\n- **identification of all equipment** by, at a minimum, type and working capacity (including make, model and equipment number, where possible);\n- **process parameters** (e.g. mixing time, mixing speed, milling screen size, processing temperature range, granulation end-point and tablet machine speed (expressed as target and range));\n- **list of in-process tests** (e.g. appearance, pH, assay, blend uniformity, viscosity, particle size distribution, loss on drying, weight variation, hardness, disintegration time, weight gain during coating, leaker test, minimum fill, clarity and filter integrity checks) and specifications;\n- **sampling plan** with regard to the:\n  - steps at which sampling should be done (e.g. drying, lubrication and compression),\n  - number of samples that should be tested (e.g. for blend uniformity testing of low-dose FPPs, blend drawn using a sampling thief from x positions in the blender),\n  - frequency of testing (e.g. weight variation every x minutes during compression or capsule filling);\n- **precautions necessary to ensure product quality** (e.g. temperature and humidity control and maximum holding times);\n- for sterile products, reference to **standard operating procedures (SOPs)** in appropriate sections and a list of all relevant SOPs at the end of the document;\n- **theoretical and actual yield;**\n- **compliance with the GMP requirements.**\n\nReference document: WHO Technical Report Series, No. 961 (48).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1978, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "ea36af88-4ddb-48a0-9aa5-ad38af5218dd": {"__data__": {"id_": "ea36af88-4ddb-48a0-9aa5-ad38af5218dd", "embedding": null, "metadata": {"page_label": "203", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.R.2 Analytical procedures and validation information\n\nThe tables presented in section 2.3.R.2 in the QOS-PD template should be used to summarize the analytical procedures and validation information from sections 3.2.S.4.2, 3.2.S.4.3, 2.3.S.4.4 (c), 2.3.S.7.3 (b), 3.2.P.5.2 and 3.2.P.5.3 where relevant.\n\n## 4.3 Literature references\n\nReferences to the scientific literature relating to both the API and FPP should be included in this section of the PD when appropriate.\n\n# References\n\n1. Procedure for prequalification of pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2011, Annex 10 (WHO Technical Report Series, No. 961).\n\n2. ICH harmonised tripartite guideline: the common technical document for the registration of pharmaceuticals for human use: quality \u2013 M4Q. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2002.\n\n3. Guidelines on submission of documentation for a multisource (generic) finished product: general format: preparation of product dossiers in common technical document format. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fifth report. Geneva, World Health Organization, 2011, Annex 5 (WHO Technical Report Series, No. 961).\n\n4. Guidelines on active pharmaceutical ingredient master file procedure. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-second report. Geneva, World Health Organization, 2008, Annex 4 (WHO Technical Report Series, No. 948).\n\n5. Common technical document for the registration of pharmaceuticals for human use \u2013 quality questions & answers/location issues. European Medicines Agency, 2009 (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002726.pdf).\n\n6. ICH harmonised tripartite guideline: specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances \u2013 Q6A. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999.\n\n7. ICH harmonised tripartite guideline: Good manufacturing practice guide for active pharmaceutical ingredients \u2013 Q7. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2000.\n\n8. WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth report. Geneva, World Health Organization, 2010, Annex 2 (WHO Technical Report Series, No. 957).\n\n9. Guidance on variations to a prequalified product dossier. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization, 2007, Annex 6 (WHO Technical Report Series, No. 943).\n\n10. ICH harmonised tripartite guideline: impurities in new drug substances \u2013 Q3A. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2006.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en los procedimientos anal\u00edticos y la informaci\u00f3n de validaci\u00f3n relacionados con productos farmac\u00e9uticos, espec\u00edficamente en el contexto de la presentaci\u00f3n de documentos para la precalificaci\u00f3n de productos farmac\u00e9uticos. Se menciona la importancia de resumir la informaci\u00f3n de validaci\u00f3n y los procedimientos anal\u00edticos en tablas espec\u00edficas del formato de documento de calidad (QOS-PD). Adem\u00e1s, se destaca la necesidad de incluir referencias a la literatura cient\u00edfica pertinente tanto para el ingrediente farmac\u00e9utico activo (API) como para el producto farmac\u00e9utico terminado (FPP).\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 se debe incluir en las tablas de la secci\u00f3n 2.3.R.2 del QOS-PD seg\u00fan el documento?**\n   - Respuesta: Las tablas de la secci\u00f3n 2.3.R.2 del QOS-PD deben resumir los procedimientos anal\u00edticos y la informaci\u00f3n de validaci\u00f3n de las secciones 3.2.S.4.2, 3.2.S.4.3, 2.3.S.4.4 (c), 2.3.S.7.3 (b), 3.2.P.5.2 y 3.2.P.5.3 donde sea relevante.\n\n2. **\u00bfCu\u00e1l es la importancia de incluir referencias a la literatura cient\u00edfica en el documento de presentaci\u00f3n (PD)?**\n   - Respuesta: Incluir referencias a la literatura cient\u00edfica en el PD es importante para proporcionar un respaldo y contexto cient\u00edfico tanto para el ingrediente farmac\u00e9utico activo (API) como para el producto farmac\u00e9utico terminado (FPP), asegurando que la informaci\u00f3n presentada est\u00e9 fundamentada en estudios y gu\u00edas reconocidas.\n\n3. **\u00bfQu\u00e9 tipo de documentos se citan como referencias en el contexto de la validaci\u00f3n de productos farmac\u00e9uticos?**\n   - Respuesta: Se citan varios documentos, incluyendo directrices de la OMS sobre la precalificaci\u00f3n de productos farmac\u00e9uticos, gu\u00edas de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) sobre el registro de productos farmac\u00e9uticos, y documentos sobre buenas pr\u00e1cticas de fabricaci\u00f3n (GMP) para ingredientes farmac\u00e9uticos activos, entre otros.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Documentaci\u00f3n Maestra de Producci\u00f3n:** Importancia de los documentos maestros para cada fuerza propuesta, tama\u00f1o de lote comercial y sitio de fabricaci\u00f3n.\n2. **Contenido Esencial:** Detalles que deben incluirse en los documentos, como la f\u00f3rmula maestra, secciones de dispensaci\u00f3n, procesamiento y empaque, c\u00e1lculos relevantes, identificaci\u00f3n de equipos, par\u00e1metros del proceso, pruebas en proceso, plan de muestreo, precauciones de calidad, procedimientos operativos est\u00e1ndar (SOPs) para productos est\u00e9riles, rendimiento te\u00f3rico y real, y cumplimiento de Buenas Pr\u00e1cticas de Manufactura (GMP).\n3. **Pruebas en Proceso:** Ejemplos de pruebas que aseguran la calidad del producto durante la producci\u00f3n.\n4. **Plan de Muestreo:** Consideraciones sobre cu\u00e1ndo y c\u00f3mo se debe realizar el muestreo durante el proceso de fabricaci\u00f3n.\n\n**Entidades:**\n- **FPP (Formulaci\u00f3n Farmac\u00e9utica de Producto):** Referencia a los productos farmac\u00e9uticos que se est\u00e1n produciendo.\n- **API (Ingrediente Activo):** Sustancia que proporciona la acci\u00f3n farmacol\u00f3gica.\n- **SOP (Procedimientos Operativos Est\u00e1ndar):** Documentos que describen c\u00f3mo realizar tareas espec\u00edficas de manera consistente.\n- **GMP (Buenas Pr\u00e1cticas de Manufactura):** Normativas que aseguran que los productos se fabriquen y controlen de acuerdo con est\u00e1ndares de calidad.\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Entidad que proporciona directrices y est\u00e1ndares para la producci\u00f3n farmac\u00e9utica.\n\nEste resumen destaca la importancia de la documentaci\u00f3n detallada y el cumplimiento de normativas en la producci\u00f3n farmac\u00e9utica para garantizar la calidad y seguridad de los productos.", "excerpt_keywords": "Keywords: analytical procedures, validation information, pharmaceutical products, WHO guidelines, quality documentation"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b154d401-9e91-4630-abf9-0e9ad9141e1f", "node_type": "4", "metadata": {"page_label": "203", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.R.2 Analytical procedures and validation information\n\nThe tables presented in section 2.3.R.2 in the QOS-PD template should be used to summarize the analytical procedures and validation information from sections 3.2.S.4.2, 3.2.S.4.3, 2.3.S.4.4 (c), 2.3.S.7.3 (b), 3.2.P.5.2 and 3.2.P.5.3 where relevant.\n\n## 4.3 Literature references\n\nReferences to the scientific literature relating to both the API and FPP should be included in this section of the PD when appropriate.\n\n# References\n\n1. Procedure for prequalification of pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2011, Annex 10 (WHO Technical Report Series, No. 961).\n\n2. ICH harmonised tripartite guideline: the common technical document for the registration of pharmaceuticals for human use: quality \u2013 M4Q. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2002.\n\n3. Guidelines on submission of documentation for a multisource (generic) finished product: general format: preparation of product dossiers in common technical document format. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fifth report. Geneva, World Health Organization, 2011, Annex 5 (WHO Technical Report Series, No. 961).\n\n4. Guidelines on active pharmaceutical ingredient master file procedure. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-second report. Geneva, World Health Organization, 2008, Annex 4 (WHO Technical Report Series, No. 948).\n\n5. Common technical document for the registration of pharmaceuticals for human use \u2013 quality questions & answers/location issues. European Medicines Agency, 2009 (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002726.pdf).\n\n6. ICH harmonised tripartite guideline: specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances \u2013 Q6A. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999.\n\n7. ICH harmonised tripartite guideline: Good manufacturing practice guide for active pharmaceutical ingredients \u2013 Q7. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2000.\n\n8. WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth report. Geneva, World Health Organization, 2010, Annex 2 (WHO Technical Report Series, No. 957).\n\n9. Guidance on variations to a prequalified product dossier. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization, 2007, Annex 6 (WHO Technical Report Series, No. 943).\n\n10. ICH harmonised tripartite guideline: impurities in new drug substances \u2013 Q3A. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2006.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "d123b1624580aae2d5d9565d4eae278153f71000ae6e57ba7cdd3b55b8ae1c95", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.2.R.2 Analytical procedures and validation information\n\nThe tables presented in section 2.3.R.2 in the QOS-PD template should be used to summarize the analytical procedures and validation information from sections 3.2.S.4.2, 3.2.S.4.3, 2.3.S.4.4 (c), 2.3.S.7.3 (b), 3.2.P.5.2 and 3.2.P.5.3 where relevant.\n\n## 4.3 Literature references\n\nReferences to the scientific literature relating to both the API and FPP should be included in this section of the PD when appropriate.\n\n# References\n\n1. Procedure for prequalification of pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2011, Annex 10 (WHO Technical Report Series, No. 961).\n\n2. ICH harmonised tripartite guideline: the common technical document for the registration of pharmaceuticals for human use: quality \u2013 M4Q. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2002.\n\n3. Guidelines on submission of documentation for a multisource (generic) finished product: general format: preparation of product dossiers in common technical document format. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fifth report. Geneva, World Health Organization, 2011, Annex 5 (WHO Technical Report Series, No. 961).\n\n4. Guidelines on active pharmaceutical ingredient master file procedure. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-second report. Geneva, World Health Organization, 2008, Annex 4 (WHO Technical Report Series, No. 948).\n\n5. Common technical document for the registration of pharmaceuticals for human use \u2013 quality questions & answers/location issues. European Medicines Agency, 2009 (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002726.pdf).\n\n6. ICH harmonised tripartite guideline: specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances \u2013 Q6A. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999.\n\n7. ICH harmonised tripartite guideline: Good manufacturing practice guide for active pharmaceutical ingredients \u2013 Q7. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2000.\n\n8. WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth report. Geneva, World Health Organization, 2010, Annex 2 (WHO Technical Report Series, No. 957).\n\n9. Guidance on variations to a prequalified product dossier. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization, 2007, Annex 6 (WHO Technical Report Series, No. 943).\n\n10. ICH harmonised tripartite guideline: impurities in new drug substances \u2013 Q3A. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2006.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3148, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "abee4531-16bd-46b8-9980-25c71b19755f": {"__data__": {"id_": "abee4531-16bd-46b8-9980-25c71b19755f", "embedding": null, "metadata": {"page_label": "204", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n11. **ICH harmonised tripartite guideline: impurities in new drug products \u2013 Q3B.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2006.\n\n12. **ICH harmonised tripartite guideline impurities: guideline for residual solvents \u2013 Q3C.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2011.\n\n13. **Committee for Medicinal Products for Human Use (CHMP). Guideline on the limits of genotoxic impurities.**  \n   European Medicines Agency, 2006 (CPMP/SWP/5199/02 EMEA/CHMP/ QWP/251344/2006).\n\n14. **US FDA Guidance for industry: Genotoxic and carcinogenic impurities in drug substances and products: recommended approaches.**  \n   US Food and Drug Administration, 2008.\n\n15. **Committee for Medicinal Products for Human Use (CHMP). Guideline on the specification limits for residues of metal catalysts or metal reagents.**  \n   London, European Medicines Agency, 2008 (EMEA/CHMP/SWP/4446/2000).\n\n16. **ICH Harmonised tripartite guideline: validation of analytical procedures: text and methodology \u2013 Q2.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1994.\n\n17. **General guidelines for the establishment, maintenance and distribution of chemical reference substances.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization, 2007, Annex 3 (WHO Technical Report Series, No. 943).\n\n18. **Guidelines on packaging for pharmaceutical products.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-sixth report. Geneva, World Health Organization, 2002, Annex 9 (WHO Technical Report Series, No. 902).\n\n19. **Stability testing of active pharmaceutical ingredients and finished pharmaceutical products.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2009, Annex 2 (WHO Technical Report Series, No. 953).\n\n20. **ICH harmonised tripartite guideline: stability testing of new drug substances and products \u2013 Q1A.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2003.\n\n21. **Guidelines for registration of fixed-dose combination medicinal products.**  \n   Appendix 3: Pharmaceutical development (or preformulation) studies. Table A1: Typical stress conditions in preformulation stability studies.  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n22. **ICH harmonised tripartite guideline: Stability testing: Photostability testing of new drug substances and products \u2013 Q1B.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.\n\n23. **ICH harmonised tripartite guideline: evaluation for stability data \u2013 Q1E.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2003.\n\n24. **ICH harmonised tripartite guideline: bracketing and matrixing designs for stability testing of new drug substances and products \u2013 Q1D.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2002.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que presenta directrices y pautas relacionadas con la preparaci\u00f3n y especificaciones de productos farmac\u00e9uticos. Incluye referencias a varias gu\u00edas de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) y de la Agencia Europea de Medicamentos (EMA), as\u00ed como de la Administraci\u00f3n de Alimentos y Medicamentos de EE. UU. (FDA). Las pautas abordan temas como impurezas en productos farmac\u00e9uticos, l\u00edmites de impurezas genot\u00f3xicas, validaci\u00f3n de procedimientos anal\u00edticos, pruebas de estabilidad y requisitos de empaquetado.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las implicaciones de las directrices de la ICH sobre las impurezas en nuevos productos farmac\u00e9uticos (Q3B) para la industria farmac\u00e9utica?**\n   - Esta pregunta busca explorar c\u00f3mo las pautas establecidas en la directriz Q3B afectan la formulaci\u00f3n, producci\u00f3n y control de calidad de nuevos medicamentos, as\u00ed como su impacto en la seguridad del paciente.\n\n2. **\u00bfQu\u00e9 criterios se establecen en la gu\u00eda de la EMA sobre los l\u00edmites de impurezas genot\u00f3xicas y c\u00f3mo se aplican en la evaluaci\u00f3n de medicamentos?**\n   - Esta pregunta se centra en los criterios espec\u00edficos que la EMA establece para evaluar las impurezas genot\u00f3xicas y c\u00f3mo estos criterios influyen en el proceso de aprobaci\u00f3n de nuevos medicamentos.\n\n3. **\u00bfC\u00f3mo se relacionan las pautas de estabilidad de la ICH (Q1A, Q1B, Q1D, Q1E) con el desarrollo de productos farmac\u00e9uticos y qu\u00e9 metodolog\u00edas se recomiendan para las pruebas de estabilidad?**\n   - Esta pregunta busca profundizar en las metodolog\u00edas y enfoques recomendados por la ICH para realizar pruebas de estabilidad en nuevos productos farmac\u00e9uticos, as\u00ed como su relevancia en el desarrollo y la formulaci\u00f3n de medicamentos.\n\nEstas preguntas est\u00e1n dise\u00f1adas para obtener informaci\u00f3n detallada y espec\u00edfica que no se puede encontrar f\u00e1cilmente en otras fuentes, bas\u00e1ndose en el contenido del documento y su contexto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Procedimientos Anal\u00edticos y Validaci\u00f3n:**\n   - La secci\u00f3n 3.2.R.2 del documento se centra en la importancia de resumir los procedimientos anal\u00edticos y la informaci\u00f3n de validaci\u00f3n en tablas espec\u00edficas del formato de documento de calidad (QOS-PD).\n   - Se mencionan secciones espec\u00edficas del documento que deben ser referenciadas para la recopilaci\u00f3n de esta informaci\u00f3n.\n\n2. **Referencias a la Literatura Cient\u00edfica:**\n   - Se destaca la necesidad de incluir referencias a la literatura cient\u00edfica relacionada con el ingrediente farmac\u00e9utico activo (API) y el producto farmac\u00e9utico terminado (FPP) en el documento de presentaci\u00f3n (PD).\n   - Esto proporciona un respaldo cient\u00edfico y contexto a la informaci\u00f3n presentada.\n\n3. **Documentos Citados:**\n   - Se citan diversas gu\u00edas y documentos relevantes, incluyendo directrices de la OMS y de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH), que son fundamentales para la validaci\u00f3n y el registro de productos farmac\u00e9uticos.\n\n**Entidades:**\n\n- **Organizaciones:**\n  - Organizaci\u00f3n Mundial de la Salud (OMS)\n  - Conferencia Internacional sobre Armonizaci\u00f3n (ICH)\n  - Agencia Europea de Medicamentos (EMA)\n\n- **Documentos y Gu\u00edas:**\n  - WHO Technical Report Series\n  - ICH M4Q\n  - Directrices sobre buenas pr\u00e1cticas de fabricaci\u00f3n (GMP)\n  - Procedimientos de precalificaci\u00f3n de productos farmac\u00e9uticos\n\nEste resumen destaca la estructura y los elementos esenciales de la secci\u00f3n, enfatizando la importancia de la validaci\u00f3n y el respaldo cient\u00edfico en la presentaci\u00f3n de documentos para productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: pharmaceutical preparations, ICH guidelines, genotoxic impurities, stability testing, WHO Technical Report Series"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "05aeff10-dc42-46a3-b61f-adfb8d7bb5c2", "node_type": "4", "metadata": {"page_label": "204", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n11. **ICH harmonised tripartite guideline: impurities in new drug products \u2013 Q3B.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2006.\n\n12. **ICH harmonised tripartite guideline impurities: guideline for residual solvents \u2013 Q3C.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2011.\n\n13. **Committee for Medicinal Products for Human Use (CHMP). Guideline on the limits of genotoxic impurities.**  \n   European Medicines Agency, 2006 (CPMP/SWP/5199/02 EMEA/CHMP/ QWP/251344/2006).\n\n14. **US FDA Guidance for industry: Genotoxic and carcinogenic impurities in drug substances and products: recommended approaches.**  \n   US Food and Drug Administration, 2008.\n\n15. **Committee for Medicinal Products for Human Use (CHMP). Guideline on the specification limits for residues of metal catalysts or metal reagents.**  \n   London, European Medicines Agency, 2008 (EMEA/CHMP/SWP/4446/2000).\n\n16. **ICH Harmonised tripartite guideline: validation of analytical procedures: text and methodology \u2013 Q2.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1994.\n\n17. **General guidelines for the establishment, maintenance and distribution of chemical reference substances.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization, 2007, Annex 3 (WHO Technical Report Series, No. 943).\n\n18. **Guidelines on packaging for pharmaceutical products.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-sixth report. Geneva, World Health Organization, 2002, Annex 9 (WHO Technical Report Series, No. 902).\n\n19. **Stability testing of active pharmaceutical ingredients and finished pharmaceutical products.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2009, Annex 2 (WHO Technical Report Series, No. 953).\n\n20. **ICH harmonised tripartite guideline: stability testing of new drug substances and products \u2013 Q1A.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2003.\n\n21. **Guidelines for registration of fixed-dose combination medicinal products.**  \n   Appendix 3: Pharmaceutical development (or preformulation) studies. Table A1: Typical stress conditions in preformulation stability studies.  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n22. **ICH harmonised tripartite guideline: Stability testing: Photostability testing of new drug substances and products \u2013 Q1B.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.\n\n23. **ICH harmonised tripartite guideline: evaluation for stability data \u2013 Q1E.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2003.\n\n24. **ICH harmonised tripartite guideline: bracketing and matrixing designs for stability testing of new drug substances and products \u2013 Q1D.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2002.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "e1d7393ca75524050bc95d6b30db5f03a1bae3b8bc1734c31db6c48c7c3bba96", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n11. **ICH harmonised tripartite guideline: impurities in new drug products \u2013 Q3B.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2006.\n\n12. **ICH harmonised tripartite guideline impurities: guideline for residual solvents \u2013 Q3C.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2011.\n\n13. **Committee for Medicinal Products for Human Use (CHMP). Guideline on the limits of genotoxic impurities.**  \n   European Medicines Agency, 2006 (CPMP/SWP/5199/02 EMEA/CHMP/ QWP/251344/2006).\n\n14. **US FDA Guidance for industry: Genotoxic and carcinogenic impurities in drug substances and products: recommended approaches.**  \n   US Food and Drug Administration, 2008.\n\n15. **Committee for Medicinal Products for Human Use (CHMP). Guideline on the specification limits for residues of metal catalysts or metal reagents.**  \n   London, European Medicines Agency, 2008 (EMEA/CHMP/SWP/4446/2000).\n\n16. **ICH Harmonised tripartite guideline: validation of analytical procedures: text and methodology \u2013 Q2.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1994.\n\n17. **General guidelines for the establishment, maintenance and distribution of chemical reference substances.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization, 2007, Annex 3 (WHO Technical Report Series, No. 943).\n\n18. **Guidelines on packaging for pharmaceutical products.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-sixth report. Geneva, World Health Organization, 2002, Annex 9 (WHO Technical Report Series, No. 902).\n\n19. **Stability testing of active pharmaceutical ingredients and finished pharmaceutical products.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2009, Annex 2 (WHO Technical Report Series, No. 953).\n\n20. **ICH harmonised tripartite guideline: stability testing of new drug substances and products \u2013 Q1A.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2003.\n\n21. **Guidelines for registration of fixed-dose combination medicinal products.**  \n   Appendix 3: Pharmaceutical development (or preformulation) studies. Table A1: Typical stress conditions in preformulation stability studies.  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n22. **ICH harmonised tripartite guideline: Stability testing: Photostability testing of new drug substances and products \u2013 Q1B.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.\n\n23. **ICH harmonised tripartite guideline: evaluation for stability data \u2013 Q1E.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2003.\n\n24. **ICH harmonised tripartite guideline: bracketing and matrixing designs for stability testing of new drug substances and products \u2013 Q1D.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2002.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3607, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "7ba4637f-0b01-45e9-9155-587c48852b55": {"__data__": {"id_": "7ba4637f-0b01-45e9-9155-587c48852b55", "embedding": null, "metadata": {"page_label": "205", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n25. **ICH Harmonised tripartite guideline: pharmaceutical development \u2013 Q8.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009.\n\n26. **ICH Harmonised tripartite guideline: quality risk management \u2013 Q9.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2005.\n\n27. **ICH harmonised tripartite guideline: pharmaceutical quality system \u2013 Q10.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008.\n\n28. **Inactive ingredient guide.** US Food and Drug Administration, http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm\n\n29. Rowe RC, Sheskey PJ, Quinn ME, eds. **Handbook of pharmaceutical excipients,** 6th ed. London, Pharmaceutical Press, 2009.\n\n30. **Excipients in the label and package leaflet of medicinal products for human use.**\n\n31. 2003 (CPMP/463/00) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003412.pdf\n\n32. **WHO Guidelines on development of paediatric medicines: points to consider in formulation.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012, Annex 5 (WHO Technical Report Series, No. 970).\n\n33. **Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n34. **Containers \u2013 glass.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n35. **Glass containers for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 303\u2013307.\n\n36. **Plastic containers and closures for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 308\u2013309.\n\n37. **Containers \u2013 plastic.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n38. **Elastomeric closures for injections.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007: 144\u2013145.\n\n39. **Rubber closures for containers.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 316\u2013317.\n\n40. **Commission regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact with food.**\n\n41. **WHO good distribution practices for pharmaceutical products.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth report. Geneva, World Health Organization, 2010, Annex 5 (WHO Technical Report Series, No. 957).\n\n42. **Good manufacturing practices for pharmaceutical products: main principles.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report. Geneva, World Health Organization, 2011, Annex 3 (WHO Technical Report Series, No. 961).\n\n43. **ICH Harmonised tripartite guideline: viral safety evaluation of biotechnology products derived from cell lines of human or animal origin \u2013 Q5A.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl contexto presenta una lista de directrices y documentos relevantes relacionados con el desarrollo y la calidad de productos farmac\u00e9uticos, emitidos por la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) y la Organizaci\u00f3n Mundial de la Salud (OMS). Incluye pautas sobre el desarrollo farmac\u00e9utico, gesti\u00f3n de riesgos de calidad, sistemas de calidad farmac\u00e9utica, y buenas pr\u00e1cticas de distribuci\u00f3n y fabricaci\u00f3n. Tambi\u00e9n se mencionan gu\u00edas sobre excipientes, contenedores y regulaciones espec\u00edficas para materiales en contacto con alimentos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los principales objetivos de la gu\u00eda ICH Q8 sobre el desarrollo farmac\u00e9utico?**\n   - Esta gu\u00eda se centra en proporcionar un marco para el desarrollo de productos farmac\u00e9uticos, enfatizando la importancia de la calidad desde las etapas iniciales del desarrollo y la necesidad de un enfoque basado en el riesgo.\n\n2. **\u00bfQu\u00e9 aspectos se consideran en las \"WHO Guidelines on development of paediatric medicines\"?**\n   - Estas pautas abordan consideraciones espec\u00edficas para la formulaci\u00f3n de medicamentos pedi\u00e1tricos, incluyendo la selecci\u00f3n de excipientes, la dosificaci\u00f3n y la presentaci\u00f3n del producto, asegurando que sean adecuados y seguros para la poblaci\u00f3n infantil.\n\n3. **\u00bfQu\u00e9 regulaciones se establecen en la \"Commission regulation (EU) No 10/2011\" respecto a los materiales pl\u00e1sticos?**\n   - Esta regulaci\u00f3n establece los requisitos para los materiales pl\u00e1sticos destinados a entrar en contacto con alimentos, asegurando que sean seguros y no transfieran sustancias nocivas a los alimentos.\n\n### Resumen de Nivel Superior\n\nEl documento proporciona un compendio de directrices y regulaciones que son fundamentales para la industria farmac\u00e9utica, enfoc\u00e1ndose en la calidad y seguridad de los productos. Las pautas de la ICH y la OMS son esenciales para garantizar que los medicamentos sean desarrollados y fabricados de manera que cumplan con los est\u00e1ndares internacionales, protegiendo as\u00ed la salud p\u00fablica. Adem\u00e1s, se abordan temas espec\u00edficos como la formulaci\u00f3n de medicamentos para ni\u00f1os y la seguridad de los materiales en contacto con alimentos, lo que refleja la diversidad de consideraciones en la producci\u00f3n farmac\u00e9utica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nLa secci\u00f3n del documento se centra en las directrices y pautas relacionadas con la preparaci\u00f3n y especificaciones de productos farmac\u00e9uticos, destacando las siguientes \u00e1reas clave:\n\n1. **Implicaciones de Impurezas en Productos Farmac\u00e9uticos:**\n   - Directrices de la ICH sobre impurezas en nuevos productos farmac\u00e9uticos (Q3B) y solventes residuales (Q3C).\n   - L\u00edmites de impurezas genot\u00f3xicas seg\u00fan la EMA y la FDA.\n\n2. **Validaci\u00f3n de Procedimientos Anal\u00edticos:**\n   - Directriz de la ICH sobre la validaci\u00f3n de procedimientos anal\u00edticos (Q2).\n\n3. **Estabilidad de Productos Farmac\u00e9uticos:**\n   - Directrices de la ICH sobre pruebas de estabilidad (Q1A, Q1B, Q1D, Q1E) y su relevancia en el desarrollo de productos farmac\u00e9uticos.\n   - Pruebas de estabilidad de ingredientes farmac\u00e9uticos activos y productos terminados.\n\n4. **Requisitos de Empaque:**\n   - Directrices de la OMS sobre el empaque de productos farmac\u00e9uticos.\n\n### Entidades Clave\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Publica directrices sobre especificaciones para productos farmac\u00e9uticos.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH):** Establece pautas armonizadas para la industria farmac\u00e9utica.\n- **Agencia Europea de Medicamentos (EMA):** Proporciona directrices sobre l\u00edmites de impurezas y evaluaci\u00f3n de medicamentos.\n- **Administraci\u00f3n de Alimentos y Medicamentos de EE. UU. (FDA):** Ofrece orientaci\u00f3n sobre impurezas genot\u00f3xicas y carcinog\u00e9nicas.\n\nEste resumen destaca la importancia de las directrices en la formulaci\u00f3n, producci\u00f3n y control de calidad de medicamentos, as\u00ed como su impacto en la seguridad del paciente y el proceso de aprobaci\u00f3n de nuevos productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: pharmaceutical development, quality risk management, pediatric medicines, excipients, good manufacturing practices"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5e607754-cc4b-417b-862f-019675bfc1a8", "node_type": "4", "metadata": {"page_label": "205", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n25. **ICH Harmonised tripartite guideline: pharmaceutical development \u2013 Q8.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009.\n\n26. **ICH Harmonised tripartite guideline: quality risk management \u2013 Q9.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2005.\n\n27. **ICH harmonised tripartite guideline: pharmaceutical quality system \u2013 Q10.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008.\n\n28. **Inactive ingredient guide.** US Food and Drug Administration, http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm\n\n29. Rowe RC, Sheskey PJ, Quinn ME, eds. **Handbook of pharmaceutical excipients,** 6th ed. London, Pharmaceutical Press, 2009.\n\n30. **Excipients in the label and package leaflet of medicinal products for human use.**\n\n31. 2003 (CPMP/463/00) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003412.pdf\n\n32. **WHO Guidelines on development of paediatric medicines: points to consider in formulation.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012, Annex 5 (WHO Technical Report Series, No. 970).\n\n33. **Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n34. **Containers \u2013 glass.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n35. **Glass containers for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 303\u2013307.\n\n36. **Plastic containers and closures for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 308\u2013309.\n\n37. **Containers \u2013 plastic.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n38. **Elastomeric closures for injections.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007: 144\u2013145.\n\n39. **Rubber closures for containers.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 316\u2013317.\n\n40. **Commission regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact with food.**\n\n41. **WHO good distribution practices for pharmaceutical products.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth report. Geneva, World Health Organization, 2010, Annex 5 (WHO Technical Report Series, No. 957).\n\n42. **Good manufacturing practices for pharmaceutical products: main principles.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report. Geneva, World Health Organization, 2011, Annex 3 (WHO Technical Report Series, No. 961).\n\n43. **ICH Harmonised tripartite guideline: viral safety evaluation of biotechnology products derived from cell lines of human or animal origin \u2013 Q5A.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "5a63f27d91e410d8b4211b620033a34e76df30b076540fcf169b43431de63973", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 4\n\n25. **ICH Harmonised tripartite guideline: pharmaceutical development \u2013 Q8.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009.\n\n26. **ICH Harmonised tripartite guideline: quality risk management \u2013 Q9.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2005.\n\n27. **ICH harmonised tripartite guideline: pharmaceutical quality system \u2013 Q10.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008.\n\n28. **Inactive ingredient guide.** US Food and Drug Administration, http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm\n\n29. Rowe RC, Sheskey PJ, Quinn ME, eds. **Handbook of pharmaceutical excipients,** 6th ed. London, Pharmaceutical Press, 2009.\n\n30. **Excipients in the label and package leaflet of medicinal products for human use.**\n\n31. 2003 (CPMP/463/00) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003412.pdf\n\n32. **WHO Guidelines on development of paediatric medicines: points to consider in formulation.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012, Annex 5 (WHO Technical Report Series, No. 970).\n\n33. **Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n34. **Containers \u2013 glass.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n35. **Glass containers for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 303\u2013307.\n\n36. **Plastic containers and closures for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 308\u2013309.\n\n37. **Containers \u2013 plastic.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n38. **Elastomeric closures for injections.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007: 144\u2013145.\n\n39. **Rubber closures for containers.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 316\u2013317.\n\n40. **Commission regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact with food.**\n\n41. **WHO good distribution practices for pharmaceutical products.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth report. Geneva, World Health Organization, 2010, Annex 5 (WHO Technical Report Series, No. 957).\n\n42. **Good manufacturing practices for pharmaceutical products: main principles.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report. Geneva, World Health Organization, 2011, Annex 3 (WHO Technical Report Series, No. 961).\n\n43. **ICH Harmonised tripartite guideline: viral safety evaluation of biotechnology products derived from cell lines of human or animal origin \u2013 Q5A.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3423, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "7ed9c02f-38ba-40c8-85c8-15f386c58885": {"__data__": {"id_": "7ed9c02f-38ba-40c8-85c8-15f386c58885", "embedding": null, "metadata": {"page_label": "206", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n44. **ICH Harmonised tripartite guideline: derivation and characterisation of cell substrates used for production of biotechnological/biological products \u2013 Q5D.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1997.\n\n45. **ICH Harmonised tripartite guideline: specifications: test procedures and acceptance criteria for biotechnological/biological products \u2013 Q6B.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999.\n\n46. **Recommendations on risk of transmitting animal spongiform encephalopathy agents via medicinal products.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report.* Geneva, World Health Organization, 2003, Annex 1 (WHO Technical Report Series, No. 908).\n\n47. **ICH harmonised tripartite guideline: stability testing for new dosage forms: Annex to the ICH harmonised tripartite guideline on stability testing for new drugs and products \u2013 Q1C.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.\n\n48. **Good manufacturing practices for sterile pharmaceutical products.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-sixth report.* Geneva, World Health Organization, 2011, Annex 6 (WHO Technical Report Series, No. 961).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que detalla las directrices y recomendaciones sobre la producci\u00f3n y control de productos farmac\u00e9uticos biotecnol\u00f3gicos y biol\u00f3gicos. Incluye pautas de la Conferencia sobre Armonizaci\u00f3n de Requisitos T\u00e9cnicos para el Registro de Productos Farmac\u00e9uticos para Uso Humano (ICH) y recomendaciones sobre la seguridad de los productos medicinales en relaci\u00f3n con agentes de encefalopat\u00eda espongiforme transmisible.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son las recomendaciones espec\u00edficas de la OMS sobre el riesgo de transmisi\u00f3n de agentes de encefalopat\u00eda espongiforme a trav\u00e9s de productos medicinales?**\n   - Esta pregunta busca detalles sobre las recomendaciones espec\u00edficas que se encuentran en el documento, que pueden no estar disponibles en otras fuentes.\n\n2. **\u00bfQu\u00e9 aspectos se abordan en la gu\u00eda ICH Q5D sobre la caracterizaci\u00f3n de sustratos celulares utilizados en la producci\u00f3n de productos biotecnol\u00f3gicos?**\n   - Esta pregunta se centra en los detalles t\u00e9cnicos de la gu\u00eda ICH Q5D, que pueden no estar ampliamente discutidos en otros documentos.\n\n3. **\u00bfQu\u00e9 pr\u00e1cticas de fabricaci\u00f3n se consideran esenciales para los productos farmac\u00e9uticos est\u00e9riles seg\u00fan el informe de la OMS?**\n   - Esta pregunta busca informaci\u00f3n sobre las buenas pr\u00e1cticas de fabricaci\u00f3n espec\u00edficas mencionadas en el contexto, que son cruciales para la producci\u00f3n de productos farmac\u00e9uticos est\u00e9riles.", "prev_section_summary": "### Temas Clave y Entidades de la Secci\u00f3n\n\n1. **Directrices de la ICH**:\n   - **Q8**: Desarrollo farmac\u00e9utico, enfatizando la calidad desde las etapas iniciales.\n   - **Q9**: Gesti\u00f3n de riesgos de calidad, abordando la identificaci\u00f3n y mitigaci\u00f3n de riesgos en el proceso de desarrollo.\n   - **Q10**: Sistema de calidad farmac\u00e9utica, estableciendo un marco para asegurar la calidad a lo largo del ciclo de vida del producto.\n   - **Q5A**: Evaluaci\u00f3n de la seguridad viral de productos biotecnol\u00f3gicos.\n\n2. **Regulaciones y Gu\u00edas de la OMS**:\n   - **Gu\u00edas sobre medicamentos pedi\u00e1tricos**: Consideraciones en la formulaci\u00f3n y dosificaci\u00f3n para la poblaci\u00f3n infantil.\n   - **Buenas pr\u00e1cticas de distribuci\u00f3n**: Normas para asegurar la calidad y seguridad en la distribuci\u00f3n de productos farmac\u00e9uticos.\n   - **Buenas pr\u00e1cticas de fabricaci\u00f3n**: Principios fundamentales para la producci\u00f3n de medicamentos.\n\n3. **Excipientes y Contenedores**:\n   - Gu\u00edas sobre excipientes en productos medicinales y su etiquetado.\n   - Regulaciones sobre contenedores de vidrio y pl\u00e1stico para uso farmac\u00e9utico, incluyendo especificaciones de la Farmacopea de EE. UU. y la Farmacopea Europea.\n\n4. **Regulaci\u00f3n de Materiales en Contacto con Alimentos**:\n   - **Reglamento (UE) No 10/2011**: Establece requisitos para materiales pl\u00e1sticos que entran en contacto con alimentos, asegurando su seguridad.\n\n5. **Referencias Importantes**:\n   - **Handbook of Pharmaceutical Excipients**: Una referencia clave para excipientes utilizados en la formulaci\u00f3n de medicamentos.\n   - Documentos de la EMA y la FDA que proporcionan gu\u00edas y regulaciones adicionales.\n\n### Entidades Clave\n- **Organizaciones**: \n  - Conferencia Internacional sobre Armonizaci\u00f3n (ICH)\n  - Organizaci\u00f3n Mundial de la Salud (OMS)\n  - Administraci\u00f3n de Alimentos y Medicamentos de EE. UU. (FDA)\n  - Agencia Europea de Medicamentos (EMA)\n\n- **Publicaciones**: \n  - WHO Technical Report Series\n  - United States Pharmacopeia\n  - European Pharmacopoeia\n\nEste resumen destaca la importancia de las directrices y regulaciones en la industria farmac\u00e9utica, enfoc\u00e1ndose en la calidad, seguridad y adecuaci\u00f3n de los productos para diferentes poblaciones, as\u00ed como en la gesti\u00f3n de riesgos y el uso de excipientes y contenedores adecuados.", "excerpt_keywords": "Keywords: ICH guidelines, biotechnological products, spongiform encephalopathy, pharmaceutical preparations, good manufacturing practices"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "707abe7c-fbce-4738-bfa7-9cb396e2436a", "node_type": "4", "metadata": {"page_label": "206", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n44. **ICH Harmonised tripartite guideline: derivation and characterisation of cell substrates used for production of biotechnological/biological products \u2013 Q5D.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1997.\n\n45. **ICH Harmonised tripartite guideline: specifications: test procedures and acceptance criteria for biotechnological/biological products \u2013 Q6B.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999.\n\n46. **Recommendations on risk of transmitting animal spongiform encephalopathy agents via medicinal products.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report.* Geneva, World Health Organization, 2003, Annex 1 (WHO Technical Report Series, No. 908).\n\n47. **ICH harmonised tripartite guideline: stability testing for new dosage forms: Annex to the ICH harmonised tripartite guideline on stability testing for new drugs and products \u2013 Q1C.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.\n\n48. **Good manufacturing practices for sterile pharmaceutical products.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-sixth report.* Geneva, World Health Organization, 2011, Annex 6 (WHO Technical Report Series, No. 961).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "12791a94ba2aa5ddf21a92756e0c85589512b12f2a2d761ad92cc2671e7df3ef", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n44. **ICH Harmonised tripartite guideline: derivation and characterisation of cell substrates used for production of biotechnological/biological products \u2013 Q5D.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1997.\n\n45. **ICH Harmonised tripartite guideline: specifications: test procedures and acceptance criteria for biotechnological/biological products \u2013 Q6B.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999.\n\n46. **Recommendations on risk of transmitting animal spongiform encephalopathy agents via medicinal products.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report.* Geneva, World Health Organization, 2003, Annex 1 (WHO Technical Report Series, No. 908).\n\n47. **ICH harmonised tripartite guideline: stability testing for new dosage forms: Annex to the ICH harmonised tripartite guideline on stability testing for new drugs and products \u2013 Q1C.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.\n\n48. **Good manufacturing practices for sterile pharmaceutical products.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-sixth report.* Geneva, World Health Organization, 2011, Annex 6 (WHO Technical Report Series, No. 961).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1475, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "db5ab5a0-969d-4c0f-b336-7176bf2083cb": {"__data__": {"id_": "db5ab5a0-969d-4c0f-b336-7176bf2083cb", "embedding": null, "metadata": {"page_label": "207", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 1\n\n## Recommendations for conducting and assessing comparative dissolution profiles\n\nThe dissolution measurements of the two FPPs (e.g. test and reference (comparator) or two different strengths) should be made under the same test conditions. A minimum of three time-points (zero excluded) should be included, the time-points for both reference (comparator) and test product being the same. The sampling intervals should be short for a scientifically sound comparison of the profiles (e.g. 5, 10, 15, 20, 30, 45 (60, 90, 120) minutes). The 15-minute time-point is critical to determine whether a product is very rapidly dissolving and to determine whether f\u2082 must be calculated. For extended-release FPPs, the time-points should be set to cover the entire duration of expected release, e.g. 1, 2, 3, 5 and 8 hours for a 12-hour release and additional test intervals for longer duration of release.\n\nStudies should be performed in at least three media covering the physiological range, including pH 1.2 hydrochloric acid, pH 4.5 buffer and pH 6.8 buffer. *International Pharmacopoeia* buffers are recommended; other pharmacopoeial buffers with the same pH and buffer capacity are also accepted. Water may be considered as an additional medium, especially when the API is unstable in the buffered media to the extent that the data are unusable.\n\nIf both the test and reference (comparator) products show more than 85% dissolution in 15 minutes, the profiles are considered similar (no calculations required). Otherwise:\n\n- Similarity of the resulting comparative dissolution profiles should be calculated using the following equation that defines a similarity factor (f\u2082):\n\n  \\[\n  f_2 = 50 \\log \\left\\{ [1 + 1/n \\sum_{t=1}^n (R_t - T_t)^2]^{-0.5} \\times 100 \\right\\}\n  \\]\n\n  where \\( R_t \\) and \\( T_t \\) are the mean per cent API dissolved in reference (comparator) and test product, respectively, at each time-point. An f\u2082 value between 50 and 100 suggests that the two dissolution profiles are similar.\n\n- A maximum of one time-point should be considered after 85% dissolution of the reference (comparator) product has been reached. In the case where 85% dissolution cannot be reached due to poor solubility of the API, the dissolution should be conducted until an asymptote (plateau) has been reached.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de Nivel Superior\n\nEl documento proporciona recomendaciones sobre c\u00f3mo llevar a cabo y evaluar perfiles de disoluci\u00f3n comparativa para productos farmac\u00e9uticos formulados (FPPs). Se enfatiza la importancia de realizar mediciones de disoluci\u00f3n bajo condiciones de prueba consistentes, utilizando al menos tres puntos de tiempo y diferentes medios que cubran el rango fisiol\u00f3gico. Se establece un m\u00e9todo para calcular la similitud de los perfiles de disoluci\u00f3n mediante un factor de similitud (f\u2082), y se especifican criterios para determinar si los perfiles son considerados similares.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los medios recomendados para realizar estudios de disoluci\u00f3n y por qu\u00e9 se sugiere el uso de estos espec\u00edficos?**\n   - El documento recomienda realizar estudios en al menos tres medios que cubran el rango fisiol\u00f3gico: \u00e1cido clorh\u00eddrico a pH 1.2, un buffer a pH 4.5 y un buffer a pH 6.8. Se sugiere el uso de buffers de la *Farmacopea Internacional* debido a su capacidad de mantener un pH y una capacidad de amortiguaci\u00f3n consistentes, lo que es crucial para obtener datos fiables sobre la disoluci\u00f3n del principio activo (API).\n\n2. **\u00bfQu\u00e9 criterios se deben cumplir para considerar que los perfiles de disoluci\u00f3n de dos productos son similares sin necesidad de c\u00e1lculos adicionales?**\n   - Si ambos productos (test y referencia) muestran m\u00e1s del 85% de disoluci\u00f3n en 15 minutos, se consideran que sus perfiles son similares y no se requieren c\u00e1lculos adicionales para determinar la similitud.\n\n3. **\u00bfC\u00f3mo se debe proceder si no se puede alcanzar el 85% de disoluci\u00f3n debido a la baja solubilidad del API?**\n   - En casos donde no se puede alcanzar el 85% de disoluci\u00f3n debido a la baja solubilidad del API, se debe continuar con el estudio de disoluci\u00f3n hasta que se alcance un asintota o un plateau, lo que permitir\u00e1 evaluar el comportamiento de disoluci\u00f3n del producto en condiciones desfavorables.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Organizaci\u00f3n Mundial de la Salud (OMS)**: El documento es parte de los informes de la OMS, espec\u00edficamente del Comit\u00e9 de Expertos sobre Especificaciones para Preparaciones Farmac\u00e9uticas.\n\n2. **Directrices ICH**: Se mencionan varias gu\u00edas armonizadas de la Conferencia sobre Armonizaci\u00f3n de Requisitos T\u00e9cnicos para el Registro de Productos Farmac\u00e9uticos para Uso Humano (ICH), que son fundamentales para la regulaci\u00f3n de productos biotecnol\u00f3gicos y biol\u00f3gicos:\n   - **Q5D**: Derivaci\u00f3n y caracterizaci\u00f3n de sustratos celulares.\n   - **Q6B**: Especificaciones, procedimientos de prueba y criterios de aceptaci\u00f3n para productos biotecnol\u00f3gicos/biol\u00f3gicos.\n   - **Q1C**: Pruebas de estabilidad para nuevas formas de dosificaci\u00f3n.\n\n3. **Recomendaciones sobre encefalopat\u00eda espongiforme**: Se incluyen recomendaciones espec\u00edficas sobre el riesgo de transmisi\u00f3n de agentes de encefalopat\u00eda espongiforme a trav\u00e9s de productos medicinales, destacando la importancia de la seguridad en la producci\u00f3n farmac\u00e9utica.\n\n4. **Buenas Pr\u00e1cticas de Fabricaci\u00f3n (BPF)**: Se abordan las pr\u00e1cticas esenciales para la fabricaci\u00f3n de productos farmac\u00e9uticos est\u00e9riles, enfatizando la necesidad de cumplir con est\u00e1ndares de calidad y seguridad.\n\n### Entidades Clave\n- **WHO (OMS)**: Organizaci\u00f3n responsable de la elaboraci\u00f3n de las directrices.\n- **ICH**: Conferencia que establece las gu\u00edas t\u00e9cnicas para la industria farmac\u00e9utica.\n- **Productos Biotecnol\u00f3gicos/Biol\u00f3gicos**: Categor\u00eda de productos farmac\u00e9uticos que requieren regulaciones espec\u00edficas.\n- **Encefalopat\u00eda Espongiforme**: Grupo de enfermedades que representan un riesgo en la producci\u00f3n de medicamentos.\n\nEste resumen destaca la importancia de las directrices y recomendaciones de la OMS y la ICH en la producci\u00f3n y control de productos farmac\u00e9uticos, as\u00ed como la atenci\u00f3n a la seguridad en relaci\u00f3n con agentes pat\u00f3genos.", "excerpt_keywords": "Keywords: dissolution profiles, pharmaceutical products, similarity factor, test conditions, release kinetics"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e4fe0ecb-2138-44e4-bc18-cc6980fb72e2", "node_type": "4", "metadata": {"page_label": "207", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 1\n\n## Recommendations for conducting and assessing comparative dissolution profiles\n\nThe dissolution measurements of the two FPPs (e.g. test and reference (comparator) or two different strengths) should be made under the same test conditions. A minimum of three time-points (zero excluded) should be included, the time-points for both reference (comparator) and test product being the same. The sampling intervals should be short for a scientifically sound comparison of the profiles (e.g. 5, 10, 15, 20, 30, 45 (60, 90, 120) minutes). The 15-minute time-point is critical to determine whether a product is very rapidly dissolving and to determine whether f\u2082 must be calculated. For extended-release FPPs, the time-points should be set to cover the entire duration of expected release, e.g. 1, 2, 3, 5 and 8 hours for a 12-hour release and additional test intervals for longer duration of release.\n\nStudies should be performed in at least three media covering the physiological range, including pH 1.2 hydrochloric acid, pH 4.5 buffer and pH 6.8 buffer. *International Pharmacopoeia* buffers are recommended; other pharmacopoeial buffers with the same pH and buffer capacity are also accepted. Water may be considered as an additional medium, especially when the API is unstable in the buffered media to the extent that the data are unusable.\n\nIf both the test and reference (comparator) products show more than 85% dissolution in 15 minutes, the profiles are considered similar (no calculations required). Otherwise:\n\n- Similarity of the resulting comparative dissolution profiles should be calculated using the following equation that defines a similarity factor (f\u2082):\n\n  \\[\n  f_2 = 50 \\log \\left\\{ [1 + 1/n \\sum_{t=1}^n (R_t - T_t)^2]^{-0.5} \\times 100 \\right\\}\n  \\]\n\n  where \\( R_t \\) and \\( T_t \\) are the mean per cent API dissolved in reference (comparator) and test product, respectively, at each time-point. An f\u2082 value between 50 and 100 suggests that the two dissolution profiles are similar.\n\n- A maximum of one time-point should be considered after 85% dissolution of the reference (comparator) product has been reached. In the case where 85% dissolution cannot be reached due to poor solubility of the API, the dissolution should be conducted until an asymptote (plateau) has been reached.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "0dbf41b003f773eb907973b4a1c9b680bf1579ddb883ce5fa5122aec83b20f0c", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Appendix 1\n\n## Recommendations for conducting and assessing comparative dissolution profiles\n\nThe dissolution measurements of the two FPPs (e.g. test and reference (comparator) or two different strengths) should be made under the same test conditions. A minimum of three time-points (zero excluded) should be included, the time-points for both reference (comparator) and test product being the same. The sampling intervals should be short for a scientifically sound comparison of the profiles (e.g. 5, 10, 15, 20, 30, 45 (60, 90, 120) minutes). The 15-minute time-point is critical to determine whether a product is very rapidly dissolving and to determine whether f\u2082 must be calculated. For extended-release FPPs, the time-points should be set to cover the entire duration of expected release, e.g. 1, 2, 3, 5 and 8 hours for a 12-hour release and additional test intervals for longer duration of release.\n\nStudies should be performed in at least three media covering the physiological range, including pH 1.2 hydrochloric acid, pH 4.5 buffer and pH 6.8 buffer. *International Pharmacopoeia* buffers are recommended; other pharmacopoeial buffers with the same pH and buffer capacity are also accepted. Water may be considered as an additional medium, especially when the API is unstable in the buffered media to the extent that the data are unusable.\n\nIf both the test and reference (comparator) products show more than 85% dissolution in 15 minutes, the profiles are considered similar (no calculations required). Otherwise:\n\n- Similarity of the resulting comparative dissolution profiles should be calculated using the following equation that defines a similarity factor (f\u2082):\n\n  \\[\n  f_2 = 50 \\log \\left\\{ [1 + 1/n \\sum_{t=1}^n (R_t - T_t)^2]^{-0.5} \\times 100 \\right\\}\n  \\]\n\n  where \\( R_t \\) and \\( T_t \\) are the mean per cent API dissolved in reference (comparator) and test product, respectively, at each time-point. An f\u2082 value between 50 and 100 suggests that the two dissolution profiles are similar.\n\n- A maximum of one time-point should be considered after 85% dissolution of the reference (comparator) product has been reached. In the case where 85% dissolution cannot be reached due to poor solubility of the API, the dissolution should be conducted until an asymptote (plateau) has been reached.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2314, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "3c950ec8-2424-49e2-8cb8-cd0fad9367e1": {"__data__": {"id_": "3c950ec8-2424-49e2-8cb8-cd0fad9367e1", "embedding": null, "metadata": {"page_label": "208", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "- At least 12 units should be used for determination of each profile. Mean dissolution values can be used to estimate the similarity factor, f\u2082. To use mean data, the percentage coefficient of variation at the first time-point should be not more than 20% and at other time-points should be not more than 10%.\n\n- When delayed-release products (e.g. enteric coated) are being compared, the recommended conditions are acid medium (pH 1.2) for 2 hours and buffer pH 6.8 medium.\n\n- When comparing extended-release beaded capsules, where different strengths have been achieved solely by means of adjusting the number of beads containing the API, one condition (normally the release condition) will suffice.\n\n- Surfactants should be avoided in comparative dissolution testing. A statement that the API is not soluble in any of the media is not sufficient and profiles in the absence of surfactant should be provided. The rationale for the choice and concentration of surfactant should be provided. The concentration of the surfactant should be such that the discriminatory power of the test will not be compromised.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Determinaci\u00f3n de perfiles de disoluci\u00f3n**: Se establece que para la determinaci\u00f3n de perfiles de disoluci\u00f3n, se deben utilizar al menos 12 unidades y se deben cumplir ciertos criterios de variabilidad en los datos para calcular el factor de similitud f\u2082.\n\n2. **Condiciones de comparaci\u00f3n para productos de liberaci\u00f3n retardada**: Se especifican las condiciones recomendadas para comparar productos de liberaci\u00f3n retardada, incluyendo el uso de medios \u00e1cidos y buffer en pH espec\u00edfico.\n\n3. **Pruebas de disoluci\u00f3n para c\u00e1psulas de liberaci\u00f3n prolongada**: Se indica que al comparar c\u00e1psulas de liberaci\u00f3n prolongada que var\u00edan en fuerza por el n\u00famero de beads, se puede utilizar una sola condici\u00f3n de liberaci\u00f3n.\n\n4. **Uso de surfactantes en pruebas de disoluci\u00f3n**: Se aconseja evitar el uso de surfactantes en las pruebas de disoluci\u00f3n comparativa y se requiere que se justifique su uso si es necesario.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1l es el n\u00famero m\u00ednimo de unidades que se deben utilizar para determinar un perfil de disoluci\u00f3n y qu\u00e9 criterios de variabilidad deben cumplirse para utilizar los valores medios?**\n   - Respuesta: Se deben utilizar al menos 12 unidades para la determinaci\u00f3n de cada perfil. El coeficiente de variaci\u00f3n porcentual en el primer punto de tiempo no debe ser superior al 20%, y en otros puntos de tiempo no debe ser superior al 10%.\n\n2. **\u00bfQu\u00e9 condiciones se recomiendan para la comparaci\u00f3n de productos de liberaci\u00f3n retardada, como los recubiertos ent\u00e9ricamente?**\n   - Respuesta: Se recomiendan condiciones de medio \u00e1cido (pH 1.2) durante 2 horas y medio buffer a pH 6.8 para la comparaci\u00f3n de productos de liberaci\u00f3n retardada.\n\n3. **\u00bfQu\u00e9 se debe considerar al utilizar surfactantes en pruebas de disoluci\u00f3n comparativa y qu\u00e9 informaci\u00f3n debe proporcionarse si se decide usarlos?**\n   - Respuesta: Se deben evitar los surfactantes en las pruebas de disoluci\u00f3n comparativa. Si se utilizan, se debe proporcionar una justificaci\u00f3n para la elecci\u00f3n y concentraci\u00f3n del surfactante, asegurando que la concentraci\u00f3n no comprometa el poder discriminatorio de la prueba. Adem\u00e1s, se deben proporcionar perfiles en ausencia de surfactante.", "prev_section_summary": "### Temas Clave\n\n1. **Mediciones de Disoluci\u00f3n**: Se deben realizar bajo condiciones de prueba consistentes para productos farmac\u00e9uticos formulados (FPPs), incluyendo un m\u00ednimo de tres puntos de tiempo.\n\n2. **Puntos de Tiempo**: Se recomienda incluir intervalos cortos (5, 10, 15, 20, 30, 45 (60, 90, 120) minutos) para una comparaci\u00f3n cient\u00edfica adecuada. El punto de 15 minutos es crucial para evaluar la rapidez de disoluci\u00f3n.\n\n3. **Medios de Estudio**: Se deben utilizar al menos tres medios que cubran el rango fisiol\u00f3gico, como \u00e1cido clorh\u00eddrico a pH 1.2, buffer a pH 4.5 y buffer a pH 6.8. Se sugiere el uso de buffers de la *Farmacopea Internacional*.\n\n4. **Similitud de Perfiles de Disoluci\u00f3n**: Si ambos productos muestran m\u00e1s del 85% de disoluci\u00f3n en 15 minutos, se consideran similares sin necesidad de c\u00e1lculos. De lo contrario, se debe calcular un factor de similitud (f\u2082).\n\n5. **C\u00e1lculo del Factor de Similitud (f\u2082)**: Se proporciona una f\u00f3rmula para calcular f\u2082, donde un valor entre 50 y 100 indica que los perfiles son similares.\n\n6. **Condiciones de Solubilidad**: Si no se alcanza el 85% de disoluci\u00f3n debido a baja solubilidad, se debe continuar el estudio hasta alcanzar un asintota o plateau.\n\n### Entidades\n\n- **FPPs**: Productos farmac\u00e9uticos formulados.\n- **pH**: Medidas de acidez o alcalinidad de los medios utilizados.\n- **API**: Principio activo.\n- **f\u2082**: Factor de similitud para evaluar la comparabilidad de perfiles de disoluci\u00f3n.\n- **Buffers**: Soluciones que mantienen un pH constante durante el estudio de disoluci\u00f3n.\n- **Farmacopea Internacional**: Referencia para la calidad de los buffers utilizados en estudios farmac\u00e9uticos.", "excerpt_keywords": "Keywords: disoluci\u00f3n, perfil, surfactantes, liberaci\u00f3n retardada, factor de similitud"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d473d4c5-7a99-4d8a-ab0c-9966f4a6aaf5", "node_type": "4", "metadata": {"page_label": "208", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "- At least 12 units should be used for determination of each profile. Mean dissolution values can be used to estimate the similarity factor, f\u2082. To use mean data, the percentage coefficient of variation at the first time-point should be not more than 20% and at other time-points should be not more than 10%.\n\n- When delayed-release products (e.g. enteric coated) are being compared, the recommended conditions are acid medium (pH 1.2) for 2 hours and buffer pH 6.8 medium.\n\n- When comparing extended-release beaded capsules, where different strengths have been achieved solely by means of adjusting the number of beads containing the API, one condition (normally the release condition) will suffice.\n\n- Surfactants should be avoided in comparative dissolution testing. A statement that the API is not soluble in any of the media is not sufficient and profiles in the absence of surfactant should be provided. The rationale for the choice and concentration of surfactant should be provided. The concentration of the surfactant should be such that the discriminatory power of the test will not be compromised.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "743feed3097a70ced48770f9cb78d35a20ffebbd514557c0634174a3db12065e", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "- At least 12 units should be used for determination of each profile. Mean dissolution values can be used to estimate the similarity factor, f\u2082. To use mean data, the percentage coefficient of variation at the first time-point should be not more than 20% and at other time-points should be not more than 10%.\n\n- When delayed-release products (e.g. enteric coated) are being compared, the recommended conditions are acid medium (pH 1.2) for 2 hours and buffer pH 6.8 medium.\n\n- When comparing extended-release beaded capsules, where different strengths have been achieved solely by means of adjusting the number of beads containing the API, one condition (normally the release condition) will suffice.\n\n- Surfactants should be avoided in comparative dissolution testing. A statement that the API is not soluble in any of the media is not sufficient and profiles in the absence of surfactant should be provided. The rationale for the choice and concentration of surfactant should be provided. The concentration of the surfactant should be such that the discriminatory power of the test will not be compromised.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1108, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "0405e7e9-855b-41c1-86b4-3f879d028883": {"__data__": {"id_": "0405e7e9-855b-41c1-86b4-3f879d028883", "embedding": null, "metadata": {"page_label": "209", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 2\n\n## Product quality review requirements for established multisource products\n\nFor an established multisource product, a product quality review may satisfy the requirements of sections 3.2.P.2.2.1 (a), 3.2.P.2.3 (a) and 3.2.P.3.5 of the PD and QOS-PD.\n\nA product quality review should be submitted with the objective of verifying the consistency of the quality of the FPP and its manufacturing process.\n\nRejected batches should not be included in the analysis but must be reported separately together with the reports of failure investigations, as indicated below.\n\nReviews should be conducted with no fewer than 10 consecutive batches manufactured over the period of the past 12 months or, where 10 batches were not manufactured in the past 12 months, no fewer than 25 consecutive batches manufactured over the period of the past 36 months and should include at least:\n\n- a review of starting and primary packaging materials used in the FPP, especially those from new sources;\n- a tabulated review and statistical analysis of quality control and in-process control results;\n- a review of all batches that failed to meet established specification(s);\n- a review of all critical deviations or non-conformances and related investigations;\n- a review of all changes carried out to the processes or analytical methods;\n- a review of the results of the stability-monitoring programme;\n- a review of all quality-related returns, complaints and recalls, including export-only medicinal products;\n- a review of the adequacy of previous corrective actions;\n- a list of validated analytical and manufacturing procedures and their revalidation dates.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS establece los requisitos para la revisi\u00f3n de la calidad del producto en productos multisource establecidos. Se enfatiza la importancia de verificar la consistencia de la calidad del producto farmac\u00e9utico terminado (FPP) y su proceso de fabricaci\u00f3n. Se especifican criterios para la revisi\u00f3n, incluyendo el an\u00e1lisis de materiales de empaque, resultados de control de calidad, y la gesti\u00f3n de lotes rechazados, entre otros. La revisi\u00f3n debe abarcar un n\u00famero m\u00ednimo de lotes fabricados en un per\u00edodo determinado.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios m\u00ednimos para la cantidad de lotes que deben ser revisados en la evaluaci\u00f3n de calidad de un producto multisource establecido?**\n   - La revisi\u00f3n debe incluir al menos 10 lotes consecutivos fabricados en los \u00faltimos 12 meses, o si no se han fabricado 10 lotes en ese per\u00edodo, al menos 25 lotes consecutivos en los \u00faltimos 36 meses.\n\n2. **\u00bfQu\u00e9 tipo de materiales deben ser revisados en el contexto de la evaluaci\u00f3n de calidad del producto farmac\u00e9utico terminado (FPP)?**\n   - Se debe realizar una revisi\u00f3n de los materiales de empaque inicial y primario utilizados en el FPP, especialmente aquellos provenientes de nuevas fuentes.\n\n3. **\u00bfQu\u00e9 acciones deben tomarse con respecto a los lotes rechazados durante la revisi\u00f3n de calidad?**\n   - Los lotes rechazados no deben incluirse en el an\u00e1lisis de la revisi\u00f3n, pero deben ser reportados por separado junto con los informes de las investigaciones de fallas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Determinaci\u00f3n de Perfiles de Disoluci\u00f3n**:\n   - **N\u00famero M\u00ednimo de Unidades**: Se requieren al menos 12 unidades para la determinaci\u00f3n de cada perfil de disoluci\u00f3n.\n   - **Criterios de Variabilidad**: El coeficiente de variaci\u00f3n porcentual debe ser \u2264 20% en el primer punto de tiempo y \u2264 10% en otros puntos de tiempo para utilizar valores medios en el c\u00e1lculo del factor de similitud f\u2082.\n\n2. **Comparaci\u00f3n de Productos de Liberaci\u00f3n Retardada**:\n   - **Condiciones Recomendadas**: Se sugiere el uso de un medio \u00e1cido (pH 1.2) durante 2 horas, seguido de un medio buffer a pH 6.8 para la comparaci\u00f3n de productos como los recubiertos ent\u00e9ricamente.\n\n3. **C\u00e1psulas de Liberaci\u00f3n Prolongada**:\n   - **Condiciones de Prueba**: Al comparar c\u00e1psulas de liberaci\u00f3n prolongada que var\u00edan en fuerza por el n\u00famero de beads, se puede utilizar una sola condici\u00f3n de liberaci\u00f3n.\n\n4. **Uso de Surfactantes en Pruebas de Disoluci\u00f3n**:\n   - **Recomendaci\u00f3n**: Se aconseja evitar el uso de surfactantes en pruebas de disoluci\u00f3n comparativa.\n   - **Justificaci\u00f3n**: Si se utilizan surfactantes, se debe proporcionar una justificaci\u00f3n para su elecci\u00f3n y concentraci\u00f3n, asegurando que no comprometan el poder discriminatorio de la prueba. Adem\u00e1s, se deben presentar perfiles de disoluci\u00f3n en ausencia de surfactante.\n\n### Entidades Clave\n- **Factor de Similitud (f\u2082)**: M\u00e9trica utilizada para estimar la similitud entre perfiles de disoluci\u00f3n.\n- **Unidades de Prueba**: M\u00ednimo de 12 unidades requeridas.\n- **Condiciones de pH**: pH 1.2 y pH 6.8 como condiciones de prueba.\n- **API (Ingrediente Activo)**: Sustancia cuya solubilidad se eval\u00faa en las pruebas de disoluci\u00f3n.\n- **Surfactantes**: Sustancias que deben ser evitadas en pruebas de disoluci\u00f3n comparativa.", "excerpt_keywords": "Keywords: product quality review, multisource products, manufacturing process, quality control, stability-monitoring programme"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "392d04a7-459d-4627-ac84-68ea6be9cf6b", "node_type": "4", "metadata": {"page_label": "209", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 2\n\n## Product quality review requirements for established multisource products\n\nFor an established multisource product, a product quality review may satisfy the requirements of sections 3.2.P.2.2.1 (a), 3.2.P.2.3 (a) and 3.2.P.3.5 of the PD and QOS-PD.\n\nA product quality review should be submitted with the objective of verifying the consistency of the quality of the FPP and its manufacturing process.\n\nRejected batches should not be included in the analysis but must be reported separately together with the reports of failure investigations, as indicated below.\n\nReviews should be conducted with no fewer than 10 consecutive batches manufactured over the period of the past 12 months or, where 10 batches were not manufactured in the past 12 months, no fewer than 25 consecutive batches manufactured over the period of the past 36 months and should include at least:\n\n- a review of starting and primary packaging materials used in the FPP, especially those from new sources;\n- a tabulated review and statistical analysis of quality control and in-process control results;\n- a review of all batches that failed to meet established specification(s);\n- a review of all critical deviations or non-conformances and related investigations;\n- a review of all changes carried out to the processes or analytical methods;\n- a review of the results of the stability-monitoring programme;\n- a review of all quality-related returns, complaints and recalls, including export-only medicinal products;\n- a review of the adequacy of previous corrective actions;\n- a list of validated analytical and manufacturing procedures and their revalidation dates.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "e8ebcdde55a3a474b8730e575336b528719d9d827f9e579c23f753d6263f8431", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Appendix 2\n\n## Product quality review requirements for established multisource products\n\nFor an established multisource product, a product quality review may satisfy the requirements of sections 3.2.P.2.2.1 (a), 3.2.P.2.3 (a) and 3.2.P.3.5 of the PD and QOS-PD.\n\nA product quality review should be submitted with the objective of verifying the consistency of the quality of the FPP and its manufacturing process.\n\nRejected batches should not be included in the analysis but must be reported separately together with the reports of failure investigations, as indicated below.\n\nReviews should be conducted with no fewer than 10 consecutive batches manufactured over the period of the past 12 months or, where 10 batches were not manufactured in the past 12 months, no fewer than 25 consecutive batches manufactured over the period of the past 36 months and should include at least:\n\n- a review of starting and primary packaging materials used in the FPP, especially those from new sources;\n- a tabulated review and statistical analysis of quality control and in-process control results;\n- a review of all batches that failed to meet established specification(s);\n- a review of all critical deviations or non-conformances and related investigations;\n- a review of all changes carried out to the processes or analytical methods;\n- a review of the results of the stability-monitoring programme;\n- a review of all quality-related returns, complaints and recalls, including export-only medicinal products;\n- a review of the adequacy of previous corrective actions;\n- a list of validated analytical and manufacturing procedures and their revalidation dates.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1651, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "3ef566e3-a96b-4a3a-b020-f401a2c5cea7": {"__data__": {"id_": "3ef566e3-a96b-4a3a-b020-f401a2c5cea7", "embedding": null, "metadata": {"page_label": "210", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Notes\n\n- Reviews must include data from all batches manufactured during the review period.\n- Data should be presented in tabular or graphical form, when applicable.\n- The above listing of requirements is specific to the dossier assessment process requirements and does not relieve the applicant of related GMP requirements.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior del contenido:\n\n### Resumen de Nivel Superior\nEl documento de la OMS, titulado \"Technical Report Series 970\", establece requisitos para la evaluaci\u00f3n de dossiers relacionados con la fabricaci\u00f3n de productos. Se enfatiza que las revisiones deben incluir datos de todos los lotes fabricados durante el per\u00edodo de revisi\u00f3n y que estos datos deben presentarse de manera clara, ya sea en forma tabular o gr\u00e1fica. Adem\u00e1s, se aclara que estos requisitos son espec\u00edficos para el proceso de evaluaci\u00f3n del dossier y no eximen al solicitante de cumplir con los requisitos de Buenas Pr\u00e1cticas de Manufactura (GMP).\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de datos deben incluirse en las revisiones seg\u00fan el documento de la OMS?**\n   - Las revisiones deben incluir datos de todos los lotes fabricados durante el per\u00edodo de revisi\u00f3n.\n\n2. **\u00bfC\u00f3mo se deben presentar los datos en las revisiones?**\n   - Los datos deben presentarse en forma tabular o gr\u00e1fica, cuando sea aplicable.\n\n3. **\u00bfLos requisitos de evaluaci\u00f3n del dossier eximen al solicitante de cumplir con otros requisitos?**\n   - No, la lista de requisitos es espec\u00edfica para el proceso de evaluaci\u00f3n del dossier y no exime al solicitante de cumplir con los requisitos de Buenas Pr\u00e1cticas de Manufactura (GMP).", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Revisi\u00f3n de Calidad del Producto:** Se establece la necesidad de realizar una revisi\u00f3n de calidad para productos multisource establecidos, con el objetivo de verificar la consistencia de la calidad del producto farmac\u00e9utico terminado (FPP) y su proceso de fabricaci\u00f3n.\n  \n2. **Criterios de Revisi\u00f3n:** La revisi\u00f3n debe incluir un an\u00e1lisis de al menos 10 lotes consecutivos fabricados en los \u00faltimos 12 meses, o 25 lotes en los \u00faltimos 36 meses si no se han fabricado suficientes lotes en el per\u00edodo m\u00e1s corto.\n\n3. **Materiales de Empaque:** Se debe revisar los materiales de empaque inicial y primario, especialmente aquellos provenientes de nuevas fuentes.\n\n4. **Gesti\u00f3n de Lotes Rechazados:** Los lotes rechazados no deben incluirse en el an\u00e1lisis de la revisi\u00f3n, pero deben ser reportados por separado junto con los informes de investigaciones de fallas.\n\n5. **Elementos de la Revisi\u00f3n:** La revisi\u00f3n debe abarcar varios aspectos, incluyendo:\n   - An\u00e1lisis de resultados de control de calidad.\n   - Revisi\u00f3n de lotes que no cumplieron con las especificaciones.\n   - Evaluaci\u00f3n de desviaciones cr\u00edticas y no conformidades.\n   - Cambios en procesos o m\u00e9todos anal\u00edticos.\n   - Resultados del programa de monitoreo de estabilidad.\n   - Quejas, devoluciones y retiros relacionados con la calidad.\n   - Eficacia de acciones correctivas previas.\n   - Listado de procedimientos anal\u00edticos y de fabricaci\u00f3n validados y sus fechas de revalidaci\u00f3n.\n\n**Entidades:**\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Entidad que emite las directrices.\n- **Productos Multisource:** Tipo de productos farmac\u00e9uticos a los que se aplican los requisitos de revisi\u00f3n.\n- **Producto Farmac\u00e9utico Terminado (FPP):** Producto cuyo proceso de calidad se est\u00e1 revisando.\n- **Lotes:** Unidades de producci\u00f3n que se analizan durante la revisi\u00f3n de calidad.\n- **Materiales de Empaque:** Componentes utilizados para el embalaje del FPP.\n\nEste resumen destaca los aspectos esenciales de la revisi\u00f3n de calidad para productos multisource establecidos, enfatizando la importancia de la consistencia y el cumplimiento de las especificaciones en la fabricaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: dossier assessment, batch data, GMP requirements, quality review, tabular presentation"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d5f145bd-f1db-4e05-8c2e-b273bbf4c7ca", "node_type": "4", "metadata": {"page_label": "210", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Notes\n\n- Reviews must include data from all batches manufactured during the review period.\n- Data should be presented in tabular or graphical form, when applicable.\n- The above listing of requirements is specific to the dossier assessment process requirements and does not relieve the applicant of related GMP requirements.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "4558735f892861c14ae47c45bdd26c2016cb34941c0ecf3c3dc9314124d02a95", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Notes\n\n- Reviews must include data from all batches manufactured during the review period.\n- Data should be presented in tabular or graphical form, when applicable.\n- The above listing of requirements is specific to the dossier assessment process requirements and does not relieve the applicant of related GMP requirements.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 325, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "bec8c423-2a60-43b8-a9d6-3d769be8fe42": {"__data__": {"id_": "bec8c423-2a60-43b8-a9d6-3d769be8fe42", "embedding": null, "metadata": {"page_label": "211", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\n## Development of paediatric medicines: points to consider in formulation\n\n### General note\n\nThe \"points to consider\" document should not contain detailed instructions for development but rather it should make reference to relevant literature. Some matters dealt with in the draft on development of multisource products have, therefore, been omitted in this proposal.\n\n1. **Introduction**  \n   Page 199\n\n2. **Glossary**  \n   Page 200\n\n3. **Paediatric dosage forms**  \n   Page 200  \n   3.1 Convenient, reliable administration  \n   Page 201  \n   3.2 Acceptability and palatability  \n   Page 202  \n   3.3 Minimum dosing frequency  \n   Page 203  \n   3.4 End-user needs  \n   Page 203\n\n4. **Particular dosage forms to be considered**  \n   Page 203  \n   4.1 Flexible solid dosage forms  \n   Page 203  \n   4.2 Oral medicines  \n   Page 204  \n   4.3 Medicines for severe conditions  \n   Page 204  \n   4.4 Rectal preparations  \n   Page 204\n\n5. **Formulation design**  \n   Page 204  \n   5.1 Quality  \n   Page 205  \n   5.2 Biopharmaceutics classification system  \n   Page 205  \n   5.3 Excipients  \n   Page 206  \n   5.4 Colouring agents  \n   Page 208  \n   5.5 Antimicrobial preservatives  \n   Page 208  \n   5.6 Sweetening agents  \n   Page 208  \n   5.7 Taste masking  \n   Page 209  \n   5.8 Solubility enhancers  \n   Page 209\n\n6. **Oral administration**  \n   Page 210  \n   6.1 Oral liquid preparations  \n   Page 210  \n   6.2 Administration through feeding tubes  \n   Page 212  \n   6.3 Oral solid dosage forms  \n   Page 212", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de nivel superior\nEl documento \"Development of paediatric medicines: points to consider in formulation\" de la OMS aborda aspectos clave en la formulaci\u00f3n de medicamentos pedi\u00e1tricos. Se enfoca en la importancia de la administraci\u00f3n conveniente y confiable, la aceptabilidad y palatabilidad de los medicamentos, y la consideraci\u00f3n de las necesidades de los usuarios finales. Adem\u00e1s, se discuten diferentes formas de dosificaci\u00f3n, el dise\u00f1o de formulaciones y la administraci\u00f3n oral, incluyendo preparaciones l\u00edquidas y s\u00f3lidas.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los factores clave que se deben considerar para garantizar la aceptabilidad y palatabilidad de los medicamentos pedi\u00e1tricos?**\n   - Esta pregunta se centra en el apartado 3.2 del documento, que aborda espec\u00edficamente la aceptabilidad y palatabilidad, y puede proporcionar detalles sobre c\u00f3mo estos factores afectan la administraci\u00f3n de medicamentos a ni\u00f1os.\n\n2. **\u00bfQu\u00e9 tipos de excipientes son recomendados para la formulaci\u00f3n de medicamentos pedi\u00e1tricos y por qu\u00e9 son importantes?**\n   - Esta pregunta se relaciona con el apartado 5.3 sobre excipientes, permitiendo explorar la funci\u00f3n y la selecci\u00f3n de excipientes en la formulaci\u00f3n de medicamentos para ni\u00f1os.\n\n3. **\u00bfQu\u00e9 consideraciones se deben tener en cuenta al dise\u00f1ar medicamentos para condiciones severas en pediatr\u00eda?**\n   - Esta pregunta se refiere al apartado 4.3 sobre medicamentos para condiciones severas, lo que permite profundizar en los desaf\u00edos y requisitos espec\u00edficos para el desarrollo de estos medicamentos en la poblaci\u00f3n pedi\u00e1trica.", "prev_section_summary": "### Temas Clave\n\n1. **Revisi\u00f3n de Dossiers**: Se establece la importancia de incluir datos de todos los lotes fabricados durante el per\u00edodo de revisi\u00f3n en las evaluaciones de dossiers.\n2. **Presentaci\u00f3n de Datos**: Se enfatiza que los datos deben ser presentados de manera clara, ya sea en formato tabular o gr\u00e1fico, cuando sea pertinente.\n3. **Cumplimiento de GMP**: Se aclara que los requisitos mencionados son espec\u00edficos para el proceso de evaluaci\u00f3n del dossier y no eximen al solicitante de cumplir con los requisitos de Buenas Pr\u00e1cticas de Manufactura (GMP).\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite el documento.\n- **Dossier**: Conjunto de documentos que se eval\u00faan en el proceso de revisi\u00f3n.\n- **Lotes**: Unidades de producci\u00f3n que deben ser consideradas en la revisi\u00f3n.\n- **Buenas Pr\u00e1cticas de Manufactura (GMP)**: Normativas que deben cumplirse adem\u00e1s de los requisitos de evaluaci\u00f3n del dossier.", "excerpt_keywords": "Keywords: paediatric medicines, formulation design, acceptability, dosage forms, oral administration"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cbeccdea-20bf-4576-9338-a19991b316ab", "node_type": "4", "metadata": {"page_label": "211", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\n## Development of paediatric medicines: points to consider in formulation\n\n### General note\n\nThe \"points to consider\" document should not contain detailed instructions for development but rather it should make reference to relevant literature. Some matters dealt with in the draft on development of multisource products have, therefore, been omitted in this proposal.\n\n1. **Introduction**  \n   Page 199\n\n2. **Glossary**  \n   Page 200\n\n3. **Paediatric dosage forms**  \n   Page 200  \n   3.1 Convenient, reliable administration  \n   Page 201  \n   3.2 Acceptability and palatability  \n   Page 202  \n   3.3 Minimum dosing frequency  \n   Page 203  \n   3.4 End-user needs  \n   Page 203\n\n4. **Particular dosage forms to be considered**  \n   Page 203  \n   4.1 Flexible solid dosage forms  \n   Page 203  \n   4.2 Oral medicines  \n   Page 204  \n   4.3 Medicines for severe conditions  \n   Page 204  \n   4.4 Rectal preparations  \n   Page 204\n\n5. **Formulation design**  \n   Page 204  \n   5.1 Quality  \n   Page 205  \n   5.2 Biopharmaceutics classification system  \n   Page 205  \n   5.3 Excipients  \n   Page 206  \n   5.4 Colouring agents  \n   Page 208  \n   5.5 Antimicrobial preservatives  \n   Page 208  \n   5.6 Sweetening agents  \n   Page 208  \n   5.7 Taste masking  \n   Page 209  \n   5.8 Solubility enhancers  \n   Page 209\n\n6. **Oral administration**  \n   Page 210  \n   6.1 Oral liquid preparations  \n   Page 210  \n   6.2 Administration through feeding tubes  \n   Page 212  \n   6.3 Oral solid dosage forms  \n   Page 212", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "36c9e5186126198804813c4b8450fc752a93d82eeb6d542ac6ba8d5cb452bfa4", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 5\n\n## Development of paediatric medicines: points to consider in formulation\n\n### General note\n\nThe \"points to consider\" document should not contain detailed instructions for development but rather it should make reference to relevant literature. Some matters dealt with in the draft on development of multisource products have, therefore, been omitted in this proposal.\n\n1. **Introduction**  \n   Page 199\n\n2. **Glossary**  \n   Page 200\n\n3. **Paediatric dosage forms**  \n   Page 200  \n   3.1 Convenient, reliable administration  \n   Page 201  \n   3.2 Acceptability and palatability  \n   Page 202  \n   3.3 Minimum dosing frequency  \n   Page 203  \n   3.4 End-user needs  \n   Page 203\n\n4. **Particular dosage forms to be considered**  \n   Page 203  \n   4.1 Flexible solid dosage forms  \n   Page 203  \n   4.2 Oral medicines  \n   Page 204  \n   4.3 Medicines for severe conditions  \n   Page 204  \n   4.4 Rectal preparations  \n   Page 204\n\n5. **Formulation design**  \n   Page 204  \n   5.1 Quality  \n   Page 205  \n   5.2 Biopharmaceutics classification system  \n   Page 205  \n   5.3 Excipients  \n   Page 206  \n   5.4 Colouring agents  \n   Page 208  \n   5.5 Antimicrobial preservatives  \n   Page 208  \n   5.6 Sweetening agents  \n   Page 208  \n   5.7 Taste masking  \n   Page 209  \n   5.8 Solubility enhancers  \n   Page 209\n\n6. **Oral administration**  \n   Page 210  \n   6.1 Oral liquid preparations  \n   Page 210  \n   6.2 Administration through feeding tubes  \n   Page 212  \n   6.3 Oral solid dosage forms  \n   Page 212", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1517, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d20a3055-ba21-417d-ae2e-32e6956b8361": {"__data__": {"id_": "d20a3055-ba21-417d-ae2e-32e6956b8361", "embedding": null, "metadata": {"page_label": "212", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Forty-sixth report\n\n### 7. Rectal administration\n- **7.1** Suppositories 217\n- **7.2** Rectal liquids (enemas) 218\n\n### 8. Parenteral administration\n- **8.1** Formulation 219\n- **8.2** Additional points to consider for parenteral preparations 219\n\n### 9. Dermal and transdermal administration\n- **9.1** Transdermal patches 221\n\n### 10. Inhalations\n221\n\n### 11. Packaging and labelling\n222\n\n### References\n223", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento es el \"Forty-sixth report\" de la \"WHO Expert Committee on Specifications for Pharmaceutical Preparations\", que aborda diversas formas de administraci\u00f3n de medicamentos, incluyendo la administraci\u00f3n rectal, parenteral, dermal y transdermal, as\u00ed como la inhalaci\u00f3n y aspectos de empaquetado y etiquetado. Cada secci\u00f3n del informe se centra en diferentes formulaciones y consideraciones espec\u00edficas para cada m\u00e9todo de administraci\u00f3n.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las secciones espec\u00edficas que se abordan en el informe relacionadas con la administraci\u00f3n rectal de medicamentos?**\n   - Respuesta: El informe aborda dos secciones espec\u00edficas relacionadas con la administraci\u00f3n rectal: **7.1 Suppositorios** y **7.2 L\u00edquidos rectales (enemas)**.\n\n2. **\u00bfQu\u00e9 puntos adicionales se consideran para las preparaciones parenterales seg\u00fan el informe?**\n   - Respuesta: En la secci\u00f3n **8.2** se mencionan los **puntos adicionales a considerar para las preparaciones parenterales**, aunque el contexto no detalla cu\u00e1les son esos puntos.\n\n3. **\u00bfQu\u00e9 tipo de administraci\u00f3n de medicamentos se menciona en la secci\u00f3n 9 del informe?**\n   - Respuesta: La secci\u00f3n **9** del informe se centra en la **administraci\u00f3n dermal y transdermal**, espec\u00edficamente en los **parches transd\u00e9rmicos**.", "prev_section_summary": "### Resumen de temas clave y entidades\n\nEl documento \"Development of paediatric medicines: points to consider in formulation\" de la OMS se centra en la formulaci\u00f3n de medicamentos pedi\u00e1tricos, abordando varios aspectos esenciales para su desarrollo. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n1. **Introducci\u00f3n y Objetivo**:\n   - El documento no proporciona instrucciones detalladas, sino que hace referencia a literatura relevante sobre el desarrollo de medicamentos pedi\u00e1tricos.\n\n2. **Formas de dosificaci\u00f3n pedi\u00e1trica**:\n   - Se discuten diferentes formas de dosificaci\u00f3n, incluyendo la administraci\u00f3n conveniente y confiable, la aceptabilidad y palatabilidad, la frecuencia m\u00ednima de dosificaci\u00f3n y las necesidades de los usuarios finales.\n\n3. **Formulaciones espec\u00edficas**:\n   - Se consideran formas de dosificaci\u00f3n particulares como:\n     - Formas s\u00f3lidas flexibles\n     - Medicamentos orales\n     - Medicamentos para condiciones severas\n     - Preparaciones rectales\n\n4. **Dise\u00f1o de formulaciones**:\n   - Se abordan aspectos del dise\u00f1o de formulaciones, incluyendo:\n     - Calidad\n     - Sistema de clasificaci\u00f3n biofarmac\u00e9utica\n     - Excipientes (importancia y selecci\u00f3n)\n     - Agentes colorantes\n     - Conservantes antimicrobianos\n     - Agentes edulcorantes\n     - Enmascaramiento del sabor\n     - Mejoradores de solubilidad\n\n5. **Administraci\u00f3n oral**:\n   - Se detallan las preparaciones l\u00edquidas orales, la administraci\u00f3n a trav\u00e9s de tubos de alimentaci\u00f3n y las formas s\u00f3lidas de dosificaci\u00f3n oral.\n\n### Entidades Clave:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite el documento.\n- **Medicamentos pedi\u00e1tricos**: Enfoque principal del documento.\n- **Excipientes**: Componentes importantes en la formulaci\u00f3n de medicamentos.\n- **Formas de dosificaci\u00f3n**: Diferentes m\u00e9todos de administraci\u00f3n de medicamentos a ni\u00f1os.\n\nEste resumen destaca la importancia de considerar m\u00faltiples factores en la formulaci\u00f3n de medicamentos pedi\u00e1tricos para asegurar su eficacia y aceptaci\u00f3n por parte de los pacientes j\u00f3venes.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, rectal administration, parenteral administration, transdermal patches"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4e5c0f32-738a-4803-9823-366f5b6e1ea9", "node_type": "4", "metadata": {"page_label": "212", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Forty-sixth report\n\n### 7. Rectal administration\n- **7.1** Suppositories 217\n- **7.2** Rectal liquids (enemas) 218\n\n### 8. Parenteral administration\n- **8.1** Formulation 219\n- **8.2** Additional points to consider for parenteral preparations 219\n\n### 9. Dermal and transdermal administration\n- **9.1** Transdermal patches 221\n\n### 10. Inhalations\n221\n\n### 11. Packaging and labelling\n222\n\n### References\n223", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "9925981f5d10ce969b2873eb47a2630c4377d56e47e1a0d54862d7041e8dc917", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Forty-sixth report\n\n### 7. Rectal administration\n- **7.1** Suppositories 217\n- **7.2** Rectal liquids (enemas) 218\n\n### 8. Parenteral administration\n- **8.1** Formulation 219\n- **8.2** Additional points to consider for parenteral preparations 219\n\n### 9. Dermal and transdermal administration\n- **9.1** Transdermal patches 221\n\n### 10. Inhalations\n221\n\n### 11. Packaging and labelling\n222\n\n### References\n223", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 485, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "103a78ff-4f2e-403c-bf10-6dfcbb99d6ea": {"__data__": {"id_": "103a78ff-4f2e-403c-bf10-6dfcbb99d6ea", "embedding": null, "metadata": {"page_label": "213", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nSafe and effective pharmacotherapy for paediatric patients requires the timely development of medicines and information on their proper use appropriate to the age, physiological condition and body size of the child. Formulations developed specifically for children are often needed. The use of unlicensed and off-label medicines for treating children is widespread. Their effects on children have not been properly studied, age-appropriate formulations are generally not available, and the medicines are not licensed for use in children.\n\nPharmacists, parents or caregivers are often faced with the need to manipulate an adult medicine in a way that is not described in the Summary of product characteristics. This manipulation can be simple, e.g. breaking tablets that do not have a score line with a tablet splitter, or complex, e.g. using tablets as a source for an active pharmaceutical ingredient (API) to prepare a suspension. Pharmacists may also be faced with the need to compound a medicine on the basis of the API.\n\nThe manipulation process itself can increase the potential for inaccurate dosing and in general can increase the variability of the product. Such handling may be potentially hazardous for the patient as it may affect the stability, bioavailability and accuracy of dosing of a finished pharmaceutical product (FPP), in particular for controlled-release preparations. The use of such medicines may expose children to overdosing and unintended side-effects or to underdosing and a resultant reduction in efficacy. Moreover, excipients that are safe for adults may not necessarily be so for children.\n\nIn December 2007 WHO launched its initiative \u201cMake medicines child size\u201d in order to raise awareness of and accelerate action to meet the need for improved availability and access to child-specific medicines. The WHO Model Formulary for children, 2010, provides independent prescriber information on dosage and treatment guidance for medicines based on the WHO Model List of essential medicines for children, first developed in 2007 and reviewed and updated every two years.\n\nAmong actions to support the \u201cMake medicines child size\u201d initiative is the present \u201cPoints to consider\u201d document on the formulation of paediatric medicines. The objective is to inform regulatory authorities and manufacturers on issues that require special attention in pharmaceutical formulation. Its focus is on the conditions and needs in developing countries. The guidance does not provide exhaustive information and does not exclude the possibility that other aspects may be relevant to the development of paediatric medicines.\n\nIt is not within the scope of this document to address extemporaneous preparations and compounding. A separate interim document entitled *Provision by health-care specialists of patient-specific preparations that are not available as authorized products \u2013 points to consider* (1) will deal with such preparations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de nivel superior del contexto\n\nEl documento de la OMS aborda la necesidad de desarrollar medicamentos seguros y efectivos para pacientes pedi\u00e1tricos, destacando la falta de formulaciones adecuadas y el uso generalizado de medicamentos no autorizados y fuera de indicaci\u00f3n. Se menciona que la manipulaci\u00f3n de medicamentos para adultos para su uso en ni\u00f1os puede llevar a dosificaciones inexactas y riesgos potenciales para la salud. La OMS lanz\u00f3 la iniciativa \"Make medicines child size\" para mejorar la disponibilidad de medicamentos espec\u00edficos para ni\u00f1os y ha creado un documento de orientaci\u00f3n para informar a las autoridades regulatorias y fabricantes sobre consideraciones especiales en la formulaci\u00f3n de medicamentos pedi\u00e1tricos, especialmente en pa\u00edses en desarrollo.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los riesgos asociados con la manipulaci\u00f3n de medicamentos para adultos al ser utilizados en ni\u00f1os, seg\u00fan el documento de la OMS?**\n   - Respuesta: La manipulaci\u00f3n de medicamentos para adultos puede aumentar el potencial de dosificaci\u00f3n inexacta, afectar la estabilidad y biodisponibilidad del producto terminado, y exponer a los ni\u00f1os a sobredosis, efectos secundarios no deseados o subdosificaci\u00f3n, lo que puede reducir la eficacia del tratamiento.\n\n2. **\u00bfQu\u00e9 iniciativas ha tomado la OMS para abordar la falta de medicamentos pedi\u00e1tricos adecuados y c\u00f3mo se relacionan con el documento de \"Puntos a considerar\"?**\n   - Respuesta: La OMS lanz\u00f3 la iniciativa \"Make medicines child size\" en diciembre de 2007 para aumentar la conciencia y mejorar el acceso a medicamentos espec\u00edficos para ni\u00f1os. El documento de \"Puntos a considerar\" se alinea con esta iniciativa al informar a las autoridades y fabricantes sobre aspectos que requieren atenci\u00f3n especial en la formulaci\u00f3n de medicamentos pedi\u00e1tricos, con un enfoque en las condiciones de los pa\u00edses en desarrollo.\n\n3. **\u00bfQu\u00e9 aspectos no se abordan en el documento de la OMS sobre la formulaci\u00f3n de medicamentos pedi\u00e1tricos y d\u00f3nde se puede encontrar informaci\u00f3n sobre esos temas?**\n   - Respuesta: El documento no aborda las preparaciones extempor\u00e1neas y la compounding de medicamentos. Para esos temas, se menciona un documento interino separado titulado *Provision by health-care specialists of patient-specific preparations that are not available as authorized products \u2013 points to consider*, que tratar\u00e1 espec\u00edficamente esas preparaciones.", "prev_section_summary": "El documento es el \"Forty-sixth report\" de la \"WHO Expert Committee on Specifications for Pharmaceutical Preparations\" y se centra en diferentes m\u00e9todos de administraci\u00f3n de medicamentos. A continuaci\u00f3n se presentan los temas clave y entidades de la secci\u00f3n:\n\n### Temas Clave:\n1. **Administraci\u00f3n Rectal**:\n   - **Suppositorios**: Formulaci\u00f3n y consideraciones para el uso de supositorios.\n   - **L\u00edquidos Rectales (Enemas)**: Aspectos relacionados con la administraci\u00f3n de l\u00edquidos a trav\u00e9s del recto.\n\n2. **Administraci\u00f3n Parenteral**:\n   - **Formulaci\u00f3n**: Detalles sobre c\u00f3mo se deben formular las preparaciones parenterales.\n   - **Puntos Adicionales**: Consideraciones adicionales que deben tenerse en cuenta para las preparaciones parenterales.\n\n3. **Administraci\u00f3n Dermal y Transdermal**:\n   - **Parches Transd\u00e9rmicos**: Informaci\u00f3n sobre el uso y formulaci\u00f3n de parches que permiten la administraci\u00f3n de medicamentos a trav\u00e9s de la piel.\n\n4. **Inhalaciones**: M\u00e9todos y consideraciones para la administraci\u00f3n de medicamentos por inhalaci\u00f3n.\n\n5. **Embalaje y Etiquetado**: Aspectos relacionados con el empaquetado y etiquetado de los productos farmac\u00e9uticos.\n\n### Entidades:\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable del informe.\n- **Expert Committee on Specifications for Pharmaceutical Preparations**: Comit\u00e9 que elabora el informe.\n- **Forty-sixth report**: T\u00edtulo del documento.\n\nEste resumen destaca las principales secciones y temas tratados en el informe, proporcionando una visi\u00f3n general de las consideraciones para diferentes formas de administraci\u00f3n de medicamentos.", "excerpt_keywords": "Keywords: paediatric medicines, pharmacotherapy, WHO initiative, drug formulation, off-label use"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "714f210f-bfa3-40be-95a5-92bbff0d6e1a", "node_type": "4", "metadata": {"page_label": "213", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nSafe and effective pharmacotherapy for paediatric patients requires the timely development of medicines and information on their proper use appropriate to the age, physiological condition and body size of the child. Formulations developed specifically for children are often needed. The use of unlicensed and off-label medicines for treating children is widespread. Their effects on children have not been properly studied, age-appropriate formulations are generally not available, and the medicines are not licensed for use in children.\n\nPharmacists, parents or caregivers are often faced with the need to manipulate an adult medicine in a way that is not described in the Summary of product characteristics. This manipulation can be simple, e.g. breaking tablets that do not have a score line with a tablet splitter, or complex, e.g. using tablets as a source for an active pharmaceutical ingredient (API) to prepare a suspension. Pharmacists may also be faced with the need to compound a medicine on the basis of the API.\n\nThe manipulation process itself can increase the potential for inaccurate dosing and in general can increase the variability of the product. Such handling may be potentially hazardous for the patient as it may affect the stability, bioavailability and accuracy of dosing of a finished pharmaceutical product (FPP), in particular for controlled-release preparations. The use of such medicines may expose children to overdosing and unintended side-effects or to underdosing and a resultant reduction in efficacy. Moreover, excipients that are safe for adults may not necessarily be so for children.\n\nIn December 2007 WHO launched its initiative \u201cMake medicines child size\u201d in order to raise awareness of and accelerate action to meet the need for improved availability and access to child-specific medicines. The WHO Model Formulary for children, 2010, provides independent prescriber information on dosage and treatment guidance for medicines based on the WHO Model List of essential medicines for children, first developed in 2007 and reviewed and updated every two years.\n\nAmong actions to support the \u201cMake medicines child size\u201d initiative is the present \u201cPoints to consider\u201d document on the formulation of paediatric medicines. The objective is to inform regulatory authorities and manufacturers on issues that require special attention in pharmaceutical formulation. Its focus is on the conditions and needs in developing countries. The guidance does not provide exhaustive information and does not exclude the possibility that other aspects may be relevant to the development of paediatric medicines.\n\nIt is not within the scope of this document to address extemporaneous preparations and compounding. A separate interim document entitled *Provision by health-care specialists of patient-specific preparations that are not available as authorized products \u2013 points to consider* (1) will deal with such preparations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "0437d40ac79b6f8438b848dc0f98a2b347220c8eb6d1b3814e8e11dc24b2fc2b", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 1. Introduction\n\nSafe and effective pharmacotherapy for paediatric patients requires the timely development of medicines and information on their proper use appropriate to the age, physiological condition and body size of the child. Formulations developed specifically for children are often needed. The use of unlicensed and off-label medicines for treating children is widespread. Their effects on children have not been properly studied, age-appropriate formulations are generally not available, and the medicines are not licensed for use in children.\n\nPharmacists, parents or caregivers are often faced with the need to manipulate an adult medicine in a way that is not described in the Summary of product characteristics. This manipulation can be simple, e.g. breaking tablets that do not have a score line with a tablet splitter, or complex, e.g. using tablets as a source for an active pharmaceutical ingredient (API) to prepare a suspension. Pharmacists may also be faced with the need to compound a medicine on the basis of the API.\n\nThe manipulation process itself can increase the potential for inaccurate dosing and in general can increase the variability of the product. Such handling may be potentially hazardous for the patient as it may affect the stability, bioavailability and accuracy of dosing of a finished pharmaceutical product (FPP), in particular for controlled-release preparations. The use of such medicines may expose children to overdosing and unintended side-effects or to underdosing and a resultant reduction in efficacy. Moreover, excipients that are safe for adults may not necessarily be so for children.\n\nIn December 2007 WHO launched its initiative \u201cMake medicines child size\u201d in order to raise awareness of and accelerate action to meet the need for improved availability and access to child-specific medicines. The WHO Model Formulary for children, 2010, provides independent prescriber information on dosage and treatment guidance for medicines based on the WHO Model List of essential medicines for children, first developed in 2007 and reviewed and updated every two years.\n\nAmong actions to support the \u201cMake medicines child size\u201d initiative is the present \u201cPoints to consider\u201d document on the formulation of paediatric medicines. The objective is to inform regulatory authorities and manufacturers on issues that require special attention in pharmaceutical formulation. Its focus is on the conditions and needs in developing countries. The guidance does not provide exhaustive information and does not exclude the possibility that other aspects may be relevant to the development of paediatric medicines.\n\nIt is not within the scope of this document to address extemporaneous preparations and compounding. A separate interim document entitled *Provision by health-care specialists of patient-specific preparations that are not available as authorized products \u2013 points to consider* (1) will deal with such preparations.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2965, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "16690876-a5a3-4c5b-8571-3d733c3fed7a": {"__data__": {"id_": "16690876-a5a3-4c5b-8571-3d733c3fed7a", "embedding": null, "metadata": {"page_label": "214", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Glossary\n\nThe definitions given below apply to the terms as used in these guidelines. They may have different meanings in other contexts.\n\n**child-resistant container**  \nA form of packaging difficult for young children to open but not unduly difficult for adults to open properly.\n\n**flexible dosage form**  \nA solid dosage form that can be administered to patients in more than one manner, e.g. may be dispersed or taken orally as a whole.\n\n**labelling information**  \nInformation to the user provided on the package label or in the patient information leaflet.\n\n**mini-tablet**  \nA tablet of no more than 4 mm diameter.\n\n**off-label use**  \nUse of a medicine outside the scope of regulatory authorization.\n\n**platform technology**  \nTechnique, including formulation and related processes, which can be used to obtain different dosage forms, different strengths and/or accommodate different APIs.\n\n# 3. Paediatric dosage forms\n\nThe paediatric population is a heterogeneous group ranging from newborns to adolescents with wide physical and developmental differences regarding pharmacokinetics and pharmacodynamics. Organ maturation, metabolic capacity, skin maturation and other factors may change with age, especially in early infancy (2). The age groups identified by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (3) have been derived mainly from physiological and pharmacokinetic differences from birth to adulthood:\n\n- preterm newborn infants\n- term newborn infants (0\u201327 days)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Serie de Informes T\u00e9cnicos 970 incluye un glosario de t\u00e9rminos relevantes para la formulaci\u00f3n y uso de medicamentos, especialmente en la poblaci\u00f3n pedi\u00e1trica. Se definen conceptos clave como \"envase a prueba de ni\u00f1os\", \"forma de dosificaci\u00f3n flexible\" y \"uso fuera de etiqueta\". Adem\u00e1s, se aborda la heterogeneidad de la poblaci\u00f3n pedi\u00e1trica, que abarca desde reci\u00e9n nacidos hasta adolescentes, y se mencionan las diferencias fisiol\u00f3gicas y farmacocin\u00e9ticas que afectan la administraci\u00f3n de medicamentos en estos grupos de edad.\n\n### Preguntas espec\u00edficas:\n1. **\u00bfQu\u00e9 caracter\u00edsticas debe tener un envase para ser considerado \"a prueba de ni\u00f1os\" seg\u00fan las directrices de la OMS?**\n   - Respuesta: Un envase a prueba de ni\u00f1os debe ser dif\u00edcil de abrir para los ni\u00f1os peque\u00f1os, pero no excesivamente complicado para que los adultos lo abran correctamente.\n\n2. **\u00bfCu\u00e1l es la definici\u00f3n de \"mini-tableta\" y por qu\u00e9 es relevante en la formulaci\u00f3n de medicamentos pedi\u00e1tricos?**\n   - Respuesta: Una mini-tableta es un comprimido que no supera los 4 mm de di\u00e1metro. Su relevancia radica en que su tama\u00f1o puede facilitar la administraci\u00f3n de medicamentos a ni\u00f1os, quienes pueden tener dificultades para tragar tabletas m\u00e1s grandes.\n\n3. **\u00bfQu\u00e9 grupos de edad se consideran en la evaluaci\u00f3n de las diferencias fisiol\u00f3gicas y farmacocin\u00e9ticas en la poblaci\u00f3n pedi\u00e1trica seg\u00fan la OMS?**\n   - Respuesta: Los grupos de edad identificados incluyen a los reci\u00e9n nacidos prematuros y a los reci\u00e9n nacidos a t\u00e9rmino, que son aquellos que tienen entre 0 y 27 d\u00edas de vida. Estas categor\u00edas se basan en las diferencias en la maduraci\u00f3n org\u00e1nica y la capacidad metab\u00f3lica que afectan la respuesta a los medicamentos.", "prev_section_summary": "### Temas Clave\n\n1. **Necesidad de Medicamentos Pedi\u00e1tricos**: Se destaca la importancia de desarrollar medicamentos seguros y efectivos espec\u00edficamente formulados para pacientes pedi\u00e1tricos, considerando su edad, condici\u00f3n fisiol\u00f3gica y tama\u00f1o corporal.\n\n2. **Uso de Medicamentos No Autorizados**: Se menciona que el uso de medicamentos no autorizados y fuera de indicaci\u00f3n es com\u00fan en el tratamiento de ni\u00f1os, lo que plantea riesgos debido a la falta de estudios adecuados sobre sus efectos en esta poblaci\u00f3n.\n\n3. **Manipulaci\u00f3n de Medicamentos para Adultos**: Los farmac\u00e9uticos, padres y cuidadores a menudo deben manipular medicamentos para adultos, lo que puede llevar a dosificaciones inexactas y aumentar la variabilidad del producto, afectando la estabilidad y biodisponibilidad.\n\n4. **Iniciativa \"Make medicines child size\"**: La OMS lanz\u00f3 esta iniciativa en 2007 para mejorar la disponibilidad y el acceso a medicamentos espec\u00edficos para ni\u00f1os, junto con la creaci\u00f3n de un formulario modelo para ni\u00f1os que proporciona informaci\u00f3n sobre dosificaci\u00f3n y tratamiento.\n\n5. **Documentaci\u00f3n de Orientaci\u00f3n**: El documento \"Puntos a considerar\" tiene como objetivo informar a las autoridades regulatorias y fabricantes sobre consideraciones especiales en la formulaci\u00f3n de medicamentos pedi\u00e1tricos, con un enfoque en las necesidades de los pa\u00edses en desarrollo.\n\n6. **Limitaciones del Documento**: Se aclara que el documento no aborda las preparaciones extempor\u00e1neas y la compounding de medicamentos, para lo cual se menciona un documento interino separado.\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organizaci\u00f3n que lidera la iniciativa y proporciona directrices sobre medicamentos pedi\u00e1tricos.\n- **Medicamentos Pedi\u00e1tricos**: Medicamentos espec\u00edficamente formulados para ni\u00f1os.\n- **Medicamentos No Autorizados y Fuera de Indicaciones**: Medicamentos que no han sido aprobados para su uso en ni\u00f1os o que se utilizan de manera no autorizada.\n- **Formulaciones**: Preparaciones farmac\u00e9uticas que pueden requerir manipulaci\u00f3n para su uso en ni\u00f1os.\n- **Iniciativa \"Make medicines child size\"**: Programa de la OMS para mejorar el acceso a medicamentos pedi\u00e1tricos.\n- **Modelo de Formulario de la OMS para Ni\u00f1os**: Documento que proporciona informaci\u00f3n sobre dosificaci\u00f3n y tratamiento para medicamentos pedi\u00e1tricos.", "excerpt_keywords": "Keywords: pediatric medications, child-resistant packaging, flexible dosage forms, mini-tablets, off-label use"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fc435afe-6d9b-4fbd-a4e9-545047747ecd", "node_type": "4", "metadata": {"page_label": "214", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Glossary\n\nThe definitions given below apply to the terms as used in these guidelines. They may have different meanings in other contexts.\n\n**child-resistant container**  \nA form of packaging difficult for young children to open but not unduly difficult for adults to open properly.\n\n**flexible dosage form**  \nA solid dosage form that can be administered to patients in more than one manner, e.g. may be dispersed or taken orally as a whole.\n\n**labelling information**  \nInformation to the user provided on the package label or in the patient information leaflet.\n\n**mini-tablet**  \nA tablet of no more than 4 mm diameter.\n\n**off-label use**  \nUse of a medicine outside the scope of regulatory authorization.\n\n**platform technology**  \nTechnique, including formulation and related processes, which can be used to obtain different dosage forms, different strengths and/or accommodate different APIs.\n\n# 3. Paediatric dosage forms\n\nThe paediatric population is a heterogeneous group ranging from newborns to adolescents with wide physical and developmental differences regarding pharmacokinetics and pharmacodynamics. Organ maturation, metabolic capacity, skin maturation and other factors may change with age, especially in early infancy (2). The age groups identified by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (3) have been derived mainly from physiological and pharmacokinetic differences from birth to adulthood:\n\n- preterm newborn infants\n- term newborn infants (0\u201327 days)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "c4427c75ffd62ea88b4ab8835d5120b9f2029e599b807630e5c96d5a35a9728f", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 2. Glossary\n\nThe definitions given below apply to the terms as used in these guidelines. They may have different meanings in other contexts.\n\n**child-resistant container**  \nA form of packaging difficult for young children to open but not unduly difficult for adults to open properly.\n\n**flexible dosage form**  \nA solid dosage form that can be administered to patients in more than one manner, e.g. may be dispersed or taken orally as a whole.\n\n**labelling information**  \nInformation to the user provided on the package label or in the patient information leaflet.\n\n**mini-tablet**  \nA tablet of no more than 4 mm diameter.\n\n**off-label use**  \nUse of a medicine outside the scope of regulatory authorization.\n\n**platform technology**  \nTechnique, including formulation and related processes, which can be used to obtain different dosage forms, different strengths and/or accommodate different APIs.\n\n# 3. Paediatric dosage forms\n\nThe paediatric population is a heterogeneous group ranging from newborns to adolescents with wide physical and developmental differences regarding pharmacokinetics and pharmacodynamics. Organ maturation, metabolic capacity, skin maturation and other factors may change with age, especially in early infancy (2). The age groups identified by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (3) have been derived mainly from physiological and pharmacokinetic differences from birth to adulthood:\n\n- preterm newborn infants\n- term newborn infants (0\u201327 days)", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1570, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "e194acc1-17a2-4fb4-a13b-ce56db26b8e2": {"__data__": {"id_": "e194acc1-17a2-4fb4-a13b-ce56db26b8e2", "embedding": null, "metadata": {"page_label": "215", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\n- infants and toddlers (28 days\u201323 months)\n- children (2\u201311 years)\n- adolescents (12 to 16\u201318 years (dependent on region)).\n\nIt is a challenge to find one formulation appropriate for all age groups. The aim should be to safely cover as wide an age range as possible with a single formulation. The guiding principle for selecting paediatric dosage forms should be \u2013 as for adults \u2013 the balance of risks and benefits taking into account the specific needs of this vulnerable population (4).\n\nDuring the development of pharmaceutical products, the assessment of individual risks related to specific products and starting materials, and the recognition of hazards at specific stages of production or distribution, will enable further enhancement of the usual quality assurance mechanisms, such as implementation of good manufacturing practices (GMP), by increasing the effectiveness of the activities of all parties involved, within the limits of the available resources. Manufacturers who have chosen a more systematic approach to product development would follow the stages of development within the broader context of quality assurance principles, including the use of quality risk management and pharmaceutical quality systems (4, 5).\n\nCurrent use of medicines for the paediatric population reflects the full range of dosage forms and routes of administration used for adult medicines. Common routes of administration in paediatric patients include oral, parenteral, dermal, pulmonary, nasal, rectal and ocular. There is, however, limited information on the acceptability of different paediatric dosage forms in relation to age and therapeutic needs and on the safety of excipients in relation to the development of the child. A European Medicines Agency (EMA) reflection paper on paediatric formulations (6) provides background information on these issues. Reviews by Ernest et al. (7) and Krause and Breitkreutz (8) discuss the needs and challenges in developing paediatric medicines.\n\nThe desirable features of high-quality paediatric medicines common to all dosage forms are outlined below. Further information on specific dosage forms is given in the following sections.\n\n## 3.1 Convenient, reliable administration\n\nThe administered dose should contain an amount of API adjusted to the age and needs of the child. The implication is that more than one dosage form of the API or more than one strength of a dosage form may be needed to cover different age groups. The intended dose volume or size should be appropriate for the target age group.\n\nPaediatric medicines should preferably be presented as formulations that are ready to administer. The need for health professionals, parents or caregivers to", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con respuestas espec\u00edficas que probablemente no se encuentren en otro lugar:\n\n### Preguntas y Respuestas\n\n1. **\u00bfCu\u00e1les son los grupos de edad definidos en el contexto de la formulaci\u00f3n de medicamentos pedi\u00e1tricos?**\n   - **Respuesta:** Los grupos de edad definidos son: infantes y ni\u00f1os peque\u00f1os (28 d\u00edas a 23 meses), ni\u00f1os (2 a 11 a\u00f1os) y adolescentes (12 a 16-18 a\u00f1os, dependiendo de la regi\u00f3n).\n\n2. **\u00bfQu\u00e9 principios gu\u00edan la selecci\u00f3n de formas de dosificaci\u00f3n pedi\u00e1trica?**\n   - **Respuesta:** El principio gu\u00eda para seleccionar formas de dosificaci\u00f3n pedi\u00e1trica es el equilibrio entre riesgos y beneficios, teniendo en cuenta las necesidades espec\u00edficas de esta poblaci\u00f3n vulnerable.\n\n3. **\u00bfQu\u00e9 desaf\u00edos se mencionan en relaci\u00f3n con la aceptaci\u00f3n de diferentes formas de dosificaci\u00f3n pedi\u00e1trica?**\n   - **Respuesta:** Se menciona que hay informaci\u00f3n limitada sobre la aceptabilidad de diferentes formas de dosificaci\u00f3n pedi\u00e1trica en relaci\u00f3n con la edad y las necesidades terap\u00e9uticas, as\u00ed como sobre la seguridad de los excipientes en relaci\u00f3n con el desarrollo del ni\u00f1o.\n\n### Resumen de Nivel Superior\n\nEl contexto aborda la complejidad de desarrollar formulaciones de medicamentos adecuadas para la poblaci\u00f3n pedi\u00e1trica, que abarca desde infantes hasta adolescentes. Se enfatiza la importancia de considerar las necesidades espec\u00edficas de cada grupo de edad y la necesidad de un enfoque sistem\u00e1tico en el desarrollo de productos farmac\u00e9uticos, que incluya la gesti\u00f3n de riesgos y la garant\u00eda de calidad. Adem\u00e1s, se destaca la variedad de formas de dosificaci\u00f3n y rutas de administraci\u00f3n utilizadas en pediatr\u00eda, as\u00ed como la falta de informaci\u00f3n sobre la aceptabilidad y seguridad de estas formulaciones.\n\n### Preguntas Mejoradas\n\n1. **\u00bfQu\u00e9 estrategias se sugieren para abordar la dificultad de encontrar una \u00fanica formulaci\u00f3n adecuada para todos los grupos de edad pedi\u00e1trica?**\n2. **\u00bfC\u00f3mo se relacionan las pr\u00e1cticas de fabricaci\u00f3n y la gesti\u00f3n de riesgos con la calidad de los medicamentos pedi\u00e1tricos?**\n3. **\u00bfQu\u00e9 informaci\u00f3n adicional se proporciona en el documento de la EMA sobre las formulaciones pedi\u00e1tricas y c\u00f3mo puede ayudar en el desarrollo de medicamentos?**", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Glosario de T\u00e9rminos**:\n   - **Envase a prueba de ni\u00f1os**: Packaging dise\u00f1ado para ser dif\u00edcil de abrir por ni\u00f1os peque\u00f1os, pero accesible para adultos.\n   - **Forma de dosificaci\u00f3n flexible**: Forma s\u00f3lida que puede ser administrada de diversas maneras, como dispersada o ingerida entera.\n   - **Informaci\u00f3n de etiquetado**: Datos proporcionados al usuario en la etiqueta del paquete o en el folleto informativo para el paciente.\n   - **Mini-tableta**: Comprimido con un di\u00e1metro m\u00e1ximo de 4 mm, facilitando su administraci\u00f3n a ni\u00f1os.\n   - **Uso fuera de etiqueta**: Administraci\u00f3n de un medicamento que no est\u00e1 autorizada por las regulaciones.\n   - **Tecnolog\u00eda de plataforma**: T\u00e9cnica que permite obtener diferentes formas de dosificaci\u00f3n y concentraciones de ingredientes activos.\n\n2. **Poblaci\u00f3n Pedi\u00e1trica**:\n   - Se describe como un grupo heterog\u00e9neo que abarca desde reci\u00e9n nacidos hasta adolescentes, con diferencias significativas en farmacocin\u00e9tica y farmacodin\u00e1mica.\n   - Se mencionan grupos de edad espec\u00edficos para la evaluaci\u00f3n de medicamentos:\n     - **Reci\u00e9n nacidos prematuros**\n     - **Reci\u00e9n nacidos a t\u00e9rmino** (0\u201327 d\u00edas)\n\n### Entidades Clave:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que proporciona las directrices.\n- **International Conference on Harmonisation (ICH)**: Organizaci\u00f3n que define los grupos de edad en la evaluaci\u00f3n de medicamentos pedi\u00e1tricos. \n\nEste resumen destaca la importancia de considerar las caracter\u00edsticas espec\u00edficas de la poblaci\u00f3n pedi\u00e1trica en la formulaci\u00f3n y administraci\u00f3n de medicamentos, as\u00ed como la necesidad de envases seguros y formas de dosificaci\u00f3n adecuadas.", "excerpt_keywords": "Keywords: paediatric medicines, dosage forms, age groups, quality assurance, pharmaceutical development"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b940a542-6e9b-4a8c-8b63-69cd6de7f010", "node_type": "4", "metadata": {"page_label": "215", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\n- infants and toddlers (28 days\u201323 months)\n- children (2\u201311 years)\n- adolescents (12 to 16\u201318 years (dependent on region)).\n\nIt is a challenge to find one formulation appropriate for all age groups. The aim should be to safely cover as wide an age range as possible with a single formulation. The guiding principle for selecting paediatric dosage forms should be \u2013 as for adults \u2013 the balance of risks and benefits taking into account the specific needs of this vulnerable population (4).\n\nDuring the development of pharmaceutical products, the assessment of individual risks related to specific products and starting materials, and the recognition of hazards at specific stages of production or distribution, will enable further enhancement of the usual quality assurance mechanisms, such as implementation of good manufacturing practices (GMP), by increasing the effectiveness of the activities of all parties involved, within the limits of the available resources. Manufacturers who have chosen a more systematic approach to product development would follow the stages of development within the broader context of quality assurance principles, including the use of quality risk management and pharmaceutical quality systems (4, 5).\n\nCurrent use of medicines for the paediatric population reflects the full range of dosage forms and routes of administration used for adult medicines. Common routes of administration in paediatric patients include oral, parenteral, dermal, pulmonary, nasal, rectal and ocular. There is, however, limited information on the acceptability of different paediatric dosage forms in relation to age and therapeutic needs and on the safety of excipients in relation to the development of the child. A European Medicines Agency (EMA) reflection paper on paediatric formulations (6) provides background information on these issues. Reviews by Ernest et al. (7) and Krause and Breitkreutz (8) discuss the needs and challenges in developing paediatric medicines.\n\nThe desirable features of high-quality paediatric medicines common to all dosage forms are outlined below. Further information on specific dosage forms is given in the following sections.\n\n## 3.1 Convenient, reliable administration\n\nThe administered dose should contain an amount of API adjusted to the age and needs of the child. The implication is that more than one dosage form of the API or more than one strength of a dosage form may be needed to cover different age groups. The intended dose volume or size should be appropriate for the target age group.\n\nPaediatric medicines should preferably be presented as formulations that are ready to administer. The need for health professionals, parents or caregivers to", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "9a9a15dd5d5ef26805d31cdad2dbaea35453d95f9a242e43cc4cc9104f98c361", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 5\n\n- infants and toddlers (28 days\u201323 months)\n- children (2\u201311 years)\n- adolescents (12 to 16\u201318 years (dependent on region)).\n\nIt is a challenge to find one formulation appropriate for all age groups. The aim should be to safely cover as wide an age range as possible with a single formulation. The guiding principle for selecting paediatric dosage forms should be \u2013 as for adults \u2013 the balance of risks and benefits taking into account the specific needs of this vulnerable population (4).\n\nDuring the development of pharmaceutical products, the assessment of individual risks related to specific products and starting materials, and the recognition of hazards at specific stages of production or distribution, will enable further enhancement of the usual quality assurance mechanisms, such as implementation of good manufacturing practices (GMP), by increasing the effectiveness of the activities of all parties involved, within the limits of the available resources. Manufacturers who have chosen a more systematic approach to product development would follow the stages of development within the broader context of quality assurance principles, including the use of quality risk management and pharmaceutical quality systems (4, 5).\n\nCurrent use of medicines for the paediatric population reflects the full range of dosage forms and routes of administration used for adult medicines. Common routes of administration in paediatric patients include oral, parenteral, dermal, pulmonary, nasal, rectal and ocular. There is, however, limited information on the acceptability of different paediatric dosage forms in relation to age and therapeutic needs and on the safety of excipients in relation to the development of the child. A European Medicines Agency (EMA) reflection paper on paediatric formulations (6) provides background information on these issues. Reviews by Ernest et al. (7) and Krause and Breitkreutz (8) discuss the needs and challenges in developing paediatric medicines.\n\nThe desirable features of high-quality paediatric medicines common to all dosage forms are outlined below. Further information on specific dosage forms is given in the following sections.\n\n## 3.1 Convenient, reliable administration\n\nThe administered dose should contain an amount of API adjusted to the age and needs of the child. The implication is that more than one dosage form of the API or more than one strength of a dosage form may be needed to cover different age groups. The intended dose volume or size should be appropriate for the target age group.\n\nPaediatric medicines should preferably be presented as formulations that are ready to administer. The need for health professionals, parents or caregivers to", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2718, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "1cefab38-3200-4ce9-8540-b3f8f328fba5": {"__data__": {"id_": "1cefab38-3200-4ce9-8540-b3f8f328fba5", "embedding": null, "metadata": {"page_label": "216", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Acceptability and Palatability\n\nAcceptability is the overall acceptance of the dosage form regardless of the mode of its administration. Acceptability of a dosage form depends on a variety of factors such as:\n\n- Suitability of the dosage form for the particular age group\n- The dosing device used for a liquid medicine\n- Palatability of an oral medicine\n- Dose volume or size to be administered\n- Appropriateness of packaging\n- Clarity and accuracy of labelling information\n- Directions for use.\n\nAcceptance of parents and caregivers is also a relevant issue, and the cultural setting may influence the understanding of and expectations of the therapy.\n\nPalatability is the overall acceptance of the taste, flavour, smell, dose volume or size, and texture of a medicine to be administered by mouth or to be swallowed. Palatability can be crucial to adherence. Palatability of the API may influence the choice of dosage form and its design, which may include taste-masking ingredients. The dosage form should not, however, be made too attractive to the child (e.g. it should not be in the form of a sugar-coated tablet resembling a sweet or candy) in order to avoid increasing the risk of accidental poisoning.\n\nIt is preferable that the dosage form is palatable in itself without any need for further modification. The caregiver may, however, attempt to improve the ease of administration and acceptance of the patient by mixing the dose with food or a beverage. Such mixing should not be encouraged unless it can be done in such a small volume that ingestion of the full dose can be guaranteed and if there are no undesirable physical or chemical interactions between the food and the medicine. If mixing with food or a beverage (including breast milk) is foreseen, this eventuality should be evaluated by appropriate compatibility studies. Information should be provided in the patient information leaflet by the manufacturer, as supported by evidence-based studies.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl texto aborda la **aceptabilidad** y **palatabilidad** de las formas de dosificaci\u00f3n de medicamentos, destacando su importancia en la administraci\u00f3n de tratamientos, especialmente en poblaciones pedi\u00e1tricas. La aceptabilidad se refiere a la aceptaci\u00f3n general de la forma de dosificaci\u00f3n, influenciada por factores como la adecuaci\u00f3n para el grupo de edad, el dispositivo de dosificaci\u00f3n, y la claridad de la informaci\u00f3n de etiquetado. Por otro lado, la palatabilidad se centra en la aceptaci\u00f3n del sabor, olor, y textura del medicamento, lo cual es crucial para la adherencia al tratamiento. Se menciona la importancia de no hacer que los medicamentos sean demasiado atractivos para los ni\u00f1os para evitar el riesgo de intoxicaci\u00f3n accidental. Adem\u00e1s, se discute la posibilidad de mezclar medicamentos con alimentos o bebidas, enfatizando la necesidad de estudios de compatibilidad y la provisi\u00f3n de informaci\u00f3n adecuada al paciente.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los factores que influyen en la aceptabilidad de una forma de dosificaci\u00f3n para un grupo de edad espec\u00edfico?**\n   - La aceptabilidad depende de la adecuaci\u00f3n de la forma de dosificaci\u00f3n para el grupo de edad, el dispositivo de dosificaci\u00f3n utilizado, la palatabilidad del medicamento, el volumen o tama\u00f1o de la dosis, la adecuaci\u00f3n del empaque, la claridad de la informaci\u00f3n de etiquetado y las instrucciones de uso.\n\n2. **\u00bfPor qu\u00e9 es importante que la palatabilidad de un medicamento no dependa de modificaciones adicionales?**\n   - Es preferible que la forma de dosificaci\u00f3n sea palatable por s\u00ed misma para asegurar que el paciente acepte el medicamento sin necesidad de mezclarlo con otros alimentos o bebidas, lo que podr\u00eda comprometer la dosis o causar interacciones no deseadas.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al mezclar un medicamento con alimentos o bebidas?**\n   - La mezcla debe realizarse en un volumen tan peque\u00f1o que garantice la ingesta de la dosis completa y debe asegurarse que no haya interacciones f\u00edsicas o qu\u00edmicas indeseables entre el alimento y el medicamento. Adem\u00e1s, se deben realizar estudios de compatibilidad y proporcionar informaci\u00f3n adecuada en el prospecto del paciente.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Grupos de Edad en la Poblaci\u00f3n Pedi\u00e1trica**:\n   - Infantes y ni\u00f1os peque\u00f1os: 28 d\u00edas a 23 meses.\n   - Ni\u00f1os: 2 a 11 a\u00f1os.\n   - Adolescentes: 12 a 16-18 a\u00f1os (dependiendo de la regi\u00f3n).\n\n2. **Desaf\u00edos en la Formulaci\u00f3n de Medicamentos**:\n   - Dificultad para encontrar una \u00fanica formulaci\u00f3n adecuada para todos los grupos de edad.\n   - Necesidad de cubrir un amplio rango de edad de manera segura con una sola formulaci\u00f3n.\n\n3. **Principios de Selecci\u00f3n de Formas de Dosificaci\u00f3n**:\n   - Equilibrio entre riesgos y beneficios, considerando las necesidades espec\u00edficas de la poblaci\u00f3n pedi\u00e1trica.\n\n4. **Desarrollo de Productos Farmac\u00e9uticos**:\n   - Evaluaci\u00f3n de riesgos individuales y reconocimiento de peligros en etapas de producci\u00f3n y distribuci\u00f3n.\n   - Importancia de las buenas pr\u00e1cticas de fabricaci\u00f3n (GMP) y la gesti\u00f3n de riesgos en la garant\u00eda de calidad.\n\n5. **Rutas de Administraci\u00f3n Comunes**:\n   - Incluyen oral, parenteral, dermal, pulmonar, nasal, rectal y ocular.\n   - Limitada informaci\u00f3n sobre la aceptabilidad y seguridad de las formas de dosificaci\u00f3n pedi\u00e1tricas.\n\n6. **Documentos de Referencia**:\n   - Un documento de la Agencia Europea de Medicamentos (EMA) proporciona informaci\u00f3n sobre formulaciones pedi\u00e1tricas.\n   - Revisiones de Ernest et al. y Krause y Breitkreutz abordan las necesidades y desaf\u00edos en el desarrollo de medicamentos pedi\u00e1tricos.\n\n7. **Caracter\u00edsticas Deseables de Medicamentos Pedi\u00e1tricos**:\n   - Dosis ajustadas a la edad y necesidades del ni\u00f1o.\n   - Presentaci\u00f3n de formulaciones listas para administrar.\n\nEste resumen destaca la complejidad y los desaf\u00edos en el desarrollo de medicamentos pedi\u00e1tricos, enfatizando la importancia de considerar las caracter\u00edsticas espec\u00edficas de cada grupo de edad y la necesidad de un enfoque sistem\u00e1tico en la formulaci\u00f3n y producci\u00f3n de estos medicamentos.", "excerpt_keywords": "Keywords: acceptability, palatability, dosage form, pediatric medicine, administration"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b3cf3ac1-867a-4608-a330-d71cf4396f46", "node_type": "4", "metadata": {"page_label": "216", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Acceptability and Palatability\n\nAcceptability is the overall acceptance of the dosage form regardless of the mode of its administration. Acceptability of a dosage form depends on a variety of factors such as:\n\n- Suitability of the dosage form for the particular age group\n- The dosing device used for a liquid medicine\n- Palatability of an oral medicine\n- Dose volume or size to be administered\n- Appropriateness of packaging\n- Clarity and accuracy of labelling information\n- Directions for use.\n\nAcceptance of parents and caregivers is also a relevant issue, and the cultural setting may influence the understanding of and expectations of the therapy.\n\nPalatability is the overall acceptance of the taste, flavour, smell, dose volume or size, and texture of a medicine to be administered by mouth or to be swallowed. Palatability can be crucial to adherence. Palatability of the API may influence the choice of dosage form and its design, which may include taste-masking ingredients. The dosage form should not, however, be made too attractive to the child (e.g. it should not be in the form of a sugar-coated tablet resembling a sweet or candy) in order to avoid increasing the risk of accidental poisoning.\n\nIt is preferable that the dosage form is palatable in itself without any need for further modification. The caregiver may, however, attempt to improve the ease of administration and acceptance of the patient by mixing the dose with food or a beverage. Such mixing should not be encouraged unless it can be done in such a small volume that ingestion of the full dose can be guaranteed and if there are no undesirable physical or chemical interactions between the food and the medicine. If mixing with food or a beverage (including breast milk) is foreseen, this eventuality should be evaluated by appropriate compatibility studies. Information should be provided in the patient information leaflet by the manufacturer, as supported by evidence-based studies.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "d44ee19368b6473347bb7157156eee129a69608e44905099cfd8da0d29590d10", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Acceptability and Palatability\n\nAcceptability is the overall acceptance of the dosage form regardless of the mode of its administration. Acceptability of a dosage form depends on a variety of factors such as:\n\n- Suitability of the dosage form for the particular age group\n- The dosing device used for a liquid medicine\n- Palatability of an oral medicine\n- Dose volume or size to be administered\n- Appropriateness of packaging\n- Clarity and accuracy of labelling information\n- Directions for use.\n\nAcceptance of parents and caregivers is also a relevant issue, and the cultural setting may influence the understanding of and expectations of the therapy.\n\nPalatability is the overall acceptance of the taste, flavour, smell, dose volume or size, and texture of a medicine to be administered by mouth or to be swallowed. Palatability can be crucial to adherence. Palatability of the API may influence the choice of dosage form and its design, which may include taste-masking ingredients. The dosage form should not, however, be made too attractive to the child (e.g. it should not be in the form of a sugar-coated tablet resembling a sweet or candy) in order to avoid increasing the risk of accidental poisoning.\n\nIt is preferable that the dosage form is palatable in itself without any need for further modification. The caregiver may, however, attempt to improve the ease of administration and acceptance of the patient by mixing the dose with food or a beverage. Such mixing should not be encouraged unless it can be done in such a small volume that ingestion of the full dose can be guaranteed and if there are no undesirable physical or chemical interactions between the food and the medicine. If mixing with food or a beverage (including breast milk) is foreseen, this eventuality should be evaluated by appropriate compatibility studies. Information should be provided in the patient information leaflet by the manufacturer, as supported by evidence-based studies.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1970, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "31806e6d-8727-41bc-b5dd-2bc469406ae8": {"__data__": {"id_": "31806e6d-8727-41bc-b5dd-2bc469406ae8", "embedding": null, "metadata": {"page_label": "217", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.3 Minimum dosing frequency\n\nParents and caregivers take care of the administration of medication to young children, whereas schoolchildren and adolescents can often manage their medication themselves. In both cases minimal dosing frequency should be aspired to. Instructions on the dosing frequency are based on the pharmacokinetic and pharmacodynamic properties of the API, but may be influenced by the design of the dosage form.\n\nFrequent dosing, i.e. more than twice daily, may have a negative impact on adherence to the dosing scheme both by caregivers and by older children, in particular when medicines are taken in settings where a trained caregiver is not available, e.g. at school. Moreover, frequent dosing may conflict with the lifestyle of older children.\n\n# 3.4 End-user needs\n\nIn addition to maximizing the acceptability and palatability of paediatric medicines it is important that they are convenient to produce and affordable. It is also important to bear in mind supply-chain considerations, such as ease of transportation and storage requirements. It is not always possible for the user to store medicines in a refrigerator.\n\nDepending on the age and clinical condition of the child, there are restrictions to the applicable dose volume or size. Generally, when developing the product, minimum dose volume and size should be the goal.\n\nLack of access to clean water is an important issue to take into consideration in the development of medicines that need to be dissolved, diluted or dispersed prior to administration, as it may compromise the quality of an FPP. It may be necessary to educate patients on how to obtain water of suitable quality, e.g. by supplying instructions on boiling or filtering. Provision of the liquid vehicle as a part of the package may be an option, or the dose may be dispersed or dissolved in a suitable food or beverage prior to administration. Some instructions on such use should be included on the label or package insert. Regional and cultural differences with regard to preferred tastes may need to be considered.\n\n# 4. Particular dosage forms to be considered\n\n## 4.1 Flexible solid dosage forms\n\nDosage forms that, in general, are likely to prove most suitable for global use, including for developing countries, and which should be prioritized, are flexible solid dosage forms such as tablets that are orodispersible and/or can be used for preparation of oral liquids suitable also for the younger age groups, e.g. dispersible and soluble tablets. The flexible dosage form design may be used for various APIs but may not be suitable for medicines requiring a precise dose titration.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Frecuencia m\u00ednima de dosificaci\u00f3n**: Se enfatiza la importancia de minimizar la frecuencia de dosificaci\u00f3n de medicamentos para ni\u00f1os, ya que una dosificaci\u00f3n frecuente puede afectar la adherencia, especialmente en entornos donde no hay cuidadores capacitados disponibles.\n\n2. **Necesidades del usuario final**: Se destaca la necesidad de que los medicamentos pedi\u00e1tricos sean aceptables, palatables, convenientes de producir y asequibles. Tambi\u00e9n se menciona la importancia de considerar la disponibilidad de agua limpia y las diferencias culturales en las preferencias de sabor.\n\n3. **Formas de dosificaci\u00f3n flexibles**: Se sugiere que las formas de dosificaci\u00f3n s\u00f3lidas flexibles, como tabletas orodispersibles, son las m\u00e1s adecuadas para su uso global, especialmente en pa\u00edses en desarrollo, aunque pueden no ser adecuadas para medicamentos que requieren una titulaci\u00f3n precisa de dosis.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son las implicaciones de la frecuencia de dosificaci\u00f3n en la adherencia al tratamiento en ni\u00f1os y adolescentes?**\n   - Respuesta: La frecuencia de dosificaci\u00f3n, especialmente si es m\u00e1s de dos veces al d\u00eda, puede tener un impacto negativo en la adherencia tanto de los cuidadores como de los ni\u00f1os mayores, especialmente en entornos como la escuela donde no hay un cuidador capacitado disponible.\n\n2. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al desarrollar medicamentos pedi\u00e1tricos en relaci\u00f3n con el acceso al agua?**\n   - Respuesta: Es crucial considerar la falta de acceso a agua limpia, ya que esto puede comprometer la calidad de los productos farmac\u00e9uticos que necesitan ser disueltos, diluidos o dispersos antes de la administraci\u00f3n. Se pueden incluir instrucciones sobre c\u00f3mo obtener agua de calidad adecuada y considerar la provisi\u00f3n de un veh\u00edculo l\u00edquido como parte del paquete.\n\n3. **\u00bfPor qu\u00e9 se priorizan las formas de dosificaci\u00f3n s\u00f3lidas flexibles para el uso global, especialmente en pa\u00edses en desarrollo?**\n   - Respuesta: Las formas de dosificaci\u00f3n s\u00f3lidas flexibles, como las tabletas orodispersibles, son preferidas porque son m\u00e1s adecuadas para su uso en diversas poblaciones, incluyendo grupos de edad m\u00e1s j\u00f3venes, y pueden facilitar la administraci\u00f3n de medicamentos en contextos donde la precisi\u00f3n en la titulaci\u00f3n de dosis no es cr\u00edtica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Aceptabilidad de Formas de Dosificaci\u00f3n:**\n   - Definici\u00f3n: Aceptaci\u00f3n general de la forma de dosificaci\u00f3n, independientemente del modo de administraci\u00f3n.\n   - Factores que influyen:\n     - Adecuaci\u00f3n para el grupo de edad.\n     - Dispositivo de dosificaci\u00f3n utilizado.\n     - Palatabilidad del medicamento.\n     - Volumen o tama\u00f1o de la dosis.\n     - Adecuaci\u00f3n del empaque.\n     - Claridad y precisi\u00f3n de la informaci\u00f3n de etiquetado.\n     - Instrucciones de uso.\n   - Importancia de la aceptaci\u00f3n por parte de padres y cuidadores, as\u00ed como el impacto del contexto cultural.\n\n2. **Palatabilidad:**\n   - Definici\u00f3n: Aceptaci\u00f3n del sabor, olor, textura y tama\u00f1o de la dosis de un medicamento administrado por v\u00eda oral.\n   - Importancia para la adherencia al tratamiento.\n   - Consideraciones sobre el dise\u00f1o de la forma de dosificaci\u00f3n, incluyendo ingredientes para enmascarar el sabor.\n   - Advertencia sobre la atracci\u00f3n excesiva de los medicamentos para evitar el riesgo de intoxicaci\u00f3n accidental.\n\n3. **Mezcla de Medicamentos con Alimentos o Bebidas:**\n   - Preferencia por que la forma de dosificaci\u00f3n sea palatable sin modificaciones.\n   - Consideraciones para mezclar medicamentos:\n     - Garantizar la ingesta de la dosis completa.\n     - Evitar interacciones indeseables entre el medicamento y los alimentos.\n     - Realizar estudios de compatibilidad.\n     - Proporcionar informaci\u00f3n adecuada en el prospecto del paciente.\n\n**Entidades:**\n- **Medicamentos:** Formas de dosificaci\u00f3n orales.\n- **Cuidadores:** Padres y otros responsables de la administraci\u00f3n de medicamentos a pacientes, especialmente ni\u00f1os.\n- **Cultura:** Influencia en la aceptaci\u00f3n y expectativas sobre la terapia.\n- **Estudios de Compatibilidad:** Investigaciones necesarias para asegurar la seguridad de mezclar medicamentos con alimentos o bebidas. \n\nEste resumen destaca la importancia de la aceptabilidad y palatabilidad en la administraci\u00f3n de medicamentos, especialmente en contextos pedi\u00e1tricos, y las consideraciones necesarias para garantizar la eficacia y seguridad del tratamiento.", "excerpt_keywords": "Keywords: pediatric medicines, dosing frequency, end-user needs, flexible dosage forms, palatability"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e7f63b90-9133-4fbd-b579-1f016bde8110", "node_type": "4", "metadata": {"page_label": "217", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.3 Minimum dosing frequency\n\nParents and caregivers take care of the administration of medication to young children, whereas schoolchildren and adolescents can often manage their medication themselves. In both cases minimal dosing frequency should be aspired to. Instructions on the dosing frequency are based on the pharmacokinetic and pharmacodynamic properties of the API, but may be influenced by the design of the dosage form.\n\nFrequent dosing, i.e. more than twice daily, may have a negative impact on adherence to the dosing scheme both by caregivers and by older children, in particular when medicines are taken in settings where a trained caregiver is not available, e.g. at school. Moreover, frequent dosing may conflict with the lifestyle of older children.\n\n# 3.4 End-user needs\n\nIn addition to maximizing the acceptability and palatability of paediatric medicines it is important that they are convenient to produce and affordable. It is also important to bear in mind supply-chain considerations, such as ease of transportation and storage requirements. It is not always possible for the user to store medicines in a refrigerator.\n\nDepending on the age and clinical condition of the child, there are restrictions to the applicable dose volume or size. Generally, when developing the product, minimum dose volume and size should be the goal.\n\nLack of access to clean water is an important issue to take into consideration in the development of medicines that need to be dissolved, diluted or dispersed prior to administration, as it may compromise the quality of an FPP. It may be necessary to educate patients on how to obtain water of suitable quality, e.g. by supplying instructions on boiling or filtering. Provision of the liquid vehicle as a part of the package may be an option, or the dose may be dispersed or dissolved in a suitable food or beverage prior to administration. Some instructions on such use should be included on the label or package insert. Regional and cultural differences with regard to preferred tastes may need to be considered.\n\n# 4. Particular dosage forms to be considered\n\n## 4.1 Flexible solid dosage forms\n\nDosage forms that, in general, are likely to prove most suitable for global use, including for developing countries, and which should be prioritized, are flexible solid dosage forms such as tablets that are orodispersible and/or can be used for preparation of oral liquids suitable also for the younger age groups, e.g. dispersible and soluble tablets. The flexible dosage form design may be used for various APIs but may not be suitable for medicines requiring a precise dose titration.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "3166674ef3412a618d50423d544b3b8540de3adc098e2a83b6f722a82b697bd8", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3.3 Minimum dosing frequency\n\nParents and caregivers take care of the administration of medication to young children, whereas schoolchildren and adolescents can often manage their medication themselves. In both cases minimal dosing frequency should be aspired to. Instructions on the dosing frequency are based on the pharmacokinetic and pharmacodynamic properties of the API, but may be influenced by the design of the dosage form.\n\nFrequent dosing, i.e. more than twice daily, may have a negative impact on adherence to the dosing scheme both by caregivers and by older children, in particular when medicines are taken in settings where a trained caregiver is not available, e.g. at school. Moreover, frequent dosing may conflict with the lifestyle of older children.\n\n# 3.4 End-user needs\n\nIn addition to maximizing the acceptability and palatability of paediatric medicines it is important that they are convenient to produce and affordable. It is also important to bear in mind supply-chain considerations, such as ease of transportation and storage requirements. It is not always possible for the user to store medicines in a refrigerator.\n\nDepending on the age and clinical condition of the child, there are restrictions to the applicable dose volume or size. Generally, when developing the product, minimum dose volume and size should be the goal.\n\nLack of access to clean water is an important issue to take into consideration in the development of medicines that need to be dissolved, diluted or dispersed prior to administration, as it may compromise the quality of an FPP. It may be necessary to educate patients on how to obtain water of suitable quality, e.g. by supplying instructions on boiling or filtering. Provision of the liquid vehicle as a part of the package may be an option, or the dose may be dispersed or dissolved in a suitable food or beverage prior to administration. Some instructions on such use should be included on the label or package insert. Regional and cultural differences with regard to preferred tastes may need to be considered.\n\n# 4. Particular dosage forms to be considered\n\n## 4.1 Flexible solid dosage forms\n\nDosage forms that, in general, are likely to prove most suitable for global use, including for developing countries, and which should be prioritized, are flexible solid dosage forms such as tablets that are orodispersible and/or can be used for preparation of oral liquids suitable also for the younger age groups, e.g. dispersible and soluble tablets. The flexible dosage form design may be used for various APIs but may not be suitable for medicines requiring a precise dose titration.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2645, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "3f82988b-9550-4f9e-9fab-08ce29ceb712": {"__data__": {"id_": "3f82988b-9550-4f9e-9fab-08ce29ceb712", "embedding": null, "metadata": {"page_label": "218", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nProvided that the medicine can be dispersed in breast milk from the mother, it could potentially be used in very young children (< 6 months). When recommending mixing medicines with breast milk, the effect on the taste should be taken into account, as unpleasant tasting medicine may cause aversion in breastfed children. In addition, the compatibility of the API with breast milk will need to be considered. The same considerations apply whenever medicines are mixed with other food.\n\nIt is necessary to identify appropriate product strengths and ratios of active ingredients for each medicine as well as to ensure that package sizes will allow optimal use under public health programmatic conditions.\n\n## 4.2 Oral medicines\n\nFor oral medicines that require precise dose measurement or titration, suitable dosage forms could be based on a platform technology to produce multiparticulate solids, e.g. mini-tablets or spherical granules (pellets), that allow production of dosage forms of varying strength as well as different dosage forms like tablets and capsules, and dosage forms to be dispersed to form a liquid dose or to be sprinkled onto food. Platform technology has potential flexibility for manufacturing appropriate fixed-dose combination products (FDCs). Breakable solid dosage forms specially designed to provide the appropriate dose may also serve the same purpose (1, 9).\n\n## 4.3 Medicines for severe conditions\n\nFor severe disease conditions, e.g. neonatal sepsis, the use of alternative dosage forms should be carefully considered. Some alternatives may be easier for untrained caregivers to administer, e.g. a rectal preparation or a spray under the tongue. For some conditions, parenteral formulations may be the best existing option; however, their use requires a trained caregiver.\n\n## 4.4 Rectal preparations\n\nAs an alternative to parenteral preparations for severely ill children or children who are unable to swallow, the use of rectal preparations for indications of severe malaria, pain, infection and also nausea and vomiting may be appropriate. There may, however, be cultural barriers to the use of rectal preparations.\n\n# 5. Formulation design\n\nWhen designing paediatric medicines, the route of administration, dosage form and dose of the API are decided on the basis of the disease state, API properties such as taste, aqueous solubility, pharmacokinetic and pharmacodynamic properties.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda las especificaciones para la preparaci\u00f3n de medicamentos, especialmente en el contexto pedi\u00e1trico. Se discuten consideraciones importantes para la administraci\u00f3n de medicamentos a ni\u00f1os menores de seis meses, incluyendo la mezcla de medicamentos con leche materna y la importancia del sabor. Tambi\u00e9n se exploran diferentes formas de dosificaci\u00f3n, como medicamentos orales, rectales y parenterales, y se enfatiza la necesidad de dise\u00f1ar formulaciones adecuadas que consideren las propiedades del principio activo (API) y las condiciones de salud p\u00fablica. Se menciona la importancia de la facilidad de administraci\u00f3n para cuidadores no entrenados, as\u00ed como las barreras culturales que pueden afectar el uso de ciertas formas de dosificaci\u00f3n.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones clave al mezclar medicamentos con leche materna para su uso en ni\u00f1os menores de seis meses?**\n   - Esta pregunta se centra en los aspectos espec\u00edficos que deben tenerse en cuenta, como el sabor del medicamento y la compatibilidad del API con la leche materna.\n\n2. **\u00bfQu\u00e9 tecnolog\u00edas de plataforma se mencionan para la producci\u00f3n de formas de dosificaci\u00f3n oral y cu\u00e1les son sus ventajas?**\n   - Esta pregunta busca detalles sobre las tecnolog\u00edas espec\u00edficas que permiten la producci\u00f3n de medicamentos en diferentes formas y dosis, as\u00ed como sus beneficios en t\u00e9rminos de flexibilidad y precisi\u00f3n.\n\n3. **\u00bfQu\u00e9 alternativas a las preparaciones parenterales se sugieren para el tratamiento de condiciones severas en ni\u00f1os y cu\u00e1les son las consideraciones culturales asociadas?**\n   - Esta pregunta se enfoca en las opciones de dosificaci\u00f3n alternativas y los posibles obst\u00e1culos culturales que pueden influir en su aceptaci\u00f3n y uso en la pr\u00e1ctica cl\u00ednica.", "prev_section_summary": "### Temas Clave:\n\n1. **Frecuencia M\u00ednima de Dosificaci\u00f3n**: Se enfatiza la importancia de minimizar la frecuencia de dosificaci\u00f3n de medicamentos para ni\u00f1os, ya que una dosificaci\u00f3n frecuente (m\u00e1s de dos veces al d\u00eda) puede afectar negativamente la adherencia al tratamiento, especialmente en entornos sin cuidadores capacitados, como las escuelas.\n\n2. **Necesidades del Usuario Final**: Los medicamentos pedi\u00e1tricos deben ser aceptables, palatables, convenientes de producir y asequibles. Tambi\u00e9n se deben considerar aspectos de la cadena de suministro, como el transporte y los requisitos de almacenamiento, as\u00ed como la disponibilidad de agua limpia para la preparaci\u00f3n de medicamentos.\n\n3. **Formas de Dosificaci\u00f3n Flexibles**: Se sugiere priorizar formas de dosificaci\u00f3n s\u00f3lidas flexibles, como tabletas orodispersibles, que son adecuadas para su uso global, especialmente en pa\u00edses en desarrollo. Estas formas son m\u00e1s accesibles para diferentes grupos de edad, aunque pueden no ser adecuadas para medicamentos que requieren una titulaci\u00f3n precisa de dosis.\n\n### Entidades:\n\n- **API (Ingrediente Activo)**: Se refiere a la sustancia activa en los medicamentos.\n- **FPP (Forma Farmac\u00e9utica del Producto)**: Se refiere a la forma en que se presenta el medicamento.\n- **Cuidadores**: Personas responsables de la administraci\u00f3n de medicamentos a ni\u00f1os.\n- **Escuelas**: Entornos donde los ni\u00f1os pueden necesitar administrar su propia medicaci\u00f3n.\n- **Agua Limpia**: Recurso esencial para la preparaci\u00f3n de ciertos medicamentos.\n- **Tabletas Orodispersibles**: Tipo de forma de dosificaci\u00f3n flexible recomendada para uso pedi\u00e1trico. \n\nEste resumen destaca la importancia de la adherencia al tratamiento, la accesibilidad y la conveniencia en el desarrollo de medicamentos pedi\u00e1tricos, as\u00ed como la consideraci\u00f3n de factores culturales y log\u00edsticos.", "excerpt_keywords": "Keywords: pediatric medicines, breast milk compatibility, dosage forms, active pharmaceutical ingredients, formulation design"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b1fb4220-db59-4cba-b172-8422eee6d5b0", "node_type": "4", "metadata": {"page_label": "218", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nProvided that the medicine can be dispersed in breast milk from the mother, it could potentially be used in very young children (< 6 months). When recommending mixing medicines with breast milk, the effect on the taste should be taken into account, as unpleasant tasting medicine may cause aversion in breastfed children. In addition, the compatibility of the API with breast milk will need to be considered. The same considerations apply whenever medicines are mixed with other food.\n\nIt is necessary to identify appropriate product strengths and ratios of active ingredients for each medicine as well as to ensure that package sizes will allow optimal use under public health programmatic conditions.\n\n## 4.2 Oral medicines\n\nFor oral medicines that require precise dose measurement or titration, suitable dosage forms could be based on a platform technology to produce multiparticulate solids, e.g. mini-tablets or spherical granules (pellets), that allow production of dosage forms of varying strength as well as different dosage forms like tablets and capsules, and dosage forms to be dispersed to form a liquid dose or to be sprinkled onto food. Platform technology has potential flexibility for manufacturing appropriate fixed-dose combination products (FDCs). Breakable solid dosage forms specially designed to provide the appropriate dose may also serve the same purpose (1, 9).\n\n## 4.3 Medicines for severe conditions\n\nFor severe disease conditions, e.g. neonatal sepsis, the use of alternative dosage forms should be carefully considered. Some alternatives may be easier for untrained caregivers to administer, e.g. a rectal preparation or a spray under the tongue. For some conditions, parenteral formulations may be the best existing option; however, their use requires a trained caregiver.\n\n## 4.4 Rectal preparations\n\nAs an alternative to parenteral preparations for severely ill children or children who are unable to swallow, the use of rectal preparations for indications of severe malaria, pain, infection and also nausea and vomiting may be appropriate. There may, however, be cultural barriers to the use of rectal preparations.\n\n# 5. Formulation design\n\nWhen designing paediatric medicines, the route of administration, dosage form and dose of the API are decided on the basis of the disease state, API properties such as taste, aqueous solubility, pharmacokinetic and pharmacodynamic properties.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "08714a7e068e79395e4a285ca91499ebce3b85e208a40ac631d41f7580ccfa69", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nProvided that the medicine can be dispersed in breast milk from the mother, it could potentially be used in very young children (< 6 months). When recommending mixing medicines with breast milk, the effect on the taste should be taken into account, as unpleasant tasting medicine may cause aversion in breastfed children. In addition, the compatibility of the API with breast milk will need to be considered. The same considerations apply whenever medicines are mixed with other food.\n\nIt is necessary to identify appropriate product strengths and ratios of active ingredients for each medicine as well as to ensure that package sizes will allow optimal use under public health programmatic conditions.\n\n## 4.2 Oral medicines\n\nFor oral medicines that require precise dose measurement or titration, suitable dosage forms could be based on a platform technology to produce multiparticulate solids, e.g. mini-tablets or spherical granules (pellets), that allow production of dosage forms of varying strength as well as different dosage forms like tablets and capsules, and dosage forms to be dispersed to form a liquid dose or to be sprinkled onto food. Platform technology has potential flexibility for manufacturing appropriate fixed-dose combination products (FDCs). Breakable solid dosage forms specially designed to provide the appropriate dose may also serve the same purpose (1, 9).\n\n## 4.3 Medicines for severe conditions\n\nFor severe disease conditions, e.g. neonatal sepsis, the use of alternative dosage forms should be carefully considered. Some alternatives may be easier for untrained caregivers to administer, e.g. a rectal preparation or a spray under the tongue. For some conditions, parenteral formulations may be the best existing option; however, their use requires a trained caregiver.\n\n## 4.4 Rectal preparations\n\nAs an alternative to parenteral preparations for severely ill children or children who are unable to swallow, the use of rectal preparations for indications of severe malaria, pain, infection and also nausea and vomiting may be appropriate. There may, however, be cultural barriers to the use of rectal preparations.\n\n# 5. Formulation design\n\nWhen designing paediatric medicines, the route of administration, dosage form and dose of the API are decided on the basis of the disease state, API properties such as taste, aqueous solubility, pharmacokinetic and pharmacodynamic properties.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2491, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "8af98032-4564-4395-89db-6c8ff85b08e5": {"__data__": {"id_": "8af98032-4564-4395-89db-6c8ff85b08e5", "embedding": null, "metadata": {"page_label": "219", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Quality\n\nIn the pharmaceutical development of paediatric medicines, attention should be paid to current quality guidelines, especially those provided by WHO (1).\n\nThe acceptable level of impurities in APIs and degradation products in finished dosage forms should be qualified and controlled according to regulatory guidelines, e.g. ICH guidelines (12\u201314). Safety margins established during toxicological studies on an API and finished dosage form usually apply to a worst-case level in adults. Such limits typically apply to both adults and children; although a child would receive a smaller dose, the exposure per kilogram is likely to be similar. Term and preterm neonates have to be considered specifically, and establishment of safety limits may require safety studies in juvenile animals. Additional guidance may be found on the EMA web site (15\u201317).\n\nThe final product should comply with the requirements in relevant pharmacopoeial monographs, preferably those in *The International Pharmacopoeia*. With regard to dissolution testing, dissolution media should be carefully reconsidered in view of the different gastric pH of children from that of adults. Testing at other pHs should be considered in relevant cases. For dissolution testing of special dosage forms, such as chewable tablets, suspensions and patches, see the International Pharmaceutical Federation/American Association of Pharmaceutical Scientists (FIP/AAPS) guidelines for dissolution testing of special dosage forms (18).\n\n# Biopharmaceutics classification system\n\nThe biopharmaceutics classification system (BCS) is a scientific framework for classification of APIs for oral administration. The BCS is based upon aqueous\n\n----\n\n1. *The International Pharmacopoeia*, 4th ed. First and Second Supplements (available online and on CD-ROM). Geneva, World Health Organization, 2011 (http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en la calidad en el desarrollo farmac\u00e9utico de medicamentos pedi\u00e1tricos, destacando la importancia de seguir las directrices de calidad actuales, especialmente las proporcionadas por la OMS. Se menciona la necesidad de calificar y controlar los niveles aceptables de impurezas en los ingredientes farmac\u00e9uticos activos (API) y productos de degradaci\u00f3n en las formas de dosificaci\u00f3n terminadas, de acuerdo con las pautas regulatorias como las de ICH. Tambi\u00e9n se discute la consideraci\u00f3n espec\u00edfica de neonatos y la importancia de realizar estudios de seguridad en animales juveniles. Adem\u00e1s, se enfatiza la necesidad de cumplir con los requisitos de las monograf\u00edas farmacop\u00e9icas relevantes y se aborda la importancia de ajustar las pruebas de disoluci\u00f3n para tener en cuenta las diferencias en el pH g\u00e1strico entre ni\u00f1os y adultos.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones espec\u00edficas que deben tenerse en cuenta al establecer l\u00edmites de seguridad para neonatos en el desarrollo de medicamentos pedi\u00e1tricos?**\n   - Esta pregunta se centra en la necesidad de realizar estudios de seguridad en animales juveniles y c\u00f3mo esto se relaciona con la evaluaci\u00f3n de la seguridad en neonatos.\n\n2. **\u00bfPor qu\u00e9 es importante reconsiderar los medios de disoluci\u00f3n en las pruebas de disoluci\u00f3n para medicamentos pedi\u00e1tricos?**\n   - Esta pregunta aborda la diferencia en el pH g\u00e1strico entre ni\u00f1os y adultos y c\u00f3mo esto afecta las pruebas de disoluci\u00f3n.\n\n3. **\u00bfQu\u00e9 directrices se deben seguir para la prueba de disoluci\u00f3n de formas de dosificaci\u00f3n especiales como tabletas masticables y parches?**\n   - Esta pregunta se refiere a las pautas espec\u00edficas proporcionadas por la Federaci\u00f3n Internacional de Farmacia y la Asociaci\u00f3n Americana de Cient\u00edficos Farmac\u00e9uticos (FIP/AAPS) para la disoluci\u00f3n de formas de dosificaci\u00f3n especiales.", "prev_section_summary": "### Temas Clave\n\n1. **Uso de Medicamentos en Ni\u00f1os Menores de Seis Meses**:\n   - Importancia de la dispersi\u00f3n de medicamentos en la leche materna.\n   - Consideraciones sobre el sabor del medicamento y su compatibilidad con la leche materna.\n\n2. **Formas de Dosificaci\u00f3n Oral**:\n   - Uso de tecnolog\u00edas de plataforma para producir formas de dosificaci\u00f3n multiparticuladas (mini-tabletas, gr\u00e1nulos esf\u00e9ricos).\n   - Flexibilidad en la producci\u00f3n de combinaciones de dosis fijas (FDCs) y formas de dosificaci\u00f3n que se pueden dispersar o espolvorear sobre alimentos.\n\n3. **Medicamentos para Condiciones Severas**:\n   - Consideraci\u00f3n de formas de dosificaci\u00f3n alternativas (preparaciones rectales, aerosoles sublinguales) para facilitar la administraci\u00f3n por cuidadores no entrenados.\n   - Reconocimiento de que las formulaciones parenterales pueden ser necesarias, pero requieren un cuidador capacitado.\n\n4. **Preparaciones Rectales**:\n   - Uso de preparaciones rectales como alternativa a las parenterales para ni\u00f1os gravemente enfermos o que no pueden tragar.\n   - Posibles barreras culturales que pueden afectar la aceptaci\u00f3n de las preparaciones rectales.\n\n5. **Dise\u00f1o de Formulaciones**:\n   - Decisiones sobre la ruta de administraci\u00f3n, forma de dosificaci\u00f3n y dosis del principio activo (API) basadas en el estado de la enfermedad y propiedades del API (sabor, solubilidad, farmacocin\u00e9tica y farmacodin\u00e1mica).\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite el documento.\n- **API (Principio Activo)**: Componente clave en la formulaci\u00f3n de medicamentos.\n- **Tecnolog\u00edas de Plataforma**: M\u00e9todos de producci\u00f3n de formas de dosificaci\u00f3n.\n- **FDC (Combinaciones de Dosis Fijas)**: Productos que combinan m\u00faltiples principios activos en una sola forma de dosificaci\u00f3n.\n- **Cuidadores No Entrenados**: Personas que administran medicamentos a ni\u00f1os sin formaci\u00f3n m\u00e9dica formal.\n- **Condiciones Severas**: Ejemplos incluyen sepsis neonatal y malaria severa. \n\nEste resumen destaca las consideraciones cr\u00edticas para la formulaci\u00f3n y administraci\u00f3n de medicamentos pedi\u00e1tricos, enfatizando la importancia de la accesibilidad y la aceptaci\u00f3n cultural en el tratamiento de enfermedades en ni\u00f1os.", "excerpt_keywords": "Keywords: pediatric medicines, quality guidelines, impurities, dissolution testing, biopharmaceutics classification system"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "46120644-c9cd-4173-94a3-7b8ca762c205", "node_type": "4", "metadata": {"page_label": "219", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Quality\n\nIn the pharmaceutical development of paediatric medicines, attention should be paid to current quality guidelines, especially those provided by WHO (1).\n\nThe acceptable level of impurities in APIs and degradation products in finished dosage forms should be qualified and controlled according to regulatory guidelines, e.g. ICH guidelines (12\u201314). Safety margins established during toxicological studies on an API and finished dosage form usually apply to a worst-case level in adults. Such limits typically apply to both adults and children; although a child would receive a smaller dose, the exposure per kilogram is likely to be similar. Term and preterm neonates have to be considered specifically, and establishment of safety limits may require safety studies in juvenile animals. Additional guidance may be found on the EMA web site (15\u201317).\n\nThe final product should comply with the requirements in relevant pharmacopoeial monographs, preferably those in *The International Pharmacopoeia*. With regard to dissolution testing, dissolution media should be carefully reconsidered in view of the different gastric pH of children from that of adults. Testing at other pHs should be considered in relevant cases. For dissolution testing of special dosage forms, such as chewable tablets, suspensions and patches, see the International Pharmaceutical Federation/American Association of Pharmaceutical Scientists (FIP/AAPS) guidelines for dissolution testing of special dosage forms (18).\n\n# Biopharmaceutics classification system\n\nThe biopharmaceutics classification system (BCS) is a scientific framework for classification of APIs for oral administration. The BCS is based upon aqueous\n\n----\n\n1. *The International Pharmacopoeia*, 4th ed. First and Second Supplements (available online and on CD-ROM). Geneva, World Health Organization, 2011 (http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "3fb864ea663cf9347f1b6d17cb7bcc898818563578c98463be142dac523b1ba5", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Quality\n\nIn the pharmaceutical development of paediatric medicines, attention should be paid to current quality guidelines, especially those provided by WHO (1).\n\nThe acceptable level of impurities in APIs and degradation products in finished dosage forms should be qualified and controlled according to regulatory guidelines, e.g. ICH guidelines (12\u201314). Safety margins established during toxicological studies on an API and finished dosage form usually apply to a worst-case level in adults. Such limits typically apply to both adults and children; although a child would receive a smaller dose, the exposure per kilogram is likely to be similar. Term and preterm neonates have to be considered specifically, and establishment of safety limits may require safety studies in juvenile animals. Additional guidance may be found on the EMA web site (15\u201317).\n\nThe final product should comply with the requirements in relevant pharmacopoeial monographs, preferably those in *The International Pharmacopoeia*. With regard to dissolution testing, dissolution media should be carefully reconsidered in view of the different gastric pH of children from that of adults. Testing at other pHs should be considered in relevant cases. For dissolution testing of special dosage forms, such as chewable tablets, suspensions and patches, see the International Pharmaceutical Federation/American Association of Pharmaceutical Scientists (FIP/AAPS) guidelines for dissolution testing of special dosage forms (18).\n\n# Biopharmaceutics classification system\n\nThe biopharmaceutics classification system (BCS) is a scientific framework for classification of APIs for oral administration. The BCS is based upon aqueous\n\n----\n\n1. *The International Pharmacopoeia*, 4th ed. First and Second Supplements (available online and on CD-ROM). Geneva, World Health Organization, 2011 (http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1935, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "7e34d3da-1fcd-49c0-9b84-7a244d95babf": {"__data__": {"id_": "7e34d3da-1fcd-49c0-9b84-7a244d95babf", "embedding": null, "metadata": {"page_label": "220", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nSolubility and intestinal permeability. An API is considered highly soluble when the highest dose is soluble in 250 ml or less of aqueous media at 37 \u00b0C over the pH range 1.2\u20136.8. The volume estimate of 250 ml is derived from typical bioequivalence study protocols that prescribe administration of a medicine together with a glass of water to fasting human volunteers. A highly permeable API is absorbed orally to an extent of 85% or more of the administered dose based on a mass-balance determination or in comparison to an intravenous dose (19).\n\nHence an API can be classified as belonging to one of four classes:\n\n- class 1 (high solubility, high permeability);\n- class 2 (low solubility, high permeability);\n- class 3 (high solubility, low permeability);\n- class 4 (low solubility, low permeability).\n\nClassification of APIs included in the WHO Model List of essential medicines is provided in the WHO Technical Report Series (20).\n\nThe BCS may be particularly helpful to assess the importance of aqueous solubility since it relates the solubility of the API to the unit dose. Aqueous solubility should not be a concern in the formulation of immediate-release dosage forms containing class 1 and 3 substances.\n\nFor class 2 substances, the effect of particle size, polymorphic form, and solubility enhancers, among others, should be considered, as the absorption of these substances may be limited by dissolution rate. The same applies to class 4 substances, although factors other than dissolution may also govern the oral absorption. However, overall the BCS classification can be used as a basis when estimating the likelihood of different absorption of paediatric medicines when the dosage form and/or excipients used in adult medicines differ from those used for paediatric medicines.\n\nIn addition, for BCS class 3 and 4 substances, where the absorption process and/or intestinal first pass also restrict bioavailability, the possibility of excipients affecting transit time (efflux), transporter function and metabolic enzymes (typically CYP3A4) should be taken into consideration.\n\n## 5.3 Excipients\n\nThe use of excipients in paediatric medicines is driven by functional requirements and should be justified through a risk-based assessment, taking into account factors such as the paediatric age group, frequency of dosing and duration of treatment.\n\nThe added challenge for paediatric medicines compared to adult medicines is that excipients may lead to adverse reactions in children that are...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS aborda la clasificaci\u00f3n de los principios activos (API) en funci\u00f3n de su solubilidad y permeabilidad intestinal, utilizando el Sistema de Clasificaci\u00f3n de Biopharmaceutics (BCS). Se definen cuatro clases de API: clase 1 (alta solubilidad, alta permeabilidad), clase 2 (baja solubilidad, alta permeabilidad), clase 3 (alta solubilidad, baja permeabilidad) y clase 4 (baja solubilidad, baja permeabilidad). Se discute la importancia de la solubilidad acuosa en la formulaci\u00f3n de medicamentos, especialmente en pediatr\u00eda, donde los excipientes deben ser evaluados cuidadosamente debido a posibles reacciones adversas en ni\u00f1os. Adem\u00e1s, se menciona la influencia de factores como el tama\u00f1o de part\u00edcula y la forma polim\u00f3rfica en la absorci\u00f3n de medicamentos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios espec\u00edficos que definen un API como altamente soluble seg\u00fan el documento de la OMS?**\n   - Respuesta: Un API se considera altamente soluble cuando la dosis m\u00e1s alta es soluble en 250 ml o menos de medios acuosos a 37 \u00b0C en un rango de pH de 1.2 a 6.8.\n\n2. **\u00bfQu\u00e9 factores deben considerarse al formular medicamentos para la clase 2 y clase 4 de API en pediatr\u00eda?**\n   - Respuesta: Para los API de clase 2, se deben considerar el tama\u00f1o de part\u00edcula, la forma polim\u00f3rfica y los potenciadores de solubilidad, ya que la absorci\u00f3n puede estar limitada por la tasa de disoluci\u00f3n. Para la clase 4, adem\u00e1s de la disoluci\u00f3n, otros factores que pueden afectar la absorci\u00f3n oral tambi\u00e9n deben ser considerados.\n\n3. **\u00bfPor qu\u00e9 es importante realizar una evaluaci\u00f3n basada en riesgos al seleccionar excipientes para medicamentos pedi\u00e1tricos?**\n   - Respuesta: Es importante porque los excipientes pueden provocar reacciones adversas en ni\u00f1os, y su uso debe justificarse teniendo en cuenta el grupo etario pedi\u00e1trico, la frecuencia de dosificaci\u00f3n y la duraci\u00f3n del tratamiento.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Calidad en el desarrollo de medicamentos pedi\u00e1tricos**: Se enfatiza la importancia de seguir las directrices de calidad actuales, especialmente las proporcionadas por la Organizaci\u00f3n Mundial de la Salud (OMS).\n\n2. **Impurezas en ingredientes farmac\u00e9uticos activos (API)**: Se requiere calificar y controlar los niveles aceptables de impurezas y productos de degradaci\u00f3n en las formas de dosificaci\u00f3n terminadas, de acuerdo con las pautas regulatorias, como las de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH).\n\n3. **L\u00edmites de seguridad para neonatos**: Se menciona que los m\u00e1rgenes de seguridad establecidos durante los estudios toxicol\u00f3gicos generalmente se aplican a adultos, pero tambi\u00e9n deben considerarse espec\u00edficamente para neonatos, lo que puede requerir estudios de seguridad en animales juveniles.\n\n4. **Cumplimiento de monograf\u00edas farmacop\u00e9icas**: El producto final debe cumplir con los requisitos de las monograf\u00edas farmacop\u00e9icas relevantes, preferiblemente de *The International Pharmacopoeia*.\n\n5. **Pruebas de disoluci\u00f3n**: Se debe reconsiderar cuidadosamente el medio de disoluci\u00f3n en funci\u00f3n del pH g\u00e1strico diferente entre ni\u00f1os y adultos. Tambi\u00e9n se sugiere realizar pruebas a otros pHs cuando sea relevante.\n\n6. **Formas de dosificaci\u00f3n especiales**: Para la prueba de disoluci\u00f3n de formas de dosificaci\u00f3n especiales, como tabletas masticables y parches, se deben seguir las directrices de la Federaci\u00f3n Internacional de Farmacia y la Asociaci\u00f3n Americana de Cient\u00edficos Farmac\u00e9uticos (FIP/AAPS).\n\n7. **Sistema de clasificaci\u00f3n biofarmac\u00e9utica (BCS)**: Se menciona que el BCS es un marco cient\u00edfico para la clasificaci\u00f3n de APIs para administraci\u00f3n oral, basado en la solubilidad y permeabilidad.\n\n### Entidades mencionadas\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**\n- **Agencia Europea de Medicamentos (EMA)**\n- **Federaci\u00f3n Internacional de Farmacia (FIP)**\n- **Asociaci\u00f3n Americana de Cient\u00edficos Farmac\u00e9uticos (AAPS)**\n- **The International Pharmacopoeia**", "excerpt_keywords": "Keywords: solubility, permeability, biopharmaceutics, excipients, pediatric medicines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9aca0595-9e33-43f9-b8a6-8978e0bf945e", "node_type": "4", "metadata": {"page_label": "220", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nSolubility and intestinal permeability. An API is considered highly soluble when the highest dose is soluble in 250 ml or less of aqueous media at 37 \u00b0C over the pH range 1.2\u20136.8. The volume estimate of 250 ml is derived from typical bioequivalence study protocols that prescribe administration of a medicine together with a glass of water to fasting human volunteers. A highly permeable API is absorbed orally to an extent of 85% or more of the administered dose based on a mass-balance determination or in comparison to an intravenous dose (19).\n\nHence an API can be classified as belonging to one of four classes:\n\n- class 1 (high solubility, high permeability);\n- class 2 (low solubility, high permeability);\n- class 3 (high solubility, low permeability);\n- class 4 (low solubility, low permeability).\n\nClassification of APIs included in the WHO Model List of essential medicines is provided in the WHO Technical Report Series (20).\n\nThe BCS may be particularly helpful to assess the importance of aqueous solubility since it relates the solubility of the API to the unit dose. Aqueous solubility should not be a concern in the formulation of immediate-release dosage forms containing class 1 and 3 substances.\n\nFor class 2 substances, the effect of particle size, polymorphic form, and solubility enhancers, among others, should be considered, as the absorption of these substances may be limited by dissolution rate. The same applies to class 4 substances, although factors other than dissolution may also govern the oral absorption. However, overall the BCS classification can be used as a basis when estimating the likelihood of different absorption of paediatric medicines when the dosage form and/or excipients used in adult medicines differ from those used for paediatric medicines.\n\nIn addition, for BCS class 3 and 4 substances, where the absorption process and/or intestinal first pass also restrict bioavailability, the possibility of excipients affecting transit time (efflux), transporter function and metabolic enzymes (typically CYP3A4) should be taken into consideration.\n\n## 5.3 Excipients\n\nThe use of excipients in paediatric medicines is driven by functional requirements and should be justified through a risk-based assessment, taking into account factors such as the paediatric age group, frequency of dosing and duration of treatment.\n\nThe added challenge for paediatric medicines compared to adult medicines is that excipients may lead to adverse reactions in children that are...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "5e09948c3d3a22eda7788c86f0fab43f36a098c94fae5a2a29f8358a66b69e21", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nSolubility and intestinal permeability. An API is considered highly soluble when the highest dose is soluble in 250 ml or less of aqueous media at 37 \u00b0C over the pH range 1.2\u20136.8. The volume estimate of 250 ml is derived from typical bioequivalence study protocols that prescribe administration of a medicine together with a glass of water to fasting human volunteers. A highly permeable API is absorbed orally to an extent of 85% or more of the administered dose based on a mass-balance determination or in comparison to an intravenous dose (19).\n\nHence an API can be classified as belonging to one of four classes:\n\n- class 1 (high solubility, high permeability);\n- class 2 (low solubility, high permeability);\n- class 3 (high solubility, low permeability);\n- class 4 (low solubility, low permeability).\n\nClassification of APIs included in the WHO Model List of essential medicines is provided in the WHO Technical Report Series (20).\n\nThe BCS may be particularly helpful to assess the importance of aqueous solubility since it relates the solubility of the API to the unit dose. Aqueous solubility should not be a concern in the formulation of immediate-release dosage forms containing class 1 and 3 substances.\n\nFor class 2 substances, the effect of particle size, polymorphic form, and solubility enhancers, among others, should be considered, as the absorption of these substances may be limited by dissolution rate. The same applies to class 4 substances, although factors other than dissolution may also govern the oral absorption. However, overall the BCS classification can be used as a basis when estimating the likelihood of different absorption of paediatric medicines when the dosage form and/or excipients used in adult medicines differ from those used for paediatric medicines.\n\nIn addition, for BCS class 3 and 4 substances, where the absorption process and/or intestinal first pass also restrict bioavailability, the possibility of excipients affecting transit time (efflux), transporter function and metabolic enzymes (typically CYP3A4) should be taken into consideration.\n\n## 5.3 Excipients\n\nThe use of excipients in paediatric medicines is driven by functional requirements and should be justified through a risk-based assessment, taking into account factors such as the paediatric age group, frequency of dosing and duration of treatment.\n\nThe added challenge for paediatric medicines compared to adult medicines is that excipients may lead to adverse reactions in children that are...", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2581, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "047a429c-7f28-43df-9b50-3e01f11c31a2": {"__data__": {"id_": "047a429c-7f28-43df-9b50-3e01f11c31a2", "embedding": null, "metadata": {"page_label": "221", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Excipients in Paediatric Medicines\n\nMajor problems with excipients in paediatric medicines, especially when used to treat infants and neonates, have been reported (21), e.g. medicines with benzyl alcohol, azo-dyes, propylene glycol, ethanol and propyl paraben. A study on the exposure to benzyl alcohol and propylene glycol of neonates receiving parenteral medication demonstrated a potential risk of toxic doses, especially for neonates receiving continuous infusion (22). The toxicity of excipients to newborns and infants can be explained by factors related to their physiological and metabolic development (2). Information on the safety of some excipients may be found, for example, in reviews published by the American Academy of Pediatrics (23). Alternative sources of information should also be consulted, e.g. the WHO Technical Report Series on Evaluation of certain food additives (24).\n\nIn the development of paediatric medicines, the number of excipients and their quantity in a formulation should be the minimum required to ensure an appropriate product with respect to performance, stability, palatability, microbial control, dose uniformity and other considerations necessary to support product quality. Risks for adverse reactions are mostly associated with excipients used for liquid dosage forms.\n\nIn the choice of excipients consideration should be given to:\n\n- the safety profile of the excipient for children of the target age groups;\n- the route of administration;\n- the single and daily dose of the excipient;\n- duration of the treatment;\n- acceptability for the intended paediatric population;\n- potential alternatives;\n- regulatory status in the intended market.\n\nPotential alternatives to excipients which pose a significant risk to children should always be considered. Another dosage form or even a different route of administration might be necessary to avoid significant risk. Although well-known excipients with well-defined safety profiles are preferred, new excipients cannot be excluded. Novel excipients should only be used when their safety, quality and appropriateness for use in children have been established. It may also be necessary to look at alternative excipients because of different cultural attitudes or for religious reasons, e.g. the use of gelatin may not be acceptable for all patients.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Problemas de excipientes en medicamentos pedi\u00e1tricos**: Se han reportado problemas significativos relacionados con el uso de excipientes en medicamentos para ni\u00f1os, especialmente en neonatos. Excipientes como el alcohol benc\u00edlico y el propilenglicol pueden presentar riesgos de toxicidad, lo que resalta la necesidad de evaluar cuidadosamente su uso en formulaciones pedi\u00e1tricas.\n\n2. **Consideraciones en el desarrollo de medicamentos pedi\u00e1tricos**: Al desarrollar medicamentos para ni\u00f1os, es crucial minimizar la cantidad y el n\u00famero de excipientes para garantizar la calidad del producto. Se deben considerar factores como la seguridad, la ruta de administraci\u00f3n y la aceptabilidad del excipiente para la poblaci\u00f3n pedi\u00e1trica.\n\n3. **Alternativas a excipientes riesgosos**: Es importante considerar alternativas a los excipientes que representan un riesgo significativo para los ni\u00f1os. Esto puede incluir la b\u00fasqueda de diferentes formas de dosificaci\u00f3n o rutas de administraci\u00f3n, as\u00ed como la evaluaci\u00f3n de excipientes nuevos, siempre que se haya establecido su seguridad y calidad.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los excipientes m\u00e1s problem\u00e1ticos en medicamentos pedi\u00e1tricos y qu\u00e9 riesgos espec\u00edficos presentan para los neonatos?**\n   - Esta pregunta se centra en los excipientes mencionados en el contexto y sus efectos potenciales en la salud de los neonatos.\n\n2. **\u00bfQu\u00e9 criterios deben considerarse al seleccionar excipientes para medicamentos destinados a diferentes grupos de edad pedi\u00e1trica?**\n   - Esta pregunta busca detallar los factores que deben evaluarse al elegir excipientes, bas\u00e1ndose en la informaci\u00f3n proporcionada sobre la seguridad y la aceptabilidad.\n\n3. **\u00bfQu\u00e9 pasos se deben seguir para evaluar la seguridad de nuevos excipientes en medicamentos pedi\u00e1tricos?**\n   - Esta pregunta se enfoca en el proceso necesario para garantizar que los nuevos excipientes sean seguros y apropiados para su uso en ni\u00f1os, tal como se menciona en el contexto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Clasificaci\u00f3n de Principios Activos (API)**:\n   - Los API se clasifican en cuatro clases seg\u00fan su solubilidad y permeabilidad intestinal:\n     - **Clase 1**: Alta solubilidad, alta permeabilidad.\n     - **Clase 2**: Baja solubilidad, alta permeabilidad.\n     - **Clase 3**: Alta solubilidad, baja permeabilidad.\n     - **Clase 4**: Baja solubilidad, baja permeabilidad.\n\n2. **Criterios de Solubilidad**:\n   - Un API se considera altamente soluble si la dosis m\u00e1s alta se disuelve en 250 ml o menos de medio acuoso a 37 \u00b0C en un rango de pH de 1.2 a 6.8.\n\n3. **Importancia de la Solubilidad Acuosa**:\n   - La solubilidad acuosa es crucial en la formulaci\u00f3n de formas de dosificaci\u00f3n de liberaci\u00f3n inmediata para las clases 1 y 3.\n   - Para las clases 2 y 4, se deben considerar factores como el tama\u00f1o de part\u00edcula, la forma polim\u00f3rfica y los potenciadores de solubilidad, ya que la absorci\u00f3n puede estar limitada por la tasa de disoluci\u00f3n.\n\n4. **Evaluaci\u00f3n de Excipientes en Medicamentos Pedi\u00e1tricos**:\n   - El uso de excipientes debe justificarse mediante una evaluaci\u00f3n basada en riesgos, considerando el grupo etario pedi\u00e1trico, la frecuencia de dosificaci\u00f3n y la duraci\u00f3n del tratamiento.\n   - Los excipientes pueden causar reacciones adversas en ni\u00f1os, lo que a\u00f1ade un desaf\u00edo en comparaci\u00f3n con los medicamentos para adultos.\n\n5. **Factores que Afectan la Absorci\u00f3n**:\n   - Para los API de clase 3 y 4, se debe considerar c\u00f3mo los excipientes pueden afectar el tiempo de tr\u00e1nsito intestinal, la funci\u00f3n de los transportadores y las enzimas metab\u00f3licas (como CYP3A4).\n\n### Entidades Clave\n- **API (Principios Activos)**\n- **BCS (Sistema de Clasificaci\u00f3n de Biopharmaceutics)**\n- **Excipientes**\n- **Medicamentos Pedi\u00e1tricos**\n- **Reacciones Adversas**\n- **Solubilidad Acuosa**\n- **Permeabilidad Intestinal**", "excerpt_keywords": "Excipients, Paediatric Medicines, Toxicity, Safety Profile, Formulation"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9063601d-c137-4e46-a9b2-84ebd44c2a4b", "node_type": "4", "metadata": {"page_label": "221", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Excipients in Paediatric Medicines\n\nMajor problems with excipients in paediatric medicines, especially when used to treat infants and neonates, have been reported (21), e.g. medicines with benzyl alcohol, azo-dyes, propylene glycol, ethanol and propyl paraben. A study on the exposure to benzyl alcohol and propylene glycol of neonates receiving parenteral medication demonstrated a potential risk of toxic doses, especially for neonates receiving continuous infusion (22). The toxicity of excipients to newborns and infants can be explained by factors related to their physiological and metabolic development (2). Information on the safety of some excipients may be found, for example, in reviews published by the American Academy of Pediatrics (23). Alternative sources of information should also be consulted, e.g. the WHO Technical Report Series on Evaluation of certain food additives (24).\n\nIn the development of paediatric medicines, the number of excipients and their quantity in a formulation should be the minimum required to ensure an appropriate product with respect to performance, stability, palatability, microbial control, dose uniformity and other considerations necessary to support product quality. Risks for adverse reactions are mostly associated with excipients used for liquid dosage forms.\n\nIn the choice of excipients consideration should be given to:\n\n- the safety profile of the excipient for children of the target age groups;\n- the route of administration;\n- the single and daily dose of the excipient;\n- duration of the treatment;\n- acceptability for the intended paediatric population;\n- potential alternatives;\n- regulatory status in the intended market.\n\nPotential alternatives to excipients which pose a significant risk to children should always be considered. Another dosage form or even a different route of administration might be necessary to avoid significant risk. Although well-known excipients with well-defined safety profiles are preferred, new excipients cannot be excluded. Novel excipients should only be used when their safety, quality and appropriateness for use in children have been established. It may also be necessary to look at alternative excipients because of different cultural attitudes or for religious reasons, e.g. the use of gelatin may not be acceptable for all patients.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "92d464af4f9edf3dc2273d2fd810c32fe7a76336e6c7f1e9a03df536cdbcf8b8", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Excipients in Paediatric Medicines\n\nMajor problems with excipients in paediatric medicines, especially when used to treat infants and neonates, have been reported (21), e.g. medicines with benzyl alcohol, azo-dyes, propylene glycol, ethanol and propyl paraben. A study on the exposure to benzyl alcohol and propylene glycol of neonates receiving parenteral medication demonstrated a potential risk of toxic doses, especially for neonates receiving continuous infusion (22). The toxicity of excipients to newborns and infants can be explained by factors related to their physiological and metabolic development (2). Information on the safety of some excipients may be found, for example, in reviews published by the American Academy of Pediatrics (23). Alternative sources of information should also be consulted, e.g. the WHO Technical Report Series on Evaluation of certain food additives (24).\n\nIn the development of paediatric medicines, the number of excipients and their quantity in a formulation should be the minimum required to ensure an appropriate product with respect to performance, stability, palatability, microbial control, dose uniformity and other considerations necessary to support product quality. Risks for adverse reactions are mostly associated with excipients used for liquid dosage forms.\n\nIn the choice of excipients consideration should be given to:\n\n- the safety profile of the excipient for children of the target age groups;\n- the route of administration;\n- the single and daily dose of the excipient;\n- duration of the treatment;\n- acceptability for the intended paediatric population;\n- potential alternatives;\n- regulatory status in the intended market.\n\nPotential alternatives to excipients which pose a significant risk to children should always be considered. Another dosage form or even a different route of administration might be necessary to avoid significant risk. Although well-known excipients with well-defined safety profiles are preferred, new excipients cannot be excluded. Novel excipients should only be used when their safety, quality and appropriateness for use in children have been established. It may also be necessary to look at alternative excipients because of different cultural attitudes or for religious reasons, e.g. the use of gelatin may not be acceptable for all patients.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2338, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "322b78c7-3e5d-4697-812e-fb3fb4d8f198": {"__data__": {"id_": "322b78c7-3e5d-4697-812e-fb3fb4d8f198", "embedding": null, "metadata": {"page_label": "222", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 5.4 Colouring agents\n\nThe use of colouring agents in paediatric medicines is generally discouraged, in particular in medicines for infants and young children. Their use may, however, be justified in certain cases, e.g. to avoid accidental dosing errors in connection with medicines produced in several strengths. In this case, a solid dosage form of the types mentioned in section 3 may be preferred because size, shape and embossing can facilitate identification of different strengths of the preparation.\n\nSome colouring agents used in paediatric medicines have been associated with hypersensitivity (25). The number of colouring agents that are acceptable for use in medicines is limited. Azo-dyes should be avoided in children\u2019s medicines and attention should be paid to the risk of allergic reactions associated with natural colourants (26).\n\n# 5.5 Antimicrobial preservatives\n\nFPPs may require antimicrobial preservatives to avoid microbial proliferation during storage, in particular under in-use conditions. Preservatives are needed in particular for aqueous multidose preparations and semi-solid preparations and may also be needed for other aqueous preparations. Usually solid dosage forms do not require preservatives.\n\nPreservatives may have a potential to cause adverse reactions, in particular in infants and neonates, and should be avoided where possible. Furthermore, complex preservative systems should be avoided.\n\nOphthalmic preparations without preservatives are strongly recommended for use in children, especially neonates. Therefore, preparations without preservatives should be developed wherever possible in order to cater for the diversity of patients\u2019 needs. When preservatives are required, their concentration should be the minimum level consistent with satisfactory antimicrobial function in each individual preparation and a thorough justification for the choice of the preservative should be established. Ophthalmic preparations without any mercury-containing preservatives, e.g. thiomersal, should also be considered. Further details on this topic are provided in a public statement (27) published on the EMA web site.\n\n# 5.6 Sweetening agents\n\nOral paediatric medicines often use sweetening agents to make them palatable. These may be either cariogenic or non-cariogenic sweeteners. In addition to the considerations listed in section 4.3, attention should be paid to:\n\n- safety of the sweetening agent in relation to specific conditions of the child, e.g. diabetes, fructose intolerance, and avoiding use of aspartame in patients with phenylketonurea;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Uso de agentes colorantes en medicamentos pedi\u00e1tricos**: Se desaconseja el uso de colorantes en medicamentos para ni\u00f1os, especialmente en infantes, aunque puede ser justificado en ciertos casos para evitar errores de dosificaci\u00f3n. Se debe tener cuidado con los colorantes azoicos y las reacciones al\u00e9rgicas asociadas con colorantes naturales.\n\n2. **Conservantes antimicrobianos en formulaciones pedi\u00e1tricas**: Los medicamentos pedi\u00e1tricos pueden necesitar conservantes antimicrobianos para prevenir la proliferaci\u00f3n microbiana, especialmente en preparaciones acuosas. Sin embargo, se deben evitar en la medida de lo posible, especialmente en neonatos, y se recomienda el uso de preparaciones oft\u00e1lmicas sin conservantes.\n\n3. **Uso de edulcorantes en medicamentos orales pedi\u00e1tricos**: Los edulcorantes se utilizan para mejorar el sabor de los medicamentos orales para ni\u00f1os, pero se debe prestar atenci\u00f3n a su seguridad en relaci\u00f3n con condiciones espec\u00edficas del ni\u00f1o, como la diabetes y la intolerancia a la fructosa.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las justificaciones para el uso de colorantes en medicamentos pedi\u00e1tricos y qu\u00e9 precauciones se deben tomar al elegirlos?**\n   - La justificaci\u00f3n para el uso de colorantes en medicamentos pedi\u00e1tricos incluye la prevenci\u00f3n de errores de dosificaci\u00f3n en medicamentos con varias concentraciones. Se deben evitar los colorantes azoicos y tener cuidado con las reacciones al\u00e9rgicas a los colorantes naturales.\n\n2. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al seleccionar conservantes antimicrobianos para medicamentos pedi\u00e1tricos?**\n   - Se deben evitar los conservantes siempre que sea posible, especialmente en infantes y neonatos. Cuando se requieran, su concentraci\u00f3n debe ser la m\u00ednima necesaria para una funci\u00f3n antimicrobiana adecuada, y se debe justificar la elecci\u00f3n del conservante.\n\n3. **\u00bfQu\u00e9 factores de seguridad se deben considerar al utilizar edulcorantes en medicamentos orales para ni\u00f1os?**\n   - Se debe considerar la seguridad del edulcorante en relaci\u00f3n con condiciones espec\u00edficas del ni\u00f1o, como la diabetes y la intolerancia a la fructosa, y evitar el uso de aspartame en pacientes con fenilcetonuria.", "prev_section_summary": "### Temas Clave\n\n1. **Problemas con Excipientes en Medicamentos Pedi\u00e1tricos**: Se han identificado riesgos significativos asociados con excipientes en medicamentos para neonatos, como el alcohol benc\u00edlico y el propilenglicol, que pueden llevar a toxicidad.\n\n2. **Desarrollo de Medicamentos Pedi\u00e1tricos**: Es fundamental minimizar la cantidad y el n\u00famero de excipientes en las formulaciones para asegurar la calidad del producto, considerando factores como la seguridad, la estabilidad y la aceptabilidad.\n\n3. **Selecci\u00f3n de Excipientes**: Al elegir excipientes, se deben evaluar aspectos como el perfil de seguridad, la ruta de administraci\u00f3n, la dosis y la duraci\u00f3n del tratamiento, as\u00ed como la aceptaci\u00f3n por parte de la poblaci\u00f3n pedi\u00e1trica.\n\n4. **Alternativas a Excipientes Riesgosos**: Se deben considerar alternativas a los excipientes que presentan riesgos significativos, lo que puede incluir cambios en la forma de dosificaci\u00f3n o la ruta de administraci\u00f3n.\n\n5. **Evaluaci\u00f3n de Nuevos Excipientes**: Los excipientes nuevos deben ser utilizados solo si se ha establecido su seguridad y calidad para su uso en ni\u00f1os, teniendo en cuenta tambi\u00e9n factores culturales y religiosos.\n\n### Entidades\n\n- **Excipientes**: Sustancias inactivas utilizadas en medicamentos.\n- **Benzyl Alcohol**: Excipiente problem\u00e1tico asociado con toxicidad en neonatos.\n- **Propylene Glycol**: Otro excipiente que presenta riesgos de toxicidad en neonatos.\n- **American Academy of Pediatrics**: Fuente de informaci\u00f3n sobre la seguridad de excipientes.\n- **WHO Technical Report Series**: Publicaciones que ofrecen informaci\u00f3n sobre la evaluaci\u00f3n de aditivos alimentarios.\n- **Poblaci\u00f3n Pedi\u00e1trica**: Ni\u00f1os y neonatos que requieren medicamentos espec\u00edficos.\n- **Criterios de Seguridad**: Factores a considerar al seleccionar excipientes para medicamentos pedi\u00e1tricos.", "excerpt_keywords": "Keywords: paediatric medicines, colouring agents, antimicrobial preservatives, sweetening agents, safety considerations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "aaf0e36a-7489-4e3d-bffd-bb314a2eb786", "node_type": "4", "metadata": {"page_label": "222", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 5.4 Colouring agents\n\nThe use of colouring agents in paediatric medicines is generally discouraged, in particular in medicines for infants and young children. Their use may, however, be justified in certain cases, e.g. to avoid accidental dosing errors in connection with medicines produced in several strengths. In this case, a solid dosage form of the types mentioned in section 3 may be preferred because size, shape and embossing can facilitate identification of different strengths of the preparation.\n\nSome colouring agents used in paediatric medicines have been associated with hypersensitivity (25). The number of colouring agents that are acceptable for use in medicines is limited. Azo-dyes should be avoided in children\u2019s medicines and attention should be paid to the risk of allergic reactions associated with natural colourants (26).\n\n# 5.5 Antimicrobial preservatives\n\nFPPs may require antimicrobial preservatives to avoid microbial proliferation during storage, in particular under in-use conditions. Preservatives are needed in particular for aqueous multidose preparations and semi-solid preparations and may also be needed for other aqueous preparations. Usually solid dosage forms do not require preservatives.\n\nPreservatives may have a potential to cause adverse reactions, in particular in infants and neonates, and should be avoided where possible. Furthermore, complex preservative systems should be avoided.\n\nOphthalmic preparations without preservatives are strongly recommended for use in children, especially neonates. Therefore, preparations without preservatives should be developed wherever possible in order to cater for the diversity of patients\u2019 needs. When preservatives are required, their concentration should be the minimum level consistent with satisfactory antimicrobial function in each individual preparation and a thorough justification for the choice of the preservative should be established. Ophthalmic preparations without any mercury-containing preservatives, e.g. thiomersal, should also be considered. Further details on this topic are provided in a public statement (27) published on the EMA web site.\n\n# 5.6 Sweetening agents\n\nOral paediatric medicines often use sweetening agents to make them palatable. These may be either cariogenic or non-cariogenic sweeteners. In addition to the considerations listed in section 4.3, attention should be paid to:\n\n- safety of the sweetening agent in relation to specific conditions of the child, e.g. diabetes, fructose intolerance, and avoiding use of aspartame in patients with phenylketonurea;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "23da46c4715a090e282d60e89536dc4362bd3e2c06aeaa457951fa105985c0ab", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 5.4 Colouring agents\n\nThe use of colouring agents in paediatric medicines is generally discouraged, in particular in medicines for infants and young children. Their use may, however, be justified in certain cases, e.g. to avoid accidental dosing errors in connection with medicines produced in several strengths. In this case, a solid dosage form of the types mentioned in section 3 may be preferred because size, shape and embossing can facilitate identification of different strengths of the preparation.\n\nSome colouring agents used in paediatric medicines have been associated with hypersensitivity (25). The number of colouring agents that are acceptable for use in medicines is limited. Azo-dyes should be avoided in children\u2019s medicines and attention should be paid to the risk of allergic reactions associated with natural colourants (26).\n\n# 5.5 Antimicrobial preservatives\n\nFPPs may require antimicrobial preservatives to avoid microbial proliferation during storage, in particular under in-use conditions. Preservatives are needed in particular for aqueous multidose preparations and semi-solid preparations and may also be needed for other aqueous preparations. Usually solid dosage forms do not require preservatives.\n\nPreservatives may have a potential to cause adverse reactions, in particular in infants and neonates, and should be avoided where possible. Furthermore, complex preservative systems should be avoided.\n\nOphthalmic preparations without preservatives are strongly recommended for use in children, especially neonates. Therefore, preparations without preservatives should be developed wherever possible in order to cater for the diversity of patients\u2019 needs. When preservatives are required, their concentration should be the minimum level consistent with satisfactory antimicrobial function in each individual preparation and a thorough justification for the choice of the preservative should be established. Ophthalmic preparations without any mercury-containing preservatives, e.g. thiomersal, should also be considered. Further details on this topic are provided in a public statement (27) published on the EMA web site.\n\n# 5.6 Sweetening agents\n\nOral paediatric medicines often use sweetening agents to make them palatable. These may be either cariogenic or non-cariogenic sweeteners. In addition to the considerations listed in section 4.3, attention should be paid to:\n\n- safety of the sweetening agent in relation to specific conditions of the child, e.g. diabetes, fructose intolerance, and avoiding use of aspartame in patients with phenylketonurea;", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2588, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "4e2c5ecf-07c1-4fee-a317-448bfdd0b592": {"__data__": {"id_": "4e2c5ecf-07c1-4fee-a317-448bfdd0b592", "embedding": null, "metadata": {"page_label": "223", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Taste Masking\n\nTaste masking in medicines for oral use or for use in the mouth is often needed to improve palatability of the medicine. Children have a well-developed sensory system for detecting tastes, smells and chemical irritants. They are able to recognize sweetness and saltiness from an early stage and are also able to recognize a sweet taste in oral liquids and the degree of sweetness (28). Children seem to prefer sweeter tastes than adults do. The unpleasant taste of an API, e.g. bitterness or a metallic taste, is, therefore, often masked in an oral liquid by the use of sweetening agents and flavours. Additional use of colouring agents that match the flavour is discouraged (see section 4.4) unless this is necessary to disguise an unpleasant colour related to the API. Some successful approaches to taste masking are discussed by Ernest et al. (7).\n\nA child\u2019s preference for particular flavours is determined by individual experiences and culture. The target for taste masking need not necessarily be good-tasting medicines; it should simply be a taste that is acceptable in as many countries as possible taking into account cultural differences.\n\nAn example of a \u201cqualitative evaluation of the taste by a taste panel\u201d for zinc formulations can be found in the United Nations Children\u2019s Fund (UNICEF)/WHO publication on production of zinc formulations (29, 30).\n\nConsideration should be given to the items listed in sections 4.3 and 4.6.\n\nTaste masking for orodispersible tablets and chewable tablets is in principle similar to taste masking for oral liquids. Non-cariogenic sweeteners and flavours are preferred.\n\n# Solubility Enhancers\n\nThe aqueous solubility of the API may limit the concentration achievable in formulated solutions and, hence, the desirable dose volume. In many cases an acceptable solution requires solubility enhancing methods, e.g. use of non-ionic surfactants and of co-solvents such as glycerol, liquid macrogols and ethanol. If solubility enhancers are to be used, consideration should be given to the safety of both the agent and the formulation, for example, the risk of irritation and damage of intestinal tissues in neonates caused by hyperosmolality or other local toxicity. Risks associated with the use of solubility enhancers are higher when they are included in parenteral preparations than when used in oral preparations.\n\nEthanol, especially in large amounts, should not be administered to children (aged 0\u201317 years) through FPPs without a clear demonstration of benefit.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de Nivel Superior\n\n1. **Importancia del Enmascaramiento del Sabor**: El enmascaramiento del sabor en medicamentos orales es crucial para mejorar la palatabilidad, especialmente en ni\u00f1os, quienes tienen una sensibilidad aguda a los sabores. Se utilizan agentes endulzantes y sabores para ocultar sabores desagradables de los principios activos (API), y se deben considerar las diferencias culturales en las preferencias de sabor.\n\n2. **Uso de Mejoradores de Solubilidad**: La solubilidad acuosa de los API puede limitar la concentraci\u00f3n en soluciones formuladas. Para lograr una soluci\u00f3n aceptable, se pueden emplear m\u00e9todos de mejora de solubilidad, como surfactantes no i\u00f3nicos y co-solventes. Sin embargo, se deben considerar los riesgos de irritaci\u00f3n y toxicidad, especialmente en preparaciones parenterales y en ni\u00f1os.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los m\u00e9todos recomendados para enmascarar sabores desagradables en medicamentos orales para ni\u00f1os?**\n   - El enmascaramiento de sabores desagradables se logra principalmente mediante el uso de agentes endulzantes y sabores que sean aceptables culturalmente. Se desaconseja el uso de colorantes a menos que sea necesario para ocultar un color desagradable relacionado con el API.\n\n2. **\u00bfQu\u00e9 consideraciones de seguridad deben tenerse en cuenta al utilizar mejoradores de solubilidad en medicamentos para ni\u00f1os?**\n   - Al utilizar mejoradores de solubilidad, es fundamental considerar la seguridad del agente y la formulaci\u00f3n, incluyendo el riesgo de irritaci\u00f3n y da\u00f1o a los tejidos intestinales en neonatos debido a la hiperosmolaridad o toxicidad local. Los riesgos son mayores en preparaciones parenterales que en orales.\n\n3. **\u00bfC\u00f3mo influyen las experiencias individuales y la cultura en las preferencias de sabor de los ni\u00f1os?**\n   - Las preferencias de sabor de los ni\u00f1os est\u00e1n determinadas por sus experiencias individuales y su cultura, lo que significa que el objetivo del enmascaramiento del sabor no debe ser necesariamente crear medicamentos que sepan bien, sino que sean aceptables en la mayor cantidad de pa\u00edses posible, teniendo en cuenta estas diferencias culturales.", "prev_section_summary": "### Temas Clave\n\n1. **Agentes Colorantes en Medicamentos Pedi\u00e1tricos**:\n   - Generalmente desaconsejados, especialmente en infantes.\n   - Pueden ser justificados para evitar errores de dosificaci\u00f3n en medicamentos con varias concentraciones.\n   - Se deben evitar colorantes azoicos y tener precauci\u00f3n con colorantes naturales debido a posibles reacciones al\u00e9rgicas.\n\n2. **Conservantes Antimicrobianos**:\n   - Necesarios para prevenir la proliferaci\u00f3n microbiana en preparaciones acuosas, especialmente en productos multidosis y semi-s\u00f3lidos.\n   - Deben evitarse en la medida de lo posible, especialmente en neonatos.\n   - Se recomienda el uso de preparaciones oft\u00e1lmicas sin conservantes y se debe justificar la elecci\u00f3n de cualquier conservante utilizado.\n\n3. **Agentes Edulcorantes**:\n   - Utilizados para mejorar el sabor de los medicamentos orales pedi\u00e1tricos.\n   - Deben considerarse la seguridad en relaci\u00f3n con condiciones espec\u00edficas del ni\u00f1o, como diabetes e intolerancia a la fructosa.\n   - Se debe evitar el uso de aspartame en pacientes con fenilcetonuria.\n\n### Entidades\n\n- **Medicamentos Pedi\u00e1tricos**: Formulaciones destinadas a ni\u00f1os, incluyendo infantes y neonatos.\n- **Agentes Colorantes**: Sustancias utilizadas para dar color a los medicamentos.\n- **Conservantes Antimicrobianos**: Sustancias que previenen el crecimiento de microorganismos en productos farmac\u00e9uticos.\n- **Agentes Edulcorantes**: Sustancias que mejoran el sabor de los medicamentos, pudiendo ser cariog\u00e9nicas o no cariog\u00e9nicas.\n- **Condiciones Espec\u00edficas**: Diabetes, intolerancia a la fructosa, fenilcetonuria.\n\nEste resumen destaca las consideraciones importantes sobre el uso de colorantes, conservantes y edulcorantes en medicamentos pedi\u00e1tricos, enfatizando la seguridad y la necesidad de justificaci\u00f3n en su uso.", "excerpt_keywords": "Taste masking, solubility enhancers, pediatric formulations, palatability, safety considerations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73fde2c4-ed6e-4b50-bcdd-02e74cada912", "node_type": "4", "metadata": {"page_label": "223", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Taste Masking\n\nTaste masking in medicines for oral use or for use in the mouth is often needed to improve palatability of the medicine. Children have a well-developed sensory system for detecting tastes, smells and chemical irritants. They are able to recognize sweetness and saltiness from an early stage and are also able to recognize a sweet taste in oral liquids and the degree of sweetness (28). Children seem to prefer sweeter tastes than adults do. The unpleasant taste of an API, e.g. bitterness or a metallic taste, is, therefore, often masked in an oral liquid by the use of sweetening agents and flavours. Additional use of colouring agents that match the flavour is discouraged (see section 4.4) unless this is necessary to disguise an unpleasant colour related to the API. Some successful approaches to taste masking are discussed by Ernest et al. (7).\n\nA child\u2019s preference for particular flavours is determined by individual experiences and culture. The target for taste masking need not necessarily be good-tasting medicines; it should simply be a taste that is acceptable in as many countries as possible taking into account cultural differences.\n\nAn example of a \u201cqualitative evaluation of the taste by a taste panel\u201d for zinc formulations can be found in the United Nations Children\u2019s Fund (UNICEF)/WHO publication on production of zinc formulations (29, 30).\n\nConsideration should be given to the items listed in sections 4.3 and 4.6.\n\nTaste masking for orodispersible tablets and chewable tablets is in principle similar to taste masking for oral liquids. Non-cariogenic sweeteners and flavours are preferred.\n\n# Solubility Enhancers\n\nThe aqueous solubility of the API may limit the concentration achievable in formulated solutions and, hence, the desirable dose volume. In many cases an acceptable solution requires solubility enhancing methods, e.g. use of non-ionic surfactants and of co-solvents such as glycerol, liquid macrogols and ethanol. If solubility enhancers are to be used, consideration should be given to the safety of both the agent and the formulation, for example, the risk of irritation and damage of intestinal tissues in neonates caused by hyperosmolality or other local toxicity. Risks associated with the use of solubility enhancers are higher when they are included in parenteral preparations than when used in oral preparations.\n\nEthanol, especially in large amounts, should not be administered to children (aged 0\u201317 years) through FPPs without a clear demonstration of benefit.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "59a391bd592cd4faa1a1aa78d2ea7e51518c6d77c2f04b1b020185badb2cb6e2", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Taste Masking\n\nTaste masking in medicines for oral use or for use in the mouth is often needed to improve palatability of the medicine. Children have a well-developed sensory system for detecting tastes, smells and chemical irritants. They are able to recognize sweetness and saltiness from an early stage and are also able to recognize a sweet taste in oral liquids and the degree of sweetness (28). Children seem to prefer sweeter tastes than adults do. The unpleasant taste of an API, e.g. bitterness or a metallic taste, is, therefore, often masked in an oral liquid by the use of sweetening agents and flavours. Additional use of colouring agents that match the flavour is discouraged (see section 4.4) unless this is necessary to disguise an unpleasant colour related to the API. Some successful approaches to taste masking are discussed by Ernest et al. (7).\n\nA child\u2019s preference for particular flavours is determined by individual experiences and culture. The target for taste masking need not necessarily be good-tasting medicines; it should simply be a taste that is acceptable in as many countries as possible taking into account cultural differences.\n\nAn example of a \u201cqualitative evaluation of the taste by a taste panel\u201d for zinc formulations can be found in the United Nations Children\u2019s Fund (UNICEF)/WHO publication on production of zinc formulations (29, 30).\n\nConsideration should be given to the items listed in sections 4.3 and 4.6.\n\nTaste masking for orodispersible tablets and chewable tablets is in principle similar to taste masking for oral liquids. Non-cariogenic sweeteners and flavours are preferred.\n\n# Solubility Enhancers\n\nThe aqueous solubility of the API may limit the concentration achievable in formulated solutions and, hence, the desirable dose volume. In many cases an acceptable solution requires solubility enhancing methods, e.g. use of non-ionic surfactants and of co-solvents such as glycerol, liquid macrogols and ethanol. If solubility enhancers are to be used, consideration should be given to the safety of both the agent and the formulation, for example, the risk of irritation and damage of intestinal tissues in neonates caused by hyperosmolality or other local toxicity. Risks associated with the use of solubility enhancers are higher when they are included in parenteral preparations than when used in oral preparations.\n\nEthanol, especially in large amounts, should not be administered to children (aged 0\u201317 years) through FPPs without a clear demonstration of benefit.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2528, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "1926b344-70e9-48cf-b7df-9d6141e54a35": {"__data__": {"id_": "1926b344-70e9-48cf-b7df-9d6141e54a35", "embedding": null, "metadata": {"page_label": "224", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAlthough it is recognized that ethanol may not always be eliminated from FPPs, and replacements may raise other issues, the smallest possible amount should be used. When ethanol is used, adequate development data demonstrating that the lowest possible concentration of ethanol is used should be established.\n\nChildren, especially under the age of 6 years, are more vulnerable to the effects of ethanol. Adverse effects on the central nervous system are already evident at blood ethanol concentrations of 10 mg/100 ml in children. Higher peak ethanol blood concentrations are also observed in children than in adults for a similar intake. Chronic exposure to ethanol (> 1 week), even to small doses, through FPPs is, in principle, contraindicated in children aged less than 6 years and should be limited to 2 weeks in children aged over 6 years, if a positive risk\u2013benefit balance is not demonstrated. Toxic effects on brain maturation in young children are highly probable and also supported by non-clinical data. Additionally, chronic exposure has been shown to be linked to ethanol dependence in adults and adolescents.\n\n## 6. Oral administration\n\nThe oral route is the preferred and most appropriate route of administration to paediatric patients. This route is generally acceptable in all age groups if the medicine is administered in a suitable dosage form, e.g. in liquid form for children in the youngest age groups who have difficulty in swallowing solid dosage forms. Strictly speaking, the choice of dosage form for oral administration depends on the gut function and, thus, on both age and clinical condition.\n\nConsideration should be given to the effects of increased gastric pH and intestinal mobility at birth and in early infancy (2). In addition, gastric emptying of sick newborns is most erratic and can be delayed. Further information can be found in an EMA guideline on medicines for term and preterm neonates (31).\n\nMixing oral dosage forms with food or a beverage is not recommended, but may be performed to enhance compliance (see section 2.2). Potential effects of foods on bioavailability should be considered. When recommending mixing medicines with food, attention should be paid to the effect on the taste, as an unpleasant taste of medicine may cause aversion in children.\n\n### 6.1 Oral liquid preparations\n\nOral liquid preparations include aqueous solutions, suspensions, emulsions and syrups. They are most appropriate for children in the youngest age groups who are unable to swallow solid dosage forms. The advantage of oral liquid preparations is that variable dose volumes can be measured and administered. The need for stabilizing agents, e.g. antimicrobial preservatives, is a major drawback as is the potential chemical instability, which may lead to a requirement for controlled storage.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Efectos del etanol en ni\u00f1os**: El etanol puede tener efectos adversos significativos en los ni\u00f1os, especialmente en aquellos menores de 6 a\u00f1os. Se menciona que la exposici\u00f3n cr\u00f3nica al etanol, incluso en peque\u00f1as dosis, es desaconsejada y puede tener consecuencias negativas en el desarrollo del cerebro.\n\n2. **Administraci\u00f3n oral en pediatr\u00eda**: La administraci\u00f3n oral es la ruta preferida para los pacientes pedi\u00e1tricos, y se debe considerar la forma de dosificaci\u00f3n adecuada, especialmente para los m\u00e1s j\u00f3venes que no pueden tragar formas s\u00f3lidas. La elecci\u00f3n de la forma de dosificaci\u00f3n depende de la funci\u00f3n intestinal y la condici\u00f3n cl\u00ednica del ni\u00f1o.\n\n3. **Preparaciones l\u00edquidas orales**: Las preparaciones l\u00edquidas orales son adecuadas para los ni\u00f1os m\u00e1s peque\u00f1os y permiten medir y administrar vol\u00famenes de dosis variables. Sin embargo, su estabilidad qu\u00edmica y la necesidad de agentes estabilizantes son desventajas importantes.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las concentraciones de etanol en sangre que pueden causar efectos adversos en ni\u00f1os y c\u00f3mo se comparan con los adultos?**\n   - Respuesta: Los efectos adversos en el sistema nervioso central en ni\u00f1os son evidentes a concentraciones de etanol en sangre de 10 mg/100 ml. Adem\u00e1s, se observa que los ni\u00f1os alcanzan concentraciones m\u00e1ximas de etanol en sangre m\u00e1s altas que los adultos con una ingesta similar.\n\n2. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al elegir la forma de dosificaci\u00f3n oral para pacientes pedi\u00e1tricos?**\n   - Respuesta: La elecci\u00f3n de la forma de dosificaci\u00f3n oral depende de la funci\u00f3n intestinal, que var\u00eda seg\u00fan la edad y la condici\u00f3n cl\u00ednica del ni\u00f1o. Tambi\u00e9n se deben considerar los efectos del pH g\u00e1strico y la movilidad intestinal en reci\u00e9n nacidos y lactantes.\n\n3. **\u00bfCu\u00e1les son las desventajas de las preparaciones l\u00edquidas orales en comparaci\u00f3n con las formas s\u00f3lidas?**\n   - Respuesta: Las desventajas de las preparaciones l\u00edquidas orales incluyen la necesidad de agentes estabilizantes, como conservantes antimicrobianos, y la potencial inestabilidad qu\u00edmica, lo que puede requerir un almacenamiento controlado.", "prev_section_summary": "### Temas Clave\n\n1. **Enmascaramiento del Sabor**:\n   - Es esencial para mejorar la palatabilidad de los medicamentos orales, especialmente en ni\u00f1os.\n   - Los ni\u00f1os tienen una sensibilidad aguda a los sabores y prefieren sabores m\u00e1s dulces que los adultos.\n   - Se utilizan agentes endulzantes y sabores para ocultar sabores desagradables de los principios activos (API).\n   - Las preferencias de sabor est\u00e1n influenciadas por experiencias individuales y diferencias culturales.\n   - Se desaconseja el uso de colorantes a menos que sea necesario para ocultar un color desagradable relacionado con el API.\n\n2. **Mejoradores de Solubilidad**:\n   - La solubilidad acuosa de los API puede limitar la concentraci\u00f3n en soluciones formuladas.\n   - Se pueden utilizar surfactantes no i\u00f3nicos y co-solventes como glicerol y etanol para mejorar la solubilidad.\n   - Es importante considerar la seguridad de los mejoradores de solubilidad, especialmente en neonatos, debido a riesgos de irritaci\u00f3n y toxicidad.\n   - Los riesgos son mayores en preparaciones parenterales que en orales.\n   - El etanol no debe ser administrado a ni\u00f1os sin una clara demostraci\u00f3n de beneficio.\n\n### Entidades\n\n- **API (Principios Activos)**: Sustancias que tienen un efecto farmacol\u00f3gico.\n- **Agentes Endulzantes**: Sustancias utilizadas para mejorar el sabor de los medicamentos.\n- **Surfactantes No I\u00f3nicos**: Compuestos que ayudan a aumentar la solubilidad de los API.\n- **Co-solventes**: Sustancias como glicerol y etanol que se utilizan para mejorar la solubilidad.\n- **UNICEF**: Fondo de las Naciones Unidas para la Infancia, que proporciona directrices sobre formulaciones de zinc.\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Organizaci\u00f3n que establece est\u00e1ndares y directrices para la salud p\u00fablica, incluyendo la formulaci\u00f3n de medicamentos.", "excerpt_keywords": "Keywords: ethanol, pediatric, oral administration, liquid preparations, pharmaceutical specifications"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e86a78f2-b8f3-429d-9ee6-b1ca08ce25f7", "node_type": "4", "metadata": {"page_label": "224", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAlthough it is recognized that ethanol may not always be eliminated from FPPs, and replacements may raise other issues, the smallest possible amount should be used. When ethanol is used, adequate development data demonstrating that the lowest possible concentration of ethanol is used should be established.\n\nChildren, especially under the age of 6 years, are more vulnerable to the effects of ethanol. Adverse effects on the central nervous system are already evident at blood ethanol concentrations of 10 mg/100 ml in children. Higher peak ethanol blood concentrations are also observed in children than in adults for a similar intake. Chronic exposure to ethanol (> 1 week), even to small doses, through FPPs is, in principle, contraindicated in children aged less than 6 years and should be limited to 2 weeks in children aged over 6 years, if a positive risk\u2013benefit balance is not demonstrated. Toxic effects on brain maturation in young children are highly probable and also supported by non-clinical data. Additionally, chronic exposure has been shown to be linked to ethanol dependence in adults and adolescents.\n\n## 6. Oral administration\n\nThe oral route is the preferred and most appropriate route of administration to paediatric patients. This route is generally acceptable in all age groups if the medicine is administered in a suitable dosage form, e.g. in liquid form for children in the youngest age groups who have difficulty in swallowing solid dosage forms. Strictly speaking, the choice of dosage form for oral administration depends on the gut function and, thus, on both age and clinical condition.\n\nConsideration should be given to the effects of increased gastric pH and intestinal mobility at birth and in early infancy (2). In addition, gastric emptying of sick newborns is most erratic and can be delayed. Further information can be found in an EMA guideline on medicines for term and preterm neonates (31).\n\nMixing oral dosage forms with food or a beverage is not recommended, but may be performed to enhance compliance (see section 2.2). Potential effects of foods on bioavailability should be considered. When recommending mixing medicines with food, attention should be paid to the effect on the taste, as an unpleasant taste of medicine may cause aversion in children.\n\n### 6.1 Oral liquid preparations\n\nOral liquid preparations include aqueous solutions, suspensions, emulsions and syrups. They are most appropriate for children in the youngest age groups who are unable to swallow solid dosage forms. The advantage of oral liquid preparations is that variable dose volumes can be measured and administered. The need for stabilizing agents, e.g. antimicrobial preservatives, is a major drawback as is the potential chemical instability, which may lead to a requirement for controlled storage.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "5ce4576aaa67f6c84ad084f71ca416be64dd19932bc5fc313ccfe2e644d2f9e8", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAlthough it is recognized that ethanol may not always be eliminated from FPPs, and replacements may raise other issues, the smallest possible amount should be used. When ethanol is used, adequate development data demonstrating that the lowest possible concentration of ethanol is used should be established.\n\nChildren, especially under the age of 6 years, are more vulnerable to the effects of ethanol. Adverse effects on the central nervous system are already evident at blood ethanol concentrations of 10 mg/100 ml in children. Higher peak ethanol blood concentrations are also observed in children than in adults for a similar intake. Chronic exposure to ethanol (> 1 week), even to small doses, through FPPs is, in principle, contraindicated in children aged less than 6 years and should be limited to 2 weeks in children aged over 6 years, if a positive risk\u2013benefit balance is not demonstrated. Toxic effects on brain maturation in young children are highly probable and also supported by non-clinical data. Additionally, chronic exposure has been shown to be linked to ethanol dependence in adults and adolescents.\n\n## 6. Oral administration\n\nThe oral route is the preferred and most appropriate route of administration to paediatric patients. This route is generally acceptable in all age groups if the medicine is administered in a suitable dosage form, e.g. in liquid form for children in the youngest age groups who have difficulty in swallowing solid dosage forms. Strictly speaking, the choice of dosage form for oral administration depends on the gut function and, thus, on both age and clinical condition.\n\nConsideration should be given to the effects of increased gastric pH and intestinal mobility at birth and in early infancy (2). In addition, gastric emptying of sick newborns is most erratic and can be delayed. Further information can be found in an EMA guideline on medicines for term and preterm neonates (31).\n\nMixing oral dosage forms with food or a beverage is not recommended, but may be performed to enhance compliance (see section 2.2). Potential effects of foods on bioavailability should be considered. When recommending mixing medicines with food, attention should be paid to the effect on the taste, as an unpleasant taste of medicine may cause aversion in children.\n\n### 6.1 Oral liquid preparations\n\nOral liquid preparations include aqueous solutions, suspensions, emulsions and syrups. They are most appropriate for children in the youngest age groups who are unable to swallow solid dosage forms. The advantage of oral liquid preparations is that variable dose volumes can be measured and administered. The need for stabilizing agents, e.g. antimicrobial preservatives, is a major drawback as is the potential chemical instability, which may lead to a requirement for controlled storage.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2899, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "3c46109a-9581-4390-9da0-f0696820da22": {"__data__": {"id_": "3c46109a-9581-4390-9da0-f0696820da22", "embedding": null, "metadata": {"page_label": "225", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\nConditions during distribution and use. Oral liquid preparations are less transportable than solid-dose preparations because of their relatively high bulk volume.\n\nThe dose volume is important for the acceptability of the preparation. High-dose volumes pose a risk of incomplete ingestion and, thus, underdosage. Efforts should, therefore, be made during pharmaceutical development to minimize the dose volume while recognizing the need to ensure accurate measurements of the dose over the anticipated range. Typical target dose volumes are 5 ml or less for children under 5 years and 10 ml or less for children of 5 years and older (32). There is some uncertainty about these limits because the more palatable the formulation, the higher the dose volume that will be accepted by the child. Target volumes and electrolyte contents are critical for neonates, especially in cases of immature renal function.\n\nOral liquid preparations may be supplied in multidose containers or single-dose containers. Usually, both forms require antimicrobial preservatives. Special attention has to be paid to the in-use stability of multidose preparations, both microbial and physicochemical.\n\nMultidose preparations should be packaged together with an appropriate dosing device. The correct graduation of the device and the accuracy of the volumes measured must be checked by the manufacturer. Generally, oral syringes are preferable because of the flexibility in dose measurement and superior accuracy compared to other devices such as graduated pipettes or plastic spoons. The accuracy in measuring and delivering a volume of liquid is influenced by the liquid\u2019s physical characteristics, especially its viscosity.\n\nThe risks associated with incorrect dosing should be considered. If correct dosing is critical, a single-dose preparation, e.g. a pre-filled oral syringe, should be considered.\n\n## Drops\n\nSome liquids are administered as drops in small volumes using a dropper or a graduated pipette to measure a volume to be dissolved or dispersed in water or another diluent before the dose is swallowed. The use of this dosage form should be evaluated using a risk-based approach to ensure it is suitable given the medicine\u2019s potency and side-effect profile and the potential for dosing errors. The in-use performance of the dose-measuring device is critical for this dosage form.\n\n## Oral suspensions\n\nFormulation of an oral suspension may be dictated by the aqueous solubility of the API and the balance between the dose of API and the dose volume. In certain cases, the unpleasant taste of an API can be reduced by choosing the suspended form.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl texto aborda las consideraciones sobre la distribuci\u00f3n y uso de preparaciones l\u00edquidas orales en comparaci\u00f3n con las preparaciones s\u00f3lidas. Se enfatiza la importancia del volumen de dosis para la aceptabilidad, especialmente en ni\u00f1os, y se discuten las implicaciones de la formulaci\u00f3n, el envasado y la medici\u00f3n de dosis. Se menciona la necesidad de dispositivos de dosificaci\u00f3n precisos y la evaluaci\u00f3n de riesgos asociados con errores de dosificaci\u00f3n. Tambi\u00e9n se abordan las suspensiones orales y la administraci\u00f3n de l\u00edquidos en forma de gotas.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los vol\u00famenes de dosis t\u00edpicos recomendados para ni\u00f1os menores de 5 a\u00f1os y para aquellos de 5 a\u00f1os o m\u00e1s, y c\u00f3mo se relaciona la palatabilidad de la formulaci\u00f3n con la aceptaci\u00f3n del volumen de dosis?**\n   - Respuesta: Los vol\u00famenes de dosis t\u00edpicos recomendados son de 5 ml o menos para ni\u00f1os menores de 5 a\u00f1os y de 10 ml o menos para ni\u00f1os de 5 a\u00f1os y mayores. La palatabilidad de la formulaci\u00f3n puede influir en la aceptaci\u00f3n del volumen de dosis, ya que una formulaci\u00f3n m\u00e1s agradable puede permitir un volumen de dosis mayor.\n\n2. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al elegir entre preparaciones de dosis \u00fanica y multidose para l\u00edquidos orales?**\n   - Respuesta: Al elegir entre preparaciones de dosis \u00fanica y multidose, se deben considerar los riesgos asociados con la dosificaci\u00f3n incorrecta. Si la dosificaci\u00f3n precisa es cr\u00edtica, se recomienda optar por una preparaci\u00f3n de dosis \u00fanica, como una jeringa oral precargada.\n\n3. **\u00bfC\u00f3mo influye la viscosidad del l\u00edquido en la precisi\u00f3n de la medici\u00f3n y entrega de un volumen de l\u00edquido en preparaciones orales?**\n   - Respuesta: La viscosidad del l\u00edquido influye en la precisi\u00f3n de la medici\u00f3n y entrega de un volumen de l\u00edquido, ya que las caracter\u00edsticas f\u00edsicas del l\u00edquido pueden afectar la capacidad del dispositivo de dosificaci\u00f3n para medir y entregar el volumen de manera precisa.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Efectos del Etanol en Ni\u00f1os**:\n   - El etanol puede causar efectos adversos significativos en ni\u00f1os, especialmente en aquellos menores de 6 a\u00f1os.\n   - Se observan efectos en el sistema nervioso central a concentraciones de etanol en sangre de 10 mg/100 ml.\n   - Los ni\u00f1os alcanzan concentraciones m\u00e1s altas de etanol en sangre en comparaci\u00f3n con los adultos para una ingesta similar.\n   - La exposici\u00f3n cr\u00f3nica al etanol est\u00e1 contraindicada en ni\u00f1os menores de 6 a\u00f1os y debe limitarse a 2 semanas en ni\u00f1os mayores de 6 a\u00f1os, a menos que se demuestre un balance positivo de riesgo-beneficio.\n\n2. **Administraci\u00f3n Oral en Pediatr\u00eda**:\n   - La administraci\u00f3n oral es la ruta preferida para pacientes pedi\u00e1tricos.\n   - La elecci\u00f3n de la forma de dosificaci\u00f3n depende de la funci\u00f3n intestinal, que var\u00eda seg\u00fan la edad y la condici\u00f3n cl\u00ednica del ni\u00f1o.\n   - Se deben considerar factores como el pH g\u00e1strico y la movilidad intestinal en reci\u00e9n nacidos y lactantes.\n\n3. **Preparaciones L\u00edquidas Orales**:\n   - Incluyen soluciones acuosas, suspensiones, emulsiones y jarabes, siendo adecuadas para los ni\u00f1os m\u00e1s peque\u00f1os que no pueden tragar formas s\u00f3lidas.\n   - Permiten medir y administrar vol\u00famenes de dosis variables.\n   - Desventajas incluyen la necesidad de agentes estabilizantes (como conservantes antimicrobianos) y la potencial inestabilidad qu\u00edmica, lo que puede requerir almacenamiento controlado.\n\n### Entidades Clave:\n- **Ethanol**: Sustancia cuyo uso en formulaciones farmac\u00e9uticas debe ser minimizado, especialmente en pediatr\u00eda.\n- **Ni\u00f1os menores de 6 a\u00f1os**: Grupo m\u00e1s vulnerable a los efectos del etanol.\n- **Administraci\u00f3n Oral**: Ruta preferida para la medicaci\u00f3n en pacientes pedi\u00e1tricos.\n- **Preparaciones L\u00edquidas**: Formas de dosificaci\u00f3n adecuadas para ni\u00f1os peque\u00f1os, con ventajas y desventajas espec\u00edficas.", "excerpt_keywords": "Keywords: oral liquid preparations, dosing accuracy, pediatric formulations, multidose containers, viscosity effects"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0af92150-be22-4777-82a0-b64b9c07bcee", "node_type": "4", "metadata": {"page_label": "225", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\nConditions during distribution and use. Oral liquid preparations are less transportable than solid-dose preparations because of their relatively high bulk volume.\n\nThe dose volume is important for the acceptability of the preparation. High-dose volumes pose a risk of incomplete ingestion and, thus, underdosage. Efforts should, therefore, be made during pharmaceutical development to minimize the dose volume while recognizing the need to ensure accurate measurements of the dose over the anticipated range. Typical target dose volumes are 5 ml or less for children under 5 years and 10 ml or less for children of 5 years and older (32). There is some uncertainty about these limits because the more palatable the formulation, the higher the dose volume that will be accepted by the child. Target volumes and electrolyte contents are critical for neonates, especially in cases of immature renal function.\n\nOral liquid preparations may be supplied in multidose containers or single-dose containers. Usually, both forms require antimicrobial preservatives. Special attention has to be paid to the in-use stability of multidose preparations, both microbial and physicochemical.\n\nMultidose preparations should be packaged together with an appropriate dosing device. The correct graduation of the device and the accuracy of the volumes measured must be checked by the manufacturer. Generally, oral syringes are preferable because of the flexibility in dose measurement and superior accuracy compared to other devices such as graduated pipettes or plastic spoons. The accuracy in measuring and delivering a volume of liquid is influenced by the liquid\u2019s physical characteristics, especially its viscosity.\n\nThe risks associated with incorrect dosing should be considered. If correct dosing is critical, a single-dose preparation, e.g. a pre-filled oral syringe, should be considered.\n\n## Drops\n\nSome liquids are administered as drops in small volumes using a dropper or a graduated pipette to measure a volume to be dissolved or dispersed in water or another diluent before the dose is swallowed. The use of this dosage form should be evaluated using a risk-based approach to ensure it is suitable given the medicine\u2019s potency and side-effect profile and the potential for dosing errors. The in-use performance of the dose-measuring device is critical for this dosage form.\n\n## Oral suspensions\n\nFormulation of an oral suspension may be dictated by the aqueous solubility of the API and the balance between the dose of API and the dose volume. In certain cases, the unpleasant taste of an API can be reduced by choosing the suspended form.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "11349790ee3014e53af07c0f6e76a8a43e09de3157055e797bb571fae01f57bb", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 5\n\nConditions during distribution and use. Oral liquid preparations are less transportable than solid-dose preparations because of their relatively high bulk volume.\n\nThe dose volume is important for the acceptability of the preparation. High-dose volumes pose a risk of incomplete ingestion and, thus, underdosage. Efforts should, therefore, be made during pharmaceutical development to minimize the dose volume while recognizing the need to ensure accurate measurements of the dose over the anticipated range. Typical target dose volumes are 5 ml or less for children under 5 years and 10 ml or less for children of 5 years and older (32). There is some uncertainty about these limits because the more palatable the formulation, the higher the dose volume that will be accepted by the child. Target volumes and electrolyte contents are critical for neonates, especially in cases of immature renal function.\n\nOral liquid preparations may be supplied in multidose containers or single-dose containers. Usually, both forms require antimicrobial preservatives. Special attention has to be paid to the in-use stability of multidose preparations, both microbial and physicochemical.\n\nMultidose preparations should be packaged together with an appropriate dosing device. The correct graduation of the device and the accuracy of the volumes measured must be checked by the manufacturer. Generally, oral syringes are preferable because of the flexibility in dose measurement and superior accuracy compared to other devices such as graduated pipettes or plastic spoons. The accuracy in measuring and delivering a volume of liquid is influenced by the liquid\u2019s physical characteristics, especially its viscosity.\n\nThe risks associated with incorrect dosing should be considered. If correct dosing is critical, a single-dose preparation, e.g. a pre-filled oral syringe, should be considered.\n\n## Drops\n\nSome liquids are administered as drops in small volumes using a dropper or a graduated pipette to measure a volume to be dissolved or dispersed in water or another diluent before the dose is swallowed. The use of this dosage form should be evaluated using a risk-based approach to ensure it is suitable given the medicine\u2019s potency and side-effect profile and the potential for dosing errors. The in-use performance of the dose-measuring device is critical for this dosage form.\n\n## Oral suspensions\n\nFormulation of an oral suspension may be dictated by the aqueous solubility of the API and the balance between the dose of API and the dose volume. In certain cases, the unpleasant taste of an API can be reduced by choosing the suspended form.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2645, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "43f63433-be30-45c9-976f-0cedf9f52860": {"__data__": {"id_": "43f63433-be30-45c9-976f-0cedf9f52860", "embedding": null, "metadata": {"page_label": "226", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nOral suspensions must be shaken before use to ensure a homogeneous liquid when the dose volume is measured. There might in some instances be a significant risk of dosing errors due to sedimentation or caking of the suspension during storage; therefore, resuspendability should be a stability parameter. The control strategy for oral suspensions includes dissolution testing (18) unless otherwise justified.\n\n## Powders and granules for reconstitution\n\nSolid preparations for reconstitution as solutions or suspensions should be considered, especially when the liquid preparation has a short shelf-life due to instability (chemical, physical or microbiological). Powders and granules for reconstitution are produced as single-dose sachets or multidose preparations, usually provided in containers that can hold the reconstituted multidose preparation. The liquid vehicle can be provided together with the dry preparation, especially when the product is intended for markets where access to clean water may be difficult. Alternatively, manufacturers can recommend on the product labels and summary of product characteristics (SmPCs) how to reconstitute the product, e.g. with boiled and cooled water.\n\nTo ensure their proper use, the solids must be easily wetted and dispersed or dissolved within a short time once the vehicle is added.\n\nThe major drawbacks of this type of formulation are the bulk volume of the preparation, i.e. it is less transportable, and the in-use microbial stability of multidose preparations, which may require use of antimicrobial agents. For these reasons, single-dose preparations of the flexible types mentioned in section 3.1 are preferable.\n\n## 6.2 Administration through feeding tubes\n\nFor neonates and seriously ill infants, enteral administration of liquids via feeding tubes is used. Hence the preparation will not be subject to the normal effects of saliva and/or gastric juice, which may affect its bioavailability.\n\nDosing accuracy should be considered, taking into account the ease of transfer along the feeding tube (including viscosity, particle size and amount of suspended components), potential absorption of the API into the tube material and rinsing by flushing of the tube. The rinsing volume should be appropriate to the target age group and an acceptable fluid intake.\n\nThese considerations should be highlighted in the SmPCs.\n\n## 6.3 Oral solid dosage forms\n\nOral solid dosage forms include a variety of final forms from powders to coated tablets intended to be swallowed directly or after application to the mouth (chewable tablets, orally dissolving tablets or orodispersible tablets). Some are...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Suspensiones orales**: Se requiere agitar las suspensiones orales antes de su uso para garantizar una mezcla homog\u00e9nea. La sedimentaci\u00f3n o el apelmazamiento durante el almacenamiento pueden causar errores de dosificaci\u00f3n, por lo que la capacidad de resuspensi\u00f3n es un par\u00e1metro de estabilidad importante. La estrategia de control incluye pruebas de disoluci\u00f3n.\n\n2. **Polvos y gr\u00e1nulos para reconstituci\u00f3n**: Las preparaciones s\u00f3lidas para reconstituci\u00f3n son \u00fatiles cuando las soluciones l\u00edquidas tienen una vida \u00fatil corta. Estas pueden presentarse en sachets de dosis \u00fanica o en preparaciones multidose. Es crucial que los s\u00f3lidos se humedezcan y se disuelvan r\u00e1pidamente al a\u00f1adir el veh\u00edculo.\n\n3. **Administraci\u00f3n a trav\u00e9s de tubos de alimentaci\u00f3n**: Para neonatos y beb\u00e9s gravemente enfermos, se utiliza la administraci\u00f3n enteral de l\u00edquidos a trav\u00e9s de tubos de alimentaci\u00f3n. Se deben considerar factores como la precisi\u00f3n de la dosificaci\u00f3n y la facilidad de transferencia a trav\u00e9s del tubo, as\u00ed como la absorci\u00f3n potencial del principio activo en el material del tubo.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfPor qu\u00e9 es importante la capacidad de resuspensi\u00f3n en las suspensiones orales y c\u00f3mo se relaciona con la estabilidad del producto?**\n   - La capacidad de resuspensi\u00f3n es crucial porque la sedimentaci\u00f3n o el apelmazamiento pueden llevar a errores de dosificaci\u00f3n. Esto se considera un par\u00e1metro de estabilidad, ya que asegura que el medicamento se administre en la dosis correcta.\n\n2. **\u00bfCu\u00e1les son las ventajas y desventajas de las preparaciones s\u00f3lidas para reconstituci\u00f3n en comparaci\u00f3n con las soluciones l\u00edquidas?**\n   - Las ventajas incluyen una mayor estabilidad y facilidad de transporte, especialmente en mercados con acceso limitado a agua limpia. Las desventajas son el volumen de preparaci\u00f3n m\u00e1s grande y la estabilidad microbiana en uso, que puede requerir agentes antimicrobianos.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al administrar medicamentos a trav\u00e9s de tubos de alimentaci\u00f3n en neonatos?**\n   - Se debe considerar la precisi\u00f3n de la dosificaci\u00f3n, la viscosidad del l\u00edquido, el tama\u00f1o de las part\u00edculas y la cantidad de componentes suspendidos. Tambi\u00e9n es importante tener en cuenta la absorci\u00f3n del principio activo en el material del tubo y el volumen de enjuague adecuado para el grupo de edad objetivo.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Preparaciones l\u00edquidas orales vs. s\u00f3lidas**: Las preparaciones l\u00edquidas orales son menos transportables debido a su mayor volumen. \n\n2. **Volumen de dosis**: \n   - Importancia del volumen de dosis para la aceptabilidad, especialmente en ni\u00f1os.\n   - Vol\u00famenes t\u00edpicos recomendados: 5 ml o menos para ni\u00f1os menores de 5 a\u00f1os y 10 ml o menos para ni\u00f1os de 5 a\u00f1os y mayores.\n   - La palatabilidad de la formulaci\u00f3n puede influir en la aceptaci\u00f3n del volumen de dosis.\n\n3. **Tipos de envases**: \n   - Preparaciones en envases multidose o de dosis \u00fanica, ambas requieren conservantes antimicrobianos.\n   - La estabilidad en uso de las preparaciones multidose es crucial.\n\n4. **Dispositivos de dosificaci\u00f3n**: \n   - Se recomienda el uso de jeringas orales por su precisi\u00f3n en la medici\u00f3n de dosis.\n   - La viscosidad del l\u00edquido afecta la precisi\u00f3n en la medici\u00f3n y entrega del volumen.\n\n5. **Riesgos de dosificaci\u00f3n incorrecta**: \n   - Se deben considerar los riesgos asociados con la dosificaci\u00f3n incorrecta; en casos cr\u00edticos, se sugiere el uso de preparaciones de dosis \u00fanica.\n\n6. **Formas de administraci\u00f3n**: \n   - **Gotas**: Se administran en peque\u00f1os vol\u00famenes y requieren una evaluaci\u00f3n basada en riesgos para evitar errores de dosificaci\u00f3n.\n   - **Suspensiones orales**: La formulaci\u00f3n puede depender de la solubilidad del principio activo y puede ayudar a enmascarar sabores desagradables.\n\n### Entidades mencionadas\n- **Ni\u00f1os**: Grupos de edad para los cuales se establecen vol\u00famenes de dosis.\n- **API (Ingrediente Activo)**: Referido en el contexto de formulaciones y suspensiones orales.\n- **Dispositivos de dosificaci\u00f3n**: Jeringas orales, pipetas graduadas, cucharas pl\u00e1sticas.\n- **Preparaciones**: L\u00edquidas orales, multidose, de dosis \u00fanica, gotas, suspensiones.", "excerpt_keywords": "Keywords: oral suspensions, reconstitution, feeding tubes, dosing accuracy, pharmaceutical preparations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1e2b685e-00f3-4cdb-8169-609db24d13b4", "node_type": "4", "metadata": {"page_label": "226", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nOral suspensions must be shaken before use to ensure a homogeneous liquid when the dose volume is measured. There might in some instances be a significant risk of dosing errors due to sedimentation or caking of the suspension during storage; therefore, resuspendability should be a stability parameter. The control strategy for oral suspensions includes dissolution testing (18) unless otherwise justified.\n\n## Powders and granules for reconstitution\n\nSolid preparations for reconstitution as solutions or suspensions should be considered, especially when the liquid preparation has a short shelf-life due to instability (chemical, physical or microbiological). Powders and granules for reconstitution are produced as single-dose sachets or multidose preparations, usually provided in containers that can hold the reconstituted multidose preparation. The liquid vehicle can be provided together with the dry preparation, especially when the product is intended for markets where access to clean water may be difficult. Alternatively, manufacturers can recommend on the product labels and summary of product characteristics (SmPCs) how to reconstitute the product, e.g. with boiled and cooled water.\n\nTo ensure their proper use, the solids must be easily wetted and dispersed or dissolved within a short time once the vehicle is added.\n\nThe major drawbacks of this type of formulation are the bulk volume of the preparation, i.e. it is less transportable, and the in-use microbial stability of multidose preparations, which may require use of antimicrobial agents. For these reasons, single-dose preparations of the flexible types mentioned in section 3.1 are preferable.\n\n## 6.2 Administration through feeding tubes\n\nFor neonates and seriously ill infants, enteral administration of liquids via feeding tubes is used. Hence the preparation will not be subject to the normal effects of saliva and/or gastric juice, which may affect its bioavailability.\n\nDosing accuracy should be considered, taking into account the ease of transfer along the feeding tube (including viscosity, particle size and amount of suspended components), potential absorption of the API into the tube material and rinsing by flushing of the tube. The rinsing volume should be appropriate to the target age group and an acceptable fluid intake.\n\nThese considerations should be highlighted in the SmPCs.\n\n## 6.3 Oral solid dosage forms\n\nOral solid dosage forms include a variety of final forms from powders to coated tablets intended to be swallowed directly or after application to the mouth (chewable tablets, orally dissolving tablets or orodispersible tablets). Some are...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "8014d8ecafc658c6c22f07118573d2a75470518b6a909dff4b869fa3b9ae8143", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nOral suspensions must be shaken before use to ensure a homogeneous liquid when the dose volume is measured. There might in some instances be a significant risk of dosing errors due to sedimentation or caking of the suspension during storage; therefore, resuspendability should be a stability parameter. The control strategy for oral suspensions includes dissolution testing (18) unless otherwise justified.\n\n## Powders and granules for reconstitution\n\nSolid preparations for reconstitution as solutions or suspensions should be considered, especially when the liquid preparation has a short shelf-life due to instability (chemical, physical or microbiological). Powders and granules for reconstitution are produced as single-dose sachets or multidose preparations, usually provided in containers that can hold the reconstituted multidose preparation. The liquid vehicle can be provided together with the dry preparation, especially when the product is intended for markets where access to clean water may be difficult. Alternatively, manufacturers can recommend on the product labels and summary of product characteristics (SmPCs) how to reconstitute the product, e.g. with boiled and cooled water.\n\nTo ensure their proper use, the solids must be easily wetted and dispersed or dissolved within a short time once the vehicle is added.\n\nThe major drawbacks of this type of formulation are the bulk volume of the preparation, i.e. it is less transportable, and the in-use microbial stability of multidose preparations, which may require use of antimicrobial agents. For these reasons, single-dose preparations of the flexible types mentioned in section 3.1 are preferable.\n\n## 6.2 Administration through feeding tubes\n\nFor neonates and seriously ill infants, enteral administration of liquids via feeding tubes is used. Hence the preparation will not be subject to the normal effects of saliva and/or gastric juice, which may affect its bioavailability.\n\nDosing accuracy should be considered, taking into account the ease of transfer along the feeding tube (including viscosity, particle size and amount of suspended components), potential absorption of the API into the tube material and rinsing by flushing of the tube. The rinsing volume should be appropriate to the target age group and an acceptable fluid intake.\n\nThese considerations should be highlighted in the SmPCs.\n\n## 6.3 Oral solid dosage forms\n\nOral solid dosage forms include a variety of final forms from powders to coated tablets intended to be swallowed directly or after application to the mouth (chewable tablets, orally dissolving tablets or orodispersible tablets). Some are...", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2722, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "68b81cbb-710f-4d23-8d96-172d14f25492": {"__data__": {"id_": "68b81cbb-710f-4d23-8d96-172d14f25492", "embedding": null, "metadata": {"page_label": "227", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "intended for swallowing after dissolution, dispersion in water or other suitable liquids. Their advantages over oral liquid preparations are improved stability, good dosage uniformity and options for different doses. The ease of administration depends on the child and the particular dosage form. These forms are convenient for packaging and ease of transport.\n\nWhile powders and multiparticulate preparations mixed with food or beverages may be acceptable from the moment when the infant is able to accept solid food, i.e. about 6 months, there are uncertainties with regard to the age at which intact tablets and capsules are acceptable. It has been thought generally that even small tablets and capsules to be taken whole are not acceptable for children below the age of 6 years. However, no good scientific evidence exists to support this notion. Recent preliminary evidence indicates that mini-tablets (with a diameter of less than 4 mm) may be acceptable even by the majority of small children (2\u20134 years old) (33).\n\n### Powders and multiparticulate preparations\n\nPowders and multiparticulates are provided in sachets or in hard capsules that allow the contents to be taken directly or after manipulation, e.g. following preparation of oral liquids or to be sprinkled on to food or liquids.\n\nMultiparticulate preparations are granules, rounded granules of uniform size (often called pellets) and mini-tablets. Pellets are often prepared by extrusion/spheronization technology, which produces uniform particles within the size range 0.5\u20132 mm. Mini-tablets are prepared by compression into units with a diameter of not more than 4 mm. Especially when only a portion of the provided dose is administered, the particle size distribution of the API may be critical to dosing accuracy. Control of dose uniformity should be performed on a level corresponding to the dose to be taken by the target age group.\n\nMultiparticulate preparations offer the same advantages as conventional tablets and capsules with regard to the use of excipients, opportunities for taste masking (e.g. by coating), stability and opportunities for modifying the release profile. Furthermore, they possess great flexibility. An age-related dose may be obtained by taking an appropriate number of pellets or mini-tablets. A counting device may be necessary when a large number of pellets or mini-tablets is required. In addition, pellets and mini-tablets are suited for the platform technology mentioned in section 3.2.\n\n### Immediate-release tablets\n\nConventional tablets are either uncoated, film-coated or sugar-coated and are intended for immediate disintegration, release and absorption when swallowed. The coating may cover an unpleasant taste and smell and will, in general, improve palatability. Film-coating is preferable because sugar-coated tablets resemble", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Formas de dosificaci\u00f3n para ni\u00f1os**: El texto discute las diferentes formas de dosificaci\u00f3n de medicamentos para ni\u00f1os, destacando las ventajas de los polvos y preparaciones multiparticuladas en comparaci\u00f3n con las tabletas y c\u00e1psulas. Se menciona la aceptaci\u00f3n de estas formas de dosificaci\u00f3n en funci\u00f3n de la edad del ni\u00f1o y su capacidad para tragar.\n\n2. **Preparaciones multiparticuladas**: Se describen las caracter\u00edsticas de las preparaciones multiparticuladas, como los pellets y mini-tabletas, y se enfatiza su flexibilidad en la dosificaci\u00f3n, as\u00ed como su capacidad para mejorar la estabilidad y la palatabilidad del medicamento.\n\n3. **Tabletas de liberaci\u00f3n inmediata**: Se aborda la formulaci\u00f3n de tabletas convencionales, que pueden ser recubiertas o no, y su prop\u00f3sito de desintegrarse y absorberse r\u00e1pidamente al ser ingeridas. Se menciona la importancia del recubrimiento para mejorar el sabor y la experiencia del paciente.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 evidencia reciente sugiere sobre la aceptaci\u00f3n de mini-tabletas en ni\u00f1os de 2 a 4 a\u00f1os?**\n   - La evidencia preliminar indica que las mini-tabletas, con un di\u00e1metro de menos de 4 mm, pueden ser aceptables para la mayor\u00eda de los ni\u00f1os peque\u00f1os de 2 a 4 a\u00f1os, a pesar de la creencia general de que las tabletas y c\u00e1psulas enteras no son adecuadas para ni\u00f1os menores de 6 a\u00f1os.\n\n2. **\u00bfCu\u00e1les son las ventajas de las preparaciones multiparticuladas en comparaci\u00f3n con las tabletas convencionales?**\n   - Las preparaciones multiparticuladas ofrecen ventajas como una mejor uniformidad de dosis, opciones para enmascarar sabores, estabilidad y flexibilidad en la dosificaci\u00f3n, permitiendo que se tomen diferentes cantidades de pellets o mini-tabletas seg\u00fan la edad del ni\u00f1o.\n\n3. **\u00bfQu\u00e9 tecnolog\u00edas se utilizan para la fabricaci\u00f3n de pellets y mini-tabletas?**\n   - Los pellets se preparan a menudo mediante tecnolog\u00eda de extrusi\u00f3n/esferonizaci\u00f3n, que produce part\u00edculas uniformes en el rango de tama\u00f1o de 0.5 a 2 mm, mientras que las mini-tabletas se fabrican mediante compresi\u00f3n en unidades con un di\u00e1metro no mayor de 4 mm.", "prev_section_summary": "### Temas Clave\n\n1. **Suspensiones Orales**: \n   - Importancia de agitar antes de usar para asegurar homogeneidad.\n   - Riesgo de errores de dosificaci\u00f3n por sedimentaci\u00f3n o apelmazamiento.\n   - La capacidad de resuspensi\u00f3n es un par\u00e1metro de estabilidad.\n   - Estrategia de control incluye pruebas de disoluci\u00f3n.\n\n2. **Polvos y Gr\u00e1nulos para Reconstituci\u00f3n**:\n   - \u00datiles cuando las soluciones l\u00edquidas tienen una vida \u00fatil corta.\n   - Presentaci\u00f3n en sachets de dosis \u00fanica o preparaciones multidose.\n   - Necesidad de que los s\u00f3lidos se humedezcan y disuelvan r\u00e1pidamente.\n   - Desventajas incluyen mayor volumen y estabilidad microbiana en uso.\n\n3. **Administraci\u00f3n a trav\u00e9s de Tubos de Alimentaci\u00f3n**:\n   - Uso en neonatos y beb\u00e9s gravemente enfermos.\n   - Consideraciones sobre precisi\u00f3n de dosificaci\u00f3n y facilidad de transferencia.\n   - Importancia de la viscosidad, tama\u00f1o de part\u00edculas y absorci\u00f3n del principio activo en el material del tubo.\n   - Volumen de enjuague debe ser adecuado para el grupo de edad objetivo.\n\n### Entidades\n\n- **WHO Expert Committee on Specifications for Pharmaceutical Preparations**: Organizaci\u00f3n responsable de las directrices.\n- **Suspensiones orales**: Formulaci\u00f3n l\u00edquida que requiere agitaci\u00f3n.\n- **Polvos y gr\u00e1nulos**: Preparaciones s\u00f3lidas para reconstituci\u00f3n.\n- **Tubos de alimentaci\u00f3n**: M\u00e9todo de administraci\u00f3n enteral para neonatos y beb\u00e9s.\n- **SmPCs (Resumen de Caracter\u00edsticas del Producto)**: Documentos que deben incluir consideraciones sobre la administraci\u00f3n y reconstituci\u00f3n.\n\nEste resumen destaca los aspectos esenciales de la secci\u00f3n, enfoc\u00e1ndose en la importancia de la estabilidad y la administraci\u00f3n adecuada de medicamentos en diferentes formas.", "excerpt_keywords": "Keywords: pediatric dosage forms, multiparticulate preparations, mini-tablets, immediate-release tablets, dosage uniformity"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "955c98ab-f764-4d88-8bd6-4816f04d161e", "node_type": "4", "metadata": {"page_label": "227", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "intended for swallowing after dissolution, dispersion in water or other suitable liquids. Their advantages over oral liquid preparations are improved stability, good dosage uniformity and options for different doses. The ease of administration depends on the child and the particular dosage form. These forms are convenient for packaging and ease of transport.\n\nWhile powders and multiparticulate preparations mixed with food or beverages may be acceptable from the moment when the infant is able to accept solid food, i.e. about 6 months, there are uncertainties with regard to the age at which intact tablets and capsules are acceptable. It has been thought generally that even small tablets and capsules to be taken whole are not acceptable for children below the age of 6 years. However, no good scientific evidence exists to support this notion. Recent preliminary evidence indicates that mini-tablets (with a diameter of less than 4 mm) may be acceptable even by the majority of small children (2\u20134 years old) (33).\n\n### Powders and multiparticulate preparations\n\nPowders and multiparticulates are provided in sachets or in hard capsules that allow the contents to be taken directly or after manipulation, e.g. following preparation of oral liquids or to be sprinkled on to food or liquids.\n\nMultiparticulate preparations are granules, rounded granules of uniform size (often called pellets) and mini-tablets. Pellets are often prepared by extrusion/spheronization technology, which produces uniform particles within the size range 0.5\u20132 mm. Mini-tablets are prepared by compression into units with a diameter of not more than 4 mm. Especially when only a portion of the provided dose is administered, the particle size distribution of the API may be critical to dosing accuracy. Control of dose uniformity should be performed on a level corresponding to the dose to be taken by the target age group.\n\nMultiparticulate preparations offer the same advantages as conventional tablets and capsules with regard to the use of excipients, opportunities for taste masking (e.g. by coating), stability and opportunities for modifying the release profile. Furthermore, they possess great flexibility. An age-related dose may be obtained by taking an appropriate number of pellets or mini-tablets. A counting device may be necessary when a large number of pellets or mini-tablets is required. In addition, pellets and mini-tablets are suited for the platform technology mentioned in section 3.2.\n\n### Immediate-release tablets\n\nConventional tablets are either uncoated, film-coated or sugar-coated and are intended for immediate disintegration, release and absorption when swallowed. The coating may cover an unpleasant taste and smell and will, in general, improve palatability. Film-coating is preferable because sugar-coated tablets resemble", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "deb7e56209b0b12d49f9352b52fa6b6956d9b10bd0ae9d79505e4a6f8562daad", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "intended for swallowing after dissolution, dispersion in water or other suitable liquids. Their advantages over oral liquid preparations are improved stability, good dosage uniformity and options for different doses. The ease of administration depends on the child and the particular dosage form. These forms are convenient for packaging and ease of transport.\n\nWhile powders and multiparticulate preparations mixed with food or beverages may be acceptable from the moment when the infant is able to accept solid food, i.e. about 6 months, there are uncertainties with regard to the age at which intact tablets and capsules are acceptable. It has been thought generally that even small tablets and capsules to be taken whole are not acceptable for children below the age of 6 years. However, no good scientific evidence exists to support this notion. Recent preliminary evidence indicates that mini-tablets (with a diameter of less than 4 mm) may be acceptable even by the majority of small children (2\u20134 years old) (33).\n\n### Powders and multiparticulate preparations\n\nPowders and multiparticulates are provided in sachets or in hard capsules that allow the contents to be taken directly or after manipulation, e.g. following preparation of oral liquids or to be sprinkled on to food or liquids.\n\nMultiparticulate preparations are granules, rounded granules of uniform size (often called pellets) and mini-tablets. Pellets are often prepared by extrusion/spheronization technology, which produces uniform particles within the size range 0.5\u20132 mm. Mini-tablets are prepared by compression into units with a diameter of not more than 4 mm. Especially when only a portion of the provided dose is administered, the particle size distribution of the API may be critical to dosing accuracy. Control of dose uniformity should be performed on a level corresponding to the dose to be taken by the target age group.\n\nMultiparticulate preparations offer the same advantages as conventional tablets and capsules with regard to the use of excipients, opportunities for taste masking (e.g. by coating), stability and opportunities for modifying the release profile. Furthermore, they possess great flexibility. An age-related dose may be obtained by taking an appropriate number of pellets or mini-tablets. A counting device may be necessary when a large number of pellets or mini-tablets is required. In addition, pellets and mini-tablets are suited for the platform technology mentioned in section 3.2.\n\n### Immediate-release tablets\n\nConventional tablets are either uncoated, film-coated or sugar-coated and are intended for immediate disintegration, release and absorption when swallowed. The coating may cover an unpleasant taste and smell and will, in general, improve palatability. Film-coating is preferable because sugar-coated tablets resemble", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2840, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "490f2c1a-52fc-43c2-85a4-b8b102f119cc": {"__data__": {"id_": "490f2c1a-52fc-43c2-85a4-b8b102f119cc", "embedding": null, "metadata": {"page_label": "228", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsweets or candies and hence may be too attractive to the child. It is critical to differentiate the appearance of tablet packs from that of confectionery packs.\n\nBreak-marks intended to enable accurate subdivision of the tablet to provide doses of less than one tablet should be proven to result in parts that comply with the requirements for uniformity of mass or uniformity of content, as appropriate. The decision whether or not to provide scored tablets will depend on a risk analysis, taking into account the safety and dose of the API. A suitable test is provided in the monograph on tablets in *The International Pharmacopoeia* (34). It is preferable that the single part of the broken tablet contains the amount of API suited to the youngest intended age group. Specially designed tablets and tablet punches may be needed.\n\nCaregivers often crush tablets to increase user-friendliness and adherence. Crushing may, however, affect the bioavailability of some medicines. The effect of crushing of tablets should be investigated by the manufacturer and this information should be provided in the patient information leaflet.\n\nTablets should not be crushed unless instructions allowing crushing are provided on the label by the manufacturer. Generally a multiparticulate formulation supplied in sachets, hard capsules or blister packs is preferred.\n\n## Chewable tablets\n\nChewable tablets are intended to be chewed and swallowed. They should possess good organoleptic properties including a good mouth feel, which is influenced by the solubility, particle size and shape of the API, and they should not leave a bitter or unpleasant aftertaste. They are usually formulated with a high content of a water-soluble sweetener, such as mannitol, which provides a sweet, cooling taste, and microcrystalline cellulose, which assists in obtaining a good mouth feel and reduces grittiness. Other sweetening agents such as sorbitol and xylitol suitable for direct compression are also used.\n\nA potential problem with chewable tablets is that they may be swallowed by a patient before being properly chewed or without being chewed at all. It is, therefore, strongly recommended that chewable tablets are formulated so that they may be swallowed whole and, thus, labelled as \u201ctablets that may be chewed or swallowed whole\u201d, or \u201ctablets that may be chewed, swallowed or crushed and mixed with food or liquid\u201d.\n\nIt is a consequence of the above that tablets that may be chewed or swallowed whole should meet the quality requirements for conventional tablets, including dissolution testing. Where applicable, dissolution test conditions should be the same as used for conventional tablets of the same API, but because of their non-disintegrating nature it may be necessary to alter the test conditions (18).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Diferenciaci\u00f3n de envases**: Es crucial que los envases de tabletas se diferencien claramente de los de golosinas para evitar que los ni\u00f1os los confundan y los ingieran accidentalmente.\n\n2. **Importancia de las marcas de ruptura**: Las tabletas con marcas de ruptura deben demostrar que las partes resultantes cumplen con los requisitos de uniformidad de masa o contenido, y su dise\u00f1o debe considerar la dosis adecuada para los grupos de edad m\u00e1s j\u00f3venes.\n\n3. **Consideraciones sobre la trituraci\u00f3n de tabletas**: La trituraci\u00f3n de tabletas puede afectar la biodisponibilidad de algunos medicamentos, por lo que los fabricantes deben investigar este efecto y proporcionar instrucciones claras en el etiquetado.\n\n4. **Propiedades de las tabletas masticables**: Las tabletas masticables deben tener buenas propiedades organol\u00e9pticas y ser formuladas para que puedan ser tragadas enteras, adem\u00e1s de cumplir con los requisitos de calidad de las tabletas convencionales.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 criterios deben cumplirse para que las tabletas con marcas de ruptura sean consideradas seguras para su uso en ni\u00f1os?**\n   - Las tabletas con marcas de ruptura deben demostrar que las partes resultantes cumplen con los requisitos de uniformidad de masa o contenido, y es preferible que cada parte contenga la dosis adecuada para el grupo de edad m\u00e1s joven.\n\n2. **\u00bfCu\u00e1les son las recomendaciones para el etiquetado de tabletas masticables en relaci\u00f3n con su consumo?**\n   - Se recomienda que las tabletas masticables sean etiquetadas como \"tabletas que pueden ser masticadas o tragadas enteras\" o \"tabletas que pueden ser masticadas, tragadas o trituradas y mezcladas con alimentos o l\u00edquidos\".\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe proporcionar el fabricante sobre la trituraci\u00f3n de tabletas y su efecto en la biodisponibilidad?**\n   - El fabricante debe investigar el efecto de la trituraci\u00f3n en la biodisponibilidad de las tabletas y proporcionar esta informaci\u00f3n en el prospecto del paciente, adem\u00e1s de indicar si la trituraci\u00f3n est\u00e1 permitida en la etiqueta.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Formas de dosificaci\u00f3n para ni\u00f1os**:\n   - Se discuten las ventajas de los polvos y preparaciones multiparticuladas en comparaci\u00f3n con tabletas y c\u00e1psulas.\n   - La aceptaci\u00f3n de estas formas de dosificaci\u00f3n var\u00eda seg\u00fan la edad del ni\u00f1o y su capacidad para tragar.\n\n2. **Preparaciones multiparticuladas**:\n   - Incluyen granulos (pellets) y mini-tabletas, que son flexibles en t\u00e9rminos de dosificaci\u00f3n.\n   - Se preparan mediante tecnolog\u00edas como extrusi\u00f3n/esferonizaci\u00f3n y compresi\u00f3n.\n   - Ofrecen beneficios como estabilidad, enmascaramiento de sabores y uniformidad de dosis.\n\n3. **Tabletas de liberaci\u00f3n inmediata**:\n   - Pueden ser recubiertas o no, y est\u00e1n dise\u00f1adas para desintegrarse y absorberse r\u00e1pidamente.\n   - El recubrimiento mejora la palatabilidad al ocultar sabores y olores desagradables.\n\n### Entidades clave:\n- **Polvos y preparaciones multiparticuladas**: Formas de dosificaci\u00f3n que pueden mezclarse con alimentos o l\u00edquidos.\n- **Mini-tabletas**: Tabletas peque\u00f1as (menos de 4 mm) que pueden ser aceptables para ni\u00f1os de 2 a 4 a\u00f1os.\n- **Pellets**: Granulos uniformes (0.5\u20132 mm) producidos por tecnolog\u00eda de extrusi\u00f3n/esferonizaci\u00f3n.\n- **Tabletas convencionales**: Pueden ser uncoated, film-coated o sugar-coated, dise\u00f1adas para liberaci\u00f3n inmediata.\n\n### Preguntas espec\u00edficas:\n1. **Evidencia sobre mini-tabletas**: Se sugiere que pueden ser aceptables para ni\u00f1os de 2 a 4 a\u00f1os.\n2. **Ventajas de las preparaciones multiparticuladas**: Mejoran la uniformidad de dosis, estabilidad y permiten enmascarar sabores.\n3. **Tecnolog\u00edas de fabricaci\u00f3n**: Extrusi\u00f3n/esferonizaci\u00f3n para pellets y compresi\u00f3n para mini-tabletas.", "excerpt_keywords": "Keywords: pharmaceutical preparations, chewable tablets, bioavailability, tablet scoring, pediatric dosing"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "960f118c-b23f-4594-a50e-827d891217d3", "node_type": "4", "metadata": {"page_label": "228", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsweets or candies and hence may be too attractive to the child. It is critical to differentiate the appearance of tablet packs from that of confectionery packs.\n\nBreak-marks intended to enable accurate subdivision of the tablet to provide doses of less than one tablet should be proven to result in parts that comply with the requirements for uniformity of mass or uniformity of content, as appropriate. The decision whether or not to provide scored tablets will depend on a risk analysis, taking into account the safety and dose of the API. A suitable test is provided in the monograph on tablets in *The International Pharmacopoeia* (34). It is preferable that the single part of the broken tablet contains the amount of API suited to the youngest intended age group. Specially designed tablets and tablet punches may be needed.\n\nCaregivers often crush tablets to increase user-friendliness and adherence. Crushing may, however, affect the bioavailability of some medicines. The effect of crushing of tablets should be investigated by the manufacturer and this information should be provided in the patient information leaflet.\n\nTablets should not be crushed unless instructions allowing crushing are provided on the label by the manufacturer. Generally a multiparticulate formulation supplied in sachets, hard capsules or blister packs is preferred.\n\n## Chewable tablets\n\nChewable tablets are intended to be chewed and swallowed. They should possess good organoleptic properties including a good mouth feel, which is influenced by the solubility, particle size and shape of the API, and they should not leave a bitter or unpleasant aftertaste. They are usually formulated with a high content of a water-soluble sweetener, such as mannitol, which provides a sweet, cooling taste, and microcrystalline cellulose, which assists in obtaining a good mouth feel and reduces grittiness. Other sweetening agents such as sorbitol and xylitol suitable for direct compression are also used.\n\nA potential problem with chewable tablets is that they may be swallowed by a patient before being properly chewed or without being chewed at all. It is, therefore, strongly recommended that chewable tablets are formulated so that they may be swallowed whole and, thus, labelled as \u201ctablets that may be chewed or swallowed whole\u201d, or \u201ctablets that may be chewed, swallowed or crushed and mixed with food or liquid\u201d.\n\nIt is a consequence of the above that tablets that may be chewed or swallowed whole should meet the quality requirements for conventional tablets, including dissolution testing. Where applicable, dissolution test conditions should be the same as used for conventional tablets of the same API, but because of their non-disintegrating nature it may be necessary to alter the test conditions (18).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "6b5661cb44939e848f9bb61f7591633df68f411966206af1d09c524815478fef", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsweets or candies and hence may be too attractive to the child. It is critical to differentiate the appearance of tablet packs from that of confectionery packs.\n\nBreak-marks intended to enable accurate subdivision of the tablet to provide doses of less than one tablet should be proven to result in parts that comply with the requirements for uniformity of mass or uniformity of content, as appropriate. The decision whether or not to provide scored tablets will depend on a risk analysis, taking into account the safety and dose of the API. A suitable test is provided in the monograph on tablets in *The International Pharmacopoeia* (34). It is preferable that the single part of the broken tablet contains the amount of API suited to the youngest intended age group. Specially designed tablets and tablet punches may be needed.\n\nCaregivers often crush tablets to increase user-friendliness and adherence. Crushing may, however, affect the bioavailability of some medicines. The effect of crushing of tablets should be investigated by the manufacturer and this information should be provided in the patient information leaflet.\n\nTablets should not be crushed unless instructions allowing crushing are provided on the label by the manufacturer. Generally a multiparticulate formulation supplied in sachets, hard capsules or blister packs is preferred.\n\n## Chewable tablets\n\nChewable tablets are intended to be chewed and swallowed. They should possess good organoleptic properties including a good mouth feel, which is influenced by the solubility, particle size and shape of the API, and they should not leave a bitter or unpleasant aftertaste. They are usually formulated with a high content of a water-soluble sweetener, such as mannitol, which provides a sweet, cooling taste, and microcrystalline cellulose, which assists in obtaining a good mouth feel and reduces grittiness. Other sweetening agents such as sorbitol and xylitol suitable for direct compression are also used.\n\nA potential problem with chewable tablets is that they may be swallowed by a patient before being properly chewed or without being chewed at all. It is, therefore, strongly recommended that chewable tablets are formulated so that they may be swallowed whole and, thus, labelled as \u201ctablets that may be chewed or swallowed whole\u201d, or \u201ctablets that may be chewed, swallowed or crushed and mixed with food or liquid\u201d.\n\nIt is a consequence of the above that tablets that may be chewed or swallowed whole should meet the quality requirements for conventional tablets, including dissolution testing. Where applicable, dissolution test conditions should be the same as used for conventional tablets of the same API, but because of their non-disintegrating nature it may be necessary to alter the test conditions (18).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2868, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "7a2a08bf-5aa0-451e-a83c-461cbb14785d": {"__data__": {"id_": "7a2a08bf-5aa0-451e-a83c-461cbb14785d", "embedding": null, "metadata": {"page_label": "229", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Effervescent Dosage Forms\n\nEffervescent dosage forms are tablets, granules or powders that are dissolved in water prior to administration. The use of these dosage forms usually requires a relatively large volume of water, the intake of which may be problematic for children. It is helpful when an indication of the minimum volume of water is given on the label. Furthermore, the label should give instructions that the solution is not to be drunk before effervescence has subsided, in order to minimize ingestion of hydrogen carbonate. Effervescent tablets require continuous attention to levels of moisture and humidity during manufacture, packaging and storage.\n\nThe drawbacks of effervescent dosage forms are the need for clean water for dissolution and the ingestion of potassium or sodium, which may make them unsuitable for patients with renal insufficiency.\n\n# Dispersible and Soluble Tablets\n\nDispersible and soluble tablets are intended to be used in the same way as effervescent tablets. Their advantage is that problems with hydrogen carbonate, potassium and sodium are avoided. For the convenience of users, the formulations should disintegrate or dissolve within a short time of being added to water. It is helpful when an indication of the minimum volume of water is provided on the label.\n\nDispersible and soluble tablets are flexible dosage forms, the formulation of which may be suited for several water-soluble APIs (see section 3.1).\n\n# Sustained-release Formulations\n\nSustained-release formulations are designed to slow the rate of release of the API in the gastrointestinal fluids. They may be provided in a variety of formulations, e.g. as multiparticulate solids provided with a barrier coating, in sachets, hard capsules or in quickly disintegrating tablets, coated tablets and matrix tablets. Among the advantages of the sustained-release design is the reduced dosing frequency compared to conventional formulations of the same API, a feature which may improve adherence (see section 2.3). Not all APIs can be formulated as sustained-release products. This will also depend on other factors such as aqueous solubility, intestinal permeability and plasma elimination half-life, which may differ between children and adults.\n\nIn the development of sustained-release formulations for paediatric use, special attention must be given to the physiological conditions of the child to be treated and their variability, e.g. gastric pH and emptying rate and intestinal mobility.\n\nThe majority of sustained-release formulations, especially coated tablets and matrix tablets, must not be broken or chewed and some will not withstand being mixed with food or a beverage. It is, therefore, vital that clear instructions on the proper use of the formulation are included on the label.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas basadas en el contexto proporcionado, junto con sus respuestas:\n\n1. **\u00bfCu\u00e1les son las consideraciones importantes al usar formas de dosificaci\u00f3n efervescentes en ni\u00f1os?**\n   - Las formas de dosificaci\u00f3n efervescentes requieren un volumen relativamente grande de agua para su disoluci\u00f3n, lo que puede ser problem\u00e1tico para los ni\u00f1os. Adem\u00e1s, es importante que el etiquetado indique el volumen m\u00ednimo de agua necesario y que se instruya a no beber la soluci\u00f3n antes de que la efervescencia haya cesado, para minimizar la ingesti\u00f3n de bicarbonato de hidr\u00f3geno.\n\n2. **\u00bfQu\u00e9 ventajas ofrecen las tabletas dispersables y solubles en comparaci\u00f3n con las efervescentes?**\n   - Las tabletas dispersables y solubles evitan los problemas asociados con el bicarbonato de hidr\u00f3geno, el potasio y el sodio, lo que las hace m\u00e1s adecuadas para pacientes con insuficiencia renal. Adem\u00e1s, estas tabletas deben disolverse o desintegrarse r\u00e1pidamente al ser a\u00f1adidas al agua, lo que mejora la conveniencia para el usuario.\n\n3. **\u00bfQu\u00e9 factores deben considerarse al desarrollar formulaciones de liberaci\u00f3n sostenida para uso pedi\u00e1trico?**\n   - En el desarrollo de formulaciones de liberaci\u00f3n sostenida para ni\u00f1os, es crucial considerar las condiciones fisiol\u00f3gicas del ni\u00f1o, como el pH g\u00e1strico, la tasa de vaciamiento y la movilidad intestinal, ya que estas pueden variar significativamente entre ni\u00f1os y adultos. Adem\u00e1s, no todas las sustancias activas pueden ser formuladas como productos de liberaci\u00f3n sostenida, lo que depende de factores como la solubilidad acuosa y la permeabilidad intestinal.\n\n### Resumen de nivel superior del contexto:\nEl documento aborda diferentes formas de dosificaci\u00f3n, incluyendo efervescentes, dispersables, solubles y de liberaci\u00f3n sostenida. Se discuten las ventajas y desventajas de cada tipo, especialmente en relaci\u00f3n con su uso en ni\u00f1os y pacientes con condiciones espec\u00edficas como insuficiencia renal. Se enfatiza la importancia de proporcionar instrucciones claras en el etiquetado para asegurar un uso adecuado y seguro de estas formulaciones.", "prev_section_summary": "### Temas Clave\n\n1. **Diferenciaci\u00f3n de Envases**: Es fundamental que los envases de tabletas sean claramente distintos de los de golosinas para prevenir confusiones y posibles ingestas accidentales por parte de los ni\u00f1os.\n\n2. **Marcas de Ruptura en Tabletas**: Las tabletas con marcas de ruptura deben demostrar que las partes resultantes cumplen con los est\u00e1ndares de uniformidad de masa o contenido. La decisi\u00f3n de incluir estas marcas debe basarse en un an\u00e1lisis de riesgo, considerando la seguridad y la dosis del principio activo (API).\n\n3. **Impacto de la Trituraci\u00f3n de Tabletas**: La trituraci\u00f3n de tabletas puede alterar la biodisponibilidad de ciertos medicamentos. Los fabricantes deben investigar este efecto y proporcionar informaci\u00f3n clara en el prospecto del paciente sobre si la trituraci\u00f3n est\u00e1 permitida.\n\n4. **Propiedades de las Tabletas Masticables**: Estas tabletas deben tener buenas propiedades organol\u00e9pticas y ser formuladas para que puedan ser tragadas enteras. Deben cumplir con los requisitos de calidad de las tabletas convencionales, incluyendo pruebas de disoluci\u00f3n.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable del documento.\n- **API (Principio Activo)**: Sustancia en los medicamentos que produce el efecto terap\u00e9utico.\n- **Mannitol, Sorbitol, Xylitol**: Edulcorantes utilizados en la formulaci\u00f3n de tabletas masticables.\n- **Microcrystalline Cellulose**: Compuesto que mejora la textura y reduce la arenosidad en tabletas.\n- **The International Pharmacopoeia**: Referencia mencionada para pruebas y est\u00e1ndares de tabletas.\n\n### Resumen\n\nLa secci\u00f3n aborda la importancia de diferenciar los envases de tabletas de los de golosinas para evitar confusiones en ni\u00f1os. Se discuten las marcas de ruptura en tabletas, enfatizando que deben cumplir con est\u00e1ndares de uniformidad y ser seguras para los grupos de edad m\u00e1s j\u00f3venes. Tambi\u00e9n se menciona que la trituraci\u00f3n de tabletas puede afectar la biodisponibilidad y que los fabricantes deben proporcionar instrucciones claras al respecto. Finalmente, se describen las caracter\u00edsticas de las tabletas masticables, que deben ser agradables al paladar y permitir ser tragadas enteras, cumpliendo con los requisitos de calidad de las tabletas convencionales.", "excerpt_keywords": "Effervescent, Dispersible, Sustained-release, Pediatric, Dosage forms"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1b908ea7-a8d8-479b-95b9-3a2cb3852110", "node_type": "4", "metadata": {"page_label": "229", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Effervescent Dosage Forms\n\nEffervescent dosage forms are tablets, granules or powders that are dissolved in water prior to administration. The use of these dosage forms usually requires a relatively large volume of water, the intake of which may be problematic for children. It is helpful when an indication of the minimum volume of water is given on the label. Furthermore, the label should give instructions that the solution is not to be drunk before effervescence has subsided, in order to minimize ingestion of hydrogen carbonate. Effervescent tablets require continuous attention to levels of moisture and humidity during manufacture, packaging and storage.\n\nThe drawbacks of effervescent dosage forms are the need for clean water for dissolution and the ingestion of potassium or sodium, which may make them unsuitable for patients with renal insufficiency.\n\n# Dispersible and Soluble Tablets\n\nDispersible and soluble tablets are intended to be used in the same way as effervescent tablets. Their advantage is that problems with hydrogen carbonate, potassium and sodium are avoided. For the convenience of users, the formulations should disintegrate or dissolve within a short time of being added to water. It is helpful when an indication of the minimum volume of water is provided on the label.\n\nDispersible and soluble tablets are flexible dosage forms, the formulation of which may be suited for several water-soluble APIs (see section 3.1).\n\n# Sustained-release Formulations\n\nSustained-release formulations are designed to slow the rate of release of the API in the gastrointestinal fluids. They may be provided in a variety of formulations, e.g. as multiparticulate solids provided with a barrier coating, in sachets, hard capsules or in quickly disintegrating tablets, coated tablets and matrix tablets. Among the advantages of the sustained-release design is the reduced dosing frequency compared to conventional formulations of the same API, a feature which may improve adherence (see section 2.3). Not all APIs can be formulated as sustained-release products. This will also depend on other factors such as aqueous solubility, intestinal permeability and plasma elimination half-life, which may differ between children and adults.\n\nIn the development of sustained-release formulations for paediatric use, special attention must be given to the physiological conditions of the child to be treated and their variability, e.g. gastric pH and emptying rate and intestinal mobility.\n\nThe majority of sustained-release formulations, especially coated tablets and matrix tablets, must not be broken or chewed and some will not withstand being mixed with food or a beverage. It is, therefore, vital that clear instructions on the proper use of the formulation are included on the label.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "0bbc42823f1b9228b5252aab63bceed827bb7ac22ff26ca7220947e35b785308", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Effervescent Dosage Forms\n\nEffervescent dosage forms are tablets, granules or powders that are dissolved in water prior to administration. The use of these dosage forms usually requires a relatively large volume of water, the intake of which may be problematic for children. It is helpful when an indication of the minimum volume of water is given on the label. Furthermore, the label should give instructions that the solution is not to be drunk before effervescence has subsided, in order to minimize ingestion of hydrogen carbonate. Effervescent tablets require continuous attention to levels of moisture and humidity during manufacture, packaging and storage.\n\nThe drawbacks of effervescent dosage forms are the need for clean water for dissolution and the ingestion of potassium or sodium, which may make them unsuitable for patients with renal insufficiency.\n\n# Dispersible and Soluble Tablets\n\nDispersible and soluble tablets are intended to be used in the same way as effervescent tablets. Their advantage is that problems with hydrogen carbonate, potassium and sodium are avoided. For the convenience of users, the formulations should disintegrate or dissolve within a short time of being added to water. It is helpful when an indication of the minimum volume of water is provided on the label.\n\nDispersible and soluble tablets are flexible dosage forms, the formulation of which may be suited for several water-soluble APIs (see section 3.1).\n\n# Sustained-release Formulations\n\nSustained-release formulations are designed to slow the rate of release of the API in the gastrointestinal fluids. They may be provided in a variety of formulations, e.g. as multiparticulate solids provided with a barrier coating, in sachets, hard capsules or in quickly disintegrating tablets, coated tablets and matrix tablets. Among the advantages of the sustained-release design is the reduced dosing frequency compared to conventional formulations of the same API, a feature which may improve adherence (see section 2.3). Not all APIs can be formulated as sustained-release products. This will also depend on other factors such as aqueous solubility, intestinal permeability and plasma elimination half-life, which may differ between children and adults.\n\nIn the development of sustained-release formulations for paediatric use, special attention must be given to the physiological conditions of the child to be treated and their variability, e.g. gastric pH and emptying rate and intestinal mobility.\n\nThe majority of sustained-release formulations, especially coated tablets and matrix tablets, must not be broken or chewed and some will not withstand being mixed with food or a beverage. It is, therefore, vital that clear instructions on the proper use of the formulation are included on the label.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2797, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "b0231d06-929c-4668-bd7f-82c3980cae8b": {"__data__": {"id_": "b0231d06-929c-4668-bd7f-82c3980cae8b", "embedding": null, "metadata": {"page_label": "230", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Capsules\n\nCapsule formulations are provided either as soft capsules, usually with a liquid or semi-solid content or as hard capsules containing powder or a multiparticulate formulation.\n\nCapsules may be taken whole. The limitations mentioned for tablets apply with regard to the ability of the child to swallow them (see introduction to section 5.3). Hard capsules may be opened and their contents taken as such or taken after mixing with food or sprinkling on to food, but this is not always appropriate.\n\nInstructions on the proper use of a capsule formulation should be provided on the label, e.g. whether the capsule has to be taken whole or whether the capsule contents can be mixed with food to facilitate intake and improve palatability.\n\n# Orodispersible dosage forms\n\nOrodispersible dosage forms are orodispersible tablets, oral lyophilisates and thin films, to be placed on the tongue where they disperse rapidly into small-sized particles or \u201cmelt\u201d by dissolution in the saliva, after which the dose is swallowed.\n\nOrodispersible tablets designed to disintegrate rapidly are prepared by compression of a formulation containing, for example, mannitol, a super-disintegrant, and a flavouring agent. The amount of API that can be incorporated depends on its physical properties. The product may be moisture-sensitive. Orodispersible tablets are flexible dosage forms (see section 3.1), particularly well-suited for highly water-soluble APIs.\n\nOral lyophilisates are prepared by freeze-drying of aqueous liquids into porous units shaped like tablets. Typical excipients are gelatin or alginate, which act as structure-forming agents, and mannitol, which facilitates formation of the porous structure and contributes to palatability. Instead of mannitol, sorbitol may be used as a crystallization inhibitor. The amount of water-soluble API to be incorporated is limited (35). Oral lyophilisates are sensitive to moisture and require a vapour-tight package.\n\nThin, flat films (wafers) to be placed in the oral cavity are prepared by casting water-soluble polymers containing the API in dissolved or dispersed form. The amount of dissolved API that can be incorporated is limited. The release profile depends on the polymer, film thickness and API solubility. The so-called flash-release wafers may have dissolution times of less than 30 seconds.\n\nOrodispersible and orosoluble dosage forms are attractive for several reasons. They may be acceptable to the same age groups as liquid preparations, and it is possible for children who cannot swallow a whole tablet to take an orodispersible dosage form. In some situations, especially with younger children,", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento proporciona informaci\u00f3n sobre dos formas de dosificaci\u00f3n: c\u00e1psulas y formas de dosificaci\u00f3n orodispersibles. Las c\u00e1psulas pueden ser blandas o duras y pueden contener l\u00edquidos, semis\u00f3lidos o polvos. Se discuten las instrucciones sobre c\u00f3mo deben tomarse las c\u00e1psulas, especialmente en el caso de los ni\u00f1os que pueden tener dificultades para tragarlas. Las formas de dosificaci\u00f3n orodispersibles incluyen tabletas orodispersibles, liofilizados orales y pel\u00edculas delgadas que se disuelven r\u00e1pidamente en la boca. Estas formas son especialmente \u00fatiles para ni\u00f1os que no pueden tragar tabletas enteras y son adecuadas para APIs altamente solubles en agua.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones sobre la palatabilidad y la administraci\u00f3n de c\u00e1psulas para ni\u00f1os?**\n   - Las c\u00e1psulas deben tener instrucciones claras sobre su uso, indicando si deben tomarse enteras o si su contenido puede mezclarse con alimentos para facilitar la ingesta y mejorar la palatabilidad.\n\n2. **\u00bfQu\u00e9 excipientes se utilizan en la preparaci\u00f3n de liofilizados orales y cu\u00e1l es su funci\u00f3n?**\n   - Los liofilizados orales se preparan utilizando excipientes como gelatina o alginato, que act\u00faan como agentes formadores de estructura, y manitol, que facilita la formaci\u00f3n de la estructura porosa y contribuye a la palatabilidad.\n\n3. **\u00bfQu\u00e9 caracter\u00edsticas hacen que las formas de dosificaci\u00f3n orodispersibles sean adecuadas para ni\u00f1os?**\n   - Las formas de dosificaci\u00f3n orodispersibles son atractivas porque pueden ser aceptables para los mismos grupos de edad que las preparaciones l\u00edquidas y permiten que los ni\u00f1os que no pueden tragar tabletas enteras puedan tomar la dosis de manera m\u00e1s f\u00e1cil y r\u00e1pida.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS detalla las caracter\u00edsticas y consideraciones de las c\u00e1psulas y las formas de dosificaci\u00f3n orodispersibles, destacando su uso en poblaciones pedi\u00e1tricas. Se enfatiza la importancia de las instrucciones de uso para garantizar la correcta administraci\u00f3n de estos medicamentos, as\u00ed como la relevancia de los excipientes en la formulaci\u00f3n para mejorar la experiencia del paciente, especialmente en ni\u00f1os que pueden tener dificultades para tragar.", "prev_section_summary": "### Temas Clave:\n\n1. **Formas de Dosificaci\u00f3n Efervescentes**:\n   - Definici\u00f3n: Tabletas, gr\u00e1nulos o polvos que se disuelven en agua antes de la administraci\u00f3n.\n   - Consideraciones: Requieren un volumen considerable de agua, lo que puede ser problem\u00e1tico para los ni\u00f1os. Importancia de indicar el volumen m\u00ednimo de agua en la etiqueta y de no beber antes de que la efervescencia haya cesado.\n   - Desventajas: Necesidad de agua limpia para la disoluci\u00f3n y la ingesti\u00f3n de potasio o sodio, lo que puede ser inapropiado para pacientes con insuficiencia renal.\n\n2. **Tabletas Dispersables y Solubles**:\n   - Definici\u00f3n: Formas de dosificaci\u00f3n que se utilizan de manera similar a las efervescentes.\n   - Ventajas: Evitan problemas relacionados con el bicarbonato de hidr\u00f3geno, potasio y sodio. Deben disolverse r\u00e1pidamente al ser a\u00f1adidas al agua.\n   - Flexibilidad: Pueden ser formuladas para varios principios activos solubles en agua.\n\n3. **Formulaciones de Liberaci\u00f3n Sostenida**:\n   - Definici\u00f3n: Dise\u00f1adas para ralentizar la liberaci\u00f3n del principio activo en los fluidos gastrointestinales.\n   - Ventajas: Menor frecuencia de dosificaci\u00f3n en comparaci\u00f3n con formulaciones convencionales, lo que puede mejorar la adherencia.\n   - Consideraciones en Pediatr\u00eda: Importancia de tener en cuenta las condiciones fisiol\u00f3gicas del ni\u00f1o, como el pH g\u00e1strico y la movilidad intestinal.\n   - Instrucciones: Es vital que las formulaciones no sean trituradas o masticadas y que se incluyan instrucciones claras en la etiqueta.\n\n### Entidades:\n\n- **Formas de Dosificaci\u00f3n**: Efervescentes, dispersables, solubles, liberaci\u00f3n sostenida.\n- **Principios Activos (APIs)**: Sustancias que pueden ser formuladas en diferentes tipos de dosificaci\u00f3n.\n- **Pacientes**: Ni\u00f1os, pacientes con insuficiencia renal.\n- **Condiciones Fisiol\u00f3gicas**: pH g\u00e1strico, tasa de vaciamiento, movilidad intestinal.\n- **Instrucciones de Uso**: Importancia de la claridad en el etiquetado para un uso seguro y adecuado. \n\nEste resumen destaca los aspectos esenciales y las entidades relevantes en la secci\u00f3n sobre formas de dosificaci\u00f3n, enfoc\u00e1ndose en su uso, ventajas, desventajas y consideraciones espec\u00edficas para la poblaci\u00f3n pedi\u00e1trica.", "excerpt_keywords": "Capsules, Orodispersible, Dosage forms, Pediatric, Palatability"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "80999d87-c5b1-47ce-bf69-69e9be5e0c42", "node_type": "4", "metadata": {"page_label": "230", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Capsules\n\nCapsule formulations are provided either as soft capsules, usually with a liquid or semi-solid content or as hard capsules containing powder or a multiparticulate formulation.\n\nCapsules may be taken whole. The limitations mentioned for tablets apply with regard to the ability of the child to swallow them (see introduction to section 5.3). Hard capsules may be opened and their contents taken as such or taken after mixing with food or sprinkling on to food, but this is not always appropriate.\n\nInstructions on the proper use of a capsule formulation should be provided on the label, e.g. whether the capsule has to be taken whole or whether the capsule contents can be mixed with food to facilitate intake and improve palatability.\n\n# Orodispersible dosage forms\n\nOrodispersible dosage forms are orodispersible tablets, oral lyophilisates and thin films, to be placed on the tongue where they disperse rapidly into small-sized particles or \u201cmelt\u201d by dissolution in the saliva, after which the dose is swallowed.\n\nOrodispersible tablets designed to disintegrate rapidly are prepared by compression of a formulation containing, for example, mannitol, a super-disintegrant, and a flavouring agent. The amount of API that can be incorporated depends on its physical properties. The product may be moisture-sensitive. Orodispersible tablets are flexible dosage forms (see section 3.1), particularly well-suited for highly water-soluble APIs.\n\nOral lyophilisates are prepared by freeze-drying of aqueous liquids into porous units shaped like tablets. Typical excipients are gelatin or alginate, which act as structure-forming agents, and mannitol, which facilitates formation of the porous structure and contributes to palatability. Instead of mannitol, sorbitol may be used as a crystallization inhibitor. The amount of water-soluble API to be incorporated is limited (35). Oral lyophilisates are sensitive to moisture and require a vapour-tight package.\n\nThin, flat films (wafers) to be placed in the oral cavity are prepared by casting water-soluble polymers containing the API in dissolved or dispersed form. The amount of dissolved API that can be incorporated is limited. The release profile depends on the polymer, film thickness and API solubility. The so-called flash-release wafers may have dissolution times of less than 30 seconds.\n\nOrodispersible and orosoluble dosage forms are attractive for several reasons. They may be acceptable to the same age groups as liquid preparations, and it is possible for children who cannot swallow a whole tablet to take an orodispersible dosage form. In some situations, especially with younger children,", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "a45c45a369d8a5baa6b518dbe726ad5bb98d4afc971b3983ceda61adafe67f18", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Capsules\n\nCapsule formulations are provided either as soft capsules, usually with a liquid or semi-solid content or as hard capsules containing powder or a multiparticulate formulation.\n\nCapsules may be taken whole. The limitations mentioned for tablets apply with regard to the ability of the child to swallow them (see introduction to section 5.3). Hard capsules may be opened and their contents taken as such or taken after mixing with food or sprinkling on to food, but this is not always appropriate.\n\nInstructions on the proper use of a capsule formulation should be provided on the label, e.g. whether the capsule has to be taken whole or whether the capsule contents can be mixed with food to facilitate intake and improve palatability.\n\n# Orodispersible dosage forms\n\nOrodispersible dosage forms are orodispersible tablets, oral lyophilisates and thin films, to be placed on the tongue where they disperse rapidly into small-sized particles or \u201cmelt\u201d by dissolution in the saliva, after which the dose is swallowed.\n\nOrodispersible tablets designed to disintegrate rapidly are prepared by compression of a formulation containing, for example, mannitol, a super-disintegrant, and a flavouring agent. The amount of API that can be incorporated depends on its physical properties. The product may be moisture-sensitive. Orodispersible tablets are flexible dosage forms (see section 3.1), particularly well-suited for highly water-soluble APIs.\n\nOral lyophilisates are prepared by freeze-drying of aqueous liquids into porous units shaped like tablets. Typical excipients are gelatin or alginate, which act as structure-forming agents, and mannitol, which facilitates formation of the porous structure and contributes to palatability. Instead of mannitol, sorbitol may be used as a crystallization inhibitor. The amount of water-soluble API to be incorporated is limited (35). Oral lyophilisates are sensitive to moisture and require a vapour-tight package.\n\nThin, flat films (wafers) to be placed in the oral cavity are prepared by casting water-soluble polymers containing the API in dissolved or dispersed form. The amount of dissolved API that can be incorporated is limited. The release profile depends on the polymer, film thickness and API solubility. The so-called flash-release wafers may have dissolution times of less than 30 seconds.\n\nOrodispersible and orosoluble dosage forms are attractive for several reasons. They may be acceptable to the same age groups as liquid preparations, and it is possible for children who cannot swallow a whole tablet to take an orodispersible dosage form. In some situations, especially with younger children,", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2661, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "b2de2bc2-cbb5-4802-aa7c-c82d0ff2cf43": {"__data__": {"id_": "b2de2bc2-cbb5-4802-aa7c-c82d0ff2cf43", "embedding": null, "metadata": {"page_label": "231", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 7. Rectal administration\n\nRectal administration is an important route that can be used for both local (e.g. laxative and anti-inflammatory) and systemic effects (e.g. antipyretic and anticonvulsive) in all age groups. This route of administration is especially valuable when oral administration is not possible because of the condition of the child and palatability issues. In certain cases it is possible to obtain immediate systemic effect by rectal administration of solutions. There is, however, limited absorption and bioavailability for many APIs. Erratic absorption due to faecal contents in the rectum may unpredictably delay absorption.\n\nDosage forms for rectal administration are primarily suppositories, rectal capsules and rectal liquids (enemas). Other dosage forms are available, e.g. rectal foams provided in pressurized containers.\n\nWhen suppositories and rectal capsules are administered to paediatric patients there is a risk of premature expulsion, especially when the dosage form constituents have an irritating effect. Rectal dosage forms should be used with extreme caution in premature infants, as they can tear very delicate tissues and, thus, introduce infection.\n\nAdherence for rectal preparations may be lower than for oral dosage forms. There are barriers to rectal administration for both caregivers and patients in some regions and cultures. Generally their acceptability among children of any age is poor.\n\n## 7.1 Suppositories\n\nSuppositories for use in paediatric patients must be tailored to the age or size of the child. Cutting of suppositories into halves should be avoided unless they are designed to be cut. The majority of suppositories contain APIs as solid particles, which may be unevenly distributed in the suppository base as a result of the manufacturing technique of moulding a molten formulation. However, it is also possible to prepare suppositories which can be cut in smaller portions, ensuring delivery of an appropriate dose. Information on acceptability of cutting suppositories should be provided. When designed to be cut, information on the technique should be provided in the patient leaflet.\n\nTwo types of suppository base are available: one is insoluble in water, e.g. hard fat, which melts below body temperature. With suppository melt formulations, special consideration has to be given to storage temperature.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl texto aborda la administraci\u00f3n rectal de medicamentos, destacando su importancia tanto para efectos locales como sist\u00e9micos en todas las edades, especialmente en situaciones donde la administraci\u00f3n oral no es viable. Se mencionan las formas de dosificaci\u00f3n m\u00e1s comunes, como supositorios, c\u00e1psulas rectales y l\u00edquidos rectales, y se discuten los desaf\u00edos asociados con su uso en pacientes pedi\u00e1tricos, incluyendo la posibilidad de expulsi\u00f3n prematura y la baja adherencia. Tambi\u00e9n se enfatiza la necesidad de adaptar los supositorios a la edad o tama\u00f1o del ni\u00f1o y se describen los tipos de bases de supositorios disponibles.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones especiales que deben tenerse en cuenta al administrar supositorios a pacientes pedi\u00e1tricos, especialmente en prematuros?**\n   - La administraci\u00f3n de supositorios en pacientes pedi\u00e1tricos, especialmente en prematuros, debe hacerse con extrema precauci\u00f3n debido al riesgo de da\u00f1ar tejidos delicados, lo que podr\u00eda introducir infecciones.\n\n2. **\u00bfQu\u00e9 tipos de bases de supositorios existen y c\u00f3mo afectan su almacenamiento?**\n   - Existen dos tipos de bases de supositorios: una que es insoluble en agua, como la grasa dura, que se derrite por debajo de la temperatura corporal. Las formulaciones de supositorios que se derriten requieren consideraciones especiales en cuanto a la temperatura de almacenamiento.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe proporcionarse en el prospecto de los supositorios que est\u00e1n dise\u00f1ados para ser cortados?**\n   - El prospecto debe incluir informaci\u00f3n sobre la aceptabilidad de cortar los supositorios y, cuando est\u00e1n dise\u00f1ados para ser cortados, debe proporcionar instrucciones sobre la t\u00e9cnica adecuada para hacerlo.", "prev_section_summary": "### Temas Clave\n\n1. **Formulaciones de C\u00e1psulas**:\n   - Tipos: c\u00e1psulas blandas (contenido l\u00edquido o semis\u00f3lido) y c\u00e1psulas duras (contenido en polvo o multiparticulado).\n   - Consideraciones para la administraci\u00f3n en ni\u00f1os: dificultad para tragar, instrucciones sobre si deben tomarse enteras o si el contenido puede mezclarse con alimentos.\n\n2. **Formas de Dosificaci\u00f3n Orodispersibles**:\n   - Tipos: tabletas orodispersibles, liofilizados orales y pel\u00edculas delgadas.\n   - Mecanismo: se disuelven r\u00e1pidamente en la boca y son f\u00e1ciles de tragar.\n   - Composici\u00f3n: uso de excipientes como mannitol, gelatina y alginato para mejorar la palatabilidad y la estructura.\n   - Ventajas: adecuadas para ni\u00f1os que no pueden tragar tabletas enteras, aceptables para grupos de edad similares a las preparaciones l\u00edquidas.\n\n### Entidades\n\n- **C\u00e1psulas**: Formas de dosificaci\u00f3n que pueden ser blandas o duras.\n- **Orodispersibles**: Formas de dosificaci\u00f3n que incluyen tabletas orodispersibles, liofilizados orales y pel\u00edculas delgadas.\n- **Excipientes**: Sustancias como mannitol, gelatina y alginato que se utilizan en la formulaci\u00f3n de medicamentos.\n- **API (Ingrediente Activo)**: Sustancia que proporciona la acci\u00f3n farmacol\u00f3gica en las formulaciones.\n\n### Resumen General\n\nLa secci\u00f3n aborda las caracter\u00edsticas y consideraciones de las c\u00e1psulas y las formas de dosificaci\u00f3n orodispersibles, enfatizando su uso en pediatr\u00eda. Se destaca la importancia de proporcionar instrucciones claras para la administraci\u00f3n de estos medicamentos, as\u00ed como el papel de los excipientes en la formulaci\u00f3n para mejorar la experiencia del paciente, especialmente en ni\u00f1os que pueden tener dificultades para tragar.", "excerpt_keywords": "Rectal administration, suppositories, pediatric patients, bioavailability, dosage forms"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "59113514-ccb4-47aa-8e20-eb08a3c2ec8e", "node_type": "4", "metadata": {"page_label": "231", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 7. Rectal administration\n\nRectal administration is an important route that can be used for both local (e.g. laxative and anti-inflammatory) and systemic effects (e.g. antipyretic and anticonvulsive) in all age groups. This route of administration is especially valuable when oral administration is not possible because of the condition of the child and palatability issues. In certain cases it is possible to obtain immediate systemic effect by rectal administration of solutions. There is, however, limited absorption and bioavailability for many APIs. Erratic absorption due to faecal contents in the rectum may unpredictably delay absorption.\n\nDosage forms for rectal administration are primarily suppositories, rectal capsules and rectal liquids (enemas). Other dosage forms are available, e.g. rectal foams provided in pressurized containers.\n\nWhen suppositories and rectal capsules are administered to paediatric patients there is a risk of premature expulsion, especially when the dosage form constituents have an irritating effect. Rectal dosage forms should be used with extreme caution in premature infants, as they can tear very delicate tissues and, thus, introduce infection.\n\nAdherence for rectal preparations may be lower than for oral dosage forms. There are barriers to rectal administration for both caregivers and patients in some regions and cultures. Generally their acceptability among children of any age is poor.\n\n## 7.1 Suppositories\n\nSuppositories for use in paediatric patients must be tailored to the age or size of the child. Cutting of suppositories into halves should be avoided unless they are designed to be cut. The majority of suppositories contain APIs as solid particles, which may be unevenly distributed in the suppository base as a result of the manufacturing technique of moulding a molten formulation. However, it is also possible to prepare suppositories which can be cut in smaller portions, ensuring delivery of an appropriate dose. Information on acceptability of cutting suppositories should be provided. When designed to be cut, information on the technique should be provided in the patient leaflet.\n\nTwo types of suppository base are available: one is insoluble in water, e.g. hard fat, which melts below body temperature. With suppository melt formulations, special consideration has to be given to storage temperature.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "73a7b4e3ad2dfd84bb4b673e20983d4a65da0e1089509f044009c92d61ab2352", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 7. Rectal administration\n\nRectal administration is an important route that can be used for both local (e.g. laxative and anti-inflammatory) and systemic effects (e.g. antipyretic and anticonvulsive) in all age groups. This route of administration is especially valuable when oral administration is not possible because of the condition of the child and palatability issues. In certain cases it is possible to obtain immediate systemic effect by rectal administration of solutions. There is, however, limited absorption and bioavailability for many APIs. Erratic absorption due to faecal contents in the rectum may unpredictably delay absorption.\n\nDosage forms for rectal administration are primarily suppositories, rectal capsules and rectal liquids (enemas). Other dosage forms are available, e.g. rectal foams provided in pressurized containers.\n\nWhen suppositories and rectal capsules are administered to paediatric patients there is a risk of premature expulsion, especially when the dosage form constituents have an irritating effect. Rectal dosage forms should be used with extreme caution in premature infants, as they can tear very delicate tissues and, thus, introduce infection.\n\nAdherence for rectal preparations may be lower than for oral dosage forms. There are barriers to rectal administration for both caregivers and patients in some regions and cultures. Generally their acceptability among children of any age is poor.\n\n## 7.1 Suppositories\n\nSuppositories for use in paediatric patients must be tailored to the age or size of the child. Cutting of suppositories into halves should be avoided unless they are designed to be cut. The majority of suppositories contain APIs as solid particles, which may be unevenly distributed in the suppository base as a result of the manufacturing technique of moulding a molten formulation. However, it is also possible to prepare suppositories which can be cut in smaller portions, ensuring delivery of an appropriate dose. Information on acceptability of cutting suppositories should be provided. When designed to be cut, information on the technique should be provided in the patient leaflet.\n\nTwo types of suppository base are available: one is insoluble in water, e.g. hard fat, which melts below body temperature. With suppository melt formulations, special consideration has to be given to storage temperature.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2372, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "03cc6c5d-7fb8-47ff-980f-aebab157bc99": {"__data__": {"id_": "03cc6c5d-7fb8-47ff-980f-aebab157bc99", "embedding": null, "metadata": {"page_label": "232", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Rectal liquids (enemas)\n\nRectal liquids are solutions, suspensions or emulsions based on water or vegetable oil. Any volume to be administered should be appropriate to the size of the child. For systemic therapy, the volume to be administered should be as small as possible to achieve accurate delivery, good absorption and to avoid irritation. Volumes of 1\u20135 ml may be acceptable.\n\nThe rectal tube should be of a length appropriate to the size of the child and should not cause injury. Use of pre-filled syringes equipped with a rectal tube facilitates individual dosing and may reduce the need for several strengths of the formulation.\n\nFormulation of aqueous rectal liquids is similar to the formulation of other aqueous liquids regarding use of stabilizing agents, including surfactants and antimicrobial agents. Non-ionic surfactants are preferred because ionic surfactants are frequently irritating to the rectal mucosa. The need for stabilizing agents, in particular antimicrobial agents, may be reduced by the formulation of rectal tablets to be dispersed or dissolved in water immediately before administration.\n\n# 8. Parenteral administration\n\nParenteral administration by the intravenous route is preferred for seriously ill children and for clinically unstable term and preterm neonates (in developed country settings). Some parenteral preparations are administered by the subcutaneous and intramuscular routes. The limited muscle mass of newborns and, in particular of preterm infants, constrains the use of intramuscular injections. Other routes of administration, e.g. intraosseous, are used in emergency cases.\n\nMost children have a fear of injection needles. Possible alternatives, especially suited for children undergoing frequent or long-duration treatment, such as needle-free injection devices (jet injectors), that drive small droplets through the skin by high pressure, could be considered, e.g. for subcutaneous administration. However, experience of their use in paediatric populations, especially in smaller children is limited.\n\nRepeated injections should be avoided for children unless they can be given intravenously via catheter or injection ports that can remain in place for the length of the treatment. Reducing the number of injections by formulation of sustained-release preparations requires consideration of increased blood perfusion in children, usually increasing absorption from tissue depots.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Uso de l\u00edquidos rectales (enemas)**: Los l\u00edquidos rectales son soluciones, suspensiones o emulsiones que se administran a trav\u00e9s del recto, y su volumen debe ser adecuado al tama\u00f1o del ni\u00f1o. Se prefiere el uso de surfactantes no i\u00f3nicos para evitar irritaciones en la mucosa rectal. Adem\u00e1s, se sugiere que los agentes estabilizantes, como los antimicrobianos, pueden ser menos necesarios si se utilizan tabletas rectales que se disuelven en agua antes de la administraci\u00f3n.\n\n2. **Administraci\u00f3n parenteral en pediatr\u00eda**: La administraci\u00f3n intravenosa es la preferida para ni\u00f1os gravemente enfermos y neonatos cl\u00ednicamente inestables. Se discuten alternativas a las inyecciones, como los dispositivos de inyecci\u00f3n sin aguja, y se enfatiza la importancia de reducir el n\u00famero de inyecciones mediante el uso de preparaciones de liberaci\u00f3n sostenida.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1l es el volumen recomendado de l\u00edquidos rectales para la administraci\u00f3n en ni\u00f1os y por qu\u00e9 es importante que este volumen sea el m\u00e1s peque\u00f1o posible?**\n   - Respuesta: Se recomienda un volumen de 1-5 ml para la administraci\u00f3n de l\u00edquidos rectales en ni\u00f1os, ya que un volumen menor ayuda a lograr una entrega precisa, una buena absorci\u00f3n y a evitar irritaciones en la mucosa rectal.\n\n2. **\u00bfQu\u00e9 tipo de surfactantes se prefieren en la formulaci\u00f3n de l\u00edquidos rectales y por qu\u00e9?**\n   - Respuesta: Se prefieren los surfactantes no i\u00f3nicos en la formulaci\u00f3n de l\u00edquidos rectales porque los surfactantes i\u00f3nicos pueden causar irritaci\u00f3n en la mucosa rectal.\n\n3. **\u00bfQu\u00e9 alternativas a las inyecciones se sugieren para ni\u00f1os que requieren tratamientos frecuentes y cu\u00e1les son las limitaciones de estas alternativas?**\n   - Respuesta: Se sugieren dispositivos de inyecci\u00f3n sin aguja (jet injectors) como alternativas a las inyecciones, especialmente para la administraci\u00f3n subcut\u00e1nea. Sin embargo, la experiencia en su uso en poblaciones pedi\u00e1tricas, especialmente en ni\u00f1os m\u00e1s peque\u00f1os, es limitada.", "prev_section_summary": "### Resumen de temas clave y entidades de la secci\u00f3n sobre administraci\u00f3n rectal\n\n1. **Importancia de la administraci\u00f3n rectal**:\n   - Utilizada para efectos locales (laxantes, antiinflamatorios) y sist\u00e9micos (antipir\u00e9ticos, anticonvulsivos).\n   - Especialmente valiosa cuando la administraci\u00f3n oral no es posible.\n\n2. **Formas de dosificaci\u00f3n**:\n   - Principales: supositorios, c\u00e1psulas rectales y l\u00edquidos rectales (enemas).\n   - Otras formas: espumas rectales en envases presurizados.\n\n3. **Desaf\u00edos en pacientes pedi\u00e1tricos**:\n   - Riesgo de expulsi\u00f3n prematura de supositorios y c\u00e1psulas rectales, especialmente si los componentes son irritantes.\n   - Precauci\u00f3n extrema en el uso en reci\u00e9n nacidos prematuros debido al riesgo de da\u00f1ar tejidos delicados.\n\n4. **Adherencia y aceptabilidad**:\n   - La adherencia a las preparaciones rectales puede ser menor que a las formas orales.\n   - Barreras culturales y de aceptaci\u00f3n entre los ni\u00f1os.\n\n5. **Consideraciones para supositorios**:\n   - Deben adaptarse a la edad o tama\u00f1o del ni\u00f1o.\n   - Evitar cortar supositorios a menos que est\u00e9n dise\u00f1ados para ello.\n   - Distribuci\u00f3n desigual de los principios activos (APIs) en la base del supositorio.\n\n6. **Tipos de bases de supositorios**:\n   - Base insoluble en agua (ej. grasa dura) que se derrite a temperatura corporal.\n   - Consideraciones especiales para el almacenamiento de formulaciones que se derriten.\n\n7. **Informaci\u00f3n en prospectos**:\n   - Debe incluir detalles sobre la aceptabilidad de cortar supositorios y t\u00e9cnicas adecuadas si est\u00e1n dise\u00f1ados para ser cortados.\n\n### Entidades clave:\n- **Rutas de administraci\u00f3n**: Rectal\n- **Efectos**: Locales y sist\u00e9micos\n- **Formas de dosificaci\u00f3n**: Supositorios, c\u00e1psulas rectales, l\u00edquidos rectales, espumas rectales\n- **Poblaci\u00f3n**: Pacientes pedi\u00e1tricos, reci\u00e9n nacidos prematuros\n- **Consideraciones de seguridad**: Riesgo de da\u00f1o a tejidos, adherencia, aceptabilidad cultural.", "excerpt_keywords": "Keywords: rectal administration, parenteral therapy, pediatric dosing, surfactants, injection alternatives"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9fbfdccf-e2cc-4cc9-8285-71e82105b1c6", "node_type": "4", "metadata": {"page_label": "232", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Rectal liquids (enemas)\n\nRectal liquids are solutions, suspensions or emulsions based on water or vegetable oil. Any volume to be administered should be appropriate to the size of the child. For systemic therapy, the volume to be administered should be as small as possible to achieve accurate delivery, good absorption and to avoid irritation. Volumes of 1\u20135 ml may be acceptable.\n\nThe rectal tube should be of a length appropriate to the size of the child and should not cause injury. Use of pre-filled syringes equipped with a rectal tube facilitates individual dosing and may reduce the need for several strengths of the formulation.\n\nFormulation of aqueous rectal liquids is similar to the formulation of other aqueous liquids regarding use of stabilizing agents, including surfactants and antimicrobial agents. Non-ionic surfactants are preferred because ionic surfactants are frequently irritating to the rectal mucosa. The need for stabilizing agents, in particular antimicrobial agents, may be reduced by the formulation of rectal tablets to be dispersed or dissolved in water immediately before administration.\n\n# 8. Parenteral administration\n\nParenteral administration by the intravenous route is preferred for seriously ill children and for clinically unstable term and preterm neonates (in developed country settings). Some parenteral preparations are administered by the subcutaneous and intramuscular routes. The limited muscle mass of newborns and, in particular of preterm infants, constrains the use of intramuscular injections. Other routes of administration, e.g. intraosseous, are used in emergency cases.\n\nMost children have a fear of injection needles. Possible alternatives, especially suited for children undergoing frequent or long-duration treatment, such as needle-free injection devices (jet injectors), that drive small droplets through the skin by high pressure, could be considered, e.g. for subcutaneous administration. However, experience of their use in paediatric populations, especially in smaller children is limited.\n\nRepeated injections should be avoided for children unless they can be given intravenously via catheter or injection ports that can remain in place for the length of the treatment. Reducing the number of injections by formulation of sustained-release preparations requires consideration of increased blood perfusion in children, usually increasing absorption from tissue depots.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "768c668020f9b6b5427d5e353f67a1225fd92907fcefbe5e8acfbe278925cd59", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Rectal liquids (enemas)\n\nRectal liquids are solutions, suspensions or emulsions based on water or vegetable oil. Any volume to be administered should be appropriate to the size of the child. For systemic therapy, the volume to be administered should be as small as possible to achieve accurate delivery, good absorption and to avoid irritation. Volumes of 1\u20135 ml may be acceptable.\n\nThe rectal tube should be of a length appropriate to the size of the child and should not cause injury. Use of pre-filled syringes equipped with a rectal tube facilitates individual dosing and may reduce the need for several strengths of the formulation.\n\nFormulation of aqueous rectal liquids is similar to the formulation of other aqueous liquids regarding use of stabilizing agents, including surfactants and antimicrobial agents. Non-ionic surfactants are preferred because ionic surfactants are frequently irritating to the rectal mucosa. The need for stabilizing agents, in particular antimicrobial agents, may be reduced by the formulation of rectal tablets to be dispersed or dissolved in water immediately before administration.\n\n# 8. Parenteral administration\n\nParenteral administration by the intravenous route is preferred for seriously ill children and for clinically unstable term and preterm neonates (in developed country settings). Some parenteral preparations are administered by the subcutaneous and intramuscular routes. The limited muscle mass of newborns and, in particular of preterm infants, constrains the use of intramuscular injections. Other routes of administration, e.g. intraosseous, are used in emergency cases.\n\nMost children have a fear of injection needles. Possible alternatives, especially suited for children undergoing frequent or long-duration treatment, such as needle-free injection devices (jet injectors), that drive small droplets through the skin by high pressure, could be considered, e.g. for subcutaneous administration. However, experience of their use in paediatric populations, especially in smaller children is limited.\n\nRepeated injections should be avoided for children unless they can be given intravenously via catheter or injection ports that can remain in place for the length of the treatment. Reducing the number of injections by formulation of sustained-release preparations requires consideration of increased blood perfusion in children, usually increasing absorption from tissue depots.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2436, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "d9dc142a-048f-4013-ac7f-05b8ad77aebf": {"__data__": {"id_": "d9dc142a-048f-4013-ac7f-05b8ad77aebf", "embedding": null, "metadata": {"page_label": "233", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Formulation\n\nAqueous preparations (solutions or suspensions) must be adapted to the physiological conditions on the application site. The tolerances for deviations in pH and osmolality are dependent on the route of administration. In particular, subcutaneous administration is highly sensitive because dilution of the injected volume and its escape from the injection site proceed slowly. Hyperosmolar injections and injections with extreme pH may cause pain and irritate peripheral veins.\n\nFormulations for neonatal patients are usually aqueous solutions intended for intravenous administration. Target volumes and electrolyte contents are important for all paediatric patients; however, these are critical for neonates (19).\n\nIt is crucial to consider the safety profile of each excipient and its suitability for the intended use (see section 4.3).\n\nAttention should be paid to the potential adsorption of the API onto the surfaces of plastic containers and catheters, and to leaching of plasticizers from containers and catheters to the parenteral preparation.\n\nSome APIs are presented as powders or lyophilisates to be reconstituted before administration. It is important that clear instructions on the reconstitution and information on storage conditions and duration appear on the label or product information.\n\n## Additional points to consider for parenteral preparations\n\n- There should be a minimal need for complex calculations for prescribing, dispensing and administration (e.g. dose in micrograms/kg/hour prescribed to be converted to volume per hour administered; conversion between mmol prescribed and mg on the label; conversion between mg prescribed and percentage concentration on the label; and decimal points).\n\n- The need for additional steps in the preparation of the product for administration should be minimized, for example, by developing ready-to-use preparations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) se centra en la formulaci\u00f3n de preparaciones acuosas para la administraci\u00f3n parenteral de medicamentos, destacando la importancia de adaptar estas formulaciones a las condiciones fisiol\u00f3gicas del sitio de aplicaci\u00f3n. Se enfatiza la sensibilidad de la administraci\u00f3n subcut\u00e1nea a las variaciones en pH y osmolalidad, as\u00ed como la necesidad de considerar la seguridad de los excipientes y el riesgo de adsorci\u00f3n de principios activos (API) en pl\u00e1sticos. Tambi\u00e9n se menciona la importancia de proporcionar instrucciones claras para la reconstituci\u00f3n de medicamentos en forma de polvo y la minimizaci\u00f3n de c\u00e1lculos complejos en la prescripci\u00f3n y administraci\u00f3n.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones espec\u00edficas que deben tenerse en cuenta al formular soluciones intravenosas para pacientes neonatales en comparaci\u00f3n con otros grupos pedi\u00e1tricos?**\n   - Esta pregunta se centra en las diferencias cr\u00edticas en la formulaci\u00f3n para neonatos, que son m\u00e1s sensibles a los vol\u00famenes y contenidos electrol\u00edticos.\n\n2. **\u00bfQu\u00e9 riesgos est\u00e1n asociados con la administraci\u00f3n de inyecciones hiperosmolares o con pH extremo, especialmente en la administraci\u00f3n subcut\u00e1nea?**\n   - Esta pregunta busca profundizar en los efectos adversos espec\u00edficos que pueden surgir de la administraci\u00f3n inadecuada de soluciones.\n\n3. **\u00bfQu\u00e9 medidas se pueden tomar para minimizar la necesidad de c\u00e1lculos complejos en la prescripci\u00f3n y administraci\u00f3n de medicamentos parenterales?**\n   - Esta pregunta se enfoca en las estrategias que pueden implementarse para simplificar el proceso de administraci\u00f3n y reducir el riesgo de errores.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n detallada y espec\u00edfica que no se puede encontrar f\u00e1cilmente en otras fuentes, bas\u00e1ndose en el contenido del documento proporcionado.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **L\u00edquidos rectales (enemas)**:\n   - **Definici\u00f3n**: Soluciones, suspensiones o emulsiones basadas en agua o aceite vegetal administradas por v\u00eda rectal.\n   - **Volumen recomendado**: 1-5 ml, ajustado al tama\u00f1o del ni\u00f1o, para asegurar una entrega precisa, buena absorci\u00f3n y evitar irritaci\u00f3n.\n   - **Equipamiento**: Uso de tubos rectales de longitud adecuada y jeringas precargadas para facilitar la dosificaci\u00f3n individual.\n   - **Formulaci\u00f3n**: Similar a otros l\u00edquidos acuosos, se prefieren surfactantes no i\u00f3nicos para evitar irritaci\u00f3n en la mucosa rectal. La necesidad de agentes estabilizantes, como antimicrobianos, puede disminuir con el uso de tabletas rectales que se disuelven en agua antes de la administraci\u00f3n.\n\n2. **Administraci\u00f3n parenteral**:\n   - **Ruta preferida**: Intravenosa para ni\u00f1os gravemente enfermos y neonatos cl\u00ednicamente inestables.\n   - **Otras rutas**: Subcut\u00e1nea e intramuscular, aunque las inyecciones intramusculares son limitadas en reci\u00e9n nacidos y prematuros debido a la masa muscular reducida.\n   - **Alternativas a las inyecciones**: Dispositivos de inyecci\u00f3n sin aguja (jet injectors) para administraci\u00f3n subcut\u00e1nea, aunque su uso en poblaciones pedi\u00e1tricas es limitado.\n   - **Consideraciones**: Evitar inyecciones repetidas, preferir cat\u00e9teres o puertos de inyecci\u00f3n para tratamientos prolongados, y considerar la formulaci\u00f3n de preparaciones de liberaci\u00f3n sostenida para reducir el n\u00famero de inyecciones.\n\n### Entidades clave:\n- **L\u00edquidos rectales**\n- **Surfactantes no i\u00f3nicos**\n- **Administraci\u00f3n intravenosa**\n- **Dispositivos de inyecci\u00f3n sin aguja**\n- **Neonatos**\n- **Preparaciones de liberaci\u00f3n sostenida**", "excerpt_keywords": "Formulation, Aqueous preparations, Neonatal patients, Parenteral administration, Safety profile"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ed179fda-c636-425a-b459-21d72f988781", "node_type": "4", "metadata": {"page_label": "233", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Formulation\n\nAqueous preparations (solutions or suspensions) must be adapted to the physiological conditions on the application site. The tolerances for deviations in pH and osmolality are dependent on the route of administration. In particular, subcutaneous administration is highly sensitive because dilution of the injected volume and its escape from the injection site proceed slowly. Hyperosmolar injections and injections with extreme pH may cause pain and irritate peripheral veins.\n\nFormulations for neonatal patients are usually aqueous solutions intended for intravenous administration. Target volumes and electrolyte contents are important for all paediatric patients; however, these are critical for neonates (19).\n\nIt is crucial to consider the safety profile of each excipient and its suitability for the intended use (see section 4.3).\n\nAttention should be paid to the potential adsorption of the API onto the surfaces of plastic containers and catheters, and to leaching of plasticizers from containers and catheters to the parenteral preparation.\n\nSome APIs are presented as powders or lyophilisates to be reconstituted before administration. It is important that clear instructions on the reconstitution and information on storage conditions and duration appear on the label or product information.\n\n## Additional points to consider for parenteral preparations\n\n- There should be a minimal need for complex calculations for prescribing, dispensing and administration (e.g. dose in micrograms/kg/hour prescribed to be converted to volume per hour administered; conversion between mmol prescribed and mg on the label; conversion between mg prescribed and percentage concentration on the label; and decimal points).\n\n- The need for additional steps in the preparation of the product for administration should be minimized, for example, by developing ready-to-use preparations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "e5b8903017234132ca1e0d576678c53948c24b25bffcd5cec6948bd52ae627b3", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Formulation\n\nAqueous preparations (solutions or suspensions) must be adapted to the physiological conditions on the application site. The tolerances for deviations in pH and osmolality are dependent on the route of administration. In particular, subcutaneous administration is highly sensitive because dilution of the injected volume and its escape from the injection site proceed slowly. Hyperosmolar injections and injections with extreme pH may cause pain and irritate peripheral veins.\n\nFormulations for neonatal patients are usually aqueous solutions intended for intravenous administration. Target volumes and electrolyte contents are important for all paediatric patients; however, these are critical for neonates (19).\n\nIt is crucial to consider the safety profile of each excipient and its suitability for the intended use (see section 4.3).\n\nAttention should be paid to the potential adsorption of the API onto the surfaces of plastic containers and catheters, and to leaching of plasticizers from containers and catheters to the parenteral preparation.\n\nSome APIs are presented as powders or lyophilisates to be reconstituted before administration. It is important that clear instructions on the reconstitution and information on storage conditions and duration appear on the label or product information.\n\n## Additional points to consider for parenteral preparations\n\n- There should be a minimal need for complex calculations for prescribing, dispensing and administration (e.g. dose in micrograms/kg/hour prescribed to be converted to volume per hour administered; conversion between mmol prescribed and mg on the label; conversion between mg prescribed and percentage concentration on the label; and decimal points).\n\n- The need for additional steps in the preparation of the product for administration should be minimized, for example, by developing ready-to-use preparations.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1893, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "62456a8f-c7eb-481e-8465-b902ef26014d": {"__data__": {"id_": "62456a8f-c7eb-481e-8465-b902ef26014d", "embedding": null, "metadata": {"page_label": "234", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- Measurement of volumes smaller than 0.1 ml should not be required. Dose volumes in hundredths of a millilitre should be avoided. Tables should be included in the product information clearly stating the dose and the volume to be measured, and how this can be achieved safely and accurately.\n- Miscalculation can lead to overdose and the amount of the API in the presentation should not allow administration of a critical overdose to the smallest patient for whom the presentation is intended.\n- Using several vials per dose or large vials that may contain several doses should be avoided if possible.\n- Other methods of preventing overdose of critical medicines can be explored and presented for consideration, e.g. tables of weight, dose (mass) and volume (ml) of preparation required.\n- Safety measures and restrictions on administration via central or peripheral cannula should be provided, including advice on maximum and minimum dilutions for safe administration.\n- Consideration should be given to the contribution to the child\u2019s fluid and electrolyte balance due to the medicine administration volume and/or electrolyte content.\n- Compatibility with other medicines that are part of a standard care plan should be investigated.\n- Information on pH of the FPP needs to be provided in the product information.\n\n## 9. Dermal and transdermal administration\n\nPreparations for dermal (or cutaneous) administration include liquid preparations (lotions and shampoos), semi-solid preparations (ointments and creams) and solid preparations (powders). They are used to obtain local effects.\n\nUnintended systemic absorption through the dermis is a potential risk with many APIs. The stratum corneum is deficient in preterm neonates. Children have a lower volume of distribution per unit area of skin.\n\nDepending on the dosage form, various excipients are needed. The safety profile of each must be considered (see section 4.3) including the risk of sensitization of the skin. Preparations containing ethanol should be avoided in very young children because ethanol may dehydrate the skin and cause pain.\n\nLiquid suspensions, semi-solid preparations and patches should be subject to dissolution testing (18).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Medidas de seguridad en la administraci\u00f3n de medicamentos pedi\u00e1tricos**: El documento enfatiza la importancia de evitar dosis en vol\u00famenes menores a 0.1 ml y la necesidad de proporcionar tablas claras sobre dosis y vol\u00famenes en la informaci\u00f3n del producto. Tambi\u00e9n se menciona el riesgo de sobredosis y la necesidad de considerar el equilibrio de fluidos y electrolitos en ni\u00f1os.\n\n2. **Consideraciones sobre la administraci\u00f3n d\u00e9rmica y transd\u00e9rmica**: Se discuten los diferentes tipos de preparaciones para administraci\u00f3n d\u00e9rmica y los riesgos asociados con la absorci\u00f3n sist\u00e9mica no intencionada, especialmente en neonatos y ni\u00f1os. Se destaca la importancia de evaluar la seguridad de los excipientes y evitar el uso de etanol en preparaciones para ni\u00f1os muy peque\u00f1os.\n\n3. **Pruebas de disoluci\u00f3n y compatibilidad de medicamentos**: Se menciona que las suspensiones l\u00edquidas, preparaciones semi-s\u00f3lidas y parches deben someterse a pruebas de disoluci\u00f3n. Adem\u00e1s, se debe investigar la compatibilidad de los medicamentos con otros que forman parte de un plan de atenci\u00f3n est\u00e1ndar.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las recomendaciones espec\u00edficas para evitar la sobredosis en pacientes pedi\u00e1tricos al administrar medicamentos en vol\u00famenes peque\u00f1os?**\n   - El documento sugiere que no se deben requerir medidas de vol\u00famenes menores a 0.1 ml y que se deben incluir tablas en la informaci\u00f3n del producto que indiquen claramente la dosis y el volumen a medir, as\u00ed como m\u00e9todos para lograrlo de manera segura y precisa.\n\n2. **\u00bfQu\u00e9 precauciones se deben tomar al utilizar preparaciones d\u00e9rmicas en neonatos y ni\u00f1os?**\n   - Se debe tener en cuenta que la absorci\u00f3n sist\u00e9mica no intencionada es un riesgo potencial, especialmente en neonatos debido a la deficiencia del estrato c\u00f3rneo. Adem\u00e1s, se deben considerar los excipientes utilizados y evitar el etanol en preparaciones para ni\u00f1os muy peque\u00f1os, ya que puede deshidratar la piel y causar dolor.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n sobre la compatibilidad de medicamentos se debe incluir en la evaluaci\u00f3n de preparaciones farmac\u00e9uticas?**\n   - Es fundamental investigar la compatibilidad de los medicamentos que forman parte de un plan de atenci\u00f3n est\u00e1ndar, as\u00ed como proporcionar informaci\u00f3n sobre el pH de la forma farmac\u00e9utica terminada (FPP) en la informaci\u00f3n del producto.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Preparaciones acuosas**: Se enfatiza la importancia de adaptar las soluciones o suspensiones a las condiciones fisiol\u00f3gicas del sitio de aplicaci\u00f3n, considerando las tolerancias en pH y osmolalidad seg\u00fan la ruta de administraci\u00f3n.\n\n2. **Administraci\u00f3n subcut\u00e1nea**: Se destaca que esta ruta es especialmente sensible a las variaciones en pH y osmolalidad, y que las inyecciones hiperosmolares o con pH extremo pueden causar dolor e irritaci\u00f3n en las venas perif\u00e9ricas.\n\n3. **Pacientes neonatales**: Las formulaciones para neonatos son generalmente soluciones acuosas destinadas a la administraci\u00f3n intravenosa, donde los vol\u00famenes objetivo y el contenido de electrolitos son cr\u00edticos.\n\n4. **Seguridad de excipientes**: Es fundamental considerar el perfil de seguridad de cada excipiente y su idoneidad para el uso previsto.\n\n5. **Adsorci\u00f3n y leaching**: Se debe prestar atenci\u00f3n a la posible adsorci\u00f3n del principio activo (API) en superficies de contenedores y cat\u00e9teres de pl\u00e1stico, as\u00ed como a la migraci\u00f3n de plastificantes hacia la preparaci\u00f3n parenteral.\n\n6. **Reconstituci\u00f3n de medicamentos**: Algunos APIs se presentan en forma de polvo o liofilizados que requieren reconstituci\u00f3n antes de la administraci\u00f3n, y es esencial que las instrucciones claras y la informaci\u00f3n sobre condiciones de almacenamiento est\u00e9n disponibles en la etiqueta.\n\n7. **Minimizaci\u00f3n de c\u00e1lculos complejos**: Se sugiere que debe haber una necesidad m\u00ednima de c\u00e1lculos complejos en la prescripci\u00f3n, dispensaci\u00f3n y administraci\u00f3n de medicamentos parenterales para reducir el riesgo de errores.\n\n8. **Preparaciones listas para usar**: Se recomienda minimizar los pasos adicionales en la preparaci\u00f3n del producto para la administraci\u00f3n, promoviendo el desarrollo de preparaciones listas para usar.\n\n### Entidades clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite el documento.\n- **API (Principio Activo)**: Sustancia que produce el efecto terap\u00e9utico.\n- **Electrolitos**: Minerales esenciales que deben ser cuidadosamente balanceados en formulaciones para neonatos.\n- **Excipientes**: Sustancias inactivas que acompa\u00f1an al principio activo en las formulaciones.\n- **Administraci\u00f3n intravenosa**: Ruta de administraci\u00f3n cr\u00edtica para neonatos. \n\nEste resumen captura los aspectos m\u00e1s relevantes de la secci\u00f3n sobre formulaciones de preparaciones acuosas para la administraci\u00f3n parenteral de medicamentos.", "excerpt_keywords": "Keywords: pediatric medication safety, dermal administration, overdose prevention, pharmaceutical preparations, excipient safety"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "98132686-4a46-4d47-bd28-b929769eece8", "node_type": "4", "metadata": {"page_label": "234", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- Measurement of volumes smaller than 0.1 ml should not be required. Dose volumes in hundredths of a millilitre should be avoided. Tables should be included in the product information clearly stating the dose and the volume to be measured, and how this can be achieved safely and accurately.\n- Miscalculation can lead to overdose and the amount of the API in the presentation should not allow administration of a critical overdose to the smallest patient for whom the presentation is intended.\n- Using several vials per dose or large vials that may contain several doses should be avoided if possible.\n- Other methods of preventing overdose of critical medicines can be explored and presented for consideration, e.g. tables of weight, dose (mass) and volume (ml) of preparation required.\n- Safety measures and restrictions on administration via central or peripheral cannula should be provided, including advice on maximum and minimum dilutions for safe administration.\n- Consideration should be given to the contribution to the child\u2019s fluid and electrolyte balance due to the medicine administration volume and/or electrolyte content.\n- Compatibility with other medicines that are part of a standard care plan should be investigated.\n- Information on pH of the FPP needs to be provided in the product information.\n\n## 9. Dermal and transdermal administration\n\nPreparations for dermal (or cutaneous) administration include liquid preparations (lotions and shampoos), semi-solid preparations (ointments and creams) and solid preparations (powders). They are used to obtain local effects.\n\nUnintended systemic absorption through the dermis is a potential risk with many APIs. The stratum corneum is deficient in preterm neonates. Children have a lower volume of distribution per unit area of skin.\n\nDepending on the dosage form, various excipients are needed. The safety profile of each must be considered (see section 4.3) including the risk of sensitization of the skin. Preparations containing ethanol should be avoided in very young children because ethanol may dehydrate the skin and cause pain.\n\nLiquid suspensions, semi-solid preparations and patches should be subject to dissolution testing (18).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "bb97bbd52310dda918b4980fb0c859d2deafb10f836667e25dce8a07c644cb48", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- Measurement of volumes smaller than 0.1 ml should not be required. Dose volumes in hundredths of a millilitre should be avoided. Tables should be included in the product information clearly stating the dose and the volume to be measured, and how this can be achieved safely and accurately.\n- Miscalculation can lead to overdose and the amount of the API in the presentation should not allow administration of a critical overdose to the smallest patient for whom the presentation is intended.\n- Using several vials per dose or large vials that may contain several doses should be avoided if possible.\n- Other methods of preventing overdose of critical medicines can be explored and presented for consideration, e.g. tables of weight, dose (mass) and volume (ml) of preparation required.\n- Safety measures and restrictions on administration via central or peripheral cannula should be provided, including advice on maximum and minimum dilutions for safe administration.\n- Consideration should be given to the contribution to the child\u2019s fluid and electrolyte balance due to the medicine administration volume and/or electrolyte content.\n- Compatibility with other medicines that are part of a standard care plan should be investigated.\n- Information on pH of the FPP needs to be provided in the product information.\n\n## 9. Dermal and transdermal administration\n\nPreparations for dermal (or cutaneous) administration include liquid preparations (lotions and shampoos), semi-solid preparations (ointments and creams) and solid preparations (powders). They are used to obtain local effects.\n\nUnintended systemic absorption through the dermis is a potential risk with many APIs. The stratum corneum is deficient in preterm neonates. Children have a lower volume of distribution per unit area of skin.\n\nDepending on the dosage form, various excipients are needed. The safety profile of each must be considered (see section 4.3) including the risk of sensitization of the skin. Preparations containing ethanol should be avoided in very young children because ethanol may dehydrate the skin and cause pain.\n\nLiquid suspensions, semi-solid preparations and patches should be subject to dissolution testing (18).", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2277, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "862036e2-1465-4d07-9fed-465e07d88438": {"__data__": {"id_": "862036e2-1465-4d07-9fed-465e07d88438", "embedding": null, "metadata": {"page_label": "235", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 9.1 Transdermal patches\n\nTransdermal patches are used for systemic delivery of APIs which are capable of diffusion through the stratum corneum and are therapeutically active at the low plasma concentrations that can be achieved. The manufacture of transdermal patches of the \u201cdrug-in-adhesive\u201d type is now well developed and less problematic than the earlier \u201cdrug-in-reservoir\u201d type; the API is dispersed in a suitable polymeric adhesive to be fixed in a thin layer on a backing and covered by a removable liner.\n\nThe size and shape of a transdermal patch should be adapted to fit the child\u2019s body. It should stick firmly to the skin and not be too difficult to remove. Application sites which cannot easily be reached by the child should be chosen to avoid removal of the patch by the child. The risk of deliberate removal and its consequences for therapy must be considered. The increased systemic absorption through the skin, for the reasons mentioned above, may increase the systemic delivery from transdermal patches, in particular in newborns and young infants.\n\nWhen designed to be cut, information on the cutting technique should be provided in the patient leaflet and facilitated by the presence of cutting lines to ensure equal division. Reservoir systems should never be cut.\n\nAdhesives should have a low allergenic potential to avoid irritation and infection. Local tolerance and acceptability should be tested.\n\n# 10. Inhalations\n\nPulmonary administration of medicines by inhalation has traditionally been used to obtain a local effect. This route of administration also has a potential for systemic delivery. Preparations for inhalation include liquids for nebulization, pressurized metered dose inhalers (MDIs) and dry powder inhalers (DPIs).\n\nThe implications of the physiology of children of different ages and their ability to use the devices correctly should be considered in the development of paediatric inhalations (8). Depending on their age, children may have more or less difficulty with some of the devices. Problems with the coordination of the inhalation for MDIs and the ability to inhale strongly enough for DPIs determine the effectiveness of getting the medicine into the lung.\n\nThe total lung deposition is important for the clinical efficacy of preparations for inhalation. Generally it is affected by the formulation and delivery device controlling size distribution of the aerosol and patient-related factors such as the current disease state. The diameter of the airways is smaller in children than in adults; hence deposition by impact in the upper and central airways may be significantly higher in children (36). The particle size of the aerosol produced by the delivery device needs to be explored during development.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl contexto aborda dos m\u00e9todos de administraci\u00f3n de medicamentos en pediatr\u00eda: parches transd\u00e9rmicos e inhalaciones. Los parches transd\u00e9rmicos son utilizados para la entrega sist\u00e9mica de principios activos (APIs) que pueden difundir a trav\u00e9s de la piel, siendo especialmente relevantes en reci\u00e9n nacidos y ni\u00f1os peque\u00f1os debido a su mayor absorci\u00f3n sist\u00e9mica. Se enfatiza la importancia de adaptar el tama\u00f1o y la forma del parche al cuerpo del ni\u00f1o, as\u00ed como la necesidad de utilizar adhesivos con bajo potencial al\u00e9rgico. Por otro lado, la administraci\u00f3n pulmonar de medicamentos por inhalaci\u00f3n se utiliza principalmente para efectos locales, aunque tambi\u00e9n puede tener un efecto sist\u00e9mico. Se discuten las dificultades que pueden enfrentar los ni\u00f1os de diferentes edades al usar dispositivos de inhalaci\u00f3n, as\u00ed como la importancia de la deposici\u00f3n pulmonar para la eficacia cl\u00ednica.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones clave al dise\u00f1ar parches transd\u00e9rmicos para ni\u00f1os, especialmente en t\u00e9rminos de tama\u00f1o y forma?**\n   - Respuesta: Los parches deben adaptarse al cuerpo del ni\u00f1o, adherirse firmemente a la piel y ser f\u00e1ciles de quitar. Se deben elegir sitios de aplicaci\u00f3n que no sean f\u00e1cilmente alcanzables por el ni\u00f1o para evitar la remoci\u00f3n deliberada.\n\n2. **\u00bfQu\u00e9 precauciones deben tomarse al utilizar adhesivos en parches transd\u00e9rmicos para evitar irritaciones?**\n   - Respuesta: Los adhesivos deben tener un bajo potencial al\u00e9rgico para evitar irritaci\u00f3n e infecci\u00f3n, y se debe probar la tolerancia local y la aceptabilidad.\n\n3. **\u00bfC\u00f3mo afecta la fisiolog\u00eda de los ni\u00f1os a la eficacia de los dispositivos de inhalaci\u00f3n?**\n   - Respuesta: La fisiolog\u00eda de los ni\u00f1os, como el di\u00e1metro m\u00e1s peque\u00f1o de las v\u00edas respiratorias, puede resultar en una mayor deposici\u00f3n de part\u00edculas en las v\u00edas respiratorias superiores y centrales, lo que afecta la eficacia de la administraci\u00f3n del medicamento.\n\n### Resumen de nivel superior\n\nEl uso de parches transd\u00e9rmicos y la administraci\u00f3n por inhalaci\u00f3n son m\u00e9todos importantes para la entrega de medicamentos en pediatr\u00eda. Los parches deben ser dise\u00f1ados espec\u00edficamente para adaptarse a las caracter\u00edsticas f\u00edsicas de los ni\u00f1os, mientras que la administraci\u00f3n por inhalaci\u00f3n requiere considerar la capacidad de los ni\u00f1os para utilizar correctamente los dispositivos. Ambos m\u00e9todos deben tener en cuenta la seguridad y la eficacia, especialmente en poblaciones vulnerables como los reci\u00e9n nacidos y los ni\u00f1os peque\u00f1os.", "prev_section_summary": "### Temas Clave\n\n1. **Medidas de Seguridad en la Administraci\u00f3n de Medicamentos Pedi\u00e1tricos**:\n   - Evitar dosis en vol\u00famenes menores a 0.1 ml.\n   - Inclusi\u00f3n de tablas en la informaci\u00f3n del producto que indiquen dosis y vol\u00famenes a medir.\n   - Prevenci\u00f3n de sobredosis, especialmente en pacientes m\u00e1s peque\u00f1os.\n\n2. **Administraci\u00f3n D\u00e9rmica y Transd\u00e9rmica**:\n   - Tipos de preparaciones: l\u00edquidas, semi-s\u00f3lidas y s\u00f3lidas.\n   - Riesgo de absorci\u00f3n sist\u00e9mica no intencionada, especialmente en neonatos.\n   - Importancia de evaluar la seguridad de los excipientes y evitar el uso de etanol en ni\u00f1os muy peque\u00f1os.\n\n3. **Pruebas de Disoluci\u00f3n y Compatibilidad de Medicamentos**:\n   - Necesidad de realizar pruebas de disoluci\u00f3n para suspensiones l\u00edquidas, preparaciones semi-s\u00f3lidas y parches.\n   - Investigaci\u00f3n de la compatibilidad de medicamentos en planes de atenci\u00f3n est\u00e1ndar.\n   - Provisi\u00f3n de informaci\u00f3n sobre el pH de la forma farmac\u00e9utica terminada (FPP).\n\n### Entidades\n\n- **WHO Expert Committee on Specifications for Pharmaceutical Preparations**: Organizaci\u00f3n responsable de las recomendaciones.\n- **API (Active Pharmaceutical Ingredient)**: Ingrediente activo en las preparaciones farmac\u00e9uticas.\n- **FPP (Finished Pharmaceutical Product)**: Producto farmac\u00e9utico terminado.\n- **Excipientes**: Sustancias inactivas utilizadas en las formulaciones.\n- **Neonatos y ni\u00f1os**: Poblaciones espec\u00edficas a las que se dirigen las recomendaciones. \n\nEste resumen destaca las consideraciones cr\u00edticas para la administraci\u00f3n segura de medicamentos en pediatr\u00eda, as\u00ed como la importancia de la formulaci\u00f3n y la evaluaci\u00f3n de la seguridad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Transdermal patches, pediatric inhalation, systemic delivery, drug formulation, airway deposition"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "511dc5cb-9aac-42f2-843c-af883b5ad86b", "node_type": "4", "metadata": {"page_label": "235", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 9.1 Transdermal patches\n\nTransdermal patches are used for systemic delivery of APIs which are capable of diffusion through the stratum corneum and are therapeutically active at the low plasma concentrations that can be achieved. The manufacture of transdermal patches of the \u201cdrug-in-adhesive\u201d type is now well developed and less problematic than the earlier \u201cdrug-in-reservoir\u201d type; the API is dispersed in a suitable polymeric adhesive to be fixed in a thin layer on a backing and covered by a removable liner.\n\nThe size and shape of a transdermal patch should be adapted to fit the child\u2019s body. It should stick firmly to the skin and not be too difficult to remove. Application sites which cannot easily be reached by the child should be chosen to avoid removal of the patch by the child. The risk of deliberate removal and its consequences for therapy must be considered. The increased systemic absorption through the skin, for the reasons mentioned above, may increase the systemic delivery from transdermal patches, in particular in newborns and young infants.\n\nWhen designed to be cut, information on the cutting technique should be provided in the patient leaflet and facilitated by the presence of cutting lines to ensure equal division. Reservoir systems should never be cut.\n\nAdhesives should have a low allergenic potential to avoid irritation and infection. Local tolerance and acceptability should be tested.\n\n# 10. Inhalations\n\nPulmonary administration of medicines by inhalation has traditionally been used to obtain a local effect. This route of administration also has a potential for systemic delivery. Preparations for inhalation include liquids for nebulization, pressurized metered dose inhalers (MDIs) and dry powder inhalers (DPIs).\n\nThe implications of the physiology of children of different ages and their ability to use the devices correctly should be considered in the development of paediatric inhalations (8). Depending on their age, children may have more or less difficulty with some of the devices. Problems with the coordination of the inhalation for MDIs and the ability to inhale strongly enough for DPIs determine the effectiveness of getting the medicine into the lung.\n\nThe total lung deposition is important for the clinical efficacy of preparations for inhalation. Generally it is affected by the formulation and delivery device controlling size distribution of the aerosol and patient-related factors such as the current disease state. The diameter of the airways is smaller in children than in adults; hence deposition by impact in the upper and central airways may be significantly higher in children (36). The particle size of the aerosol produced by the delivery device needs to be explored during development.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "420d2d3e1215ecb6c6edf4cf551d6db8d99a6174c7e0308d1ac056fbc30b61b0", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 9.1 Transdermal patches\n\nTransdermal patches are used for systemic delivery of APIs which are capable of diffusion through the stratum corneum and are therapeutically active at the low plasma concentrations that can be achieved. The manufacture of transdermal patches of the \u201cdrug-in-adhesive\u201d type is now well developed and less problematic than the earlier \u201cdrug-in-reservoir\u201d type; the API is dispersed in a suitable polymeric adhesive to be fixed in a thin layer on a backing and covered by a removable liner.\n\nThe size and shape of a transdermal patch should be adapted to fit the child\u2019s body. It should stick firmly to the skin and not be too difficult to remove. Application sites which cannot easily be reached by the child should be chosen to avoid removal of the patch by the child. The risk of deliberate removal and its consequences for therapy must be considered. The increased systemic absorption through the skin, for the reasons mentioned above, may increase the systemic delivery from transdermal patches, in particular in newborns and young infants.\n\nWhen designed to be cut, information on the cutting technique should be provided in the patient leaflet and facilitated by the presence of cutting lines to ensure equal division. Reservoir systems should never be cut.\n\nAdhesives should have a low allergenic potential to avoid irritation and infection. Local tolerance and acceptability should be tested.\n\n# 10. Inhalations\n\nPulmonary administration of medicines by inhalation has traditionally been used to obtain a local effect. This route of administration also has a potential for systemic delivery. Preparations for inhalation include liquids for nebulization, pressurized metered dose inhalers (MDIs) and dry powder inhalers (DPIs).\n\nThe implications of the physiology of children of different ages and their ability to use the devices correctly should be considered in the development of paediatric inhalations (8). Depending on their age, children may have more or less difficulty with some of the devices. Problems with the coordination of the inhalation for MDIs and the ability to inhale strongly enough for DPIs determine the effectiveness of getting the medicine into the lung.\n\nThe total lung deposition is important for the clinical efficacy of preparations for inhalation. Generally it is affected by the formulation and delivery device controlling size distribution of the aerosol and patient-related factors such as the current disease state. The diameter of the airways is smaller in children than in adults; hence deposition by impact in the upper and central airways may be significantly higher in children (36). The particle size of the aerosol produced by the delivery device needs to be explored during development.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2761, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c5d9097f-7430-4a87-b120-5789e3d901f2": {"__data__": {"id_": "c5d9097f-7430-4a87-b120-5789e3d901f2", "embedding": null, "metadata": {"page_label": "236", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nNebulized liquids are potentially suitable for young children who cannot use MDIs and DPIs. Their use, however, requires nebulizing devices and access to electricity.\n\nMDIs may be suitable for children from birth when combined with a spacer. A spacer eliminates the need for coordinating the MDI actuation and the start of inhalation. For children younger than 2\u20133 years a facemask is also required. This can be replaced by a mouthpiece when the child is able to manage the system.\n\nDPIs may be used for children from the age of 4\u20135 years, as minimum inspiratory flow is required. DPIs and MDIs are preferred for older children because of their portability and convenience.\n\n## 11. Packaging and labelling\n\nContainer-closure systems for paediatric medicines are designed and constructed from materials meeting relevant regulatory requirements, and taking into account the stability of the medicine during transport, storage and use. In addition they are designed to ensure that they:\n\n- permit accurate dosing and convenient administration;\n- are robust and convenient for the supply chain, i.e. transportable;\n- are tailored to the target age group;\n- contribute to in-use stability;\n- provide appropriate information on the use of the medicine.\n\nIn cases where the paediatric medicine is significantly different from a similar adult medicine, it would be important to have noticeably different product packaging for the two products. It is necessary that consideration be given to whether the medicine is to be packed in a child-resistant container, i.e. a packaging that is difficult for young children to open, but not unduly difficult for adults to open properly.\n\nSelf-administration of medicine by schoolchildren and adolescents is facilitated when:\n\n- the medicine is easy to use;\n- separation of the day dose pack is facilitated; this should be easily carried by the patient in his or her bag;\n- clear instructions for use are contained with the medicine.\n\nAdequate information about the medicine and how to use it is important. Information about the dosage should be clearly spelt out, e.g. as milligrams per...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda las especificaciones para preparaciones farmac\u00e9uticas, centr\u00e1ndose en la administraci\u00f3n de medicamentos a ni\u00f1os. Se discuten diferentes m\u00e9todos de inhalaci\u00f3n, como los aerosoles de dosis medida (MDIs), los inhaladores de polvo seco (DPIs) y l\u00edquidos nebulizados, destacando su idoneidad seg\u00fan la edad del ni\u00f1o. Adem\u00e1s, se enfatiza la importancia del dise\u00f1o de envases y etiquetado para medicamentos pedi\u00e1tricos, asegurando que sean seguros, f\u00e1ciles de usar y que proporcionen informaci\u00f3n clara sobre el uso y la dosificaci\u00f3n.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones clave para el dise\u00f1o de envases de medicamentos pedi\u00e1tricos seg\u00fan la OMS?**\n   - La OMS se\u00f1ala que los envases deben permitir una dosificaci\u00f3n precisa, ser robustos y convenientes para el transporte, estar adaptados al grupo de edad objetivo, contribuir a la estabilidad en uso y proporcionar informaci\u00f3n adecuada sobre el uso del medicamento.\n\n2. **\u00bfQu\u00e9 requisitos se deben cumplir para que un MDI sea adecuado para ni\u00f1os menores de 2-3 a\u00f1os?**\n   - Para que un MDI sea adecuado para ni\u00f1os menores de 2-3 a\u00f1os, debe utilizarse con un espaciador y se requiere una mascarilla facial, que puede ser reemplazada por una boquilla cuando el ni\u00f1o sea capaz de manejar el sistema.\n\n3. **\u00bfC\u00f3mo se facilita la auto-administraci\u00f3n de medicamentos en escolares y adolescentes?**\n   - La auto-administraci\u00f3n se facilita cuando el medicamento es f\u00e1cil de usar, se permite la separaci\u00f3n de las dosis diarias en empaques que sean f\u00e1ciles de llevar, y se incluyen instrucciones claras sobre su uso.", "prev_section_summary": "### Temas Clave\n\n1. **Parches Transd\u00e9rmicos**:\n   - Utilizados para la entrega sist\u00e9mica de principios activos (APIs) que pueden difundir a trav\u00e9s de la piel.\n   - La fabricaci\u00f3n de parches del tipo \"drug-in-adhesive\" es m\u00e1s avanzada y menos problem\u00e1tica que el tipo \"drug-in-reservoir\".\n   - Importancia de adaptar el tama\u00f1o y la forma del parche al cuerpo del ni\u00f1o.\n   - Necesidad de elegir sitios de aplicaci\u00f3n que no sean f\u00e1cilmente alcanzables por el ni\u00f1o para evitar la remoci\u00f3n deliberada.\n   - Consideraciones sobre la absorci\u00f3n sist\u00e9mica, especialmente en reci\u00e9n nacidos y ni\u00f1os peque\u00f1os.\n   - Precauciones sobre el uso de adhesivos con bajo potencial al\u00e9rgico para evitar irritaciones.\n\n2. **Inhalaciones**:\n   - Administraci\u00f3n pulmonar de medicamentos, tradicionalmente para efectos locales, pero tambi\u00e9n con potencial para efectos sist\u00e9micos.\n   - Tipos de preparaciones: l\u00edquidos para nebulizaci\u00f3n, inhaladores de dosis medida (MDIs) y inhaladores de polvo seco (DPIs).\n   - Consideraciones sobre la fisiolog\u00eda de los ni\u00f1os y su capacidad para usar correctamente los dispositivos de inhalaci\u00f3n.\n   - Importancia de la deposici\u00f3n pulmonar para la eficacia cl\u00ednica de las preparaciones para inhalaci\u00f3n.\n   - Diferencias en el di\u00e1metro de las v\u00edas respiratorias entre ni\u00f1os y adultos, lo que afecta la deposici\u00f3n de part\u00edculas.\n\n### Entidades\n\n- **Parches Transd\u00e9rmicos**: Dispositivos para la entrega de medicamentos a trav\u00e9s de la piel.\n- **Principios Activos (APIs)**: Sustancias que tienen un efecto terap\u00e9utico.\n- **Adhesivos**: Materiales utilizados en parches que deben ser hipoalerg\u00e9nicos.\n- **Inhaladores**: Dispositivos para la administraci\u00f3n de medicamentos por v\u00eda pulmonar (MDIs y DPIs).\n- **Fisiolog\u00eda Infantil**: Consideraciones sobre el desarrollo y las caracter\u00edsticas f\u00edsicas de los ni\u00f1os que afectan la administraci\u00f3n de medicamentos.\n- **Dep\u00f3sito Pulmonar**: Cantidad de medicamento que llega a los pulmones y su importancia para la eficacia del tratamiento. \n\nEste resumen destaca los aspectos esenciales de la administraci\u00f3n de medicamentos en pediatr\u00eda a trav\u00e9s de parches transd\u00e9rmicos e inhalaciones, enfatizando la necesidad de un dise\u00f1o adecuado y consideraciones de seguridad.", "excerpt_keywords": "Keywords: pediatric medicines, inhalation devices, packaging design, self-administration, dosage instructions"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a176f135-5d92-4b95-9bf4-725e7978e70c", "node_type": "4", "metadata": {"page_label": "236", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nNebulized liquids are potentially suitable for young children who cannot use MDIs and DPIs. Their use, however, requires nebulizing devices and access to electricity.\n\nMDIs may be suitable for children from birth when combined with a spacer. A spacer eliminates the need for coordinating the MDI actuation and the start of inhalation. For children younger than 2\u20133 years a facemask is also required. This can be replaced by a mouthpiece when the child is able to manage the system.\n\nDPIs may be used for children from the age of 4\u20135 years, as minimum inspiratory flow is required. DPIs and MDIs are preferred for older children because of their portability and convenience.\n\n## 11. Packaging and labelling\n\nContainer-closure systems for paediatric medicines are designed and constructed from materials meeting relevant regulatory requirements, and taking into account the stability of the medicine during transport, storage and use. In addition they are designed to ensure that they:\n\n- permit accurate dosing and convenient administration;\n- are robust and convenient for the supply chain, i.e. transportable;\n- are tailored to the target age group;\n- contribute to in-use stability;\n- provide appropriate information on the use of the medicine.\n\nIn cases where the paediatric medicine is significantly different from a similar adult medicine, it would be important to have noticeably different product packaging for the two products. It is necessary that consideration be given to whether the medicine is to be packed in a child-resistant container, i.e. a packaging that is difficult for young children to open, but not unduly difficult for adults to open properly.\n\nSelf-administration of medicine by schoolchildren and adolescents is facilitated when:\n\n- the medicine is easy to use;\n- separation of the day dose pack is facilitated; this should be easily carried by the patient in his or her bag;\n- clear instructions for use are contained with the medicine.\n\nAdequate information about the medicine and how to use it is important. Information about the dosage should be clearly spelt out, e.g. as milligrams per...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "d662015ef96efb5e7d44737f29d59d441882a6ba7583f6ce49d97cdd3dd2278f", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nNebulized liquids are potentially suitable for young children who cannot use MDIs and DPIs. Their use, however, requires nebulizing devices and access to electricity.\n\nMDIs may be suitable for children from birth when combined with a spacer. A spacer eliminates the need for coordinating the MDI actuation and the start of inhalation. For children younger than 2\u20133 years a facemask is also required. This can be replaced by a mouthpiece when the child is able to manage the system.\n\nDPIs may be used for children from the age of 4\u20135 years, as minimum inspiratory flow is required. DPIs and MDIs are preferred for older children because of their portability and convenience.\n\n## 11. Packaging and labelling\n\nContainer-closure systems for paediatric medicines are designed and constructed from materials meeting relevant regulatory requirements, and taking into account the stability of the medicine during transport, storage and use. In addition they are designed to ensure that they:\n\n- permit accurate dosing and convenient administration;\n- are robust and convenient for the supply chain, i.e. transportable;\n- are tailored to the target age group;\n- contribute to in-use stability;\n- provide appropriate information on the use of the medicine.\n\nIn cases where the paediatric medicine is significantly different from a similar adult medicine, it would be important to have noticeably different product packaging for the two products. It is necessary that consideration be given to whether the medicine is to be packed in a child-resistant container, i.e. a packaging that is difficult for young children to open, but not unduly difficult for adults to open properly.\n\nSelf-administration of medicine by schoolchildren and adolescents is facilitated when:\n\n- the medicine is easy to use;\n- separation of the day dose pack is facilitated; this should be easily carried by the patient in his or her bag;\n- clear instructions for use are contained with the medicine.\n\nAdequate information about the medicine and how to use it is important. Information about the dosage should be clearly spelt out, e.g. as milligrams per...", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2195, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "0e76bd68-46e7-4f03-a114-02bbe51bca58": {"__data__": {"id_": "0e76bd68-46e7-4f03-a114-02bbe51bca58", "embedding": null, "metadata": {"page_label": "237", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# References\n\n1. **Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products \u2013 points to consider.** Geneva, World Health Organization, 2010 (working document QAS/11.399/Rev. 1).\n\n2. Kearns GL et al. Developmental pharmacology \u2013 drug disposition, action and therapy in infants and children. *New England Journal of Medicine*, 2003, 349:1157\u20131167.\n\n3. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Clinical investigation of medicinal products in the paediatric population. Implementation: EU, MHLW, FDA. Adopted by CPMP, July 2000, issued as CPMP/ICH/2711/99; adopted 15 December 2000, PMSB/ELD Notification No. 1334. *Federal Register*, 12 April 2000, 65(71): 19777\u201319781.\n\n4. **WHO draft guideline on quality risk management.** Geneva, World Health Organization, 2010 (working document QAS/10.376).\n\n5. **Pharmaceutical development for multisource (generic) pharmaceutical products.** Geneva, World Health Organization, 2010 (working document QAS/08.251/Rev.1).\n\n6. Committee for Medicinal Products for Human Use (CHMP). *Reflection paper: formulations of choice for the paediatric population.* London, EMEA, 2006 (EMEA/CHMP/PEG/196810/2005).\n\n7. Ernest TB et al. Developing paediatric medicines: identifying the needs and recognizing the challenges. *Journal of Pharmacy and Pharmacology*, 2007, 59: 1043\u20131055.\n\n8. Krause J, Breitkreutz J. Improving drug delivery in paediatric medicine. *Pharmaceutical Medicine*, 2008, 22: 41\u201350.\n\n9. Zhao N et al. Tablet splitting: product quality assessment of metoprolol succinate extended release tablets. *International Journal of Pharmaceutics*, 2010, 401: 25\u201331.\n\n10. Allen LV. Dosage form design and development. *Clinical Therapeutics*, 2008, 30: 2102\u20132111.\n\n11. Guidelines for registration of fixed-dose combination medicinal products. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth Report.* Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n12. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities in new drug substances. Implementation: EU, MHLW, FDA. Adopted by CPMP, October 2006, issued as CPMP/ICH/142/95; adopted 4 December 2006, PFSB/ELD Notification No. 1204001. *Federal Register*, June 2008.\n\n13. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities in new drug products. Implementation: EU, MHLW, FDA. Adopted by CPMP, June 2006, issued as CPMP/ICH/2738/99; adopted 3 July 2006, PFSB/ELD Notification No. 0703004. *Federal Register*, 2003, 68: 64628\u201364629 with the revised attachment 2.\n\n14. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities: guideline for", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que se centra en la investigaci\u00f3n y desarrollo de medicamentos pedi\u00e1tricos. Incluye referencias a directrices, estudios y documentos de trabajo relacionados con la formulaci\u00f3n, calidad y regulaci\u00f3n de productos farmac\u00e9uticos para la poblaci\u00f3n infantil. Se abordan temas como la necesidad de preparaciones espec\u00edficas para ni\u00f1os, el desarrollo farmacol\u00f3gico en infantes y los desaf\u00edos en la creaci\u00f3n de medicamentos pedi\u00e1tricos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los puntos clave que deben considerar los profesionales de la salud al proporcionar preparaciones espec\u00edficas para ni\u00f1os que no est\u00e1n disponibles como productos autorizados?**\n   - Esta pregunta se refiere directamente al primer punto de la lista de referencias, que menciona un documento de trabajo de la OMS sobre el tema.\n\n2. **\u00bfQu\u00e9 desaf\u00edos se identifican en el desarrollo de medicamentos pedi\u00e1tricos seg\u00fan el art\u00edculo de Ernest TB et al. en el *Journal of Pharmacy and Pharmacology*?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre los desaf\u00edos mencionados en la referencia 7, que podr\u00eda no estar ampliamente discutida en otras fuentes.\n\n3. **\u00bfQu\u00e9 directrices proporciona la OMS sobre la gesti\u00f3n de riesgos de calidad en la fabricaci\u00f3n de medicamentos pedi\u00e1tricos?**\n   - Esta pregunta se relaciona con el cuarto punto de la lista de referencias, que menciona una gu\u00eda de la OMS sobre gesti\u00f3n de riesgos de calidad, y podr\u00eda ofrecer detalles que no se encuentran f\u00e1cilmente en otros documentos.\n\n### Resumen de Nivel Superior\n\nEl informe de la OMS destaca la importancia de adaptar los medicamentos para la poblaci\u00f3n pedi\u00e1trica, abordando la falta de productos autorizados y la necesidad de formulaciones espec\u00edficas. Se mencionan directrices y estudios que abordan la investigaci\u00f3n cl\u00ednica, la calidad de los productos y los desaf\u00edos en el desarrollo de medicamentos para ni\u00f1os. La OMS y otras organizaciones han establecido pautas para garantizar que los medicamentos sean seguros y efectivos para los m\u00e1s j\u00f3venes, reconociendo las diferencias en la farmacolog\u00eda entre ni\u00f1os y adultos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **M\u00e9todos de Inhalaci\u00f3n para Ni\u00f1os**:\n   - **L\u00edquidos Nebulizados**: Adecuados para ni\u00f1os peque\u00f1os que no pueden usar MDIs o DPIs, pero requieren dispositivos de nebulizaci\u00f3n y acceso a electricidad.\n   - **Aerosoles de Dosis Medida (MDIs)**: Pueden ser utilizados desde el nacimiento con un espaciador; se requiere mascarilla para ni\u00f1os menores de 2-3 a\u00f1os.\n   - **Inhaladores de Polvo Seco (DPIs)**: A partir de los 4-5 a\u00f1os, debido a la necesidad de un flujo inspiratorio m\u00ednimo. Preferidos para ni\u00f1os mayores por su portabilidad y conveniencia.\n\n2. **Dise\u00f1o de Envases y Etiquetado para Medicamentos Pedi\u00e1tricos**:\n   - Los sistemas de cierre de envases deben cumplir con requisitos regulatorios y asegurar la estabilidad del medicamento.\n   - Consideraciones clave incluyen:\n     - Dosificaci\u00f3n precisa y administraci\u00f3n conveniente.\n     - Robustez y conveniencia para el transporte.\n     - Adaptaci\u00f3n al grupo de edad objetivo.\n     - Contribuci\u00f3n a la estabilidad en uso.\n     - Informaci\u00f3n adecuada sobre el uso del medicamento.\n\n3. **Diferenciaci\u00f3n en el Empaque**:\n   - Es importante que el empaque de medicamentos pedi\u00e1tricos sea notablemente diferente al de los medicamentos para adultos, especialmente si son significativamente distintos.\n\n4. **Auto-administraci\u00f3n en Escolares y Adolescentes**:\n   - Facilidades para la auto-administraci\u00f3n incluyen:\n     - Medicamentos f\u00e1ciles de usar.\n     - Empaques que permiten la separaci\u00f3n de dosis diarias y son f\u00e1ciles de transportar.\n     - Instrucciones claras sobre el uso del medicamento.\n\n5. **Importancia de la Informaci\u00f3n**:\n   - La informaci\u00f3n sobre el medicamento y su uso debe ser clara, incluyendo detalles sobre la dosificaci\u00f3n.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las recomendaciones.\n- **MDIs (Aerosoles de Dosis Medida)**: Dispositivos de inhalaci\u00f3n.\n- **DPIs (Inhaladores de Polvo Seco)**: Otro tipo de dispositivo de inhalaci\u00f3n.\n- **L\u00edquidos Nebulizados**: Forma de medicaci\u00f3n para inhalaci\u00f3n.\n- **Espaciador**: Dispositivo que ayuda en la administraci\u00f3n de MDIs.\n- **Mascarilla Facial**: Accesorio necesario para el uso de MDIs en ni\u00f1os peque\u00f1os.\n- **Envases de Medicamentos**: Sistemas de empaque dise\u00f1ados para medicamentos pedi\u00e1tricos.", "excerpt_keywords": "Keywords: pediatric medicines, drug formulation, quality risk management, pharmaceutical guidelines, health care professionals"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "696d063f-9d11-4f86-8258-c80db5178fb4", "node_type": "4", "metadata": {"page_label": "237", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# References\n\n1. **Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products \u2013 points to consider.** Geneva, World Health Organization, 2010 (working document QAS/11.399/Rev. 1).\n\n2. Kearns GL et al. Developmental pharmacology \u2013 drug disposition, action and therapy in infants and children. *New England Journal of Medicine*, 2003, 349:1157\u20131167.\n\n3. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Clinical investigation of medicinal products in the paediatric population. Implementation: EU, MHLW, FDA. Adopted by CPMP, July 2000, issued as CPMP/ICH/2711/99; adopted 15 December 2000, PMSB/ELD Notification No. 1334. *Federal Register*, 12 April 2000, 65(71): 19777\u201319781.\n\n4. **WHO draft guideline on quality risk management.** Geneva, World Health Organization, 2010 (working document QAS/10.376).\n\n5. **Pharmaceutical development for multisource (generic) pharmaceutical products.** Geneva, World Health Organization, 2010 (working document QAS/08.251/Rev.1).\n\n6. Committee for Medicinal Products for Human Use (CHMP). *Reflection paper: formulations of choice for the paediatric population.* London, EMEA, 2006 (EMEA/CHMP/PEG/196810/2005).\n\n7. Ernest TB et al. Developing paediatric medicines: identifying the needs and recognizing the challenges. *Journal of Pharmacy and Pharmacology*, 2007, 59: 1043\u20131055.\n\n8. Krause J, Breitkreutz J. Improving drug delivery in paediatric medicine. *Pharmaceutical Medicine*, 2008, 22: 41\u201350.\n\n9. Zhao N et al. Tablet splitting: product quality assessment of metoprolol succinate extended release tablets. *International Journal of Pharmaceutics*, 2010, 401: 25\u201331.\n\n10. Allen LV. Dosage form design and development. *Clinical Therapeutics*, 2008, 30: 2102\u20132111.\n\n11. Guidelines for registration of fixed-dose combination medicinal products. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth Report.* Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n12. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities in new drug substances. Implementation: EU, MHLW, FDA. Adopted by CPMP, October 2006, issued as CPMP/ICH/142/95; adopted 4 December 2006, PFSB/ELD Notification No. 1204001. *Federal Register*, June 2008.\n\n13. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities in new drug products. Implementation: EU, MHLW, FDA. Adopted by CPMP, June 2006, issued as CPMP/ICH/2738/99; adopted 3 July 2006, PFSB/ELD Notification No. 0703004. *Federal Register*, 2003, 68: 64628\u201364629 with the revised attachment 2.\n\n14. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities: guideline for", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "60f2622d73f06db7c00b00b0a994cf8947343d99178d707d8c70ba513f4c41f3", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# References\n\n1. **Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products \u2013 points to consider.** Geneva, World Health Organization, 2010 (working document QAS/11.399/Rev. 1).\n\n2. Kearns GL et al. Developmental pharmacology \u2013 drug disposition, action and therapy in infants and children. *New England Journal of Medicine*, 2003, 349:1157\u20131167.\n\n3. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Clinical investigation of medicinal products in the paediatric population. Implementation: EU, MHLW, FDA. Adopted by CPMP, July 2000, issued as CPMP/ICH/2711/99; adopted 15 December 2000, PMSB/ELD Notification No. 1334. *Federal Register*, 12 April 2000, 65(71): 19777\u201319781.\n\n4. **WHO draft guideline on quality risk management.** Geneva, World Health Organization, 2010 (working document QAS/10.376).\n\n5. **Pharmaceutical development for multisource (generic) pharmaceutical products.** Geneva, World Health Organization, 2010 (working document QAS/08.251/Rev.1).\n\n6. Committee for Medicinal Products for Human Use (CHMP). *Reflection paper: formulations of choice for the paediatric population.* London, EMEA, 2006 (EMEA/CHMP/PEG/196810/2005).\n\n7. Ernest TB et al. Developing paediatric medicines: identifying the needs and recognizing the challenges. *Journal of Pharmacy and Pharmacology*, 2007, 59: 1043\u20131055.\n\n8. Krause J, Breitkreutz J. Improving drug delivery in paediatric medicine. *Pharmaceutical Medicine*, 2008, 22: 41\u201350.\n\n9. Zhao N et al. Tablet splitting: product quality assessment of metoprolol succinate extended release tablets. *International Journal of Pharmaceutics*, 2010, 401: 25\u201331.\n\n10. Allen LV. Dosage form design and development. *Clinical Therapeutics*, 2008, 30: 2102\u20132111.\n\n11. Guidelines for registration of fixed-dose combination medicinal products. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth Report.* Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n12. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities in new drug substances. Implementation: EU, MHLW, FDA. Adopted by CPMP, October 2006, issued as CPMP/ICH/142/95; adopted 4 December 2006, PFSB/ELD Notification No. 1204001. *Federal Register*, June 2008.\n\n13. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities in new drug products. Implementation: EU, MHLW, FDA. Adopted by CPMP, June 2006, issued as CPMP/ICH/2738/99; adopted 3 July 2006, PFSB/ELD Notification No. 0703004. *Federal Register*, 2003, 68: 64628\u201364629 with the revised attachment 2.\n\n14. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities: guideline for", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3126, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "4e2fabbb-061f-4541-a2d5-c908a0f3ea20": {"__data__": {"id_": "4e2fabbb-061f-4541-a2d5-c908a0f3ea20", "embedding": null, "metadata": {"page_label": "238", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n15. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). *Guideline on the limits of genotoxic impurities*. London, 28 June 2006 (CPMP/SWP/5199/02, EMEA/CHMP/ QWP/251344/2006).\n\n16. European Medicines Agency. *Questions and answers on the \u201cGuideline on the limits of genotoxic impurities\u201d*. London, EMEA, 2010 (EMEA/CHMP/SWP/431994/2007).\n\n17. European Medicines Agency. *Guideline on the specification limits for residues of metal catalysts or metal reagents*. London, 21 February 2008 (EMEA/CHMP/SWP/QWP/4446/2000).\n\n18. Siewert M et al. FIP/AAPS guidelines to dissolution/in vitro release testing of novel/special dosage forms. *AAPS PharmSciTech*, 2003, 4:Article 7 (http://www.aapspharmscitech.org/view. asp?art=pt040107).\n\n19. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth Report*. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n20. Proposal to waive in vivo bioequivalence requirements for WHO Model List of essential medicines immediate-release, solid dosage forms. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth Report*. Geneva, World Health Organization, 2006, Annex 8 (WHO Technical Report Series, No. 937).\n\n21. Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. *Expert Opinion on Drug Delivery*, 2007, 4: 37\u201345.\n\n22. Shehab N et al. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. *Pediatric Critical Care Medicine*, 2009, 10(2): 256\u2013259.\n\n23. American Academy of Pediatrics. \u201cInactive\u201d ingredients in pharmaceutical products: update (subject review). *Pediatrics*, 1997, 99:268\u2013278 (http://www.pediatrics.org/cgi/content/ full/99/2/268).\n\n24. WHO Technical Report Series on evaluation of certain food additives. *List of publications* (http:// www.who.int/ipcs/publications/jecfa/reports/en/index.html).\n\n25. Pollock I et al. Survey of colourings and preservatives in drugs. *BMJ*, 1989, 299: 649\u2013651.\n\n26. Pefferi G, Restani P. The safety of pharmaceutical excipients. *Il Farmaco*, 2003, 58: 541\u2013550.\n\n27. European Medicines Agency. EMEA Public Statement on antimicrobial preservatives in ophthalmic preparations for human use. London, EMEA, 2009 (EMEA/622721/2009).\n\n28. Mennella JA, Beauchamp GK. Optimizing oral medications for children. *Clinical Therapeutics*, 2008, 30: 2120\u20132132.\n\n29. *Production of zinc tablets and zinc oral solutions: guidelines for programme managers and pharmaceutical manufacturers*, Annex 7. Geneva, World Health Organization, 2007.\n\n30. Cram A et al. Challenges of developing palatable oral paediatric formulations. *International Journal of Pharmaceutics*, 2009, 365: 1\u20133.\n\n31. Committee for Medicinal Products for Human Use. *Guideline on the investigation of medicinal products in the term and preterm neonate*. London, European Medicines Agency, 2007.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que presenta las recomendaciones y directrices de un comit\u00e9 de expertos sobre las especificaciones para preparaciones farmac\u00e9uticas. Incluye referencias a diversas gu\u00edas y estudios relacionados con la seguridad de los excipientes farmac\u00e9uticos, l\u00edmites de impurezas genot\u00f3xicas, y la formulaci\u00f3n de medicamentos para poblaciones espec\u00edficas como neonatos y ancianos. Tambi\u00e9n se abordan temas como la bioequivalencia y la optimizaci\u00f3n de medicamentos orales para ni\u00f1os.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las recomendaciones de la OMS sobre los l\u00edmites de impurezas genot\u00f3xicas en productos farmac\u00e9uticos?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las directrices emitidas por la Agencia Europea de Medicamentos (EMA) en relaci\u00f3n con las impurezas genot\u00f3xicas, que son cruciales para garantizar la seguridad de los medicamentos.\n\n2. **\u00bfQu\u00e9 consideraciones se deben tener en cuenta al formular medicamentos para neonatos seg\u00fan el informe?**\n   - Esta pregunta se centra en las pautas espec\u00edficas para la formulaci\u00f3n de medicamentos dirigidos a neonatos, un grupo vulnerable que requiere atenci\u00f3n especial en el desarrollo de medicamentos.\n\n3. **\u00bfQu\u00e9 desaf\u00edos se mencionan en el desarrollo de formulaciones orales palatables para pediatr\u00eda?**\n   - Esta pregunta busca explorar los problemas espec\u00edficos que enfrentan los fabricantes al crear medicamentos que sean aceptables y agradables para los ni\u00f1os, un aspecto importante en la adherencia al tratamiento.\n\n### Resumen de Nivel Superior\nEl informe de la OMS proporciona un marco para la regulaci\u00f3n y desarrollo de productos farmac\u00e9uticos, enfatizando la importancia de la seguridad y eficacia en la formulaci\u00f3n de medicamentos. Se abordan temas cr\u00edticos como la evaluaci\u00f3n de excipientes, la bioequivalencia, y la adaptaci\u00f3n de medicamentos para poblaciones espec\u00edficas, destacando la necesidad de directrices claras y basadas en evidencia para proteger la salud p\u00fablica.", "prev_section_summary": "### Temas Clave\n\n1. **Desarrollo de Medicamentos Pedi\u00e1tricos**: El informe aborda la necesidad de crear medicamentos espec\u00edficos para la poblaci\u00f3n infantil, destacando la falta de productos autorizados y la importancia de formulaciones adaptadas.\n\n2. **Directrices de la OMS**: Se mencionan varias directrices y documentos de trabajo de la Organizaci\u00f3n Mundial de la Salud (OMS) que proporcionan pautas sobre la gesti\u00f3n de riesgos de calidad, el desarrollo farmac\u00e9utico y la formulaci\u00f3n de medicamentos para ni\u00f1os.\n\n3. **Investigaci\u00f3n y Regulaci\u00f3n**: Se discuten las normativas y gu\u00edas de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) relacionadas con la investigaci\u00f3n cl\u00ednica y la regulaci\u00f3n de productos farmac\u00e9uticos para la poblaci\u00f3n pedi\u00e1trica.\n\n4. **Desaf\u00edos en el Desarrollo**: Se identifican los desaf\u00edos que enfrentan los profesionales de la salud y la industria farmac\u00e9utica en el desarrollo de medicamentos pedi\u00e1tricos, incluyendo la necesidad de adaptaciones en la dosificaci\u00f3n y formulaci\u00f3n.\n\n5. **Calidad y Seguridad**: Se enfatiza la importancia de garantizar la calidad y seguridad de los medicamentos para ni\u00f1os, considerando las diferencias en la farmacolog\u00eda entre ni\u00f1os y adultos.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Proporciona directrices y documentos de trabajo sobre medicamentos pedi\u00e1tricos.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Establece pautas para la investigaci\u00f3n y regulaci\u00f3n de medicamentos.\n- **Revistas Cient\u00edficas**: Se citan art\u00edculos de revistas como el *New England Journal of Medicine* y el *Journal of Pharmacy and Pharmacology*, que abordan temas relevantes en farmacolog\u00eda pedi\u00e1trica.\n- **Comit\u00e9 de Medicamentos para Uso Humano (CHMP)**: Ofrece reflexiones sobre formulaciones adecuadas para la poblaci\u00f3n pedi\u00e1trica.\n\n### Conclusi\u00f3n\n\nEl informe de la OMS subraya la necesidad de un enfoque espec\u00edfico para el desarrollo de medicamentos pedi\u00e1tricos, abordando tanto la falta de productos autorizados como los desaf\u00edos en la formulaci\u00f3n y regulaci\u00f3n. Se destaca la importancia de seguir directrices establecidas para asegurar que los medicamentos sean seguros y efectivos para los ni\u00f1os.", "excerpt_keywords": "Keywords: pharmaceutical preparations, genotoxic impurities, pediatric formulations, drug safety, WHO guidelines"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cef4e6f5-afff-4486-bae7-16451af83c5d", "node_type": "4", "metadata": {"page_label": "238", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n15. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). *Guideline on the limits of genotoxic impurities*. London, 28 June 2006 (CPMP/SWP/5199/02, EMEA/CHMP/ QWP/251344/2006).\n\n16. European Medicines Agency. *Questions and answers on the \u201cGuideline on the limits of genotoxic impurities\u201d*. London, EMEA, 2010 (EMEA/CHMP/SWP/431994/2007).\n\n17. European Medicines Agency. *Guideline on the specification limits for residues of metal catalysts or metal reagents*. London, 21 February 2008 (EMEA/CHMP/SWP/QWP/4446/2000).\n\n18. Siewert M et al. FIP/AAPS guidelines to dissolution/in vitro release testing of novel/special dosage forms. *AAPS PharmSciTech*, 2003, 4:Article 7 (http://www.aapspharmscitech.org/view. asp?art=pt040107).\n\n19. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth Report*. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n20. Proposal to waive in vivo bioequivalence requirements for WHO Model List of essential medicines immediate-release, solid dosage forms. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth Report*. Geneva, World Health Organization, 2006, Annex 8 (WHO Technical Report Series, No. 937).\n\n21. Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. *Expert Opinion on Drug Delivery*, 2007, 4: 37\u201345.\n\n22. Shehab N et al. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. *Pediatric Critical Care Medicine*, 2009, 10(2): 256\u2013259.\n\n23. American Academy of Pediatrics. \u201cInactive\u201d ingredients in pharmaceutical products: update (subject review). *Pediatrics*, 1997, 99:268\u2013278 (http://www.pediatrics.org/cgi/content/ full/99/2/268).\n\n24. WHO Technical Report Series on evaluation of certain food additives. *List of publications* (http:// www.who.int/ipcs/publications/jecfa/reports/en/index.html).\n\n25. Pollock I et al. Survey of colourings and preservatives in drugs. *BMJ*, 1989, 299: 649\u2013651.\n\n26. Pefferi G, Restani P. The safety of pharmaceutical excipients. *Il Farmaco*, 2003, 58: 541\u2013550.\n\n27. European Medicines Agency. EMEA Public Statement on antimicrobial preservatives in ophthalmic preparations for human use. London, EMEA, 2009 (EMEA/622721/2009).\n\n28. Mennella JA, Beauchamp GK. Optimizing oral medications for children. *Clinical Therapeutics*, 2008, 30: 2120\u20132132.\n\n29. *Production of zinc tablets and zinc oral solutions: guidelines for programme managers and pharmaceutical manufacturers*, Annex 7. Geneva, World Health Organization, 2007.\n\n30. Cram A et al. Challenges of developing palatable oral paediatric formulations. *International Journal of Pharmaceutics*, 2009, 365: 1\u20133.\n\n31. Committee for Medicinal Products for Human Use. *Guideline on the investigation of medicinal products in the term and preterm neonate*. London, European Medicines Agency, 2007.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "2d15c1236853c689f2f97e79d8e2f35fe4af4312e963e535e914fdd485131219", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n15. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). *Guideline on the limits of genotoxic impurities*. London, 28 June 2006 (CPMP/SWP/5199/02, EMEA/CHMP/ QWP/251344/2006).\n\n16. European Medicines Agency. *Questions and answers on the \u201cGuideline on the limits of genotoxic impurities\u201d*. London, EMEA, 2010 (EMEA/CHMP/SWP/431994/2007).\n\n17. European Medicines Agency. *Guideline on the specification limits for residues of metal catalysts or metal reagents*. London, 21 February 2008 (EMEA/CHMP/SWP/QWP/4446/2000).\n\n18. Siewert M et al. FIP/AAPS guidelines to dissolution/in vitro release testing of novel/special dosage forms. *AAPS PharmSciTech*, 2003, 4:Article 7 (http://www.aapspharmscitech.org/view. asp?art=pt040107).\n\n19. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth Report*. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n20. Proposal to waive in vivo bioequivalence requirements for WHO Model List of essential medicines immediate-release, solid dosage forms. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth Report*. Geneva, World Health Organization, 2006, Annex 8 (WHO Technical Report Series, No. 937).\n\n21. Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. *Expert Opinion on Drug Delivery*, 2007, 4: 37\u201345.\n\n22. Shehab N et al. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. *Pediatric Critical Care Medicine*, 2009, 10(2): 256\u2013259.\n\n23. American Academy of Pediatrics. \u201cInactive\u201d ingredients in pharmaceutical products: update (subject review). *Pediatrics*, 1997, 99:268\u2013278 (http://www.pediatrics.org/cgi/content/ full/99/2/268).\n\n24. WHO Technical Report Series on evaluation of certain food additives. *List of publications* (http:// www.who.int/ipcs/publications/jecfa/reports/en/index.html).\n\n25. Pollock I et al. Survey of colourings and preservatives in drugs. *BMJ*, 1989, 299: 649\u2013651.\n\n26. Pefferi G, Restani P. The safety of pharmaceutical excipients. *Il Farmaco*, 2003, 58: 541\u2013550.\n\n27. European Medicines Agency. EMEA Public Statement on antimicrobial preservatives in ophthalmic preparations for human use. London, EMEA, 2009 (EMEA/622721/2009).\n\n28. Mennella JA, Beauchamp GK. Optimizing oral medications for children. *Clinical Therapeutics*, 2008, 30: 2120\u20132132.\n\n29. *Production of zinc tablets and zinc oral solutions: guidelines for programme managers and pharmaceutical manufacturers*, Annex 7. Geneva, World Health Organization, 2007.\n\n30. Cram A et al. Challenges of developing palatable oral paediatric formulations. *International Journal of Pharmaceutics*, 2009, 365: 1\u20133.\n\n31. Committee for Medicinal Products for Human Use. *Guideline on the investigation of medicinal products in the term and preterm neonate*. London, European Medicines Agency, 2007.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 3122, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "552cceae-f751-4319-8b5d-b4f53df0385a": {"__data__": {"id_": "552cceae-f751-4319-8b5d-b4f53df0385a", "embedding": null, "metadata": {"page_label": "239", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\n(EMEA/566810/2008).\n\n32. Strickly RG et al. Paediatric drugs \u2013 a review of commercially available oral formulations. *Journal of Pharmaceutical Sciences* 2007, 97: 1731\u20131774.\n\n33. Thomson SA et al. Mini-tablets: new modality to deliver medicines to preschool-aged children. *Paediatrics*, 2009, 123:e235\u2013e238.\n\n34. *The International Pharmacopoeia*, 4th ed. First and Second Supplements (available online and on CD-ROM). Geneva, World Health Organization, 2011 (http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html).\n\n35. Seager H. Drug-delivery products and the zydis fast-dissolving dosage form. *Journal of Pharmacy and Pharmacology*, 1998, 50: 375\u2013382.\n\n36. Dolovich M. Influence of inspiratory flow rate, particle size and airway caliber in aerosolized drug delivery to the lung. *Respiratory Care*, 2000, 45: 597\u2013608.\n\n## Web sites\n\n- **WHO** World Health Organization: http://www.who.int\n- **ICH** International Conference on Harmonisation: http://www.ich.org\n- **EMA** European Medicines Agency: http://www.ema.europa.eu", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl contexto proviene del Anexo 5 del Informe T\u00e9cnico de la OMS (WHO - Technical Report Series 970), que incluye referencias sobre formulaciones de medicamentos pedi\u00e1tricos, modalidades de entrega de medicamentos para ni\u00f1os en edad preescolar, y aspectos t\u00e9cnicos de la entrega de medicamentos a trav\u00e9s de aerosoles. Tambi\u00e9n se mencionan recursos en l\u00ednea de organizaciones relevantes como la OMS, ICH y EMA.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones clave en la formulaci\u00f3n de medicamentos pedi\u00e1tricos seg\u00fan Strickly RG et al. en su revisi\u00f3n de 2007?**\n   - Esta pregunta busca detalles espec\u00edficos sobre los hallazgos y recomendaciones presentados en el art\u00edculo mencionado, que no se pueden encontrar f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfQu\u00e9 innovaciones en la entrega de medicamentos se discuten en el estudio de Thomson SA et al. sobre mini-tabletas para ni\u00f1os?**\n   - Esta pregunta se centra en las caracter\u00edsticas y beneficios de las mini-tabletas como una nueva modalidad de entrega, que podr\u00eda no estar ampliamente documentada en otras publicaciones.\n\n3. **\u00bfC\u00f3mo afecta el flujo inspiratorio y el tama\u00f1o de las part\u00edculas en la entrega de medicamentos aerosolizados seg\u00fan Dolovich M?**\n   - Esta pregunta busca una comprensi\u00f3n m\u00e1s profunda de los factores t\u00e9cnicos que influyen en la eficacia de la entrega de medicamentos a los pulmones, un tema que puede no ser ampliamente cubierto en otras fuentes.\n\n### Resumen de Nivel Superior\nEl Anexo 5 del Informe T\u00e9cnico de la OMS aborda temas relacionados con la formulaci\u00f3n y entrega de medicamentos, especialmente en el contexto pedi\u00e1trico. Se destacan estudios sobre formulaciones orales y nuevas modalidades de entrega, as\u00ed como consideraciones t\u00e9cnicas para la administraci\u00f3n de medicamentos a trav\u00e9s de aerosoles. Adem\u00e1s, se proporcionan enlaces a recursos de organizaciones clave en el \u00e1mbito de la salud y la regulaci\u00f3n de medicamentos.", "prev_section_summary": "### Temas Clave\n\n1. **L\u00edmites de Impurezas Genot\u00f3xicas**: Se mencionan directrices de la Agencia Europea de Medicamentos (EMA) sobre los l\u00edmites permitidos de impurezas genot\u00f3xicas en productos farmac\u00e9uticos, lo cual es crucial para garantizar la seguridad de los medicamentos.\n\n2. **Formulaci\u00f3n de Medicamentos para Neonatos y Ancianos**: Se abordan pautas espec\u00edficas para la formulaci\u00f3n de medicamentos dirigidos a poblaciones vulnerables, como neonatos y ancianos, destacando la necesidad de atenci\u00f3n especial en su desarrollo.\n\n3. **Desarrollo de Formulaciones Orales Palatables**: Se discuten los desaf\u00edos que enfrentan los fabricantes al crear medicamentos orales que sean aceptables y agradables para los ni\u00f1os, lo que es fundamental para la adherencia al tratamiento.\n\n4. **Evaluaci\u00f3n de Excipientes**: Se enfatiza la importancia de evaluar la seguridad de los excipientes farmac\u00e9uticos y su impacto en la salud p\u00fablica.\n\n5. **Bioequivalencia**: Se menciona la propuesta de eximir ciertos requisitos de bioequivalencia para medicamentos en la lista de medicamentos esenciales de la OMS.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la elaboraci\u00f3n del informe y las directrices.\n- **Agencia Europea de Medicamentos (EMA)**: Proporciona directrices sobre l\u00edmites de impurezas y evaluaci\u00f3n de medicamentos.\n- **FIP/AAPS**: Referencia a las gu\u00edas sobre pruebas de disoluci\u00f3n y liberaci\u00f3n in vitro.\n- **American Academy of Pediatrics**: Proporciona actualizaciones sobre ingredientes inactivos en productos farmac\u00e9uticos.\n- **Revistas Cient\u00edficas**: Se citan varias publicaciones como *AAPS PharmSciTech*, *Pediatrics*, y *Clinical Therapeutics* que abordan temas relevantes en la formulaci\u00f3n y seguridad de medicamentos.\n\n### Conclusi\u00f3n\nEl informe de la OMS proporciona un marco regulatorio y directrices para el desarrollo de productos farmac\u00e9uticos, enfatizando la seguridad, eficacia y adaptaci\u00f3n de medicamentos para poblaciones espec\u00edficas, lo que es esencial para proteger la salud p\u00fablica.", "excerpt_keywords": "Keywords: pediatrics, drug delivery, formulations, aerosolized medication, WHO"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d1b55ead-81a3-47a1-ae5c-572aaf62bfc1", "node_type": "4", "metadata": {"page_label": "239", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\n(EMEA/566810/2008).\n\n32. Strickly RG et al. Paediatric drugs \u2013 a review of commercially available oral formulations. *Journal of Pharmaceutical Sciences* 2007, 97: 1731\u20131774.\n\n33. Thomson SA et al. Mini-tablets: new modality to deliver medicines to preschool-aged children. *Paediatrics*, 2009, 123:e235\u2013e238.\n\n34. *The International Pharmacopoeia*, 4th ed. First and Second Supplements (available online and on CD-ROM). Geneva, World Health Organization, 2011 (http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html).\n\n35. Seager H. Drug-delivery products and the zydis fast-dissolving dosage form. *Journal of Pharmacy and Pharmacology*, 1998, 50: 375\u2013382.\n\n36. Dolovich M. Influence of inspiratory flow rate, particle size and airway caliber in aerosolized drug delivery to the lung. *Respiratory Care*, 2000, 45: 597\u2013608.\n\n## Web sites\n\n- **WHO** World Health Organization: http://www.who.int\n- **ICH** International Conference on Harmonisation: http://www.ich.org\n- **EMA** European Medicines Agency: http://www.ema.europa.eu", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "a910ac15d0b59dd392dfef1d5da21a6a91c6544a6ba2648ba81682226147ebb4", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 5\n\n(EMEA/566810/2008).\n\n32. Strickly RG et al. Paediatric drugs \u2013 a review of commercially available oral formulations. *Journal of Pharmaceutical Sciences* 2007, 97: 1731\u20131774.\n\n33. Thomson SA et al. Mini-tablets: new modality to deliver medicines to preschool-aged children. *Paediatrics*, 2009, 123:e235\u2013e238.\n\n34. *The International Pharmacopoeia*, 4th ed. First and Second Supplements (available online and on CD-ROM). Geneva, World Health Organization, 2011 (http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html).\n\n35. Seager H. Drug-delivery products and the zydis fast-dissolving dosage form. *Journal of Pharmacy and Pharmacology*, 1998, 50: 375\u2013382.\n\n36. Dolovich M. Influence of inspiratory flow rate, particle size and airway caliber in aerosolized drug delivery to the lung. *Respiratory Care*, 2000, 45: 597\u2013608.\n\n## Web sites\n\n- **WHO** World Health Organization: http://www.who.int\n- **ICH** International Conference on Harmonisation: http://www.ich.org\n- **EMA** European Medicines Agency: http://www.ema.europa.eu", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1065, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "34600602-5ea1-41c6-b830-6079017979e8": {"__data__": {"id_": "34600602-5ea1-41c6-b830-6079017979e8", "embedding": null, "metadata": {"page_label": "240", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que probablemente contiene informaci\u00f3n t\u00e9cnica y recomendaciones de la Organizaci\u00f3n Mundial de la Salud (OMS) sobre un tema espec\u00edfico relacionado con la salud p\u00fablica. Sin embargo, el contenido espec\u00edfico no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS en el Informe T\u00e9cnico 970 sobre la salud p\u00fablica?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre las recomendaciones que se presentan en el informe, que podr\u00edan ser relevantes para profesionales de la salud y responsables de pol\u00edticas.\n\n2. **\u00bfQu\u00e9 temas espec\u00edficos se abordan en el documento WHO TRS 970 y c\u00f3mo se relacionan con las tendencias actuales en salud global?**\n   - Esta pregunta indaga sobre los temas tratados en el informe y su relevancia en el contexto de los desaf\u00edos actuales en salud p\u00fablica, lo que podr\u00eda no estar disponible en otras fuentes.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizan en el Informe T\u00e9cnico 970 para evaluar la efectividad de las intervenciones de salud p\u00fablica?**\n   - Esta pregunta se centra en las metodolog\u00edas espec\u00edficas que la OMS podr\u00eda haber utilizado en el informe, lo que podr\u00eda proporcionar informaci\u00f3n valiosa para investigadores y profesionales en el campo de la salud.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que podr\u00eda no estar f\u00e1cilmente disponible en otras fuentes, bas\u00e1ndose en el contexto del documento de la OMS.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Formulaci\u00f3n de Medicamentos Pedi\u00e1tricos:** Se revisan las formulaciones orales disponibles comercialmente para ni\u00f1os, destacando la importancia de adaptar los medicamentos a las necesidades espec\u00edficas de esta poblaci\u00f3n.\n2. **Innovaciones en la Entrega de Medicamentos:** Se discuten las mini-tabletas como una nueva modalidad para administrar medicamentos a ni\u00f1os en edad preescolar, enfatizando sus beneficios y caracter\u00edsticas.\n3. **Entrega de Medicamentos Aerosolizados:** Se analizan factores t\u00e9cnicos que afectan la eficacia de la entrega de medicamentos a los pulmones, como el flujo inspiratorio, el tama\u00f1o de las part\u00edculas y el calibre de las v\u00edas respiratorias.\n\n**Entidades:**\n- **Organizaciones de Salud:**\n  - **OMS (World Health Organization):** Proporciona recursos y directrices sobre medicamentos y salud p\u00fablica.\n  - **ICH (International Conference on Harmonisation):** Se enfoca en la armonizaci\u00f3n de regulaciones para la investigaci\u00f3n y desarrollo de medicamentos.\n  - **EMA (European Medicines Agency):** Agencia responsable de la evaluaci\u00f3n y supervisi\u00f3n de medicamentos en la Uni\u00f3n Europea.\n\n**Referencias Clave:**\n- Art\u00edculos de revistas cient\u00edficas que abordan la formulaci\u00f3n y entrega de medicamentos pedi\u00e1tricos, as\u00ed como estudios sobre la administraci\u00f3n de medicamentos aerosolizados.\n\nEste resumen destaca la relevancia de la investigaci\u00f3n en la formulaci\u00f3n y entrega de medicamentos para ni\u00f1os, as\u00ed como la importancia de las organizaciones de salud en la regulaci\u00f3n y promoci\u00f3n de pr\u00e1cticas seguras y efectivas en el uso de medicamentos pedi\u00e1tricos.", "excerpt_keywords": "Keywords: OMS, medicamentos pedi\u00e1tricos, formulaci\u00f3n, entrega de medicamentos, salud p\u00fablica"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3afa8eb3-7ceb-4bec-820c-931c1c48c854", "node_type": "4", "metadata": {"page_label": "240", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "87cde7667e39aee0f6c078473e3142295073cdf90d4e524012f1dce2377de44f", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "b9a1fdde-814e-4583-b03a-88024944775a": {"__data__": {"id_": "b9a1fdde-814e-4583-b03a-88024944775a", "embedding": null, "metadata": {"page_label": "241", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 6\n\n**Recommendations for quality requirements when artemisinin is used as a starting material in the production of antimalarial active pharmaceutical ingredients**\n\n1. Introduction  \n2. Characterization of artemisinin  \n3. Tests and specifications for artemisinin starting material  \n   References  \n\n|   | Page |\n|---|------|\n| 1. | Introduction | 229 |\n| 2. | Characterization of artemisinin | 231 |\n| 3. | Tests and specifications for artemisinin starting material | 232 |\n|    | References | 235 |", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento \"WHO - Technical Report Series 970\" incluye un anexo que presenta recomendaciones sobre los requisitos de calidad para el uso de artemisinina como material de partida en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos. El anexo se divide en varias secciones, que incluyen una introducci\u00f3n, la caracterizaci\u00f3n de la artemisinina, pruebas y especificaciones para el material de partida de artemisinina, y referencias.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son los principales aspectos que se abordan en la caracterizaci\u00f3n de la artemisinina seg\u00fan el documento?**\n   - Esta pregunta busca detalles espec\u00edficos sobre los m\u00e9todos y criterios utilizados para caracterizar la artemisinina, que son fundamentales para garantizar su calidad en la producci\u00f3n de medicamentos antimal\u00e1ricos.\n\n2. **\u00bfQu\u00e9 tipo de pruebas y especificaciones se recomiendan para el material de partida de artemisinina en la producci\u00f3n de ingredientes farmac\u00e9uticos activos?**\n   - Esta pregunta se centra en las pruebas espec\u00edficas que deben realizarse y las especificaciones que deben cumplirse para asegurar que la artemisinina utilizada en la producci\u00f3n sea de alta calidad y adecuada para su uso en medicamentos.\n\n3. **\u00bfQu\u00e9 importancia tiene la calidad de la artemisinina en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos seg\u00fan las recomendaciones del informe?**\n   - Esta pregunta busca explorar la relaci\u00f3n entre la calidad de la artemisinina y la eficacia de los tratamientos antimal\u00e1ricos, as\u00ed como las implicaciones para la salud p\u00fablica y el control de la malaria.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" de la Organizaci\u00f3n Mundial de la Salud (OMS) se centra en aspectos t\u00e9cnicos y recomendaciones relacionadas con la salud p\u00fablica. Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n#### Temas Clave\n1. **Recomendaciones de Salud P\u00fablica**: Es probable que el informe contenga directrices y recomendaciones para mejorar la salud p\u00fablica a nivel global.\n2. **Evaluaci\u00f3n de Intervenciones**: Se sugiere que el documento podr\u00eda abordar metodolog\u00edas para evaluar la efectividad de diversas intervenciones en salud p\u00fablica.\n3. **Tendencias en Salud Global**: El informe podr\u00eda relacionar sus hallazgos con las tendencias actuales y desaf\u00edos en el \u00e1mbito de la salud a nivel mundial.\n\n#### Entidades\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la elaboraci\u00f3n del informe, que se enfoca en la salud p\u00fablica y el bienestar global.\n- **Salud P\u00fablica**: El campo de estudio y pr\u00e1ctica que se aborda en el documento, incluyendo pol\u00edticas, intervenciones y recomendaciones.\n\nEste resumen proporciona una visi\u00f3n general de los posibles temas y entidades que podr\u00edan estar presentes en el informe, aunque el contenido espec\u00edfico no est\u00e9 disponible en el contexto proporcionado.", "excerpt_keywords": "Keywords: artemisinin, antimalarial, pharmaceutical, quality requirements, WHO"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "df771ecf-a17a-49dc-8a89-d36e9d0fdf5c", "node_type": "4", "metadata": {"page_label": "241", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 6\n\n**Recommendations for quality requirements when artemisinin is used as a starting material in the production of antimalarial active pharmaceutical ingredients**\n\n1. Introduction  \n2. Characterization of artemisinin  \n3. Tests and specifications for artemisinin starting material  \n   References  \n\n|   | Page |\n|---|------|\n| 1. | Introduction | 229 |\n| 2. | Characterization of artemisinin | 231 |\n| 3. | Tests and specifications for artemisinin starting material | 232 |\n|    | References | 235 |", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "8954fcaed9aa7d369ffacd44dcafd4248b083667a147d96974467182befbea02", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Annex 6\n\n**Recommendations for quality requirements when artemisinin is used as a starting material in the production of antimalarial active pharmaceutical ingredients**\n\n1. Introduction  \n2. Characterization of artemisinin  \n3. Tests and specifications for artemisinin starting material  \n   References  \n\n|   | Page |\n|---|------|\n| 1. | Introduction | 229 |\n| 2. | Characterization of artemisinin | 231 |\n| 3. | Tests and specifications for artemisinin starting material | 232 |\n|    | References | 235 |", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 509, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "6174e8c5-a4c5-4fe5-83f1-61fa8e2e7897": {"__data__": {"id_": "6174e8c5-a4c5-4fe5-83f1-61fa8e2e7897", "embedding": null, "metadata": {"page_label": "242", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto del documento \"WHO - Technical Report Series 970\":\n\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre el contenido del informe, que puede no estar disponible en otros documentos o res\u00famenes.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en el estudio o an\u00e1lisis presentado en el documento de la OMS?**\n   - Esta pregunta se centra en las t\u00e9cnicas y enfoques utilizados en la investigaci\u00f3n, lo cual es crucial para entender la validez y aplicabilidad de los resultados.\n\n3. **\u00bfQu\u00e9 implicaciones tienen los resultados del Informe 46 para la salud p\u00fablica a nivel global?**\n   - Esta pregunta busca explorar c\u00f3mo los hallazgos del informe pueden influir en pol\u00edticas de salud p\u00fablica, lo que puede no estar claramente delineado en otros textos.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS), que abordan diversos temas relacionados con la salud p\u00fablica, investigaci\u00f3n y recomendaciones para mejorar la salud a nivel global. El Informe 46 en particular puede contener an\u00e1lisis, datos y recomendaciones que son relevantes para profesionales de la salud, investigadores y responsables de pol\u00edticas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl **Anexo 6** del documento \"WHO - Technical Report Series 970\" se centra en las **recomendaciones de calidad** para el uso de **artemisinina** como material de partida en la producci\u00f3n de **ingredientes farmac\u00e9uticos activos** antimal\u00e1ricos. Los temas clave abordados en esta secci\u00f3n incluyen:\n\n1. **Introducci\u00f3n**: Presenta el contexto y la importancia de la artemisinina en la producci\u00f3n de medicamentos antimal\u00e1ricos.\n   \n2. **Caracterizaci\u00f3n de la artemisinina**: Detalla los m\u00e9todos y criterios necesarios para evaluar la calidad de la artemisinina, asegurando que cumpla con los est\u00e1ndares requeridos para su uso en la fabricaci\u00f3n de f\u00e1rmacos.\n\n3. **Pruebas y especificaciones**: Describe las pruebas espec\u00edficas que deben realizarse y las especificaciones que deben cumplirse para garantizar que el material de partida de artemisinina sea de alta calidad y adecuado para la producci\u00f3n de ingredientes farmac\u00e9uticos activos.\n\n4. **Referencias**: Proporciona las fuentes y documentos relevantes que respaldan las recomendaciones presentadas.\n\n### Entidades Clave\n- **Artemisinina**: Compuesto utilizado como material de partida en la producci\u00f3n de medicamentos antimal\u00e1ricos.\n- **Ingredientes farmac\u00e9uticos activos**: Sustancias que proporcionan la actividad farmacol\u00f3gica en los medicamentos.\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad que emite el informe y establece las recomendaciones.\n\nEste resumen destaca la importancia de la calidad de la artemisinina en la producci\u00f3n de tratamientos antimal\u00e1ricos y su impacto en la salud p\u00fablica.", "excerpt_keywords": "Keywords: artemisinina, salud p\u00fablica, ingredientes farmac\u00e9uticos activos, recomendaciones de calidad, Organizaci\u00f3n Mundial de la Salud"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9e1c8945-ab0a-4c85-b9c7-e065a9f8d138", "node_type": "4", "metadata": {"page_label": "242", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "57dbcc48536bb7afdfb61df88e5973ec9112e79123946a134b093864cad3a09d", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "NO_CONTENT_HERE", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 15, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "47bbaf8f-e5dc-4b07-b9a3-aefd289d9811": {"__data__": {"id_": "47bbaf8f-e5dc-4b07-b9a3-aefd289d9811", "embedding": null, "metadata": {"page_label": "243", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nThe harmonized good manufacturing practices (GMP) (1,2) describe requirements for the production of active pharmaceutical ingredients (APIs). The applicability of these requirements begins with a defined starting material as follows:\n\n> \"An API starting material is a raw material, intermediate, or an API that is used in the production and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials normally have defined chemical properties and structure.\"\n\nThe focus of GMP for APIs is for field inspector use, rather than in applications for marketing authorization. It defines what may be considered as a starting material and provides guidance on where GMP is applied. The GMP guidelines do not apply to steps taken prior to the first introduction of the defined starting material. The manufacturer should designate and document the rationale for the point at which production of the API begins. For a synthesis process, this is known as the point at which the starting materials are entered into processes.\n\nFrom a regulatory standpoint, the use of API starting materials marks the beginning of the detailed description of the process. The applicant for marketing authorization should propose and justify which substance should be considered as the API starting material, e.g. incorporated as a significant structural fragment into the structure of the active substance.\n\nIn practice the designation of a starting material may be difficult. The number of steps separating the starting material from the final API is an issue to be decided on a case-by-case basis, subject to the manufacturer\u2019s proposal and assessors\u2019 evaluation. Since a designated starting material may be obtained from multiple sources, it is necessary to have well-defined quality requirements to ensure that the APIs produced meet specifications. Establishing these requirements may involve a compromise between the desire for a pure starting material and the impact of this on cost of API production. Impurities can be tolerated in the starting material if the API manufacturing process has been shown to efficiently remove them. Redundant purification steps may reduce the yield of the final API and thus further increase its cost.\n\nArtemisinin derivatives used in artemisinin-based combination therapy (ACT) are synthesized from artemisinin in one or two synthetic steps. Artemisinin is typically produced as an isolate from *Artemisia annua* L. Artemisinin complies with the definition of a \u201cstarting material\u201d, as defined above and described in certain national, regional and international guidelines. It is:", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento aborda las Buenas Pr\u00e1cticas de Manufactura (GMP) armonizadas para la producci\u00f3n de Ingredientes Farmac\u00e9uticos Activos (API). Se define el concepto de \"material de partida\" y se establece que este es un componente esencial en la producci\u00f3n de un API. El texto enfatiza que la designaci\u00f3n de un material de partida puede ser compleja y debe ser evaluada caso por caso, considerando la calidad y pureza del material en relaci\u00f3n con los costos de producci\u00f3n. Adem\u00e1s, se menciona el caso espec\u00edfico de los derivados de artemisinina, que se sintetizan a partir de la artemisinina, un material de partida que cumple con las definiciones establecidas.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son los criterios que un fabricante debe considerar al designar un material de partida para la producci\u00f3n de un API?**\n   - La designaci\u00f3n de un material de partida debe considerar la cantidad de pasos entre el material de partida y el API final, la calidad del material, y la capacidad del proceso de manufactura para eliminar impurezas. Adem\u00e1s, el fabricante debe documentar y justificar su elecci\u00f3n.\n\n2. **\u00bfQu\u00e9 implicaciones tiene la elecci\u00f3n de un material de partida en el costo de producci\u00f3n de un API?**\n   - La elecci\u00f3n de un material de partida puede afectar significativamente el costo de producci\u00f3n. Un material de partida m\u00e1s puro puede requerir pasos de purificaci\u00f3n adicionales, lo que puede reducir el rendimiento del API final y aumentar los costos. Por lo tanto, es necesario encontrar un equilibrio entre la pureza del material y los costos asociados.\n\n3. **\u00bfC\u00f3mo se relaciona la artemisinina con las Buenas Pr\u00e1cticas de Manufactura y su uso en terapias combinadas?**\n   - La artemisinina es un material de partida que se utiliza en la s\u00edntesis de derivados de artemisinina para terapias combinadas basadas en artemisinina (ACT). Cumple con la definici\u00f3n de material de partida seg\u00fan las GMP, lo que implica que su producci\u00f3n y uso deben seguir las pautas establecidas para garantizar la calidad y eficacia del API resultante.", "prev_section_summary": "El contenido de la secci\u00f3n se refiere al \"WHO - Technical Report Series 970\", espec\u00edficamente al Informe 46 de esta serie. A continuaci\u00f3n se presentan los temas clave y entidades relevantes:\n\n### Temas Clave:\n1. **Hallazgos y Recomendaciones**: Se busca informaci\u00f3n sobre los principales hallazgos y recomendaciones del Informe 46, que son cruciales para entender su impacto en la salud p\u00fablica.\n2. **Metodolog\u00edas**: Se enfatiza la importancia de conocer las metodolog\u00edas utilizadas en el estudio o an\u00e1lisis presentado en el informe, lo que ayuda a evaluar la validez de los resultados.\n3. **Implicaciones para la Salud P\u00fablica**: Se exploran las posibles implicaciones de los resultados del informe en pol\u00edticas de salud p\u00fablica a nivel global.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe y de la serie t\u00e9cnica.\n- **Informe 46**: El documento espec\u00edfico dentro de la serie que se est\u00e1 analizando.\n\n### Contexto General:\nEl informe forma parte de una serie m\u00e1s amplia que aborda temas de salud p\u00fablica y proporciona recomendaciones basadas en investigaciones y an\u00e1lisis, dirigidas a profesionales de la salud, investigadores y responsables de pol\u00edticas. \n\nEste resumen destaca la relevancia del Informe 46 en el contexto de la salud p\u00fablica global y la necesidad de comprender sus hallazgos y metodolog\u00edas.", "excerpt_keywords": "Keywords: Good Manufacturing Practices, active pharmaceutical ingredients, starting material, artemisinin, quality requirements"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6029e08a-3d2c-4b86-b545-8b1a1334cfbf", "node_type": "4", "metadata": {"page_label": "243", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nThe harmonized good manufacturing practices (GMP) (1,2) describe requirements for the production of active pharmaceutical ingredients (APIs). The applicability of these requirements begins with a defined starting material as follows:\n\n> \"An API starting material is a raw material, intermediate, or an API that is used in the production and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials normally have defined chemical properties and structure.\"\n\nThe focus of GMP for APIs is for field inspector use, rather than in applications for marketing authorization. It defines what may be considered as a starting material and provides guidance on where GMP is applied. The GMP guidelines do not apply to steps taken prior to the first introduction of the defined starting material. The manufacturer should designate and document the rationale for the point at which production of the API begins. For a synthesis process, this is known as the point at which the starting materials are entered into processes.\n\nFrom a regulatory standpoint, the use of API starting materials marks the beginning of the detailed description of the process. The applicant for marketing authorization should propose and justify which substance should be considered as the API starting material, e.g. incorporated as a significant structural fragment into the structure of the active substance.\n\nIn practice the designation of a starting material may be difficult. The number of steps separating the starting material from the final API is an issue to be decided on a case-by-case basis, subject to the manufacturer\u2019s proposal and assessors\u2019 evaluation. Since a designated starting material may be obtained from multiple sources, it is necessary to have well-defined quality requirements to ensure that the APIs produced meet specifications. Establishing these requirements may involve a compromise between the desire for a pure starting material and the impact of this on cost of API production. Impurities can be tolerated in the starting material if the API manufacturing process has been shown to efficiently remove them. Redundant purification steps may reduce the yield of the final API and thus further increase its cost.\n\nArtemisinin derivatives used in artemisinin-based combination therapy (ACT) are synthesized from artemisinin in one or two synthetic steps. Artemisinin is typically produced as an isolate from *Artemisia annua* L. Artemisinin complies with the definition of a \u201cstarting material\u201d, as defined above and described in certain national, regional and international guidelines. It is:", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "aa0ee7b2656f919acd5ed9da88e54f812dc668154407fbaced8cca8a03625f60", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 1. Introduction\n\nThe harmonized good manufacturing practices (GMP) (1,2) describe requirements for the production of active pharmaceutical ingredients (APIs). The applicability of these requirements begins with a defined starting material as follows:\n\n> \"An API starting material is a raw material, intermediate, or an API that is used in the production and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials normally have defined chemical properties and structure.\"\n\nThe focus of GMP for APIs is for field inspector use, rather than in applications for marketing authorization. It defines what may be considered as a starting material and provides guidance on where GMP is applied. The GMP guidelines do not apply to steps taken prior to the first introduction of the defined starting material. The manufacturer should designate and document the rationale for the point at which production of the API begins. For a synthesis process, this is known as the point at which the starting materials are entered into processes.\n\nFrom a regulatory standpoint, the use of API starting materials marks the beginning of the detailed description of the process. The applicant for marketing authorization should propose and justify which substance should be considered as the API starting material, e.g. incorporated as a significant structural fragment into the structure of the active substance.\n\nIn practice the designation of a starting material may be difficult. The number of steps separating the starting material from the final API is an issue to be decided on a case-by-case basis, subject to the manufacturer\u2019s proposal and assessors\u2019 evaluation. Since a designated starting material may be obtained from multiple sources, it is necessary to have well-defined quality requirements to ensure that the APIs produced meet specifications. Establishing these requirements may involve a compromise between the desire for a pure starting material and the impact of this on cost of API production. Impurities can be tolerated in the starting material if the API manufacturing process has been shown to efficiently remove them. Redundant purification steps may reduce the yield of the final API and thus further increase its cost.\n\nArtemisinin derivatives used in artemisinin-based combination therapy (ACT) are synthesized from artemisinin in one or two synthetic steps. Artemisinin is typically produced as an isolate from *Artemisia annua* L. Artemisinin complies with the definition of a \u201cstarting material\u201d, as defined above and described in certain national, regional and international guidelines. It is:", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2828, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "637a57ee-7d7a-4462-ab5c-8a76d1bffa0a": {"__data__": {"id_": "637a57ee-7d7a-4462-ab5c-8a76d1bffa0a", "embedding": null, "metadata": {"page_label": "244", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- a material used in the production of the API that is incorporated into the API as a significant structural element;\n- commercially available;\n- a compound whose name, chemical structure, chemical and physical characteristics, properties and impurity profile are well defined;\n- obtained by commonly known procedures.\n\nAs artemisinin is extracted from plant material and prior intermediates are thus not available, it is logical to designate this compound as the starting material for its derivatives.\n\nA monograph appears in *The International Pharmacopoeia* for artemisinin used as an API. However, at present, artemisinin is mainly used as a starting material for artemisinin-derived APIs, and not as an API.\n\nThe level of quality of the artemisinin should be acceptable for its intended use as the starting material for the production of artemisinin derivatives. The specifications presented below take into account an acceptable balance of benefit versus risk between the quality of artemisinin used as a starting material and the quality required for artemisinin derivatives for use as APIs.\n\nHowever, competent authorities may accept other impurity profile levels depending on the capability of the manufacturing process to lead to artemisinin-derived APIs at least compliant with the relevant monographs of *The International Pharmacopoeia*.\n\nThe purpose of this document is to offer a global approach to defining the level of quality requirements of artemisinin when used as a starting material for the production of its API derivatives used in ACT formulations. It does not apply to cases where artemisinin is used as an API. It is intended that the recommendations for requirements outlined in this document will apply to artemisinin extracted from *Artemisia annua* L. regardless of variations in agricultural environment or variations in extraction and purification steps. In addition, in order to ensure appropriate quality of the derived APIs, the manufacturer may add additional tests, such as tests for residual solvents and heavy metals, among others, and/or require tighter specifications. In the eventuality that artemisinin is produced using synthetic chemical processes or by fermentation, other requirements may be applicable.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Uso de Artemisinin**: Artemisinin es un compuesto extra\u00eddo de *Artemisia annua* L. que se utiliza principalmente como material de partida para la producci\u00f3n de APIs derivados, en lugar de ser utilizado directamente como un API. La calidad de artemisinin debe ser adecuada para su uso en la producci\u00f3n de estos derivados.\n\n2. **Especificaciones de Calidad**: El documento establece que las especificaciones de calidad para artemisinin como material de partida deben equilibrar los beneficios y riesgos, y que las autoridades competentes pueden aceptar diferentes niveles de perfil de impurezas seg\u00fan el proceso de fabricaci\u00f3n.\n\n3. **Recomendaciones Globales**: Se ofrecen recomendaciones globales sobre los requisitos de calidad de artemisinin, que deben aplicarse independientemente de las variaciones en el entorno agr\u00edcola o en los pasos de extracci\u00f3n y purificaci\u00f3n. Tambi\u00e9n se menciona que se pueden requerir pruebas adicionales para garantizar la calidad de los APIs derivados.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 criterios se utilizan para definir la calidad aceptable de artemisinin como material de partida para la producci\u00f3n de APIs derivados?**\n   - Esta pregunta busca detalles sobre los criterios espec\u00edficos que se consideran al evaluar la calidad de artemisinin, que no se encuentran f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfQu\u00e9 implicaciones tiene el uso de artemisinin producido por procesos sint\u00e9ticos o fermentaci\u00f3n en los requisitos de calidad establecidos en el documento?**\n   - Esta pregunta se centra en las diferencias en los requisitos de calidad que pueden surgir dependiendo del m\u00e9todo de producci\u00f3n de artemisinin, un aspecto que puede no estar ampliamente discutido en otros documentos.\n\n3. **\u00bfQu\u00e9 tipo de pruebas adicionales pueden ser requeridas por los fabricantes para asegurar la calidad de los APIs derivados de artemisinin?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las pruebas adicionales que los fabricantes pueden implementar, lo cual puede no estar detallado en otras fuentes relacionadas con la producci\u00f3n de APIs.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Buenas Pr\u00e1cticas de Manufactura (GMP)**:\n   - Se establecen requisitos para la producci\u00f3n de Ingredientes Farmac\u00e9uticos Activos (API).\n   - La aplicaci\u00f3n de estas pr\u00e1cticas comienza con la definici\u00f3n de un \"material de partida\".\n\n2. **Definici\u00f3n de Material de Partida**:\n   - Se describe como un material crudo, intermedio o un API que se incorpora como un fragmento estructural significativo en la producci\u00f3n del API.\n   - Puede ser un art\u00edculo comercial, material adquirido de proveedores o producido internamente.\n\n3. **Importancia de la Designaci\u00f3n del Material de Partida**:\n   - La designaci\u00f3n debe ser documentada y justificada por el fabricante.\n   - La elecci\u00f3n del material de partida afecta la calidad y el costo de producci\u00f3n del API.\n\n4. **Desaf\u00edos en la Designaci\u00f3n**:\n   - La complejidad de designar un material de partida se eval\u00faa caso por caso, considerando el n\u00famero de pasos entre el material de partida y el API final.\n   - Es necesario establecer requisitos de calidad bien definidos para asegurar que los APIs cumplan con las especificaciones.\n\n5. **Compromiso entre Pureza y Costo**:\n   - Se debe encontrar un equilibrio entre la pureza del material de partida y los costos de producci\u00f3n.\n   - Las impurezas pueden ser toleradas si el proceso de manufactura del API puede eliminarlas eficientemente.\n\n6. **Derivados de Artemisinina**:\n   - Se sintetizan a partir de artemisinina en uno o dos pasos sint\u00e9ticos.\n   - Artemisinina, obtenida de *Artemisia annua* L, cumple con la definici\u00f3n de material de partida seg\u00fan las GMP.\n\n### Entidades Clave\n- **Artemisinina**: Material de partida utilizado en la producci\u00f3n de derivados para terapias combinadas basadas en artemisinina (ACT).\n- **Ingredientes Farmac\u00e9uticos Activos (API)**: Sustancias utilizadas en la fabricaci\u00f3n de medicamentos.\n- **Artemisia annua**: Planta de la cual se a\u00edsla la artemisinina. \n\nEste resumen destaca la importancia de las GMP en la producci\u00f3n de APIs, la complejidad de la designaci\u00f3n de materiales de partida y el caso espec\u00edfico de la artemisinina en la producci\u00f3n de medicamentos.", "excerpt_keywords": "Artemisinin, API, quality specifications, starting material, pharmaceutical preparations"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a63f6deb-a1f9-42fa-be71-f4868b604d80", "node_type": "4", "metadata": {"page_label": "244", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- a material used in the production of the API that is incorporated into the API as a significant structural element;\n- commercially available;\n- a compound whose name, chemical structure, chemical and physical characteristics, properties and impurity profile are well defined;\n- obtained by commonly known procedures.\n\nAs artemisinin is extracted from plant material and prior intermediates are thus not available, it is logical to designate this compound as the starting material for its derivatives.\n\nA monograph appears in *The International Pharmacopoeia* for artemisinin used as an API. However, at present, artemisinin is mainly used as a starting material for artemisinin-derived APIs, and not as an API.\n\nThe level of quality of the artemisinin should be acceptable for its intended use as the starting material for the production of artemisinin derivatives. The specifications presented below take into account an acceptable balance of benefit versus risk between the quality of artemisinin used as a starting material and the quality required for artemisinin derivatives for use as APIs.\n\nHowever, competent authorities may accept other impurity profile levels depending on the capability of the manufacturing process to lead to artemisinin-derived APIs at least compliant with the relevant monographs of *The International Pharmacopoeia*.\n\nThe purpose of this document is to offer a global approach to defining the level of quality requirements of artemisinin when used as a starting material for the production of its API derivatives used in ACT formulations. It does not apply to cases where artemisinin is used as an API. It is intended that the recommendations for requirements outlined in this document will apply to artemisinin extracted from *Artemisia annua* L. regardless of variations in agricultural environment or variations in extraction and purification steps. In addition, in order to ensure appropriate quality of the derived APIs, the manufacturer may add additional tests, such as tests for residual solvents and heavy metals, among others, and/or require tighter specifications. In the eventuality that artemisinin is produced using synthetic chemical processes or by fermentation, other requirements may be applicable.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "a2060d1fa6ed045c3ee0c816b9e3639d9ba2473324f458316f0fa492c68ab9df", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- a material used in the production of the API that is incorporated into the API as a significant structural element;\n- commercially available;\n- a compound whose name, chemical structure, chemical and physical characteristics, properties and impurity profile are well defined;\n- obtained by commonly known procedures.\n\nAs artemisinin is extracted from plant material and prior intermediates are thus not available, it is logical to designate this compound as the starting material for its derivatives.\n\nA monograph appears in *The International Pharmacopoeia* for artemisinin used as an API. However, at present, artemisinin is mainly used as a starting material for artemisinin-derived APIs, and not as an API.\n\nThe level of quality of the artemisinin should be acceptable for its intended use as the starting material for the production of artemisinin derivatives. The specifications presented below take into account an acceptable balance of benefit versus risk between the quality of artemisinin used as a starting material and the quality required for artemisinin derivatives for use as APIs.\n\nHowever, competent authorities may accept other impurity profile levels depending on the capability of the manufacturing process to lead to artemisinin-derived APIs at least compliant with the relevant monographs of *The International Pharmacopoeia*.\n\nThe purpose of this document is to offer a global approach to defining the level of quality requirements of artemisinin when used as a starting material for the production of its API derivatives used in ACT formulations. It does not apply to cases where artemisinin is used as an API. It is intended that the recommendations for requirements outlined in this document will apply to artemisinin extracted from *Artemisia annua* L. regardless of variations in agricultural environment or variations in extraction and purification steps. In addition, in order to ensure appropriate quality of the derived APIs, the manufacturer may add additional tests, such as tests for residual solvents and heavy metals, among others, and/or require tighter specifications. In the eventuality that artemisinin is produced using synthetic chemical processes or by fermentation, other requirements may be applicable.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2324, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "80d8e6f1-5c4b-48c5-977a-ec8e66cc4723": {"__data__": {"id_": "80d8e6f1-5c4b-48c5-977a-ec8e66cc4723", "embedding": null, "metadata": {"page_label": "245", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Characterization of artemisinin\n\nProvided that artemisinin intended for use as a starting material has been correctly identified, the major quality concern is the presence and level of impurities with the potential to affect the purity of subsequent API derivatives. Impurities may originate from the plant extracts or arise from the purification process or from degradation. Different biosynthetic routes may be used at different stages in the plant\u2019s development and there are claims of variability between growing regions and environments. Despite a lack of consensus on a single biosynthetic route, several potential impurities are common to different routes. These include artemisinic acid, dihydroartemisinic acid, arteannuin B and artemisitene. Of these only artemisitene has been reported in isolated artemisinin. Recent work (3, 4) has contributed towards a clearer understanding of existing impurities and their analysis.\n\nExamination of a wide variety of artemisinin samples produced in various regions indicated the consistent presence of two impurities: artemisitene and an artemisinin diastereomer with the stereochemistry inverted at C-9 (9-epi-artemisinin). A possible concern is that artemisinin impurities may not be detected with high-performance liquid chromatography analysis using ultraviolet detection, as used in the majority of testing laboratories. Recent work (5) using more sensitive general detection by mass spectrometry, however, demonstrated that additional impurities occur only in trace amounts. Isolated artemisinin is very stable. The potential degradants proposed on the basis of mechanistic studies do not occur at temperatures below 100 \u00b0C. These degradants are not observed in isolated artemisinin.\n\nIn the chemical conversion of the artemisinin starting material to its API derivatives (e.g. artesunate), the artemisinin diastereomeric impurity may be converted to a corresponding diastereomer at the C-9 position in the API derivative. However, these resulting diastereomers have not been observed in isolated APIs. The fate of artemisitene is less clear as it may be converted to the same intermediate as artemisinin.\n\nArtemisitene-derived impurities have not been observed in artemisinin derivative APIs. Proposed limits for these impurities are based on historical results. The specifications for artemisinin starting material are based on experience with artemether and artesunate. For a new artemisinin-derived API the suitability of the specifications to control potential impurities arising during its synthesis should be demonstrated.\n\nAs the artemisinin extraction processes use solvents like dichloromethane, chloroform, ether and others, residual solvents should be indicated on the certificate of analysis issued by the supplier.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl texto proporciona una caracterizaci\u00f3n de la artemisinina, un compuesto utilizado como material de partida para la producci\u00f3n de derivados farmac\u00e9uticos. Se discuten las preocupaciones sobre la calidad, espec\u00edficamente la presencia de impurezas que pueden afectar la pureza de los derivados de API (ingredientes farmac\u00e9uticos activos). Se mencionan varias impurezas comunes, como el \u00e1cido artemisinico y la dihidroartemisinina, y se destaca la importancia de la detecci\u00f3n de impurezas mediante t\u00e9cnicas anal\u00edticas adecuadas. Adem\u00e1s, se aborda la estabilidad de la artemisinina aislada y la necesidad de especificaciones adecuadas para controlar las impurezas durante la s\u00edntesis de nuevos derivados.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las impurezas m\u00e1s comunes encontradas en las muestras de artemisinina y c\u00f3mo pueden afectar la calidad de los derivados de API?**\n   - Respuesta: Las impurezas m\u00e1s comunes son el artemisitene y el diastere\u00f3mero 9-epi-artemisinin. Estas impurezas pueden afectar la pureza de los derivados de API, como el artesunato, y su detecci\u00f3n es crucial para garantizar la calidad del producto final.\n\n2. **\u00bfPor qu\u00e9 las t\u00e9cnicas de cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n con detecci\u00f3n ultravioleta pueden no ser suficientes para detectar impurezas en la artemisinina?**\n   - Respuesta: Estas t\u00e9cnicas pueden no detectar ciertas impurezas debido a su sensibilidad limitada. Se ha demostrado que el uso de espectrometr\u00eda de masas, que es m\u00e1s sensible, puede revelar impurezas adicionales que ocurren solo en cantidades traza.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al establecer especificaciones para nuevos derivados de artemisinina en relaci\u00f3n con las impurezas?**\n   - Respuesta: Las especificaciones deben basarse en la experiencia con derivados existentes como el artemeter y el artesunato, y se debe demostrar que son adecuadas para controlar las impurezas potenciales que puedan surgir durante la s\u00edntesis de nuevos derivados. Adem\u00e1s, es importante indicar la presencia de solventes residuales en el certificado de an\u00e1lisis.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Uso de Artemisinin**:\n   - Artemisinin es un compuesto extra\u00eddo de la planta *Artemisia annua* L.\n   - Se utiliza principalmente como material de partida para la producci\u00f3n de APIs derivados, en lugar de ser un API en s\u00ed mismo.\n\n2. **Especificaciones de Calidad**:\n   - La calidad de artemisinin debe ser adecuada para su uso como material de partida en la producci\u00f3n de derivados.\n   - Se establece un equilibrio entre los beneficios y riesgos en las especificaciones de calidad.\n   - Las autoridades competentes pueden aceptar diferentes niveles de impurezas seg\u00fan el proceso de fabricaci\u00f3n.\n\n3. **Recomendaciones Globales**:\n   - Se ofrecen directrices sobre los requisitos de calidad que deben aplicarse independientemente de las variaciones en el entorno agr\u00edcola o en los m\u00e9todos de extracci\u00f3n y purificaci\u00f3n.\n   - Los fabricantes pueden implementar pruebas adicionales (como pruebas de solventes residuales y metales pesados) para asegurar la calidad de los APIs derivados.\n\n4. **Producci\u00f3n Sint\u00e9tica y Fermentaci\u00f3n**:\n   - Si artemisinin se produce mediante procesos sint\u00e9ticos o fermentaci\u00f3n, pueden aplicarse requisitos de calidad diferentes.\n\n### Entidades Clave:\n- **Artemisinin**: Compuesto activo utilizado como material de partida.\n- ***Artemisia annua* L.**: Planta de la cual se extrae artemisinin.\n- **APIs (Active Pharmaceutical Ingredients)**: Ingredientes farmac\u00e9uticos activos derivados de artemisinin.\n- ***The International Pharmacopoeia***: Referencia que contiene monograf\u00edas sobre la calidad de artemisinin y sus derivados.\n- **Autoridades Competentes**: Entidades que regulan y aceptan diferentes niveles de calidad e impurezas en la producci\u00f3n de APIs.", "excerpt_keywords": "Keywords: artemisinin, impurities, API derivatives, quality control, extraction solvents"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a3d6d309-605e-497a-ae17-c9ca1d8794d8", "node_type": "4", "metadata": {"page_label": "245", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Characterization of artemisinin\n\nProvided that artemisinin intended for use as a starting material has been correctly identified, the major quality concern is the presence and level of impurities with the potential to affect the purity of subsequent API derivatives. Impurities may originate from the plant extracts or arise from the purification process or from degradation. Different biosynthetic routes may be used at different stages in the plant\u2019s development and there are claims of variability between growing regions and environments. Despite a lack of consensus on a single biosynthetic route, several potential impurities are common to different routes. These include artemisinic acid, dihydroartemisinic acid, arteannuin B and artemisitene. Of these only artemisitene has been reported in isolated artemisinin. Recent work (3, 4) has contributed towards a clearer understanding of existing impurities and their analysis.\n\nExamination of a wide variety of artemisinin samples produced in various regions indicated the consistent presence of two impurities: artemisitene and an artemisinin diastereomer with the stereochemistry inverted at C-9 (9-epi-artemisinin). A possible concern is that artemisinin impurities may not be detected with high-performance liquid chromatography analysis using ultraviolet detection, as used in the majority of testing laboratories. Recent work (5) using more sensitive general detection by mass spectrometry, however, demonstrated that additional impurities occur only in trace amounts. Isolated artemisinin is very stable. The potential degradants proposed on the basis of mechanistic studies do not occur at temperatures below 100 \u00b0C. These degradants are not observed in isolated artemisinin.\n\nIn the chemical conversion of the artemisinin starting material to its API derivatives (e.g. artesunate), the artemisinin diastereomeric impurity may be converted to a corresponding diastereomer at the C-9 position in the API derivative. However, these resulting diastereomers have not been observed in isolated APIs. The fate of artemisitene is less clear as it may be converted to the same intermediate as artemisinin.\n\nArtemisitene-derived impurities have not been observed in artemisinin derivative APIs. Proposed limits for these impurities are based on historical results. The specifications for artemisinin starting material are based on experience with artemether and artesunate. For a new artemisinin-derived API the suitability of the specifications to control potential impurities arising during its synthesis should be demonstrated.\n\nAs the artemisinin extraction processes use solvents like dichloromethane, chloroform, ether and others, residual solvents should be indicated on the certificate of analysis issued by the supplier.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "773a5ac635b4d2b2375c75353d44fd46ddb64ca41822d0ef237c917d9c660fee", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 2. Characterization of artemisinin\n\nProvided that artemisinin intended for use as a starting material has been correctly identified, the major quality concern is the presence and level of impurities with the potential to affect the purity of subsequent API derivatives. Impurities may originate from the plant extracts or arise from the purification process or from degradation. Different biosynthetic routes may be used at different stages in the plant\u2019s development and there are claims of variability between growing regions and environments. Despite a lack of consensus on a single biosynthetic route, several potential impurities are common to different routes. These include artemisinic acid, dihydroartemisinic acid, arteannuin B and artemisitene. Of these only artemisitene has been reported in isolated artemisinin. Recent work (3, 4) has contributed towards a clearer understanding of existing impurities and their analysis.\n\nExamination of a wide variety of artemisinin samples produced in various regions indicated the consistent presence of two impurities: artemisitene and an artemisinin diastereomer with the stereochemistry inverted at C-9 (9-epi-artemisinin). A possible concern is that artemisinin impurities may not be detected with high-performance liquid chromatography analysis using ultraviolet detection, as used in the majority of testing laboratories. Recent work (5) using more sensitive general detection by mass spectrometry, however, demonstrated that additional impurities occur only in trace amounts. Isolated artemisinin is very stable. The potential degradants proposed on the basis of mechanistic studies do not occur at temperatures below 100 \u00b0C. These degradants are not observed in isolated artemisinin.\n\nIn the chemical conversion of the artemisinin starting material to its API derivatives (e.g. artesunate), the artemisinin diastereomeric impurity may be converted to a corresponding diastereomer at the C-9 position in the API derivative. However, these resulting diastereomers have not been observed in isolated APIs. The fate of artemisitene is less clear as it may be converted to the same intermediate as artemisinin.\n\nArtemisitene-derived impurities have not been observed in artemisinin derivative APIs. Proposed limits for these impurities are based on historical results. The specifications for artemisinin starting material are based on experience with artemether and artesunate. For a new artemisinin-derived API the suitability of the specifications to control potential impurities arising during its synthesis should be demonstrated.\n\nAs the artemisinin extraction processes use solvents like dichloromethane, chloroform, ether and others, residual solvents should be indicated on the certificate of analysis issued by the supplier.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2788, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "c3b7e3a8-8b1f-4e13-89a9-b22003e01a01": {"__data__": {"id_": "c3b7e3a8-8b1f-4e13-89a9-b22003e01a01", "embedding": null, "metadata": {"page_label": "246", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3. Tests and specifications for artemisinin starting material\n\n!Chemical Structure\n\n**Relative molecular mass:** 282.3\n\n**Chemical name:**  \n(3R,5aS,6R,8aS,9R,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one; CAS Reg. No. 63968-64-9.\n\n**Description:**  \nColourless needles or a white to almost white to slightly yellow, crystalline powder.\n\n**Category:**  \nStarting material for the synthesis of artemisinin derivative APIs.\n\n**Storage:**  \nArtemisinin should be kept in a well-closed container, protected from light.\n\n## Requirements\n\nArtemisinin contains not less than 95.0% and not more than the equivalent of 102.0% of C\u2081\u2085H\u2082\u2082O\u2085 calculated with reference to the dried substance.\n\n## Identity tests\n\nCarry out the examination as described under 1.7 \"Spectrophotometry in the infrared region\" of *The International Pharmacopoeia* (6). The infrared absorption spectrum is concordant with the spectrum obtained from artemisinin RS or with the reference spectrum of artemisinin in *The International Pharmacopoeia*.\n\n**Specific optical rotation:**  \nUse a 10 mg/ml solution in dehydrated ethanol R;  \n\\[\u03b1\\]\u2082\u2080\u00b0C\\_D = 75\u00b0 to + 78\u00b0\n\n**Loss on drying:**  \nDry to constant mass at 80 \u00b0C; it loses not more than 10.0 mg/g.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento proporciona especificaciones y pruebas para el material inicial de artemisinina, un compuesto qu\u00edmico utilizado en la s\u00edntesis de APIs derivados de artemisinina. Se detalla la estructura qu\u00edmica, el nombre, la masa molecular relativa, la descripci\u00f3n f\u00edsica, las condiciones de almacenamiento y los requisitos de pureza. Adem\u00e1s, se incluyen pruebas de identidad, como la espectrofotometr\u00eda en el infrarrojo y la rotaci\u00f3n \u00f3ptica espec\u00edfica, as\u00ed como el an\u00e1lisis de p\u00e9rdida por secado.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1l es la importancia de la pureza del material inicial de artemisinina y qu\u00e9 porcentaje se requiere seg\u00fan las especificaciones?**\n   - La pureza del material inicial de artemisinina es crucial para garantizar la eficacia y seguridad de los derivados de artemisinina en aplicaciones farmac\u00e9uticas. Seg\u00fan las especificaciones, la artemisinina debe contener no menos del 95.0% y no m\u00e1s del equivalente al 102.0% de C\u2081\u2085H\u2082\u2082O\u2085, calculado con referencia a la sustancia seca.\n\n2. **\u00bfQu\u00e9 m\u00e9todo se utiliza para verificar la identidad de la artemisinina y qu\u00e9 caracter\u00edsticas se buscan en el espectro?**\n   - Para verificar la identidad de la artemisinina, se utiliza la espectrofotometr\u00eda en el infrarrojo, como se describe en la *Farmacopea Internacional*. Se busca que el espectro de absorci\u00f3n infrarroja sea concordante con el espectro obtenido de artemisinina de referencia (RS) o con el espectro de referencia de artemisinina en la misma farmacopea.\n\n3. **\u00bfQu\u00e9 condiciones de almacenamiento se recomiendan para la artemisinina y por qu\u00e9 son importantes?**\n   - Se recomienda almacenar la artemisinina en un recipiente bien cerrado y protegido de la luz. Estas condiciones son importantes para prevenir la degradaci\u00f3n del compuesto, lo que podr\u00eda afectar su eficacia y estabilidad en aplicaciones farmac\u00e9uticas.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Artemisinina**: Compuesto utilizado como material de partida para la producci\u00f3n de derivados farmac\u00e9uticos (API).\n\n2. **Calidad y Pureza**: La principal preocupaci\u00f3n es la presencia y nivel de impurezas que pueden afectar la pureza de los derivados de API.\n\n3. **Impuridades Comunes**: \n   - **Artemisinic acid**\n   - **Dihydroartemisinic acid**\n   - **Arteannuin B**\n   - **Artemisitene**: Solo se ha reportado en artemisinina aislada.\n   - **9-epi-artemisinin**: Un diastere\u00f3mero de artemisinina con la estereoisomer\u00eda invertida en C-9.\n\n4. **T\u00e9cnicas de Detecci\u00f3n**: \n   - **Cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n (HPLC)**: Puede no ser suficiente para detectar impurezas debido a su sensibilidad limitada.\n   - **Espectrometr\u00eda de masas**: Se ha demostrado que es m\u00e1s sensible y puede detectar impurezas adicionales en cantidades traza.\n\n5. **Estabilidad de la Artemisinina**: La artemisinina aislada es muy estable y no presenta degradantes a temperaturas inferiores a 100 \u00b0C.\n\n6. **Conversi\u00f3n Qu\u00edmica**: Durante la conversi\u00f3n de artemisinina a sus derivados (ej. artesunato), las impurezas diastereom\u00e9ricas pueden convertirse en diastere\u00f3meros correspondientes, aunque no se han observado en APIs aislados.\n\n7. **Especificaciones para Nuevos Derivados**: Las especificaciones deben basarse en la experiencia con derivados existentes (como artemeter y artesunato) y demostrar su adecuaci\u00f3n para controlar impurezas potenciales.\n\n8. **Solventes Residuales**: Los procesos de extracci\u00f3n de artemisinina utilizan solventes como diclorometano, cloroformo y \u00e9ter, y se debe indicar la presencia de solventes residuales en el certificado de an\u00e1lisis.\n\n### Entidades Clave\n- **Artemisinina**\n- **API (Ingredientes Farmac\u00e9uticos Activos)**\n- **Artemisinic acid**\n- **Dihydroartemisinic acid**\n- **Arteannuin B**\n- **Artemisitene**\n- **9-epi-artemisinin**\n- **Artemether**\n- **Artesunate**\n- **Cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n (HPLC)**\n- **Espectrometr\u00eda de masas**", "excerpt_keywords": "Keywords: artemisinin, specifications, identity tests, purity, pharmacopoeia"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "726f3590-fa0f-477b-9f27-aa8fd6c6d2f9", "node_type": "4", "metadata": {"page_label": "246", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3. Tests and specifications for artemisinin starting material\n\n!Chemical Structure\n\n**Relative molecular mass:** 282.3\n\n**Chemical name:**  \n(3R,5aS,6R,8aS,9R,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one; CAS Reg. No. 63968-64-9.\n\n**Description:**  \nColourless needles or a white to almost white to slightly yellow, crystalline powder.\n\n**Category:**  \nStarting material for the synthesis of artemisinin derivative APIs.\n\n**Storage:**  \nArtemisinin should be kept in a well-closed container, protected from light.\n\n## Requirements\n\nArtemisinin contains not less than 95.0% and not more than the equivalent of 102.0% of C\u2081\u2085H\u2082\u2082O\u2085 calculated with reference to the dried substance.\n\n## Identity tests\n\nCarry out the examination as described under 1.7 \"Spectrophotometry in the infrared region\" of *The International Pharmacopoeia* (6). The infrared absorption spectrum is concordant with the spectrum obtained from artemisinin RS or with the reference spectrum of artemisinin in *The International Pharmacopoeia*.\n\n**Specific optical rotation:**  \nUse a 10 mg/ml solution in dehydrated ethanol R;  \n\\[\u03b1\\]\u2082\u2080\u00b0C\\_D = 75\u00b0 to + 78\u00b0\n\n**Loss on drying:**  \nDry to constant mass at 80 \u00b0C; it loses not more than 10.0 mg/g.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "84838fad9ac2392afa25de0e919883bd89040f1d0132f34a52be8b5c9764b447", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# 3. Tests and specifications for artemisinin starting material\n\n!Chemical Structure\n\n**Relative molecular mass:** 282.3\n\n**Chemical name:**  \n(3R,5aS,6R,8aS,9R,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one; CAS Reg. No. 63968-64-9.\n\n**Description:**  \nColourless needles or a white to almost white to slightly yellow, crystalline powder.\n\n**Category:**  \nStarting material for the synthesis of artemisinin derivative APIs.\n\n**Storage:**  \nArtemisinin should be kept in a well-closed container, protected from light.\n\n## Requirements\n\nArtemisinin contains not less than 95.0% and not more than the equivalent of 102.0% of C\u2081\u2085H\u2082\u2082O\u2085 calculated with reference to the dried substance.\n\n## Identity tests\n\nCarry out the examination as described under 1.7 \"Spectrophotometry in the infrared region\" of *The International Pharmacopoeia* (6). The infrared absorption spectrum is concordant with the spectrum obtained from artemisinin RS or with the reference spectrum of artemisinin in *The International Pharmacopoeia*.\n\n**Specific optical rotation:**  \nUse a 10 mg/ml solution in dehydrated ethanol R;  \n\\[\u03b1\\]\u2082\u2080\u00b0C\\_D = 75\u00b0 to + 78\u00b0\n\n**Loss on drying:**  \nDry to constant mass at 80 \u00b0C; it loses not more than 10.0 mg/g.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1255, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "1bf2d69c-3df6-4190-838f-d930b354c86c": {"__data__": {"id_": "1bf2d69c-3df6-4190-838f-d930b354c86c", "embedding": null, "metadata": {"page_label": "247", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Related Substances\n\n*Note:* It may be possible to justify other limits when artemisinin as a starting material is used in a particular synthesis and manufacturing process, by validation of the levels and limits of the impurities in the final API.\n\nCarry out the test as described under 1.14.4 \u201cHigh performance liquid chromatography\u201d of *The International Pharmacopoeia* (6). Use the chromatographic conditions and prepare solutions (1) and (2) as described below under Assay. For solution (3) dilute 1 ml of solution (1) to 100 ml with the mobile phase.\n\nInject separately 20 \u03bcl of solutions (1), (2) and (3). Record the chromatograms for about 1.5 times the retention time of artemisinin. In the chromatogram obtained with solution (2), artemisitene (impurity A) is eluted at the relative retention of about 0.79 with reference to artemisinin (retention time about 10 minutes). The test is not valid unless the resolution between the peak of artemisitene and the peak of artemisinin is at least 4. The chromatogram obtained with solution (1) may show a peak due to impurity B eluting at a retention of about 0.85 with reference to artemisinin.\n\nIn the chromatogram obtained with solution (1):\n\n- the area of any peak corresponding to impurity A, when multiplied by a correction factor of 0.027 is not greater than 0.15 times the area of the peak in the chromatogram obtained with solution (3) (0.2%);\n- the area of any peak corresponding to impurity B is not greater than the area of the peak in the chromatogram obtained with solution (3) (1.0%);\n- the area of any peak other than the principal peak is not greater than 0.5 times the area of the peak in the chromatogram obtained with solution (3) (0.5%);\n- the sum of the corrected area of any peak corresponding to impurity A and the areas of all the peaks, apart from the principal peak, is not greater than 3 times the area of the peak obtained with solution (3) (3.0%). Disregard any peak with an area less than 0.1 times the area of the principal peak obtained with solution (3) (0.1%).\n\n# Assay\n\nCarry out the test as described under 1.14.4 \u201cHigh performance liquid chromatography\u201d of *The International Pharmacopoeia* (6), using a stainless steel column (15 cm \u00d7 4.6 mm) packed with 5 \u03bcm particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups. The", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas basadas en el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla un procedimiento para la prueba de sustancias relacionadas con la artemisinina utilizando cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n (HPLC). Se describen las condiciones de la prueba, la preparaci\u00f3n de soluciones y los criterios de aceptaci\u00f3n para las impurezas A y B. Se enfatiza la importancia de la resoluci\u00f3n entre los picos de las impurezas y el principio activo, as\u00ed como los l\u00edmites espec\u00edficos para las \u00e1reas de los picos en los cromatogramas obtenidos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios de aceptaci\u00f3n para las \u00e1reas de los picos correspondientes a las impurezas A y B en el cromatograma obtenido con la soluci\u00f3n (1)?**\n   - La pregunta se centra en los l\u00edmites espec\u00edficos establecidos para las impurezas, que son cruciales para validar la calidad del producto.\n\n2. **\u00bfQu\u00e9 condiciones cromatogr\u00e1ficas se deben utilizar para llevar a cabo la prueba de HPLC seg\u00fan el documento de la OMS?**\n   - Esta pregunta busca detalles sobre el equipo y las condiciones necesarias para realizar la prueba, que son esenciales para replicar el procedimiento.\n\n3. **\u00bfPor qu\u00e9 es importante la resoluci\u00f3n entre el pico de artemisitene y el pico de artemisinina en el an\u00e1lisis cromatogr\u00e1fico?**\n   - Esta pregunta aborda la relevancia de la resoluci\u00f3n en el contexto de la validaci\u00f3n del m\u00e9todo anal\u00edtico, lo que es fundamental para asegurar la precisi\u00f3n de los resultados obtenidos.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Artemisinina**:\n   - **Nombre qu\u00edmico**: (3R,5aS,6R,8aS,9R,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one.\n   - **N\u00famero CAS**: 63968-64-9.\n   - **Masa molecular relativa**: 282.3.\n\n2. **Descripci\u00f3n f\u00edsica**:\n   - Presenta forma de agujas incoloras o un polvo cristalino blanco a casi blanco, ligeramente amarillo.\n\n3. **Categor\u00eda**:\n   - Material inicial para la s\u00edntesis de APIs derivados de artemisinina.\n\n4. **Almacenamiento**:\n   - Debe guardarse en un recipiente bien cerrado y protegido de la luz para evitar degradaci\u00f3n.\n\n5. **Requisitos de pureza**:\n   - Contenido de artemisinina: no menos del 95.0% y no m\u00e1s del equivalente al 102.0% de C\u2081\u2085H\u2082\u2082O\u2085, calculado con referencia a la sustancia seca.\n\n6. **Pruebas de identidad**:\n   - **Espectrofotometr\u00eda en el infrarrojo**: El espectro de absorci\u00f3n debe concordar con el espectro de referencia de artemisinina.\n   - **Rotaci\u00f3n \u00f3ptica espec\u00edfica**: Se utiliza una soluci\u00f3n de 10 mg/ml en etanol deshidratado; el rango es de 75\u00b0 a +78\u00b0.\n   - **P\u00e9rdida por secado**: No debe exceder 10.0 mg/g al secar a 80 \u00b0C hasta masa constante.\n\n### Entidades clave\n- **Artemisinina**: Compuesto qu\u00edmico utilizado en la s\u00edntesis de medicamentos.\n- **CAS Reg. No.**: Identificador \u00fanico para sustancias qu\u00edmicas.\n- **Espectrofotometr\u00eda**: M\u00e9todo anal\u00edtico para verificar la identidad del compuesto.\n- **Farmacopea Internacional**: Referencia para est\u00e1ndares y m\u00e9todos en farmacolog\u00eda.", "excerpt_keywords": "Keywords: artemisinin, high performance liquid chromatography, impurities, chromatogram, International Pharmacopoeia"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d03945a3-f4b2-4406-8e21-381ba7d3f88e", "node_type": "4", "metadata": {"page_label": "247", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Related Substances\n\n*Note:* It may be possible to justify other limits when artemisinin as a starting material is used in a particular synthesis and manufacturing process, by validation of the levels and limits of the impurities in the final API.\n\nCarry out the test as described under 1.14.4 \u201cHigh performance liquid chromatography\u201d of *The International Pharmacopoeia* (6). Use the chromatographic conditions and prepare solutions (1) and (2) as described below under Assay. For solution (3) dilute 1 ml of solution (1) to 100 ml with the mobile phase.\n\nInject separately 20 \u03bcl of solutions (1), (2) and (3). Record the chromatograms for about 1.5 times the retention time of artemisinin. In the chromatogram obtained with solution (2), artemisitene (impurity A) is eluted at the relative retention of about 0.79 with reference to artemisinin (retention time about 10 minutes). The test is not valid unless the resolution between the peak of artemisitene and the peak of artemisinin is at least 4. The chromatogram obtained with solution (1) may show a peak due to impurity B eluting at a retention of about 0.85 with reference to artemisinin.\n\nIn the chromatogram obtained with solution (1):\n\n- the area of any peak corresponding to impurity A, when multiplied by a correction factor of 0.027 is not greater than 0.15 times the area of the peak in the chromatogram obtained with solution (3) (0.2%);\n- the area of any peak corresponding to impurity B is not greater than the area of the peak in the chromatogram obtained with solution (3) (1.0%);\n- the area of any peak other than the principal peak is not greater than 0.5 times the area of the peak in the chromatogram obtained with solution (3) (0.5%);\n- the sum of the corrected area of any peak corresponding to impurity A and the areas of all the peaks, apart from the principal peak, is not greater than 3 times the area of the peak obtained with solution (3) (3.0%). Disregard any peak with an area less than 0.1 times the area of the principal peak obtained with solution (3) (0.1%).\n\n# Assay\n\nCarry out the test as described under 1.14.4 \u201cHigh performance liquid chromatography\u201d of *The International Pharmacopoeia* (6), using a stainless steel column (15 cm \u00d7 4.6 mm) packed with 5 \u03bcm particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups. The", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "2edb634f6274c270559f3541a4acd0e881593b460fccaea1bb2f35d59a28f236", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# Related Substances\n\n*Note:* It may be possible to justify other limits when artemisinin as a starting material is used in a particular synthesis and manufacturing process, by validation of the levels and limits of the impurities in the final API.\n\nCarry out the test as described under 1.14.4 \u201cHigh performance liquid chromatography\u201d of *The International Pharmacopoeia* (6). Use the chromatographic conditions and prepare solutions (1) and (2) as described below under Assay. For solution (3) dilute 1 ml of solution (1) to 100 ml with the mobile phase.\n\nInject separately 20 \u03bcl of solutions (1), (2) and (3). Record the chromatograms for about 1.5 times the retention time of artemisinin. In the chromatogram obtained with solution (2), artemisitene (impurity A) is eluted at the relative retention of about 0.79 with reference to artemisinin (retention time about 10 minutes). The test is not valid unless the resolution between the peak of artemisitene and the peak of artemisinin is at least 4. The chromatogram obtained with solution (1) may show a peak due to impurity B eluting at a retention of about 0.85 with reference to artemisinin.\n\nIn the chromatogram obtained with solution (1):\n\n- the area of any peak corresponding to impurity A, when multiplied by a correction factor of 0.027 is not greater than 0.15 times the area of the peak in the chromatogram obtained with solution (3) (0.2%);\n- the area of any peak corresponding to impurity B is not greater than the area of the peak in the chromatogram obtained with solution (3) (1.0%);\n- the area of any peak other than the principal peak is not greater than 0.5 times the area of the peak in the chromatogram obtained with solution (3) (0.5%);\n- the sum of the corrected area of any peak corresponding to impurity A and the areas of all the peaks, apart from the principal peak, is not greater than 3 times the area of the peak obtained with solution (3) (3.0%). Disregard any peak with an area less than 0.1 times the area of the principal peak obtained with solution (3) (0.1%).\n\n# Assay\n\nCarry out the test as described under 1.14.4 \u201cHigh performance liquid chromatography\u201d of *The International Pharmacopoeia* (6), using a stainless steel column (15 cm \u00d7 4.6 mm) packed with 5 \u03bcm particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups. The", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 2364, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "768c2ff4-8f90-40b6-9eff-dbf956fe24dd": {"__data__": {"id_": "768c2ff4-8f90-40b6-9eff-dbf956fe24dd", "embedding": null, "metadata": {"page_label": "248", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe mobile phase consists of a 50:50 mixture of acetonitrile and water, pumped at a flow rate of 1.0 ml/minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 210 nm.\n\nPrepare the following solutions. For solution (1) prepare a 5.0 mg/ml solution of the test substance in the mobile phase. For solution (2) prepare a 5.0 mg/ml solution of artemisinin RS in the mobile phase.\n\nInject separately 20 \u03bcl of solutions (1) and (2). Record the chromatograms for about 1.5 times the retention time of artemisinin. In the chromatogram obtained with solution (2), artemisitene (impurity A) is eluted at the relative retention of 0.79 with reference to artemisinin (retention time about 10 minutes). The test is not valid unless the resolution between the peak of artemisitene and the peak of artemisinin is at least 4. The chromatogram obtained with solution (1) may show a peak due to impurity B eluting at a retention of about 0.85 with reference to artemisinin.\n\nMeasure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2), and calculate the content of C\u2081\u2085H\u2082\u2082O\u2085 with reference to the dried substance.\n\n## Impurities\n\n!Chemical Structure\n\n(3R,5aS,6R,8aS,12S,12aR)-3,6-dimethyl-9-methyleneoctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one (artemisitene)\n\n!Chemical Structure\n\n(3R,5aS,6R,8aS,9S,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one (9-epi-artemisinin)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en un procedimiento anal\u00edtico para evaluar la pureza de artemisinin y sus impurezas mediante cromatograf\u00eda. Se describe la preparaci\u00f3n de soluciones, el uso de un espectrofot\u00f3metro UV, y los criterios de validez del test, incluyendo la resoluci\u00f3n entre picos en el cromatograma. Se mencionan dos impurezas espec\u00edficas, artemisitene y 9-epi-artemisinin, junto con sus estructuras qu\u00edmicas.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1l es la importancia de la resoluci\u00f3n m\u00ednima de 4 entre los picos de artemisitene y artemisinin en el an\u00e1lisis cromatogr\u00e1fico?**\n   - La resoluci\u00f3n m\u00ednima de 4 es crucial para asegurar que los picos de artemisitene y artemisinin se separen adecuadamente, lo que permite una identificaci\u00f3n y cuantificaci\u00f3n precisas de las sustancias en la muestra. Si la resoluci\u00f3n es menor, puede haber interferencias que afecten la validez del an\u00e1lisis.\n\n2. **\u00bfQu\u00e9 pasos deben seguirse si la cromatograf\u00eda muestra una resoluci\u00f3n menor a 4 entre los picos de artemisitene y artemisinin?**\n   - Si la resoluci\u00f3n es menor a 4, el test no es v\u00e1lido. Se deben revisar las condiciones del experimento, como la preparaci\u00f3n de las soluciones, el flujo del m\u00f3vil, y la calibraci\u00f3n del espectrofot\u00f3metro. Puede ser necesario ajustar la composici\u00f3n de la fase m\u00f3vil o el tiempo de inyecci\u00f3n para mejorar la separaci\u00f3n.\n\n3. **\u00bfC\u00f3mo se calcula el contenido de C\u2081\u2085H\u2082\u2082O\u2085 a partir de las \u00e1reas de los picos en los cromatogramas?**\n   - El contenido de C\u2081\u2085H\u2082\u2082O\u2085 se calcula utilizando las \u00e1reas de los picos obtenidos de las soluciones (1) y (2). Se puede aplicar una f\u00f3rmula que relaciona las \u00e1reas de los picos con las concentraciones conocidas de artemisinin y el test substance, permitiendo determinar la cantidad de C\u2081\u2085H\u2082\u2082O\u2085 en la muestra analizada.\n\n### Resumen de Nivel Superior\n\nEl documento proporciona un protocolo detallado para la evaluaci\u00f3n de la pureza de artemisinin mediante cromatograf\u00eda, enfatizando la importancia de la resoluci\u00f3n entre picos para validar los resultados. Se describen las preparaciones de soluciones y el uso de un espectrofot\u00f3metro UV, as\u00ed como la identificaci\u00f3n de impurezas espec\u00edficas. Este procedimiento es fundamental para asegurar la calidad y eficacia de productos farmac\u00e9uticos que contienen artemisinin.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Sustancias Relacionadas**: El documento se centra en la evaluaci\u00f3n de impurezas relacionadas con la artemisinina, un compuesto activo importante en tratamientos m\u00e9dicos.\n\n2. **Cromatograf\u00eda L\u00edquida de Alta Resoluci\u00f3n (HPLC)**: Se describe el procedimiento para llevar a cabo pruebas de HPLC, incluyendo la preparaci\u00f3n de soluciones y las condiciones cromatogr\u00e1ficas necesarias.\n\n3. **Criterios de Aceptaci\u00f3n**: Se establecen l\u00edmites espec\u00edficos para las \u00e1reas de los picos correspondientes a las impurezas A (artemisitene) y B, as\u00ed como otros picos en el cromatograma. Estos criterios son esenciales para validar la calidad del producto.\n\n4. **Resoluci\u00f3n de Picos**: Se enfatiza la importancia de la resoluci\u00f3n entre los picos de artemisitene y artemisinina, que debe ser al menos 4 para que la prueba sea v\u00e1lida.\n\n5. **Preparaci\u00f3n de Soluciones**: Se indican las instrucciones para preparar las soluciones necesarias para el an\u00e1lisis, incluyendo la diluci\u00f3n de la soluci\u00f3n (1) para obtener la soluci\u00f3n (3).\n\n6. **Condiciones Cromatogr\u00e1ficas**: Se especifica el uso de una columna de acero inoxidable con caracter\u00edsticas particulares para realizar el an\u00e1lisis.\n\n### Entidades Clave\n\n- **Artemisinina**: Compuesto activo en el an\u00e1lisis.\n- **Artemisitene (Impureza A)**: Impureza espec\u00edfica que se eval\u00faa en el an\u00e1lisis.\n- **Impureza B**: Otra impureza que se menciona en el procedimiento.\n- **HPLC**: T\u00e9cnica anal\u00edtica utilizada para la evaluaci\u00f3n de impurezas.\n- **Cromatograma**: Resultado visual del an\u00e1lisis que se eval\u00faa seg\u00fan criterios espec\u00edficos.\n\nEste resumen proporciona una visi\u00f3n general de los aspectos m\u00e1s relevantes del procedimiento anal\u00edtico descrito en el documento de la OMS.", "excerpt_keywords": "Keywords: artemisinin, chromatography, impurities, HPLC, resolution"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8f0696c5-1b32-41fe-82b5-962e3f66a853", "node_type": "4", "metadata": {"page_label": "248", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe mobile phase consists of a 50:50 mixture of acetonitrile and water, pumped at a flow rate of 1.0 ml/minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 210 nm.\n\nPrepare the following solutions. For solution (1) prepare a 5.0 mg/ml solution of the test substance in the mobile phase. For solution (2) prepare a 5.0 mg/ml solution of artemisinin RS in the mobile phase.\n\nInject separately 20 \u03bcl of solutions (1) and (2). Record the chromatograms for about 1.5 times the retention time of artemisinin. In the chromatogram obtained with solution (2), artemisitene (impurity A) is eluted at the relative retention of 0.79 with reference to artemisinin (retention time about 10 minutes). The test is not valid unless the resolution between the peak of artemisitene and the peak of artemisinin is at least 4. The chromatogram obtained with solution (1) may show a peak due to impurity B eluting at a retention of about 0.85 with reference to artemisinin.\n\nMeasure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2), and calculate the content of C\u2081\u2085H\u2082\u2082O\u2085 with reference to the dried substance.\n\n## Impurities\n\n!Chemical Structure\n\n(3R,5aS,6R,8aS,12S,12aR)-3,6-dimethyl-9-methyleneoctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one (artemisitene)\n\n!Chemical Structure\n\n(3R,5aS,6R,8aS,9S,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one (9-epi-artemisinin)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "423f5539e705c444f60f37176616b88d693e361995c93bbcfd88ac05d4b7fda1", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe mobile phase consists of a 50:50 mixture of acetonitrile and water, pumped at a flow rate of 1.0 ml/minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 210 nm.\n\nPrepare the following solutions. For solution (1) prepare a 5.0 mg/ml solution of the test substance in the mobile phase. For solution (2) prepare a 5.0 mg/ml solution of artemisinin RS in the mobile phase.\n\nInject separately 20 \u03bcl of solutions (1) and (2). Record the chromatograms for about 1.5 times the retention time of artemisinin. In the chromatogram obtained with solution (2), artemisitene (impurity A) is eluted at the relative retention of 0.79 with reference to artemisinin (retention time about 10 minutes). The test is not valid unless the resolution between the peak of artemisitene and the peak of artemisinin is at least 4. The chromatogram obtained with solution (1) may show a peak due to impurity B eluting at a retention of about 0.85 with reference to artemisinin.\n\nMeasure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2), and calculate the content of C\u2081\u2085H\u2082\u2082O\u2085 with reference to the dried substance.\n\n## Impurities\n\n!Chemical Structure\n\n(3R,5aS,6R,8aS,12S,12aR)-3,6-dimethyl-9-methyleneoctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one (artemisitene)\n\n!Chemical Structure\n\n(3R,5aS,6R,8aS,9S,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one (9-epi-artemisinin)", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1544, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "84f1f4aa-64a1-4cbe-9a9e-8775c5924be7": {"__data__": {"id_": "84f1f4aa-64a1-4cbe-9a9e-8775c5924be7", "embedding": null, "metadata": {"page_label": "249", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# References\n\n1. WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth Report. Geneva, World Health Organization, 2010, Annex 2 (WHO Technical Report Series, No. 957).\n\n2. International Conference on Harmonisation (ICH) Topic Q7: Note for guidance on good manufacturing practice for active pharmaceutical ingredients. London, EMEA, 2006 (CPMP/ICH/4106/00); http://www.ema.europa.eu/pdfs/human/ich/410600en.pdf\n\n3. Lapkin AA et al. Development of HPLC analytical protocols for quantification of artemisinin in biomass and extracts. *Journal of Pharmaceutical and Biomedical Analysis*, 2009, 49: 908\u2013915.\n\n4. Stringham RW et al. High performance liquid chromatographic evaluation of artemisinin, raw material in the synthesis of artesunate and artemether. *Journal of Chromatography A*, 2009, 1216: 8918\u20138925.\n\n5. Stringham RW et al. Verification of the identities of impurities in artemisinin and correction of their elution order in high performance liquid chromatography. *Journal of Chromatography A*, 2011, 1218: 6838\u20136842.\n\n6. *The International Pharmacopoeia*, 4th ed., Vol. 1: General notices; monographs for pharmaceutical substances (A\u2013O) and Vol. 2: Monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents. Geneva, World Health Organization, 2006, also available in CD-ROM format and online.\n\n   - *The International Pharmacopoeia*, 4th ed., First and Second supplements, 2011, available on CD-ROM.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que forma parte de la Serie de Informes T\u00e9cnicos (No. 970). En la secci\u00f3n de referencias, se citan diversas fuentes relacionadas con las buenas pr\u00e1cticas de fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos, as\u00ed como estudios espec\u00edficos sobre la artemisinina, un compuesto utilizado en tratamientos contra la malaria. Se mencionan gu\u00edas de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) y se hace referencia a la Farmacopea Internacional, que proporciona monograf\u00edas y m\u00e9todos de an\u00e1lisis para sustancias farmac\u00e9uticas.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS sobre las buenas pr\u00e1cticas de fabricaci\u00f3n para los ingredientes farmac\u00e9uticos activos seg\u00fan el informe mencionado?**\n   - Esta pregunta busca detalles espec\u00edficos sobre las directrices de la OMS que no se encuentran f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas anal\u00edticas se han desarrollado para la cuantificaci\u00f3n de artemisinina en biomasa y extractos, seg\u00fan el estudio de Lapkin et al.?**\n   - Esta pregunta se centra en los m\u00e9todos espec\u00edficos utilizados en la investigaci\u00f3n, que pueden no estar ampliamente documentados en otras publicaciones.\n\n3. **\u00bfC\u00f3mo se verificaron las identidades de las impurezas en artemisinina y cu\u00e1l fue la correcci\u00f3n realizada en su orden de eluci\u00f3n en cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n, seg\u00fan el estudio de Stringham et al.?**\n   - Esta pregunta busca informaci\u00f3n t\u00e9cnica detallada sobre un aspecto espec\u00edfico de la investigaci\u00f3n que podr\u00eda no estar disponible en otras fuentes.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n t\u00e9cnica y espec\u00edfica que el documento proporciona, lo que puede ser \u00fatil para investigadores o profesionales en el campo farmac\u00e9utico.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Tema Principal:**\nEl documento describe un procedimiento anal\u00edtico para evaluar la pureza de artemisinin y sus impurezas mediante cromatograf\u00eda, destacando la importancia de la resoluci\u00f3n entre picos en el cromatograma.\n\n**M\u00e9todo Anal\u00edtico:**\n- **Fase M\u00f3vil:** Mezcla 50:50 de acetonitrilo y agua, con un flujo de 1.0 ml/min.\n- **Detector:** Espectrofot\u00f3metro UV a 210 nm.\n- **Preparaci\u00f3n de Soluciones:**\n  - **Soluci\u00f3n (1):** 5.0 mg/ml del test substance en la fase m\u00f3vil.\n  - **Soluci\u00f3n (2):** 5.0 mg/ml de artemisinin RS en la fase m\u00f3vil.\n- **Inyecci\u00f3n:** 20 \u03bcl de cada soluci\u00f3n.\n- **Registro de Cromatogramas:** Durante aproximadamente 1.5 veces el tiempo de retenci\u00f3n de artemisinin.\n\n**Criterios de Validez:**\n- La resoluci\u00f3n m\u00ednima entre los picos de artemisitene (impureza A) y artemisinin debe ser al menos 4 para que el test sea v\u00e1lido.\n\n**Implicaciones de Resultados:**\n- **C\u00e1lculo del Contenido:** Se mide el \u00e1rea de los picos en los cromatogramas para calcular el contenido de C\u2081\u2085H\u2082\u2082O\u2085 en la muestra.\n\n**Impurezas Identificadas:**\n1. **Artemisitene:** (3R,5aS,6R,8aS,12S,12aR)-3,6-dimethyl-9-methyleneoctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one.\n2. **9-epi-artemisinin:** (3R,5aS,6R,8aS,9S,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one.\n\n### Entidades Clave:\n- **Compuestos Qu\u00edmicos:** Artemisinin, artemisitene, 9-epi-artemisinin.\n- **T\u00e9cnicas Anal\u00edticas:** Cromatograf\u00eda, espectrofotometr\u00eda UV.\n- **Par\u00e1metros de An\u00e1lisis:** Resoluci\u00f3n, tiempo de retenci\u00f3n, \u00e1reas de picos. \n\nEste resumen proporciona una visi\u00f3n general de los procedimientos y criterios establecidos para la evaluaci\u00f3n de la pureza de artemisinin, as\u00ed como las impurezas relevantes que se deben considerar en el an\u00e1lisis.", "excerpt_keywords": "Keywords: artemisinin, good manufacturing practices, high performance liquid chromatography, pharmaceutical analysis, WHO Technical Report Series"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "542cd442-db1e-4e4a-8009-dd5c5d9cb7d5", "node_type": "4", "metadata": {"page_label": "249", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# References\n\n1. WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth Report. Geneva, World Health Organization, 2010, Annex 2 (WHO Technical Report Series, No. 957).\n\n2. International Conference on Harmonisation (ICH) Topic Q7: Note for guidance on good manufacturing practice for active pharmaceutical ingredients. London, EMEA, 2006 (CPMP/ICH/4106/00); http://www.ema.europa.eu/pdfs/human/ich/410600en.pdf\n\n3. Lapkin AA et al. Development of HPLC analytical protocols for quantification of artemisinin in biomass and extracts. *Journal of Pharmaceutical and Biomedical Analysis*, 2009, 49: 908\u2013915.\n\n4. Stringham RW et al. High performance liquid chromatographic evaluation of artemisinin, raw material in the synthesis of artesunate and artemether. *Journal of Chromatography A*, 2009, 1216: 8918\u20138925.\n\n5. Stringham RW et al. Verification of the identities of impurities in artemisinin and correction of their elution order in high performance liquid chromatography. *Journal of Chromatography A*, 2011, 1218: 6838\u20136842.\n\n6. *The International Pharmacopoeia*, 4th ed., Vol. 1: General notices; monographs for pharmaceutical substances (A\u2013O) and Vol. 2: Monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents. Geneva, World Health Organization, 2006, also available in CD-ROM format and online.\n\n   - *The International Pharmacopoeia*, 4th ed., First and Second supplements, 2011, available on CD-ROM.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": "5a1b480f38b7634c6916d40a9283f0f06e9ad82bb11ddcc970a2dadb3c1ff37b", "class_name": "RelatedNodeInfo"}}, "metadata_template": "{key}: {value}", "metadata_separator": "\n", "text": "# References\n\n1. WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth Report. Geneva, World Health Organization, 2010, Annex 2 (WHO Technical Report Series, No. 957).\n\n2. International Conference on Harmonisation (ICH) Topic Q7: Note for guidance on good manufacturing practice for active pharmaceutical ingredients. London, EMEA, 2006 (CPMP/ICH/4106/00); http://www.ema.europa.eu/pdfs/human/ich/410600en.pdf\n\n3. Lapkin AA et al. Development of HPLC analytical protocols for quantification of artemisinin in biomass and extracts. *Journal of Pharmaceutical and Biomedical Analysis*, 2009, 49: 908\u2013915.\n\n4. Stringham RW et al. High performance liquid chromatographic evaluation of artemisinin, raw material in the synthesis of artesunate and artemether. *Journal of Chromatography A*, 2009, 1216: 8918\u20138925.\n\n5. Stringham RW et al. Verification of the identities of impurities in artemisinin and correction of their elution order in high performance liquid chromatography. *Journal of Chromatography A*, 2011, 1218: 6838\u20136842.\n\n6. *The International Pharmacopoeia*, 4th ed., Vol. 1: General notices; monographs for pharmaceutical substances (A\u2013O) and Vol. 2: Monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents. Geneva, World Health Organization, 2006, also available in CD-ROM format and online.\n\n   - *The International Pharmacopoeia*, 4th ed., First and Second supplements, 2011, available on CD-ROM.", "mimetype": "text/plain", "start_char_idx": 0, "end_char_idx": 1602, "metadata_seperator": "\n", "text_template": "[Excerpt from document]\n{metadata_str}\nExcerpt:\n-----\n{content}\n-----\n", "class_name": "TextNode"}, "__type__": "1"}, "744b6c3d-2862-4873-abb9-924297879f9d": {"__data__": {"id_": "744b6c3d-2862-4873-abb9-924297879f9d", "embedding": null, "metadata": {"page_label": "250", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que forma parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica y recomendaciones para la pr\u00e1ctica cl\u00ednica y la pol\u00edtica de salud. Aunque el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado, es probable que contenga informaci\u00f3n relevante sobre temas de salud global, directrices para la investigaci\u00f3n y an\u00e1lisis de datos epidemiol\u00f3gicos.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el informe WHO - Technical Report Series 970?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe que no se puede encontrar en otros documentos.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en el informe y c\u00f3mo se relacionan con las tendencias actuales en la salud global?**\n   - Esta pregunta se centra en la relevancia del informe en el contexto de la salud p\u00fablica contempor\u00e1nea, lo que podr\u00eda no estar documentado en otras fuentes.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas de investigaci\u00f3n se utilizan en el informe para abordar los problemas de salud discutidos?**\n   - Esta pregunta indaga sobre las t\u00e9cnicas y enfoques de investigaci\u00f3n que se presentan en el informe, lo que podr\u00eda ser \u00fanico a este documento y no estar disponible en otros lugares.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Buenas Pr\u00e1cticas de Fabricaci\u00f3n (BPF)**:\n   - Se citan directrices de la OMS sobre BPF para ingredientes farmac\u00e9uticos activos, destacando la importancia de seguir est\u00e1ndares de calidad en la producci\u00f3n.\n\n2. **Artemisinina**:\n   - Se mencionan estudios sobre la artemisinina, un compuesto crucial en el tratamiento de la malaria, incluyendo metodolog\u00edas anal\u00edticas para su cuantificaci\u00f3n en biomasa y extractos.\n\n3. **Cromatograf\u00eda L\u00edquida de Alta Resoluci\u00f3n (HPLC)**:\n   - Se discuten evaluaciones y correcciones relacionadas con la identificaci\u00f3n de impurezas en artemisinina, as\u00ed como su orden de eluci\u00f3n en HPLC.\n\n4. **Referencias Normativas**:\n   - Se hace referencia a la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) y a la Farmacopea Internacional, que proporcionan marcos normativos y metodolog\u00edas para el an\u00e1lisis de sustancias farmac\u00e9uticas.\n\n5. **Publicaciones Cient\u00edficas**:\n   - Se citan varios art\u00edculos de revistas cient\u00edficas que abordan el desarrollo de protocolos anal\u00edticos y evaluaciones de la artemisinina, contribuyendo al conocimiento en el campo farmac\u00e9utico.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad en la regulaci\u00f3n de pr\u00e1cticas de fabricaci\u00f3n farmac\u00e9utica.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Entidad que establece gu\u00edas para la BPF.\n- **Lapkin AA**: Autor de un estudio sobre la cuantificaci\u00f3n de artemisinina.\n- **Stringham RW**: Autor de estudios sobre la evaluaci\u00f3n y verificaci\u00f3n de impurezas en artemisinina.\n- **Farmacopea Internacional**: Publicaci\u00f3n que contiene monograf\u00edas y m\u00e9todos de an\u00e1lisis para sustancias farmac\u00e9uticas. \n\nEste resumen destaca la relevancia de las buenas pr\u00e1cticas en la fabricaci\u00f3n de ingredientes farmac\u00e9uticos, as\u00ed como la investigaci\u00f3n relacionada con la artemisinina, un compuesto vital en la lucha contra la malaria.", "excerpt_keywords": "Keywords: OMS, artemisinina, buenas pr\u00e1cticas de fabricaci\u00f3n, cromatograf\u00eda l\u00edquida, salud p\u00fablica"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6c427f0d-c8b2-4d31-b46b-a2b9f837d792", "node_type": "4", "metadata": {"page_label": "250", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970"}, "hash": 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"6c427f0d-c8b2-4d31-b46b-a2b9f837d792"}}, "docstore/ref_doc_info": {"856b2a05-511a-4cdd-af5c-b5e4124c8464": {"node_ids": ["6dd467cf-1cf2-448b-b9d6-ce147cc7e4c3"], "metadata": {"page_label": "1", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento titulado \"WHO - Technical Report Series 970\" es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que probablemente aborda temas relacionados con la salud p\u00fablica, investigaciones cient\u00edficas, recomendaciones de pol\u00edticas o directrices sobre pr\u00e1cticas de salud. Sin embargo, el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el informe \"WHO - Technical Report Series 970\"?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe que no se puede encontrar en otros lugares sin acceso al documento completo.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en el informe y c\u00f3mo se relacionan con las tendencias actuales en la salud global?**\n   - Esta pregunta se centra en la relevancia del informe en el contexto de los desaf\u00edos de salud contempor\u00e1neos, lo que podr\u00eda no estar disponible en otras fuentes.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas o enfoques se utilizan en el informe para abordar los problemas de salud discutidos?**\n   - Esta pregunta indaga sobre los m\u00e9todos espec\u00edficos que la OMS podr\u00eda haber utilizado en su investigaci\u00f3n o an\u00e1lisis, lo que podr\u00eda ser \u00fanico para este informe en particular.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que probablemente no se encuentre en otros documentos o fuentes, dado que el contenido del informe no est\u00e1 disponible en el contexto proporcionado.", "excerpt_keywords": "Keywords: salud p\u00fablica, OMS, informe t\u00e9cnico, recomendaciones, investigaci\u00f3n cient\u00edfica"}}, "8240b5ee-3182-4924-bdd0-b77459465681": {"node_ids": ["acb87d03-d7b5-40e1-be4d-2b8bdbd3469d", "ef48ffb3-43e3-4b4e-861f-8d8be7d02d9f"], "metadata": {"page_label": "2", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# The World Health Organization\n\nThe World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority for international health matters and public health. One of WHO\u2019s constitutional functions is to provide objective and reliable information and advice in the field of human health, a responsibility that it fulfills in part through its extensive programme of publications. The Organization seeks through its publications to support national health strategies and address the most pressing public health concerns of populations around the world. To respond to the needs of Member States at all levels of development, WHO publishes practical manuals, handbooks and training material for specific categories of health workers; internationally applicable guidelines and standards; reviews and analyses of health policies, programmes and research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision-makers. These books are closely tied to the Organization\u2019s priority activities, encompassing disease prevention and control, the development of equitable health systems based on primary health care, and health promotion for individuals and communities. Progress towards better health for all also demands the global dissemination and exchange of information that draws on the knowledge and experience of all WHO\u2019s Member countries and the collaboration of world leaders in public health and the biomedical sciences. To ensure the widest possible availability of authoritative information and guidance on health matters, WHO secures the broad international distribution of its publications and encourages their translation and adaptation. By helping to promote and protect health and prevent and control disease throughout the world, WHO\u2019s books contribute to achieving the Organization\u2019s principal objective \u2014 the attainment by all people of the highest possible level of health.\n\nThe WHO Technical Report Series makes available the findings of various international groups of experts that provide WHO with the latest scientific and technical advice on a broad range of medical and public health subjects. Members of such expert groups serve without remuneration in their personal capacities rather than as representatives of governments or other bodies; their views do not necessarily reflect the decisions of the stated policy of WHO. An annual subscription to this series, comprising about four to six issues a year, costs CHF 150.00/US$ 180.00 (CHF 105.00/US$ 126.00 in developing countries). For further information, please contact: WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order on line: http://www.who.int/bookorders).\n\n# SELECTED WHO PUBLICATIONS OF RELATED INTEREST\n\n**The International Pharmacopoeia**, fourth edition.  \nVolume 1: general notices; monographs for pharmaceutical substances (A\u2013O)  \nVolume 2: monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents.  \n2006 (1500 pages), also available on CD-ROM and online  \nFirst supplement: general notices; monographs for pharmaceutical substances; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2008 (309 pages), also available on CD-ROM and online  \nSecond supplement: general notices; monographs for pharmaceutical substances and radiopharmaceuticals; monographs for dosage forms; general and specific monographs; methods of analysis; International Chemical Reference Substances; International Infrared Reference Spectra; reagents, test solutions and volumetric solutions.  \n2011 (CD-ROM and online)\n\n**Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms**  \n1998 (94 pages)\n\n**Basic tests for pharmaceutical dosage forms**  \n1991 (134 pages)\n\n**Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials**  \nUpdated, comprehensive edition, 2011 (CD-ROM and online)  \nAlso available on: WHO training modules on GMP. A resource and study pack for trainers, 2007 (CD-ROM).\n\n**WHO Expert Committee on Specifications for Pharmaceutical Preparations**  \nForty-fifth report.  \nWHO Technical Report Series, No. 961, 2011 (428 pages)\n\n**International Nonproprietary Names (INN) for pharmaceutical substances**  \nCumulative List No. 14  \n2011 (available on CD-ROM only)\n\n**The selection and use of essential medicines**  \nReport of the WHO Expert Committee (including the Model List of Essential Medicines for Children).  \nWHO Technical Report Series, No. 965, 2011 (249 pages)\n\n----\n\nFurther information on these and other WHO publications can be obtained from  \nWHO Press, World Health Organization \u2022 1211 Geneva 27, Switzerland \u2022 www.who.int/bookorders  \n**tel.:** +41 22 791 3264; **fax:** +41 22 791 4857; **e-mail:** bookorders@who.int", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento proporciona una visi\u00f3n general sobre la Organizaci\u00f3n Mundial de la Salud (OMS), su establecimiento en 1948, y su funci\u00f3n como autoridad coordinadora en asuntos de salud p\u00fablica a nivel internacional. Se destaca la importancia de las publicaciones de la OMS, que buscan apoyar las estrategias de salud nacionales y abordar preocupaciones de salud p\u00fablica. Adem\u00e1s, se menciona la serie de informes t\u00e9cnicos de la OMS, que incluye hallazgos de grupos de expertos en diversas \u00e1reas de la salud. Tambi\u00e9n se enumeran algunas publicaciones seleccionadas de la OMS relacionadas con la farmacolog\u00eda y la calidad de los medicamentos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las principales \u00e1reas de enfoque de las publicaciones de la OMS y c\u00f3mo contribuyen a la salud global?**\n   - Respuesta: Las publicaciones de la OMS se centran en la prevenci\u00f3n y control de enfermedades, el desarrollo de sistemas de salud equitativos basados en la atenci\u00f3n primaria y la promoci\u00f3n de la salud para individuos y comunidades. Estas publicaciones ayudan a promover y proteger la salud, contribuyendo al objetivo principal de la OMS de alcanzar el m\u00e1s alto nivel de salud posible para todas las personas.\n\n2. **\u00bfQu\u00e9 tipo de expertos contribuyen a la serie de informes t\u00e9cnicos de la OMS y cu\u00e1l es su relaci\u00f3n con las pol\u00edticas de la organizaci\u00f3n?**\n   - Respuesta: Los expertos que contribuyen a la serie de informes t\u00e9cnicos de la OMS sirven sin remuneraci\u00f3n y en sus capacidades personales, no como representantes de gobiernos u otras entidades. Sus opiniones no necesariamente reflejan las decisiones pol\u00edticas de la OMS, lo que subraya la independencia y objetividad de sus recomendaciones.\n\n3. **\u00bfQu\u00e9 costos est\u00e1n asociados con la suscripci\u00f3n a la serie de informes t\u00e9cnicos de la OMS y c\u00f3mo var\u00edan seg\u00fan el nivel de desarrollo de los pa\u00edses?**\n   - Respuesta: La suscripci\u00f3n anual a la serie de informes t\u00e9cnicos de la OMS cuesta CHF 150.00/US$ 180.00, mientras que en los pa\u00edses en desarrollo el costo es de CHF 105.00/US$ 126.00, lo que refleja un esfuerzo por hacer accesible la informaci\u00f3n a diferentes contextos econ\u00f3micos.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\nEl documento \"WHO - Technical Report Series 970\" es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque el contenido espec\u00edfico no est\u00e1 disponible, se puede inferir que el informe aborda temas relevantes en el \u00e1mbito de la salud p\u00fablica, investigaciones cient\u00edficas y recomendaciones de pol\u00edticas de salud. \n\n#### Temas clave:\n- Salud p\u00fablica\n- Investigaciones cient\u00edficas\n- Pol\u00edticas y directrices de salud\n- Tendencias en salud global\n\n#### Entidades:\n- Organizaci\u00f3n Mundial de la Salud (OMS)\n\nEste resumen destaca la naturaleza del informe y su posible enfoque en cuestiones cr\u00edticas de salud, aunque no proporciona detalles espec\u00edficos debido a la falta de contenido disponible.", "excerpt_keywords": "Keywords: World Health Organization, public health, technical report series, pharmaceutical guidelines, health promotion"}}, "d0aa6eb7-3f95-44b6-8d83-02973af17394": {"node_ids": ["f98983b1-0f57-47a9-86ed-a7eb89bb7b18"], "metadata": {"page_label": "3", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior:\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que probablemente contiene informaci\u00f3n t\u00e9cnica y recomendaciones de la Organizaci\u00f3n Mundial de la Salud (OMS) sobre un tema espec\u00edfico relacionado con la salud p\u00fablica. Sin embargo, el contenido espec\u00edfico del documento no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el \"WHO - Technical Report Series 970\"?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir recomendaciones de salud p\u00fablica o descubrimientos cient\u00edficos.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en el \"WHO - Technical Report Series 970\"?**\n   - Esta pregunta se centra en identificar los temas espec\u00edficos que el informe cubre, lo que podr\u00eda incluir enfermedades, tratamientos, pol\u00edticas de salud, etc.\n\n3. **\u00bfC\u00f3mo se relaciona el \"WHO - Technical Report Series 970\" con otros informes t\u00e9cnicos de la OMS?**\n   - Esta pregunta busca establecer conexiones entre este informe y otros documentos de la OMS, lo que podr\u00eda ayudar a entender su relevancia y contexto dentro de la serie de informes t\u00e9cnicos de la organizaci\u00f3n.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n que probablemente no se encuentre f\u00e1cilmente en otros lugares, dado que el contenido espec\u00edfico del documento no est\u00e1 disponible en el contexto proporcionado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Organizaci\u00f3n Mundial de la Salud (OMS)**:\n   - Establecida en 1948 como agencia especializada de la ONU.\n   - Funci\u00f3n principal: autoridad en salud p\u00fablica y coordinaci\u00f3n de asuntos de salud internacional.\n   - Publica informaci\u00f3n objetiva y confiable para apoyar estrategias de salud nacionales y abordar preocupaciones de salud p\u00fablica.\n\n2. **Publicaciones de la OMS**:\n   - La OMS produce manuales, gu\u00edas, est\u00e1ndares, revisiones de pol\u00edticas y materiales de capacitaci\u00f3n para trabajadores de la salud.\n   - La serie de informes t\u00e9cnicos de la OMS proporciona hallazgos y recomendaciones de grupos de expertos en diversas \u00e1reas de la salud.\n\n3. **Costo de Suscripci\u00f3n**:\n   - Costo anual de la serie de informes t\u00e9cnicos: CHF 150.00/US$ 180.00.\n   - Precio reducido para pa\u00edses en desarrollo: CHF 105.00/US$ 126.00.\n\n4. **Publicaciones Seleccionadas**:\n   - **Pruebas b\u00e1sicas para medicamentos** (1998, 94 p\u00e1ginas).\n   - **Aseguramiento de la calidad de productos farmac\u00e9uticos** (edici\u00f3n actualizada, 2011, CD-ROM y en l\u00ednea).\n   - **Informe sobre la selecci\u00f3n y uso de medicamentos esenciales** (Informe de la Comisi\u00f3n de Expertos, 2011, 249 p\u00e1ginas).\n\n5. **Contacto y Acceso a Publicaciones**:\n   - Informaci\u00f3n adicional disponible a trav\u00e9s de WHO Press, Ginebra, Suiza.\n   - Contacto: tel. +41 22 791 3264; e-mail: bookorders@who.int; sitio web: www.who.int/bookorders.\n\nEste resumen destaca la misi\u00f3n de la OMS, su enfoque en la publicaci\u00f3n de materiales de salud y el acceso a informaci\u00f3n relevante para la comunidad de salud global.", "excerpt_keywords": "Keywords: OMS, salud p\u00fablica, informes t\u00e9cnicos, recomendaciones, publicaciones"}}, "c21ebae7-9488-4c5e-b6e3-af4c9f0d03df": {"node_ids": ["7138c1f3-148e-4558-81fb-2e26cba2d878"], "metadata": {"page_label": "4", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Basado en el contexto proporcionado sobre el documento \"WHO - Technical Report Series 970\", aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el Informe T\u00e9cnico de la OMS 970?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir recomendaciones sobre salud p\u00fablica, pol\u00edticas sanitarias o investigaciones cient\u00edficas.\n\n2. **\u00bfQu\u00e9 temas de salud global se abordan en el documento y c\u00f3mo se relacionan con las tendencias actuales en salud p\u00fablica?**\n   - Esta pregunta se centra en identificar los temas tratados en el informe y su relevancia en el contexto de los desaf\u00edos actuales en salud p\u00fablica, lo que podr\u00eda no estar disponible en otras fuentes.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en la elaboraci\u00f3n del Informe T\u00e9cnico de la OMS 970 y c\u00f3mo se justifican estas elecciones?**\n   - Esta pregunta busca profundizar en el enfoque metodol\u00f3gico del informe, lo que podr\u00eda ofrecer una comprensi\u00f3n m\u00e1s clara de la validez y la aplicabilidad de los hallazgos presentados.\n\n### Resumen de nivel superior del contexto circundante:\nEl \"WHO - Technical Report Series 970\" es un documento publicado por la Organizaci\u00f3n Mundial de la Salud que aborda temas relevantes en el \u00e1mbito de la salud global. Estos informes t\u00e9cnicos suelen incluir investigaciones, recomendaciones y directrices que son fundamentales para la formulaci\u00f3n de pol\u00edticas de salud y la pr\u00e1ctica m\u00e9dica. Aunque el contenido espec\u00edfico del documento no est\u00e1 disponible en el contexto proporcionado, es probable que contenga informaci\u00f3n valiosa sobre la salud p\u00fablica y las estrategias de intervenci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades:\n\nEl documento mencionado, \"WHO - Technical Report Series 970\", es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n1. **Organizaci\u00f3n Mundial de la Salud (OMS)**:\n   - Entidad responsable de la elaboraci\u00f3n del informe, que se enfoca en la salud p\u00fablica a nivel global.\n\n2. **Informe T\u00e9cnico**:\n   - El documento forma parte de la serie de informes t\u00e9cnicos de la OMS, que generalmente abordan temas de salud p\u00fablica, investigaciones cient\u00edficas y recomendaciones para pol\u00edticas de salud.\n\n3. **Salud P\u00fablica**:\n   - Aunque no se especifican los temas tratados, es probable que el informe incluya recomendaciones y hallazgos relacionados con enfermedades, tratamientos, prevenci\u00f3n y pol\u00edticas de salud.\n\n### Temas Potenciales:\n- Recomendaciones de salud p\u00fablica.\n- Hallazgos cient\u00edficos sobre enfermedades o tratamientos.\n- Pol\u00edticas de salud y su implementaci\u00f3n.\n- Comparaciones con otros informes t\u00e9cnicos de la OMS.\n\nEste resumen proporciona una visi\u00f3n general de lo que podr\u00eda abarcar el documento, a pesar de la falta de contenido espec\u00edfico en el contexto proporcionado.", "excerpt_keywords": "Keywords: OMS, salud p\u00fablica, informe t\u00e9cnico, recomendaciones, pol\u00edticas de salud"}}, "5e9c97ff-6be9-4b1f-be69-221abbe68dfc": {"node_ids": ["d1f3dc7d-adff-43bb-acf0-892659c3965d"], "metadata": {"page_label": "5", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "\n# Contents\n\n1. **Introduction**  \n   1\n\n2. **General policy**  \n   6  \n   2.1 International collaboration  \n   6  \n   2.1.1 Collaboration with international organizations and agencies  \n   6  \n   2.1.2 Pharmacopoeial Discussion Group  \n   7  \n   2.1.3 International Conference on Harmonisation  \n   7  \n   2.1.4 International Conference of Drug Regulatory Authorities  \n   8  \n   2.2 Cross-cutting pharmaceuticals \u2013 quality assurance issues  \n   8  \n   2.2.1 Biological standardization  \n   8  \n   2.2.2 Essential medicines  \n   9  \n   2.2.3 Herbal and complementary medicines  \n   9  \n   2.2.4 Working group meeting on substandard/spurious/falsely-labelled/falsified/  \n   counterfeit medical products  \n   10\n\n3. **Quality control \u2013 specifications and tests**  \n   10  \n   3.1 *The International Pharmacopoeia*  \n   10  \n   3.1.1 Fourth edition update  \n   10  \n   3.1.2 Outreach with stakeholders  \n   11  \n   3.1.3 Annotated work plan  \n   11  \n   3.1.4 Monograph development  \n   12  \n   3.2 Specifications for medicines, including children\u2019s medicines  \n   12  \n   3.2.1 Medicines for HIV and related conditions  \n   12  \n   3.2.2 Antimalarial medicines  \n   13  \n   3.2.3 Antituberculosis medicines  \n   14  \n   3.2.4 Anti-infectives  \n   14  \n   3.2.5 Other medicines  \n   15  \n   3.2.6 Other paediatrics  \n   16  \n   3.3 General monographs for dosage forms and associated method texts  \n   16  \n   3.3.1 Pharmacopoeial Discussion Group-harmonized general texts  \n   16  \n   3.3.2 Uniformity of content single-dose preparations  \n   21  \n   3.3.3 General monograph on tablets  \n   23  \n   3.4 Preface, general notices and supplementary information sections of  \n   *The International Pharmacopoeia*  \n   24\n\n4. **Quality control \u2013 International Reference Materials (International Chemical Reference Substances and Infrared Reference Spectra)**  \n   25  \n   4.1 Update on International Chemical Reference Substances  \n   25  \n   4.1.1 Report on activities of the host organization related to International  \n   Chemical Reference Substances  \n   25  \n   4.1.2 Frequently asked questions about collaborative trials  \n   26  \n   4.1.3 Annual report on International Chemical Reference Substances 2010  \n   26  \n   4.1.4 Lumefantrine for system suitability testing  \n   27  \n   4.1.5 Bacterial endotoxin  \n   27\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con res\u00famenes de nivel superior que pueden ayudar a entender mejor el contenido:\n\n### Resumen de nivel superior:\nEl documento \"WHO - Technical Report Series 970\" aborda temas relacionados con la pol\u00edtica general de colaboraci\u00f3n internacional en el \u00e1mbito farmac\u00e9utico, el control de calidad de los medicamentos y la estandarizaci\u00f3n de productos farmac\u00e9uticos. Se discuten aspectos como la colaboraci\u00f3n con organizaciones internacionales, la calidad de los medicamentos esenciales, y la importancia de los materiales de referencia internacional en el control de calidad.\n\n### Preguntas:\n\n1. **\u00bfCu\u00e1les son los principales objetivos de la colaboraci\u00f3n internacional mencionados en el informe y c\u00f3mo se implementan en el contexto de la calidad de los medicamentos?**\n   - Esta pregunta busca detalles espec\u00edficos sobre los objetivos y m\u00e9todos de colaboraci\u00f3n internacional que se describen en el documento, lo cual puede no estar disponible en otras fuentes.\n\n2. **\u00bfQu\u00e9 avances se han realizado en la cuarta edici\u00f3n de *The International Pharmacopoeia* seg\u00fan el informe, y cu\u00e1les son las implicaciones para la calidad de los medicamentos?**\n   - Esta pregunta se centra en los cambios y actualizaciones en la cuarta edici\u00f3n de *The International Pharmacopoeia*, proporcionando informaci\u00f3n que puede ser \u00fanica para este documento.\n\n3. **\u00bfQu\u00e9 papel juegan los materiales de referencia internacional en el control de calidad de los productos farmac\u00e9uticos, seg\u00fan el informe?**\n   - Esta pregunta busca profundizar en la importancia y el uso de los materiales de referencia internacional, un tema que puede no ser ampliamente discutido en otras fuentes.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y detallada que se encuentra en el contexto del informe, lo que puede no estar disponible en otros documentos o fuentes.", "prev_section_summary": "El \"WHO - Technical Report Series 970\" es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que aborda temas relevantes en el \u00e1mbito de la salud global. Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relacionadas:\n\n### Temas Clave:\n1. **Hallazgos y Recomendaciones**: El informe probablemente presenta hallazgos significativos y recomendaciones sobre salud p\u00fablica, pol\u00edticas sanitarias y pr\u00e1cticas m\u00e9dicas.\n2. **Salud Global**: Se abordan temas de salud global que son pertinentes a los desaf\u00edos actuales en el \u00e1mbito de la salud p\u00fablica.\n3. **Metodolog\u00edas de Investigaci\u00f3n**: Se discuten las metodolog\u00edas utilizadas en la elaboraci\u00f3n del informe, lo que puede ofrecer una comprensi\u00f3n sobre la validez de los hallazgos.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe, que se centra en mejorar la salud a nivel global.\n- **Salud P\u00fablica**: Un tema central del informe, que incluye estrategias de intervenci\u00f3n y pol\u00edticas de salud.\n\nEste resumen destaca la importancia del informe en la formulaci\u00f3n de pol\u00edticas de salud y su relevancia en el contexto actual de la salud p\u00fablica.", "excerpt_keywords": "Keywords: collaboration, quality assurance, pharmacopoeia, international standards, reference materials"}}, "6d05f927-6f40-4cb9-9f69-11509e2ade9c": {"node_ids": ["30f94eef-47f8-4ba0-ac43-1d015f4914e8"], "metadata": {"page_label": "6", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 5. Quality control \u2013 national laboratories\n5.1 External Quality Assurance Assessment Scheme\n\n## 6. Quality assurance \u2013 good manufacturing practices\n6.1 WHO good manufacturing practices: water for pharmaceutical use\n\n## 7. Quality assurance \u2013 new approaches\n7.1 WHO guidelines on quality risk management\n\n## 8. Quality assurance \u2013 distribution and trade of pharmaceuticals\n8.1 WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce  \n8.2 Update on Joint FIP/WHO guidelines on good pharmacy practice: standards for quality of pharmacy services\n\n## 9. Prequalification of priority essential medicines including active pharmaceutical ingredients\n9.1 Update on the Prequalification of Medicines Programme managed by WHO\n\n## 10. Prequalification of quality control laboratories\n10.1 Update on the prequalification of quality control laboratories  \n10.2 Update on the surveys of the quality of medicines\n\n## 11. Regulatory guidance\n11.1 Policy on oseltamivir and zanamivir  \n11.2 Assessment criteria for blood regulatory systems  \n11.3 Pharmaceutical development for multisource (generic) pharmaceutical products \u2013 points to consider  \n11.4 Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part  \n11.5 Development of paediatric medicines: points to consider in pharmaceutical formulation  \n11.6 Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products: points to consider  \n11.7 Quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients  \n11.8 Update on comparator products\n\n## 12. Nomenclature, terminology and databases\n12.1 Quality assurance terminology  \n12.2 International Nonproprietary Names for pharmaceutical substances\n\n## 13. Miscellaneous\n13.1 Brochures on the Expert Committee and on quality assurance of pharmaceuticals  \n13.2 Sampling procedures for monitoring of market situations  \n13.3 *Index of pharmacopoeias*  \n13.4 Collaboration with pharmacopoeias\n\n## 14. Summary and recommendations\n\nAcknowledgements", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder espec\u00edficamente con el contexto proporcionado, junto con un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de nivel superior:\nEl documento es un informe t\u00e9cnico de la OMS que aborda diversas \u00e1reas relacionadas con la calidad y regulaci\u00f3n de los productos farmac\u00e9uticos. Se centra en la garant\u00eda de calidad, buenas pr\u00e1cticas de manufactura, precalificaci\u00f3n de medicamentos y laboratorios, y proporciona directrices regulatorias. Tambi\u00e9n incluye aspectos sobre nomenclatura y terminolog\u00eda en el \u00e1mbito farmac\u00e9utico, as\u00ed como recomendaciones y procedimientos de muestreo para el monitoreo de la calidad de los medicamentos en el mercado.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son los puntos clave de las directrices de la OMS sobre la gesti\u00f3n de riesgos de calidad en la fabricaci\u00f3n de productos farmac\u00e9uticos?**\n   - Esta pregunta busca detalles espec\u00edficos sobre las nuevas aproximaciones a la garant\u00eda de calidad mencionadas en la secci\u00f3n 7.1.\n\n2. **\u00bfQu\u00e9 criterios se utilizan para la evaluaci\u00f3n de los sistemas regulatorios de sangre seg\u00fan el informe?**\n   - Esta pregunta se enfoca en la secci\u00f3n 11.2, que trata sobre los criterios de evaluaci\u00f3n de los sistemas regulatorios de sangre, un tema que puede no estar ampliamente cubierto en otras fuentes.\n\n3. **\u00bfQu\u00e9 actualizaciones se han realizado en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Esta pregunta se refiere a la secci\u00f3n 9.1, que proporciona informaci\u00f3n sobre el estado actual y las mejoras en el programa de precalificaci\u00f3n, un aspecto crucial para la calidad de los medicamentos esenciales.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" aborda varios temas fundamentales relacionados con la pol\u00edtica farmac\u00e9utica y el control de calidad de los medicamentos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas en la secci\u00f3n:\n\n1. **Colaboraci\u00f3n Internacional**:\n   - **Objetivos**: Fomentar la cooperaci\u00f3n entre organizaciones internacionales y agencias para mejorar la calidad de los medicamentos.\n   - **Entidades Involucradas**:\n     - Organizaciones internacionales (ej. OMS).\n     - **Pharmacopoeial Discussion Group**: Grupo que discute y armoniza est\u00e1ndares farmac\u00e9uticos.\n     - **International Conference on Harmonisation**: Conferencia que busca armonizar regulaciones y est\u00e1ndares en la industria farmac\u00e9utica.\n     - **International Conference of Drug Regulatory Authorities**: Conferencia que re\u00fane a autoridades reguladoras de medicamentos.\n\n2. **Calidad de los Medicamentos**:\n   - **Medicamentos Esenciales**: Enfoque en la calidad y disponibilidad de medicamentos esenciales.\n   - **Medicamentos Herbales y Complementarios**: Consideraciones sobre la calidad y regulaci\u00f3n de estos productos.\n   - **Problemas de Calidad**: Reuniones de grupos de trabajo sobre productos m\u00e9dicos subest\u00e1ndar, falsificados y mal etiquetados.\n\n3. **Control de Calidad**:\n   - **Especificaciones y Pruebas**: Establecimiento de est\u00e1ndares para la calidad de los medicamentos.\n   - **The International Pharmacopoeia**: Documento clave que proporciona est\u00e1ndares y m\u00e9todos para la calidad de los medicamentos.\n     - **Actualizaci\u00f3n de la Cuarta Edici\u00f3n**: Cambios y mejoras en la cuarta edici\u00f3n de este documento.\n     - **Desarrollo de Monograf\u00edas**: Creaci\u00f3n de documentos que describen las especificaciones de diferentes medicamentos.\n\n4. **Materiales de Referencia Internacional**:\n   - **Sustancias Qu\u00edmicas de Referencia Internacional**: Importancia de estos materiales en el control de calidad de productos farmac\u00e9uticos.\n   - **Espectroscop\u00eda Infrarroja**: Uso de espectros de referencia para asegurar la calidad de los productos.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Principal organismo que coordina las pol\u00edticas de salud y calidad de medicamentos a nivel internacional.\n- **Pharmacopoeial Discussion Group**: Grupo que trabaja en la armonizaci\u00f3n de est\u00e1ndares farmac\u00e9uticos.\n- **Autoridades Reguladoras de Medicamentos**: Entidades que supervisan y regulan la calidad de los medicamentos en diferentes pa\u00edses.\n\nEste resumen destaca la importancia de la colaboraci\u00f3n internacional y el establecimiento de est\u00e1ndares para asegurar la calidad y seguridad de los medicamentos a nivel global.", "excerpt_keywords": "Keywords: quality assurance, pharmaceutical preparations, WHO guidelines, prequalification, good manufacturing practices"}}, "19c5ed07-df43-4982-9fbb-0a971c023ded": {"node_ids": ["c6dae6d1-7c09-4ae5-8fa0-9d9c9536aaae"], "metadata": {"page_label": "7", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Annex 1\nDevelopment of monographs for *The International Pharmacopoeia*  \nPage 63\n\n## Annex 2\nWHO good manufacturing practices: water for pharmaceutical use  \nPage 67\n\n## Annex 3\nPharmaceutical development of multisource (generic) pharmaceutical products - points to consider  \nPage 91\n\n## Annex 4\nGuidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part  \nPage 121\n\n## Annex 5\nDevelopment of paediatric medicines: points to consider in formulation  \nPage 197\n\n## Annex 6\nRecommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients  \nPage 227", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que detalla las especificaciones para preparaciones farmac\u00e9uticas. Incluye varios anexos que abordan temas como el desarrollo de monograf\u00edas para la Farmacopea Internacional, buenas pr\u00e1cticas de fabricaci\u00f3n, desarrollo de productos farmac\u00e9uticos multisource (gen\u00e9ricos), y recomendaciones espec\u00edficas para la producci\u00f3n de ingredientes farmac\u00e9uticos activos, entre otros.\n\n### Preguntas:\n\n1. **\u00bfQu\u00e9 temas espec\u00edficos se abordan en el Anexo 3 sobre el desarrollo farmac\u00e9utico de productos multisource?**\n   - Esta pregunta busca detalles sobre los puntos clave que se consideran en el desarrollo de productos farmac\u00e9uticos gen\u00e9ricos, que son esenciales para garantizar su calidad y eficacia.\n\n2. **\u00bfCu\u00e1les son las recomendaciones clave para la calidad del artemisinina seg\u00fan el Anexo 6?**\n   - Esta pregunta se centra en las especificaciones y requisitos de calidad que se deben cumplir para el artemisinina, un ingrediente activo crucial en el tratamiento de la malaria.\n\n3. **\u00bfQu\u00e9 aspectos se consideran en la formulaci\u00f3n de medicamentos pedi\u00e1tricos seg\u00fan el Anexo 5?**\n   - Esta pregunta busca informaci\u00f3n sobre las consideraciones espec\u00edficas que deben tenerse en cuenta al desarrollar medicamentos para la poblaci\u00f3n pedi\u00e1trica, que pueden diferir significativamente de los medicamentos para adultos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS, titulado \"WHO - Technical Report Series 970\", aborda aspectos fundamentales relacionados con la calidad y regulaci\u00f3n de los productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas en la secci\u00f3n:\n\n1. **Control de Calidad en Laboratorios Nacionales**:\n   - **Esquema de Evaluaci\u00f3n de Aseguramiento de Calidad Externa**: Se enfoca en la evaluaci\u00f3n de la calidad en laboratorios nacionales.\n\n2. **Aseguramiento de Calidad y Buenas Pr\u00e1cticas de Manufactura**:\n   - **Buenas Pr\u00e1cticas de Manufactura de la OMS**: Incluye directrices sobre el uso de agua para fines farmac\u00e9uticos.\n\n3. **Nuevas Aproximaciones en Aseguramiento de Calidad**:\n   - **Directrices de la OMS sobre Gesti\u00f3n de Riesgos de Calidad**: Proporciona un marco para la gesti\u00f3n de riesgos en la fabricaci\u00f3n de productos farmac\u00e9uticos.\n\n4. **Distribuci\u00f3n y Comercio de Productos Farmac\u00e9uticos**:\n   - **Esquema de Certificaci\u00f3n de la OMS**: Asegura la calidad de los productos farmac\u00e9uticos en el comercio internacional.\n   - **Actualizaci\u00f3n sobre las Directrices de Buenas Pr\u00e1cticas Farmac\u00e9uticas**: Establece est\u00e1ndares para la calidad de los servicios farmac\u00e9uticos.\n\n5. **Precalificaci\u00f3n de Medicamentos Esenciales**:\n   - **Programa de Precalificaci\u00f3n de Medicamentos**: Actualizaciones sobre la precalificaci\u00f3n de medicamentos y principios activos esenciales.\n\n6. **Precalificaci\u00f3n de Laboratorios de Control de Calidad**:\n   - **Actualizaciones sobre la Precalificaci\u00f3n de Laboratorios**: Informaci\u00f3n sobre la calidad de los laboratorios de control.\n\n7. **Orientaci\u00f3n Regulatoria**:\n   - **Pol\u00edticas sobre Oseltamivir y Zanamivir**: Directrices espec\u00edficas para estos medicamentos.\n   - **Criterios de Evaluaci\u00f3n para Sistemas Regulatorios de Sangre**: Establece criterios para la regulaci\u00f3n de productos sangu\u00edneos.\n   - **Desarrollo de Medicamentos Pedi\u00e1tricos**: Consideraciones para la formulaci\u00f3n de medicamentos para ni\u00f1os.\n\n8. **Nomenclatura y Terminolog\u00eda**:\n   - **Terminolog\u00eda de Aseguramiento de Calidad**: Definiciones y t\u00e9rminos clave en el \u00e1mbito farmac\u00e9utico.\n   - **Nombres Internacionales No Propietarios**: Normas para la nomenclatura de sustancias farmac\u00e9uticas.\n\n9. **Miscellaneous**:\n   - **Procedimientos de Muestreo**: M\u00e9todos para monitorear la calidad de los medicamentos en el mercado.\n   - **Colaboraci\u00f3n con Farmacopeas**: Interacci\u00f3n con diferentes farmacopeas para asegurar est\u00e1ndares de calidad.\n\n10. **Resumen y Recomendaciones**: Conclusiones y sugerencias basadas en los hallazgos del informe.\n\nEste resumen destaca la importancia de la calidad y regulaci\u00f3n en la industria farmac\u00e9utica, as\u00ed como las iniciativas de la OMS para mejorar estos aspectos a nivel global.", "excerpt_keywords": "Keywords: pharmaceutical preparations, WHO guidelines, generic products, quality requirements, pediatric medicines"}}, "be097802-4de1-432f-a2a1-72aaa735b7e7": {"node_ids": ["21dd4fde-9e5d-4b6e-85fe-9fe696229e88"], "metadata": {"page_label": "8", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Geneva, 10\u201314 October 2011**\n\n## Members\n\n- **Professor S.A. Bawazir**, Head of Drug Sector and Vice-President, Saudi Food and Drug Authority, Riyadh, Saudi Arabia *(Chairperson)*\n\n- **Mr A.C. da Costa Bezerra**, Senior Pharmacist, Gerente-General de Inspecao e Controle de Medicamentos e Produtos, Agencia Nacional de Vigilancia Sanitaria \u2013 Brazilian Health Surveillance Agency, Brasilia, Brazil\n\n- **Mr E. Wondemagegnehu Biwota**, Addis Ababa, Ethiopia\n\n- **Professor T.G. Dekker**, Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa\n\n- **Professor J. Hoogmartens**, Professor Emeritus, Laboratorium voor Farmaceutische Analyse, Leuven, Belgium\n\n- **Professor S. Jin**, Chief Expert for Pharmaceutical Products, National Institutes for Food and Drug Control, Beijing, People\u2019s Republic of China *(Co-Chairperson)*\n\n- **Dr T. Kawanishi**, Head, Division of Drugs, National Institute of Health Sciences, Tokyo, Japan *(Rapporteur)*\n\n- **Professor H.G. Kristensen**, Vedbaek, Denmark\n\n- **Dr J.A. Molzon**, Associate Director for International Programs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA *(Rapporteur)*\n\n- **Ms C. Munyimba-Yeta**, Director, Inspectorate and Licensing, Pharmaceutical Regulatory Agency, Lusaka, Zambia\n\n- **Ms L. Slamet**, Deputy for Therapeutic Products, Narcotics, Psychotropic and Addictive Substance Control, National Agency of Drug and Food Control, Jakarta Pusat, Indonesia\n\n## Temporary Advisers\n\n- **Mr J.-M. Caudron**, Braine-le-Ch\u00e2teau, Belgium\n\n- **Dr M. Hinds**, Director, Barbados Drug Service, St Michael, Barbados\n\n- **Dr S. Mills**, Ware, Hertfordshire, England\n\n- **Dr L. Paleshnuik**, Val-des-Mont, QC, Canada\n\n- **Ms M.-L. Rabouhans**, Chiswick, London, England\n\n----\n\n\u00b9 Unable to attend.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder espec\u00edficamente con la informaci\u00f3n proporcionada en el contexto:\n\n1. **\u00bfQui\u00e9nes son los miembros del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas y cu\u00e1les son sus roles?**\n   - Esta pregunta se puede responder detallando los nombres, cargos y pa\u00edses de origen de los miembros del comit\u00e9, as\u00ed como sus roles espec\u00edficos, como el de presidente y co-presidente.\n\n2. **\u00bfCu\u00e1les son las fechas y el lugar de la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS en 2011?**\n   - La respuesta a esta pregunta se encuentra en el contexto, que menciona que la reuni\u00f3n tuvo lugar en Ginebra del 10 al 14 de octubre de 2011.\n\n3. **\u00bfQui\u00e9nes son los asesores temporales que participaron en la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS y de d\u00f3nde provienen?**\n   - Esta pregunta puede ser respondida enumerando los nombres y lugares de origen de los asesores temporales mencionados en el documento.\n\n### Resumen de nivel superior:\nEl contexto proporciona informaci\u00f3n sobre la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, celebrada en Ginebra en octubre de 2011. Se enumeran los miembros del comit\u00e9, sus roles y los asesores temporales que participaron. Esta informaci\u00f3n es relevante para entender la composici\u00f3n y el enfoque del comit\u00e9 en la regulaci\u00f3n y control de productos farmac\u00e9uticos a nivel internacional.", "prev_section_summary": "El documento \"WHO - Technical Report Series 970\" de la Organizaci\u00f3n Mundial de la Salud (OMS) se centra en las especificaciones para preparaciones farmac\u00e9uticas y presenta varios anexos que abordan temas cruciales en el \u00e1mbito farmac\u00e9utico. A continuaci\u00f3n se resumen los temas clave y entidades de la secci\u00f3n:\n\n### Temas Clave:\n1. **Desarrollo de Monograf\u00edas**: Se refiere a la creaci\u00f3n de documentos estandarizados para *La Farmacopea Internacional*, que establecen criterios de calidad y especificaciones para medicamentos.\n   \n2. **Buenas Pr\u00e1cticas de Fabricaci\u00f3n**: Incluye directrices sobre el uso de agua en la producci\u00f3n farmac\u00e9utica, asegurando que cumpla con los est\u00e1ndares de calidad necesarios.\n\n3. **Desarrollo de Productos Multisource (Gen\u00e9ricos)**: Se enfoca en los puntos a considerar en el desarrollo de productos farmac\u00e9uticos gen\u00e9ricos, garantizando su calidad y eficacia.\n\n4. **Documentaci\u00f3n para Precalificaci\u00f3n de Medicamentos**: Proporciona pautas sobre la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos gen\u00e9ricos que buscan la precalificaci\u00f3n por parte de la OMS.\n\n5. **Medicamentos Pedi\u00e1tricos**: Aborda consideraciones espec\u00edficas en la formulaci\u00f3n de medicamentos destinados a la poblaci\u00f3n infantil, que requieren un enfoque diferente al de los adultos.\n\n6. **Requisitos de Calidad para Artemisinina**: Establece recomendaciones sobre los est\u00e1ndares de calidad que deben cumplirse para la artemisinina, un ingrediente activo esencial en el tratamiento de la malaria.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable del documento.\n- **Farmacopea Internacional**: Referencia a la colecci\u00f3n de est\u00e1ndares de calidad para medicamentos.\n- **Artemisinina**: Ingrediente activo mencionado en el contexto de la producci\u00f3n de medicamentos antimal\u00e1ricos.\n\nEste resumen proporciona una visi\u00f3n general de los temas tratados en el documento y las entidades relevantes en el contexto de las especificaciones para preparaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, expert committee, specifications, global health"}}, "97fa287a-fc10-400c-9d79-b12f727b7930": {"node_ids": ["ba889a8a-24d7-42c4-b86b-7422d63ecef3"], "metadata": {"page_label": "9", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Dr J.-L. Robert\nService du Contr\u00f4le des M\u00e9dicaments, Laboratoire National de Sant\u00e9, Luxembourg\n\n## Dr S. Singh\nDrug Controller General (India), Ministry of Health & Family Welfare, Government of India, New Delhi, India\n\n## Professor C. Tuleu\nSenior Lecturer in Pharmaceutics, Deputy Director, Centre for Paediatric Pharmacy Research, The School of Pharmacy, University of London, London, England\n\n## Dr A. J. van Zyl\nSea Point, South Africa\n\n## Ms O. del Rosario Villalva Rojas\nExecutive Director of Quality Control Laboratories, National Quality Control Center, National Institute of Health, Lima, Peru\n\n----\n\n## Representation from United Nations offices\n\n### United Nations Children\u2019s Fund (UNICEF)\nDr H.K. Nielsen, Technical Specialist, Essential Medicines, Medicines and Nutrition Centre, UNICEF Supply Division, Copenhagen, Denmark\n\n----\n\n## Representation from specialized agencies and related organizations\n\n### The Global Fund to Fight AIDS, Tuberculosis and Malaria\nMs J. Daviaud, Senior Pharmaceutical QA Technical Officer, Pharmaceutical Procurement Unit, Geneva, Switzerland\n\n### World Intellectual Property Organization (WIPO)\nMs M. Kira, Consultant, Non-Governmental Organizations and Industry Relations Section, Department of External Relations, Geneva, Switzerland\n\n### World Trade Organization (WTO)\nMs X. Wu, Counsellor, Intellectual Property Division, Geneva, Switzerland\n\n----\n\n## Representation from intergovernmental organizations\n\n### Council of Europe\nDr A. Lodi, Head, Laboratory Department, European Directorate for the Quality of Medicines and HealthCare (EDQM), Strasbourg, France\n\n----\n\n*Unable to attend:*\n\n2. United Nations Development Programme (UNDP), New York, NY, USA.\n3. International Atomic Energy Agency (IAEA), Vienna, Austria; United Nations Industrial Development Organization (UNIDO), Vienna, Austria; The World Bank, Washington, DC, USA; World Customs Organization (WCO), Brussels, Belgium.\n5. European Union (EU), Brussels, Belgium.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Composici\u00f3n del Comit\u00e9 de Expertos de la OMS**: El documento presenta a los miembros del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, incluyendo profesionales de diversas organizaciones y pa\u00edses, as\u00ed como sus respectivas funciones y ubicaciones.\n\n2. **Representaci\u00f3n de organizaciones internacionales**: Se detalla la representaci\u00f3n de varias agencias de las Naciones Unidas y organizaciones intergubernamentales, destacando sus roles en la salud p\u00fablica y la farmac\u00e9utica, as\u00ed como la importancia de la colaboraci\u00f3n internacional en estos \u00e1mbitos.\n\n3. **Asistencia y ausencias**: Se menciona a aquellos que no pudieron asistir a la reuni\u00f3n, lo que indica la diversidad de organizaciones involucradas y la relevancia de su participaci\u00f3n en la discusi\u00f3n sobre est\u00e1ndares farmac\u00e9uticos.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 roles desempe\u00f1an los miembros del Comit\u00e9 de Expertos de la OMS en sus respectivas organizaciones y c\u00f3mo contribuyen a la regulaci\u00f3n de las preparaciones farmac\u00e9uticas?**\n   - Esta pregunta busca profundizar en las funciones espec\u00edficas de cada miembro y su impacto en la regulaci\u00f3n farmac\u00e9utica, informaci\u00f3n que no se detalla en el contexto.\n\n2. **\u00bfCu\u00e1les son los objetivos espec\u00edficos de la colaboraci\u00f3n entre la OMS y las organizaciones mencionadas, como UNICEF y el Global Fund, en el \u00e1mbito de las preparaciones farmac\u00e9uticas?**\n   - Esta pregunta se centra en los objetivos y metas de colaboraci\u00f3n que pueden no estar expl\u00edcitamente mencionados en el documento, pero que son cruciales para entender el contexto de la cooperaci\u00f3n internacional.\n\n3. **\u00bfQu\u00e9 criterios se utilizan para seleccionar a los representantes de las organizaciones intergubernamentales y no gubernamentales que asisten a las reuniones del Comit\u00e9 de Expertos de la OMS?**\n   - Esta pregunta busca explorar el proceso de selecci\u00f3n y los criterios que determinan qui\u00e9nes son elegidos para representar a sus organizaciones en estas importantes discusiones, lo cual no se aborda en el texto proporcionado.", "prev_section_summary": "La secci\u00f3n proporciona informaci\u00f3n sobre la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, que tuvo lugar en Ginebra del 10 al 14 de octubre de 2011. Se destacan los siguientes temas y entidades clave:\n\n1. **Composici\u00f3n del Comit\u00e9**: Se enumeran los miembros del comit\u00e9, incluyendo sus nombres, cargos y pa\u00edses de origen. El presidente es el Profesor S.A. Bawazir de Arabia Saudita, y el co-presidente es el Profesor S. Jin de China. Tambi\u00e9n se mencionan dos relatores: el Dr. T. Kawanishi de Jap\u00f3n y el Dr. J.A. Molzon de EE. UU.\n\n2. **Miembros del Comit\u00e9**: Incluye expertos de diversas instituciones y pa\u00edses, como farmac\u00e9uticos, acad\u00e9micos y funcionarios de agencias reguladoras de salud.\n\n3. **Asesores Temporales**: Se mencionan varios asesores temporales que participaron en la reuni\u00f3n, provenientes de diferentes pa\u00edses, como B\u00e9lgica, Barbados, Inglaterra y Canad\u00e1.\n\n4. **Objetivo de la reuni\u00f3n**: Aunque no se detalla en el extracto, el contexto sugiere que el enfoque del comit\u00e9 es la regulaci\u00f3n y control de productos farmac\u00e9uticos a nivel internacional.\n\nEste resumen destaca la diversidad y la experiencia de los miembros y asesores del comit\u00e9, as\u00ed como la importancia de su trabajo en el \u00e1mbito de la salud p\u00fablica global.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, international collaboration, health regulation, expert committee"}}, "c9b9c6e4-4acb-4260-9241-059b6f5ba980": {"node_ids": ["310f7f05-2db3-49ae-bade-bdaf8f9b9f26"], "metadata": {"page_label": "10", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## European Medicines Agency (EMA)\n\nDr P. Kozarewicz, Scientific Administrator, London, England\n\n## Representation from nongovernmental organizations\n\n### European Chemical Industry Council (CEFIC)/APIC\n\nDr B. Pimentel, Board Member, APIC, and Global Regulatory Affairs Manager, DSM Nutritional Products, Basel, Switzerland\n\n### International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)\n\nDr G. France, Pfizer, United Kingdom; and Dr R. Horder, Abbott, United Kingdom\n\n### International Generic Pharmaceutical Alliance (IGPA)\n\nMr T. Fujino, Director, International Affairs, Japan Generic Medicines Association (JGA), Tokyo, Japan\n\n### International Pharmaceutical Excipients Council (IPEC)\n\nMs L. Vignoli, IPEC Europe, Brussels, Belgium\n\n### World Self-Medication Industry (WSMI)\n\nDr R. Torano, Pharmacopoeial Technical Expert, GlaxoSmithKline, United Kingdom\n\n## Pharmacopoeias\n\n### British Pharmacopoeia Commission\n\nMrs M. Vallender, Acting Group Manager, BP and Laboratory Services, London, England\n\n### Pharmacopoeia of the Republic of Korea\n\nDr Y.H. Choi, Pharmaceutical Standardization Research and Testing Division, Pharmaceuticals and Medical Devices Research Department, National Institute of Food and Drug Safety Evaluation (NIFDS), Korea Food and Drug Administration (KFDA), Cheongwon-gun, Chungbuk, Republic of Korea\n\n### United States Pharmacopeia\n\nDr K.A. Russo, Vice President, Small Molecules, Documentary Standards Division, Rockville, MD, USA\n\n----\n\n6 Unable to attend: Commonwealth Pharmacists Association (CPA), London, England; International Society for Pharmaceutical Engineering (ISPE), Tampa, Florida, USA; International Pharmaceutical Federation (FIP), The Hague, The Netherlands.\n\n7 Unable to attend: Farmacopea Argentina, Buenos Aires, Argentina; Farmacopeia Brasileira, Belo Horizonte MG, Brazil; Pharmacopoeia of the People\u2019s Republic of China, Beijing, People\u2019s Republic of China; Indian Pharmacopoeia, New Delhi, India; Japanese Pharmacopoeia, Tokyo, Japan; State Pharmacopoeia of the Russian Federation, Moscow, Russian Federation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que detalla la reuni\u00f3n del Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas. Se mencionan representantes de diversas organizaciones, incluidos organismos reguladores, asociaciones de la industria farmac\u00e9utica y farmacopoeias de diferentes pa\u00edses. Tambi\u00e9n se indica que algunas organizaciones no pudieron asistir a la reuni\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQui\u00e9nes son los representantes de la Agencia Europea de Medicamentos (EMA) y qu\u00e9 rol desempe\u00f1an en la reuni\u00f3n?**\n   - Respuesta: Dr. P. Kozarewicz es el Administrador Cient\u00edfico de la EMA y representa a esta agencia en la reuni\u00f3n.\n\n2. **\u00bfQu\u00e9 organizaciones no gubernamentales estuvieron representadas en la reuni\u00f3n y qui\u00e9nes fueron sus representantes?**\n   - Respuesta: Las organizaciones no gubernamentales representadas incluyen el Consejo Europeo de la Industria Qu\u00edmica (CEFIC)/APIC con Dr. B. Pimentel, la Federaci\u00f3n Internacional de Asociaciones de Fabricantes de Productos Farmac\u00e9uticos (IFPMA) con Dr. G. France y Dr. R. Horder, la Alianza Internacional de Medicamentos Gen\u00e9ricos (IGPA) con Mr. T. Fujino, el Consejo Internacional de Excipientes Farmac\u00e9uticos (IPEC) con Ms. L. Vignoli, y la Industria Mundial de Autocuidado (WSMI) con Dr. R. Torano.\n\n3. **\u00bfCu\u00e1les son las farmacopoeias representadas en la reuni\u00f3n y qui\u00e9nes son sus respectivos representantes?**\n   - Respuesta: Las farmacopoeias representadas incluyen la Comisi\u00f3n de Farmacopea Brit\u00e1nica con Mrs. M. Vallender, la Farmacopea de la Rep\u00fablica de Corea con Dr. Y.H. Choi, y la Farmacopea de los Estados Unidos con Dr. K.A. Russo.\n\n### Resumen de Nivel Superior\n\nEl informe de la OMS presenta a los miembros del Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas, destacando la participaci\u00f3n de representantes de la Agencia Europea de Medicamentos, diversas organizaciones no gubernamentales y farmacopoeias de varios pa\u00edses. Tambi\u00e9n se menciona que algunas organizaciones no pudieron asistir a la reuni\u00f3n, lo que refleja la diversidad de intereses y la importancia de la colaboraci\u00f3n internacional en la regulaci\u00f3n y estandarizaci\u00f3n de productos farmac\u00e9uticos.", "prev_section_summary": "La secci\u00f3n presenta la composici\u00f3n del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, destacando a sus miembros y sus respectivas organizaciones. Entre los participantes se encuentran profesionales de diversas instituciones, como el Laboratorio Nacional de Salud de Luxemburgo, el Ministerio de Salud y Bienestar Familiar de India, y la Universidad de Londres, entre otros.\n\nAdem\u00e1s, se menciona la representaci\u00f3n de varias agencias de las Naciones Unidas, como UNICEF, as\u00ed como de organizaciones especializadas y relacionadas, como el Global Fund, la Organizaci\u00f3n Mundial de la Propiedad Intelectual (WIPO) y la Organizaci\u00f3n Mundial del Comercio (WTO). Tambi\u00e9n se incluye la representaci\u00f3n de organizaciones intergubernamentales, como el Consejo de Europa.\n\nFinalmente, se se\u00f1ala que algunas organizaciones, como el Programa de las Naciones Unidas para el Desarrollo (UNDP) y la Uni\u00f3n Europea (UE), no pudieron asistir a la reuni\u00f3n, lo que resalta la diversidad y la importancia de la colaboraci\u00f3n internacional en el \u00e1mbito de la regulaci\u00f3n farmac\u00e9utica y la salud p\u00fablica.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, regulatory affairs, pharmacopoeias, international collaboration"}}, "a8b9ffeb-5ac4-4202-9f83-d91020ba5559": {"node_ids": ["feffce4f-5ead-49f1-a417-289ff4f668fb"], "metadata": {"page_label": "11", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Representation from WHO Regional Offices\n\n## WHO Secretariat\n\n- **Dr C.F. Etienne**  \n  Assistant Director-General, Health Systems and Services, WHO, Geneva, Switzerland\n\n- **Dr L. R\u00e4go**  \n  Coordinator, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Kopp**  \n  Manager, Medicines Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland  \n  *(Secretary)*\n\n- **Mr M. Deats**  \n  Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms C. Mendy**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr H. Schmidt**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr Xiaoqiong Zheng**  \n  Quality Assurance Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr A. Padilla**  \n  Manager, Blood Products and Related Biologicals, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr R. Balocco**  \n  Manager, International Nonproprietary Names Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Croft**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr A. Fake**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Mr D. Mubangizi**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms J. Sabartova**  \n  Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n----\n\n8 Unable to attend: Regional Office for Africa, Brazzaville, Republic of Congo; Regional Office for the Americas, Pan American Health Organization, Washington, DC, United States of America; Regional Office for the Eastern Mediterranean, Cairo, Egypt; Regional Office for Europe, Copenhagen, Denmark; Regional Office for South-East Asia, New Delhi, India; Regional Office for the Western Pacific, Manila, Philippines.\n\n9 Unable to attend.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que incluye una lista de representantes de la Secretar\u00eda de la OMS y sus respectivas funciones. Se menciona que varios representantes de las oficinas regionales de la OMS no pudieron asistir a la reuni\u00f3n, lo que incluye oficinas en \u00c1frica, las Am\u00e9ricas, el Mediterr\u00e1neo Oriental, Europa, el Sudeste Asi\u00e1tico y el Pac\u00edfico Occidental.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQui\u00e9n es el Secretario de la reuni\u00f3n y cu\u00e1l es su funci\u00f3n espec\u00edfica dentro de la OMS?**\n   - Respuesta: El Secretario de la reuni\u00f3n es el Dr. S. Kopp, quien es el Manager del Programa de Aseguramiento de Calidad de Medicamentos en la OMS.\n\n2. **\u00bfQu\u00e9 programas espec\u00edficos est\u00e1n bajo la coordinaci\u00f3n de la Dra. L. R\u00e4go en la OMS?**\n   - Respuesta: La Dra. L. R\u00e4go es la Coordinadora de Calidad y Seguridad: Medicamentos, Medicamentos Esenciales y Productos de Salud en la OMS.\n\n3. **\u00bfCu\u00e1les son las razones por las que las oficinas regionales de la OMS no pudieron asistir a la reuni\u00f3n?**\n   - Respuesta: El documento indica que las oficinas regionales de la OMS en \u00c1frica, las Am\u00e9ricas, el Mediterr\u00e1neo Oriental, Europa, el Sudeste Asi\u00e1tico y el Pac\u00edfico Occidental no pudieron asistir, aunque no se especifican las razones en el texto.", "prev_section_summary": "El documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que presenta la reuni\u00f3n del Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas. A continuaci\u00f3n se resumen los temas clave y las entidades mencionadas:\n\n### Temas Clave:\n1. **Participaci\u00f3n de Organismos Reguladores**: Se destaca la representaci\u00f3n de la Agencia Europea de Medicamentos (EMA) por el Dr. P. Kozarewicz.\n2. **Representaci\u00f3n de Organizaciones No Gubernamentales**: Varias organizaciones de la industria farmac\u00e9utica est\u00e1n representadas, reflejando la colaboraci\u00f3n entre el sector p\u00fablico y privado.\n3. **Farmacopoeias**: Se mencionan las farmacopoeias de diferentes pa\u00edses, lo que subraya la importancia de la estandarizaci\u00f3n en la regulaci\u00f3n de productos farmac\u00e9uticos.\n4. **Asistencia y Ausencias**: Se indica que algunas organizaciones no pudieron asistir a la reuni\u00f3n, lo que resalta la diversidad de intereses en el \u00e1mbito farmac\u00e9utico.\n\n### Entidades Mencionadas:\n- **Agencia Europea de Medicamentos (EMA)**: Dr. P. Kozarewicz.\n- **Consejo Europeo de la Industria Qu\u00edmica (CEFIC)/APIC**: Dr. B. Pimentel.\n- **Federaci\u00f3n Internacional de Asociaciones de Fabricantes de Productos Farmac\u00e9uticos (IFPMA)**: Dr. G. France y Dr. R. Horder.\n- **Alianza Internacional de Medicamentos Gen\u00e9ricos (IGPA)**: Mr. T. Fujino.\n- **Consejo Internacional de Excipientes Farmac\u00e9uticos (IPEC)**: Ms. L. Vignoli.\n- **Industria Mundial de Autocuidado (WSMI)**: Dr. R. Torano.\n- **Comisi\u00f3n de Farmacopea Brit\u00e1nica**: Mrs. M. Vallender.\n- **Farmacopea de la Rep\u00fablica de Corea**: Dr. Y.H. Choi.\n- **Farmacopea de los Estados Unidos**: Dr. K.A. Russo.\n\n### Ausencias Notables:\n- **Commonwealth Pharmacists Association (CPA)**\n- **International Society for Pharmaceutical Engineering (ISPE)**\n- **International Pharmaceutical Federation (FIP)**\n- **Farmacopea Argentina**\n- **Farmacopeia Brasileira**\n- **Pharmacopoeia of the People\u2019s Republic of China**\n- **Indian Pharmacopoeia**\n- **Japanese Pharmacopoeia**\n- **State Pharmacopoeia of the Russian Federation**\n\nEste resumen refleja la diversidad de participantes y la importancia de la colaboraci\u00f3n internacional en la regulaci\u00f3n y estandarizaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: WHO, Quality Assurance, Medicines, Regional Offices, Health Products"}}, "cc2d711f-ec21-4266-bb0f-2ea49c50c45a": {"node_ids": ["f1b07dca-2c4e-4cc3-bdb8-7e89e754424a"], "metadata": {"page_label": "12", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Forty-sixth report**\n\n- **Dr M. Stahl,\u00b9\u2070** Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr Hua Yin,\u00b9\u2070** Prequalification Programme, Quality and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr S. Azatyan,** Manager, Medicines Regulatory Support Programme, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr G.B. Forte,\u00b9\u2070** Coordinator, Medicines Programme Coordination, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms L. Hedman,** Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr C. Ondari,\u00b9\u2070** Coordinator, Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Dr K. Weerasuriya,** Medicines Access and Rational Use, Essential Medicines and Health Products, WHO, Geneva, Switzerland\n\n- **Ms Y. Maruyama,** Traditional Medicine, Health Policy, Development and Services, Health Systems and Services, WHO, Geneva, Switzerland\n\n- **Dr I. Knezevic,** Quality, Safety and Standards, Immunization, Vaccines and Biologicals, Family and Community Health, WHO, Geneva, Switzerland\n\n- **Dr J. Shin,** Quality, Safety and Standards, Immunization, Vaccines and Biologicals, Family and Community Health, WHO, Geneva, Switzerland\n\n- **Dr C.R. Penn,** Disease Monitoring, Assessment and Control, Global Influenza Programme, Health Security and the Environment, WHO, Geneva, Switzerland\n\n- **Dr V. Reggi,** Control of Neglected Tropical Diseases, HIV/AIDS, TB, Malaria and Neglected Tropical Diseases, WHO, Geneva, Switzerland\n\n- **Mr D. Bramley** (Former Editor, *World Health Processing*), Prangins, Switzerland\n\n----\n\n\u00b9\u2070 Unable to attend.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento es el \"Cuarenta y sexto informe\" de la \"Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas\". Enumera a varios expertos y sus roles dentro de la Organizaci\u00f3n Mundial de la Salud (OMS) en Ginebra, Suiza, destacando sus contribuciones a programas relacionados con medicamentos, acceso a medicamentos, y control de enfermedades. Algunos de los expertos mencionados no pudieron asistir a la reuni\u00f3n.\n\n### Preguntas espec\u00edficas:\n1. **\u00bfQui\u00e9nes son los expertos que no pudieron asistir a la reuni\u00f3n seg\u00fan el informe?**\n   - Respuesta: Dr. M. Stahl, Dr. Hua Yin, Dr. G.B. Forte y Dr. C. Ondari.\n\n2. **\u00bfCu\u00e1l es el enfoque principal de la Comisi\u00f3n de Expertos de la OMS mencionado en el informe?**\n   - Respuesta: El enfoque principal es la especificaci\u00f3n y regulaci\u00f3n de preparaciones farmac\u00e9uticas, as\u00ed como la calidad y seguridad de los medicamentos.\n\n3. **\u00bfQu\u00e9 programas espec\u00edficos est\u00e1n relacionados con los roles de los expertos mencionados en el informe?**\n   - Respuesta: Los programas incluyen el Programa de Precalificaci\u00f3n, el Programa de Soporte Regulatorio de Medicamentos, y el Control de Enfermedades Tropicales Desatendidas, entre otros.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que presenta la representaci\u00f3n de la Secretar\u00eda de la OMS en una reuni\u00f3n. A continuaci\u00f3n se detallan los temas clave y las entidades mencionadas:\n\n#### Temas Clave:\n1. **Representaci\u00f3n de la OMS**: Se proporciona una lista de representantes de la Secretar\u00eda de la OMS, junto con sus cargos y \u00e1reas de responsabilidad.\n2. **Calidad y Seguridad de Medicamentos**: Se destaca la importancia de los programas relacionados con la calidad y seguridad de los medicamentos y productos de salud.\n3. **Asistencia a la Reuni\u00f3n**: Se menciona que varias oficinas regionales de la OMS no pudieron asistir a la reuni\u00f3n, aunque no se especifican las razones.\n\n#### Entidades Mencionadas:\n- **Dr. C.F. Etienne**: Assistant Director-General, Health Systems and Services.\n- **Dr. L. R\u00e4go**: Coordinadora de Calidad y Seguridad: Medicamentos, Medicamentos Esenciales y Productos de Salud.\n- **Dr. S. Kopp**: Manager del Programa de Aseguramiento de Calidad de Medicamentos (Secretario de la reuni\u00f3n).\n- **Mr. M. Deats**: Miembro del equipo de Calidad y Seguridad.\n- **Ms. C. Mendy**: Programa de Aseguramiento de Calidad.\n- **Dr. H. Schmidt**: Programa de Aseguramiento de Calidad.\n- **Dr. Xiaoqiong Zheng**: Programa de Aseguramiento de Calidad.\n- **Dr. A. Padilla**: Manager de Productos Sangu\u00edneos y Biol\u00f3gicos Relacionados.\n- **Dr. R. Balocco**: Manager del Programa de Nombres No Propietarios Internacionales.\n- **Dr. S. Croft**: Programa de Precalificaci\u00f3n.\n- **Dr. A. Fake**: Programa de Precalificaci\u00f3n.\n- **Mr. D. Mubangizi**: Programa de Precalificaci\u00f3n.\n- **Ms. J. Sabartova**: Programa de Precalificaci\u00f3n.\n\n#### Oficinas Regionales que No Asistieron:\n- Oficina Regional para \u00c1frica, Brazzaville, Rep\u00fablica del Congo.\n- Oficina Regional para las Am\u00e9ricas, Washington, D.C., Estados Unidos.\n- Oficina Regional para el Mediterr\u00e1neo Oriental, El Cairo, Egipto.\n- Oficina Regional para Europa, Copenhague, Dinamarca.\n- Oficina Regional para el Sudeste Asi\u00e1tico, Nueva Delhi, India.\n- Oficina Regional para el Pac\u00edfico Occidental, Manila, Filipinas.\n\nEste resumen destaca la estructura organizativa de la OMS en relaci\u00f3n con la calidad y seguridad de los medicamentos, as\u00ed como la participaci\u00f3n de sus representantes en la reuni\u00f3n.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, quality and safety, expert committee, medicines access"}}, "cd30e9c1-971c-46c5-9b64-d5ab03e8ba2b": {"node_ids": ["ef21ebee-7244-4de8-8a42-07eb52b7cf4f"], "metadata": {"page_label": "13", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Declarations of interest\n\nMembers and temporary advisers of the WHO Expert Committee on Specifications for Pharmaceutical Preparations reported the following:\n\nProfessor S. Bawazir, Mr A.C. da Costa Bezerra, Mr E. Wondemagegnehu Biwota, Professor T.G. Dekker, Dr M. Karga-Hinds, Professor J. Hoogmartens, Professor S. Jin, Dr T. Kawanishi, Dr J.A. Molzon, Ms C. Munyimba-Yeta, Dr L. Paleshnuik, Ms M.-L. Rabouhans, Dr J.-L. Robert and Ms O. del Rosario Villalva Rojas reported no conflict of interest.\n\nProfessor H. Kristensen: His wife is a former employee of Novo Nordisk and holds approximately US$ 20 000 in stocks in this company. The WHO Expert Committee on Specifications for Pharmaceutical Preparations does not consider any of the products manufactured by Novo Nordisk.\n\nDr S. Mills was an employee of the company GlaxoSmithKline until July 2009. Dr Mills did not participate in any sessions of the Committee during which specific products were considered.\n\nProfessor C. Tuleu: The School of Pharmacy of the University of London (now: UCL School of Pharmacy), where Professor Tuleu works, received educational grants to support research projects on paediatric formulation and drug delivery from UNICEF and the company Vidopharm SPRL. In addition, the School of Pharmacy has received grants from Pfizer, the Medicine for Children Research Network and Global Research in Paediatrics to support research fellows in Professor Tuleu\u2019s team. Professor Tuleu did not participate in any sessions of the Committee during which specific products were considered.\n\nDr A.J. van Zyl has provided an expert opinion on WHO GMP to the United States Pharmacopeia (USP). This work focused on the preparation of a checklist to assess compliance with WHO GMP for the USP Prequalification of Medicines.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Declaraciones de inter\u00e9s de miembros del Comit\u00e9 de la OMS**: El documento detalla las declaraciones de inter\u00e9s de los miembros y asesores temporales del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. La mayor\u00eda de los miembros no reportan conflictos de inter\u00e9s, mientras que algunos tienen v\u00ednculos financieros o laborales con empresas farmac\u00e9uticas.\n\n2. **Conflictos de inter\u00e9s espec\u00edficos**: Se mencionan casos espec\u00edficos de conflictos de inter\u00e9s, como el de un miembro que tiene acciones en Novo Nordisk y otro que fue empleado de GlaxoSmithKline. Sin embargo, se aclara que estos miembros no participaron en discusiones sobre productos espec\u00edficos de estas empresas.\n\n3. **Financiamiento de investigaciones**: Se destaca que la UCL School of Pharmacy ha recibido financiamiento de varias organizaciones y empresas para proyectos de investigaci\u00f3n, lo que podr\u00eda influir en la percepci\u00f3n de imparcialidad en las recomendaciones del Comit\u00e9.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 medidas se han tomado para asegurar que los miembros del Comit\u00e9 no participen en discusiones sobre productos de empresas con las que tienen conflictos de inter\u00e9s?**\n   - Respuesta: Se indica que los miembros que reportaron conflictos de inter\u00e9s no participaron en sesiones del Comit\u00e9 donde se consideraron productos espec\u00edficos de las empresas involucradas.\n\n2. **\u00bfQu\u00e9 tipo de financiamiento ha recibido la UCL School of Pharmacy y c\u00f3mo podr\u00eda esto afectar la investigaci\u00f3n en formulaciones pedi\u00e1tricas?**\n   - Respuesta: La UCL School of Pharmacy ha recibido subvenciones educativas de UNICEF, Vidopharm SPRL, Pfizer, y otros, lo que podr\u00eda influir en la direcci\u00f3n y los resultados de la investigaci\u00f3n en formulaciones pedi\u00e1tricas.\n\n3. **\u00bfCu\u00e1l es la relaci\u00f3n entre el trabajo de Dr. A.J. van Zyl y la preparaci\u00f3n de medicamentos en el contexto de la OMS?**\n   - Respuesta: Dr. A.J. van Zyl ha proporcionado una opini\u00f3n experta sobre las Buenas Pr\u00e1cticas de Manufactura (GMP) de la OMS al USP, enfoc\u00e1ndose en la creaci\u00f3n de una lista de verificaci\u00f3n para evaluar el cumplimiento con las GMP de la OMS para la Precalificaci\u00f3n de Medicamentos del USP.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\nEl documento es el \"Cuarenta y sexto informe\" de la \"Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas\". A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n#### Temas Clave:\n1. **Especificaciones para Preparaciones Farmac\u00e9uticas**: El enfoque principal del informe es la regulaci\u00f3n y especificaci\u00f3n de medicamentos, asegurando su calidad y seguridad.\n2. **Programas de la OMS**: Se mencionan varios programas relacionados con la calidad y acceso a medicamentos, as\u00ed como el control de enfermedades.\n3. **Contribuciones de Expertos**: Se destaca la participaci\u00f3n de expertos en diferentes \u00e1reas de la salud p\u00fablica y farmac\u00e9utica.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Instituci\u00f3n responsable del informe y de los programas mencionados.\n- **Expertos Mencionados**:\n  - Dr. M. Stahl (Prequalification Programme)\n  - Dr. Hua Yin (Prequalification Programme)\n  - Dr. S. Azatyan (Medicines Regulatory Support Programme)\n  - Dr. G.B. Forte (Medicines Programme Coordination)\n  - Ms. L. Hedman (Medicines Access and Rational Use)\n  - Dr. C. Ondari (Medicines Access and Rational Use)\n  - Dr. K. Weerasuriya (Medicines Access and Rational Use)\n  - Ms. Y. Maruyama (Traditional Medicine)\n  - Dr. I. Knezevic (Quality, Safety and Standards)\n  - Dr. J. Shin (Quality, Safety and Standards)\n  - Dr. C.R. Penn (Global Influenza Programme)\n  - Dr. V. Reggi (Control of Neglected Tropical Diseases)\n  - Mr. D. Bramley (Former Editor, *World Health Processing*)\n\n#### Notas Adicionales:\n- Algunos expertos, como el Dr. M. Stahl, Dr. Hua Yin, Dr. G.B. Forte y Dr. C. Ondari, no pudieron asistir a la reuni\u00f3n. \n\nEste resumen proporciona una visi\u00f3n general de los temas tratados en el informe y las entidades involucradas en la regulaci\u00f3n y especificaci\u00f3n de preparaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, conflict of interest, research funding, GMP compliance"}}, "1ba60660-569f-4c3b-9fbe-9c0d3413ffaa": {"node_ids": ["dbbc2d54-734a-4bf3-89bf-6e9c053b98fb"], "metadata": {"page_label": "14", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Dado el contexto proporcionado sobre el documento \"WHO - Technical Report Series 970\", aqu\u00ed tienes tres preguntas que podr\u00edan tener respuestas espec\u00edficas en este informe:\n\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS en el Informe T\u00e9cnico 970 sobre la salud p\u00fablica y la prevenci\u00f3n de enfermedades?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre las directrices o recomendaciones que la OMS ha emitido en este informe, que pueden no estar disponibles en otras fuentes.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas se describen en el Informe T\u00e9cnico 970 para la evaluaci\u00f3n de intervenciones en salud?**\n   - Esta pregunta se centra en las t\u00e9cnicas o enfoques que la OMS sugiere para evaluar la efectividad de diferentes intervenciones en el \u00e1mbito de la salud, lo cual puede ser \u00fanico a este documento.\n\n3. **\u00bfQu\u00e9 datos o estad\u00edsticas clave se presentan en el Informe T\u00e9cnico 970 que respaldan las conclusiones sobre la carga de enfermedades a nivel global?**\n   - Esta pregunta busca informaci\u00f3n cuantitativa que pueda ser espec\u00edfica del informe y que no se encuentre f\u00e1cilmente en otras publicaciones o reportes.\n\n### Resumen de nivel superior del contexto circundante:\nEl \"WHO - Technical Report Series 970\" es un documento que forma parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas cr\u00edticos en salud p\u00fablica, proporcionando an\u00e1lisis, recomendaciones y directrices basadas en la evidencia. La serie es conocida por su enfoque en la investigaci\u00f3n y la evaluaci\u00f3n de pol\u00edticas de salud, as\u00ed como por su contribuci\u00f3n a la formulaci\u00f3n de estrategias para mejorar la salud a nivel global.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Declaraciones de Inter\u00e9s**: Se presenta un informe sobre los conflictos de inter\u00e9s de los miembros y asesores del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. La mayor\u00eda de los miembros no reportan conflictos, mientras que algunos tienen v\u00ednculos financieros o laborales con empresas farmac\u00e9uticas.\n\n2. **Miembros sin Conflictos de Inter\u00e9s**: La mayor\u00eda de los miembros, incluyendo a:\n   - Professor S. Bawazir\n   - Mr A.C. da Costa Bezerra\n   - Mr E. Wondemagegnehu Biwota\n   - Professor T.G. Dekker\n   - Dr M. Karga-Hinds\n   - Professor J. Hoogmartens\n   - Professor S. Jin\n   - Dr T. Kawanishi\n   - Dr J.A. Molzon\n   - Ms C. Munyimba-Yeta\n   - Dr L. Paleshnuik\n   - Ms M.-L. Rabouhans\n   - Dr J.-L. Robert\n   - Ms O. del Rosario Villalva Rojas\n   reportan no tener conflictos de inter\u00e9s.\n\n3. **Conflictos de Inter\u00e9s Espec\u00edficos**:\n   - **Professor H. Kristensen**: Su esposa es ex-empleada de Novo Nordisk y posee acciones en la compa\u00f1\u00eda, pero el Comit\u00e9 no considera productos de Novo Nordisk.\n   - **Dr S. Mills**: Fue empleado de GlaxoSmithKline hasta julio de 2009 y no particip\u00f3 en discusiones sobre productos espec\u00edficos.\n   - **Professor C. Tuleu**: La UCL School of Pharmacy recibi\u00f3 subvenciones de UNICEF, Vidopharm SPRL, Pfizer y otros para proyectos de investigaci\u00f3n, pero no particip\u00f3 en discusiones sobre productos espec\u00edficos.\n\n4. **Contribuciones de Dr. A.J. van Zyl**: Proporcion\u00f3 una opini\u00f3n experta sobre las Buenas Pr\u00e1cticas de Manufactura (GMP) de la OMS al USP, enfoc\u00e1ndose en la creaci\u00f3n de una lista de verificaci\u00f3n para evaluar el cumplimiento con las GMP de la OMS.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**\n- **Novo Nordisk**\n- **GlaxoSmithKline**\n- **UCL School of Pharmacy**\n- **UNICEF**\n- **Vidopharm SPRL**\n- **Pfizer**\n- **Medicine for Children Research Network**\n- **Global Research in Paediatrics**\n- **United States Pharmacopeia (USP)**\n\nEste resumen destaca los conflictos de inter\u00e9s y las relaciones financieras de los miembros del Comit\u00e9, as\u00ed como las medidas tomadas para evitar la influencia en las decisiones del Comit\u00e9.", "excerpt_keywords": "Keywords: OMS, salud p\u00fablica, recomendaciones, intervenciones, conflictos de inter\u00e9s"}}, "43ca5fb2-5960-45ca-8006-1ac2effce097": {"node_ids": ["5f862cc1-690c-4db0-b2c2-c6cdf68dbc9b"], "metadata": {"page_label": "15", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nThe WHO Expert Committee on Specifications for Pharmaceutical Preparations met in Geneva from 10 to 14 October 2011. Dr C.F. Etienne, Assistant Director-General for the Health Systems and Services Cluster opened the meeting and, on behalf of the Director-General of the World Health Organization, welcomed all the participants to the forty-sixth meeting of the Expert Committee. She thanked the members of the Expert Committee for contributing their knowledge and expertise to the work of WHO in the area of quality assurance of medicines as well as with practical laboratory studies.\n\nDr Etienne briefly described the reform process in WHO, adding that the Member States had expressed the view that the work on norms and standards was fundamental to the work of WHO. The work of the Expert Committee had provided considerable support to the Prequalification Programme of the United Nations to the extent that the work of that programme depended on the Expert Committee.\n\nThe Expert Committee may have a role to play in dealing with substandard/spurious/falsely-labelled/falsified/counterfeit (SSFFC) medical products, an area on which discussions had increased considerably and the role of WHO in the group was being reviewed.\n\nDr Etienne acknowledged the elected Chairs, i.e. Professors S.A. Bawazir (Chairperson) and S. Jin (Co-Chairperson), and the Rapporteurs, Dr J.A. Molzon and Dr T. Kawanishi.\n\nShe also welcomed the other members of the Committee and the temporary advisers; representatives of the United Nations Children\u2019s Fund (UNICEF), the Global Fund to Fight AIDS, Tuberculosis and Malaria, World Intellectual Property Organization (WIPO), World Trade Organization (WTO), Council of Europe/European Directorate for the Quality of Medicines and HealthCare (EDQM), European Chemical Industry Council/Active Pharmaceutical Ingredients Committee, International Federation of Pharmaceutical Manufacturers and Associations, International Generic Pharmaceutical Alliance, International Pharmaceutical Excipients Council and the World Self-Medication Industry; and representatives of the Pharmacopoeias of Great Britain, the Republic of Korea and of the United States of America.\n\nThe Coordinator of the Quality Assurance and Safety: Medicines team added his welcome to that of Dr Etienne and said that for the second time the Expert Committee would hold an open session to respond to the interest raised by Member States during the World Health Assembly in the quality of medicines, and especially on prevention and control of SSFFC medical products. The Prequalification Programme was based entirely on the guidelines and standards recommended by the Expert Committee. The work of the Expert Committee was closely linked to other organizations such as United Nations bodies and other international organizations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas se reuni\u00f3 en Ginebra del 10 al 14 de octubre de 2011. Durante la reuni\u00f3n, se discutieron temas relacionados con la calidad de los medicamentos y la lucha contra productos m\u00e9dicos subest\u00e1ndar, falsificados y etiquetados incorrectamente (SSFFC). La reuni\u00f3n fue inaugurada por la Dra. C.F. Etienne, quien destac\u00f3 la importancia de las normas y est\u00e1ndares en el trabajo de la OMS y su relaci\u00f3n con el Programa de Precalificaci\u00f3n de las Naciones Unidas. Tambi\u00e9n se reconoci\u00f3 la participaci\u00f3n de varios representantes de organizaciones internacionales y se anunci\u00f3 la celebraci\u00f3n de una sesi\u00f3n abierta para abordar las preocupaciones de los Estados Miembros sobre la calidad de los medicamentos.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1l fue el enfoque principal de la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS en octubre de 2011?**\n   - La reuni\u00f3n se centr\u00f3 en la calidad de los medicamentos y en la prevenci\u00f3n y control de productos m\u00e9dicos subest\u00e1ndar, falsificados y etiquetados incorrectamente (SSFFC).\n\n2. **\u00bfQu\u00e9 papel desempe\u00f1a el Comit\u00e9 de Expertos en relaci\u00f3n con el Programa de Precalificaci\u00f3n de las Naciones Unidas?**\n   - El trabajo del Comit\u00e9 de Expertos proporciona un apoyo considerable al Programa de Precalificaci\u00f3n, ya que este \u00faltimo depende de las directrices y est\u00e1ndares recomendados por el Comit\u00e9.\n\n3. **\u00bfQu\u00e9 organizaciones internacionales estuvieron representadas en la reuni\u00f3n del Comit\u00e9 de Expertos?**\n   - Estuvieron presentes representantes de UNICEF, el Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria, la Organizaci\u00f3n Mundial de la Propiedad Intelectual (WIPO), la Organizaci\u00f3n Mundial del Comercio (WTO), entre otros.", "prev_section_summary": "El contenido proporcionado se refiere al \"WHO - Technical Report Series 970\", un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS). A continuaci\u00f3n se resumen los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Recomendaciones de Salud P\u00fablica**: El informe incluye directrices y recomendaciones de la OMS sobre la salud p\u00fablica y la prevenci\u00f3n de enfermedades.\n2. **Metodolog\u00edas de Evaluaci\u00f3n**: Se describen t\u00e9cnicas y enfoques para evaluar la efectividad de intervenciones en salud.\n3. **Datos y Estad\u00edsticas**: Presenta informaci\u00f3n cuantitativa que respalda las conclusiones sobre la carga de enfermedades a nivel global.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe y de la formulaci\u00f3n de recomendaciones en salud p\u00fablica.\n- **Informe T\u00e9cnico 970**: El documento espec\u00edfico que se analiza, que forma parte de una serie de informes t\u00e9cnicos de la OMS.\n\n### Contexto General:\nEl informe es parte de una serie que aborda temas cr\u00edticos en salud p\u00fablica, proporcionando an\u00e1lisis basados en evidencia y contribuyendo a la formulaci\u00f3n de estrategias para mejorar la salud a nivel global.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, quality assurance, SSFFC, international organizations"}}, "61cab5a4-b158-4254-bde8-7296f1ce3f80": {"node_ids": ["c607e83b-bc04-4774-9b99-9fc1d5c74d08"], "metadata": {"page_label": "16", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nintergovernmental organizations, other international and regional bodies, the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria, UNICEF, WIPO, the World Bank, manufacturers\u2019 associations, national and regional pharmacopoeias, other institutions, and other WHO Expert Committees. He said that the Expert Committee structure had been and will in the future be the \u201cbackbone\u201d of the Organization\u2019s standard-setting process.\n\nHe stated that the international donor community was becoming increasingly aware of the problem of poor quality medicines. Countries with this problem were more open to recognizing it but there was still a long way to go before poor people would have access to good quality medicines. There was a continuing need for a comprehensive set of guidelines and standards in the area of quality assurance as part of the process of strengthening health systems to prevent the occurrence of, and to detect, medicines of compromised quality, including SFFC and substandard medicines.\n\n## Open session\n\nThe open session, held during the morning of Monday, 10 October 2011, was opened by Dr Etienne, who welcomed representation from permanent representatives to the United Nations Offices, international organizations based in Geneva, and specialized agencies in Switzerland.\n\nShe stated that the aim of the open session of the forty-sixth WHO Expert Committee on Specifications for Pharmaceutical Preparations was to provide more information on the Expert Committee, particularly to WHO Member States, in an open and transparent manner.\n\nPoor quality of medicines and SFFC medicines were unfortunately a major threat to public health, putting the health of numerous patients and the trust of these patients in their health systems at risk; thus this issue was of critical importance for WHO. In the medicines area, standard-setting work continued to be a pillar of WHO\u2019s activities and priorities in support of WHO Member States.\n\nWHO had been involved in medicines\u2019 quality assurance and quality control since 1948. The Expert Committee was created in the very first World Health Assembly. Its work had already begun in 1947, during the transition of health issues previously dealt with under the League of Nations. Thus medicines\u2019 quality assurance was one of WHO\u2019s oldest programmes.\n\nStrong links existed with other WHO activities, such as support of national medicines regulatory authorities (NMRAs), the Prequalification Programme, the Expert Committee on Biological Standardization, the Expert Committee on Selection and Use of Essential Medicines, Traditional Medicine and specific disease programmes.\n\nThe normative activities covered by this Expert Committee not only directly served WHO Member States, but also through implementation by", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en la labor del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, que se ocupa de la calidad de los medicamentos a nivel internacional. Se destaca la creciente preocupaci\u00f3n de la comunidad internacional sobre los medicamentos de mala calidad y la necesidad de establecer directrices y est\u00e1ndares para asegurar la calidad de los medicamentos. La sesi\u00f3n abierta del Comit\u00e9, celebrada el 10 de octubre de 2011, ten\u00eda como objetivo informar a los Estados Miembros de la OMS sobre las actividades del Comit\u00e9 y la importancia de la calidad de los medicamentos para la salud p\u00fablica. La OMS ha estado involucrada en la garant\u00eda y control de calidad de los medicamentos desde 1948, y el trabajo del Comit\u00e9 es fundamental para fortalecer los sistemas de salud y proteger la confianza de los pacientes.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las principales amenazas a la salud p\u00fablica relacionadas con los medicamentos de mala calidad mencionadas en el contexto?**\n   - Respuesta: Las principales amenazas incluyen el riesgo para la salud de numerosos pacientes y la erosi\u00f3n de la confianza de estos pacientes en sus sistemas de salud, lo que puede llevar a un deterioro general de la salud p\u00fablica.\n\n2. **\u00bfQu\u00e9 papel ha desempe\u00f1ado la OMS en la garant\u00eda de calidad de los medicamentos desde su creaci\u00f3n?**\n   - Respuesta: La OMS ha estado involucrada en la garant\u00eda y control de calidad de los medicamentos desde 1948, siendo uno de sus programas m\u00e1s antiguos, y ha establecido un marco normativo que apoya a los Estados Miembros en la regulaci\u00f3n y control de la calidad de los medicamentos.\n\n3. **\u00bfQu\u00e9 iniciativas o programas espec\u00edficos de la OMS est\u00e1n relacionados con la calidad de los medicamentos, seg\u00fan el contexto?**\n   - Respuesta: Las iniciativas incluyen el apoyo a las autoridades nacionales de regulaci\u00f3n de medicamentos (NMRAs), el Programa de Precalificaci\u00f3n, y la colaboraci\u00f3n con otros comit\u00e9s de expertos en \u00e1reas como la estandarizaci\u00f3n biol\u00f3gica y el uso de medicamentos esenciales.\n\n### Resumen de Nivel Superior\n\nEl Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas es crucial para abordar la calidad de los medicamentos a nivel global. La OMS ha estado trabajando en este \u00e1mbito desde su fundaci\u00f3n, y su labor es esencial para fortalecer los sistemas de salud y garantizar que los pacientes tengan acceso a medicamentos de calidad. La creciente preocupaci\u00f3n por los medicamentos de mala calidad resalta la necesidad de establecer directrices y est\u00e1ndares claros para proteger la salud p\u00fablica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Reuni\u00f3n del Comit\u00e9 de Expertos de la OMS:** El Comit\u00e9 se reuni\u00f3 en Ginebra del 10 al 14 de octubre de 2011 para discutir la calidad de los medicamentos.\n2. **Calidad de Medicamentos:** Se abordaron temas relacionados con la prevenci\u00f3n y control de productos m\u00e9dicos subest\u00e1ndar, falsificados y etiquetados incorrectamente (SSFFC).\n3. **Normas y Est\u00e1ndares:** Se destac\u00f3 la importancia de las normas y est\u00e1ndares en el trabajo de la OMS, considerados fundamentales por los Estados Miembros.\n4. **Programa de Precalificaci\u00f3n:** El trabajo del Comit\u00e9 proporciona apoyo significativo al Programa de Precalificaci\u00f3n de las Naciones Unidas, que depende de las directrices y est\u00e1ndares recomendados por el Comit\u00e9.\n5. **Sesi\u00f3n Abierta:** Se anunci\u00f3 la celebraci\u00f3n de una sesi\u00f3n abierta para abordar las preocupaciones de los Estados Miembros sobre la calidad de los medicamentos.\n\n**Entidades Representadas:**\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**\n- **UNICEF (Fondo de las Naciones Unidas para la Infancia)**\n- **Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria**\n- **Organizaci\u00f3n Mundial de la Propiedad Intelectual (WIPO)**\n- **Organizaci\u00f3n Mundial del Comercio (WTO)**\n- **Consejo de Europa/Directorio Europeo para la Calidad de Medicamentos y Atenci\u00f3n Sanitaria (EDQM)**\n- **Consejo Europeo de la Industria Qu\u00edmica/Comit\u00e9 de Ingredientes Farmac\u00e9uticos Activos**\n- **Federaci\u00f3n Internacional de Fabricantes y Asociaciones Farmac\u00e9uticas**\n- **Alianza Internacional de Medicamentos Gen\u00e9ricos**\n- **Consejo Internacional de Excipientes Farmac\u00e9uticos**\n- **Industria Mundial de la Automedicaci\u00f3n**\n- **Representantes de las Farmacopeas de Gran Breta\u00f1a, Corea del Sur y Estados Unidos.**\n\nEste resumen destaca los aspectos m\u00e1s relevantes de la reuni\u00f3n y las entidades involucradas en la discusi\u00f3n sobre la calidad de los medicamentos y la lucha contra productos m\u00e9dicos de calidad inferior.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, quality assurance, public health, standard-setting"}}, "e367d65a-a684-4f2a-940e-5b711ebd5473": {"node_ids": ["eacc2d5e-810b-45dd-aa5b-60581a151852"], "metadata": {"page_label": "17", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nProgrammes within WHO and international organizations such as UNICEF and the Global Fund to Fight AIDS, Tuberculosis and Malaria.\n\nMost of the secretariat\u2019s activities had in the past been funded from WHO\u2019s regular budget. Nowadays more than 80% of the finance was secured through extrabudgetary funding by donors. The Organization took great care to ensure that money did not come from the pharmaceutical industry.\n\nDr Etienne stated that the work of the Expert Committee was becoming a focus of interest. Its meetings were held annually in response to the increased need for normative work. The work of this Expert Committee was of the highest level of normative work at WHO and the outcome of each meeting was published in the WHO Technical Report Series, and was then presented to the WHO Executive Board. Committee members were invited in a personal capacity and did not represent their respective governments.\n\nThe Coordinator of the Quality Assurance and Safety: Medicines team explained that many issues regarding quality assurance would be discussed during the meeting. He suggested that some highlights would be capacity-building, the development and interchangeability of generic pharmaceuticals, paediatric formulations, water for pharmaceutical use, an update on the Prequalification Programme, an update on International Nonproprietary Names (INNs) and a new text on quality risk management. He strongly encouraged members of the Committee to guide WHO on future activities in quality assurance with regard to these and other issues.\n\nThe Secretary of the Expert Committee on Specifications for Pharmaceutical Preparations gave an overview of the governance and operational structure of WHO. She said that the main technical work of the Organization was based on the contributions of experts from around the world. In the area of pharmaceuticals WHO works with a range of national quality control laboratories worldwide, with regulatory bodies, international organizations, nongovernmental organizations (NGOs) and international industry associations.\n\nThe Secretary described the process for selecting experts, the requirements to be fulfilled, the areas of work in WHO covered by expert committees, and the relationship of the expert committees to the WHO Executive Board and the World Health Assembly. She further explained the wide consultation process used by the Expert Committee and the strict clearance process to be followed before issuing any guidelines or specifications. She also summarized the work of the Secretariat during the past year.\n\nThe forty-fifth report of the Expert Committee, which had met in October 2010, had been published and distributed, and its main contents were outlined to members of this Committee.\n\nThere was discussion of the relationship between the International Conference of Drug Regulatory Authorities (ICDRA) and the Expert Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Financiamiento de la OMS**: La mayor\u00eda de las actividades de la secretar\u00eda de la OMS se financiaban anteriormente con el presupuesto regular de la organizaci\u00f3n, pero actualmente m\u00e1s del 80% de los fondos provienen de donaciones extrabudgetarias, asegurando que no provengan de la industria farmac\u00e9utica.\n\n2. **Funci\u00f3n del Comit\u00e9 de Expertos**: El Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas se re\u00fane anualmente para abordar la creciente necesidad de trabajo normativo en el \u00e1mbito farmac\u00e9utico. Sus resultados se publican en la Serie de Informes T\u00e9cnicos de la OMS y se presentan a la Junta Ejecutiva de la OMS.\n\n3. **Colaboraci\u00f3n y Estructura**: La OMS colabora con laboratorios de control de calidad nacionales, organismos reguladores, ONG y asociaciones de la industria para asegurar la calidad y seguridad de los medicamentos. El proceso de selecci\u00f3n de expertos y la consulta amplia son fundamentales para la emisi\u00f3n de directrices y especificaciones.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los temas destacados que se discutir\u00e1n en la reuni\u00f3n del Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas?**\n   - Se discutir\u00e1n temas como la capacidad de construcci\u00f3n, el desarrollo e intercambiabilidad de productos farmac\u00e9uticos gen\u00e9ricos, formulaciones pedi\u00e1tricas, agua para uso farmac\u00e9utico, actualizaciones sobre el Programa de Precalificaci\u00f3n, nombres no propietarios internacionales (INNs) y un nuevo texto sobre gesti\u00f3n de riesgos de calidad.\n\n2. **\u00bfC\u00f3mo se asegura la OMS de que los fondos que recibe no provengan de la industria farmac\u00e9utica?**\n   - La OMS toma gran cuidado para garantizar que m\u00e1s del 80% de su financiamiento, que proviene de donaciones extrabudgetarias, no tenga origen en la industria farmac\u00e9utica, lo que refuerza su independencia y objetividad en el trabajo normativo.\n\n3. **\u00bfQu\u00e9 proceso sigue la OMS para seleccionar a los expertos que participan en el Comit\u00e9 de Expertos?**\n   - La Secretaria del Comit\u00e9 explic\u00f3 que hay un proceso riguroso para seleccionar expertos, que incluye cumplir con ciertos requisitos y seguir un proceso de consulta amplia y un estricto proceso de aprobaci\u00f3n antes de emitir cualquier directriz o especificaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: El Comit\u00e9 se centra en las especificaciones para preparaciones farmac\u00e9uticas y es fundamental para el establecimiento de normas sobre la calidad de los medicamentos a nivel internacional.\n\n2. **Problemas de Calidad de Medicamentos**: Se destaca la creciente preocupaci\u00f3n de la comunidad internacional sobre los medicamentos de mala calidad, incluyendo los medicamentos falsificados, subest\u00e1ndar y de calidad comprometida (SFFC). Esto representa una amenaza significativa para la salud p\u00fablica y la confianza de los pacientes en los sistemas de salud.\n\n3. **Necesidad de Directrices y Est\u00e1ndares**: Existe una necesidad continua de un conjunto integral de directrices y est\u00e1ndares en el \u00e1rea de aseguramiento de la calidad para fortalecer los sistemas de salud y prevenir la aparici\u00f3n de medicamentos de mala calidad.\n\n4. **Historia y Rol de la OMS**: La OMS ha estado involucrada en la garant\u00eda y control de calidad de los medicamentos desde 1948, siendo uno de sus programas m\u00e1s antiguos. El Comit\u00e9 fue creado en la primera Asamblea Mundial de la Salud y ha mantenido un papel crucial en la regulaci\u00f3n de la calidad de los medicamentos.\n\n5. **Colaboraciones y Programas Relacionados**: La OMS colabora con diversas entidades, incluyendo:\n   - **Organizaciones Intergubernamentales**: Como el Fondo Global para la Lucha contra el VIH/SIDA, la Tuberculosis y la Malaria, UNICEF, WIPO, y el Banco Mundial.\n   - **Autoridades Nacionales de Regulaci\u00f3n de Medicamentos (NMRAs)**: Apoyo a las autoridades que regulan la calidad de los medicamentos en los pa\u00edses.\n   - **Programas de Precalificaci\u00f3n**: Para asegurar que los medicamentos cumplan con est\u00e1ndares de calidad antes de ser utilizados en programas de salud p\u00fablica.\n\n6. **Importancia de la Transparencia**: La sesi\u00f3n abierta del Comit\u00e9, celebrada el 10 de octubre de 2011, ten\u00eda como objetivo informar a los Estados Miembros de la OMS sobre las actividades del Comit\u00e9 de manera abierta y transparente, subrayando la importancia de la calidad de los medicamentos para la salud p\u00fablica.\n\n### Conclusi\u00f3n\nEl trabajo del Comit\u00e9 de Expertos de la OMS es esencial para abordar los desaf\u00edos relacionados con la calidad de los medicamentos, garantizando que los pacientes tengan acceso a productos farmac\u00e9uticos seguros y efectivos, y fortaleciendo la confianza en los sistemas de salud a nivel global.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, quality assurance, expert committee, extrabudgetary funding"}}, "91441d9c-80a0-4f95-b15f-12d9d52ff18a": {"node_ids": ["6bfdf2f7-b462-4125-af41-d5ee3d611662"], "metadata": {"page_label": "18", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# The International Pharmacopoeia\n\nThe World Health Assembly approved **The International Pharmacopoeia** in 1948. Since 1975, it has focused on the WHO Model list of essential medicines. New medicines to be included were proposed by WHO disease control programmes to ensure they met the needs of Member States. **The International Pharmacopoeia**, based on the work and decisions of the Expert Committee, gained legal status once a Member State recognized it as official. The consultation procedure for a specification to be entered into **The International Pharmacopoeia** was particularly thorough. Recently, it has held briefing sessions for interested parties, with two sessions conducted so far.\n\nThe current edition is the fourth, issued in 2006, with the first supplement in 2008 and the second in 2011. The second supplement includes a new section on monographs for radiopharmaceuticals. Future texts will be accessible online and widely distributed. New trends impacting **The International Pharmacopoeia** include a shift towards more sophisticated methods for better quality control. Earlier inadequate methods are being reviewed in light of common analytical practices worldwide.\n\nThe advantages of **The International Pharmacopoeia** include internationally validated specifications through an independent process, input from WHO collaborating centres, collaboration with manufacturers worldwide, cost analysis consideration, collaboration with standard-setting organizations, links to other WHO activities, and free use by WHO Member States.\n\n# Other Developments\n\nArtemisinin, widely used in antimalarial medicines, is derived from the plant *Artemisia annua*, a herb in Chinese traditional medicine. A guidance document on artemisinin starting material was proposed.\n\nThe WHO External Quality Assurance Assessment Scheme, advising laboratories on procedure and performance review, was described. In April 2010, EDQM took over responsibility for the preparation and storage of WHO International Chemical Reference Substances (ICRS).\n\nParticipants in the open session suggested that **The International Pharmacopoeia** should include an explanation of how the pharmacopoeia should...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl contexto se centra en **La Farmacopea Internacional**, aprobada por la Asamblea Mundial de la Salud en 1948, que se ha enfocado en la lista de medicamentos esenciales de la OMS desde 1975. La farmacopea ha ganado estatus legal al ser reconocida oficialmente por los Estados Miembros y ha implementado un proceso de consulta exhaustivo para la inclusi\u00f3n de nuevas especificaciones. La cuarta edici\u00f3n fue publicada en 2006, con suplementos en 2008 y 2011, y se est\u00e1n adoptando m\u00e9todos m\u00e1s sofisticados para el control de calidad. Adem\u00e1s, se menciona el uso de artemisinina en medicamentos antipal\u00fadicos y el esquema de evaluaci\u00f3n de calidad externa de la OMS.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los beneficios espec\u00edficos que ofrece La Farmacopea Internacional a los Estados Miembros de la OMS?**\n   - Respuesta: La Farmacopea Internacional proporciona especificaciones validadas internacionalmente a trav\u00e9s de un proceso independiente, colaboraci\u00f3n con centros de referencia de la OMS, interacci\u00f3n con fabricantes a nivel mundial, consideraci\u00f3n de an\u00e1lisis de costos, colaboraci\u00f3n con organizaciones de normalizaci\u00f3n, v\u00ednculos con otras actividades de la OMS y uso gratuito por parte de los Estados Miembros.\n\n2. **\u00bfQu\u00e9 cambios recientes se han implementado en La Farmacopea Internacional en relaci\u00f3n con los m\u00e9todos de control de calidad?**\n   - Respuesta: Se ha observado un cambio hacia m\u00e9todos m\u00e1s sofisticados para un mejor control de calidad, y se est\u00e1n revisando m\u00e9todos anteriores que eran considerados inadecuados, en funci\u00f3n de las pr\u00e1cticas anal\u00edticas comunes a nivel mundial.\n\n3. **\u00bfQu\u00e9 papel juega la planta *Artemisia annua* en el contexto de La Farmacopea Internacional y qu\u00e9 documento se propuso relacionado con ella?**\n   - Respuesta: La planta *Artemisia annua* es la fuente de artemisinina, ampliamente utilizada en medicamentos antipal\u00fadicos. Se propuso un documento de orientaci\u00f3n sobre el material de partida de artemisinina para su inclusi\u00f3n en la farmacopea.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que puede no ser f\u00e1cilmente accesible en otras fuentes, bas\u00e1ndose en los detalles proporcionados en el contexto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Financiamiento de la OMS**:\n   - La mayor\u00eda de las actividades de la secretar\u00eda de la OMS se financiaban anteriormente con el presupuesto regular, pero actualmente m\u00e1s del 80% proviene de donaciones extrabudgetarias, asegurando que no provengan de la industria farmac\u00e9utica.\n\n2. **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**:\n   - Se re\u00fane anualmente para abordar la creciente necesidad de trabajo normativo en el \u00e1mbito farmac\u00e9utico. Los resultados de sus reuniones se publican en la Serie de Informes T\u00e9cnicos de la OMS y se presentan a la Junta Ejecutiva de la OMS.\n\n3. **Temas a Discutir en la Reuni\u00f3n**:\n   - Se abordar\u00e1n temas como:\n     - Capacitaci\u00f3n y desarrollo de capacidades.\n     - Intercambiabilidad de productos farmac\u00e9uticos gen\u00e9ricos.\n     - Formulaciones pedi\u00e1tricas.\n     - Agua para uso farmac\u00e9utico.\n     - Actualizaciones sobre el Programa de Precalificaci\u00f3n.\n     - Nombres no propietarios internacionales (INNs).\n     - Gesti\u00f3n de riesgos de calidad.\n\n4. **Colaboraci\u00f3n y Estructura de la OMS**:\n   - La OMS colabora con laboratorios de control de calidad nacionales, organismos reguladores, ONG y asociaciones de la industria para asegurar la calidad y seguridad de los medicamentos.\n\n5. **Proceso de Selecci\u00f3n de Expertos**:\n   - La selecci\u00f3n de expertos implica cumplir con requisitos espec\u00edficos y seguir un proceso de consulta amplia y un estricto proceso de aprobaci\u00f3n antes de emitir directrices o especificaciones.\n\n6. **Relaci\u00f3n con la Conferencia Internacional de Autoridades Reguladoras de Medicamentos (ICDRA)**:\n   - Se discuti\u00f3 la relaci\u00f3n entre el ICDRA y el Comit\u00e9 de Expertos.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Principal organismo responsable de la salud p\u00fablica a nivel internacional.\n- **UNICEF**: Fondo de las Naciones Unidas para la Infancia, que colabora en programas de salud.\n- **Global Fund**: Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria.\n- **Expert Committee on Specifications for Pharmaceutical Preparations**: Comit\u00e9 que se enfoca en la normativa de preparaciones farmac\u00e9uticas.\n- **ICDRA (International Conference of Drug Regulatory Authorities)**: Conferencia que re\u00fane a autoridades reguladoras de medicamentos.", "excerpt_keywords": "Keywords: International Pharmacopoeia, WHO, artemisinin, quality control, essential medicines"}}, "931a8253-1f7b-4543-8cee-3104592ade0c": {"node_ids": ["653b65f0-1c6d-492f-bb37-59b92c19e8d1"], "metadata": {"page_label": "19", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nbe used, including advice on impurities. It was felt that a distinct and clearly defined section of *The International Pharmacopoeia* containing supplementary information would be very helpful to users.\n\nIn response to a question from a participant regarding the future of the International Medical Products Anti-Counterfeit Taskforce (IMPACT), it was stated that in 2010 the World Health Assembly had set up a working group of Member States to review WHO\u2019s future activities in the area of SSFFC medicines, including the Organization\u2019s involvement in IMPACT. WHO\u2019s function as the secretariat of IMPACT had been put on hold pending the outcome of the working group and the subsequent decision by the World Health Assembly.\n\nThe Committee members responded to questions raised by the audience. The Chair thanked the Member States\u2019 representatives for their attendance and the open session was closed.\n\nThe Expert Committee reconvened and was held in accordance with established procedures.\n\n## Major publications since October 2010\n\nThe forty-fifth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations (WHO Technical Report Series, No. 961) was presented to the meeting of the WHO Executive Board in May 2011 and had since been made available in both print and electronic formats. Published copies were distributed to the participants at the forty-sixth meeting of the Expert Committee.\n\nThe fourth edition of *The International Pharmacopoeia*, including the second supplement, had been issued both on CD-ROM and online.\n\nTwo information brochures about the Expert Committee, its procedure and functioning, and one on the technical areas covered, had been prepared and printed. One was translated into all six official languages of WHO.\n\nAn updated version of the CD-ROM, including all current WHO quality assurance guidelines adopted by the Expert Committee on Specifications for Pharmaceutical Preparations, would be available in a comprehensive and structured form by the end of 2011.\n\nThe Committee wished to thank the secretariat for its efforts in finalizing these publications as they would help to promote the outcome of the work and increase transparency.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Se discuten temas como la necesidad de una secci\u00f3n claramente definida en *La Farmacopea Internacional* que contenga informaci\u00f3n suplementaria, as\u00ed como el futuro del Grupo de Trabajo sobre Productos M\u00e9dicos Falsificados y de Calidad Subest\u00e1ndar (IMPACT). Tambi\u00e9n se mencionan las publicaciones importantes desde octubre de 2010, incluyendo el informe del Comit\u00e9 y la cuarta edici\u00f3n de *La Farmacopea Internacional*. Se destaca el agradecimiento del Comit\u00e9 al secretariado por sus esfuerzos en la finalizaci\u00f3n de estas publicaciones.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 se propuso en relaci\u00f3n con *La Farmacopea Internacional* para ayudar a los usuarios en la identificaci\u00f3n de impurezas?**\n   - Se propuso la creaci\u00f3n de una secci\u00f3n claramente definida en *La Farmacopea Internacional* que contenga informaci\u00f3n suplementaria sobre impurezas, lo cual ser\u00eda de gran ayuda para los usuarios.\n\n2. **\u00bfCu\u00e1l fue la decisi\u00f3n tomada por la Asamblea Mundial de la Salud en 2010 respecto a IMPACT y su funci\u00f3n?**\n   - En 2010, la Asamblea Mundial de la Salud estableci\u00f3 un grupo de trabajo de Estados Miembros para revisar las futuras actividades de la OMS en el \u00e1rea de medicamentos falsificados y de calidad subest\u00e1ndar (SSFFC), lo que llev\u00f3 a que la funci\u00f3n de la OMS como secretar\u00eda de IMPACT se pusiera en espera hasta que se tomara una decisi\u00f3n posterior.\n\n3. **\u00bfQu\u00e9 tipo de materiales informativos se prepararon y distribuyeron en la reuni\u00f3n del Comit\u00e9?**\n   - Se prepararon y distribuyeron dos folletos informativos sobre el Comit\u00e9 de Expertos, su procedimiento y funcionamiento, as\u00ed como uno sobre las \u00e1reas t\u00e9cnicas cubiertas. Uno de estos folletos fue traducido a los seis idiomas oficiales de la OMS.\n\n### Resumen de Nivel Superior\n\nEl Comit\u00e9 de Expertos de la OMS se reuni\u00f3 para discutir la mejora de las especificaciones para preparaciones farmac\u00e9uticas, la necesidad de informaci\u00f3n adicional en *La Farmacopea Internacional*, y el futuro de la lucha contra los medicamentos falsificados a trav\u00e9s de IMPACT. Se presentaron informes y se distribuyeron materiales informativos, destacando la importancia de la transparencia y la calidad en la farmacolog\u00eda.\n\n### Preguntas Adicionales\n\n1. **\u00bfQu\u00e9 impacto se espera que tengan las publicaciones recientes del Comit\u00e9 en la transparencia y la calidad de los medicamentos?**\n   - Las publicaciones recientes, incluyendo el informe del Comit\u00e9 y la actualizaci\u00f3n de la CD-ROM con directrices de calidad, se espera que promuevan la transparencia y mejoren la calidad de los medicamentos al proporcionar informaci\u00f3n clara y accesible.\n\n2. **\u00bfC\u00f3mo se distribuyeron las copias del informe del Comit\u00e9 a los participantes de la reuni\u00f3n?**\n   - Las copias publicadas del informe del Comit\u00e9 fueron distribuidas a los participantes durante la cuarenta y sexta reuni\u00f3n del Comit\u00e9, asegurando que todos tuvieran acceso a la informaci\u00f3n m\u00e1s reciente.\n\n3. **\u00bfQu\u00e9 se incluy\u00f3 en la cuarta edici\u00f3n de *La Farmacopea Internacional* y c\u00f3mo se present\u00f3?**\n   - La cuarta edici\u00f3n de *La Farmacopea Internacional*, que incluye un segundo suplemento, fue emitida tanto en formato CD-ROM como en l\u00ednea, facilitando el acceso a la informaci\u00f3n actualizada sobre est\u00e1ndares farmac\u00e9uticos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **La Farmacopea Internacional**:\n   - Aprobada por la Asamblea Mundial de la Salud en 1948.\n   - Enfoque en la lista de medicamentos esenciales de la OMS desde 1975.\n   - Gana estatus legal al ser reconocida oficialmente por los Estados Miembros.\n   - Proceso de consulta exhaustivo para la inclusi\u00f3n de nuevas especificaciones.\n\n2. **Ediciones y Suplementos**:\n   - Cuarta edici\u00f3n publicada en 2006.\n   - Primer suplemento en 2008 y segundo en 2011, que incluye monograf\u00edas para radiopharmaceuticals.\n   - Acceso futuro a textos en l\u00ednea y distribuci\u00f3n amplia.\n\n3. **Control de Calidad**:\n   - Cambio hacia m\u00e9todos m\u00e1s sofisticados para mejorar el control de calidad.\n   - Revisi\u00f3n de m\u00e9todos anteriores considerados inadecuados.\n\n4. **Beneficios para los Estados Miembros**:\n   - Especificaciones validadas internacionalmente.\n   - Colaboraci\u00f3n con centros de referencia de la OMS y fabricantes globales.\n   - Consideraci\u00f3n de an\u00e1lisis de costos y colaboraci\u00f3n con organizaciones de normalizaci\u00f3n.\n   - Uso gratuito por parte de los Estados Miembros.\n\n5. **Desarrollos Adicionales**:\n   - **Artemisinina**: Derivada de la planta *Artemisia annua*, utilizada en medicamentos antipal\u00fadicos.\n   - Propuesta de un documento de orientaci\u00f3n sobre el material de partida de artemisinina.\n   - Descripci\u00f3n del esquema de evaluaci\u00f3n de calidad externa de la OMS.\n   - Transferencia de responsabilidad a EDQM para la preparaci\u00f3n y almacenamiento de sustancias qu\u00edmicas de referencia internacional de la OMS (ICRS).\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la aprobaci\u00f3n y desarrollo de la Farmacopea Internacional.\n- **Artemisia annua**: Planta de la cual se extrae la artemisinina, utilizada en tratamientos antipal\u00fadicos.\n- **EDQM**: Organizaci\u00f3n que asumi\u00f3 la responsabilidad de las sustancias qu\u00edmicas de referencia de la OMS.", "excerpt_keywords": "Keywords: WHO, International Pharmacopoeia, SSFFC medicines, IMPACT, pharmaceutical preparations"}}, "4392d2bb-1ed5-4c0b-99fe-44007a025dc8": {"node_ids": ["54aae74b-fce9-4fb4-b008-8ef59a901a4d"], "metadata": {"page_label": "20", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. General policy\n\n## 2.1 International collaboration\n\n### 2.1.1 Collaboration with international organizations and agencies\n\n**The Global Fund to Fight AIDS, Tuberculosis and Malaria**\n\nThe procurement principles of the Global Fund to Fight AIDS, Tuberculosis and Malaria were outlined for the Expert Committee. The general principles are: best value for money, fairness, integrity and transparency. The Global Fund has procurement guidelines (as published by WHO in 2010) and a quality assurance policy on pharmaceuticals that includes clinical and quality criteria, plus the monitoring of quality. Products are monitored throughout the supply chain; there is systematic random testing and recipients report their test results to the Global Fund. Testing is carried out using the methods of the *British Pharmacopoeia, United States Pharmacopeia* or *International Pharmacopoeia*. Quality control is most difficult at country level.\n\nThe challenges of limited access to additional qualified laboratories were described. Difficulty and delay in achieving methods transfer from manufacturers and in obtaining access to reference substances were also noted. However, it was hoped that in the future it would be possible to access additional monographs so as to be able to avoid transfer of manufacturers\u2019 methods. The need for clear guidance on how to interpret monographs was raised.\n\nIn August 2011 the Global Fund and WHO held a joint meeting on quality assurance of essential medicines which recommended that WHO should continue its work towards common quality requirements for medicines that are not antiviral, antituberculosis and antimalarial (non-ATM) medicines, and should develop a risk categorization of essential medicines. The Global Fund explained its approach to quality assurance of grant-funded medicines, which is particularly thorough for antiretroviral medicines.\n\nThe Committee noted the report and expressed its appreciation to the Global Fund.\n\nThe Expert Committee recommended that the experience of the Global Fund in this area should be shared with the WHO regions to facilitate future collaboration. It was noted that the proposal for revision of the WHO guidance for national procurement agencies (WHO Technical Report Series, No. 937, Annex 6) may be presented in the future to the Expert Committee.\n\n**United Nations Children\u2019s Fund**\n\nThe United Nations Children\u2019s Fund (UNICEF) Supply Division procures supplies such as medicines for itself and for partners, including governments, agencies and NGOs. For pharmaceuticals, UNICEF uses several means to assess", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento aborda la colaboraci\u00f3n internacional en la adquisici\u00f3n y aseguramiento de la calidad de medicamentos, centr\u00e1ndose en dos organizaciones clave: el Global Fund to Fight AIDS, Tuberculosis and Malaria y el United Nations Children\u2019s Fund (UNICEF). Se destacan los principios de adquisici\u00f3n del Global Fund, que incluyen la b\u00fasqueda del mejor valor por dinero, la equidad, la integridad y la transparencia. Tambi\u00e9n se discuten los desaf\u00edos en el control de calidad a nivel nacional y la necesidad de una gu\u00eda clara para interpretar los monogr\u00e1ficos. Adem\u00e1s, se menciona una reuni\u00f3n conjunta entre el Global Fund y la OMS sobre la calidad de los medicamentos esenciales y la recomendaci\u00f3n de compartir experiencias para mejorar la colaboraci\u00f3n futura.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los principios generales de adquisici\u00f3n del Global Fund y c\u00f3mo se implementan en la pr\u00e1ctica?**\n   - Respuesta: Los principios generales de adquisici\u00f3n del Global Fund son el mejor valor por dinero, la equidad, la integridad y la transparencia. Se implementan a trav\u00e9s de directrices de adquisici\u00f3n y una pol\u00edtica de aseguramiento de calidad que incluye criterios cl\u00ednicos y de calidad, as\u00ed como el monitoreo de productos a lo largo de la cadena de suministro.\n\n2. **\u00bfQu\u00e9 desaf\u00edos enfrenta el Global Fund en el control de calidad de los medicamentos a nivel nacional?**\n   - Respuesta: Los desaf\u00edos incluyen el acceso limitado a laboratorios calificados, dificultades y retrasos en la transferencia de m\u00e9todos de los fabricantes, y la obtenci\u00f3n de sustancias de referencia. Adem\u00e1s, se menciona la necesidad de acceso a monogr\u00e1ficos adicionales y una gu\u00eda clara para su interpretaci\u00f3n.\n\n3. **\u00bfQu\u00e9 recomendaciones se hicieron en la reuni\u00f3n conjunta entre el Global Fund y la OMS en agosto de 2011?**\n   - Respuesta: Se recomend\u00f3 que la OMS contin\u00fae trabajando hacia requisitos comunes de calidad para medicamentos no antivirales, antituberculosos y antimal\u00e1ricos, y que desarrolle una categorizaci\u00f3n de riesgo para medicamentos esenciales. Tambi\u00e9n se sugiri\u00f3 compartir la experiencia del Global Fund con las regiones de la OMS para facilitar la colaboraci\u00f3n futura.", "prev_section_summary": "### Temas Clave\n\n1. **Especificaciones para Preparaciones Farmac\u00e9uticas**: Se discuti\u00f3 la necesidad de una secci\u00f3n claramente definida en *La Farmacopea Internacional* que incluya informaci\u00f3n suplementaria sobre impurezas, lo que ser\u00eda \u00fatil para los usuarios.\n\n2. **Futuro de IMPACT**: Se mencion\u00f3 que en 2010, la Asamblea Mundial de la Salud estableci\u00f3 un grupo de trabajo para revisar las actividades futuras de la OMS en relaci\u00f3n con los medicamentos falsificados y de calidad subest\u00e1ndar (SSFFC), lo que llev\u00f3 a que la funci\u00f3n de la OMS como secretar\u00eda de IMPACT se pusiera en espera.\n\n3. **Publicaciones Importantes**: Se presentaron varias publicaciones desde octubre de 2010, incluyendo el informe del Comit\u00e9 (No. 961) y la cuarta edici\u00f3n de *La Farmacopea Internacional*, que ahora est\u00e1 disponible en formato CD-ROM y en l\u00ednea.\n\n4. **Materiales Informativos**: Se prepararon y distribuyeron folletos informativos sobre el Comit\u00e9 y sus procedimientos, as\u00ed como sobre las \u00e1reas t\u00e9cnicas cubiertas, con traducciones a los seis idiomas oficiales de la OMS.\n\n5. **Transparencia y Calidad**: Se destac\u00f3 la importancia de las publicaciones recientes para promover la transparencia y mejorar la calidad de los medicamentos.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la reuni\u00f3n y de las publicaciones discutidas.\n- **IMPACT (International Medical Products Anti-Counterfeit Taskforce)**: Grupo de trabajo relacionado con la lucha contra los medicamentos falsificados.\n- **La Farmacopea Internacional**: Documento clave que se est\u00e1 actualizando para incluir informaci\u00f3n sobre impurezas y est\u00e1ndares farmac\u00e9uticos.\n- **Comit\u00e9 de Expertos de la OMS**: Grupo que se reuni\u00f3 para discutir las especificaciones y publicaciones relacionadas con preparaciones farmac\u00e9uticas. \n\nEste resumen abarca los puntos principales discutidos en la secci\u00f3n, as\u00ed como las entidades involucradas en el contexto de la reuni\u00f3n del Comit\u00e9 de Expertos de la OMS.", "excerpt_keywords": "Keywords: Global Fund, quality assurance, procurement principles, international collaboration, UNICEF"}}, "3b17cd96-7914-4462-8bfc-00da9b3c50cc": {"node_ids": ["a1b39fec-eccb-4660-8d28-f3c09bb6ed97"], "metadata": {"page_label": "21", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\npotential manufacturers, including the WHO guidance for procurement agencies and a technical questionnaire. The medicines have to be identical to those prequalified by WHO. For those not prequalified by WHO (i.e. non-ATM) other criteria are used, including the United Nations Agency Product Questionnaire and the requirement that the medicines are on the receiving country\u2019s national essential medicines list. UNICEF also carries out good manufacturing practices (GMP) inspections and 103 inspections were carried out between 2006 and 2010. Products kept in the UNICEF warehouse are visually inspected with tests on randomly selected samples. The prequalification of medical products is always done in connection with a tendering process.\n\nThe Committee noted the report and expressed its appreciation to UNICEF.\n\n## 2.1.2 Pharmacopoeial Discussion Group\n\nThe Pharmacopoeial Discussion Group (PDG), which consists of the *European Pharmacopoeia, Japanese Pharmacopoeia* and *United States Pharmacopeia*, met in June 2011. At present 28 of the 35 General chapters and 41 of the 62 excipient monographs of the current work programme have been harmonized. The General chapter for Microcalorimetry is newly harmonized. Revised General chapters include Bacterial endotoxins and Bulk and tapped density. Excipient sign-offs include revisions to monographs on Benzyl alcohol, Potato starch, Wheat starch, Calcium phosphate dibasic and Calcium phosphate dibasic anhydrous. The last four revisions are the outcome of PDG\u2019s review of previously harmonized excipient monographs.\n\nA press release from the PDG was distributed, which stated that the PDG would no longer meet at the same time and place as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Thus, the PDG will strengthen its independence, but the intention nevertheless is to strengthen harmonization activities among the three pharmacopoeias. WHO is an observer to this group.\n\nThe Expert Committee noted the report.\n\n## 2.1.3 International Conference on Harmonisation\n\nAn update on quality issues was provided to the Expert Committee by the European Union (EU) Quality Lead of the ICH. The concept of \u201cquality by design\u201d was explained and the procedure for developing a product according to this process was outlined. The relationship between risk management, development and a suitable quality management system was highlighted. The ICH quality group carried out six training courses for industry and regulatory staff. A \u201cquestion and answer\u201d document is available on the ICH web site and a series of \u201cpoints to consider\u201d documents were produced.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las actividades y discusiones del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Se abordan temas como la precalificaci\u00f3n de medicamentos por parte de la OMS y UNICEF, la armonizaci\u00f3n de cap\u00edtulos generales y monograf\u00edas de excipientes por parte del Grupo de Discusi\u00f3n Farmacopea (PDG), y la actualizaci\u00f3n sobre cuestiones de calidad proporcionada por la Conferencia Internacional sobre Armonizaci\u00f3n (ICH). Se destaca la importancia de las buenas pr\u00e1cticas de manufactura (GMP) y la necesidad de que los medicamentos cumplan con criterios espec\u00edficos para ser considerados en procesos de licitaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios espec\u00edficos que deben cumplir los medicamentos no precalificados por la OMS para ser considerados en el proceso de licitaci\u00f3n de UNICEF?**\n   - Respuesta: Los medicamentos no precalificados por la OMS deben cumplir con criterios como el cuestionario de productos de la Agencia de las Naciones Unidas y la exigencia de que est\u00e9n en la lista nacional de medicamentos esenciales del pa\u00eds receptor.\n\n2. **\u00bfQu\u00e9 cambios se han realizado en las monograf\u00edas de excipientes por parte del Grupo de Discusi\u00f3n Farmacopea (PDG) desde su \u00faltima reuni\u00f3n?**\n   - Respuesta: Se han revisado las monograf\u00edas de excipientes para Benzyl alcohol, Potato starch, Wheat starch, Calcium phosphate dibasic y Calcium phosphate dibasic anhydrous, como resultado de la revisi\u00f3n de monograf\u00edas de excipientes previamente armonizadas.\n\n3. **\u00bfQu\u00e9 es el concepto de \"calidad por dise\u00f1o\" y c\u00f3mo se relaciona con la gesti\u00f3n de riesgos en el desarrollo de productos farmac\u00e9uticos seg\u00fan la ICH?**\n   - Respuesta: El concepto de \"calidad por dise\u00f1o\" implica desarrollar un producto teniendo en cuenta la calidad desde el inicio del proceso, lo que se relaciona con la gesti\u00f3n de riesgos y el establecimiento de un sistema de gesti\u00f3n de calidad adecuado para asegurar que el producto final cumpla con los est\u00e1ndares requeridos.", "prev_section_summary": "La secci\u00f3n aborda la colaboraci\u00f3n internacional en la adquisici\u00f3n y aseguramiento de la calidad de medicamentos, centr\u00e1ndose en dos organizaciones clave: el Global Fund to Fight AIDS, Tuberculosis and Malaria y el United Nations Children\u2019s Fund (UNICEF).\n\n### Temas clave:\n\n1. **Principios de adquisici\u00f3n del Global Fund**:\n   - Mejor valor por dinero.\n   - Equidad.\n   - Integridad.\n   - Transparencia.\n   - Directrices de adquisici\u00f3n y pol\u00edtica de aseguramiento de calidad que incluye criterios cl\u00ednicos y de calidad.\n\n2. **Control de calidad**:\n   - Monitoreo de productos a lo largo de la cadena de suministro.\n   - Pruebas sistem\u00e1ticas y aleatorias.\n   - Dificultades en el control de calidad a nivel nacional, incluyendo acceso limitado a laboratorios calificados y retrasos en la transferencia de m\u00e9todos de los fabricantes.\n\n3. **Recomendaciones de la reuni\u00f3n conjunta (agosto de 2011)**:\n   - Continuar el trabajo hacia requisitos comunes de calidad para medicamentos no antivirales, antituberculosos y antimal\u00e1ricos.\n   - Desarrollar una categorizaci\u00f3n de riesgo para medicamentos esenciales.\n   - Compartir la experiencia del Global Fund con las regiones de la OMS para facilitar la colaboraci\u00f3n futura.\n\n### Entidades mencionadas:\n\n- **Global Fund to Fight AIDS, Tuberculosis and Malaria**: Enfocado en la adquisici\u00f3n y aseguramiento de la calidad de medicamentos, especialmente antirretrovirales.\n- **United Nations Children\u2019s Fund (UNICEF)**: Encargado de la adquisici\u00f3n de suministros, incluyendo medicamentos, para s\u00ed mismo y para socios como gobiernos y ONGs. \n\nEste resumen destaca la importancia de la colaboraci\u00f3n internacional y los desaf\u00edos en la calidad de los medicamentos, as\u00ed como las recomendaciones para mejorar los procesos de adquisici\u00f3n y control de calidad.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, prequalification, Pharmacopoeial Discussion Group, quality by design"}}, "0852ac1a-2060-4d42-9bdf-3a442f137ac9": {"node_ids": ["982456b4-6978-4779-9a9b-373251aee9ee"], "metadata": {"page_label": "22", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nA new draft guideline will address the development and manufacturing of active pharmaceutical ingredients (APIs) including chemical, biotechnological and biological entities.\n\nA further ICH guideline is being drawn up for metal residues, with the aim of providing a global policy for limiting metal impurities in medicines and ingredients.\n\nFollowing wide consultation, it was decided that the guideline on genotoxic testing and data interpretation for medicines will be revised.\n\nThe Expert Committee noted the report.\n\n## 2.1.4 International Conference of Drug Regulatory Authorities\n\nThe 14th International Conference of Drug Regulatory Authorities (ICDRA) was held in Singapore from 30 November to 3 December 2010 and was attended by 345 participants from over 90 agencies in both developing and developed countries. The conference was hosted by the Health Sciences Authority of Singapore in collaboration with the World Health Organization.\n\nThe ICDRA conferences have been held since the early 1980s and are intended as a platform for achieving consensus on regulatory matters. Issues discussed at the 2010 conference included quality and safety, with a workshop on this topic which presented experience in implementation of WHO guidelines. The conference also issued recommendations to national authorities for updating requirements for stability studies in line with the recommendations of WHO. Recommendations to WHO included updating its annex on national requirements for stability guidelines for medicines and to encourage further developments in the area of stability testing for vaccines and providing additional tools for thermal testing for vaccines.\n\nThe Expert Committee recognized the importance of ICDRA meetings because they bring together regulators from the majority of Member States and recommended the WHO secretariat to pursue its efforts to ensure that the next meeting takes place.\n\n## 2.2 Cross-cutting pharmaceuticals \u2013 quality assurance issues\n\n### 2.2.1 Biological standardization\n\nThe secretary of the Expert Committee on Biological Standardization summarized four cross-cutting issues on that Expert Committee\u2019s agenda. One was an assessment tool for regulatory authorities on the quality of blood products, and a second was a proposal to set up a replacement for the international standard on endotoxin, both of which were proposed for discussion by the Expert Committee on Specifications for Pharmaceutical Preparations.\n\nA third cross-cutting issue related to the labelling of vaccines. This issue had originally been raised by the Immunization Practices Advisory Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento trata sobre las actividades y decisiones de la Comisi\u00f3n de Expertos de la OMS en relaci\u00f3n con la preparaci\u00f3n farmac\u00e9utica. Se discuten nuevas directrices para el desarrollo y fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (APIs), as\u00ed como la revisi\u00f3n de directrices sobre pruebas genot\u00f3xicas. Tambi\u00e9n se menciona la 14\u00aa Conferencia Internacional de Autoridades Reguladoras de Medicamentos (ICDRA) celebrada en Singapur, donde se abordaron temas de calidad y seguridad, y se hicieron recomendaciones para actualizar los requisitos de estudios de estabilidad. Adem\u00e1s, se presentan cuestiones transversales sobre la estandarizaci\u00f3n biol\u00f3gica y la calidad de productos sangu\u00edneos.\n\n### Preguntas espec\u00edficas:\n1. **\u00bfCu\u00e1les son los objetivos de la nueva directriz propuesta para el desarrollo y fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (APIs)?**\n   - La nueva directriz tiene como objetivo abordar el desarrollo y la fabricaci\u00f3n de APIs, incluyendo entidades qu\u00edmicas, biotecnol\u00f3gicas y biol\u00f3gicas, para mejorar la calidad y seguridad de los medicamentos.\n\n2. **\u00bfQu\u00e9 recomendaciones se hicieron a las autoridades nacionales durante la 14\u00aa ICDRA en relaci\u00f3n con los estudios de estabilidad?**\n   - Se recomendaron actualizaciones a los requisitos para los estudios de estabilidad en l\u00ednea con las recomendaciones de la OMS, as\u00ed como la actualizaci\u00f3n del anexo sobre requisitos nacionales para las directrices de estabilidad de medicamentos y el fomento de desarrollos adicionales en pruebas de estabilidad para vacunas.\n\n3. **\u00bfQu\u00e9 cuestiones transversales sobre la estandarizaci\u00f3n biol\u00f3gica se discutieron en la reuni\u00f3n de la Comisi\u00f3n de Expertos?**\n   - Se discutieron cuatro cuestiones transversales, incluyendo la creaci\u00f3n de una herramienta de evaluaci\u00f3n para las autoridades regulatorias sobre la calidad de los productos sangu\u00edneos, la propuesta de un nuevo est\u00e1ndar internacional para endotoxinas, y la cuesti\u00f3n del etiquetado de vacunas, que fue planteada originalmente por el Comit\u00e9 Asesor de Pr\u00e1cticas de Inmunizaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**:\n   - Se centra en las especificaciones para preparaciones farmac\u00e9uticas.\n   - Aprecia el trabajo de UNICEF en la precalificaci\u00f3n de medicamentos.\n\n2. **Precalificaci\u00f3n de Medicamentos**:\n   - Los medicamentos deben ser id\u00e9nticos a los precalificados por la OMS.\n   - Medicamentos no precalificados deben cumplir con el cuestionario de productos de la ONU y estar en la lista nacional de medicamentos esenciales del pa\u00eds receptor.\n   - UNICEF realiza inspecciones de buenas pr\u00e1cticas de manufactura (GMP).\n\n3. **Grupo de Discusi\u00f3n Farmacopea (PDG)**:\n   - Compuesto por la *Farmacopea Europea*, *Farmacopea Japonesa* y *Farmacopea de los Estados Unidos*.\n   - Se han armonizado 28 de 35 cap\u00edtulos generales y 41 de 62 monograf\u00edas de excipientes.\n   - Nuevas armonizaciones incluyen el cap\u00edtulo general de Microcalorimetr\u00eda y revisiones de monograf\u00edas de excipientes como Benzyl alcohol y almidones.\n\n4. **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**:\n   - Se actualizan cuestiones de calidad, destacando el concepto de \"calidad por dise\u00f1o\".\n   - Se enfatiza la relaci\u00f3n entre gesti\u00f3n de riesgos, desarrollo y sistemas de gesti\u00f3n de calidad.\n   - Se han realizado cursos de capacitaci\u00f3n para la industria y el personal regulador.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo que establece est\u00e1ndares para la precalificaci\u00f3n de medicamentos.\n- **UNICEF**: Realiza inspecciones y gestiona la precalificaci\u00f3n de productos m\u00e9dicos.\n- **PDG (Pharmacopoeial Discussion Group)**: Grupo que trabaja en la armonizaci\u00f3n de est\u00e1ndares farmac\u00e9uticos.\n- **ICH (International Conference on Harmonisation)**: Organismo que promueve la armonizaci\u00f3n de requisitos t\u00e9cnicos para la regulaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: pharmaceutical preparations, active pharmaceutical ingredients, regulatory authorities, stability studies, biological standardization"}}, "9f1a79c0-dbc3-4a1b-84cb-6ca958c1c3e7": {"node_ids": ["673f60da-1474-491c-825f-363517757bac"], "metadata": {"page_label": "23", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n(IPAC) and derived from a concern that the labels attached to vaccines varied enormously. IPAC had requested WHO to devise a standardized format for labels for vaccines. This request would go to the Expert Committee on Biological Standardization. Issues raised related to the format and content of labels, their size, the languages used, the date format, and whether there should be bar coding or another machine-readable system. Also mentioned was the need to improve the readability of labelling.\n\nThe fourth cross-cutting issue was a proposed, legally-binding treaty on mercury that was currently being negotiated by the Member States of the United Nations. The United Nations Environment Programme has coordinated the negotiation process. One issue that has arisen is whether the use of mercury in vaccines should be prohibited completely. The substance thiomersal is used as a preservative in the manufacture of vaccines and WHO has evidence of its safety.\n\nThe Expert Committee noted that some regulators are already involved in this discussion and encouraged giving further emphasis to the use of these mercury derivatives for medicines.\n\n## 2.2.2 Essential medicines\n\nIt was reported to the Expert Committee that the March 2011 meeting of the Expert Committee on the Selection and Use of Essential Medicines had revised the WHO Model list of essential medicines, and especially the list for children. Although there were some divergent opinions within the Committee regarding guidance about extemporaneous preparations, it had been noted that age-appropriate formulations for children were not available for most medicines. The Expert Committee on Essential Medicines had raised the issue of whether WHO could consider drafting guidelines for the compounding of paediatric medicines.\n\n## 2.2.3 Herbal and complementary medicines\n\nWHO\u2019s work on traditional medicine has been expanding, in part because of the growing interest in herbal and complementary medicine worldwide. Among recently issued guidelines relating to traditional medicine was the updated edition of *Quality control methods for herbal materials* which was discussed by this Expert Committee in 2008. Other guidelines describing different aspects of herbal and traditional medicines had been published, as had three documents aimed at expanding the evidence base on quality, safety and efficacy of herbal medicines. An update was currently under way of guidelines on the conservation of medicinal plants, which is being developed jointly with the International Union for the Conservation of Nature and the World Wildlife Fund, to provide a framework for the conservation and sustainable use of herbal medicines. Furthermore, a second WHO global survey on national policy regarding herbal medicines was under way.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS aborda varios temas relacionados con la estandarizaci\u00f3n de etiquetas para vacunas, la revisi\u00f3n de la lista de medicamentos esenciales, y el trabajo en medicina tradicional y complementaria. Se destaca la necesidad de un formato uniforme para las etiquetas de vacunas, la discusi\u00f3n sobre el uso de mercurio en vacunas, la falta de formulaciones adecuadas para ni\u00f1os en medicamentos esenciales, y el creciente inter\u00e9s en las medicinas herbales y complementarias, junto con la conservaci\u00f3n de plantas medicinales.\n\n### Preguntas:\n\n1. **\u00bfCu\u00e1les son los principales problemas identificados en la estandarizaci\u00f3n de etiquetas para vacunas seg\u00fan el IPAC y la OMS?**\n   - Respuesta: Los problemas incluyen la variabilidad en el formato y contenido de las etiquetas, su tama\u00f1o, los idiomas utilizados, el formato de la fecha, la posible inclusi\u00f3n de c\u00f3digos de barras o sistemas legibles por m\u00e1quina, y la necesidad de mejorar la legibilidad de las etiquetas.\n\n2. **\u00bfQu\u00e9 posici\u00f3n tiene la OMS respecto al uso de thiomersal como preservativo en vacunas en el contexto de la negociaci\u00f3n de un tratado sobre mercurio?**\n   - Respuesta: La OMS tiene evidencia de la seguridad del thiomersal y ha alentado a los reguladores a considerar el uso de derivados de mercurio en medicamentos, a pesar de las discusiones sobre la prohibici\u00f3n del uso de mercurio en vacunas.\n\n3. **\u00bfQu\u00e9 iniciativas est\u00e1 llevando a cabo la OMS para abordar la falta de formulaciones adecuadas para medicamentos pedi\u00e1tricos?**\n   - Respuesta: La OMS est\u00e1 considerando la posibilidad de redactar directrices para la preparaci\u00f3n de medicamentos pedi\u00e1tricos, dado que se ha observado que no hay formulaciones adecuadas para la mayor\u00eda de los medicamentos en ni\u00f1os, seg\u00fan lo discutido en la reuni\u00f3n de marzo de 2011 del Comit\u00e9 de Expertos en Medicamentos Esenciales.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Directrices para Ingredientes Farmac\u00e9uticos Activos (APIs)**:\n   - Se est\u00e1 desarrollando una nueva directriz que aborda la fabricaci\u00f3n y desarrollo de APIs, incluyendo entidades qu\u00edmicas, biotecnol\u00f3gicas y biol\u00f3gicas.\n\n2. **Gu\u00eda sobre Residuos Met\u00e1licos**:\n   - Se est\u00e1 elaborando una directriz del ICH para establecer una pol\u00edtica global que limite las impurezas met\u00e1licas en medicamentos e ingredientes.\n\n3. **Revisi\u00f3n de Pruebas Genot\u00f3xicas**:\n   - Se decidi\u00f3 revisar la directriz sobre pruebas genot\u00f3xicas y la interpretaci\u00f3n de datos para medicamentos tras una amplia consulta.\n\n4. **14\u00aa Conferencia Internacional de Autoridades Reguladoras de Medicamentos (ICDRA)**:\n   - Celebrada en Singapur en diciembre de 2010, con la participaci\u00f3n de 345 representantes de m\u00e1s de 90 agencias. Se discutieron temas de calidad y seguridad, y se hicieron recomendaciones para actualizar los requisitos de estudios de estabilidad de acuerdo con las directrices de la OMS.\n\n5. **Recomendaciones a Autoridades Nacionales**:\n   - Se sugiri\u00f3 actualizar los requisitos para estudios de estabilidad y fomentar el desarrollo de pruebas de estabilidad para vacunas.\n\n6. **Estandarizaci\u00f3n Biol\u00f3gica**:\n   - Se abordaron cuatro cuestiones transversales, incluyendo la creaci\u00f3n de una herramienta de evaluaci\u00f3n para la calidad de productos sangu\u00edneos y la propuesta de un nuevo est\u00e1ndar internacional para endotoxinas.\n\n7. **Etiquetado de Vacunas**:\n   - Se discuti\u00f3 la cuesti\u00f3n del etiquetado de vacunas, planteada por el Comit\u00e9 Asesor de Pr\u00e1cticas de Inmunizaci\u00f3n.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo que coordina las directrices y conferencias.\n- **ICDRA (Conferencia Internacional de Autoridades Reguladoras de Medicamentos)**: Plataforma para el consenso en asuntos regulatorios.\n- **Comit\u00e9 de Expertos en Estandarizaci\u00f3n Biol\u00f3gica**: Grupo que aborda cuestiones relacionadas con la calidad y estandarizaci\u00f3n de productos biol\u00f3gicos.", "excerpt_keywords": "Keywords: vaccines, labeling, essential medicines, herbal medicine, thiomersal"}}, "906d3430-5932-44b9-b239-c005669fd97f": {"node_ids": ["49974359-ce7e-420a-99a2-99771dfd6d4c"], "metadata": {"page_label": "24", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 2.2.4 Working group meeting on substandard/spurious/falsely-labelled/falsified/counterfeit medical products\n\nThere had been much discussion of the issue of SSFFC medical products at recent meetings of WHO\u2019s governing bodies, including the nomenclature and focus for WHO activity. In 2010 the Expert Committee also discussed the issue and decided to leave the terminology for the time being until the concerns of the Member States had been resolved. A working group on SSFFC medical products was set up in 2010 and its meetings are organized by a board composed of Member States, with WHO providing secretarial assistance. The first meeting of the SSFFC working group took place at the beginning of 2011 and the second meeting was due to be held in October 2011. The governing body documents on the working group are available in different languages on the WHO governing bodies\u2019 web site.\n\n## 3. Quality control \u2013 specifications and tests\n\n### 3.1 The International Pharmacopoeia\n\n#### 3.1.1 Fourth edition update\n\nThe second supplement to the fourth edition of *The International Pharmacopoeia* was issued in July 2011. The fourth edition thus comprised the two main volumes published in 2006, the first supplement published in 2008 and the second supplement. *The International Pharmacopoeia* was now available as a cumulative CD-ROM and freely accessible on the WHO medicines web site (http://www.who.int/phint).\n\nThe second supplement includes more than 60 new texts as well as about 20 texts that have been revised.\n\nThe second supplement comprises the monographs adopted by the Expert Committee at its forty-second, forty-third and forty-fourth meetings in October 2007, 2008 and 2009, respectively, with the addition of two texts adopted in October 2010 (artesunate and oseltamivir phosphate) which were also included in this supplement. Two further texts (amikacin injection and kanamycin injection) were erroneously omitted from the compilation of texts in the second supplement and will be published on the WHO medicines web site as errata to the supplement.\n\nTexts adopted as of October 2010 will be posted on the WHO medicines web site according to the usual procedure, before they are compiled into a forthcoming supplement of *The International Pharmacopoeia*. Finalization work before publication was ongoing for a few remaining texts and it was expected that they would soon be made available.\n\nWhile most of the texts have been posted on the WHO medicines web site, some of them, such as that for levonorgestrel tablets, required significant changes.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda dos temas principales: la reuni\u00f3n del grupo de trabajo sobre productos m\u00e9dicos subest\u00e1ndar, espurios, falsamente etiquetados, falsificados y de contrabando (SSFFC) y la actualizaci\u00f3n de la cuarta edici\u00f3n de *The International Pharmacopoeia*. En la primera secci\u00f3n, se discute la creaci\u00f3n de un grupo de trabajo en 2010 para abordar las preocupaciones sobre los productos SSFFC, con reuniones organizadas por un consejo de Estados Miembros y asistencia de la OMS. En la segunda secci\u00f3n, se detalla la publicaci\u00f3n del segundo suplemento de la cuarta edici\u00f3n de *The International Pharmacopoeia* en julio de 2011, que incluye nuevos textos y revisiones de monograf\u00edas adoptadas en reuniones anteriores del Comit\u00e9 de Expertos.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les fueron las decisiones tomadas por el Comit\u00e9 de Expertos de la OMS respecto a la terminolog\u00eda de los productos SSFFC en 2010?**\n   - Respuesta: En 2010, el Comit\u00e9 de Expertos decidi\u00f3 no cambiar la terminolog\u00eda relacionada con los productos SSFFC hasta que se resolvieran las preocupaciones de los Estados Miembros.\n\n2. **\u00bfQu\u00e9 novedades se incluyeron en el segundo suplemento de la cuarta edici\u00f3n de *The International Pharmacopoeia* publicado en julio de 2011?**\n   - Respuesta: El segundo suplemento incluy\u00f3 m\u00e1s de 60 nuevos textos y alrededor de 20 textos revisados, adem\u00e1s de monograf\u00edas adoptadas en reuniones anteriores del Comit\u00e9 de Expertos, incluyendo dos textos adicionales sobre artesunate y oseltamivir fosfato.\n\n3. **\u00bfQu\u00e9 errores se identificaron en la compilaci\u00f3n del segundo suplemento de *The International Pharmacopoeia* y c\u00f3mo se abordar\u00e1n?**\n   - Respuesta: Se identificaron errores en la omisi\u00f3n de los textos sobre inyecci\u00f3n de amikacina y kanamicina, que se publicar\u00e1n como erratas en el sitio web de medicamentos de la OMS.\n\n### Resumen de nivel superior\n\nEl documento de la OMS destaca la importancia de abordar los problemas relacionados con los productos m\u00e9dicos SSFFC y la necesidad de establecer una terminolog\u00eda clara y consensuada entre los Estados Miembros. Adem\u00e1s, se enfatiza la actualizaci\u00f3n de *The International Pharmacopoeia*, que es crucial para garantizar la calidad y la seguridad de los medicamentos a nivel internacional. La publicaci\u00f3n de suplementos y la correcci\u00f3n de errores en los textos son pasos importantes para mantener la integridad de esta referencia farmac\u00e9utica.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Estandarizaci\u00f3n de Etiquetas para Vacunas**:\n   - **Entidad**: IPAC (Comit\u00e9 de Expertos de la OMS).\n   - **Problemas Identificados**: Variabilidad en el formato y contenido de las etiquetas, tama\u00f1o, idiomas, formato de fecha, inclusi\u00f3n de c\u00f3digos de barras y legibilidad.\n\n2. **Uso de Mercurio en Vacunas**:\n   - **Entidad**: Organizaci\u00f3n Mundial de la Salud (OMS).\n   - **Tema**: Negociaci\u00f3n de un tratado sobre mercurio; discusi\u00f3n sobre la prohibici\u00f3n del uso de mercurio en vacunas.\n   - **Sustancia**: Thiomersal, utilizado como preservativo en vacunas, con evidencia de seguridad por parte de la OMS.\n\n3. **Medicamentos Esenciales**:\n   - **Entidad**: Comit\u00e9 de Expertos en Medicamentos Esenciales de la OMS.\n   - **Tema**: Revisi\u00f3n de la lista de medicamentos esenciales, especialmente para ni\u00f1os.\n   - **Problema**: Falta de formulaciones adecuadas para medicamentos pedi\u00e1tricos y consideraci\u00f3n de directrices para su preparaci\u00f3n.\n\n4. **Medicinas Herbales y Complementarias**:\n   - **Entidad**: OMS.\n   - **Tema**: Expansi\u00f3n del trabajo en medicina tradicional y complementaria.\n   - **Iniciativas**: Publicaci\u00f3n de gu\u00edas sobre control de calidad de materiales herbales, conservaci\u00f3n de plantas medicinales, y una encuesta global sobre pol\u00edticas nacionales respecto a las medicinas herbales.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**\n- **IPAC (Comit\u00e9 de Expertos de la OMS)**\n- **Uni\u00f3n Internacional para la Conservaci\u00f3n de la Naturaleza**\n- **Fondo Mundial para la Naturaleza** \n\nEste resumen destaca los principales temas tratados en la secci\u00f3n, as\u00ed como las entidades involucradas en cada uno de ellos.", "excerpt_keywords": "SSFFC, International Pharmacopoeia, quality control, WHO, medical products"}}, "81c67c78-35d8-47cf-a38a-45c4cabec174": {"node_ids": ["eb662ee7-5b25-48dc-b61a-10272d88c509"], "metadata": {"page_label": "25", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.1.2 Outreach with stakeholders\n\nA summary was presented to the Expert Committee on the briefing for stakeholders held in July 2011 to obtain their feedback on *The International Pharmacopoeia*. An earlier briefing had been organized for industry in 2009. The intention of the meetings was to have an informal discussion with manufacturers and to obtain their feedback on *The International Pharmacopoeia*. The July 2011 session was open not only to industry but to all interested parties as a response to many requests from NGOs, Member States and others. Thirty participants attended. The participants were asked to send questions in advance so that detailed responses could be prepared. WHO learned of the interest in having more information available on the web site, such as the draft monographs.\n\nThe briefing was also an opportunity for WHO to request samples from manufacturers to support the development of monographs for *The International Pharmacopoeia*. The stakeholders emphasized the importance of these briefings and hoped that they would continue to be held in the future.\n\n# 3.1.3 Annotated work plan\n\nIn October 2010, the Expert Committee had adopted a work plan for monographs to be included in future editions of *The International Pharmacopoeia*. A list of these monographs, updated with their current status (i.e. whether already adopted by the Expert Committee), and with new proposals for developing specifications for active substances and dosage forms, including those for paediatric use, was presented to the Committee. The work plan was updated on the basis of the second supplement of *The International Pharmacopoeia* and the current WHO Model list of essential medicines and with reference to the invitations for expressions of interest of the Prequalification Programme.\n\nThe work plan included medicines used in treatment of HIV/AIDS, malaria and tuberculosis treatment, anti-infectives, oral rehydration therapy, and other medicines. The work plan was discussed during the consultation on specifications for medicines and quality control laboratory issues held in July 2011 and, on the advice of the consultation, the work plan had been amended to include not only the individual monographs for products, but also the important general texts or sections intended to be either developed or revised.\n\nThe different categories of medicines in the work plan were reviewed. There are monographs on the APIs of most antiretroviral medicines already, and monographs on the new ones are in preparation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de nivel superior:\nEl documento detalla las actividades de la Organizaci\u00f3n Mundial de la Salud (OMS) en relaci\u00f3n con *La Farmacopea Internacional*, incluyendo reuniones con partes interesadas para obtener retroalimentaci\u00f3n y un plan de trabajo para el desarrollo de monograf\u00edas. Se menciona la importancia de la colaboraci\u00f3n con fabricantes y la inclusi\u00f3n de medicamentos esenciales en el plan de trabajo, que abarca tratamientos para enfermedades como el VIH/SIDA, malaria y tuberculosis.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 tipo de retroalimentaci\u00f3n se busc\u00f3 de los participantes en la reuni\u00f3n de julio de 2011 sobre *La Farmacopea Internacional* y c\u00f3mo se prepar\u00f3 la OMS para abordar sus preguntas?**\n   - Esta pregunta se centra en el proceso de recopilaci\u00f3n de retroalimentaci\u00f3n y la preparaci\u00f3n de la OMS para la reuni\u00f3n, aspectos que no se encuentran f\u00e1cilmente en otros documentos.\n\n2. **\u00bfCu\u00e1les son algunos de los medicamentos espec\u00edficos que se incluyeron en el plan de trabajo adoptado por el Comit\u00e9 de Expertos en octubre de 2010 y qu\u00e9 importancia tienen para la salud p\u00fablica?**\n   - Esta pregunta busca detalles sobre los medicamentos espec\u00edficos mencionados en el plan de trabajo y su relevancia, lo cual puede no estar ampliamente documentado en otras fuentes.\n\n3. **\u00bfC\u00f3mo se ha adaptado el plan de trabajo para incluir no solo monograf\u00edas individuales, sino tambi\u00e9n textos generales o secciones importantes?**\n   - Esta pregunta se enfoca en la evoluci\u00f3n del plan de trabajo y las razones detr\u00e1s de la inclusi\u00f3n de textos generales, un aspecto que puede no ser evidente en otros documentos relacionados.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Productos M\u00e9dicos SSFFC**:\n   - **Terminolog\u00eda**: En 2010, el Comit\u00e9 de Expertos de la OMS decidi\u00f3 no modificar la terminolog\u00eda relacionada con los productos subest\u00e1ndar, espurios, falsamente etiquetados, falsificados y de contrabando (SSFFC) hasta que se resolvieran las preocupaciones de los Estados Miembros.\n   - **Grupo de Trabajo**: Se estableci\u00f3 un grupo de trabajo sobre productos SSFFC en 2010, con reuniones organizadas por un consejo de Estados Miembros y asistencia de la OMS. La primera reuni\u00f3n se llev\u00f3 a cabo a principios de 2011.\n\n2. **La Internacional Pharmacopoeia**:\n   - **Actualizaci\u00f3n de la Cuarta Edici\u00f3n**: En julio de 2011 se public\u00f3 el segundo suplemento de la cuarta edici\u00f3n de *The International Pharmacopoeia*, que incluye m\u00e1s de 60 nuevos textos y alrededor de 20 textos revisados.\n   - **Monograf\u00edas**: El suplemento incluye monograf\u00edas adoptadas en reuniones anteriores del Comit\u00e9 de Expertos, as\u00ed como dos textos adicionales sobre artesunate y oseltamivir fosfato.\n   - **Errores en la Compilaci\u00f3n**: Se identificaron errores en la omisi\u00f3n de textos sobre inyecci\u00f3n de amikacina y kanamicina, que se publicar\u00e1n como erratas en el sitio web de medicamentos de la OMS.\n\n3. **Accesibilidad**: *The International Pharmacopoeia* est\u00e1 disponible como un CD-ROM acumulativo y de forma gratuita en el sitio web de la OMS.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la salud p\u00fablica internacional que facilita la discusi\u00f3n y regulaci\u00f3n de productos m\u00e9dicos.\n- **Estados Miembros**: Pa\u00edses que forman parte de la OMS y que participan en la toma de decisiones sobre la terminolog\u00eda y regulaci\u00f3n de productos m\u00e9dicos.\n- **Comit\u00e9 de Expertos**: Grupo que asesora a la OMS sobre cuestiones relacionadas con la calidad y seguridad de los medicamentos.\n- ***The International Pharmacopoeia***: Referencia internacional que establece est\u00e1ndares de calidad para medicamentos.", "excerpt_keywords": "Keywords: International Pharmacopoeia, WHO, stakeholder engagement, monographs, essential medicines"}}, "1231e3e5-3e8e-45f5-93b6-134a3b17d0eb": {"node_ids": ["3abaaa6a-ddaf-411e-9ca8-200fbe15b05d"], "metadata": {"page_label": "26", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Monograph development\n\nThe monographs in *The International Pharmacopoeia* provide the quality aspects for the medicines in the WHO lists of essential medicines and in WHO treatment guidelines. Therefore, major WHO programmes, such as that on Prequalification of Medicines, and international organizations such as UNICEF and the Global Fund to Fight AIDS, Tuberculosis and Malaria, rely heavily upon the quality specifications of *The International Pharmacopoeia*. A \u201cschedule for the adoption process\u201d outlining the development history of a draft monograph is included in each working document that is circulated for comment. The phases involved in the development of new monographs were discussed by the Expert Committee and the comments already received were outlined.\n\nThe process was revised by the Expert Committee in order to appropriately reflect each of the phases involved in developing new monographs.\n\nThe Expert Committee adopted the phases which are involved in the development of monographs for *The International Pharmacopoeia* (Annex 1).\n\n## Specifications for medicines, including children\u2019s medicines\n\n### 3.2.1 Medicines for HIV and related conditions\n\n**Antiretrovirals**\n\n**Ritonavir tablets**\n\nThe monograph on the ritonavir API had been adopted by the Expert Committee and was included in the second supplement of *The International Pharmacopoeia*. A draft monograph on ritonavir tablets was then proposed. The present draft monograph on tablets had been sent for comments and these had been consolidated by the secretariat. The Expert Committee reviewed the draft monograph and the comments received.\n\nThe Expert Committee adopted the monograph on ritonavir tablets subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.\n\n**Tenofovir disoproxil fumarate**\n\nWork by the collaborating laboratory on the test for optical rotation was ongoing. The investigation was in progress, but the necessity to obtain additional samples had delayed completion of the proposal for discussion.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en el desarrollo de monograf\u00edas en *The International Pharmacopoeia*, que establece especificaciones de calidad para medicamentos esenciales seg\u00fan la OMS. Se menciona la importancia de estas monograf\u00edas para programas de la OMS y organizaciones internacionales como UNICEF y el Global Fund. El proceso de adopci\u00f3n de nuevas monograf\u00edas fue revisado por un Comit\u00e9 de Expertos, que tambi\u00e9n discuti\u00f3 y adopt\u00f3 monograf\u00edas espec\u00edficas, como la de los comprimidos de ritonavir y el trabajo en curso sobre tenofovir disoproxil fumarato.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 importancia tienen las monograf\u00edas de *The International Pharmacopoeia* para programas de la OMS y organizaciones internacionales?**\n   - Las monograf\u00edas proporcionan especificaciones de calidad que son fundamentales para la precalificaci\u00f3n de medicamentos y gu\u00edas de tratamiento, lo que asegura que los medicamentos esenciales cumplan con est\u00e1ndares de calidad.\n\n2. **\u00bfQu\u00e9 cambios se acordaron en la monograf\u00eda de los comprimidos de ritonavir durante la revisi\u00f3n del Comit\u00e9 de Expertos?**\n   - La monograf\u00eda fue adoptada por el Comit\u00e9 de Expertos, sujeto a la inclusi\u00f3n de cambios acordados basados en los comentarios recibidos y las discusiones mantenidas.\n\n3. **\u00bfCu\u00e1l es el estado actual del trabajo sobre el tenofovir disoproxil fumarato seg\u00fan el documento?**\n   - El trabajo en el laboratorio colaborador sobre la prueba de rotaci\u00f3n \u00f3ptica est\u00e1 en curso, pero la necesidad de obtener muestras adicionales ha retrasado la finalizaci\u00f3n de la propuesta para discusi\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Interacci\u00f3n con Partes Interesadas**:\n   - Se llevaron a cabo reuniones con partes interesadas, incluyendo una sesi\u00f3n en julio de 2011, para obtener retroalimentaci\u00f3n sobre *La Farmacopea Internacional*.\n   - La reuni\u00f3n de julio fue abierta a todos los interesados, no solo a la industria, y se solicit\u00f3 a los participantes que enviaran preguntas con anticipaci\u00f3n para preparar respuestas detalladas.\n   - Se destac\u00f3 la importancia de estas reuniones y el inter\u00e9s en tener m\u00e1s informaci\u00f3n disponible en el sitio web de la OMS.\n\n2. **Plan de Trabajo Anotado**:\n   - En octubre de 2010, el Comit\u00e9 de Expertos adopt\u00f3 un plan de trabajo para las monograf\u00edas que se incluir\u00edan en futuras ediciones de *La Farmacopea Internacional*.\n   - El plan de trabajo abarca medicamentos utilizados en el tratamiento de enfermedades como VIH/SIDA, malaria y tuberculosis, as\u00ed como anti-infectivos y terapia de rehidrataci\u00f3n oral.\n   - Se revisaron las categor\u00edas de medicamentos y se mencion\u00f3 que ya existen monograf\u00edas para la mayor\u00eda de los medicamentos antirretrovirales, mientras que se est\u00e1n preparando monograf\u00edas para nuevos medicamentos.\n\n3. **Desarrollo de Monograf\u00edas**:\n   - El plan de trabajo fue actualizado en base a la segunda suplementaci\u00f3n de *La Farmacopea Internacional* y la lista modelo de medicamentos esenciales de la OMS.\n   - Se incluyeron no solo monograf\u00edas individuales, sino tambi\u00e9n textos generales o secciones importantes que se desarrollar\u00e1n o revisar\u00e1n.\n\n### Entidades Clave:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la coordinaci\u00f3n de las reuniones y el desarrollo de *La Farmacopea Internacional*.\n- **Expert Committee**: Comit\u00e9 que adopta el plan de trabajo y revisa las monograf\u00edas.\n- **Partes Interesadas**: Incluyen fabricantes, ONG, Estados Miembros y otros interesados que participan en las reuniones y proporcionan retroalimentaci\u00f3n.\n- **Medicamentos Esenciales**: Incluyen tratamientos para VIH/SIDA, malaria, tuberculosis y otros medicamentos relevantes para la salud p\u00fablica.", "excerpt_keywords": "Keywords: monographs, International Pharmacopoeia, WHO, antiretrovirals, quality specifications"}}, "5ed5d1ae-63e8-4f6d-80e7-4182f761c365": {"node_ids": ["9a3a9f4c-7956-48d7-8225-3d3a2d7e1cea"], "metadata": {"page_label": "27", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.2 Antimalarial medicines\n\n## Update on artemisinin derivatives\n\nDuring review of the monograph on artesunate for inclusion in the second supplement, several corrections regarding nomenclature were identified. In consequence, an in-depth review of related WHO publications was carried out and ambiguity regarding the nomenclature was resolved. It was, therefore, proposed to implement the necessary corrections in the relevant texts of *The International Pharmacopoeia*.\n\nIn June 2011 a teleconference was organized with the experts involved in the revision of the artemisinin derivatives monographs in order to discuss the approach that should be followed for implementing the corrections identified. Proposals made concerning the different aspects of the monographs to be modified were discussed at the consultation on specifications for medicines and quality control laboratory issues held in July 2011. The monographs concerning artesunate and arteminol were, therefore, presented for discussion by the Expert Committee.\n\nIt was noted that both these substances were widely used in artemisinin-based combination therapy and that arteminol was also present as a related substance in the APIs of other artemisinin-derivatives. The Committee emphasized, therefore, that any change made to the monographs for these two substances would need to be implemented in other related monographs.\n\n### Artesunate\n\nThis monograph on artesunate was initially revised by the Expert Committee in 2009 and again in 2010. Following the correction of the ambiguity regarding the nomenclature, the monograph was presented once more to the Expert Committee for further review.\n\nThe Expert Committee adopted the monograph on artesunate subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.\n\n### Arteminol\n\nThe current monograph was still under review in the context of the general revision of monographs on artemisinin derivatives. Although the revised draft presented to the Expert Committee for review took account of the changes proposed to the monograph with regard to the correction of information related to nomenclature, it was considered that other changes might be required.\n\nThe Expert Committee adopted the monograph on arteminol subject to inclusion of the agreed changes, based on the comments received and those made during the discussion.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en la revisi\u00f3n de las monograf\u00edas de los derivados de artemisinina, espec\u00edficamente artesunato y arteminol, por parte de un Comit\u00e9 de Expertos de la OMS. Se identificaron correcciones en la nomenclatura durante la revisi\u00f3n del artesunato, lo que llev\u00f3 a una revisi\u00f3n m\u00e1s profunda de las publicaciones relacionadas de la OMS. Se organiz\u00f3 una teleconferencia en 2011 para discutir las correcciones necesarias y se presentaron las monograf\u00edas para su discusi\u00f3n. Ambas sustancias son ampliamente utilizadas en la terapia combinada basada en artemisinina, y cualquier cambio en sus monograf\u00edas debe reflejarse en otras monograf\u00edas relacionadas.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 acciones se tomaron para resolver la ambig\u00fcedad en la nomenclatura de los derivados de artemisinina?**\n   - Se llev\u00f3 a cabo una revisi\u00f3n en profundidad de las publicaciones relacionadas de la OMS y se organiz\u00f3 una teleconferencia con expertos para discutir las correcciones necesarias.\n\n2. **\u00bfCu\u00e1les son las implicaciones de los cambios en las monograf\u00edas de artesunato y arteminol para otras monograf\u00edas relacionadas?**\n   - Cualquier cambio realizado en las monograf\u00edas de artesunato y arteminol debe ser implementado en otras monograf\u00edas relacionadas, dado que ambas sustancias son utilizadas en artemisinin-based combination therapy.\n\n3. **\u00bfQu\u00e9 revisiones se realizaron en las monograf\u00edas de artesunato y arteminol antes de su adopci\u00f3n por el Comit\u00e9 de Expertos?**\n   - La monograf\u00eda de artesunato fue revisada en 2009 y 2010, y se present\u00f3 nuevamente despu\u00e9s de corregir la ambig\u00fcedad en la nomenclatura. La monograf\u00eda de arteminol estaba en revisi\u00f3n general, y aunque se consideraron cambios en la nomenclatura, se pens\u00f3 que podr\u00edan ser necesarios otros ajustes.", "prev_section_summary": "### Temas clave\n\n1. **Desarrollo de Monograf\u00edas**: Las monograf\u00edas en *The International Pharmacopoeia* establecen especificaciones de calidad para medicamentos esenciales seg\u00fan la OMS.\n  \n2. **Importancia para Programas de la OMS**: Estas monograf\u00edas son fundamentales para la precalificaci\u00f3n de medicamentos y gu\u00edas de tratamiento, siendo utilizadas por programas de la OMS y organizaciones internacionales como UNICEF y el Global Fund.\n\n3. **Proceso de Adopci\u00f3n**: El proceso de adopci\u00f3n de nuevas monograf\u00edas fue revisado por un Comit\u00e9 de Expertos, que discuti\u00f3 y adopt\u00f3 las fases involucradas en el desarrollo de monograf\u00edas.\n\n4. **Medicamentos Espec\u00edficos**: Se mencionan monograf\u00edas espec\u00edficas, como la de los comprimidos de ritonavir, que fue adoptada con cambios acordados, y el estado del trabajo en curso sobre el tenofovir disoproxil fumarato.\n\n### Entidades\n\n- **Organizaciones**: \n  - OMS (Organizaci\u00f3n Mundial de la Salud)\n  - UNICEF (Fondo de las Naciones Unidas para la Infancia)\n  - Global Fund to Fight AIDS, Tuberculosis and Malaria\n\n- **Medicamentos**:\n  - Ritonavir (API y comprimidos)\n  - Tenofovir disoproxil fumarato\n\n- **Comit\u00e9**: Comit\u00e9 de Expertos de la OMS\n\nEste resumen destaca la relevancia de las monograf\u00edas en la regulaci\u00f3n y calidad de los medicamentos esenciales, as\u00ed como el proceso colaborativo involucrado en su desarrollo y revisi\u00f3n.", "excerpt_keywords": "Keywords: artesunate, arteminol, WHO, antimalarial medicines, nomenclature corrections"}}, "dbe47d98-cb04-4ae8-8598-a0ad58f41fe9": {"node_ids": ["1eaab0c7-75cf-4461-be2e-44a8c1459177"], "metadata": {"page_label": "28", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Mefloquine hydrochloride\n\nFollowing the adoption of the monograph for mefloquine tablets in October 2010, it was pointed out that the published monograph on mefloquine hydrochloride would need to be reviewed in order to replace the current thin-layer chromatography (TLC) method used for Related substances by a high-performance liquid chromatography (HPLC) method and to revise the limits for impurities.\n\nA first draft of the proposed revision was discussed at the consultation on specifications for medicines and quality control issues held in July 2011 and, in response to the comments made, further analytical work and verifications had been carried out by the collaborating laboratory to which the project was assigned.\n\nThe Expert Committee reviewed a revised version of the tests reflecting the changes and approved the text, subject to comments made during the discussion, for submission for wide consultation in line with the usual procedure.\n\n## New basic tests for antimalarials\n\nThe Expert Committee was informed about the progress made with the basic tests series for antimalarials. These would soon be made available on the web site.\n\n### 3.2.3 Antituberculosis medicines\n\n#### Rifampicin\n\nRifampicin exhibits polymorphism. The polymorph forms I and II, and mixtures of forms I and II, are available on the market. The infrared reference spectrum of Rifampicin RS, published in the first supplement to *The International Pharmacopoeia*, is concordant with form II. It is not intended to place a restriction on the polymorphic form. To this effect the monograph was revised and presented to the Expert Committee with the proposal to add a recrystallization step to the existing infrared (IR) identification method for both the test substance and the reference substance, in case their IR spectra are not concordant. Comments received on the document were reviewed.\n\nThe Expert Committee adopted the monograph on rifampicin subject to inclusion of the agreed changes, based on the comments received and those made during the discussion. Moreover, it recommended proceeding with a similar revision of the monographs for tablets and capsules.\n\n### 3.2.4 Anti-infectives\n\n#### Pyrantel oral suspension\n\nThe Expert Committee reviewed the draft monograph on pyrantel oral suspension and the major comments received. The Expert Committee agreed that the discussion of the monograph should be deferred until a number of issues could be clarified.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Preguntas\n\n1. **\u00bfQu\u00e9 cambios se propusieron para la monograf\u00eda de mefloquina hidrocloruro y por qu\u00e9 fueron necesarios?**\n   - Se propuso reemplazar el m\u00e9todo actual de cromatograf\u00eda en capa fina (TLC) utilizado para las sustancias relacionadas por un m\u00e9todo de cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n (HPLC) y revisar los l\u00edmites para impurezas, debido a la necesidad de mejorar la calidad y precisi\u00f3n en el an\u00e1lisis de este medicamento.\n\n2. **\u00bfCu\u00e1l fue la decisi\u00f3n del Comit\u00e9 de Expertos respecto a la monograf\u00eda de rifampicina y qu\u00e9 cambios se incluyeron?**\n   - El Comit\u00e9 de Expertos adopt\u00f3 la monograf\u00eda de rifampicina con la inclusi\u00f3n de un paso de recristalizaci\u00f3n en el m\u00e9todo de identificaci\u00f3n por espectroscop\u00eda infrarroja (IR) para asegurar la concordancia de los espectros IR entre la sustancia de prueba y la sustancia de referencia, dado que rifampicina exhibe polimorfismo.\n\n3. **\u00bfQu\u00e9 se decidi\u00f3 sobre la monograf\u00eda de la suspensi\u00f3n oral de pirantel y cu\u00e1les fueron las razones para esta decisi\u00f3n?**\n   - El Comit\u00e9 de Expertos decidi\u00f3 posponer la discusi\u00f3n de la monograf\u00eda de la suspensi\u00f3n oral de pirantel hasta que se pudieran aclarar varios problemas importantes que hab\u00edan surgido durante la revisi\u00f3n del borrador.\n\n### Resumen de nivel superior\n\nEl contexto aborda la revisi\u00f3n de varias monograf\u00edas de medicamentos, incluyendo mefloquina hidrocloruro y rifampicina, por parte de un Comit\u00e9 de Expertos. Se destaca la necesidad de actualizar m\u00e9todos anal\u00edticos, como el cambio de TLC a HPLC para mefloquina, y la consideraci\u00f3n del polimorfismo en rifampicina, lo que llev\u00f3 a la adopci\u00f3n de cambios en su monograf\u00eda. Adem\u00e1s, se menciona que la discusi\u00f3n sobre la monograf\u00eda de pirantel se pospuso debido a la necesidad de aclarar ciertos problemas. Estos procesos reflejan un esfuerzo continuo por mejorar la calidad y la especificaci\u00f3n de los medicamentos antimal\u00e1ricos y antituberculosos.", "prev_section_summary": "### Temas Clave\n\n1. **Revisi\u00f3n de Monograf\u00edas**: Se llev\u00f3 a cabo una revisi\u00f3n de las monograf\u00edas de los derivados de artemisinina, espec\u00edficamente artesunato y arteminol, por parte de un Comit\u00e9 de Expertos de la OMS.\n\n2. **Correcciones en Nomenclatura**: Durante la revisi\u00f3n del artesunato, se identificaron varias correcciones necesarias en la nomenclatura, lo que llev\u00f3 a una revisi\u00f3n m\u00e1s profunda de las publicaciones relacionadas de la OMS.\n\n3. **Teleconferencia y Consulta**: En junio de 2011, se organiz\u00f3 una teleconferencia con expertos para discutir las correcciones necesarias, y se llevaron a cabo consultas sobre especificaciones para medicamentos y cuestiones de control de calidad en julio de 2011.\n\n4. **Uso en Terapia Combinada**: Tanto el artesunato como el arteminol son ampliamente utilizados en la terapia combinada basada en artemisinina, lo que implica que cualquier cambio en sus monograf\u00edas debe reflejarse en otras monograf\u00edas relacionadas.\n\n5. **Adopci\u00f3n de Monograf\u00edas**: La monograf\u00eda de artesunato fue adoptada por el Comit\u00e9 de Expertos despu\u00e9s de realizar las correcciones acordadas, mientras que la monograf\u00eda de arteminol a\u00fan estaba bajo revisi\u00f3n, aunque se adopt\u00f3 su versi\u00f3n revisada sujeta a cambios adicionales.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la revisi\u00f3n y adopci\u00f3n de las monograf\u00edas.\n- **Artesunato**: Derivado de artemisinina que fue revisado y adoptado por el Comit\u00e9 de Expertos.\n- **Arteminol**: Otro derivado de artemisinina que estaba en revisi\u00f3n y fue adoptado con cambios acordados.\n- **Comit\u00e9 de Expertos**: Grupo encargado de revisar y adoptar las monograf\u00edas de los medicamentos antimal\u00e1ricos.\n- **Terapia Combinada Basada en Artemisinina**: Tratamiento que utiliza artesunato y arteminol como componentes clave.", "excerpt_keywords": "Mefloquine, Rifampicin, Polymorphism, High-performance liquid chromatography, Antimalarials"}}, "eb7dced0-5bd9-4c14-9766-51c7c34ac194": {"node_ids": ["89694800-3724-4b32-8bd6-dc0e87c52b92"], "metadata": {"page_label": "29", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Pyrantel chewable tablets\n\nThe Expert Committee reviewed the draft monograph on pyrantel chewable tablets and the major comments received. The Expert Committee adopted the monograph on pyrantel chewable tablets subject to inclusion of the agreed changes based on the comments received and those made during the discussion.\n\n# Albendazole chewable tablets\n\nThe Expert Committee reviewed the draft monograph on albendazole chewable tablets. A first draft of the monograph was received from the collaborating laboratory, subsequently amended by the secretariat and sent for wide consultation in September 2011 according to the usual consultative procedure. The monograph remained open for public comment.\n\nThe Expert Committee recommended that further consultation be sought. Furthermore, it was proposed that the API monograph be considered for revision.\n\n## 3.2.5 Other medicines\n\n### Heparins\n\nFollowing alerts regarding some contaminated heparin injections, discussions were held on detection of impurities in the product, with a view to revising the monographs published in a number of pharmacopoeias. The issue of the revision of the heparins monographs in *The International Pharmacopoeia* had been discussed on several occasions during Expert Committee meetings and consultations, notably in 2008 and 2009.\n\nA new method for the determination of dermatan sulfate and other glycosaminoglycans in heparin was presented to the Expert Committee for possible inclusion in *The International Pharmacopoeia*.\n\nThe Expert Committee reviewed this method and approved its inclusion in the monograph, subject to inclusion of the agreed changes. The monograph will be submitted for wide consultation in line with the usual procedure.\n\n### Medroxyprogesterone injection\n\nA new monograph on the contraceptive medroxyprogesterone injection was presented to the Expert Committee for review. The monograph had recently been received by the secretariat and had been sent out for comments. The monograph is still open for public comment.\n\nThe Expert Committee adopted the monograph on medroxyprogesterone injection subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, and also allowing for further comments by members of the Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento revisa varias monograf\u00edas de medicamentos, incluyendo tabletas masticables de pirantel y albendazol, as\u00ed como inyecciones de medroxiprogesterona. La Comisi\u00f3n de Expertos adopt\u00f3 la monograf\u00eda de pirantel con cambios acordados y recomend\u00f3 m\u00e1s consultas para la de albendazol. Tambi\u00e9n se discutieron las heparinas, especialmente en relaci\u00f3n con la detecci\u00f3n de impurezas tras alertas sobre inyecciones contaminadas. Se present\u00f3 un nuevo m\u00e9todo para determinar sulfato de dermatan y otros glicosaminoglicanos en heparina, que fue aprobado para su inclusi\u00f3n en la monograf\u00eda. La monograf\u00eda de medroxiprogesterona fue adoptada con cambios acordados y se mantuvo abierta para comentarios adicionales.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 cambios se acordaron para la monograf\u00eda de las tabletas masticables de pirantel y c\u00f3mo se determinaron?**\n   - La monograf\u00eda fue adoptada por la Comisi\u00f3n de Expertos, sujeta a la inclusi\u00f3n de cambios acordados basados en los comentarios recibidos durante la discusi\u00f3n.\n\n2. **\u00bfCu\u00e1l fue el motivo de la revisi\u00f3n de las monograf\u00edas de heparinas y qu\u00e9 m\u00e9todo nuevo se propuso?**\n   - La revisi\u00f3n se debi\u00f3 a alertas sobre inyecciones de heparina contaminadas. Se present\u00f3 un nuevo m\u00e9todo para la determinaci\u00f3n de sulfato de dermatan y otros glicosaminoglicanos en heparina, que fue aprobado para su inclusi\u00f3n en la monograf\u00eda.\n\n3. **\u00bfQu\u00e9 pasos se est\u00e1n tomando para la monograf\u00eda de albendazol y cu\u00e1l es su estado actual?**\n   - La monograf\u00eda de albendazol fue revisada y se recomend\u00f3 buscar m\u00e1s consultas. Actualmente, la monograf\u00eda permanece abierta para comentarios p\u00fablicos.\n\n### Resumen de nivel superior\n\nEl documento aborda la revisi\u00f3n y adopci\u00f3n de varias monograf\u00edas de medicamentos por parte de un Comit\u00e9 de Expertos, destacando la importancia de la consulta p\u00fablica y la revisi\u00f3n de m\u00e9todos para garantizar la calidad y seguridad de los medicamentos. Se enfatiza la necesidad de abordar problemas de contaminaci\u00f3n en productos farmac\u00e9uticos y la continua evoluci\u00f3n de las monograf\u00edas para reflejar los est\u00e1ndares actuales.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Mefloquina Hidrocloruro**:\n   - **Revisi\u00f3n de Monograf\u00eda**: Se propuso actualizar la monograf\u00eda de mefloquina hidrocloruro para reemplazar el m\u00e9todo de cromatograf\u00eda en capa fina (TLC) por cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n (HPLC) y revisar los l\u00edmites de impurezas.\n   - **Consulta y Aprobaci\u00f3n**: Un primer borrador fue discutido en una consulta en julio de 2011, y se realizaron trabajos anal\u00edticos adicionales. El Comit\u00e9 de Expertos aprob\u00f3 la versi\u00f3n revisada para su consulta amplia.\n\n2. **Medicamentos Antituberculosos**:\n   - **Rifampicina**: \n     - **Polimorfismo**: Rifampicina presenta polimorfismo con formas I y II disponibles en el mercado.\n     - **Revisi\u00f3n de Monograf\u00eda**: Se propuso a\u00f1adir un paso de recristalizaci\u00f3n al m\u00e9todo de identificaci\u00f3n por espectroscop\u00eda infrarroja (IR) para asegurar la concordancia de los espectros entre la sustancia de prueba y la sustancia de referencia.\n     - **Aprobaci\u00f3n**: El Comit\u00e9 de Expertos adopt\u00f3 la monograf\u00eda con los cambios acordados y recomend\u00f3 revisiones similares para las monograf\u00edas de tabletas y c\u00e1psulas.\n\n3. **Medicamentos Anti-infecciosos**:\n   - **Suspensi\u00f3n Oral de Pirantel**: \n     - **Posposici\u00f3n de Discusi\u00f3n**: El Comit\u00e9 de Expertos decidi\u00f3 posponer la discusi\u00f3n de la monograf\u00eda de la suspensi\u00f3n oral de pirantel hasta que se aclararan varios problemas importantes.\n\n### Entidades Clave\n- **Comit\u00e9 de Expertos**: Grupo responsable de revisar y aprobar las monograf\u00edas de medicamentos.\n- **Mefloquina**: Medicamento antimal\u00e1rico cuya monograf\u00eda fue revisada.\n- **Rifampicina**: Medicamento antituberculoso con caracter\u00edsticas de polimorfismo.\n- **Pirantel**: Medicamento anti-infeccioso cuya monograf\u00eda fue pospuesta para discusi\u00f3n.\n\nEste resumen refleja un esfuerzo continuo por mejorar la calidad y especificaci\u00f3n de medicamentos antimal\u00e1ricos y antituberculosos a trav\u00e9s de la revisi\u00f3n de sus monograf\u00edas.", "excerpt_keywords": "Pyrantel, Albendazole, Heparins, Medroxyprogesterone, Monograph"}}, "489c27ba-7a24-4e92-9ec5-77b4ea2a7429": {"node_ids": ["54a96d7d-d376-408e-902a-4f9f02183db5"], "metadata": {"page_label": "30", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Levonorgestrel tablets\n\nThe text on levonorgestrel tablets was adopted in 2010, and following the recommendation made by the Expert Committee, specific requirements for the 30 \u00b5g tablets had been added with regard to the preparation of test solutions and the dissolution test conditions. As these agreed changes were important, the final text was re-presented to the Expert Committee for final endorsement (see also section 3.3.2).\n\nThe proposed modifications were adopted by the Expert Committee.\n\n## 3.2.6 Other paediatrics\n\n### Paediatric retinol oral solution\n\nDraft versions of the monographs on retinol concentrate (oily form), paediatric retinol capsules and paediatric retinol oral solution were discussed at the forty-fifth meeting of the Expert Committee in October 2010. The monograph on retinol concentrate, oily form, was adopted.\n\nThe Committee decided to incorporate the dosage form paediatric retinol soft-gel capsules into the monograph on retinol oral solution, considering the soft gelatin shell as a single-unit container and the liquid content as the actual dosage form. Following the meeting held in 2010, the Expert Committee recommended that the monograph on paediatric retinol oral solution should be modified so that its specifications could also be applied to these single-dose units and that the capsule monograph should be withdrawn.\n\nFollowing the 2010 meeting, revised versions of the monograph on paediatric retinol oral solution were circulated twice according to the usual consultative procedure. The monograph was also discussed at the consultation on specifications for medicines and quality control issues held in July 2011.\n\nThe Expert Committee adopted the monograph on paediatric retinol oral solution subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, and subject to the requirement that the monograph on retinol concentrate (oily form) be adapted in line with the changes to that on retinol oral solution.\n\n## 3.3 General monographs for dosage forms and associated method texts\n\n### 3.3.1 Pharmacopoeial Discussion Group-harmonized general texts\n\nFollowing discussion by the Expert Committee on Specifications for Pharmaceutical Preparations at its forty-fifth meeting in 2010, a number of internationally harmonized, PDG-texts had been adapted to the editorial style of *The International Pharmacopoeia* and sent out for wide consultation as per the usual consultative procedure.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en las modificaciones y adopciones de monograf\u00edas relacionadas con medicamentos, espec\u00edficamente sobre tabletas de levonorgestrel y soluciones orales de retinol pedi\u00e1trico. En 2010, se adoptaron cambios importantes en la monograf\u00eda de tabletas de levonorgestrel, incluyendo requisitos espec\u00edficos para tabletas de 30 \u00b5g. Tambi\u00e9n se discuten las decisiones tomadas por el Comit\u00e9 de Expertos sobre la incorporaci\u00f3n de c\u00e1psulas de gelatina blanda de retinol pedi\u00e1trico en la monograf\u00eda de soluci\u00f3n oral de retinol, as\u00ed como la adaptaci\u00f3n de las especificaciones de la monograf\u00eda de retinol concentrado en forma oleosa. Se menciona el proceso de consulta y revisi\u00f3n que sigui\u00f3 a estas decisiones.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les fueron los cambios espec\u00edficos adoptados para las tabletas de levonorgestrel de 30 \u00b5g en 2010?**\n   - Respuesta: Se a\u00f1adieron requisitos espec\u00edficos con respecto a la preparaci\u00f3n de soluciones de prueba y las condiciones de la prueba de disoluci\u00f3n.\n\n2. **\u00bfQu\u00e9 decisi\u00f3n tom\u00f3 el Comit\u00e9 de Expertos respecto a las c\u00e1psulas de gelatina blanda de retinol pedi\u00e1trico y su relaci\u00f3n con la monograf\u00eda de soluci\u00f3n oral de retinol?**\n   - Respuesta: El Comit\u00e9 decidi\u00f3 incorporar las c\u00e1psulas de gelatina blanda en la monograf\u00eda de soluci\u00f3n oral de retinol, considerando la c\u00e1psula como un contenedor de unidad \u00fanica y el contenido l\u00edquido como la forma de dosificaci\u00f3n real.\n\n3. **\u00bfQu\u00e9 procedimiento se sigui\u00f3 para la revisi\u00f3n de la monograf\u00eda de soluci\u00f3n oral de retinol pedi\u00e1trico despu\u00e9s de la reuni\u00f3n de 2010?**\n   - Respuesta: Se circularon versiones revisadas de la monograf\u00eda dos veces seg\u00fan el procedimiento consultivo habitual y se discuti\u00f3 en una consulta sobre especificaciones para medicamentos y cuestiones de control de calidad en julio de 2011.", "prev_section_summary": "### Temas clave\n\n1. **Revisi\u00f3n de Monograf\u00edas de Medicamentos**:\n   - Se revisaron las monograf\u00edas de tabletas masticables de **pirantel** y **albendazol**.\n   - La monograf\u00eda de pirantel fue adoptada con cambios acordados, mientras que la de albendazol permanece abierta para comentarios p\u00fablicos y se recomienda m\u00e1s consultas.\n\n2. **Heparinas**:\n   - Se discutieron las heparinas en el contexto de alertas sobre inyecciones contaminadas.\n   - Se propuso un nuevo m\u00e9todo para la determinaci\u00f3n de **sulfato de dermatan** y otros **glicosaminoglicanos** en heparina, que fue aprobado para su inclusi\u00f3n en la monograf\u00eda.\n\n3. **Inyecci\u00f3n de Medroxiprogesterona**:\n   - Se present\u00f3 una nueva monograf\u00eda sobre la inyecci\u00f3n contraceptiva de **medroxiprogesterona**, que fue adoptada con cambios acordados y se mantiene abierta para comentarios adicionales.\n\n### Entidades\n\n- **Medicamentos**:\n  - Pirantel (tabletas masticables)\n  - Albendazol (tabletas masticables)\n  - Heparinas\n  - Medroxiprogesterona (inyecci\u00f3n)\n\n- **Comit\u00e9**:\n  - Comit\u00e9 de Expertos de la OMS\n\n- **M\u00e9todos**:\n  - M\u00e9todo para la determinaci\u00f3n de sulfato de dermatan y glicosaminoglicanos en heparina\n\n- **Documentos**:\n  - Monograf\u00edas en *The International Pharmacopoeia*\n\n### Resumen\n\nLa secci\u00f3n aborda la revisi\u00f3n y adopci\u00f3n de monograf\u00edas de medicamentos por parte de un Comit\u00e9 de Expertos, destacando la importancia de la consulta p\u00fablica y la revisi\u00f3n de m\u00e9todos para garantizar la calidad y seguridad de los medicamentos. Se enfatiza la necesidad de abordar problemas de contaminaci\u00f3n en productos farmac\u00e9uticos y la continua evoluci\u00f3n de las monograf\u00edas para reflejar los est\u00e1ndares actuales.", "excerpt_keywords": "Levonorgestrel, paediatric retinol, monographs, Expert Committee, pharmaceutical preparations"}}, "b4f9d5ae-bf0d-4211-8ec2-fed0aeecbead": {"node_ids": ["b8d2e10f-b387-4b17-98ce-0df352e88f0c"], "metadata": {"page_label": "31", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nA first set of texts with the comments received were initially reviewed at the consultation on specifications for medicines and quality control issues held in July 2011. These texts covered:\n\n- sulfated ash\n- test for extractable volume of parenteral preparations\n- disintegration test\n- test for particulate contamination: subvisible particles\n- microbial examination of non-sterile products: acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use\n- microbial examination of non-sterile products: tests for specified microorganisms\n- microbial examination of non-sterile products: microbial enumeration tests.\n\nA set of additional texts was then prepared in the same way and sent out for wide consultation in August and September 2011:\n\n- sterility test\n- tablet friability\n- bulk and tapped density of powders\n- bacterial endotoxins test.\n\nAs a consequence of the inclusion of these internationally harmonized monographs it was pointed out that certain texts in *The International Pharmacopoeia* would also require adaptation, for example, the monograph on parenteral preparations.\n\nThe Expert Committee proposed the following maintenance procedure for these texts: when the methods concerned are revised by the PDG and where this will have repercussions for the texts above included in *The International Pharmacopoeia*, the secretariat should consult with selected members of the Expert Committee and then make the required changes to *The International Pharmacopoeia* without the necessity for consulting the full Expert Committee.\n\nFor all following general texts, the Expert Committee acknowledged that they were sent out for wide consultation and duly revised, taking into account the comments received. All the texts described and listed were adopted, subject to inclusion of the agreed changes, based on the comments received and those made during the discussion, unless stated otherwise.\n\n## Test for sulfated ash\n\nDuring its meeting in October 2010, the Expert Committee recommended that the current method described in *The International Pharmacopoeia* for the test", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las actividades de un Comit\u00e9 de Expertos de la OMS sobre especificaciones para preparaciones farmac\u00e9uticas. En 2011, se revisaron y consultaron varios textos relacionados con m\u00e9todos de control de calidad de medicamentos, incluyendo pruebas para cenizas sulfatadas, volumen extra\u00edble de preparaciones parenterales, y pruebas microbiol\u00f3gicas. Se propuso un procedimiento de mantenimiento para adaptar los textos de *La Farmacopea Internacional* en funci\u00f3n de las revisiones realizadas por el Grupo de Trabajo de Farmacopeas (PDG). Adem\u00e1s, se menciona que ciertos textos requerir\u00edan adaptaci\u00f3n debido a la inclusi\u00f3n de monograf\u00edas armonizadas internacionalmente.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 procedimiento se propuso para la adaptaci\u00f3n de los textos de *La Farmacopea Internacional* cuando se revisan los m\u00e9todos por el PDG?**\n   - El procedimiento propuesto establece que, cuando los m\u00e9todos son revisados por el PDG y esto afecta a los textos incluidos en *La Farmacopea Internacional*, la secretar\u00eda debe consultar a miembros seleccionados del Comit\u00e9 de Expertos y realizar los cambios necesarios sin necesidad de consultar al Comit\u00e9 completo.\n\n2. **\u00bfCu\u00e1les son algunos de los textos que se revisaron y enviaron para consulta en agosto y septiembre de 2011?**\n   - Los textos revisados y enviados para consulta incluyen: prueba de esterilidad, friabilidad de tabletas, densidad a granel y densidad apilada de polvos, y prueba de endotoxinas bacterianas.\n\n3. **\u00bfQu\u00e9 se destac\u00f3 sobre la necesidad de adaptar ciertos textos en *La Farmacopea Internacional*?**\n   - Se destac\u00f3 que, debido a la inclusi\u00f3n de monograf\u00edas armonizadas internacionalmente, ciertos textos en *La Farmacopea Internacional* requerir\u00edan adaptaci\u00f3n, como la monograf\u00eda sobre preparaciones parenterales.\n\nEstas preguntas y respuestas est\u00e1n dise\u00f1adas para proporcionar informaci\u00f3n espec\u00edfica que no se puede encontrar f\u00e1cilmente en otros documentos, centr\u00e1ndose en los procedimientos y decisiones del Comit\u00e9 de Expertos de la OMS.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Levonorgestrel Tablets**:\n   - **A\u00f1o de adopci\u00f3n**: 2010.\n   - **Cambios adoptados**: Se a\u00f1adieron requisitos espec\u00edficos para la preparaci\u00f3n de soluciones de prueba y las condiciones de la prueba de disoluci\u00f3n para tabletas de 30 \u00b5g.\n   - **Proceso**: El texto final fue re-presentado al Comit\u00e9 de Expertos para su aprobaci\u00f3n final.\n\n2. **Paediatric Retinol Oral Solution**:\n   - **Monograf\u00edas discutidas**: Incluyen retinol concentrado (forma oleosa), c\u00e1psulas de gelatina blanda pedi\u00e1tricas y soluci\u00f3n oral de retinol pedi\u00e1trico.\n   - **Decisi\u00f3n del Comit\u00e9**: Incorporar las c\u00e1psulas de gelatina blanda en la monograf\u00eda de soluci\u00f3n oral de retinol, considerando la c\u00e1psula como un contenedor de unidad \u00fanica.\n   - **Modificaciones**: Se recomend\u00f3 modificar la monograf\u00eda de soluci\u00f3n oral para que sus especificaciones se aplicaran tambi\u00e9n a las unidades de dosis \u00fanica y se retir\u00f3 la monograf\u00eda de c\u00e1psulas.\n\n3. **Proceso de revisi\u00f3n**:\n   - **Circulaci\u00f3n de versiones revisadas**: Se realizaron dos circulaciones de versiones revisadas de la monograf\u00eda de soluci\u00f3n oral de retinol pedi\u00e1trico.\n   - **Consulta adicional**: Se discuti\u00f3 en una consulta sobre especificaciones para medicamentos y control de calidad en julio de 2011.\n\n4. **General Monographs for Dosage Forms**:\n   - **Grupo de discusi\u00f3n**: Se adaptaron textos armonizados internacionalmente al estilo editorial de *The International Pharmacopoeia* y se enviaron para consulta.\n\n### Entidades Clave:\n- **Levonorgestrel**: Compuesto farmac\u00e9utico.\n- **Retinol**: Vitamina A en forma de soluci\u00f3n y c\u00e1psulas.\n- **Comit\u00e9 de Expertos**: Grupo responsable de la revisi\u00f3n y adopci\u00f3n de monograf\u00edas.\n- **Monograf\u00edas**: Documentos que especifican los est\u00e1ndares para medicamentos.", "excerpt_keywords": "Keywords: pharmaceutical preparations, quality control, International Pharmacopoeia, Expert Committee, microbial examination"}}, "7c09f339-8b10-4c50-ac9c-5b3e52099451": {"node_ids": ["71efd5b3-5fb5-4c36-b696-304ffbdc13c0"], "metadata": {"page_label": "32", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nof sulfated ash be replaced progressively by the internationally harmonized general test on residue on ignition/sulfated ash test. To this effect the method \u201c2.3 Sulfated ash\u201d was revised and sent for wide consultation in April and August 2011. Both methods would be included in *The International Pharmacopoeia* for an interim period. The internationally harmonized test would be specified in new monographs while, for existing monographs, the current test would be specified until it is replaced during the revision of the monographs in question.\n\n## Bulk density and tapped density of powders\n\nThis new general method text was proposed for inclusion in the Supplementary information section of *The International Pharmacopoeia*. The text was based on the internationally harmonized test on bulk density and tapped density of powders.\n\nIt was intended to revise the Supplementary information section of *The International Pharmacopoeia* (structure and contents). In the proposal being reviewed, a new section on test methods used during pharmaceutical development and/or manufacture of dosage forms was included. The general method for bulk density and tapped density of powders would, therefore, be included in this section and a specific number would be assigned to this method once the proposed format and the methods considered for this section have been adopted.\n\n## Tablet friability\n\nIn October 2009 the Expert Committee on Specifications for Pharmaceutical Preparations adopted a revision of the general monograph on Tablets where a reference was made under the Manufacture section to a method of friability testing. Based on the internationally harmonized tablet friability test, a general method text was, therefore, proposed for inclusion in the Supplementary information section of *The International Pharmacopoeia*.\n\n## Disintegration test\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the disintegration test for tablets and capsules should be replaced by the internationally harmonized general test.\n\nThe revision implies both changes to and additions to dimensions and tolerances in the description of the disintegration apparatus. The possibility for retesting when one or two units fail in the first step of the procedure is introduced, as is the possibility to use automatic detection employing modified discs in cases where the use of discs is prescribed.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Revisi\u00f3n de M\u00e9todos de Prueba**: El Comit\u00e9 de Expertos de la OMS en Especificaciones para Preparaciones Farmac\u00e9uticas ha revisado varios m\u00e9todos de prueba, incluyendo el de cenizas sulfatadas, densidad a granel y densidad compactada de polvos, friabilidad de tabletas y pruebas de desintegraci\u00f3n. Estas revisiones buscan armonizar los m\u00e9todos a nivel internacional y mejorar la calidad de las monograf\u00edas en *La Farmacopea Internacional*.\n\n2. **Implementaci\u00f3n de Nuevos M\u00e9todos**: Se est\u00e1n introduciendo nuevos m\u00e9todos de prueba en la secci\u00f3n de informaci\u00f3n suplementaria de *La Farmacopea Internacional*, con un enfoque en la estandarizaci\u00f3n y la mejora de los procedimientos utilizados en el desarrollo y fabricaci\u00f3n de formas de dosificaci\u00f3n.\n\n3. **Cambios en la Prueba de Desintegraci\u00f3n**: Se recomienda reemplazar el m\u00e9todo actual de prueba de desintegraci\u00f3n para tabletas y c\u00e1psulas por un m\u00e9todo armonizado internacionalmente, que incluye cambios en las dimensiones y tolerancias del aparato de desintegraci\u00f3n, as\u00ed como nuevas posibilidades de retesting y detecci\u00f3n autom\u00e1tica.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las implicaciones de la revisi\u00f3n del m\u00e9todo de cenizas sulfatadas en las monograf\u00edas existentes de *La Farmacopea Internacional*?**\n   - La revisi\u00f3n implica que el m\u00e9todo de cenizas sulfatadas ser\u00e1 reemplazado progresivamente por un test armonizado internacionalmente, lo que significa que las monograf\u00edas existentes seguir\u00e1n utilizando el m\u00e9todo actual hasta que sean revisadas y actualizadas.\n\n2. **\u00bfQu\u00e9 cambios se proponen en el m\u00e9todo de prueba de friabilidad de tabletas y c\u00f3mo se relacionan con la armonizaci\u00f3n internacional?**\n   - Se propone un texto de m\u00e9todo general basado en la prueba de friabilidad de tabletas armonizada internacionalmente, que se incluir\u00e1 en la secci\u00f3n de informaci\u00f3n suplementaria de *La Farmacopea Internacional*, lo que busca estandarizar el proceso de prueba y asegurar la calidad de las tabletas.\n\n3. **\u00bfQu\u00e9 nuevas caracter\u00edsticas se introducen en la prueba de desintegraci\u00f3n para tabletas y c\u00e1psulas seg\u00fan las recomendaciones del Comit\u00e9 de Expertos?**\n   - Las nuevas caracter\u00edsticas incluyen cambios en las dimensiones y tolerancias del aparato de desintegraci\u00f3n, la posibilidad de retesting si una o dos unidades fallan en la primera prueba, y la opci\u00f3n de utilizar detecci\u00f3n autom\u00e1tica con discos modificados cuando se requiera el uso de discos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: Se centra en las especificaciones para preparaciones farmac\u00e9uticas y en el control de calidad de medicamentos.\n\n2. **Consultas y Revisi\u00f3n de Textos**: En 2011, se revisaron textos relacionados con m\u00e9todos de control de calidad, incluyendo:\n   - Cenizas sulfatadas\n   - Volumen extra\u00edble de preparaciones parenterales\n   - Prueba de desintegraci\u00f3n\n   - Contaminaci\u00f3n por part\u00edculas subvisibles\n   - Ex\u00e1menes microbiol\u00f3gicos de productos no est\u00e9riles (criterios de aceptaci\u00f3n, microorganismos espec\u00edficos, y pruebas de enumeraci\u00f3n microbiana).\n\n3. **Textos Adicionales**: En agosto y septiembre de 2011, se enviaron para consulta textos adicionales, que incluyen:\n   - Prueba de esterilidad\n   - Friabilidad de tabletas\n   - Densidad a granel y apilada de polvos\n   - Prueba de endotoxinas bacterianas.\n\n4. **Adaptaci\u00f3n de Textos**: Se destac\u00f3 la necesidad de adaptar ciertos textos en *La Farmacopea Internacional* debido a la inclusi\u00f3n de monograf\u00edas armonizadas internacionalmente, como la monograf\u00eda sobre preparaciones parenterales.\n\n5. **Procedimiento de Mantenimiento**: Se propuso un procedimiento donde, si los m\u00e9todos son revisados por el Grupo de Trabajo de Farmacopeas (PDG) y afectan a los textos de *La Farmacopea Internacional*, la secretar\u00eda consultar\u00e1 a miembros seleccionados del Comit\u00e9 de Expertos para realizar los cambios necesarios sin consultar al Comit\u00e9 completo.\n\n6. **Adopci\u00f3n de Textos**: Todos los textos revisados fueron adoptados, considerando los cambios acordados basados en los comentarios recibidos.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**\n- **La Farmacopea Internacional**\n- **Grupo de Trabajo de Farmacopeas (PDG)**\n\nEste resumen proporciona una visi\u00f3n general de los temas tratados en la secci\u00f3n, destacando la importancia de la revisi\u00f3n y adaptaci\u00f3n de los m\u00e9todos de control de calidad en la farmacolog\u00eda.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, international harmonization, testing methods, disintegration test"}}, "96bea8da-c8b0-47b4-8501-703eccd238b5": {"node_ids": ["b69f4437-bf76-469d-971f-e9b502e41ba0"], "metadata": {"page_label": "33", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Dissolution test\n\nThe dissolution test had been reviewed for adaptation for inclusion in *The International Pharmacopoeia*. The Expert Committee judged that the test should be subjected to a thorough review and should be considered by a future Expert Committee.\n\n# Test for extractable volume for parenteral preparations\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the test for extractable volume for parenteral preparations be replaced by the internationally harmonized general test.\n\n# Tests for particulate contamination\n\nDuring its meeting in October 2010, the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the current method described in *The International Pharmacopoeia* for the tests for particulate contamination should be replaced by the internationally harmonized general test, as a revision of method \u201c5.7 Tests for particulate contamination\u201d. The revision includes a distinction between small volume parenterals and large volume parenterals with a limit at 100 ml. The 100 ml preparation is exempted from the pharmacopoeial harmonization and it was proposed to include the 100 ml preparation among the small volume parenterals. As a consequence of the revision of this method, other changes would be made to the headings in chapter 5.7.\n\n# Microbial quality of pharmaceutical preparations\n\nThis relates to the following headings:\n\n- Microbiological examination of non-sterile products;\n- Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use;\n- Microbial enumeration tests;\n- Tests for specified microorganisms.\n\nMicrobiological examination of non-sterile products had been a subject for harmonization, which has resulted in three texts:\n\n- Microbial enumeration tests;\n- Tests for specified microorganisms;\n- Acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS, *Technical Report Series 970*, aborda varios aspectos relacionados con la farmacopoeia internacional, incluyendo la revisi\u00f3n de pruebas de disoluci\u00f3n, el volumen extra\u00edble en preparaciones parenterales, la contaminaci\u00f3n particulada y la calidad microbiana de las preparaciones farmac\u00e9uticas. Se destaca que el Comit\u00e9 de Expertos ha recomendado la adaptaci\u00f3n de m\u00e9todos existentes a pruebas armonizadas internacionalmente, as\u00ed como la distinci\u00f3n entre parenterales de peque\u00f1o y gran volumen. Tambi\u00e9n se menciona la armonizaci\u00f3n de criterios de calidad microbiol\u00f3gica para productos no est\u00e9riles.\n\n### Preguntas\n\n1. **\u00bfQu\u00e9 cambios espec\u00edficos se proponen para la prueba de volumen extra\u00edble en preparaciones parenterales seg\u00fan el Comit\u00e9 de Expertos?**\n   - Respuesta: Se recomienda que el m\u00e9todo actual para la prueba de volumen extra\u00edble en preparaciones parenterales sea reemplazado por un test general armonizado internacionalmente.\n\n2. **\u00bfC\u00f3mo se distingue entre parenterales de peque\u00f1o y gran volumen en la revisi\u00f3n de la prueba de contaminaci\u00f3n particulada?**\n   - Respuesta: La revisi\u00f3n incluye una distinci\u00f3n entre parenterales de peque\u00f1o volumen y de gran volumen, estableciendo un l\u00edmite de 100 ml, donde las preparaciones de 100 ml est\u00e1n exentas de la armonizaci\u00f3n farmacopoeial y se propone incluirlas entre las de peque\u00f1o volumen.\n\n3. **\u00bfCu\u00e1les son los cuatro aspectos clave relacionados con la calidad microbiana de las preparaciones farmac\u00e9uticas que se mencionan en el documento?**\n   - Respuesta: Los cuatro aspectos clave son: la microbiolog\u00eda de productos no est\u00e9riles, los criterios de aceptaci\u00f3n para preparaciones farmac\u00e9uticas y sustancias para uso farmac\u00e9utico, las pruebas de enumeraci\u00f3n microbiana y las pruebas para microorganismos espec\u00edficos.", "prev_section_summary": "### Temas Clave\n\n1. **Revisi\u00f3n de M\u00e9todos de Prueba**: Se han revisado varios m\u00e9todos de prueba en el \u00e1mbito farmac\u00e9utico, incluyendo el m\u00e9todo de cenizas sulfatadas, densidad a granel y densidad compactada de polvos, friabilidad de tabletas y pruebas de desintegraci\u00f3n, con el objetivo de armonizar y mejorar la calidad de las monograf\u00edas en *La Farmacopea Internacional*.\n\n2. **Armonizaci\u00f3n Internacional**: Se est\u00e1n implementando m\u00e9todos de prueba armonizados internacionalmente, lo que implica la inclusi\u00f3n de nuevos textos en la secci\u00f3n de informaci\u00f3n suplementaria de *La Farmacopea Internacional*.\n\n3. **Cambios en la Prueba de Desintegraci\u00f3n**: Se recomienda reemplazar el m\u00e9todo actual de prueba de desintegraci\u00f3n para tabletas y c\u00e1psulas por un m\u00e9todo armonizado, que incluye modificaciones en el aparato de desintegraci\u00f3n y nuevas opciones para retesting y detecci\u00f3n autom\u00e1tica.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la revisi\u00f3n y armonizaci\u00f3n de los m\u00e9todos de prueba.\n- **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**: Grupo que adopta y revisa los m\u00e9todos de prueba.\n- **La Farmacopea Internacional**: Publicaci\u00f3n que contiene los m\u00e9todos de prueba y monograf\u00edas para productos farmac\u00e9uticos.\n- **M\u00e9todos de Prueba**: Incluyen cenizas sulfatadas, densidad a granel, densidad compactada, friabilidad de tabletas y pruebas de desintegraci\u00f3n. \n\n### Resumen\n\nEl Comit\u00e9 de Expertos de la OMS ha revisado y propuesto la armonizaci\u00f3n de varios m\u00e9todos de prueba utilizados en la industria farmac\u00e9utica, con el fin de mejorar la calidad y estandarizaci\u00f3n de los procedimientos en *La Farmacopea Internacional*. Se est\u00e1n introduciendo nuevos m\u00e9todos, como el de cenizas sulfatadas y la prueba de friabilidad de tabletas, y se recomienda la adopci\u00f3n de un m\u00e9todo armonizado para la prueba de desintegraci\u00f3n, que incluye cambios significativos en el equipo y el procedimiento.", "excerpt_keywords": "Keywords: dissolution test, extractable volume, particulate contamination, microbial quality, International Pharmacopoeia"}}, "b12d1c22-c55c-4e3b-905f-17ab7e95a52f": {"node_ids": ["83fbff23-011a-4b0a-92fb-c9c604eaba83"], "metadata": {"page_label": "34", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIt was agreed that the texts on microbial enumeration tests and tests for specified microorganisms would be new (3.3.1 and 3.3.2) in the Methods of analysis section. Furthermore, it was agreed to replace the current text on microbial quality (3.3) with the internationally harmonized text on Microbiological examination of non-sterile products: acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use. This text would be provided for information and would, therefore, be moved to the Supplementary information section and renamed as follows: Microbiological quality of non-sterile products: recommended acceptance criteria for pharmaceutical preparations.\n\nFollowing adoption, the inclusion of methods 3.3.1 and 3.3.2 in *The International Pharmacopoeia* would be reviewed in terms of their applicability within the existing texts of *The International Pharmacopoeia*. Such a review would include excipients and would consider in which monographs of *The International Pharmacopoeia* the methods would be invoked, and would propose limits.\n\n## Test for Sterility\n\nFollowing adoption, the current methods \u201c3.2 test for sterility of non-injectable preparations\u201d and that for \u201c3.2.2 sterility testing of antibiotics\u201d will be replaced with the internationally harmonized test for sterility. Testing of surgical materials was not included in the revision.\n\nThe revision would result in the need for additional advice concerning the testing of antibiotics within the Supplementary information section of *The International Pharmacopoeia*. Further, it would be necessary to change all references to these monographs.\n\nThe clause \u201cunless otherwise prescribed, justified and authorized\u201d is included in the harmonized text. It was felt that the meaning of \u201cjustified and authorized\u201d in the context of *The International Pharmacopoeia* needed explanation. It was, therefore, agreed to include the following wording in the General notices of *The International Pharmacopoeia*:\n\n> \u201cThe expression \u2018unless otherwise justified and authorized\u2019 means that the requirements have to be met or instructions to be followed, unless the relevant national or regional authority authorizes an exemption or modification, where justified in a particular case.\u201d\n\n## Test for Bacterial Endotoxins\n\nThe proposed revision for inclusion in *The International Pharmacopoeia* contained three method texts in contrast to the current text.\n\nThe Expert Committee, therefore, agreed that selected experts would continue to work on the implementation of this new text for existing monographs in *The International Pharmacopoeia*.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las decisiones tomadas por el Comit\u00e9 de Expertos de la OMS sobre las especificaciones para preparaciones farmac\u00e9uticas. Se acord\u00f3 introducir nuevos textos sobre pruebas de enumeraci\u00f3n microbiana y pruebas para microorganismos espec\u00edficos en la secci\u00f3n de M\u00e9todos de an\u00e1lisis. Adem\u00e1s, se reemplazar\u00e1 el texto actual sobre calidad microbiana con uno armonizado internacionalmente. Tambi\u00e9n se revisar\u00e1n los m\u00e9todos de prueba de esterilidad y endotoxinas bacterianas para su inclusi\u00f3n en la Farmacopea Internacional. Se enfatiza la necesidad de aclarar el significado de \"justificado y autorizado\" en el contexto de la Farmacopea.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 cambios se realizar\u00e1n en la secci\u00f3n de M\u00e9todos de an\u00e1lisis de la Farmacopea Internacional respecto a las pruebas de calidad microbiana?**\n   - Se introducir\u00e1n nuevos textos sobre pruebas de enumeraci\u00f3n microbiana (3.3.1 y 3.3.2) y se reemplazar\u00e1 el texto actual sobre calidad microbiana con uno armonizado internacionalmente, que se mover\u00e1 a la secci\u00f3n de informaci\u00f3n suplementaria y se renombrar\u00e1.\n\n2. **\u00bfC\u00f3mo se abordar\u00e1 la necesidad de asesoramiento adicional sobre las pruebas de antibi\u00f3ticos en la Farmacopea Internacional?**\n   - Se requerir\u00e1 asesoramiento adicional en la secci\u00f3n de informaci\u00f3n suplementaria sobre las pruebas de antibi\u00f3ticos, y ser\u00e1 necesario cambiar todas las referencias a los monogr\u00e1ficos relacionados.\n\n3. **\u00bfQu\u00e9 implica la cl\u00e1usula \u201ca menos que se prescriba, justifique y autorice de otra manera\u201d en el contexto de la Farmacopea Internacional?**\n   - Esta cl\u00e1usula significa que los requisitos deben cumplirse o las instrucciones deben seguirse, a menos que una autoridad nacional o regional relevante autorice una exenci\u00f3n o modificaci\u00f3n, donde est\u00e9 justificada en un caso particular.\n\n### Resumen de Nivel Superior\n\nEl Comit\u00e9 de Expertos de la OMS ha acordado realizar varias revisiones importantes en la Farmacopea Internacional, incluyendo la introducci\u00f3n de nuevos m\u00e9todos de an\u00e1lisis para pruebas microbianas y la actualizaci\u00f3n de los m\u00e9todos de prueba de esterilidad y endotoxinas. Estas revisiones buscan armonizar los est\u00e1ndares internacionales y proporcionar claridad sobre la aplicaci\u00f3n de requisitos espec\u00edficos en el contexto de la regulaci\u00f3n farmac\u00e9utica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Prueba de Disoluci\u00f3n**:\n   - Se revis\u00f3 la prueba de disoluci\u00f3n para su posible inclusi\u00f3n en *La Farmacopea Internacional*.\n   - El Comit\u00e9 de Expertos considera que debe ser sometida a una revisi\u00f3n exhaustiva y discutida por un futuro Comit\u00e9 de Expertos.\n\n2. **Volumen Extra\u00edble en Preparaciones Parenterales**:\n   - Se recomienda reemplazar el m\u00e9todo actual para la prueba de volumen extra\u00edble en preparaciones parenterales por un test general armonizado internacionalmente.\n\n3. **Contaminaci\u00f3n Particulada**:\n   - Se sugiere reemplazar el m\u00e9todo actual para las pruebas de contaminaci\u00f3n particulada por un test armonizado internacionalmente.\n   - Se establece una distinci\u00f3n entre parenterales de peque\u00f1o y gran volumen, con un l\u00edmite de 100 ml. Las preparaciones de 100 ml se proponen incluirlas entre las de peque\u00f1o volumen.\n\n4. **Calidad Microbiana de Preparaciones Farmac\u00e9uticas**:\n   - Se abordan cuatro aspectos clave:\n     - Examen microbiol\u00f3gico de productos no est\u00e9riles.\n     - Criterios de aceptaci\u00f3n para preparaciones farmac\u00e9uticas y sustancias para uso farmac\u00e9utico.\n     - Pruebas de enumeraci\u00f3n microbiana.\n     - Pruebas para microorganismos espec\u00edficos.\n   - La armonizaci\u00f3n de la microbiolog\u00eda de productos no est\u00e9riles ha dado lugar a tres textos relacionados.\n\n### Entidades Clave\n- **Comit\u00e9 de Expertos**: Grupo responsable de las recomendaciones sobre las pruebas y m\u00e9todos.\n- **La Farmacopea Internacional**: Referencia para los est\u00e1ndares farmac\u00e9uticos.\n- **Preparaciones Parenterales**: Formas farmac\u00e9uticas que se administran por inyecci\u00f3n.\n- **Contaminaci\u00f3n Particulada**: Problema relacionado con la calidad de las preparaciones inyectables.\n- **Calidad Microbiana**: Aspecto cr\u00edtico en la evaluaci\u00f3n de productos farmac\u00e9uticos, especialmente en productos no est\u00e9riles.", "excerpt_keywords": "Keywords: microbial enumeration, sterility testing, bacterial endotoxins, International Pharmacopoeia, pharmaceutical preparations"}}, "39de5418-1783-4815-a065-de6f82340e7f": {"node_ids": ["839d123a-18ad-49f1-b57c-ba71c2ef2934"], "metadata": {"page_label": "35", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.3.2 Uniformity of content single-dose preparations\n\nA review and explanation of the current pharmacopoeial approach as well as a review of application to published monographs for the general method \u201c5.1 Uniformity of content of single-dose preparations\u201d, was presented to the Expert Committee for consideration.\n\nThe Committee discussed the background document, endorsed the explanatory text as summarized below and adopted the proposed revisions of the relevant monographs. It further agreed that, as a basis for a future policy, this background document and explanatory text would be helpful to assist those involved in the development of new and revised monographs. In this respect, the document might also be made available more widely to provide explanatory information to users of *The International Pharmacopoeia* by its inclusion in the Supplementary information section of the pharmacopoeia.\n\n## Rationale of the review of method 5.1 and its application to tablets and capsules monographs\n\nAt its meeting in October 2010, the Committee discussed the application of uniformity of content testing to monographs in *The International Pharmacopoeia* especially those for tablets and capsules containing two or more APIs, commonly known as fixed-dose combinations (FDCs).\n\nQuestions had arisen with respect to the different testing thresholds applied in the WHO Guidelines for registration of fixed-dose combination medicinal products<sup>1</sup> and in the method of analysis 5.1 of *The International Pharmacopoeia*; the threshold in the WHO guidelines being 25 mg/25% whereas that applied in *The International Pharmacopoeia* was 5 mg/5% (see the agreed correction as regards this threshold under Method of analysis 5.1 Uniformity of content of single-dose preparations below).\n\nIn light of the discussion by the Committee, a review had been carried out of the test and of its application to all tablets and capsules that were the subject of an individual monograph in *The International Pharmacopoeia*, i.e. both those containing a single API and those that were FDCs.\n\nA review document was discussed at the informal consultation on specifications for medicines and quality control laboratory issues in July 2011. A revised version of this document, reflecting the points raised and the recommendations made during the consultation was presented to the Committee for further discussion.\n\n----\n\n<sup>1</sup> In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento presenta una revisi\u00f3n del enfoque farmacopoeial sobre la uniformidad de contenido en preparaciones de dosis \u00fanica, espec\u00edficamente en tabletas y c\u00e1psulas. Se discuten las diferencias en los umbrales de prueba entre las directrices de la OMS para combinaciones de dosis fijas (FDCs) y el m\u00e9todo de an\u00e1lisis de la Farmacopea Internacional. La revisi\u00f3n se llev\u00f3 a cabo en respuesta a preguntas sobre estos umbrales y se discuti\u00f3 en una consulta informal sobre especificaciones para medicamentos y cuestiones de control de calidad en 2011. El Comit\u00e9 de Expertos de la OMS aprob\u00f3 revisiones a las monograf\u00edas relevantes y acord\u00f3 que el documento de fondo ser\u00eda \u00fatil para el desarrollo de nuevas monograf\u00edas.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los umbrales de prueba para la uniformidad de contenido en las combinaciones de dosis fijas seg\u00fan las directrices de la OMS y la Farmacopea Internacional?**\n   - Respuesta: Seg\u00fan las directrices de la OMS, el umbral es de 25 mg/25%, mientras que en la Farmacopea Internacional es de 5 mg/5%.\n\n2. **\u00bfQu\u00e9 se discuti\u00f3 en la reuni\u00f3n del Comit\u00e9 en octubre de 2010 respecto a las monograf\u00edas de tabletas y c\u00e1psulas?**\n   - Respuesta: Se discuti\u00f3 la aplicaci\u00f3n de las pruebas de uniformidad de contenido a las monograf\u00edas de tabletas y c\u00e1psulas, especialmente aquellas que contienen dos o m\u00e1s principios activos (FDCs), y se abordaron las diferencias en los umbrales de prueba.\n\n3. **\u00bfQu\u00e9 se acord\u00f3 en la consulta informal sobre especificaciones para medicamentos en julio de 2011?**\n   - Respuesta: Se discuti\u00f3 un documento de revisi\u00f3n que reflejaba los puntos y recomendaciones planteados durante la consulta, y se present\u00f3 una versi\u00f3n revisada del documento al Comit\u00e9 para su discusi\u00f3n adicional.\n\n### Resumen de nivel superior\n\nEl documento aborda la uniformidad de contenido en preparaciones de dosis \u00fanica, destacando la necesidad de revisar y armonizar los umbrales de prueba entre las directrices de la OMS y la Farmacopea Internacional. Se enfatiza la importancia de esta revisi\u00f3n para el desarrollo de nuevas monograf\u00edas y la mejora de la calidad de los medicamentos, especialmente en el contexto de combinaciones de dosis fijas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: Se centra en las especificaciones para preparaciones farmac\u00e9uticas y la armonizaci\u00f3n de m\u00e9todos de an\u00e1lisis.\n\n2. **M\u00e9todos de An\u00e1lisis**:\n   - **Nuevos Textos**: Se introducir\u00e1n nuevos textos sobre pruebas de enumeraci\u00f3n microbiana (3.3.1 y 3.3.2).\n   - **Reemplazo de Texto**: El texto actual sobre calidad microbiana (3.3) ser\u00e1 reemplazado por uno armonizado internacionalmente y se mover\u00e1 a la secci\u00f3n de informaci\u00f3n suplementaria, renombr\u00e1ndose como \"Calidad microbiol\u00f3gica de productos no est\u00e9riles: criterios de aceptaci\u00f3n recomendados para preparaciones farmac\u00e9uticas\".\n\n3. **Pruebas de Esterilidad**:\n   - Se reemplazar\u00e1n los m\u00e9todos actuales de prueba de esterilidad para preparaciones no inyectables y para antibi\u00f3ticos con un m\u00e9todo armonizado internacionalmente.\n   - Se requerir\u00e1 asesoramiento adicional sobre las pruebas de antibi\u00f3ticos en la secci\u00f3n de informaci\u00f3n suplementaria.\n\n4. **Cl\u00e1usula de Justificaci\u00f3n y Autorizaci\u00f3n**:\n   - Se aclarar\u00e1 el significado de \"a menos que se prescriba, justifique y autorice de otra manera\", indicando que los requisitos deben cumplirse a menos que una autoridad relevante autorice una exenci\u00f3n o modificaci\u00f3n.\n\n5. **Pruebas de Endotoxinas Bacterianas**:\n   - Se propondr\u00e1n tres textos de m\u00e9todos para su inclusi\u00f3n en la Farmacopea Internacional, en contraste con el texto actual.\n\n6. **Revisi\u00f3n de Aplicabilidad**: Se revisar\u00e1 la aplicabilidad de los nuevos m\u00e9todos en los textos existentes de la Farmacopea Internacional, incluyendo excipientes y monograf\u00edas relevantes.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la regulaci\u00f3n y est\u00e1ndares en salud p\u00fablica.\n- **Farmacopea Internacional**: Compendio que establece est\u00e1ndares para la calidad de medicamentos y preparaciones farmac\u00e9uticas.\n- **M\u00e9todos de An\u00e1lisis**: Incluyen pruebas de enumeraci\u00f3n microbiana, pruebas de esterilidad y pruebas de endotoxinas bacterianas. \n\nEste resumen destaca los cambios propuestos y la importancia de la armonizaci\u00f3n en los est\u00e1ndares de calidad farmac\u00e9utica a nivel internacional.", "excerpt_keywords": "Keywords: uniformity of content, single-dose preparations, fixed-dose combinations, pharmacopoeial approach, WHO guidelines"}}, "c7daf445-be7d-4aae-9b6c-3fa1e5d7d0e6": {"node_ids": ["6bcf847d-af2d-4a5e-ba1a-a444efc8058f"], "metadata": {"page_label": "36", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Method of Analysis\n\nWhile it had been confirmed by the Expert Committee in 2010 that the technical basis of test 5.1 should not be modified, it was, however, recommended at the informal consultation in July 2011 that the text of the method would benefit from editorial improvement. Notably, an important omission in the method was corrected by including a reference to 5 mg or less in the statement concerning the application threshold. The current text referred only to 5% or less and it was recognized that a threshold expressed in terms of the declared weight of API per tablet was more transparent with respect to individual monographs than one expressed in terms of the percentage of the tablet weight represented by the API. A threshold of 5 mg was actually already stated in the relevant specific monographs.\n\nThe Committee adopted and endorsed the edited text of method 5.1.\n\n## Application to Tablets and Capsules Monographs\n\nThe Committee adopted and endorsed the general approach of adding, where appropriate:\n\n- \u201cThe use of the average of the uniformity of content results as an option under Assay (Method B) while retaining the current Assay applicable to a mixed sample of 20 tablets/capsules as Method A.\u201d\n\nIt further agreed to the revision proposals for the following individual monographs for tablets and capsules containing either a single or several APIs; these revisions would be made in accordance with normal procedures:\n\n- **a single API**\n  - atropine (sulfate) tablets\n  - chlorphenamine hydrogen maleate tablets\n  - colchicine tablets\n  - dexamethasone tablets\n  - ergometrine hydrogen maleate tablets\n  - glyceryl trinitrate tablets\n  - levonorgestrel tablets\n  - prednisolone tablets\n\n- **two or more APIs (FDCs)**\n  - rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride tablets\n  - sulfadoxine and pyrimethamine tablets.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder espec\u00edficamente con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento se centra en las recomendaciones y decisiones tomadas por el Comit\u00e9 de Expertos de la OMS sobre las Especificaciones para Preparaciones Farmac\u00e9uticas. En particular, se discuten las mejoras editoriales en el m\u00e9todo de an\u00e1lisis 5.1, la inclusi\u00f3n de un umbral de 5 mg para la aplicaci\u00f3n de pruebas, y la adopci\u00f3n de un enfoque general para la uniformidad de contenido en tabletas y c\u00e1psulas. Adem\u00e1s, se enumeran las monograf\u00edas espec\u00edficas que ser\u00e1n revisadas, tanto para productos con un solo API como para combinaciones de m\u00faltiples APIs.\n\n### Preguntas\n1. **\u00bfCu\u00e1l fue la raz\u00f3n principal para modificar el texto del m\u00e9todo 5.1 en el an\u00e1lisis de tabletas y c\u00e1psulas?**\n   - La modificaci\u00f3n se realiz\u00f3 para corregir una omisi\u00f3n importante al incluir una referencia a un umbral de 5 mg o menos, lo que proporciona una mayor transparencia en comparaci\u00f3n con el umbral anterior expresado en t\u00e9rminos de porcentaje del peso de la tableta.\n\n2. **\u00bfQu\u00e9 enfoque general se adopt\u00f3 respecto a la uniformidad de contenido en los ensayos de tabletas y c\u00e1psulas?**\n   - Se adopt\u00f3 el enfoque de permitir el uso del promedio de los resultados de uniformidad de contenido como una opci\u00f3n bajo el Ensayo (M\u00e9todo B), mientras se mantiene el Ensayo actual aplicable a una muestra mixta de 20 tabletas/c\u00e1psulas como M\u00e9todo A.\n\n3. **\u00bfCu\u00e1les son algunos ejemplos de monograf\u00edas que se revisar\u00e1n seg\u00fan las decisiones del Comit\u00e9?**\n   - Se revisar\u00e1n monograf\u00edas para tabletas que contienen un solo API, como las tabletas de atropina (sulfato) y prednisolona, as\u00ed como combinaciones de m\u00faltiples APIs, como las tabletas de rifampicina, isoniazida, pirazinamida y etambutol hidrocloruro.", "prev_section_summary": "### Temas Clave\n\n1. **Uniformidad de Contenido**: Se revisa el enfoque farmacopoeial sobre la uniformidad de contenido en preparaciones de dosis \u00fanica, espec\u00edficamente en tabletas y c\u00e1psulas.\n\n2. **Combinaciones de Dosis Fijas (FDCs)**: Se discute la aplicaci\u00f3n de pruebas de uniformidad de contenido a monograf\u00edas que contienen dos o m\u00e1s principios activos.\n\n3. **Umbrales de Prueba**: Se identifican diferencias en los umbrales de prueba entre las directrices de la OMS (25 mg/25%) y la Farmacopea Internacional (5 mg/5%).\n\n4. **Revisi\u00f3n y Aprobaci\u00f3n**: El Comit\u00e9 de Expertos de la OMS aprob\u00f3 revisiones a las monograf\u00edas relevantes y consider\u00f3 \u00fatil el documento de fondo para el desarrollo de nuevas monograf\u00edas.\n\n5. **Consulta Informal**: Se llev\u00f3 a cabo una consulta informal en julio de 2011 sobre especificaciones para medicamentos y control de calidad, donde se discuti\u00f3 un documento de revisi\u00f3n.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de las directrices y recomendaciones discutidas.\n- **Farmacopea Internacional**: Referencia para los m\u00e9todos de an\u00e1lisis y monograf\u00edas de medicamentos.\n- **Comit\u00e9 de Expertos**: Grupo que revisa y aprueba las monograf\u00edas y m\u00e9todos de an\u00e1lisis.\n- **Preparaciones de Dosis \u00danica**: Tipo de medicamentos que se analizan en el contexto de uniformidad de contenido.\n- **Principios Activos (APIs)**: Sustancias que se analizan en las tabletas y c\u00e1psulas, tanto en monograf\u00edas individuales como en combinaciones.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, method of analysis, uniformity of content, monographs"}}, "bbc13e56-caf7-45c2-8fcd-d094d562260b": {"node_ids": ["05f678f1-ace1-4366-91c0-c958aadbc00f"], "metadata": {"page_label": "37", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations - Forty-sixth Report\n\n**Note:** It was noted that for the monograph on levonorgestrel tablets and that for sulfadoxine and pyrimethamine tablets adopted in October 2010, this approach had already been implemented and endorsed during the finalization of the monographs, prior to their publication on the WHO Medicines web site.\n\n## Related WHO Quality Assurance Guidelines\n\nAs noted during the review, an important issue was the existence of different thresholds applied in the WHO guidelines on FDCs and in *The International Pharmacopoeia*. After careful consideration of the possible options, the Expert Committee recommended that the WHO guidelines on FDCs, or any other WHO guidelines concerned, should be revised to bring them into line with *The International Pharmacopoeia*.\n\nThe Committee, therefore, endorsed the need for revising the following WHO guidelines referring to uniformity of content as a quality control test for finished pharmaceutical products:\n\n- **WHO Guidelines for registration of fixed-dose combination medicinal products**\n- **WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part.**\n\n### 3.3.3 General Monograph on Tablets\n\nThe general monograph on tablets was adopted by the Expert Committee in 2009 but was not included in the second supplement of *The International Pharmacopoeia* owing to the absence of some texts to be included in the Supplementary information.\n\nFollowing comments from the WHO Department of Neglected Tropical Diseases (NTD) and from assessors from the WHO Prequalification of Medicines Programme, changes to the general monograph on tablets were proposed. A survey on solid oral forms of albendazole, azithromycin, mebendazole, diethylcarbamazine, ivermectin and praziquantel, which was conducted in six WHO Member States showed that 41 samples out of 72 did not conform with *United States Pharmacopoeia* requirements for dissolution. In the majority of the cases of non-conformity the product was in chewable tablet form. The fact that such a high proportion of samples failed to meet dissolution rate requirements raised concerns about the efficacy of these NTD medicines.\n\nThe Expert Committee considered this issue and discussed possibilities for reviewing the existing monograph with a view to making appropriate changes. Several small changes to the document were made and it was agreed to include references in the monograph to the relevant sections of the Supplementary information. With regard to the monograph\u2019s definition of chewable tablets, it...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de Nivel Superior del Contexto\n\nEl documento es el informe de la 46\u00aa reuni\u00f3n del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Se discuten las directrices de calidad de la OMS, especialmente en relaci\u00f3n con las combinaciones de dosis fijas (FDC) y la monograf\u00eda general sobre tabletas. Se menciona la necesidad de alinear las directrices de la OMS con *The International Pharmacopoeia* y se abordan preocupaciones sobre la eficacia de ciertos medicamentos para enfermedades tropicales desatendidas, basadas en un estudio que mostr\u00f3 que una alta proporci\u00f3n de muestras de tabletas masticables no cumpl\u00eda con los requisitos de disoluci\u00f3n establecidos por la Farmacopea de los Estados Unidos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 cambios se propusieron para la monograf\u00eda general sobre tabletas y por qu\u00e9?**\n   - Se propusieron cambios a la monograf\u00eda general sobre tabletas debido a comentarios de la OMS sobre Enfermedades Tropicales Desatendidas y a los resultados de un estudio que mostr\u00f3 que 41 de 72 muestras de tabletas s\u00f3lidas no cumpl\u00edan con los requisitos de disoluci\u00f3n de la Farmacopea de los Estados Unidos, lo que gener\u00f3 preocupaciones sobre la eficacia de estos medicamentos.\n\n2. **\u00bfCu\u00e1les son las directrices de la OMS que se recomendaron para ser revisadas en relaci\u00f3n con la uniformidad de contenido?**\n   - Se recomend\u00f3 revisar las siguientes directrices de la OMS: las **Directrices para el registro de productos medicinales de combinaci\u00f3n de dosis fijas** y las **Directrices sobre la presentaci\u00f3n de documentaci\u00f3n para un producto farmac\u00e9utico terminado de m\u00faltiples fuentes (gen\u00e9rico): parte de calidad**.\n\n3. **\u00bfQu\u00e9 porcentaje de muestras de tabletas masticables no cumpli\u00f3 con los requisitos de disoluci\u00f3n y qu\u00e9 implicaciones tiene esto?**\n   - El 57% de las muestras (41 de 72) de tabletas s\u00f3lidas no cumpli\u00f3 con los requisitos de disoluci\u00f3n de la Farmacopea de los Estados Unidos, lo que plantea serias preocupaciones sobre la eficacia de los medicamentos utilizados para tratar enfermedades tropicales desatendidas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Revisi\u00f3n del M\u00e9todo de An\u00e1lisis 5.1:** Se realizaron mejoras editoriales en el m\u00e9todo de an\u00e1lisis 5.1, incluyendo la correcci\u00f3n de una omisi\u00f3n importante al establecer un umbral de 5 mg o menos para la aplicaci\u00f3n de pruebas, en lugar de solo referirse a un porcentaje del peso de la tableta.\n   \n2. **Uniformidad de Contenido en Tabletas y C\u00e1psulas:** Se adopt\u00f3 un enfoque que permite el uso del promedio de los resultados de uniformidad de contenido como opci\u00f3n bajo el Ensayo (M\u00e9todo B), manteniendo el Ensayo actual para una muestra mixta de 20 tabletas/c\u00e1psulas como M\u00e9todo A.\n\n3. **Revisiones de Monograf\u00edas:** Se acordaron revisiones para varias monograf\u00edas de tabletas y c\u00e1psulas, tanto para aquellas que contienen un solo API como para combinaciones de m\u00faltiples APIs.\n\n**Entidades:**\n- **Comit\u00e9 de Expertos de la OMS:** Organismo responsable de las recomendaciones sobre especificaciones para preparaciones farmac\u00e9uticas.\n- **M\u00e9todo de An\u00e1lisis 5.1:** M\u00e9todo espec\u00edfico que fue objeto de revisi\u00f3n y mejora.\n- **API (Ingrediente Activo):** Sustancia activa en las tabletas y c\u00e1psulas que se menciona en las monograf\u00edas.\n- **Monograf\u00edas Espec\u00edficas:** Documentos que describen las especificaciones de productos farmac\u00e9uticos, incluyendo:\n  - **Monograf\u00edas de un solo API:** Ejemplos incluyen tabletas de atropina (sulfato), prednisolona, y dexametasona.\n  - **Monograf\u00edas de m\u00faltiples APIs (FDCs):** Ejemplos incluyen tabletas de rifampicina, isoniazida, pirazinamida y etambutol hidrocloruro, as\u00ed como tabletas de sulfadoxina y pirimetamina. \n\nEste resumen destaca los cambios en los m\u00e9todos de an\u00e1lisis y las revisiones de las monograf\u00edas, reflejando el enfoque del Comit\u00e9 de Expertos de la OMS en mejorar la transparencia y la precisi\u00f3n en las especificaciones farmac\u00e9uticas.", "excerpt_keywords": "WHO, pharmaceutical preparations, fixed-dose combinations, quality assurance, dissolution requirements"}}, "08574bc6-2f93-456f-9dbd-0f63453993a1": {"node_ids": ["9d4c1dfc-36af-4032-8d5f-97068360188d"], "metadata": {"page_label": "38", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Preface, General Notices and Supplementary Information Sections of *The International Pharmacopoeia*\n\n## Supplementary Information Section\n\nIt was appreciated that the reason for including the Supplementary information section in *The International Pharmacopoeia* was to inform and guide users so as to facilitate the proper use and interpretation of the specifications. It was considered important that users could easily find the relevant guidance. It was agreed that, as this section of *The International Pharmacopoeia* was expanding (for example, guidance on Polymorphism and identity tests had been approved in October 2009), it would be advisable to provide a more structured approach to the contents.\n\nIt was recommended that the present texts, together with others agreed or proposed for inclusion under Supplementary information, be presented in a structured format with related texts being grouped together. Adoption of a numbering system similar to that used for Methods of analysis would provide a flexible structure that could accommodate new texts being added to the appropriate section. It was agreed that the structured format preliminarily discussed and presented to the Expert Committee was suitable and it was recommended that it be adopted for the next publication.\n\nIt was noted that the document included both existing texts and a number of suggestions as to possible future components of the different subsections of a restructured Supplementary information section. Existing texts could be incorporated into the structured format from the start and new components added as and when they were approved.\n\nIt was recognized that providing guidance on certain aspects of pharmacopoeial control, such as impurity control and dissolution testing, would be very helpful to users of *The International Pharmacopoeia*, especially in the context of the Prequalification Programme. It was also recognized that providing details of certain test methods used during pharmaceutical development and manufacture of dosage forms was necessary to support the revised general monograph for Tablets.\n\nIt was agreed that Supplementary information for those policy topics considered appropriate should be developed in a similar manner to that for the text.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl contexto se centra en la secci\u00f3n de Informaci\u00f3n Suplementaria de *The International Pharmacopoeia*, destacando la importancia de estructurar esta secci\u00f3n para facilitar la b\u00fasqueda y comprensi\u00f3n de las especificaciones. Se menciona la necesidad de agrupar textos relacionados y adoptar un sistema de numeraci\u00f3n similar al de los M\u00e9todos de an\u00e1lisis. Tambi\u00e9n se reconoce la utilidad de proporcionar orientaci\u00f3n sobre el control de impurezas y pruebas de disoluci\u00f3n, as\u00ed como detalles sobre m\u00e9todos de prueba utilizados en el desarrollo y fabricaci\u00f3n de formas de dosificaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1l es el prop\u00f3sito principal de incluir la secci\u00f3n de Informaci\u00f3n Suplementaria en *The International Pharmacopoeia*?**\n   - Respuesta: El prop\u00f3sito principal es informar y guiar a los usuarios para facilitar el uso y la interpretaci\u00f3n adecuada de las especificaciones.\n\n2. **\u00bfQu\u00e9 se recomend\u00f3 para mejorar la estructura de la secci\u00f3n de Informaci\u00f3n Suplementaria?**\n   - Respuesta: Se recomend\u00f3 presentar los textos en un formato estructurado, agrupando textos relacionados y adoptando un sistema de numeraci\u00f3n similar al de los M\u00e9todos de an\u00e1lisis para acomodar nuevos textos.\n\n3. **\u00bfQu\u00e9 aspectos espec\u00edficos del control farmacopoeico se consideraron \u00fatiles para los usuarios en el contexto del Programa de Precalificaci\u00f3n?**\n   - Respuesta: Se consider\u00f3 \u00fatil proporcionar orientaci\u00f3n sobre el control de impurezas y las pruebas de disoluci\u00f3n, as\u00ed como detalles sobre m\u00e9todos de prueba utilizados en el desarrollo y fabricaci\u00f3n de formas de dosificaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: Se trata de la 46\u00aa reuni\u00f3n del Comit\u00e9 de Expertos sobre Especificaciones para Preparaciones Farmac\u00e9uticas de la OMS.\n\n2. **Directrices de Calidad de la OMS**: Se discuten las directrices relacionadas con las combinaciones de dosis fijas (FDC) y la necesidad de alinearlas con *The International Pharmacopoeia*.\n\n3. **Revisi\u00f3n de Directrices**: Se recomienda la revisi\u00f3n de las siguientes directrices de la OMS:\n   - **Directrices para el registro de productos medicinales de combinaci\u00f3n de dosis fijas**.\n   - **Directrices sobre la presentaci\u00f3n de documentaci\u00f3n para un producto farmac\u00e9utico terminado de m\u00faltiples fuentes (gen\u00e9rico): parte de calidad**.\n\n4. **Monograf\u00eda General sobre Tabletas**: Adoptada en 2009, pero no incluida en el segundo suplemento de *The International Pharmacopoeia* debido a la falta de textos necesarios. Se proponen cambios tras comentarios de la OMS sobre Enfermedades Tropicales Desatendidas.\n\n5. **Estudio de Conformidad**: Un estudio realizado en seis Estados Miembros de la OMS revel\u00f3 que el 57% de las muestras de tabletas s\u00f3lidas (41 de 72) no cumpl\u00edan con los requisitos de disoluci\u00f3n de la Farmacopea de los Estados Unidos, lo que plantea preocupaciones sobre la eficacia de los medicamentos para enfermedades tropicales desatendidas.\n\n6. **Preocupaciones sobre Eficacia**: La alta tasa de no conformidad en las tabletas masticables genera inquietudes sobre la eficacia de los medicamentos utilizados para tratar enfermedades tropicales desatendidas.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organizaci\u00f3n responsable de la salud p\u00fablica internacional.\n- **FDC (Combinaciones de Dosis Fijas)**: Medicamentos que combinan dos o m\u00e1s principios activos en una sola forma de dosificaci\u00f3n.\n- **Farmacopea de los Estados Unidos**: Est\u00e1ndar de calidad para medicamentos en los Estados Unidos.\n- **Enfermedades Tropicales Desatendidas (NTD)**: Grupo de enfermedades que afectan a las poblaciones m\u00e1s vulnerables y que a menudo reciben poca atenci\u00f3n.", "excerpt_keywords": "Keywords: International Pharmacopoeia, Supplementary Information, pharmacopoeial control, impurity control, dissolution testing"}}, "cfb0675c-ea9a-4ecf-9cb6-0c956ce60dcb": {"node_ids": ["01e7a72b-f8b0-437a-a2c4-388fe92d62df"], "metadata": {"page_label": "39", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\non Polymorphism and identity tests adopted in 2009. Whenever a specific draft text was prepared, it would be circulated for comment to members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations, notably those involved in monograph development, discussed at an informal consultation and presented to the Expert Committee. It was noted that some supplementary information on monograph development could be compiled from material already available, notably on the WHO Medicines website and/or in reports of the Expert Committee.\n\nThe Expert Committee endorsed the recommendations and encouraged the secretariat to further develop relevant texts for consideration.\n\n## 4. Quality control \u2013 International Reference Materials (International Chemical Reference Substances and Infrared Reference Spectra)\n\n### 4.1 Update on International Chemical Reference Substances\n\nInternational Chemical Reference Substances (ICRS) are reference substances for use as primary standards in physical and chemical tests described in *The International Pharmacopoeia*. The standards are suitable for their intended use and officially adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations. In April 2010 the European Directorate for the Quality of Medicines and HealthCare (EDQM) of the Council of Europe, Strasbourg, France, took over the responsibility for the establishment, preparation, storage and distribution of WHO ICRS from Apoteket AB, previously the WHO Collaborating Centre for Chemical Reference Substances.\n\nSince the meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2010 the secretariat had invited national control laboratories to participate in collaborative studies to characterize ICRS. The invitation had received a positive response. In addition, the secretariat had established a database with information on all reference substances described in *The International Pharmacopoeia*. Furthermore, a document on frequently asked questions about collaborative trials to characterize ICRS had been prepared and circulated for comments.\n\nThe Expert Committee noted the report.\n\n#### 4.1.1 Report on activities of the host organization related to International Chemical Reference Substances\n\nThe Expert Committee received a report from EDQM on progress with regard to the ICRS. A new ICRS, alpha-artemether, would be established in October 2011, and the establishment of beclometasone dipropionate, replacement", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las actividades del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, con un enfoque en la adopci\u00f3n de pruebas de polimorfismo e identidad en 2009. Se menciona la importancia de los Sustancias de Referencia Qu\u00edmica Internacional (ICRS) como est\u00e1ndares primarios en pruebas f\u00edsicas y qu\u00edmicas, y se detalla la transici\u00f3n de la responsabilidad de la preparaci\u00f3n y distribuci\u00f3n de estos est\u00e1ndares al EDQM en 2010. Adem\u00e1s, se destaca la colaboraci\u00f3n con laboratorios de control nacionales para caracterizar los ICRS y la creaci\u00f3n de una base de datos sobre estas sustancias.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1l es el papel del EDQM en la gesti\u00f3n de los ICRS desde 2010?**\n   - El EDQM asumi\u00f3 la responsabilidad de la establecimiento, preparaci\u00f3n, almacenamiento y distribuci\u00f3n de los ICRS de la OMS, que anteriormente estaba a cargo de Apoteket AB.\n\n2. **\u00bfQu\u00e9 tipo de estudios se han invitado a participar a los laboratorios de control nacionales en relaci\u00f3n con los ICRS?**\n   - Se invit\u00f3 a los laboratorios de control nacionales a participar en estudios colaborativos para caracterizar los ICRS, lo cual recibi\u00f3 una respuesta positiva.\n\n3. **\u00bfQu\u00e9 nuevo ICRS se establecer\u00e1 en octubre de 2011 y qu\u00e9 otro ICRS se menciona en el contexto?**\n   - Se establecer\u00e1 un nuevo ICRS, alpha-artemether, en octubre de 2011, y se menciona la creaci\u00f3n de beclometasone dipropionate como un ICRS en desarrollo.\n\n### Resumen de Nivel Superior\n\nEl Comit\u00e9 de Expertos de la OMS se encarga de establecer y revisar est\u00e1ndares para preparaciones farmac\u00e9uticas, incluyendo pruebas de polimorfismo e identidad. Desde 2010, el EDQM gestiona los ICRS, colaborando con laboratorios nacionales para su caracterizaci\u00f3n y manteniendo una base de datos sobre estos est\u00e1ndares. Se est\u00e1n desarrollando nuevos ICRS para mejorar la calidad y la precisi\u00f3n en las pruebas farmac\u00e9uticas.", "prev_section_summary": "### Temas Clave\n\n1. **Prop\u00f3sito de la Informaci\u00f3n Suplementaria**: La secci\u00f3n de Informaci\u00f3n Suplementaria en *The International Pharmacopoeia* tiene como objetivo informar y guiar a los usuarios para facilitar la correcta utilizaci\u00f3n e interpretaci\u00f3n de las especificaciones.\n\n2. **Estructuraci\u00f3n de Contenidos**: Se recomienda adoptar un enfoque m\u00e1s estructurado para la secci\u00f3n, agrupando textos relacionados y utilizando un sistema de numeraci\u00f3n similar al de los M\u00e9todos de an\u00e1lisis, lo que permitir\u00eda una mejor organizaci\u00f3n y la incorporaci\u00f3n de nuevos textos.\n\n3. **Expansi\u00f3n de la Secci\u00f3n**: La secci\u00f3n est\u00e1 en expansi\u00f3n, con la inclusi\u00f3n de nuevos temas como la polimorf\u00eda y pruebas de identidad, lo que subraya la necesidad de un formato que pueda adaptarse a futuros contenidos.\n\n4. **Orientaci\u00f3n sobre Control Farmac\u00e9utico**: Se destaca la importancia de proporcionar orientaci\u00f3n sobre el control de impurezas y pruebas de disoluci\u00f3n, as\u00ed como detalles sobre m\u00e9todos de prueba utilizados en el desarrollo y fabricaci\u00f3n de formas de dosificaci\u00f3n, especialmente en el contexto del Programa de Precalificaci\u00f3n.\n\n5. **Desarrollo de Informaci\u00f3n Suplementaria**: Se acuerda que la informaci\u00f3n suplementaria sobre temas de pol\u00edtica debe desarrollarse de manera similar a la del texto principal.\n\n### Entidades\n\n- ***The International Pharmacopoeia***: Documento que contiene especificaciones y gu\u00edas para el uso de productos farmac\u00e9uticos.\n- **Secci\u00f3n de Informaci\u00f3n Suplementaria**: Parte del documento dedicada a proporcionar orientaci\u00f3n adicional a los usuarios.\n- **M\u00e9todos de an\u00e1lisis**: Sistema de numeraci\u00f3n y organizaci\u00f3n que se propone adoptar para la secci\u00f3n de Informaci\u00f3n Suplementaria.\n- **Programa de Precalificaci\u00f3n**: Iniciativa que busca asegurar la calidad de los productos farmac\u00e9uticos en el contexto de la salud p\u00fablica.\n- **Polimorfismo y pruebas de identidad**: Ejemplos de temas que se han incluido en la secci\u00f3n de Informaci\u00f3n Suplementaria. \n\nEste resumen destaca la importancia de la estructura y la orientaci\u00f3n en el uso de *The International Pharmacopoeia*, as\u00ed como la necesidad de adaptarse a las nuevas demandas y temas relevantes en el campo farmac\u00e9utico.", "excerpt_keywords": "WHO, International Chemical Reference Substances, quality control, pharmacopoeia, EDQM"}}, "06b7d832-e90d-4a77-a0e3-ffd134b4649b": {"node_ids": ["e5768383-922d-40a6-8c02-906d1be338b6"], "metadata": {"page_label": "40", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nbatch, was under way. The internal study for a further ICRS, azobenzene, replacement batch, had been completed and a collaborative study was due to begin in October 2011.\n\nWhile not within the scope of the WHO\u2013EDQM cooperation agreement, the EDQM laboratory had exceptionally performed a study to support the development of *The International Pharmacopoeia* monograph for artemisinin. The study subjects were the correction/response factor artemisinin and the verification of a liquid chromatography (LC) method.\n\nIt was reported that the ICRS database included 215 ICRS. They had been ranked according to their demand and this ranking was being used to assign priority in monitoring. A monitoring programme had been established and was currently monitoring 23 ICRS. Of the 15 monitored to date, no deficiencies had been detected. In terms of quality control, eight batches have been subjected to quality control for identification.\n\nThe Expert Committee noted the report.\n\n## 4.1.2 Frequently asked questions about collaborative trials\n\nReference standards to be used for assay determinations are examined in collaborative trials. The results obtained are used to assign a content or other analytical values to the standards. WHO had invited national quality control laboratories to join in trials to characterize ICRS, and a document that had been prepared to inform candidates about these studies was presented to the Expert Committee for information.\n\nThe overall goal of this project was to establish a worldwide distribution of ICRS to assist low- and middle-income countries to test for the quality of essential medicines described in *The International Pharmacopoeia* and used, for example, in the treatment of HIV/AIDS, tuberculosis and malaria. The Expert Committee noted the document.\n\n## 4.1.3 Annual report on International Chemical Reference Substances 2010\n\nBased on an umbrella agreement signed between WHO and EDQM in March 2010, and after having received the physical stock of existing ICRS from Apoteket, EDQM restarted the distribution of ICRS in May 2010.\n\nCoordination meetings between WHO and EDQM took place in April and September 2010 to agree upon the details of the ICRS establishment workflow and to prioritize the work for the establishment of new ICRS.\n\nIn 2010 the total number of ICRS distributed by EDQM was 957. The five most frequently requested substances were, in order of demand: artesunate, vanillin, arteminol, artemether and lumefantrine.\n\nThe Expert Committee noted the report and thanked EDQM for its contribution and work in support of WHO Member States.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las actividades del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, destacando el trabajo relacionado con las Sustancias de Referencia Qu\u00edmica Internacional (ICRS). Se menciona la colaboraci\u00f3n entre la OMS y el EDQM, la distribuci\u00f3n de ICRS, y la importancia de estas sustancias para garantizar la calidad de medicamentos esenciales en pa\u00edses de ingresos bajos y medios. Tambi\u00e9n se discuten los ensayos colaborativos para caracterizar ICRS y se presenta un informe anual sobre la distribuci\u00f3n de estas sustancias.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1l fue el objetivo principal del proyecto mencionado en el contexto sobre la distribuci\u00f3n de ICRS?**\n   - El objetivo principal del proyecto fue establecer una distribuci\u00f3n mundial de ICRS para ayudar a los pa\u00edses de ingresos bajos y medios a evaluar la calidad de los medicamentos esenciales descritos en *The International Pharmacopoeia*, utilizados en el tratamiento de enfermedades como el VIH/SIDA, la tuberculosis y la malaria.\n\n2. **\u00bfCu\u00e1ntas ICRS fueron distribuidas por el EDQM en 2010 y cu\u00e1les fueron las cinco sustancias m\u00e1s solicitadas?**\n   - En 2010, el EDQM distribuy\u00f3 un total de 957 ICRS. Las cinco sustancias m\u00e1s solicitadas, en orden de demanda, fueron: artesunate, vanillin, arteminol, artemether y lumefantrine.\n\n3. **\u00bfQu\u00e9 se inform\u00f3 sobre el estado de las ICRS monitoreadas hasta la fecha del informe?**\n   - Se inform\u00f3 que de las 15 ICRS monitoreadas hasta la fecha, no se hab\u00edan detectado deficiencias. Adem\u00e1s, se hab\u00eda establecido un programa de monitoreo que actualmente supervisa 23 ICRS, y ocho lotes hab\u00edan sido sometidos a control de calidad para identificaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: Se encarga de establecer y revisar est\u00e1ndares para preparaciones farmac\u00e9uticas, incluyendo pruebas de polimorfismo e identidad adoptadas en 2009.\n\n2. **Sustancias de Referencia Qu\u00edmica Internacional (ICRS)**: Son sustancias de referencia utilizadas como est\u00e1ndares primarios en pruebas f\u00edsicas y qu\u00edmicas, oficialmente adoptadas por el Comit\u00e9 de Expertos de la OMS.\n\n3. **European Directorate for the Quality of Medicines and HealthCare (EDQM)**: Desde abril de 2010, el EDQM asumi\u00f3 la responsabilidad de la establecimiento, preparaci\u00f3n, almacenamiento y distribuci\u00f3n de los ICRS, anteriormente gestionados por Apoteket AB.\n\n4. **Colaboraci\u00f3n con Laboratorios Nacionales**: Se han invitado a laboratorios de control nacionales a participar en estudios colaborativos para caracterizar los ICRS, lo que ha recibido una respuesta positiva.\n\n5. **Base de Datos de ICRS**: Se ha establecido una base de datos con informaci\u00f3n sobre todas las sustancias de referencia descritas en *The International Pharmacopoeia*.\n\n6. **Nuevos ICRS**: Se anunci\u00f3 la creaci\u00f3n de un nuevo ICRS, alpha-artemether, en octubre de 2011, y se menciona el desarrollo de beclometasone dipropionate como otro ICRS en proceso.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**\n- **EDQM (Direcci\u00f3n Europea de Calidad de Medicamentos y Atenci\u00f3n Sanitaria)**\n- **Apoteket AB** (anteriormente colaborador de la OMS en sustancias de referencia qu\u00edmica) \n\nEste resumen destaca la importancia de los ICRS en el control de calidad de las preparaciones farmac\u00e9uticas y la colaboraci\u00f3n internacional para su desarrollo y caracterizaci\u00f3n.", "excerpt_keywords": "Keywords: ICRS, WHO, EDQM, pharmaceutical preparations, quality control"}}, "0eb6e449-2c27-4c1b-b3e1-9386f26fc2c7": {"node_ids": ["d517bbcd-8035-43f5-ac95-1e7ca4c0035b"], "metadata": {"page_label": "41", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 4.1.4 Lumefantrine for system suitability testing\n\nThe report of the EDQM on Lumefantrine for system suitability testing, the first ICRS to be developed by EDQM, was submitted to the Expert Committee. This substance was adopted by the Expert Committee as an International Chemical Reference Substance.\n\n# 4.1.5 Bacterial endotoxin\n\nA request to develop a replacement for the existing standard on bacterial endotoxin had been submitted to the Expert Committee by the WHO team for Quality, Safety and Standards.\n\nBased on earlier agreement that the only reliable approach to maintaining harmonization of the endotoxin unit for pyrogen testing is the establishment of a shared, harmonized reference material, the establishment of a new material becomes necessary once one of the regional stocks is nearing depletion. This was the case for the EDQM material, necessitating the establishment of a new joint material. It was, therefore, proposed to establish the 3rd International Standard for bacterial endotoxin through an international collaborative study.\n\nSince *The International Pharmacopoeia* includes the general test using this standard the Expert Committee considered that it would be important to maintain the continuity of the International Standard. The proposal was consequently endorsed by the Expert Committee.\n\n# 5. Quality control \u2013 national laboratories\n\n## 5.1 External Quality Assurance Assessment Scheme\n\nThe External Quality Assurance Assessment Scheme (EQAAS) is a programme for the external evaluation of quality control management systems in chemical control laboratories. It uses inter-laboratory comparisons to determine the performance of participating laboratories in carrying out specific tests or measurements. The Scheme supplements laboratories\u2019 internal quality assurance procedures by providing an external measure for their testing capabilities.\n\nAnalytical laboratories are required by the WHO good practices for pharmaceutical quality control laboratories and by other regulations, such as ISO/IEC 17025, to participate in proficiency tests. WHO regularly organizes proficiency studies using physicochemical methods described in *The International Pharmacopoeia* (including methods used in pharmaceutical technology such as dissolution testing).\n\nUp to 60 quality control laboratories from all six WHO regions usually participate in this Scheme.\n\n----\n\n*ISO/IEC 17025:2005. General requirements for the competence of testing and calibration laboratories. Geneva, International Organization for Standardization, 2005.*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS detalla el desarrollo de sustancias de referencia qu\u00edmica internacional, como la Lumefantrine, y la necesidad de establecer un nuevo est\u00e1ndar internacional para endotoxinas bacterianas debido al agotamiento de materiales existentes. Adem\u00e1s, se describe el esquema de evaluaci\u00f3n externa de calidad (EQAAS) que permite la comparaci\u00f3n interlaboratorios para asegurar la calidad en los laboratorios de control qu\u00edmico, en cumplimiento con las buenas pr\u00e1cticas y regulaciones internacionales.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1l fue la raz\u00f3n para desarrollar un nuevo est\u00e1ndar internacional para endotoxinas bacterianas?**\n   - La raz\u00f3n para desarrollar un nuevo est\u00e1ndar internacional para endotoxinas bacterianas fue el agotamiento de los materiales existentes en los stocks regionales, lo que hizo necesario establecer un nuevo material conjunto para mantener la armonizaci\u00f3n de la unidad de endotoxinas para pruebas de pirogenos.\n\n2. **\u00bfQu\u00e9 papel desempe\u00f1a la Lumefantrine en el contexto de las sustancias de referencia qu\u00edmica internacional?**\n   - La Lumefantrine fue adoptada como una Sustancia de Referencia Qu\u00edmica Internacional (ICRS) por el Comit\u00e9 de Expertos de la OMS, tras la presentaci\u00f3n de un informe del EDQM sobre su uso para pruebas de idoneidad del sistema.\n\n3. **\u00bfC\u00f3mo contribuye el Esquema de Evaluaci\u00f3n Externa de Calidad (EQAAS) a la gesti\u00f3n de calidad en laboratorios de control qu\u00edmico?**\n   - El EQAAS contribuye a la gesti\u00f3n de calidad en laboratorios de control qu\u00edmico mediante la evaluaci\u00f3n externa de los sistemas de gesti\u00f3n de calidad, utilizando comparaciones interlaboratorios para determinar el rendimiento en pruebas espec\u00edficas, lo que complementa los procedimientos internos de aseguramiento de calidad de los laboratorios.", "prev_section_summary": "### Temas Clave\n\n1. **Colaboraci\u00f3n OMS-EDQM**: Se destaca la cooperaci\u00f3n entre la Organizaci\u00f3n Mundial de la Salud (OMS) y el European Directorate for the Quality of Medicines & HealthCare (EDQM) para el desarrollo y distribuci\u00f3n de Sustancias de Referencia Qu\u00edmica Internacional (ICRS).\n\n2. **Distribuci\u00f3n de ICRS**: En 2010, el EDQM distribuy\u00f3 un total de 957 ICRS, con un enfoque en ayudar a pa\u00edses de ingresos bajos y medios a evaluar la calidad de medicamentos esenciales.\n\n3. **Monitoreo y Control de Calidad**: Se estableci\u00f3 un programa de monitoreo para 23 ICRS, y de las 15 ICRS monitoreadas hasta la fecha, no se detectaron deficiencias. Ocho lotes fueron sometidos a control de calidad para identificaci\u00f3n.\n\n4. **Ensayos Colaborativos**: Se llevaron a cabo ensayos colaborativos para caracterizar ICRS, invitando a laboratorios nacionales de control de calidad a participar.\n\n5. **Sustancias M\u00e1s Solicitadas**: Las cinco sustancias m\u00e1s solicitadas en 2010 fueron artesunate, vanillin, arteminol, artemether y lumefantrine.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Agencia de la ONU responsable de la salud p\u00fablica internacional.\n- **European Directorate for the Quality of Medicines & HealthCare (EDQM)**: Organizaci\u00f3n que establece est\u00e1ndares de calidad para medicamentos en Europa.\n- **Sustancias de Referencia Qu\u00edmica Internacional (ICRS)**: Sustancias utilizadas como est\u00e1ndares en ensayos de calidad de medicamentos.\n- **Medicamentos Esenciales**: Medicamentos que satisfacen las necesidades de salud de la poblaci\u00f3n y son de costo accesible.\n- **Enfermedades Tratadas**: VIH/SIDA, tuberculosis y malaria, que son foco de atenci\u00f3n en la distribuci\u00f3n de ICRS.", "excerpt_keywords": "Keywords: Lumefantrine, bacterial endotoxin, International Chemical Reference Substance, quality control, External Quality Assurance Assessment Scheme"}}, "843766f4-943b-4205-b43e-438b1bf94d63": {"node_ids": ["e9ded452-e4ce-43ab-8f20-ae76617576cc"], "metadata": {"page_label": "42", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nSo far, EQAAS offers proficiency tests which enable participating laboratories to demonstrate their competence by analysing a common test sample. Results are evaluated and participants are judged according to their individual deviation from the true value.\n\nExamples of three tests were described \u2013 namely on the water content of amodiaquine hydrochloride by Karl Fischer titration, dissolution tests of artemether and lumefantrine tablets, and assessment of the density and pH measurement of abacavir oral solution (still in progress at the time of the meeting). Three further tests are scheduled to take place in 2012 including an assay by HPLC of amodiaquine and artesunate tablets, a dissolution test of rifampicin capsules, and assay by titration of chloroquine sulfate oral suspension.\n\nThe Expert Committee raised concerns about the results of some studies which showed considerable variability between laboratories and indicated the need for training in some laboratories.\n\nIt was proposed to extend EQAAS in the future and to encourage participants not only to analyse a common test sample but also, if appropriate, to include commercial medicines drawn from their regional or national markets in the study. Participating laboratories would be given the necessary information to enable them to perform a proficiency test and a market surveillance study concurrently. The plan would be for study participants to receive in advance the protocols and all other details so that they would also be able to collect medicines with a similar composition from their local or regional markets. All samples \u2013 the market surveillance samples as well as the proficiency sample(s) \u2013 would be analysed in one series under repeatable conditions.\n\nDuring the consultation on specifications for medicines and quality control laboratory issues in July 2011, national control laboratories expressed appreciation of the proposal to extend the programme.\n\nMembers of the Expert Committee noted that the extension of the Scheme could bring certain advantages, namely that:\n\n- WHO could assist national authorities to identify and monitor products of low quality;\n- WHO would learn more about the global applicability of methods of *The International Pharmacopoeia* and study results might support revision of relevant monographs and/or general chapters and methods;\n- participants could more easily and confidently verify that the performance of the method applied is suitable by referring to their test result for the common sample (provided that it is satisfactory).\n\nThe Expert Committee approved the proposed extension of the scheme. It was pointed out that the studies for the extended scheme should be selected with care.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en el programa de Evaluaci\u00f3n de la Calidad de los Laboratorios (EQAAS) de la OMS, que ofrece pruebas de competencia para laboratorios mediante el an\u00e1lisis de muestras de prueba comunes. Se describen ejemplos de pruebas realizadas y se expresan preocupaciones sobre la variabilidad de los resultados entre laboratorios, lo que indica la necesidad de capacitaci\u00f3n. Se propone extender el programa para incluir medicamentos comerciales de mercados regionales o nacionales, lo que permitir\u00eda a los laboratorios realizar pruebas de competencia y estudios de vigilancia del mercado simult\u00e1neamente. La extensi\u00f3n del programa podr\u00eda ayudar a identificar productos de baja calidad y mejorar la aplicabilidad de los m\u00e9todos de la Farmacopea Internacional.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los beneficios espec\u00edficos que se esperan al incluir medicamentos comerciales en el programa EQAAS?**\n   - Se espera que la inclusi\u00f3n de medicamentos comerciales permita a los laboratorios realizar pruebas de competencia y estudios de vigilancia del mercado simult\u00e1neamente, lo que facilitar\u00eda la identificaci\u00f3n de productos de baja calidad y mejorar\u00eda la confianza en los m\u00e9todos de an\u00e1lisis aplicados.\n\n2. **\u00bfQu\u00e9 tipo de pruebas se llevaron a cabo en el marco del programa EQAAS y cu\u00e1les est\u00e1n programadas para el futuro?**\n   - Se realizaron pruebas sobre el contenido de agua de la amodiaquina clorhidrato, pruebas de disoluci\u00f3n de tabletas de artemeter y lumefantrina, y mediciones de densidad y pH de la soluci\u00f3n oral de abacavir. Para el futuro, se programaron pruebas de HPLC de tabletas de amodiaquina y artesunato, una prueba de disoluci\u00f3n de c\u00e1psulas de rifampicina y un ensayo por titulaci\u00f3n de suspensi\u00f3n oral de cloroquina.\n\n3. **\u00bfQu\u00e9 preocupaciones se expresaron sobre la variabilidad de los resultados entre laboratorios y c\u00f3mo se planea abordar este problema?**\n   - Se expresaron preocupaciones sobre la considerable variabilidad de los resultados entre laboratorios, lo que indica la necesidad de capacitaci\u00f3n en algunos de ellos. Se planea abordar este problema mediante la extensi\u00f3n del programa EQAAS y la provisi\u00f3n de informaci\u00f3n y protocolos adecuados a los laboratorios participantes para mejorar su competencia y resultados.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Lumefantrine**:\n   - Adoptada como Sustancia de Referencia Qu\u00edmica Internacional (ICRS) por el Comit\u00e9 de Expertos de la OMS.\n   - Utilizada para pruebas de idoneidad del sistema.\n\n2. **Endotoxinas Bacterianas**:\n   - Se solicit\u00f3 el desarrollo de un nuevo est\u00e1ndar internacional debido al agotamiento de los materiales existentes.\n   - Se propuso establecer el 3er Est\u00e1ndar Internacional para endotoxinas bacterianas a trav\u00e9s de un estudio colaborativo internacional.\n   - Importancia de mantener la continuidad del Est\u00e1ndar Internacional en *The International Pharmacopoeia*.\n\n3. **Esquema de Evaluaci\u00f3n Externa de Calidad (EQAAS)**:\n   - Programa para la evaluaci\u00f3n externa de sistemas de gesti\u00f3n de calidad en laboratorios de control qu\u00edmico.\n   - Utiliza comparaciones interlaboratorios para evaluar el rendimiento en pruebas espec\u00edficas.\n   - Complementa los procedimientos internos de aseguramiento de calidad.\n   - Participaci\u00f3n de hasta 60 laboratorios de control de calidad de todas las regiones de la OMS.\n\n4. **Regulaciones y Normativas**:\n   - Cumplimiento con las buenas pr\u00e1cticas de la OMS para laboratorios de control de calidad farmac\u00e9utica.\n   - Referencia a la norma ISO/IEC 17025:2005, que establece requisitos generales para la competencia de laboratorios de ensayo y calibraci\u00f3n.\n\n### Entidades:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo que supervisa y regula los est\u00e1ndares de calidad y seguridad.\n- **EDQM (European Directorate for the Quality of Medicines)**: Entidad que report\u00f3 sobre Lumefantrine y cuyo material de endotoxinas estaba cerca de agotarse.\n- **Comit\u00e9 de Expertos**: Grupo que adopta y respalda las propuestas relacionadas con sustancias de referencia y est\u00e1ndares internacionales.", "excerpt_keywords": "Keywords: EQAAS, pharmaceutical quality, proficiency tests, WHO, laboratory training"}}, "a9559d59-2d70-48b6-a129-2e0e28c2fd62": {"node_ids": ["af3e0057-2f17-4d76-a591-3ddf77b5d92a"], "metadata": {"page_label": "43", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 6. Quality assurance \u2013 good manufacturing practices\n\n## 6.1 WHO good manufacturing practices: water for pharmaceutical use\n\nA draft document on water for pharmaceutical use was presented to the Expert Committee for discussion. The document was intended to supplement the general guidelines on good manufacturing practices (GMP) for pharmaceutical products published by WHO in 2003. The text of the document presented was discussed by the Expert Committee in 2009 when the Committee was requested to bring the document into line with pharmaceutical water systems. The revision had been under way since and all comments received had been discussed at informal consultations. The Expert Committee reviewed the document together with the major comments received during the latest circulation phase.\n\nThe Expert Committee adopted the document subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 2).\n\n# 7. Quality assurance \u2013 new approaches\n\n## 7.1 WHO guidelines on quality risk management\n\nIt was reported that a restructured text of the quality risk management document, incorporating all changes proposed during consultations and discussions to date, was in preparation and would be sent to members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations, and would go through the usual wide circulation process in due course. This new guidance is intended to replace the current WHO guidelines on hazard analysis and critical control points to cover new trends. The Expert Committee agreed to defer its discussion of this topic until the most recent version of the document was available.\n\n# 8. Quality assurance \u2013 distribution and trade of pharmaceuticals\n\n## 8.1 WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce\n\nThe WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce is a voluntary agreement between WHO Member States. Dating from 1969 the Scheme has attracted both controversy and support and there have been many discussions about its value. In 2008 the Expert Committee asked for the Scheme to be reviewed in light of the changing situation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Pr\u00e1cticas de fabricaci\u00f3n y agua farmac\u00e9utica**: Se present\u00f3 un documento en borrador sobre el uso de agua en la fabricaci\u00f3n farmac\u00e9utica, destinado a complementar las directrices generales de buenas pr\u00e1cticas de fabricaci\u00f3n (GMP) publicadas por la OMS en 2003. Este documento fue revisado por el Comit\u00e9 de Expertos, que adopt\u00f3 el texto con cambios acordados tras discusiones y comentarios.\n\n2. **Gesti\u00f3n de riesgos de calidad**: Se est\u00e1 preparando un texto reestructurado sobre gesti\u00f3n de riesgos de calidad que reemplazar\u00e1 las directrices actuales de la OMS sobre an\u00e1lisis de peligros y puntos cr\u00edticos de control. Este nuevo enfoque busca adaptarse a las tendencias actuales y se discutir\u00e1 una vez que est\u00e9 disponible la versi\u00f3n m\u00e1s reciente.\n\n3. **Esquema de certificaci\u00f3n de productos farmac\u00e9uticos**: El Esquema de Certificaci\u00f3n de la OMS sobre la calidad de productos farmac\u00e9uticos en comercio internacional es un acuerdo voluntario entre los Estados Miembros de la OMS, que ha sido objeto de controversia y apoyo desde su creaci\u00f3n en 1969. En 2008, se solicit\u00f3 una revisi\u00f3n del esquema debido a la evoluci\u00f3n de la situaci\u00f3n.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los principales cambios que se discutieron y se acordaron en el documento sobre el uso de agua para productos farmac\u00e9uticos?**\n   - Esta pregunta busca detalles sobre las modificaciones espec\u00edficas que se realizaron en el documento, que no se encuentran en las directrices generales de GMP.\n\n2. **\u00bfQu\u00e9 tendencias actuales se est\u00e1n considerando en la nueva gu\u00eda de gesti\u00f3n de riesgos de calidad que reemplazar\u00e1 las directrices sobre an\u00e1lisis de peligros?**\n   - Esta pregunta se centra en las nuevas tendencias que est\u00e1n influyendo en la reestructuraci\u00f3n de las directrices de gesti\u00f3n de riesgos, lo que puede no estar documentado en otras fuentes.\n\n3. **\u00bfCu\u00e1les son las principales controversias y apoyos que ha recibido el Esquema de Certificaci\u00f3n de la OMS desde su creaci\u00f3n en 1969?**\n   - Esta pregunta busca informaci\u00f3n sobre las discusiones y debates espec\u00edficos que han rodeado al esquema de certificaci\u00f3n, proporcionando un contexto hist\u00f3rico que puede no estar disponible en otros documentos.", "prev_section_summary": "### Temas Clave\n\n1. **Programa EQAAS**: El programa de Evaluaci\u00f3n de la Calidad de los Laboratorios (EQAAS) de la OMS ofrece pruebas de competencia para laboratorios mediante el an\u00e1lisis de muestras de prueba comunes.\n\n2. **Pruebas Realizadas y Futuras**: Se han realizado pruebas sobre el contenido de agua de amodiaquina clorhidrato, disoluci\u00f3n de tabletas de artemeter y lumefantrina, y mediciones de densidad y pH de la soluci\u00f3n oral de abacavir. Se programaron pruebas adicionales para 2012, incluyendo ensayos de HPLC y disoluci\u00f3n de otros medicamentos.\n\n3. **Variabilidad de Resultados**: Se expresaron preocupaciones sobre la considerable variabilidad de los resultados entre laboratorios, lo que indica la necesidad de capacitaci\u00f3n.\n\n4. **Propuesta de Extensi\u00f3n del Programa**: Se propone extender EQAAS para incluir medicamentos comerciales de mercados regionales o nacionales, permitiendo a los laboratorios realizar pruebas de competencia y estudios de vigilancia del mercado simult\u00e1neamente.\n\n5. **Beneficios de la Extensi\u00f3n**: La extensi\u00f3n del programa podr\u00eda ayudar a identificar productos de baja calidad, mejorar la aplicabilidad de los m\u00e9todos de la Farmacopea Internacional y aumentar la confianza en los resultados de las pruebas.\n\n### Entidades\n\n- **EQAAS**: Evaluaci\u00f3n de la Calidad de los Laboratorios.\n- **OMS**: Organizaci\u00f3n Mundial de la Salud.\n- **Amodiaquina clorhidrato**: Medicamento analizado en las pruebas.\n- **Artemeter y lumefantrina**: Medicamentos cuyas tabletas fueron sometidas a pruebas de disoluci\u00f3n.\n- **Abacavir**: Soluci\u00f3n oral cuya densidad y pH fueron evaluados.\n- **HPLC**: Cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n, m\u00e9todo utilizado en las pruebas programadas.\n- **Chloroquine sulfate**: Suspensi\u00f3n oral que ser\u00e1 analizada por titulaci\u00f3n.\n- **Farmacopea Internacional**: Referencia para los m\u00e9todos de an\u00e1lisis utilizados en el programa.", "excerpt_keywords": "Keywords: quality assurance, good manufacturing practices, pharmaceutical water, risk management, certification scheme"}}, "0cfcd139-22f1-468e-9743-d84edc7889c5": {"node_ids": ["05e81e71-019d-450d-a698-58d5438572e3"], "metadata": {"page_label": "44", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nTwo question and answer documents on the Scheme had been prepared by the secretariat and approved by the Expert Committee for publication on the WHO Medicines web site. Moreover, in 2010, a circular letter was prepared asking Member States to comment on the recommendations included in the report of the previous Expert Committee and to submit comments and suggestions about the Scheme. Only 12 responses out of 194 Member States were received, examples of which were presented to the Committee. The conclusion was drawn that in spite of some limitations, Member States acknowledged the value of the WHO Certification Scheme.\n\nIn 2003 the Expert Committee proposed an extension of the Scheme to include starting materials in addition to finished products, and Poland joined this extended scheme. The WHO Medicines web site will in future have a special section dedicated to the Scheme, anticipating that more countries would join.\n\nThe Expert Committee noted the report and stressed the importance of the WHO Certification Scheme for APIs and requested follow-up to make sure that appropriate staff received the communication.\n\n## 8.2 Update on Joint FIP/WHO guidelines on good pharmacy practice: standards for quality of pharmacy services\n\nThe Expert Committee was informed that the good pharmacy practices (GPP) adopted during its forty-fifth meeting had received much attention and had been translated into several languages. It was an important topic on the agenda of the ninety-ninth International Pharmaceutical Federation (FIP) meeting in 2011. The GPP text was endorsed by the FIP Council meeting for implementation by the national pharmaceutical associations of FIP.\n\nThe Expert Committee took note of this news.\n\n# 9. Prequalification of priority essential medicines including active pharmaceutical ingredients\n\n## 9.1 Update on the Prequalification of Medicines Programme managed by WHO\n\nThe Acting Manager of the WHO Prequalification of Medicines Programme reported that, since the 2010 meeting of the Expert Committee, 35 products had been prequalified. These included the new tenofovir/lamivudine + nevirapine combination; amikacin injection; a generic reproductive health product (ethinylestradiol/levonorgestrel); and an artesunate powder for injection. The Programme had also initiated prequalification of APIs during the year and had already prequalified five APIs. The Prequalification Programme had also begun assisting in an external review for the United Nations Population Fund.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en las actividades y actualizaciones del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Se discuten varios temas, incluyendo la importancia del Esquema de Certificaci\u00f3n de la OMS para Ingredientes Farmac\u00e9uticos Activos (APIs), la actualizaci\u00f3n sobre las Buenas Pr\u00e1cticas Farmac\u00e9uticas (GPP) y el Programa de Precalificaci\u00f3n de Medicamentos de la OMS. Se menciona que, a pesar de recibir solo 12 respuestas de 194 Estados Miembros sobre el Esquema de Certificaci\u00f3n, se reconoce su valor. Adem\u00e1s, se informa sobre la precalificaci\u00f3n de 35 productos y 5 APIs desde la \u00faltima reuni\u00f3n del Comit\u00e9 en 2010.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 acciones se tomaron en 2010 para fomentar la participaci\u00f3n de los Estados Miembros en el Esquema de Certificaci\u00f3n de la OMS?**\n   - En 2010, se prepar\u00f3 una carta circular solicitando a los Estados Miembros que comentaran sobre las recomendaciones del informe del Comit\u00e9 anterior y que enviaran comentarios y sugerencias sobre el Esquema.\n\n2. **\u00bfCu\u00e1ntos productos y APIs fueron precalificados por el Programa de Precalificaci\u00f3n de Medicamentos de la OMS desde la reuni\u00f3n de 2010 del Comit\u00e9 de Expertos?**\n   - Desde la reuni\u00f3n de 2010, se precalificaron 35 productos y 5 APIs.\n\n3. **\u00bfCu\u00e1l fue la respuesta del Comit\u00e9 de Expertos respecto a la importancia del Esquema de Certificaci\u00f3n para los APIs?**\n   - El Comit\u00e9 de Expertos destac\u00f3 la importancia del Esquema de Certificaci\u00f3n de la OMS para los APIs y solicit\u00f3 un seguimiento para asegurar que el personal adecuado recibiera la comunicaci\u00f3n relacionada.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Buenas Pr\u00e1cticas de Fabricaci\u00f3n (GMP)**:\n   - Se present\u00f3 un documento en borrador sobre el uso de agua para productos farmac\u00e9uticos, destinado a complementar las directrices de GMP publicadas por la OMS en 2003.\n   - El Comit\u00e9 de Expertos revis\u00f3 y adopt\u00f3 el documento con cambios acordados tras discusiones y comentarios.\n\n2. **Gesti\u00f3n de Riesgos de Calidad**:\n   - Se est\u00e1 preparando un texto reestructurado sobre gesti\u00f3n de riesgos de calidad que reemplazar\u00e1 las directrices actuales sobre an\u00e1lisis de peligros y puntos cr\u00edticos de control.\n   - Este nuevo enfoque busca adaptarse a tendencias actuales y se discutir\u00e1 una vez que est\u00e9 disponible la versi\u00f3n m\u00e1s reciente.\n\n3. **Esquema de Certificaci\u00f3n de Productos Farmac\u00e9uticos**:\n   - El Esquema de Certificaci\u00f3n de la OMS es un acuerdo voluntario entre Estados Miembros, creado en 1969, que ha generado tanto controversia como apoyo.\n   - En 2008, se solicit\u00f3 una revisi\u00f3n del esquema debido a cambios en el contexto internacional.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la publicaci\u00f3n de las directrices y documentos discutidos.\n- **Comit\u00e9 de Expertos**: Grupo encargado de revisar y adoptar los documentos relacionados con las buenas pr\u00e1cticas de fabricaci\u00f3n y gesti\u00f3n de riesgos.\n- **Estados Miembros de la OMS**: Participantes en el Esquema de Certificaci\u00f3n y sujetos a las directrices de la OMS.", "excerpt_keywords": "Keywords: WHO, Certification Scheme, Prequalification, Active Pharmaceutical Ingredients, Good Pharmacy Practice"}}, "195ab8b7-4578-46d1-b960-0763bc2c5c9a": {"node_ids": ["cbd5024c-55c4-4c27-8130-5341087d03b5"], "metadata": {"page_label": "45", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nof reproductive health products. The Programme had continued to work closely with the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria.\n\nThe number of applications for products to be prequalified in 2011 was 54 (as at 10 October 2011), and of these 35 had been accepted. Twenty-one applications for APIs had been received, two of which had been prequalified and 19 were under assessment. As for the prequalification of control laboratories, five laboratories had been prequalified since October 2010. There are now six prequalified control laboratories in all WHO regions.\n\nIn addition, a retrospective study of generic product dossiers had been conducted. The results showed a number of deficiencies and indicated the need for capacity building for a number of manufacturers of generic products. An external assessment of the WHO Prequalification of Medicines Programme had been conducted and the results were generally positive.\n\nTraining in capacity building for NMRAs was increasing. In 2010 the WHO Prequalification of Medicines Programme organized 16 workshops and was involved in a further five. In 2011 the Programme organized 10 workshops and was involved in a further seven. However, the challenge was to ensure that training was translated into improved implementation of the best practices.\n\nPrequalification is highly dependent on the support from national regulators who are assisting WHO in this programme.\n\nIt was reported that donor funds were declining and that technical expertise was increasingly difficult to obtain. As in many other areas, the WHO Prequalification of Medicines Programme had been trying to do more with less funds.\n\nThe Expert Committee considered that the presentation had highlighted the importance of the WHO Prequalification of Medicines Programme, which was having an influence in a number of areas, such as strengthening capacity at local level and making medicines accessible to those who need them most.\n\n## 10. Prequalification of quality control laboratories\n\n### 10.1 Update on the prequalification of quality control laboratories\n\nThe prequalification procedure for quality control laboratories was originally established in 2004 for Africa only and has since expanded globally. Any quality control laboratory (whether public or private) may participate in the programme. Participation is voluntary and many laboratories have asked to participate. Most of the interested laboratories have been in the African region (the first to be focused on in the expression of interest), where 22 laboratories have expressed interest and so far six have been prequalified. Six laboratories had also been prequalified in Europe. The programme involves initial inspections and pre-audits to assess capacity, followed by a strong capacity-building component involving training.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Precalificaci\u00f3n de Medicamentos y Laboratorios de Control de Calidad**: El Programa de Precalificaci\u00f3n de Medicamentos de la OMS ha estado trabajando para mejorar la calidad y el acceso a los productos farmac\u00e9uticos, especialmente en el contexto de la salud reproductiva y enfermedades como el VIH/SIDA, la tuberculosis y la malaria. En 2011, se recibieron 54 solicitudes para la precalificaci\u00f3n de productos, de las cuales 35 fueron aceptadas. Adem\u00e1s, se ha observado un aumento en la capacitaci\u00f3n de las Autoridades Nacionales de Regulaci\u00f3n de Medicamentos (NMRAs) y se han precalificado laboratorios de control de calidad en varias regiones.\n\n2. **Desaf\u00edos y Necesidades de Capacitaci\u00f3n**: A pesar de los avances, el Programa enfrenta desaf\u00edos significativos, como la disminuci\u00f3n de fondos de donantes y la dificultad para obtener experiencia t\u00e9cnica. Se ha identificado la necesidad de construir capacidades en los fabricantes de productos gen\u00e9ricos y asegurar que la capacitaci\u00f3n se traduzca en la implementaci\u00f3n de mejores pr\u00e1cticas.\n\n3. **Expansi\u00f3n Global del Programa**: Originalmente establecido en 2004 para \u00c1frica, el procedimiento de precalificaci\u00f3n de laboratorios de control de calidad se ha expandido a nivel global, permitiendo la participaci\u00f3n voluntaria de laboratorios p\u00fablicos y privados. Hasta la fecha, se han precalificado laboratorios en \u00c1frica y Europa, con un enfoque en la capacitaci\u00f3n y la evaluaci\u00f3n de capacidades.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los principales desaf\u00edos que enfrenta el Programa de Precalificaci\u00f3n de Medicamentos de la OMS en t\u00e9rminos de financiamiento y experiencia t\u00e9cnica?**\n   - Respuesta: El Programa ha reportado una disminuci\u00f3n en los fondos de donantes y una creciente dificultad para obtener experiencia t\u00e9cnica, lo que complica su capacidad para operar y expandir sus actividades.\n\n2. **\u00bfQu\u00e9 medidas se est\u00e1n tomando para abordar las deficiencias identificadas en los expedientes de productos gen\u00e9ricos?**\n   - Respuesta: Se ha llevado a cabo un estudio retrospectivo que mostr\u00f3 varias deficiencias, lo que indica la necesidad de construir capacidades en los fabricantes de productos gen\u00e9ricos. Esto se est\u00e1 abordando a trav\u00e9s de talleres y capacitaci\u00f3n organizados por el Programa.\n\n3. **\u00bfC\u00f3mo ha evolucionado la participaci\u00f3n de laboratorios en el programa de precalificaci\u00f3n desde su inicio en 2004?**\n   - Respuesta: El programa comenz\u00f3 en 2004 con un enfoque en \u00c1frica y ha expandido su alcance globalmente. Hasta ahora, 22 laboratorios en \u00c1frica han expresado inter\u00e9s, de los cuales seis han sido precalificados, y se han precalificado seis laboratorios adicionales en Europa.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Esquema de Certificaci\u00f3n de la OMS**:\n   - Se prepararon documentos de preguntas y respuestas sobre el Esquema, aprobados para su publicaci\u00f3n en el sitio web de Medicamentos de la OMS.\n   - En 2010, se envi\u00f3 una carta circular a los Estados Miembros solicitando comentarios sobre las recomendaciones del informe anterior del Comit\u00e9, recibiendo solo 12 respuestas de 194 Estados Miembros.\n   - A pesar de las limitaciones, se reconoci\u00f3 el valor del Esquema de Certificaci\u00f3n.\n\n2. **Extensi\u00f3n del Esquema**:\n   - En 2003, se propuso extender el Esquema para incluir materiales de partida adem\u00e1s de productos terminados, con Polonia uni\u00e9ndose a esta extensi\u00f3n.\n   - Se anticipa que m\u00e1s pa\u00edses se unir\u00e1n al Esquema, con una secci\u00f3n especial dedicada en el sitio web de la OMS.\n\n3. **Buenas Pr\u00e1cticas Farmac\u00e9uticas (GPP)**:\n   - Las GPP adoptadas en la reuni\u00f3n n\u00famero 45 del Comit\u00e9 recibieron atenci\u00f3n y fueron traducidas a varios idiomas.\n   - Se discutieron en la reuni\u00f3n de la Federaci\u00f3n Internacional Farmac\u00e9utica (FIP) en 2011, y el texto fue respaldado para su implementaci\u00f3n por asociaciones farmac\u00e9uticas nacionales.\n\n4. **Programa de Precalificaci\u00f3n de Medicamentos de la OMS**:\n   - Desde la reuni\u00f3n de 2010, se han precalificado 35 productos, incluyendo combinaciones de medicamentos y un producto de salud reproductiva.\n   - Se han precalificado 5 APIs y se ha comenzado a asistir en una revisi\u00f3n externa para el Fondo de Poblaci\u00f3n de las Naciones Unidas.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la salud p\u00fablica internacional y de la implementaci\u00f3n de los esquemas de certificaci\u00f3n y precalificaci\u00f3n.\n- **FIP (Federaci\u00f3n Internacional Farmac\u00e9utica)**: Organizaci\u00f3n que apoya la implementaci\u00f3n de buenas pr\u00e1cticas farmac\u00e9uticas a nivel nacional.\n- **Estados Miembros**: Pa\u00edses que forman parte de la OMS y que participan en el Esquema de Certificaci\u00f3n y otras iniciativas.", "excerpt_keywords": "Keywords: Prequalification, WHO, Pharmaceuticals, Quality Control Laboratories, Capacity Building"}}, "d59777bf-575f-4902-9541-6b451dc23450": {"node_ids": ["77645e93-5106-4199-bce8-637d3cfdcc91"], "metadata": {"page_label": "46", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 10.2 Update on the surveys of the quality of medicines\n\nA survey on the quality of antimalarials in Africa was carried out in cooperation with NMRAs in Cameroon, Ethiopia, Ghana, Kenya, Nigeria and the United Republic of Tanzania. A total of 935 samples was collected at all distribution levels and screened, with 306 of them being tested in a laboratory according to either *The International Pharmacopoeia* or the *United States Pharmacopeia*. There was a 28.5% failure rate overall; two countries showed a 63% and 58% failure rate, respectively. The failure rate for prequalified products was 4% and that for non-prequalified products was 40%. The survey also revealed that some products tested were not registered in the country concerned and some samples contained no active ingredients.\n\nA further study of TB medicines in the newly independent states showed much less deviation from acceptable standards, and none of the WHO-prequalified products failed. However, the study found that several medicines raised quality concerns. This led to a further study which showed that, for example, rifampicin capsules showed problems in assay, probably as a result of stability problems. An additional study of isoniazid/rifampicin tablets revealed a high rate of failure when tested according to *The International Pharmacopoeia* but samples passed when tested with *British Pharmacopoeia* methods.\n\nThe Expert Committee noted the outcome of the study and recommended that feedback should be provided to the respective pharmacopoeias.\n\n# 11. Regulatory guidance\n\n## 11.1 Policy on oseltamivir and zanamivir\n\nA draft document on the shelf-life expiry of oseltamivir was reviewed by the Expert Committee. The issue had arisen since, during the recent H1N1 pandemic, much of the stock of oseltamivir was assigned a shelf-life of five years; it also had a five-year expiry date on the package label. Recently, however, some regulators had extended the shelf-life from five to seven years and some special measures were put in place to enable this extension. Much of the stockpile was manufactured five or six years ago and questions had now been received from Member States as to what they should do with the material.\n\nThe issue was presented to the Expert Committee with a view to obtaining guidance on the retention or disposal of expired stocks of oseltamivir capsules and zanamivir for finished products for which the shelf-life had been extended from five to seven years by a number of national and regional regulatory authorities.\n\nWHO would not normally recommend use of medicines after their expiration since the manufacturer would have tested the product as being within specifications during that period. However, it was noted that the document acknowledged that countries were reluctant to destroy stockpiled medicines since...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Calidad de Medicamentos Antimal\u00e1ricos en \u00c1frica**: Se realiz\u00f3 una encuesta sobre la calidad de los medicamentos antimal\u00e1ricos en varios pa\u00edses africanos, donde se recolectaron 935 muestras. La tasa de fallos fue del 28.5%, con productos precalificados mostrando una tasa de fallo del 4% en comparaci\u00f3n con el 40% de los productos no precalificados. Adem\u00e1s, se encontraron productos no registrados y algunos sin ingredientes activos.\n\n2. **Estudio de Medicamentos para la Tuberculosis**: Un estudio adicional sobre medicamentos para la tuberculosis en estados reci\u00e9n independientes mostr\u00f3 que, aunque no hubo fallos en productos precalificados por la OMS, se identificaron preocupaciones de calidad en varios medicamentos. Se realizaron pruebas que revelaron problemas de estabilidad en c\u00e1psulas de rifampicina y una alta tasa de fallos en tabletas de isoniazida/rifampicina seg\u00fan la *Farmacopea Internacional*.\n\n3. **Pol\u00edtica sobre Oseltamivir y Zanamivir**: La Comisi\u00f3n de Expertos revis\u00f3 un documento sobre la vida \u00fatil de oseltamivir, que hab\u00eda sido extendida de cinco a siete a\u00f1os por algunos reguladores. Se discuti\u00f3 la retenci\u00f3n o eliminaci\u00f3n de existencias de medicamentos caducados, considerando que la OMS generalmente no recomienda el uso de medicamentos despu\u00e9s de su fecha de caducidad, aunque se reconoci\u00f3 la renuencia de los pa\u00edses a destruir medicamentos almacenados.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1l fue la tasa de fallo de los productos antimal\u00e1ricos en los pa\u00edses que participaron en la encuesta y qu\u00e9 diferencias se observaron entre productos precalificados y no precalificados?**\n   - La tasa de fallo general fue del 28.5%, con productos precalificados mostrando una tasa de fallo del 4% y productos no precalificados del 40%.\n\n2. **\u00bfQu\u00e9 problemas de calidad se identificaron en los medicamentos para la tuberculosis y qu\u00e9 m\u00e9todos de prueba mostraron resultados contradictorios?**\n   - Se identificaron problemas de calidad en las c\u00e1psulas de rifampicina, probablemente debido a problemas de estabilidad. Las tabletas de isoniazida/rifampicina mostraron una alta tasa de fallo seg\u00fan la *Farmacopea Internacional*, pero pasaron las pruebas con m\u00e9todos de la *Farmacopea Brit\u00e1nica*.\n\n3. **\u00bfQu\u00e9 consideraciones se discutieron en relaci\u00f3n con la eliminaci\u00f3n de existencias de oseltamivir y zanamivir que hab\u00edan sido extendidas m\u00e1s all\u00e1 de su fecha de caducidad?**\n   - La OMS generalmente no recomienda el uso de medicamentos despu\u00e9s de su fecha de caducidad, pero se reconoci\u00f3 que los pa\u00edses son reacios a destruir medicamentos almacenados, lo que llev\u00f3 a la necesidad de orientaci\u00f3n sobre la retenci\u00f3n o eliminaci\u00f3n de estos productos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Programa de Precalificaci\u00f3n de Medicamentos de la OMS**:\n   - **Objetivo**: Mejorar la calidad y el acceso a productos farmac\u00e9uticos, especialmente en salud reproductiva y enfermedades como VIH/SIDA, tuberculosis y malaria.\n   - **Resultados de 2011**: Se recibieron 54 solicitudes para precalificaci\u00f3n, de las cuales 35 fueron aceptadas. Se recibieron 21 solicitudes para Ingredientes Farmac\u00e9uticos Activos (APIs), con 2 precalificados y 19 en evaluaci\u00f3n.\n\n2. **Capacitaci\u00f3n y Desarrollo de Capacidades**:\n   - **Aumento de Talleres**: En 2010, se organizaron 16 talleres y en 2011, 10 talleres adicionales, con el objetivo de capacitar a las Autoridades Nacionales de Regulaci\u00f3n de Medicamentos (NMRAs).\n   - **Desaf\u00edos**: Asegurar que la capacitaci\u00f3n se traduzca en la implementaci\u00f3n de mejores pr\u00e1cticas.\n\n3. **Desaf\u00edos Financieros y T\u00e9cnicos**:\n   - **Disminuci\u00f3n de Fondos**: Se report\u00f3 una disminuci\u00f3n en los fondos de donantes y dificultades para obtener experiencia t\u00e9cnica, lo que afecta la operaci\u00f3n del programa.\n\n4. **Precalificaci\u00f3n de Laboratorios de Control de Calidad**:\n   - **Expansi\u00f3n Global**: Originalmente establecido en 2004 para \u00c1frica, el programa se ha expandido globalmente. Hasta la fecha, 22 laboratorios en \u00c1frica han mostrado inter\u00e9s, de los cuales 6 han sido precalificados, y otros 6 en Europa.\n   - **Proceso de Participaci\u00f3n**: La participaci\u00f3n es voluntaria y se basa en inspecciones iniciales y auditor\u00edas previas para evaluar la capacidad, seguidas de un componente de capacitaci\u00f3n.\n\n5. **Entidades Involucradas**:\n   - **OMS (Organizaci\u00f3n Mundial de la Salud)**: Coordinadora del programa de precalificaci\u00f3n.\n   - **NMRAs (Autoridades Nacionales de Regulaci\u00f3n de Medicamentos)**: Colaboradores clave en el proceso de precalificaci\u00f3n.\n   - **Global Fund**: Colaboraci\u00f3n en el contexto de salud reproductiva y enfermedades infecciosas.\n\nEste resumen destaca la importancia del Programa de Precalificaci\u00f3n de Medicamentos de la OMS en la mejora de la calidad y el acceso a medicamentos, as\u00ed como los desaf\u00edos que enfrenta en t\u00e9rminos de financiamiento y capacitaci\u00f3n.", "excerpt_keywords": "Keywords: antimalarials, quality survey, oseltamivir, tuberculosis, pharmacopoeia"}}, "3eed0323-55fb-44b3-b8e5-ebce1e2f7553": {"node_ids": ["f2957087-6ef6-4edd-bb35-baf9abfb1e1d"], "metadata": {"page_label": "47", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nthe scale and severity of a future pandemic could not be predicted and demand may exceed stockpile and manufacturing capacity. The document drafted for discussion included advice that, where a national authority elected to extend shelf-life, this should be considered only for stocks that had been stored under controlled conditions in accordance with manufacturers\u2019 recommendations, and such stocks should be used only in emergencies and where no alternative stocks or alternative medicines were available.\n\nThe Expert Committee recommended that such action should be under the sole responsibility of each national authority, taking into consideration the following points, to ensure that there was no negative impact on the patients.\n\n- The manufacturer should be consulted for evidence to support extending the shelf-life.\n- The products are maintained under storage conditions which comply with the label requirements.\n- The national regulatory authority may wish to follow up with its own testing.\n\n## 11.2 Assessment criteria for blood regulatory systems\n\nThe inherent risks of blood and the difficulty of providing adequate, timely and equitable access to safe blood products require an organized national or regional blood regulatory system in which a competent blood products regulatory authority ensures that appropriate standards are met for production of such products and that safety is monitored. In 2010 the World Health Assembly urged Member States to update their national regulations on donor assessment and deferral: the collection, testing, processing, storage, transportation and use of blood products, and operation of regulatory authorities in order to \u201censure that regulatory control in the area of quality and safety of blood products across the entire transfusion chain meets internationally recognized standards\u201d.\n\nAt the 13th meeting of ICDRA in 2008 it was recommended that WHO should take steps to further develop and strengthen national and regional blood regulatory authorities, and provide harmonized assessment criteria for blood regulatory systems.\n\nTo achieve the aim of an international best practice national blood regulatory framework, the WHO Blood Regulators Network (BRN) had identified a set of integrated general and specific regulatory functions applicable from the time of the collection of source material through to the quality control of the final product, not only covering blood products but also associated substances and medical devices such as in vitro diagnostics. The secretariat had subsequently developed a document on assessment criteria for national blood regulatory systems which was presented to the Expert Committee for discussion. The set of functions identified by the BRN was used to develop an assessment tool for regulatory authorities.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Extensi\u00f3n de la vida \u00fatil de medicamentos**: El documento discute la posibilidad de que las autoridades nacionales extiendan la vida \u00fatil de los medicamentos almacenados bajo condiciones controladas, enfatizando que esto debe hacerse con precauci\u00f3n y solo en situaciones de emergencia. Se recomienda consultar al fabricante y seguir las condiciones de almacenamiento adecuadas.\n\n2. **Regulaci\u00f3n de productos sangu\u00edneos**: Se aborda la necesidad de un sistema regulatorio organizado para la sangre y los productos sangu\u00edneos, destacando la importancia de que las autoridades competentes aseguren que se cumplan los est\u00e1ndares de producci\u00f3n y seguridad. Se menciona la urgencia de actualizar las regulaciones nacionales sobre la evaluaci\u00f3n y la deferencia de donantes.\n\n3. **Red de Reguladores de Sangre de la OMS**: La OMS ha identificado funciones regulatorias integradas para establecer un marco de mejores pr\u00e1cticas en la regulaci\u00f3n de la sangre, que abarca desde la recolecci\u00f3n del material hasta el control de calidad del producto final. Se ha desarrollado un documento sobre criterios de evaluaci\u00f3n para sistemas regulatorios de sangre.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios que deben considerarse al extender la vida \u00fatil de los medicamentos seg\u00fan el documento de la OMS?**\n   - Respuesta: Los criterios incluyen consultar al fabricante para obtener evidencia que respalde la extensi\u00f3n de la vida \u00fatil, asegurarse de que los productos se mantengan bajo condiciones de almacenamiento que cumplan con los requisitos de la etiqueta, y que la autoridad reguladora nacional pueda realizar pruebas adicionales.\n\n2. **\u00bfQu\u00e9 recomendaciones se hicieron en la 13\u00aa reuni\u00f3n de ICDRA en 2008 respecto a las autoridades regulatorias de sangre?**\n   - Respuesta: Se recomend\u00f3 que la OMS tomara medidas para desarrollar y fortalecer las autoridades regulatorias nacionales y regionales de sangre, as\u00ed como proporcionar criterios de evaluaci\u00f3n armonizados para los sistemas regulatorios de sangre.\n\n3. **\u00bfQu\u00e9 papel juega la Red de Reguladores de Sangre de la OMS en la regulaci\u00f3n de productos sangu\u00edneos?**\n   - Respuesta: La Red de Reguladores de Sangre de la OMS ha identificado un conjunto de funciones regulatorias integradas que se aplican desde la recolecci\u00f3n del material fuente hasta el control de calidad del producto final, abarcando no solo productos sangu\u00edneos, sino tambi\u00e9n sustancias asociadas y dispositivos m\u00e9dicos como diagn\u00f3sticos in vitro.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Encuesta sobre la Calidad de Medicamentos Antimal\u00e1ricos en \u00c1frica**:\n   - **Participantes**: Cooperaci\u00f3n con Autoridades Nacionales de Regulaci\u00f3n de Medicamentos (NMRAs) en pa\u00edses como Camer\u00fan, Etiop\u00eda, Ghana, Kenia, Nigeria y Tanzania.\n   - **Muestras**: Se recolectaron 935 muestras, de las cuales 306 fueron analizadas en laboratorio.\n   - **Tasa de Fallo**: 28.5% en general; 4% para productos precalificados y 40% para no precalificados. Se encontraron productos no registrados y algunos sin ingredientes activos.\n\n2. **Estudio de Medicamentos para la Tuberculosis**:\n   - **Resultados**: Menos desviaciones de los est\u00e1ndares aceptables; ning\u00fan producto precalificado por la OMS fall\u00f3.\n   - **Preocupaciones de Calidad**: Problemas de estabilidad en c\u00e1psulas de rifampicina y alta tasa de fallos en tabletas de isoniazida/rifampicina seg\u00fan la *Farmacopea Internacional*, aunque pasaron pruebas con m\u00e9todos de la *Farmacopea Brit\u00e1nica*.\n\n3. **Pol\u00edtica sobre Oseltamivir y Zanamivir**:\n   - **Revisi\u00f3n de Vida \u00datil**: Se discuti\u00f3 la extensi\u00f3n de la vida \u00fatil de oseltamivir de cinco a siete a\u00f1os por algunos reguladores.\n   - **Orientaci\u00f3n sobre Medicamentos Caducados**: La OMS generalmente no recomienda el uso de medicamentos despu\u00e9s de su fecha de caducidad, pero se reconoci\u00f3 la renuencia de los pa\u00edses a destruir existencias almacenadas.\n\n### Entidades Clave\n- **Medicamentos**: Antimal\u00e1ricos, Rifampicina, Isoniazida, Oseltamivir, Zanamivir.\n- **Organismos**: Organizaci\u00f3n Mundial de la Salud (OMS), Autoridades Nacionales de Regulaci\u00f3n de Medicamentos (NMRAs).\n- **Normativas**: *Farmacopea Internacional*, *Farmacopea Brit\u00e1nica*, *Farmacopea de los Estados Unidos*. \n\nEste resumen destaca los hallazgos sobre la calidad de los medicamentos en \u00c1frica y los estudios relacionados con la tuberculosis, as\u00ed como las consideraciones regulatorias sobre la vida \u00fatil de ciertos medicamentos antivirales.", "excerpt_keywords": "Keywords: shelf-life extension, blood regulatory systems, pharmaceutical preparations, WHO recommendations, emergency stockpiles"}}, "a9744e23-27fe-48db-a6d4-f0ee6f67754e": {"node_ids": ["d807e6d0-7085-4c9f-8ba3-96102b8d9cdc"], "metadata": {"page_label": "48", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Pharmaceutical Development for Multisource (Generic) Pharmaceutical Products \u2013 Points to Consider\n\nFollowing drafting of the original document at a BRN meeting in 2008, Health Canada and Swissmedic had carried out self-assessment exercises on the basis of the draft and further self-assessment was carried out in Argentina, Brazil and Indonesia. In 2010 the document was introduced to ICDRA at a BRN workshop.\n\nThe Expert Committee took note of the assessment tool presented.\n\n## 11.3 Pharmaceutical Development for Multisource (Generic) Pharmaceutical Products \u2013 Points to Consider\n\nThe development of the document on pharmaceutical development for multisource (generic) pharmaceutical products had been originally endorsed by the Expert Committee in 2007 and, following the collation of comments, was discussed by a WHO expert working group in 2008. The draft was subsequently revised, taking into account the comments received and those made by the working group, and the revised draft was submitted to the Expert Committee in 2008. All comments were incorporated and the Expert Committee discussed the guidelines again in 2009. The draft was further discussed both at the WHO consultation on paediatrics and generics guidelines in 2010 and by the Expert Committee that same year. During 2011 the draft was discussed once more at the WHO consultation on paediatrics and generics guidelines and mailed globally for comments before being resubmitted to the Expert Committee.\n\nThe document provides guidance on the contents of a pharmaceutical development plan for multisource pharmaceutical products including both pre-development activities and the development period, for both the applicants for marketing authorizations and NMRAs. The guidance focuses on the development of multisource finished pharmaceutical products (FPPs) which are intended to be bioequivalent to the relevant comparator product. Multisource FPPs are usually required to be therapeutically equivalent to the comparator product. It aims to provide a structured approach for industry, following the ICH common technical document format for developing high quality, multisource FPPs.\n\nThe Expert Committee reviewed the document and the comments received and made a number of changes to the text. The Committee adopted the document on pharmaceutical development of multisource (generic) pharmaceutical products \u2013 points to consider subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 3).\n\n## 11.4 Guidelines on Submission of Documentation for a Multisource (Generic) Finished Pharmaceutical Product: Quality Part\n\nThese guidelines, which relate to submission of documentation in an application for the evaluation of a product for prequalification, were drafted in June 2010 and discussed within the WHO Prequalification of Medicines Programme assessment.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS, titulado \"Desarrollo Farmac\u00e9utico para Productos Farmac\u00e9uticos Multifuente (Gen\u00e9ricos) \u2013 Puntos a Considerar\", aborda la evoluci\u00f3n y las pautas para el desarrollo de productos farmac\u00e9uticos gen\u00e9ricos. Se menciona que el documento fue inicialmente respaldado por el Comit\u00e9 de Expertos en 2007 y ha pasado por m\u00faltiples revisiones y discusiones en diferentes a\u00f1os y foros, incluyendo consultas sobre pediatr\u00eda y gu\u00edas de gen\u00e9ricos. El objetivo principal es proporcionar una gu\u00eda estructurada para la industria sobre c\u00f3mo desarrollar productos farmac\u00e9uticos terminados (FPPs) que sean bioequivalentes a productos comparadores relevantes. Tambi\u00e9n se discuten las pautas para la presentaci\u00f3n de documentaci\u00f3n relacionada con la evaluaci\u00f3n de productos para la pre-calificaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los principales objetivos del documento sobre el desarrollo farmac\u00e9utico para productos gen\u00e9ricos, y c\u00f3mo se relacionan con la bioequivalencia?**\n   - El documento tiene como objetivo proporcionar una gu\u00eda sobre el contenido de un plan de desarrollo farmac\u00e9utico para productos farmac\u00e9uticos multifuente, enfoc\u00e1ndose en la necesidad de que los productos terminados sean bioequivalentes y terap\u00e9uticamente equivalentes a los productos comparadores.\n\n2. **\u00bfQu\u00e9 procesos de revisi\u00f3n y consulta se llevaron a cabo antes de la adopci\u00f3n final del documento por parte del Comit\u00e9 de Expertos?**\n   - El documento fue discutido en m\u00faltiples ocasiones desde su redacci\u00f3n inicial en 2008, incluyendo revisiones en 2009, 2010 y 2011, donde se recopilaron comentarios de diversas consultas y se realizaron revisiones basadas en esos comentarios antes de su adopci\u00f3n final.\n\n3. **\u00bfQu\u00e9 importancia tienen las pautas sobre la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos multifuente en el contexto de la pre-calificaci\u00f3n de medicamentos?**\n   - Estas pautas son cruciales para asegurar que la documentaci\u00f3n presentada para la evaluaci\u00f3n de productos para la pre-calificaci\u00f3n cumpla con los est\u00e1ndares de calidad necesarios, facilitando as\u00ed el acceso a medicamentos seguros y efectivos en el mercado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Extensi\u00f3n de la Vida \u00datil de Medicamentos**:\n   - Se discute la posibilidad de que las autoridades nacionales extiendan la vida \u00fatil de medicamentos almacenados bajo condiciones controladas.\n   - Se enfatiza que esta acci\u00f3n debe ser considerada solo en emergencias y tras consultar al fabricante, asegurando que se mantengan las condiciones de almacenamiento adecuadas.\n\n2. **Regulaci\u00f3n de Productos Sangu\u00edneos**:\n   - Se destaca la necesidad de un sistema regulatorio organizado para garantizar la seguridad y calidad de los productos sangu\u00edneos.\n   - La Asamblea Mundial de la Salud inst\u00f3 a los Estados Miembros a actualizar sus regulaciones nacionales sobre la evaluaci\u00f3n de donantes y el manejo de productos sangu\u00edneos.\n\n3. **Red de Reguladores de Sangre de la OMS (BRN)**:\n   - La OMS ha identificado funciones regulatorias integradas para establecer un marco de mejores pr\u00e1cticas en la regulaci\u00f3n de la sangre, abarcando desde la recolecci\u00f3n hasta el control de calidad del producto final.\n   - Se ha desarrollado un documento sobre criterios de evaluaci\u00f3n para sistemas regulatorios de sangre, presentado a la Comisi\u00f3n de Expertos para discusi\u00f3n.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la regulaci\u00f3n y est\u00e1ndares de salud a nivel internacional.\n- **Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas**: Grupo que proporciona recomendaciones sobre la regulaci\u00f3n de medicamentos.\n- **Red de Reguladores de Sangre de la OMS (BRN)**: Iniciativa para mejorar la regulaci\u00f3n de productos sangu\u00edneos a nivel nacional e internacional.", "excerpt_keywords": "Keywords: pharmaceutical development, multisource products, bioequivalence, WHO guidelines, prequalification"}}, "42dc5d37-72d3-4d2a-8aeb-c2ff4f7adf67": {"node_ids": ["9007136c-8a64-4bfe-b5f1-bc12b6876612"], "metadata": {"page_label": "49", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\ngroup. Following further comments and review, the draft was first presented to the Expert Committee in October 2010. In early 2011 the text was once more reviewed in connection with the draft working document on *Points to consider for the development of multisource (generic) medicines*. Further discussion took place during the informal consultation on development of paediatric and generic medicines in May 2011. A further round of comments ensued, and the draft was also discussed by a small subgroup in September 2011 before being presented to the Expert Committee in October.\n\nDuring the development of the guidelines, some 26 manufacturers who participate in the WHO Prequalification of Medicines Programme also contributed and were involved in the consultation process which led to the first draft of the document. The document was also open for public comment on the WHO Medicines web site, and was presented at workshops organized by the WHO Prequalification of Medicines Programme. The concept behind the guidelines had been implemented since September 2010 with regard to submission to the prequalification process.\n\nThe Expert Committee reviewed the document and the comments received. There was concern about the title of the document and it was requested that the document be adapted to make it clear that the general principles outlined were also applicable to the general process of application for prequalification.\n\nThe members of the Expert Committee agreed to change the title of the guidelines to read: *Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part*.\n\nThe Expert Committee adopted the guidelines, subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 4). Furthermore, the Expert Committee proposed that a new general document be considered.\n\n## 11.5 Development of paediatric medicines: points to consider in pharmaceutical formulation\n\nSafe and effective pharmacotherapy in paediatric patients requires the timely development of medicines and information on their proper use to suit the age, physiological condition and body size of the child. Formulations developed specifically for children are often needed. The use of unlicensed and off-label medicines in children is widespread. Their effects on children have not been properly studied and age-appropriate formulations are generally not available.\n\nPharmacists, parents or caregivers are often faced with the need to manipulate an adult medicine in a way that is not described in the summary of product characteristics. This manipulation can be simple (e.g. breaking tablets", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Preguntas\n\n1. **\u00bfQu\u00e9 cambios se realizaron en el t\u00edtulo de las directrices propuestas por el Comit\u00e9 de Expertos de la OMS y por qu\u00e9?**\n   - El t\u00edtulo de las directrices se cambi\u00f3 a *Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part* para aclarar que los principios generales tambi\u00e9n eran aplicables al proceso de solicitud de precalificaci\u00f3n.\n\n2. **\u00bfCu\u00e1l fue el papel de los fabricantes en el desarrollo de las directrices sobre medicamentos multisource (gen\u00e9ricos)?**\n   - Durante el desarrollo de las directrices, 26 fabricantes que participan en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS contribuyeron y participaron en el proceso de consulta que llev\u00f3 al primer borrador del documento.\n\n3. **\u00bfCu\u00e1les son los desaf\u00edos asociados con la formulaci\u00f3n de medicamentos para pacientes pedi\u00e1tricos seg\u00fan el documento?**\n   - Los desaf\u00edos incluyen la necesidad de desarrollar formulaciones espec\u00edficas para ni\u00f1os, el uso generalizado de medicamentos no autorizados y fuera de indicaci\u00f3n, y la falta de estudios adecuados sobre los efectos de estos medicamentos en ni\u00f1os, lo que resulta en una disponibilidad limitada de formulaciones apropiadas para su edad.\n\n### Resumen de nivel superior\n\nEl documento de la OMS aborda la necesidad de directrices para la presentaci\u00f3n de documentaci\u00f3n relacionada con medicamentos gen\u00e9ricos en el contexto del Programa de Precalificaci\u00f3n de Medicamentos. Se destaca la importancia de adaptar las formulaciones para pacientes pedi\u00e1tricos, dado que los medicamentos para adultos a menudo no son adecuados para ni\u00f1os. La participaci\u00f3n de fabricantes en el desarrollo de estas directrices y la revisi\u00f3n del documento por parte del Comit\u00e9 de Expertos son aspectos clave del proceso. Adem\u00e1s, se subraya la preocupaci\u00f3n por el uso de medicamentos no autorizados en la poblaci\u00f3n pedi\u00e1trica y la falta de formulaciones adecuadas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Desarrollo Farmac\u00e9utico para Productos Gen\u00e9ricos**:\n   - El documento aborda el desarrollo de productos farmac\u00e9uticos multifuente (gen\u00e9ricos) y proporciona pautas sobre el contenido de un plan de desarrollo farmac\u00e9utico.\n   - Se enfoca en la bioequivalencia y la equivalencia terap\u00e9utica de los productos terminados en relaci\u00f3n con los productos comparadores.\n\n2. **Proceso de Revisi\u00f3n y Consulta**:\n   - El documento fue inicialmente respaldado por el Comit\u00e9 de Expertos en 2007 y ha pasado por m\u00faltiples revisiones y discusiones en 2008, 2009, 2010 y 2011.\n   - Se realizaron autoevaluaciones en varios pa\u00edses (Canad\u00e1, Suiza, Argentina, Brasil e Indonesia) y se recopilaron comentarios de diversas consultas antes de su adopci\u00f3n final.\n\n3. **Estructura y Enfoque**:\n   - Se propone un enfoque estructurado para la industria, siguiendo el formato del documento t\u00e9cnico com\u00fan de ICH, para desarrollar productos farmac\u00e9uticos de alta calidad.\n   - El documento incluye actividades de pre-desarrollo y el per\u00edodo de desarrollo para solicitantes de autorizaciones de comercializaci\u00f3n y autoridades reguladoras nacionales de medicamentos (NMRAs).\n\n4. **Pautas de Presentaci\u00f3n de Documentaci\u00f3n**:\n   - Se mencionan pautas espec\u00edficas para la presentaci\u00f3n de documentaci\u00f3n en aplicaciones para la evaluaci\u00f3n de productos para la pre-calificaci\u00f3n, redactadas en junio de 2010.\n   - Estas pautas son esenciales para asegurar que la documentaci\u00f3n cumpla con los est\u00e1ndares de calidad necesarios para la evaluaci\u00f3n de medicamentos.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la elaboraci\u00f3n del documento.\n- **Comit\u00e9 de Expertos**: Grupo que revis\u00f3 y aprob\u00f3 el documento.\n- **NMRAs (National Medicines Regulatory Authorities)**: Autoridades reguladoras que se ven afectadas por las pautas.\n- **ICH (International Council for Harmonisation)**: Organizaci\u00f3n que proporciona el formato t\u00e9cnico com\u00fan mencionado en el documento.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, generic medicines, paediatric formulations, prequalification"}}, "eae1add7-6e17-45c5-b0d8-d402f7f21160": {"node_ids": ["8fe82c9b-e3ef-4fbb-bd2a-b28aa86da32b"], "metadata": {"page_label": "50", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nthat do not have a score line with a tablet splitter) or complex (e.g. using tablets as a source for an API to prepare a suspension). Pharmacists may also be faced with the need to compound a medicine on the basis of the API.\n\nThis process itself can increase the potential for errors in dosage accuracy and in general can increase the variability of the product. Such handling may be potentially hazardous for the patient as it may affect the stability, bioavailability and accuracy of dosing of an FPP, in particular for controlled-release preparations. The use of such manipulated medicines may expose children to overdosing and unintended side-effects or underdosing without the expected efficacy. Moreover, excipients that are safe for adults may not necessarily be so for children.\n\nIn December 2007, WHO launched its initiative \u201cMake medicines child size\u201d in order to raise awareness and accelerate action in response to the need for improved availability and access to child-specific medicines. Among actions to support the \u201cMake medicines child size\u201d initiative was the *Development of paediatric medicines: points to consider* guidance on pharmaceutical development of paediatric medicines. The intention is to inform regulatory authorities and manufacturers on issues that require special attention during the pharmaceutical development of paediatric medicines, with a focus on the conditions and needs in developing countries.\n\nAt the meeting of the Expert Committee in October 2007, a draft of *Development of paediatric medicines: points to consider* was discussed with a view to contributing to the pharmaceutical part of the document. An extended revision of the part on pharmaceutical development as a stand-alone text was drafted in February 2008 and, following circulation of this document, a great number of comments were received.\n\nIn April 2010 a consultation on paediatrics and generics draft guidelines discussed the draft together with an outline of the paediatric guidelines. Another version of the working document was prepared, based on the discussions during that meeting, the feedback and comments received on the previous version, and the report of the 2008 WHO Informal Meeting on Dosage Forms of Medicines for Children. Following wide circulation, comments were again received and the feedback was discussed by the Expert Committee in October 2010. A new revision was then prepared, taking into account new developments, such as efforts being undertaken by regulatory authorities. Following further discussion during an informal consultation in May 2011 the document, as revised after that meeting, was once again distributed widely for comments.\n\nIt was noted that, among other things, the points to consider document attempted to take into account convenience, reliability, acceptability, minimum dosing and end-user needs. The issues addressed by the guidelines included paediatric dosage forms, formulation design, different means of administration, inhalation, and packaging and labelling. The Expert Committee adopted the", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en la importancia de desarrollar medicamentos pedi\u00e1tricos adecuados y seguros, destacando los riesgos asociados con la manipulaci\u00f3n de medicamentos que no est\u00e1n dise\u00f1ados espec\u00edficamente para ni\u00f1os. Se menciona la iniciativa de la OMS \"Make medicines child size\", que busca mejorar la disponibilidad y el acceso a medicamentos espec\u00edficos para ni\u00f1os. Adem\u00e1s, se discuten las revisiones y consultas realizadas por el Comit\u00e9 de Expertos de la OMS sobre el desarrollo de medicamentos pedi\u00e1tricos, abordando aspectos como la formulaci\u00f3n, la dosificaci\u00f3n y la administraci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los riesgos asociados con la manipulaci\u00f3n de medicamentos en pediatr\u00eda seg\u00fan el documento?**\n   - El documento menciona que la manipulaci\u00f3n de medicamentos puede aumentar la posibilidad de errores en la precisi\u00f3n de la dosificaci\u00f3n, afectar la estabilidad y la biodisponibilidad del producto, y exponer a los ni\u00f1os a sobredosis o subdosificaci\u00f3n, lo que puede resultar en efectos secundarios no deseados o falta de eficacia.\n\n2. **\u00bfQu\u00e9 acciones espec\u00edficas se han tomado en el marco de la iniciativa \"Make medicines child size\"?**\n   - La iniciativa incluye el desarrollo de la gu\u00eda *Development of paediatric medicines: points to consider*, que tiene como objetivo informar a las autoridades regulatorias y a los fabricantes sobre los aspectos que requieren atenci\u00f3n especial en el desarrollo de medicamentos pedi\u00e1tricos, especialmente en los pa\u00edses en desarrollo.\n\n3. **\u00bfQu\u00e9 aspectos se consideraron en las revisiones del documento sobre medicamentos pedi\u00e1tricos?**\n   - Las revisiones del documento tomaron en cuenta la conveniencia, la fiabilidad, la aceptabilidad, la dosificaci\u00f3n m\u00ednima y las necesidades del usuario final. Tambi\u00e9n se abordaron temas como las formas de dosificaci\u00f3n pedi\u00e1trica, el dise\u00f1o de formulaciones, los diferentes m\u00e9todos de administraci\u00f3n, la inhalaci\u00f3n, y el empaquetado y etiquetado de los medicamentos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Desarrollo de Directrices**:\n   - Se presentaron borradores de directrices al Comit\u00e9 de Expertos de la OMS en varias ocasiones entre 2010 y 2011, con revisiones y comentarios continuos.\n   - La participaci\u00f3n de 26 fabricantes en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS fue fundamental en el proceso de consulta.\n\n2. **Cambio de T\u00edtulo**:\n   - El t\u00edtulo de las directrices se modific\u00f3 a *Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part* para aclarar su aplicabilidad al proceso de precalificaci\u00f3n.\n\n3. **Desarrollo de Medicamentos Pedi\u00e1tricos**:\n   - Se enfatiza la necesidad de desarrollar formulaciones espec\u00edficas para ni\u00f1os, dado que los medicamentos para adultos no son adecuados.\n   - Se menciona el uso generalizado de medicamentos no autorizados y fuera de indicaci\u00f3n en la poblaci\u00f3n pedi\u00e1trica, as\u00ed como la falta de estudios sobre sus efectos.\n\n4. **Desaf\u00edos en la Formulaci\u00f3n**:\n   - La falta de formulaciones adecuadas para la edad de los ni\u00f1os y la necesidad de manipular medicamentos adultos son desaf\u00edos significativos.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Instituci\u00f3n responsable de la elaboraci\u00f3n de las directrices.\n- **Comit\u00e9 de Expertos**: Grupo que revis\u00f3 y adopt\u00f3 las directrices.\n- **Programa de Precalificaci\u00f3n de Medicamentos de la OMS**: Iniciativa que involucra a fabricantes en el desarrollo de medicamentos.\n- **Fabricantes**: 26 empresas que participaron en el proceso de consulta para las directrices.\n- **Pacientes Pedi\u00e1tricos**: Grupo objetivo para el desarrollo de formulaciones adecuadas. \n\nEste resumen destaca la importancia de la colaboraci\u00f3n entre fabricantes y la OMS en la creaci\u00f3n de directrices para medicamentos gen\u00e9ricos y la necesidad urgente de abordar los desaf\u00edos en la formulaci\u00f3n de medicamentos para ni\u00f1os.", "excerpt_keywords": "Keywords: pediatric medicines, dosage accuracy, WHO initiative, pharmaceutical development, formulation design"}}, "c00e0952-bef5-421a-961e-2802215a3203": {"node_ids": ["90460357-fb8e-4818-8d70-6d781b75a5f2"], "metadata": {"page_label": "51", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Provision by Health-Care Professionals of Patient-Specific Preparations for Children That Are Not Available as Authorized Products: Points to Consider\n\nIn March 2011, the Expert Committee on the Selection and Use of Essential Medicines reviewed the current development of guidance on the extemporaneous preparation of medicines for children and noted the preliminary draft commissioned by the WHO Department of Essential Medicines and Pharmaceutical Policies (now WHO Department of Essential Medicines and Health Products). The Expert Committee on the Selection and Use of Essential Medicines accepted that there may be situations where extemporaneous preparation of medicines for children was necessary, but members expressed concern about the risks of inappropriate preparations. The Committee also considered the risks of diverting efforts aimed at the development of age-appropriate dosage forms for children and indicated that WHO\u2019s endorsement of extemporaneous use should not be seen in any way as indicating a lack of need for commercially available paediatric dosage forms. The Committee raised concerns about potentially conflicting signals arising from a WHO publication that might appear to endorse wider use of manipulation of adult dosage forms for children. Notwithstanding these concerns, the Committee on the Selection and Use of Essential Medicines agreed that the document should be finalized for publication as a time-limited guidance that addresses the current need for advice, including review by the Expert Committee on Specifications for Pharmaceutical Preparations. It was noted that consideration could be given to publication of this guidance document by an organization other than WHO.\n\nThe document was discussed during the informal consultation on paediatric and generics guidelines in May 2011 under the auspices of the Expert Committee on Specifications for Pharmaceutical Preparations. The participants suggested modifying the title to avoid reference to \u201cextemporaneous\u201d and also suggested aligning the title of this document with other similar guidance texts currently under development as \u201cpoints to consider\u201d.\n\nThe document makes it clear that children should have access to authorized, ready-to-administer, age-appropriate preparations of medicines and nothing in the document should detract from this objective. However, the document recognized that such preparations will not always be available and a safe and effective alternative must be sought. In the context of neonatal and paediatric pharmacy practice, the technique of compounding is used by pharmacists to produce medicines from ingredients when no commercially available, authorized, age-appropriate dosage form exists. Compared to the use of authorized medicines there are significant risks; quality, safety and efficacy can", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de Nivel Superior\n\nEl documento de la OMS aborda la necesidad de preparar medicamentos espec\u00edficos para ni\u00f1os cuando no est\u00e1n disponibles en formas autorizadas y adecuadas para su edad. En marzo de 2011, un comit\u00e9 de expertos revis\u00f3 la gu\u00eda sobre la preparaci\u00f3n extempor\u00e1nea de medicamentos para ni\u00f1os, reconociendo que, aunque puede ser necesaria, existen riesgos asociados con estas pr\u00e1cticas. Se enfatiza que los ni\u00f1os deben tener acceso a medicamentos autorizados y que la preparaci\u00f3n de medicamentos debe ser una alternativa segura y efectiva solo cuando no haya opciones disponibles. Adem\u00e1s, se discute la importancia de no desviar esfuerzos hacia la creaci\u00f3n de formas de dosificaci\u00f3n adecuadas para la pediatr\u00eda.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los riesgos asociados con la preparaci\u00f3n extempor\u00e1nea de medicamentos para ni\u00f1os seg\u00fan el documento de la OMS?**\n   - El documento menciona que existen riesgos significativos en t\u00e9rminos de calidad, seguridad y eficacia al utilizar preparaciones extempor\u00e1neas en comparaci\u00f3n con medicamentos autorizados.\n\n2. **\u00bfQu\u00e9 recomendaciones se hicieron durante la consulta informal sobre las pautas pedi\u00e1tricas y de gen\u00e9ricos en mayo de 2011?**\n   - Durante la consulta, se sugiri\u00f3 modificar el t\u00edtulo del documento para evitar la referencia a \"extempor\u00e1neo\" y alinearlo con otros textos de orientaci\u00f3n similares en desarrollo, denomin\u00e1ndolo \"puntos a considerar\".\n\n3. **\u00bfQu\u00e9 papel juega la t\u00e9cnica de compounding en la pr\u00e1ctica farmac\u00e9utica neonatal y pedi\u00e1trica seg\u00fan el documento?**\n   - La t\u00e9cnica de compounding permite a los farmac\u00e9uticos producir medicamentos a partir de ingredientes cuando no existe una forma de dosificaci\u00f3n autorizada y adecuada para la edad en el mercado, aunque conlleva riesgos adicionales en comparaci\u00f3n con el uso de medicamentos autorizados.", "prev_section_summary": "### Temas Clave\n\n1. **Riesgos de Manipulaci\u00f3n de Medicamentos**: Se destaca que la manipulaci\u00f3n de medicamentos no dise\u00f1ados espec\u00edficamente para ni\u00f1os puede aumentar el riesgo de errores en la dosificaci\u00f3n, afectar la estabilidad y biodisponibilidad del producto, y exponer a los ni\u00f1os a sobredosis o subdosificaci\u00f3n.\n\n2. **Iniciativa \"Make medicines child size\"**: Lanzada por la OMS en diciembre de 2007, esta iniciativa busca mejorar la disponibilidad y el acceso a medicamentos espec\u00edficos para ni\u00f1os. Incluye el desarrollo de gu\u00edas sobre la formulaci\u00f3n de medicamentos pedi\u00e1tricos.\n\n3. **Desarrollo de Medicamentos Pedi\u00e1tricos**: Se discuten las revisiones y consultas realizadas por el Comit\u00e9 de Expertos de la OMS sobre el desarrollo de medicamentos pedi\u00e1tricos, abordando aspectos como la formulaci\u00f3n, dosificaci\u00f3n y administraci\u00f3n.\n\n4. **Consideraciones en la Formulaci\u00f3n**: Las gu\u00edas abordan la conveniencia, fiabilidad, aceptabilidad, dosificaci\u00f3n m\u00ednima y necesidades del usuario final, as\u00ed como las formas de dosificaci\u00f3n pedi\u00e1trica, dise\u00f1o de formulaciones, m\u00e9todos de administraci\u00f3n, y empaquetado y etiquetado.\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo que lidera la iniciativa y desarrolla gu\u00edas para medicamentos pedi\u00e1tricos.\n- **Comit\u00e9 de Expertos de la OMS**: Grupo que revisa y discute las gu\u00edas y documentos relacionados con medicamentos pedi\u00e1tricos.\n- **Medicamentos Pedi\u00e1tricos**: Medicamentos dise\u00f1ados espec\u00edficamente para el uso en ni\u00f1os, considerando sus necesidades y caracter\u00edsticas particulares. \n\nEste resumen encapsula los puntos m\u00e1s relevantes y las entidades involucradas en el desarrollo y la regulaci\u00f3n de medicamentos pedi\u00e1tricos seg\u00fan el documento.", "excerpt_keywords": "Keywords: extemporaneous preparation, pediatric medicines, compounding, authorized dosage forms, WHO guidelines"}}, "7235eb94-381a-4475-92f9-fbc7dc5a06fc": {"node_ids": ["030800a8-66a7-4742-8fff-16fa98f54973"], "metadata": {"page_label": "52", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Quality Requirements for Artemisinin as a Starting Material in the Production of Antimalarial Active Pharmaceutical Ingredients\n\nOn various occasions, including at workshops organized by WHO and the Medicines for Malaria Venture, issues relating to quality control specifications applicable to active substances used not only by themselves, but also as starting materials for other active substances, have been discussed. The main challenge identified was that often, when used as starting materials for derivatives, for example when artemisinin is used in the manufacture of artemisinin-derived APIs, these substances were dealt with by some national authorities applying the same control requirements as when they are used directly for manufacturing of FPPs.\n\nQuality control specifications applicable to APIs are often used not only for the active substance itself but also to control the quality of starting materials for the production of other active substances. An example is artemisinin which is an important API and also serves as a starting material for the production of artemisinin-derived antimalarials.\n\nSome national authorities require the same quality standard (i.e. they apply the same limits) for an API and for a starting material. However, it is sufficient for a starting material to have a quality that guarantees that the final product meets the relevant pharmacopoeial standard. Demanding that a starting material meets a quality standard that is too exacting is likely to increase the price and to reduce access to the related FPPs.\n\nOn the basis of a request from the international community, a guidance document on *Quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients* was prepared to clarify the need for different quality levels for artemisinin. The document includes a specification for artemisinin used as a starting material, which was based on proposals made by the manufacturers.\n\n----\n\n3 Regulatory support: Paediatric Medicines Regulatory Network. *WHO Drug Information*, 2011, 25:240\u2013241.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Importancia de la calidad de artemisinina**: La artemisinina es un ingrediente farmac\u00e9utico activo (API) crucial en la producci\u00f3n de medicamentos antipal\u00fadicos. Su calidad es fundamental no solo para su uso directo, sino tambi\u00e9n como material de partida para la fabricaci\u00f3n de derivados antipal\u00fadicos.\n\n2. **Desaf\u00edos en la regulaci\u00f3n**: Existen desaf\u00edos en la regulaci\u00f3n de la calidad de los materiales de partida, ya que algunas autoridades nacionales aplican los mismos est\u00e1ndares de calidad para los API y los materiales de partida, lo que puede ser excesivo y afectar el acceso a los medicamentos.\n\n3. **Gu\u00eda de calidad**: En respuesta a la necesidad de aclarar los diferentes niveles de calidad requeridos para la artemisinina, se elabor\u00f3 un documento de orientaci\u00f3n que establece especificaciones para su uso como material de partida, basado en propuestas de los fabricantes.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las implicaciones de aplicar los mismos est\u00e1ndares de calidad para artemisinina como API y como material de partida?**\n   - Esta pregunta busca explorar c\u00f3mo la aplicaci\u00f3n de est\u00e1ndares de calidad excesivos puede afectar el costo y la disponibilidad de los medicamentos antipal\u00fadicos.\n\n2. **\u00bfQu\u00e9 criterios se consideran suficientes para garantizar que un material de partida cumpla con los est\u00e1ndares farmacop\u00e9uticos relevantes?**\n   - Esta pregunta se centra en los criterios espec\u00edficos que se deben cumplir para que un material de partida sea considerado adecuado para la producci\u00f3n de medicamentos, sin necesidad de cumplir con est\u00e1ndares excesivos.\n\n3. **\u00bfQu\u00e9 propuestas de los fabricantes se incluyeron en el documento de orientaci\u00f3n sobre los requisitos de calidad para la artemisinina?**\n   - Esta pregunta busca detalles sobre las contribuciones espec\u00edficas de los fabricantes que llevaron a la elaboraci\u00f3n de las especificaciones de calidad para la artemisinina como material de partida.", "prev_section_summary": "### Temas Clave\n\n1. **Preparaci\u00f3n Extempor\u00e1nea de Medicamentos para Ni\u00f1os**: El documento aborda la necesidad de preparar medicamentos espec\u00edficos para ni\u00f1os cuando no est\u00e1n disponibles en formas autorizadas y adecuadas para su edad.\n\n2. **Riesgos Asociados**: Se reconocen los riesgos significativos en t\u00e9rminos de calidad, seguridad y eficacia al utilizar preparaciones extempor\u00e1neas en comparaci\u00f3n con medicamentos autorizados.\n\n3. **Acceso a Medicamentos Autorizados**: Se enfatiza que los ni\u00f1os deben tener acceso a medicamentos autorizados y que la preparaci\u00f3n de medicamentos debe ser una alternativa segura y efectiva solo cuando no haya opciones disponibles.\n\n4. **Desarrollo de Formas de Dosificaci\u00f3n Adecuadas**: Se discute la importancia de no desviar esfuerzos hacia la creaci\u00f3n de formas de dosificaci\u00f3n adecuadas para la pediatr\u00eda.\n\n5. **Consulta Informal y Recomendaciones**: Durante una consulta informal en mayo de 2011, se sugiri\u00f3 modificar el t\u00edtulo del documento para evitar la referencia a \"extempor\u00e1neo\" y alinearlo con otros textos de orientaci\u00f3n similares.\n\n6. **T\u00e9cnica de Compounding**: La t\u00e9cnica de compounding permite a los farmac\u00e9uticos producir medicamentos a partir de ingredientes cuando no existe una forma de dosificaci\u00f3n autorizada y adecuada para la edad en el mercado, aunque conlleva riesgos adicionales.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Instituci\u00f3n que comision\u00f3 el desarrollo de la gu\u00eda sobre la preparaci\u00f3n extempor\u00e1nea de medicamentos.\n- **Comit\u00e9 de Expertos en la Selecci\u00f3n y Uso de Medicamentos Esenciales**: Grupo que revis\u00f3 la gu\u00eda y expres\u00f3 preocupaciones sobre los riesgos de las preparaciones extempor\u00e1neas.\n- **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**: Particip\u00f3 en la discusi\u00f3n del documento y en la consulta informal sobre pautas pedi\u00e1tricas y de gen\u00e9ricos. \n\nEste resumen destaca los puntos clave y las entidades relevantes en el contexto de la preparaci\u00f3n de medicamentos para ni\u00f1os, seg\u00fan el documento de la OMS.", "excerpt_keywords": "Keywords: artemisinin, quality control, active pharmaceutical ingredients, regulatory standards, antimalarial"}}, "f37dd787-a0ae-4e22-ad33-736fb2312c06": {"node_ids": ["1c042233-d725-4cf0-b685-5e86b722927d"], "metadata": {"page_label": "53", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe first working document was circulated in March\u2013April 2010 and comments received were first discussed during an informal consultation. A revised version was circulated and the further comments received were discussed at the meeting of the Expert Committee in October 2010. As the assignment of the impurities in the test for related substances in the first revision was tentative and based on the available scientific publications, the Expert Committee members recognized the need to clarify the impurity profile before the document could be completed.\n\nThe task of elucidating the impurity pattern was carried out by EDQM. The retention times of artemisitene and 9-epi artemisinin were identified and a correction factor for artemisitene was determined. It was revealed that the impurity assignment published in the first revision was incorrect. On the basis of this information, a second revision was prepared and circulated for comments in August 2011.\n\nThe Expert Committee reviewed the second revision of the quality requirements and considered the comments received.\n\nThe Expert Committee adopted the document on *Recommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients* subject to inclusion of the agreed changes, based on the comments received and those made during the discussion (Annex 6).\n\n## 11.8 Update on comparator products\n\nIt was reported to the Expert Committee that the secretariat was working on the update of the list of comparator products and the assistance of the members of the Committee was requested in order that the list might be published on the website as soon as possible to replace the version adopted in 2002.\n\n# 12. Nomenclature, terminology and databases\n\n## 12.1 Quality assurance terminology\n\n### Quality assurance database\n\nThe WHO quality assurance terminology database was established in August 2005. The entries in this database are taken from the glossary definitions in WHO guidelines pertaining to quality assurance activities. The objectives of the database are to foster the understanding of quality assurance-related activities, promote harmonization in quality assurance terminology globally, and to avoid misunderstandings that may result from the different terms used in various publications and their interpretations. The publications used as a source of information to create the WHO quality assurance terminology database are the quality assurance guidelines adopted by the Expert Committee on Specifications for Pharmaceutical Preparations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas basadas en el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento se centra en las actividades del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, destacando el proceso de revisi\u00f3n y actualizaci\u00f3n de los requisitos de calidad para la artemisinina, un material de partida en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos. Se menciona la importancia de clarificar el perfil de impurezas y la creaci\u00f3n de una base de datos de terminolog\u00eda de aseguramiento de calidad para promover la armonizaci\u00f3n global en este \u00e1mbito.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 errores se identificaron en la primera revisi\u00f3n del perfil de impurezas de la artemisinina y c\u00f3mo se corrigieron en la segunda revisi\u00f3n?**\n   - La primera revisi\u00f3n conten\u00eda una asignaci\u00f3n incorrecta de impurezas, que fue corregida tras la identificaci\u00f3n de los tiempos de retenci\u00f3n de artemisitene y 9-epi artemisinin, as\u00ed como la determinaci\u00f3n de un factor de correcci\u00f3n para artemisitene.\n\n2. **\u00bfCu\u00e1l es el objetivo principal de la base de datos de terminolog\u00eda de aseguramiento de calidad de la OMS?**\n   - El objetivo principal es fomentar la comprensi\u00f3n de las actividades relacionadas con el aseguramiento de calidad, promover la armonizaci\u00f3n en la terminolog\u00eda de aseguramiento de calidad a nivel global y evitar malentendidos derivados de los diferentes t\u00e9rminos utilizados en diversas publicaciones.\n\n3. **\u00bfQu\u00e9 acciones se est\u00e1n tomando para actualizar la lista de productos comparadores y por qu\u00e9 es importante esta actualizaci\u00f3n?**\n   - Se est\u00e1 trabajando en la actualizaci\u00f3n de la lista de productos comparadores, y se solicit\u00f3 la asistencia de los miembros del Comit\u00e9 para que la lista se publique en el sitio web lo antes posible, reemplazando la versi\u00f3n adoptada en 2002, lo que es crucial para mantener la relevancia y precisi\u00f3n de la informaci\u00f3n disponible.", "prev_section_summary": "### Temas Clave\n\n1. **Calidad de la Artemisinina**: La artemisinina es un ingrediente farmac\u00e9utico activo (API) esencial en la producci\u00f3n de medicamentos antipal\u00fadicos y tambi\u00e9n se utiliza como material de partida para la fabricaci\u00f3n de derivados antipal\u00fadicos.\n\n2. **Desaf\u00edos Regulatorios**: Existen dificultades en la regulaci\u00f3n de los est\u00e1ndares de calidad, ya que algunas autoridades nacionales aplican los mismos requisitos para los API y los materiales de partida, lo que puede ser excesivo y afectar la accesibilidad de los medicamentos.\n\n3. **Gu\u00eda de Calidad**: Se elabor\u00f3 un documento de orientaci\u00f3n para establecer diferentes niveles de calidad requeridos para la artemisinina, basado en propuestas de los fabricantes, con el fin de aclarar las especificaciones necesarias para su uso como material de partida.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Organismo que ha organizado talleres y ha participado en la elaboraci\u00f3n de gu\u00edas sobre la calidad de la artemisinina.\n- **Medicines for Malaria Venture**: Organizaci\u00f3n que ha colaborado con la OMS en la discusi\u00f3n de especificaciones de control de calidad.\n- **Fabricantes de Artemisinina**: Proveedores que han contribuido con propuestas para la elaboraci\u00f3n de especificaciones de calidad en el documento de orientaci\u00f3n.\n\n### Resumen\n\nLa secci\u00f3n aborda la importancia de la calidad de la artemisinina como un API y material de partida en la producci\u00f3n de medicamentos antipal\u00fadicos. Se identifican desaf\u00edos regulatorios relacionados con la aplicaci\u00f3n de est\u00e1ndares de calidad excesivos por parte de algunas autoridades nacionales, lo que puede limitar el acceso a los medicamentos. En respuesta a estas preocupaciones, se ha desarrollado un documento de orientaci\u00f3n que establece especificaciones de calidad diferenciadas para la artemisinina, basado en las propuestas de los fabricantes.", "excerpt_keywords": "Keywords: artemisinin, quality assurance, impurities, pharmaceutical preparations, WHO Expert Committee"}}, "0f9cfec0-3710-475b-98d8-3a7e1b5d3913": {"node_ids": ["56e788c1-6606-4f05-ad81-1981de9b5d5a"], "metadata": {"page_label": "54", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe WHO quality assurance terminology database has been updated to include all definitions published in glossaries of guidelines from the Expert Committee meeting reports since the Committee was established in 1947. The database currently includes terms and their definitions from a total of 52 guidelines. The number of terms and their definitions is 528; however, the number of entries of terms is more than 800 because many of the terms have been defined differently in various publications or may have differing definitions according to their context. The database clearly indicates in which publication(s) a particular term was defined.\n\nThe terminology database is intended to be a simple tool for editing and retrieving terminology records and should be updated and enlarged periodically.\n\nThe Expert Committee much appreciated this work carried out by the secretariat and decided to set up a group of experts to continue the work on the preferred terminology.\n\n## Definition of API\n\nIn many WHO guidelines the definition for an active pharmaceutical ingredient (API) (singular) is found in the Glossary (for instance it appears three times in the WHO Technical Report Series, No. 961). The definition currently used is:\n\n*\"active pharmaceutical ingredient (API)  \nAny substance or combination of substances used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.\"*\n\nThis definition may imply that commercially available premixes of APIs (such as the popular amoxicillin + clavulanic acid premix) can be regarded as an API, although this would normally be considered to be incorrect. Once an API is mixed with another API, or with an excipient, it is usually no longer considered an API. Thus the current definition may lead to misinterpretation.\n\nThe Expert Committee decided to defer this matter to the group of experts mentioned above who would continue the work on the quality assurance terminology.\n\n## 12.2 International Nonproprietary Names for pharmaceutical substances\n\nThe International Nonproprietary Names (INN) team presented the current status of the INN list. Some 61 names were currently in preparation. Six new stems and two new pre-stems were published recently.\n\nOf 92 INN requests in the past year, 44 were for biologicals. A revised naming policy for biologicals had been adopted and would be published in Bioreview in 2011. According to this policy, additional Arabic numbers might be used to distinguish subspecies which differ significantly.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en la actualizaci\u00f3n de la base de datos de terminolog\u00eda de aseguramiento de calidad de la OMS, que incluye definiciones de t\u00e9rminos utilizados en gu\u00edas desde 1947. Se menciona la definici\u00f3n de \"ingrediente farmac\u00e9utico activo\" (API) y se discuten las implicaciones de esta definici\u00f3n, especialmente en relaci\u00f3n con las mezclas comerciales de APIs. Adem\u00e1s, se presenta el estado actual de los Nombres Comunes Internacionales (INN) para sustancias farmac\u00e9uticas, destacando la preparaci\u00f3n de nuevos nombres y una pol\u00edtica revisada para los biol\u00f3gicos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1ntas definiciones de t\u00e9rminos est\u00e1n actualmente incluidas en la base de datos de terminolog\u00eda de la OMS y cu\u00e1ntas entradas de t\u00e9rminos hay en total?**\n   - La base de datos incluye 528 definiciones de t\u00e9rminos, pero hay m\u00e1s de 800 entradas de t\u00e9rminos debido a las diferentes definiciones en diversas publicaciones.\n\n2. **\u00bfQu\u00e9 implicaciones tiene la definici\u00f3n actual de \"ingrediente farmac\u00e9utico activo\" (API) en relaci\u00f3n con las mezclas comerciales de APIs?**\n   - La definici\u00f3n actual puede llevar a la interpretaci\u00f3n err\u00f3nea de que las mezclas comerciales de APIs, como el premix de amoxicilina + \u00e1cido clavul\u00e1nico, pueden considerarse como un API, aunque normalmente no se considera correcto. Una vez que un API se mezcla con otro API o con un excipiente, generalmente ya no se considera un API.\n\n3. **\u00bfCu\u00e1l es el estado actual de los Nombres Comunes Internacionales (INN) y qu\u00e9 cambios se han realizado en la pol\u00edtica de nombramiento para biol\u00f3gicos?**\n   - Actualmente, hay 61 nombres en preparaci\u00f3n y se han recibido 92 solicitudes de INN en el \u00faltimo a\u00f1o, de las cuales 44 eran para biol\u00f3gicos. Se ha adoptado una pol\u00edtica de nombramiento revisada para biol\u00f3gicos que se publicar\u00e1 en Bioreview en 2011, permitiendo el uso de n\u00fameros \u00e1rabes adicionales para distinguir subspecies que difieren significativamente.", "prev_section_summary": "### Temas Clave\n\n1. **Revisi\u00f3n de Requisitos de Calidad**: El documento detalla el proceso de revisi\u00f3n y actualizaci\u00f3n de los requisitos de calidad para la artemisinina, un material esencial en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos.\n\n2. **Clarificaci\u00f3n del Perfil de Impurezas**: Se identific\u00f3 que la asignaci\u00f3n de impurezas en la primera revisi\u00f3n era incorrecta, lo que llev\u00f3 a la necesidad de clarificar el perfil de impurezas antes de finalizar el documento.\n\n3. **Colaboraci\u00f3n con EDQM**: La tarea de elucidaci\u00f3n del patr\u00f3n de impurezas fue realizada por la Oficina Europea de Calidad de los Medicamentos (EDQM), que ayud\u00f3 a identificar tiempos de retenci\u00f3n y a establecer un factor de correcci\u00f3n.\n\n4. **Actualizaci\u00f3n de Productos Comparadores**: Se est\u00e1 trabajando en la actualizaci\u00f3n de la lista de productos comparadores, con el objetivo de reemplazar la versi\u00f3n adoptada en 2002, lo que es crucial para mantener la precisi\u00f3n de la informaci\u00f3n.\n\n5. **Base de Datos de Terminolog\u00eda de Aseguramiento de Calidad**: Se estableci\u00f3 una base de datos en 2005 para promover la comprensi\u00f3n y la armonizaci\u00f3n de la terminolog\u00eda relacionada con el aseguramiento de calidad a nivel global.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Organismo responsable de la elaboraci\u00f3n de directrices y recomendaciones en el \u00e1mbito de la salud p\u00fablica.\n- **EDQM (Oficina Europea de Calidad de los Medicamentos)**: Entidad que colabor\u00f3 en la clarificaci\u00f3n del perfil de impurezas de la artemisinina.\n- **Artemisinina**: Material de partida en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos.\n- **Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas**: Grupo encargado de revisar y adoptar documentos relacionados con los est\u00e1ndares de calidad en farmac\u00e9uticos.\n- **Base de Datos de Terminolog\u00eda de Aseguramiento de Calidad de la OMS**: Recurso creado para estandarizar y clarificar la terminolog\u00eda utilizada en actividades de aseguramiento de calidad.", "excerpt_keywords": "Keywords: WHO, quality assurance, active pharmaceutical ingredient, International Nonproprietary Names, terminology database"}}, "a47584cc-401a-483b-80c0-3467e6a1ba9d": {"node_ids": ["69b4525d-bed7-4d07-b0c3-df453f703535"], "metadata": {"page_label": "55", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe INN team had also worked on establishing definitions of the different INNs. This meant attempting to obtain further information from the companies concerned, but this task had been complicated by the fact that some companies no longer existed or had been incorporated into other companies. An internal document on these definitions had been prepared.\n\nApplications for new INNs could now be made through an online interface, which enables more data to be collected than is possible in print form. There is an online application form which, when filled in, is transferred to the user by a secure transfer (in an encrypted file as used in e-banking). Once stored on the server, the data are also encrypted, and the server is protected by the usual WHO firewall and security systems. The aim was to create a global INN data hub to which access would be very restricted and secure. Any use of the data not in line with the rules of the INN application process would lead to refusal of access. Beta-testing was due to take place later in 2011.\n\nThe Expert Committee took note of the INN report.\n\n## 13. Miscellaneous\n\n### 13.1 Brochures on the Expert Committee and on quality assurance of pharmaceuticals\n\nThe new brochure on the Expert Committee on Specifications for Pharmaceutical Preparations summarizes how the Expert Committee works and provides detailed information on the process of the Committee. The second information brochure on quality assurance of pharmaceuticals summarizes the main areas covered by the Expert Committee in the past three years.\n\nIn addition, a CD-ROM had been prepared, including all current guidelines and guidance texts adopted by the Expert Committee and which are also available on the WHO web site in a structured manner according to their subjects, e.g. production, distribution, and so on. A new updated CD-ROM would be issued in due course with the recommendations from the 2011 meeting.\n\nThe Expert Committee expressed its appreciation to the Secretary for the content and design of the brochures developed and the CD-ROM on medicines quality assurance.\n\n### 13.2 Sampling procedures for monitoring of market situations\n\nThe development of sampling procedures for monitoring of market situations had been initiated in response to multiple requests from colleagues carrying out studies. Following a wide enquiry a great deal of material had been received from many countries. The outcome and draft procedures resulting from the evaluation of the material received would be presented to the next Expert Committee meeting.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento se centra en las actividades del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas, destacando el trabajo del equipo de Nombres Comunes Internacionales (INN) en la definici\u00f3n de INNs y la implementaci\u00f3n de un sistema en l\u00ednea para la solicitud de nuevos INNs. Tambi\u00e9n se menciona la creaci\u00f3n de folletos informativos sobre el funcionamiento del Comit\u00e9 y la garant\u00eda de calidad de los productos farmac\u00e9uticos, as\u00ed como el desarrollo de procedimientos de muestreo para el monitoreo de situaciones del mercado.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las medidas de seguridad implementadas para proteger los datos en el nuevo sistema de solicitud de INNs?**\n   - El sistema utiliza transferencia segura de datos en archivos encriptados, almacenamiento en un servidor protegido por un firewall de la OMS y sistemas de seguridad, asegurando que el acceso a los datos sea muy restringido y seguro.\n\n2. **\u00bfQu\u00e9 tipo de materiales se incluyeron en el CD-ROM preparado por el Comit\u00e9 de Expertos?**\n   - El CD-ROM incluye todas las gu\u00edas y textos de orientaci\u00f3n actuales adoptados por el Comit\u00e9 de Expertos, organizados de manera estructurada seg\u00fan sus temas, como producci\u00f3n y distribuci\u00f3n.\n\n3. **\u00bfQu\u00e9 motiv\u00f3 el desarrollo de procedimientos de muestreo para el monitoreo de situaciones del mercado?**\n   - El desarrollo de estos procedimientos fue iniciado en respuesta a m\u00faltiples solicitudes de colegas que llevaban a cabo estudios, lo que llev\u00f3 a una amplia recopilaci\u00f3n de material de muchos pa\u00edses para su evaluaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Actualizaci\u00f3n de la Base de Datos de Terminolog\u00eda de Aseguramiento de Calidad de la OMS**:\n   - La base de datos incluye definiciones de t\u00e9rminos de 52 gu\u00edas desde 1947.\n   - Contiene 528 definiciones de t\u00e9rminos, con m\u00e1s de 800 entradas debido a variaciones en las definiciones.\n\n2. **Definici\u00f3n de Ingrediente Farmac\u00e9utico Activo (API)**:\n   - La definici\u00f3n actual de API implica que cualquier sustancia en un producto farmac\u00e9utico terminado que tenga actividad farmacol\u00f3gica se considera un API.\n   - Se se\u00f1ala que las mezclas comerciales de APIs pueden ser malinterpretadas como APIs, lo cual no es correcto seg\u00fan la definici\u00f3n.\n\n3. **Nombres Comunes Internacionales (INN)**:\n   - Actualmente hay 61 nombres en preparaci\u00f3n y 92 solicitudes de INN en el \u00faltimo a\u00f1o, de las cuales 44 son para biol\u00f3gicos.\n   - Se ha adoptado una pol\u00edtica revisada para el nombramiento de biol\u00f3gicos, que se publicar\u00e1 en Bioreview en 2011, permitiendo el uso de n\u00fameros \u00e1rabes para distinguir subspecies.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la actualizaci\u00f3n de la base de datos y la definici\u00f3n de t\u00e9rminos.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: T\u00e9rmino clave definido en las gu\u00edas de la OMS.\n- **INN (Nombres Comunes Internacionales)**: Sistema de nomenclatura para sustancias farmac\u00e9uticas.\n- **Grupo de Expertos**: Se establece para continuar el trabajo sobre la terminolog\u00eda de aseguramiento de calidad.", "excerpt_keywords": "Keywords: INN, WHO, pharmaceutical preparations, quality assurance, sampling procedures"}}, "ddae9636-e1bb-4092-b751-008b1668c704": {"node_ids": ["b1c0805c-b0ae-447a-bd24-953d6550461a"], "metadata": {"page_label": "56", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThere was also a presentation on a new project within this area of work, particularly focusing on the SSFFC products. There was a deficiency of hard data on this issue and the project aimed to establish a global monitoring and surveillance system and disseminate data, to collate best practice and establish a minimum reporting standard on SSFFC products, to assist regulatory authorities to identify SSFFC products, to establish where the risks were greatest, and to encourage collaboration between regulatory authorities on this issue. This is a four-year project in five phases and is being carried out by the team for Quality Assurance and Safety: Medicines in WHO in close collaboration with the regional offices and countries.\n\nThe Expert Committee expressed its appreciation for the project and gave its endorsement. The Committee considered that the idea of having a watch list of products that were frequently falsified would be very helpful to NMRAs.\n\n## 13.3 Index of pharmacopoeias\n\nThis index, including all pharmacopoeias around the world, was first prepared in 2001 and has been regularly updated. In accordance with the recommendations made by the Expert Committee at its forty-fifth meeting, the Index of Pharmacopoeias had been revised. Africa has one pharmacopoeia (this is the African Pharmacopoeia and not a national pharmacopoeia), the Americas four, the Western Pacific has five, and Europe has 30. Of these, five national pharmacopoeias offer free online access, as does The International Pharmacopoeia of WHO. The index contains all contact information for the pharmacopoeias.\n\nThe Expert Committee took note of the report and advised the Secretary to complete and update the missing information in the index as notified by the respective pharmacopoeias.\n\n## 13.4 Collaboration with pharmacopoeias\n\nWHO was working on closer collaboration with a view to exchanging information with other pharmacopoeias and achieving further harmonization. A meeting was held in July 2011 with a number of representatives from secretariats of national pharmacopoeias. FIP would provide an opportunity for a meeting of pharmacopoeia representatives with other stakeholders in 2012, and WHO would offer to organize a private meeting for pharmacopoeia representatives only, to discuss common issues and concerns following up on discussions that had started during a side-meeting held at the 10th ICDRA meeting in Hong Kong Special Administrative Region of the People\u2019s Republic of China in 2002.\n\nThe Expert Committee took note of this initiative and expressed its support for an international meeting of world pharmacopoeias organized by WHO.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Proyecto sobre productos SSFFC**: Se present\u00f3 un nuevo proyecto enfocado en productos farmac\u00e9uticos falsificados y de calidad subest\u00e1ndar (SSFFC). Este proyecto tiene como objetivo establecer un sistema global de monitoreo y vigilancia, recopilar datos y mejores pr\u00e1cticas, y fomentar la colaboraci\u00f3n entre las autoridades regulatorias para identificar y gestionar los riesgos asociados con estos productos.\n\n2. **\u00cdndice de farmacopoeias**: Se ha actualizado el \u00cdndice de Farmacopeas, que incluye informaci\u00f3n sobre todas las farmacopeas del mundo. Este \u00edndice es una herramienta importante para las autoridades regulatorias y proporciona acceso a informaci\u00f3n de contacto y recursos sobre las farmacopeas.\n\n3. **Colaboraci\u00f3n con farmacopeas**: La OMS est\u00e1 trabajando en una colaboraci\u00f3n m\u00e1s estrecha con las farmacopeas nacionales para intercambiar informaci\u00f3n y lograr una mayor armonizaci\u00f3n. Se han planificado reuniones para discutir problemas comunes y fomentar la cooperaci\u00f3n internacional en este \u00e1mbito.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las fases del proyecto de monitoreo y vigilancia de productos SSFFC y qu\u00e9 objetivos espec\u00edficos se buscan alcanzar en cada fase?**\n   - Esta pregunta busca detalles sobre la estructura y los objetivos del proyecto, que no se mencionan expl\u00edcitamente en el texto.\n\n2. **\u00bfQu\u00e9 criterios se est\u00e1n considerando para la creaci\u00f3n de la lista de vigilancia de productos frecuentemente falsificados y c\u00f3mo se determinar\u00e1n los riesgos asociados?**\n   - Esta pregunta se centra en los criterios y metodolog\u00edas que se utilizar\u00e1n para identificar los productos en riesgo, lo cual no se detalla en el contexto.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n espec\u00edfica se est\u00e1 recopilando para completar y actualizar el \u00cdndice de Farmacopeas y cu\u00e1les son los desaf\u00edos que enfrenta la OMS en este proceso?**\n   - Esta pregunta busca informaci\u00f3n sobre el proceso de actualizaci\u00f3n del \u00edndice y los posibles obst\u00e1culos que la OMS podr\u00eda encontrar, que no se abordan en el texto proporcionado.", "prev_section_summary": "### Temas Clave\n\n1. **Nombres Comunes Internacionales (INN)**: El equipo de INN trabaj\u00f3 en la definici\u00f3n de diferentes INNs, enfrentando desaf\u00edos debido a la desaparici\u00f3n o fusi\u00f3n de algunas empresas.\n\n2. **Sistema de Solicitud en L\u00ednea**: Se implement\u00f3 un sistema en l\u00ednea para la solicitud de nuevos INNs, que permite la recolecci\u00f3n de datos de manera m\u00e1s eficiente y segura, utilizando transferencias encriptadas y almacenamiento protegido.\n\n3. **Folletos Informativos**: Se desarrollaron folletos que resumen el funcionamiento del Comit\u00e9 de Expertos y la garant\u00eda de calidad de los productos farmac\u00e9uticos.\n\n4. **CD-ROM de Directrices**: Se prepar\u00f3 un CD-ROM que incluye todas las gu\u00edas y textos de orientaci\u00f3n adoptados por el Comit\u00e9, organizados por temas.\n\n5. **Procedimientos de Muestreo**: Se iniciaron procedimientos de muestreo para monitorear situaciones del mercado en respuesta a solicitudes de colegas, con la evaluaci\u00f3n de material recibido de varios pa\u00edses.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Instituci\u00f3n responsable del Comit\u00e9 de Expertos y de la implementaci\u00f3n de los sistemas de INN.\n- **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**: Grupo que trabaja en la regulaci\u00f3n y calidad de los productos farmac\u00e9uticos.\n- **INN (Nombres Comunes Internacionales)**: Sistema de nomenclatura para medicamentos que busca estandarizar los nombres de los f\u00e1rmacos a nivel global.\n- **Empresas farmac\u00e9uticas**: Entidades involucradas en la provisi\u00f3n de informaci\u00f3n para la definici\u00f3n de INNs.\n\nEste resumen destaca los aspectos m\u00e1s relevantes y las entidades involucradas en la secci\u00f3n del documento.", "excerpt_keywords": "SSFFC, pharmacopoeias, global monitoring, regulatory authorities, collaboration"}}, "dc9219bc-3b73-47b7-bab5-523ceaf7cbc5": {"node_ids": ["f14f2f8a-bffa-4a5e-a747-fbb4633f2f62"], "metadata": {"page_label": "57", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 14. Summary and Recommendations\n\nThe Expert Committee on Specifications for Pharmaceutical Preparations provides recommendations and tools to assure the quality of medicines from their development phase to their final distribution to the patients. It advises the Director-General of the World Health Organization in the area of quality assurance of medicines.\n\nThe international guidelines, specifications and nomenclature developed under the aegis of this Committee serve all Member States, international organizations, United Nations agencies, regional and interregional harmonization efforts, and underpin important initiatives, including the prequalification of medicines, the Roll Back Malaria Programme, Stop TB, essential medicines and medicines for children.\n\nThe advice and recommendations provided by this Expert Committee are intended to help national and regional authorities and procurement agencies, as well as major international bodies and institutions, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria, and international organizations such as the United Nations Children\u2019s Fund (UNICEF) to combat circulation of substandard medicines and to work towards access to good-quality medicines.\n\nSince the inception of this WHO Expert Committee in 1948, its members have worked towards making available clear, independent and practical recommendations, written and physical standards, as well as international guidelines for good-quality medicines. Standards in the area of quality assurance for medicines are developed by the Committee through a wide global consultation process building on consensus to reach internationally recognized and up-to-date standards. Detailed recommendations can be found under each relevant section in the report.\n\nThe topics are related to various programmes and activities within WHO. There are joint activities, specifically in collaboration with the WHO Expert Committees on Biological Standardization, and on the Selection and Use of Essential Medicines and its Subcommittee on Medicines for Children. In addition, the Committee serves to develop specific additional guidance and specifications as needed for the various medicines recommended by WHO programmes.\n\nThis Committee also serves the United Nations Prequalification of Medicines Programme managed and operated by WHO, as the Programme could not function without the guidelines, standards and specifications adopted by this Committee after passage through its rigorous, international and wide consultative process. The advantage for the Committee is that, as a result of implementing these guidelines and specifications, practical suggestions for potential revision or on the need for additional guidance are communicated to the Expert Committee.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de Nivel Superior\n\nEl Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas de la OMS proporciona recomendaciones y herramientas para asegurar la calidad de los medicamentos desde su desarrollo hasta su distribuci\u00f3n final. Este Comit\u00e9 asesora al Director General de la OMS en materia de garant\u00eda de calidad de los medicamentos y desarrolla directrices, especificaciones y nomenclatura que benefician a todos los Estados miembros y organizaciones internacionales. Desde su creaci\u00f3n en 1948, ha trabajado en la elaboraci\u00f3n de est\u00e1ndares internacionales a trav\u00e9s de un proceso de consulta global. Adem\u00e1s, colabora con otros comit\u00e9s de la OMS y apoya el Programa de Precalificaci\u00f3n de Medicamentos de la ONU.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los principales programas e iniciativas que se benefician de las directrices y est\u00e1ndares desarrollados por el Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas?**\n   - Esta pregunta busca identificar los programas espec\u00edficos, como el Programa de Precalificaci\u00f3n de Medicamentos y otros, que dependen de las recomendaciones del Comit\u00e9.\n\n2. **\u00bfC\u00f3mo se asegura el Comit\u00e9 que sus recomendaciones y est\u00e1ndares sean actualizados y reconocidos internacionalmente?**\n   - Esta pregunta se centra en el proceso de consulta global y consenso que utiliza el Comit\u00e9 para desarrollar sus est\u00e1ndares, lo que puede no estar documentado en otros lugares.\n\n3. **\u00bfQu\u00e9 papel juega el Comit\u00e9 en la lucha contra la circulaci\u00f3n de medicamentos subest\u00e1ndar y c\u00f3mo colabora con otras organizaciones internacionales?**\n   - Esta pregunta busca explorar la funci\u00f3n espec\u00edfica del Comit\u00e9 en la mejora del acceso a medicamentos de buena calidad y su colaboraci\u00f3n con entidades como UNICEF y el Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Proyecto sobre Productos SSFFC**:\n   - **Objetivo**: Establecer un sistema global de monitoreo y vigilancia para productos farmac\u00e9uticos falsificados y de calidad subest\u00e1ndar (SSFFC).\n   - **Componentes**: Recopilaci\u00f3n de datos, establecimiento de est\u00e1ndares de reporte, identificaci\u00f3n de riesgos y fomento de la colaboraci\u00f3n entre autoridades regulatorias.\n   - **Duraci\u00f3n**: Proyecto de cuatro a\u00f1os dividido en cinco fases.\n   - **Entidades Involucradas**: Equipo de Aseguramiento de Calidad y Seguridad de Medicamentos de la OMS, oficinas regionales y pa\u00edses.\n\n2. **\u00cdndice de Farmacopeas**:\n   - **Descripci\u00f3n**: Compilaci\u00f3n de todas las farmacopeas del mundo, actualizada regularmente desde 2001.\n   - **Acceso**: Incluye informaci\u00f3n de contacto y recursos, con algunas farmacopeas nacionales ofreciendo acceso gratuito en l\u00ednea.\n   - **Distribuci\u00f3n Geogr\u00e1fica**: \u00c1frica (1), Am\u00e9ricas (4), Pac\u00edfico Occidental (5), Europa (30).\n   - **Recomendaciones**: La OMS debe completar y actualizar la informaci\u00f3n faltante en el \u00edndice.\n\n3. **Colaboraci\u00f3n con Farmacopeas**:\n   - **Iniciativa**: Fomentar la colaboraci\u00f3n y el intercambio de informaci\u00f3n entre farmacopeas nacionales para lograr una mayor armonizaci\u00f3n.\n   - **Reuniones**: Se han planificado encuentros para discutir problemas comunes y promover la cooperaci\u00f3n internacional.\n   - **Apoyo**: La Comisi\u00f3n de Expertos de la OMS respalda la organizaci\u00f3n de una reuni\u00f3n internacional de farmacopeas.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Coordinadora del proyecto y de las iniciativas de colaboraci\u00f3n.\n- **NMRAs (Autoridades Nacionales Reguladoras de Medicamentos)**: Beneficiarias de la lista de vigilancia de productos falsificados.\n- **FIP (Federaci\u00f3n Internacional Farmac\u00e9utica)**: Participante en la organizaci\u00f3n de reuniones de farmacopeas.\n\nEste resumen destaca los esfuerzos de la OMS para abordar la falsificaci\u00f3n de medicamentos y mejorar la colaboraci\u00f3n entre farmacopeas a nivel global.", "excerpt_keywords": "Keywords: quality assurance, pharmaceutical preparations, WHO guidelines, substandard medicines, international collaboration"}}, "ce329c44-b0da-402a-ab47-7055dd4d09c4": {"node_ids": ["7986a624-f104-4916-98a2-ca844c458894"], "metadata": {"page_label": "58", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIn conclusion, the Expert Committee on Specifications for Pharmaceutical Preparations gives recommendations and provides independent international standards and guidelines in the area of quality assurance for implementation by WHO Member States, international organizations, United Nations agencies, regional and interregional harmonization efforts, as well as WHO\u2019s medicines-related programmes and initiatives. Making resources available for these activities is, therefore, very cost-effective.\n\n## The following new guidelines were adopted and recommended for use:\n\n- Development of monographs for *The International Pharmacopoeia* (Annex 1)\n- WHO good manufacturing practices: water for pharmaceutical use (Annex 2)\n- Pharmaceutical development of multisource (generic) pharmaceutical products \u2013 points to consider (Annex 3)\n- Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (Annex 4)\n- Development of paediatric medicines: points to consider in formulation (Annex 5)\n- Recommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients (Annex 6)\n\n## For inclusion in *The International Pharmacopoeia*\n\nThe following monographs were adopted:\n\n- **For antiretroviral medicines**\n  - ritonavir tablets\n- **For antimalarial medicines**\n  - artesunate\n  - artenimol\n- **For antituberculosis medicines**\n  - rifampicin (API)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento es un informe de la Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. En \u00e9l se presentan recomendaciones y est\u00e1ndares internacionales en el \u00e1mbito de la garant\u00eda de calidad para su implementaci\u00f3n por parte de los Estados Miembros de la OMS y otras organizaciones. Se adoptaron nuevas directrices y monograf\u00edas para la *Farmacopea Internacional*, incluyendo pautas sobre buenas pr\u00e1cticas de fabricaci\u00f3n y el desarrollo de medicamentos pedi\u00e1tricos, as\u00ed como monograf\u00edas espec\u00edficas para medicamentos antirretrovirales, antimal\u00e1ricos y antituberculosos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las nuevas directrices adoptadas por la Comisi\u00f3n de Expertos de la OMS y qu\u00e9 \u00e1reas espec\u00edficas abordan?**\n   - Esta pregunta busca detalles sobre las directrices espec\u00edficas que se han adoptado, que no se encuentran f\u00e1cilmente en otros documentos.\n\n2. **\u00bfQu\u00e9 monograf\u00edas espec\u00edficas fueron adoptadas para la inclusi\u00f3n en la *Farmacopea Internacional* y para qu\u00e9 tipos de medicamentos?**\n   - Esta pregunta se centra en las monograf\u00edas adoptadas, proporcionando informaci\u00f3n espec\u00edfica sobre los medicamentos que se est\u00e1n regulando.\n\n3. **\u00bfPor qu\u00e9 se considera que hacer disponibles recursos para las actividades de la OMS es una medida costo-efectiva?**\n   - Esta pregunta busca una explicaci\u00f3n sobre la relaci\u00f3n costo-beneficio de las actividades de la OMS en el contexto de la calidad de los medicamentos, un aspecto que puede no estar ampliamente discutido en otros documentos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**: Este comit\u00e9 de la OMS proporciona recomendaciones y herramientas para asegurar la calidad de los medicamentos desde su desarrollo hasta su distribuci\u00f3n final.\n\n2. **Asesoramiento al Director General de la OMS**: El comit\u00e9 asesora en materia de garant\u00eda de calidad de los medicamentos.\n\n3. **Directrices y Especificaciones Internacionales**: Desarrolla normas y nomenclatura que benefician a todos los Estados miembros, organizaciones internacionales y agencias de la ONU, apoyando iniciativas como:\n   - Programa de Precalificaci\u00f3n de Medicamentos\n   - Programa Roll Back Malaria\n   - Stop TB\n   - Medicamentos esenciales y medicamentos para ni\u00f1os\n\n4. **Colaboraci\u00f3n con Otras Entidades**: Trabaja con autoridades nacionales y regionales, agencias de adquisici\u00f3n y organizaciones internacionales como:\n   - Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria\n   - UNICEF\n\n5. **Proceso de Consulta Global**: Los est\u00e1ndares se desarrollan a trav\u00e9s de un proceso de consulta amplia y consenso, asegurando que sean reconocidos y actualizados internacionalmente.\n\n6. **Actividades Conjuntas**: Colabora con otros comit\u00e9s de la OMS, como el de Estandarizaci\u00f3n Biol\u00f3gica y el de Selecci\u00f3n y Uso de Medicamentos Esenciales.\n\n7. **Programa de Precalificaci\u00f3n de Medicamentos de la ONU**: El comit\u00e9 proporciona las directrices y est\u00e1ndares necesarios para el funcionamiento de este programa.\n\nEste resumen destaca la importancia del Comit\u00e9 en la mejora de la calidad de los medicamentos y su papel en la colaboraci\u00f3n internacional para combatir medicamentos subest\u00e1ndar y mejorar el acceso a medicamentos de calidad.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, quality assurance, International Pharmacopoeia, guidelines"}}, "6658c379-d7e9-4694-822c-a280d86a3eb8": {"node_ids": ["8beb214c-52a8-4ed5-9bf7-a3917b88a815"], "metadata": {"page_label": "59", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- **rifampicin tablets**\n- **rifampicin capsules**\n\n## For anti-infectives\n- pyrantel chewable tablets\n\n## For other medicines\n- levonorgestrel tablets\n- medroxyprogesterone injection\n- paediatric retinol oral solution\n- retinol concentrate (oily form)\n\n## For harmonized general texts (based on PDG texts)\n- test for sulfated ash\n- test for bacterial endotoxins\n- test for sterility\n- tablet friability\n- disintegration test for tablets and capsules\n- bulk density and tapped density of powders\n- test for extractable volume for parenteral preparations\n- microbiological examination of non-sterile products: microbial enumeration tests\n- microbiological examination of non-sterile products: tests for specified microorganisms\n- microbial quality of pharmaceutical preparations\n- test for particulate contamination\n\n## General policy topics and general revision issues for:\n- uniformity of content for single-dose preparations\n- supplementary information section\n\n## The Committee adopted the following new ICRS:\n- Lumefantrine for system suitability\n\n## The following monograph was released for the wide consultation process:\n\n### For antimalarial medicines\n- mefloquine hydrochloride", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 tipos de medicamentos se mencionan en el informe de la OMS y cu\u00e1les son sus formas farmac\u00e9uticas?**\n   - El informe menciona varios medicamentos, incluyendo:\n     - **Rifampicina** en tabletas y c\u00e1psulas.\n     - **Pyrantel** en tabletas masticables (para anti-infectivos).\n     - **Levonorgestrel** en tabletas.\n     - **Medroxiprogesterona** en inyecci\u00f3n.\n     - **Soluci\u00f3n oral de retinol pedi\u00e1trica**.\n     - **Concentrado de retinol** (forma oleosa).\n\n2. **\u00bfCu\u00e1les son algunos de los m\u00e9todos de prueba estandarizados que se adoptaron para los textos generales armonizados?**\n   - Los m\u00e9todos de prueba estandarizados adoptados incluyen:\n     - Prueba de cenizas sulfatadas.\n     - Prueba de endotoxinas bacterianas.\n     - Prueba de esterilidad.\n     - Friabilidad de tabletas.\n     - Prueba de desintegraci\u00f3n para tabletas y c\u00e1psulas.\n     - Densidad a granel y densidad apilada de polvos.\n     - Prueba de volumen extra\u00edble para preparaciones parenterales.\n     - Examen microbiol\u00f3gico de productos no est\u00e9riles: pruebas de enumeraci\u00f3n microbiana y pruebas para microorganismos especificados.\n     - Calidad microbiana de preparaciones farmac\u00e9uticas.\n     - Prueba de contaminaci\u00f3n particulada.\n\n3. **\u00bfQu\u00e9 nuevo ICRS fue adoptado por el Comit\u00e9 y para qu\u00e9 se utiliza?**\n   - El Comit\u00e9 adopt\u00f3 un nuevo ICRS para **Lumefantrina**, que se utiliza para la idoneidad del sistema. Esto sugiere que se est\u00e1 estableciendo un est\u00e1ndar para asegurar que los sistemas de prueba sean adecuados para evaluar la calidad de este medicamento.\n\n### Resumen de nivel superior:\nEl informe de la OMS detalla las especificaciones para varios medicamentos, incluyendo rifampicina, pyrantel, levonorgestrel, y otros, as\u00ed como m\u00e9todos de prueba estandarizados para asegurar la calidad de las preparaciones farmac\u00e9uticas. Tambi\u00e9n se discuten temas de pol\u00edtica general y se adopta un nuevo ICRS para Lumefantrina, que se somete a un proceso de consulta amplia para la monograf\u00eda de mefloquina.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comisi\u00f3n de Expertos de la OMS**: Se centra en la elaboraci\u00f3n de recomendaciones y est\u00e1ndares internacionales para la garant\u00eda de calidad en preparaciones farmac\u00e9uticas.\n\n2. **Recomendaciones y Directrices**:\n   - Desarrollo de monograf\u00edas para *La Farmacopea Internacional*.\n   - Buenas pr\u00e1cticas de fabricaci\u00f3n de la OMS, espec\u00edficamente sobre agua para uso farmac\u00e9utico.\n   - Desarrollo farmac\u00e9utico de productos farmac\u00e9uticos multisource (gen\u00e9ricos).\n   - Pautas para la documentaci\u00f3n de productos farmac\u00e9uticos multisource para el Programa de Precalificaci\u00f3n de Medicamentos de la OMS.\n   - Consideraciones para el desarrollo de medicamentos pedi\u00e1tricos.\n   - Requisitos de calidad para la artemisinina como materia prima en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos.\n\n3. **Monograf\u00edas Adoptadas para la *Farmacopea Internacional***:\n   - **Medicamentos Antirretrovirales**: Ritonavir (tabletas).\n   - **Medicamentos Antimal\u00e1ricos**: Artesunato, artenimol.\n   - **Medicamentos Antituberculosos**: Rifampicina (API).\n\n4. **Costo-efectividad**: Se menciona que hacer disponibles recursos para las actividades de la OMS es una medida costo-efectiva, lo que implica un enfoque en la eficiencia y el impacto positivo de estas iniciativas en la calidad de los medicamentos a nivel global.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, rifampicin, ICRS, antimalarial medicines"}}, "649c3c29-abf1-4df6-99b3-8d65d2f0e119": {"node_ids": ["a26d3d50-863c-461b-aef6-8af8bc793082"], "metadata": {"page_label": "60", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Regulatory guidance\n\n## Extension of shelf-life\n\nThe Expert Committee recommended that each national authority, if opting to extend the shelf-life of oseltamivir and zanamivir, should take into consideration the following points to ensure that there was no negative impact on the patients:\n\n- The manufacturer should be consulted for evidence in support of extended shelf-life.\n- The products are maintained under storage conditions in compliance with the label requirements.\n- The national regulatory authority may wish to follow up with its own testing.\n\n# Recommendations in the quality assurance-related areas\n\nThe following recommendations were made in the various quality assurance-related areas. Progress on the suggested actions should be reported to the Expert Committee on Specifications for Pharmaceutical Preparations at its next meeting.\n\n## Collaboration with and among pharmacopoeias\n\n- The Expert Committee expressed support for WHO\u2019s initiative to work more closely with other pharmacopoeias. It also endorsed the proposed international meeting bringing together representatives of all the world\u2019s pharmacopoeias to enable them to discuss common issues and concerns.\n\n## The International Pharmacopoeia\n\n- Continue development of specifications for medicines, general methods and texts and general supplementary information in accordance with the work plan and as decided at the forty-sixth meeting.\n- Continue the efforts at international collaboration in relation to the revision and inclusion of specific monographs and general methods.\n- Continue the preparatory work for a subsequent supplement to *The International Pharmacopoeia*, or towards a fifth edition, especially in electronic form (CD-ROM and online).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda la extensi\u00f3n de la vida \u00fatil de los medicamentos oseltamivir y zanamivir, recomendando que las autoridades nacionales consideren ciertos puntos para garantizar la seguridad de los pacientes. Adem\u00e1s, se discuten recomendaciones en \u00e1reas relacionadas con la garant\u00eda de calidad, destacando la colaboraci\u00f3n entre farmacopoeias y el desarrollo continuo de especificaciones para medicamentos en *The International Pharmacopoeia*.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 pasos deben seguir las autoridades nacionales antes de extender la vida \u00fatil de oseltamivir y zanamivir?**\n   - Las autoridades nacionales deben consultar al fabricante para obtener evidencia que respalde la extensi\u00f3n de la vida \u00fatil, asegurarse de que los productos se mantengan bajo condiciones de almacenamiento adecuadas y considerar realizar pruebas adicionales.\n\n2. **\u00bfCu\u00e1l es el prop\u00f3sito de la reuni\u00f3n internacional propuesta por la OMS entre representantes de las farmacopoeias del mundo?**\n   - El prop\u00f3sito de la reuni\u00f3n es permitir que los representantes de las farmacopoeias discutan problemas y preocupaciones comunes, fomentando as\u00ed una colaboraci\u00f3n m\u00e1s estrecha entre ellas.\n\n3. **\u00bfQu\u00e9 acciones se espera que reporten las autoridades nacionales al Comit\u00e9 de Expertos en su pr\u00f3xima reuni\u00f3n?**\n   - Se espera que las autoridades nacionales informen sobre el progreso de las acciones sugeridas en las \u00e1reas de garant\u00eda de calidad, as\u00ed como sobre la colaboraci\u00f3n con otras farmacopoeias y el desarrollo de especificaciones para medicamentos.", "prev_section_summary": "El contenido de la secci\u00f3n del informe de la OMS se centra en las especificaciones para preparaciones farmac\u00e9uticas y abarca varios temas clave:\n\n1. **Medicamentos Mencionados**:\n   - **Rifampicina**: disponible en tabletas y c\u00e1psulas.\n   - **Pyrantel**: en tabletas masticables, utilizado como anti-infectivo.\n   - **Levonorgestrel**: en tabletas.\n   - **Medroxiprogesterona**: en forma de inyecci\u00f3n.\n   - **Retinol**: en soluci\u00f3n oral pedi\u00e1trica y en forma oleosa concentrada.\n\n2. **M\u00e9todos de Prueba Estandarizados**:\n   - Pruebas para cenizas sulfatadas, endotoxinas bacterianas, esterilidad, friabilidad de tabletas, desintegraci\u00f3n de tabletas y c\u00e1psulas, densidad de polvos, volumen extra\u00edble para preparaciones parenterales, y ex\u00e1menes microbiol\u00f3gicos de productos no est\u00e9riles.\n\n3. **Temas de Pol\u00edtica General**:\n   - Uniformidad del contenido para preparaciones de dosis \u00fanica y secci\u00f3n de informaci\u00f3n suplementaria.\n\n4. **Nuevos ICRS Adoptados**:\n   - Se adopt\u00f3 un nuevo ICRS para **Lumefantrina**, relacionado con la idoneidad del sistema.\n\n5. **Monograf\u00eda en Consulta**:\n   - Se lanz\u00f3 una monograf\u00eda para **Mefloquina** como parte del proceso de consulta amplia.\n\nEste resumen destaca la importancia de asegurar la calidad y la uniformidad en las preparaciones farmac\u00e9uticas, as\u00ed como la adopci\u00f3n de nuevos est\u00e1ndares y la consulta sobre medicamentos antimal\u00e1ricos.", "excerpt_keywords": "Keywords: shelf-life extension, oseltamivir, zanamivir, quality assurance, International Pharmacopoeia"}}, "99815b42-2756-47d1-8ad4-0882c099bc0d": {"node_ids": ["d439ab49-8299-4696-9dfc-070b0589dcba"], "metadata": {"page_label": "61", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## International Chemical Reference Substances (ICRS)\n\n- Continue to promote the use of ICRS through various activities, including a promotional offer to national authorities.\n- Continue the efforts to further enhance the development of new ICRS.\n\n## External Quality Assurance Assessment Scheme (EQAAS)\n\n- Continue the EQAAS for pharmaceutical quality control laboratories, Phase 5, test series 4 onwards.\n- Further prepare the extension of the Scheme starting with Phase 6 to encourage participants to include commercial medicines drawn from their local and regional markets in the studies, when the test protocol allows doing so.\n\n## Good manufacturing practices (GMP) and manufacture\n\n- Follow up on the revision process for GMP for biologicals undertaken under the aegis of the Expert Committee on Biological Standardization.\n- Continue the consultation process on the quality risk management principles with a view to updating the WHO guidelines on hazard analysis and critical control points to cover new trends.\n\n## WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce\n\n- Continue efforts towards a possible review of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce.\n- Develop a special WHO web site for the WHO Certification Scheme for APIs.\n\n## Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part\n\n- A new general document is to be prepared based on the specific guidance developed for the WHO Prequalification Programme (see Annex 4).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las actividades y directrices del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Se abordan varios temas clave, incluyendo el uso de Sustancias Qu\u00edmicas de Referencia Internacional (ICRS), el Esquema de Evaluaci\u00f3n de Aseguramiento de Calidad Externa (EQAAS), las Buenas Pr\u00e1cticas de Manufactura (GMP), el Esquema de Certificaci\u00f3n de la OMS para productos farmac\u00e9uticos en comercio internacional, y las directrices para la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos gen\u00e9ricos. Se enfatiza la promoci\u00f3n de ICRS, la mejora de GMP, y la revisi\u00f3n del esquema de certificaci\u00f3n, entre otros.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las nuevas iniciativas propuestas para el desarrollo de Sustancias Qu\u00edmicas de Referencia Internacional (ICRS) y c\u00f3mo se espera que impacten en la calidad de los productos farmac\u00e9uticos?**\n   - Esta pregunta busca informaci\u00f3n sobre las actividades espec\u00edficas y los objetivos relacionados con el desarrollo de ICRS que no se detallen en otros documentos.\n\n2. **\u00bfQu\u00e9 cambios se est\u00e1n considerando en el Esquema de Certificaci\u00f3n de la OMS para productos farmac\u00e9uticos en comercio internacional y qu\u00e9 implicaciones podr\u00edan tener para los fabricantes?**\n   - Esta pregunta se centra en los posibles cambios en el esquema de certificaci\u00f3n y c\u00f3mo estos podr\u00edan afectar a la industria farmac\u00e9utica, algo que podr\u00eda no estar ampliamente discutido en otros contextos.\n\n3. **\u00bfC\u00f3mo se planea integrar los principios de gesti\u00f3n de riesgos de calidad en las directrices de la OMS sobre an\u00e1lisis de peligros y puntos cr\u00edticos de control (HACCP) en el contexto de las Buenas Pr\u00e1cticas de Manufactura (GMP)?**\n   - Esta pregunta busca detalles sobre la integraci\u00f3n de nuevos enfoques en la gesti\u00f3n de riesgos de calidad, que podr\u00edan no estar disponibles en otras fuentes.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y detallada que se encuentra en el contexto proporcionado, y que puede no estar disponible en otros documentos o fuentes.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Extensi\u00f3n de la vida \u00fatil de medicamentos**:\n   - Se recomienda que las autoridades nacionales consideren ciertos puntos antes de extender la vida \u00fatil de oseltamivir y zanamivir para garantizar la seguridad de los pacientes.\n   - Pasos a seguir:\n     - Consultar al fabricante para obtener evidencia que respalde la extensi\u00f3n.\n     - Asegurarse de que los productos se mantengan bajo condiciones de almacenamiento adecuadas.\n     - Realizar pruebas adicionales si es necesario.\n\n2. **Recomendaciones en garant\u00eda de calidad**:\n   - Se insta a las autoridades nacionales a informar sobre el progreso de las acciones sugeridas en \u00e1reas de garant\u00eda de calidad en la pr\u00f3xima reuni\u00f3n del Comit\u00e9 de Expertos.\n\n3. **Colaboraci\u00f3n entre farmacopoeias**:\n   - Apoyo a la iniciativa de la OMS para fomentar una colaboraci\u00f3n m\u00e1s estrecha entre farmacopoeias a nivel mundial.\n   - Propuesta de una reuni\u00f3n internacional para discutir problemas y preocupaciones comunes.\n\n4. **Desarrollo de *The International Pharmacopoeia***:\n   - Continuar el desarrollo de especificaciones para medicamentos y m\u00e9todos generales.\n   - Fomentar la colaboraci\u00f3n internacional en la revisi\u00f3n e inclusi\u00f3n de monograf\u00edas espec\u00edficas.\n   - Preparar un suplemento o una quinta edici\u00f3n de *The International Pharmacopoeia*, especialmente en formato electr\u00f3nico.\n\n### Entidades mencionadas:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organismo que emite las recomendaciones.\n- **Oseltamivir y Zanamivir**: Medicamentos cuyo shelf-life se est\u00e1 considerando extender.\n- **Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas**: Entidad que supervisa el progreso de las acciones recomendadas.\n- **Farmacopoeias**: Colecciones de est\u00e1ndares de medicamentos que se busca integrar y colaborar.", "excerpt_keywords": "Keywords: ICRS, EQAAS, GMP, WHO Certification Scheme, pharmaceutical quality"}}, "fcc73d72-acd3-4cbe-b658-c2ac5c380af3": {"node_ids": ["c3ecfc9a-2d45-4223-8c29-3bc42d255dff"], "metadata": {"page_label": "62", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products: points to consider\n\n- Further explore development of these \u201cpoints to consider\u201d jointly with the International Pharmaceutical Federation (FIP) as practice guidance for compounding.\n\n## Update on comparator products\n\n- Provide an update of the list of comparator products on the web site, following review by the members of the Expert Committee, to replace the version from 2002.\n\n## Sampling procedures for monitoring of market situations\n\n- Continue development of sampling procedures based on the numerous examples obtained from many countries as feedback to the secretariat\u2019s communications.\n\n## Quality assurance terminology\n\n- Continue the work on the preferred terms included in the current quality assurance terminology database based on the analysis prepared by the secretariat, with a group of experts, including the definition for an API, on which consultation had already started.\n\n## Index of pharmacopoeias\n\n- Consult with the secretariat representatives of the individual world pharmacopoeias included in the *Index of pharmacopoeias* in order to complete and validate the information therein and update the current version on the web site accordingly.\n\n## WHO databases\n\n- Maintain the International Nonproprietary Names (INN) database and continue to make it available on the web site.\n- Maintain the Quality Assurance database and continue to make it available on the web site.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfCu\u00e1les son los pasos propuestos para el desarrollo de puntos de consideraci\u00f3n para la preparaci\u00f3n de medicamentos espec\u00edficos para ni\u00f1os?**\n   - Respuesta: Se sugiere explorar el desarrollo de estos \"puntos a considerar\" en colaboraci\u00f3n con la Federaci\u00f3n Internacional Farmac\u00e9utica (FIP) como gu\u00eda de pr\u00e1ctica para la preparaci\u00f3n de medicamentos.\n\n2. **\u00bfQu\u00e9 acciones se est\u00e1n tomando para actualizar la lista de productos comparadores en el sitio web de la OMS?**\n   - Respuesta: Se planea proporcionar una actualizaci\u00f3n de la lista de productos comparadores en el sitio web, tras la revisi\u00f3n por parte de los miembros del Comit\u00e9 de Expertos, para reemplazar la versi\u00f3n de 2002.\n\n3. **\u00bfQu\u00e9 bases de datos de la OMS se est\u00e1n manteniendo y actualizando, y cu\u00e1l es su prop\u00f3sito?**\n   - Respuesta: Se est\u00e1n manteniendo la base de datos de Nombres No Propietarios Internacionales (INN) y la base de datos de Aseguramiento de Calidad, ambas disponibles en el sitio web de la OMS, con el prop\u00f3sito de facilitar el acceso a informaci\u00f3n relevante sobre medicamentos y su calidad.\n\n### Resumen de nivel superior del contexto:\nEl documento aborda varios puntos clave relacionados con la preparaci\u00f3n y regulaci\u00f3n de productos farmac\u00e9uticos, especialmente en el contexto de la atenci\u00f3n pedi\u00e1trica. Se enfatiza la necesidad de colaboraci\u00f3n con organizaciones como la FIP para desarrollar gu\u00edas de pr\u00e1ctica, la actualizaci\u00f3n de listas de productos comparadores, el desarrollo de procedimientos de muestreo para monitorear el mercado, y la mejora de la terminolog\u00eda de aseguramiento de calidad. Adem\u00e1s, se menciona la importancia de mantener y actualizar bases de datos cr\u00edticas de la OMS para asegurar la disponibilidad de informaci\u00f3n sobre medicamentos.", "prev_section_summary": "La secci\u00f3n del documento de la OMS se centra en varias iniciativas y directrices relacionadas con la calidad de los productos farmac\u00e9uticos. A continuaci\u00f3n se resumen los temas clave y las entidades mencionadas:\n\n1. **Sustancias Qu\u00edmicas de Referencia Internacional (ICRS)**:\n   - Promoci\u00f3n del uso de ICRS a trav\u00e9s de diversas actividades, incluyendo ofertas promocionales a autoridades nacionales.\n   - Esfuerzos continuos para el desarrollo de nuevas ICRS.\n\n2. **Esquema de Evaluaci\u00f3n de Aseguramiento de Calidad Externa (EQAAS)**:\n   - Continuaci\u00f3n del EQAAS para laboratorios de control de calidad farmac\u00e9utica, avanzando hacia la Fase 5 y m\u00e1s all\u00e1.\n   - Preparaci\u00f3n para la extensi\u00f3n del esquema a la Fase 6, incentivando la inclusi\u00f3n de medicamentos comerciales de mercados locales y regionales en los estudios.\n\n3. **Buenas Pr\u00e1cticas de Manufactura (GMP)**:\n   - Seguimiento del proceso de revisi\u00f3n de GMP para productos biol\u00f3gicos bajo el Comit\u00e9 de Expertos en Estandarizaci\u00f3n Biol\u00f3gica.\n   - Consulta sobre principios de gesti\u00f3n de riesgos de calidad para actualizar las directrices de la OMS sobre an\u00e1lisis de peligros y puntos cr\u00edticos de control (HACCP).\n\n4. **Esquema de Certificaci\u00f3n de la OMS**:\n   - Revisi\u00f3n posible del Esquema de Certificaci\u00f3n de la OMS para productos farmac\u00e9uticos en comercio internacional.\n   - Desarrollo de un sitio web especial de la OMS para el Esquema de Certificaci\u00f3n de Ingredientes Farmac\u00e9uticos Activos (APIs).\n\n5. **Directrices para la presentaci\u00f3n de documentaci\u00f3n de productos farmac\u00e9uticos gen\u00e9ricos**:\n   - Preparaci\u00f3n de un nuevo documento general basado en la orientaci\u00f3n espec\u00edfica desarrollada para el Programa de Precalificaci\u00f3n de la OMS.\n\nEstos temas reflejan el compromiso de la OMS con la mejora continua de la calidad y la seguridad de los productos farmac\u00e9uticos a nivel internacional.", "excerpt_keywords": "Keywords: pharmaceutical preparations, quality assurance, pediatric compounding, comparator products, WHO databases"}}, "624c8607-e97f-49d2-a581-72abbf7ad270": {"node_ids": ["556db45a-d248-4f43-9f2f-4f9f7c6a2afe"], "metadata": {"page_label": "63", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Summary of additional recommendations from the closed session of the Expert Committee\n\n1. **Drafting of the Expert Committee report**\n\n   The Expert Committee appreciated the additional assistance, provided to the rapporteurs by a professional editor during this meeting to speed up and facilitate the report-writing process. Additional practical advice on the future drafting process was given, for example, to enable a review of the draft report by the Expert Committee members each day.\n\n2. **New proceeding**\n\n   The Expert Committee suggested providing e-links to the various documents on the agenda to replace the paper versions of these documents at future meetings. It was also suggested that all presentations be given on the first day to assist in the smooth running of the meeting agenda and to discuss related topics later during the Committee meeting under each agenda item. Moreover, the Expert Committee members suggested providing time slots every day to facilitate the creation of specific subgroups to discuss pending issues during each day of the meeting.\n\n3. **Financial situation analysis**\n\n   The Expert Committee noted that, from the presentations of the various related programmes during the meeting, it had become apparent that some WHO programmes seemed to have considerably more staff and financial resources than the Quality Assurance of Medicines Programme in QSM. This would result in a certain imbalance in comparison with the work of the Quality Assurance of Medicines Programme. As WHO resources seemed to be decreasing within the Organization and affecting this programme and its related activities even more, the Expert Committee wished the following to appear as a note in the report concerning current achievements:", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas basadas en el contexto proporcionado, junto con sus respuestas:\n\n1. **\u00bfQu\u00e9 tipo de asistencia se proporcion\u00f3 a los rapporteurs durante la reuni\u00f3n del Comit\u00e9 de Expertos?**\n   - Se proporcion\u00f3 asistencia adicional a los rapporteurs por parte de un editor profesional, lo que facilit\u00f3 y aceler\u00f3 el proceso de redacci\u00f3n del informe del Comit\u00e9 de Expertos.\n\n2. **\u00bfQu\u00e9 recomendaciones hizo el Comit\u00e9 de Expertos para mejorar la organizaci\u00f3n de futuras reuniones?**\n   - El Comit\u00e9 de Expertos recomend\u00f3 el uso de enlaces electr\u00f3nicos para los documentos de la agenda en lugar de versiones impresas, que todas las presentaciones se realicen el primer d\u00eda, y que se asignen franjas horarias diarias para la creaci\u00f3n de subgrupos espec\u00edficos que discutan temas pendientes.\n\n3. **\u00bfCu\u00e1l fue la preocupaci\u00f3n principal del Comit\u00e9 de Expertos respecto a la situaci\u00f3n financiera de los programas de la OMS?**\n   - El Comit\u00e9 de Expertos expres\u00f3 su preocupaci\u00f3n por el desequilibrio en los recursos y personal entre los diferentes programas de la OMS, se\u00f1alando que algunos programas ten\u00edan considerablemente m\u00e1s recursos que el Programa de Aseguramiento de la Calidad de Medicamentos, lo que podr\u00eda afectar negativamente a este \u00faltimo, especialmente dado que los recursos de la OMS estaban disminuyendo.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento es un resumen de las recomendaciones adicionales del Comit\u00e9 de Expertos de la OMS, que se centr\u00f3 en la mejora del proceso de redacci\u00f3n de informes, la organizaci\u00f3n de futuras reuniones y la evaluaci\u00f3n de la situaci\u00f3n financiera de los programas de la OMS. Se destaca la necesidad de un enfoque m\u00e1s equilibrado en la asignaci\u00f3n de recursos y la importancia de la colaboraci\u00f3n y la comunicaci\u00f3n efectiva durante las reuniones.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Preparaciones Espec\u00edficas para Ni\u00f1os**:\n   - Se propone desarrollar \"puntos a considerar\" en colaboraci\u00f3n con la **Federaci\u00f3n Internacional Farmac\u00e9utica (FIP)** para guiar la pr\u00e1ctica de la preparaci\u00f3n de medicamentos pedi\u00e1tricos que no est\u00e1n disponibles como productos autorizados.\n\n2. **Actualizaci\u00f3n de Productos Comparadores**:\n   - Se planea actualizar la lista de productos comparadores en el sitio web de la **OMS**, reemplazando la versi\u00f3n de 2002, tras la revisi\u00f3n por parte del Comit\u00e9 de Expertos.\n\n3. **Procedimientos de Muestreo**:\n   - Se continuar\u00e1 el desarrollo de procedimientos de muestreo para monitorear situaciones del mercado, bas\u00e1ndose en ejemplos obtenidos de varios pa\u00edses.\n\n4. **Terminolog\u00eda de Aseguramiento de Calidad**:\n   - Se seguir\u00e1 trabajando en los t\u00e9rminos preferidos de la base de datos de terminolog\u00eda de aseguramiento de calidad, incluyendo la definici\u00f3n de un **API (Ingrediente Farmac\u00e9utico Activo)**, con la participaci\u00f3n de un grupo de expertos.\n\n5. **\u00cdndice de Farmacopeas**:\n   - Se consultar\u00e1 con representantes de las farmacopeas mundiales para completar y validar la informaci\u00f3n en el *\u00cdndice de farmacopeas* y actualizar la versi\u00f3n actual en el sitio web.\n\n6. **Bases de Datos de la OMS**:\n   - Se mantendr\u00e1n y actualizar\u00e1n las bases de datos de **Nombres No Propietarios Internacionales (INN)** y de **Aseguramiento de Calidad**, asegurando su disponibilidad en el sitio web de la OMS.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**\n- **FIP (Federaci\u00f3n Internacional Farmac\u00e9utica)**\n- **API (Ingrediente Farmac\u00e9utico Activo)**\n\nEste resumen destaca los esfuerzos de la OMS en la regulaci\u00f3n y mejora de la calidad de los productos farmac\u00e9uticos, especialmente en el contexto de la atenci\u00f3n pedi\u00e1trica y la colaboraci\u00f3n con otras organizaciones.", "excerpt_keywords": "Keywords: Expert Committee, WHO, report drafting, financial analysis, meeting recommendations"}}, "56d8d206-3f86-41fd-918e-af8b270d0ec6": {"node_ids": ["e848e92d-708d-4ce8-aae1-94846c178e8c"], "metadata": {"page_label": "64", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- Since 2003 the meetings of the WHO Expert Committee on Specifications for Pharmaceutical Preparations have been held on an annual basis;\n- The total number of guidelines which have been produced is 70;\n- The staff currently working in the Quality Assurance of Medicines Programme is two-and-a-half professionals, one secondment and two general-service assistants.\n\nThe Expert Committee wishes to express its recognition of the hard work undertaken and the increasing workload faced by the secretariat, which aims to cope with the frequency of meetings and new trends, in order to respond to the international demands and those of the WHO-associated programmes to provide timely advice and guidance as an up-to-date service to WHO Member States and United Nations programmes. The Expert Committee members strongly recommend the Director-General to provide this programme with adequate resources in the future to carry out this important function of providing independent international standards and guidelines in the area of quality assurance of medicines.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Frecuencia y Producci\u00f3n de Directrices**: Desde 2003, la Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas se re\u00fane anualmente y ha producido un total de 70 directrices.\n\n2. **Recursos y Carga de Trabajo**: La carga de trabajo del secretariado ha aumentado, lo que ha llevado a la Comisi\u00f3n a reconocer la necesidad de m\u00e1s recursos para poder cumplir con las demandas internacionales y proporcionar asesoramiento oportuno a los Estados Miembros de la OMS y programas de las Naciones Unidas.\n\n3. **Composici\u00f3n del Personal**: Actualmente, el programa de Aseguramiento de Calidad de Medicamentos cuenta con un equipo limitado de personal, compuesto por dos profesionales a tiempo completo, un segundo y dos asistentes de servicio general.\n\n### Preguntas espec\u00edficas que este contexto puede responder:\n\n1. **\u00bfCu\u00e1ntas directrices ha producido la Comisi\u00f3n de Expertos de la OMS desde su establecimiento en 2003 y cu\u00e1l es la frecuencia de sus reuniones?**\n   - Respuesta: La Comisi\u00f3n ha producido un total de 70 directrices y se re\u00fane anualmente desde 2003.\n\n2. **\u00bfQu\u00e9 desaf\u00edos enfrenta actualmente el secretariado de la Comisi\u00f3n de Expertos en relaci\u00f3n con su carga de trabajo y recursos?**\n   - Respuesta: El secretariado enfrenta una carga de trabajo creciente debido a la frecuencia de las reuniones y las nuevas tendencias, lo que requiere m\u00e1s recursos para poder responder adecuadamente a las demandas internacionales y proporcionar asesoramiento oportuno.\n\n3. **\u00bfCu\u00e1l es la composici\u00f3n actual del personal que trabaja en el Programa de Aseguramiento de Calidad de Medicamentos de la OMS?**\n   - Respuesta: El programa cuenta con dos profesionales a tiempo completo, un segundo y dos asistentes de servicio general, lo que suma un total de dos y medio profesionales.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Asistencia en la redacci\u00f3n del informe**:\n   - Se destac\u00f3 la ayuda de un editor profesional para los rapporteurs, lo que facilit\u00f3 y aceler\u00f3 el proceso de redacci\u00f3n del informe del Comit\u00e9 de Expertos.\n\n2. **Recomendaciones para futuras reuniones**:\n   - Uso de enlaces electr\u00f3nicos en lugar de documentos impresos.\n   - Realizaci\u00f3n de todas las presentaciones el primer d\u00eda.\n   - Asignaci\u00f3n de franjas horarias diarias para la creaci\u00f3n de subgrupos que discutan temas pendientes.\n\n3. **An\u00e1lisis de la situaci\u00f3n financiera**:\n   - Observaci\u00f3n de un desequilibrio en recursos y personal entre los programas de la OMS, con algunos programas teniendo m\u00e1s recursos que el Programa de Aseguramiento de la Calidad de Medicamentos.\n   - Preocupaci\u00f3n por la disminuci\u00f3n de recursos de la OMS que afecta negativamente al Programa de Aseguramiento de la Calidad de Medicamentos.\n\n### Entidades mencionadas:\n- **Comit\u00e9 de Expertos de la OMS**: Grupo encargado de realizar recomendaciones y an\u00e1lisis sobre programas de la OMS.\n- **Programa de Aseguramiento de la Calidad de Medicamentos**: Programa espec\u00edfico mencionado que enfrenta desaf\u00edos en comparaci\u00f3n con otros programas de la OMS.\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad que se ocupa de la salud p\u00fablica a nivel global y que est\u00e1 experimentando una disminuci\u00f3n en sus recursos.", "excerpt_keywords": "Keywords: WHO, Pharmaceutical Preparations, Quality Assurance, Guidelines, Resources"}}, "bc7db81c-1445-45dd-acba-c18d0da3d36f": {"node_ids": ["f628fed5-5e3e-4ea1-80cf-3445627c802c"], "metadata": {"page_label": "65", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Acknowledgements\n\nSpecial acknowledgement was made by the Committee to Mrs W. Bonny, Ms M. Gaspard, Dr S. Kopp, Ms C. Mendy, Dr H. Schmidt, Dr X. Zheng and to Dr L. R\u00e4go, Quality Assurance and Safety: Medicines, Essential Medicines and Health Products, WHO, Geneva, Switzerland, and to Mr D. Bramley, Prangins, Switzerland, who were instrumental in the preparation and proceedings of the meeting.\n\nTechnical guidance included in this report has been produced with the financial assistance of the European Union, the Bill & Melinda Gates Foundation and UNITAID.\n\nThe Committee also acknowledged with thanks the valuable contributions made to its work by the following agencies, institutions, organizations, WHO collaborating centres, WHO programmes and persons:\n\nActive Pharmaceutical Ingredients Committee, European Chemical Industry Council, Brussels, Belgium; Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Danish Medicines Agency, Copenhagen, Denmark; European Commission, Brussels, Belgium; European Directorate for the Quality of Medicines and HealthCare, Council of Europe, Strasbourg, France; European Federation of Pharmaceutical Industries and Associations, Brussels, Belgium; European Medicines Agency, London, England; Fedefarma, Ciudad, Guatemala; Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland; Healthcare Distribution Management Association, Arlington, VA, USA; Indian Drug Manufacturers\u2019 Association, Worli, Mumbai, India; International Federation of Pharmaceutical Manufacturers and Associations, Geneva, Switzerland; International Generic Pharmaceutical Alliance, Brussels, Belgium; International Pharmaceutical Excipients Council, Strasbourg, France; International Pharmaceutical Federation, The Hague, Netherlands; International Society for Pharmaceutical Engineering, Tampa, Florida, USA; Medicines and Healthcare products Regulatory Agency, Inspection and Standards Division, London, England; Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland; Pharmaceutical Research and Manufacturers of America, Washington, DC, USA; Swissmedic, Swiss Agency for Therapeutic Products, Berne, Switzerland; Therapeutic Goods Administration, Woden, ACT, Australia; United Nations Children\u2019s Fund, New York, USA; United Nations Development Programme, New York, USA; The World Bank, Washington, DC, USA; United States of America Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA; United States of America Food and Drug Administration, Office of Pediatric Therapeutics, Office of the Commissioner, Rockville, MD, USA; World Intellectual Property", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que incluye un apartado de agradecimientos. En este apartado, se reconoce la contribuci\u00f3n de varias personas y organizaciones que participaron en la preparaci\u00f3n y desarrollo de la reuni\u00f3n. Tambi\u00e9n se menciona el apoyo financiero recibido de la Uni\u00f3n Europea, la Fundaci\u00f3n Bill y Melinda Gates y UNITAID. Adem\u00e1s, se enumeran diversas agencias, instituciones y organizaciones que colaboraron en el trabajo del Comit\u00e9.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 papel desempe\u00f1aron las personas mencionadas en los agradecimientos en la preparaci\u00f3n del informe?**\n   - Esta pregunta busca detalles sobre las funciones espec\u00edficas de los individuos reconocidos, que no se detallan en el texto.\n\n2. **\u00bfCu\u00e1les son las principales \u00e1reas de enfoque de las organizaciones y agencias mencionadas en el apartado de agradecimientos?**\n   - Esta pregunta se centra en entender mejor las especialidades y contribuciones de las diversas entidades listadas, lo que no se aborda directamente en el texto.\n\n3. **\u00bfQu\u00e9 tipo de asistencia financiera se menciona en el informe y c\u00f3mo se relaciona con el contenido t\u00e9cnico del mismo?**\n   - Esta pregunta busca explorar la conexi\u00f3n entre el apoyo financiero recibido y el contenido t\u00e9cnico del informe, algo que no se detalla expl\u00edcitamente en el texto. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n m\u00e1s profunda y espec\u00edfica que no se encuentra directamente en el texto, fomentando una comprensi\u00f3n m\u00e1s completa del contexto y las contribuciones al informe.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comisi\u00f3n de Expertos de la OMS**: Se encarga de establecer especificaciones para preparaciones farmac\u00e9uticas y se re\u00fane anualmente desde 2003.\n\n2. **Producci\u00f3n de Directrices**: Desde su establecimiento, la Comisi\u00f3n ha producido un total de 70 directrices relacionadas con la calidad de los medicamentos.\n\n3. **Carga de Trabajo y Recursos**: El secretariado enfrenta un aumento en la carga de trabajo debido a la frecuencia de las reuniones y nuevas tendencias, lo que ha llevado a la necesidad de m\u00e1s recursos para cumplir con las demandas internacionales y proporcionar asesoramiento oportuno.\n\n4. **Composici\u00f3n del Personal**: El Programa de Aseguramiento de Calidad de Medicamentos cuenta actualmente con un equipo limitado de personal, compuesto por dos profesionales a tiempo completo, un segundo y dos asistentes de servicio general, sumando un total de dos y medio profesionales.\n\n5. **Recomendaciones**: La Comisi\u00f3n recomienda al Director-General de la OMS que se proporcionen recursos adecuados para llevar a cabo su funci\u00f3n de establecer est\u00e1ndares y directrices internacionales en el \u00e1rea de calidad de los medicamentos. \n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organizaci\u00f3n internacional que coordina esfuerzos en salud p\u00fablica.\n- **Comisi\u00f3n de Expertos**: Grupo encargado de desarrollar directrices sobre especificaciones farmac\u00e9uticas.\n- **Programa de Aseguramiento de Calidad de Medicamentos**: Programa espec\u00edfico dentro de la OMS que se ocupa de la calidad de los medicamentos.", "excerpt_keywords": "Keywords: WHO, acknowledgements, pharmaceutical, technical report, quality assurance"}}, "f225fb9e-1844-479a-9744-6340271bc56d": {"node_ids": ["f408a4b4-f360-43c6-8b14-f12fc11f1baf"], "metadata": {"page_label": "66", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que forma parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pol\u00edticas de salud. Sin embargo, en este caso espec\u00edfico, no se proporciona contenido detallado en el texto extra\u00eddo.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son los principales temas o hallazgos discutidos en el informe t\u00e9cnico de la OMS en la serie 970?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe, que no se puede deducir solo del t\u00edtulo.\n\n2. **\u00bfQu\u00e9 recomendaciones espec\u00edficas se hacen en el informe de la OMS para abordar problemas de salud p\u00fablica?**\n   - Dado que los informes t\u00e9cnicos de la OMS suelen incluir recomendaciones, esta pregunta se enfoca en obtener detalles sobre las sugerencias pr\u00e1cticas que se derivan del informe.\n\n3. **\u00bfC\u00f3mo se compara el informe 970 con otros informes anteriores de la serie en t\u00e9rminos de enfoque y contenido?**\n   - Esta pregunta busca establecer un contexto comparativo que podr\u00eda revelar tendencias o cambios en las prioridades de la OMS a lo largo del tiempo.\n\nEstas preguntas est\u00e1n dise\u00f1adas para obtener informaci\u00f3n que probablemente no est\u00e9 disponible en otras fuentes, dado que se centran en el contenido espec\u00edfico del informe mencionado.", "prev_section_summary": "### Resumen de la Secci\u00f3n de Agradecimientos\n\nLa secci\u00f3n de agradecimientos del informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) destaca la contribuci\u00f3n de diversas personas y organizaciones en la preparaci\u00f3n y desarrollo de la reuni\u00f3n. Se menciona un reconocimiento especial a individuos clave, incluyendo a:\n\n- **Mrs W. Bonny**\n- **Ms M. Gaspard**\n- **Dr S. Kopp**\n- **Ms C. Mendy**\n- **Dr H. Schmidt**\n- **Dr X. Zheng**\n- **Dr L. R\u00e4go** (OMS, Ginebra, Suiza)\n- **Mr D. Bramley** (Prangins, Suiza)\n\nEstos individuos fueron fundamentales en la organizaci\u00f3n y los procedimientos de la reuni\u00f3n.\n\n### Asistencia Financiera\nEl informe tambi\u00e9n se\u00f1ala que la orientaci\u00f3n t\u00e9cnica incluida fue producida con el apoyo financiero de:\n\n- **Uni\u00f3n Europea**\n- **Fundaci\u00f3n Bill y Melinda Gates**\n- **UNITAID**\n\n### Contribuciones de Agencias y Organizaciones\nAdem\u00e1s, se agradece a una amplia variedad de agencias, instituciones y organizaciones que colaboraron en el trabajo del Comit\u00e9, incluyendo:\n\n- **Active Pharmaceutical Ingredients Committee** (Bruselas, B\u00e9lgica)\n- **Bureau of Drug and Narcotic, Department of Medical Sciences** (Tailandia)\n- **Danish Medicines Agency** (Copenhague, Dinamarca)\n- **European Medicines Agency** (Londres, Inglaterra)\n- **Global Fund to Fight AIDS, Tuberculosis and Malaria** (Ginebra, Suiza)\n- **United Nations Children\u2019s Fund (UNICEF)** (Nueva York, EE. UU.)\n- **World Bank** (Washington, DC, EE. UU.)\n- **United States Food and Drug Administration (FDA)** (Silver Spring, MD, EE. UU.)\n\n### Temas Clave\n- Reconocimiento a contribuciones individuales y colectivas en el \u00e1mbito de la salud y medicamentos.\n- Importancia del apoyo financiero para la producci\u00f3n de orientaci\u00f3n t\u00e9cnica.\n- Colaboraci\u00f3n internacional entre diversas entidades en el sector farmac\u00e9utico y de salud.\n\nEste resumen encapsula los temas clave y las entidades mencionadas en la secci\u00f3n de agradecimientos del informe.", "excerpt_keywords": "Keywords: OMS, informe t\u00e9cnico, salud p\u00fablica, colaboraci\u00f3n internacional, agradecimientos"}}, "9690fa98-3bb8-4870-989b-9d1cd9112d53": {"node_ids": ["8f41e028-54c4-4df0-8653-0698f26fa25f"], "metadata": {"page_label": "67", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "North-West University, Potchefstroom, South Africa; Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa; National Drug Quality Assurance Laboratory, Colombo, Sri Lanka; Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Laboratoire National de Contr\u00f4le des M\u00e9dicaments, Tunis, Tunisia; National Drug Quality Control Laboratory, National Drug Authority, Kampala, Uganda; Central Laboratory for Quality Control of Medicines of the Ministry of Health of Ukraine, Kiev, Ukraine; School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, United Republic of Tanzania; Tanzania Food and Drugs Authority, Dar es Salaam, United Republic of Tanzania; Laboratorio Control de Productos MSP, Comisi\u00f3n Para El Control de Calidad de Medicamentos, Montevideo, Uruguay; Instituto Nacional de Higiene \u201cRafael Rangel\u201d, Caracas, Venezuela; National Institute of Drug Quality Control, Hanoi, Viet Nam; Medicines Control Authority, Control Laboratory of Zimbabwe, Harare, Zimbabwe.\n\nWHO Centre Collaborateur pour la Conformit\u00e9 des M\u00e9dicaments, Laboratoire national de Contr\u00f4le des Produits Pharmaceutiques, Alger, Algeria; WHO Collaborating Centre for Drug Quality Assurance, Therapeutic Goods Administration Laboratories, Woden, ACT, Australia; WHO Collaborating Centre for Drug Quality Assurance, National Institute for the Control of Pharmaceutical and Biological Products, Beijing, People\u2019s Republic of China; WHO Collaborating Centre for Research on Bioequivalence Testing of Medicines, Frankfurt am Main, Germany; WHO Collaborating Centre for Drug Information and Quality Assurance, National Institute of Pharmacy, Budapest, Hungary; WHO Collaborating Centre for Quality Assurance of Essential Drugs, Central Drugs Laboratory, Calcutta, India; WHO Collaborating Centre for Regulatory Control of Pharmaceuticals, National Pharmaceutical Control Bureau, Jalan University, Ministry of Health, Petaling Jaya, Malaysia; WHO Collaborating Centre for Drug Quality Assurance, Pharmaceutical Laboratory, Centre for Analytical Science, Health Sciences Authority, Singapore; WHO Collaborating Centre for Quality Assurance of Medicines, North-West University, Potchefstroom, South Africa; WHO Collaborating Centre for Quality Assurance of Essential Drugs, Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.\n\nAnti-Counterfeiting Medicines Programme, WHO, Geneva, Switzerland; Blood Products and Related Biologicals Programme, WHO, Geneva, Switzerland; Global Malaria Programme, WHO, Geneva, Switzerland; HIV/AIDS Programme, WHO, Geneva, Switzerland; International Medical Products Anti-Counterfeiting Taskforce (IMPACT), WHO, Geneva, Switzerland; Medicine Access and Rational Use Team, WHO, Geneva, Switzerland; Medicines Regulatory Support Programme, WHO, Geneva, Switzerland; Office of the Legal Counsel, WHO, Geneva, Switzerland.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que detalla diversas instituciones y programas relacionados con la calidad y regulaci\u00f3n de medicamentos a nivel mundial. Se mencionan m\u00faltiples centros colaboradores de la OMS en diferentes pa\u00edses, as\u00ed como programas espec\u00edficos de la OMS que abordan temas como la lucha contra medicamentos falsificados, productos biol\u00f3gicos, malaria y VIH/SIDA. La informaci\u00f3n destaca la importancia de la colaboraci\u00f3n internacional en la garant\u00eda de la calidad de los medicamentos y la regulaci\u00f3n de productos farmac\u00e9uticos.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfCu\u00e1les son los principales objetivos del Programa de Medicamentos Anti-Falsificaci\u00f3n de la OMS mencionado en el informe?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las metas y estrategias del programa, que no se detalla en el contexto.\n\n2. **\u00bfQu\u00e9 papel desempe\u00f1a el Laboratorio Nacional de Control de Medicamentos en T\u00fanez dentro de la red de colaboraci\u00f3n de la OMS?**\n   - Esta pregunta se centra en el rol particular de una de las instituciones mencionadas, lo que puede no estar claramente definido en el documento.\n\n3. **\u00bfC\u00f3mo se coordinan las actividades entre los diferentes centros colaboradores de la OMS para asegurar la calidad de los medicamentos a nivel global?**\n   - Esta pregunta busca entender el mecanismo de colaboraci\u00f3n y coordinaci\u00f3n entre las diversas instituciones, un aspecto que puede no estar expl\u00edcitamente abordado en el texto.\n\n### Resumen de Nivel Superior\nEl informe de la OMS destaca la colaboraci\u00f3n internacional en la regulaci\u00f3n y control de la calidad de medicamentos. Se enumeran m\u00faltiples centros de calidad y programas de la OMS que trabajan en la prevenci\u00f3n de medicamentos falsificados y en la mejora del acceso a medicamentos esenciales. La diversidad geogr\u00e1fica de los centros colaboradores subraya la importancia de un enfoque global para abordar los desaf\u00edos en la calidad de los productos farmac\u00e9uticos.", "prev_section_summary": "### Resumen de la Secci\u00f3n\n\nEl contenido extra\u00eddo del documento \"WHO - Technical Report Series 970\" no proporciona informaci\u00f3n espec\u00edfica, ya que se indica \"NO_CONTENT_HERE\". Sin embargo, se puede inferir que el informe forma parte de una serie de publicaciones de la Organizaci\u00f3n Mundial de la Salud (OMS) que abordan temas relevantes en el \u00e1mbito de la salud p\u00fablica y la investigaci\u00f3n m\u00e9dica.\n\n### Temas Clave\n- **Salud P\u00fablica**: El informe probablemente discute cuestiones relacionadas con la salud p\u00fablica, aunque no se especifican detalles.\n- **Investigaci\u00f3n M\u00e9dica**: Es probable que el documento incluya hallazgos o recomendaciones basadas en investigaciones recientes.\n- **Pol\u00edticas de Salud**: Se espera que el informe ofrezca recomendaciones para la formulaci\u00f3n de pol\u00edticas en el sector salud.\n\n### Entidades\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe.\n- **Informe T\u00e9cnico**: Tipo de documento que se espera contenga an\u00e1lisis y recomendaciones sobre temas de salud.\n\nDado que no hay contenido espec\u00edfico disponible, el resumen se basa en la naturaleza general de los informes de la OMS y su prop\u00f3sito en el \u00e1mbito de la salud.", "excerpt_keywords": "Keywords: WHO, drug quality assurance, anti-counterfeiting, international collaboration, pharmaceutical regulation"}}, "861fec67-942f-4ea1-8c78-52a087ea1c80": {"node_ids": ["67b93b5b-8b93-4225-b9fd-59a00313f38b"], "metadata": {"page_label": "68", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pr\u00e1cticas de salud a nivel global. Sin embargo, el contenido espec\u00edfico de la p\u00e1gina 68 no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS en el informe t\u00e9cnico 970 sobre el manejo de enfermedades espec\u00edficas?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las directrices o recomendaciones que la OMS podr\u00eda haber proporcionado en este informe, que podr\u00eda no estar disponible en otros documentos.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas de investigaci\u00f3n se discuten en la p\u00e1gina 68 del informe t\u00e9cnico 970?**\n   - Esta pregunta se centra en las t\u00e9cnicas o enfoques de investigaci\u00f3n que la OMS podr\u00eda haber descrito, lo cual es crucial para entender c\u00f3mo se desarrollaron las conclusiones del informe.\n\n3. **\u00bfQu\u00e9 datos o estad\u00edsticas relevantes se presentan en el informe t\u00e9cnico 970 que podr\u00edan influir en pol\u00edticas de salud p\u00fablica?**\n   - Esta pregunta busca informaci\u00f3n sobre datos espec\u00edficos que podr\u00edan ser utilizados para fundamentar decisiones en pol\u00edticas de salud, lo cual es un aspecto clave en los informes de la OMS.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que podr\u00eda ser \u00fanica para el documento mencionado y que no se podr\u00eda encontrar f\u00e1cilmente en otras fuentes.", "prev_section_summary": "La secci\u00f3n del informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) se centra en la colaboraci\u00f3n internacional para garantizar la calidad y regulaci\u00f3n de medicamentos. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Colaboraci\u00f3n Internacional**: Se destaca la importancia de la cooperaci\u00f3n entre diferentes instituciones y pa\u00edses para asegurar la calidad de los medicamentos.\n2. **Centros Colaboradores de la OMS**: Se enumeran m\u00faltiples centros en diversos pa\u00edses que trabajan en la regulaci\u00f3n y control de la calidad de los productos farmac\u00e9uticos.\n3. **Programas de la OMS**: Se mencionan varios programas espec\u00edficos de la OMS que abordan temas cr\u00edticos como la lucha contra medicamentos falsificados, productos biol\u00f3gicos, malaria y VIH/SIDA.\n\n### Entidades Mencionadas:\n- **Centros de Calidad y Control de Medicamentos**:\n  - North-West University, Potchefstroom, Sud\u00e1frica\n  - Laboratoire National de Contr\u00f4le des M\u00e9dicaments, T\u00fanez\n  - National Drug Quality Assurance Laboratory, Sri Lanka\n  - Bureau of Drug and Narcotic, Tailandia\n  - National Drug Quality Control Laboratory, Uganda\n  - Central Laboratory for Quality Control of Medicines, Ucrania\n  - Muhimbili University of Health and Allied Sciences, Tanzania\n  - Instituto Nacional de Higiene \u201cRafael Rangel\u201d, Venezuela\n  - National Institute of Drug Quality Control, Vietnam\n  - Medicines Control Authority, Zimbabue\n\n- **Programas de la OMS**:\n  - Programa de Medicamentos Anti-Falsificaci\u00f3n\n  - Programa de Productos Biol\u00f3gicos y Relacionados\n  - Programa Global de Malaria\n  - Programa de VIH/SIDA\n  - International Medical Products Anti-Counterfeiting Taskforce (IMPACT)\n  - Medicines Regulatory Support Programme\n\nEste resumen resalta la red de colaboraci\u00f3n y los esfuerzos globales para mejorar la calidad y el acceso a medicamentos esenciales, as\u00ed como la lucha contra la falsificaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: OMS, medicamentos, calidad, regulaci\u00f3n, colaboraci\u00f3n"}}, "3049056f-f021-4c09-809d-188606bae6e8": {"node_ids": ["9e721ec9-fc23-461a-bf7c-06f31fd60a0b"], "metadata": {"page_label": "69", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que forma parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pr\u00e1cticas de salud a nivel global. Sin embargo, el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el informe WHO TRS 970?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir datos sobre salud p\u00fablica, pol\u00edticas recomendadas o resultados de investigaciones.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en la serie de informes t\u00e9cnicos de la OMS, y c\u00f3mo se relaciona el informe 970 con esos temas?**\n   - Esta pregunta se centra en el contexto m\u00e1s amplio de la serie de informes, permitiendo entender c\u00f3mo el informe 970 se integra en la discusi\u00f3n general sobre salud p\u00fablica.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizan en el informe WHO TRS 970 para evaluar los problemas de salud discutidos?**\n   - Esta pregunta indaga sobre los enfoques y m\u00e9todos de investigaci\u00f3n que podr\u00edan haber sido utilizados en el informe, lo cual es crucial para entender la validez y aplicabilidad de los hallazgos.\n\nEstas preguntas est\u00e1n dise\u00f1adas para obtener informaci\u00f3n espec\u00edfica que probablemente no se encuentre f\u00e1cilmente en otras fuentes, dado que se centran en el contenido particular del informe y su contexto en la serie de la OMS.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS) que aborda temas relevantes en salud p\u00fablica y medicina. Aunque el contenido espec\u00edfico de la p\u00e1gina 68 no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes basados en el contexto general de la serie:\n\n#### Temas Clave:\n1. **Salud P\u00fablica**: El informe probablemente discute estrategias y recomendaciones para mejorar la salud p\u00fablica a nivel global.\n2. **Investigaci\u00f3n M\u00e9dica**: Es posible que se aborden metodolog\u00edas de investigaci\u00f3n y su aplicaci\u00f3n en el contexto de la salud.\n3. **Pol\u00edticas de Salud**: El informe puede incluir datos y estad\u00edsticas que influyan en la formulaci\u00f3n de pol\u00edticas de salud p\u00fablica.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe y de proporcionar directrices y recomendaciones en el \u00e1mbito de la salud.\n- **Enfermedades Espec\u00edficas**: Aunque no se mencionan en el contenido proporcionado, es probable que el informe trate sobre enfermedades relevantes y su manejo.\n\nEste resumen destaca la importancia del informe en el contexto de la salud global y su potencial impacto en pol\u00edticas y pr\u00e1cticas de salud.", "excerpt_keywords": "Keywords: salud p\u00fablica, investigaci\u00f3n m\u00e9dica, pol\u00edticas de salud, Organizaci\u00f3n Mundial de la Salud, recomendaciones"}}, "c8a7699c-25ef-4005-8221-8054837ecd26": {"node_ids": ["0e690dd3-4dcc-4405-9d44-d4483e155d84"], "metadata": {"page_label": "70", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**Forty-sixth report**\n\nAssociation Training and Research Institute, Parenteral Drug Association, Bethesda, MD, USA; Mr M.M. Das, Kolkata, India; Dr J. Daviaud, Senior Pharmaceutical QA Officer, Pharmaceutical Procurement Unit, Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland; Dr V. Davoust, Quality & Regulatory Policy, Global CMC, WW Pharmaceutical Sciences, Pfizer Global Research & Development, Paris, France; Professor T. Dekker, Research Institute for Industrial Pharmacy, North-West University, Potchefstroom, South Africa; Dr L. De-Moor, GlaxoSmithKline, Belgium; Dr J. DiLoreto, Executive Director, Bulk Pharmaceuticals Task Force, Washington, DC, USA; Dr V. Divecha, Cipla, India; Professor J.B. Dressman, Professor of Pharmaceutical Technology, Institut f\u00fcr Pharmazeutische Technologie, Biozentrum, Johann Wolfgang Goethe-Universit\u00e4t, Frankfurt am Main, Germany; Dr A.T. Ducca, Senior Director, Regulatory Affairs, Healthcare Distribution Management Association, Arlington, VA, USA; Dr S. Durand-Stamatidas, Director, Information and Communication, World Self-Medication Industry, Ferney-Voltaire, France; Dr P. Ellis, Director, External Advocacy, Quality Centre of Excellence, GlaxoSmithKline, Brentford, Middlesex, England; Dr A. Falodun, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Benin, Benin City, Nigeria; Dr E. Fefer, Member, United States Pharmacopeia International Health Expert Committee, Rockville, MD, USA; Dr R. Fendt, Head, Global Regulatory & GMP Compliance Pharma, Care Chemicals Division, BASF, Limburgerhof, Germany; Mr A. Ferreira do Nascimento, Ag\u00eancia Nacional de Vigil\u00e2ncia, Bras\u00edlia, Brazil; Dr A. Fleuckiger, Head, Corporate Health Protection, Corporate Safety, Health and Environmental Protection, F. Hoffmann-La Roche, Basel, Switzerland; Dr G.L. France, Vice-President, Quality Strategy, Pfizer Limited and Vice-Chair, IFPMA/RPTS, Maidenhead, England; Dr N.C. Franklin, Wuppertal, Germany; Mr T. Fujino, Director, International Affairs, Japan Generic Medicines Association, Tokyo, Japan; Dr M. Garvin, Senior Director, Scientific and Regulatory Affairs, Pharmaceutical Research and Manufacturers of America, Washington, DC, USA; Dr F. Giorgi, Research and Development, Analytical Development Manager, Sigma-tau Industrie Farmaceutiche Riunite, Pomezia, Italy; Dr L. Girard, Head, Global Pharmacopoeial Affairs, Novartis Group Quality, Quality Systems and Standards, Basel, Switzerland; Dr N. Goldschmidt, USA; Dr E. Gomez, Ridgefield Park, New Jersey, USA; Ms J. Gouws, Department of Health, Medicines Control Council, Pretoria, South Africa; Dr M. Goverde, QC Expert Microbiology, Novartis Pharma, Basel, Switzerland; Ms R.Govithavatangaphong, Director, Bureau of Drug and Narcotic, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Dr J. Grande, Manager, Regulatory Affairs, McNeil Consumer Healthcare, Markham, England; Dr A. Gray, Senior Lecturer, Department of Therapeutics and Medicines Management and Consultant Pharmacist, Centre for the AIDS Programme of Research in South Africa.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es el \"Cuarenta y sexto informe\" del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Incluye una lista de expertos y sus afiliaciones, que abarcan diversas organizaciones y pa\u00edses, destacando la colaboraci\u00f3n internacional en el \u00e1mbito de la calidad y regulaci\u00f3n de productos farmac\u00e9uticos.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfCu\u00e1les son las principales \u00e1reas de especializaci\u00f3n de los miembros del Comit\u00e9 de Expertos mencionados en el informe?**\n   - Esta pregunta busca identificar las diversas disciplinas y campos de experiencia que aportan los miembros del comit\u00e9, lo que puede no estar claramente delineado en otros documentos.\n\n2. **\u00bfQu\u00e9 papel desempe\u00f1a el Global Fund to Fight AIDS, Tuberculosis and Malaria en la regulaci\u00f3n de productos farmac\u00e9uticos seg\u00fan el informe?**\n   - Esta pregunta se centra en el impacto y la funci\u00f3n espec\u00edfica de esta organizaci\u00f3n en el contexto de la regulaci\u00f3n farmac\u00e9utica, un aspecto que podr\u00eda no estar ampliamente discutido en otras fuentes.\n\n3. **\u00bfC\u00f3mo se refleja la diversidad geogr\u00e1fica en la composici\u00f3n del Comit\u00e9 de Expertos y qu\u00e9 implicaciones podr\u00eda tener esto para la regulaci\u00f3n farmac\u00e9utica global?**\n   - Esta pregunta busca explorar la representaci\u00f3n internacional en el comit\u00e9 y c\u00f3mo esto podr\u00eda influir en las decisiones y recomendaciones sobre est\u00e1ndares farmac\u00e9uticos a nivel global.\n\n### Resumen de Nivel Superior\nEl informe destaca la importancia de la colaboraci\u00f3n internacional en la regulaci\u00f3n y calidad de los productos farmac\u00e9uticos, reflejada en la diversidad de expertos de diferentes pa\u00edses y organizaciones. Esto sugiere un enfoque global para abordar los desaf\u00edos en la industria farmac\u00e9utica, especialmente en el contexto de enfermedades como el VIH/SIDA, la tuberculosis y la malaria.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n#### Temas Clave:\n1. **Salud P\u00fablica**: El informe probablemente aborda cuestiones relacionadas con la salud p\u00fablica, incluyendo pol\u00edticas, pr\u00e1cticas y recomendaciones para mejorar la salud a nivel global.\n2. **Investigaci\u00f3n M\u00e9dica**: Es posible que se presenten hallazgos de investigaciones recientes en el campo de la medicina y la salud.\n3. **Recomendaciones de Pol\u00edticas**: El informe podr\u00eda incluir recomendaciones para gobiernos y organizaciones de salud sobre c\u00f3mo abordar problemas de salud espec\u00edficos.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe, que se dedica a coordinar esfuerzos internacionales en salud p\u00fablica.\n- **Informe T\u00e9cnico**: El tipo de documento que se presenta, que suele contener an\u00e1lisis detallados y recomendaciones basadas en evidencia.\n\nEste resumen proporciona una visi\u00f3n general de los posibles temas y entidades que podr\u00edan estar presentes en el informe, a pesar de la falta de contenido espec\u00edfico en el contexto proporcionado.", "excerpt_keywords": "Keywords: pharmaceutical preparations, WHO Expert Committee, global health, regulatory affairs, international collaboration"}}, "bc39baf5-1ee6-4a1e-9235-af38d3fb89af": {"node_ids": ["98fb631e-07c4-4dbc-ba69-2b3bd56f1207"], "metadata": {"page_label": "71", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\n(CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Congella, South Africa; Dr M. Guazzaroni Jacobs, Director, Quality and Regulatory Policy, Pfizer, New York, NY, USA; Ms N.M. Guerrero-Rivas, Head, Quality Assurance Section, Instituto Especializado de An\u00e1lisis, Estafeta Universitaria, Panam\u00e1, Panama; Guilin Pharmaceutical Company Ltd, Guilin, People\u2019s Republic of China; Dr R. Guinet, Agence fran\u00e7aise de s\u00e9curit\u00e9 sanitaire des produits de sant\u00e9, Saint-Denis, France; Dr G.T. Gunnarsson, Iceland; Professor R. Guy, Professor of Pharmaceutical Sciences, Department of Pharmacy and Pharmacology, University of Bath, Bath, England; Dr N. Habib, Director General of Medical Supplies, Ministry of Health, Oman; Dr N. Hamilton, Industrial Quality and Compliance, Industrial Affairs, Sanofi Aventis, West Malling, Kent, England; Dr A. Hawwa, Lecturer in Pharmacy (Medicines in Children), Medical Biology Centre, Queen\u2019s University Belfast, Belfast, Northern Ireland; Dr M. Hayes-Bachmeyer, TRIS Management, Technical Regulatory Affairs, Pharmaceuticals Division, F. Hoffmann-la Roche, Basel, Switzerland; Dr G.W. Heddell, Director, Inspection Enforcement and Standards Division, Medicines and Healthcare products Regulatory Agency, London, England; Dr D. Hege-Voelksen, Swissmedic, Berne, Switzerland; Dr M. Helling-Borda, Commugny, Switzerland; Ms J. Hiep, QA Pharmacist and Auditor, Adcock Ingram, Bryanston, South Africa; Ms M. Hirschhorn, Chief, Quality Assurance and Analytical Chemistry, Comisi\u00f3n para el Control de Calidad de Medicamentos, Montevideo, Uruguay; Professor J. Hoogmartens, Professor Emeritus, Laboratorium voor Farmaceutische Analyse, Leuven, Belgium; Dr K. Hoppu, Director, Poison Information Centre, Helsinki University Central Hospital, Helsinki, Finland; Dr R. Horder, Consultant, Abbott, Maidencombe, England; Dr H. Hoseh, Head of Registration Unit, Drug Directorate, Jordan Food and Drug Administration, Jordan; Dr Hou Xinping, T\u00dcV S\u00dcD PSB Chemical & Materials, Singapore; Dr N. Ibrahim, National Pharmaceutical Control Bureau, Ministry of Health, Jalan University, Petaling Jaya, Indonesia; Professor R. Jachowicz, Head, Department of Pharmaceutical Technology and Biopharmaceutics, Jagiellonian University Medical College, Faculty of Pharmacy, Krak\u00f3w, Poland; Dr R. J\u00e4hnke, Global Pharma Health Fund e.V., Frankfurt, Germany; Dr M. James, GlaxoSmithKline, Brentford, Middlesex, England; Dr A. Janssen, Manager, Regulatory Affairs, DMV Fonterra Excipients, Friesland Campina Ingredients Innovation, Goch, Germany; Professor Jin Shaohong, Chief Expert for Pharmaceutical Products, National Institutes for Food and Drug Control, Beijing, People\u2019s Republic of China; Dr P. Jones, Director, Analytical Control, Pharmaceutical Sciences, Pfizer Global R&D, Sandwich, England; Dr Y. Juillet, France; Mr D. J\u00fcnemann, Teaching Assistant; Institut f\u00fcr Pharmazeutische Technologie, Biozentrum, Johann Wolfgang Goethe-Universit\u00e4t, Frankfurt and Main, Germany; Ms A. Junttonen, Senior Pharmaceutical Inspector, National\n```\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl texto proviene del \"WHO - Technical Report Series 970\" y presenta una lista de profesionales y acad\u00e9micos de diversas instituciones y empresas relacionadas con la salud y la farmac\u00e9utica. Incluye nombres, t\u00edtulos y afiliaciones de personas de diferentes pa\u00edses, lo que sugiere un enfoque en la colaboraci\u00f3n internacional en el \u00e1mbito de la regulaci\u00f3n y calidad de productos farmac\u00e9uticos.\n\n### Preguntas Generadas\n\n1. **\u00bfQu\u00e9 tipo de instituciones est\u00e1n representadas por los profesionales mencionados en el documento?**\n   - Respuesta: Las instituciones incluyen universidades, agencias reguladoras de salud, empresas farmac\u00e9uticas y centros de investigaci\u00f3n, como la Universidad de KwaZulu-Natal, Pfizer, y la Agencia Francesa de Seguridad Sanitaria de Productos de Salud.\n\n2. **\u00bfCu\u00e1l es el enfoque principal de los profesionales listados en el documento?**\n   - Respuesta: El enfoque principal de los profesionales es la calidad y regulaci\u00f3n de productos farmac\u00e9uticos, as\u00ed como la investigaci\u00f3n y desarrollo en el \u00e1mbito de la farmacolog\u00eda y la salud p\u00fablica.\n\n3. **\u00bfQu\u00e9 regiones del mundo est\u00e1n representadas en la lista de profesionales y sus respectivas instituciones?**\n   - Respuesta: La lista incluye representantes de diversas regiones, como Am\u00e9rica del Norte (EE. UU.), Europa (Reino Unido, Francia, Alemania, Polonia, entre otros), Asia (China, Indonesia, Singapur), y \u00c1frica (Sud\u00e1frica, Om\u00e1n), lo que indica una colaboraci\u00f3n global en el campo de la salud y la farmac\u00e9utica.", "prev_section_summary": "El contenido de la secci\u00f3n se centra en el \"Cuarenta y sexto informe\" del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Colaboraci\u00f3n Internacional**: El informe destaca la importancia de la cooperaci\u00f3n entre expertos de diversas organizaciones y pa\u00edses en el \u00e1mbito de la regulaci\u00f3n y calidad de productos farmac\u00e9uticos.\n2. **Diversidad de Expertos**: Se menciona la amplia gama de especializaciones y experiencias de los miembros del comit\u00e9, lo que refleja un enfoque multidisciplinario en la regulaci\u00f3n farmac\u00e9utica.\n3. **Enfoque en Enfermedades Globales**: El informe subraya la relevancia de la regulaci\u00f3n farmac\u00e9utica en el contexto de enfermedades como el VIH/SIDA, la tuberculosis y la malaria.\n\n### Entidades Mencionadas:\n- **Organizaciones**:\n  - Organizaci\u00f3n Mundial de la Salud (OMS)\n  - Global Fund to Fight AIDS, Tuberculosis and Malaria\n  - Parenteral Drug Association\n  - GlaxoSmithKline\n  - Pfizer Global Research & Development\n  - Novartis Group Quality\n  - Pharmaceutical Research and Manufacturers of America\n\n- **Expertos y sus Afiliaciones**:\n  - Dr. J. Daviaud (Global Fund to Fight AIDS, Tuberculosis and Malaria, Suiza)\n  - Dr. V. Davoust (Pfizer, Francia)\n  - Dr. A. Fleuckiger (F. Hoffmann-La Roche, Suiza)\n  - Dr. M. Garvin (Pharmaceutical Research and Manufacturers of America, EE. UU.)\n  - Dr. A. Gray (Centro para el Programa de Investigaci\u00f3n del SIDA en Sud\u00e1frica)\n\n### Implicaciones:\nLa diversidad geogr\u00e1fica y de especializaci\u00f3n en el comit\u00e9 sugiere que las decisiones y recomendaciones sobre est\u00e1ndares farmac\u00e9uticos se ven influenciadas por una amplia gama de perspectivas, lo que es crucial para abordar los desaf\u00edos globales en la industria farmac\u00e9utica.", "excerpt_keywords": "Keywords: regulaci\u00f3n farmac\u00e9utica, calidad, colaboraci\u00f3n internacional, expertos, salud p\u00fablica"}}, "d82ea119-ba17-487c-8f51-2e61ac949ccf": {"node_ids": ["c6bfddb8-8940-447c-bb9b-4a02603c98f4"], "metadata": {"page_label": "72", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAgency for Medicines, Helsinki, Finland; Dr M. Kaplan, Director, Institute for Standardization and Control of Pharmaceuticals, Jerusalem, Israel; Dr M. Karga-Hinds, Director, Barbados Drug Service, Christchurch, Barbados; Dr A.M. Kaukonen, National Agency for Medicines, Helsinki, Finland; Dr T. Kawanishi, Deputy Director General, National Institute of Health Sciences, Tokyo, Japan; Ms H. Kavale, Cipla, Mumbai, India; Dr S. Keitel, Director, European Directorate for the Quality of Medicines and HealthCare, Strasbourg, France; Dr K. Keller, Director and Professor, Federal Ministry of Health, Bonn, Germany; Dr M. Keller, Inspector, Division of Certificates and Licencing, Swissmedic, Berne, Switzerland; Dr L. Kerr, Scientific Operations Adviser, Office of Laboratories and Scientific Services, Therapeutic Goods Administration, Woden, ACT, Australia; Dr M. Khan, Director, Federal Research Center Life Sciences, US Food and Drug Administration, Silver Spring, MD, USA; Professor Kazuko Kimura, Institute of Medicine, Pharmacy and Health Sciences, Kanazawa University, Kanazawa-city, Japan; Ms M. Kira, Consultant, Non-Governmental Organizations and Industry Relations Section, Department of External Relations, World Intellectual Property Organization, Geneva, Switzerland; Dr H. K\u0151szegi-Szalai, Head, Department for Quality Assessment and Control, National Institute of Pharmacy, Budapest, Hungary; Dr A. Kovacs, Secretariat, Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland; Ms S. Kox, Senior Director, Scientific Affairs, European Generic Medicines Association, Brussels, Belgium; Dr P. Kozarewicz, Scientific Administrator, Quality of Medicines Sector, Human Unit Pre-Authorization, European Medicines Agency, London, England; Dr A. Krauss, Principal Scientist, Chemist Laboratory, Therapeutic Goods Administration Laboratories, Woden, ACT, Australia; Professor H.G. Kristensen, Vedbaek, Denmark; Mr A. Kupferman, Industry Pharmacist, Strasbourg, France; Professor S. L\u00e4er, Institut f\u00fcr Klinische Pharmazie und Pharmakotherapie, Heinrich-Heine-Universit\u00e4t, D\u00fcsseldorf, Germany; Dr J.-M. Legrand, GlaxoSmithKline Biologicals, Wavre, Belgium; Dr A. Lodi, Head, Laboratory Department, European Directorate for the Quality of Medicines and HealthCare, Strasbourg, France; Mr M. Lok, Head of Office, Office of Manufacturing Quality, Therapeutic Goods Administration, Woden, ACT, Australia; Ms Low Min Yong, Director, Pharmaceutical Division, Applied Sciences Group, Health Sciences Authority, Singapore; Dr J.C. Lyda, Senior Director, Regulatory Affairs, Parenteral Drug Association Europe, Glienicke, Berlin, Germany; Mr D. Mader, Compliance Auditor, GlaxoSmithKline, Cape Town, South Africa; Dr F. Malik, Pakistan; Reverend J.Y. Martey, Head, Laboratory Services, Quality Control Laboratory, Food and Drugs Board, Accra, Ghana; Dr T. Massa, Vice President, Global Regulatory Sciences \u2013 Chemistry, Manufacturing and Control, Bristol-Myers Squibb, USA; Dr B. Matthews, Alcon, Hemel Hempstead, Herts, England; Dr Y. Matthews, Regulatory Operations Executive, GE Healthcare, Amersham, Bucks.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) titulado \"WHO - Technical Report Series 970\", que presenta las contribuciones de un comit\u00e9 de expertos sobre especificaciones para preparaciones farmac\u00e9uticas. Incluye una lista de participantes de diversas organizaciones y pa\u00edses, destacando sus roles y afiliaciones. Este comit\u00e9 est\u00e1 compuesto por profesionales de la salud, reguladores y expertos en farmacolog\u00eda, que colaboran para establecer est\u00e1ndares y directrices en la calidad de los medicamentos.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQui\u00e9nes son algunos de los miembros clave del comit\u00e9 y cu\u00e1les son sus roles espec\u00edficos en sus respectivas organizaciones?**\n   - Esta pregunta busca detalles sobre la composici\u00f3n del comit\u00e9 y las funciones de sus miembros, que no se encuentran f\u00e1cilmente en otros documentos.\n\n2. **\u00bfQu\u00e9 organizaciones est\u00e1n representadas en el comit\u00e9 y c\u00f3mo contribuyen a la regulaci\u00f3n de los medicamentos a nivel internacional?**\n   - Esta pregunta se centra en las organizaciones mencionadas y su impacto en la regulaci\u00f3n farmac\u00e9utica global, proporcionando un contexto sobre la colaboraci\u00f3n internacional en este \u00e1mbito.\n\n3. **\u00bfCu\u00e1les son los objetivos principales del comit\u00e9 de expertos de la OMS en relaci\u00f3n con las especificaciones para preparaciones farmac\u00e9uticas?**\n   - Esta pregunta busca entender los prop\u00f3sitos y metas del comit\u00e9, lo que puede no estar expl\u00edcitamente detallado en otros informes o documentos relacionados.\n\n### Resumen de Nivel Superior\nEl informe de la OMS presenta un grupo diverso de expertos en farmacolog\u00eda y regulaci\u00f3n de medicamentos, que se re\u00fanen para discutir y establecer est\u00e1ndares para la calidad de las preparaciones farmac\u00e9uticas. Este comit\u00e9 incluye representantes de diferentes pa\u00edses y organizaciones, lo que refleja un esfuerzo colaborativo para mejorar la seguridad y eficacia de los medicamentos a nivel mundial.", "prev_section_summary": "La secci\u00f3n del documento \"WHO - Technical Report Series 970\" presenta una lista de profesionales y acad\u00e9micos de diversas instituciones y empresas relacionadas con la salud y la farmac\u00e9utica. Los temas clave incluyen:\n\n1. **Colaboraci\u00f3n Internacional**: La lista refleja un enfoque global en la regulaci\u00f3n y calidad de productos farmac\u00e9uticos, con representantes de m\u00faltiples pa\u00edses y organizaciones.\n\n2. **Diversidad de Instituciones**: Se mencionan diversas entidades, incluyendo universidades (como la Universidad de KwaZulu-Natal y la Universidad de Bath), agencias reguladoras (como la Agencia Francesa de Seguridad Sanitaria de Productos de Salud y Swissmedic), y empresas farmac\u00e9uticas (como Pfizer y GlaxoSmithKline).\n\n3. **\u00c1reas de Especializaci\u00f3n**: Los profesionales tienen experiencia en \u00e1reas como calidad y regulaci\u00f3n de productos farmac\u00e9uticos, farmacolog\u00eda, an\u00e1lisis qu\u00edmico, y medicina pedi\u00e1trica, lo que indica un enfoque multidisciplinario.\n\n4. **Representaci\u00f3n Geogr\u00e1fica**: La lista incluye profesionales de regiones como Am\u00e9rica del Norte, Europa, Asia y \u00c1frica, lo que subraya la importancia de la cooperaci\u00f3n internacional en el \u00e1mbito de la salud.\n\nEn resumen, la secci\u00f3n destaca la colaboraci\u00f3n entre expertos de diferentes disciplinas y pa\u00edses en la mejora de la calidad y regulaci\u00f3n de productos farmac\u00e9uticos a nivel global.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, regulatory affairs, international collaboration, quality standards"}}, "a95a1b3b-9314-4732-a61c-8ef433a20fdb": {"node_ids": ["7b454f18-aaac-4c39-9eb8-b58fa09aa93c"], "metadata": {"page_label": "73", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior:\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pr\u00e1cticas de salud a nivel global. Aunque el contenido espec\u00edfico de la p\u00e1gina 73 no est\u00e1 disponible, el informe en su conjunto puede contener informaci\u00f3n relevante sobre pol\u00edticas de salud, directrices de tratamiento, o datos epidemiol\u00f3gicos.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las principales recomendaciones de salud p\u00fablica presentadas en el informe WHO - Technical Report Series 970?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre las directrices o recomendaciones que la OMS ha emitido en este informe, que podr\u00edan no estar disponibles en otros documentos.\n\n2. **\u00bfQu\u00e9 temas de investigaci\u00f3n m\u00e9dica se abordan en el informe y c\u00f3mo se relacionan con las tendencias actuales en salud global?**\n   - Esta pregunta se centra en identificar los temas tratados en el informe y su relevancia en el contexto de la salud global contempor\u00e1nea, lo que podr\u00eda no estar claramente documentado en otras fuentes.\n\n3. **\u00bfQu\u00e9 datos epidemiol\u00f3gicos espec\u00edficos se presentan en el informe y c\u00f3mo pueden influir en la formulaci\u00f3n de pol\u00edticas de salud?**\n   - Esta pregunta busca detalles sobre los datos espec\u00edficos que se incluyen en el informe y su posible impacto en la toma de decisiones en el \u00e1mbito de la salud p\u00fablica, lo que podr\u00eda no estar disponible en otros lugares.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y relevante que podr\u00eda ser \u00fanica para el documento mencionado.", "prev_section_summary": "La secci\u00f3n del documento \"WHO - Technical Report Series 970\" presenta un informe del Comit\u00e9 de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. A continuaci\u00f3n se resumen los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Composici\u00f3n del Comit\u00e9**: El comit\u00e9 est\u00e1 formado por expertos de diversas organizaciones y pa\u00edses, incluyendo reguladores, cient\u00edficos y profesionales de la salud, que colaboran para establecer est\u00e1ndares de calidad en medicamentos.\n  \n2. **Colaboraci\u00f3n Internacional**: La diversidad de miembros refleja un esfuerzo global para mejorar la regulaci\u00f3n y la calidad de los medicamentos, destacando la importancia de la cooperaci\u00f3n entre diferentes entidades y pa\u00edses.\n\n3. **Objetivos del Comit\u00e9**: Aunque no se detallan expl\u00edcitamente en el texto, se infiere que el comit\u00e9 busca establecer directrices y est\u00e1ndares que aseguren la seguridad y eficacia de las preparaciones farmac\u00e9uticas a nivel mundial.\n\n### Entidades Mencionadas:\n- **Organizaciones**: \n  - Agencia para Medicamentos (Finlandia)\n  - Instituto de Estandarizaci\u00f3n y Control de Medicamentos (Israel)\n  - Servicio de Medicamentos de Barbados\n  - Administraci\u00f3n de Alimentos y Medicamentos de EE. UU.\n  - Agencia Europea de Medicamentos\n  - Autoridad de Salud de Singapur\n  - Organizaci\u00f3n Mundial de la Propiedad Intelectual\n\n- **Profesionales Clave**: \n  - Dr. M. Kaplan (Israel)\n  - Dr. S. Keitel (Francia)\n  - Dr. M. Khan (EE. UU.)\n  - Dr. T. Massa (EE. UU.)\n  - Reverend J.Y. Martey (Ghana)\n\nEste resumen destaca la importancia del comit\u00e9 en la regulaci\u00f3n farmac\u00e9utica internacional y la colaboraci\u00f3n entre diversas entidades para mejorar la calidad de los medicamentos.", "excerpt_keywords": "Keywords: OMS, medicamentos, regulaci\u00f3n, est\u00e1ndares, salud p\u00fablica"}}, "7b6dd1ed-dbd1-48bd-a558-97e81cc86270": {"node_ids": ["bd77a95f-d125-46a9-9a77-9e13ce291a5a"], "metadata": {"page_label": "74", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto del documento \"WHO - Technical Report Series 970\":\n\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir recomendaciones sobre salud p\u00fablica, pol\u00edticas sanitarias o investigaciones cient\u00edficas.\n\n2. **\u00bfQu\u00e9 temas de salud global se abordan en el documento y c\u00f3mo se relacionan con las tendencias actuales en la salud p\u00fablica?**\n   - Esta pregunta se enfoca en identificar los temas tratados en el informe y su relevancia en el contexto de los desaf\u00edos actuales en salud p\u00fablica, lo que podr\u00eda no estar disponible en otras fuentes.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron para recopilar datos y elaborar las conclusiones en el Informe 46 de la OMS?**\n   - Esta pregunta busca detalles sobre los m\u00e9todos de investigaci\u00f3n y an\u00e1lisis utilizados en el informe, lo que puede proporcionar una comprensi\u00f3n m\u00e1s profunda de la validez y aplicabilidad de los hallazgos.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS) que abordan diversos temas relacionados con la salud global. Estos informes suelen incluir investigaciones, recomendaciones y directrices sobre pr\u00e1cticas de salud, pol\u00edticas y estrategias para mejorar la salud p\u00fablica a nivel mundial. El Informe 46 en particular podr\u00eda contener informaci\u00f3n relevante sobre un tema espec\u00edfico de salud, as\u00ed como datos y an\u00e1lisis que respaldan sus conclusiones.", "prev_section_summary": "### Resumen de Temas Clave y Entidades:\n\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS) que abordan cuestiones de salud p\u00fablica y recomendaciones para pr\u00e1cticas de salud a nivel global. Aunque el contenido espec\u00edfico de la p\u00e1gina 73 no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n#### Temas Clave:\n1. **Salud P\u00fablica**: El informe probablemente incluye recomendaciones y directrices sobre pr\u00e1cticas de salud p\u00fablica.\n2. **Investigaci\u00f3n M\u00e9dica**: Es posible que se aborden temas de investigaci\u00f3n que son relevantes para la salud global.\n3. **Pol\u00edticas de Salud**: El informe puede contener datos y an\u00e1lisis que influyan en la formulaci\u00f3n de pol\u00edticas de salud.\n4. **Epidemiolog\u00eda**: Se espera que se presenten datos epidemiol\u00f3gicos que ayuden a entender tendencias y problemas de salud.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe y de la formulaci\u00f3n de recomendaciones de salud.\n- **Informe T\u00e9cnico**: El documento en s\u00ed, que forma parte de una serie m\u00e1s amplia de informes t\u00e9cnicos sobre salud.\n\nEste resumen proporciona una visi\u00f3n general de los temas y entidades que podr\u00edan estar presentes en el informe, a pesar de la falta de contenido espec\u00edfico en la secci\u00f3n mencionada.", "excerpt_keywords": "Keywords: salud p\u00fablica, OMS, recomendaciones, investigaci\u00f3n m\u00e9dica, pol\u00edticas de salud"}}, "9b2c4f3e-783e-47e2-8495-cb812d7ea3e5": {"node_ids": ["c8bcdff2-acde-4392-87b5-ec18539b5ec2"], "metadata": {"page_label": "75", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto del documento \"WHO - Technical Report Series 970\":\n\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir recomendaciones sobre salud p\u00fablica, pol\u00edticas sanitarias o investigaciones cient\u00edficas.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en el estudio o an\u00e1lisis presentado en el documento de la OMS?**\n   - Esta pregunta se centra en las t\u00e9cnicas y enfoques utilizados en la investigaci\u00f3n, lo que puede ser crucial para entender la validez y aplicabilidad de los resultados.\n\n3. **\u00bfC\u00f3mo se relaciona el contenido del Informe 46 con otros informes previos de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta busca establecer conexiones entre diferentes informes, lo que puede ayudar a contextualizar los hallazgos y recomendaciones en un marco m\u00e1s amplio de investigaci\u00f3n y pol\u00edticas de salud.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS), que abordan diversos temas relacionados con la salud p\u00fablica, la investigaci\u00f3n m\u00e9dica y las pol\u00edticas sanitarias. Estos informes son fundamentales para la formulaci\u00f3n de directrices y recomendaciones a nivel global, y suelen incluir an\u00e1lisis de datos, revisiones de literatura y propuestas para futuras investigaciones.", "prev_section_summary": "El documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS) que abordan temas de salud global. El Informe 46, en particular, se centra en hallazgos y recomendaciones relevantes para la salud p\u00fablica, as\u00ed como en metodolog\u00edas de investigaci\u00f3n utilizadas para recopilar datos y elaborar conclusiones. \n\n### Temas clave:\n1. **Hallazgos y recomendaciones**: Informaci\u00f3n espec\u00edfica sobre pol\u00edticas de salud y pr\u00e1cticas recomendadas.\n2. **Temas de salud global**: Identificaci\u00f3n de problemas de salud actuales y su relaci\u00f3n con tendencias en salud p\u00fablica.\n3. **Metodolog\u00edas de investigaci\u00f3n**: M\u00e9todos utilizados para la recopilaci\u00f3n de datos y an\u00e1lisis en el informe.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la publicaci\u00f3n del informe.\n- **Informe 46**: Espec\u00edfico dentro de la serie de informes t\u00e9cnicos que aborda un tema particular de salud.\n\nEste resumen proporciona una visi\u00f3n general de los aspectos m\u00e1s relevantes del documento y su contexto en el \u00e1mbito de la salud p\u00fablica.", "excerpt_keywords": "Keywords: salud p\u00fablica, recomendaciones, metodolog\u00edas, investigaci\u00f3n, Organizaci\u00f3n Mundial de la Salud"}}, "f0958b35-f6ae-4803-94d5-10b24520a433": {"node_ids": ["d799eac2-7d35-48c5-9797-b5ae36f3ac74"], "metadata": {"page_label": "76", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfCu\u00e1l es el enfoque principal del Informe T\u00e9cnico de la OMS en la Serie 970?**\n   - Esta pregunta busca obtener informaci\u00f3n sobre el tema central o los objetivos del informe, que podr\u00eda no estar disponible en otras fuentes.\n\n2. **\u00bfQu\u00e9 recomendaciones espec\u00edficas se presentan en el Informe T\u00e9cnico de la OMS, seg\u00fan la p\u00e1gina 76?**\n   - Esta pregunta se centra en las recomendaciones o conclusiones que se pueden encontrar en la p\u00e1gina espec\u00edfica del documento, lo que podr\u00eda ofrecer informaci\u00f3n detallada y \u00fatil.\n\n3. **\u00bfQu\u00e9 metodolog\u00eda se utiliz\u00f3 para recopilar los datos presentados en el Informe T\u00e9cnico de la OMS?**\n   - Esta pregunta indaga sobre el enfoque metodol\u00f3gico del informe, lo que podr\u00eda proporcionar una comprensi\u00f3n m\u00e1s profunda de la validez y la fiabilidad de los hallazgos presentados.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento mencionado es un Informe T\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) en la Serie 970, que probablemente aborda temas relacionados con la salud p\u00fablica, investigaciones cient\u00edficas o recomendaciones para pol\u00edticas de salud. La falta de contenido espec\u00edfico en la p\u00e1gina 76 sugiere que podr\u00eda haber informaci\u00f3n relevante en otras secciones del informe que no se ha incluido en el contexto proporcionado.", "prev_section_summary": "El contenido de la secci\u00f3n se refiere al documento titulado \"WHO - Technical Report Series 970\", espec\u00edficamente al Informe 46 de esta serie publicada por la Organizaci\u00f3n Mundial de la Salud (OMS). A continuaci\u00f3n se presentan los temas clave y entidades relevantes:\n\n### Temas Clave:\n1. **Hallazgos y Recomendaciones**: Se busca informaci\u00f3n sobre los principales hallazgos y recomendaciones del informe, que pueden incluir aspectos de salud p\u00fablica y pol\u00edticas sanitarias.\n2. **Metodolog\u00edas de Investigaci\u00f3n**: Se indaga sobre las metodolog\u00edas utilizadas en el estudio o an\u00e1lisis presentado, lo que es esencial para evaluar la validez de los resultados.\n3. **Relaci\u00f3n con Informes Previos**: Se explora c\u00f3mo el contenido del Informe 46 se relaciona con otros informes de la misma serie, proporcionando un contexto m\u00e1s amplio.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la publicaci\u00f3n del informe.\n- **Serie de Informes T\u00e9cnicos de la OMS**: Conjunto de documentos que abordan temas de salud p\u00fablica y pol\u00edticas sanitarias.\n\n### Contexto General:\nEl documento es parte de una serie que tiene como objetivo proporcionar directrices y recomendaciones basadas en investigaciones y an\u00e1lisis de datos en el \u00e1mbito de la salud global. Estos informes son cruciales para la formulaci\u00f3n de pol\u00edticas y la promoci\u00f3n de la salud p\u00fablica a nivel internacional.", "excerpt_keywords": "Keywords: OMS, Informe T\u00e9cnico, salud p\u00fablica, recomendaciones, metodolog\u00eda"}}, "2a70502c-e3e6-4cc9-9502-33cc9904b57d": {"node_ids": ["ba896e1d-ab87-4a75-bf2f-5ee224f2ee56"], "metadata": {"page_label": "77", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 1\n\n## Development of monographs for *The International Pharmacopoeia*\n\nThe process described below is designed to ensure wide consultation and transparency during monograph development and that the adopted texts are made available in a timely manner.\n\nProvision of monographs in *The International Pharmacopoeia* provides the quality dimension for the medicines (included on the basis of their efficacy and safety) in the World Health Organization (WHO) Model lists of essential medicines and in WHO treatment guidelines.\n\nMajor WHO programmes such as the Prequalification of Medicines Programme (funded by the Bill & Melinda Gates Foundation and UNITAID) and others funded or managed by partner organizations such as the United Nations Children\u2019s Fund and the Global Fund to Fight AIDS, Tuberculosis and Malaria, rely heavily upon the quality specifications of *The International Pharmacopoeia*.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en el desarrollo de monograf\u00edas para *La Farmacopea Internacional*, un recurso clave de la Organizaci\u00f3n Mundial de la Salud (OMS) que establece especificaciones de calidad para medicamentos. Este proceso busca asegurar la consulta amplia y la transparencia en el desarrollo de las monograf\u00edas, garantizando que los textos adoptados est\u00e9n disponibles de manera oportuna. Las monograf\u00edas son fundamentales para la calidad de los medicamentos incluidos en las listas de medicamentos esenciales de la OMS y en sus gu\u00edas de tratamiento. Programas importantes de la OMS, como el Programa de Precalificaci\u00f3n de Medicamentos, dependen de estas especificaciones de calidad.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1l es el objetivo principal del desarrollo de monograf\u00edas para *La Farmacopea Internacional* seg\u00fan el documento?**\n   - Respuesta: El objetivo principal es asegurar una consulta amplia y transparencia durante el desarrollo de las monograf\u00edas, garantizando que los textos adoptados est\u00e9n disponibles de manera oportuna.\n\n2. **\u00bfQu\u00e9 papel juegan las monograf\u00edas de *La Farmacopea Internacional* en los programas de la OMS, como el Programa de Precalificaci\u00f3n de Medicamentos?**\n   - Respuesta: Las monograf\u00edas proporcionan las especificaciones de calidad necesarias para los medicamentos, que son fundamentales para la eficacia y seguridad de los tratamientos en programas como el de Precalificaci\u00f3n de Medicamentos, as\u00ed como en otras iniciativas gestionadas por organizaciones asociadas.\n\n3. **\u00bfQu\u00e9 organizaciones financian o gestionan programas que dependen de las especificaciones de calidad de *La Farmacopea Internacional*?**\n   - Respuesta: Programas como el de Precalificaci\u00f3n de Medicamentos son financiados por la Fundaci\u00f3n Bill y Melinda Gates y UNITAID, y tambi\u00e9n dependen de la colaboraci\u00f3n con organizaciones como el Fondo de las Naciones Unidas para la Infancia (UNICEF) y el Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria.", "prev_section_summary": "El contenido proporcionado se refiere a un Informe T\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) en la Serie 970, aunque no se incluye informaci\u00f3n espec\u00edfica de la p\u00e1gina 76. A continuaci\u00f3n se presenta un resumen de los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Informe T\u00e9cnico de la OMS**: El documento es parte de una serie que aborda temas relevantes para la salud p\u00fablica y pol\u00edticas de salud.\n2. **Recomendaciones y Conclusiones**: Se espera que el informe contenga recomendaciones espec\u00edficas que podr\u00edan ser \u00fatiles para la implementaci\u00f3n de pol\u00edticas de salud.\n3. **Metodolog\u00eda de Investigaci\u00f3n**: Se indaga sobre los m\u00e9todos utilizados para recopilar datos, lo que es crucial para evaluar la validez de los hallazgos.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la elaboraci\u00f3n del informe.\n- **Serie 970**: Parte de la colecci\u00f3n de informes t\u00e9cnicos de la OMS que abordan diversos temas de salud.\n\n### Contexto General:\nEl informe probablemente se centra en la investigaci\u00f3n cient\u00edfica y las recomendaciones para mejorar la salud p\u00fablica, aunque la falta de contenido espec\u00edfico en la p\u00e1gina 76 limita la informaci\u00f3n disponible sobre los detalles concretos del documento.", "excerpt_keywords": "Keywords: monographs, International Pharmacopoeia, WHO, quality specifications, essential medicines"}}, "458e5489-d3fb-42b0-ad91-b1c8d49d50dd": {"node_ids": ["3c9f397b-a190-4b65-a646-e35703602319"], "metadata": {"page_label": "78", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Process: phases in the development of new monographs\n\n*Note:* A \u201cschedule for the adoption process\u201d outlining the development history of a draft monograph is included in each working document that is circulated for comment.\n\n- **Phase 1:** Identify specific pharmaceutical products for which quality control (QC) specifications need to be developed, following confirmation by all WHO parties concerned (including the Department of Essential Medicines and Health Products, specific disease programmes and the Prequalification of Medicines Programme). Establish whether monographs also need to be developed for the active pharmaceutical ingredients (APIs) contained in the pharmaceutical products identified. Update the current work plan on *The International Pharmacopoeia* web site.\n\n- **Phase 2:** Obtain the contact details for the manufacturers of the selected APIs and pharmaceutical products, as applicable, in collaboration with all parties concerned.\n\n- **Phase 3:** Contact manufacturers for provision of QC specifications and samples.\n\n- **Phase 4:** Identify and contact QC laboratories for collaboration in the project (the number of laboratories will depend on how many APIs and pharmaceutical products have been identified in Phase 1).\n\n- **Phase 5:** Make arrangements with the collaborating laboratories for drafting the specifications and undertaking the necessary laboratory work.\n\n- **Phase 6:** Search for information on QC specifications available in the public domain.\n\n- **Phase 7:** Perform laboratory testing, development and validation, if needed, of QC specifications.\n\n- **Phase 8:** Follow the WHO Expert Committee consultative process: mail draft specifications to the Expert Advisory Panel and specialists, provide drafts on the web site.\n\n- **Phase 9:** Contact collaborating manufacturers to ascertain the availability of the respective substances to establish International Chemical Reference Substances (ICRS), as necessary.\n\n- **Phase 10:** Support the WHO host organization (European Directorate for the Quality of Medicines and HealthCare, Council of Europe) responsible for the establishment of ICRS.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento detalla un proceso estructurado en diez fases para el desarrollo de nuevas monograf\u00edas de productos farmac\u00e9uticos, que incluye la identificaci\u00f3n de productos, la colaboraci\u00f3n con fabricantes y laboratorios, la obtenci\u00f3n de especificaciones de control de calidad (QC), y la validaci\u00f3n de estas especificaciones. Este proceso es parte de un esfuerzo m\u00e1s amplio de la OMS para asegurar la calidad de los medicamentos a nivel internacional.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 criterios se utilizan para identificar los productos farmac\u00e9uticos que necesitan especificaciones de control de calidad en la Fase 1?**\n   - Esta pregunta busca entender los factores espec\u00edficos que gu\u00edan la selecci\u00f3n de productos farmac\u00e9uticos para el desarrollo de monograf\u00edas.\n\n2. **\u00bfCu\u00e1l es el papel de los laboratorios de control de calidad en las fases posteriores del proceso de desarrollo de monograf\u00edas?**\n   - Esta pregunta se centra en la colaboraci\u00f3n con laboratorios y c\u00f3mo contribuyen a la elaboraci\u00f3n y validaci\u00f3n de las especificaciones de QC.\n\n3. **\u00bfQu\u00e9 pasos se siguen para asegurar la disponibilidad de sustancias necesarias para establecer Sustancias de Referencia Qu\u00edmica Internacional (ICRS) en la Fase 9?**\n   - Esta pregunta indaga sobre el proceso espec\u00edfico que se lleva a cabo para garantizar que las sustancias requeridas est\u00e9n disponibles para la creaci\u00f3n de ICRS, lo cual es crucial para la estandarizaci\u00f3n y control de calidad.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Desarrollo de Monograf\u00edas:** El proceso de creaci\u00f3n de monograf\u00edas para *La Farmacopea Internacional* busca asegurar una consulta amplia y transparencia, garantizando la disponibilidad oportuna de los textos adoptados.\n2. **Especificaciones de Calidad:** Las monograf\u00edas establecen las especificaciones de calidad para los medicamentos, que son fundamentales para su eficacia y seguridad.\n3. **Medicamentos Esenciales:** Las monograf\u00edas son cruciales para los medicamentos incluidos en las listas de medicamentos esenciales de la OMS y en sus gu\u00edas de tratamiento.\n4. **Programas de la OMS:** Programas importantes, como el Programa de Precalificaci\u00f3n de Medicamentos, dependen de estas especificaciones de calidad.\n\n**Entidades:**\n1. **Organizaci\u00f3n Mundial de la Salud (OMS):** Responsable del desarrollo de las monograf\u00edas y de la provisi\u00f3n de est\u00e1ndares de calidad para medicamentos.\n2. **Fundaci\u00f3n Bill y Melinda Gates:** Financia el Programa de Precalificaci\u00f3n de Medicamentos.\n3. **UNITAID:** Tambi\u00e9n financia el Programa de Precalificaci\u00f3n de Medicamentos.\n4. **Fondo de las Naciones Unidas para la Infancia (UNICEF):** Colabora en programas que dependen de las especificaciones de calidad.\n5. **Fondo Global para la Lucha contra el SIDA, la Tuberculosis y la Malaria:** Otro socio que gestiona programas basados en las especificaciones de *La Farmacopea Internacional*.", "excerpt_keywords": "Keywords: monographs, quality control, pharmaceutical products, WHO, International Chemical Reference Substances"}}, "73f84789-0869-46f4-988c-7d5c04dbe2db": {"node_ids": ["d79c1417-8b57-4088-8e6d-682978e07b40"], "metadata": {"page_label": "79", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "- **Phase 11**: Collect and collate the comments received during the global consultative process.\n- **Phase 12**: Discuss comments received during the consultation process with contract laboratories, WHO collaborating centres, and if relevant with the ICRS host organization; conduct additional laboratory testing to add, verify and/or validate specifications.\n- **Phase 13**: Discuss the comments received during the consultation process and test results received as feedback from the collaborating laboratories in an informal consultation with experts and specialists.\n- **Phase 14**: Recirculate draft monograph extensively for comments.\n- **Phase 15**: Repeat Phases 8\u201315, until the agreed draft is suitable for adoption.\n- **Phase 16**: Present the drafts to the WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) for possible formal adoption. If not adopted repeat Phases 8\u201314 as often as necessary. If the draft is adopted, proceed to Phase 17.\n- **Phase 17**: Incorporate all changes agreed during the discussion leading to adoption together with any editorial corrections.\n- **Phase 18**: Where necessary, also take account of any further comments that may be received due to comment deadlines for recirculated texts (Phase 12 and subsequent) falling shortly after the relevant consultation or ECSPP meeting.\n- **Phase 19**: In all cases, confirm the amended text by correspondence with the relevant experts and/or contract laboratory before making it available on *The International Pharmacopoeia* web site.\n- **Phase 20**: Make \u201cfinal texts\u201d available on *The International Pharmacopoeia* web site to provide users, such as prequalification assessors and manufacturers, with the approved specifications in advance of the next publication date.\n- **Phase 21**: Include in *The International Pharmacopoeia*.\n\nThe \u201cfinal texts\u201d on *The International Pharmacopoeia* web site for the monographs adopted at the October 2011 meeting, for example, are prefaced with the following wording: \u201cThis monograph was adopted at the Forty-sixth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2011 for inclusion in *The International Pharmacopoeia*\u201d.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento describe un proceso estructurado en varias fases para la elaboraci\u00f3n y adopci\u00f3n de monograf\u00edas en *The International Pharmacopoeia* por parte de la OMS. Este proceso incluye la recopilaci\u00f3n de comentarios, discusiones con laboratorios y expertos, pruebas de laboratorio, y la recirculaci\u00f3n de borradores para obtener m\u00e1s comentarios. Finalmente, se presentan los borradores al Comit\u00e9 de Expertos de la OMS para su adopci\u00f3n formal, y se realizan correcciones editoriales antes de hacer disponibles los textos finales en el sitio web de la farmacopoeia.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 criterios se utilizan para determinar si un borrador de monograf\u00eda es adecuado para su adopci\u00f3n en el Comit\u00e9 de Expertos de la OMS?**\n   - Esta pregunta busca entender los est\u00e1ndares y criterios espec\u00edficos que se aplican durante la evaluaci\u00f3n de los borradores, lo cual no se detalla en el contexto.\n\n2. **\u00bfQu\u00e9 tipo de comentarios se consideran durante el proceso de consulta global y c\u00f3mo se priorizan estos comentarios en las fases posteriores?**\n   - Esta pregunta se centra en la naturaleza de los comentarios recibidos y el proceso de priorizaci\u00f3n, lo que podr\u00eda no estar expl\u00edcitamente mencionado en el texto.\n\n3. **\u00bfC\u00f3mo se asegura la transparencia y la trazabilidad de los cambios realizados en las monograf\u00edas a lo largo de las fases del proceso?**\n   - Esta pregunta indaga sobre los mecanismos implementados para documentar y comunicar los cambios en las monograf\u00edas, un aspecto que podr\u00eda no estar claramente abordado en el contexto proporcionado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento describe un proceso detallado en diez fases para el desarrollo de nuevas monograf\u00edas de productos farmac\u00e9uticos, con el objetivo de establecer especificaciones de control de calidad (QC) que aseguren la calidad de los medicamentos a nivel internacional. A continuaci\u00f3n se presentan los temas clave y las entidades involucradas:\n\n#### Temas Clave:\n1. **Identificaci\u00f3n de Productos:** La primera fase implica la selecci\u00f3n de productos farmac\u00e9uticos que requieren especificaciones de QC, en colaboraci\u00f3n con diversas partes interesadas de la OMS.\n2. **Colaboraci\u00f3n con Fabricantes:** Se establece un proceso para obtener informaci\u00f3n y muestras de los fabricantes de los productos y principios activos seleccionados.\n3. **Laboratorios de Control de Calidad:** Se identifican y contactan laboratorios para colaborar en la elaboraci\u00f3n y validaci\u00f3n de las especificaciones de QC.\n4. **Desarrollo y Validaci\u00f3n de Especificaciones:** Se realizan pruebas de laboratorio y se desarrollan especificaciones, que pueden requerir validaci\u00f3n adicional.\n5. **Proceso Consultivo de la OMS:** Se sigue un proceso consultivo que incluye la revisi\u00f3n de borradores por parte de paneles de expertos y la publicaci\u00f3n de documentos en l\u00ednea.\n6. **Establecimiento de Sustancias de Referencia:** Se asegura la disponibilidad de sustancias necesarias para crear Sustancias de Referencia Qu\u00edmica Internacional (ICRS).\n\n#### Entidades Involucradas:\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Coordinadora del proceso y responsable de la calidad de los medicamentos.\n- **Departamento de Medicamentos Esenciales y Productos de Salud de la OMS:** Participa en la identificaci\u00f3n de productos.\n- **Programas de Enfermedades Espec\u00edficas y Programa de Precalificaci\u00f3n de Medicamentos:** Colaboran en la confirmaci\u00f3n de productos.\n- **Fabricantes de Productos Farmac\u00e9uticos y APIs:** Proporcionan informaci\u00f3n y muestras necesarias para el desarrollo de especificaciones.\n- **Laboratorios de Control de Calidad:** Colaboran en la elaboraci\u00f3n y validaci\u00f3n de especificaciones de QC.\n- **Comit\u00e9 de Expertos de la OMS:** Revisa y proporciona retroalimentaci\u00f3n sobre las especificaciones propuestas.\n\nEste proceso es fundamental para garantizar que los medicamentos cumplan con est\u00e1ndares de calidad internacionales, contribuyendo as\u00ed a la seguridad y eficacia de los tratamientos farmacol\u00f3gicos.", "excerpt_keywords": "Keywords: WHO, International Pharmacopoeia, monographs, pharmaceutical preparations, quality control"}}, "11af49c1-7fd9-4420-9edb-29564c85e0f9": {"node_ids": ["0f05b645-e441-4785-9662-72a0b9e59f26"], "metadata": {"page_label": "80", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones sobre pr\u00e1cticas de salud. Sin embargo, el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentadas en el informe WHO - Technical Report Series 970?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda incluir recomendaciones sobre pol\u00edticas de salud, resultados de investigaciones o gu\u00edas para la pr\u00e1ctica cl\u00ednica.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en el informe y c\u00f3mo se relacionan con las tendencias actuales en salud global?**\n   - Esta pregunta se centra en la relevancia del informe en el contexto de los desaf\u00edos actuales en salud p\u00fablica, como enfermedades infecciosas, salud mental, o sistemas de salud.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en la investigaci\u00f3n presentada en el informe y c\u00f3mo se validaron los resultados?**\n   - Esta pregunta indaga sobre la rigurosidad cient\u00edfica del informe, buscando detalles sobre los m\u00e9todos de investigaci\u00f3n y la validez de los datos presentados.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que podr\u00eda no estar disponible en otras fuentes, dado que el contenido del informe no se ha proporcionado.", "prev_section_summary": "### Temas Clave\n\n1. **Proceso de Elaboraci\u00f3n de Monograf\u00edas**: Se describe un proceso estructurado en varias fases para la creaci\u00f3n y adopci\u00f3n de monograf\u00edas en *The International Pharmacopoeia* por parte de la OMS.\n\n2. **Recopilaci\u00f3n de Comentarios**: La fase inicial implica la recolecci\u00f3n y organizaci\u00f3n de comentarios recibidos durante un proceso de consulta global.\n\n3. **Discusi\u00f3n y Validaci\u00f3n**: Se llevan a cabo discusiones sobre los comentarios y resultados de pruebas de laboratorio con laboratorios contratados y centros colaboradores de la OMS.\n\n4. **Recirculaci\u00f3n de Borradores**: Los borradores de las monograf\u00edas se recirculan para obtener m\u00e1s comentarios, y este proceso se repite hasta que se considera que el borrador es adecuado para su adopci\u00f3n.\n\n5. **Adopci\u00f3n Formal**: Los borradores se presentan al Comit\u00e9 de Expertos de la OMS para su posible adopci\u00f3n formal, y si no son adoptados, se repiten ciertas fases del proceso.\n\n6. **Incorporaci\u00f3n de Cambios**: Se incorporan todos los cambios acordados y correcciones editoriales antes de hacer disponibles los textos finales.\n\n7. **Disponibilidad de Textos Finales**: Los textos finales se publican en el sitio web de *The International Pharmacopoeia* para su acceso por parte de usuarios como evaluadores de precalificaci\u00f3n y fabricantes.\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la elaboraci\u00f3n y adopci\u00f3n de las monograf\u00edas.\n- **ECSPP (Comit\u00e9 de Expertos en Especificaciones para Preparaciones Farmac\u00e9uticas)**: Comit\u00e9 que eval\u00faa y adopta formalmente las monograf\u00edas.\n- **ICRS (Sistema Internacional de Referencia de Sustancias)**: Organizaci\u00f3n que puede estar involucrada en el proceso de consulta.\n- **Laboratorios Contratados y Centros Colaboradores**: Entidades que participan en la discusi\u00f3n y validaci\u00f3n de las especificaciones.\n\nEste resumen destaca la estructura y los pasos del proceso de elaboraci\u00f3n de monograf\u00edas, as\u00ed como las entidades involucradas en el mismo.", "excerpt_keywords": "Keywords: OMS, monograf\u00edas, salud p\u00fablica, farmacopoeia, validaci\u00f3n"}}, "54ef2f10-2c38-4b1e-a624-4aa7effec6aa": {"node_ids": ["448f1cf9-0007-4839-9a5a-2d597db9a610"], "metadata": {"page_label": "81", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 2\n\n## WHO good manufacturing practices: water for pharmaceutical use\n\n1. **Introduction**  \n   1.1 Scope of the document - 68  \n   1.2 Background to water requirements and uses - 68  \n   1.3 Applicable guides - 69  \n\n2. **General principles for pharmaceutical water systems** - 69  \n\n3. **Water quality specifications**  \n   3.1 General - 70  \n   3.2 Drinking-water - 70  \n   3.3 Bulk purified water - 71  \n   3.4 Bulk highly purified water - 71  \n   3.5 Bulk water for injections - 72  \n   3.6 Other grades of water - 72  \n\n4. **Application of specific types of water to processes and dosage forms** - 72  \n\n5. **Water purification systems**  \n   5.1 General considerations - 73  \n   5.2 Production of drinking-water - 74  \n   5.3 Production of purified water - 76  \n   5.4 Production of highly purified water - 77  \n   5.5 Production of water for injection(s) - 77  \n\n6. **Water storage and distribution systems**  \n   6.1 General - 78  \n   6.2 Materials that come into contact with systems for water for pharmaceutical use - 78  \n   6.3 System sanitization and bioburden control - 80  \n   6.4 Storage vessel requirements - 80  \n   6.5 Requirements for water distribution pipework - 81  \n\n7. **Operational considerations**  \n   7.1 Start-up and commissioning of water systems - 83  \n   7.2 Qualification - 83  \n   7.3 Continuous system monitoring - 85  \n   7.4 Maintenance of water systems - 86  \n   7.5 System reviews - 86  \n\n8. **Inspection of water systems** - 87  \n\n**Further reading** - 88  \n\n----\n\n1 The current document is a revision of WHO good manufacturing practices: water for pharmaceutical use, previously published in WHO Technical Report Series, No. 929, Annex 3, 2005.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento es una revisi\u00f3n de las buenas pr\u00e1cticas de fabricaci\u00f3n de la OMS relacionadas con el agua para uso farmac\u00e9utico. Se detalla la importancia del agua en la producci\u00f3n farmac\u00e9utica, especificando diferentes tipos de agua y sus aplicaciones, as\u00ed como los sistemas de purificaci\u00f3n, almacenamiento y distribuci\u00f3n. Tambi\u00e9n se abordan consideraciones operativas y de inspecci\u00f3n para garantizar la calidad y seguridad del agua utilizada en la industria farmac\u00e9utica.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son las especificaciones de calidad del agua para inyecciones seg\u00fan el documento?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre los est\u00e1ndares y requisitos que debe cumplir el agua destinada a inyecciones, que es crucial para la seguridad de los productos farmac\u00e9uticos.\n\n2. **\u00bfQu\u00e9 materiales se recomiendan para los sistemas de almacenamiento y distribuci\u00f3n de agua para uso farmac\u00e9utico?**\n   - Esta pregunta se centra en los materiales que deben utilizarse en los sistemas que entran en contacto con el agua, lo cual es fundamental para evitar la contaminaci\u00f3n y asegurar la calidad del agua.\n\n3. **\u00bfCu\u00e1les son las consideraciones operativas clave para el inicio y la puesta en marcha de sistemas de agua en la industria farmac\u00e9utica?**\n   - Esta pregunta busca detalles sobre los pasos y procedimientos necesarios para garantizar que los sistemas de agua est\u00e9n correctamente configurados y operativos desde el principio, lo que es esencial para el cumplimiento de las buenas pr\u00e1cticas de fabricaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n#### Temas Clave:\n1. **Salud P\u00fablica**: El informe probablemente aborda cuestiones relacionadas con la salud p\u00fablica, incluyendo pol\u00edticas, pr\u00e1cticas y recomendaciones para mejorar la salud global.\n2. **Investigaci\u00f3n M\u00e9dica**: Es probable que se presenten hallazgos de investigaciones recientes en el campo de la medicina y la salud.\n3. **Recomendaciones de Salud**: El informe podr\u00eda incluir gu\u00edas y recomendaciones para profesionales de la salud y responsables de pol\u00edticas.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe, que se enfoca en la salud global y la promoci\u00f3n de pr\u00e1cticas de salud efectivas.\n- **Investigadores y Expertos en Salud**: Posiblemente, el informe incluye contribuciones de expertos en diversas \u00e1reas de la salud y la medicina.\n\nEste resumen proporciona una visi\u00f3n general de los temas y entidades que podr\u00edan estar presentes en el informe, a pesar de la falta de contenido espec\u00edfico en el extracto proporcionado.", "excerpt_keywords": "Keywords: pharmaceutical water, good manufacturing practices, water quality specifications, water purification systems, operational considerations"}}, "6e773651-0dd8-4438-8f09-dc5e0be2aa18": {"node_ids": ["cccf2d91-ae6c-4b40-83b9-1a2998333833"], "metadata": {"page_label": "82", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\n## 1.1 Scope of the document\n\n1.1.1 The guidance contained in this document is intended to provide information about the available specifications for water for pharmaceutical use (WPU), guidance about which quality of water to use for specific applications, such as the manufacture of active pharmaceutical ingredients (APIs) and dosage forms, and to provide guidance on good manufacturing practices (GMP) regarding the design, installation and operation of pharmaceutical water systems. Although the focus of this document is on water for pharmaceutical applications, the guidelines may also be relevant to other industrial or specific uses where the specifications and practices can be applied.\n\n*Note:* This document does not cover water for administration to patients in the formulated state or the use of small quantities of water in pharmacies to compound individually prescribed medicines.\n\n1.1.2 The GMP guidance for WPU contained in this document is intended to be supplementary to the general GMP guidelines for pharmaceutical products published by WHO (*WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report.* Geneva, World Health Organization, 2003 (WHO Technical Report Series, No. 908), Annex 4).\n\n1.1.3 This document refers to available specifications, such as the pharmacopoeias and industry guidance for the use, production, storage and distribution of water in bulk form. In order to avoid confusion it does not attempt to duplicate such material.\n\n1.1.4 The guidance provided in this document can be used in whole or in part as appropriate to the application under consideration.\n\n1.1.5 Where subtle points of difference exist between pharmacopoeial specifications, the manufacturer will be expected to decide which option to choose in accordance with the related marketing authorization submitted to the national medicines regulatory authority.\n\n## 1.2 Background to water requirements and uses\n\n1.2.1 Water is the most widely used substance, raw material or starting material in the production, processing and formulation of pharmaceutical products. It has unique chemical properties due to its polarity and hydrogen bonds. This means it is able to dissolve, absorb, adsorb or suspend many different compounds. These include contaminants that may represent hazards in themselves or that may be able to react with intended product substances, resulting in hazards to health.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Alcance del documento**: Este documento proporciona directrices sobre las especificaciones del agua para uso farmac\u00e9utico (WPU), incluyendo la calidad del agua necesaria para la fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (APIs) y formas de dosificaci\u00f3n. Tambi\u00e9n aborda las buenas pr\u00e1cticas de manufactura (GMP) relacionadas con el dise\u00f1o, instalaci\u00f3n y operaci\u00f3n de sistemas de agua farmac\u00e9utica.\n\n2. **Relevancia del agua en la industria farmac\u00e9utica**: El agua es un componente esencial en la producci\u00f3n y formulaci\u00f3n de productos farmac\u00e9uticos debido a sus propiedades qu\u00edmicas \u00fanicas. Su capacidad para disolver y suspender compuestos la convierte en un material cr\u00edtico, aunque tambi\u00e9n puede ser un veh\u00edculo para contaminantes que representan riesgos para la salud.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de aplicaciones farmac\u00e9uticas requieren diferentes calidades de agua seg\u00fan el documento?**\n   - El documento proporciona orientaci\u00f3n sobre qu\u00e9 calidad de agua utilizar para aplicaciones espec\u00edficas, como la fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (APIs) y formas de dosificaci\u00f3n, aunque no detalla cada aplicaci\u00f3n espec\u00edfica.\n\n2. **\u00bfC\u00f3mo se espera que los fabricantes manejen las diferencias sutiles entre las especificaciones farmacop\u00e9uticas?**\n   - Se espera que los fabricantes decidan qu\u00e9 opci\u00f3n elegir en funci\u00f3n de las diferencias sutiles entre las especificaciones farmacop\u00e9uticas, de acuerdo con la autorizaci\u00f3n de comercializaci\u00f3n relacionada presentada a la autoridad reguladora nacional de medicamentos.\n\n3. **\u00bfQu\u00e9 aspectos de las buenas pr\u00e1cticas de manufactura (GMP) se abordan en relaci\u00f3n con el agua para uso farmac\u00e9utico?**\n   - El documento ofrece directrices sobre las buenas pr\u00e1cticas de manufactura (GMP) espec\u00edficamente para el agua para uso farmac\u00e9utico, que son complementarias a las directrices generales de GMP para productos farmac\u00e9uticos publicadas por la OMS. Esto incluye aspectos del dise\u00f1o, instalaci\u00f3n y operaci\u00f3n de sistemas de agua farmac\u00e9utica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO good manufacturing practices: water for pharmaceutical use\" aborda las buenas pr\u00e1cticas de fabricaci\u00f3n relacionadas con el agua utilizada en la industria farmac\u00e9utica. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n#### Temas Clave:\n1. **Introducci\u00f3n**: Se establece el alcance del documento y se proporciona un contexto sobre los requisitos y usos del agua en la producci\u00f3n farmac\u00e9utica.\n2. **Principios Generales**: Se describen los principios fundamentales que deben seguirse en los sistemas de agua farmac\u00e9utica.\n3. **Especificaciones de Calidad del Agua**: Se detallan las diferentes categor\u00edas de agua (agua potable, agua purificada, agua altamente purificada, agua para inyecciones, entre otros) y sus respectivas especificaciones de calidad.\n4. **Aplicaciones de Agua**: Se discuten las aplicaciones espec\u00edficas de los diferentes tipos de agua en procesos y formas de dosificaci\u00f3n.\n5. **Sistemas de Purificaci\u00f3n de Agua**: Se abordan las consideraciones generales y los m\u00e9todos para la producci\u00f3n de los distintos tipos de agua.\n6. **Almacenamiento y Distribuci\u00f3n**: Se analizan los sistemas de almacenamiento y distribuci\u00f3n, incluyendo los materiales recomendados y los requisitos para evitar la contaminaci\u00f3n.\n7. **Consideraciones Operativas**: Se describen los procedimientos para la puesta en marcha, calificaci\u00f3n, monitoreo continuo, mantenimiento y revisi\u00f3n de los sistemas de agua.\n8. **Inspecci\u00f3n de Sistemas de Agua**: Se menciona la importancia de la inspecci\u00f3n para garantizar la calidad y seguridad del agua utilizada.\n\n#### Entidades:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que establece las buenas pr\u00e1cticas de fabricaci\u00f3n.\n- **Agua para Uso Farmac\u00e9utico**: Categor\u00eda principal del documento, que incluye diferentes tipos de agua y sus especificaciones.\n- **Sistemas de Purificaci\u00f3n**: Infraestructura necesaria para garantizar la calidad del agua.\n- **Materiales de Contacto**: Materiales que deben ser utilizados en los sistemas de almacenamiento y distribuci\u00f3n para evitar la contaminaci\u00f3n.\n\nEste resumen proporciona una visi\u00f3n general de los aspectos m\u00e1s importantes del documento, destacando su enfoque en la calidad y seguridad del agua en la producci\u00f3n farmac\u00e9utica.", "excerpt_keywords": "Keywords: water for pharmaceutical use, good manufacturing practices, active pharmaceutical ingredients, quality specifications, contamination hazards"}}, "5fc28e43-694e-4589-a202-ba39a5eb920b": {"node_ids": ["3f078a28-a949-44fb-9963-569912012378"], "metadata": {"page_label": "83", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 1.2.2\n\nControl of the quality of water throughout the production, storage and distribution processes, including microbiological and chemical quality, is a major concern. Unlike other product and process ingredients, water is usually drawn from a system on demand, and is not subject to testing and batch or lot release before use. Assurance of quality to meet the on-demand expectation is, therefore, essential. Additionally, certain microbiological tests may require periods of incubation and, therefore, the results are likely to lag behind the water use.\n\n## 1.2.3\n\nControl of the microbiological quality of WPU is a high priority. Some types of microorganism may proliferate in water treatment components and in the storage and distribution systems. It is crucial to minimize microbial contamination by proper design of the system, periodic sanitization and by taking appropriate measures to prevent microbial proliferation.\n\n## 1.2.4\n\nDifferent grades of water quality are required depending on the route of administration of the pharmaceutical products. Other sources of guidance about different grades of water can be found in pharmacopoeias and related documents.\n\n## 1.3 Applicable guides\n\n### 1.3.1\n\nIn addition to the specific guidance provided in this document, the Further reading section includes some relevant publications that can serve as additional background material when planning, installing and using systems intended to provide WPU.\n\n# 2. General principles for pharmaceutical water systems\n\n## 2.1\n\nPharmaceutical water production, storage and distribution systems should be designed, installed, commissioned, qualified and maintained to ensure the reliable production of water of an appropriate quality. It is necessary to validate the water production process to ensure the water generated, stored and distributed is not beyond the designed capacity and meets its specifications.\n\n## 2.2\n\nThe capacity of the system should be designed to meet the average and the peak flow demand of the current operation. If necessary, depending on planned future demands, the system should be designed to permit increases in the capacity or designed to permit modification. All systems, regardless of their size and capacity, should have appropriate recirculation and turnover to assure the system is well controlled chemically and microbiologically.\n\n## 2.3\n\nThe use of the systems following initial validation (installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ)) and after any planned and unplanned maintenance or modification work should be approved by the quality assurance (QA) department using change control documentation.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Control de la calidad del agua**: El control de la calidad del agua en los procesos de producci\u00f3n, almacenamiento y distribuci\u00f3n es fundamental, ya que el agua se utiliza bajo demanda y no se somete a pruebas de lotes antes de su uso. Esto implica que se deben implementar medidas para asegurar la calidad microbiol\u00f3gica y qu\u00edmica del agua.\n\n2. **Importancia de la calidad microbiol\u00f3gica**: La calidad microbiol\u00f3gica del agua para uso farmac\u00e9utico (WPU) es una prioridad alta, ya que ciertos microorganismos pueden proliferar en los sistemas de tratamiento y distribuci\u00f3n. Se deben tomar medidas adecuadas para minimizar la contaminaci\u00f3n microbiana.\n\n3. **Dise\u00f1o y mantenimiento de sistemas de agua farmac\u00e9utica**: Los sistemas de producci\u00f3n, almacenamiento y distribuci\u00f3n de agua farmac\u00e9utica deben ser dise\u00f1ados y mantenidos para garantizar la producci\u00f3n confiable de agua de calidad adecuada. Esto incluye la validaci\u00f3n del proceso de producci\u00f3n de agua y la capacidad del sistema para satisfacer la demanda.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las medidas espec\u00edficas que se deben implementar para minimizar la contaminaci\u00f3n microbiana en los sistemas de tratamiento de agua?**\n   - Esta pregunta busca detalles sobre las pr\u00e1cticas de dise\u00f1o y sanitizaci\u00f3n que no se mencionan expl\u00edcitamente en el texto.\n\n2. **\u00bfQu\u00e9 criterios se utilizan para determinar las diferentes calidades de agua requeridas seg\u00fan la ruta de administraci\u00f3n de los productos farmac\u00e9uticos?**\n   - La respuesta a esta pregunta podr\u00eda incluir informaci\u00f3n sobre normativas espec\u00edficas o gu\u00edas que no se detallan en el documento.\n\n3. **\u00bfQu\u00e9 tipo de documentaci\u00f3n de control de cambios es necesaria para la aprobaci\u00f3n del uso de sistemas de agua despu\u00e9s de modificaciones o mantenimiento?**\n   - Esta pregunta se centra en los procedimientos espec\u00edficos de documentaci\u00f3n y aprobaci\u00f3n que son cruciales para el cumplimiento de las normativas, pero que no se explican en profundidad en el texto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Alcance del Documento**:\n   - Proporciona directrices sobre las especificaciones del agua para uso farmac\u00e9utico (WPU).\n   - Incluye orientaci\u00f3n sobre la calidad del agua necesaria para la fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (APIs) y formas de dosificaci\u00f3n.\n   - Aborda las buenas pr\u00e1cticas de manufactura (GMP) relacionadas con el dise\u00f1o, instalaci\u00f3n y operaci\u00f3n de sistemas de agua farmac\u00e9utica.\n   - No cubre el agua para administraci\u00f3n a pacientes ni el uso de peque\u00f1as cantidades en farmacias.\n\n2. **Buenas Pr\u00e1cticas de Manufactura (GMP)**:\n   - La gu\u00eda sobre GMP para WPU es complementaria a las directrices generales de GMP publicadas por la OMS.\n\n3. **Especificaciones y Normativas**:\n   - Hace referencia a especificaciones disponibles, como farmacopoeias y gu\u00edas de la industria sobre el uso, producci\u00f3n, almacenamiento y distribuci\u00f3n de agua en forma a granel.\n   - Los fabricantes deben decidir entre opciones de especificaciones farmacop\u00e9uticas bas\u00e1ndose en la autorizaci\u00f3n de comercializaci\u00f3n presentada a la autoridad reguladora nacional.\n\n4. **Importancia del Agua en la Industria Farmac\u00e9utica**:\n   - El agua es el material m\u00e1s utilizado en la producci\u00f3n y formulaci\u00f3n de productos farmac\u00e9uticos.\n   - Sus propiedades qu\u00edmicas \u00fanicas permiten disolver y suspender diversos compuestos, aunque tambi\u00e9n puede ser un veh\u00edculo para contaminantes que representan riesgos para la salud.\n\n### Entidades Clave:\n- **Agua para Uso Farmac\u00e9utico (WPU)**: Especificaciones y calidad del agua en la industria farmac\u00e9utica.\n- **Ingredientes Farmac\u00e9uticos Activos (APIs)**: Productos cuya fabricaci\u00f3n requiere agua de calidad espec\u00edfica.\n- **Buenas Pr\u00e1cticas de Manufactura (GMP)**: Normativas que gu\u00edan el dise\u00f1o y operaci\u00f3n de sistemas de agua farmac\u00e9utica.\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Publica directrices generales de GMP para productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: water quality, pharmaceutical water systems, microbiological control, good manufacturing practices, validation processes"}}, "19bbe2bd-1687-4345-9ebe-85661becb0ce": {"node_ids": ["fc813c6b-9932-4ab0-8bfd-d0eddfe0f0b7"], "metadata": {"page_label": "84", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2.4 \nWater sources and treated water should be monitored regularly for chemical, microbiological and, as appropriate, endotoxin contamination. The performance of water purification, storage and distribution systems should also be monitored. Records of the monitoring results, trend analysis and any actions taken should be maintained.\n\n2.5 \nWhere chemical sanitization of the water systems is part of the biocontamination control programme a validated procedure should be followed to ensure that the sanitizing process has been effective and that the sanitizing agent has been effectively removed.\n\n# 3. Water quality specifications\n\n## 3.1 General\n\n3.1.1 \nThe following requirements concern water processed, stored and distributed in bulk form. They do not cover the specification of water formulated for patient administration. Pharmacopoeias include specifications for both bulk and dosage-form types of water.\n\n3.1.2 \nPharmacopoeial requirements or guidance for WPU are described in national, regional and international pharmacopoeias and limits for various impurities or classes of impurities are either specified or recommended. Companies wishing to supply multiple markets should set specifications that meet the strictest requirements from each of the relevant pharmacopoeias.\n\nSimilarly, requirements or guidance are given in pharmacopoeias on the microbiological quality of water.\n\n## 3.2 Drinking-water\n\n3.2.1 \nDrinking-water should be supplied under continuous positive pressure in a plumbing system free of any defects that could lead to contamination of any product.\n\n3.2.2 \nDrinking-water is unmodified except for limited treatment of the water derived from a natural or stored source. Examples of natural sources include springs, wells, rivers, lakes and the sea. The condition of the source water will dictate the treatment required to render it safe for human consumption (drinking). Typical treatment includes desalinization, softening, removal of specific ions, particle reduction and antimicrobial treatment.\n\n3.2.3 \nIt is common for drinking-water to be derived from a public water supply that may be a combination of more than one of the natural sources listed above. It may also be supplied either from an offsite source, e.g. a municipality, or appropriate quality may be achieved onsite through appropriate processing.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de nivel superior del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda la importancia de la calidad del agua, espec\u00edficamente en relaci\u00f3n con su monitoreo y tratamiento. Se enfatiza la necesidad de supervisar regularmente las fuentes de agua y el agua tratada para detectar contaminantes qu\u00edmicos, microbiol\u00f3gicos y endotoxinas. Adem\u00e1s, se establecen especificaciones para el agua potable, que debe ser suministrada bajo presi\u00f3n positiva y libre de defectos que puedan causar contaminaci\u00f3n. Se discuten los tratamientos necesarios para asegurar que el agua derivada de fuentes naturales sea segura para el consumo humano.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 procedimientos deben seguirse para validar la efectividad de la sanitizaci\u00f3n qu\u00edmica en los sistemas de agua?**\n   - El contexto menciona que se debe seguir un procedimiento validado para asegurar que el proceso de sanitizaci\u00f3n ha sido efectivo y que el agente sanitizante ha sido eliminado de manera efectiva.\n\n2. **\u00bfCu\u00e1les son los tratamientos t\u00edpicos que se aplican al agua derivada de fuentes naturales para hacerla segura para el consumo humano?**\n   - Se indican tratamientos como desalinizaci\u00f3n, ablandamiento, eliminaci\u00f3n de iones espec\u00edficos, reducci\u00f3n de part\u00edculas y tratamiento antimicrobiano.\n\n3. **\u00bfQu\u00e9 requisitos deben cumplir las empresas que desean suministrar agua a m\u00faltiples mercados en relaci\u00f3n con las especificaciones de calidad del agua?**\n   - Las empresas deben establecer especificaciones que cumplan con los requisitos m\u00e1s estrictos de cada una de las farmacopoeias relevantes para los mercados en los que desean operar.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Control de la calidad del agua**:\n   - La calidad del agua en los procesos de producci\u00f3n, almacenamiento y distribuci\u00f3n es cr\u00edtica, abarcando tanto la calidad microbiol\u00f3gica como qu\u00edmica.\n   - El agua se utiliza bajo demanda y no se somete a pruebas de lotes antes de su uso, lo que hace esencial asegurar su calidad.\n\n2. **Calidad microbiol\u00f3gica**:\n   - La calidad microbiol\u00f3gica del agua para uso farmac\u00e9utico (WPU) es una alta prioridad.\n   - Se deben implementar medidas para minimizar la contaminaci\u00f3n microbiana, incluyendo un dise\u00f1o adecuado del sistema y sanitizaci\u00f3n peri\u00f3dica.\n\n3. **Grados de calidad del agua**:\n   - Se requieren diferentes grados de calidad del agua seg\u00fan la ruta de administraci\u00f3n de los productos farmac\u00e9uticos.\n   - Se sugiere consultar farmacopoeias y documentos relacionados para obtener m\u00e1s orientaci\u00f3n sobre los diferentes grados de agua.\n\n4. **Principios generales para sistemas de agua farmac\u00e9utica**:\n   - Los sistemas de producci\u00f3n, almacenamiento y distribuci\u00f3n de agua farmac\u00e9utica deben ser dise\u00f1ados, instalados y mantenidos para garantizar la producci\u00f3n confiable de agua de calidad adecuada.\n   - Es necesario validar el proceso de producci\u00f3n de agua para asegurar que cumple con las especificaciones y capacidades dise\u00f1adas.\n\n5. **Capacidad del sistema**:\n   - El sistema debe estar dise\u00f1ado para satisfacer tanto la demanda promedio como la demanda m\u00e1xima de operaci\u00f3n.\n   - Debe permitir modificaciones futuras y contar con recirculaci\u00f3n adecuada para el control qu\u00edmico y microbiol\u00f3gico.\n\n6. **Documentaci\u00f3n de control de cambios**:\n   - Cualquier uso del sistema despu\u00e9s de la validaci\u00f3n inicial y tras mantenimiento o modificaciones debe ser aprobado por el departamento de aseguramiento de calidad (QA) mediante documentaci\u00f3n de control de cambios.\n\n### Entidades clave\n- **Agua para uso farmac\u00e9utico (WPU)**: Agua utilizado en la producci\u00f3n de productos farmac\u00e9uticos.\n- **Microorganismos**: Organismos que pueden proliferar en sistemas de tratamiento y distribuci\u00f3n de agua.\n- **Farmacopeas**: Documentos que proporcionan gu\u00edas sobre los est\u00e1ndares de calidad del agua.\n- **Aseguramiento de calidad (QA)**: Departamento responsable de la aprobaci\u00f3n de cambios y validaciones en los sistemas de agua.", "excerpt_keywords": "Keywords: water quality, microbiological contamination, chemical sanitization, pharmacopoeias, drinking-water treatment"}}, "fe21ea0f-0a31-483d-aeea-8762f821fa86": {"node_ids": ["40e5379f-32ba-4b8c-a8e3-22d17c1da1f3"], "metadata": {"page_label": "85", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.4\nIt is also common for public water supply organizations to conduct tests and guarantee that the drinking-water delivered is of drinking quality. This testing is typically performed on water from the water source.\n\n# 3.2.5\nIt is the responsibility of the pharmaceutical manufacturer to assure that the source water supplying the purified water (PW) treatment system meets the appropriate drinking-water requirements. There may be situations where the water treatment system is used first to achieve drinking-water quality and subsequently purified water. In these situations the point at which drinking-water quality is achieved should be identified and tested.\n\n# 3.2.6\nDrinking-water quality is covered by the WHO drinking-water guidelines, standards from the International Organization for Standardization (ISO) and other regional and national agencies. Drinking-water should comply with the relevant regulations laid down by the competent authority.\n\n# 3.2.7\nIf drinking-water is used directly in certain stages of pharmaceutical manufacture or is the feed-water for the production of higher qualities of WPU, then testing should be carried out periodically by the water user\u2019s site to confirm that the quality meets the standards required for drinking-water.\n\n# 3.3 Bulk purified water\n\n## 3.3.1\nBulk purified water (BPW) should be prepared from a drinking-water source as a minimum-quality feed-water. It should meet the relevant pharmacopoeial specifications for chemical and microbiological purity with appropriate action and alert limits. It should also be protected from recontamination and microbial proliferation. BPW may be prepared by a combination of reverse osmosis (RO) RO/electro-deionization (EDI) and vapour compression (VC). Alert levels for the water system should be determined from knowledge of the system and are not specified in the pharmacopoeias.\n\n# 3.4 Bulk highly purified water\n\n## 3.4.1\nBulk highly purified water (BHPW) should be prepared from drinking-water as a minimum-quality feed-water. BHPW is a unique specification for water found only in the *European Pharmacopoeia*. This grade of water must meet the same quality standard as water for injections (WFI), including the limit for endotoxins, but the water-treatment process used may be different. Current production methods include, for example, double-pass RO coupled with other suitable techniques such as ultrafiltration and deionization.\n\nBHPW may be prepared by a combination of different methods such as RO, ultrafiltration and deionization.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda la calidad del agua potable y su importancia en la fabricaci\u00f3n farmac\u00e9utica. Se menciona que las organizaciones de suministro de agua p\u00fablica realizan pruebas para garantizar que el agua entregada cumpla con los est\u00e1ndares de calidad. Los fabricantes farmac\u00e9uticos son responsables de asegurar que el agua de origen utilizada en sus sistemas de tratamiento cumpla con los requisitos de calidad del agua potable. Se describen diferentes tipos de agua, como el agua purificada a granel (BPW) y el agua altamente purificada a granel (BHPW), y se especifican los m\u00e9todos de tratamiento y las normas que deben cumplirse para cada tipo.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 m\u00e9todos de tratamiento se pueden utilizar para preparar el agua purificada a granel (BPW) y cu\u00e1les son las especificaciones que debe cumplir?**\n   - La BPW debe ser preparada a partir de una fuente de agua potable y cumplir con las especificaciones farmacop\u00e9icas para pureza qu\u00edmica y microbiol\u00f3gica. Los m\u00e9todos de tratamiento incluyen la \u00f3smosis inversa (RO), la electrodi\u00e1lisis (EDI) y la compresi\u00f3n de vapor (VC).\n\n2. **\u00bfCu\u00e1l es la diferencia entre el agua altamente purificada a granel (BHPW) y el agua para inyecciones (WFI) en t\u00e9rminos de est\u00e1ndares de calidad?**\n   - El BHPW debe cumplir con los mismos est\u00e1ndares de calidad que el WFI, incluyendo l\u00edmites para endotoxinas, pero el proceso de tratamiento del agua puede ser diferente. El BHPW es una especificaci\u00f3n \u00fanica que se encuentra solo en la *Farmacopea Europea*.\n\n3. **\u00bfQu\u00e9 responsabilidad tienen los fabricantes farmac\u00e9uticos en relaci\u00f3n con la calidad del agua utilizada en sus procesos de producci\u00f3n?**\n   - Los fabricantes farmac\u00e9uticos son responsables de asegurar que el agua de origen que alimenta su sistema de tratamiento de agua purificada cumpla con los requisitos de calidad del agua potable. Adem\u00e1s, deben realizar pruebas peri\u00f3dicas para confirmar que el agua utilizada en la fabricaci\u00f3n cumple con los est\u00e1ndares requeridos.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Monitoreo de Agua**:\n   - Se requiere un monitoreo regular de las fuentes de agua y del agua tratada para detectar contaminantes qu\u00edmicos, microbiol\u00f3gicos y endotoxinas.\n   - Es esencial mantener registros de los resultados del monitoreo, an\u00e1lisis de tendencias y acciones tomadas.\n\n2. **Sanitizaci\u00f3n Qu\u00edmica**:\n   - Cuando se utiliza la sanitizaci\u00f3n qu\u00edmica en los sistemas de agua, debe seguirse un procedimiento validado para asegurar la efectividad del proceso y la eliminaci\u00f3n del agente sanitizante.\n\n3. **Especificaciones de Calidad del Agua**:\n   - Las especificaciones se aplican al agua procesada, almacenada y distribuida en forma a granel, excluyendo el agua formulada para administraci\u00f3n a pacientes.\n   - Las empresas que deseen operar en m\u00faltiples mercados deben cumplir con los requisitos m\u00e1s estrictos de las farmacopoeias relevantes.\n\n4. **Agua Potable**:\n   - El agua potable debe suministrarse bajo presi\u00f3n positiva continua y en sistemas de plomer\u00eda sin defectos que puedan causar contaminaci\u00f3n.\n   - El agua potable puede derivarse de fuentes naturales (manantiales, pozos, r\u00edos, lagos, mar) y requiere tratamientos espec\u00edficos para ser segura para el consumo humano, como desalinizaci\u00f3n, ablandamiento, eliminaci\u00f3n de iones espec\u00edficos, reducci\u00f3n de part\u00edculas y tratamiento antimicrobiano.\n\n5. **Fuentes de Agua**:\n   - Es com\u00fan que el agua potable provenga de un suministro p\u00fablico que puede combinar varias fuentes naturales, o que se procese en el lugar para alcanzar la calidad adecuada.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las directrices sobre la calidad del agua.\n- **Farmacopeas**: Documentos que establecen especificaciones y requisitos para la calidad del agua.\n- **Contaminantes**: Incluyen qu\u00edmicos, microorganismos y endotoxinas que deben ser monitoreados.\n- **Sistemas de Agua**: Incluyen purificaci\u00f3n, almacenamiento y distribuci\u00f3n que deben ser monitoreados para asegurar su efectividad y seguridad.", "excerpt_keywords": "Keywords: water quality, pharmaceutical manufacturing, purified water, WHO guidelines, water treatment methods"}}, "c810956a-8a6f-4e58-b734-e8627455b54d": {"node_ids": ["92aecebc-69be-496e-901c-b4a44c9341e9"], "metadata": {"page_label": "86", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 3.4.2\nBHPW should also be protected from recontamination and microbial proliferation.\n\n## 3.4.3\nBHPW and WFI have identical microbiological requirements.\n\n## 3.5 Bulk water for injections\n\n### 3.5.1\nBulk water for injections (BWFI) should be prepared from drinking-water (usually with further treatment) or purified water as a minimum-quality feed-water. BWFI is not sterile water and is not a final dosage form. It is an intermediate bulk product and suitable to be used as an ingredient during formulation. BWFI is the highest quality of pharmacopoeial WPU.\n\n### 3.5.2\nCertain pharmacopoeias place constraints upon the permitted purification techniques as part of the specification of the BWFI. *The International Pharmacopoeia* and the *European Pharmacopoeia*, for example, allow only distillation as the final purification step.\n\n### 3.5.3\nBWFI should meet the relevant pharmacopoeial specifications for chemical and microbiological purity (including endotoxin) with appropriate action and alert limits.\n\n### 3.5.4\nBWFI should also be protected from recontamination and microbial proliferation.\n\n## 3.6 Other grades of water\n\n### 3.6.1\nWhen a specific process requires a special non-pharmacopoeial grade of water, its specification must be documented within the company quality system. As a minimum it must meet the pharmacopoeial requirements relating to the grade of WPU required for the type of dosage form or process step.\n\n# 4. Application of specific types of water to processes and dosage forms\n\n## 4.1\nProduct licensing authorities specify the minimum grade of WPU that must be used during the manufacture of the different dosage forms or for different stages in washing, preparation, synthesis, manufacturing or formulation.\n\n## 4.2\nThe grade of water used should take into account the nature and intended use of the intermediate or finished product and the stage in the manufacturing process at which the water is used.\n\n## 4.3\nBHPW can be used in the preparation of products when water of high quality (i.e. very low in microorganisms and endotoxins) is needed, but the", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS detalla las especificaciones para diferentes tipos de agua utilizados en la preparaci\u00f3n farmac\u00e9utica. Se enfatiza la importancia de la calidad del agua, especialmente en la producci\u00f3n de productos inyectables, como el agua para inyecciones en bloque (BWFI) y el agua purificada de alta calidad (BHPW). Se establecen requisitos microbiol\u00f3gicos y qu\u00edmicos, as\u00ed como las t\u00e9cnicas de purificaci\u00f3n permitidas. Adem\u00e1s, se menciona que las autoridades de licencias de productos especifican el grado m\u00ednimo de agua que debe utilizarse en diferentes etapas del proceso de fabricaci\u00f3n.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las diferencias clave entre el agua purificada de alta calidad (BHPW) y el agua para inyecciones en bloque (BWFI) en t\u00e9rminos de su uso y requisitos de calidad?**\n   - Respuesta: BHPW y BWFI tienen requisitos microbiol\u00f3gicos id\u00e9nticos, pero BWFI es un producto intermedio que no es est\u00e9ril y se utiliza como ingrediente en la formulaci\u00f3n, mientras que BHPW se utiliza cuando se necesita agua de alta calidad con muy bajos niveles de microorganismos y endotoxinas.\n\n2. **\u00bfQu\u00e9 t\u00e9cnicas de purificaci\u00f3n son aceptables para la producci\u00f3n de BWFI seg\u00fan las farmacopoeias internacionales?**\n   - Respuesta: Seg\u00fan *The International Pharmacopoeia* y la *European Pharmacopoeia*, la \u00fanica t\u00e9cnica de purificaci\u00f3n permitida como paso final para la producci\u00f3n de BWFI es la destilaci\u00f3n.\n\n3. **\u00bfQu\u00e9 medidas deben tomarse para proteger BWFI de la recontaminaci\u00f3n y la proliferaci\u00f3n microbiana?**\n   - Respuesta: BWFI debe ser protegido de la recontaminaci\u00f3n y la proliferaci\u00f3n microbiana mediante pr\u00e1cticas adecuadas de manejo y almacenamiento, aunque el documento no detalla las medidas espec\u00edficas, se infiere que deben seguirse protocolos de calidad y control en su manipulaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Calidad del Agua Potable**:\n   - Las organizaciones de suministro de agua p\u00fablica realizan pruebas para garantizar que el agua entregada cumpla con los est\u00e1ndares de calidad de agua potable.\n\n2. **Responsabilidad de los Fabricantes Farmac\u00e9uticos**:\n   - Los fabricantes son responsables de asegurar que el agua de origen utilizada en sus sistemas de tratamiento cumpla con los requisitos de calidad del agua potable.\n   - Deben identificar y probar el punto en el que se logra la calidad de agua potable en el proceso de tratamiento.\n\n3. **Normativas y Est\u00e1ndares**:\n   - La calidad del agua potable est\u00e1 regulada por las directrices de la OMS, normas de la ISO y otras agencias regionales y nacionales.\n   - El agua debe cumplir con las regulaciones establecidas por la autoridad competente.\n\n4. **Pruebas Peri\u00f3dicas**:\n   - Si el agua potable se utiliza en la fabricaci\u00f3n farmac\u00e9utica, se deben realizar pruebas peri\u00f3dicas para confirmar que cumple con los est\u00e1ndares requeridos.\n\n5. **Agua Purificada a Granel (BPW)**:\n   - Debe ser preparada a partir de una fuente de agua potable y cumplir con especificaciones farmacop\u00e9icas para pureza qu\u00edmica y microbiol\u00f3gica.\n   - M\u00e9todos de tratamiento incluyen \u00f3smosis inversa (RO), electrodi\u00e1lisis (EDI) y compresi\u00f3n de vapor (VC).\n\n6. **Agua Altamente Purificada a Granel (BHPW)**:\n   - Debe ser preparada a partir de agua potable y cumplir con los mismos est\u00e1ndares de calidad que el agua para inyecciones (WFI), incluyendo l\u00edmites para endotoxinas.\n   - M\u00e9todos de producci\u00f3n incluyen RO de doble paso, ultrafiltraci\u00f3n y desionizaci\u00f3n.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Establece directrices sobre la calidad del agua potable.\n- **ISO (Organizaci\u00f3n Internacional de Normalizaci\u00f3n)**: Proporciona est\u00e1ndares para la calidad del agua.\n- **Agua Purificada a Granel (BPW)**: Tipo de agua que debe cumplir con especificaciones farmac\u00e9uticas.\n- **Agua Altamente Purificada a Granel (BHPW)**: Especificaci\u00f3n \u00fanica en la *Farmacopea Europea* que debe cumplir con est\u00e1ndares de calidad espec\u00edficos.", "excerpt_keywords": "Keywords: BHPW, BWFI, microbiological requirements, purification techniques, pharmaceutical preparations"}}, "d5f01d8b-e0a7-4f6d-bb4f-1b447da46e6d": {"node_ids": ["da85478b-1be1-49ba-a964-76bda3eeb2b0"], "metadata": {"page_label": "87", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 4.4\n\nBWFI should be used in the manufacture of injectable products for dissolving or diluting substances or preparations during the manufacturing of parenterals, and for manufacture of sterile water for preparation of injections. BWFI should also be used for the final rinse after cleaning of equipment and components that come into contact with injectable products as well as for the final rinse in a washing process in which no subsequent thermal or chemical depyrogenization process is applied.\n\n4.5 When steam comes into contact with an injectable product in its final container or with equipment for preparing injectable products, it should conform to the specification for BWFI when condensed.\n\n# 5. Water purification systems\n\n## 5.1 General considerations\n\n5.1.1 The specifications for WPU found in compendia (e.g. pharmacopoeias) do not define the permissible water purification methods apart from for BWFI (refer to section 3.5).\n\n5.1.2 The chosen water purification method or sequence of purification steps must be appropriate to the application in question. The following should be considered when selecting the water treatment method:\n\n- the final water quality specification;\n- the quantity of water required by the user;\n- the available feed-water quality and the variation over time (seasonal changes);\n- the availability of suitable support facilities for system connection (raw water, electricity, heating steam, chilled water, compressed air, sewage system, exhaust air);\n- the sanitization strategy;\n- the availability of water-treatment equipment on the market;\n- the reliability and robustness of the water-treatment equipment in operation;\n- the yield or efficiency of the purification system;\n- the ability to adequately support and maintain the water purification equipment;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda la importancia del agua para inyecci\u00f3n (BWFI) en la fabricaci\u00f3n de productos inyectables y en la purificaci\u00f3n del agua. Se especifica que el BWFI debe ser utilizado para disolver o diluir sustancias durante la fabricaci\u00f3n de parenterales y para el enjuague final de equipos que entran en contacto con productos inyectables. Adem\u00e1s, se discuten consideraciones generales sobre los sistemas de purificaci\u00f3n de agua, enfatizando que el m\u00e9todo de purificaci\u00f3n debe ser adecuado para la aplicaci\u00f3n espec\u00edfica y que se deben tener en cuenta varios factores, como la calidad del agua, la cantidad requerida y la disponibilidad de equipos.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las condiciones bajo las cuales el BWFI debe ser utilizado para el enjuague final de equipos en contacto con productos inyectables?**\n   - Esta pregunta se centra en las especificaciones del uso de BWFI en el proceso de fabricaci\u00f3n y limpieza, que no se detalla en otras fuentes.\n\n2. **\u00bfQu\u00e9 factores deben considerarse al seleccionar un m\u00e9todo de tratamiento de agua para aplicaciones espec\u00edficas en la industria farmac\u00e9utica?**\n   - Esta pregunta aborda los criterios espec\u00edficos que deben evaluarse al elegir un sistema de purificaci\u00f3n de agua, lo cual es crucial para garantizar la calidad del producto final.\n\n3. **\u00bfQu\u00e9 especificaciones debe cumplir el vapor que entra en contacto con productos inyectables en su envase final?**\n   - Esta pregunta se refiere a las normas que deben seguirse para asegurar que el vapor no comprometa la calidad del producto, un aspecto que puede no estar ampliamente cubierto en otras fuentes.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n detallada y espec\u00edfica que se encuentra en el contexto proporcionado, lo que puede no estar disponible en otras partes de la literatura o documentos relacionados.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Tipos de Agua en Preparaci\u00f3n Farmac\u00e9utica**:\n   - **Agua Purificada de Alta Calidad (BHPW)**: Debe ser protegida de la recontaminaci\u00f3n y la proliferaci\u00f3n microbiana. Tiene requisitos microbiol\u00f3gicos id\u00e9nticos a los del agua para inyecciones (WFI).\n   - **Agua para Inyecciones en Bloque (BWFI)**: Preparada a partir de agua potable o agua purificada, no es est\u00e9ril y se utiliza como ingrediente en formulaciones. Es el m\u00e1s alto est\u00e1ndar de agua farmacopoeial.\n\n2. **Requisitos de Calidad**:\n   - Tanto BHPW como BWFI deben cumplir con especificaciones farmacopoeiales para pureza qu\u00edmica y microbiol\u00f3gica, incluyendo l\u00edmites de endotoxinas.\n   - BWFI debe ser protegido de la recontaminaci\u00f3n y la proliferaci\u00f3n microbiana.\n\n3. **T\u00e9cnicas de Purificaci\u00f3n**:\n   - Las farmacopoeias internacionales, como *The International Pharmacopoeia* y la *European Pharmacopoeia*, permiten solo la destilaci\u00f3n como paso final de purificaci\u00f3n para BWFI.\n\n4. **Documentaci\u00f3n y Especificaciones**:\n   - Cualquier grado de agua no farmacopoeial utilizado en un proceso espec\u00edfico debe ser documentado en el sistema de calidad de la empresa, cumpliendo al menos con los requisitos farmacopoeiales para el tipo de forma de dosificaci\u00f3n o etapa del proceso.\n\n5. **Aplicaci\u00f3n en Procesos de Fabricaci\u00f3n**:\n   - Las autoridades de licencias de productos establecen el grado m\u00ednimo de agua que debe utilizarse en la fabricaci\u00f3n de diferentes formas de dosificaci\u00f3n y en diversas etapas del proceso de producci\u00f3n.\n\n### Entidades Clave:\n- **BHPW** (Agua Purificada de Alta Calidad)\n- **BWFI** (Agua para Inyecciones en Bloque)\n- **The International Pharmacopoeia**\n- **European Pharmacopoeia**\n- **Autoridades de Licencias de Productos** \n\nEste resumen destaca la importancia de la calidad del agua en la producci\u00f3n farmac\u00e9utica y las regulaciones que rigen su uso.", "excerpt_keywords": "Keywords: BWFI, water purification, injectable products, pharmaceutical standards, sanitization strategy"}}, "86804cc6-b330-4558-87fe-9b3270a80325": {"node_ids": ["410cac17-4089-4d58-a2ce-41696af05fbf"], "metadata": {"page_label": "88", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- the continuity of operational usage considering hours/days, days/years and planned downtime;\n- the total life-cycle costs (capital and operational including maintenance).\n\n## 5.1.3\n\nThe specifications for water purification equipment, storage and distribution systems should take into account the following:\n\n- the location of the plant room;\n- extremes in temperature that the system will encounter;\n- the risk of contamination from leachates from contact materials;\n- the adverse impact of adsorptive contact materials;\n- hygienic or sanitary design, where required;\n- corrosion resistance;\n- freedom from leakage;\n- a system configuration to avoid proliferation of microbiological organisms;\n- tolerance to cleaning and sanitizing agents (thermal and/or chemical);\n- the sanitization strategy;\n- the system capacity and output requirements;\n- the provision of all necessary instruments, test and sampling points to allow all the relevant critical quality parameters of the complete system to be monitored.\n\n## 5.1.4\n\nThe design, configuration and layout of the water purification equipment, storage and distribution systems should also take into account the following physical considerations:\n\n- ability to collect samples;\n- the space available for the installation;\n- structural loadings on buildings;\n- the provision of adequate access for maintenance;\n- the ability to safely handle regeneration and sanitization chemicals.\n\n## 5.2 Production of drinking-water\n\n### 5.2.1\n\nDrinking-water is derived from a raw water source such as a well, river or reservoir. There are no prescribed methods for the treatment of raw water to produce drinking-water from a specific raw water source.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS aborda las especificaciones para equipos de purificaci\u00f3n de agua, sistemas de almacenamiento y distribuci\u00f3n, as\u00ed como la producci\u00f3n de agua potable. Se destacan consideraciones clave para el dise\u00f1o y la operaci\u00f3n de estos sistemas, incluyendo la ubicaci\u00f3n, resistencia a la corrosi\u00f3n, dise\u00f1o higi\u00e9nico, y la capacidad de monitorear par\u00e1metros de calidad. Adem\u00e1s, se menciona que no existen m\u00e9todos prescritos para el tratamiento de agua cruda para producir agua potable, lo que sugiere una flexibilidad en los enfoques utilizados.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las consideraciones clave que deben tenerse en cuenta al dise\u00f1ar sistemas de purificaci\u00f3n de agua seg\u00fan la OMS?**\n   - Respuesta: Las consideraciones incluyen la ubicaci\u00f3n de la planta, las temperaturas extremas, el riesgo de contaminaci\u00f3n, el dise\u00f1o higi\u00e9nico, la resistencia a la corrosi\u00f3n, la libertad de fugas, la configuraci\u00f3n del sistema para evitar la proliferaci\u00f3n de microorganismos, y la capacidad de monitorear par\u00e1metros de calidad.\n\n2. **\u00bfQu\u00e9 aspectos f\u00edsicos deben considerarse en la configuraci\u00f3n de los sistemas de purificaci\u00f3n de agua?**\n   - Respuesta: Los aspectos f\u00edsicos incluyen la capacidad de recolectar muestras, el espacio disponible para la instalaci\u00f3n, las cargas estructurales en los edificios, el acceso adecuado para el mantenimiento, y la capacidad de manejar de manera segura los productos qu\u00edmicos de regeneraci\u00f3n y sanitizaci\u00f3n.\n\n3. **\u00bfQu\u00e9 se menciona sobre la producci\u00f3n de agua potable a partir de fuentes de agua cruda?**\n   - Respuesta: Se indica que el agua potable se deriva de fuentes de agua cruda como pozos, r\u00edos o embalses, y que no existen m\u00e9todos prescritos para el tratamiento de esta agua cruda, lo que permite una variedad de enfoques en su tratamiento.", "prev_section_summary": "### Temas Clave\n\n1. **Uso de BWFI (Agua para Inyecci\u00f3n)**\n   - BWFI es esencial en la fabricaci\u00f3n de productos inyectables, utilizado para disolver o diluir sustancias y para la fabricaci\u00f3n de agua est\u00e9ril para inyecciones.\n   - Debe emplearse para el enjuague final de equipos que entran en contacto con productos inyectables, as\u00ed como en procesos de lavado sin depirogenizaci\u00f3n posterior.\n\n2. **Especificaciones del Vapor**\n   - El vapor que entra en contacto con productos inyectables debe cumplir con las especificaciones de BWFI cuando se condensa.\n\n3. **Sistemas de Purificaci\u00f3n de Agua**\n   - No se definen m\u00e9todos de purificaci\u00f3n de agua en las farmacopeas, excepto para BWFI.\n   - La selecci\u00f3n del m\u00e9todo de purificaci\u00f3n debe ser adecuada para la aplicaci\u00f3n espec\u00edfica, considerando factores como calidad del agua, cantidad requerida, calidad del agua de alimentaci\u00f3n, y disponibilidad de instalaciones de soporte.\n\n### Entidades\n\n- **BWFI (Agua para Inyecci\u00f3n)**\n- **Productos Inyectables**\n- **Equipos de Fabricaci\u00f3n**\n- **Sistemas de Purificaci\u00f3n de Agua**\n- **Farmacopeas**\n- **Estrategia de Sanitizaci\u00f3n**\n- **Equipos de Tratamiento de Agua**\n\nEste resumen destaca la importancia del BWFI en la industria farmac\u00e9utica y los criterios necesarios para la selecci\u00f3n de m\u00e9todos de purificaci\u00f3n de agua, asegurando la calidad y seguridad de los productos inyectables.", "excerpt_keywords": "Keywords: water purification, drinking-water production, sanitary design, contamination risk, system specifications"}}, "50c34126-af66-4385-b6f9-d83ac2fd748b": {"node_ids": ["4b02c493-43ad-47a1-a349-960214a17dc5"], "metadata": {"page_label": "89", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 5.2.2\n\nTypical processes employed at a user plant or by a water supply authority include:\n\n- desalinization;\n- filtration;\n- softening;\n- disinfection or sanitization (e.g. by sodium hypochlorite (chlorine) injection);\n- iron (ferrous) removal;\n- precipitation;\n- reduction of concentration of specific inorganic and/or organic materials.\n\n## 5.2.3\n\nThe drinking-water quality should be monitored routinely to account for environmental, seasonal or supply changes which have an impact on the source water quality.\n\n## 5.2.4\n\nAdditional testing should be considered if there is any change in the raw-water source, treatment techniques or system configuration.\n\n## 5.2.5\n\nTrend review may be used to identify changes. If the drinking-water quality changes significantly, but is still within specification, the direct use of this water as a WPU, or as the feed-water to downstream treatment stages, should be reviewed and the result of the review documented.\n\n## 5.2.6\n\nWhere drinking-water is derived from an \u201cin-house\u201d system for the treatment of raw water, the water-treatment steps used and the system configuration should be documented. Changes to the system or to its operation should not be made until a review has been completed and the change approved by the QA department in accordance with change control procedures.\n\n## 5.2.7\n\nWhere drinking-water is stored and distributed by the user, the storage systems must not allow degradation of the water quality before use. After any such storage, testing should be carried out routinely in accordance with a defined method. Where water is stored, the system design and operation should ensure a turnover or recirculation of the stored water sufficient to prevent stagnation.\n\n## 5.2.8\n\nThe drinking-water system is usually considered to be an \u201cindirect impact system\u201d and does not need to be qualified.\n\n## 5.2.9\n\nDrinking-water purchased in bulk and transported to the user by tanker has additional problems and risks not associated with drinking-water delivered by pipeline. Vendor assessment and authorized certification activities, including confirmation of the acceptability of the delivery vehicle, should be undertaken in a similar way to that used for any other starting material.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Procesos de Tratamiento de Agua**: El documento describe los procesos t\u00edpicos utilizados en plantas de tratamiento de agua y por autoridades de suministro de agua, que incluyen desalinizaci\u00f3n, filtraci\u00f3n, desinfecci\u00f3n y eliminaci\u00f3n de hierro, entre otros.\n\n2. **Monitoreo de Calidad del Agua**: Se enfatiza la importancia del monitoreo rutinario de la calidad del agua potable para adaptarse a cambios ambientales, estacionales o en el suministro, as\u00ed como la necesidad de pruebas adicionales ante cambios en la fuente de agua cruda o en las t\u00e9cnicas de tratamiento.\n\n3. **Almacenamiento y Distribuci\u00f3n del Agua**: Se aborda la necesidad de que los sistemas de almacenamiento y distribuci\u00f3n de agua potable mantengan la calidad del agua y se realicen pruebas rutinarias para evitar la degradaci\u00f3n del agua antes de su uso.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 procedimientos deben seguirse antes de realizar cambios en un sistema de tratamiento de agua \"in-house\"?**\n   - El documento establece que cualquier cambio en el sistema o en su operaci\u00f3n debe ser revisado y aprobado por el departamento de aseguramiento de calidad (QA) de acuerdo con los procedimientos de control de cambios.\n\n2. **\u00bfCu\u00e1les son las implicaciones de utilizar agua potable comprada en bulk y transportada por cami\u00f3n?**\n   - El texto menciona que el agua potable comprada en bulk y transportada por cami\u00f3n presenta problemas y riesgos adicionales que no est\u00e1n asociados con el agua entregada por tuber\u00eda, lo que requiere una evaluaci\u00f3n del proveedor y actividades de certificaci\u00f3n autorizadas.\n\n3. **\u00bfQu\u00e9 medidas se deben tomar para asegurar que el agua almacenada no degrade su calidad?**\n   - Se indica que los sistemas de almacenamiento deben estar dise\u00f1ados y operados de tal manera que se garantice un recambio o recirculaci\u00f3n suficiente del agua almacenada para prevenir la estancaci\u00f3n, y que se deben realizar pruebas rutinarias de calidad del agua despu\u00e9s de cualquier almacenamiento.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS se centra en las especificaciones y consideraciones para los sistemas de purificaci\u00f3n de agua, almacenamiento y distribuci\u00f3n, as\u00ed como en la producci\u00f3n de agua potable. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n#### Temas Clave:\n1. **Especificaciones para Equipos de Purificaci\u00f3n de Agua**:\n   - Ubicaci\u00f3n de la planta.\n   - Temperaturas extremas.\n   - Riesgo de contaminaci\u00f3n.\n   - Dise\u00f1o higi\u00e9nico y resistencia a la corrosi\u00f3n.\n   - Prevenci\u00f3n de fugas y proliferaci\u00f3n de microorganismos.\n   - Estrategias de sanitizaci\u00f3n y monitoreo de calidad.\n\n2. **Consideraciones F\u00edsicas en el Dise\u00f1o**:\n   - Capacidad de recolecci\u00f3n de muestras.\n   - Espacio disponible para la instalaci\u00f3n.\n   - Cargas estructurales en edificios.\n   - Acceso para mantenimiento.\n   - Manejo seguro de productos qu\u00edmicos.\n\n3. **Producci\u00f3n de Agua Potable**:\n   - Fuentes de agua cruda (pozos, r\u00edos, embalses).\n   - Flexibilidad en los m\u00e9todos de tratamiento de agua cruda.\n\n#### Entidades:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que establece las directrices y especificaciones.\n- **Equipos de Purificaci\u00f3n de Agua**: Sistemas dise\u00f1ados para tratar agua cruda.\n- **Agua Potable**: Producto final derivado de fuentes de agua cruda.\n\nEste resumen destaca la importancia de un dise\u00f1o cuidadoso y la consideraci\u00f3n de m\u00faltiples factores para garantizar la calidad y seguridad del agua potable.", "excerpt_keywords": "Keywords: water treatment, drinking-water quality, monitoring, storage systems, vendor assessment"}}, "ba4a0582-994b-47b0-87d8-a8fb8d256b79": {"node_ids": ["c02a74fa-176a-48d3-9c85-6a9aea8ae409"], "metadata": {"page_label": "90", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 5.2.10\n\nEquipment and systems used to produce drinking-water should be able to be drained and sanitized. Storage tanks should be closed with appropriately protected vents, and should allow for visual inspection and for being drained and sanitized. Distribution pipework should be able to be drained or flushed and sanitized.\n\n## 5.2.11\n\nSpecial care should be taken to control microbiological contamination of sand filters, carbon beds and water softeners. Once microorganisms have infected a system, the contamination can rapidly form biofilms and spread throughout the system. Techniques for controlling contamination such as back-flushing, chemical and/or thermal sanitization and frequent regeneration should be considered as appropriate.\n\n# 5.3 Production of purified water\n\n## 5.3.1\n\nAny appropriate qualified purification technique or sequence of techniques may be used to prepare purified water (PW). PW is commonly produced by ion exchange, RO, ultrafiltration and/or electro-deionization processes and distillation.\n\n## 5.3.2\n\nThe following should be considered when configuring a water purification system or defining user requirement specifications (URS):\n\n- the feed-water quality and its variation over seasons;\n- the quantity of water required by the user;\n- the required water-quality specification;\n- the sequence of purification stages required;\n- the energy consumption;\n- the extent of pretreatment required to protect the final purification steps;\n- performance optimization, including yield and efficiency of unit treatment-process steps;\n- appropriately located sampling points designed in such a way as to avoid potential contamination;\n- unit process steps should be provided with appropriate instrumentation to measure parameters such as flow, pressure, temperature, conductivity, pH and total organic carbon.\n\n## 5.3.3\n\nAmbient-temperature systems such as ion exchange, RO and ultrafiltration are especially susceptible to microbiological contamination, particularly when equipment is static during periods of no or low demand for water. It is essential to consider the mechanisms for microbiological control and sanitization.\n\nThe method for sanitizing each stage of purification needs to be defined and must include verification of the removal of any agents used. There should be documented evidence of its efficacy.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Mantenimiento y Sanitizaci\u00f3n de Equipos de Agua**: Los equipos y sistemas utilizados para la producci\u00f3n de agua potable deben ser capaces de drenarse y desinfectarse adecuadamente. Esto incluye tanques de almacenamiento que deben estar cerrados con ventilaciones protegidas y permitir inspecciones visuales, as\u00ed como tuber\u00edas de distribuci\u00f3n que deben poder drenarse o enjuagarse.\n\n2. **Control de Contaminaci\u00f3n Microbiol\u00f3gica**: Es crucial controlar la contaminaci\u00f3n microbiol\u00f3gica en sistemas como filtros de arena, lechos de carbono y suavizadores de agua. La contaminaci\u00f3n puede formar biofilms r\u00e1pidamente, por lo que se deben considerar t\u00e9cnicas de control como el retro-lavado y la desinfecci\u00f3n qu\u00edmica o t\u00e9rmica.\n\n3. **Producci\u00f3n de Agua Purificada**: Se pueden utilizar diversas t\u00e9cnicas de purificaci\u00f3n para preparar agua purificada (PW), como intercambio i\u00f3nico, \u00f3smosis inversa (RO), ultrafiltraci\u00f3n y destilaci\u00f3n. Al configurar un sistema de purificaci\u00f3n, se deben considerar factores como la calidad del agua de entrada, la cantidad requerida, las especificaciones de calidad del agua y la optimizaci\u00f3n del rendimiento.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones clave al definir las especificaciones de requisitos del usuario (URS) para un sistema de purificaci\u00f3n de agua?**\n   - Esta pregunta se centra en los factores que deben tenerse en cuenta al configurar un sistema de purificaci\u00f3n, como la calidad del agua de entrada y la cantidad requerida.\n\n2. **\u00bfQu\u00e9 t\u00e9cnicas se pueden implementar para controlar la contaminaci\u00f3n microbiol\u00f3gica en filtros de agua y suavizadores?**\n   - Esta pregunta busca profundizar en las t\u00e9cnicas espec\u00edficas que se pueden utilizar para prevenir la contaminaci\u00f3n microbiol\u00f3gica en sistemas de tratamiento de agua.\n\n3. **\u00bfQu\u00e9 m\u00e9todos de sanitizaci\u00f3n son necesarios para cada etapa del proceso de purificaci\u00f3n de agua y c\u00f3mo se verifica su eficacia?**\n   - Esta pregunta aborda la importancia de definir m\u00e9todos de sanitizaci\u00f3n y la necesidad de documentaci\u00f3n que respalde su efectividad en el proceso de purificaci\u00f3n.", "prev_section_summary": "### Temas Clave\n\n1. **Procesos de Tratamiento de Agua**: Se describen los m\u00e9todos t\u00edpicos utilizados en plantas de tratamiento y por autoridades de suministro de agua, que incluyen:\n   - Desalinizaci\u00f3n\n   - Filtraci\u00f3n\n   - Ablandamiento\n   - Desinfecci\u00f3n (por ejemplo, inyecci\u00f3n de hipoclorito de sodio)\n   - Eliminaci\u00f3n de hierro\n   - Precipitaci\u00f3n\n   - Reducci\u00f3n de la concentraci\u00f3n de materiales inorg\u00e1nicos y/o org\u00e1nicos espec\u00edficos\n\n2. **Monitoreo de Calidad del Agua**: Se destaca la necesidad de monitorear rutinariamente la calidad del agua potable para adaptarse a cambios ambientales, estacionales o en el suministro.\n\n3. **Pruebas Adicionales**: Se sugiere realizar pruebas adicionales si hay cambios en la fuente de agua cruda, t\u00e9cnicas de tratamiento o configuraci\u00f3n del sistema.\n\n4. **Revisi\u00f3n de Tendencias**: Se puede utilizar la revisi\u00f3n de tendencias para identificar cambios en la calidad del agua potable y documentar los resultados de la revisi\u00f3n si hay cambios significativos.\n\n5. **Documentaci\u00f3n de Sistemas \"In-House\"**: Los pasos de tratamiento y la configuraci\u00f3n del sistema deben ser documentados, y cualquier cambio debe ser revisado y aprobado por el departamento de aseguramiento de calidad (QA).\n\n6. **Almacenamiento y Distribuci\u00f3n**: Los sistemas de almacenamiento deben prevenir la degradaci\u00f3n de la calidad del agua y asegurar un recambio suficiente para evitar la estancaci\u00f3n. Se deben realizar pruebas rutinarias despu\u00e9s del almacenamiento.\n\n7. **Agua Comprada en Bulk**: El agua potable comprada en bulk y transportada por cami\u00f3n presenta riesgos adicionales, lo que requiere evaluaci\u00f3n del proveedor y certificaci\u00f3n de la aceptabilidad del veh\u00edculo de entrega.\n\n### Entidades\n\n- **Agua Potable**: El foco principal del documento.\n- **Plantas de Tratamiento de Agua**: Entidades que realizan los procesos de tratamiento.\n- **Autoridades de Suministro de Agua**: Organismos responsables de la calidad del agua potable.\n- **Departamento de Aseguramiento de Calidad (QA)**: Entidad que aprueba cambios en los sistemas de tratamiento.\n- **Proveedores de Agua**: Entidades que suministran agua, especialmente en el contexto de agua comprada en bulk. \n\nEste resumen encapsula los aspectos esenciales de la secci\u00f3n, destacando tanto los procesos como las consideraciones de calidad y gesti\u00f3n del agua potable.", "excerpt_keywords": "Keywords: drinking-water, purification, microbiological contamination, sanitization, water quality"}}, "259e8698-ea01-4173-a0d0-d04aed835eb6": {"node_ids": ["6c0dc010-6c1b-450b-95b9-9567e4777bf4"], "metadata": {"page_label": "91", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "## 5.3.4\n\nThe following should be considered:\n\n- Maintenance of minimum flow through the water generation system is recommended at all times;\n- Control of temperature in the system by heat exchanger or plant-room cooling to reduce the risk of microbial growth (guidance value < 25 \u00b0C);\n- Provision of ultraviolet disinfection;\n- Selection of water-treatment components that can periodically be thermally sanitized;\n- Application of chemical sanitization (including agents such as ozone, hydrogen peroxide and/or peracetic acid);\n- Thermal sanitization at > 65 \u00b0C.\n\n## 5.4 Production of highly purified water\n\n5.4.1 Highly purified water (HPW) can be produced by double-pass reverse osmosis coupled with ultrafiltration or by any other appropriate qualified purification technique or sequence of techniques.\n\n5.4.2 The guidance provided in section 5.3 for PW is equally applicable to HPW.\n\n## 5.5 Production of water for injection(s)\n\n5.5.1 Some pharmacopoeias prescribe or limit the permitted final water purification stage in the production of BWFI. Distillation is the preferred technique; it is considered a more robust technique based on phase change, and in some cases, high-temperature operation of the process equipment.\n\n5.5.2 The following should be considered when designing a water purification system and defining URS:\n\n- The feed-water quality;\n- The required water quality specification;\n- The quantity of water;\n- The optimum generator size or generators with variable control to avoid over-frequent start/stop cycling;\n- Blow-down and dump functions;\n- Cool-down venting to avoid contamination ingress.\n\n5.5.3 The system configuration guidance provided in section 5.3 for PW is equally applicable to water for injection.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda la producci\u00f3n y tratamiento de agua para diferentes usos, incluyendo agua purificada (PW), agua altamente purificada (HPW) y agua para inyecciones (BWFI). Se destacan las mejores pr\u00e1cticas para el mantenimiento de sistemas de generaci\u00f3n de agua, el control de temperatura, la desinfecci\u00f3n y la selecci\u00f3n de componentes de tratamiento. Tambi\u00e9n se discuten las t\u00e9cnicas de purificaci\u00f3n recomendadas, como la \u00f3smosis inversa y la destilaci\u00f3n, as\u00ed como consideraciones importantes al dise\u00f1ar sistemas de purificaci\u00f3n de agua.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las recomendaciones espec\u00edficas para el control de temperatura en los sistemas de generaci\u00f3n de agua para minimizar el crecimiento microbiano?**\n   - Respuesta: Se recomienda mantener la temperatura del sistema por debajo de 25 \u00b0C mediante el uso de intercambiadores de calor o enfriamiento en la sala de planta.\n\n2. **\u00bfQu\u00e9 t\u00e9cnicas de desinfecci\u00f3n se sugieren para asegurar la calidad del agua purificada y c\u00f3mo se pueden aplicar?**\n   - Respuesta: Se sugiere la provisi\u00f3n de desinfecci\u00f3n ultravioleta, la selecci\u00f3n de componentes que puedan ser termalmente desinfectados peri\u00f3dicamente, y la aplicaci\u00f3n de sanitizaci\u00f3n qu\u00edmica utilizando agentes como ozono, per\u00f3xido de hidr\u00f3geno y/o \u00e1cido perac\u00e9tico.\n\n3. **Al dise\u00f1ar un sistema de purificaci\u00f3n de agua para inyecciones, \u00bfqu\u00e9 factores deben considerarse en la especificaci\u00f3n de requisitos del usuario (URS)?**\n   - Respuesta: Se deben considerar la calidad del agua de alimentaci\u00f3n, la especificaci\u00f3n de calidad del agua requerida, la cantidad de agua necesaria, el tama\u00f1o \u00f3ptimo del generador, las funciones de blow-down y dump, y el venting de enfriamiento para evitar la entrada de contaminantes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Mantenimiento y Sanitizaci\u00f3n de Equipos de Agua**:\n   - Los equipos y sistemas para la producci\u00f3n de agua potable deben ser drenables y desinfectables.\n   - Los tanques de almacenamiento deben tener ventilaciones protegidas y permitir inspecciones visuales.\n   - Las tuber\u00edas de distribuci\u00f3n deben poder drenarse o enjuagarse.\n\n2. **Control de Contaminaci\u00f3n Microbiol\u00f3gica**:\n   - Es esencial controlar la contaminaci\u00f3n en filtros de arena, lechos de carbono y suavizadores de agua.\n   - La contaminaci\u00f3n puede formar biofilms r\u00e1pidamente, lo que requiere t\u00e9cnicas de control como retro-lavado y desinfecci\u00f3n qu\u00edmica o t\u00e9rmica.\n\n3. **Producci\u00f3n de Agua Purificada (PW)**:\n   - Se pueden utilizar diversas t\u00e9cnicas de purificaci\u00f3n, incluyendo intercambio i\u00f3nico, \u00f3smosis inversa (RO), ultrafiltraci\u00f3n, electro-deionizaci\u00f3n y destilaci\u00f3n.\n   - Al configurar un sistema de purificaci\u00f3n, se deben considerar:\n     - Calidad del agua de entrada y su variaci\u00f3n estacional.\n     - Cantidad de agua requerida.\n     - Especificaciones de calidad del agua.\n     - Secuencia de etapas de purificaci\u00f3n.\n     - Consumo energ\u00e9tico.\n     - Necesidades de pretreatment para proteger etapas finales de purificaci\u00f3n.\n     - Optimizaci\u00f3n del rendimiento, incluyendo rendimiento y eficiencia de los procesos.\n     - Puntos de muestreo ubicados adecuadamente para evitar contaminaci\u00f3n.\n     - Instrumentaci\u00f3n adecuada para medir par\u00e1metros como flujo, presi\u00f3n, temperatura, conductividad, pH y carbono org\u00e1nico total.\n\n4. **Contaminaci\u00f3n Microbiol\u00f3gica en Sistemas de Temperatura Ambiente**:\n   - Sistemas como intercambio i\u00f3nico, RO y ultrafiltraci\u00f3n son susceptibles a contaminaci\u00f3n microbiol\u00f3gica, especialmente cuando est\u00e1n inactivos.\n   - Es crucial definir m\u00e9todos de sanitizaci\u00f3n para cada etapa de purificaci\u00f3n y verificar la eficacia de los agentes utilizados.\n\n### Entidades Clave\n- **Equipos y Sistemas**: Equipos de producci\u00f3n de agua potable, tanques de almacenamiento, tuber\u00edas de distribuci\u00f3n.\n- **Contaminaci\u00f3n Microbiol\u00f3gica**: Filtros de arena, lechos de carbono, suavizadores de agua, biofilms.\n- **T\u00e9cnicas de Purificaci\u00f3n**: Intercambio i\u00f3nico, \u00f3smosis inversa (RO), ultrafiltraci\u00f3n, electro-deionizaci\u00f3n, destilaci\u00f3n.\n- **Par\u00e1metros de Medici\u00f3n**: Flujo, presi\u00f3n, temperatura, conductividad, pH, carbono org\u00e1nico total. \n\nEste resumen destaca la importancia del mantenimiento, control de contaminaci\u00f3n y t\u00e9cnicas de purificaci\u00f3n en la producci\u00f3n de agua potable y purificada.", "excerpt_keywords": "Keywords: water purification, microbial control, highly purified water, water for injection, sanitization techniques"}}, "c43262cd-2e2c-48f0-b267-deb394deda79": {"node_ids": ["ae95e94f-d395-4dd8-8434-54230be7bb5c"], "metadata": {"page_label": "92", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 6. Water storage and distribution systems\n\n6.1 This section applies to WPU systems for PW, BHPW and BWFI. The water storage and distribution should work in conjunction with the purification plant to ensure delivery of water of consistent quality to the user points, and to ensure optimum operation of the water purification equipment.\n\n## 6.1 General\n\n6.1.1 The storage and distribution system should be considered as a key part of the whole system and should be designed to be fully integrated with the water purification components of the system.\n\n6.1.2 Once water has been purified using an appropriate method it can either be used directly or, more frequently, it will be fed into a storage vessel for subsequent distribution to points of use. The following text describes the requirements for storage and distribution systems and point of use (POU).\n\n6.1.3 The storage and distribution system should be configured to prevent microbial proliferation and recontamination of the water (PW, BHPW, BWFI) after treatment. It should be subjected to a combination of online and offline monitoring to ensure that the appropriate water specification is maintained.\n\n## 6.2 Materials that come into contact with systems for water for pharmaceutical use\n\n6.2.1 This section applies to generation equipment for PW, BHPW and BWFI and the associated storage and distribution systems.\n\n6.2.2 The materials that come into contact with WPU, including pipework, valves and fittings, seals, diaphragms and instruments, should be selected to satisfy the following objectives.\n\n- **Compatibility.** The compatibility and suitability of the materials should encompass the full range of its working temperature and potential chemicals that will come into contact with the system at rest, in operation and during sanitization.\n\n- **Prevention of leaching.** All materials that come into contact with WPU should be non-leaching at the range of working and sanitization temperatures of the system.\n\n- **Corrosion resistance.** PW, BHPW and BWFI are highly corrosive.\n\nTo prevent failure of the system and contamination of the water, the materials selected must be appropriate, the method of jointing must be carefully controlled and all fittings and components must be compatible with the pipework.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Importancia de los sistemas de almacenamiento y distribuci\u00f3n de agua**: Los sistemas de almacenamiento y distribuci\u00f3n de agua son componentes cr\u00edticos en la infraestructura de agua para uso farmac\u00e9utico (PW, BHPW y BWFI). Deben integrarse completamente con las plantas de purificaci\u00f3n para garantizar la entrega de agua de calidad constante y el funcionamiento \u00f3ptimo del equipo de purificaci\u00f3n.\n\n2. **Requisitos de dise\u00f1o y materiales**: Los sistemas de almacenamiento y distribuci\u00f3n deben estar dise\u00f1ados para prevenir la proliferaci\u00f3n microbiana y la recontaminaci\u00f3n del agua. Adem\u00e1s, los materiales que entran en contacto con el agua deben ser compatibles, no permitir la lixiviaci\u00f3n y ser resistentes a la corrosi\u00f3n.\n\n3. **Monitoreo y control**: Es esencial implementar un monitoreo tanto en l\u00ednea como fuera de l\u00ednea para asegurar que se mantengan las especificaciones adecuadas del agua despu\u00e9s del tratamiento.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las caracter\u00edsticas clave que deben tener los materiales utilizados en los sistemas de almacenamiento y distribuci\u00f3n de agua para uso farmac\u00e9utico?**\n   - Respuesta: Los materiales deben ser compatibles con el rango de temperatura de trabajo y los qu\u00edmicos en contacto, no deben permitir la lixiviaci\u00f3n a las temperaturas de trabajo y sanitizaci\u00f3n, y deben ser resistentes a la corrosi\u00f3n.\n\n2. **\u00bfQu\u00e9 medidas se deben tomar para prevenir la recontaminaci\u00f3n del agua en los sistemas de almacenamiento y distribuci\u00f3n?**\n   - Respuesta: Los sistemas deben estar configurados para prevenir la proliferaci\u00f3n microbiana y la recontaminaci\u00f3n, y deben ser sometidos a un monitoreo combinado en l\u00ednea y fuera de l\u00ednea para asegurar que se mantengan las especificaciones del agua.\n\n3. **\u00bfPor qu\u00e9 es importante la integraci\u00f3n de los sistemas de almacenamiento y distribuci\u00f3n con las plantas de purificaci\u00f3n de agua?**\n   - Respuesta: La integraci\u00f3n es crucial para asegurar la entrega de agua de calidad constante a los puntos de uso y para garantizar el funcionamiento \u00f3ptimo del equipo de purificaci\u00f3n, lo que es esencial en aplicaciones farmac\u00e9uticas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Mantenimiento de Sistemas de Generaci\u00f3n de Agua**:\n   - Se recomienda mantener un flujo m\u00ednimo en todo momento.\n   - Control de temperatura para minimizar el crecimiento microbiano, con un valor gu\u00eda de < 25 \u00b0C.\n\n2. **Desinfecci\u00f3n**:\n   - Provisi\u00f3n de desinfecci\u00f3n ultravioleta.\n   - Selecci\u00f3n de componentes de tratamiento que puedan ser desinfectados t\u00e9rmicamente.\n   - Aplicaci\u00f3n de sanitizaci\u00f3n qu\u00edmica (ozono, per\u00f3xido de hidr\u00f3geno, \u00e1cido perac\u00e9tico).\n   - Sanitizaci\u00f3n t\u00e9rmica a temperaturas superiores a 65 \u00b0C.\n\n3. **Producci\u00f3n de Agua Altamente Purificada (HPW)**:\n   - Producci\u00f3n mediante \u00f3smosis inversa de doble paso y ultrafiltraci\u00f3n o t\u00e9cnicas de purificaci\u00f3n calificadas.\n   - Las recomendaciones para agua purificada (PW) son aplicables a HPW.\n\n4. **Producci\u00f3n de Agua para Inyecciones (BWFI)**:\n   - La destilaci\u00f3n es la t\u00e9cnica preferida para la purificaci\u00f3n final.\n   - Consideraciones al dise\u00f1ar un sistema de purificaci\u00f3n:\n     - Calidad del agua de alimentaci\u00f3n.\n     - Especificaciones de calidad del agua requerida.\n     - Cantidad de agua necesaria.\n     - Tama\u00f1o \u00f3ptimo del generador y control variable para evitar ciclos de inicio/parada frecuentes.\n     - Funciones de blow-down y dump.\n     - Ventilaci\u00f3n de enfriamiento para evitar la entrada de contaminantes.\n\n5. **Relevancia de las Normas Farmacopeas**:\n   - Algunas farmacopeas prescriben o limitan las etapas de purificaci\u00f3n permitidas para BWFI.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad del documento.\n- **Agentes Qu\u00edmicos**: Ozono, per\u00f3xido de hidr\u00f3geno, \u00e1cido perac\u00e9tico.\n- **T\u00e9cnicas de Purificaci\u00f3n**: \u00d3smosis inversa, ultrafiltraci\u00f3n, destilaci\u00f3n.\n- **Tipos de Agua**: Agua Purificada (PW), Agua Altamente Purificada (HPW), Agua para Inyecciones (BWFI).", "excerpt_keywords": "Keywords: water storage, distribution systems, pharmaceutical use, microbial prevention, material compatibility"}}, "20f17999-4fc6-4de6-a275-e9d79a741b88": {"node_ids": ["59c7a740-ed8a-44f1-8ee1-e724aaef4765"], "metadata": {"page_label": "93", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The system should be passivated after initial installation or after significant modification. When accelerated passivation is undertaken the system should be thoroughly cleaned first and the passivation process should be undertaken in accordance with a clearly defined documented procedure.\n\n- **Smooth internal finish.** Once water has been purified it is susceptible to microbiological contamination and the system is subject to the formation of biofilms when cold storage and distribution are employed. Smooth internal surfaces help to avoid roughness and crevices within the WPU system. Crevices can be the source of contamination because of possible accumulation of microorganisms and formation of biofilms. Crevices are also frequently sites where corrosion can commence. The internal material finish should have an arithmetical average surface roughness of not greater than 0.8 micrometre (Ra). When stainless steel is used, mechanical and electro-polishing techniques may be employed. Electro-polishing improves the resistance of the stainless-steel material to surface corrosion.\n\n- **Jointing.** The selected system materials should be easily joined by welding in a controlled manner. The control of the process should include, as a minimum, qualification of the operator, documentation of the welder set-up, work session test pieces (coupons), logs of all welds and visual inspection of a defined proportion of welds, e.g. 100% hand welds, 10% automatic welds.\n\n- **Design of flanges, unions and valves.** Where flanges, unions or valves are used they should be of a hygienic or sanitary design. Appropriate checks should be carried out to ensure that the correct seals and diaphragms are used and that they are fitted and tightened correctly. Threaded connections should be avoided.\n\n- **Documentation.** All system components should be fully documented and be supported by original or certified copies of material certificates.\n\n- **Materials.** Suitable materials that may be considered for sanitary elements of the system include 316L (low carbon) stainless steel, polypropylene, polyvinylidene-difluoride and perfluoroalkoxy. The choice of material should take into account the intended sanitization method. Other materials such as unplasticized polyvinyl-chloride (uPVC) may be used for treatment equipment designed for less pure water such as ion exchangers and softeners.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS (Informe T\u00e9cnico 970) aborda las mejores pr\u00e1cticas para el dise\u00f1o y mantenimiento de sistemas de purificaci\u00f3n de agua (WPU). Se enfatiza la importancia de la pasivaci\u00f3n del sistema, la necesidad de superficies internas lisas para prevenir la contaminaci\u00f3n microbiol\u00f3gica, y la correcta uni\u00f3n de materiales mediante soldadura controlada. Tambi\u00e9n se discuten los dise\u00f1os higi\u00e9nicos de componentes como bridas y v\u00e1lvulas, la documentaci\u00f3n necesaria para los componentes del sistema, y los materiales adecuados para su construcci\u00f3n.\n\n### Preguntas Espec\u00edficas:\n\n1. **\u00bfCu\u00e1l es la importancia de la pasivaci\u00f3n en un sistema de purificaci\u00f3n de agua y qu\u00e9 pasos deben seguirse antes de realizarla?**\n   - La pasivaci\u00f3n es crucial para prevenir la corrosi\u00f3n y asegurar la integridad del sistema despu\u00e9s de la instalaci\u00f3n o modificaciones significativas. Antes de realizar la pasivaci\u00f3n, el sistema debe ser limpiado a fondo y el proceso debe seguir un procedimiento documentado claramente definido.\n\n2. **\u00bfQu\u00e9 caracter\u00edsticas deben tener las superficies internas de un sistema de purificaci\u00f3n de agua para minimizar el riesgo de contaminaci\u00f3n?**\n   - Las superficies internas deben ser lisas, con una rugosidad superficial aritm\u00e9tica promedio no mayor a 0.8 micr\u00f3metros (Ra). Esto ayuda a evitar la acumulaci\u00f3n de microorganismos y la formaci\u00f3n de biofilms, que pueden ser fuentes de contaminaci\u00f3n.\n\n3. **\u00bfQu\u00e9 materiales son recomendados para los elementos sanitarios de un sistema de purificaci\u00f3n de agua y qu\u00e9 factores deben considerarse al elegirlos?**\n   - Se recomiendan materiales como acero inoxidable 316L (bajo carbono), polipropileno, polivinilideno difluoruro y perfluoroalcoxi. La elecci\u00f3n del material debe tener en cuenta el m\u00e9todo de sanitizaci\u00f3n previsto, as\u00ed como la pureza del agua que se va a tratar.", "prev_section_summary": "### Temas Clave\n\n1. **Importancia de los Sistemas de Almacenamiento y Distribuci\u00f3n**: Estos sistemas son esenciales para el suministro de agua de calidad en aplicaciones farmac\u00e9uticas (PW, BHPW y BWFI) y deben integrarse con las plantas de purificaci\u00f3n para asegurar un funcionamiento \u00f3ptimo.\n\n2. **Dise\u00f1o y Requisitos de Materiales**: Los sistemas deben ser dise\u00f1ados para prevenir la proliferaci\u00f3n microbiana y la recontaminaci\u00f3n del agua. Los materiales en contacto con el agua deben ser compatibles, no permitir la lixiviaci\u00f3n y ser resistentes a la corrosi\u00f3n.\n\n3. **Monitoreo y Control de Calidad**: Es fundamental implementar un monitoreo tanto en l\u00ednea como fuera de l\u00ednea para mantener las especificaciones del agua despu\u00e9s del tratamiento.\n\n### Entidades\n\n- **Sistemas de Almacenamiento y Distribuci\u00f3n de Agua**: PW (agua purificada), BHPW (agua para inyecci\u00f3n de alta calidad) y BWFI (agua para inyecci\u00f3n).\n- **Componentes del Sistema**: Plantas de purificaci\u00f3n, tanques de almacenamiento, tuber\u00edas, v\u00e1lvulas, accesorios, sellos, diafragmas e instrumentos.\n- **Propiedades de Materiales**:\n  - **Compatibilidad**: Deben soportar temperaturas de trabajo y qu\u00edmicos.\n  - **Prevenci\u00f3n de Lixiviaci\u00f3n**: No deben liberar sustancias en el agua.\n  - **Resistencia a la Corrosi\u00f3n**: Deben ser capaces de resistir la corrosi\u00f3n causada por el agua purificada.\n\n### Conclusi\u00f3n\n\nLa secci\u00f3n enfatiza la necesidad de un dise\u00f1o cuidadoso y la selecci\u00f3n de materiales adecuados en los sistemas de almacenamiento y distribuci\u00f3n de agua para uso farmac\u00e9utico, as\u00ed como la importancia del monitoreo para garantizar la calidad del agua.", "excerpt_keywords": "Keywords: passivation, microbiological contamination, sanitary design, welding, materials selection"}}, "07555395-8bc5-4ac6-a4a0-02e817753654": {"node_ids": ["a6ed1492-6f65-4cdd-93a0-64c82f54845a"], "metadata": {"page_label": "94", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nNone of the materials that come into contact with WPU should contain chemicals that will be extracted by the water. Plastics should be non-toxic and should be compatible with all chemicals used. They should be manufactured from materials that should at least meet minimum food grade standards. Their chemical and biological characteristics should meet any relevant pharmacopoeia specifications or recommendations.\n\nPrecautions should be taken to define operational limits for areas where water circulation is reduced and turbulent flow cannot be achieved. Minimum flow rate and change volumes should be defined.\n\n## 6.3 System sanitization and bioburden control\n\n### 6.3.1\nWater treatment equipment, storage and distribution systems used for BPW, BHPW and BWFI should be provided with features to control the proliferation of microbiological organisms during normal use, as well as techniques for sanitizing the system after intervention for maintenance or modification. The techniques employed should be considered during the design of the system and should take into account the interdependency between the materials and the sanitization techniques.\n\n### 6.3.2\nSystems that operate and are maintained at elevated temperatures (e.g. > 65) are generally less susceptible to microbiological contamination than systems that are maintained at lower temperatures. When lower temperatures are required due to the water treatment processes employed or the temperature requirements for the water in use, special precautions should be taken to prevent the ingress and proliferation of microbiological contaminants (see section 6.4.3 for guidance).\n\n## 6.4 Storage vessel requirements\n\n### 6.4.1 General\n\n#### 6.4.1.1\nThe water storage vessel used in a system serves a number of important functions. The design and size of the vessel should take into consideration the following.\n\n### 6.4.2 Capacity\n\n#### 6.4.2.1\nThe capacity of the storage vessel should be determined on the basis of the following requirements:\n\n- It is necessary to provide a buffer capacity between the steady-state generation rate of the water-treatment equipment and the potentially variable simultaneous demand from user points.\n- The water-treatment equipment should be able to operate continuously for significant periods to avoid the inefficiencies and", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS se centra en las especificaciones para los preparativos farmac\u00e9uticos, haciendo hincapi\u00e9 en la importancia de los materiales que entran en contacto con el agua purificada (WPU). Se establece que estos materiales no deben liberar sustancias qu\u00edmicas en el agua y deben cumplir con est\u00e1ndares de calidad alimentaria. Adem\u00e1s, se discuten las medidas de control de biocarga y sanitizaci\u00f3n de los sistemas de tratamiento de agua, as\u00ed como los requisitos para los recipientes de almacenamiento, que deben tener en cuenta la capacidad y la demanda variable.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las caracter\u00edsticas m\u00ednimas que deben cumplir los materiales en contacto con el agua purificada seg\u00fan el documento de la OMS?**\n   - Respuesta: Los materiales deben ser no t\u00f3xicos, compatibles con todos los qu\u00edmicos utilizados, fabricados de acuerdo con est\u00e1ndares m\u00ednimos de calidad alimentaria y cumplir con las especificaciones o recomendaciones de la farmacopoeia relevante.\n\n2. **\u00bfQu\u00e9 precauciones se deben tomar para prevenir la proliferaci\u00f3n de organismos microbiol\u00f3gicos en sistemas de tratamiento de agua que operan a temperaturas m\u00e1s bajas?**\n   - Respuesta: Se deben tomar precauciones especiales para prevenir la entrada y proliferaci\u00f3n de contaminantes microbiol\u00f3gicos, especialmente si se requieren temperaturas m\u00e1s bajas debido a los procesos de tratamiento de agua o a los requisitos de temperatura del agua en uso.\n\n3. **\u00bfC\u00f3mo se determina la capacidad de un recipiente de almacenamiento de agua en un sistema de tratamiento seg\u00fan el informe?**\n   - Respuesta: La capacidad del recipiente debe determinarse considerando la necesidad de proporcionar una capacidad de amortiguamiento entre la tasa de generaci\u00f3n constante del equipo de tratamiento de agua y la demanda variable potencial de los puntos de uso. Adem\u00e1s, el equipo de tratamiento de agua debe poder operar de manera continua durante per\u00edodos significativos para evitar ineficiencias.", "prev_section_summary": "### Temas Clave:\n\n1. **Pasivaci\u00f3n del Sistema:**\n   - Importancia de la pasivaci\u00f3n despu\u00e9s de la instalaci\u00f3n inicial o modificaciones significativas.\n   - Necesidad de limpieza exhaustiva antes de la pasivaci\u00f3n.\n   - Proceso de pasivaci\u00f3n debe seguir un procedimiento documentado.\n\n2. **Acabado Interno Liso:**\n   - Prevenci\u00f3n de contaminaci\u00f3n microbiol\u00f3gica y formaci\u00f3n de biofilms.\n   - Superficies internas deben tener una rugosidad promedio no mayor a 0.8 micr\u00f3metros (Ra).\n   - Uso de t\u00e9cnicas de pulido mec\u00e1nico y electro-pulido para acero inoxidable.\n\n3. **Uni\u00f3n de Materiales:**\n   - Importancia de la soldadura controlada para unir materiales del sistema.\n   - Requisitos de calificaci\u00f3n del operador y documentaci\u00f3n del proceso de soldadura.\n\n4. **Dise\u00f1o Higi\u00e9nico de Componentes:**\n   - Bridas, uniones y v\u00e1lvulas deben tener un dise\u00f1o sanitario.\n   - Verificaci\u00f3n de sellos y diafragmas, evitando conexiones roscadas.\n\n5. **Documentaci\u00f3n:**\n   - Necesidad de documentaci\u00f3n completa de todos los componentes del sistema.\n   - Soporte con copias originales o certificadas de certificados de materiales.\n\n6. **Materiales Adecuados:**\n   - Materiales recomendados incluyen acero inoxidable 316L, polipropileno, polivinilideno difluoruro y perfluoroalcoxi.\n   - Consideraci\u00f3n del m\u00e9todo de sanitizaci\u00f3n y pureza del agua al elegir materiales.\n\n### Entidades:\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**\n- **Acero Inoxidable 316L**\n- **Polipropileno**\n- **Polivinilideno Difluoruro**\n- **Perfluoroalcoxi**\n- **Unplasticized Polyvinyl Chloride (uPVC)**\n- **WPU (Water Purification System)**\n\nEste resumen destaca los aspectos fundamentales y las entidades relevantes en el contexto del dise\u00f1o y mantenimiento de sistemas de purificaci\u00f3n de agua seg\u00fan el informe t\u00e9cnico de la OMS.", "excerpt_keywords": "Keywords: water purification, microbiological control, storage vessel requirements, pharmaceutical preparations, sanitization techniques"}}, "b49d29fd-640d-4a12-af03-f7adf3ed712a": {"node_ids": ["17e9fd90-2780-4d17-b626-a2d8de5e4ab8"], "metadata": {"page_label": "95", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Contamination control considerations\n\n## 6.4.3\n\n### 6.4.3.1\n\nThe following should be taken into account for the efficient control of contamination:\n\n- The headspace in the storage vessel is an area of risk where water droplets and air can come into contact at temperatures that encourage the proliferation of microbiological organisms. The use of spray-ball or distributor devices should be considered in these systems to wet the surfaces during normal operation, chemical and/or thermal sanitization.\n\n- Nozzles within the storage vessels should be configured to avoid dead zones where microbiological contamination might be harboured.\n\n- Vent filters are fitted to storage vessels to allow the internal level of liquid to fluctuate. The filters should be bacteria-retentive, hydrophobic and should ideally be configured to allow in situ testing of integrity. Offline testing is also acceptable. The use of heated vent filters should be considered for continuous hot storage or systems using periodic heat sanitization to prevent condensation within the filter matrix that might lead to filter blockage and to microbial growth that could contaminate the storage vessels.\n\n- Where pressure-relief valves and bursting discs are provided on storage vessels to protect them from under- and over-pressurization, these devices should be of a sanitary design. Bursting discs should be provided with external rupture indicators to ensure that loss of system integrity is detected.\n\n# Requirements for water distribution pipework\n\n## 6.5\n\n### 6.5.1 General\n\n#### 6.5.1.1\n\nThe distribution of BPW, BHPW and BWFI should be accomplished using a continuously circulating pipework loop. Proliferation of contaminants within", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda consideraciones sobre el control de la contaminaci\u00f3n en sistemas de almacenamiento y distribuci\u00f3n de agua. Se enfatiza la importancia de gestionar el espacio de cabeza en los recipientes de almacenamiento, la configuraci\u00f3n de boquillas para evitar zonas muertas, el uso de filtros de ventilaci\u00f3n adecuados y el dise\u00f1o sanitario de v\u00e1lvulas de alivio de presi\u00f3n y discos de ruptura. Adem\u00e1s, se menciona que la distribuci\u00f3n de agua purificada debe realizarse mediante un sistema de tuber\u00edas de circulaci\u00f3n continua para prevenir la proliferaci\u00f3n de contaminantes.\n\n### Preguntas espec\u00edficas:\n1. **\u00bfQu\u00e9 caracter\u00edsticas deben tener los filtros de ventilaci\u00f3n en los recipientes de almacenamiento para garantizar la seguridad microbiol\u00f3gica?**\n   - Respuesta: Los filtros de ventilaci\u00f3n deben ser retentivos de bacterias, hidrof\u00f3bicos y, idealmente, deben estar configurados para permitir pruebas de integridad in situ. Tambi\u00e9n se acepta la realizaci\u00f3n de pruebas fuera de l\u00ednea.\n\n2. **\u00bfPor qu\u00e9 es importante evitar zonas muertas en las boquillas dentro de los recipientes de almacenamiento?**\n   - Respuesta: Es importante evitar zonas muertas porque son \u00e1reas donde puede acumularse contaminaci\u00f3n microbiol\u00f3gica, lo que representa un riesgo para la calidad del agua almacenada.\n\n3. **\u00bfQu\u00e9 medidas se deben tomar en relaci\u00f3n con los dispositivos de alivio de presi\u00f3n en los recipientes de almacenamiento?**\n   - Respuesta: Los dispositivos de alivio de presi\u00f3n y los discos de ruptura deben ser de dise\u00f1o sanitario y deben estar equipados con indicadores de ruptura externos para detectar la p\u00e9rdida de integridad del sistema.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Materiales en contacto con agua purificada (WPU)**:\n   - Los materiales no deben liberar sustancias qu\u00edmicas en el agua.\n   - Deben ser no t\u00f3xicos y compatibles con todos los qu\u00edmicos utilizados.\n   - Deben cumplir con est\u00e1ndares m\u00ednimos de calidad alimentaria y especificaciones de farmacopoeia.\n\n2. **Control de biocarga y sanitizaci\u00f3n**:\n   - Los sistemas de tratamiento de agua deben incluir caracter\u00edsticas para controlar la proliferaci\u00f3n de organismos microbiol\u00f3gicos.\n   - Se deben implementar t\u00e9cnicas de sanitizaci\u00f3n despu\u00e9s de mantenimiento o modificaciones.\n   - Los sistemas a temperaturas elevadas son menos susceptibles a la contaminaci\u00f3n microbiol\u00f3gica.\n\n3. **Requisitos de recipientes de almacenamiento**:\n   - La capacidad del recipiente debe proporcionar un buffer entre la generaci\u00f3n constante de agua y la demanda variable.\n   - El equipo de tratamiento debe operar de manera continua para evitar ineficiencias.\n\n### Entidades:\n- **WPU**: Agua purificada.\n- **BPW, BHPW, BWFI**: Tipos de agua utilizados en farmac\u00e9utica.\n- **Farmacopoeia**: Referencia para est\u00e1ndares de calidad en productos farmac\u00e9uticos.\n- **Temperaturas**: Se menciona un umbral de 65 grados Celsius para el control de contaminaci\u00f3n microbiol\u00f3gica. \n\nEste resumen destaca la importancia de la calidad de los materiales, el control microbiol\u00f3gico y la adecuada capacidad de almacenamiento en los sistemas de tratamiento de agua para aplicaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: contamination control, storage vessels, vent filters, pressure-relief valves, water distribution"}}, "0e574a20-f5af-40a4-897d-57c9b23b8a3d": {"node_ids": ["0ce27bd2-cdd2-4176-a2d9-a7777c24096d"], "metadata": {"page_label": "96", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## 6.5.1.2\nFiltration should not usually be used in distribution loops or at take off-user points to control biocontamination. Such filters are likely to conceal system contamination.\n\n## 6.5.2 Temperature control and heat exchangers\n\n### 6.5.2.1\nWhere heat exchangers are employed to heat or cool WPU within a system, precautions should be taken to prevent the heating or cooling utility from contaminating the water. The more secure types of heat exchangers of the double tube plate or double plate and frame or tube and shell configuration should be considered. Where these types are not used, an alternative approach whereby the utility is maintained and monitored at a lower pressure than the WPU may be considered. The latter approach is not usually adopted in BWFI systems.\n\n### 6.5.2.2\nWhere heat exchangers are used they should be arranged in continually circulating loops or subloops of the system to avoid unacceptable static water in systems.\n\n### 6.5.2.3\nWhen the temperature is reduced for processing purposes the reduction should occur for the minimum necessary time. The cooling cycles and their duration should be proven satisfactory during the qualification of the system.\n\n## 6.5.3 Circulation pumps\n\n### 6.5.3.1\nCirculation pumps should be of a sanitary design with appropriate seals that prevent contamination of the system. Where stand-by pumps are provided, they should be configured or managed to avoid dead zones trapped within the system.\n\nConsideration should be given to preventing contamination in systems where parallel pump systems are used, especially if there is stagnant water when one of the pumps is not being used.\n\n## 6.5.4 Biocontamination control techniques\n\n### 6.5.4.1\nWater purification systems should be sanitized using chemical or thermal sanitization procedures as appropriate (production and distribution). The procedure and conditions used (such as times and temperatures) should be suitable.\n\n### 6.5.4.2\nThe following control techniques may be used alone or more commonly in combination:\n\n- Maintenance of continuous turbulent flow circulation within water distribution systems reduces the propensity for the formation of biofilms;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Control de Biocontaminaci\u00f3n en Sistemas de Distribuci\u00f3n de Agua**: El documento aborda las mejores pr\u00e1cticas para el control de biocontaminaci\u00f3n en sistemas de distribuci\u00f3n de agua purificada, enfatizando la importancia de evitar la filtraci\u00f3n en puntos cr\u00edticos y la necesidad de mantener un flujo turbulento continuo para prevenir la formaci\u00f3n de biofilmes.\n\n2. **Dise\u00f1o y Mantenimiento de Intercambiadores de Calor**: Se discuten las precauciones necesarias al utilizar intercambiadores de calor en sistemas de agua purificada, incluyendo la selecci\u00f3n de configuraciones seguras y la importancia de evitar el agua est\u00e1tica en el sistema.\n\n3. **Requisitos para Bombas de Circulaci\u00f3n**: Se especifican las caracter\u00edsticas que deben tener las bombas de circulaci\u00f3n, incluyendo un dise\u00f1o sanitario y la gesti\u00f3n adecuada de bombas de reserva para evitar zonas muertas que puedan acumular contaminantes.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfPor qu\u00e9 no se recomienda el uso de filtros en los bucles de distribuci\u00f3n o en los puntos de toma de agua purificada?**\n   - La filtraci\u00f3n no se recomienda en estos puntos porque puede ocultar la contaminaci\u00f3n del sistema, lo que podr\u00eda llevar a un riesgo mayor de biocontaminaci\u00f3n.\n\n2. **\u00bfCu\u00e1les son las configuraciones de intercambiadores de calor m\u00e1s seguras recomendadas para evitar la contaminaci\u00f3n del agua purificada?**\n   - Se recomiendan intercambiadores de calor de doble tubo, de doble placa y marco, o de tubo y carcasa, ya que son considerados m\u00e1s seguros para evitar la contaminaci\u00f3n del agua purificada.\n\n3. **\u00bfQu\u00e9 t\u00e9cnicas de control de biocontaminaci\u00f3n se pueden implementar en sistemas de purificaci\u00f3n de agua?**\n   - Las t\u00e9cnicas incluyen la sanitizaci\u00f3n qu\u00edmica o t\u00e9rmica de los sistemas de purificaci\u00f3n de agua y el mantenimiento de un flujo turbulento continuo en los sistemas de distribuci\u00f3n para reducir la formaci\u00f3n de biofilmes.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Control de Contaminaci\u00f3n**: Se enfatiza la importancia de gestionar adecuadamente el espacio de cabeza en los recipientes de almacenamiento para prevenir la proliferaci\u00f3n de organismos microbiol\u00f3gicos.\n\n2. **Configuraci\u00f3n de Boquillas**: Las boquillas dentro de los recipientes deben estar dise\u00f1adas para evitar zonas muertas, donde la contaminaci\u00f3n microbiol\u00f3gica puede acumularse.\n\n3. **Filtros de Ventilaci\u00f3n**: Los filtros deben ser:\n   - Retentivos de bacterias.\n   - Hidrof\u00f3bicos.\n   - Configurados para permitir pruebas de integridad in situ y pruebas fuera de l\u00ednea.\n   - Se sugiere el uso de filtros de ventilaci\u00f3n calentados para almacenamiento continuo a altas temperaturas.\n\n4. **Dispositivos de Alivio de Presi\u00f3n**: \n   - Deben ser de dise\u00f1o sanitario.\n   - Los discos de ruptura deben contar con indicadores externos para detectar la p\u00e9rdida de integridad del sistema.\n\n5. **Distribuci\u00f3n de Agua**: La distribuci\u00f3n de agua purificada (BPW, BHPW y BWFI) debe realizarse mediante un sistema de tuber\u00edas de circulaci\u00f3n continua para evitar la proliferaci\u00f3n de contaminantes.\n\n### Entidades:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las recomendaciones.\n- **BPW (Agua Purificada)**, **BHPW (Agua Purificada para Uso Farmac\u00e9utico)**, **BWFI (Agua para Inyecciones)**: Tipos de agua mencionados en el contexto de distribuci\u00f3n.\n- **Dispositivos de Alivio de Presi\u00f3n** y **Discos de Ruptura**: Equipos de seguridad en los recipientes de almacenamiento.", "excerpt_keywords": "Keywords: biocontamination, water purification, heat exchangers, circulation pumps, sanitary design"}}, "0f5aab5f-f66d-4512-aedc-eff952bf3e01": {"node_ids": ["63a370a6-fda6-4da3-ad86-1cc258841a03"], "metadata": {"page_label": "97", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "- the system design should ensure the shortest possible length of pipework;\n- for ambient temperature systems, pipework should be isolated from adjacent hot pipes;\n- deadlegs in the pipework should be minimized through appropriate design, and as a guide should not significantly exceed three times the branch diameter as measured from the ID pipe wall to centre line of the point-of-use valve where significant stagnation potential exists;\n- pressure gauges should be separated from the system by membranes;\n- hygienic pattern diaphragm valves should be used;\n- pipework for steam-sanitized systems should be sloped and fully drainable;\n- the growth of microorganisms can be inhibited by:\n  - ultraviolet radiation sources in pipework;\n  - maintaining the system heated (greater than 65 \u00b0C);\n  - sanitizing the system periodically using hot water (guidance temperature > 70 \u00b0C);\n  - sanitizing the system periodically using superheated hot water or clean steam;\n  - routine chemical sanitization using ozone or other suitable chemical agents. When chemical sanitization is used, it is essential to prove that the agent has been removed prior to using the water. Ozone can be effectively removed by using ultraviolet radiation.\n\n# 7. Operational considerations\n\n## 7.1 Start-up and commissioning of water systems\n\n7.1.1 Planned, well-defined, successful and well-documented commissioning and qualification is an essential precursor to successful validation of water systems.\n\n7.1.2 The commissioning work should include setting to work, system set-up, controls, loop tuning and recording of all system performance parameters. If it is intended to use or to refer to commissioning data within the validation work then the quality of the commissioning work and associated data and documentation must be commensurate with the validation plan requirements.\n\n## 7.2 Qualification\n\n7.2.1 WPU, BPW, BHPW and BWFI systems are all considered to be direct impact, quality critical systems that should be qualified. The qualification", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Informe T\u00e9cnico 970 aborda el dise\u00f1o y la operaci\u00f3n de sistemas de agua, enfatizando la importancia de minimizar la longitud de las tuber\u00edas, el aislamiento de tuber\u00edas calientes, y la reducci\u00f3n de \"deadlegs\" en el sistema. Tambi\u00e9n se discuten m\u00e9todos para inhibir el crecimiento de microorganismos, como el uso de radiaci\u00f3n ultravioleta y la sanitizaci\u00f3n peri\u00f3dica. Adem\u00e1s, se subraya la necesidad de una correcta puesta en marcha y calificaci\u00f3n de los sistemas de agua, asegurando que la documentaci\u00f3n y los datos sean adecuados para la validaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfCu\u00e1les son las recomendaciones para el dise\u00f1o de tuber\u00edas en sistemas de agua para minimizar el crecimiento de microorganismos?**\n   - El dise\u00f1o debe asegurar la menor longitud posible de tuber\u00edas, aislar las tuber\u00edas de temperatura ambiente de las tuber\u00edas calientes, y minimizar los \"deadlegs\" para evitar la estancaci\u00f3n, siguiendo la gu\u00eda de no exceder tres veces el di\u00e1metro de la rama.\n\n2. **\u00bfQu\u00e9 m\u00e9todos se sugieren para la sanitizaci\u00f3n de sistemas de agua y c\u00f3mo se debe manejar el uso de agentes qu\u00edmicos?**\n   - Se sugiere la sanitizaci\u00f3n peri\u00f3dica utilizando agua caliente (temperatura > 70 \u00b0C), agua caliente sobrecalentada o vapor limpio, y la sanitizaci\u00f3n qu\u00edmica con ozono u otros agentes. Es crucial demostrar que el agente qu\u00edmico ha sido eliminado antes de usar el agua, y el ozono puede ser eliminado eficazmente mediante radiaci\u00f3n ultravioleta.\n\n3. **\u00bfQu\u00e9 aspectos deben considerarse durante la puesta en marcha y calificaci\u00f3n de sistemas de agua seg\u00fan el documento?**\n   - La puesta en marcha debe ser planificada, bien definida y documentada, incluyendo la configuraci\u00f3n del sistema, controles, ajuste de bucles y registro de par\u00e1metros de rendimiento. La calidad de los datos de la puesta en marcha debe ser adecuada para los requisitos del plan de validaci\u00f3n si se van a utilizar en el trabajo de validaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Control de Biocontaminaci\u00f3n**:\n   - Se enfatiza que la filtraci\u00f3n no debe utilizarse en bucles de distribuci\u00f3n o puntos de toma de agua purificada, ya que puede ocultar la contaminaci\u00f3n del sistema.\n\n2. **Intercambiadores de Calor**:\n   - Se recomienda el uso de intercambiadores de calor de configuraciones seguras (doble tubo, doble placa y marco, tubo y carcasa) para evitar la contaminaci\u00f3n del agua purificada.\n   - Los intercambiadores deben estar dispuestos en bucles de circulaci\u00f3n continua para evitar agua est\u00e1tica.\n\n3. **Bombas de Circulaci\u00f3n**:\n   - Las bombas deben tener un dise\u00f1o sanitario y sellos adecuados para prevenir la contaminaci\u00f3n.\n   - Se debe evitar la formaci\u00f3n de zonas muertas, especialmente en sistemas con bombas en paralelo.\n\n4. **T\u00e9cnicas de Control de Biocontaminaci\u00f3n**:\n   - Se deben aplicar procedimientos de sanitizaci\u00f3n qu\u00edmica o t\u00e9rmica en los sistemas de purificaci\u00f3n de agua.\n   - Mantener un flujo turbulento continuo en los sistemas de distribuci\u00f3n es crucial para reducir la formaci\u00f3n de biofilmes.\n\n### Entidades Clave\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las recomendaciones.\n- **WPU (Water for Pharmaceutical Use)**: Agua purificada para uso farmac\u00e9utico.\n- **BWFI (Bacteriostatic Water for Injection)**: Agua bacteriost\u00e1tica para inyecci\u00f3n.\n- **Intercambiadores de Calor**: Equipos utilizados para calentar o enfriar el agua purificada.\n- **Bombas de Circulaci\u00f3n**: Dispositivos que mantienen el flujo del agua purificada en el sistema. \n\nEste resumen destaca las mejores pr\u00e1cticas y consideraciones cr\u00edticas para el manejo y control de biocontaminaci\u00f3n en sistemas de agua purificada, as\u00ed como los requisitos de dise\u00f1o y operaci\u00f3n de los equipos involucrados.", "excerpt_keywords": "Keywords: water systems, microorganism control, sanitization, commissioning, qualification"}}, "113bffda-6339-49b1-a394-176bff5f6844": {"node_ids": ["75cb7679-b5d7-4b9d-9662-c0bc3ec05210"], "metadata": {"page_label": "98", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nshould follow the validation convention of design review or design qualification (DQ), IQ, OQ, and PQ.\n\n## 7.2.2\n\nThis guidance does not define the standard requirements for the conventional qualification stages DQ, IQ and OQ, but concentrates on the particular PQ approach that should be used for WPU systems to demonstrate their consistent and reliable performance. A three-phase approach should be used to satisfy the objective of proving the reliability and robustness of the system in service over an extended period.\n\nTests on the source water must be included within the validation programme and continued as part of the routine monitoring. The source water should meet the requirements for drinking-water and any internal specification.\n\n**Phase 1.** Sample daily or continuously monitor the incoming feed-water to verify its quality.\n\nA test period of two weeks should be spent monitoring the system intensively. During this period, the system should operate continuously without failure or performance deviation. Usually water is not used for finished pharmaceutical product (FPP) manufacturing during this period. The following activities should be included in the testing approach.\n\n- Undertake chemical and microbiological testing in accordance with a defined plan.\n- Sample or continuously monitor the incoming feed-water daily to verify its quality.\n- Sample or continuously monitor after each step in the purification process.\n- Sample or continuously monitor at each point of use and at other defined sample points.\n- Develop appropriate operating ranges.\n- Develop and finalize operating, cleaning, sanitizing and maintenance procedures.\n- Demonstrate production and delivery of product water of the required quality and quantity.\n- Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting.\n- Verify provisional alert levels.\n- Develop and refine test-failure procedure.\n\n**Phase 2.** A further test period of two weeks should be spent carrying out further intensive monitoring while deploying all the refined SOPs after the satisfactory completion of phase 1. The sampling scheme should be generally the same.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS se centra en las especificaciones para los sistemas de agua purificada (WPU) utilizados en la fabricaci\u00f3n de productos farmac\u00e9uticos. Se describe un enfoque de validaci\u00f3n en tres fases que incluye la revisi\u00f3n del dise\u00f1o (DQ), la calificaci\u00f3n de instalaci\u00f3n (IQ), la calificaci\u00f3n operativa (OQ) y la calificaci\u00f3n de rendimiento (PQ). La gu\u00eda enfatiza la importancia de monitorear la calidad del agua de entrada y realizar pruebas qu\u00edmicas y microbiol\u00f3gicas para asegurar que el sistema funcione de manera confiable y consistente a lo largo del tiempo.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfCu\u00e1les son las actividades espec\u00edficas que deben llevarse a cabo durante la Fase 1 del programa de validaci\u00f3n para los sistemas de agua purificada?**\n   - La Fase 1 incluye actividades como la realizaci\u00f3n de pruebas qu\u00edmicas y microbiol\u00f3gicas, el monitoreo diario de la calidad del agua de entrada, el desarrollo de procedimientos operativos est\u00e1ndar (SOPs), y la verificaci\u00f3n de los niveles de alerta provisionales, entre otros.\n\n2. **\u00bfQu\u00e9 requisitos debe cumplir el agua de origen seg\u00fan el documento de la OMS?**\n   - El agua de origen debe cumplir con los requisitos para el agua potable y cualquier especificaci\u00f3n interna establecida por la organizaci\u00f3n que utiliza el sistema de agua purificada.\n\n3. **\u00bfQu\u00e9 se espera lograr al finalizar la Fase 2 del programa de validaci\u00f3n?**\n   - Al finalizar la Fase 2, se espera que el sistema haya sido monitoreado intensivamente utilizando los SOPs refinados, y que se haya demostrado la producci\u00f3n y entrega de agua de calidad y cantidad requeridas, asegurando as\u00ed la confiabilidad y robustez del sistema en servicio.", "prev_section_summary": "### Temas Clave\n\n1. **Dise\u00f1o de Sistemas de Agua**:\n   - Importancia de minimizar la longitud de las tuber\u00edas.\n   - Aislamiento de tuber\u00edas de temperatura ambiente de tuber\u00edas calientes.\n   - Minimizaci\u00f3n de \"deadlegs\" en el sistema para evitar estancamiento.\n\n2. **Inhibici\u00f3n del Crecimiento de Microorganismos**:\n   - Uso de radiaci\u00f3n ultravioleta en las tuber\u00edas.\n   - Mantenimiento de temperaturas superiores a 65 \u00b0C.\n   - Sanitizaci\u00f3n peri\u00f3dica con agua caliente (> 70 \u00b0C), agua sobrecalentada o vapor limpio.\n   - Sanitizaci\u00f3n qu\u00edmica con ozono y otros agentes, asegurando la eliminaci\u00f3n del agente antes de usar el agua.\n\n3. **Puesta en Marcha y Calificaci\u00f3n de Sistemas**:\n   - Necesidad de una puesta en marcha planificada, bien definida y documentada.\n   - Inclusi\u00f3n de configuraci\u00f3n del sistema, controles, ajuste de bucles y registro de par\u00e1metros de rendimiento.\n   - Calidad de los datos de la puesta en marcha debe ser adecuada para los requisitos del plan de validaci\u00f3n.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad del documento.\n- **Sistemas de Agua**: Incluye WPU (Water Purified Unit), BPW (Bacteriologically Pure Water), BHPW (Bacteriologically High Purity Water) y BWFI (Bacteriologically Water for Injection).\n- **Microorganismos**: Organismos cuyo crecimiento se busca inhibir en los sistemas de agua.\n- **Radiaci\u00f3n Ultravioleta**: M\u00e9todo propuesto para la inhibici\u00f3n del crecimiento microbiano.\n- **Agentes Qu\u00edmicos**: Incluye ozono y otros agentes utilizados para la sanitizaci\u00f3n.\n\n### Resumen General\nEl documento de la OMS en su Informe T\u00e9cnico 970 proporciona directrices sobre el dise\u00f1o y operaci\u00f3n de sistemas de agua, enfatizando la minimizaci\u00f3n de la longitud de las tuber\u00edas y el aislamiento de tuber\u00edas calientes para prevenir el crecimiento de microorganismos. Se sugieren m\u00e9todos de sanitizaci\u00f3n, tanto t\u00e9rmicos como qu\u00edmicos, y se destaca la importancia de una puesta en marcha y calificaci\u00f3n adecuadas para asegurar la calidad y validaci\u00f3n de los sistemas de agua.", "excerpt_keywords": "Keywords: validation, pharmaceutical preparations, water purification, quality monitoring, standard operating procedures"}}, "53f0535e-26e5-4aa6-b534-c90b59b1a0bd": {"node_ids": ["c9fb4783-d0bb-4268-ad25-32aa37ff1b38"], "metadata": {"page_label": "99", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Phase 3\n\nPhase 3 typically runs for one year after the satisfactory completion of phase 2. Water can be used for FPP manufacturing purposes during this phase which has the following objectives:\n\n- to demonstrate reliable performance over an extended period;\n- to ensure that seasonal variations are evaluated.\n\nThe sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2.\n\n## 7.3 Continuous system monitoring\n\n### 7.3.1\n\nAfter completion of phase 3 of the qualification programme for the WPU system, a system review should be undertaken. Following this review a routine monitoring plan should be established based on the results of phase 3.\n\nMonitoring should include a combination of monitoring with online instruments (with appropriately qualified alarm systems) of parameters such as flow, pressure, temperature, conductivity and total organic carbon, and offline sample testing for physical, chemical and microbiological attributes. Offline samples should be taken from points of use or dedicated sample points where points of use cannot be sampled. All water samples should be taken using the same methodology as detailed in production procedures. There should be a suitable flushing and drainage procedure in place.\n\n### 7.3.2\n\nTests should be carried out to ensure that the approved pharmacopoeial and company specification has been met.\n\nThis may include the microbiological quality of water as appropriate.\n\nMonitoring data should be subject to trend analysis (trending should typically be within 2 sigma). Suitable alert and action levels should be established based on historical reported data.\n\n### 7.3.3\n\nAny trend towards frequently exceeding alert limits should trigger a thorough investigation of the root cause, followed by appropriate corrective actions.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto circundante\n\n1. **Objetivos de la Fase 3**: La Fase 3 del programa de calificaci\u00f3n para sistemas de agua purificada (WPU) se centra en demostrar un rendimiento confiable a lo largo del tiempo y evaluar las variaciones estacionales. Esta fase se lleva a cabo durante un a\u00f1o despu\u00e9s de la finalizaci\u00f3n satisfactoria de la Fase 2.\n\n2. **Monitoreo continuo del sistema**: Despu\u00e9s de completar la Fase 3, se debe realizar una revisi\u00f3n del sistema y establecer un plan de monitoreo rutinario. Este monitoreo incluye el uso de instrumentos en l\u00ednea para medir par\u00e1metros cr\u00edticos y pruebas de muestras fuera de l\u00ednea para evaluar atributos f\u00edsicos, qu\u00edmicos y microbiol\u00f3gicos.\n\n3. **An\u00e1lisis de tendencias y acciones correctivas**: Los datos de monitoreo deben ser analizados para identificar tendencias, y cualquier tendencia que indique un exceso frecuente de los l\u00edmites de alerta debe ser investigada a fondo para determinar la causa ra\u00edz y aplicar acciones correctivas adecuadas.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los par\u00e1metros espec\u00edficos que deben ser monitoreados durante la Fase 3 y c\u00f3mo se deben tomar las muestras?**\n   - Respuesta: Durante la Fase 3, se deben monitorear par\u00e1metros como flujo, presi\u00f3n, temperatura, conductividad y carbono org\u00e1nico total. Las muestras deben tomarse de puntos de uso o puntos de muestreo dedicados, utilizando la misma metodolog\u00eda que se detalla en los procedimientos de producci\u00f3n.\n\n2. **\u00bfQu\u00e9 acciones deben tomarse si se detecta una tendencia que excede frecuentemente los l\u00edmites de alerta durante el monitoreo?**\n   - Respuesta: Si se detecta una tendencia que excede frecuentemente los l\u00edmites de alerta, se debe llevar a cabo una investigaci\u00f3n exhaustiva de la causa ra\u00edz y aplicar las acciones correctivas apropiadas.\n\n3. **\u00bfQu\u00e9 tipo de pruebas se deben realizar para asegurar que se cumplen las especificaciones aprobadas durante la Fase 3?**\n   - Respuesta: Se deben realizar pruebas para garantizar que se cumplan las especificaciones farmacop\u00e9icas y de la empresa, lo que puede incluir la evaluaci\u00f3n de la calidad microbiol\u00f3gica del agua, seg\u00fan sea apropiado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Validaci\u00f3n de Sistemas de Agua Purificada (WPU):** El documento establece un enfoque de validaci\u00f3n en tres fases para asegurar el rendimiento consistente y confiable de los sistemas de agua purificada utilizados en la fabricaci\u00f3n de productos farmac\u00e9uticos.\n  \n2. **Fases de Validaci\u00f3n:**\n   - **Fase 1:** Monitoreo intensivo del agua de entrada durante un per\u00edodo de dos semanas, incluyendo pruebas qu\u00edmicas y microbiol\u00f3gicas, desarrollo de procedimientos operativos est\u00e1ndar (SOPs), y verificaci\u00f3n de la calidad del agua.\n   - **Fase 2:** Continuaci\u00f3n del monitoreo intensivo utilizando SOPs refinados, tambi\u00e9n durante un per\u00edodo de dos semanas.\n\n3. **Requisitos del Agua de Origen:** El agua de origen debe cumplir con los est\u00e1ndares de agua potable y cualquier especificaci\u00f3n interna relevante.\n\n4. **Importancia del Monitoreo:** Se enfatiza la necesidad de realizar pruebas continuas y monitoreo para garantizar la calidad del agua a lo largo del tiempo.\n\n**Entidades:**\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Autoridad que emite las directrices sobre las especificaciones para los sistemas de agua purificada.\n- **Sistemas de Agua Purificada (WPU):** Sistemas utilizados en la fabricaci\u00f3n de productos farmac\u00e9uticos que requieren validaci\u00f3n rigurosa.\n- **Procedimientos Operativos Est\u00e1ndar (SOPs):** Documentos que describen los procedimientos para la operaci\u00f3n, mantenimiento, sanitizaci\u00f3n y resoluci\u00f3n de problemas de los sistemas de agua purificada.\n\nEste resumen destaca la estructura y los requisitos de validaci\u00f3n para los sistemas de agua purificada, as\u00ed como la importancia del monitoreo continuo para asegurar su rendimiento en la producci\u00f3n farmac\u00e9utica.", "excerpt_keywords": "Keywords: Phase 3, water purification, continuous monitoring, trend analysis, corrective actions"}}, "f003df69-4da6-4bc0-a4d0-de46fe501090": {"node_ids": ["0c0ee7ff-947c-4ffa-b713-841296e7a9d8"], "metadata": {"page_label": "100", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Maintenance of water systems\n\n7.4.1 WPU systems should be maintained in accordance with a controlled, documented maintenance programme that takes into account the following:\n\n- defined frequency for system elements;\n- the calibration programme;\n- SOPs for specific tasks;\n- control of approved spares;\n- issue of a clear maintenance plan and instructions;\n- review and approval of systems for use upon completion of work;\n- record and review of problems and faults during maintenance.\n\n# System reviews\n\n7.5.1 WPU (BPW, BHPW and BWFI) systems should be reviewed at appropriate regular intervals. The review team should comprise representatives from engineering, QA, microbiology, operations and maintenance. The review should consider matters such as:\n\n- changes made since the last review;\n- system performance;\n- reliability;\n- quality trends;\n- failure events;\n- investigations;\n- out-of-specifications results from monitoring;\n- changes to the installation;\n- updated installation documentation;\n- log books;\n- the status of the current SOP list.\n\n7.5.2 For new systems, or systems that display instability or unreliability, the following should also be reviewed:\n\n- need for investigation;\n- corrective actions and preventative actions (CAPA);", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Informe T\u00e9cnico 970) aborda la importancia del mantenimiento y revisi\u00f3n de los sistemas de agua (WPU) en entornos de calidad controlada. Se establece que los sistemas deben seguir un programa de mantenimiento documentado que incluya la frecuencia de mantenimiento, calibraciones, procedimientos operativos est\u00e1ndar (SOPs), y un plan claro de mantenimiento. Adem\u00e1s, se enfatiza la necesidad de revisiones regulares por un equipo multidisciplinario para evaluar el rendimiento, la fiabilidad y cualquier cambio en el sistema.\n\n### Preguntas:\n\n1. **\u00bfCu\u00e1les son los elementos clave que deben incluirse en un programa de mantenimiento documentado para los sistemas WPU?**\n   - Respuesta: Un programa de mantenimiento documentado debe incluir la frecuencia definida para los elementos del sistema, un programa de calibraci\u00f3n, SOPs para tareas espec\u00edficas, control de repuestos aprobados, un plan de mantenimiento claro, revisi\u00f3n y aprobaci\u00f3n de sistemas tras el trabajo, y un registro de problemas y fallos durante el mantenimiento.\n\n2. **\u00bfQu\u00e9 aspectos deben considerarse durante la revisi\u00f3n de los sistemas WPU en intervalos regulares?**\n   - Respuesta: La revisi\u00f3n debe considerar cambios desde la \u00faltima revisi\u00f3n, rendimiento del sistema, fiabilidad, tendencias de calidad, eventos de fallo, investigaciones, resultados fuera de especificaciones, cambios en la instalaci\u00f3n, documentaci\u00f3n actualizada, libros de registro y el estado de la lista actual de SOPs.\n\n3. **\u00bfQu\u00e9 acciones deben tomarse para sistemas nuevos o inestables durante la revisi\u00f3n?**\n   - Respuesta: Para sistemas nuevos o aquellos que muestran inestabilidad o falta de fiabilidad, se debe revisar la necesidad de investigaci\u00f3n y las acciones correctivas y preventivas (CAPA).", "prev_section_summary": "### Resumen de Temas Clave y Entidades de la Secci\u00f3n\n\n1. **Fase 3 del Programa de Calificaci\u00f3n**:\n   - **Duraci\u00f3n**: Se extiende por un a\u00f1o tras la finalizaci\u00f3n satisfactoria de la Fase 2.\n   - **Objetivos**:\n     - Demostrar un rendimiento confiable a lo largo del tiempo.\n     - Evaluar las variaciones estacionales.\n\n2. **Monitoreo Continuo del Sistema**:\n   - **Revisi\u00f3n del Sistema**: Se debe realizar una revisi\u00f3n del sistema al finalizar la Fase 3 y establecer un plan de monitoreo rutinario.\n   - **Par\u00e1metros a Monitorear**:\n     - Flujo\n     - Presi\u00f3n\n     - Temperatura\n     - Conductividad\n     - Carbono Org\u00e1nico Total\n   - **M\u00e9todo de Muestreo**: Las muestras deben tomarse de puntos de uso o puntos de muestreo dedicados, siguiendo la metodolog\u00eda de los procedimientos de producci\u00f3n.\n\n3. **Pruebas y Cumplimiento de Especificaciones**:\n   - Se deben realizar pruebas para asegurar que se cumplen las especificaciones farmacop\u00e9icas y de la empresa, incluyendo la calidad microbiol\u00f3gica del agua.\n\n4. **An\u00e1lisis de Tendencias**:\n   - Los datos de monitoreo deben ser analizados para identificar tendencias, con un enfoque en mantener las tendencias dentro de 2 sigma.\n   - Se deben establecer niveles de alerta y acci\u00f3n basados en datos hist\u00f3ricos.\n\n5. **Acciones Correctivas**:\n   - Si se detecta una tendencia que excede frecuentemente los l\u00edmites de alerta, se debe realizar una investigaci\u00f3n exhaustiva de la causa ra\u00edz y aplicar acciones correctivas adecuadas.\n\n### Entidades Clave:\n- **Fase 3**: Parte del programa de calificaci\u00f3n para sistemas de agua purificada (WPU).\n- **Par\u00e1metros de Monitoreo**: Flujo, presi\u00f3n, temperatura, conductividad, carbono org\u00e1nico total.\n- **Especificaciones**: Farmacop\u00e9icas y de la empresa.\n- **M\u00e9todos de Muestreo**: Puntos de uso y puntos de muestreo dedicados.", "excerpt_keywords": "Keywords: maintenance, water systems, quality assurance, system reviews, corrective actions"}}, "d2fb1903-c63d-4042-9caa-f761d725f4e4": {"node_ids": ["318dbfc8-07bb-4b8f-beee-a7d380bce559"], "metadata": {"page_label": "101", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 8. Inspection of water systems\n\n8.1 WPU (BPW, BHPW and BWFI) systems are likely to be the subject of regulatory inspection from time to time. Users should consider conducting routine audit and self-inspection of established water systems.\n\n8.2 This GMP guidance can be used as the basis of inspection. A tour of the water generation plant and visible pipework (including user points) should be performed to ensure that the system is appropriately designed, installed and maintained (e.g. that there are no leaks and that the system matches the piping and instrumentation diagram or drawing (P&ID)).\n\nThe following list identifies items and a logical sequence for a WPU system inspection or audit:\n\n- a current drawing of the water system showing all equipment in the system from the inlet to the points of use along with sampling points and their designations;\n- approved piping drawings (e.g. orthographic and/or isometric);\n- a sampling and monitoring plan with a drawing of all sample points;\n- training programme for sample collection and testing;\n- the setting of monitoring alert and action levels;\n- monitoring results and evaluation of trends;\n- inspection of the last annual system review;\n- review of any changes made to the system since the last audit and a check that the change control has been implemented;\n- review of deviations recorded and their investigation;\n- general inspection of system for status and condition;\n- review of maintenance, failure and repair logs;\n- checking calibration and standardization of critical instruments.\n\n8.3 For an established system that is demonstrably under control this scope of review should prove adequate.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Informe T\u00e9cnico 970) aborda la inspecci\u00f3n de sistemas de agua, espec\u00edficamente los sistemas de agua purificada (WPU), que incluyen BPW, BHPW y BWFI. Se enfatiza la importancia de las auditor\u00edas y autoinspecciones rutinarias para garantizar que estos sistemas est\u00e9n dise\u00f1ados, instalados y mantenidos adecuadamente. Se proporciona una lista detallada de elementos a considerar durante una inspecci\u00f3n o auditor\u00eda, que incluye la revisi\u00f3n de dibujos actuales, planes de muestreo, programas de capacitaci\u00f3n y registros de mantenimiento.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 elementos espec\u00edficos deben incluirse en un dibujo actual del sistema de agua para cumplir con los requisitos de inspecci\u00f3n?**\n   - La respuesta se encuentra en la lista de elementos que se deben considerar durante la inspecci\u00f3n, que incluye la representaci\u00f3n de todo el equipo desde la entrada hasta los puntos de uso, as\u00ed como los puntos de muestreo y sus designaciones.\n\n2. **\u00bfCu\u00e1les son los pasos recomendados para llevar a cabo una auditor\u00eda o autoinspecci\u00f3n de un sistema de agua purificada?**\n   - El contexto proporciona una secuencia l\u00f3gica de inspecci\u00f3n que incluye la revisi\u00f3n de dibujos aprobados, planes de muestreo, resultados de monitoreo, y la evaluaci\u00f3n de tendencias, entre otros.\n\n3. **\u00bfQu\u00e9 condiciones se deben cumplir para que un sistema de agua establecido sea considerado \"demostrablemente bajo control\"?**\n   - Seg\u00fan el documento, un sistema que cumple con los requisitos de revisi\u00f3n y que ha sido inspeccionado adecuadamente, con registros de mantenimiento y calibraci\u00f3n, puede ser considerado bajo control.", "prev_section_summary": "### Temas Clave:\n\n1. **Mantenimiento de Sistemas de Agua (WPU)**:\n   - Importancia de un programa de mantenimiento controlado y documentado.\n   - Elementos esenciales del programa de mantenimiento, como frecuencia, calibraci\u00f3n, SOPs, control de repuestos, y planificaci\u00f3n clara.\n\n2. **Revisiones de Sistemas**:\n   - Necesidad de revisiones regulares por un equipo multidisciplinario.\n   - Aspectos a considerar durante la revisi\u00f3n, incluyendo cambios, rendimiento, fiabilidad, tendencias de calidad, y eventos de fallo.\n\n3. **Sistemas Nuevos o Inestables**:\n   - Evaluaci\u00f3n de la necesidad de investigaci\u00f3n y acciones correctivas y preventivas (CAPA) para sistemas que muestran inestabilidad o falta de fiabilidad.\n\n### Entidades:\n\n- **WPU**: Sistemas de agua (Water Purification Units).\n- **BPW, BHPW, BWFI**: Tipos espec\u00edficos de sistemas de agua.\n- **Equipo de Revisi\u00f3n**: Representantes de ingenier\u00eda, aseguramiento de calidad (QA), microbiolog\u00eda, operaciones y mantenimiento.\n- **SOPs**: Procedimientos Operativos Est\u00e1ndar.\n- **CAPA**: Acciones Correctivas y Preventivas.\n\n### Resumen:\nEl documento de la OMS enfatiza la necesidad de un mantenimiento riguroso y revisiones peri\u00f3dicas de los sistemas de agua para asegurar su eficacia y fiabilidad. Se establece un marco claro para el mantenimiento, que incluye la documentaci\u00f3n y el control de procesos, as\u00ed como la importancia de un equipo multidisciplinario para las revisiones, que deben abordar tanto el rendimiento del sistema como cualquier problema que pueda surgir. Para sistemas nuevos o inestables, se requiere un enfoque adicional en la investigaci\u00f3n y la implementaci\u00f3n de acciones correctivas.", "excerpt_keywords": "Keywords: water systems, inspection, WPU, GMP guidance, maintenance"}}, "4e240693-3668-44c0-acb2-fd42c9a2ab45": {"node_ids": ["f7fcc978-4133-46b0-b2eb-a38b93d12d73"], "metadata": {"page_label": "102", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Further reading\n\n**The International Pharmacopoeia.** Geneva, World Health Organization; http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html.\n\n**WHO guidelines on good manufacturing practices: validation.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 4 (WHO Technical Report Series, No. 937); http://www.who.int/medicines/publications/pharmprep/TRS_937.pdf#page=119.\n\n**WHO Guidelines for drinking-water quality, 3rd edition.** Geneva, World Health Organization, 2008; http://www.who.int/water_sanitation_health/dwq/gdwq3rev/en/index.html.\n\n**American Society of Mechanical Engineers.** Bioprocessing Equipment Standard. ASME \u2014 BPE 2000.\n\n**Banes PH.** Passivation; understanding and performing procedures on austenitic stainless steel systems. *Pharmaceutical Engineering*, 1990: 41.\n\n**Guide to inspections of high purity water systems.** Maryland, US Food and Drug Administration, 1993; http://www.fda.gov/ICECI/InspectionGuides.\n\n**Biotechnology. Equipment. Guidance on testing procedures for cleanability.** British Standards Publishing. BS EN 12296, 1998.\n\n**European Medicines Agency.** Note for guidance on the quality of water for pharmaceutical use. London, 2002 (CPMP/QWP/158-01); http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003394.pdf.\n\n**European Pharmacopoeia:** see web site for the publishers of the European Pharmacopoeia and supplements; http://www.pheur.org/.\n\n**Harfst WH.** Selecting piping materials for high-purity water systems. *Ultra Pure Water*, May/June 1994.\n\n**ISPE Good practice guide: commissioning and qualification of pharmaceutical water and steam systems.** ISPE Baseline TM Pharmaceutical Engineering Guide, Vol. 4. International Society for Pharmaceutical Engineering, 2007.\n\n**ISPE Baseline Guide Volume 4: Water and Steam Systems.** International Society for Pharmaceutical Engineering, 2001.\n\n**Noble PT.** Transport considerations for microbial control in piping. *Journal of Pharmaceutical Science and Technology*, 1994, 48: 76\u201385.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que forma parte de la Serie de Informes T\u00e9cnicos (Technical Report Series) y se centra en temas relacionados con la calidad del agua y las buenas pr\u00e1cticas de fabricaci\u00f3n en la industria farmac\u00e9utica. Incluye referencias a diversas gu\u00edas, est\u00e1ndares y publicaciones relevantes que abordan la calidad del agua para uso farmac\u00e9utico, la validaci\u00f3n de procesos de fabricaci\u00f3n y la selecci\u00f3n de materiales para sistemas de agua de alta pureza.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS sobre la calidad del agua para uso farmac\u00e9utico seg\u00fan el documento mencionado?**\n   - Esta pregunta busca respuestas espec\u00edficas sobre las pautas y est\u00e1ndares que la OMS establece para garantizar la calidad del agua en la industria farmac\u00e9utica, que pueden no estar disponibles en otras fuentes.\n\n2. **\u00bfQu\u00e9 aspectos se consideran en la validaci\u00f3n de buenas pr\u00e1cticas de fabricaci\u00f3n seg\u00fan las directrices de la OMS?**\n   - Esta pregunta se enfoca en los criterios y procedimientos que la OMS sugiere para validar las pr\u00e1cticas de fabricaci\u00f3n, lo que puede proporcionar informaci\u00f3n detallada que no se encuentra f\u00e1cilmente en otros documentos.\n\n3. **\u00bfQu\u00e9 materiales se recomiendan para sistemas de agua de alta pureza y cu\u00e1les son las consideraciones para su selecci\u00f3n?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre los materiales adecuados para sistemas de agua de alta pureza, as\u00ed como las razones detr\u00e1s de su selecci\u00f3n, que pueden no estar ampliamente discutidas en otras publicaciones.", "prev_section_summary": "### Temas Clave\n\n1. **Inspecci\u00f3n de Sistemas de Agua**: Se enfatiza la importancia de las inspecciones regulatorias y la necesidad de auditor\u00edas y autoinspecciones rutinarias para los sistemas de agua purificada (WPU), que incluyen BPW, BHPW y BWFI.\n\n2. **Gu\u00eda de Buenas Pr\u00e1cticas de Manufactura (GMP)**: Se menciona que la gu\u00eda GMP puede servir como base para las inspecciones, asegurando que los sistemas est\u00e9n dise\u00f1ados, instalados y mantenidos adecuadamente.\n\n3. **Elementos de Inspecci\u00f3n**: Se proporciona una lista detallada de elementos a considerar durante una auditor\u00eda, que incluye:\n   - Dibujos actuales del sistema de agua.\n   - Planes de muestreo y monitoreo.\n   - Programas de capacitaci\u00f3n.\n   - Resultados de monitoreo y evaluaci\u00f3n de tendencias.\n   - Registros de mantenimiento y calibraci\u00f3n.\n\n4. **Condiciones de Control**: Se establece que un sistema de agua que ha sido revisado adecuadamente y cumple con los requisitos de mantenimiento puede considerarse \"demostrablemente bajo control\".\n\n### Entidades\n\n- **WPU**: Sistemas de Agua Purificada (incluyendo BPW, BHPW y BWFI).\n- **GMP**: Buenas Pr\u00e1cticas de Manufactura.\n- **P&ID**: Diagramas de Tuber\u00edas e Instrumentaci\u00f3n.\n- **Elementos de Inspecci\u00f3n**: Dibujos, planes de muestreo, programas de capacitaci\u00f3n, registros de mantenimiento, etc.\n\nEste resumen destaca la importancia de la inspecci\u00f3n y el mantenimiento de los sistemas de agua purificada, as\u00ed como los elementos clave que deben ser revisados para garantizar su correcto funcionamiento.", "excerpt_keywords": "Keywords: water quality, pharmaceutical manufacturing, good manufacturing practices, high-purity water systems, WHO guidelines"}}, "0b79dacd-f069-4bc1-a10c-be60467b0d6d": {"node_ids": ["da1932ce-1c9d-49f2-b1e0-faa5f273affc"], "metadata": {"page_label": "103", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "Pharmaceutical Inspection Co-operation Scheme. *PIC/S; Inspection of utilities; P1 009-1*. Geneva, Pharmaceutical Inspection Co-operation Scheme, 2002.\n\nTverberg JC, Kerber SJ. Effect of nitric acid passivation on the surface composition of mechanically polished type 316 L sanitary tube. *European Journal of Parenteral Sciences*, 1998, 3: 117\u2013124.\n\nUS Food and Drug Administration. *Guide to inspections of high purity water systems, high purity water systems* (7/93), 2009; http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074905.htm.\n\n*US Pharmacopeia*: Published annually; see http://www.usp.org/.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Normativas y gu\u00edas de inspecci\u00f3n**: El contexto menciona documentos y gu\u00edas relevantes para la inspecci\u00f3n de sistemas de agua de alta pureza, as\u00ed como normativas de la Pharmaceutical Inspection Co-operation Scheme (PIC/S) y la US Food and Drug Administration (FDA).\n\n2. **Investigaci\u00f3n sobre materiales sanitarios**: Se incluye un estudio espec\u00edfico sobre el efecto de la pasivaci\u00f3n con \u00e1cido n\u00edtrico en la composici\u00f3n superficial de tubos sanitarios de acero inoxidable tipo 316 L, lo que puede ser relevante para la industria farmac\u00e9utica y de dispositivos m\u00e9dicos.\n\n3. **Referencias a publicaciones**: Se hace referencia a la US Pharmacopeia, que es una fuente importante de est\u00e1ndares de calidad para medicamentos y productos farmac\u00e9uticos.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1l es el prop\u00f3sito del documento \"PIC/S; Inspection of utilities; P1 009-1\" y qu\u00e9 aspectos cubre en relaci\u00f3n con la inspecci\u00f3n de utilidades?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido y la finalidad del documento de la PIC/S mencionado en el contexto.\n\n2. **\u00bfQu\u00e9 conclusiones se pueden extraer del estudio de Tverberg y Kerber sobre la pasivaci\u00f3n con \u00e1cido n\u00edtrico en tubos sanitarios de acero inoxidable tipo 316 L?**\n   - Esta pregunta se centra en los hallazgos del estudio mencionado, que podr\u00eda no estar ampliamente disponible en otras fuentes.\n\n3. **\u00bfQu\u00e9 aspectos clave se abordan en la \"Gu\u00eda para inspecciones de sistemas de agua de alta pureza\" de la FDA y c\u00f3mo se relacionan con las pr\u00e1cticas actuales en la industria farmac\u00e9utica?**\n   - Esta pregunta busca detalles sobre las recomendaciones y pr\u00e1cticas que la FDA establece en su gu\u00eda, lo que puede ser crucial para la conformidad en la industria.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nLa secci\u00f3n \"Further reading\" del documento de la Organizaci\u00f3n Mundial de la Salud (OMS) proporciona una lista de referencias y recursos relevantes sobre la calidad del agua y las buenas pr\u00e1cticas de fabricaci\u00f3n en la industria farmac\u00e9utica. Los temas clave incluyen:\n\n1. **Calidad del Agua**:\n   - Directrices de la OMS sobre la calidad del agua para uso farmac\u00e9utico.\n   - Normativas y est\u00e1ndares relacionados con sistemas de agua de alta pureza.\n\n2. **Buenas Pr\u00e1cticas de Fabricaci\u00f3n (BPF)**:\n   - Recomendaciones sobre la validaci\u00f3n de procesos de fabricaci\u00f3n.\n   - Gu\u00edas para la inspecci\u00f3n de sistemas de agua de alta pureza.\n\n3. **Materiales y Equipos**:\n   - Selecci\u00f3n de materiales para sistemas de agua de alta pureza.\n   - Est\u00e1ndares de la American Society of Mechanical Engineers (ASME) para equipos de bioprocesamiento.\n\n4. **Publicaciones y Normativas**:\n   - Referencias a la Farmacopea Internacional y la Farmacopea Europea.\n   - Documentos de la FDA y la Agencia Europea de Medicamentos sobre calidad del agua y procedimientos de limpieza.\n\n### Entidades Mencionadas\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Publica directrices y est\u00e1ndares sobre la calidad del agua y BPF.\n- **American Society of Mechanical Engineers (ASME)**: Establece est\u00e1ndares para equipos de bioprocesamiento.\n- **US Food and Drug Administration (FDA)**: Proporciona gu\u00edas para la inspecci\u00f3n de sistemas de agua de alta pureza.\n- **European Medicines Agency**: Ofrece notas de orientaci\u00f3n sobre la calidad del agua para uso farmac\u00e9utico.\n- **International Society for Pharmaceutical Engineering (ISPE)**: Publica gu\u00edas sobre la calificaci\u00f3n y puesta en marcha de sistemas de agua y vapor farmac\u00e9uticos.\n\nEste resumen destaca la importancia de la calidad del agua y las buenas pr\u00e1cticas en la fabricaci\u00f3n farmac\u00e9utica, as\u00ed como las entidades que establecen y regulan estos est\u00e1ndares.", "excerpt_keywords": "Keywords: Pharmaceutical Inspection, high purity water systems, nitric acid passivation, US Pharmacopeia, good manufacturing practices"}}, "74136141-b915-46d1-a1ce-c85e9c1011a2": {"node_ids": ["bd484162-c11c-4cae-a30a-9e83517f4cea"], "metadata": {"page_label": "104", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que forma parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pol\u00edticas de salud. Sin embargo, el contenido espec\u00edfico del informe en la p\u00e1gina 104 no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las principales recomendaciones de salud p\u00fablica que se presentan en la p\u00e1gina 104 del informe \"WHO - Technical Report Series 970\"?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las recomendaciones que podr\u00edan estar incluidas en esa secci\u00f3n del informe.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas de investigaci\u00f3n se discuten en el informe y c\u00f3mo se aplican a los temas tratados en la p\u00e1gina 104?**\n   - Esta pregunta se centra en las metodolog\u00edas que podr\u00edan ser relevantes para entender los hallazgos o recomendaciones presentadas en esa parte del documento.\n\n3. **\u00bfQu\u00e9 datos o estad\u00edsticas relevantes se presentan en la p\u00e1gina 104 que podr\u00edan influir en la formulaci\u00f3n de pol\u00edticas de salud p\u00fablica?**\n   - Esta pregunta busca informaci\u00f3n sobre datos espec\u00edficos que podr\u00edan ser cruciales para la toma de decisiones en el \u00e1mbito de la salud p\u00fablica, que podr\u00edan estar documentados en esa p\u00e1gina. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n que probablemente no se encuentre f\u00e1cilmente en otros lugares, dado que se centran en el contenido espec\u00edfico de un informe t\u00e9cnico de la OMS.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Normativas y Gu\u00edas de Inspecci\u00f3n**:\n   - **Pharmaceutical Inspection Co-operation Scheme (PIC/S)**: Se menciona el documento *PIC/S; Inspection of utilities; P1 009-1*, que aborda aspectos relacionados con la inspecci\u00f3n de utilidades en la industria farmac\u00e9utica.\n   - **US Food and Drug Administration (FDA)**: Se hace referencia a la *Gu\u00eda para inspecciones de sistemas de agua de alta pureza*, que proporciona directrices sobre la conformidad y las mejores pr\u00e1cticas en la industria.\n\n2. **Investigaci\u00f3n sobre Materiales Sanitarios**:\n   - **Estudio de Tverberg y Kerber**: Se presenta un estudio que investiga el efecto de la pasivaci\u00f3n con \u00e1cido n\u00edtrico en la composici\u00f3n superficial de tubos sanitarios de acero inoxidable tipo 316 L, relevante para la fabricaci\u00f3n de dispositivos m\u00e9dicos y productos farmac\u00e9uticos.\n\n3. **Referencias a Publicaciones Importantes**:\n   - **US Pharmacopeia**: Se menciona como una fuente anual de est\u00e1ndares de calidad para medicamentos y productos farmac\u00e9uticos, esencial para la regulaci\u00f3n y control de calidad en la industria.\n\n### Entidades Clave:\n- **PIC/S**: Pharmaceutical Inspection Co-operation Scheme\n- **FDA**: US Food and Drug Administration\n- **Tverberg JC y Kerber SJ**: Autores del estudio sobre pasivaci\u00f3n de tubos sanitarios\n- **US Pharmacopeia**: Publicaci\u00f3n de est\u00e1ndares farmac\u00e9uticos\n\nEste resumen destaca la importancia de las normativas y gu\u00edas de inspecci\u00f3n, la investigaci\u00f3n sobre materiales utilizados en la industria y las publicaciones que establecen est\u00e1ndares de calidad.", "excerpt_keywords": "Keywords: salud p\u00fablica, investigaci\u00f3n m\u00e9dica, normativas, calidad farmac\u00e9utica, OMS"}}, "28ac18dd-db95-4102-a63e-72c59e956554": {"node_ids": ["d9b454c1-7c1a-4181-9747-725d87293c5f"], "metadata": {"page_label": "105", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 3\n\n**Pharmaceutical development of multisource (generic) finished pharmaceutical products \u2013 points to consider**\n\n## 1. Introduction\n1.1 General principles  \n1.2 Scope  \n\n## 2. Predevelopment activities\n2.1 Desk research  \n    2.1.1 Quality risk management  \n2.2 Additional considerations  \n    2.2.1 Selection and characterization of comparator finished pharmaceutical product(s)  \n    2.2.2 Benchmarking for formulation experiments and stability studies  \n    2.2.3 Formulation selection experiments  \n    2.2.4 Bioequivalence and dissolution studies  \n\n## 3. Pharmaceutical development\n3.1 Components of the finished pharmaceutical product  \n    3.1.1 Active pharmaceutical ingredient  \n    3.1.2 Excipients  \n3.2 Finished pharmaceutical product  \n    3.2.1 Formulation development  \n    3.2.2 Overages  \n    3.2.3 Physicochemical and biological properties  \n3.3 Manufacturing process development  \n3.4 Container-closure system  \n3.5 Microbiological attributes  \n3.6 Compatibility  \n\n## 4. Glossary\n\n**References**\n\n**Appendix 1**  \nExamples of presenting quality attributes of active pharmaceutical ingredients\n\n**Appendix 2**  \nInformation on development batches\n\n| Section | Page |\n|---------|------|\n| 1. Introduction | 92 |\n| 1.1 General principles | 92 |\n| 1.2 Scope | 92 |\n| 2. Predevelopment activities | 93 |\n| 2.1 Desk research | 93 |\n| 2.1.1 Quality risk management | 93 |\n| 2.2 Additional considerations | 94 |\n| 2.2.1 Selection and characterization of comparator finished pharmaceutical product(s) | 94 |\n| 2.2.2 Benchmarking for formulation experiments and stability studies | 95 |\n| 2.2.3 Formulation selection experiments | 95 |\n| 2.2.4 Bioequivalence and dissolution studies | 96 |\n| 3. Pharmaceutical development | 96 |\n| 3.1 Components of the finished pharmaceutical product | 98 |\n| 3.1.1 Active pharmaceutical ingredient | 98 |\n| 3.1.2 Excipients | 99 |\n| 3.2 Finished pharmaceutical product | 100 |\n| 3.2.1 Formulation development | 100 |\n| 3.2.2 Overages | 102 |\n| 3.2.3 Physicochemical and biological properties | 103 |\n| 3.3 Manufacturing process development | 103 |\n| 3.4 Container-closure system | 104 |\n| 3.5 Microbiological attributes | 107 |\n| 3.6 Compatibility | 108 |\n| 4. Glossary | 109 |\n| References | 113 |\n| Appendix 1 | 115 |\n| Appendix 2 | 118 |", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n### Preguntas y Respuestas\n\n1. **\u00bfCu\u00e1les son los componentes clave que se deben considerar en el desarrollo farmac\u00e9utico de productos farmac\u00e9uticos terminados multisource (gen\u00e9ricos)?**\n   - **Respuesta:** Los componentes clave incluyen el ingrediente farmac\u00e9utico activo (API), los excipientes, el desarrollo de la formulaci\u00f3n, las propiedades fisicoqu\u00edmicas y biol\u00f3gicas, el desarrollo del proceso de fabricaci\u00f3n, el sistema de cierre del envase, los atributos microbiol\u00f3gicos y la compatibilidad.\n\n2. **\u00bfQu\u00e9 actividades se incluyen en la fase de predesarrollo para productos farmac\u00e9uticos gen\u00e9ricos?**\n   - **Respuesta:** Las actividades de predesarrollo incluyen la investigaci\u00f3n de escritorio, la gesti\u00f3n de riesgos de calidad, la selecci\u00f3n y caracterizaci\u00f3n de productos farmac\u00e9uticos terminados comparadores, el benchmarking para experimentos de formulaci\u00f3n y estudios de estabilidad, experimentos de selecci\u00f3n de formulaci\u00f3n, y estudios de bioequivalencia y disoluci\u00f3n.\n\n3. **\u00bfQu\u00e9 se entiende por \"overages\" en el contexto del desarrollo de productos farmac\u00e9uticos?**\n   - **Respuesta:** \"Overages\" se refiere a la cantidad adicional de ingrediente activo o excipientes que se a\u00f1ade a la formulaci\u00f3n para compensar las p\u00e9rdidas que pueden ocurrir durante el proceso de fabricaci\u00f3n, asegurando as\u00ed que el producto final cumpla con las especificaciones de calidad y potencia.\n\n### Resumen de Nivel Superior\n\nEl documento se centra en el desarrollo farmac\u00e9utico de productos farmac\u00e9uticos terminados multisource (gen\u00e9ricos), proporcionando directrices sobre los principios generales, las actividades de predesarrollo y los componentes esenciales del producto. Se abordan aspectos como la investigaci\u00f3n de escritorio, la gesti\u00f3n de riesgos, la formulaci\u00f3n y el proceso de fabricaci\u00f3n, as\u00ed como la importancia de la bioequivalencia y la estabilidad del producto. Adem\u00e1s, se incluyen glosarios y ap\u00e9ndices que ofrecen ejemplos y detalles sobre atributos de calidad y lotes de desarrollo.\n\n### Preguntas Generadas a Partir del Resumen\n\n1. **\u00bfQu\u00e9 importancia tiene la bioequivalencia en el desarrollo de productos farmac\u00e9uticos gen\u00e9ricos?**\n2. **\u00bfC\u00f3mo se lleva a cabo la gesti\u00f3n de riesgos de calidad en el desarrollo farmac\u00e9utico?**\n3. **\u00bfQu\u00e9 ejemplos se proporcionan en el ap\u00e9ndice sobre atributos de calidad de los ingredientes farmac\u00e9uticos activos?**", "prev_section_summary": "### Resumen de temas clave y entidades:\n\nEl contenido proporcionado se refiere al \"WHO - Technical Report Series 970\", un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque no se presenta informaci\u00f3n espec\u00edfica de la p\u00e1gina 104, se pueden inferir algunos temas clave y entidades relevantes:\n\n1. **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la publicaci\u00f3n del informe, que se centra en la salud p\u00fablica y la investigaci\u00f3n m\u00e9dica.\n\n2. **Informe T\u00e9cnico**: Parte de una serie que aborda diversas cuestiones relacionadas con la salud, incluyendo recomendaciones y pol\u00edticas.\n\n3. **Salud P\u00fablica**: Tema central del informe, que probablemente incluye recomendaciones y estrategias para mejorar la salud a nivel global.\n\n4. **Metodolog\u00edas de Investigaci\u00f3n**: Es probable que el informe discuta diferentes enfoques y m\u00e9todos utilizados en la investigaci\u00f3n de salud p\u00fablica.\n\n5. **Datos y Estad\u00edsticas**: Aunque no se especifican, es com\u00fan que tales informes incluyan datos relevantes que apoyen las recomendaciones y conclusiones presentadas.\n\n### Conclusi\u00f3n:\nEl informe \"WHO - Technical Report Series 970\" es un documento t\u00e9cnico que aborda temas de salud p\u00fablica, aunque el contenido espec\u00edfico de la p\u00e1gina 104 no est\u00e1 disponible. Las preguntas formuladas buscan profundizar en las recomendaciones, metodolog\u00edas y datos que podr\u00edan estar presentes en esa secci\u00f3n del informe.", "excerpt_keywords": "Keywords: pharmaceutical development, generic products, bioequivalence, quality risk management, formulation experiments"}}, "dd988d37-6248-4055-822e-339f587c09a9": {"node_ids": ["9664255d-3845-4c5b-b7e9-69d114d7c410"], "metadata": {"page_label": "106", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nThe aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies provide scientific understanding to support the establishment of specifications and manufacturing controls.\n\nThis document focuses on the development of multisource finished pharmaceutical products (FPPs) which are intended to be bioequivalent to the relevant comparator product. Multisource FPPs should<sup>1</sup> accordingly be therapeutically equivalent to the comparator product.\n\nThis document provides a structured approach for industry following the International Conference on Harmonisation (ICH) common technical document (CTD) format, for developing high-quality, multisource FPPs. The ICH-CTD structure for pharmaceutical development information allows for a logical, progressive description of the development process.\n\nThe document is also intended to provide assessors and inspectors with a good understanding of best practices in the development of multisource FPPs and their manufacturing processes.\n\nManufacturers who have chosen a more systematic approach to product development would follow the development within the broader context of quality assurance principles, including the use of quality risk management and pharmaceutical quality systems.\n\nThis document is designed to be used in conjunction with other WHO guidelines and guidance documents (1).\n\n## 1.1 General principles\n\nThe pharmaceutical development studies and the manufacture of primary batches are essential elements for the science and risk-based approach to establish the critical quality attributes (CQAs) of the FPP and the critical process parameters (CPPs) of the manufacturing process.\n\n## 1.2 Scope\n\nThis document addresses the pharmaceutical development of multisource FPPs containing existing active pharmaceutical ingredients (APIs) of synthetic or semi-synthetic origin. For the purposes of this document an existing API is one that has been previously authorized through a finished product by a stringent regulatory authority (SRA) or, for the purposes of a national medicines regulatory authority\n\n----\n\n<sup>1</sup> For the purpose of this document the term \u201cshould\u201d is generally to be interpreted as \u201cis recommended\u201d or \u201cis usually required\u201d.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Objetivo del desarrollo farmac\u00e9utico**: El desarrollo farmac\u00e9utico busca dise\u00f1ar productos de calidad y procesos de fabricaci\u00f3n que aseguren un rendimiento consistente del producto. Esto implica la creaci\u00f3n de especificaciones y controles de fabricaci\u00f3n basados en estudios cient\u00edficos.\n\n2. **Multisource Finished Pharmaceutical Products (FPPs)**: El documento se centra en el desarrollo de productos farmac\u00e9uticos terminados multisource que son bioequivalentes a un producto comparador. Estos productos deben ser terap\u00e9uticamente equivalentes y seguir un enfoque estructurado basado en el formato del Documento T\u00e9cnico Com\u00fan (CTD) de la ICH.\n\n3. **Principios generales y alcance**: Se enfatiza la importancia de los estudios de desarrollo farmac\u00e9utico y la fabricaci\u00f3n de lotes primarios para establecer atributos de calidad cr\u00edticos (CQAs) y par\u00e1metros de proceso cr\u00edticos (CPPs). El documento se aplica a FPPs que contienen ingredientes farmac\u00e9uticos activos (APIs) existentes de origen sint\u00e9tico o semisint\u00e9tico.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 papel juegan los estudios de desarrollo farmac\u00e9utico en la determinaci\u00f3n de los atributos de calidad cr\u00edticos (CQAs) y los par\u00e1metros de proceso cr\u00edticos (CPPs) en la fabricaci\u00f3n de productos farmac\u00e9uticos multisource?**\n   - Esta pregunta se centra en la relaci\u00f3n entre los estudios de desarrollo y la calidad del producto, un aspecto que puede no estar claramente definido en otros documentos.\n\n2. **\u00bfC\u00f3mo se define un ingrediente farmac\u00e9utico activo (API) existente seg\u00fan el contexto de este documento y qu\u00e9 implicaciones tiene esto para el desarrollo de productos farmac\u00e9uticos?**\n   - Esta pregunta busca aclarar la definici\u00f3n espec\u00edfica de un API existente y su relevancia en el contexto del desarrollo de FPPs, lo cual puede no ser evidente en otras fuentes.\n\n3. **\u00bfCu\u00e1les son las mejores pr\u00e1cticas recomendadas para la fabricaci\u00f3n de productos farmac\u00e9uticos multisource seg\u00fan las directrices de la OMS y c\u00f3mo se relacionan con los principios de aseguramiento de la calidad?**\n   - Esta pregunta se enfoca en las mejores pr\u00e1cticas y su alineaci\u00f3n con los principios de calidad, un tema que puede no ser abordado de manera exhaustiva en otros documentos relacionados.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nLa secci\u00f3n del documento se centra en el desarrollo farmac\u00e9utico de productos farmac\u00e9uticos terminados multisource (gen\u00e9ricos) y abarca varios aspectos fundamentales:\n\n1. **Introducci\u00f3n**:\n   - Principios generales y alcance del desarrollo farmac\u00e9utico.\n\n2. **Actividades de Predesarrollo**:\n   - **Investigaci\u00f3n de escritorio**: Incluye la gesti\u00f3n de riesgos de calidad.\n   - **Consideraciones adicionales**: Selecci\u00f3n y caracterizaci\u00f3n de productos farmac\u00e9uticos comparadores, benchmarking para experimentos de formulaci\u00f3n y estabilidad, experimentos de selecci\u00f3n de formulaci\u00f3n, y estudios de bioequivalencia y disoluci\u00f3n.\n\n3. **Desarrollo Farmac\u00e9utico**:\n   - **Componentes del producto farmac\u00e9utico terminado**:\n     - Ingrediente farmac\u00e9utico activo (API).\n     - Excipientes.\n   - **Desarrollo de la formulaci\u00f3n**: Incluye la consideraci\u00f3n de \"overages\", propiedades fisicoqu\u00edmicas y biol\u00f3gicas.\n   - **Desarrollo del proceso de fabricaci\u00f3n**.\n   - **Sistema de cierre del envase**.\n   - **Atributos microbiol\u00f3gicos**.\n   - **Compatibilidad**.\n\n4. **Glosario**: Definiciones de t\u00e9rminos clave utilizados en el documento.\n\n5. **Referencias**: Fuentes citadas en el documento.\n\n6. **Ap\u00e9ndices**:\n   - **Ap\u00e9ndice 1**: Ejemplos de atributos de calidad de ingredientes farmac\u00e9uticos activos.\n   - **Ap\u00e9ndice 2**: Informaci\u00f3n sobre lotes de desarrollo.\n\n### Entidades Clave\n- **Productos farmac\u00e9uticos terminados multisource (gen\u00e9ricos)**.\n- **Ingredientes farmac\u00e9uticos activos (API)**.\n- **Excipientes**.\n- **Bioequivalencia**.\n- **Gesti\u00f3n de riesgos de calidad**.\n- **Formulaci\u00f3n y desarrollo de procesos**.\n- **Atributos microbiol\u00f3gicos y de compatibilidad**.\n\nEste resumen destaca los temas y entidades m\u00e1s relevantes en el contexto del desarrollo farmac\u00e9utico de productos gen\u00e9ricos, proporcionando una visi\u00f3n general de las consideraciones y procesos involucrados.", "excerpt_keywords": "Keywords: pharmaceutical development, multisource FPPs, bioequivalence, quality assurance, active pharmaceutical ingredients"}}, "c3c64c67-34e4-4d6d-a450-5b443c705a5a": {"node_ids": ["f5fb77e8-fee0-4817-8053-3b5816997d1a"], "metadata": {"page_label": "107", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Predevelopment activities\n\n## 2.1 Desk research\n\nDesk research includes all relevant documentation being collected and evaluated prior to initiation of any laboratory activities. This documentation may include information such as is found in:\n\n- WHO, European Medicines Agency (EMA) and United States Food and Drug Administration (US-FDA) web sites that contain regulatory information, for example, the qualitative composition, mode of administration and the primary packing materials of the innovator and multisource FPPs;\n- compendial monographs, scientific literature, patents, technical information typically found in the applicant\u2019s (open) part of the API master file (APIMF), technical information on excipients and prior company knowledge.\n\n### 2.1.1 Quality risk management\n\nAn essential part of desk research entails the identification of possible risks prior to the development of a multisource product.\n\nAn important consideration when selecting the API manufacturer is the fact that the FPP manufacturer is responsible for the control of the API and as such must have a comprehensive understanding of the API. Analysis of the applicant\u2019s part of the APIMF (or drug master file) is, therefore, important.\n\nPoor solubility in aqueous medium is an important quality risk factor for APIs administered in the solid state as there is a high risk that inter-batch variability in physical properties may translate into significant differences in the in vivo performance.\n\nIt is recommended that polymorphism, pseudo-polymorphism and the implications of variability in particle size be routinely considered. Variability in any of these key physical properties is likely to be of particular significance for APIs that have low solubility according to the biopharmaceutics classification.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda las actividades de predesarrollo en la investigaci\u00f3n de productos farmac\u00e9uticos multisource. Se enfatiza la importancia de la investigaci\u00f3n de escritorio, que implica la recopilaci\u00f3n y evaluaci\u00f3n de documentaci\u00f3n relevante antes de iniciar actividades de laboratorio. Esta documentaci\u00f3n incluye informaci\u00f3n de agencias reguladoras, literatura cient\u00edfica y detalles t\u00e9cnicos sobre los ingredientes activos (API) y excipientes. Adem\u00e1s, se destaca la gesti\u00f3n de riesgos de calidad, donde se identifican posibles riesgos asociados con la solubilidad de los API y la variabilidad en sus propiedades f\u00edsicas, lo que puede afectar el rendimiento in vivo del producto.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los principales factores de riesgo de calidad que deben considerarse al desarrollar un producto farmac\u00e9utico multisource?**\n   - Esta pregunta se centra en los riesgos espec\u00edficos mencionados en el contexto, como la solubilidad y la variabilidad de las propiedades f\u00edsicas de los API.\n\n2. **\u00bfPor qu\u00e9 es crucial que el fabricante del producto farmac\u00e9utico terminado (FPP) tenga un entendimiento completo del API?**\n   - Esta pregunta aborda la responsabilidad del fabricante del FPP en el control del API y la importancia de la comprensi\u00f3n t\u00e9cnica para garantizar la calidad del producto final.\n\n3. **\u00bfQu\u00e9 aspectos de la variabilidad en las propiedades f\u00edsicas de los API se deben considerar rutinariamente durante la investigaci\u00f3n de escritorio?**\n   - Esta pregunta se enfoca en los aspectos espec\u00edficos de la variabilidad, como el polimorfismo y el tama\u00f1o de part\u00edcula, que son relevantes para la formulaci\u00f3n de productos con baja solubilidad.\n\n### Resumen de nivel superior\n\nEl documento de la OMS proporciona directrices sobre las actividades de predesarrollo en la investigaci\u00f3n de productos farmac\u00e9uticos, destacando la importancia de la investigaci\u00f3n de escritorio y la gesti\u00f3n de riesgos de calidad. Se enfatiza la necesidad de recopilar informaci\u00f3n de diversas fuentes y de evaluar los riesgos asociados con las propiedades f\u00edsicas de los ingredientes activos, lo que es crucial para el \u00e9xito del desarrollo de productos multisource.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Objetivo del Desarrollo Farmac\u00e9utico**:\n   - Dise\u00f1ar productos farmac\u00e9uticos de calidad y procesos de fabricaci\u00f3n que aseguren un rendimiento consistente.\n   - Establecimiento de especificaciones y controles de fabricaci\u00f3n basados en estudios cient\u00edficos.\n\n2. **Productos Farmac\u00e9uticos Terminados Multisource (FPPs)**:\n   - Enfoque en el desarrollo de FPPs que sean bioequivalentes a un producto comparador.\n   - Los FPPs deben ser terap\u00e9uticamente equivalentes al producto comparador.\n\n3. **Estructura del Documento**:\n   - Proporciona un enfoque estructurado siguiendo el formato del Documento T\u00e9cnico Com\u00fan (CTD) de la ICH.\n   - Facilita una descripci\u00f3n l\u00f3gica y progresiva del proceso de desarrollo.\n\n4. **Mejores Pr\u00e1cticas**:\n   - Orientaci\u00f3n para evaluadores e inspectores sobre las mejores pr\u00e1cticas en el desarrollo y fabricaci\u00f3n de FPPs multisource.\n   - Importancia de un enfoque sistem\u00e1tico en el desarrollo del producto, alineado con principios de aseguramiento de la calidad.\n\n5. **Principios Generales**:\n   - Los estudios de desarrollo farmac\u00e9utico y la fabricaci\u00f3n de lotes primarios son esenciales para establecer atributos de calidad cr\u00edticos (CQAs) y par\u00e1metros de proceso cr\u00edticos (CPPs).\n\n6. **Alcance del Documento**:\n   - Se centra en el desarrollo de FPPs que contienen ingredientes farmac\u00e9uticos activos (APIs) existentes de origen sint\u00e9tico o semisint\u00e9tico.\n   - Definici\u00f3n de un API existente como aquel autorizado previamente por una autoridad reguladora estricta (SRA).\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Emisora del documento.\n- **International Conference on Harmonisation (ICH)**: Referencia para el formato del documento.\n- **Ingredientes Farmac\u00e9uticos Activos (APIs)**: Elementos centrales en el desarrollo de FPPs.\n- **Atributos de Calidad Cr\u00edticos (CQAs)**: Elementos que definen la calidad del producto.\n- **Par\u00e1metros de Proceso Cr\u00edticos (CPPs)**: Elementos que definen el proceso de fabricaci\u00f3n.\n\nEste resumen destaca los aspectos fundamentales del desarrollo farmac\u00e9utico y la importancia de seguir directrices espec\u00edficas para asegurar la calidad y eficacia de los productos farmac\u00e9uticos multisource.", "excerpt_keywords": "Keywords: predevelopment activities, desk research, quality risk management, active pharmaceutical ingredients, solubility variability"}}, "9adcc032-2e8a-4735-8b05-fbaef4df10bb": {"node_ids": ["a7a0a66c-0a63-40d9-a9ca-9f95244abead"], "metadata": {"page_label": "108", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsystem (BCS). The requirement for routine control of polymorphic form and particle size should be considered in accordance with advice in Decision Trees 3 and 4 of ICH Q6A (2). When controls are necessary they should be established based on the results obtained for the API lot(s) used in the biostudies.\n\nFor example, *The International Pharmacopoeia* (Ph. Int.) (3) restricts the polymorphic form of mebendazole API to form C and furthermore states that the formulation, manufacturing process and product packaging of chewable mebendazole tablets are designed and controlled so as to minimize the conversion of the polymorphic form of mebendazole from C to A.\n\nThe initial risk assessment of potential CQAs and CPPs of a multisource product should be based on desk research and the applicant\u2019s own experience with the manufacture of the dosage form.\n\nLiterature, preferably peer-reviewed, may contain risk information essential for predevelopment. For example, the presence of meso-ethambutol hydrochloride in commercial ethambutol hydrochloride API material has been demonstrated in the literature (4), although some pharmacopoeial monographs do not clearly reveal the presence of this impurity. Recently a specific test was included in the *European Pharmacopoeia* (Ph. Eur.) (5) for control of this impurity.\n\nThe least risky strategy for multisource product development is to use the same qualitative and, where possible, quantitative formula as that of the comparator FPP \u2013 so long as this does not lead to the possibility of patent infringement \u2013 in order to minimize the risks related to compatibility, stability and bioequivalence.\n\nAccompanying reconstitution diluents should also be included in the development strategy where appropriate. This topic is discussed further in section 3.\n\n## 2.2 Additional considerations\n\n### 2.2.1 Selection and characterization of comparator finished pharmaceutical product(s)\n\nIn many countries the NMRA provides a list of comparator products. Alternatively, references are available from WHO (Prequalification of Medicines Programme), and in international lists of comparator products. Note that for a dossier to be submitted to the Prequalification of Medicines Programme the comparator must be selected from the published lists. Guidance regarding Prequalification of Medicines Programme comparator products is available under Guidance on bioequivalence studies on the Prequalification of Medicines Programme web site (apps.who.int/prequal/).\n\nIn the case of fixed-dose combination (FDC) FPPs, there will be instances when a combination of APIs is recommended for clinical use but an innovator FDC FPP containing these APIs, whose approval was based on clinical trial data, will not be available as a comparator product. FDCs approved based on data.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con respuestas espec\u00edficas que probablemente no se encuentren en otro lugar:\n\n### Preguntas y Respuestas\n\n1. **\u00bfCu\u00e1l es la importancia del control de la forma polim\u00f3rfica y el tama\u00f1o de part\u00edcula en el desarrollo de productos farmac\u00e9uticos multisource?**\n   - La importancia radica en que el control de la forma polim\u00f3rfica y el tama\u00f1o de part\u00edcula es crucial para garantizar la calidad, eficacia y seguridad del producto farmac\u00e9utico. Seg\u00fan el contexto, se deben establecer controles basados en los resultados obtenidos de los lotes de API utilizados en los estudios de bioequivalencia, lo que ayuda a minimizar riesgos relacionados con la estabilidad y la bioequivalencia del producto.\n\n2. **\u00bfQu\u00e9 estrategia se sugiere para minimizar los riesgos en el desarrollo de productos farmac\u00e9uticos multisource?**\n   - La estrategia menos arriesgada es utilizar la misma f\u00f3rmula cualitativa y, cuando sea posible, cuantitativa que la del producto farmac\u00e9utico de referencia (FPP), siempre que esto no infrinja patentes. Esto ayuda a reducir los riesgos asociados con la compatibilidad, estabilidad y bioequivalencia del producto.\n\n3. **\u00bfQu\u00e9 recursos est\u00e1n disponibles para la selecci\u00f3n de productos farmac\u00e9uticos de referencia en el contexto de la Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - En muchos pa\u00edses, la Autoridad Nacional Reguladora de Medicamentos (NMRA) proporciona listas de productos de referencia. Adem\u00e1s, la OMS ofrece referencias a trav\u00e9s de su Programa de Precalificaci\u00f3n de Medicamentos y en listas internacionales de productos de referencia. Para que un expediente sea presentado al Programa de Precalificaci\u00f3n, el producto de referencia debe seleccionarse de estas listas publicadas.\n\n### Resumen de Nivel Superior\n\nEl contexto aborda la importancia del control de la forma polim\u00f3rfica y el tama\u00f1o de part\u00edcula en el desarrollo de productos farmac\u00e9uticos multisource, destacando la necesidad de establecer controles basados en estudios de bioequivalencia. Se sugiere que la estrategia menos arriesgada para el desarrollo de estos productos es replicar la f\u00f3rmula del producto de referencia, evitando infracciones de patentes. Adem\u00e1s, se mencionan recursos disponibles para la selecci\u00f3n de productos de referencia, incluyendo listas proporcionadas por la NMRA y la OMS, que son esenciales para el proceso de precalificaci\u00f3n de medicamentos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Investigaci\u00f3n de Escritorio:**\n   - Importancia de recopilar y evaluar documentaci\u00f3n relevante antes de iniciar actividades de laboratorio.\n   - Fuentes de informaci\u00f3n incluyen sitios web de agencias reguladoras (OMS, EMA, US-FDA), literatura cient\u00edfica, monograf\u00edas, patentes y archivos maestros de ingredientes activos (API).\n\n2. **Gesti\u00f3n de Riesgos de Calidad:**\n   - Identificaci\u00f3n de riesgos potenciales antes del desarrollo de productos multisource.\n   - La comprensi\u00f3n del API por parte del fabricante del producto farmac\u00e9utico terminado (FPP) es crucial para el control de calidad.\n\n3. **Factores de Riesgo:**\n   - La solubilidad deficiente en medios acuosos es un factor de riesgo importante para los API en estado s\u00f3lido.\n   - Variabilidad en propiedades f\u00edsicas (polimorfismo, pseudo-polimorfismo, tama\u00f1o de part\u00edcula) puede afectar el rendimiento in vivo del producto.\n\n**Entidades:**\n\n- **Organizaciones Reguladoras:**\n  - Organizaci\u00f3n Mundial de la Salud (OMS)\n  - Agencia Europea de Medicamentos (EMA)\n  - Administraci\u00f3n de Alimentos y Medicamentos de EE. UU. (US-FDA)\n\n- **Documentaci\u00f3n:**\n  - Archivos maestros de ingredientes activos (APIMF)\n  - Monograf\u00edas compendiales\n  - Literatura cient\u00edfica y patentes\n\n- **Conceptos T\u00e9cnicos:**\n  - API (Ingrediente Activo)\n  - FPP (Producto Farmac\u00e9utico Terminado)\n  - Clasificaci\u00f3n biofarmac\u00e9utica\n\nEste resumen destaca la importancia de la investigaci\u00f3n de escritorio y la gesti\u00f3n de riesgos en el desarrollo de productos farmac\u00e9uticos multisource, enfatizando la necesidad de un entendimiento profundo de los ingredientes activos y sus propiedades f\u00edsicas.", "excerpt_keywords": "Keywords: pharmaceutical preparations, polymorphic form, risk assessment, bioequivalence, comparator products"}}, "a11a13ec-fda5-4e30-8174-20c1ac545181": {"node_ids": ["c90df2eb-941b-440f-84a4-0a6f6c3d05db"], "metadata": {"page_label": "109", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, y recomendaciones para pol\u00edticas de salud. Sin embargo, el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el informe WHO - Technical Report Series 970?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe que podr\u00eda no estar disponible en otras fuentes.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en el documento y c\u00f3mo se relacionan con las pol\u00edticas actuales de la OMS?**\n   - Esta pregunta se centra en la conexi\u00f3n entre el informe y las pol\u00edticas de salud p\u00fablica, lo que podr\u00eda ofrecer una perspectiva \u00fanica sobre la direcci\u00f3n de la OMS.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en la investigaci\u00f3n presentada en el WHO - Technical Report Series 970?**\n   - Esta pregunta indaga sobre los m\u00e9todos de investigaci\u00f3n que podr\u00edan haber sido utilizados en el informe, lo que podr\u00eda ser relevante para investigadores y profesionales de la salud.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que podr\u00eda no estar f\u00e1cilmente disponible en otras fuentes, bas\u00e1ndose en el contexto del informe t\u00e9cnico de la OMS.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Control de Forma Polim\u00f3rfica y Tama\u00f1o de Part\u00edcula:**\n   - Importancia en el desarrollo de productos farmac\u00e9uticos multisource.\n   - Necesidad de establecer controles basados en los resultados de los lotes de API utilizados en estudios de bioequivalencia.\n\n2. **Estrategia de Desarrollo:**\n   - Uso de la misma f\u00f3rmula cualitativa y cuantitativa que el producto farmac\u00e9utico de referencia (FPP) para minimizar riesgos de compatibilidad, estabilidad y bioequivalencia, evitando infracciones de patentes.\n\n3. **Evaluaci\u00f3n de Riesgos:**\n   - La evaluaci\u00f3n inicial de riesgos debe basarse en investigaci\u00f3n de escritorio y experiencia del solicitante en la fabricaci\u00f3n del formulario de dosificaci\u00f3n.\n\n4. **Recursos para Selecci\u00f3n de Productos de Referencia:**\n   - Listas proporcionadas por la Autoridad Nacional Reguladora de Medicamentos (NMRA) y la OMS para la selecci\u00f3n de productos de referencia en el contexto de la Precalificaci\u00f3n de Medicamentos.\n\n5. **Consideraciones sobre Combinaciones de Dosis Fijas (FDC):**\n   - Desaf\u00edos en la selecci\u00f3n de productos de referencia cuando no hay un FPP innovador disponible que contenga las combinaciones de API recomendadas.\n\n**Entidades:**\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Proporciona directrices y listas de productos de referencia.\n- **NMRA (Autoridad Nacional Reguladora de Medicamentos):** Ofrece listas de productos de referencia en varios pa\u00edses.\n- **Ph. Int. (Farmacopea Internacional):** Regula la forma polim\u00f3rfica del API de mebendazol.\n- **Ph. Eur. (Farmacopea Europea):** Incluye pruebas espec\u00edficas para el control de impurezas en el API de etambutol.\n- **FPP (Producto Farmac\u00e9utico Terminado):** Referido en el contexto de productos de comparaci\u00f3n y desarrollo de multisource.\n\nEste resumen destaca la importancia del control de calidad en el desarrollo de productos farmac\u00e9uticos, as\u00ed como los recursos y estrategias recomendadas para asegurar la bioequivalencia y la seguridad del producto.", "excerpt_keywords": "Keywords: salud p\u00fablica, bioequivalencia, productos farmac\u00e9uticos, OMS, evaluaci\u00f3n de riesgos"}}, "9f94aa06-cba1-489d-8d44-4bbb66a563d6": {"node_ids": ["5843445d-758c-4b89-a761-c65dd1f83bdf"], "metadata": {"page_label": "110", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Bioequivalence and dissolution studies\n\nBioequivalence and comparative dissolution studies should be conducted with samples from a batch of the FPP of at least pilot size. The dissolution conditions and acceptance criteria should be derived from the dissolution profiles obtained for the biobatch.\n\nWhere an in vivo bioequivalence study could be waived, similarity of the formulations may be required, in particular with respect to excipients that may have an influence on the extent and rate of absorption, e.g. sorbitol in liquid formulations or mannitol in solid dosage forms. For instance, when considering a biowaiver for an immediate-release solid oral dosage form containing a BCS class 3 API, the risk of reaching an inappropriate biowaiver decision needs to be critically evaluated, especially when the extent of absorption (f_abs) is less than 50%. As part of the risk assessment the excipients used will also need to be scrutinized carefully in terms of both qualitative and quantitative composition \u2013 the greater the deviation from the comparator composition, the greater the risk of an inappropriate biowaiver decision.\n\nInclusion of summaries of all bioequivalence studies (passed and failed) on the final formulation in the PD may be required.\n\n# 3. Pharmaceutical development\n\nIt is recommended to use an internationally harmonized structure when submitting a dossier for obtaining a marketing authorization. This section therefore follows the ICH-CTD structure according to ICH M4 (8).\n\n> The text of the M4Q (CTD-Q) guideline (9) is reproduced verbatim in this document in *italic text*, with minor modifications to accommodate WHO terminology and to include certain changes to the text that would be appropriate for multisource pharmaceutical products, notably:\n> \n> - drug substance is replaced with active pharmaceutical ingredient or API;\n> - drug product is replaced with finished pharmaceutical product or FPP;\n> - application is replaced with product dossier or PD;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (WHO - Technical Report Series 970) aborda la importancia de realizar estudios de bioequivalencia y disoluci\u00f3n comparativa para productos farmac\u00e9uticos terminados (FPP). Se enfatiza que estos estudios deben llevarse a cabo con muestras de al menos tama\u00f1o piloto y que las condiciones de disoluci\u00f3n y criterios de aceptaci\u00f3n deben derivarse de los perfiles de disoluci\u00f3n obtenidos de un biobatch. Adem\u00e1s, se discute la posibilidad de renunciar a un estudio de bioequivalencia in vivo bajo ciertas condiciones, especialmente en relaci\u00f3n con los excipientes que pueden afectar la absorci\u00f3n. Tambi\u00e9n se menciona la necesidad de incluir res\u00famenes de todos los estudios de bioequivalencia en el expediente del producto (PD).\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son los criterios que deben considerarse al evaluar la similitud de formulaciones para renunciar a un estudio de bioequivalencia in vivo?**\n   - El contexto menciona que se debe prestar especial atenci\u00f3n a los excipientes que pueden influir en la absorci\u00f3n, como el sorbitol en formulaciones l\u00edquidas o el manitol en formas de dosificaci\u00f3n s\u00f3lidas. La evaluaci\u00f3n de la similitud tambi\u00e9n debe considerar la composici\u00f3n cualitativa y cuantitativa de los excipientes.\n\n2. **\u00bfQu\u00e9 riesgos se deben evaluar al considerar un biowaiver para un API de clase 3 del BCS?**\n   - Se debe evaluar el riesgo de tomar una decisi\u00f3n inapropiada sobre el biowaiver, especialmente si la extensi\u00f3n de la absorci\u00f3n (f_abs) es inferior al 50%. Cuanto mayor sea la desviaci\u00f3n de la composici\u00f3n del comparador, mayor ser\u00e1 el riesgo de una decisi\u00f3n inapropiada.\n\n3. **\u00bfQu\u00e9 modificaciones se han realizado en el texto del M4Q (CTD-Q) para adaptarlo a la terminolog\u00eda de la OMS?**\n   - Las modificaciones incluyen el reemplazo de \"drug substance\" por \"active pharmaceutical ingredient\" (API), \"drug product\" por \"finished pharmaceutical product\" (FPP) y \"application\" por \"product dossier\" (PD). Estas adaptaciones son relevantes para productos farmac\u00e9uticos multisource.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos de la Organizaci\u00f3n Mundial de la Salud (OMS). Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n#### Temas Clave\n1. **Salud P\u00fablica**: El informe probablemente aborda cuestiones relacionadas con la salud p\u00fablica, incluyendo enfermedades, prevenci\u00f3n y promoci\u00f3n de la salud.\n2. **Investigaci\u00f3n M\u00e9dica**: Es posible que se presenten hallazgos de investigaciones recientes en el campo de la medicina y la salud.\n3. **Pol\u00edticas de Salud**: El documento puede incluir recomendaciones para la formulaci\u00f3n de pol\u00edticas de salud basadas en la evidencia presentada.\n4. **Metodolog\u00edas de Investigaci\u00f3n**: Se podr\u00eda discutir sobre los m\u00e9todos utilizados para llevar a cabo la investigaci\u00f3n, lo que es crucial para la validez de los hallazgos.\n\n#### Entidades\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe, que se centra en mejorar la salud a nivel global.\n- **Investigadores y Profesionales de la Salud**: Los posibles destinatarios del informe, quienes podr\u00edan beneficiarse de los hallazgos y recomendaciones presentados.\n\nEste resumen proporciona una visi\u00f3n general de los temas y entidades que podr\u00edan estar presentes en el informe, a pesar de la falta de contenido espec\u00edfico en el contexto proporcionado.", "excerpt_keywords": "Keywords: bioequivalence, dissolution studies, pharmaceutical development, excipients, biowaiver"}}, "1405dce6-3f38-4b97-95ae-7f02f2b153e5": {"node_ids": ["ea60fd28-f36f-41c0-a8d2-97535a840a2d"], "metadata": {"page_label": "111", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\n- combination product is replaced with fixed-dose combination or FDC;\n- clinical batches is replaced with comparative bioavailability or biowaiver batches.\n\nFollowing the *italic* text of the M4Q (CTD-Q) guideline (9), additional guidance by WHO is added in normal type to enable it to be easily distinguishable from the ICH text. This additional text is included to further clarify WHO\u2019s expectations and requirements. This approach is intended to facilitate the identification and origin of the text in the document (i.e. whether from ICH or WHO).\n\nIn section 3.2.P.2 below, reference may be made to CTD sections that are not discussed in this document. This is done to guide the manufacturer in completing the PD according to national or regional requirements.\n\n### 3.2.P.2\n\n*The Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this section should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier.*\n\nPharmaceutical development information usually includes, at a minimum:\n\n- the definition of the QTPP as it relates to quality, safety and efficacy, considering, for example, the route of administration, dosage form, bioavailability, strength and stability;\n- identification of the potential CQAs of the FPP so as to adequately control product characteristics that could have an impact on quality;\n- discussion of the potential CQAs of the API(s), excipients and container-closure system(s) including the selection of the type, grade and amount necessary to deliver the product of the desired quality;\n- discussion of the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner.\n```", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS, parte de la Serie de Informes T\u00e9cnicos 970, proporciona directrices sobre el desarrollo farmac\u00e9utico, espec\u00edficamente en la secci\u00f3n 3.2.P.2. Se enfatiza la importancia de realizar estudios de desarrollo para garantizar que la forma de dosificaci\u00f3n, la formulaci\u00f3n, el proceso de fabricaci\u00f3n y otros atributos sean adecuados para el prop\u00f3sito del dossier del producto. Tambi\u00e9n se discuten los par\u00e1metros cr\u00edticos que pueden influir en la reproducibilidad del lote, el rendimiento del producto y la calidad del producto farmac\u00e9utico terminado (FPP). Se menciona la necesidad de identificar y controlar atributos cr\u00edticos de calidad (CQA) tanto del producto terminado como de los ingredientes activos (API) y excipientes.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la secci\u00f3n de desarrollo farmac\u00e9utico seg\u00fan las directrices de la OMS?**\n   - La secci\u00f3n de desarrollo farmac\u00e9utico debe contener informaci\u00f3n sobre los estudios de desarrollo realizados, que establecen la adecuaci\u00f3n de la forma de dosificaci\u00f3n, la formulaci\u00f3n, el proceso de fabricaci\u00f3n, el sistema de cierre del envase, los atributos microbiol\u00f3gicos y las instrucciones de uso. Tambi\u00e9n debe identificar y describir los atributos de formulaci\u00f3n y proceso que pueden influir en la reproducibilidad del lote y la calidad del FPP.\n\n2. **\u00bfCu\u00e1les son los atributos cr\u00edticos de calidad (CQA) que deben considerarse en el desarrollo de un producto farmac\u00e9utico?**\n   - Los atributos cr\u00edticos de calidad (CQA) del producto farmac\u00e9utico terminado (FPP) deben ser identificados para controlar adecuadamente las caracter\u00edsticas del producto que podr\u00edan impactar en la calidad. Esto incluye discutir los CQAs de los ingredientes activos (API), excipientes y sistemas de cierre del envase, as\u00ed como los criterios de selecci\u00f3n para el proceso de fabricaci\u00f3n.\n\n3. **\u00bfC\u00f3mo se diferencia la informaci\u00f3n de desarrollo farmac\u00e9utico de las pruebas de control rutinarias seg\u00fan el documento?**\n   - La informaci\u00f3n de desarrollo farmac\u00e9utico se distingue de las pruebas de control rutinarias en que se centra en los estudios de desarrollo realizados para establecer la adecuaci\u00f3n de varios aspectos del producto, mientras que las pruebas de control rutinarias se llevan a cabo de acuerdo con especificaciones predefinidas y no est\u00e1n orientadas a la investigaci\u00f3n y el desarrollo del producto.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Bioequivalencia y estudios de disoluci\u00f3n**:\n   - Se deben realizar estudios de bioequivalencia y disoluci\u00f3n comparativa con muestras de al menos tama\u00f1o piloto del producto farmac\u00e9utico terminado (FPP).\n   - Las condiciones de disoluci\u00f3n y los criterios de aceptaci\u00f3n deben basarse en los perfiles de disoluci\u00f3n obtenidos de un biobatch.\n\n2. **Renuncia a estudios in vivo**:\n   - En ciertos casos, se puede renunciar a un estudio de bioequivalencia in vivo, pero se requiere evaluar la similitud de las formulaciones, especialmente en relaci\u00f3n con excipientes que afectan la absorci\u00f3n (ej. sorbitol y manitol).\n   - Se debe evaluar el riesgo de decisiones inapropiadas sobre biowaivers, especialmente si la extensi\u00f3n de absorci\u00f3n (f_abs) es menor al 50%.\n\n3. **Evaluaci\u00f3n de excipientes**:\n   - La composici\u00f3n cualitativa y cuantitativa de los excipientes debe ser analizada; mayores desviaciones de la composici\u00f3n del comparador incrementan el riesgo de decisiones inapropiadas.\n\n4. **Inclusi\u00f3n de estudios de bioequivalencia**:\n   - Es posible que se requiera incluir res\u00famenes de todos los estudios de bioequivalencia (tanto aprobados como fallidos) en el expediente del producto (PD).\n\n5. **Desarrollo farmac\u00e9utico**:\n   - Se recomienda seguir una estructura armonizada internacionalmente al presentar un expediente para la autorizaci\u00f3n de comercializaci\u00f3n, siguiendo la estructura ICH-CTD seg\u00fan ICH M4.\n\n6. **Modificaciones terminol\u00f3gicas**:\n   - Se han realizado adaptaciones en el texto del M4Q (CTD-Q) para alinearlo con la terminolog\u00eda de la OMS, como el uso de \"active pharmaceutical ingredient\" (API) en lugar de \"drug substance\", \"finished pharmaceutical product\" (FPP) en lugar de \"drug product\", y \"product dossier\" (PD) en lugar de \"application\".\n\n### Entidades clave:\n- **FPP**: Producto farmac\u00e9utico terminado.\n- **API**: Ingrediente farmac\u00e9utico activo.\n- **Biowaiver**: Renuncia a estudios de bioequivalencia in vivo.\n- **BCS**: Sistema de clasificaci\u00f3n biol\u00f3gica.\n- **ICH**: Consejo Internacional de Armonizaci\u00f3n.", "excerpt_keywords": "Keywords: pharmaceutical development, quality attributes, fixed-dose combination, bioavailability, product dossier"}}, "abd80673-3b60-4f1c-b9ec-3e95fa27fd57": {"node_ids": ["c5621bc9-59f6-4f16-a74a-4d09f63c0999"], "metadata": {"page_label": "112", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Components of the Finished Pharmaceutical Product\n\nThese features should be discussed as part of the product development, using the principles of risk management over the entire life-cycle of the product (ICH Q8 (10)). The information gained through the predevelopment activities may already have disclosed some of these features and could form an integral part of pharmaceutical development.\n\nFor a discussion of additional pharmaceutical development issues specific to the development of FDCs, reference can be made to WHO Technical Report Series, No. 929, Annex 5, section 6.3.2 (6).\n\nReference documents for pharmaceutical development include ICH guidelines Q6A, Q8, Q9 and Q10 (2, 10\u201312).\n\n## 3.1 Components of the Finished Pharmaceutical Product\n\n### 3.2.P.2.1\n\nThe components of the FPP are the ingredients listed under section 3.2.1.P.1 (Description and composition of the FPP in the PD). The components thus include the API(s) and all the excipients, as well as those excipients that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. water for granulation) and any others (e.g. nitrogen or silicone for stoppers).\n\n### 3.1.1 Active Pharmaceutical Ingredient\n\n#### 3.2.P.2.1.1\n\nThe compatibility of the API with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (e.g. water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For FDCs, the compatibility of APIs with each other should be discussed.\n\nPhysicochemical characteristics of the API may influence both the manufacturing capability and the performance of the FPP.\n\nInformation on the intrinsic physicochemical properties of the molecule, e.g. solubility, solid-state properties, including polymorphism and habit, melting range, pK\u2090 and hygroscopicity, is needed for the development of the product to allow the manufacturer of the FPP to take full responsibility for the quality and quality control (QC) of the API and the FPP.\n\nAdditionally, the manufacturer will need information (either from the API manufacturer, or gathered by another party, or by itself) on potentially critical properties of the API, together with specifications, as applicable, e.g. solubility at 37 \u00b0C at relevant physiological pH values to permit BCS classification of the API, partition coefficient (octanol/water) at 37 \u00b0C and particle size distribution, which may affect dissolution rate and bioavailability, as well as density, bulk and tapped density, flowability, compressibility, and other factors which may influence processibility. The above-mentioned properties of the API should usually be supported by experimental data (or by information from peer-reviewed literature) and discussed with respect to CQAs and CPPs.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado, as\u00ed como un resumen de nivel superior del contenido:\n\n### Resumen de Nivel Superior\nEl documento de la OMS discute los componentes del Producto Farmac\u00e9utico Terminado (FPP) y la importancia de la gesti\u00f3n de riesgos en el desarrollo de productos farmac\u00e9uticos. Se enfatiza la necesidad de evaluar la compatibilidad del Ingrediente Farmac\u00e9utico Activo (API) con excipientes y otros factores fisicoqu\u00edmicos que pueden influir en la calidad y el rendimiento del FPP. Adem\u00e1s, se menciona la importancia de la informaci\u00f3n sobre las propiedades intr\u00ednsecas del API para garantizar la calidad y el control de calidad del producto final.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n sobre las propiedades fisicoqu\u00edmicas del API es crucial para el desarrollo del FPP y por qu\u00e9?**\n   - Esta pregunta busca respuestas sobre las propiedades espec\u00edficas del API que son necesarias para garantizar la calidad y el rendimiento del FPP, as\u00ed como su impacto en el proceso de fabricaci\u00f3n.\n\n2. **\u00bfC\u00f3mo se debe abordar la compatibilidad de los APIs en formulaciones de Combinaciones de F\u00e1rmacos (FDCs) seg\u00fan el documento?**\n   - Esta pregunta se centra en la discusi\u00f3n sobre la compatibilidad entre diferentes APIs en FDCs, un aspecto que puede no estar ampliamente cubierto en otras fuentes.\n\n3. **\u00bfQu\u00e9 documentos de referencia se mencionan en el contexto del desarrollo farmac\u00e9utico y cu\u00e1l es su relevancia?**\n   - Esta pregunta busca identificar y explicar la importancia de los documentos de referencia, como las gu\u00edas ICH, en el proceso de desarrollo farmac\u00e9utico, lo que puede no ser evidente en otros textos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS, parte de la Serie de Informes T\u00e9cnicos 970, se centra en las directrices para el desarrollo farmac\u00e9utico, espec\u00edficamente en la secci\u00f3n 3.2.P.2. A continuaci\u00f3n se presentan los temas clave y entidades relevantes:\n\n#### Temas Clave\n\n1. **Desarrollo Farmac\u00e9utico**: La secci\u00f3n debe incluir informaci\u00f3n sobre estudios de desarrollo que validen la adecuaci\u00f3n de la forma de dosificaci\u00f3n, formulaci\u00f3n, proceso de fabricaci\u00f3n, sistema de cierre del envase, atributos microbiol\u00f3gicos e instrucciones de uso.\n\n2. **Atributos Cr\u00edticos de Calidad (CQA)**: Se enfatiza la identificaci\u00f3n y control de los CQAs del producto farmac\u00e9utico terminado (FPP), as\u00ed como de los ingredientes activos (API) y excipientes.\n\n3. **Par\u00e1metros Cr\u00edticos**: Se deben identificar y describir los atributos de formulaci\u00f3n y proceso que pueden influir en la reproducibilidad del lote y la calidad del FPP.\n\n4. **Diferenciaci\u00f3n de Pruebas**: La informaci\u00f3n de desarrollo farmac\u00e9utico se distingue de las pruebas de control rutinarias, ya que se centra en estudios de desarrollo en lugar de pruebas de conformidad con especificaciones.\n\n5. **QTPP (Quality Target Product Profile)**: Se debe definir el QTPP en relaci\u00f3n con la calidad, seguridad y eficacia, considerando aspectos como la v\u00eda de administraci\u00f3n, forma de dosificaci\u00f3n, biodisponibilidad, potencia y estabilidad.\n\n6. **Estrategia de Control de Proceso**: Se discuten los criterios de selecci\u00f3n para el proceso de fabricaci\u00f3n y la estrategia de control necesaria para producir lotes comerciales que cumplan consistentemente con el QTPP.\n\n#### Entidades Relevantes\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que proporciona las directrices.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que se eval\u00faa en t\u00e9rminos de calidad.\n- **API (Ingrediente Activo)**: Sustancia que proporciona la acci\u00f3n farmacol\u00f3gica.\n- **Excipientes**: Sustancias inactivas que se utilizan en la formulaci\u00f3n del producto.\n- **Sistema de Cierre del Envase**: Elemento cr\u00edtico para la preservaci\u00f3n y calidad del producto.\n\nEste resumen destaca la importancia de un enfoque sistem\u00e1tico en el desarrollo farmac\u00e9utico, asegurando que todos los aspectos del producto sean cuidadosamente considerados y validados para cumplir con los est\u00e1ndares de calidad y eficacia.", "excerpt_keywords": "Keywords: pharmaceutical development, active pharmaceutical ingredient, excipients, risk management, quality control"}}, "2d2d8d1b-3daf-4121-9e94-94377f07cc0d": {"node_ids": ["f433dedc-f74a-4482-ad62-531e3bf3d065"], "metadata": {"page_label": "113", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The specifications of the API manufacturer and the retest period or expiry date derived from formal regulatory stability studies should also be available to the manufacturer of the FPP.\n\nGuidance on compatibility studies is provided in Appendix 3 of the WHO *Guidelines for registration of fixed-dose combination medicinal products* (6). In addition to visual examination, chromatography results (assay, purity) are required to demonstrate API\u2013API and API\u2013excipient compatibility. In general, API\u2013excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product.\n\nStress testing of the API should be designed to include simulation, as far as possible, of the conditions that may be encountered during the manufacturing process of the FPP. An example is provided in Appendix 1.\n\n### 3.1.2 Excipients\n\n\u201c3.2.P.2.1.2 *The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions.*\u201d\n\nWhen choosing excipients, those with a compendial monograph are generally preferred and may be required in certain jurisdictions. Other resources are available for information on acceptable excipients and their concentrations such as the US-FDA IIG (13) list and the *Handbook of pharmaceutical excipients* (14). Use of excipients at concentrations outside the established ranges is discouraged and generally requires justification. In addition, available guidelines which address particular excipients to be avoided should usually be consulted, for example, azo colourants as listed in EMA guideline CPMP/463/00 (15). Other guidelines such as WHO\u2019s *Development of paediatric medicines: points to consider in pharmaceutical development* (16) may provide useful general guidance in this regard.\n\nThe characteristics and amounts of excipients that can influence the performance of the pharmaceutical product or its manufacturing capability should usually be discussed relative to the respective function. The ability of functional excipients, e.g. pH-adjusting agents, buffers, stabilizers (such as antioxidants and chelating agents), preservatives and dissolution modifiers (such as surface active agents), to perform throughout the intended shelf-life of the FPP should usually be demonstrated.\n\nAntimicrobial preservatives are discussed in 3.2.P.2.5.\n\nMany excipients such as povidone, microcrystalline cellulose and lactose are by nature multifunctional. The chemically identical excipients may have different grades (physical properties) with different functional characteristics; therefore, conformance to pharmacopoeial specifications does not always...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl texto proporciona directrices sobre la elecci\u00f3n y uso de excipientes en la formulaci\u00f3n de productos farmac\u00e9uticos, as\u00ed como la importancia de la compatibilidad entre el principio activo (API) y los excipientes. Se menciona que los excipientes deben ser seleccionados cuidadosamente, preferiblemente aquellos que tienen una monograf\u00eda en una farmacopea, y que su concentraci\u00f3n y caracter\u00edsticas deben discutirse en relaci\u00f3n con su funci\u00f3n en el producto final. Tambi\u00e9n se aborda la necesidad de realizar estudios de compatibilidad y pruebas de estr\u00e9s para asegurar que los excipientes mantengan su funcionalidad a lo largo de la vida \u00fatil del producto.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de estudios son necesarios para demostrar la compatibilidad entre el API y los excipientes, y qu\u00e9 resultados se requieren?**\n   - El texto menciona que se requieren resultados de cromatograf\u00eda (an\u00e1lisis y pureza) adem\u00e1s de una evaluaci\u00f3n visual para demostrar la compatibilidad entre el API y los excipientes.\n\n2. **\u00bfCu\u00e1les son las consideraciones clave al seleccionar excipientes para un producto farmac\u00e9utico?**\n   - Al seleccionar excipientes, se deben considerar aquellos que tienen una monograf\u00eda en una farmacopea, su concentraci\u00f3n, caracter\u00edsticas que influyen en el rendimiento del producto, y se debe evitar el uso de excipientes en concentraciones fuera de los rangos establecidos sin justificaci\u00f3n.\n\n3. **\u00bfQu\u00e9 papel juegan los excipientes multifuncionales en la formulaci\u00f3n de productos farmac\u00e9uticos y c\u00f3mo se deben evaluar?**\n   - Los excipientes multifuncionales, como la povidona y la celulosa microcristalina, pueden tener diferentes grados con propiedades f\u00edsicas y caracter\u00edsticas funcionales distintas. Por lo tanto, es importante evaluar su conformidad con las especificaciones farmacop\u00e9icas y su capacidad para desempe\u00f1ar su funci\u00f3n a lo largo de la vida \u00fatil del producto.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS proporciona directrices sobre la selecci\u00f3n y evaluaci\u00f3n de excipientes en la formulaci\u00f3n de productos farmac\u00e9uticos, enfatizando la importancia de la compatibilidad entre el principio activo y los excipientes, as\u00ed como la necesidad de realizar estudios de estabilidad y pruebas de estr\u00e9s. Se destaca que la elecci\u00f3n de excipientes debe basarse en su funci\u00f3n, caracter\u00edsticas, y cumplimiento con las normativas establecidas, y se deben evitar excipientes que no cumplan con los est\u00e1ndares de seguridad y eficacia.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Desarrollo del Producto Farmac\u00e9utico:**\n   - Importancia de discutir las caracter\u00edsticas del Producto Farmac\u00e9utico Terminado (FPP) en el contexto del desarrollo del producto, aplicando principios de gesti\u00f3n de riesgos a lo largo de su ciclo de vida.\n\n2. **Componentes del FPP:**\n   - El FPP incluye el Ingrediente Farmac\u00e9utico Activo (API) y excipientes, as\u00ed como excipientes que pueden no estar presentes en cada lote o que se eliminan durante el procesamiento.\n\n3. **Compatibilidad del API:**\n   - Necesidad de evaluar la compatibilidad del API con los excipientes y entre diferentes APIs en formulaciones de Combinaciones de F\u00e1rmacos (FDCs).\n\n4. **Propiedades Fisicoqu\u00edmicas del API:**\n   - Discusi\u00f3n sobre caracter\u00edsticas como contenido de agua, solubilidad, distribuci\u00f3n del tama\u00f1o de part\u00edculas, forma polim\u00f3rfica y otras propiedades que pueden influir en el rendimiento del FPP.\n\n5. **Documentos de Referencia:**\n   - Menci\u00f3n de las gu\u00edas ICH (Q6A, Q8, Q9 y Q10) como documentos clave para el desarrollo farmac\u00e9utico.\n\n**Entidades:**\n\n- **FPP (Producto Farmac\u00e9utico Terminado):** Compuesto por el API y excipientes.\n- **API (Ingrediente Farmac\u00e9utico Activo):** Sustancia que proporciona la acci\u00f3n farmacol\u00f3gica.\n- **Excipientes:** Sustancias inactivas que acompa\u00f1an al API en la formulaci\u00f3n.\n- **FDC (Combinaciones de F\u00e1rmacos):** Formulaciones que contienen m\u00e1s de un API.\n- **ICH (International Council for Harmonisation):** Organizaci\u00f3n que proporciona directrices para el desarrollo farmac\u00e9utico.\n\nEste resumen destaca la importancia de la evaluaci\u00f3n de la compatibilidad y las propiedades fisicoqu\u00edmicas del API en el desarrollo de productos farmac\u00e9uticos, as\u00ed como la referencia a documentos normativos que gu\u00edan este proceso.", "excerpt_keywords": "Keywords: excipients, API compatibility, pharmaceutical formulation, stability studies, regulatory guidelines"}}, "e35e2f64-5674-4687-8d0d-78db08777150": {"node_ids": ["bf64bd9c-b5dd-444f-9d09-630a977ae9a6"], "metadata": {"page_label": "114", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Finished Pharmaceutical Product \"3.2.P.2.2\"\n\n## 3.2.1 Formulation Development\n\n### 3.2.P.2.2.1\n\nA brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed when appropriate.\n\nWhen preparing the PD for submission, the data requirements of the NMRA regarding formulation development may depend on whether the multisource product has been newly developed by the applicant or manufacturer or whether it is an established multisource product.\n\nThe WHO Prequalification of Medicines Programme defines an established multisource product as one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier should usually be completed with the exception of P.2.2.1 (a). In addition, a product quality review should usually be provided in the PD as outlined in Appendix 2 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1).\n\nThe requirements for bioequivalence studies should be taken into consideration, for example, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (e.g.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los requisitos para el desarrollo de productos farmac\u00e9uticos terminados (FPP) en el contexto de la precalificaci\u00f3n de medicamentos. Se enfatiza la importancia de proporcionar un resumen del desarrollo de la formulaci\u00f3n, considerando la ruta de administraci\u00f3n y el uso propuesto. Se discuten las diferencias entre formulaciones de bioequivalencia y biowaiver, as\u00ed como los requisitos de datos para productos multisource, diferenciando entre productos reci\u00e9n desarrollados y aquellos establecidos. Se establece que un producto multisource se considera establecido si ha estado en el mercado durante al menos cinco a\u00f1os y cumple con ciertos criterios de producci\u00f3n.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfCu\u00e1les son los criterios que definen un producto multisource establecido seg\u00fan el Programa de Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Un producto multisource se considera establecido si ha sido comercializado por el solicitante o fabricante asociado con el dossier durante al menos cinco a\u00f1os y ha producido al menos 10 lotes de producci\u00f3n en el \u00faltimo a\u00f1o, o si ha producido menos de 10 lotes en el \u00faltimo a\u00f1o, debe haber producido no menos de 25 lotes en los \u00faltimos tres a\u00f1os.\n\n2. **\u00bfQu\u00e9 se debe incluir en el resumen del desarrollo de la formulaci\u00f3n de un FPP?**\n   - El resumen debe incluir consideraciones sobre la ruta de administraci\u00f3n y el uso propuesto, as\u00ed como discutir las diferencias entre las formulaciones de bioequivalencia o biowaiver y la formulaci\u00f3n descrita en 3.2.P.1. Tambi\u00e9n se deben discutir los resultados de estudios comparativos in vitro (como la disoluci\u00f3n) o in vivo (como la bioequivalencia) cuando sea apropiado.\n\n3. **\u00bfQu\u00e9 se requiere en la preparaci\u00f3n del dossier (PD) para productos multisource reci\u00e9n desarrollados en comparaci\u00f3n con los establecidos?**\n   - Para productos multisource reci\u00e9n desarrollados, los requisitos de datos del NMRA sobre el desarrollo de la formulaci\u00f3n pueden variar, mientras que para productos establecidos, generalmente se deben completar todas las secciones de P.2.2.1 del dossier, excepto P.2.2.1 (a), y se debe proporcionar una revisi\u00f3n de calidad del producto seg\u00fan lo indicado en las directrices de la OMS.", "prev_section_summary": "### Temas Clave\n\n1. **Compatibilidad de Excipientes y Principios Activos (API)**:\n   - Se requiere realizar estudios de compatibilidad, incluyendo an\u00e1lisis cromatogr\u00e1ficos y evaluaciones visuales, para demostrar la compatibilidad entre el API y los excipientes.\n   - La compatibilidad no es necesaria para excipientes espec\u00edficos si hay evidencia de su presencia en productos comparadores.\n\n2. **Selecci\u00f3n de Excipientes**:\n   - Se prefieren excipientes con monograf\u00edas en farmacopeas y se deben discutir sus concentraciones y caracter\u00edsticas en relaci\u00f3n con su funci\u00f3n en el producto final.\n   - El uso de excipientes fuera de los rangos establecidos requiere justificaci\u00f3n.\n\n3. **Pruebas de Estr\u00e9s**:\n   - Las pruebas de estr\u00e9s del API deben simular las condiciones del proceso de fabricaci\u00f3n del producto farmac\u00e9utico terminado (FPP).\n\n4. **Excipientes Multifuncionales**:\n   - Excipientes como la povidona y la celulosa microcristalina pueden tener diferentes grados y propiedades, lo que requiere una evaluaci\u00f3n cuidadosa de su conformidad con las especificaciones farmacop\u00e9icas.\n\n5. **Gu\u00edas y Recursos**:\n   - Se mencionan varias gu\u00edas y recursos, como la lista de excipientes aceptables de la FDA y el *Handbook of pharmaceutical excipients*, que pueden ser consultados para la selecci\u00f3n de excipientes.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Proporciona directrices sobre la formulaci\u00f3n de productos farmac\u00e9uticos.\n- **API (Active Pharmaceutical Ingredient)**: Ingrediente activo en productos farmac\u00e9uticos.\n- **FPP (Finished Pharmaceutical Product)**: Producto farmac\u00e9utico terminado.\n- **Excipientes**: Sustancias inactivas que se utilizan en la formulaci\u00f3n de medicamentos.\n- **Farmacopeas**: Compendios que contienen est\u00e1ndares para la calidad de medicamentos y excipientes.\n- **Gu\u00edas de la FDA y EMA**: Documentos que ofrecen directrices sobre la selecci\u00f3n y uso de excipientes.\n\nEste resumen destaca la importancia de la compatibilidad, la selecci\u00f3n adecuada de excipientes y la necesidad de realizar pruebas de estr\u00e9s para asegurar la calidad y eficacia de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: formulation development, multisource product, bioequivalence, WHO Prequalification, pharmaceutical guidelines"}}, "ebd7dd76-9f68-4dc0-8bfc-4e60e4c5c408": {"node_ids": ["84189e88-1910-4d54-94a0-aa08d830e255"], "metadata": {"page_label": "115", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Guidelines on Registration Requirements\n\n**WHO guidelines on registration requirements to establish interchangeability for multisource (generic) pharmaceutical products (7)** can be consulted.\n\nTablet scoring may be recommended or required in certain jurisdictions or, for example, when scoring is indicated in the WHO invitation for expression of interest, or is specified for an invited FPP in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology.\n\nIf the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should usually include a description of the test method, individual values, mean and relative standard deviation of the results. Uniformity testing (i.e. content uniformity or mass variation, depending on the requirement for the whole tablet) should be performed on each split portion from a minimum of 10 randomly selected whole tablets. As an example the number of units (i.e. the splits) would be 10 halves for bisected tablets (one half of each tablet is retained for the test) or 10 quarters for quadrisected tablets (one quarter of each tablet is retained for the test). At least one batch of each strength should be tested. Ideally the study should cover a range of the hardness values. The splitting of the tablets should be performed in a manner that would be representative of that used by the consumer (e.g. manually split by hand). The uniformity test on split portions only needs to be demonstrated once and does not need to be added to the FPP specification(s). The tablet description in the FPP specification and in the product information (e.g. SmPC, labelling or package leaflet) should reflect the presence of a score line.\n\nIf a paediatric dose is to be obtained by splitting a tablet, a demonstration of content uniformity of tablet fragments may be required.\n\nFor modified-release tablets designed to be divided into equal halves, demonstration of dissolution profile similarity of the tablet halves against the whole tablet may be required.\n\nWhere relevant, labelling should state that the score line is only intended to facilitate breaking for ease of swallowing and not to divide the tablet into equal doses. In this case a demonstration of uniformity is unlikely to be required.\n\n## In Vitro Dissolution or Drug Release\n\nA discussion should usually be included as to how the development of the formulation relates to development of the dissolution method(s) and the generation of the dissolution profile.\n\nThe results of studies justifying the choice of in vitro dissolution or drug release conditions (e.g. apparatus, rotation speed and medium) are usually required in the PD. Data should also usually demonstrate whether the method is sensitive to changes in manufacturing processes and/or changes in grades and/or...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento proporciona directrices de la OMS sobre los requisitos de registro para establecer la intercambiabilidad de productos farmac\u00e9uticos multisource (gen\u00e9ricos). Se discuten aspectos relacionados con el dise\u00f1o y la evaluaci\u00f3n de tabletas, incluyendo la importancia de las l\u00edneas de puntuaci\u00f3n para facilitar la divisi\u00f3n de las tabletas, la uniformidad de dosis en fragmentos de tabletas, y la necesidad de estudios de disoluci\u00f3n para tabletas modificadas. Tambi\u00e9n se menciona que la informaci\u00f3n en el etiquetado debe aclarar el prop\u00f3sito de la l\u00ednea de puntuaci\u00f3n y que se deben realizar pruebas de uniformidad en tabletas divididas.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de pruebas de uniformidad se requieren para tabletas que se pueden dividir y c\u00f3mo se deben llevar a cabo?**\n   - Se requiere realizar pruebas de uniformidad (ya sea de contenido o de variaci\u00f3n de masa) en cada porci\u00f3n dividida de un m\u00ednimo de 10 tabletas enteras seleccionadas al azar. Por ejemplo, para tabletas bisecadas, se retendr\u00eda una mitad de cada tableta para la prueba.\n\n2. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al etiquetar tabletas con l\u00edneas de puntuaci\u00f3n?**\n   - El etiquetado debe indicar que la l\u00ednea de puntuaci\u00f3n est\u00e1 destinada a facilitar la ruptura para facilitar la degluci\u00f3n y no para dividir la tableta en dosis iguales. En este caso, es poco probable que se requiera una demostraci\u00f3n de uniformidad.\n\n3. **\u00bfQu\u00e9 requisitos se establecen para las tabletas modificadas que est\u00e1n dise\u00f1adas para ser divididas en mitades iguales?**\n   - Para tabletas modificadas que se pueden dividir en mitades, se puede requerir una demostraci\u00f3n de similitud del perfil de disoluci\u00f3n entre las mitades de la tableta y la tableta entera.\n\n### Resumen de Nivel Superior\n\nLas directrices de la OMS sobre los requisitos de registro para productos farmac\u00e9uticos gen\u00e9ricos abordan la importancia de la puntuaci\u00f3n en tabletas, la necesidad de pruebas de uniformidad en tabletas divididas, y los requisitos de disoluci\u00f3n para tabletas modificadas. Se enfatiza que la informaci\u00f3n en el etiquetado debe ser clara respecto al uso de las l\u00edneas de puntuaci\u00f3n y que las pruebas de uniformidad son esenciales para garantizar la dosificaci\u00f3n adecuada en tabletas que se pueden dividir.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Desarrollo de Formulaci\u00f3n de Productos Farmac\u00e9uticos Terminados (FPP)**:\n   - Se requiere un resumen que describa el desarrollo del FPP, considerando la ruta de administraci\u00f3n y el uso propuesto.\n   - Es importante discutir las diferencias entre formulaciones de bioequivalencia y biowaiver, as\u00ed como los resultados de estudios comparativos in vitro e in vivo.\n\n2. **Productos Multisource**:\n   - Un producto multisource se considera \"establecido\" si ha estado en el mercado durante al menos cinco a\u00f1os y ha producido al menos 10 lotes en el \u00faltimo a\u00f1o, o 25 lotes en los \u00faltimos tres a\u00f1os si ha producido menos de 10 en el \u00faltimo a\u00f1o.\n   - Para productos establecidos, se deben completar todas las secciones del dossier, excepto P.2.2.1 (a), y se debe incluir una revisi\u00f3n de calidad del producto.\n\n3. **Requisitos de Datos para el Dossier (PD)**:\n   - Los requisitos de datos del NMRA pueden variar seg\u00fan si el producto multisource es nuevo o establecido.\n   - Se deben considerar los requisitos para estudios de bioequivalencia, especialmente al formular m\u00faltiples concentraciones o cuando el producto puede ser elegible para un biowaiver.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad que establece directrices para la precalificaci\u00f3n de medicamentos.\n- **NMRA (Autoridad Nacional Reguladora de Medicamentos)**: Entidad que regula los requisitos de datos para el desarrollo de formulaciones.\n- **Productos Multisource**: Medicamentos gen\u00e9ricos que cumplen con criterios espec\u00edficos de comercializaci\u00f3n y producci\u00f3n.\n- **Bioequivalencia y Biowaiver**: Conceptos relacionados con la comparaci\u00f3n de formulaciones y la elegibilidad para exenciones en estudios de bioequivalencia.", "excerpt_keywords": "Keywords: WHO guidelines, registration requirements, multisource pharmaceuticals, tablet scoring, content uniformity"}}, "24226fc8-3443-47eb-bcd9-ca845f16edb7": {"node_ids": ["4d12be5d-fdff-4aa2-b4ba-92f0122faa62"], "metadata": {"page_label": "116", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nor amounts of critical excipients and particle size where relevant. The dissolution method should be sensitive to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters.\n\nRecommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1).\n\nIn the case of rapidly dissolving FPPs containing highly soluble APIs (BCS classes 1 and 3), a single-point dissolution test limit of 80% in 30 minutes or less is considered sufficient as a routine QC test for batch-to-batch uniformity. For slowly dissolving or poorly water-soluble APIs (BCS classes 2 and 4) in immediate-release products, a two-point dissolution range (a dissolution window), one at an early time-point (e.g. Q = 60% in 45 minutes) and the other at a later point (e.g. Q = 80% in 90 minutes), is recommended to characterize the quality of the product. Note that in some cases the later point may be lower than 80% if a plateau is reached.\n\nModified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine QC. Preferably, this test should possess in vitro\u2013in vivo correlation. Results demonstrating the effect of pH on the dissolution profile are usually required, if appropriate for the type of dosage form.\n\nFor extended-release FPPs the testing conditions should be set to cover the entire period of expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test period, upper and lower limits should be set for individual units. Generally the acceptance range at each intermediate test point should not exceed 25% or \u00b1 12.5% of the targeted value. Dissolution results are usually required for several lots including those used for pharmacokinetic and bioavailability or biowaiver studies.\n\nThe dissolution acceptance limit(s) should also be incorporated into the stability programmes.\n\nWhere there are scientific grounds that the defined release characteristics of oral pharmaceutical products may be adversely affected by the presence of alcohol, e.g. for modified-release products containing opiates, 5%, 10% and 20% ethanol should be added to the dissolution medium proposed for routine testing in order to demonstrate that no dose dumping will occur through intake with alcoholic beverages.\n\n## 3.2.2 Overages\n\n### 3.2.P.2.2.2 Any overages in the formulation(s) described in 3.2.P.1 should be justified.\n\nJustification of an overage to compensate for loss during manufacture", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Dissoluci\u00f3n y Control de Calidad**: El documento establece directrices sobre los m\u00e9todos de disoluci\u00f3n para productos farmac\u00e9uticos terminados (FPPs), diferenciando entre productos de liberaci\u00f3n r\u00e1pida y lenta, y enfatiza la importancia de la correlaci\u00f3n in vitro-in vivo. Se especifican l\u00edmites de aceptaci\u00f3n para pruebas de disoluci\u00f3n y se discuten las condiciones de prueba para productos de liberaci\u00f3n modificada y extendida.\n\n2. **Impacto del Alcohol en la Liberaci\u00f3n de Medicamentos**: Se menciona que la presencia de alcohol puede afectar negativamente las caracter\u00edsticas de liberaci\u00f3n de ciertos productos farmac\u00e9uticos, especialmente aquellos de liberaci\u00f3n modificada que contienen opi\u00e1ceos. Se recomienda incluir etanol en el medio de disoluci\u00f3n para evaluar el riesgo de liberaci\u00f3n excesiva (dose dumping).\n\n3. **Justificaci\u00f3n de Overages en Formulaciones**: Se requiere que cualquier exceso en la formulaci\u00f3n de un producto farmac\u00e9utico sea justificado, especialmente para compensar las p\u00e9rdidas durante el proceso de fabricaci\u00f3n.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios espec\u00edficos para establecer l\u00edmites de aceptaci\u00f3n en las pruebas de disoluci\u00f3n para productos de liberaci\u00f3n extendida?**\n   - Esta pregunta busca detalles sobre los criterios y rangos de aceptaci\u00f3n que deben cumplirse durante las pruebas de disoluci\u00f3n para productos de liberaci\u00f3n extendida, que no se encuentran f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfQu\u00e9 justificaciones son aceptables para los overages en las formulaciones de productos farmac\u00e9uticos?**\n   - Esta pregunta se centra en las razones que pueden ser consideradas v\u00e1lidas para incluir overages en las formulaciones, lo que puede no estar claramente definido en otras gu\u00edas o documentos.\n\n3. **\u00bfC\u00f3mo se debe evaluar el efecto del pH en el perfil de disoluci\u00f3n de un producto farmac\u00e9utico?**\n   - Esta pregunta busca informaci\u00f3n sobre los m\u00e9todos y consideraciones espec\u00edficas para evaluar c\u00f3mo el pH afecta la disoluci\u00f3n de un producto, un aspecto que puede ser crucial para la formulaci\u00f3n y que no siempre se aborda en otras fuentes.", "prev_section_summary": "### Temas Clave\n\n1. **Requisitos de Registro de la OMS**: Directrices sobre la intercambiabilidad de productos farmac\u00e9uticos multisource (gen\u00e9ricos).\n  \n2. **Puntuaci\u00f3n de Tabletas**: La puntuaci\u00f3n puede ser recomendada o requerida en ciertas jurisdicciones y es importante para facilitar la divisi\u00f3n en dosis fraccionadas.\n\n3. **Uniformidad de Dosis**: Se requiere un estudio para asegurar la uniformidad de dosis en fragmentos de tabletas, incluyendo pruebas de uniformidad de contenido o variaci\u00f3n de masa en tabletas divididas.\n\n4. **Pruebas de Uniformidad**: Deben realizarse en al menos 10 tabletas enteras seleccionadas al azar, con ejemplos espec\u00edficos para tabletas bisecadas y cuadrisecadas.\n\n5. **Dosis Pedi\u00e1trica**: Puede ser necesaria una demostraci\u00f3n de uniformidad de contenido en fragmentos de tabletas si se obtiene una dosis pedi\u00e1trica al dividir una tableta.\n\n6. **Tabletas de Liberaci\u00f3n Modificada**: Se puede requerir una demostraci\u00f3n de similitud del perfil de disoluci\u00f3n entre las mitades de la tableta y la tableta entera.\n\n7. **Etiquetado**: Debe aclarar que la l\u00ednea de puntuaci\u00f3n es para facilitar la ruptura y no para dividir en dosis iguales, lo que puede eximir de la necesidad de demostrar uniformidad.\n\n8. **Disoluci\u00f3n In Vitro**: Se debe discutir c\u00f3mo el desarrollo de la formulaci\u00f3n se relaciona con el m\u00e9todo de disoluci\u00f3n y la generaci\u00f3n del perfil de disoluci\u00f3n.\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad que proporciona las directrices.\n- **FPP (Forma Farmac\u00e9utica de Producto)**: Referencia a los productos farmac\u00e9uticos en cuesti\u00f3n.\n- **Tabletas**: Forma farmac\u00e9utica que se discute en t\u00e9rminos de puntuaci\u00f3n y divisi\u00f3n.\n- **Dosis Pedi\u00e1trica**: Consideraci\u00f3n especial para la administraci\u00f3n de medicamentos a ni\u00f1os.\n- **Pruebas de Uniformidad**: M\u00e9todos de evaluaci\u00f3n de la consistencia en la dosificaci\u00f3n de tabletas.\n- **Liberaci\u00f3n Modificada**: Tipo de formulaci\u00f3n de tabletas que requiere consideraciones especiales en su evaluaci\u00f3n.\n\nEste resumen destaca los aspectos esenciales de las directrices de la OMS sobre la puntuaci\u00f3n y la uniformidad de las tabletas, as\u00ed como los requisitos de etiquetado y pruebas de disoluci\u00f3n.", "excerpt_keywords": "Keywords: dissolution, pharmaceutical preparations, overages, quality control, modified-release"}}, "297f027c-390c-4d80-a0f2-8a468881a433": {"node_ids": ["9d04f46c-e82e-48a6-b451-22e7ca2f5b35"], "metadata": {"page_label": "117", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.3 Physicochemical and biological properties\n\n3.2.P.2.2.3 Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency and/or immunological activity, should be addressed.\n\n# 3.3 Manufacturing process development\n\n3.2.P.2.3 The selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.\n\nFor products that meet the criteria of an established multisource product, in order to fulfil the requirements of section P.2.3, section P.2.3 (b) of the dossier should be completed and a product quality review should usually be submitted as outlined in Appendix 2 of the WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1). The guidance below applies to all other products, for which section P.2.3 should be completed in its entirety.\n\nThe rationale for choosing the particular pharmaceutical product (e.g. dosage form, delivery system) should be provided in the PD. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence quality and performance of the FPP should usually be explained (e.g. wet granulation using high-shear granulator). The results of an API stress study may be included in the rationale. Any developmental work undertaken on protecting the FPP from deterioration (e.g. protection from light or moisture) should also be included.\n\nThe manufacturing process of the multisource FPP should be appropriate for the product that is in development. It does not need to be the same as that of the comparator FPP.\n\nEfforts should be primarily directed towards reducing variability in process and product quality. In order to achieve this, all critical sources of variability should be identified and explained and the sources of variability should be minimized and controlled.\n\nProcess development studies should provide the basis for process improvement, process validation and any process control requirements. All CPPs should usually be identified, monitored or controlled to ensure that the product is of the desired quality.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda las propiedades fisicoqu\u00edmicas y biol\u00f3gicas de los productos farmac\u00e9uticos terminados (FPP) y el desarrollo del proceso de fabricaci\u00f3n. Se enfatiza la importancia de par\u00e1metros como pH, fuerza i\u00f3nica, disoluci\u00f3n y actividad biol\u00f3gica, as\u00ed como la necesidad de justificar la selecci\u00f3n y optimizaci\u00f3n del proceso de fabricaci\u00f3n. Se menciona que para productos que cumplen con los criterios de un producto multisource establecido, se deben completar secciones espec\u00edficas del dossier y realizar revisiones de calidad del producto. Adem\u00e1s, se destaca la importancia de reducir la variabilidad en la calidad del proceso y del producto, y se requiere que todos los par\u00e1metros cr\u00edticos del proceso (CPP) sean identificados y controlados.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los par\u00e1metros fisicoqu\u00edmicos y biol\u00f3gicos que deben ser considerados para evaluar el rendimiento de un FPP, y por qu\u00e9 son importantes?**\n   - Esta pregunta busca respuestas sobre la relevancia de par\u00e1metros como pH, fuerza i\u00f3nica y actividad biol\u00f3gica, que son fundamentales para la eficacia y seguridad del producto.\n\n2. **\u00bfQu\u00e9 justificaciones se deben proporcionar al seleccionar un proceso de fabricaci\u00f3n espec\u00edfico para un FPP, y c\u00f3mo se relacionan con la calidad del producto final?**\n   - Esta pregunta se centra en la necesidad de una justificaci\u00f3n cient\u00edfica para las decisiones de fabricaci\u00f3n, lo que puede incluir la elecci\u00f3n de m\u00e9todos de llenado y envasado.\n\n3. **\u00bfCu\u00e1les son las estrategias recomendadas para minimizar la variabilidad en el proceso de fabricaci\u00f3n de un FPP, y qu\u00e9 impacto tiene esto en la calidad del producto?**\n   - Esta pregunta busca explorar las pr\u00e1cticas espec\u00edficas que se deben implementar para controlar la variabilidad y asegurar que el producto cumpla con los est\u00e1ndares de calidad deseados.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **M\u00e9todos de Disoluci\u00f3n y Control de Calidad**:\n   - Se establecen directrices para la realizaci\u00f3n de pruebas de disoluci\u00f3n en productos farmac\u00e9uticos terminados (FPPs).\n   - Se diferencian los m\u00e9todos para FPPs de liberaci\u00f3n r\u00e1pida (BCS clases 1 y 3) y de liberaci\u00f3n lenta o poco soluble (BCS clases 2 y 4).\n   - Se recomienda un l\u00edmite de disoluci\u00f3n del 80% en 30 minutos para FPPs de liberaci\u00f3n r\u00e1pida y un rango de dos puntos para FPPs de liberaci\u00f3n lenta.\n\n2. **Pruebas para Productos de Liberaci\u00f3n Modificada y Extendida**:\n   - Se requiere una prueba de disoluci\u00f3n significativa para FPPs de liberaci\u00f3n modificada, preferiblemente con correlaci\u00f3n in vitro-in vivo.\n   - Para FPPs de liberaci\u00f3n extendida, se deben establecer condiciones de prueba que cubran todo el periodo de liberaci\u00f3n esperado, con l\u00edmites de aceptaci\u00f3n espec\u00edficos.\n\n3. **Impacto del Alcohol en la Liberaci\u00f3n de Medicamentos**:\n   - Se menciona que el alcohol puede afectar negativamente la liberaci\u00f3n de ciertos productos, especialmente los que contienen opi\u00e1ceos.\n   - Se recomienda a\u00f1adir etanol al medio de disoluci\u00f3n para evaluar el riesgo de liberaci\u00f3n excesiva (dose dumping).\n\n4. **Justificaci\u00f3n de Overages en Formulaciones**:\n   - Cualquier exceso en la formulaci\u00f3n debe ser justificado, especialmente para compensar p\u00e9rdidas durante la fabricaci\u00f3n.\n\n### Entidades Clave\n- **FPP (Finished Pharmaceutical Products)**: Productos farmac\u00e9uticos terminados.\n- **API (Active Pharmaceutical Ingredients)**: Ingredientes farmac\u00e9uticos activos.\n- **BCS (Biopharmaceutics Classification System)**: Sistema de clasificaci\u00f3n biofarmac\u00e9utica que categoriza los f\u00e1rmacos seg\u00fan su solubilidad y permeabilidad.\n- **WHO (World Health Organization)**: Organizaci\u00f3n Mundial de la Salud, responsable de establecer directrices y est\u00e1ndares en salud p\u00fablica y farmac\u00e9utica. \n\nEste resumen abarca los aspectos fundamentales de la secci\u00f3n, incluyendo las recomendaciones sobre disoluci\u00f3n, el impacto del alcohol y la justificaci\u00f3n de overages en formulaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: physicochemical properties, manufacturing process, product quality, variability control, WHO guidelines"}}, "f5562bb0-66ea-4dea-a888-eff8fa330095": {"node_ids": ["0c5dd78b-ff61-45fb-83d3-cc319dc3ebe5"], "metadata": {"page_label": "118", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nFor sterile products, an appropriate method of sterilization for the pharmaceutical product and primary packaging material should be chosen. Where relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided in the PD.\n\n*Differences between the manufacturing process(es) used to produce comparative bioavailability or biowaiver batches and the process described in 3.2.P.3.3 that can influence the performance of the product should be discussed.*\n\nThe scientific rationale for the selection, optimization, and scale-up of the manufacturing process described in 3.2.P.3.3 should usually be explained, in particular the CPPs (e.g. rate of addition of granulating fluid, massing time, and granulation end-point). A discussion of the CPPs, controls, and process robustness with respect to the QTPP and CQA of the product should usually be included (10).\n\nBased on close monitoring of the manufacturing process in the pilot batches, provisional acceptance ranges should be proposed for the CQAs of intermediates and CPPs that impact on downstream processing. Interim acceptance criteria may be approved until enough knowledge is available to finalize CQAs of intermediates and CPPs for production batches.\n\nThe manufacturing process used for pilot batches should be the same as the one proposed to be applied to production batches and should provide product of the same quality and meeting the same specifications as that intended for marketing.\n\n## 3.4 Container-closure system\n\n### 3.2.P.2.4\n\n*The suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider, e.g. choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP).*\n\nThe properties of the container-closure systems should be defined by the characteristics of the FPP and the conditions prevailing in the intended market (e.g. climatic zone IVb).\n\nStability testing of primary batches of the FPP is conducted on samples packaged in the container-closure system selected for marketing in order to confirm compatibility and product stability to support PDs for marketing authorization.\n\nWhen the container-closure system is a critical factor for FPP stability, batch or supplier variations need to be minimized through tight specifications and extended sampling plans for QC testing.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS se centra en las especificaciones para la preparaci\u00f3n farmac\u00e9utica, especialmente en la producci\u00f3n de productos est\u00e9riles. Se discuten aspectos cr\u00edticos como la elecci\u00f3n del m\u00e9todo de esterilizaci\u00f3n, la justificaci\u00f3n de procesos de fabricaci\u00f3n, la importancia de los par\u00e1metros cr\u00edticos de proceso (CPP) y la robustez del proceso en relaci\u00f3n con la calidad del producto. Tambi\u00e9n se aborda la idoneidad del sistema de cierre del envase, considerando factores como la compatibilidad de materiales, la protecci\u00f3n contra la humedad y la luz, y la estabilidad del producto.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 justificaciones se deben proporcionar al elegir m\u00e9todos de procesamiento as\u00e9ptico sobre la esterilizaci\u00f3n terminal para productos farmac\u00e9uticos est\u00e9riles?**\n   - El contexto menciona que se debe proporcionar una justificaci\u00f3n en el expediente de producto (PD) para la selecci\u00f3n de m\u00e9todos de procesamiento as\u00e9ptico o de otros m\u00e9todos de esterilizaci\u00f3n en lugar de la esterilizaci\u00f3n terminal.\n\n2. **\u00bfCu\u00e1les son los par\u00e1metros cr\u00edticos de proceso (CPP) que deben ser discutidos en relaci\u00f3n con la optimizaci\u00f3n y escalado del proceso de fabricaci\u00f3n?**\n   - Se debe explicar la selecci\u00f3n, optimizaci\u00f3n y escalado del proceso de fabricaci\u00f3n, incluyendo CPPs como la tasa de adici\u00f3n del l\u00edquido aglutinante, el tiempo de masificaci\u00f3n y el punto final de granulaci\u00f3n.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al evaluar la idoneidad del sistema de cierre del envase para un producto farmac\u00e9utico?**\n   - La discusi\u00f3n sobre la idoneidad del sistema de cierre debe incluir la elecci\u00f3n de materiales, la protecci\u00f3n contra la humedad y la luz, la compatibilidad de los materiales de construcci\u00f3n con la forma de dosificaci\u00f3n, y la seguridad y rendimiento de estos materiales en la entrega de dosis.", "prev_section_summary": "### Temas Clave\n\n1. **Propiedades Fisicoqu\u00edmicas y Biol\u00f3gicas**:\n   - Importancia de par\u00e1metros como pH, fuerza i\u00f3nica, disoluci\u00f3n, redispersi\u00f3n, reconstituci\u00f3n, distribuci\u00f3n del tama\u00f1o de part\u00edculas, agregaci\u00f3n, polimorfismo, propiedades reol\u00f3gicas, y actividad biol\u00f3gica o inmunol\u00f3gica en el rendimiento de los productos farmac\u00e9uticos terminados (FPP).\n\n2. **Desarrollo del Proceso de Fabricaci\u00f3n**:\n   - Selecci\u00f3n y optimizaci\u00f3n del proceso de fabricaci\u00f3n, incluyendo aspectos cr\u00edticos y justificaci\u00f3n del m\u00e9todo de esterilizaci\u00f3n.\n   - Para productos multisource, se requiere completar secciones espec\u00edficas del dossier y realizar revisiones de calidad del producto.\n\n3. **Justificaci\u00f3n Cient\u00edfica**:\n   - Necesidad de proporcionar una justificaci\u00f3n cient\u00edfica para la elecci\u00f3n del producto farmac\u00e9utico, as\u00ed como de los procesos de fabricaci\u00f3n, llenado y envasado que afectan la calidad y el rendimiento del FPP.\n\n4. **Minimizaci\u00f3n de Variabilidad**:\n   - Estrategias para identificar, minimizar y controlar las fuentes de variabilidad en el proceso y la calidad del producto.\n   - Importancia de los estudios de desarrollo del proceso para la mejora, validaci\u00f3n y control de procesos.\n\n### Entidades\n\n- **FPP (Finished Pharmaceutical Product)**: Producto farmac\u00e9utico terminado.\n- **CPP (Critical Process Parameters)**: Par\u00e1metros cr\u00edticos del proceso que deben ser identificados y controlados.\n- **API (Active Pharmaceutical Ingredient)**: Ingrediente farmac\u00e9utico activo.\n- **Multisource Product**: Producto farmac\u00e9utico que cumple con criterios establecidos para ser considerado equivalente a un producto de referencia.\n- **WHO (World Health Organization)**: Organizaci\u00f3n Mundial de la Salud, que proporciona directrices y est\u00e1ndares para la calidad de los medicamentos.\n\nEste resumen destaca la importancia de los par\u00e1metros fisicoqu\u00edmicos y biol\u00f3gicos en el desarrollo y fabricaci\u00f3n de productos farmac\u00e9uticos, as\u00ed como la necesidad de un enfoque riguroso para garantizar la calidad y eficacia del producto final.", "excerpt_keywords": "Keywords: sterilization, pharmaceutical preparations, critical process parameters, container-closure system, product stability"}}, "a9080536-b406-41d9-82f9-24902fb6b68a": {"node_ids": ["2dcde4b8-bd33-4e5a-b832-725da0d4cb74"], "metadata": {"page_label": "119", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "To facilitate the visual identification of spuriously or falsely-labelled, falsified or counterfeit (SFFC) medicines (including by the public) the description needs to be completely detailed in the product information. Details may include information on the container-closure system, such as \u201cround, white opaque, high-density polyethylene (HDPE) bottles fitted with white opaque, polypropylene continuous thread closures with induction sealing liner\u201d, or \u201ca blister package comprising clear transparent polyvinyl chloride (PVC) film with a backing of aluminium foil coated with heat-seal lacquer\u201d.\n\nPrimary packing materials, particularly plastics, should comply with relevant pharmacopoeial and food contact regulations.\n\nTesting requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration and possibly, the manufacturing process. The pharmacopoeias provide standards that are required for packaging materials; examples include the following:\n\n- glass containers (17, 18);\n- plastic containers (19, 20);\n- rubber/elastomeric closures (21, 22).\n\nTable 1 outlines the general recommendations for the various dosage forms for once-only studies to establish the suitability of the container-closure system contact materials.\n\n### Table 1\n**Studies to establish the suitability of the container-closure system contact materials**\n\n|                                  | Solid oral products | Oral liquid and topical products | Sterile products (including ophthalmic preparations) |\n|----------------------------------|---------------------|----------------------------------|------------------------------------------------------|\n| Description of any additional treatments<sup>a</sup> | \u00d7                   | \u00d7                                | \u00d7 (sterilization and depyrogenation of the components) |\n| Extraction studies               | \u2013                   | \u00d7                                | \u00d7                                                    |\n| Interaction studies (migration/sorption) | \u2013                   | \u00d7                                | \u00d7                                                    |\n| Moisture permeability            | \u00d7 (uptake)          | \u00d7 (usually loss)                 | \u00d7 (usually loss)                                     |\n| Light transmission               | \u00d7<sup>b</sup>       | \u00d7                                |                                                      |\n\n<sup>\u00d7</sup> Information should usually be submitted.  \n<sup>\u2013</sup> Information does not need to be submitted.  \n<sup>a</sup> E.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials.  \n<sup>b</sup> Not required if product has been shown to be photostable.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con res\u00famenes de nivel superior que pueden ayudar a formularlas:\n\n### Resumen de nivel superior:\nEl documento de la OMS detalla la importancia de una descripci\u00f3n precisa de los medicamentos para identificar aquellos que son falsificados o mal etiquetados. Se enfatiza la necesidad de cumplir con regulaciones pertinentes para los materiales de embalaje y se presentan recomendaciones sobre estudios necesarios para verificar la idoneidad de los sistemas de cierre de envases seg\u00fan el tipo de producto.\n\n### Preguntas:\n\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n se debe incluir en la descripci\u00f3n del sistema de cierre del envase para facilitar la identificaci\u00f3n de medicamentos falsificados?**\n   - Respuesta: La descripci\u00f3n debe ser completamente detallada e incluir informaci\u00f3n sobre el sistema de cierre del envase, como el tipo de material (por ejemplo, \"botellas de polietileno de alta densidad (HDPE) opacas y blancas\") y el dise\u00f1o del envase (por ejemplo, \"un paquete de bl\u00edster que comprende una pel\u00edcula de cloruro de polivinilo (PVC) transparente con un respaldo de papel de aluminio\").\n\n2. **\u00bfCu\u00e1les son los requisitos de prueba para los materiales de contacto del sistema de cierre del envase seg\u00fan el tipo de producto?**\n   - Respuesta: Los requisitos de prueba dependen del tipo de forma de dosificaci\u00f3n y la v\u00eda de administraci\u00f3n. Por ejemplo, para productos orales s\u00f3lidos, se recomienda realizar estudios de permeabilidad a la humedad y transmisi\u00f3n de luz, mientras que para productos est\u00e9riles, se requieren estudios de extracci\u00f3n e interacci\u00f3n.\n\n3. **\u00bfQu\u00e9 regulaciones deben cumplir los materiales de embalaje primarios, especialmente los pl\u00e1sticos?**\n   - Respuesta: Los materiales de embalaje primarios, particularmente los pl\u00e1sticos, deben cumplir con las regulaciones farmacop\u00e9icas y de contacto alimentario pertinentes, asegurando que sean seguros para su uso en productos farmac\u00e9uticos.", "prev_section_summary": "### Temas Clave\n\n1. **M\u00e9todos de Esterilizaci\u00f3n**: Se enfatiza la importancia de elegir un m\u00e9todo adecuado de esterilizaci\u00f3n para productos farmac\u00e9uticos est\u00e9riles y la necesidad de justificar la elecci\u00f3n de procesamiento as\u00e9ptico o m\u00e9todos alternativos en lugar de la esterilizaci\u00f3n terminal.\n\n2. **Par\u00e1metros Cr\u00edticos de Proceso (CPP)**: Se requiere una explicaci\u00f3n detallada sobre la selecci\u00f3n, optimizaci\u00f3n y escalado del proceso de fabricaci\u00f3n, incluyendo la discusi\u00f3n de CPPs como la tasa de adici\u00f3n de l\u00edquido aglutinante, el tiempo de masificaci\u00f3n y el punto final de granulaci\u00f3n.\n\n3. **Robustez del Proceso**: Se debe discutir la robustez del proceso en relaci\u00f3n con la calidad del producto (CQA) y el perfil de calidad del producto (QTPP).\n\n4. **Sistema de Cierre del Envase**: Se aborda la idoneidad del sistema de cierre del envase, considerando la elecci\u00f3n de materiales, protecci\u00f3n contra humedad y luz, compatibilidad de materiales con la forma de dosificaci\u00f3n, y la seguridad y rendimiento en la entrega de dosis.\n\n5. **Pruebas de Estabilidad**: Se menciona la importancia de realizar pruebas de estabilidad en lotes primarios del producto farmac\u00e9utico empaquetados en el sistema de cierre seleccionado para confirmar la compatibilidad y estabilidad del producto.\n\n6. **Variaciones en Lotes o Proveedores**: Se destaca la necesidad de minimizar variaciones en lotes o proveedores cuando el sistema de cierre es un factor cr\u00edtico para la estabilidad del producto.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite directrices sobre especificaciones para preparaciones farmac\u00e9uticas.\n- **FPP (Forma Farmac\u00e9utica Final)**: Producto farmac\u00e9utico que se est\u00e1 evaluando.\n- **CPP (Par\u00e1metro Cr\u00edtico de Proceso)**: Factores que afectan el proceso de fabricaci\u00f3n y la calidad del producto.\n- **CQA (Atributo Cr\u00edtico de Calidad)**: Caracter\u00edsticas del producto que deben ser controladas para asegurar la calidad.\n- **QTPP (Perfil de Calidad del Producto)**: Especificaciones que definen la calidad del producto final.\n- **Sistema de Cierre del Envase**: Componentes utilizados para sellar y proteger el producto farmac\u00e9utico durante su almacenamiento y transporte.", "excerpt_keywords": "Keywords: medicines, falsified, container-closure system, testing requirements, pharmacopoeial regulations"}}, "c0d9f3cb-162a-466e-b5cd-2f82a3fa1cca": {"node_ids": ["d77ede86-c56a-4a03-9b4a-6fd8d3a5c4b6"], "metadata": {"page_label": "120", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe suitability of the container-closure system used for the storage, transportation (shipping) and use of any intermediate or in-process products (e.g. premixes, bulk FPP) should also be discussed.\n\n## Devices\n\nThere are certain situations in which pharmaceutical dosage forms are developed in association with specific devices. The device might be critical to enabling delivery of the medicine or it might be included in order to facilitate administration.\n\nWhere the device is critical to drug delivery and fully integrated with the product formulation, this product formulation\u2013device combination should be considered as the primary product for the purposes of regulatory submission. Examples of such products include metered dose inhalers (MDIs), dry powder inhalers, intranasal sprays and ready-made intravenous infusions. For these products the data necessary to support a regulatory submission would include:\n\n- Physical and chemical stability data for the product formulation\u2013device combination in its primary pack in order to support the claimed shelf-life and storage conditions;\n- Relevant data on extractables and leachables;\n- For multidose products, demonstration of accurate dose delivery over the shelf-life of the product under the registered storage conditions;\n- For multidose products with a dose-counting mechanism, stability data to demonstrate reliable performance of that mechanism over the shelf-life of the product under the registered storage conditions;\n- Specification control and secure sourcing of all device components;\n- Relevant information on any secondary device associated with the FPP, such as a spacer device sometimes associated with inhaled products such as MDIs and nebulizers. This device enables dose delivery in situations where the patient cannot easily use the primary product to inhale the dose, particularly where administration to children is involved. The device acts as a temporary reservoir for the dose which can then be inhaled more easily by the patient. There will be some variability inherent to a spacer device but, nevertheless, an acceptable accuracy of dose delivery when using this device needs to be demonstrated.\n\nAlternatively, the co-developed device may be intended to facilitate measurement of the prescribed dose prior to administration; this is particularly important for paediatric products where flexibility of dose may also be a requirement. Examples include spoons, cups, syringes or droppers for oral administration.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder espec\u00edficamente con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS aborda la importancia de los sistemas de contenedores y cierres para el almacenamiento y transporte de productos farmac\u00e9uticos intermedios y en proceso. Tambi\u00e9n se discute la relaci\u00f3n entre formas de dosificaci\u00f3n farmac\u00e9utica y dispositivos espec\u00edficos que facilitan la entrega del medicamento. Se enfatiza que cuando un dispositivo es cr\u00edtico para la entrega del f\u00e1rmaco, debe considerarse como parte integral del producto para fines de presentaci\u00f3n regulatoria. Se enumeran los datos necesarios para respaldar la presentaci\u00f3n regulatoria de combinaciones de formulaciones de productos y dispositivos, as\u00ed como la importancia de la precisi\u00f3n en la entrega de dosis, especialmente en productos multidose y en aplicaciones pedi\u00e1tricas.\n\n### Preguntas\n1. **\u00bfQu\u00e9 tipo de datos son necesarios para respaldar la presentaci\u00f3n regulatoria de un producto que combina una formulaci\u00f3n farmac\u00e9utica y un dispositivo cr\u00edtico para la entrega del medicamento?**\n   - Esta pregunta se centra en los requisitos espec\u00edficos de datos mencionados en el contexto, que incluyen estabilidad f\u00edsica y qu\u00edmica, datos sobre extractables y leachables, y demostraciones de entrega precisa de dosis.\n\n2. **\u00bfC\u00f3mo se debe abordar la variabilidad inherente a los dispositivos secundarios, como los espaciadores, en la entrega de dosis de productos farmac\u00e9uticos?**\n   - Esta pregunta explora la necesidad de demostrar la precisi\u00f3n en la entrega de dosis al utilizar dispositivos secundarios, lo cual es crucial para la administraci\u00f3n efectiva, especialmente en poblaciones vulnerables como los ni\u00f1os.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al desarrollar dispositivos co-dise\u00f1ados para la medici\u00f3n de dosis en productos pedi\u00e1tricos?**\n   - Esta pregunta se enfoca en las caracter\u00edsticas espec\u00edficas que deben considerarse al dise\u00f1ar dispositivos que faciliten la medici\u00f3n de dosis, destacando la flexibilidad de dosis como un requisito importante para los productos dirigidos a ni\u00f1os.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Identificaci\u00f3n de Medicamentos Falsificados**: Se enfatiza la necesidad de descripciones detalladas en la informaci\u00f3n del producto para facilitar la identificaci\u00f3n visual de medicamentos falsificados o mal etiquetados (SFFC).\n\n2. **Descripci\u00f3n del Sistema de Cierre del Envase**: Se requiere que la descripci\u00f3n incluya detalles espec\u00edficos sobre el sistema de cierre del envase, como el tipo de material y el dise\u00f1o del envase (ejemplos: botellas de HDPE, paquetes de bl\u00edster de PVC).\n\n3. **Regulaciones de Materiales de Embalaje**: Los materiales de embalaje primarios, especialmente los pl\u00e1sticos, deben cumplir con regulaciones farmacop\u00e9icas y de contacto alimentario.\n\n4. **Requisitos de Prueba**: Los requisitos de prueba para verificar la idoneidad de los materiales de contacto del sistema de cierre dependen de la forma de dosificaci\u00f3n y la v\u00eda de administraci\u00f3n. Se presentan recomendaciones espec\u00edficas para diferentes tipos de productos (s\u00f3lidos orales, l\u00edquidos orales y productos est\u00e9riles).\n\n5. **Tabla de Estudios Recomendados**: Se incluye una tabla que detalla los estudios necesarios para establecer la idoneidad de los materiales de contacto del sistema de cierre, como estudios de extracci\u00f3n, interacci\u00f3n, permeabilidad a la humedad y transmisi\u00f3n de luz.\n\n### Entidades Clave\n\n- **Medicamentos SFFC**: Medicamentos falsificados o mal etiquetados.\n- **Materiales de Embalaje**: Incluyen pl\u00e1sticos, vidrio y cierres de goma/elast\u00f3meros.\n- **Regulaciones**: Normativas farmacop\u00e9icas y de contacto alimentario.\n- **Tipos de Productos**: Productos orales s\u00f3lidos, l\u00edquidos orales, productos t\u00f3picos y productos est\u00e9riles (incluyendo preparaciones oft\u00e1lmicas).\n- **Estudios de Prueba**: Estudios de extracci\u00f3n, interacci\u00f3n, permeabilidad a la humedad y transmisi\u00f3n de luz. \n\nEste resumen destaca la importancia de la informaci\u00f3n detallada y el cumplimiento normativo en la identificaci\u00f3n y seguridad de los medicamentos.", "excerpt_keywords": "Keywords: pharmaceutical preparations, container-closure system, drug delivery devices, regulatory submission, dose measurement"}}, "e7092195-8be5-4e16-9d25-72de8e816ef5": {"node_ids": ["753f1a10-5a3b-46b0-9a39-8a1116b19b96"], "metadata": {"page_label": "121", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\ndelivery and droppers for nasal or aural delivery. A device is required to be \nincluded with the container-closure system for oral liquids or solids (e.g. \nsolutions, emulsions, suspensions and powders or granules), whenever the \npackage provides for multiple doses. \n\nIn accordance with the Ph. Int. (3) general chapter Liquid preparations \nfor oral use: \n\"Each dose from a multidose container is administered by means of a \ndevice suitable for measuring the prescribed volume. The device is usually a \nspoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for \nother volumes or, for oral drops, a suitable dropper.\" \n\nIn these cases the following data would be required to support a \nregulatory submission: \n\n- for a device accompanying a multidose container, the results \n  of a study demonstrating the reproducibility of the device (e.g. \n  consistent delivery of the intended volume), generally at the lowest \n  intended dose; \n- specifications for the device materials, including specific identification \n  testing of the material which will be in contact with the FPP. \n\nWhen the intention is to submit a PD in CTD format a sample of the \ndevice should usually be provided with Module 1 of the PD. \n\n### 3.5 Microbiological attributes\n\n#### 3.2.P.2.5 Where appropriate the microbiological attributes of the dosage form \nshould be discussed, including, for example, the rationale for not performing \nmicrobial limits testing for non-sterile products and the selection and effectiveness \nof preservative systems in products containing antimicrobial preservatives. For \nsterile products the integrity of the container-closure system to prevent microbial \ncontamination should be addressed. \n\nWhere an antimicrobial preservative is included in the formulation the \namount used needs to be justified by submission of results of studies of the product \nformulated with different concentrations of the preservative(s) to demonstrate the \nlowest necessary but still effective concentration. The effectiveness of the agent \nneeds to be justified and verified by appropriate studies (e.g. national, regional or \ninternational pharmacopoeial general chapters on antimicrobial preservatives) \nusing a batch of the FPP. If the lower limit for the proposed acceptance criterion for \nthe assay of the preservative is less than 90.0%, the effectiveness of the agent has to be \nestablished with a batch of the FPP containing a concentration of the antimicrobial \npreservative corresponding to the lower proposed acceptance criteria. \n\nAs outlined in the WHO guidelines on Stability testing of active \npharmaceutical ingredients and finished pharmaceutical products (23), a single \n```\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los requisitos para la presentaci\u00f3n de dispositivos de dosificaci\u00f3n que acompa\u00f1an a envases de medicamentos orales de m\u00faltiples dosis. Se enfatiza la necesidad de incluir un dispositivo adecuado para medir la dosis, as\u00ed como la importancia de demostrar la reproducibilidad del dispositivo y la calidad de los materiales utilizados. Adem\u00e1s, se abordan los atributos microbiol\u00f3gicos de las formas de dosificaci\u00f3n, incluyendo la justificaci\u00f3n del uso de conservantes antimicrobianos y la necesidad de estudios que respalden su efectividad.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de estudios son necesarios para demostrar la reproducibilidad de un dispositivo de dosificaci\u00f3n que acompa\u00f1a a un envase multidose?**\n   - Respuesta: Se requiere la presentaci\u00f3n de resultados de un estudio que demuestre la consistencia en la entrega del volumen destinado, generalmente en la dosis m\u00e1s baja prevista.\n\n2. **\u00bfCu\u00e1les son las especificaciones que deben cumplirse para los materiales del dispositivo de dosificaci\u00f3n en contacto con el producto farmac\u00e9utico terminado (FPP)?**\n   - Respuesta: Se deben proporcionar especificaciones para los materiales del dispositivo, incluyendo pruebas de identificaci\u00f3n espec\u00edficas del material que estar\u00e1 en contacto con el FPP.\n\n3. **\u00bfQu\u00e9 justificaciones son necesarias para el uso de conservantes antimicrobianos en productos farmac\u00e9uticos no est\u00e9riles?**\n   - Respuesta: Se debe discutir la selecci\u00f3n y efectividad de los sistemas de preservaci\u00f3n, as\u00ed como la raz\u00f3n para no realizar pruebas de l\u00edmites microbianos en productos no est\u00e9riles, y se deben presentar estudios que demuestren la concentraci\u00f3n m\u00e1s baja necesaria pero a\u00fan efectiva del conservante.", "prev_section_summary": "### Temas Clave\n\n1. **Sistemas de Contenedores y Cierres**: Se discute la importancia de los sistemas de contenedores y cierres para el almacenamiento, transporte y uso de productos farmac\u00e9uticos intermedios y en proceso.\n\n2. **Dispositivos Asociados a Formas de Dosificaci\u00f3n**: Se aborda la relaci\u00f3n entre las formas de dosificaci\u00f3n farmac\u00e9utica y dispositivos espec\u00edficos que facilitan la entrega del medicamento.\n\n3. **Combinaciones de Formulaciones y Dispositivos**: Cuando un dispositivo es cr\u00edtico para la entrega del f\u00e1rmaco, se considera parte integral del producto para fines de presentaci\u00f3n regulatoria.\n\n4. **Datos Necesarios para Presentaci\u00f3n Regulatoria**: Se enumeran los datos necesarios para respaldar la presentaci\u00f3n regulatoria de combinaciones de formulaciones de productos y dispositivos, incluyendo estabilidad, extractables y leachables, y precisi\u00f3n en la entrega de dosis.\n\n5. **Variabilidad en Dispositivos Secundarios**: Se menciona la necesidad de demostrar la precisi\u00f3n en la entrega de dosis al utilizar dispositivos secundarios, como espaciadores, especialmente en la administraci\u00f3n pedi\u00e1trica.\n\n6. **Dispositivos para Medici\u00f3n de Dosis**: Se discuten consideraciones para el desarrollo de dispositivos co-dise\u00f1ados que faciliten la medici\u00f3n de dosis, destacando la flexibilidad de dosis como un requisito importante para productos pedi\u00e1tricos.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite el documento.\n- **Comit\u00e9 de Expertos de la OMS**: Grupo responsable de las especificaciones para preparaciones farmac\u00e9uticas.\n- **Formas de Dosificaci\u00f3n**: Incluye inhaladores de dosis medida (MDIs), inhaladores de polvo seco, aerosoles intranasales y soluciones intravenosas listas para usar.\n- **Dispositivos**: Incluyen espaciadores, cucharas, tazas, jeringas y goteros para la administraci\u00f3n oral.\n- **Productos Multidose**: Productos que permiten m\u00faltiples dosis, donde se requiere demostrar la entrega precisa de dosis a lo largo de su vida \u00fatil.\n\nEste resumen destaca los aspectos fundamentales y las entidades relevantes en la secci\u00f3n proporcionada del documento de la OMS.", "excerpt_keywords": "Keywords: dosage forms, antimicrobial preservatives, regulatory submission, device reproducibility, microbiological attributes"}}, "bd65de1e-eb09-452c-ad7e-c905d7e24f79": {"node_ids": ["953ec761-5ec7-4190-9c25-17f1d6bc1dd4"], "metadata": {"page_label": "122", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Compatibility\n\n## 3.2.P.2.6\n\nThe compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation of API in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labelling.\n\nWhere a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules for reconstitution), which are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required.\n\nWhere sterile, reconstituted products are to be further diluted, compatibility will have to be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of individual and total degradation products, subvisible particulate matter and extractables from the packaging components) should be demonstrated in glass, PVC and polyolefin containers. However, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers.\n\nIn the case of infusion sets where a product formulation is added to an infusion vehicle in an intravenous administration set (giving set) immediately prior to administration, the following data would be required:\n\n- physical and chemical stability data for the prepared infusion to support the claimed in-use shelf-life and storage conditions;\n- compatibility data to support the claimed in-use shelf-life and storage conditions;\n- specification control and secure sourcing of all giving set contact materials.\n\nStudies are usually required to cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies co-administration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the co-administered FPP (i.e. in addition to the other, aforementioned parameters for the mixture, the assay and degradation levels of each co-administered FPP should be reported).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS aborda la compatibilidad de productos farmac\u00e9uticos (FPP) con diluyentes y dispositivos de dosificaci\u00f3n. Se especifica que, en ciertos casos, no se requieren estudios de compatibilidad, especialmente para l\u00edquidos orales que se administran inmediatamente. Sin embargo, para productos reconstituidos que se diluyen posteriormente, se deben realizar estudios de compatibilidad con todos los diluyentes propuestos. Tambi\u00e9n se menciona la necesidad de datos sobre estabilidad f\u00edsica y qu\u00edmica, as\u00ed como la compatibilidad en el caso de conjuntos de infusi\u00f3n. Se enfatiza la importancia de realizar estudios en diferentes tipos de envases y bajo condiciones espec\u00edficas de almacenamiento.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de estudios de compatibilidad son necesarios para productos reconstituidos que se diluyen antes de la administraci\u00f3n?**\n   - Respuesta: Se deben demostrar la compatibilidad con todos los diluyentes sobre el rango de diluci\u00f3n propuesto en el etiquetado, preferiblemente utilizando muestras envejecidas.\n\n2. **\u00bfQu\u00e9 par\u00e1metros deben evaluarse para demostrar la compatibilidad en diferentes tipos de envases?**\n   - Respuesta: Se deben evaluar par\u00e1metros como apariencia, pH, ensayo, niveles de productos de degradaci\u00f3n individuales y totales, materia particulada subvisible y extractables de los componentes del envase en vidrio, PVC y poliolefina.\n\n3. **\u00bfQu\u00e9 datos son necesarios para respaldar la vida \u00fatil en uso y las condiciones de almacenamiento de una infusi\u00f3n preparada?**\n   - Respuesta: Se requieren datos sobre la estabilidad f\u00edsica y qu\u00edmica de la infusi\u00f3n preparada, datos de compatibilidad y control de especificaciones y abastecimiento seguro de todos los materiales de contacto del conjunto de infusi\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Dispositivos de Dosificaci\u00f3n**:\n   - Se requiere un dispositivo adecuado para medir la dosis en envases de medicamentos orales de m\u00faltiples dosis (ej. cucharas, jeringas orales, goteros).\n   - Es necesario demostrar la reproducibilidad del dispositivo, especialmente en la dosis m\u00e1s baja prevista.\n\n2. **Especificaciones de Materiales**:\n   - Se deben proporcionar especificaciones para los materiales del dispositivo, incluyendo pruebas de identificaci\u00f3n de los materiales en contacto con el producto farmac\u00e9utico terminado (FPP).\n\n3. **Presentaci\u00f3n Regulatoria**:\n   - Al presentar un Dossier de Producto (PD) en formato CTD, se debe incluir una muestra del dispositivo en el M\u00f3dulo 1.\n\n4. **Atributos Microbiol\u00f3gicos**:\n   - Se debe discutir la justificaci\u00f3n para no realizar pruebas de l\u00edmites microbianos en productos no est\u00e9riles y la efectividad de los sistemas de preservaci\u00f3n.\n   - Para productos est\u00e9riles, se debe asegurar la integridad del sistema de cierre del envase para prevenir la contaminaci\u00f3n microbiana.\n\n5. **Conservantes Antimicrobianos**:\n   - La cantidad de conservante antimicrobiano debe ser justificada mediante estudios que demuestren la concentraci\u00f3n m\u00e1s baja necesaria pero efectiva.\n   - La efectividad del conservante debe ser verificada por estudios apropiados, y si el l\u00edmite inferior de aceptaci\u00f3n es menor al 90.0%, se debe establecer la efectividad con un lote del FPP que contenga la concentraci\u00f3n correspondiente.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las directrices.\n- **Ph. Int.**: Referencia a la Farmacopea Internacional que establece normas para preparaciones l\u00edquidas orales.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que se presenta para su regulaci\u00f3n.\n- **Conservantes Antimicrobianos**: Sustancias utilizadas para prevenir el crecimiento microbiano en productos farmac\u00e9uticos. \n\nEste resumen abarca los aspectos esenciales relacionados con la presentaci\u00f3n de dispositivos de dosificaci\u00f3n y los atributos microbiol\u00f3gicos de los productos farmac\u00e9uticos, seg\u00fan lo estipulado en el documento de la OMS.", "excerpt_keywords": "compatibility, reconstitution, diluents, infusion sets, stability"}}, "c68bbc49-bf45-42f2-b4ca-69a24edab1bd": {"node_ids": ["6d8bbf84-7fe8-4636-b2ad-0b4fb5bdc171"], "metadata": {"page_label": "123", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 4. Glossary\n\nThe definitions given below apply to the terms as used in these guidelines. They may have different meanings in other contexts.\n\n**active pharmaceutical ingredient**\n\nAny substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.\n\n**comparator product**\n\nThe comparator product is a pharmaceutical product with which the multisource product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality have been established. The selection of the comparator product is usually made at the national level by the medicines regulatory authority. (For the WHO Prequalification of Medicines Programme, the selection of the comparator product is based on the information presented under Guidance on bioequivalence studies available on the Prequalification web site.)\n\n**control strategy**\n\nA planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to active pharmaceutical ingredient and finished pharmaceutical product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.\n\n**critical process parameter (CPP)**\n\nA process parameter whose variability has an impact on a critical quality attribute and, therefore, should be monitored or controlled to ensure the process produces the desired quality.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento \"WHO - Technical Report Series 970\" incluye un glosario que define t\u00e9rminos clave relacionados con la fabricaci\u00f3n de productos farmac\u00e9uticos. Se abordan conceptos como el \"ingrediente farmac\u00e9utico activo\", el \"producto comparador\", la \"estrategia de control\" y el \"par\u00e1metro cr\u00edtico del proceso\". Estas definiciones son esenciales para entender las directrices sobre la calidad y la regulaci\u00f3n de los medicamentos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1l es la diferencia entre un ingrediente farmac\u00e9utico activo y un producto comparador seg\u00fan el documento?**\n   - Esta pregunta busca aclarar las definiciones y roles de estos dos t\u00e9rminos en el contexto de la fabricaci\u00f3n y regulaci\u00f3n de medicamentos.\n\n2. **\u00bfQu\u00e9 elementos se consideran en una estrategia de control para asegurar la calidad del producto farmac\u00e9utico?**\n   - Esta pregunta se enfoca en los componentes espec\u00edficos que forman parte de una estrategia de control, lo que puede ser crucial para la calidad del proceso de fabricaci\u00f3n.\n\n3. **\u00bfPor qu\u00e9 es importante monitorear los par\u00e1metros cr\u00edticos del proceso (CPP) en la producci\u00f3n farmac\u00e9utica?**\n   - Esta pregunta indaga sobre la relevancia de los CPP y su impacto en la calidad del producto final, lo que es fundamental para garantizar la eficacia y seguridad de los medicamentos.", "prev_section_summary": "### Temas Clave\n\n1. **Compatibilidad de Productos Farmac\u00e9uticos (FPP)**: Se aborda la necesidad de evaluar la compatibilidad de los FPP con diluyentes y dispositivos de dosificaci\u00f3n, considerando factores como la estabilidad y la interacci\u00f3n con los materiales de los envases.\n\n2. **Estudios de Compatibilidad**: Se especifica que no se requieren estudios de compatibilidad para l\u00edquidos orales que se administran inmediatamente. Sin embargo, para productos reconstituidos que se diluyen posteriormente, se deben realizar estudios de compatibilidad con todos los diluyentes propuestos.\n\n3. **Par\u00e1metros de Evaluaci\u00f3n**: Se deben evaluar varios par\u00e1metros para demostrar la compatibilidad, incluyendo apariencia, pH, niveles de productos de degradaci\u00f3n, materia particulada subvisible y extractables de los envases.\n\n4. **Conjuntos de Infusi\u00f3n**: Se requiere informaci\u00f3n sobre la estabilidad f\u00edsica y qu\u00edmica de las infusiones preparadas, as\u00ed como datos de compatibilidad y control de especificaciones para los materiales de contacto en conjuntos de infusi\u00f3n.\n\n5. **Condiciones de Almacenamiento**: Los estudios de compatibilidad deben cubrir la duraci\u00f3n de almacenamiento especificada en el etiquetado, con ejemplos de 24 horas a temperatura ambiente y 72 horas en refrigeraci\u00f3n.\n\n### Entidades\n\n- **FPP (Formulaciones Farmac\u00e9uticas)**: Productos que requieren evaluaci\u00f3n de compatibilidad.\n- **Diluyentes**: Sustancias con las que se eval\u00faa la compatibilidad de los FPP.\n- **Dispositivos de Dosificaci\u00f3n**: Equipos utilizados para administrar los FPP.\n- **Envases**: Materiales en los que se almacenan los FPP, como vidrio, PVC y poliolefina.\n- **Conjuntos de Infusi\u00f3n**: Sistemas utilizados para la administraci\u00f3n intravenosa de FPP.\n- **Estudios de Estabilidad**: Evaluaciones necesarias para respaldar la vida \u00fatil y las condiciones de almacenamiento de los FPP.\n\nEste resumen destaca la importancia de la compatibilidad en la formulaci\u00f3n y administraci\u00f3n de productos farmac\u00e9uticos, as\u00ed como los requisitos espec\u00edficos para garantizar su seguridad y eficacia.", "excerpt_keywords": "Keywords: pharmaceutical, active ingredient, comparator product, control strategy, critical process parameter"}}, "9dd249be-54a1-4ad2-806b-e254f70eba29": {"node_ids": ["cf94848a-9e25-454b-99fc-a20a34583b09"], "metadata": {"page_label": "124", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## critical quality attribute (CQA)\n\nA physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality.\n\n## finished pharmaceutical product (FPP)\n\nA finished dosage form of a pharmaceutical product, which has undergone all stages of manufacture, including packaging in its final container and labelling.\n\n## fixed-dose combination finished pharmaceutical product (FDC-FPP)\n\nA finished pharmaceutical product that contains two or more active pharmaceutical ingredients.\n\n## formal experimental design\n\nA structured, organized method for determining the relationship between factors affecting a process and the output of that process. Also known as \u201cdesign of experiments\u201d.\n\n## generic product\n\nSee multisource (generic) pharmaceutical products.\n\n## life-cycle\n\nAll phases in the life of a product from the initial development through marketing until the product\u2019s discontinuation.\n\n## multisource (generic) pharmaceutical products\n\nMultisource pharmaceutical products are pharmaceutically equivalent or pharmaceutically alternative products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable.\n\n## pharmaceutical alternatives\n\nProducts are pharmaceutical alternative(s) if they contain the same molar amount of the same active pharmaceutical moiety(s) but differ in dosage form (e.g. tablets versus capsules), and/or chemical form (e.g. different salts, different esters). Pharmaceutical alternatives deliver the same active moiety by the same route of administration but are otherwise not pharmaceutically equivalent. They may or may not be bioequivalent or therapeutically equivalent to the comparator product.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder con la informaci\u00f3n proporcionada en el contexto, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) se centra en las especificaciones para preparaciones farmac\u00e9uticas. Define varios t\u00e9rminos clave relacionados con la calidad y la fabricaci\u00f3n de productos farmac\u00e9uticos, incluyendo atributos cr\u00edticos de calidad, productos farmac\u00e9uticos terminados, combinaciones de dosis fijas, y alternativas farmac\u00e9uticas. Tambi\u00e9n se menciona el ciclo de vida de un producto y la equivalencia de productos gen\u00e9ricos.\n\n### Preguntas\n\n1. **\u00bfQu\u00e9 se entiende por \"atributo cr\u00edtico de calidad\" (CQA) y por qu\u00e9 es importante en la fabricaci\u00f3n de productos farmac\u00e9uticos?**\n   - Respuesta: Un CQA es una propiedad f\u00edsica, qu\u00edmica, biol\u00f3gica o microbiol\u00f3gica que debe estar dentro de un l\u00edmite, rango o distribuci\u00f3n apropiados para asegurar la calidad deseada del producto. Es importante porque garantiza que el producto final cumpla con los est\u00e1ndares de calidad necesarios para su eficacia y seguridad.\n\n2. **\u00bfCu\u00e1l es la diferencia entre un producto farmac\u00e9utico terminado (FPP) y un producto farmac\u00e9utico de combinaci\u00f3n de dosis fija (FDC-FPP)?**\n   - Respuesta: Un FPP es una forma de dosificaci\u00f3n final que ha pasado por todas las etapas de fabricaci\u00f3n, incluyendo el envasado y etiquetado. En cambio, un FDC-FPP es un tipo espec\u00edfico de FPP que contiene dos o m\u00e1s ingredientes farmac\u00e9uticos activos en una sola formulaci\u00f3n.\n\n3. **\u00bfQu\u00e9 son los productos farmac\u00e9uticos multisource y c\u00f3mo se relacionan con la equivalencia terap\u00e9utica?**\n   - Respuesta: Los productos farmac\u00e9uticos multisource son productos que son farmac\u00e9uticamente equivalentes o alternativos, y pueden o no ser terap\u00e9uticamente equivalentes. Aquellos que son terap\u00e9uticamente equivalentes son intercambiables, lo que significa que pueden ser utilizados de manera similar en el tratamiento de una condici\u00f3n m\u00e9dica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Ingredientes Farmac\u00e9uticos Activos (API)**:\n   - Definici\u00f3n: Sustancias o mezclas utilizadas en la fabricaci\u00f3n de formas farmac\u00e9uticas que tienen actividad farmacol\u00f3gica o efectos directos en la salud.\n\n2. **Producto Comparador**:\n   - Definici\u00f3n: Producto farmac\u00e9utico con el que se espera que un producto multisource sea intercambiable en la pr\u00e1ctica cl\u00ednica. Generalmente, es el producto innovador con eficacia, seguridad y calidad establecidas.\n\n3. **Estrategia de Control**:\n   - Definici\u00f3n: Conjunto planificado de controles que asegura el rendimiento del proceso y la calidad del producto. Incluye par\u00e1metros relacionados con los ingredientes activos, condiciones de operaci\u00f3n, controles en proceso y especificaciones del producto terminado.\n\n4. **Par\u00e1metro Cr\u00edtico del Proceso (CPP)**:\n   - Definici\u00f3n: Par\u00e1metro del proceso cuya variabilidad afecta a un atributo cr\u00edtico de calidad y que debe ser monitoreado o controlado para garantizar la calidad del producto final.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que establece directrices sobre la calidad y regulaci\u00f3n de medicamentos.\n- **Reguladores de Medicamentos**: Autoridades nacionales responsables de la selecci\u00f3n de productos comparadores y la regulaci\u00f3n de medicamentos.\n- **Productos Farmac\u00e9uticos**: Incluyen tanto ingredientes activos como productos terminados que se utilizan en el diagn\u00f3stico y tratamiento de enfermedades. \n\nEste resumen proporciona una visi\u00f3n general de los t\u00e9rminos y conceptos esenciales relacionados con la fabricaci\u00f3n y regulaci\u00f3n de productos farmac\u00e9uticos seg\u00fan el documento de la OMS.", "excerpt_keywords": "Keywords: pharmaceutical preparations, critical quality attribute, finished pharmaceutical product, fixed-dose combination, multisource products"}}, "a005cb34-0c8b-4e7a-9348-5d001a0a4ab6": {"node_ids": ["7691c42e-9737-4bbc-9c10-bf924ab02f8c"], "metadata": {"page_label": "125", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 3\n\n**pharmaceutical equivalence**  \nProducts are pharmaceutical equivalents if they contain the same molar amount of the same active pharmaceutical ingredient(s) in the same dosage form, if they meet comparable standards, and if they are intended to be administered by the same route. Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, as differences in the excipients and/or the manufacturing process and some other variables can lead to differences in product performance.\n\n**pharmaceutical product**  \nAny preparation for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient.\n\n**pilot-scale batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For example, for solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger; unless otherwise adequately justified.\n\n**primary batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product used in a stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf-life, as the case may be.\n\n**process robustness**  \nAbility of a process to tolerate variability of materials and changes of the process and equipment without negative impact on quality.\n\n**production batch**  \nA batch of an active pharmaceutical ingredient or finished pharmaceutical product manufactured at production scale by using production equipment in a production facility as specified in the application.\n\n**quality**  \nThe suitability of either an active pharmaceutical ingredient or a pharmaceutical product for its intended use. This term includes such attributes as the identity, strength and purity.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Anexo 3 aborda definiciones clave relacionadas con la equivalencia farmac\u00e9utica, los productos farmac\u00e9uticos, y los procesos de fabricaci\u00f3n. Se definen t\u00e9rminos como \"equivalencia farmac\u00e9utica\", \"producto farmac\u00e9utico\", \"lote a escala piloto\", \"lote primario\", \"robustez del proceso\", \"lote de producci\u00f3n\" y \"calidad\". Estas definiciones son fundamentales para entender la regulaci\u00f3n y el desarrollo de productos farmac\u00e9uticos, as\u00ed como su evaluaci\u00f3n en t\u00e9rminos de seguridad y eficacia.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 criterios deben cumplirse para que dos productos sean considerados equivalentes farmac\u00e9uticos?**\n   - Respuesta: Dos productos son considerados equivalentes farmac\u00e9uticos si contienen la misma cantidad molar del mismo(s) ingrediente(s) farmac\u00e9utico(s) activo(s) en la misma forma de dosificaci\u00f3n, cumplen con est\u00e1ndares comparables y est\u00e1n destinados a ser administrados por la misma v\u00eda.\n\n2. **\u00bfCu\u00e1l es la diferencia entre un lote a escala piloto y un lote de producci\u00f3n en la fabricaci\u00f3n de productos farmac\u00e9uticos?**\n   - Respuesta: Un lote a escala piloto es fabricado mediante un procedimiento que simula el proceso de un lote a escala de producci\u00f3n, generalmente siendo al menos una d\u00e9cima parte del tama\u00f1o de un lote de producci\u00f3n completo. En cambio, un lote de producci\u00f3n es fabricado a escala de producci\u00f3n utilizando equipos de producci\u00f3n en una instalaci\u00f3n especificada en la solicitud.\n\n3. **\u00bfQu\u00e9 se entiende por \"robustez del proceso\" en el contexto de la fabricaci\u00f3n farmac\u00e9utica?**\n   - Respuesta: La robustez del proceso se refiere a la capacidad de un proceso para tolerar variaciones en los materiales y cambios en el proceso y el equipo sin que esto afecte negativamente la calidad del producto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS aborda las especificaciones para preparaciones farmac\u00e9uticas y define varios t\u00e9rminos esenciales relacionados con la calidad y la fabricaci\u00f3n de productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n1. **Atributo Cr\u00edtico de Calidad (CQA)**: Propiedades f\u00edsicas, qu\u00edmicas, biol\u00f3gicas o microbiol\u00f3gicas que deben estar dentro de l\u00edmites apropiados para asegurar la calidad del producto.\n\n2. **Producto Farmac\u00e9utico Terminado (FPP)**: Forma de dosificaci\u00f3n final que ha completado todas las etapas de fabricaci\u00f3n, incluyendo el envasado y etiquetado.\n\n3. **Producto Farmac\u00e9utico de Combinaci\u00f3n de Dosis Fija (FDC-FPP)**: FPP que contiene dos o m\u00e1s ingredientes farmac\u00e9uticos activos en una sola formulaci\u00f3n.\n\n4. **Dise\u00f1o Experimental Formal**: M\u00e9todo estructurado para determinar la relaci\u00f3n entre factores que afectan un proceso y su resultado, tambi\u00e9n conocido como \"dise\u00f1o de experimentos\".\n\n5. **Producto Gen\u00e9rico**: Se refiere a productos farmac\u00e9uticos multisource.\n\n6. **Ciclo de Vida**: Todas las fases en la vida de un producto, desde su desarrollo inicial hasta su discontinuaci\u00f3n.\n\n7. **Productos Farmac\u00e9uticos Multisource**: Productos que son farmac\u00e9uticamente equivalentes o alternativos, que pueden o no ser terap\u00e9uticamente equivalentes. Los que son terap\u00e9uticamente equivalentes son intercambiables.\n\n8. **Alternativas Farmac\u00e9uticas**: Productos que contienen la misma cantidad molar del mismo principio activo, pero que difieren en forma de dosificaci\u00f3n o forma qu\u00edmica. Pueden no ser equivalentes farmac\u00e9uticamente, y su bioequivalencia o equivalencia terap\u00e9utica puede variar.\n\nEste resumen destaca la importancia de la calidad y la equivalencia en la fabricaci\u00f3n y regulaci\u00f3n de productos farmac\u00e9uticos, as\u00ed como los t\u00e9rminos clave que son fundamentales para entender el contexto de las especificaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: pharmaceutical equivalence, production batch, process robustness, quality, pilot-scale batch"}}, "9c587bd7-fbc5-49da-b7f0-a9031035e859": {"node_ids": ["1a723ba4-6ce9-427c-8d68-dfb5a3f81bac"], "metadata": {"page_label": "126", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## quality target product profile (QTPP)\n\nA prospective summary of the quality characteristics of a finished pharmaceutical product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the finished pharmaceutical product.\n\n## stringent regulatory authority (SRA)\n\nFor the purpose of this document, a stringent regulatory authority (SRA) is the medicines regulatory authority in a country which is:\n\n- (a) a member of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (European Union, Japan and the United States of America); or (b) an ICH Observer, being the European Free Trade Association as represented by SwissMedic and Health Canada (as may be updated from time to time); or (c) a regulatory authority associated with an ICH member through a legally binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time);\n\n- only in relation to good manufacturing practices inspections: a medicines regulatory authority that is a member of the Pharmaceutical Inspection Co-operation Scheme as specified at http://www.picscheme.org.\n\n## therapeutic equivalence\n\nTwo pharmaceutical products are considered to be therapeutically equivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and after administration in the same molar dose, their effects, with respect to both efficacy and safety, are essentially the same when administered to patients by the same route under the conditions specified in the labelling. This can be demonstrated by appropriate bioequivalence studies, such as pharmacokinetic, pharmacodynamic, clinical or in vitro studies.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento es un informe t\u00e9cnico de la Organizaci\u00f3n Mundial de la Salud (OMS) que aborda las especificaciones para preparaciones farmac\u00e9uticas. Se definen conceptos clave como el \"perfil de calidad del producto objetivo\" (QTPP), la \"autoridad reguladora estricta\" (SRA) y la \"equivalencia terap\u00e9utica\". El QTPP es un resumen prospectivo de las caracter\u00edsticas de calidad que un producto farmac\u00e9utico terminado debe alcanzar para garantizar su calidad, seguridad y eficacia. La SRA se refiere a las autoridades reguladoras de medicamentos en pa\u00edses que cumplen con ciertos est\u00e1ndares internacionales. La equivalencia terap\u00e9utica se refiere a la comparaci\u00f3n de productos farmac\u00e9uticos en t\u00e9rminos de eficacia y seguridad.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios que definen a una autoridad reguladora estricta (SRA) seg\u00fan el documento?**\n   - Respuesta: Una SRA es una autoridad reguladora de medicamentos en un pa\u00eds que es miembro de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH), un observador de la ICH, o una autoridad asociada a un miembro de la ICH a trav\u00e9s de un acuerdo de reconocimiento mutuo. Adem\u00e1s, en relaci\u00f3n con las inspecciones de buenas pr\u00e1cticas de fabricaci\u00f3n, debe ser miembro del Esquema de Cooperaci\u00f3n de Inspecci\u00f3n Farmac\u00e9utica.\n\n2. **\u00bfQu\u00e9 estudios son necesarios para demostrar la equivalencia terap\u00e9utica entre dos productos farmac\u00e9uticos?**\n   - Respuesta: La equivalencia terap\u00e9utica puede demostrarse mediante estudios de bioequivalencia apropiados, que pueden incluir estudios farmacocin\u00e9ticos, farmacodin\u00e1micos, cl\u00ednicos o in vitro.\n\n3. **\u00bfQu\u00e9 aspectos se consideran al definir el perfil de calidad del producto objetivo (QTPP) de un producto farmac\u00e9utico?**\n   - Respuesta: El QTPP es un resumen prospectivo que incluye las caracter\u00edsticas de calidad que se deben lograr en un producto farmac\u00e9utico terminado, teniendo en cuenta tanto la seguridad como la eficacia del producto.\n\nEstas preguntas y respuestas est\u00e1n dise\u00f1adas para proporcionar informaci\u00f3n espec\u00edfica que puede no estar f\u00e1cilmente disponible en otros documentos o fuentes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl Anexo 3 del documento de la OMS (Organizaci\u00f3n Mundial de la Salud) proporciona definiciones esenciales relacionadas con la equivalencia y calidad de los productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n1. **Equivalencia Farmac\u00e9utica**: Se refiere a productos que contienen la misma cantidad molar del mismo(s) ingrediente(s) activo(s) en la misma forma de dosificaci\u00f3n, cumplen con est\u00e1ndares comparables y est\u00e1n destinados a ser administrados por la misma v\u00eda. Se destaca que la equivalencia farmac\u00e9utica no garantiza equivalencia terap\u00e9utica.\n\n2. **Producto Farmac\u00e9utico**: Cualquier preparaci\u00f3n destinada a modificar o explorar sistemas fisiol\u00f3gicos o estados patol\u00f3gicos en humanos o animales, con el fin de beneficiar al receptor.\n\n3. **Lote a Escala Piloto**: Un lote fabricado que simula el proceso de producci\u00f3n a gran escala, generalmente siendo al menos una d\u00e9cima parte del tama\u00f1o de un lote de producci\u00f3n completo.\n\n4. **Lote Primario**: Lote utilizado en estudios de estabilidad para establecer per\u00edodos de rean\u00e1lisis o vida \u00fatil, cuyos datos se presentan en una solicitud de registro.\n\n5. **Robustez del Proceso**: Capacidad de un proceso para manejar variaciones en los materiales y cambios en el proceso y equipo sin afectar negativamente la calidad del producto.\n\n6. **Lote de Producci\u00f3n**: Lote fabricado a escala de producci\u00f3n utilizando equipos y instalaciones especificadas en la solicitud.\n\n7. **Calidad**: Se refiere a la idoneidad de un ingrediente activo o producto farmac\u00e9utico para su uso previsto, incluyendo atributos como identidad, potencia y pureza.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite el documento.\n- **Ingredientes Farmac\u00e9uticos Activos**: Sustancias que tienen un efecto terap\u00e9utico.\n- **Formas de Dosificaci\u00f3n**: M\u00e9todos en que se administran los medicamentos (tabletas, c\u00e1psulas, etc.).\n- **Estudios de Estabilidad**: Evaluaciones para determinar la duraci\u00f3n y condiciones de almacenamiento de un producto farmac\u00e9utico.\n\nEste resumen proporciona una visi\u00f3n general de los conceptos fundamentales que son cruciales para la regulaci\u00f3n y desarrollo de productos farmac\u00e9uticos, as\u00ed como su evaluaci\u00f3n en t\u00e9rminos de seguridad y eficacia.", "excerpt_keywords": "Keywords: pharmaceutical preparations, quality target product profile, stringent regulatory authority, therapeutic equivalence, bioequivalence studies"}}, "2105e4e1-e23e-4a6d-8f0b-197296e45d91": {"node_ids": ["6744ab3b-c7cc-4f5c-886a-a49cdd6bf4a7"], "metadata": {"page_label": "127", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# References\n\n1. WHO Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012, Annex 4 (WHO Technical Report Series, No. 970).\n\n2. Q6A: Specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999; http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q6A/Step4/Q6Astep4.pdf.\n\n3. The International Pharmacopoeia, 4th ed., Vol. 1. General notices; monographs for pharmaceutical substances (A\u2013O) and Vol. 2: Monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents. Geneva, World Health Organization, 2006, also available in CD-ROM format and online.\n\n   *The International Pharmacopoeia, 4th ed., First supplement.* Geneva, World Health Organization, 2008 (http://apps.who.int/phint/en/p/docf/).\n\n   *The International Pharmacopoeia, 4th ed., Second supplement,* 2011, available on CD-ROM.\n\n4. Prasad B et al. A new validated differential scanning calorimetric procedure for monitoring the less active R,S isomer of ethambutol dihydrochloride in bulk drug samples and anti-tuberculosis formulations. *Pharmacopeial Forum,* 2007, 33: 326-333.\n\n5. European pharmacopoeia, 7th ed. Strasbourg, European Directorate for the Quality of Medicines, 2010.\n\n6. Guidelines for registration of fixed-dose combination medicinal products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n7. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n8. M4: ICH Harmonised Tripartite Guideline \u2013 Organisation of the common technical document for the registration of pharmaceuticals for human use. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2004 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R3_Organisation/M4_R3__organisation.pdf).\n\n9. M4Q: ICH Harmonised Tripartite Guideline \u2013 The common technical document for the registration of pharmaceuticals for human use: quality. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2000.\n\n10. Q8: Pharmaceutical development. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf).\n\n11. Q9: Quality risk management. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2005 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento es el \"WHO Technical Report Series 970\", que incluye referencias sobre directrices y especificaciones para la presentaci\u00f3n de documentaci\u00f3n relacionada con productos farmac\u00e9uticos gen\u00e9ricos y multisource. Se mencionan varias gu\u00edas de la Organizaci\u00f3n Mundial de la Salud (OMS) y de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) que abordan aspectos de calidad, desarrollo farmac\u00e9utico, gesti\u00f3n de riesgos y requisitos de registro para productos farmac\u00e9uticos. Tambi\u00e9n se citan publicaciones relevantes, como la Farmacopea Internacional y la Farmacopea Europea.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las principales diferencias entre las gu\u00edas de la OMS y las de la ICH en relaci\u00f3n con la calidad de los productos farmac\u00e9uticos?**\n   - Esta pregunta busca una comparaci\u00f3n directa que no se aborda expl\u00edcitamente en el documento, pero que puede ser inferida a partir de las referencias.\n\n2. **\u00bfQu\u00e9 procedimientos espec\u00edficos se recomiendan para la validaci\u00f3n de m\u00e9todos anal\u00edticos en la evaluaci\u00f3n de is\u00f3meros de medicamentos, seg\u00fan el art\u00edculo de Prasad et al.?**\n   - Esta pregunta se centra en un estudio espec\u00edfico mencionado en el documento, que podr\u00eda no estar ampliamente disponible en otras fuentes.\n\n3. **\u00bfC\u00f3mo se define la \"intercambiabilidad\" en el contexto de los productos farmac\u00e9uticos multisource seg\u00fan las directrices de la OMS?**\n   - Esta pregunta busca una definici\u00f3n precisa que puede no estar claramente explicada en otras partes del documento o en otras fuentes.\n\n### Resumen de Nivel Superior\n\nEl \"WHO Technical Report Series 970\" proporciona un marco de referencia para la calidad y el registro de productos farmac\u00e9uticos gen\u00e9ricos y multisource. Incluye directrices sobre la presentaci\u00f3n de documentaci\u00f3n, especificaciones de calidad, y m\u00e9todos anal\u00edticos, as\u00ed como referencias a normativas internacionales. Este documento es crucial para asegurar que los productos farmac\u00e9uticos cumplan con los est\u00e1ndares necesarios para su aprobaci\u00f3n y uso en el mercado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Perfil de Calidad del Producto Objetivo (QTPP)**:\n   - Definici\u00f3n: Un resumen prospectivo de las caracter\u00edsticas de calidad que un producto farmac\u00e9utico terminado debe alcanzar para garantizar su calidad, seguridad y eficacia.\n\n2. **Autoridad Reguladora Estricta (SRA)**:\n   - Definici\u00f3n: Autoridad reguladora de medicamentos en un pa\u00eds que cumple con ciertos est\u00e1ndares internacionales.\n   - Criterios:\n     - Miembro de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) (ej. Uni\u00f3n Europea, Jap\u00f3n, EE. UU.).\n     - Observador de la ICH (ej. Asociaci\u00f3n Europea de Libre Comercio).\n     - Autoridad asociada a un miembro de la ICH mediante un acuerdo de reconocimiento mutuo (ej. Australia, Islandia, Liechtenstein, Noruega).\n     - En relaci\u00f3n con las inspecciones de buenas pr\u00e1cticas de fabricaci\u00f3n, debe ser miembro del Esquema de Cooperaci\u00f3n de Inspecci\u00f3n Farmac\u00e9utica.\n\n3. **Equivalencia Terap\u00e9utica**:\n   - Definici\u00f3n: Dos productos farmac\u00e9uticos son considerados equivalentes si son equivalentes farmac\u00e9uticos o alternativas farmac\u00e9uticas y, tras la administraci\u00f3n en la misma dosis molar, sus efectos en eficacia y seguridad son esencialmente los mismos.\n   - Demostraci\u00f3n: A trav\u00e9s de estudios de bioequivalencia, que pueden incluir estudios farmacocin\u00e9ticos, farmacodin\u00e1micos, cl\u00ednicos o in vitro.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable del documento.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Organizaci\u00f3n que establece est\u00e1ndares para la regulaci\u00f3n de productos farmac\u00e9uticos.\n- **Esquema de Cooperaci\u00f3n de Inspecci\u00f3n Farmac\u00e9utica**: Iniciativa que agrupa a autoridades reguladoras para asegurar buenas pr\u00e1cticas de fabricaci\u00f3n.\n\nEste resumen destaca los conceptos fundamentales y las entidades relevantes en el contexto de las especificaciones para preparaciones farmac\u00e9uticas seg\u00fan el informe de la OMS.", "excerpt_keywords": "Keywords: pharmaceutical quality, WHO guidelines, ICH standards, generic medicines, regulatory requirements"}}, "54f6c785-bd93-4e5d-afa7-c140b98a27e1": {"node_ids": ["c6344b35-2f14-4950-945c-4987c7a7cac5"], "metadata": {"page_label": "128", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Forty-sixth report\n\n12. **Q10: Pharmaceutical quality system.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008 http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf.\n\n13. **Inactive ingredient guide.** US Food and Drug Administration http://www.accessdata.fda.gov/ scripts/cder/iig/index.cfm.\n\n14. Rowe RC, Sheskey PJ, Quinn ME, eds. **Handbook of pharmaceutical excipients, 6th ed.** London, Pharmaceutical Press, 2009.\n\n15. **Excipients in the label and package leaflet of medicinal products for human use.** Committee for Proprietary Medicinal Products, 2003 (CPMP/463/00Final).\n\n16. **Development of paediatric medicines: points to consider in pharmaceutical development.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report.* Geneva, World Health Organization, 2012, Annex 5 (WHO Technical Report Series, No. 970).\n\n17. **Containers \u2013 glass.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n18. **Glass containers for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 303\u2013307\n\n19. **Plastic containers and closures for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 308\u2013309.\n\n20. **Containers \u2013 plastic.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n21. **Elastomeric closures for injections.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007: 144\u2013145.\n\n22. **Rubber closures for containers.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 316\u2013317.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento es el \"Cuarenta y sexto informe\" de la Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas. Incluye referencias a gu\u00edas y manuales sobre sistemas de calidad farmac\u00e9utica, excipientes, y contenedores para productos farmac\u00e9uticos. Se mencionan normativas y documentos relevantes de la FDA, la Farmacopea de los Estados Unidos y la Farmacopea Europea, as\u00ed como consideraciones para el desarrollo de medicamentos pedi\u00e1tricos.\n\n### Preguntas\n\n1. **\u00bfQu\u00e9 documento de la Conferencia Internacional sobre Armonizaci\u00f3n se menciona en el informe y cu\u00e1l es su enfoque principal?**\n   - Respuesta: Se menciona el documento \"Q10: Pharmaceutical quality system\", que se centra en los requisitos t\u00e9cnicos para el registro de productos farmac\u00e9uticos para uso humano, publicado en 2008.\n\n2. **\u00bfCu\u00e1les son algunas de las consideraciones espec\u00edficas para el desarrollo de medicamentos pedi\u00e1tricos seg\u00fan el informe?**\n   - Respuesta: El informe incluye un anexo titulado \"Development of paediatric medicines: points to consider in pharmaceutical development\", que aborda aspectos clave en el desarrollo de medicamentos destinados a la poblaci\u00f3n pedi\u00e1trica.\n\n3. **\u00bfQu\u00e9 tipos de contenedores para productos farmac\u00e9uticos se discuten en el informe y qu\u00e9 normativas se citan para cada tipo?**\n   - Respuesta: Se discuten contenedores de vidrio y pl\u00e1stico, as\u00ed como cierres elastom\u00e9ricos y de goma. Se citan normativas de la Farmacopea de los Estados Unidos y la Farmacopea Europea para cada tipo de contenedor, especificando las ediciones y secciones relevantes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Directrices de la OMS**:\n   - Se mencionan las \"Gu\u00edas de la OMS sobre la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos gen\u00e9ricos\" y otros informes relevantes que establecen est\u00e1ndares de calidad y requisitos de registro.\n\n2. **Especificaciones de Calidad**:\n   - Referencias a documentos como Q6A, Q8 y Q9 de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) que abordan especificaciones, desarrollo farmac\u00e9utico y gesti\u00f3n de riesgos.\n\n3. **Farmacopeas**:\n   - Se citan la \"Farmacopea Internacional\" y la \"Farmacopea Europea\", que proporcionan monograf\u00edas y m\u00e9todos de an\u00e1lisis para sustancias farmac\u00e9uticas.\n\n4. **Intercambiabilidad de Productos**:\n   - Directrices sobre la intercambiabilidad de productos farmac\u00e9uticos multisource, destacando la importancia de establecer requisitos claros para su registro.\n\n5. **M\u00e9todos Anal\u00edticos**:\n   - Se menciona un estudio espec\u00edfico sobre un procedimiento de calorimetr\u00eda diferencial para monitorear is\u00f3meros de etambutol, lo que resalta la importancia de la validaci\u00f3n de m\u00e9todos anal\u00edticos en la evaluaci\u00f3n de medicamentos.\n\n6. **Publicaciones y Documentos**:\n   - Se listan varios documentos y gu\u00edas relevantes que son fundamentales para la regulaci\u00f3n y calidad de los productos farmac\u00e9uticos, incluyendo enlaces a recursos en l\u00ednea.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad en la regulaci\u00f3n de medicamentos y directrices de calidad.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Organizaci\u00f3n que establece est\u00e1ndares internacionales para la regulaci\u00f3n de productos farmac\u00e9uticos.\n- **Farmacopea Internacional**: Compendio de est\u00e1ndares de calidad para medicamentos.\n- **Farmacopea Europea**: Documento que establece normas para la calidad de medicamentos en Europa.\n- **Prasad B et al.**: Autores de un estudio sobre m\u00e9todos anal\u00edticos para is\u00f3meros de medicamentos.\n\nEste resumen destaca la importancia de las directrices y est\u00e1ndares internacionales en la regulaci\u00f3n y calidad de los productos farmac\u00e9uticos, as\u00ed como la necesidad de m\u00e9todos anal\u00edticos validados para asegurar la eficacia y seguridad de los medicamentos.", "excerpt_keywords": "Keywords: pharmaceutical quality, excipients, pediatric medicines, containers, regulatory guidelines"}}, "69bbb4d5-e909-4839-90eb-28083551b8d5": {"node_ids": ["24299a43-9dae-4a0f-accc-ad39c237b7dc"], "metadata": {"page_label": "129", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 1\n\n## Examples of presenting quality attributes of active pharmaceutical ingredients\n\nPhysicochemical characteristics of the active pharmaceutical ingredient (API) that can influence manufacturing capability and the performance of the finished pharmaceutical product (FPP) should be tabulated and discussed, for example, as in the following tables.\n\n| pH (of the buffer) | Solubility (mg/ml) |\n|--------------------|--------------------|\n| 1.2                |                    |\n| 4.5                |                    |\n| 6.8                |                    |\n| pKa of API         |                    |\n\nMethod (compendial):\n\n### Particle size of API used in relevant laboratory and pilot-scale batches\n\n| Measured data (\u00b5m)\\<br/>\\<API batch no.> \\<FPP batch no.> (design) | Batch number (and use)\\<br/>\\<API batch no.> \\<FPP batch no.> (final laboratory) | Batch number (and use)\\<br/>Proposed acceptance range (\u00b5m)\\<br/>\\<API batch no.> \\<FPP batch no.> (stability) | Batch number (and use)\\<br/>\\<API batch no.> \\<FPP batch no.> (bioequivalence) | Batch number (and use) | |\n| - | - | - | - | - | - |\n| D 10 | | | | | |\n| D 50 | | | | | |\n| D 90 | | | | | |\n\n\n*Add rows as needed. Change data range as relevant.*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Informe T\u00e9cnico 970 incluye un ap\u00e9ndice que presenta ejemplos de c\u00f3mo se pueden presentar los atributos de calidad de los ingredientes farmac\u00e9uticos activos (API). Se enfatiza la importancia de las caracter\u00edsticas fisicoqu\u00edmicas del API, que pueden influir en la capacidad de fabricaci\u00f3n y el rendimiento del producto farmac\u00e9utico terminado (FPP). Se proporcionan tablas para registrar datos sobre el pH, la solubilidad y el tama\u00f1o de part\u00edcula del API en diferentes lotes, as\u00ed como su uso en estudios de estabilidad y bioequivalencia.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 atributos fisicoqu\u00edmicos del API se consideran importantes para la fabricaci\u00f3n y el rendimiento del FPP seg\u00fan el documento?**\n   - Respuesta: El documento menciona el pH del buffer, la solubilidad (mg/ml) y el pKa del API como atributos fisicoqu\u00edmicos importantes que pueden influir en la capacidad de fabricaci\u00f3n y el rendimiento del producto farmac\u00e9utico terminado.\n\n2. **\u00bfC\u00f3mo se debe presentar la informaci\u00f3n sobre el tama\u00f1o de part\u00edcula del API en los lotes de laboratorio y piloto seg\u00fan las directrices de la OMS?**\n   - Respuesta: La informaci\u00f3n sobre el tama\u00f1o de part\u00edcula del API debe presentarse en una tabla que incluya datos medidos (D10, D50, D90) junto con los n\u00fameros de lote y su uso en diferentes contextos, como laboratorio final, estabilidad y bioequivalencia.\n\n3. **\u00bfQu\u00e9 se sugiere hacer con las tablas presentadas en el ap\u00e9ndice en t\u00e9rminos de personalizaci\u00f3n y adaptaci\u00f3n?**\n   - Respuesta: Se sugiere que se pueden agregar filas seg\u00fan sea necesario y que se pueden cambiar los rangos de datos para que sean relevantes a las circunstancias espec\u00edficas de cada API y FPP.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl **Cuarenta y sexto informe** de la **Comisi\u00f3n de Expertos de la OMS sobre Especificaciones para Preparaciones Farmac\u00e9uticas** aborda varios temas relevantes en el \u00e1mbito de la calidad farmac\u00e9utica y el desarrollo de medicamentos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n#### Temas Clave:\n1. **Sistema de Calidad Farmac\u00e9utica (Q10)**: Se menciona el documento de la Conferencia Internacional sobre Armonizaci\u00f3n que establece los requisitos t\u00e9cnicos para el registro de productos farmac\u00e9uticos.\n2. **Gu\u00eda de Excipientes Inactivos**: Referencia a la FDA sobre la regulaci\u00f3n de excipientes en productos farmac\u00e9uticos.\n3. **Desarrollo de Medicamentos Pedi\u00e1tricos**: Consideraciones espec\u00edficas para la formulaci\u00f3n y desarrollo de medicamentos dirigidos a la poblaci\u00f3n infantil.\n4. **Contenedores Farmac\u00e9uticos**: Discusi\u00f3n sobre diferentes tipos de contenedores (vidrio y pl\u00e1stico) y sus normativas asociadas, incluyendo cierres elastom\u00e9ricos y de goma.\n\n#### Entidades Mencionadas:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Publicador del informe.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Entidad que proporciona directrices sobre calidad farmac\u00e9utica.\n- **Administraci\u00f3n de Alimentos y Medicamentos de EE. UU. (FDA)**: Referenciada en relaci\u00f3n con la gu\u00eda de excipientes.\n- **Farmacopea de los Estados Unidos**: Cita de normativas sobre contenedores y cierres.\n- **Farmacopea Europea**: Referencias a normativas sobre contenedores y cierres para uso farmac\u00e9utico.\n\nEste informe es fundamental para entender las normativas y consideraciones en la calidad y desarrollo de productos farmac\u00e9uticos, especialmente en el contexto de la pediatr\u00eda y el uso de excipientes.", "excerpt_keywords": "Keywords: active pharmaceutical ingredients, physicochemical characteristics, manufacturing capability, finished pharmaceutical product, particle size"}}, "3159bb96-360a-4dd3-930d-90d1bd0a30d6": {"node_ids": ["d0be2c9e-bc73-462c-9081-a083f1e48e3d"], "metadata": {"page_label": "130", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Method (compendial):\n\n### Apparent density of API used in relevant laboratory and pilot-scale batches\n\n| \\<API batch no.> \\<FPP batch no.> (design) | \\<API batch no.> \\<FPP batch no.> (final laboratory) | \\<API batch no.> \\<FPP batch no.> (stability) | \\<API batch no.> \\<FPP batch no.> (bioequivalence) | Proposed acceptance range (g/ml) |\n| - | - | - | - | - |\n| Bulk | | | | |\n| Tapped | | | | |\n\n\n## Method (compendial):\n\n| Stress Condition | Treatment | Observations |\n| - | - | - |\n| None | Initial values of the API | Assay: S1: *Insert as many rows as necessary* D1: *Insert as many rows as necessary* Total unspecified: Total impurities: |\n| Temperature | A thin layer of the API is kept at 80 \u00b0C for 4 weeks in a Petri dish (open system) with sampling once a week | Assay: S1: D1: Total unspecified: Total impurities: |\n\n\n*continues*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 par\u00e1metros se eval\u00faan en el m\u00e9todo de densidad aparente del API en lotes de laboratorio y escala piloto?**\n   - En el m\u00e9todo de densidad aparente del API, se eval\u00faan dos tipos de densidad: la densidad a granel (Bulk) y la densidad compactada (Tapped). Se registran los n\u00fameros de lote del API y del producto farmac\u00e9utico terminado (FPP) en diferentes etapas: dise\u00f1o, laboratorio final, estabilidad y bioequivalencia, junto con un rango de aceptaci\u00f3n propuesto en gramos por mililitro (g/ml).\n\n2. **\u00bfQu\u00e9 condiciones de estr\u00e9s se consideran en el m\u00e9todo compendial para evaluar la estabilidad del API?**\n   - En el m\u00e9todo compendial, se consideran condiciones de estr\u00e9s como la temperatura. Un tratamiento espec\u00edfico implica mantener una delgada capa del API a 80 \u00b0C durante 4 semanas en un plato de Petri (sistema abierto), con muestreo una vez por semana. Las observaciones incluyen el an\u00e1lisis de la pureza y las impurezas del API a lo largo del tiempo.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n se debe registrar en las observaciones durante el tratamiento del API bajo condiciones de estr\u00e9s?**\n   - Durante el tratamiento del API bajo condiciones de estr\u00e9s, se deben registrar los valores iniciales del API y los resultados del ensayo, que incluyen S1 (primer conjunto de datos) y D1 (segundo conjunto de datos). Tambi\u00e9n se debe documentar el total de impurezas no especificadas y el total de impurezas encontradas.\n\n### Resumen de nivel superior del contexto:\nEl documento se centra en los m\u00e9todos compendiales utilizados para evaluar la densidad aparente y la estabilidad de los ingredientes farmac\u00e9uticos activos (API) en diferentes etapas de producci\u00f3n. Se describen las condiciones de estr\u00e9s que se aplican al API, as\u00ed como los par\u00e1metros que se deben observar y registrar durante las pruebas de estabilidad. Esto es crucial para garantizar la calidad y la eficacia de los productos farmac\u00e9uticos.", "prev_section_summary": "### Resumen de los temas clave y entidades de la secci\u00f3n:\n\n1. **Atributos de Calidad de los Ingredientes Farmac\u00e9uticos Activos (API)**:\n   - Se destacan las caracter\u00edsticas fisicoqu\u00edmicas del API que son cruciales para la fabricaci\u00f3n y el rendimiento del producto farmac\u00e9utico terminado (FPP).\n\n2. **Caracter\u00edsticas Fisicoqu\u00edmicas**:\n   - **pH del buffer**: Se presentan valores espec\u00edficos (1.2, 4.5, 6.8) y el pKa del API.\n   - **Solubilidad**: Se menciona la necesidad de registrar la solubilidad en mg/ml.\n\n3. **Tama\u00f1o de Part\u00edcula**:\n   - Se proporciona un formato tabular para registrar el tama\u00f1o de part\u00edcula del API (D10, D50, D90) en diferentes lotes y contextos, como laboratorio, estabilidad y bioequivalencia.\n\n4. **Personalizaci\u00f3n de Tablas**:\n   - Se sugiere que las tablas pueden ser adaptadas a\u00f1adiendo filas y modificando los rangos de datos seg\u00fan las necesidades espec\u00edficas de cada API y FPP.\n\n5. **M\u00e9todo Compendial**:\n   - Se menciona la importancia de seguir m\u00e9todos estandarizados para la medici\u00f3n y presentaci\u00f3n de datos.\n\n### Entidades Clave:\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que tiene un efecto farmacol\u00f3gico.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que contiene el API.\n- **pH, Solubilidad, pKa**: Atributos fisicoqu\u00edmicos relevantes.\n- **D10, D50, D90**: Medidas del tama\u00f1o de part\u00edcula del API.\n\nEste resumen encapsula los elementos esenciales del ap\u00e9ndice, destacando la importancia de los atributos de calidad en la industria farmac\u00e9utica y la necesidad de una presentaci\u00f3n clara y adaptable de los datos.", "excerpt_keywords": "Keywords: API, FPP, compendial methods, stability testing, apparent density"}}, "ec6a0bf9-fa5d-49c4-8d80-2e465d447d0e": {"node_ids": ["ab278607-253c-4e06-b01a-eea4dbed8d61"], "metadata": {"page_label": "131", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "\n| Stress Condition | Treatment | Observations |\n| - | - | - |\n| Humidity | A thin layer of the API is kept at 40 \u00b0C / 100% relative humidity for 4 weeks in a Petri dish (open system) with sampling once a fortnight | Assay: S1: D1: Total unspecified: Total impurities: |\n| Oxidation | Oxygen is bubbled slowly through the oxygen-saturated aqueous solution/suspension (under constant mixing) of the API for 24 hours with sampling every 8 hours | Assay: S1: D1: Total unspecified: Total impurities: |\n\n\nS1, S2, etc., are synthesis impurities (as in API specifications).  \nD1, D2, etc., are degradation products.\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Technical Report Series 970) presenta un estudio sobre la estabilidad de un principio activo (API) bajo diferentes condiciones de estr\u00e9s, como la humedad y la oxidaci\u00f3n. Se describen los tratamientos aplicados, que incluyen mantener el API en condiciones espec\u00edficas de temperatura y humedad, as\u00ed como la exposici\u00f3n a ox\u00edgeno. Se realizan muestreos peri\u00f3dicos para evaluar la presencia de impurezas de s\u00edntesis (S1, S2, etc.) y productos de degradaci\u00f3n (D1, D2, etc.).\n\n### Preguntas\n1. **\u00bfQu\u00e9 condiciones espec\u00edficas de temperatura y humedad se utilizan para evaluar la estabilidad del API en el estudio?**\n   - Respuesta: Se mantiene una capa del API a 40 \u00b0C y 100% de humedad relativa durante 4 semanas en un plato de Petri.\n\n2. **\u00bfCon qu\u00e9 frecuencia se realizan los muestreos durante el tratamiento de oxidaci\u00f3n del API?**\n   - Respuesta: Se realizan muestreos cada 8 horas durante un tratamiento de 24 horas en el que se burbujea ox\u00edgeno a trav\u00e9s de una soluci\u00f3n/suspensi\u00f3n acuosa saturada de ox\u00edgeno del API.\n\n3. **\u00bfQu\u00e9 tipos de impurezas se analizan en el estudio y c\u00f3mo se clasifican?**\n   - Respuesta: Se analizan impurezas de s\u00edntesis (S1, S2, etc.) y productos de degradaci\u00f3n (D1, D2, etc.), que se reportan en los resultados de los ensayos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Comit\u00e9 de Expertos de la OMS**: El documento es parte de un informe del Comit\u00e9 de Expertos de la Organizaci\u00f3n Mundial de la Salud (OMS) sobre especificaciones para preparaciones farmac\u00e9uticas.\n\n2. **M\u00e9todos Compendiales**: Se describen m\u00e9todos estandarizados para evaluar la densidad aparente y la estabilidad de los ingredientes farmac\u00e9uticos activos (API).\n\n3. **Densidad Aparente del API**:\n   - **Tipos de Densidad**: Se eval\u00faan dos tipos de densidad: \n     - **Densidad a Granel (Bulk)**: Medida de la densidad del API en su estado suelto.\n     - **Densidad Compactada (Tapped)**: Medida de la densidad del API despu\u00e9s de ser compactado.\n   - **Registro de Datos**: Se requiere el registro de n\u00fameros de lote del API y del producto farmac\u00e9utico terminado (FPP) en diferentes etapas (dise\u00f1o, laboratorio final, estabilidad, bioequivalencia) y un rango de aceptaci\u00f3n propuesto en gramos por mililitro (g/ml).\n\n4. **Condiciones de Estr\u00e9s para Evaluaci\u00f3n de Estabilidad**:\n   - **Condiciones Consideradas**: Se menciona el estr\u00e9s t\u00e9rmico como una condici\u00f3n de evaluaci\u00f3n.\n   - **Tratamiento**: Un tratamiento espec\u00edfico implica mantener una delgada capa del API a 80 \u00b0C durante 4 semanas en un plato de Petri, con muestreo semanal.\n   - **Observaciones**: Se deben registrar los valores iniciales del API y los resultados del ensayo, incluyendo datos sobre pureza y total de impurezas.\n\n5. **Importancia de la Evaluaci\u00f3n**: La evaluaci\u00f3n de la densidad y estabilidad del API es crucial para garantizar la calidad y eficacia de los productos farmac\u00e9uticos.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable del documento.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia cuya densidad y estabilidad se eval\u00faan.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que contiene el API.\n- **Condiciones de Estr\u00e9s**: Factores como temperatura que afectan la estabilidad del API. \n\nEste resumen destaca los aspectos fundamentales del documento, centr\u00e1ndose en los m\u00e9todos de evaluaci\u00f3n de la calidad de los ingredientes farmac\u00e9uticos activos.", "excerpt_keywords": "Keywords: API, stability, humidity, oxidation, impurities"}}, "ac100f0d-cbf6-4a98-ab6f-0f592ba87c58": {"node_ids": ["5550e6d3-2f8d-4930-834f-79ddbf9b1ebe"], "metadata": {"page_label": "132", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 2\n\n## Information on development batches\n\n**Table 1**  \nScreening laboratory batches with different proportions of excipients to match comparator dissolution\n\n| Ingredients\\<br/>Grams | Lab01\\<br/>% | Lab01\\<br/>Lab02\\<br/>Grams | Lab02\\<br/>Lab03\\<br/>% | Lab03\\<br/>Lab04\\<br/>Grams | Lab04\\<br/>% | Grams | % | |\n| - | - | - | - | - | - | - | - | - |\n| active pharmaceutical ingredient (API) 1 | | | | | | | | |\n| API 2 | | | | | | | | |\n| API 3 | | | | | | | | |\n| Excipient 1 | | | | | | | | |\n| Excipient 2 | | | | | | | | |\n| Excipient 3 | | | | | | | | |\n| Excipient 4 | | | | | | | | |\n| Excipient 5 | | | | | | | | |\n| Dissolution, % at pH \u2026 | | | | | | | | |\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento \"WHO - Technical Report Series 970\" incluye un ap\u00e9ndice que proporciona informaci\u00f3n sobre lotes de desarrollo de productos farmac\u00e9uticos. En particular, se presenta una tabla que detalla las proporciones de excipientes utilizados en diferentes lotes de laboratorio para igualar la disoluci\u00f3n de un comparador. La tabla incluye ingredientes activos y excipientes, as\u00ed como datos sobre la disoluci\u00f3n en diferentes condiciones.\n\n### Preguntas\n1. **\u00bfQu\u00e9 ingredientes activos y excipientes se est\u00e1n evaluando en los lotes de laboratorio seg\u00fan la tabla presentada en el ap\u00e9ndice?**\n   - Esta pregunta busca identificar los componentes espec\u00edficos que se est\u00e1n utilizando en el desarrollo de los lotes, lo cual es crucial para entender la formulaci\u00f3n del producto.\n\n2. **\u00bfC\u00f3mo se comparan las proporciones de excipientes entre los diferentes laboratorios seg\u00fan la tabla?**\n   - Esta pregunta se centra en las diferencias en las formulaciones entre los laboratorios, lo que puede ser relevante para evaluar la consistencia y la eficacia de los lotes desarrollados.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n se proporciona sobre la disoluci\u00f3n de los lotes en diferentes pH, y por qu\u00e9 es importante esta informaci\u00f3n en el desarrollo de productos farmac\u00e9uticos?**\n   - Esta pregunta busca profundizar en la importancia de los datos de disoluci\u00f3n en el contexto del desarrollo farmac\u00e9utico, lo que puede influir en la biodisponibilidad y la eficacia del medicamento.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl contenido extra\u00eddo del documento de la OMS (Technical Report Series 970) se centra en la evaluaci\u00f3n de la estabilidad de un principio activo (API) bajo condiciones de estr\u00e9s espec\u00edficas. Los temas clave incluyen:\n\n1. **Condiciones de Estr\u00e9s**:\n   - **Humedad**: Se mantiene el API a 40 \u00b0C y 100% de humedad relativa durante 4 semanas en un sistema abierto (plato de Petri).\n   - **Oxidaci\u00f3n**: Se introduce ox\u00edgeno en una soluci\u00f3n acuosa saturada de ox\u00edgeno del API durante 24 horas, con agitaci\u00f3n constante.\n\n2. **Muestreo**:\n   - En la prueba de humedad, se realiza un muestreo cada dos semanas.\n   - En la prueba de oxidaci\u00f3n, se realizan muestreos cada 8 horas.\n\n3. **An\u00e1lisis de Impurezas**:\n   - Se analizan impurezas de s\u00edntesis (designadas como S1, S2, etc.) y productos de degradaci\u00f3n (designados como D1, D2, etc.).\n   - Los resultados de los ensayos incluyen la evaluaci\u00f3n de impurezas totales y productos no especificados.\n\n### Entidades Clave\n- **API (Principio Activo)**: Sustancia cuyo comportamiento se estudia bajo condiciones de estr\u00e9s.\n- **Condiciones de Estr\u00e9s**: Humedad y oxidaci\u00f3n.\n- **M\u00e9todos de Muestreo**: Muestreo cada 8 horas y cada dos semanas.\n- **Clasificaci\u00f3n de Impurezas**: Impurezas de s\u00edntesis (S1, S2, etc.) y productos de degradaci\u00f3n (D1, D2, etc.).\n\nEste resumen proporciona una visi\u00f3n general de los m\u00e9todos y objetivos del estudio sobre la estabilidad del API, as\u00ed como la clasificaci\u00f3n de los compuestos analizados.", "excerpt_keywords": "Keywords: pharmaceutical development, excipients, dissolution testing, active pharmaceutical ingredients, laboratory batches"}}, "42611fbf-9e27-4460-97ab-f140e973c97f": {"node_ids": ["43875ca6-a304-4b9b-9232-223bf97212d5"], "metadata": {"page_label": "133", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Table 2\nExample table for developmental multipoint dissolution profiles (hypothetical example \u2013 Ph. Int., paddle, 75 rpm, 900 ml)\n\n| Time (min) | Percentage API dissolved | Percentage API dissolved | Percentage API dissolved |\n|------------|--------------------------|--------------------------|--------------------------|\n|            | pH 1.2 buffer            | pH 4.5 buffer            | pH 6.8 buffer            |\n| 5          |                          |                          |                          |\n| 10         |                          |                          |                          |\n| 15         |                          |                          |                          |\n| 20         |                          |                          |                          |\n| 30         |                          |                          |                          |\n| 45         |                          |                          |                          |\n| 60         |                          |                          |                          |\n| 90         |                          |                          |                          |\n\nRepeat the table as needed, for example, for comparator product and development batch chosen for scale-up.\n\nWhen comparing dissolution profiles of products, for example, comparator and test products or different strengths of the same product, the dissolution conditions and sampling intervals must be the same.\n\n**Graphical presentation and summary evaluation of the results of comparative dissolution studies of the test (samples taken from the bioequivalence batch no. \u2026) and comparator products:**", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) presenta un ejemplo de tabla para perfiles de disoluci\u00f3n multipunto en el desarrollo de productos farmac\u00e9uticos. Se menciona la importancia de mantener condiciones de disoluci\u00f3n y intervalos de muestreo consistentes al comparar perfiles de disoluci\u00f3n de productos, como productos de referencia y productos en desarrollo. La tabla incluye tiempos espec\u00edficos y porcentajes de API (ingrediente farmac\u00e9utico activo) disueltos en diferentes buffers (pH 1.2, 4.5 y 6.8). Tambi\u00e9n se sugiere que se repita la tabla para productos comparadores y lotes de desarrollo seleccionados para escalado.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 condiciones de disoluci\u00f3n se deben mantener al comparar perfiles de disoluci\u00f3n de productos farmac\u00e9uticos?**\n   - Las condiciones de disoluci\u00f3n y los intervalos de muestreo deben ser los mismos al comparar perfiles de disoluci\u00f3n de productos, como productos comparadores y productos de prueba o diferentes concentraciones del mismo producto.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n se debe incluir en la tabla de perfiles de disoluci\u00f3n multipunto seg\u00fan el ejemplo proporcionado?**\n   - La tabla debe incluir el tiempo en minutos y el porcentaje de API disuelto en diferentes buffers (pH 1.2, 4.5 y 6.8) en intervalos de tiempo espec\u00edficos (5, 10, 15, 20, 30, 45, 60 y 90 minutos).\n\n3. **\u00bfCu\u00e1l es el prop\u00f3sito de repetir la tabla de perfiles de disoluci\u00f3n en el contexto del desarrollo farmac\u00e9utico?**\n   - La tabla debe repetirse para incluir datos de productos comparadores y lotes de desarrollo seleccionados para escalado, lo que permite una evaluaci\u00f3n comparativa de la disoluci\u00f3n entre diferentes formulaciones y condiciones de prueba.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl ap\u00e9ndice 2 del documento \"WHO - Technical Report Series 970\" se centra en la informaci\u00f3n sobre lotes de desarrollo de productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n#### Temas Clave:\n1. **Desarrollo de Lotes**: Se discuten los lotes de laboratorio que se est\u00e1n evaluando para determinar la formulaci\u00f3n adecuada de un producto farmac\u00e9utico.\n2. **Proporciones de Excipientes**: La tabla presenta diferentes proporciones de excipientes utilizadas en varios laboratorios para igualar la disoluci\u00f3n de un comparador, lo que es esencial para la formulaci\u00f3n del medicamento.\n3. **Dissoluci\u00f3n**: Se incluye informaci\u00f3n sobre la disoluci\u00f3n de los lotes en diferentes condiciones de pH, lo que es crucial para evaluar la biodisponibilidad y eficacia del producto.\n\n#### Entidades:\n- **Ingredientes Activos**: Se mencionan varios ingredientes activos (API 1, API 2, API 3) que son componentes clave en la formulaci\u00f3n del medicamento.\n- **Excipientes**: Se listan varios excipientes (Excipient 1, Excipient 2, Excipient 3, Excipient 4, Excipient 5) que se utilizan en las formulaciones.\n- **Laboratorios**: Se hace referencia a diferentes laboratorios (Lab01, Lab02, Lab03, Lab04) que est\u00e1n involucrados en el desarrollo y evaluaci\u00f3n de los lotes.\n\nEste resumen destaca la importancia de la formulaci\u00f3n y la evaluaci\u00f3n de la disoluci\u00f3n en el desarrollo de productos farmac\u00e9uticos, as\u00ed como los componentes espec\u00edficos involucrados en este proceso.", "excerpt_keywords": "Keywords: dissolution profiles, pharmaceutical development, bioequivalence, API dissolution, comparative studies"}}, "a07d034b-4d9d-4cc0-8cd9-217e47bc64ec": {"node_ids": ["25abcf89-fe4a-4276-8f60-1e1726783f01"], "metadata": {"page_label": "134", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto del documento \"WHO - Technical Report Series 970\":\n\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentadas en el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre el contenido del informe, que podr\u00eda no estar disponible en otros documentos o res\u00famenes.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en el estudio presentado en el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta se centra en las t\u00e9cnicas y enfoques utilizados en la investigaci\u00f3n, lo que puede ser crucial para entender la validez y aplicabilidad de los resultados.\n\n3. **\u00bfC\u00f3mo se relaciona el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS con otros informes previos en la misma serie?**\n   - Esta pregunta busca establecer conexiones y comparaciones entre diferentes informes, lo que puede proporcionar una visi\u00f3n m\u00e1s amplia del desarrollo de la investigaci\u00f3n en el \u00e1rea tratada.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica y recomendaciones para pol\u00edticas de salud. El Informe 46 en particular podr\u00eda contener hallazgos significativos, metodolog\u00edas de investigaci\u00f3n y recomendaciones que impacten en la pr\u00e1ctica de la salud p\u00fablica a nivel global.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Perfiles de Disoluci\u00f3n Multipunto**: Se presenta un ejemplo de tabla para registrar los perfiles de disoluci\u00f3n multipunto de productos farmac\u00e9uticos, destacando la importancia de evaluar la disoluci\u00f3n en diferentes condiciones de pH (1.2, 4.5 y 6.8).\n\n2. **Condiciones de Disoluci\u00f3n**: Se enfatiza que al comparar perfiles de disoluci\u00f3n de productos (como productos de prueba y productos comparadores), es crucial mantener las mismas condiciones de disoluci\u00f3n y los mismos intervalos de muestreo.\n\n3. **Intervalos de Tiempo**: La tabla incluye intervalos de tiempo espec\u00edficos (5, 10, 15, 20, 30, 45, 60 y 90 minutos) para medir el porcentaje de ingrediente farmac\u00e9utico activo (API) disuelto.\n\n4. **Repetici\u00f3n de la Tabla**: Se sugiere que la tabla se repita para incluir datos de productos comparadores y lotes de desarrollo seleccionados para escalado, lo que permite una evaluaci\u00f3n comparativa m\u00e1s completa.\n\n5. **Evaluaci\u00f3n Gr\u00e1fica**: Se menciona la necesidad de una presentaci\u00f3n gr\u00e1fica y una evaluaci\u00f3n resumida de los resultados de los estudios de disoluci\u00f3n comparativa entre los productos de prueba y los productos comparadores.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad del documento.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Componente clave en la evaluaci\u00f3n de disoluci\u00f3n.\n- **Buffers**: Soluciones utilizadas en las pruebas de disoluci\u00f3n (pH 1.2, 4.5, 6.8).\n- **Productos Comparadores y de Prueba**: Tipos de productos farmac\u00e9uticos en estudio.\n- **Lotes de Desarrollo**: Referencia a las formulaciones en desarrollo que se est\u00e1n evaluando.\n\nEste resumen destaca la estructura y los elementos esenciales del contenido relacionado con los perfiles de disoluci\u00f3n en el contexto del desarrollo farmac\u00e9utico.", "excerpt_keywords": "Keywords: OMS, Informe 46, disoluci\u00f3n, farmac\u00e9uticos, salud p\u00fablica"}}, "d0a7e4f7-a1d4-40b2-99f2-cba800ec62b6": {"node_ids": ["0ce96b3e-5784-4f06-9825-b55e7ad9e8b2"], "metadata": {"page_label": "135", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n**Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part**\n\n## 1. Introduction\n1.1 Background  \n1.2 Objectives  \n1.3 Scope  \n1.4 General principles  \n1.5 Guidance on format  \n\n## 2. Glossary\n\n## 3. Quality summaries\n3.1 Module 2.3: Quality overall summary \u2013 product dossiers (QOS-PD)  \n3.2 Module 1.4.2: Quality information summary (QIS)  \n\n## 4. Module 3: Quality\n4.1 Table of contents of Module 3  \n4.2 Body of data  \n    3.2.S Drug substance (or active pharmaceutical ingredient (API))  \n    3.2.P Drug product (or finished pharmaceutical product (FPP))  \n    3.2.A Appendices  \n    3.2.R Regional information  \n4.3 Literature references  \n\n## References\n\n## Appendix 1\nRecommendations for conducting and assessing comparative dissolution profiles  \n\n## Appendix 2\nProduct quality review requirements for *established multisource products*  \n\n----\n\n| Section | Page |\n|---------|------|\n| 1. Introduction | 122 |\n| 2. Glossary | 125 |\n| 3. Quality summaries | 128 |\n| 4. Module 3: Quality | 129 |\n| References | 189 |\n| Appendix 1 | 193 |\n| Appendix 2 | 195 |", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder espec\u00edficamente con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento es una gu\u00eda de la Organizaci\u00f3n Mundial de la Salud (OMS) sobre la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos gen\u00e9ricos en el marco del Programa de Precalificaci\u00f3n de Medicamentos. Se centra en la parte de calidad y detalla los m\u00f3dulos y secciones que deben incluirse en la documentaci\u00f3n, as\u00ed como las recomendaciones para la evaluaci\u00f3n de perfiles de disoluci\u00f3n y los requisitos de revisi\u00f3n de calidad para productos multisource establecidos.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son los m\u00f3dulos espec\u00edficos que se deben incluir en la documentaci\u00f3n de calidad para productos farmac\u00e9uticos gen\u00e9ricos seg\u00fan la gu\u00eda de la OMS?**\n   - Respuesta: La gu\u00eda menciona varios m\u00f3dulos, incluyendo el M\u00f3dulo 2.3 (Quality overall summary \u2013 product dossiers) y el M\u00f3dulo 1.4.2 (Quality information summary), as\u00ed como el M\u00f3dulo 3 que abarca el contenido del cuerpo de datos, que incluye informaci\u00f3n sobre la sustancia activa (API) y el producto terminado (FPP).\n\n2. **\u00bfQu\u00e9 secciones se recomiendan para la evaluaci\u00f3n de perfiles de disoluci\u00f3n comparativa en productos farmac\u00e9uticos gen\u00e9ricos?**\n   - Respuesta: El documento incluye un Ap\u00e9ndice 1 que proporciona recomendaciones espec\u00edficas para la realizaci\u00f3n y evaluaci\u00f3n de perfiles de disoluci\u00f3n comparativa, lo cual es crucial para demostrar la equivalencia de calidad entre productos gen\u00e9ricos y sus productos de referencia.\n\n3. **\u00bfQu\u00e9 requisitos se establecen para la revisi\u00f3n de calidad de productos multisource establecidos en el contexto de la precalificaci\u00f3n de medicamentos?**\n   - Respuesta: El Ap\u00e9ndice 2 del documento detalla los requisitos de revisi\u00f3n de calidad para productos multisource establecidos, lo que implica que se deben cumplir ciertos criterios para asegurar que estos productos mantengan est\u00e1ndares de calidad adecuados para su aprobaci\u00f3n en el programa de precalificaci\u00f3n de la OMS.", "prev_section_summary": "El contenido de la secci\u00f3n se refiere al \"WHO - Technical Report Series 970\", espec\u00edficamente al Informe 46 de esta serie. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas:\n\n### Temas Clave:\n1. **Hallazgos y Recomendaciones**: Se busca informaci\u00f3n sobre los principales hallazgos y recomendaciones del Informe 46, lo que indica que el documento aborda aspectos relevantes para la salud p\u00fablica.\n2. **Metodolog\u00edas de Investigaci\u00f3n**: Se menciona la importancia de las metodolog\u00edas utilizadas en el estudio, sugiriendo que el informe detalla los enfoques y t\u00e9cnicas aplicadas en la investigaci\u00f3n.\n3. **Relaci\u00f3n con Informes Previos**: Se plantea la necesidad de comparar el Informe 46 con otros informes de la misma serie, lo que sugiere un inter\u00e9s en la evoluci\u00f3n y continuidad de la investigaci\u00f3n en el \u00e1rea de salud p\u00fablica.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la publicaci\u00f3n de la serie de informes t\u00e9cnicos.\n- **Informe 46**: Espec\u00edfico documento dentro de la serie que se est\u00e1 analizando.\n\n### Contexto General:\nEl documento forma parte de una serie de informes t\u00e9cnicos que abordan temas de salud p\u00fablica y recomendaciones para pol\u00edticas de salud, lo que resalta su relevancia en el \u00e1mbito global de la salud.", "excerpt_keywords": "Keywords: WHO, pharmaceutical, quality, guidelines, prequalification"}}, "c3f6b3a9-15f0-4d0d-a2fb-cffc0cfd0688": {"node_ids": ["64f5df98-cd81-4d72-b32e-db8b0dfc98ae"], "metadata": {"page_label": "136", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\n## 1.1 Background\n\nThe *Procedure for prequalification of pharmaceutical products* (1) outlines the procedure and considerations for the process undertaken by WHO in providing United Nations agencies with advice on the acceptability, in principle, of pharmaceutical products for procurement by such agencies. It states:\n\n> \"This activity of WHO aims to facilitate access to priority essential medicines that meet WHO-recommended norms and standards of acceptable quality.\"\n\nAs mentioned in WHO Technical Report Series, No. 961 (1), in submitting an expression of interest (EOI) for product evaluation, the applicant should send a product dossier (PD) to the WHO focal point (together with the other data required), in the format specified in the WHO guidance documents on submitting product data and information.\n\nThrough the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) process, considerable harmonization has been achieved on the organization for the Quality module of the registration documents with the issuance of the *Common technical document (CTD) - quality (ICH M4Q)* guideline (2). This format, recommended in the M4Q guideline for the quality information of registration applications, has become widely accepted by regulatory authorities both within and beyond the ICH regions.\n\nThe current document provides recommendations on the quality information for active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs) that should be submitted to WHO to support PDs.\n\nAlternative approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. It is also important to note that the WHO Prequalification of Medicines Programme may request information or material, or define conditions not specifically described in this guidance, in order to adequately assess the quality of a pharmaceutical product.\n\n## 1.2 Objectives\n\nThese guidelines are intended to:\n\n- assist applicants in the preparation of the *Quality Module* of PDs for multisource products by providing clear general guidance on the format of these dossiers;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que pueden ser respondidas por el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla el procedimiento para la precalificaci\u00f3n de productos farmac\u00e9uticos, que busca facilitar el acceso a medicamentos esenciales que cumplan con los est\u00e1ndares de calidad recomendados por la OMS. Se menciona la importancia de enviar un expediente de producto (PD) en un formato espec\u00edfico y se hace referencia a la armonizaci\u00f3n lograda a trav\u00e9s de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH). Adem\u00e1s, se establecen recomendaciones sobre la informaci\u00f3n de calidad que debe incluirse en los PDs para ingredientes farmac\u00e9uticos activos (APIs) y productos farmac\u00e9uticos terminados (FPPs).\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 es un expediente de producto (PD) y qu\u00e9 informaci\u00f3n debe incluir para la evaluaci\u00f3n de la OMS?**\n   - El expediente de producto (PD) es un conjunto de documentos que los solicitantes deben enviar a la OMS al presentar una expresi\u00f3n de inter\u00e9s para la evaluaci\u00f3n de un producto. Debe incluir informaci\u00f3n sobre la calidad de los ingredientes farmac\u00e9uticos activos (APIs) y productos farmac\u00e9uticos terminados (FPPs), siguiendo el formato especificado en las gu\u00edas de la OMS.\n\n2. **\u00bfC\u00f3mo ha influido la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) en el proceso de registro de productos farmac\u00e9uticos?**\n   - La ICH ha logrado una considerable armonizaci\u00f3n en la organizaci\u00f3n del m\u00f3dulo de calidad de los documentos de registro mediante la emisi\u00f3n de la gu\u00eda del *Common Technical Document (CTD) - quality (ICH M4Q)*, que ha sido ampliamente aceptada por las autoridades regulatorias tanto dentro como fuera de las regiones de la ICH.\n\n3. **\u00bfQu\u00e9 alternativas pueden ser aceptables en el proceso de precalificaci\u00f3n de medicamentos seg\u00fan la OMS?**\n   - Alternativas a los principios y pr\u00e1cticas descritos en el documento pueden ser aceptables siempre que est\u00e9n respaldadas por una justificaci\u00f3n cient\u00edfica adecuada. Adem\u00e1s, el Programa de Precalificaci\u00f3n de Medicamentos de la OMS puede solicitar informaci\u00f3n o material adicional que no est\u00e9 espec\u00edficamente descrito en la gu\u00eda para evaluar adecuadamente la calidad de un producto farmac\u00e9utico.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento es una gu\u00eda de la Organizaci\u00f3n Mundial de la Salud (OMS) que proporciona directrices sobre la presentaci\u00f3n de documentaci\u00f3n para productos farmac\u00e9uticos gen\u00e9ricos en el contexto del Programa de Precalificaci\u00f3n de Medicamentos, espec\u00edficamente en la parte de calidad. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n#### Temas Clave:\n1. **Introducci\u00f3n**: Contexto, objetivos, alcance, principios generales y formato de la documentaci\u00f3n.\n2. **Glosario**: Definiciones de t\u00e9rminos relevantes utilizados en el documento.\n3. **Res\u00famenes de Calidad**:\n   - M\u00f3dulo 2.3: Resumen general de calidad para dossiers de productos.\n   - M\u00f3dulo 1.4.2: Resumen de informaci\u00f3n de calidad.\n4. **M\u00f3dulo 3: Calidad**:\n   - Contenido del cuerpo de datos, incluyendo informaci\u00f3n sobre la sustancia activa (API) y el producto terminado (FPP).\n   - Informaci\u00f3n regional y ap\u00e9ndices.\n5. **Referencias**: Fuentes citadas en el documento.\n6. **Ap\u00e9ndices**:\n   - Ap\u00e9ndice 1: Recomendaciones para la evaluaci\u00f3n de perfiles de disoluci\u00f3n comparativa.\n   - Ap\u00e9ndice 2: Requisitos de revisi\u00f3n de calidad para productos multisource establecidos.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la gu\u00eda.\n- **Productos farmac\u00e9uticos gen\u00e9ricos**: Tipo de productos a los que se aplica la gu\u00eda.\n- **Sustancia activa (API)**: Componente clave en la formulaci\u00f3n de medicamentos.\n- **Producto farmac\u00e9utico terminado (FPP)**: Producto final que se presenta para la precalificaci\u00f3n.\n- **M\u00f3dulos y Ap\u00e9ndices**: Estructura organizativa del documento que detalla los requisitos y recomendaciones.\n\nEste resumen proporciona una visi\u00f3n general de los elementos esenciales de la secci\u00f3n, destacando la importancia de la calidad en la documentaci\u00f3n para la precalificaci\u00f3n de medicamentos gen\u00e9ricos.", "excerpt_keywords": "Keywords: prequalification, pharmaceutical products, WHO, quality module, active pharmaceutical ingredients"}}, "8e1aadaa-9fa1-4746-b72c-b81eeec34e8a": {"node_ids": ["f9333025-a1fc-4b2f-a546-8f7031fead66"], "metadata": {"page_label": "137", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Scope\n\nThese guidelines apply to PDs for multisource pharmaceutical products containing existing APIs of synthetic or semi-synthetic origin. For the purposes of these guidelines, an existing API is one that has been previously approved through a finished product by a stringent regulatory authority (SRA)<sup>1</sup> or by WHO. Fermentation, biological, biotechnological and herbal APIs are covered by other guidelines.\n\n# General principles\n\nTo facilitate the preparation of the PD, these guidelines are organized in accordance with the structure of the ICH Common technical document \u2013 quality (M4Q) guideline (2).\n\nThe text of the M4Q (CTD-Q) guideline (2) has been restated verbatim in these guidelines in **bold text**, with minor modifications to accommodate WHO terminology and to include certain text that would be appropriate for multisource pharmaceutical products, notably:\n\n- \u201cDrug substance\u201d is replaced with \u201cactive pharmaceutical ingredient\u201d or \u201cAPI\u201d.\n- \u201cDrug product\u201d is replaced with \u201cfinished pharmaceutical product\u201d or \u201cFPP\u201d.\n- \u201cApplication\u201d is replaced with \u201cproduct dossier\u201d or \u201cPD\u201d.\n- \u201cCombination product\u201d is replaced with \u201cfixed-dose combination\u201d or \u201cFDC\u201d.\n- \u201cClinical batches\u201d is replaced with \u201ccomparative bioavailability\u201d or \u201cbiowaiver batches\u201d.\n\n----\n\n<sup>1</sup> A stringent regulatory authority (SRA): a regulatory authority which is:\n- a member of the International Conference on Harmonisation (ICH) (as specified on www.ich.org); or\n- an ICH observer, being the European Free Trade Association (EFTA), as represented by SwissMedic, and Health Canada (as may be updated from time to time); or\n- a regulatory authority associated with an ICH member through a legally-binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento es un conjunto de directrices de la OMS que se aplica a los expedientes de productos (PD) para productos farmac\u00e9uticos multisource que contienen ingredientes farmac\u00e9uticos activos (API) existentes de origen sint\u00e9tico o semisint\u00e9tico. Se establece que un API existente es aquel que ha sido aprobado previamente por una autoridad reguladora estricta (SRA) o por la OMS. Las directrices est\u00e1n organizadas seg\u00fan la estructura del documento t\u00e9cnico com\u00fan de ICH y contienen modificaciones para adaptarse a la terminolog\u00eda de la OMS.\n\n### Preguntas\n1. **\u00bfQu\u00e9 se entiende por un \"API existente\" seg\u00fan las directrices de la OMS?**\n   - Un \"API existente\" es un ingrediente farmac\u00e9utico activo que ha sido previamente aprobado a trav\u00e9s de un producto terminado por una autoridad reguladora estricta (SRA) o por la OMS.\n\n2. **\u00bfC\u00f3mo se han adaptado las terminolog\u00edas del documento t\u00e9cnico com\u00fan de ICH en las directrices de la OMS?**\n   - Las terminolog\u00edas han sido adaptadas de la siguiente manera: \"Drug substance\" se convierte en \"active pharmaceutical ingredient\" (API), \"Drug product\" en \"finished pharmaceutical product\" (FPP), \"Application\" en \"product dossier\" (PD), \"Combination product\" en \"fixed-dose combination\" (FDC), y \"Clinical batches\" en \"comparative bioavailability\" o \"biowaiver batches\".\n\n3. **\u00bfQu\u00e9 tipos de APIs no est\u00e1n cubiertos por estas directrices de la OMS?**\n   - Las directrices no cubren APIs de fermentaci\u00f3n, biol\u00f3gicos, biotecnol\u00f3gicos y herbales, ya que estos est\u00e1n regulados por otras directrices espec\u00edficas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Procedimiento de Precalificaci\u00f3n de Productos Farmac\u00e9uticos**: El documento describe el proceso que sigue la OMS para evaluar la aceptabilidad de productos farmac\u00e9uticos para su adquisici\u00f3n por agencias de las Naciones Unidas, con el objetivo de facilitar el acceso a medicamentos esenciales que cumplan con los est\u00e1ndares de calidad recomendados.\n\n2. **Expediente de Producto (PD)**: Se requiere que los solicitantes env\u00eden un expediente de producto al presentar una expresi\u00f3n de inter\u00e9s para la evaluaci\u00f3n. Este expediente debe incluir informaci\u00f3n sobre la calidad de los ingredientes farmac\u00e9uticos activos (APIs) y productos farmac\u00e9uticos terminados (FPPs), siguiendo un formato espec\u00edfico.\n\n3. **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Se menciona la influencia de la ICH en la armonizaci\u00f3n de los documentos de registro, destacando la gu\u00eda del *Common Technical Document (CTD) - quality (ICH M4Q)*, que ha sido adoptada por diversas autoridades regulatorias.\n\n4. **Recomendaciones sobre Informaci\u00f3n de Calidad**: El documento proporciona directrices sobre la informaci\u00f3n de calidad que debe incluirse en los PDs para APIs y FPPs, y permite enfoques alternativos siempre que est\u00e9n respaldados por justificaci\u00f3n cient\u00edfica.\n\n5. **Programa de Precalificaci\u00f3n de Medicamentos de la OMS**: Este programa puede solicitar informaci\u00f3n adicional o definir condiciones no descritas en la gu\u00eda para evaluar adecuadamente la calidad de un producto farmac\u00e9utico.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la precalificaci\u00f3n de productos farmac\u00e9uticos.\n- **Naciones Unidas**: Agencias que adquieren productos farmac\u00e9uticos basados en la evaluaci\u00f3n de la OMS.\n- **ICH (Conferencia Internacional sobre Armonizaci\u00f3n)**: Organizaci\u00f3n que ha contribuido a la armonizaci\u00f3n de los requisitos de registro de productos farmac\u00e9uticos.\n- **APIs (Ingredientes Farmac\u00e9uticos Activos)**: Componentes activos de los productos farmac\u00e9uticos.\n- **FPPs (Productos Farmac\u00e9uticos Terminados)**: Productos finales que se ofrecen para su uso.", "excerpt_keywords": "Keywords: guidelines, pharmaceutical products, active pharmaceutical ingredient, stringent regulatory authority, product dossier"}}, "fbd651a4-130b-4d0a-9c8c-a1f88756886b": {"node_ids": ["b80d8c2b-cec7-43c7-a79d-81ea60249f06"], "metadata": {"page_label": "138", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAdditional guidance by WHO, following the **bold** text reproduced from the M4Q (CTD-Q) guideline (2), is printed in plain text to make it easily distinguishable from the ICH text and is included to provide further clarity on WHO\u2019s expectations for the content of PDs. This approach is intended to facilitate the identification and origin of the text in these guidelines (i.e. from ICH or from WHO).\n\nThe content of these guidelines should be read in conjunction with relevant information described in other existing WHO or ICH reference documents and guidelines. The quality of existing APIs and corresponding multisource products should not be inferior to new APIs and innovator (comparator) FPPs. Therefore, the principles of the ICH guidelines that are referenced throughout this document and in other WHO guidelines may equally apply to existing APIs and multisource products.\n\nScientific literature may be appropriate to fulfill the requirements for some of the information or parameters outlined in these guidelines (e.g. qualification of specified identified impurities). Furthermore, the requirements outlined in certain sections may not be applicable to the proposed API or FPP. In these situations, either a summary and the full reference to the scientific literature should be provided, or the non-applicability of the requested information should be clearly indicated with an accompanying explanatory note.\n\n## 1.5 Guidance on format\n\nThe recommendations outlined in the WHO general filing guideline *Guidelines on submission of documentation for a multisource (generic) finished product: general format: preparation of product dossiers in common technical document format* (3) should be followed for the format and presentation of the PD.\n\nThere may be a number of instances where repetition of sections can be considered appropriate. Whenever a section is repeated, it should be made clear what the section refers to by creating a distinguishing title in parentheses following the M4Q (CTD-Q) guideline heading, e.g. 3.2.S Drug substance (or API) (name, Manufacturer A).\n\nThe following are recommendations for the presentation of the information in the Quality module for different scenarios that may be encountered:\n\n- The Open part (non-proprietary information) of each APIMF should always be included in its entirety in the PD, as an annex to 3.2.S.\n- For an FPP containing more than one API, one complete \u201c3.2.S\u201d section should be provided for one API, followed by another complete \u201c3.2.S\u201d section for each of the other APIs.\n- For an API from multiple manufacturers, one complete \u201c3.2.S\u201d section should be provided for the API from one manufacturer, followed by", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con respuestas espec\u00edficas que probablemente no se encuentren en otro lugar:\n\n### Preguntas y Respuestas\n\n1. **\u00bfCu\u00e1l es la importancia de la calidad de los APIs existentes en comparaci\u00f3n con los nuevos APIs y FPPs innovadores seg\u00fan las directrices de la OMS?**\n   - La OMS establece que la calidad de los APIs existentes y los productos multisource no debe ser inferior a la de los nuevos APIs y los productos farmac\u00e9uticos terminados (FPPs) innovadores. Esto implica que los principios de las directrices de ICH aplicables a nuevos productos tambi\u00e9n son relevantes para los productos existentes, asegurando as\u00ed un est\u00e1ndar de calidad uniforme en el mercado.\n\n2. **\u00bfQu\u00e9 se debe hacer si ciertos requisitos de las directrices no son aplicables a un API o FPP propuesto?**\n   - En situaciones donde los requisitos de las directrices no son aplicables, se debe proporcionar un resumen y la referencia completa a la literatura cient\u00edfica que respalde esta decisi\u00f3n. Alternativamente, se debe indicar claramente la no aplicabilidad de la informaci\u00f3n solicitada, acompa\u00f1ada de una nota explicativa que justifique esta exclusi\u00f3n.\n\n3. **\u00bfC\u00f3mo se debe estructurar la presentaci\u00f3n de la informaci\u00f3n en el m\u00f3dulo de Calidad para un FPP que contiene m\u00faltiples APIs?**\n   - Para un FPP que contiene m\u00e1s de un API, se debe proporcionar una secci\u00f3n completa \u201c3.2.S\u201d para cada API. Esto significa que despu\u00e9s de la secci\u00f3n correspondiente a un API, se debe incluir otra secci\u00f3n \u201c3.2.S\u201d completa para cada uno de los otros APIs, asegurando que cada uno est\u00e9 claramente identificado y documentado.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS proporciona directrices sobre la calidad y presentaci\u00f3n de la documentaci\u00f3n para productos farmac\u00e9uticos, enfatizando que la calidad de los APIs existentes debe ser comparable a la de los nuevos productos. Se destaca la importancia de la literatura cient\u00edfica para justificar la no aplicabilidad de ciertos requisitos y se ofrecen recomendaciones espec\u00edficas sobre c\u00f3mo estructurar la informaci\u00f3n en el m\u00f3dulo de Calidad, especialmente en casos de m\u00faltiples APIs en un FPP.", "prev_section_summary": "### Temas Clave\n\n1. **Alcance de las Directrices**: Las directrices se aplican a los expedientes de productos (PD) para productos farmac\u00e9uticos multisource que contienen ingredientes farmac\u00e9uticos activos (API) existentes de origen sint\u00e9tico o semisint\u00e9tico.\n\n2. **Definici\u00f3n de API Existente**: Un API existente es aquel que ha sido aprobado previamente por una autoridad reguladora estricta (SRA) o por la OMS.\n\n3. **Exclusiones**: Las directrices no cubren APIs de fermentaci\u00f3n, biol\u00f3gicos, biotecnol\u00f3gicos y herbales, que est\u00e1n regulados por otras directrices.\n\n4. **Adaptaci\u00f3n de Terminolog\u00eda**: Las directrices han modificado la terminolog\u00eda del documento t\u00e9cnico com\u00fan de ICH para alinearse con la terminolog\u00eda de la OMS, incluyendo cambios en t\u00e9rminos como \"drug substance\" a \"active pharmaceutical ingredient\" (API) y \"drug product\" a \"finished pharmaceutical product\" (FPP).\n\n5. **Estructura de las Directrices**: Las directrices est\u00e1n organizadas de acuerdo con la estructura del documento t\u00e9cnico com\u00fan de ICH \u2013 calidad (M4Q).\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las directrices.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en los productos farmac\u00e9uticos.\n- **SRA (Autoridad Reguladora Estricta)**: Autoridades que han aprobado los APIs existentes.\n- **ICH (Conferencia Internacional sobre Armonizaci\u00f3n)**: Organizaci\u00f3n que establece directrices para la regulaci\u00f3n de productos farmac\u00e9uticos.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que contiene el API.\n- **FDC (Combinaci\u00f3n de Dosis Fija)**: Tipo de producto que combina m\u00faltiples APIs en una sola formulaci\u00f3n.\n- **Biowaiver Batches**: Lotes utilizados para estudios de bioequivalencia comparativa. \n\nEste resumen proporciona una visi\u00f3n general de los temas y entidades clave abordados en la secci\u00f3n del documento.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, APIs, quality guidelines, product dossiers"}}, "ca8015f2-eeeb-4445-be94-d759ed58a52d": {"node_ids": ["bb93380b-8a37-4065-bc66-1f9d7ebf18d9"], "metadata": {"page_label": "139", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Glossary\n\nThe definitions provided below apply to the words and phrases used in these guidelines. Although an effort has been made to use standard definitions as far as possible, they may have different meanings in other contexts and documents. The following definitions are provided to facilitate interpretation of the guidelines.\n\n### active pharmaceutical ingredient (API)\n\nAny substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form, and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body.\n\n### active pharmaceutical ingredient (API) starting material\n\nA raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house (ICH Q7). See also starting materials for synthesis.\n\n----\n\n- For an FPP with multiple strengths (e.g. 10, 50, 100 mg) one complete \"3.2.P\" section should be provided with the information for the different strengths provided within the subsections. One complete copy of the PD should be provided for each FPP strength.\n- For an FPP with multiple container-closure systems (e.g. bottles and unit dose blisters) one complete \"3.2.P\" section should be provided with the information for the different presentations provided within the subsections.\n- For multiple FPPs (e.g. tablets and a parenteral product) a separate dossier is required for each FPP.\n- For an FPP supplied with reconstitution diluent(s) one complete \"3.2.P\" section should be provided for the FPP, followed by the information on the diluent(s) in a separate part \"3.2.P\", as appropriate.\n- For a co-blistered FPP one complete \"3.2.P\" section should be provided for each product.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) presenta un glosario de t\u00e9rminos relacionados con los ingredientes farmac\u00e9uticos activos (API) y sus materiales de inicio. Define qu\u00e9 constituye un API y un material de inicio de API, adem\u00e1s de proporcionar directrices sobre la presentaci\u00f3n de informaci\u00f3n para productos farmac\u00e9uticos terminados (FPP) con diferentes caracter\u00edsticas, como m\u00faltiples concentraciones, sistemas de cierre y formulaciones.\n\n### Preguntas:\n\n1. **\u00bfQu\u00e9 se considera un \"material de inicio de API\" y c\u00f3mo se relaciona con la producci\u00f3n de un API?**\n   - Respuesta: Un material de inicio de API es una materia prima, intermedio o un API que se utiliza en la producci\u00f3n de un API y que se incorpora como un fragmento estructural significativo en la estructura del API. Puede ser un art\u00edculo comercial, un material adquirido de proveedores bajo contrato o producido internamente.\n\n2. **\u00bfQu\u00e9 requisitos se establecen para la presentaci\u00f3n de informaci\u00f3n sobre un FPP que tiene m\u00faltiples concentraciones?**\n   - Respuesta: Para un FPP con m\u00faltiples concentraciones (por ejemplo, 10, 50, 100 mg), se debe proporcionar una secci\u00f3n completa \"3.2.P\" que incluya la informaci\u00f3n para las diferentes concentraciones dentro de las subsecciones. Adem\u00e1s, se debe proporcionar una copia completa del documento de presentaci\u00f3n (PD) para cada concentraci\u00f3n del FPP.\n\n3. **\u00bfC\u00f3mo se debe manejar la informaci\u00f3n sobre un FPP que se suministra con diluyentes de reconstituci\u00f3n?**\n   - Respuesta: Para un FPP que se suministra con diluyentes de reconstituci\u00f3n, se debe proporcionar una secci\u00f3n completa \"3.2.P\" para el FPP, seguida de la informaci\u00f3n sobre los diluyentes en una parte separada \"3.2.P\", seg\u00fan sea apropiado.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Calidad de APIs y FPPs**:\n   - La OMS establece que la calidad de los APIs existentes y los productos multisource no debe ser inferior a la de los nuevos APIs y FPPs innovadores. Esto asegura un est\u00e1ndar de calidad uniforme en el mercado.\n\n2. **Uso de Literatura Cient\u00edfica**:\n   - Se permite el uso de literatura cient\u00edfica para cumplir con ciertos requisitos de las directrices. Si un requisito no es aplicable, se debe proporcionar un resumen y la referencia completa a la literatura o indicar claramente su no aplicabilidad con una nota explicativa.\n\n3. **Estructura de Documentaci\u00f3n**:\n   - Se recomienda seguir las directrices de la OMS para la presentaci\u00f3n de la documentaci\u00f3n de productos farmac\u00e9uticos. Esto incluye la inclusi\u00f3n de secciones completas \u201c3.2.S\u201d para cada API en un FPP que contenga m\u00faltiples APIs.\n\n4. **Repetici\u00f3n de Secciones**:\n   - Se permite la repetici\u00f3n de secciones en la documentaci\u00f3n, siempre que se indique claramente a qu\u00e9 se refiere cada secci\u00f3n mediante t\u00edtulos distintivos.\n\n### Entidades Clave\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite directrices sobre la calidad de productos farmac\u00e9uticos.\n- **APIs (Ingredientes Activos Farmac\u00e9uticos)**: Sustancias que proporcionan la acci\u00f3n farmacol\u00f3gica en los productos.\n- **FPPs (Productos Farmac\u00e9uticos Terminados)**: Formulaciones finales que contienen uno o m\u00e1s APIs.\n- **ICH (Conferencia Internacional sobre Armonizaci\u00f3n)**: Organizaci\u00f3n que proporciona directrices sobre la calidad y regulaci\u00f3n de productos farmac\u00e9uticos.\n- **APIMF (Maestro de Informaci\u00f3n del Ingrediente Activo)**: Documento que contiene informaci\u00f3n sobre un API.\n\nEste resumen destaca la importancia de la calidad en la industria farmac\u00e9utica y proporciona directrices claras sobre c\u00f3mo estructurar la documentaci\u00f3n necesaria para cumplir con los est\u00e1ndares establecidos por la OMS.", "excerpt_keywords": "Keywords: active pharmaceutical ingredient, API starting material, pharmaceutical dosage form, product information presentation, WHO guidelines"}}, "70b50c8c-46fd-4af1-afb4-96d4a26b73e3": {"node_ids": ["523fee71-5347-4a93-a83f-d9dfefc0df0b"], "metadata": {"page_label": "140", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Applicant\n\nThe person or entity who, by the deadline mentioned in the invitation, submits an expression of interest (EOI) to participate in this procedure in respect of the product(s) listed in the invitation, together with the required documentation on such product(s).\n\n## Biopharmaceutics Classification System (BCS) Highly Soluble\n\nAn API for which the highest dose recommended by WHO (if the API appears on the WHO Model list of essential medicines) or highest dose strength available on the market as an oral solid dosage form (if the API does not appear on the WHO Model list of essential medicines) is soluble in 250 ml or less of aqueous media over the pH range of 1.2\u20136.8 at 37 \u00b0C.\n\n## Commitment Batches\n\nProduction batches of an API or FPP for which the stability studies are initiated or completed post-approval through a commitment made in a regulatory application.\n\n## Comparator Product\n\nA pharmaceutical product with which the generic product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality have been established. For the Prequalification of Medicines Programme, the selection of the comparator product is based on the information presented under Guidance on bioequivalence studies available on the Prequalification web site.\n\n## Established Multisource (Generic) Product\n\nA multisource product that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year, or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years.\n\n## Existing API\n\nAn API that is not considered a new active substance, which has been previously approved through a finished product by a stringent regulatory authority or by WHO, but requires the filing of a dossier. This would include, for example, new PDs and variations to multisource products.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento se centra en las especificaciones para preparaciones farmac\u00e9uticas, abordando conceptos clave como el proceso de solicitud para participar en la evaluaci\u00f3n de productos, la clasificaci\u00f3n de sustancias activas seg\u00fan su solubilidad, la definici\u00f3n de lotes de compromiso, productos comparadores, productos multisource establecidos y sustancias activas existentes. Estos t\u00e9rminos son relevantes para la regulaci\u00f3n y evaluaci\u00f3n de medicamentos, especialmente en el contexto de la pre-calificaci\u00f3n de medicamentos por parte de la OMS.\n\n### Preguntas\n\n1. **\u00bfQu\u00e9 criterios debe cumplir un producto para ser considerado un \"Established Multisource (Generic) Product\"?**\n   - Respuesta: Un producto multisource debe haber sido comercializado por el solicitante o fabricante asociado con el expediente durante al menos cinco a\u00f1os y debe haber producido al menos 10 lotes de producci\u00f3n en el a\u00f1o anterior, o si se produjeron menos de 10 lotes en el a\u00f1o anterior, no menos de 25 lotes en los \u00faltimos tres a\u00f1os.\n\n2. **\u00bfC\u00f3mo se define un \"Comparator Product\" en el contexto de la evaluaci\u00f3n de medicamentos?**\n   - Respuesta: Un \"Comparator Product\" es un producto farmac\u00e9utico con el cual se pretende que el producto gen\u00e9rico sea intercambiable en la pr\u00e1ctica cl\u00ednica. Normalmente, este producto es el innovador para el cual se han establecido la eficacia, seguridad y calidad.\n\n3. **\u00bfQu\u00e9 implica la categor\u00eda de \"Existing API\" y qu\u00e9 requisitos se deben cumplir para su presentaci\u00f3n?**\n   - Respuesta: Un \"Existing API\" es una sustancia activa que no se considera una nueva sustancia activa y que ha sido previamente aprobada a trav\u00e9s de un producto terminado por una autoridad reguladora estricta o por la OMS, pero que requiere la presentaci\u00f3n de un expediente. Esto incluye, por ejemplo, nuevos documentos de producto (PDs) y variaciones a productos multisource.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Definiciones de t\u00e9rminos**:\n   - **Ingrediente farmac\u00e9utico activo (API)**: Sustancia o mezcla utilizada en la fabricaci\u00f3n de formas farmac\u00e9uticas que proporciona actividad farmacol\u00f3gica o efecto directo en el diagn\u00f3stico, tratamiento o prevenci\u00f3n de enfermedades.\n   - **Material de inicio de API**: Materia prima, intermedio o API utilizado en la producci\u00f3n de un API, que se incorpora como un fragmento estructural significativo en su estructura. Puede ser adquirido comercialmente, comprado bajo contrato o producido internamente.\n\n2. **Directrices para la presentaci\u00f3n de informaci\u00f3n sobre productos farmac\u00e9uticos terminados (FPP)**:\n   - **M\u00faltiples concentraciones**: Se requiere una secci\u00f3n completa \"3.2.P\" para cada concentraci\u00f3n, junto con una copia del documento de presentaci\u00f3n (PD) para cada una.\n   - **M\u00faltiples sistemas de cierre**: Se debe proporcionar una secci\u00f3n \"3.2.P\" completa para cada presentaci\u00f3n.\n   - **M\u00faltiples FPPs**: Se necesita un expediente separado para cada FPP.\n   - **FPP con diluyentes de reconstituci\u00f3n**: Se debe incluir una secci\u00f3n \"3.2.P\" para el FPP y otra para los diluyentes.\n   - **FPP co-blisterados**: Se requiere una secci\u00f3n \"3.2.P\" completa para cada producto.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las directrices.\n- **API**: Ingrediente clave en la fabricaci\u00f3n de medicamentos.\n- **FPP**: Producto farmac\u00e9utico terminado que se presenta en diversas formas y concentraciones. \n\nEste resumen proporciona una visi\u00f3n general de los conceptos y requisitos establecidos en la secci\u00f3n del glosario y las directrices de presentaci\u00f3n.", "excerpt_keywords": "Keywords: pharmaceutical preparations, biopharmaceutics, comparator product, multisource product, active pharmaceutical ingredient"}}, "9671cd89-3633-4761-b8a0-9d1279cd6c94": {"node_ids": ["d1fd6a00-0c33-4fb1-bb6e-72556af5aa70"], "metadata": {"page_label": "141", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n**finished pharmaceutical product (FPP)**  \nA finished dosage form of a pharmaceutical product which has undergone all stages of manufacture, including packaging in its final container and labelling.\n\n**innovator pharmaceutical product**  \nGenerally the pharmaceutical product that was first authorized for marketing (normally as a patented product) on the basis of documentation of efficacy, safety and quality.\n\n**manufacturer**  \nA company that carries out operations such as production, packaging, repackaging, labelling and relabelling of pharmaceuticals.\n\n**multisource (generic) pharmaceutical products**  \nPharmaceutically equivalent or pharmaceutically alternative products that may or may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable.\n\n**officially recognized pharmacopoeia (or compendium)**  \nThose pharmacopoeias recognized in the WHO Prequalification of Medicines Programme (i.e. *British Pharmacopoeia* (BP), *European Pharmacopoeia* (Ph.Eur.), *The International Pharmacopoeia* (Ph.Int.), *Japanese Pharmacopoeia* (JP) and *United States Pharmacopeia* (USP)).\n\n**ongoing stability study**  \nThe study carried out by the manufacturer on production batches according to a predetermined schedule in order to monitor, confirm and extend the projected retest period (or shelf-life) of the API, or confirm or extend the shelf-life of the FPP.\n\n**pilot-scale batch**  \nA batch of an API or FPP manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For example, for solid oral dosage forms a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger; unless otherwise adequately justified.\n\n**primary batch**  \nA batch of an API or FPP used in a stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf-life. For the WHO Prequalification of Medicines Programme, primary batch requirements are outlined in 3.2.S.7.1 and 3.2.P.8.1 for the API and FPP, respectively.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Informe T\u00e9cnico 970 incluye definiciones clave relacionadas con productos farmac\u00e9uticos. Se abordan conceptos como el producto farmac\u00e9utico terminado (FPP), el producto farmac\u00e9utico innovador, el fabricante, los productos farmac\u00e9uticos multisource (gen\u00e9ricos), las farmacopeas reconocidas oficialmente, estudios de estabilidad en curso, lotes a escala piloto y lotes primarios. Estas definiciones son fundamentales para entender los procesos de fabricaci\u00f3n, regulaci\u00f3n y evaluaci\u00f3n de medicamentos en el contexto de la pre-calificaci\u00f3n de medicamentos por parte de la OMS.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 requisitos espec\u00edficos se establecen para los lotes primarios en el contexto de la pre-calificaci\u00f3n de medicamentos de la OMS?**\n   - Esta pregunta busca informaci\u00f3n sobre los requisitos detallados que se mencionan en las secciones 3.2.S.7.1 y 3.2.P.8.1, que no se encuentran f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfCu\u00e1l es la diferencia entre un producto farmac\u00e9utico innovador y un producto farmac\u00e9utico multisource (gen\u00e9rico) seg\u00fan el documento?**\n   - Esta pregunta se centra en las definiciones y caracter\u00edsticas que distinguen a estos dos tipos de productos farmac\u00e9uticos, proporcionando claridad sobre su clasificaci\u00f3n.\n\n3. **\u00bfQu\u00e9 implica un estudio de estabilidad en curso y c\u00f3mo se relaciona con la vida \u00fatil de un producto farmac\u00e9utico terminado (FPP)?**\n   - Esta pregunta busca una comprensi\u00f3n m\u00e1s profunda del proceso y la importancia de los estudios de estabilidad en la determinaci\u00f3n de la vida \u00fatil de los productos farmac\u00e9uticos, un aspecto cr\u00edtico en la fabricaci\u00f3n y regulaci\u00f3n de medicamentos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS se centra en las especificaciones para las preparaciones farmac\u00e9uticas y define varios t\u00e9rminos importantes relacionados con la regulaci\u00f3n y evaluaci\u00f3n de medicamentos. A continuaci\u00f3n se presentan los temas clave y las entidades mencionadas:\n\n1. **Solicitante (Applicant)**: Persona o entidad que presenta una expresi\u00f3n de inter\u00e9s para participar en el procedimiento de evaluaci\u00f3n de productos, junto con la documentaci\u00f3n requerida.\n\n2. **Sistema de Clasificaci\u00f3n Biofarmac\u00e9utica (BCS) - Alta Solubilidad**: Se refiere a un API cuya dosis m\u00e1s alta recomendada es soluble en 250 ml o menos de medio acuoso en un rango de pH de 1.2 a 6.8 a 37 \u00b0C.\n\n3. **Lotes de Compromiso (Commitment Batches)**: Lotes de producci\u00f3n de un API o FPP para los cuales se inician o completan estudios de estabilidad despu\u00e9s de la aprobaci\u00f3n, como parte de un compromiso en una solicitud regulatoria.\n\n4. **Producto Comparador (Comparator Product)**: Producto farmac\u00e9utico con el cual se espera que el producto gen\u00e9rico sea intercambiable en la pr\u00e1ctica cl\u00ednica, normalmente el producto innovador que ha demostrado eficacia, seguridad y calidad.\n\n5. **Producto Multisource Establecido (Established Multisource (Generic) Product)**: Producto multisource que ha estado en el mercado durante al menos cinco a\u00f1os y ha producido al menos 10 lotes en el \u00faltimo a\u00f1o, o al menos 25 lotes en los \u00faltimos tres a\u00f1os si se produjeron menos de 10 en el \u00faltimo a\u00f1o.\n\n6. **API Existente (Existing API)**: Sustancia activa que no se considera nueva y que ha sido aprobada previamente por una autoridad reguladora estricta o por la OMS, pero que requiere la presentaci\u00f3n de un expediente.\n\n### Conclusi\u00f3n\nEstos t\u00e9rminos son fundamentales para entender el proceso de evaluaci\u00f3n y regulaci\u00f3n de medicamentos, especialmente en el contexto de la pre-calificaci\u00f3n de medicamentos por parte de la OMS.", "excerpt_keywords": "Keywords: pharmaceutical product, stability study, innovator product, multisource product, pharmacopoeia"}}, "73ce251c-79aa-4fd8-a566-ac38d8d60c88": {"node_ids": ["5537eedb-e456-447c-8a71-228e367c86a0"], "metadata": {"page_label": "142", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3. Quality summaries\n\n## 3.1 Module 2.3: Quality overall summary \u2013 product dossiers (QOS-PD)\n\nThe Quality overall summary (QOS) is a summary that follows the scope and the outline of the Body of data in Module 3. The QOS should not include information, data or justification that was not already included in Module 3 or in other parts of the CTD.\n\nThe QOS should include sufficient information from each section to provide the Quality assessor with an overview of Module 3. The QOS should also emphasize critical key parameters of the product and provide, for instance, justification in cases where guidelines were not followed. The QOS should include a discussion of key issues that integrates information from sections in the Quality module and supporting information from other Modules (e.g. qualification of impurities via toxicological studies), including cross-referencing to volume and page number in other Modules.\n\nThe WHO *Quality overall summary \u2013 product dossiers (QOS-PD)* template should be completed for multisource pharmaceutical products containing APIs of synthetic or semi-synthetic origin (see 1.3 Scope for further clarification) and their corresponding FPPs.\n\nAll sections and fields in the QOS-PD template that would be applicable should be completed. It is understood that certain sections and fields may not apply and should be indicated as such by reporting \u201cnot applicable\u201d in the appropriate area with an accompanying explanatory note.\n\nThe use of tables to summarize the information is encouraged where possible. The tables included in the template may need to be expanded or duplicated (e.g. for multiple strengths). These tables are included as illustrative examples of how to summarize information. Other approaches can be used to summarize the information if they fulfil the same purpose.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n### Preguntas y Respuestas\n\n1. **\u00bfCu\u00e1l es el prop\u00f3sito principal del Quality overall summary (QOS) en el contexto de los dossiers de productos farmac\u00e9uticos?**\n   - **Respuesta:** El prop\u00f3sito principal del QOS es proporcionar un resumen que siga el alcance y el esquema del Cuerpo de datos en el M\u00f3dulo 3, ofreciendo al evaluador de calidad una visi\u00f3n general de este m\u00f3dulo. Debe incluir informaci\u00f3n cr\u00edtica y justificaciones en caso de que no se sigan las directrices establecidas.\n\n2. **\u00bfQu\u00e9 se debe hacer si hay secciones o campos en el QOS-PD que no son aplicables?**\n   - **Respuesta:** Si hay secciones o campos en el QOS-PD que no son aplicables, se debe indicar como \"no aplicable\" en el \u00e1rea correspondiente, acompa\u00f1\u00e1ndolo con una nota explicativa que justifique la raz\u00f3n de su no aplicaci\u00f3n.\n\n3. **\u00bfC\u00f3mo se recomienda presentar la informaci\u00f3n en el QOS-PD para facilitar su comprensi\u00f3n?**\n   - **Respuesta:** Se recomienda el uso de tablas para resumir la informaci\u00f3n donde sea posible. Las tablas incluidas en el template pueden necesitar ser ampliadas o duplicadas para reflejar m\u00faltiples concentraciones, y se pueden utilizar otros enfoques siempre que cumplan el mismo prop\u00f3sito de resumir la informaci\u00f3n.\n\n### Resumen de Nivel Superior\n\nEl documento se centra en la importancia del Quality overall summary (QOS) dentro de los dossiers de productos farmac\u00e9uticos, espec\u00edficamente para productos multisource que contienen ingredientes activos de origen sint\u00e9tico o semi-sint\u00e9tico. Se enfatiza que el QOS debe ser un resumen conciso que no incluya informaci\u00f3n no presente en el M\u00f3dulo 3 o en otras partes del CTD. Adem\u00e1s, se destaca la necesidad de justificar cualquier desviaci\u00f3n de las directrices y la recomendaci\u00f3n de utilizar tablas para una mejor presentaci\u00f3n de la informaci\u00f3n.\n\n### Preguntas Mejoradas\n\n1. **\u00bfQu\u00e9 tipo de productos farmac\u00e9uticos deben completar el template del QOS-PD seg\u00fan las directrices de la OMS?**\n2. **\u00bfQu\u00e9 tipo de informaci\u00f3n se debe integrar en el QOS para abordar cuestiones clave relacionadas con la calidad del producto?**\n3. **\u00bfQu\u00e9 se sugiere hacer si se requiere resumir informaci\u00f3n de m\u00faltiples fortalezas en el QOS-PD?**", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nLa secci\u00f3n del documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en el Informe T\u00e9cnico 970 aborda definiciones fundamentales relacionadas con la fabricaci\u00f3n y regulaci\u00f3n de productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas:\n\n1. **Productos Farmac\u00e9uticos Terminados (FPP)**: Se define como la forma de dosificaci\u00f3n final de un producto farmac\u00e9utico que ha completado todas las etapas de fabricaci\u00f3n, incluyendo el empaquetado y etiquetado.\n\n2. **Productos Farmac\u00e9uticos Innovadores**: Se refiere a los productos que fueron autorizados por primera vez para su comercializaci\u00f3n, generalmente bajo patente, bas\u00e1ndose en documentaci\u00f3n que demuestra su eficacia, seguridad y calidad.\n\n3. **Fabricantes**: Empresas que realizan operaciones de producci\u00f3n, empaquetado, reempaquetado, etiquetado y reetiquetado de productos farmac\u00e9uticos.\n\n4. **Productos Farmac\u00e9uticos Multisource (Gen\u00e9ricos)**: Productos que son equivalentes farmac\u00e9uticamente o alternativos, que pueden o no ser terap\u00e9uticamente equivalentes. Los que son terap\u00e9uticamente equivalentes son intercambiables.\n\n5. **Farmacopeas Reconocidas Oficialmente**: Incluye farmacopeas que son reconocidas en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS, como la *British Pharmacopoeia*, *European Pharmacopoeia*, *The International Pharmacopoeia*, *Japanese Pharmacopoeia* y *United States Pharmacopeia*.\n\n6. **Estudios de Estabilidad en Curso**: Estudios realizados por el fabricante sobre lotes de producci\u00f3n para monitorear y extender el per\u00edodo de rean\u00e1lisis o la vida \u00fatil del ingrediente activo (API) o del FPP.\n\n7. **Lotes a Escala Piloto**: Lotes de un API o FPP fabricados mediante un procedimiento que simula el que se aplicar\u00e1 a un lote de producci\u00f3n a gran escala, con un tama\u00f1o m\u00ednimo generalmente de una d\u00e9cima parte del lote de producci\u00f3n completo.\n\n8. **Lotes Primarios**: Lotes de un API o FPP utilizados en un estudio de estabilidad, cuyos datos se presentan en una solicitud de registro para establecer un per\u00edodo de rean\u00e1lisis o vida \u00fatil. Los requisitos para los lotes primarios est\u00e1n especificados en secciones espec\u00edficas del documento.\n\nEste resumen proporciona una visi\u00f3n general de los t\u00e9rminos y conceptos clave que son esenciales para entender el contexto de la fabricaci\u00f3n y regulaci\u00f3n de medicamentos en el marco de la OMS.", "excerpt_keywords": "Keywords: Quality overall summary, product dossiers, multisource pharmaceutical products, CTD, regulatory guidelines"}}, "27710dcf-7213-4281-9466-a60e34752b54": {"node_ids": ["5fdfa9cb-9525-467d-86f0-38c6d40daa46"], "metadata": {"page_label": "143", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Module 1.4.2: Quality information summary (QIS)\n\nThe QIS template should be completed to provide a condensed summary of the key quality information for the PD and constitutes part of the submission package. The QIS provides an accurate record of technical data in the PD at the time of prequalification. The QIS is a condensed version of the QOS-PD and represents the final agreed-upon key information on the API and FPP from the PD assessment (including, but not limited to, identification of the manufacturer(s), site addresses, API/FPP specifications, stability conclusions and relevant commitments).\n\nThe QIS template is structured according to the numbering and section headings of the ICH M4Q (CTD-Q) guideline to permit the rapid assembly of the QIS by copying the requisite information from the corresponding portions of the QOS-PD filed with the PD. It is acknowledged that the numbering of the sections in the QIS may not be entirely sequential. Those sections not considered necessary for inclusion in the QIS have been removed (e.g. 2.3.S.5 Reference standards or materials) and the remaining sections have retained their original numbering to maintain consistency with the original PD.\n\nThe QIS will serve as an official reference document in the course of good manufacturing practices (GMP) inspections, variation assessments and requalification assessments as performed by WHO.\n\n# 4. Module 3: Quality\n\n## 4.1 Table of contents of Module 3\n\nA Table of contents for the filed product dossier should be provided.\n\n## 4.2 Body of data\n\n### 3.2.S Drug substance (or active pharmaceutical ingredient, API)\n\nThere are four options for submitting the API information to WHO:\n\n- **Option 1:** confirmation of API prequalification document;\n- **Option 2:** Certificate of Suitability of the *European Pharmacopoeia* (Ph.Eur.) (CEP); or\n- **Option 3:** active pharmaceutical ingredient master file (APIMF) procedure; or\n- **Option 4:** full details in the PD.\n\nThe applicant should clearly indicate at the beginning of the API section (in the PD and in the QOS-PD) how the information on the API for each API manufacturer is being submitted. The API information submitted by the applicant or FPP manufacturer should include the following according to the options used.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (WHO - Technical Report Series 970) aborda la importancia del Quality Information Summary (QIS) como parte del paquete de presentaci\u00f3n para la precalificaci\u00f3n de productos farmac\u00e9uticos. El QIS resume la informaci\u00f3n clave sobre la calidad del principio activo (API) y el producto farmac\u00e9utico terminado (FPP), y se estructura de acuerdo con las directrices ICH M4Q. Adem\u00e1s, se describen las cuatro opciones disponibles para presentar la informaci\u00f3n del API a la OMS.\n\n### Preguntas:\n1. **\u00bfCu\u00e1l es la funci\u00f3n principal del Quality Information Summary (QIS) en el proceso de precalificaci\u00f3n de productos farmac\u00e9uticos?**\n   - El QIS proporciona un resumen condensado de la informaci\u00f3n clave sobre la calidad del producto, sirviendo como un documento de referencia oficial durante las inspecciones de buenas pr\u00e1cticas de manufactura (GMP) y evaluaciones de variaciones.\n\n2. **\u00bfQu\u00e9 opciones tiene un solicitante para presentar la informaci\u00f3n del principio activo (API) a la OMS, y qu\u00e9 debe incluir cada opci\u00f3n?**\n   - Las cuatro opciones son: 1) confirmaci\u00f3n del documento de precalificaci\u00f3n del API, 2) Certificado de Idoneidad de la Farmacopea Europea (CEP), 3) procedimiento de archivo maestro del principio activo (APIMF), y 4) detalles completos en el dossier del producto (PD). Cada opci\u00f3n tiene requisitos espec\u00edficos que deben ser indicados claramente al inicio de la secci\u00f3n del API.\n\n3. **\u00bfPor qu\u00e9 se ha estructurado el QIS de acuerdo con las secciones del ICH M4Q (CTD-Q) y qu\u00e9 implicaciones tiene esto para su uso?**\n   - La estructura del QIS seg\u00fan las secciones del ICH M4Q permite una r\u00e1pida recopilaci\u00f3n de informaci\u00f3n al copiar datos relevantes del QOS-PD. Esto asegura consistencia y facilita la revisi\u00f3n durante las evaluaciones de calidad, aunque algunas secciones no necesarias han sido eliminadas para mantener la concisi\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Quality Overall Summary (QOS):** \n   - Es un resumen que sigue el esquema del Cuerpo de datos en el M\u00f3dulo 3 del CTD (Common Technical Document).\n   - No debe incluir informaci\u00f3n que no est\u00e9 presente en el M\u00f3dulo 3 o en otras partes del CTD.\n\n2. **Prop\u00f3sito del QOS:**\n   - Proporcionar al evaluador de calidad una visi\u00f3n general del M\u00f3dulo 3.\n   - Enfatizar par\u00e1metros cr\u00edticos del producto y justificar desviaciones de las directrices.\n\n3. **Integraci\u00f3n de Informaci\u00f3n:**\n   - Debe incluir una discusi\u00f3n de cuestiones clave que integre informaci\u00f3n de diferentes secciones del m\u00f3dulo de calidad y de otros m\u00f3dulos, como estudios toxicol\u00f3gicos.\n\n4. **Template del QOS-PD:**\n   - Debe ser completado para productos farmac\u00e9uticos multisource con APIs de origen sint\u00e9tico o semi-sint\u00e9tico.\n   - Secciones no aplicables deben ser marcadas como \"no aplicable\" con una nota explicativa.\n\n5. **Presentaci\u00f3n de Informaci\u00f3n:**\n   - Se recomienda el uso de tablas para resumir informaci\u00f3n, que pueden ser ampliadas o duplicadas seg\u00fan sea necesario.\n\n**Entidades:**\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Autoridad que proporciona las directrices para la elaboraci\u00f3n del QOS.\n- **QOS-PD (Quality Overall Summary \u2013 Product Dossiers):** Template espec\u00edfico para productos farmac\u00e9uticos.\n- **M\u00f3dulo 3:** Parte del CTD que contiene datos sobre la calidad del producto.\n- **APIs (Active Pharmaceutical Ingredients):** Ingredientes activos de origen sint\u00e9tico o semi-sint\u00e9tico que se analizan en el QOS.\n- **FPPs (Finished Pharmaceutical Products):** Productos farmac\u00e9uticos terminados que corresponden a los APIs analizados.\n\nEste resumen destaca la importancia del QOS en la evaluaci\u00f3n de la calidad de productos farmac\u00e9uticos y las directrices espec\u00edficas que deben seguirse para su elaboraci\u00f3n.", "excerpt_keywords": "Keywords: Quality Information Summary, API, prequalification, WHO, pharmaceutical products"}}, "01c293c0-fd29-46ea-8531-be827130344f": {"node_ids": ["03755e8c-9597-4f7b-bb45-bd03903bda9b"], "metadata": {"page_label": "144", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Option 1: Confirmation of API prequalification document.\n\nA complete copy of the Confirmation of API prequalification document should be provided in Module 1, together with the duly filled out authorization box in the name of the FPP manufacturer or applicant.\n\nThe applicant should supply the following information in the dossier, with data summarized in the QOS-PD.\n\n- **3.2.S.1.3 General properties** \u2013 discussions on any additional applicable physiochemical and other relevant API properties that are not controlled by the API manufacturer\u2019s specifications, e.g. solubilities and polymorphs according to the guidance in this section.\n- **3.2.S.2** \u2013 if the sterility of the FPP is based upon the sterile manufacture of the API then data on the sterilization process together with full validation data should be provided.\n- **3.2.S.3.1 Elucidation of structure and other characteristics** \u2013 studies to identify polymorphs and particle size distribution, where applicable, according to the guidance in this section.\n- **3.2.S.4.1 Specification** \u2013 the specifications of the FPP manufacturer including all tests and limits of the API manufacturer\u2019s specifications and any additional tests and acceptance criteria that are not controlled by the API manufacturer\u2019s specifications such as polymorphs and/or particle size distribution.\n- **3.2.S.4.2/3.2.S.4.3 Analytical procedures and validation** \u2013 any methods used by the FPP manufacturer in addition to those in the API manufacturer\u2019s specifications.\n- **3.2.S.4.4 Batch analysis** \u2013 results from two batches of at least pilot-scale, demonstrating compliance with the FPP manufacturer\u2019s API specifications.\n- **3.2.S.5 Reference standards or materials** \u2013 information on the FPP manufacturer\u2019s reference standards.\n- **3.2.S.7 Stability** \u2013 data to support the retest period if either the proposed retest period is longer or the proposed storage conditions are at a higher temperature or humidity to that of the prequalified API.\n\n## Option 2: Certificate of Suitability of the European Pharmacopoeia (CEP)\n\nA complete copy of the CEP (including any annexes) should be provided in Module 1. The declaration of access for the CEP should be", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las especificaciones para la preparaci\u00f3n farmac\u00e9utica, espec\u00edficamente en los requisitos para la presentaci\u00f3n de documentos relacionados con la pre-calificaci\u00f3n de ingredientes farmac\u00e9uticos activos (API) y el Certificado de Idoneidad de la Farmacopea Europea (CEP). Se detallan los elementos que deben incluirse en el dossier del solicitante, como propiedades generales, especificaciones, procedimientos anal\u00edticos, an\u00e1lisis de lotes, est\u00e1ndares de referencia y estabilidad.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n adicional sobre las propiedades fisicoqu\u00edmicas del API debe incluirse en la secci\u00f3n 3.2.S.1.3 del dossier?**\n   - Respuesta: Debe incluir discusiones sobre cualquier propiedad fisicoqu\u00edmica y relevante del API que no est\u00e9 controlada por las especificaciones del fabricante del API, como solubilidades y polimorfos.\n\n2. **\u00bfQu\u00e9 datos son necesarios para demostrar la esterilidad del producto farmac\u00e9utico terminado (FPP) si se basa en la fabricaci\u00f3n est\u00e9ril del API?**\n   - Respuesta: Se deben proporcionar datos sobre el proceso de esterilizaci\u00f3n junto con la validaci\u00f3n completa de dicho proceso.\n\n3. **\u00bfCu\u00e1les son los requisitos para la secci\u00f3n de estabilidad (3.2.S.7) en el dossier del solicitante?**\n   - Respuesta: Se debe proporcionar datos que respalden el per\u00edodo de rean\u00e1lisis si el per\u00edodo propuesto es m\u00e1s largo o si las condiciones de almacenamiento propuestas son a una temperatura o humedad m\u00e1s alta que las del API pre-calificado.\n\n### Resumen de Nivel Superior\n\nEl documento establece directrices para la presentaci\u00f3n de informaci\u00f3n relacionada con la pre-calificaci\u00f3n de APIs y la obtenci\u00f3n de un CEP. Se enfatiza la importancia de proporcionar datos completos y espec\u00edficos sobre las propiedades del API, los procesos de esterilizaci\u00f3n, las especificaciones del fabricante y la estabilidad del producto. Estas directrices son cruciales para garantizar la calidad y seguridad de los productos farmac\u00e9uticos.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Quality Information Summary (QIS)**:\n   - El QIS es un resumen condensado de la informaci\u00f3n clave sobre la calidad del producto farmac\u00e9utico (PD) y es parte del paquete de presentaci\u00f3n para la precalificaci\u00f3n.\n   - Proporciona un registro preciso de los datos t\u00e9cnicos en el PD al momento de la precalificaci\u00f3n.\n   - Representa la informaci\u00f3n clave acordada sobre el principio activo (API) y el producto farmac\u00e9utico terminado (FPP) tras la evaluaci\u00f3n del PD.\n\n2. **Estructura del QIS**:\n   - El QIS est\u00e1 estructurado seg\u00fan las secciones y numeraci\u00f3n de las directrices ICH M4Q (CTD-Q) para facilitar la recopilaci\u00f3n de informaci\u00f3n.\n   - Algunas secciones no necesarias han sido eliminadas para mantener la concisi\u00f3n, pero se ha mantenido la numeraci\u00f3n original para asegurar consistencia.\n\n3. **Uso del QIS**:\n   - Servir\u00e1 como documento de referencia oficial durante las inspecciones de buenas pr\u00e1cticas de manufactura (GMP), evaluaciones de variaciones y requalificaciones realizadas por la OMS.\n\n4. **Opciones para presentar informaci\u00f3n del API**:\n   - **Opci\u00f3n 1**: Confirmaci\u00f3n del documento de precalificaci\u00f3n del API.\n   - **Opci\u00f3n 2**: Certificado de Idoneidad de la Farmacopea Europea (CEP).\n   - **Opci\u00f3n 3**: Procedimiento de archivo maestro del principio activo (APIMF).\n   - **Opci\u00f3n 4**: Detalles completos en el dossier del producto (PD).\n   - El solicitante debe indicar claramente c\u00f3mo se est\u00e1 presentando la informaci\u00f3n del API al inicio de la secci\u00f3n correspondiente.\n\n### Entidades clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la evaluaci\u00f3n y precalificaci\u00f3n de productos farmac\u00e9uticos.\n- **API (Active Pharmaceutical Ingredient)**: Principio activo del producto farmac\u00e9utico.\n- **FPP (Finished Pharmaceutical Product)**: Producto farmac\u00e9utico terminado.\n- **ICH M4Q (CTD-Q)**: Directrices que estructuran la presentaci\u00f3n de informaci\u00f3n sobre calidad en los dossiers de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: API prequalification, pharmaceutical specifications, stability data, European Pharmacopoeia, analytical procedures"}}, "10703599-ba09-4126-9f2e-8e013ea480c8": {"node_ids": ["d42ca7a8-196c-4454-be53-a88a054ba49c"], "metadata": {"page_label": "145", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "```\nduly filled out by the CEP holder on behalf of the FPP manufacturer or applicant to the WHO Prequalification of Medicines Programme who refers to the CEP.\n\nIn addition, a written commitment should be included that the applicant will inform WHO in the event that the CEP is withdrawn. It should also be acknowledged by the applicant that withdrawal of the CEP will require additional consideration of the API data requirements to support the PD. The written commitment should accompany the copy of the CEP in Module 1.\n\nTogether with the CEP, the applicant should supply the following information in the dossier, with data summarized in the QOS-PD.\n\n- **3.2.S.1.3 General properties** \u2013 discussions on any additional applicable physicochemical and other relevant properties of the API that are not controlled by the CEP and Ph.Eur. monograph, e.g. solubilities and polymorphs according to the guidance in this section.\n\n- **3.2.S.3.1 Elucidation of structure and other characteristics** \u2013 studies to identify polymorphs (except where the CEP specifies a polymorphic form) and particle size distribution, where applicable, according to the guidance in this section.\n\n- **3.2.S.4.1 Specification** \u2013 the specifications of the FPP manufacturer including all tests and limits of the CEP and Ph.Eur. monograph and any additional tests and acceptance criteria that are not controlled in the CEP and Ph.Eur. monograph, such as polymorphs and/or particle size distribution.\n\n- **3.2.S.4.2/3.2.S.4.3 Analytical procedures and validation** \u2013 for any methods used by the FPP manufacturer in addition to those in the CEP and Ph.Eur. monograph.\n\n- **3.2.S.4.4 Batch analysis** \u2013 results from two batches of at least pilot-scale, demonstrating compliance with the FPP manufacturer\u2019s API specifications.\n\n- **3.2.S.5 Reference standards or materials** \u2013 information on the FPP manufacturer\u2019s reference standards.\n\n- **3.2.S.6 Container-closure system** \u2013 specifications including descriptions and identification of primary packaging components except where the CEP specifies a container-closure system and the applicant declares the intent to use the same container-closure system.\n\n- **3.2.S.7 Stability** \u2013 except where the CEP specifies a retest period that is the same as or longer than that proposed by the applicant, and storage conditions are the same or at a higher temperature and humidity than those proposed by the applicant.\n```\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 tipo de compromiso debe incluir el solicitante al presentar la solicitud de precalificaci\u00f3n de medicamentos a la OMS?**\n   - El solicitante debe incluir un compromiso por escrito en el que se compromete a informar a la OMS en caso de que se retire el Certificado de Producto Espec\u00edfico (CEP). Adem\u00e1s, debe reconocer que la retirada del CEP requerir\u00e1 una consideraci\u00f3n adicional de los requisitos de datos del ingrediente farmac\u00e9utico activo (API) para respaldar el expediente de producto (PD).\n\n2. **\u00bfQu\u00e9 informaci\u00f3n adicional debe proporcionar el solicitante junto con el CEP en el expediente?**\n   - Junto con el CEP, el solicitante debe proporcionar informaci\u00f3n resumida en el QOS-PD, que incluye propiedades generales del API, estudios de identificaci\u00f3n de polimorfos y distribuci\u00f3n del tama\u00f1o de part\u00edculas, especificaciones del fabricante del producto farmac\u00e9utico terminado (FPP), procedimientos anal\u00edticos y validaci\u00f3n, an\u00e1lisis de lotes, est\u00e1ndares de referencia, especificaciones del sistema de cierre del contenedor y datos de estabilidad.\n\n3. **\u00bfQu\u00e9 condiciones deben cumplirse en relaci\u00f3n con la estabilidad del API seg\u00fan el CEP?**\n   - La estabilidad del API debe ser evaluada, excepto en los casos en que el CEP especifique un per\u00edodo de rean\u00e1lisis que sea igual o m\u00e1s largo que el propuesto por el solicitante. Adem\u00e1s, las condiciones de almacenamiento deben ser las mismas o de mayor temperatura y humedad que las propuestas por el solicitante.\n\n### Resumen de nivel superior del contexto:\nEl documento detalla los requisitos que deben cumplir los solicitantes al presentar un expediente para la pre-calificaci\u00f3n de medicamentos a la OMS, espec\u00edficamente en relaci\u00f3n con el Certificado de Producto Espec\u00edfico (CEP). Se enfatiza la importancia de proporcionar informaci\u00f3n adicional sobre las propiedades del ingrediente farmac\u00e9utico activo (API), as\u00ed como compromisos relacionados con la retirada del CEP y la estabilidad del producto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Documentaci\u00f3n para la Precalificaci\u00f3n de APIs**:\n   - Se requiere una copia completa del documento de confirmaci\u00f3n de la precalificaci\u00f3n del ingrediente farmac\u00e9utico activo (API) en el M\u00f3dulo 1, junto con una autorizaci\u00f3n debidamente completada a nombre del fabricante o solicitante del producto farmac\u00e9utico terminado (FPP).\n\n2. **Informaci\u00f3n a Incluir en el Dossier**:\n   - **Propiedades Generales (3.2.S.1.3)**: Discusiones sobre propiedades fisicoqu\u00edmicas adicionales del API no controladas por las especificaciones del fabricante, como solubilidades y polimorfos.\n   - **Esterilidad (3.2.S.2)**: Datos sobre el proceso de esterilizaci\u00f3n y validaci\u00f3n si la esterilidad del FPP se basa en la fabricaci\u00f3n est\u00e9ril del API.\n   - **Estructura y Caracter\u00edsticas (3.2.S.3.1)**: Estudios para identificar polimorfos y distribuci\u00f3n del tama\u00f1o de part\u00edculas.\n   - **Especificaciones (3.2.S.4.1)**: Especificaciones del fabricante del FPP, incluyendo pruebas y l\u00edmites de las especificaciones del fabricante del API.\n   - **Procedimientos Anal\u00edticos (3.2.S.4.2/3.2.S.4.3)**: M\u00e9todos utilizados por el fabricante del FPP adem\u00e1s de los especificados por el fabricante del API.\n   - **An\u00e1lisis de Lotes (3.2.S.4.4)**: Resultados de al menos dos lotes a escala piloto que demuestren el cumplimiento con las especificaciones del API del fabricante del FPP.\n   - **Est\u00e1ndares de Referencia (3.2.S.5)**: Informaci\u00f3n sobre los est\u00e1ndares de referencia del fabricante del FPP.\n   - **Estabilidad (3.2.S.7)**: Datos que respalden el per\u00edodo de rean\u00e1lisis si es m\u00e1s largo o si las condiciones de almacenamiento son m\u00e1s exigentes que las del API precalificado.\n\n3. **Certificado de Idoneidad de la Farmacopea Europea (CEP)**:\n   - Se debe proporcionar una copia completa del CEP, incluyendo anexos, en el M\u00f3dulo 1, junto con la declaraci\u00f3n de acceso correspondiente.\n\n### Entidades Clave\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en productos farmac\u00e9uticos.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que contiene el API.\n- **CEP (Certificado de Idoneidad de la Farmacopea Europea)**: Certificaci\u00f3n que garantiza que un API cumple con los est\u00e1ndares de la Farmacopea Europea.\n- **Especificaciones**: Requisitos y pruebas que deben cumplir los productos farmac\u00e9uticos.\n- **Estabilidad**: Capacidad de un producto para mantener su calidad bajo condiciones espec\u00edficas durante un per\u00edodo determinado. \n\nEste resumen destaca la importancia de la documentaci\u00f3n y los requisitos espec\u00edficos para garantizar la calidad y seguridad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: WHO, Prequalification, CEP, API, Stability"}}, "c131b967-dab6-4fe4-8cca-8fb69c0a27e1": {"node_ids": ["e0449bf8-5b98-4275-b964-431b437d7b04"], "metadata": {"page_label": "146", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIn the case of sterile APIs, data on the process for sterilization of the API including validation data should be included in the PD.\n\n- **Option 3: Active pharmaceutical ingredient master file (APIMF) procedure**  \n  Full details of the chemistry, manufacturing process, quality controls during manufacturing and process validation for the API may be submitted as an APIMF by the API manufacturer as outlined in WHO\u2019s *Guidelines on active pharmaceutical ingredient master file procedure* (4).  \n  In such cases, the Open part (non-proprietary information) needs to be included in its entirety in the PD as an annex to 3.2.S. In addition, the applicant or FPP manufacturer should complete the following sections in the PD and QOS-PD in full according to the guidance provided unless otherwise indicated in the respective sections:  \n  **General information S.1.1\u2013S.1.3**  \n  **Manufacture S.2**  \n  - **Manufacturer(s) S.2.1**  \n  - **Description of manufacturing process and process controls S.2.2**  \n  - **Controls of critical steps and intermediates S.2.4**  \n  **Elucidation of structure and other characteristics S.3.1**  \n  **Impurities S.3.2**  \n  **Control of the API S.4.1\u2013S.4.5**  \n  **Reference standards or materials S.5**  \n  **Container-closure system S.6**  \n  **Stability S.7.1\u2013S.7.3**  \n\n  It is the responsibility of the applicant to ensure that the complete APIMF (i.e. both the applicant\u2019s Open part and the API manufacturer\u2019s Restricted part) is supplied to WHO directly by the API manufacturer and that the applicant has access to the relevant information in the APIMF concerning the current manufacture of the API.  \n  A copy of the letter of access should be provided in the PD Module 1. APIMF holders can use the guidance provided for the option \u201cFull details in the PD\u201d for preparation of the relevant sections of the Open and Restricted parts of their APIMFs. Reference should also be made to the APIMF guidelines in WHO Technical Report Series, No. 948, Annex 4 (4).\n\n- **Option 4: Full details in the PD**  \n  Information on the 3.2.S *Active pharmaceutical ingredient* sections, including full details of chemistry, manufacturing process, quality controls during manufacturing and process validation for the API,", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las especificaciones para la preparaci\u00f3n de productos farmac\u00e9uticos, espec\u00edficamente en la presentaci\u00f3n de informaci\u00f3n sobre ingredientes farmac\u00e9uticos activos (API) en el contexto de la Organizaci\u00f3n Mundial de la Salud (OMS). Se describen dos opciones para la presentaci\u00f3n de datos sobre el API: la opci\u00f3n de presentar un archivo maestro de ingredientes farmac\u00e9uticos activos (APIMF) y la opci\u00f3n de proporcionar todos los detalles directamente en el expediente de producto (PD). Se enfatiza la importancia de incluir informaci\u00f3n sobre el proceso de esterilizaci\u00f3n, la validaci\u00f3n, y la responsabilidad del solicitante de asegurar que la informaci\u00f3n relevante est\u00e9 disponible y accesible.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en el expediente de producto (PD) si se opta por la opci\u00f3n de archivo maestro de ingredientes farmac\u00e9uticos activos (APIMF)?**\n   - La informaci\u00f3n que debe incluirse en el PD incluye la parte abierta del APIMF, as\u00ed como secciones espec\u00edficas como informaci\u00f3n general, fabricaci\u00f3n, control de impurezas, y estabilidad, entre otras.\n\n2. **\u00bfCu\u00e1l es la responsabilidad del solicitante en relaci\u00f3n con el archivo maestro de ingredientes farmac\u00e9uticos activos (APIMF)?**\n   - El solicitante es responsable de asegurarse de que el APIMF completo, que incluye tanto la parte abierta como la parte restringida, sea suministrado a la OMS directamente por el fabricante del API y de que tenga acceso a la informaci\u00f3n relevante sobre la fabricaci\u00f3n actual del API.\n\n3. **\u00bfQu\u00e9 se debe proporcionar en el m\u00f3dulo 1 del expediente de producto en relaci\u00f3n con el acceso al APIMF?**\n   - Se debe proporcionar una copia de la carta de acceso en el m\u00f3dulo 1 del expediente de producto, que demuestre que el solicitante tiene acceso a la parte restringida del APIMF.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS establece directrices sobre c\u00f3mo presentar informaci\u00f3n sobre ingredientes farmac\u00e9uticos activos en el contexto de la regulaci\u00f3n de productos farmac\u00e9uticos. Se ofrecen dos opciones para la presentaci\u00f3n de datos: a trav\u00e9s de un archivo maestro (APIMF) o directamente en el expediente de producto. Se subraya la importancia de la validaci\u00f3n de procesos, el control de calidad y la responsabilidad del solicitante en la gesti\u00f3n de la informaci\u00f3n relacionada con el API.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Compromiso del Solicitante**:\n   - El solicitante debe incluir un compromiso por escrito para informar a la OMS en caso de que se retire el Certificado de Producto Espec\u00edfico (CEP).\n   - Reconocimiento de que la retirada del CEP requerir\u00e1 una revisi\u00f3n adicional de los requisitos de datos del ingrediente farmac\u00e9utico activo (API).\n\n2. **Informaci\u00f3n a Proporcionar**:\n   - Junto con el CEP, el solicitante debe presentar informaci\u00f3n resumida en el QOS-PD, que incluye:\n     - **Propiedades Generales**: Propiedades fisicoqu\u00edmicas adicionales del API no controladas por el CEP.\n     - **Elucidaci\u00f3n de Estructura**: Estudios sobre polimorfos y distribuci\u00f3n del tama\u00f1o de part\u00edculas.\n     - **Especificaciones**: Especificaciones del fabricante del producto farmac\u00e9utico terminado (FPP) que incluyen pruebas y l\u00edmites del CEP.\n     - **Procedimientos Anal\u00edticos**: M\u00e9todos utilizados por el fabricante que no est\u00e1n en el CEP.\n     - **An\u00e1lisis de Lotes**: Resultados de al menos dos lotes a escala piloto.\n     - **Est\u00e1ndares de Referencia**: Informaci\u00f3n sobre los est\u00e1ndares de referencia del fabricante.\n     - **Sistema de Cierre del Contenedor**: Especificaciones de los componentes de embalaje primario.\n     - **Estabilidad**: Evaluaci\u00f3n de estabilidad del API, considerando condiciones de almacenamiento y per\u00edodos de rean\u00e1lisis.\n\n3. **Requisitos de Estabilidad**:\n   - La estabilidad debe ser evaluada, salvo que el CEP indique un per\u00edodo de rean\u00e1lisis igual o m\u00e1s largo que el propuesto por el solicitante.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad que supervisa la precalificaci\u00f3n de medicamentos.\n- **CEP (Certificado de Producto Espec\u00edfico)**: Documento que certifica la calidad del ingrediente farmac\u00e9utico activo.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en un medicamento.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que contiene el API.\n- **QOS-PD (Quality Overall Summary - Product Dossier)**: Resumen de calidad que acompa\u00f1a la solicitud.\n\nEste resumen destaca los requisitos y compromisos que deben cumplir los solicitantes al presentar su documentaci\u00f3n para la precalificaci\u00f3n de medicamentos ante la OMS, as\u00ed como la informaci\u00f3n espec\u00edfica que debe ser proporcionada.", "excerpt_keywords": "Keywords: pharmaceutical preparations, active pharmaceutical ingredient, APIMF, sterilization process, quality control"}}, "d26994a3-e397-48a8-9339-acdba202d583": {"node_ids": ["f754e854-6f3d-49d3-a7d8-7210188c0a9a"], "metadata": {"page_label": "147", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.S.1 General information (name, manufacturer)\n\n## 3.2.S.1.1 Nomenclature (name, manufacturer)\n\nInformation on the nomenclature of the API should be provided. For example:\n\n- (recommended) International Nonproprietary Name (INN);\n- compendial name, if relevant;\n- chemical name(s);\n- company or laboratory code;\n- other nonproprietary name(s) (e.g. national name, United States Adopted Name (USAN), British Approved Name (BAN));\n- Chemical Abstracts Service (CAS) registry number.\n\nThe chemical names listed should be consistent with those appearing in the scientific literature and those appearing on the product labelling information (e.g. in the summary of product characteristics (SmPC) and package leaflet, also known as the patient information leaflet (PIL)). Where several names exist the preferred name should be indicated.\n\n## 3.2.S.1.2 Structure (name, manufacturer)\n\nThe structural formula, including relative and absolute stereochemistry, the molecular formula, and the relative molecular mass should be provided.\n\nThis information should be consistent with that provided in section 3.2.S.1.1. For APIs existing as salts the molecular mass of the free base or acid should also be provided.\n\n## 3.2.S.1.3 General properties (name, manufacturer)\n\nA list should be provided of physicochemical and other relevant properties of the API.\n\nThis information can be used in developing the specifications, in formulating FPPs and in the testing for release and stability purposes.\n\nThe physical and chemical properties of the API should be discussed, including the physical description, solubilities in common solvents (e.g. water, alcohols, dichloromethane and acetone), quantitative aqueous pH solubility profile (e.g. pH 1.2\u20136.8, dose/solubility volume), polymorphism, pH and pKa values, ultraviolet (UV) absorption maxima and molar absorptivity, melting point, refractive index (for a liquid), hygroscopicity and partition coefficient (see...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n### Preguntas y Respuestas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n se recomienda incluir sobre la nomenclatura del API seg\u00fan el documento?**\n   - Se recomienda incluir el Nombre No Propietario Internacional (INN), el nombre de la farmacopea si es relevante, los nombres qu\u00edmicos, el c\u00f3digo de la empresa o laboratorio, otros nombres no propietarios (como el nombre nacional, el Nombre Adoptado en Estados Unidos (USAN) o el Nombre Aprobado Brit\u00e1nico (BAN)), y el n\u00famero de registro del Servicio de Res\u00famenes Qu\u00edmicos (CAS). Adem\u00e1s, los nombres qu\u00edmicos deben ser consistentes con la literatura cient\u00edfica y la informaci\u00f3n de etiquetado del producto.\n\n2. **\u00bfQu\u00e9 detalles estructurales deben proporcionarse para el API?**\n   - Debe proporcionarse la f\u00f3rmula estructural, incluyendo la estereoqu\u00edmica relativa y absoluta, la f\u00f3rmula molecular y la masa molecular relativa. Para los APIs que existen como sales, tambi\u00e9n se debe incluir la masa molecular de la base libre o del \u00e1cido.\n\n3. **\u00bfCu\u00e1les son algunas propiedades fisicoqu\u00edmicas relevantes que deben listarse para el API?**\n   - Se deben discutir propiedades como la descripci\u00f3n f\u00edsica, solubilidades en disolventes comunes (agua, alcoholes, diclorometano y acetona), el perfil de solubilidad en pH cuantitativo (pH 1.2\u20136.8), polimorfismo, valores de pH y pKa, m\u00e1ximos de absorci\u00f3n ultravioleta (UV) y absorptividad molar, punto de fusi\u00f3n, \u00edndice de refracci\u00f3n (para l\u00edquidos), higroscopicidad y coeficiente de partici\u00f3n.\n\n### Resumen de Nivel Superior\n\nEl documento proporciona directrices sobre la informaci\u00f3n que debe incluirse en la secci\u00f3n 3.2.S.1 sobre la informaci\u00f3n general del API, que abarca la nomenclatura, la estructura y las propiedades generales. Se enfatiza la importancia de la consistencia en la nomenclatura y la presentaci\u00f3n de datos estructurales y fisicoqu\u00edmicos, que son esenciales para el desarrollo de especificaciones, formulaciones de productos farmac\u00e9uticos y pruebas de liberaci\u00f3n y estabilidad.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Organizaci\u00f3n Mundial de la Salud (OMS)**: La secci\u00f3n se centra en las directrices de la OMS para la presentaci\u00f3n de informaci\u00f3n sobre ingredientes farmac\u00e9uticos activos (API) en el contexto de la regulaci\u00f3n de productos farmac\u00e9uticos.\n\n2. **Ingredientes Farmac\u00e9uticos Activos (API)**: Se discuten dos opciones para la presentaci\u00f3n de datos sobre los API: \n   - **Opci\u00f3n 3**: Procedimiento de archivo maestro de ingredientes farmac\u00e9uticos activos (APIMF).\n   - **Opci\u00f3n 4**: Presentaci\u00f3n de todos los detalles directamente en el expediente de producto (PD).\n\n3. **Proceso de Esterilizaci\u00f3n**: Se enfatiza la necesidad de incluir datos sobre el proceso de esterilizaci\u00f3n y la validaci\u00f3n de los API est\u00e9riles en el PD.\n\n4. **Estructura del PD**: Se detallan las secciones espec\u00edficas que deben completarse en el PD y el QOS-PD, incluyendo:\n   - Informaci\u00f3n general (S.1.1\u2013S.1.3)\n   - Fabricaci\u00f3n (S.2)\n   - Control de impurezas (S.3.2)\n   - Control del API (S.4.1\u2013S.4.5)\n   - Estabilidad (S.7.1\u2013S.7.3)\n\n5. **Responsabilidad del Solicitante**: Se establece que el solicitante debe asegurarse de que el APIMF completo sea suministrado a la OMS por el fabricante del API y que tenga acceso a la informaci\u00f3n relevante.\n\n6. **Carta de Acceso**: Se requiere que el solicitante proporcione una copia de la carta de acceso en el m\u00f3dulo 1 del PD, que demuestre el acceso a la parte restringida del APIMF.\n\n7. **Referencias**: Se menciona la necesidad de referirse a las directrices del APIMF en el Informe T\u00e9cnico de la OMS, No. 948, Anexo 4.\n\n### Entidades Clave\n- **OMS**: Organizaci\u00f3n Mundial de la Salud.\n- **APIMF**: Archivo Maestro de Ingredientes Farmac\u00e9uticos Activos.\n- **PD**: Expediente de Producto.\n- **QOS-PD**: Calidad del Expediente de Producto. \n\nEste resumen destaca los aspectos esenciales relacionados con la presentaci\u00f3n de informaci\u00f3n sobre API y las responsabilidades de los solicitantes en el contexto de la regulaci\u00f3n farmac\u00e9utica.", "excerpt_keywords": "Keywords: API, nomenclature, physicochemical properties, structural formula, WHO guidelines"}}, "82aef7ce-e536-49d0-a6bd-2527cec16a24": {"node_ids": ["c27bb1f2-0b9f-4494-8fb9-25140dcf4c76"], "metadata": {"page_label": "148", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Physical Description\n\nThe physical description should include appearance, colour and physical state. Solid forms should be identified as being crystalline or amorphous (see 3.2.S.3.1 for further information on API solid forms).\n\n# Solubilities and Quantitative Aqueous pH Solubility Profile\n\nThe following should be provided for all options for the submission of API data.\n\n- The solubilities in a number of common solvents should be provided (e.g. in water, alcohols, dichloromethane and acetone).\n- The solubilities over the physiological pH range (pH 1.2\u20136.8) in several buffered media should be provided in mg/ml. If this information is not readily available (e.g. from literature references), it should be generated in-house.\n\nFor solid oral dosage forms, the dose/solubility volume should be provided as determined according to the formula:\n\n\\[\n\\text{dose/solubility volume} = \\frac{\\text{largest dosage strength (mg)}}{\\text{the minimum concentration of the drug (mg/ml)*}}\n\\]\n\n*corresponding to the lowest solubility determined over the physiological pH range (pH 1.2\u20136.8) and temperature (37 \u00b1 0.5 \u00b0C).\n\nAccording to the Biopharmaceutics Classification System (BCS), highly soluble (or highly water soluble) APIs are those with a dose/solubility volume of \u2264 250 ml.\n\nFor example, compound A has as its lowest solubility at 37 \u00b1 0.5\u00b0C, 1.0 mg/ml at pH 6.8 and is available in 100 mg, 200 mg and 400 mg strengths. This API would not be considered a BCS highly soluble API as its dose/solubility volume is greater than 250 ml (400 mg/1.0 mg/ml = 400 ml).\n\n# Polymorphism\n\nAs recommended in ICH\u2019s *CTD-Q Questions and answers/location issues document* (5) the following list explains where specific data should be located in the PD:\n\n- The polymorphic form(s) present in the proposed API should be listed in section 3.2.S.1.3.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfQu\u00e9 informaci\u00f3n se debe incluir en la descripci\u00f3n f\u00edsica de un API seg\u00fan el documento?**\n   - La descripci\u00f3n f\u00edsica debe incluir la apariencia, el color y el estado f\u00edsico del API. Adem\u00e1s, se debe identificar si las formas s\u00f3lidas son cristalinas o amorfas.\n\n2. **\u00bfC\u00f3mo se determina el volumen de dosis/solubilidad para formas de dosificaci\u00f3n oral s\u00f3lida y qu\u00e9 implica un volumen de dosis/solubilidad mayor a 250 ml?**\n   - El volumen de dosis/solubilidad se determina utilizando la f\u00f3rmula: \\(\\text{dose/solubility volume} = \\frac{\\text{largest dosage strength (mg)}}{\\text{the minimum concentration of the drug (mg/ml)*}}\\), donde el denominador corresponde a la menor solubilidad determinada en el rango de pH fisiol\u00f3gico (pH 1.2\u20136.8) y a una temperatura de 37 \u00b1 0.5 \u00b0C. Un volumen de dosis/solubilidad mayor a 250 ml indica que el API no es considerado altamente soluble seg\u00fan el Sistema de Clasificaci\u00f3n Biofarmac\u00e9utica (BCS).\n\n3. **\u00bfD\u00f3nde se debe listar la(s) forma(s) polim\u00f3rfica(s) presente(s) en el API propuesto seg\u00fan las recomendaciones del ICH?**\n   - Las formas polim\u00f3rficas presentes en el API propuesto deben ser listadas en la secci\u00f3n 3.2.S.1.3 del documento.\n\n### Resumen de nivel superior del contexto:\nEl documento proporciona directrices sobre la descripci\u00f3n f\u00edsica de los ingredientes farmac\u00e9uticos activos (API), incluyendo su apariencia, color y estado f\u00edsico, as\u00ed como la identificaci\u00f3n de formas s\u00f3lidas. Tambi\u00e9n se detalla la necesidad de presentar datos sobre la solubilidad del API en varios disolventes y en un rango de pH fisiol\u00f3gico, junto con el c\u00e1lculo del volumen de dosis/solubilidad para formas de dosificaci\u00f3n oral s\u00f3lida. Adem\u00e1s, se menciona la importancia de documentar las formas polim\u00f3rficas del API en una secci\u00f3n espec\u00edfica del informe.", "prev_section_summary": "### Resumen de Temas Clave y Entidades de la Secci\u00f3n 3.2.S.1\n\n1. **Nomenclatura del API**:\n   - Se debe proporcionar informaci\u00f3n sobre el nombre del API, incluyendo:\n     - Nombre No Propietario Internacional (INN).\n     - Nombre de la farmacopea, si es relevante.\n     - Nombres qu\u00edmicos.\n     - C\u00f3digo de la empresa o laboratorio.\n     - Otros nombres no propietarios (nombres nacionales, USAN, BAN).\n     - N\u00famero de registro del Servicio de Res\u00famenes Qu\u00edmicos (CAS).\n   - Consistencia con la literatura cient\u00edfica y etiquetado del producto es esencial.\n\n2. **Estructura del API**:\n   - Se requiere la f\u00f3rmula estructural, que debe incluir:\n     - Estereoqu\u00edmica relativa y absoluta.\n     - F\u00f3rmula molecular.\n     - Masa molecular relativa.\n   - Para APIs en forma de sales, se debe incluir la masa molecular de la base libre o del \u00e1cido.\n\n3. **Propiedades Generales del API**:\n   - Se debe listar propiedades fisicoqu\u00edmicas relevantes, que incluyen:\n     - Descripci\u00f3n f\u00edsica.\n     - Solubilidades en disolventes comunes (agua, alcoholes, diclorometano, acetona).\n     - Perfil de solubilidad en pH cuantitativo (pH 1.2\u20136.8).\n     - Polimorfismo.\n     - Valores de pH y pKa.\n     - M\u00e1ximos de absorci\u00f3n UV y absorptividad molar.\n     - Punto de fusi\u00f3n.\n     - \u00cdndice de refracci\u00f3n (para l\u00edquidos).\n     - Higroscopicidad.\n     - Coeficiente de partici\u00f3n.\n\n### Entidades Clave:\n- **API** (Ingrediente Farmac\u00e9utico Activo)\n- **INN** (Nombre No Propietario Internacional)\n- **USAN** (Nombre Adoptado en Estados Unidos)\n- **BAN** (Nombre Aprobado Brit\u00e1nico)\n- **CAS** (Servicio de Res\u00famenes Qu\u00edmicos)\n- **FPP** (Forma Farmac\u00e9utica del Producto)\n- **SmPC** (Resumen de Caracter\u00edsticas del Producto)\n- **PIL** (Prospecto de Informaci\u00f3n para el Paciente)\n\nEste resumen destaca la importancia de la nomenclatura, la estructura y las propiedades fisicoqu\u00edmicas del API, que son fundamentales para el desarrollo y la regulaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: API, solubility, polymorphism, physical description, Biopharmaceutics Classification System"}}, "2378cabc-e59e-4cef-82c7-3fe7d77ac3db": {"node_ids": ["4748c33a-b29f-450d-9457-6384e1374c39"], "metadata": {"page_label": "149", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n- The description of manufacturing process and process controls (3.2.S.2.2) should indicate which polymorphic form is manufactured, where relevant.\n- The literature references or studies performed to identify the potential polymorphic forms of the API, including the study results, should be provided in section 3.2.S.3.1.\n- If a polymorphic form is to be defined or limited (e.g. for APIs that are not BCS highly soluble and/or where polymorphism has been identified as an issue), details should be included in 3.2.S.4.1-3.2.S.4.5.\n\nAdditional information is included in the referenced sections of these guidelines.\n\n## Particle size distribution\n\nAs recommended in ICH\u2019s *CTD-Q Questions and answers/location issues* document (5), the studies performed to determine the particle size distribution of the API should be provided in section 3.2.S.3.1 (refer to this section of these guidelines for additional information).\n\n## Information from the literature\n\nSupportive data and results from specific studies or published literature can be included within or attached to this section.\n\nReference documents: ICH Q6A (6).\n\n### 3.2.S.2 Manufacture (name, manufacturer)\n\n#### 3.2.S.2.1 Manufacturer(s) (name, manufacturer)\n\nThe name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.\n\nThe facilities involved in the manufacturing, packaging, labelling, testing and storage of the API should be listed. If certain companies are responsible only for specific steps (e.g. milling of the API) this should be clearly indicated.\n\nThe list of manufacturers or companies should specify the actual addresses of the production or manufacturing site(s) involved (including block(s) and unit(s)), rather than the administrative offices. Telephone number(s), fax number(s) and e-mail address(es) should be provided.\n\nA valid manufacturing authorization should be provided for the production of APIs. If available, a certificate of compliance with GMP should be provided in the PD in Module 1.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfQu\u00e9 informaci\u00f3n espec\u00edfica debe incluirse en la secci\u00f3n 3.2.S.3.1 sobre los estudios realizados para identificar las formas polim\u00f3rficas del API?**\n   - Respuesta: En la secci\u00f3n 3.2.S.3.1, se deben incluir las referencias literarias o los estudios realizados para identificar las formas polim\u00f3rficas potenciales del API, as\u00ed como los resultados de dichos estudios.\n\n2. **\u00bfCu\u00e1les son los requisitos para la documentaci\u00f3n de los fabricantes involucrados en la producci\u00f3n del API seg\u00fan la secci\u00f3n 3.2.S.2.1?**\n   - Respuesta: La secci\u00f3n 3.2.S.2.1 requiere que se proporcione el nombre, direcci\u00f3n y responsabilidad de cada fabricante, incluidos los contratistas, as\u00ed como los sitios de producci\u00f3n o instalaciones involucradas en la fabricaci\u00f3n y prueba del API. Tambi\u00e9n se deben incluir los n\u00fameros de tel\u00e9fono, fax y direcciones de correo electr\u00f3nico, y se debe presentar una autorizaci\u00f3n de fabricaci\u00f3n v\u00e1lida.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta si se define o limita una forma polim\u00f3rfica del API?**\n   - Respuesta: Si se define o limita una forma polim\u00f3rfica del API, se deben incluir detalles en las secciones 3.2.S.4.1 a 3.2.S.4.5, especialmente si el API no es altamente soluble seg\u00fan el BCS o si se ha identificado el polimorfismo como un problema.\n\n### Resumen de nivel superior del contexto:\nEl documento proporciona directrices sobre la fabricaci\u00f3n y control de procesos de ingredientes farmac\u00e9uticos activos (API), enfatizando la importancia de documentar las formas polim\u00f3rficas y la distribuci\u00f3n del tama\u00f1o de part\u00edculas. Se requiere informaci\u00f3n detallada sobre los fabricantes y las instalaciones involucradas en la producci\u00f3n del API, as\u00ed como la necesidad de cumplir con las normativas de Buenas Pr\u00e1cticas de Manufactura (GMP).", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Descripci\u00f3n F\u00edsica del API**:\n   - **Aspectos a Incluir**: Apariencia, color y estado f\u00edsico.\n   - **Formas S\u00f3lidas**: Identificaci\u00f3n como cristalinas o amorfas.\n\n2. **Solubilidades y Perfil de Solubilidad en pH Aqueoso Cuantitativo**:\n   - **Datos Requeridos**: Solubilidades en disolventes comunes (agua, alcoholes, diclorometano, acetona).\n   - **Rango de pH**: Solubilidades en el rango fisiol\u00f3gico (pH 1.2\u20136.8) en medios tamponados, expresadas en mg/ml.\n   - **C\u00e1lculo de Volumen de Dosis/Solubilidad**: \n     - F\u00f3rmula: \\(\\text{dose/solubility volume} = \\frac{\\text{largest dosage strength (mg)}}{\\text{the minimum concentration of the drug (mg/ml)*}}\\)\n     - **Interpretaci\u00f3n**: Un volumen de dosis/susolubilidad \u2264 250 ml indica que el API es altamente soluble seg\u00fan el Sistema de Clasificaci\u00f3n Biofarmac\u00e9utica (BCS).\n\n3. **Polimorfismo**:\n   - **Recomendaciones del ICH**: Las formas polim\u00f3rficas del API propuesto deben ser listadas en la secci\u00f3n 3.2.S.1.3 del documento.\n\n### Entidades Clave:\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en medicamentos.\n- **BCS (Sistema de Clasificaci\u00f3n Biofarmac\u00e9utica)**: Clasificaci\u00f3n que determina la solubilidad y permeabilidad de los APIs.\n- **pH**: Medida de acidez o alcalinidad, relevante para la solubilidad del API.\n- **Secci\u00f3n 3.2.S.1.3**: Parte del documento donde se debe listar la informaci\u00f3n sobre polimorfismo.\n\nEste resumen destaca los aspectos esenciales relacionados con la descripci\u00f3n f\u00edsica, solubilidad y polimorfismo de los APIs seg\u00fan las directrices del documento.", "excerpt_keywords": "Keywords: manufacturing process, polymorphic forms, API, particle size distribution, GMP compliance"}}, "a528b92f-99f3-42fb-bda4-d558acd6d6fe": {"node_ids": ["ceedf2a3-7da6-48b7-95a9-48b135cb8332"], "metadata": {"page_label": "150", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.S.2.2 Description of manufacturing process and process controls (name, manufacturer)\n\nThe description of the API manufacturing process represents the applicant\u2019s commitment for the manufacture of the API. Information should be provided to adequately describe the manufacturing process and process controls. For example:\n\n- A flow diagram of the synthetic process(es) should be provided that includes molecular formulas, weights, yield ranges, chemical structures of starting materials, intermediates, reagents and API reflecting stereochemistry, and identifies operating conditions and solvents.\n\n- A sequential procedural narrative of the manufacturing process should be submitted. The narrative should include, for example, quantities of raw materials, solvents, catalysts and reagents reflecting the representative batch scale for commercial manufacture, identification of critical steps, process controls, equipment and operating conditions (e.g. temperature, pressure, pH, time).\n\n- Alternative processes should be explained and described with the same level of detail as the primary process. Reprocessing steps should be identified and justified. Any data to support this justification should be either referenced or filed in 3.2.S.2.5.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF may be indicated for confidential information. In this case, if detailed information is presented in the Restricted part, the information to be provided for this section of the PD includes a flow chart (including molecular structures and all reagents and solvents) and a brief outline of the manufacturing process, with special emphasis on the final steps, including purification procedures. However, for sterile APIs, full validation data on the sterilization process should be provided in the Open part (in cases where there is no further sterilization of the final product).\n\nThe following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier.\n\nAs discussed in ICH Q7 (7) and WHO Technical Report Series, No. 957, Annex 2 (8), the point at which the API starting material is introduced into the manufacturing process is the starting point for the application of GMP requirements. The API starting material itself needs to be proposed and its choice justified by the manufacturer and accepted as such by assessors. The API starting material should be proposed taking into account the complexity of the molecule, the proximity of the API starting material to the final API, the availability of the API starting material as a commercial chemical and the quality controls placed upon the API starting material. This justification should be documented in the dossier and be available for review by WHO GMP inspectors.\n\nIn situations where the API starting material is a complex molecule and only a minimal number of synthetic steps from the final API, a further molecule called the starting material for synthesis should be proposed and its choice justified.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n se requiere para describir el proceso de fabricaci\u00f3n del API y los controles de proceso?**\n   - Se requiere un diagrama de flujo del proceso sint\u00e9tico que incluya f\u00f3rmulas moleculares, pesos, rangos de rendimiento, estructuras qu\u00edmicas de los materiales iniciales, intermedios, reactivos y el API, as\u00ed como condiciones operativas y solventes. Adem\u00e1s, se debe presentar una narrativa secuencial del proceso de fabricaci\u00f3n que detalle las cantidades de materias primas, solventes, catalizadores y reactivos, identificando pasos cr\u00edticos y condiciones operativas.\n\n2. **\u00bfC\u00f3mo se debe justificar la elecci\u00f3n del material de partida del API en el proceso de fabricaci\u00f3n?**\n   - La elecci\u00f3n del material de partida del API debe ser propuesta y justificada por el fabricante, teniendo en cuenta la complejidad de la mol\u00e9cula, la proximidad del material de partida al API final, la disponibilidad del material como un qu\u00edmico comercial y los controles de calidad aplicados. Esta justificaci\u00f3n debe estar documentada en el expediente y ser accesible para la revisi\u00f3n de los inspectores de GMP de la OMS.\n\n3. **\u00bfQu\u00e9 requisitos adicionales se aplican cuando se utiliza el procedimiento APIMF para la presentaci\u00f3n de informaci\u00f3n del API?**\n   - Cuando se utiliza el procedimiento APIMF, se puede indicar una referencia cruzada a la parte restringida del APIMF para informaci\u00f3n confidencial. En este caso, se debe proporcionar un diagrama de flujo que incluya estructuras moleculares y todos los reactivos y solventes, as\u00ed como un esquema breve del proceso de fabricaci\u00f3n, enfatizando los pasos finales y los procedimientos de purificaci\u00f3n. Para APIs est\u00e9riles, se deben proporcionar datos completos de validaci\u00f3n del proceso de esterilizaci\u00f3n en la parte abierta.\n\n### Resumen de nivel superior del contexto:\nEl contexto se centra en la descripci\u00f3n del proceso de fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (API) y los controles de proceso necesarios para cumplir con los requisitos de Buenas Pr\u00e1cticas de Manufactura (GMP). Se enfatiza la importancia de proporcionar informaci\u00f3n detallada sobre el proceso, incluyendo diagramas de flujo, narrativas secuenciales y justificaciones para la elecci\u00f3n de materiales de partida. Tambi\u00e9n se menciona el procedimiento APIMF y los requisitos espec\u00edficos para la presentaci\u00f3n de informaci\u00f3n confidencial y est\u00e9ril.", "prev_section_summary": "### Resumen de temas clave y entidades de la secci\u00f3n:\n\n1. **Polimorfismo de API**:\n   - Se requiere que la descripci\u00f3n del proceso de fabricaci\u00f3n y controles (secci\u00f3n 3.2.S.2.2) indique la forma polim\u00f3rfica que se fabrica.\n   - En la secci\u00f3n 3.2.S.3.1, se deben incluir referencias literarias y estudios realizados para identificar las formas polim\u00f3rficas potenciales del API, junto con los resultados de dichos estudios.\n   - Si se define o limita una forma polim\u00f3rfica, se deben proporcionar detalles en las secciones 3.2.S.4.1 a 3.2.S.4.5, especialmente para APIs que no son altamente solubles o donde el polimorfismo es un problema.\n\n2. **Distribuci\u00f3n del tama\u00f1o de part\u00edculas**:\n   - Se recomienda que los estudios sobre la distribuci\u00f3n del tama\u00f1o de part\u00edculas del API se incluyan en la secci\u00f3n 3.2.S.3.1, conforme a las directrices del documento ICH *CTD-Q Questions and answers/location issues*.\n\n3. **Informaci\u00f3n de fabricantes**:\n   - En la secci\u00f3n 3.2.S.2.1, se debe proporcionar el nombre, direcci\u00f3n y responsabilidad de cada fabricante, incluidos los contratistas, as\u00ed como los sitios de producci\u00f3n o instalaciones involucradas en la fabricaci\u00f3n y prueba del API.\n   - Se debe listar las instalaciones de fabricaci\u00f3n, envasado, etiquetado, prueba y almacenamiento del API, especificando direcciones reales y no solo oficinas administrativas.\n   - Se requiere presentar una autorizaci\u00f3n de fabricaci\u00f3n v\u00e1lida y, si est\u00e1 disponible, un certificado de cumplimiento con las Buenas Pr\u00e1cticas de Manufactura (GMP).\n\n### Entidades clave:\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que se fabrica y se controla en el proceso.\n- **Fabricantes**: Entidades responsables de la producci\u00f3n del API, incluyendo contratistas.\n- **Secciones del documento**: 3.2.S.2.2, 3.2.S.3.1, 3.2.S.4.1-3.2.S.4.5.\n- **Documentos de referencia**: ICH Q6A, ICH *CTD-Q Questions and answers/location issues*. \n\nEste resumen destaca la importancia de la documentaci\u00f3n y el cumplimiento normativo en la fabricaci\u00f3n de APIs, as\u00ed como la consideraci\u00f3n del polimorfismo y la distribuci\u00f3n del tama\u00f1o de part\u00edculas.", "excerpt_keywords": "Keywords: API manufacturing, process controls, GMP requirements, flow diagram, starting material"}}, "ed50dd58-9570-430c-99b2-094156895bbe": {"node_ids": ["d2a824d0-9d54-4bc7-ae4c-645d0950c071"], "metadata": {"page_label": "151", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The starting material for synthesis defines the starting point in the manufacturing process for an API to be described in an application. The applicant should propose and justify which substances should be considered as starting materials for synthesis (see section 3.2.S.2.3 for further guidance). In the case where the precursor to the API is obtained by fermentation, or is of plant or animal origin, such a molecule can be considered the API starting material regardless of complexity.\n\nA one-step synthesis may be accepted in exceptional cases, for example, where the API starting material is covered by a CEP, or where the API starting material is an API accepted through the APIMF or API prequalification procedure within the WHO Prequalification of Medicines Programme, or when the structure of the API is so simple that a one-step synthesis can be justified, e.g. ethambutol or ethionamide.\n\nIn addition to the detailed description of the manufacturing process as per ICH M4Q, the recovery of materials, if any, should be described in detail with the step in which they are introduced into the process. Recovery operations should be adequately controlled such that impurity levels do not increase over time. For recovery of solvents, any processing to improve the quality of the recovered solvent should be described. Regarding recycling of filtrates (mother liquors) to obtain second crops, information should be available on maximum holding times for mother liquors and maximum number of times the material can be recycled. Data on impurity levels should be provided to justify recycling of filtrates.\n\nWhere there are multiple manufacturing sites being used by one API manufacturer, a comprehensive list in tabular form should be provided comparing the processes at each of the sites and highlighting any differences.\n\nAll solvents used in the manufacture (including purification and/or crystallization step(s)) should be clearly identified. Solvents used in the final steps should be of high purity. Use of recovered solvents in the final steps of purification and/or crystallization is not recommended; however their use can be justified on presentation of sufficient data demonstrating that recovered solvents meet appropriate standards as outlined in ICH Q7 (7).\n\nWhere polymorphic or amorphous forms have been identified, the form resulting from the synthesis should be stated.\n\nWhere particle size is considered a critical attribute (see 3.2.S.3.1 for details) the particle size reduction method(s) (e.g. milling or micronization) should be described.\n\nJustification should be provided for use of alternative manufacturing processes. Alternative processes should be explained with the same level of detail as for the primary process. It should be demonstrated that batches obtained by the alternative processes have the same impurity profile as obtained by the principal process. If the impurity profile obtained is different it should be demonstrated to be acceptable according to the requirements described under S.3.2.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS detalla los requisitos para la fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (API), enfoc\u00e1ndose en la definici\u00f3n de materiales de partida, procesos de s\u00edntesis, recuperaci\u00f3n de materiales, uso de disolventes, y justificaci\u00f3n de procesos alternativos. Se enfatiza la necesidad de un control riguroso de impurezas y la documentaci\u00f3n de procesos en m\u00faltiples sitios de fabricaci\u00f3n.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las condiciones excepcionales bajo las cuales se puede aceptar una s\u00edntesis de un solo paso para un API, y qu\u00e9 ejemplos se mencionan en el documento?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las excepciones a la regla general de s\u00edntesis y ejemplos concretos que se mencionan.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n se requiere para justificar el reciclaje de filtrados (madres licuores) en el proceso de fabricaci\u00f3n de un API?**\n   - Esta pregunta se centra en los requisitos espec\u00edficos que deben cumplirse para considerar el reciclaje de ciertos materiales en el proceso de fabricaci\u00f3n.\n\n3. **\u00bfQu\u00e9 criterios se deben cumplir para que los disolventes recuperados sean aceptables en las etapas finales de purificaci\u00f3n y/o cristalizaci\u00f3n?**\n   - Esta pregunta busca detalles sobre los est\u00e1ndares que deben cumplir los disolventes recuperados para ser utilizados en etapas cr\u00edticas del proceso de fabricaci\u00f3n. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n que puede no estar f\u00e1cilmente disponible en otras fuentes, enfoc\u00e1ndose en detalles espec\u00edficos del proceso de fabricaci\u00f3n de APIs seg\u00fan lo descrito en el documento de la OMS.", "prev_section_summary": "### Temas Clave:\n\n1. **Descripci\u00f3n del Proceso de Fabricaci\u00f3n del API**:\n   - Importancia de proporcionar informaci\u00f3n detallada sobre el proceso de fabricaci\u00f3n y los controles de proceso.\n   - Requisitos para incluir diagramas de flujo, narrativas secuenciales y justificaciones para la elecci\u00f3n de materiales.\n\n2. **Diagrama de Flujo**:\n   - Debe incluir f\u00f3rmulas moleculares, pesos, rangos de rendimiento, estructuras qu\u00edmicas de materiales iniciales, intermedios, reactivos y el API, as\u00ed como condiciones operativas y solventes.\n\n3. **Narrativa Secuencial**:\n   - Detalles sobre cantidades de materias primas, solventes, catalizadores y reactivos, identificaci\u00f3n de pasos cr\u00edticos y condiciones operativas (temperatura, presi\u00f3n, pH, tiempo).\n\n4. **Procesos Alternativos**:\n   - Descripci\u00f3n y justificaci\u00f3n de procesos alternativos y pasos de reprocesamiento.\n\n5. **Procedimiento APIMF**:\n   - Referencias cruzadas a la parte restringida para informaci\u00f3n confidencial y requisitos espec\u00edficos para la presentaci\u00f3n de informaci\u00f3n sobre APIs est\u00e9riles.\n\n6. **Material de Partida del API**:\n   - Justificaci\u00f3n de la elecci\u00f3n del material de partida, considerando la complejidad de la mol\u00e9cula y los controles de calidad.\n\n### Entidades:\n\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa utilizada en la fabricaci\u00f3n de medicamentos.\n- **GMP (Buenas Pr\u00e1cticas de Manufactura)**: Normativas que aseguran que los productos se fabrican y controlan de acuerdo con est\u00e1ndares de calidad.\n- **APIMF (Active Pharmaceutical Ingredient Master File)**: Archivo maestro que contiene informaci\u00f3n sobre el API.\n- **ICH Q7**: Directrices sobre las Buenas Pr\u00e1cticas de Manufactura para APIs.\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad que establece est\u00e1ndares y directrices para la salud p\u00fablica y la fabricaci\u00f3n de medicamentos.\n\n### Resumen:\nLa secci\u00f3n aborda la necesidad de una descripci\u00f3n exhaustiva del proceso de fabricaci\u00f3n de APIs, incluyendo diagramas de flujo y narrativas detalladas. Se enfatiza la justificaci\u00f3n de la elecci\u00f3n del material de partida y se mencionan requisitos espec\u00edficos para la presentaci\u00f3n de informaci\u00f3n confidencial bajo el procedimiento APIMF. Adem\u00e1s, se destaca la importancia de cumplir con las Buenas Pr\u00e1cticas de Manufactura (GMP) y la documentaci\u00f3n necesaria para la revisi\u00f3n por parte de inspectores de la OMS.", "excerpt_keywords": "Keywords: API, synthesis, manufacturing process, solvents, impurity profile"}}, "4ef45487-dbfa-45bb-8f39-80408f2176a3": {"node_ids": ["a7934f11-86c3-41fc-a032-cbb5daa9a85c"], "metadata": {"page_label": "152", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIt is acceptable to provide information on pilot-scale manufacture, provided it is representative of production scale and scale-up is reported immediately to WHO according to the requirements of the WHO variation guidelines (9).\n\n## 3.2.S.2.3 Control of materials (name, manufacturer)\n\nMaterials used in the manufacture of the API (e.g. raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process. Information on the quality and control of these materials should be provided. Information demonstrating that materials meet standards appropriate for their intended use should be provided, as appropriate (details in 3.2.A.2).\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section.\n\nThe following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier.\n\nThe API starting material should be fully characterized and suitable specifications proposed and justified, including, at a minimum, control for identity, assay, impurity content and any other critical attribute of the material. For each API starting material, the name and address of the manufacturing site(s) of the manufacturer(s) should be indicated. A brief description of the preparation of the API starting material should be provided for each manufacturer, including the solvents, catalysts and reagents used. A single set of specifications should be proposed for the starting material that applies to material from all sources. Any future changes to the API starting material manufacturers, mode of preparation or specifications should be notified.\n\nAs indicated in section 3.2.S.2 there are occasions where a starting material for synthesis may also need to be defined. In general, the starting material for synthesis described in the PD should:\n\n- be a synthetic precursor of one or more synthesis steps prior to the final API intermediate. Acids, bases, salts, esters and similar derivatives of the API, as well as the racemate of a single enantiomer API, are not considered final intermediates;\n- be a well characterized, isolated and purified substance with its structure fully elucidated including its stereochemistry (when applicable);\n- have well-defined specifications that include among others one or more specific identity tests and tests and limits for assay and specified, unspecified and total impurities;\n- be incorporated as a significant structural fragment into the structure of the API.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS establece directrices sobre la fabricaci\u00f3n y control de materiales para la producci\u00f3n de ingredientes farmac\u00e9uticos activos (API). Se enfatiza la importancia de caracterizar completamente los materiales de partida, proponer especificaciones adecuadas y notificar cualquier cambio en los fabricantes o en el proceso de preparaci\u00f3n. Tambi\u00e9n se menciona la posibilidad de proporcionar informaci\u00f3n sobre la fabricaci\u00f3n a escala piloto, siempre que sea representativa de la escala de producci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n se debe proporcionar sobre los materiales utilizados en la fabricaci\u00f3n de un API?**\n   - Se debe listar cada material, identificando su uso en el proceso, y proporcionar informaci\u00f3n sobre su calidad y control, asegurando que cumplan con los est\u00e1ndares apropiados para su uso previsto.\n\n2. **\u00bfCu\u00e1les son los requisitos para la caracterizaci\u00f3n de los materiales de partida en la producci\u00f3n de un API?**\n   - Los materiales de partida deben estar completamente caracterizados, con especificaciones adecuadas que incluyan control de identidad, ensayo, contenido de impurezas y otros atributos cr\u00edticos. Adem\u00e1s, se debe indicar el nombre y la direcci\u00f3n del fabricante.\n\n3. **\u00bfQu\u00e9 condiciones deben cumplirse para que un material de partida se considere adecuado para la s\u00edntesis de un API?**\n   - Debe ser un precursor sint\u00e9tico bien caracterizado, aislado y purificado, con su estructura completamente elucidada, y tener especificaciones bien definidas que incluyan pruebas de identidad y l\u00edmites para impurezas. Adem\u00e1s, debe ser un fragmento estructural significativo del API.", "prev_section_summary": "### Temas Clave:\n\n1. **Materiales de Partida para S\u00edntesis**: Se define el material inicial en el proceso de fabricaci\u00f3n de un ingrediente farmac\u00e9utico activo (API) y se requiere que el solicitante proponga y justifique qu\u00e9 sustancias se consideran como tales.\n\n2. **S\u00edntesis de un Solo Paso**: Se aceptan excepciones para la s\u00edntesis de un solo paso en casos espec\u00edficos, como cuando el material de partida est\u00e1 cubierto por un CEP o es aceptado a trav\u00e9s de procedimientos de precalificaci\u00f3n de la OMS.\n\n3. **Recuperaci\u00f3n de Materiales**: Se debe detallar la recuperaci\u00f3n de materiales en el proceso de fabricaci\u00f3n, asegurando que los niveles de impurezas no aumenten con el tiempo. Se requiere informaci\u00f3n sobre el reciclaje de filtrados, incluyendo tiempos de retenci\u00f3n y n\u00famero m\u00e1ximo de reciclajes.\n\n4. **Uso de Disolventes**: Todos los disolventes utilizados deben ser identificados y se recomienda que los disolventes recuperados no se usen en etapas finales, a menos que se justifique su uso con datos que demuestren que cumplen con los est\u00e1ndares adecuados.\n\n5. **Formas Polim\u00f3rficas y Tama\u00f1o de Part\u00edcula**: Se debe indicar la forma resultante de la s\u00edntesis si se han identificado formas polim\u00f3rficas o amorfas, y se deben describir los m\u00e9todos de reducci\u00f3n de tama\u00f1o de part\u00edcula si este es un atributo cr\u00edtico.\n\n6. **Procesos de Fabricaci\u00f3n Alternativos**: Se requiere justificaci\u00f3n para el uso de procesos alternativos, que deben ser explicados con el mismo nivel de detalle que el proceso principal, asegurando que el perfil de impurezas sea comparable.\n\n### Entidades:\n\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que se utiliza en la fabricaci\u00f3n de medicamentos.\n- **CEP (Certificado de Excipiente Farmac\u00e9utico)**: Certificaci\u00f3n que asegura la calidad de un excipiente.\n- **APIMF (Maestro de Ingredientes Farmac\u00e9uticos Activos)**: Documentaci\u00f3n que proporciona informaci\u00f3n sobre un API.\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organizaci\u00f3n que establece directrices y est\u00e1ndares para la salud p\u00fablica.\n- **ICH Q7**: Directrices sobre buenas pr\u00e1cticas de fabricaci\u00f3n para ingredientes farmac\u00e9uticos activos.\n- **Filtrados (Madres Licuores)**: Soluciones que quedan despu\u00e9s de la cristalizaci\u00f3n o filtraci\u00f3n, que pueden ser recicladas.\n\nEste resumen abarca los aspectos esenciales del proceso de fabricaci\u00f3n de APIs seg\u00fan el documento de la OMS, destacando la importancia de la justificaci\u00f3n y el control en cada etapa del proceso.", "excerpt_keywords": "Keywords: pharmaceutical preparations, API manufacturing, quality control, starting materials, WHO guidelines"}}, "d16bd0e8-1a48-432c-aa5f-32cc52824bc4": {"node_ids": ["9d9af543-5d33-4950-b811-4f18a9c62814"], "metadata": {"page_label": "153", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\nCopies of the specifications for the materials used in the synthesis, extraction, isolation and purification steps should be provided in the PD, including starting materials, reagents, solvents, catalysts and recovered materials. Confirmation should be provided that the specifications apply to materials used at each manufacturing site. A certificate of analysis of the starting material for synthesis should be provided. A summary of the information on starting materials should be provided in the QOS-PD.\n\nThe carry-over of impurities of the starting materials for synthesis into the final API should be considered and discussed.\n\nA letter of attestation should be provided confirming that the API and the starting materials and reagents used to manufacture the API are without risk of transmitting agents of animal spongiform encephalopathies.\n\nWhen available a CEP demonstrating compliance with recommendations on transmissible spongiform encephalopathy (TSE) should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.2.4 Controls of critical steps and intermediates (name, manufacturer)\n\n**Critical steps:** Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to ensure that the process is controlled should be provided.\n\n**Intermediates:** Information on the quality and control of intermediates isolated during the process should be provided.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD, with the exception of information that is also relevant for the applicant (4).\n\nThe following requirements apply to the fourth option for submission of API information where full details are provided in the dossier.\n\nThe critical steps should be identified. These can include: steps where significant impurities are removed or introduced; steps introducing an essential molecular structural element such as a chiral centre or resulting in a major chemical transformation; steps having an impact on solid-state properties and homogeneity of the API that may be relevant for use in solid dosage forms.\n\nSpecifications for isolated intermediates should be provided and should include tests and acceptance criteria for identity, purity and assay, where applicable.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.2.5 Process validation and/or evaluation (name, manufacturer)\n\nProcess validation and/or evaluation studies for aseptic processing and sterilization should be included.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior del contenido:\n\n### Resumen de Nivel Superior\nEl documento detalla los requisitos para la presentaci\u00f3n de informaci\u00f3n sobre la fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos (API), centr\u00e1ndose en las especificaciones de los materiales utilizados en los procesos de s\u00edntesis, extracci\u00f3n, aislamiento y purificaci\u00f3n. Se enfatiza la importancia de la calidad y control de los materiales, as\u00ed como la validaci\u00f3n de procesos cr\u00edticos. Tambi\u00e9n se menciona la necesidad de garantizar que los materiales no transmitan agentes de encefalopat\u00edas espongiformes transmisibles (TSE) y se requiere documentaci\u00f3n espec\u00edfica, como certificados de an\u00e1lisis y cartas de atestaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de documentaci\u00f3n se requiere para asegurar que los materiales utilizados en la fabricaci\u00f3n del API no transmiten agentes de encefalopat\u00edas espongiformes transmisibles?**\n   - Se requiere una carta de atestaci\u00f3n que confirme que el API y los materiales de partida y reactivos utilizados en su fabricaci\u00f3n no presentan riesgo de transmitir agentes de TSE. Adem\u00e1s, cuando est\u00e9 disponible, se debe proporcionar un Certificado de Excepci\u00f3n (CEP) que demuestre el cumplimiento de las recomendaciones sobre TSE.\n\n2. **\u00bfCu\u00e1les son los criterios de aceptaci\u00f3n que deben incluirse para los pasos cr\u00edticos en el proceso de fabricaci\u00f3n del API?**\n   - Los criterios de aceptaci\u00f3n deben incluir pruebas y criterios de aceptaci\u00f3n con justificaci\u00f3n, que incluyan datos experimentales, para los pasos cr\u00edticos identificados en el proceso de fabricaci\u00f3n. Estos pasos pueden incluir aquellos donde se eliminan o introducen impurezas significativas, se introduce un elemento estructural molecular esencial, o se impactan las propiedades del estado s\u00f3lido y la homogeneidad del API.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n se debe proporcionar sobre los intermediarios aislados durante el proceso de fabricaci\u00f3n del API?**\n   - Se debe proporcionar informaci\u00f3n sobre la calidad y control de los intermediarios aislados, incluyendo especificaciones que contengan pruebas y criterios de aceptaci\u00f3n para identidad, pureza y ensayo, cuando sea aplicable. Esto es crucial para asegurar que los intermediarios cumplen con los est\u00e1ndares requeridos antes de avanzar en el proceso de fabricaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Fabricaci\u00f3n a Escala Piloto**: Se permite proporcionar informaci\u00f3n sobre la fabricaci\u00f3n a escala piloto, siempre que sea representativa de la escala de producci\u00f3n y se notifique cualquier escalado a la OMS seg\u00fan las directrices de variaci\u00f3n.\n\n2. **Control de Materiales**: \n   - Se deben listar todos los materiales utilizados en la fabricaci\u00f3n del ingrediente farmac\u00e9utico activo (API), incluyendo materias primas, materiales de partida, disolventes, reactivos y catalizadores.\n   - Es necesario proporcionar informaci\u00f3n sobre la calidad y el control de estos materiales, asegurando que cumplan con los est\u00e1ndares apropiados para su uso.\n\n3. **Materiales de Partida**:\n   - Los materiales de partida deben estar completamente caracterizados y se deben proponer especificaciones adecuadas que incluyan control de identidad, ensayo, contenido de impurezas y otros atributos cr\u00edticos.\n   - Se debe indicar el nombre y la direcci\u00f3n de los fabricantes de los materiales de partida, as\u00ed como una breve descripci\u00f3n de su preparaci\u00f3n.\n\n4. **Especificaciones**: \n   - Se debe proponer un conjunto \u00fanico de especificaciones para los materiales de partida que se aplique a todos los proveedores.\n   - Cualquier cambio futuro en los fabricantes, modo de preparaci\u00f3n o especificaciones debe ser notificado.\n\n5. **Definici\u00f3n de Materiales de Partida para S\u00edntesis**:\n   - Deben ser precursores sint\u00e9ticos bien caracterizados, aislados y purificados, con estructura completamente elucidada.\n   - Deben tener especificaciones bien definidas que incluyan pruebas de identidad y l\u00edmites para impurezas.\n   - Deben ser incorporados como fragmentos estructurales significativos en la estructura del API.\n\n### Entidades Clave\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia utilizada en la fabricaci\u00f3n de medicamentos.\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad que establece directrices y requisitos para la fabricaci\u00f3n y control de materiales farmac\u00e9uticos.\n- **APIMF (Active Pharmaceutical Ingredient Master File)**: Procedimiento que permite la presentaci\u00f3n de informaci\u00f3n sobre el API.\n- **Materiales de Partida**: Sustancias utilizadas en la s\u00edntesis del API que deben cumplir con especificaciones rigurosas.", "excerpt_keywords": "Keywords: API, specifications, process validation, TSE, intermediates"}}, "c602926f-4207-4a7a-b67b-799298ac3592": {"node_ids": ["baa6c284-364b-4ef4-b452-eed7b74497e1"], "metadata": {"page_label": "154", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD.\n\nThe following requirements apply to the fourth option for submission of API information where full details are provided in the dossier.\n\nIt is expected that the manufacturing processes for all APIs are properly controlled. If the API is prepared as sterile a complete description should be provided of the aseptic processing and/or sterilization methods. A description of the controls used to maintain the sterility of the API during storage and transportation should also be provided. Alternative processes should be justified and described (see guidance in 3.2.S.2.2 for the level of detail expected).\n\n## 3.2.S.2.6 Manufacturing process development (name, manufacturer)\n\nA description and discussion should be provided of the significant changes made to the manufacturing process and/or manufacturing site of the API used in producing comparative bioavailability or biowaiver, scale-up, pilot, and, if available, production scale batches.\n\nReference should be made to the API data provided in Section 3.2.S.4.4.\n\nWhere the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD.\n\n## 3.2.S.3 Characterization (name, manufacturer)\n\n### 3.2.S.3.1 Elucidation of structure and other characteristics (name, manufacturer)\n\nConfirmation of structure based on, e.g. synthetic route and spectral analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included.\n\n**Elucidation of structure**\n\nThe PD should include quality assurance (QA) certified copies of the spectra, peak assignments and a detailed interpretation of the data from the studies performed to elucidate and/or confirm the structure of the API. The QOS-PD should include a list of the studies performed and a conclusion from the studies (e.g. whether the results support the proposed structure).\n\nFor APIs that are not described in an officially recognized pharmacopoeia, the studies carried out to elucidate and/or confirm the chemical structure normally include elemental analysis, infrared (IR), ultraviolet (UV), nuclear magnetic resonance (NMR) and mass spectra (MS) studies. Other tests could include X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).\n\nFor APIs that are described in an officially recognized pharmacopoeia it is generally sufficient to provide copies of the IR spectrum of the API from each.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas basadas en el contexto proporcionado, junto con un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los requisitos para la presentaci\u00f3n de informaci\u00f3n sobre ingredientes farmac\u00e9uticos activos (API) en el contexto de la preparaci\u00f3n de medicamentos. Se enfatiza la importancia del control de los procesos de fabricaci\u00f3n, especialmente para APIs est\u00e9riles, y se requiere una descripci\u00f3n exhaustiva de los m\u00e9todos de procesamiento y control de calidad. Adem\u00e1s, se abordan los procedimientos para la caracterizaci\u00f3n de la estructura qu\u00edmica de los APIs, incluyendo la necesidad de estudios espectrosc\u00f3picos y otros an\u00e1lisis para confirmar su identidad y pureza.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n se requiere para justificar los procesos alternativos de fabricaci\u00f3n de un API est\u00e9ril?**\n   - La respuesta a esta pregunta se puede encontrar en la secci\u00f3n que menciona la necesidad de justificar y describir los procesos alternativos, as\u00ed como la referencia a la gu\u00eda en 3.2.S.2.2 sobre el nivel de detalle esperado.\n\n2. **\u00bfCu\u00e1les son los estudios espec\u00edficos que se deben realizar para confirmar la estructura qu\u00edmica de un API que no est\u00e1 descrito en una farmacopea oficialmente reconocida?**\n   - La respuesta se puede extraer de la secci\u00f3n que enumera los estudios necesarios, como an\u00e1lisis elemental, espectroscop\u00eda IR, UV, NMR y MS, as\u00ed como pruebas adicionales como XRPD y DSC.\n\n3. **\u00bfQu\u00e9 documentos de calidad se deben incluir en el dossier para respaldar la elucidaci\u00f3n de la estructura de un API?**\n   - Esta pregunta se relaciona con la parte del texto que menciona que el PD debe incluir copias certificadas por aseguramiento de calidad (QA) de los espectros, asignaciones de picos y una interpretaci\u00f3n detallada de los datos de los estudios realizados para confirmar la estructura del API.", "prev_section_summary": "### Temas Clave\n\n1. **Especificaciones de Materiales**: Se requiere proporcionar copias de las especificaciones para los materiales utilizados en los procesos de s\u00edntesis, extracci\u00f3n, aislamiento y purificaci\u00f3n de ingredientes farmac\u00e9uticos activos (API). Esto incluye materiales de partida, reactivos, disolventes, catalizadores y materiales recuperados.\n\n2. **Control de Impurezas**: Es importante considerar y discutir la transferencia de impurezas de los materiales de partida al API final.\n\n3. **Transmisi\u00f3n de TSE**: Se debe incluir una carta de atestaci\u00f3n que confirme que el API y los materiales utilizados en su fabricaci\u00f3n no presentan riesgo de transmitir agentes de encefalopat\u00edas espongiformes transmisibles (TSE). Tambi\u00e9n se debe proporcionar un Certificado de Excepci\u00f3n (CEP) cuando est\u00e9 disponible.\n\n4. **Controles de Pasos Cr\u00edticos**: Se deben proporcionar pruebas y criterios de aceptaci\u00f3n para los pasos cr\u00edticos en el proceso de fabricaci\u00f3n, as\u00ed como informaci\u00f3n sobre la calidad y control de los intermediarios aislados.\n\n5. **Validaci\u00f3n de Procesos**: Se deben incluir estudios de validaci\u00f3n y/o evaluaci\u00f3n de procesos para el procesamiento as\u00e9ptico y la esterilizaci\u00f3n.\n\n### Entidades\n\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa utilizada en la fabricaci\u00f3n de medicamentos.\n- **TSE (Encefalopat\u00edas Espongiformes Transmisibles)**: Grupo de enfermedades que afectan el sistema nervioso central de los animales y humanos.\n- **CEP (Certificado de Excepci\u00f3n)**: Documento que demuestra el cumplimiento de las recomendaciones sobre TSE.\n- **ICH Q6A**: Documento de referencia que establece directrices sobre la calidad de los productos farmac\u00e9uticos.\n\n### Resumen\n\nLa secci\u00f3n aborda los requisitos para la presentaci\u00f3n de informaci\u00f3n sobre la fabricaci\u00f3n de API, enfatizando la importancia de las especificaciones de materiales, el control de impurezas, la prevenci\u00f3n de la transmisi\u00f3n de TSE, y la validaci\u00f3n de procesos cr\u00edticos. Se requiere documentaci\u00f3n espec\u00edfica para asegurar la calidad y seguridad de los materiales utilizados en la producci\u00f3n de API.", "excerpt_keywords": "Keywords: API, manufacturing process, characterization, quality assurance, pharmacopoeia"}}, "f0530cee-c154-448d-a118-7d210549d390": {"node_ids": ["f439938c-cb88-45ec-995a-5ed80ac8cfdc"], "metadata": {"page_label": "155", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Isomerism/stereochemistry\n\nWhen an API is chiral, it should be specified whether specific stereoisomers or a mixture of stereoisomers have been used in the comparative biostudies, and information should be given as to the stereoisomer of the API that is to be used in the FPP.\n\nWhere the potential for stereoisomerism exists, a discussion should be included of the possible isomers that can result from the manufacturing process and the steps where chirality was introduced. The identicality of the isomeric composition of the API to that of the API in the comparator product should be established. Information on the physical and chemical properties of the isomeric mixture or single enantiomer should be provided, as appropriate. The API specification should include a test to ensure isomeric identity and purity.\n\nThe potential for interconversion of the isomers in the isomeric mixture, or racemization of the single enantiomer should be discussed.\n\nWhen a single enantiomer of the API is claimed for non-pharmacopoeial APIs, unequivocal proof of absolute configuration of asymmetric centres should be provided, such as determined by X-ray of a single crystal.\n\nIf, based on the structure of the API, there is not a potential for stereoisomerism, it is sufficient to include a statement to this effect.\n\n# Polymorphism\n\nMany APIs can exist in different physical forms in the solid state. Polymorphism is characterized as the ability of an API to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water the solvates are also commonly known as hydrates.\n\nPolymorphic forms of the same chemical compound differ in internal solid-state structure and, therefore, may possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These properties can have a direct impact on API processability, pharmaceutical product manufacturability and product quality and performance, including stability, dissolution and bioavailability. The unexpected appearance or disappearance of a polymorphic form may lead to serious pharmaceutical consequences.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior\nEl documento de la OMS aborda dos conceptos clave en la farmacolog\u00eda: el isomerismo/estereoisomer\u00eda y el polimorfismo de los principios activos (API). Se enfatiza la importancia de especificar la composici\u00f3n estereoisom\u00e9rica de un API, especialmente cuando es quiral, y se requiere informaci\u00f3n sobre su pureza y propiedades. Adem\u00e1s, se discute c\u00f3mo los diferentes formas polim\u00f3rficas de un API pueden afectar sus propiedades qu\u00edmicas y f\u00edsicas, lo que a su vez puede influir en la manufacturabilidad y calidad del producto farmac\u00e9utico.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de pruebas se deben incluir en la especificaci\u00f3n del API para garantizar la identidad y pureza isom\u00e9rica?**\n   - Esta pregunta busca detalles sobre los m\u00e9todos espec\u00edficos que se deben utilizar para verificar la composici\u00f3n isom\u00e9rica de un API.\n\n2. **\u00bfCu\u00e1les son las implicaciones farmac\u00e9uticas de la aparici\u00f3n inesperada de una forma polim\u00f3rfica de un API?**\n   - Esta pregunta se centra en las consecuencias pr\u00e1cticas y potencialmente graves que pueden surgir de cambios en la forma polim\u00f3rfica de un API.\n\n3. **\u00bfQu\u00e9 tipo de evidencia se requiere para demostrar la configuraci\u00f3n absoluta de los centros asim\u00e9tricos en un enanti\u00f3mero \u00fanico de un API no farmacopoeial?**\n   - Esta pregunta busca informaci\u00f3n sobre los est\u00e1ndares de evidencia necesarios para validar la configuraci\u00f3n estereoisom\u00e9rica de un API que no est\u00e1 regulado por una farmacopea.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Procedimiento APIMF**: Se menciona que, cuando se utiliza el procedimiento APIMF, una referencia cruzada a la parte restringida del APIMF es suficiente para la secci\u00f3n del Dossier (PD).\n\n2. **Control de Procesos de Fabricaci\u00f3n**: Se enfatiza la necesidad de que los procesos de fabricaci\u00f3n de todos los Ingredientes Farmac\u00e9uticos Activos (API) est\u00e9n adecuadamente controlados. Para los APIs est\u00e9riles, se requiere una descripci\u00f3n completa de los m\u00e9todos de procesamiento as\u00e9ptico y/o de esterilizaci\u00f3n, as\u00ed como de los controles para mantener la esterilidad durante el almacenamiento y transporte.\n\n3. **Desarrollo del Proceso de Fabricaci\u00f3n**: Se debe proporcionar una descripci\u00f3n y discusi\u00f3n de los cambios significativos en el proceso de fabricaci\u00f3n y/o en el sitio de fabricaci\u00f3n del API, especialmente en relaci\u00f3n con lotes de bioequivalencia comparativa, escalado, piloto y producci\u00f3n.\n\n4. **Caracterizaci\u00f3n de la Estructura**: Se requiere la confirmaci\u00f3n de la estructura del API mediante an\u00e1lisis espectrosc\u00f3picos y otros m\u00e9todos. Se debe incluir informaci\u00f3n sobre isomerismo, estereoqu\u00edmica y formaci\u00f3n de polimorfos.\n\n5. **Documentaci\u00f3n de Calidad**: El Dossier debe incluir copias certificadas por aseguramiento de calidad (QA) de los espectros, asignaciones de picos y una interpretaci\u00f3n detallada de los datos de los estudios realizados para confirmar la estructura del API.\n\n6. **Estudios Espec\u00edficos para APIs No Reconocidos**: Para APIs que no est\u00e1n descritos en una farmacopea oficialmente reconocida, se requieren estudios como an\u00e1lisis elemental, espectroscop\u00eda IR, UV, NMR y MS, as\u00ed como pruebas adicionales como XRPD y DSC.\n\n7. **Farmacopeas Reconocidas**: Para APIs descritos en farmacopeas reconocidas, generalmente es suficiente proporcionar copias del espectro IR del API.\n\n### Entidades Clave\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite el documento.\n- **APIMF (Active Pharmaceutical Ingredient Master File)**: Procedimiento mencionado para la presentaci\u00f3n de informaci\u00f3n sobre APIs.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia cuya fabricaci\u00f3n y caracterizaci\u00f3n se detalla en el documento.\n- **QA (Quality Assurance)**: Aseguramiento de calidad relacionado con la documentaci\u00f3n requerida.\n- **Espectroscop\u00eda**: M\u00e9todos anal\u00edticos mencionados para la caracterizaci\u00f3n de la estructura del API. \n\nEste resumen abarca los aspectos fundamentales y las entidades relevantes del contenido proporcionado, destacando la importancia de la regulaci\u00f3n y el control en la fabricaci\u00f3n y caracterizaci\u00f3n de los APIs.", "excerpt_keywords": "Keywords: isomerism, stereochemistry, polymorphism, active pharmaceutical ingredient, pharmaceutical quality"}}, "4d592e77-b313-4a73-b501-480d7634fdcf": {"node_ids": ["e87de8ed-5afb-4bcb-8331-bc33b99c3681"], "metadata": {"page_label": "156", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nApplicants to the WHO Prequalification of Medicines Programme and API manufacturers are expected to have adequate knowledge about the polymorphism of the APIs used and/or produced. Information on polymorphism can come from the scientific literature, patents, compendia or other references to determine if polymorphism is a concern, e.g. for APIs that are not BCS highly soluble. In the absence of published data for APIs that are not BSC highly soluble, polymorphic screening will be necessary to determine if the API can exist in more than one crystalline form. Polymorphic screening is generally accomplished via crystallization studies using different solvents and conditions.\n\nA number of methods can be used to characterize the polymorphic forms of an API. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. XRPD can also be used to provide unequivocal proof of polymorphism. Other methods, including microscopy, thermal analysis (e.g. DSC, thermal gravimetric analysis and hot-stage microscopy) and spectroscopy (e.g. IR, Raman, and solid-state nuclear magnetic resonance (ssNMR)) are helpful for further characterization of polymorphic forms. Where polymorphism is a concern, the applicants or manufacturers of APIs should demonstrate that a suitable method, capable of distinguishing different polymorphs, is available to them.\n\nDecision tree 4(1) of ICH Q6A (6) can be used where screening is necessary and 4(2) can be used to investigate if different polymorphic forms have different properties that may affect performance, bioavailability and stability of the FPP and to decide whether a preferred polymorph should be monitored at release and on storage of the API. Where there is a preferred polymorph, acceptance criteria should be incorporated into the API specification to ensure polymorphic equivalence of the commercial material and that of the API batches used in the comparative bioavailability or biowaiver studies. The polymorphic characterization of the API batches used in comparative bioavailability or biowaiver studies by the above-mentioned methods should be provided. The method used to control polymorphic form should be demonstrated to be specific for the preferred form.\n\nPolymorphism can also include solvation or hydration products (also known as pseudopolymorphs). If the API is used in a solvated form, the following information should be provided:\n\n- specifications for the solvent-free API in 3.2.S.2.4, if that compound is a synthetic precursor;\n- specifications for the solvated API including appropriate limits on the weight ratio of API to solvent (with data to support the proposed limits);\n- a description of the method used to prepare the solvate in 3.2.S.2.2.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS aborda la importancia del conocimiento sobre el polimorfismo de los principios activos (API) en el contexto de la precalificaci\u00f3n de medicamentos. Se enfatiza la necesidad de realizar estudios de cribado polim\u00f3rfico para determinar si un API puede existir en m\u00e1s de una forma cristalina, especialmente si no es altamente soluble seg\u00fan el sistema BCS. Se describen m\u00e9todos para caracterizar las formas polim\u00f3rficas, siendo la difracci\u00f3n de rayos X de cristal \u00fanico el est\u00e1ndar de oro. Adem\u00e1s, se menciona la importancia de establecer criterios de aceptaci\u00f3n para asegurar la equivalencia polim\u00f3rfica y se discuten los productos de solvataci\u00f3n o hidrataci\u00f3n como pseudopolimorfos.\n\n### Preguntas Espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los m\u00e9todos m\u00e1s confiables para demostrar la existencia de polimorfismo en un API y cu\u00e1l se considera el est\u00e1ndar de oro?**\n   - Respuesta: La demostraci\u00f3n de una estructura no equivalente mediante difracci\u00f3n de rayos X de cristal \u00fanico es actualmente considerada como la evidencia definitiva de polimorfismo. Adem\u00e1s, la difracci\u00f3n de rayos X en polvo (XRPD) tambi\u00e9n puede proporcionar prueba inequ\u00edvoca de polimorfismo.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n se debe proporcionar si un API se utiliza en forma de solvatado?**\n   - Respuesta: Se debe proporcionar especificaciones para el API libre de solvente, especificaciones para el API solvado que incluyan l\u00edmites apropiados en la relaci\u00f3n peso de API a solvente, y una descripci\u00f3n del m\u00e9todo utilizado para preparar el solvatado.\n\n3. **\u00bfC\u00f3mo se deben manejar las formas polim\u00f3rficas preferidas en los estudios de bioequivalencia o biowaiver?**\n   - Respuesta: Donde hay un polimorfo preferido, se deben incorporar criterios de aceptaci\u00f3n en la especificaci\u00f3n del API para asegurar la equivalencia polim\u00f3rfica del material comercial y de los lotes de API utilizados en los estudios de bioequivalencia o biowaiver. Adem\u00e1s, la caracterizaci\u00f3n polim\u00f3rfica de los lotes de API utilizados en estos estudios debe ser proporcionada, y el m\u00e9todo utilizado para controlar la forma polim\u00f3rfica debe ser espec\u00edfico para la forma preferida.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n#### Temas Clave\n\n1. **Isomerismo y Estereoisomer\u00eda**:\n   - Importancia de especificar si se utilizan estereois\u00f3meros espec\u00edficos o una mezcla en estudios comparativos.\n   - Necesidad de establecer la identidad isom\u00e9rica del API en comparaci\u00f3n con el producto de referencia.\n   - Requerimiento de pruebas para garantizar la pureza y la identidad isom\u00e9rica.\n   - Discusi\u00f3n sobre la posibilidad de interconversi\u00f3n de is\u00f3meros y racemizaci\u00f3n de enanti\u00f3meros.\n   - Para APIs no farmacopoeiales, se requiere prueba inequ\u00edvoca de la configuraci\u00f3n absoluta de los centros asim\u00e9tricos.\n\n2. **Polimorfismo**:\n   - Definici\u00f3n de polimorfismo como la capacidad de un API para existir en diferentes fases cristalinas.\n   - Diferencias en propiedades qu\u00edmicas y f\u00edsicas entre formas polim\u00f3rficas que pueden afectar la manufacturabilidad y calidad del producto.\n   - Consecuencias farmac\u00e9uticas de la aparici\u00f3n o desaparici\u00f3n inesperada de formas polim\u00f3rficas.\n\n#### Entidades\n\n- **API (Active Pharmaceutical Ingredient)**: Componente activo en medicamentos que puede presentar isomerismo y polimorfismo.\n- **Estereois\u00f3meros**: Is\u00f3meros que tienen la misma f\u00f3rmula molecular pero diferente disposici\u00f3n espacial.\n- **Enantiomeros**: Is\u00f3meros \u00f3pticos que son im\u00e1genes especulares no superponibles.\n- **Polimorfismo**: Fen\u00f3meno que permite a un compuesto qu\u00edmico existir en m\u00faltiples formas cristalinas.\n- **Solvatos y Hidrataci\u00f3n**: Formas cristalinas que contienen solventes, siendo los hidratos aquellos que contienen agua.\n\nEste resumen destaca la relevancia de la estereoisomer\u00eda y el polimorfismo en el desarrollo y la calidad de los productos farmac\u00e9uticos, as\u00ed como los requisitos espec\u00edficos para la caracterizaci\u00f3n de APIs.", "excerpt_keywords": "Keywords: polymorphism, active pharmaceutical ingredient, crystallization, bioavailability, solvation"}}, "2a64fb6a-e529-470b-b5c9-b8cff93fa8ab": {"node_ids": ["10082ae2-3613-4802-840a-818a641b43da"], "metadata": {"page_label": "157", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Particle size distribution\n\nFor APIs that are not BCS highly soluble contained in solid FPPs, or liquid FPPs containing undissolved API, the particle size distribution of the material can have an effect on the in vitro and/or in vivo behaviour of the FPP. Particle size distribution can also be important in dosage form performance (e.g., delivery of inhalation products), achieving uniformity of content in low-dose tablets (e.g. 2 mg or less), desired smoothness in ophthalmic preparations and stability of suspensions.\n\nIf particle size distribution is an important parameter (e.g. as in the above cases), results from an investigation of several batches of the API should be provided, including characterization of the batch(es) used in the comparative bioavailability or biowaiver studies. API specifications should include controls on the particle size distribution to ensure consistency with the material in the batch(es) used in the comparative bioavailability and biowaiver studies (e.g. limits for d10, d50 and d90). The criteria should be established statistically, based on the standard deviation of the test results from the previously mentioned studies. The following example is provided for illustrative purposes as possible acceptance criteria for particle size distribution limits:\n\n- d10 not more than (NMT) 10% of total volume less than X \u00b5m;\n- d50 XX \u00b5m\u2013XXX \u00b5m;\n- d90 not less than (NLT) 90% of total volume less than XXXX \u00b5m.\n\nOther controls on particle size distribution can be considered acceptable, if scientifically justified.\n\nReference documents: ICH Q6A (6).\n\n## 3.2.S.3.2 Impurities (name, manufacturer)\n\n### Information on impurities should be provided.\n\nDetails on the principles for the control of impurities (e.g. reporting, identification and qualification) are outlined in the ICH Q3A, Q3B and Q3C impurity guidelines (10\u201312). Additional information elaborating on some of the elements discussed in the ICH guidelines is outlined below.\n\nRegardless of whether a pharmacopoeial standard is claimed, a discussion should be provided of the potential and actual impurities arising from the synthesis, manufacture or degradation of the API. This should cover starting materials, by-products, intermediates, chiral impurities and degradation products and should include the chemical names, structures and origins of the impurities. The discussion of pharmacopoeial APIs should not be limited to the impurities specified in the API monograph.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl texto aborda la importancia de la distribuci\u00f3n del tama\u00f1o de part\u00edculas en los principios activos (API) que no son altamente solubles seg\u00fan el sistema BCS, especialmente en formas farmac\u00e9uticas s\u00f3lidas y l\u00edquidas. Se destaca c\u00f3mo la distribuci\u00f3n del tama\u00f1o de part\u00edculas puede influir en el comportamiento in vitro e in vivo de los productos farmac\u00e9uticos. Adem\u00e1s, se menciona la necesidad de proporcionar resultados de investigaciones sobre varias lotes de API y establecer especificaciones que incluyan controles sobre la distribuci\u00f3n del tama\u00f1o de part\u00edculas. Tambi\u00e9n se discuten las impurezas en los API, enfatizando la importancia de identificar y controlar las impurezas que pueden surgir durante la s\u00edntesis, fabricaci\u00f3n o degradaci\u00f3n del API.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios estad\u00edsticos sugeridos para establecer los l\u00edmites de distribuci\u00f3n del tama\u00f1o de part\u00edculas en los API?**\n   - El texto menciona que los criterios deben establecerse estad\u00edsticamente, bas\u00e1ndose en la desviaci\u00f3n est\u00e1ndar de los resultados de las pruebas de los estudios de bioequivalencia o biowaiver previos.\n\n2. **\u00bfQu\u00e9 tipos de impurezas deben ser discutidos en relaci\u00f3n con los API, seg\u00fan las pautas ICH?**\n   - Se deben discutir impurezas potenciales y reales que surjan de la s\u00edntesis, fabricaci\u00f3n o degradaci\u00f3n del API, incluyendo materiales de partida, subproductos, intermedios, impurezas quirales y productos de degradaci\u00f3n, junto con sus nombres qu\u00edmicos, estructuras y or\u00edgenes.\n\n3. **\u00bfQu\u00e9 ejemplos de l\u00edmites de aceptaci\u00f3n para la distribuci\u00f3n del tama\u00f1o de part\u00edculas se proporcionan en el texto?**\n   - Se proporcionan ejemplos como: \n     - d10 no m\u00e1s del 10% del volumen total menor que X \u00b5m;\n     - d50 en el rango de XX \u00b5m a XXX \u00b5m;\n     - d90 no menos del 90% del volumen total menor que XXXX \u00b5m.\n\n### Resumen de nivel superior\n\nEl documento enfatiza la relevancia de la distribuci\u00f3n del tama\u00f1o de part\u00edculas en la formulaci\u00f3n y eficacia de los productos farmac\u00e9uticos, especialmente para aquellos que no son altamente solubles. Se requiere un an\u00e1lisis detallado de varios lotes de API para asegurar la consistencia y se establecen criterios espec\u00edficos para el control de la distribuci\u00f3n del tama\u00f1o de part\u00edculas. Adem\u00e1s, se subraya la necesidad de un enfoque exhaustivo para identificar y controlar las impurezas en los API, siguiendo las pautas establecidas por la ICH.", "prev_section_summary": "### Temas Clave:\n\n1. **Polimorfismo de APIs**: La secci\u00f3n destaca la importancia del conocimiento sobre el polimorfismo de los principios activos (APIs) en el contexto de la precalificaci\u00f3n de medicamentos por parte de la OMS.\n\n2. **Cribado Polim\u00f3rfico**: Se enfatiza la necesidad de realizar estudios de cribado polim\u00f3rfico para determinar si un API puede existir en m\u00e1s de una forma cristalina, especialmente si no es altamente soluble seg\u00fan el sistema BCS.\n\n3. **M\u00e9todos de Caracterizaci\u00f3n**: Se describen varios m\u00e9todos para caracterizar las formas polim\u00f3rficas, siendo la difracci\u00f3n de rayos X de cristal \u00fanico el est\u00e1ndar de oro, junto con XRPD y otras t\u00e9cnicas como microscop\u00eda, an\u00e1lisis t\u00e9rmico y espectroscopia.\n\n4. **Criterios de Aceptaci\u00f3n**: Se menciona la importancia de establecer criterios de aceptaci\u00f3n para asegurar la equivalencia polim\u00f3rfica entre el material comercial y los lotes de API utilizados en estudios de bioequivalencia o biowaiver.\n\n5. **Solvataci\u00f3n y Pseudopolimorfos**: Se aborda el tema de los productos de solvataci\u00f3n o hidrataci\u00f3n, conocidos como pseudopolimorfos, y la informaci\u00f3n que debe proporcionarse si un API se utiliza en forma de solvatado.\n\n### Entidades:\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable de la precalificaci\u00f3n de medicamentos.\n- **APIs (Principios Activos)**: Sustancias utilizadas en la fabricaci\u00f3n de medicamentos.\n- **BCS (Biopharmaceutics Classification System)**: Sistema que clasifica los f\u00e1rmacos seg\u00fan su solubilidad y permeabilidad.\n- **M\u00e9todos de Caracterizaci\u00f3n**: Incluyen difracci\u00f3n de rayos X de cristal \u00fanico, XRPD, microscop\u00eda, an\u00e1lisis t\u00e9rmico (DSC, TGA, microscop\u00eda de etapa caliente) y espectroscopia (IR, Raman, ssNMR).\n- **ICH Q6A**: Directrices que incluyen \u00e1rboles de decisi\u00f3n para evaluar el polimorfismo.\n- **Pseudopolimorfos**: Formas de un API que incluyen productos de solvataci\u00f3n o hidrataci\u00f3n. \n\nEste resumen proporciona una visi\u00f3n general de los aspectos m\u00e1s relevantes del polimorfismo en la fabricaci\u00f3n y evaluaci\u00f3n de APIs, as\u00ed como los m\u00e9todos y criterios necesarios para su caracterizaci\u00f3n y control.", "excerpt_keywords": "Keywords: particle size distribution, APIs, impurities, bioavailability, ICH guidelines"}}, "0386e271-02a3-4979-98eb-153e8c51cc26": {"node_ids": ["163ad738-7dd9-4a8a-951d-78d43e5ce287"], "metadata": {"page_label": "158", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe tables in the QOS-PD template should be used to summarize the information on the API-related and process-related impurities. In the QOS-PD, the term \u201corigin\u201d refers to how and where the impurity was introduced (e.g. \u201cSynthetic intermediate from Step 4 of the synthesis\u201d or \u201cPotential by-product due to rearrangement from Step 6 of the synthesis\u201d). It should also be indicated if the impurity is a metabolite of the API.\n\nThe ICH thresholds for reporting, identification (used to set the limit for individual unknown impurities) and qualification are determined on the basis of potential exposure to the impurity, e.g. by the maximum daily dose (MDD) of the API. For APIs available in multiple dosage forms and strengths having different MDD values, it is imperative that the thresholds and corresponding controls for each of the presentations be considered to ensure that the risks posed by impurities have been addressed. This is normally achieved by using the highest potential daily MDD, rather than the maintenance dose. For parenteral products the maximum hourly dose of the API should also be included.\n\nIt is acknowledged that APIs of semi-synthetic origin do not fall within the scope of the ICH impurity guidelines. However, depending on the nature of the API and the extent of the chemical modification steps, the principles regarding the control of impurities (e.g. reporting, identification and qualification) could be extended to apply to APIs of semi-synthetic origin. As an illustrative example, an API whose precursor molecule was derived from a fermentation process or a natural product of plant or animal origin, which has subsequently undergone several chemical modification reactions, would generally fall within the scope of the ICH impurity guidelines, whereas an API whose sole chemical step was the formation of a salt from a fermentation product generally would not. It is understood that there is some latitude for these types of APIs.\n\n## Identification of impurities\n\nIt is recognized by the pharmacopoeias that APIs can be obtained from various sources and thus can contain impurities not considered during the development of the monograph. Furthermore, a change in the production or source may give rise to additional impurities that are not adequately controlled by the official compendial monograph. As a result each PD is assessed independently to consider the potential impurities that may arise from the proposed route(s) of synthesis. For these reasons the ICH limits for unspecified impurities (e.g. NMT 0.10% or 1.0 mg per day intake (whichever is lower) for APIs having an MDD \u2264 2 g/day) are generally recommended, rather than the general limits for unspecified impurities that may appear in the official compendial monograph, which could potentially be higher than the applicable ICH limit.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS aborda las especificaciones para las preparaciones farmac\u00e9uticas, centr\u00e1ndose en la identificaci\u00f3n y control de impurezas en los principios activos (API). Se discuten los umbrales establecidos por la ICH para la notificaci\u00f3n, identificaci\u00f3n y calificaci\u00f3n de impurezas, que dependen de la exposici\u00f3n potencial a estas impurezas, medida a trav\u00e9s de la dosis diaria m\u00e1xima (MDD) del API. Tambi\u00e9n se menciona que los APIs de origen semisint\u00e9tico pueden no estar completamente cubiertos por las directrices de impurezas de la ICH, pero se pueden aplicar principios similares dependiendo de la naturaleza del API. Adem\u00e1s, se enfatiza la importancia de evaluar cada dossier de producto (PD) de manera independiente para identificar impurezas potenciales.\n\n### Preguntas:\n1. **\u00bfC\u00f3mo se determina el l\u00edmite para las impurezas desconocidas en los APIs seg\u00fan las directrices de la ICH?**\n   - La determinaci\u00f3n del l\u00edmite para las impurezas desconocidas se basa en la exposici\u00f3n potencial a la impureza, que se mide a trav\u00e9s de la dosis diaria m\u00e1xima (MDD) del API. Para APIs con m\u00faltiples formas de dosificaci\u00f3n y MDD, se utiliza la MDD m\u00e1s alta para establecer los l\u00edmites y controles correspondientes.\n\n2. **\u00bfQu\u00e9 consideraciones se deben tener en cuenta para los APIs de origen semisint\u00e9tico en relaci\u00f3n con las impurezas?**\n   - Aunque los APIs de origen semisint\u00e9tico no caen estrictamente bajo las directrices de impurezas de la ICH, los principios de control de impurezas pueden extenderse a ellos dependiendo de la naturaleza del API y la extensi\u00f3n de los pasos de modificaci\u00f3n qu\u00edmica. Por ejemplo, un API derivado de un proceso de fermentaci\u00f3n que ha pasado por varias reacciones qu\u00edmicas podr\u00eda estar sujeto a estas directrices.\n\n3. **\u00bfPor qu\u00e9 es importante evaluar cada dossier de producto (PD) de manera independiente en relaci\u00f3n con las impurezas?**\n   - Es crucial evaluar cada PD de manera independiente porque los APIs pueden ser obtenidos de diversas fuentes y pueden contener impurezas no consideradas en la monograf\u00eda oficial. Adem\u00e1s, un cambio en la producci\u00f3n o la fuente puede dar lugar a impurezas adicionales que no est\u00e1n adecuadamente controladas por la monograf\u00eda, lo que requiere una evaluaci\u00f3n espec\u00edfica para cada caso.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Distribuci\u00f3n del Tama\u00f1o de Part\u00edculas**:\n   - La distribuci\u00f3n del tama\u00f1o de part\u00edculas es crucial para los principios activos (API) que no son altamente solubles seg\u00fan el sistema BCS, especialmente en formas farmac\u00e9uticas s\u00f3lidas y l\u00edquidas.\n   - Afecta el comportamiento in vitro e in vivo de los productos farmac\u00e9uticos, as\u00ed como el rendimiento de las formas de dosificaci\u00f3n (por ejemplo, en productos de inhalaci\u00f3n y tabletas de baja dosis).\n\n2. **Investigaci\u00f3n y Especificaciones**:\n   - Se deben proporcionar resultados de investigaciones sobre varios lotes de API, incluyendo la caracterizaci\u00f3n de los lotes utilizados en estudios de bioequivalencia o biowaiver.\n   - Las especificaciones del API deben incluir controles sobre la distribuci\u00f3n del tama\u00f1o de part\u00edculas, con l\u00edmites establecidos para d10, d50 y d90.\n\n3. **Criterios Estad\u00edsticos**:\n   - Los criterios para establecer l\u00edmites de distribuci\u00f3n del tama\u00f1o de part\u00edculas deben basarse en la desviaci\u00f3n est\u00e1ndar de los resultados de pruebas de estudios previos.\n\n4. **Ejemplos de L\u00edmites de Aceptaci\u00f3n**:\n   - d10: no m\u00e1s del 10% del volumen total menor que X \u00b5m.\n   - d50: en el rango de XX \u00b5m a XXX \u00b5m.\n   - d90: no menos del 90% del volumen total menor que XXXX \u00b5m.\n\n5. **Impurezas**:\n   - Se debe proporcionar informaci\u00f3n sobre las impurezas potenciales y reales que pueden surgir de la s\u00edntesis, fabricaci\u00f3n o degradaci\u00f3n del API.\n   - Esto incluye materiales de partida, subproductos, intermedios, impurezas quirales y productos de degradaci\u00f3n, junto con sus nombres qu\u00edmicos, estructuras y or\u00edgenes.\n\n6. **Referencias**:\n   - Se hace referencia a las pautas ICH Q3A, Q3B y Q3C para el control de impurezas y a ICH Q6A para la distribuci\u00f3n del tama\u00f1o de part\u00edculas.\n\n### Entidades Clave:\n- **API (Principios Activos)**: Sustancias que tienen un efecto farmacol\u00f3gico.\n- **FPP (Formas Farmac\u00e9uticas de Producto)**: Formas en las que se presenta el medicamento.\n- **BCS (Biopharmaceutics Classification System)**: Sistema que clasifica los f\u00e1rmacos seg\u00fan su solubilidad y permeabilidad.\n- **ICH (International Council for Harmonisation)**: Consejo que establece pautas para la regulaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: impurities, API, ICH guidelines, maximum daily dose, pharmaceutical preparations"}}, "80f4c462-d87a-44f5-92d4-34f861740ca3": {"node_ids": ["73252ccd-1488-4c08-a7fd-356d0bf3b34b"], "metadata": {"page_label": "159", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Qualification of Impurities\n\nThe ICH impurity guidelines should be consulted for options on the qualification of impurities. The limit specified for an identified impurity in an officially recognized pharmacopoeia is generally considered to be qualified. The following is an additional option for qualification of impurities in existing APIs:\n\nThe limit for an impurity present in an existing API can be accepted by comparing the results of tests for impurities found in the existing API with those observed in an innovator product using the same validated, stability-indicating analytical procedure (e.g. comparative (high-performance liquid chromatography (HPLC) studies). If samples of the innovator product are not available, the impurity profile may also be compared to a different prequalified FPP with the same route of administration and similar characteristics (e.g. tablet versus capsule). It is recommended that the studies be conducted on comparable samples (e.g. samples of a similar age) to obtain a meaningful comparison of the impurity profiles.\n\nLevels of impurities generated from studies under accelerated or stressed storage conditions of the innovator or prequalified FPP are not considered acceptable/qualified.\n\nA specified impurity present in the existing API is considered qualified if the amount of the impurity in the existing API reflects the levels observed in the innovator or prequalified FPP.\n\n# Basis for Setting the Acceptance Criteria\n\nThe basis for setting the acceptance criteria for the impurities should be provided. This is established by considering the identification and qualification thresholds for API-related impurities (e.g. starting materials, by-products, intermediates, chiral impurities or degradation products) and the concentration limits for process-related impurities (e.g. residual solvents) according to the applicable ICH guidelines (e.g. Q3A (10), Q3C (12)).\n\nThe qualified level should be considered as the maximum allowable limit. However, limits which are considerably wider than the actual manufacturing process capability are generally discouraged. For this reason the acceptance criteria are also set taking into consideration the actual levels of impurities found in several batches of the API from each manufacturer, including the levels found in the batches used for the comparative bioavailability or biowaiver studies. When reporting the results of quantitative tests, the actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. In cases where a large number of batches have been tested it is acceptable to summarize the results of all the batches tested with a range of analytical results.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento aborda la calificaci\u00f3n de impurezas en ingredientes farmac\u00e9uticos activos (API) seg\u00fan las directrices del ICH. Se establece que los l\u00edmites de impurezas identificadas en una farmacopoeia reconocida son generalmente considerados calificados. Se sugiere que la calificaci\u00f3n de impurezas en APIs existentes puede realizarse comparando los resultados de pruebas de impurezas con un producto innovador o un producto farmac\u00e9utico precalificado. Adem\u00e1s, se discute c\u00f3mo establecer criterios de aceptaci\u00f3n para impurezas, considerando los niveles observados en lotes de API y las directrices aplicables del ICH.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 procedimiento se recomienda para calificar impurezas en un API existente si no se dispone de muestras del producto innovador?**\n   - Respuesta: Se recomienda comparar el perfil de impurezas del API existente con el de un producto farmac\u00e9utico prequalificado que tenga la misma v\u00eda de administraci\u00f3n y caracter\u00edsticas similares.\n\n2. **\u00bfCu\u00e1les son las consideraciones clave al establecer criterios de aceptaci\u00f3n para impurezas en un API?**\n   - Respuesta: Los criterios de aceptaci\u00f3n deben basarse en los umbrales de identificaci\u00f3n y calificaci\u00f3n para impurezas relacionadas con el API, as\u00ed como en los l\u00edmites de concentraci\u00f3n para impurezas relacionadas con el proceso, de acuerdo con las directrices del ICH.\n\n3. **\u00bfPor qu\u00e9 no se consideran aceptables los niveles de impurezas generados en estudios bajo condiciones de almacenamiento acelerado o estresado?**\n   - Respuesta: Los niveles de impurezas generados en tales estudios no se consideran aceptables o calificados porque no reflejan las condiciones normales de almacenamiento y estabilidad del producto.", "prev_section_summary": "### Temas Clave:\n\n1. **Especificaciones para Impurezas en APIs**: El documento aborda c\u00f3mo se deben resumir las impurezas relacionadas con el principio activo (API) y el proceso en el formato QOS-PD, destacando la importancia de identificar el origen de las impurezas.\n\n2. **Umbrales de la ICH**: Se discuten los umbrales establecidos por la ICH para la notificaci\u00f3n, identificaci\u00f3n y calificaci\u00f3n de impurezas, que dependen de la dosis diaria m\u00e1xima (MDD) del API. Se enfatiza la necesidad de considerar la MDD m\u00e1s alta para establecer l\u00edmites y controles.\n\n3. **APIs de Origen Semisint\u00e9tico**: Aunque no est\u00e1n completamente cubiertos por las directrices de impurezas de la ICH, se menciona que los principios de control de impurezas pueden aplicarse a estos APIs dependiendo de su naturaleza y los pasos de modificaci\u00f3n qu\u00edmica.\n\n4. **Evaluaci\u00f3n Independiente de Dossiers de Producto (PD)**: Se subraya la importancia de evaluar cada PD de manera independiente para identificar impurezas potenciales, dado que los APIs pueden provenir de diversas fuentes y cambios en la producci\u00f3n pueden introducir nuevas impurezas.\n\n### Entidades:\n\n- **API (Principio Activo)**: Sustancia activa en un medicamento.\n- **ICH (International Council for Harmonisation)**: Organizaci\u00f3n que establece directrices para la regulaci\u00f3n de productos farmac\u00e9uticos.\n- **MDD (Dosis Diaria M\u00e1xima)**: Cantidad m\u00e1xima de un API que se puede administrar diariamente.\n- **QOS-PD (Quality Overall Summary - Product Dossier)**: Plantilla utilizada para resumir informaci\u00f3n sobre impurezas en APIs.\n- **Monograf\u00eda Oficial**: Documento que establece est\u00e1ndares para la calidad de un medicamento.\n\nEste resumen destaca los aspectos m\u00e1s relevantes del documento, centr\u00e1ndose en la identificaci\u00f3n y control de impurezas en los APIs, as\u00ed como en la importancia de la evaluaci\u00f3n individual de cada producto farmac\u00e9utico.", "excerpt_keywords": "Keywords: impurities, qualification, ICH guidelines, acceptance criteria, pharmaceutical products"}}, "6dad416f-c01e-4274-a8be-573e0dd6ec65": {"node_ids": ["b341402b-49cb-473d-87b6-be46ea8d2ddc"], "metadata": {"page_label": "160", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIf there are identified impurities specified in an official compendial monograph that are not controlled by the proposed routine in-house analytical procedure, a justification for their exclusion from routine analyses should be provided (e.g. \u201cImpurities D, E and F listed in *The International Pharmacopoeia* (Ph.Int.) monograph are not potential impurities from the proposed route of synthesis used by manufacturer X\u201d). If acceptable justification cannot be provided it should be demonstrated that the routine in-house method is capable of separating and detecting the impurities specified in the official compendial monograph at an acceptable level (e.g. 0.10%). If such a demonstration cannot be performed, a one-time study should be conducted applying the pharmacopoeial method to several recent batches to demonstrate the absence of the impurities listed in the pharmacopoeia.\n\nICH class II solvent(s) used prior to the last step of the manufacturing process may be exempted from routine control in API specifications if suitable justification is provided. Submission of results demonstrating less than 10% of the ICH Q3C limit (option 1) of the solvent(s) in three consecutive production-scale batches or six consecutive pilot-scale batches of the API or a suitable intermediate would be considered acceptable justification. The last step solvents used in the process should always be routinely controlled in the final API.\n\nFor guidance on acceptable residual solvent limits refer to ICH Q3C (12). The limit for residues of triethylamine (TEA) is either 320 ppm on the basis of ICH Q3C option 1 or 3.2 mg/day on the basis of permitted daily exposure (PDE).\n\nThe absence of known, established highly toxic impurities (genotoxic) used in the process or formed as a by-product should be discussed and suitable limits should be proposed. The limits should be justified by appropriate reference to available guidance (e.g. EMEA/CHMP/QWP/ 251344/2006 (13) or USFDA Guidance for Industry. *Genotoxic and carcinogenic impurities in drug substances and products, recommended approaches (14)*) or by providing experimental safety data or published data in peer-reviewed journals.\n\nResidues of metal catalysts used in the manufacturing process and determined to be present in batches of API are to be controlled in specifications. This requirement does not apply to metals that are deliberate components of the pharmaceutical substance (such as a counter ion of a salt) or metals that are used as a pharmaceutical excipient in the FPP (e.g. an iron oxide pigment). The guideline on the specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000 (15)) or any equivalent approaches can be used to address this issue. The requirement normally does not apply to extraneous metal contaminants that are more appropriately addressed by GMP, good distribution practices (GDP) or any other relevant quality provision such as the heavy metal test in monographs of recognized pharmacopoeias that cover metal contamination originating from manufacturing equipment and the environment.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS aborda las especificaciones para preparaciones farmac\u00e9uticas, centr\u00e1ndose en el control de impurezas en productos farmac\u00e9uticos. Se discuten las justificaciones necesarias para la exclusi\u00f3n de impurezas identificadas en monograf\u00edas oficiales, el manejo de solventes residuales, la evaluaci\u00f3n de impurezas genot\u00f3xicas y los l\u00edmites para residuos de catalizadores met\u00e1licos. Se enfatiza la importancia de demostrar la ausencia de impurezas y de seguir directrices establecidas para garantizar la seguridad y calidad de los productos farmac\u00e9uticos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 justificaci\u00f3n se requiere para excluir impurezas identificadas en una monograf\u00eda oficial de los an\u00e1lisis rutinarios?**\n   - La justificaci\u00f3n debe demostrar que las impurezas no son potenciales impurezas del proceso de s\u00edntesis utilizado por el fabricante. Si no se puede proporcionar una justificaci\u00f3n aceptable, se debe demostrar que el m\u00e9todo anal\u00edtico rutinario puede separar y detectar las impurezas especificadas en la monograf\u00eda oficial a un nivel aceptable (por ejemplo, 0.10%).\n\n2. **\u00bfCu\u00e1les son los l\u00edmites aceptables para los residuos de triethylamine (TEA) seg\u00fan las directrices de ICH Q3C?**\n   - Los l\u00edmites aceptables para los residuos de triethylamine son 320 ppm seg\u00fan la opci\u00f3n 1 de ICH Q3C o 3.2 mg/d\u00eda basado en la exposici\u00f3n diaria permitida (PDE).\n\n3. **\u00bfQu\u00e9 requisitos se aplican a los residuos de catalizadores met\u00e1licos en las especificaciones de API?**\n   - Los residuos de catalizadores met\u00e1licos utilizados en el proceso de fabricaci\u00f3n y que se determinan presentes en lotes de API deben ser controlados en las especificaciones. Sin embargo, esta exigencia no se aplica a los metales que son componentes deliberados de la sustancia farmac\u00e9utica o que se utilizan como excipientes farmac\u00e9uticos en el producto farmac\u00e9utico terminado (FPP). \n\nEstas preguntas y respuestas est\u00e1n dise\u00f1adas para proporcionar informaci\u00f3n espec\u00edfica que puede no estar f\u00e1cilmente disponible en otras fuentes, centr\u00e1ndose en aspectos t\u00e9cnicos y normativos del control de calidad en la fabricaci\u00f3n de productos farmac\u00e9uticos.", "prev_section_summary": "### Temas Clave\n\n1. **Calificaci\u00f3n de Impurezas**: Se discuten las directrices del ICH para la calificaci\u00f3n de impurezas en ingredientes farmac\u00e9uticos activos (API). Se establece que los l\u00edmites de impurezas identificadas en farmacopoeias reconocidas son generalmente considerados calificados.\n\n2. **Comparaci\u00f3n de Perfiles de Impurezas**: Se sugiere que la calificaci\u00f3n de impurezas en APIs existentes puede realizarse comparando los resultados de pruebas de impurezas con un producto innovador o un producto farmac\u00e9utico precalificado, utilizando procedimientos anal\u00edticos validados.\n\n3. **Condiciones de Almacenamiento**: Se aclara que los niveles de impurezas generados en estudios bajo condiciones de almacenamiento acelerado o estresado no son aceptables para la calificaci\u00f3n.\n\n4. **Criterios de Aceptaci\u00f3n**: Se establece la necesidad de proporcionar una base para los criterios de aceptaci\u00f3n de impurezas, considerando los umbrales de identificaci\u00f3n y calificaci\u00f3n, as\u00ed como los l\u00edmites de concentraci\u00f3n para impurezas relacionadas con el proceso.\n\n5. **Informe de Resultados**: Se enfatiza la importancia de reportar resultados cuantitativos de manera precisa, evitando declaraciones vagas.\n\n### Entidades\n\n- **ICH**: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.\n- **API**: Ingrediente Farmac\u00e9utico Activo.\n- **FPP**: Producto Farmac\u00e9utico Final.\n- **HPLC**: Cromatograf\u00eda L\u00edquida de Alta Eficiencia.\n- **Directrices ICH**: Incluyen Q3A y Q3C, que abordan la identificaci\u00f3n y calificaci\u00f3n de impurezas.\n\nEste resumen proporciona una visi\u00f3n general de los aspectos clave relacionados con la calificaci\u00f3n de impurezas en APIs y los criterios de aceptaci\u00f3n establecidos en el documento.", "excerpt_keywords": "Keywords: impurities, pharmaceutical preparations, ICH guidelines, residual solvents, metal catalysts"}}, "75ae3cee-9d58-40e3-9b68-3ce4930426b5": {"node_ids": ["61c15370-f1b6-4b2f-b372-61916784255b"], "metadata": {"page_label": "161", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Reference documents: ICH Q6A, Q3A, Q3C (6, 10, 12).\n\n## 3.2.S.4 Control of the API (name, manufacturer)\n\n### 3.2.S.4.1 Specification (name, manufacturer)\n\n**The specification for the API should be provided.**\n\nAs defined in ICH\u2019s Q6A guideline (6), a specification is:\n\n> \u201cA list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. \u2018Conformance to specifications\u2019 means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.\u201d\n\nCopies of the API specifications, dated and signed by authorized personnel (e.g. the person in charge of the quality control or quality assurance department) should be provided in the PD, including specifications from each API manufacturer as well as those of the FPP manufacturer.\n\nThe FPP manufacturer\u2019s API specification should be summarized according to the table in the QOS-PD template under the headings: tests, acceptance criteria and analytical procedures (including types, sources and versions for the methods).\n\n- The **standard** declared by the applicant could be an officially recognized compendial standard (e.g. BP, JP, Ph.Eur., Ph.Int., USP) or an in-house (manufacturer\u2019s) standard.\n- The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes.\n- For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV, HPLC or laser diffraction), the source refers to the origin of the analytical procedure (e.g. BP, JP, Ph.Eur., Ph.Int., USP or in-house) and the version (e.g. code number/version/date) should be provided for version control purposes.\n\nIn cases where there is more than one API manufacturer, the FPP manufacturer\u2019s API specifications should be one single compiled set of specifications that is identical for each manufacturer. It is acceptable to lay down in the specification more than one acceptance criterion and/or analytical method.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento se centra en la especificaci\u00f3n del Ingrediente Farmac\u00e9utico Activo (API) seg\u00fan las directrices de ICH Q6A. Se define la especificaci\u00f3n como un conjunto de pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n que deben cumplirse para que un API o un Producto Farmac\u00e9utico Final (FPP) se considere aceptable para su uso. Se enfatiza la importancia de que las especificaciones sean firmadas por personal autorizado y que se mantenga un control de versiones adecuado. Adem\u00e1s, se menciona que en caso de m\u00faltiples fabricantes de API, se debe proporcionar un conjunto de especificaciones compiladas que sean id\u00e9nticas para cada fabricante.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 tipo de personal debe firmar las especificaciones del API y por qu\u00e9 es importante esta firma?**\n   - La firma debe ser de personal autorizado, como el encargado del control de calidad o del departamento de aseguramiento de la calidad. Esta firma es importante porque valida que las especificaciones han sido revisadas y aprobadas, asegurando su conformidad con los est\u00e1ndares de calidad requeridos por las autoridades regulatorias.\n\n2. **\u00bfCu\u00e1les son los elementos clave que deben incluirse en la tabla de especificaciones del API seg\u00fan el formato QOS-PD?**\n   - La tabla debe incluir los encabezados de pruebas, criterios de aceptaci\u00f3n y procedimientos anal\u00edticos. Adem\u00e1s, debe detallar el tipo de procedimiento anal\u00edtico utilizado, la fuente de dicho procedimiento y la versi\u00f3n correspondiente para el control de versiones.\n\n3. **\u00bfQu\u00e9 se debe hacer si hay m\u00e1s de un fabricante de API en relaci\u00f3n con las especificaciones del FPP?**\n   - En caso de que haya m\u00e1s de un fabricante de API, el fabricante del FPP debe proporcionar un \u00fanico conjunto de especificaciones compiladas que sea id\u00e9ntico para cada fabricante. Esto asegura la consistencia y la conformidad en los criterios de calidad establecidos para el API utilizado en el FPP.", "prev_section_summary": "### Temas Clave\n\n1. **Control de Impurezas**: Se requiere justificaci\u00f3n para excluir impurezas identificadas en monograf\u00edas oficiales de los an\u00e1lisis rutinarios. Si no se puede justificar su exclusi\u00f3n, se debe demostrar que el m\u00e9todo anal\u00edtico puede detectar dichas impurezas a un nivel aceptable.\n\n2. **Solventes Residuales**: Los solventes de clase II de ICH utilizados antes del \u00faltimo paso del proceso de fabricaci\u00f3n pueden ser exentos de control rutinario si se proporciona una justificaci\u00f3n adecuada. Se aceptan resultados que demuestren menos del 10% del l\u00edmite de ICH Q3C en lotes consecutivos.\n\n3. **Impurezas Genot\u00f3xicas**: Se debe discutir la ausencia de impurezas altamente t\u00f3xicas y establecer l\u00edmites adecuados, justific\u00e1ndolos con referencias a gu\u00edas disponibles o datos experimentales.\n\n4. **Residuos de Catalizadores Met\u00e1licos**: Los residuos de catalizadores met\u00e1licos presentes en lotes de API deben ser controlados en las especificaciones, excepto aquellos que son componentes deliberados de la sustancia farmac\u00e9utica o excipientes en el producto terminado.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite directrices sobre especificaciones para preparaciones farmac\u00e9uticas.\n- **ICH (International Council for Harmonisation)**: Proporciona directrices sobre l\u00edmites de solventes residuales y otros aspectos de calidad.\n- **EMEA/CHMP**: Referencias a gu\u00edas espec\u00edficas sobre l\u00edmites de impurezas y residuos de catalizadores met\u00e1licos.\n- **USFDA**: Proporciona orientaci\u00f3n sobre impurezas genot\u00f3xicas y carcinog\u00e9nicas en sustancias y productos farmac\u00e9uticos.\n\nEste resumen destaca los aspectos t\u00e9cnicos y normativos relacionados con el control de calidad en la fabricaci\u00f3n de productos farmac\u00e9uticos, enfatizando la importancia de la justificaci\u00f3n y el cumplimiento de las directrices establecidas.", "excerpt_keywords": "Keywords: API specifications, ICH guidelines, quality control, analytical procedures, regulatory compliance"}}, "4eaab0db-e4b0-434a-a506-b5fa198267a3": {"node_ids": ["079c0ba0-2385-4b18-94c0-0174b2589b60"], "metadata": {"page_label": "162", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nfor a single parameter with the statement \u201cfor API from manufacturer A\u201d (e.g. in the case of residual solvents).\n\nAny non-routine testing should be clearly identified as such and justified together with the proposal on the frequency of non-routine testing.\n\nThe ICH Q6A guideline (6) outlines recommendations for a number of universal and specific tests and criteria for APIs.\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12) and officially recognized pharmacopoeias.\n\n## 3.2.S.4.2 Analytical procedures (name, manufacturer)\n\n**The analytical procedures used for testing the API should be provided.**\n\nCopies of the in-house analytical procedures used to generate testing results provided in the PD, as well as those proposed for routine testing of the API by the FPP manufacturer, should be provided. Unless modified it is not necessary to provide copies of officially recognized compendial analytical procedures.\n\nTables for summarizing a number of the different analytical procedures and validation information (e.g. HPLC assay/impurity methods, gas chromatography (GC) methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the in-house analytical procedures of the FPP manufacturer for determination of the residual solvents, assay and purity of the API, in section 2.3.S.4.2 of the QOS-PD. Other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD. Officially recognized compendial methods need not be summarized unless modifications have been made.\n\nAlthough HPLC is normally considered the method of choice for determining API-related impurities, other chromatographic methods such as GC and thin-layer chromatography (TLC) can also be used if appropriately validated. For determination of related substances, reference standards should normally be available for each of the identified impurities, particularly those known to be toxic and the concentration of the impurities should be quantified against their own reference standards. Impurity standards may be obtained from pharmacopoeias (individual impurities or resolution mixtures), from commercial sources or prepared in-house. It is considered acceptable to use the API as an external standard to estimate the levels of impurities, provided the response factors of those impurities are sufficiently close to that of the API, i.e. between 80 and 120%. In cases where the response factor is outside this range it may still be acceptable to use the API, provided a correction factor is applied. Data to support calculation of the correction factor should be provided for an in-house method. Unspecified impurities may be quantified using a solution of the API as the reference standard at a concentration corresponding to the limit established for individual unspecified impurities.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS detalla las especificaciones para los procedimientos anal\u00edticos de las sustancias farmac\u00e9uticas activas (API). Se enfatiza la importancia de proporcionar procedimientos anal\u00edticos in-house y la necesidad de justificar cualquier prueba no rutinaria. Adem\u00e1s, se mencionan las recomendaciones de la gu\u00eda ICH Q6A sobre pruebas universales y espec\u00edficas, as\u00ed como la utilizaci\u00f3n de m\u00e9todos cromatogr\u00e1ficos validados para la determinaci\u00f3n de impurezas y la cuantificaci\u00f3n de sustancias relacionadas.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n se debe incluir sobre los procedimientos anal\u00edticos utilizados para las pruebas de API?**\n   - Se debe proporcionar copias de los procedimientos anal\u00edticos in-house utilizados para generar resultados de pruebas, as\u00ed como aquellos propuestos para las pruebas rutinarias por el fabricante del producto farmac\u00e9utico terminado (FPP). No es necesario incluir copias de procedimientos compendiales oficialmente reconocidos a menos que se hayan modificado.\n\n2. **\u00bfCu\u00e1les son las condiciones bajo las cuales se puede utilizar el API como est\u00e1ndar externo para la cuantificaci\u00f3n de impurezas?**\n   - El API puede ser utilizado como est\u00e1ndar externo para estimar los niveles de impurezas siempre que los factores de respuesta de esas impurezas est\u00e9n suficientemente cerca del del API, es decir, entre el 80% y el 120%. Si el factor de respuesta est\u00e1 fuera de este rango, a\u00fan puede ser aceptable usar el API, siempre que se aplique un factor de correcci\u00f3n.\n\n3. **\u00bfQu\u00e9 se debe hacer en caso de que se realicen pruebas no rutinarias en el API?**\n   - Cualquier prueba no rutinaria debe ser claramente identificada y justificada, junto con una propuesta sobre la frecuencia de dichas pruebas no rutinarias. Esto asegura que se mantenga la transparencia y la justificaci\u00f3n en el proceso de control de calidad del API.", "prev_section_summary": "### Temas Clave:\n\n1. **Especificaci\u00f3n del API**: Se define como un conjunto de pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n que deben cumplirse para que un API o un Producto Farmac\u00e9utico Final (FPP) sea considerado aceptable para su uso.\n\n2. **Importancia de la Firma**: Las especificaciones deben ser firmadas por personal autorizado, como el encargado del control de calidad o del aseguramiento de la calidad, para validar su revisi\u00f3n y aprobaci\u00f3n.\n\n3. **Control de Versiones**: Es esencial proporcionar el n\u00famero de referencia y la versi\u00f3n de las especificaciones para asegurar un control adecuado de las versiones.\n\n4. **Tabla de Especificaciones**: Debe incluir encabezados como pruebas, criterios de aceptaci\u00f3n y procedimientos anal\u00edticos, detallando el tipo de procedimiento, su fuente y la versi\u00f3n correspondiente.\n\n5. **M\u00faltiples Fabricantes de API**: Si hay m\u00e1s de un fabricante de API, el fabricante del FPP debe proporcionar un conjunto \u00fanico de especificaciones que sea id\u00e9ntico para cada fabricante, garantizando consistencia en los criterios de calidad.\n\n### Entidades:\n\n- **ICH Q6A**: Directriz que define la especificaci\u00f3n del API.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en un medicamento.\n- **FPP (Producto Farmac\u00e9utico Final)**: Producto terminado que contiene el API.\n- **Personal Autorizado**: Individuos responsables de la revisi\u00f3n y aprobaci\u00f3n de las especificaciones.\n- **Est\u00e1ndares Compendiales**: Normas reconocidas oficialmente (ej. BP, JP, Ph.Eur., USP).\n- **Procedimientos Anal\u00edticos**: M\u00e9todos utilizados para evaluar la calidad del API (ej. HPLC, UV, IR).\n\nEste resumen destaca la importancia de las especificaciones del API en el contexto de la calidad y la regulaci\u00f3n farmac\u00e9utica, as\u00ed como los requisitos para su documentaci\u00f3n y control.", "excerpt_keywords": "Keywords: API, analytical procedures, ICH Q6A, impurities, non-routine testing"}}, "8c784ec5-b6d9-4c53-ba1f-ee148b85ce51": {"node_ids": ["5efb52a4-8346-435a-94e8-389dc0f7b37e"], "metadata": {"page_label": "163", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "(e.g. 0.10%). The test for related substances in the Ph.Int. monograph for lamivudine serves as a typical example.\n\nThe system suitability tests (SSTs) represent an integral part of the method and are used to ensure the satisfactory performance of the chosen chromatographic system. As a minimum, HPLC and GC purity methods should include SSTs for resolution and repeatability. For HPLC methods to control API-related impurities, this is typically done using a solution of the API with a concentration corresponding to the limit for unspecified impurities. Resolution of the two closest eluting peaks is generally recommended. However, the choice of alternative peaks can be used if justified (e.g. choice of a toxic impurity). In accordance with the Ph.Int. section on Methods of analysis the repeatability test should include an acceptable number of replicate injections. HPLC assay methods should include SSTs for repeatability and in addition either peak asymmetry, theoretical plates or resolution. For TLC methods, the SSTs should verify the ability of the system to separate and detect the analyte(s) (e.g. by applying a spot corresponding to the API at a concentration corresponding to the limit of unspecified impurities).\n\nReference documents: ICH Q2 (16), WHO Technical Report Series, No. 943, Annex 3 (17).\n\n### 3.2.S.4.3 Validation of analytical procedures (name, manufacturer)\n\n**Analytical validation information, including experimental data for the analytical procedures used for testing the API, should be provided.**\n\nCopies should be provided of the validation reports for the analytical procedures used to generate testing results provided in the PD, as well as those proposed for routine testing of the API by the FPP manufacturer.\n\nTables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods, GC methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures of the FPP manufacturer for determination of residual solvents, assay and purity of the API, in section 2.3.S.4.3 of the QOS-PD. The validation data for other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD.\n\nAs recognized by regulatory authorities and pharmacopoeias themselves, verification of compendial methods can be necessary. The compendial methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. Different sources of the same API or FPP can contain impurities and/or degradation products that were not considered during the development of the monograph. Therefore, the monograph and compendial", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl texto se centra en la validaci\u00f3n de procedimientos anal\u00edticos para el control de impurezas y la pureza de los ingredientes farmac\u00e9uticos activos (API) en la industria farmac\u00e9utica. Se discuten las pruebas de idoneidad del sistema (SST) que son esenciales para garantizar el rendimiento adecuado de los m\u00e9todos cromatogr\u00e1ficos, como HPLC y GC. Se enfatiza la importancia de proporcionar informaci\u00f3n de validaci\u00f3n anal\u00edtica, incluyendo datos experimentales y copias de informes de validaci\u00f3n, as\u00ed como la necesidad de verificar m\u00e9todos compendiales debido a posibles variaciones en impurezas de diferentes fuentes del mismo API o producto farmac\u00e9utico terminado (FPP).\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 criterios se deben cumplir para las pruebas de idoneidad del sistema (SST) en m\u00e9todos HPLC y GC seg\u00fan el contexto proporcionado?**\n   - Respuesta: Las SST deben incluir pruebas de resoluci\u00f3n y repetibilidad. Para HPLC, se recomienda usar una soluci\u00f3n del API con una concentraci\u00f3n correspondiente al l\u00edmite de impurezas no especificadas, y se debe verificar la resoluci\u00f3n de los dos picos m\u00e1s cercanos que eluyen.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n se requiere en los informes de validaci\u00f3n anal\u00edtica para los procedimientos utilizados en la prueba del API?**\n   - Respuesta: Se deben proporcionar copias de los informes de validaci\u00f3n de los procedimientos anal\u00edticos utilizados para generar los resultados de las pruebas presentadas en el dossier de producto (PD), as\u00ed como aquellos propuestos para las pruebas rutinarias del API por el fabricante del FPP.\n\n3. **\u00bfPor qu\u00e9 es importante la verificaci\u00f3n de los m\u00e9todos compendiales seg\u00fan el texto?**\n   - Respuesta: La verificaci\u00f3n de los m\u00e9todos compendiales es importante porque estos m\u00e9todos suelen estar validados en base a un API o FPP de un fabricante espec\u00edfico. Diferentes fuentes del mismo API o FPP pueden contener impurezas y/o productos de degradaci\u00f3n que no fueron considerados durante el desarrollo de la monograf\u00eda, lo que puede afectar la calidad del producto.", "prev_section_summary": "### Temas Clave:\n1. **Procedimientos Anal\u00edticos para API**: Se requiere que se proporcionen copias de los procedimientos anal\u00edticos in-house utilizados para las pruebas de las sustancias farmac\u00e9uticas activas (API) y aquellos propuestos para pruebas rutinarias por el fabricante del producto farmac\u00e9utico terminado (FPP).\n\n2. **Pruebas No Rutinarias**: Cualquier prueba no rutinaria debe ser claramente identificada y justificada, junto con una propuesta sobre la frecuencia de dichas pruebas.\n\n3. **Gu\u00eda ICH Q6A**: Se mencionan las recomendaciones de la gu\u00eda ICH Q6A, que abarca pruebas universales y espec\u00edficas para APIs.\n\n4. **M\u00e9todos Cromatogr\u00e1ficos**: Se destaca el uso de m\u00e9todos como HPLC, GC y cromatograf\u00eda en capa fina (TLC) para la determinaci\u00f3n de impurezas, siempre que est\u00e9n debidamente validados.\n\n5. **Est\u00e1ndares de Impurezas**: Se requiere que existan est\u00e1ndares de referencia para cada impureza identificada, especialmente aquellas conocidas por ser t\u00f3xicas.\n\n6. **Uso del API como Est\u00e1ndar Externo**: Se permite el uso del API como est\u00e1ndar externo para la cuantificaci\u00f3n de impurezas, siempre que los factores de respuesta est\u00e9n entre el 80% y el 120% del del API.\n\n### Entidades:\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las recomendaciones y especificaciones.\n- **ICH (International Council for Harmonisation)**: Proporciona directrices como la Q6A, Q3A y Q3C.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Fabricante que realiza pruebas rutinarias del API.\n- **API (Sustancia Farmac\u00e9utica Activa)**: Compuesto que se est\u00e1 evaluando y probando.\n- **M\u00e9todos Anal\u00edticos**: HPLC, GC, TLC, entre otros, utilizados para la evaluaci\u00f3n de impurezas y pureza del API.\n\n### Resumen:\nEl documento de la OMS establece directrices sobre los procedimientos anal\u00edticos para las sustancias farmac\u00e9uticas activas, enfatizando la necesidad de proporcionar procedimientos in-house y justificar pruebas no rutinarias. Se mencionan las recomendaciones de la gu\u00eda ICH Q6A y se permite el uso del API como est\u00e1ndar externo para la cuantificaci\u00f3n de impurezas bajo ciertas condiciones. Adem\u00e1s, se requiere la disponibilidad de est\u00e1ndares de referencia para impurezas identificadas.", "excerpt_keywords": "Keywords: validation, analytical procedures, impurities, chromatographic methods, system suitability tests"}}, "ddca21ae-6682-4219-a780-5129c180a003": {"node_ids": ["95efb0a1-5f90-42fe-acec-bf69bfa19db2"], "metadata": {"page_label": "164", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe method should be demonstrated as suitable to control the impurity profile of the API from the intended source(s).\n\nIn general, verification is not necessary for compendial API assay methods. However, specificity of a specific compendial assay method should be demonstrated if there are any potential impurities that are not specified in the compendial monograph. If an officially recognized compendial method is used to control API-related impurities that are not specified in the monograph, full validation of the method is expected with respect to those impurities.\n\nIf an officially recognized compendial standard is claimed and an in-house method is used in lieu of the compendial method (e.g. for assay or for specified impurities), equivalence of the in-house and compendial methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For impurity methods, the sample analysed should be the API spiked with impurities at concentrations equivalent to their specification limits.\n\nReference documents: ICH Q2 (16).\n\n## 3.2.S.4.4 Batch analyses (name, manufacturer)\n\n**Description of batches and results of batch analyses should be provided.**\n\nThe information provided should include batch number, batch size, date and production site of relevant API batches used in comparative bioavailability or biowaiver studies, preclinical and clinical data (if relevant), stability, pilot, scale-up and, if available, production-scale batches. These data are used to establish the specifications and evaluate consistency in API quality.\n\nAnalytical results should be provided from at least two batches of at least pilot scale from each proposed manufacturing site of the API and should include the batch(es) used in the comparative bioavailability or biowaiver studies. A pilot-scale batch should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nCopies of the certificates of analysis, both from the API manufacturer(s) and the FPP manufacturer, should be provided for the profiled batches and any company responsible for generating the test results should be identified. The FPP manufacturer\u2019s test results should be summarized in the QOS-PD.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.\n\nA discussion and justification should be provided for any incomplete analyses (e.g. results not tested according to the proposed specification).\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS establece directrices sobre la validaci\u00f3n de m\u00e9todos anal\u00edticos para el control de impurezas en ingredientes farmac\u00e9uticos activos (API). Se menciona que, aunque la verificaci\u00f3n no es necesaria para m\u00e9todos de ensayo compendiales, la especificidad debe ser demostrada si hay impurezas no especificadas. Adem\u00e1s, se requiere que se proporcionen an\u00e1lisis de lotes de API, incluyendo resultados anal\u00edticos y certificados de an\u00e1lisis, para evaluar la calidad y consistencia del API en estudios de bioequivalencia o biowaiver.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 se debe demostrar si se utiliza un m\u00e9todo compendial para controlar impurezas no especificadas en la monograf\u00eda?**\n   - Se debe demostrar la especificidad del m\u00e9todo y, si se utiliza un m\u00e9todo compendial reconocido, se espera una validaci\u00f3n completa del mismo con respecto a esas impurezas.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la descripci\u00f3n de los lotes de API utilizados en estudios de bioequivalencia?**\n   - La descripci\u00f3n debe incluir el n\u00famero de lote, tama\u00f1o del lote, fecha y sitio de producci\u00f3n de los lotes relevantes de API, as\u00ed como datos de estabilidad, lotes piloto, escalado y, si est\u00e1n disponibles, lotes a escala de producci\u00f3n.\n\n3. **\u00bfQu\u00e9 tipo de resultados anal\u00edticos se deben proporcionar para los lotes de API y c\u00f3mo deben ser presentados?**\n   - Se deben proporcionar resultados anal\u00edticos de al menos dos lotes de escala piloto de cada sitio de fabricaci\u00f3n propuesto, incluyendo resultados num\u00e9ricos espec\u00edficos en lugar de declaraciones vagas como \"dentro de los l\u00edmites\" o \"conforma\". Adem\u00e1s, se debe discutir cualquier an\u00e1lisis incompleto y justificarlo.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Validaci\u00f3n de Procedimientos Anal\u00edticos**:\n   - Se enfatiza la importancia de la validaci\u00f3n de los procedimientos anal\u00edticos utilizados para el control de impurezas y la pureza de los ingredientes farmac\u00e9uticos activos (API).\n   - Se requiere informaci\u00f3n anal\u00edtica, incluyendo datos experimentales y copias de informes de validaci\u00f3n.\n\n2. **Pruebas de Idoneidad del Sistema (SST)**:\n   - Las SST son esenciales para garantizar el rendimiento adecuado de los m\u00e9todos cromatogr\u00e1ficos, como HPLC (Cromatograf\u00eda L\u00edquida de Alta Eficiencia) y GC (Cromatograf\u00eda de Gases).\n   - Deben incluir pruebas de resoluci\u00f3n y repetibilidad.\n   - Para HPLC, se recomienda usar una soluci\u00f3n del API con una concentraci\u00f3n correspondiente al l\u00edmite de impurezas no especificadas.\n\n3. **Requisitos de Informes de Validaci\u00f3n**:\n   - Se deben proporcionar copias de los informes de validaci\u00f3n de los procedimientos anal\u00edticos utilizados para generar resultados de pruebas en el dossier de producto (PD).\n   - Se deben resumir las diferentes metodolog\u00edas anal\u00edticas y su informaci\u00f3n de validaci\u00f3n en tablas espec\u00edficas del QOS-PD (Quality Overall Summary - Product Dossier).\n\n4. **Verificaci\u00f3n de M\u00e9todos Compendiales**:\n   - La verificaci\u00f3n de m\u00e9todos compendiales es necesaria debido a que estos m\u00e9todos pueden estar validados en base a un API o FPP de un fabricante espec\u00edfico.\n   - Diferentes fuentes del mismo API o FPP pueden contener impurezas y productos de degradaci\u00f3n no considerados en la monograf\u00eda original.\n\n### Entidades Clave\n- **API**: Ingrediente Farmac\u00e9utico Activo.\n- **FPP**: Producto Farmac\u00e9utico Terminado.\n- **HPLC**: Cromatograf\u00eda L\u00edquida de Alta Eficiencia.\n- **GC**: Cromatograf\u00eda de Gases.\n- **SST**: Pruebas de Idoneidad del Sistema.\n- **QOS-PD**: Dossier de Producto - Resumen General de Calidad.\n- **ICH Q2**: Directrices sobre validaci\u00f3n de m\u00e9todos anal\u00edticos.\n- **Ph.Int.**: Farmacopea Internacional. \n\nEste resumen destaca la importancia de la validaci\u00f3n y verificaci\u00f3n en los procedimientos anal\u00edticos dentro de la industria farmac\u00e9utica, asegurando la calidad y seguridad de los productos.", "excerpt_keywords": "Keywords: validation, impurities, pharmaceutical preparations, batch analysis, compendial methods"}}, "e7c25dfc-bbeb-42b4-8186-1bae326c47b8": {"node_ids": ["a58a57b5-e983-4d51-aec3-85f5b92f9f87"], "metadata": {"page_label": "165", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.S.4.5 Justification of specification (name, manufacturer)\n\n**Justification for the API specification should be provided.**\n\nA discussion should be provided on the inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendial standard(s). If the officially recognized compendial methods have been modified or replaced a discussion of the modifications or replacement method(s) should be included.\n\nThe justification for certain tests, analytical procedures and acceptance criteria may have been discussed in other sections of the PD (e.g. for impurities or particle size distribution) and does not need to be repeated here, although a cross-reference should be provided.\n\nReference documents: ICH Q6A, Q3A, Q3C (6, 10, 12), and officially recognized pharmacopoeias.\n\n# 3.2.S.5.5 Reference standards or materials (name, manufacturer)\n\n**Information on the reference standards or reference materials used for testing of the API should be provided.**\n\nInformation should be provided on the reference standard(s) used to generate data in the PD, as well as those to be used by the FPP manufacturer in routine API and FPP testing.\n\nThe source(s) of the reference standards or materials used in the testing of the API should be provided (e.g. those used for the identification, purity and assay tests). These could be classified as primary or secondary reference standards.\n\nA suitable primary reference standard should be obtained from an officially recognized pharmacopoeial source (e.g. BP, JP, Ph.Eur., Ph.Int., USP) where one exists, and the lot number should be provided. Where a pharmacopoeial standard is claimed for the API and/or the FPP, the primary reference standard should be obtained from that pharmacopoeia when available. Primary reference standards from officially recognized pharmacopoeial sources do not need further structural elucidation.\n\nOtherwise a primary standard may be a batch of the API that has been fully characterized (e.g. by IR, UV, NMR and mass spectrometry (MS) analyses). Further purification techniques may be needed to render the material acceptable for use as a chemical reference standard. The purity requirements for a chemical reference substance depend upon its intended use. A chemical reference substance proposed for an identification test does not require meticulous purification since the presence of a small percentage of impurities in the substance often has no noticeable effect on the test. On the other hand, chemical reference substances that are to be used in assays should possess a high degree of purity (such as 99.5% on the dried or water/solvent free basis). Absolute content of the primary", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS (WHO - Technical Report Series 970) aborda la justificaci\u00f3n de las especificaciones para los ingredientes farmac\u00e9uticos activos (API) y la informaci\u00f3n sobre los est\u00e1ndares de referencia utilizados en las pruebas de estos API. Se enfatiza la necesidad de discutir la inclusi\u00f3n de pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n, as\u00ed como las diferencias con los est\u00e1ndares compendiales reconocidos. Tambi\u00e9n se detalla la clasificaci\u00f3n de los est\u00e1ndares de referencia en primarios y secundarios, y se especifica la importancia de la pureza de los est\u00e1ndares seg\u00fan su uso previsto.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 criterios se deben considerar al justificar la inclusi\u00f3n de pruebas y procedimientos anal\u00edticos para un API en el documento de presentaci\u00f3n (PD)?**\n   - Esta pregunta se centra en los aspectos espec\u00edficos que deben discutirse al justificar las especificaciones de un API, como la evoluci\u00f3n de las pruebas y las diferencias con los est\u00e1ndares compendiales.\n\n2. **\u00bfCu\u00e1les son las diferencias entre un est\u00e1ndar de referencia primario y uno secundario, y c\u00f3mo se determina la pureza requerida para cada tipo?**\n   - Esta pregunta busca aclarar la clasificaci\u00f3n de los est\u00e1ndares de referencia y los criterios de pureza que se aplican a cada uno, lo que no se detalla en otros documentos.\n\n3. **\u00bfQu\u00e9 pasos deben seguirse para obtener un est\u00e1ndar de referencia primario de una fuente farmacop\u00e9ica reconocida y qu\u00e9 informaci\u00f3n adicional se debe incluir en la documentaci\u00f3n?**\n   - Esta pregunta se enfoca en el proceso de obtenci\u00f3n de est\u00e1ndares de referencia primarios y la informaci\u00f3n necesaria, como el n\u00famero de lote y la necesidad de caracterizaci\u00f3n estructural, que son aspectos cr\u00edticos en la documentaci\u00f3n de un API.", "prev_section_summary": "### Temas Clave\n\n1. **Validaci\u00f3n de M\u00e9todos Anal\u00edticos**: Se establece que los m\u00e9todos anal\u00edticos para el control de impurezas en ingredientes farmac\u00e9uticos activos (API) deben ser adecuados y, en ciertos casos, se requiere demostrar la especificidad del m\u00e9todo si hay impurezas no especificadas en la monograf\u00eda compendial.\n\n2. **M\u00e9todos Compendiales vs. M\u00e9todos In-House**: Si se utiliza un m\u00e9todo in-house en lugar de un m\u00e9todo compendial reconocido, se debe demostrar la equivalencia entre ambos m\u00e9todos mediante an\u00e1lisis duplicados.\n\n3. **An\u00e1lisis de Lotes**: Se requiere proporcionar informaci\u00f3n detallada sobre los lotes de API utilizados en estudios de bioequivalencia, incluyendo n\u00famero de lote, tama\u00f1o, fecha y sitio de producci\u00f3n, as\u00ed como resultados anal\u00edticos de al menos dos lotes de escala piloto.\n\n4. **Resultados Anal\u00edticos**: Los resultados deben ser presentados de manera num\u00e9rica y espec\u00edfica, evitando declaraciones vagas. Adem\u00e1s, se debe discutir cualquier an\u00e1lisis incompleto y justificarlo.\n\n5. **Documentaci\u00f3n de Referencia**: Se mencionan documentos de referencia relevantes, como ICH Q2, Q6A, Q3A y Q3C, que gu\u00edan las pr\u00e1cticas de validaci\u00f3n y an\u00e1lisis.\n\n### Entidades\n\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que se utiliza en la fabricaci\u00f3n de medicamentos.\n- **M\u00e9todos Compendiales**: M\u00e9todos anal\u00edticos oficialmente reconocidos que se utilizan para el control de calidad.\n- **M\u00e9todos In-House**: M\u00e9todos desarrollados internamente por una empresa para el an\u00e1lisis de productos.\n- **Lotes**: Cantidades espec\u00edficas de API producidas en un per\u00edodo determinado.\n- **Bioequivalencia**: Comparaci\u00f3n de la biodisponibilidad de dos formulaciones de un mismo medicamento.\n- **Certificados de An\u00e1lisis**: Documentos que certifican que un lote de producto cumple con las especificaciones establecidas.\n\nEste resumen abarca los aspectos esenciales de la secci\u00f3n, destacando la importancia de la validaci\u00f3n de m\u00e9todos anal\u00edticos y la documentaci\u00f3n necesaria para garantizar la calidad y consistencia de los API.", "excerpt_keywords": "Keywords: API specification, reference standards, analytical procedures, compendial methods, purity requirements"}}, "951eda41-bf45-4adf-a145-08741c8d55aa": {"node_ids": ["b0a9ea4c-7b8b-4bdb-b818-523adc5f15d6"], "metadata": {"page_label": "166", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nReference standard must be declared and should follow the scheme: 100% minus organic impurities (quantified by an assay procedure, e.g. HPLC or DSC) minus inorganic impurities minus volatile impurities by loss on drying (or water content minus residual solvents).\n\nA secondary (or in-house) reference standard can be used by establishing it against a suitable primary reference standard, e.g. by providing legible copies of the IR of the primary and secondary reference standards run concomitantly and by providing its certificate of analysis, including assay determined against the primary reference standard. A secondary reference standard is often characterized and evaluated for its intended purpose with additional procedures other than those used in routine testing (e.g. if additional solvents are used during the additional purification process that are not used for routine purposes).\n\nReference standards should normally be established for specified impurities. Refer to 3.2.S.4.2 for additional guidance.\n\nReference documents: ICH Q6A (6), *WHO Technical Report Series*, No. 943, Annex 3 (17).\n\n## 3.2.S.6 Container-closure system (name, manufacturer)\n\nA description of the container-closure system(s) should be provided, including the identity of materials of construction of each primary packaging component, and their specifications. The specifications should include description and identification (and critical dimensions with drawings, where appropriate). Non-compendial methods (with validation) should be included, where appropriate.\n\nFor non-functional secondary packaging components (e.g. those that do not provide additional protection), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.\n\nThe suitability should be discussed with respect to, for example, choice of materials, protection from moisture and light, compatibility of the materials of construction with the API, including sorption to container and leaching, and/or safety of materials of construction.\n\nThe WHO *Guidelines on packaging for pharmaceutical products* (18) and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for APIs.\n\nPrimary packaging components are those that are in direct contact with the API or FPP. The specifications for the primary packaging components should be provided and should include a specific test for identification (e.g. IR).\n\nCopies of the labels applied on the secondary packaging of the API should be provided and should include the conditions of storage. In addition, the name and address of the manufacturer of the API should be stated on the label.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS se centra en las especificaciones para preparaciones farmac\u00e9uticas, destacando la importancia de los est\u00e1ndares de referencia y la descripci\u00f3n del sistema de envase y cierre. Se establece un esquema para declarar los est\u00e1ndares de referencia, que incluye la cuantificaci\u00f3n de impurezas org\u00e1nicas, inorg\u00e1nicas y vol\u00e1tiles. Tambi\u00e9n se menciona la posibilidad de utilizar est\u00e1ndares de referencia secundarios, siempre que se establezcan adecuadamente en relaci\u00f3n con un est\u00e1ndar primario. Adem\u00e1s, se requiere una descripci\u00f3n detallada del sistema de envase, incluyendo materiales de construcci\u00f3n, especificaciones y pruebas de identificaci\u00f3n, as\u00ed como informaci\u00f3n sobre el etiquetado y almacenamiento del producto.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 procedimientos adicionales se pueden utilizar para caracterizar y evaluar un est\u00e1ndar de referencia secundario en comparaci\u00f3n con los utilizados en las pruebas rutinarias?**\n   - Esta pregunta busca informaci\u00f3n sobre los m\u00e9todos espec\u00edficos que pueden diferir de los procedimientos est\u00e1ndar, lo cual no se detalla en otros documentos.\n\n2. **\u00bfCu\u00e1les son los criterios espec\u00edficos que deben considerarse al seleccionar materiales para el sistema de envase y cierre en relaci\u00f3n con la protecci\u00f3n del API?**\n   - Esta pregunta se enfoca en los factores cr\u00edticos que afectan la elecci\u00f3n de materiales, que pueden no estar claramente definidos en otras gu\u00edas.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en el certificado de an\u00e1lisis de un est\u00e1ndar de referencia secundario para que sea considerado adecuado?**\n   - Esta pregunta busca detalles sobre los requisitos espec\u00edficos que deben cumplirse en el certificado de an\u00e1lisis, que pueden no estar disponibles en otras fuentes.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS proporciona directrices sobre la declaraci\u00f3n y establecimiento de est\u00e1ndares de referencia para preparaciones farmac\u00e9uticas, as\u00ed como sobre la descripci\u00f3n y especificaciones de los sistemas de envase y cierre. Se enfatiza la importancia de la caracterizaci\u00f3n de impurezas y la necesidad de pruebas de identificaci\u00f3n para los componentes de envase en contacto directo con el API. Adem\u00e1s, se menciona la necesidad de cumplir con las recomendaciones de las gu\u00edas de la OMS y las farmacopeas reconocidas oficialmente.", "prev_section_summary": "### Temas Clave:\n\n1. **Justificaci\u00f3n de Especificaciones para API**:\n   - Se requiere una discusi\u00f3n sobre la inclusi\u00f3n de pruebas, evoluci\u00f3n de pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n.\n   - Es importante se\u00f1alar las diferencias con los est\u00e1ndares compendiales reconocidos y discutir cualquier modificaci\u00f3n o m\u00e9todo de reemplazo.\n\n2. **Est\u00e1ndares de Referencia**:\n   - Se debe proporcionar informaci\u00f3n sobre los est\u00e1ndares de referencia utilizados en las pruebas de los API, incluyendo su clasificaci\u00f3n como primarios o secundarios.\n   - Los est\u00e1ndares primarios deben ser obtenidos de fuentes farmacop\u00e9icas reconocidas y se debe incluir el n\u00famero de lote.\n\n3. **Pureza de los Est\u00e1ndares**:\n   - La pureza de los est\u00e1ndares de referencia var\u00eda seg\u00fan su uso: los est\u00e1ndares para pruebas de identificaci\u00f3n pueden tener un porcentaje de impurezas, mientras que los utilizados en ensayos deben tener una alta pureza (por ejemplo, 99.5%).\n\n### Entidades:\n\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en medicamentos.\n- **FPP (Forma Farmac\u00e9utica del Producto)**: Producto final que contiene el API.\n- **Est\u00e1ndares de Referencia**: Materiales utilizados para asegurar la calidad y consistencia en las pruebas.\n- **Fuentes Farmacop\u00e9icas**: Documentos oficiales que establecen est\u00e1ndares de calidad (ej. BP, JP, Ph.Eur., Ph.Int., USP).\n- **M\u00e9todos Anal\u00edticos**: Procedimientos utilizados para evaluar la calidad del API.\n- **Criterios de Aceptaci\u00f3n**: Normas que determinan si un producto cumple con los requisitos establecidos.\n\nEste resumen destaca la importancia de la justificaci\u00f3n y documentaci\u00f3n adecuada en la evaluaci\u00f3n de ingredientes farmac\u00e9uticos activos y sus est\u00e1ndares de referencia.", "excerpt_keywords": "Keywords: reference standards, pharmaceutical preparations, container-closure system, impurities characterization, packaging specifications"}}, "0f0dc63d-ff2a-4732-9025-37698ee47597": {"node_ids": ["c825f6d6-cb1d-4a7a-be38-c7bc57b6714a"], "metadata": {"page_label": "167", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Stability (name, manufacturer)\n\n## Stability summary and conclusions (name, manufacturer)\n\nThe types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include results, for example, from forced degradation studies and stress conditions, as well as conclusions with respect to storage conditions and retest date or shelf-life, as appropriate.\n\nThe WHO guidelines *Stability testing of active pharmaceutical ingredients and finished pharmaceutical products* (19) should be consulted for recommendations on the core stability data package required for the prequalification of APIs and FPPs.\n\nAs outlined in the WHO stability guidelines, the purpose of stability testing is to: \u201cprovide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light.\u201d\n\nThe tables in the QOS-PD template should be used to summarize the results from the stability studies and related information (e.g. conditions, testing parameters, conclusions and commitments).\n\n### Stress testing\n\nAs outlined in the ICH Q1A guidance document (20), stress testing of the API can help identify the likely degradation products which, in turn, can help to establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual API and the type of FPP involved.\n\nStress testing may be carried out on a single batch of the API. For examples of typical stress conditions refer to section 2.1.2 of *WHO Technical Report Series, No. 953, Annex 2* (19), as well as, \u201cA typical set of studies of the degradation paths of an active pharmaceutical ingredient\u201d, in: *WHO Technical Report Series, No. 929, Annex 5, Table A1* (21).\n\nThe objective of stress testing is not to completely degrade the API but to cause degradation to occur to a small extent, typically 10\u201330% loss of API by assay when compared with non-degraded API. This target is chosen so that some degradation occurs, but not enough to generate secondary products. For this reason the conditions and duration may need to be varied when the API is especially susceptible to a particular stress factor. In the total absence of degradation products after 10 days the API is considered stable under the particular stress condition.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas:\n\n1. **\u00bfCu\u00e1l es el objetivo principal de las pruebas de estabilidad seg\u00fan las directrices de la OMS?**\n   - El objetivo principal de las pruebas de estabilidad, seg\u00fan las directrices de la OMS, es proporcionar evidencia de c\u00f3mo la calidad de un ingrediente farmac\u00e9utico activo (API) o un producto farmac\u00e9utico terminado (FPP) var\u00eda con el tiempo bajo la influencia de diversos factores ambientales, como temperatura, humedad y luz.\n\n2. **\u00bfQu\u00e9 se busca lograr con las pruebas de estr\u00e9s en los ingredientes farmac\u00e9uticos activos (API)?**\n   - Las pruebas de estr\u00e9s buscan identificar los productos de degradaci\u00f3n probables, establecer las v\u00edas de degradaci\u00f3n y validar el poder indicativo de estabilidad de los procedimientos anal\u00edticos utilizados. El objetivo no es degradar completamente el API, sino causar una degradaci\u00f3n leve, t\u00edpicamente del 10 al 30% en comparaci\u00f3n con el API no degradado.\n\n3. **\u00bfQu\u00e9 se debe incluir en el resumen de los estudios de estabilidad seg\u00fan el contexto proporcionado?**\n   - El resumen de los estudios de estabilidad debe incluir los tipos de estudios realizados, los protocolos utilizados, los resultados de los estudios (incluyendo estudios de degradaci\u00f3n forzada y condiciones de estr\u00e9s), as\u00ed como conclusiones sobre las condiciones de almacenamiento y la fecha de rean\u00e1lisis o vida \u00fatil, seg\u00fan sea apropiado.\n\n### Resumen de nivel superior del contexto:\nEl contexto aborda las pruebas de estabilidad de ingredientes farmac\u00e9uticos activos y productos farmac\u00e9uticos terminados, destacando la importancia de estas pruebas para garantizar la calidad a lo largo del tiempo bajo diversas condiciones ambientales. Se menciona la necesidad de realizar pruebas de estr\u00e9s para identificar productos de degradaci\u00f3n y se enfatiza la consulta de las directrices de la OMS para obtener recomendaciones sobre los datos de estabilidad necesarios para la precalificaci\u00f3n de estos productos. Adem\u00e1s, se detalla que el objetivo de las pruebas de estr\u00e9s es provocar una degradaci\u00f3n controlada sin llegar a generar productos secundarios.", "prev_section_summary": "### Temas Clave\n\n1. **Est\u00e1ndares de Referencia**:\n   - Importancia de declarar los est\u00e1ndares de referencia en la evaluaci\u00f3n de impurezas.\n   - Proceso de cuantificaci\u00f3n de impurezas org\u00e1nicas, inorg\u00e1nicas y vol\u00e1tiles.\n   - Uso de est\u00e1ndares de referencia secundarios, que deben establecerse en relaci\u00f3n con un est\u00e1ndar primario y caracterizarse adecuadamente.\n\n2. **Sistema de Envase y Cierre**:\n   - Descripci\u00f3n detallada de los componentes del sistema de envase, incluyendo materiales de construcci\u00f3n y especificaciones.\n   - Consideraciones sobre la protecci\u00f3n del API, compatibilidad de materiales y seguridad.\n   - Requisitos para la identificaci\u00f3n y etiquetado de los componentes de envase, as\u00ed como las condiciones de almacenamiento.\n\n3. **Documentaci\u00f3n y Normativas**:\n   - Referencias a documentos de orientaci\u00f3n como ICH Q6A y las gu\u00edas de la OMS sobre envase para productos farmac\u00e9uticos.\n   - Necesidad de incluir m\u00e9todos no compendiales con validaci\u00f3n en las especificaciones.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite directrices sobre est\u00e1ndares de referencia y envase para productos farmac\u00e9uticos.\n- **Est\u00e1ndares de Referencia Primarios y Secundarios**: Clasificaci\u00f3n de est\u00e1ndares utilizados para la evaluaci\u00f3n de impurezas.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que se encuentra en contacto directo con el envase primario.\n- **FPP (Producto Farmac\u00e9utico Final)**: Producto que contiene el API y est\u00e1 destinado al consumidor.\n- **M\u00e9todos Anal\u00edticos**: T\u00e9cnicas como HPLC (Cromatograf\u00eda L\u00edquida de Alta Resoluci\u00f3n) y DSC (Calorimetr\u00eda Diferencial de Barrido) para la cuantificaci\u00f3n de impurezas.\n- **Farmacopeas Reconocidas**: Documentos oficiales que establecen est\u00e1ndares de calidad y especificaciones para productos farmac\u00e9uticos. \n\nEste resumen destaca la importancia de los est\u00e1ndares de referencia y la adecuada descripci\u00f3n del sistema de envase y cierre en la producci\u00f3n de preparaciones farmac\u00e9uticas, as\u00ed como la necesidad de cumplir con normativas y directrices establecidas.", "excerpt_keywords": "Stability testing, Stress testing, Active pharmaceutical ingredients, WHO guidelines, Degradation products"}}, "5bd14002-6873-4259-a6a8-4ae9d152653d": {"node_ids": ["a3b68da5-ec96-4ffd-8e10-8f275cf56bbf"], "metadata": {"page_label": "168", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe tables in the QOS-PD template should be used to summarize the results of the stress testing and should include the treatment conditions (e.g. temperatures, relative humidities, concentrations of solutions and durations) and the observations for the various test parameters (e.g. assay, degradation products). The discussion of results should highlight whether mass balance was observed.\n\nPhotostability testing should be an integral part of stress testing. The standard conditions are described in ICH Q1B (22). If \u201cprotect from light\u201d is stated in one of the officially recognized pharmacopoeias for the API, it is sufficient to state \u201cprotect from light\u201d on labelling, in lieu of photostability studies when the container-closure system is shown to be light protective.\n\nWhen available it is acceptable to provide the relevant data published in the scientific literature (including, but not limited to, WHO Public Assessment Reports (WHOPARs), European Public Assessment Reports (EPARs)) to support the identified degradation products and pathways.\n\n## Accelerated and long-term testing\n\nAvailable information on the stability of the API under accelerated and long-term storage conditions should be provided, including information in the public domain or obtained from scientific literature. The source of the information should be identified.\n\nThe required long-term storage conditions for APIs in the WHO Prequalification of Medicines Programme are either 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH or 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH. Studies covering the proposed retest period under the above-mentioned long-term storage conditions will provide better assurance of the stability of APIs at the conditions of the supply chain corresponding to the WHO and its Prequalification of Medicines Programme environments. Alternative conditions should be supported with appropriate evidence, which may include literature references or in-house studies, demonstrating that storage at 30 \u00b0C is inappropriate for the API. For APIs intended for storage in a refrigerator and those intended for storage in a freezer, refer to the WHO stability guidelines in the *WHO Technical Report Series*, No. 953, Annex 2 (19). APIs intended for storage below \u201320 \u00b0C should be treated on a case-by-case basis.\n\nTo establish the retest period, data should be provided on not less than three batches of at least pilot scale. The batches should be manufactured by the same synthesis route as production batches and using a method of manufacture and a procedure that simulates the final process to be used for production batches. The stability testing programme should be summarized and the results of stability testing should be summarized in the dossier and in the tables in the QOS-PD.\n\nThe information on the stability studies should include details such as storage conditions, batch number, batch size, container-closure system and completed (and proposed) test intervals. The discussion of results should focus on the stability of the API under the specified conditions.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS proporciona directrices sobre las pruebas de estabilidad de los ingredientes farmac\u00e9uticos activos (API) en el contexto de la precalificaci\u00f3n de medicamentos. Se enfatiza la importancia de realizar pruebas de estr\u00e9s, que incluyen condiciones de temperatura, humedad y fotoprotecci\u00f3n, as\u00ed como la necesidad de documentar los resultados de estas pruebas. Tambi\u00e9n se discuten las condiciones de almacenamiento a largo plazo requeridas y la necesidad de datos de estabilidad de al menos tres lotes para establecer el per\u00edodo de rean\u00e1lisis. Se menciona que la informaci\u00f3n sobre la estabilidad puede provenir de literatura cient\u00edfica y que se deben seguir pautas espec\u00edficas para diferentes condiciones de almacenamiento.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las condiciones de almacenamiento a largo plazo requeridas para los API en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Las condiciones de almacenamiento a largo plazo requeridas son 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH o 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n se debe incluir al establecer el per\u00edodo de rean\u00e1lisis para un API?**\n   - Se debe proporcionar informaci\u00f3n sobre al menos tres lotes de escala piloto, incluyendo condiciones de almacenamiento, n\u00famero de lote, tama\u00f1o del lote, sistema de cierre del contenedor y los intervalos de prueba completados (y propuestos).\n\n3. **\u00bfQu\u00e9 se debe hacer si un API est\u00e1 destinado a ser almacenado a temperaturas inferiores a -20 \u00b0C?**\n   - Los API destinados a almacenamiento por debajo de -20 \u00b0C deben ser tratados caso por caso, lo que implica que se debe proporcionar evidencia adecuada para justificar las condiciones de almacenamiento elegidas.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS establece directrices para la evaluaci\u00f3n de la estabilidad de los ingredientes farmac\u00e9uticos activos, enfatizando la importancia de las pruebas de estr\u00e9s y la documentaci\u00f3n de los resultados. Se especifican las condiciones de almacenamiento a largo plazo y se requiere que los datos de estabilidad provengan de m\u00faltiples lotes para garantizar la validez de los resultados. Adem\u00e1s, se menciona la posibilidad de utilizar datos de literatura cient\u00edfica para respaldar los hallazgos sobre productos de degradaci\u00f3n y v\u00edas.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Pruebas de estabilidad**:\n   - Objetivo: Proporcionar evidencia sobre c\u00f3mo la calidad de un ingrediente farmac\u00e9utico activo (API) o un producto farmac\u00e9utico terminado (FPP) var\u00eda con el tiempo bajo diferentes factores ambientales (temperatura, humedad, luz).\n   - Importancia: Garantizar la calidad y seguridad de los productos farmac\u00e9uticos a lo largo de su vida \u00fatil.\n\n2. **Directrices de la OMS**:\n   - Se deben consultar las directrices de la OMS sobre pruebas de estabilidad para obtener recomendaciones sobre el paquete de datos de estabilidad necesario para la precalificaci\u00f3n de APIs y FPPs.\n\n3. **Resumen de estudios de estabilidad**:\n   - Debe incluir: tipos de estudios realizados, protocolos utilizados, resultados de estudios de degradaci\u00f3n forzada y condiciones de estr\u00e9s, conclusiones sobre condiciones de almacenamiento, y fechas de rean\u00e1lisis o vida \u00fatil.\n\n4. **Pruebas de estr\u00e9s**:\n   - Definici\u00f3n: Ayudan a identificar productos de degradaci\u00f3n, establecer v\u00edas de degradaci\u00f3n y validar la capacidad de los procedimientos anal\u00edticos para indicar estabilidad.\n   - Objetivo: Provocar una degradaci\u00f3n controlada (10-30% de p\u00e9rdida del API) sin generar productos secundarios.\n   - Ejecuci\u00f3n: Puede realizarse en un solo lote de API, y las condiciones de estr\u00e9s pueden variar seg\u00fan la susceptibilidad del API.\n\n5. **Referencias**:\n   - Se mencionan documentos de la OMS y la ICH (International Council for Harmonisation) como fuentes de orientaci\u00f3n sobre las pruebas de estabilidad y estr\u00e9s.\n\n### Entidades clave:\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Proporciona directrices sobre pruebas de estabilidad.\n- **ICH (Consejo Internacional para la Armonizaci\u00f3n)**: Ofrece documentos de orientaci\u00f3n sobre pruebas de estr\u00e9s.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia que se somete a pruebas de estabilidad y estr\u00e9s.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que tambi\u00e9n se eval\u00faa en t\u00e9rminos de estabilidad.", "excerpt_keywords": "Keywords: stability testing, pharmaceutical preparations, WHO guidelines, stress testing, active pharmaceutical ingredient"}}, "8283c45b-f991-4c63-a212-97bc08b389ae": {"node_ids": ["a8271676-c9de-4261-b9e7-28d9b8477a74"], "metadata": {"page_label": "169", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. Ranges of analytical results where relevant and any trends that were observed should be included. For quantitative tests (e.g. individual and total degradation product tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. Where methods are different from those described in S.4.2, descriptions and validation of the methodology used in stability studies should be provided.\n\nThe minimum data required at the time of submitting the dossier (in the general case) are shown in Table 1.\n\n**Table 1**  \nMinimum data required at the time of submitting the dossier\n\n| Storage temperature (\u00b0C) | Relative humidity (%) | Minimum time period (months) |\n| - | - | - |\n| Accelerated 40 \u00b1 2 | 75 \u00b1 5 | 6 |\n| Intermediatea | \u2013a | \u2013a |\n| Long-term 30 \u00b1 2 | 65 \u00b1 5 or 75 \u00b1 5 | 6 |\n\n\n<sup>a</sup>Where long-term conditions are 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH or 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, there is no intermediate condition.\n\nRefer to WHO Technical Report Series, No. 953, Annex 2 (19) for further information regarding the storage conditions, container-closure system, test specifications and testing frequency.\n\n**Proposed storage statement and retest period**\n\nA storage statement should be established for display on the label, based on the stability evaluation of the API. The WHO stability guidelines include a number of recommended storage statements that should be used when supported by the stability studies.\n\nA retest period should be derived from the stability information and should be displayed on the container label.\n\nAfter this retest period a batch of API destined for use in the manufacture of an FPP could be retested and then, if in compliance with the specification, could be used immediately (e.g. within 30 days). If retested and found compliant, the batch does not receive an additional period corresponding to the time established for the retest period. However, an API batch can be retested multiple times and a different portion of the batch used after each retest, as long as it", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los requisitos m\u00ednimos de datos necesarios para la presentaci\u00f3n de un dossier relacionado con la estabilidad de los ingredientes farmac\u00e9uticos activos (API). Se especifican las condiciones de almacenamiento, la humedad relativa y los per\u00edodos de tiempo m\u00ednimos para las pruebas de estabilidad. Adem\u00e1s, se enfatiza la importancia de proporcionar resultados num\u00e9ricos concretos en las pruebas anal\u00edticas y se establece la necesidad de un enunciado de almacenamiento y un per\u00edodo de rean\u00e1lisis que deben ser claramente indicados en las etiquetas de los productos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en los resultados de las pruebas anal\u00edticas para cumplir con las directrices de la OMS?**\n   - Las pruebas anal\u00edticas deben incluir rangos de resultados y tendencias observadas, as\u00ed como resultados num\u00e9ricos concretos en lugar de declaraciones vagas como \"dentro de los l\u00edmites\" o \"conforma\".\n\n2. **\u00bfCu\u00e1les son las condiciones de almacenamiento y los per\u00edodos m\u00ednimos requeridos para las pruebas de estabilidad de un API seg\u00fan la OMS?**\n   - Las condiciones de almacenamiento incluyen: \n     - Acelerado: 40 \u00b1 2 \u00b0C y 75 \u00b1 5% de humedad relativa por un m\u00ednimo de 6 meses.\n     - A largo plazo: 30 \u00b1 2 \u00b0C y 65 \u00b1 5% o 75 \u00b1 5% de humedad relativa, tambi\u00e9n por un m\u00ednimo de 6 meses.\n     - No hay condiciones intermedias si se cumplen las condiciones a largo plazo.\n\n3. **\u00bfQu\u00e9 debe hacerse despu\u00e9s del per\u00edodo de rean\u00e1lisis de un lote de API y c\u00f3mo se puede utilizar el lote despu\u00e9s de ser retestado?**\n   - Despu\u00e9s del per\u00edodo de rean\u00e1lisis, un lote de API puede ser retestado y, si cumple con las especificaciones, puede ser utilizado inmediatamente (dentro de 30 d\u00edas). No se a\u00f1ade un per\u00edodo adicional al lote si se retesta y se encuentra conforme, y se puede retestar m\u00faltiples veces utilizando diferentes porciones del lote.", "prev_section_summary": "### Temas Clave\n\n1. **Pruebas de Estr\u00e9s**: Se enfatiza la importancia de realizar pruebas de estr\u00e9s para evaluar la estabilidad de los ingredientes farmac\u00e9uticos activos (API). Esto incluye condiciones de temperatura, humedad, concentraciones de soluciones y duraci\u00f3n de las pruebas.\n\n2. **Fotostabilidad**: Las pruebas de fotostabilidad deben ser parte integral de las pruebas de estr\u00e9s. Si un API requiere protecci\u00f3n contra la luz, se puede indicar en el etiquetado si el sistema de cierre del contenedor es adecuado.\n\n3. **Datos de Literatura Cient\u00edfica**: Se permite el uso de datos publicados en la literatura cient\u00edfica, como informes de evaluaci\u00f3n p\u00fablica de la OMS y la EMA, para respaldar los productos de degradaci\u00f3n y las v\u00edas identificadas.\n\n4. **Condiciones de Almacenamiento a Largo Plazo**: Las condiciones requeridas para el almacenamiento a largo plazo de los API son 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH o 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH. Se requiere evidencia adecuada para condiciones alternativas.\n\n5. **Establecimiento del Per\u00edodo de Rean\u00e1lisis**: Para establecer el per\u00edodo de rean\u00e1lisis, se deben proporcionar datos de al menos tres lotes de escala piloto, fabricados con el mismo m\u00e9todo que los lotes de producci\u00f3n.\n\n6. **Documentaci\u00f3n de Resultados**: Los resultados de las pruebas de estabilidad deben ser resumidos en el expediente y en las tablas del QOS-PD, incluyendo detalles como condiciones de almacenamiento, n\u00famero de lote, tama\u00f1o del lote y sistema de cierre del contenedor.\n\n### Entidades\n\n- **API (Ingredientes Farmac\u00e9uticos Activos)**: Sustancias que se utilizan en la fabricaci\u00f3n de medicamentos.\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Entidad que proporciona directrices sobre la precalificaci\u00f3n de medicamentos.\n- **ICH Q1B**: Directrices sobre pruebas de fotostabilidad.\n- **QOS-PD**: Plantilla para resumir los resultados de las pruebas de estabilidad.\n- **WHOPARs y EPARs**: Informes de evaluaci\u00f3n p\u00fablica de la OMS y la EMA, respectivamente.\n- **Condiciones de Almacenamiento**: 30 \u00b0C \u00b1 2 \u00b0C/65% \u00b1 5% RH o 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH.\n- **Estudios de Estabilidad**: Evaluaciones necesarias para determinar la estabilidad de los API bajo condiciones espec\u00edficas.", "excerpt_keywords": "Keywords: stability evaluation, active pharmaceutical ingredients, storage conditions, retest period, analytical results"}}, "750a8c4e-af00-4283-a0c0-fe7ec781bdfa": {"node_ids": ["c080c747-fefd-46ef-a159-6e8ba184f7e6"], "metadata": {"page_label": "170", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\ncontinues to comply with the specification. For APIs known to be labile (e.g. certain antibiotics) it is more appropriate to establish a shelf-life than a retest period (20).\n\nLimited extrapolation of the real-time data from the long-term storage condition beyond the observed range to extend the retest period can be done at the time of assessment of the PD, if justified. Applicants should consult the ICH Q1E guideline (23) for further details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated conditions and the data show little or no variability, the proposed retest period could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months).\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), WHO Technical Report Series, No. 953, Annex 2 (19).\n\n## 3.2.S.7.2 Post-approval stability protocol and stability commitment (name, manufacturer)\n\nThe post-approval stability protocol and stability commitment should be provided.\n\n### Primary stability study commitment\n\nWhen the available long-term stability data on primary batches do not cover the proposed retest period granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the retest period. A written commitment (signed and dated) to continue long-term testing over the retest period should be included in the dossier when relevant.\n\n### Commitment stability studies\n\nThe long-term stability studies for the commitment batches should be conducted through the proposed retest period on at least three production batches. Where stability data were not provided for three production batches, a written commitment (signed and dated) should be included in the dossier.\n\nThe stability protocol for the commitment batches should be provided and should include, but not be limited to, the following parameters:\n\n- number of batch(es) and different batch sizes, if applicable;\n- relevant physical, chemical, microbiological and biological test methods;\n- acceptance criteria;\n- reference to test methods;\n- description of the container-closure system(s);", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento se centra en las especificaciones para los estudios de estabilidad de los principios activos (APIs) en la industria farmac\u00e9utica, destacando la importancia de establecer per\u00edodos de rean\u00e1lisis y compromisos de estabilidad post-aprobaci\u00f3n. Se menciona que para ciertos APIs labiles, es m\u00e1s adecuado establecer una vida \u00fatil en lugar de un per\u00edodo de rean\u00e1lisis. Tambi\u00e9n se discuten las condiciones bajo las cuales se puede extrapolar la informaci\u00f3n de estabilidad y se detallan los requisitos para los estudios de estabilidad de compromiso.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las condiciones bajo las cuales se puede extrapolar la informaci\u00f3n de estabilidad para extender el per\u00edodo de rean\u00e1lisis de un API?**\n   - La extrapolaci\u00f3n de datos de estabilidad a largo plazo puede hacerse si no se observan cambios significativos en un per\u00edodo de 6 meses bajo condiciones aceleradas y si los datos muestran poca o ninguna variabilidad. En este caso, el per\u00edodo de rean\u00e1lisis propuesto podr\u00eda ser hasta el doble del per\u00edodo cubierto por los datos a largo plazo, pero no debe exceder los datos a largo plazo por m\u00e1s de 12 meses.\n\n2. **\u00bfQu\u00e9 tipo de compromiso se requiere si los datos de estabilidad a largo plazo no cubren el per\u00edodo de rean\u00e1lisis propuesto?**\n   - Se requiere un compromiso escrito (firmado y fechado) para continuar los estudios de estabilidad a largo plazo durante el per\u00edodo de rean\u00e1lisis. Este compromiso debe incluir la realizaci\u00f3n de estudios de estabilidad en al menos tres lotes de producci\u00f3n.\n\n3. **\u00bfQu\u00e9 par\u00e1metros deben incluirse en el protocolo de estabilidad para los lotes de compromiso?**\n   - El protocolo de estabilidad debe incluir, entre otros, el n\u00famero de lotes y diferentes tama\u00f1os de lote, m\u00e9todos de prueba f\u00edsicos, qu\u00edmicos, microbiol\u00f3gicos y biol\u00f3gicos relevantes, criterios de aceptaci\u00f3n, referencia a m\u00e9todos de prueba y una descripci\u00f3n del sistema de cierre del envase.", "prev_section_summary": "### Temas Clave\n\n1. **Requisitos de Datos para Dossier de Estabilidad**: Se especifican los datos m\u00ednimos necesarios al presentar un dossier relacionado con la estabilidad de los ingredientes farmac\u00e9uticos activos (API), incluyendo condiciones de almacenamiento y per\u00edodos de tiempo.\n\n2. **Condiciones de Almacenamiento**: Se detallan las condiciones de almacenamiento para pruebas de estabilidad, que incluyen:\n   - **Acelerado**: 40 \u00b1 2 \u00b0C y 75 \u00b1 5% de humedad relativa por un m\u00ednimo de 6 meses.\n   - **A Largo Plazo**: 30 \u00b1 2 \u00b0C con 65 \u00b1 5% o 75 \u00b1 5% de humedad relativa, tambi\u00e9n por un m\u00ednimo de 6 meses.\n   - **Condiciones Intermedias**: No aplicables si se cumplen las condiciones a largo plazo.\n\n3. **Resultados de Pruebas Anal\u00edticas**: Se enfatiza la necesidad de proporcionar resultados num\u00e9ricos concretos y no declaraciones vagas en las pruebas anal\u00edticas.\n\n4. **Declaraci\u00f3n de Almacenamiento y Per\u00edodo de Rean\u00e1lisis**: Se requiere establecer una declaraci\u00f3n de almacenamiento basada en la evaluaci\u00f3n de estabilidad del API y un per\u00edodo de rean\u00e1lisis que debe ser indicado en la etiqueta del producto.\n\n5. **Uso de Lotes Retestados**: Un lote de API puede ser retestado despu\u00e9s del per\u00edodo de rean\u00e1lisis y, si cumple con las especificaciones, puede ser utilizado inmediatamente. Se permite el rean\u00e1lisis m\u00faltiple de un lote.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad que proporciona las directrices sobre estabilidad de API.\n- **Ingredientes Farmac\u00e9uticos Activos (API)**: Sustancias que se utilizan en la fabricaci\u00f3n de productos farmac\u00e9uticos.\n- **Condiciones de Almacenamiento**: Incluyen temperatura y humedad relativa.\n- **Pruebas Anal\u00edticas**: M\u00e9todos utilizados para evaluar la estabilidad y calidad de los API.\n- **Dossier**: Documentaci\u00f3n que se presenta para la evaluaci\u00f3n de la estabilidad de los API.\n- **Per\u00edodo de Rean\u00e1lisis**: Tiempo establecido para volver a evaluar un lote de API. \n\nEste resumen abarca los aspectos esenciales y las entidades relevantes en la secci\u00f3n proporcionada del documento de la OMS.", "excerpt_keywords": "Keywords: stability studies, retest period, pharmaceutical preparations, active pharmaceutical ingredients, post-approval commitment"}}, "7aa740e2-5d6a-469e-850e-6fc60c1c6e3e": {"node_ids": ["ed1bfa32-9c1b-47b2-a255-92009ccc23f4"], "metadata": {"page_label": "171", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "\n- testing frequency;\n- description of the conditions of storage (standardized conditions for long-term testing as described in these guidelines and consistent with the API labelling, should be used);\n- other applicable parameters specific to the API.\n\n### Ongoing stability studies\n\nThe stability of the API should be monitored according to a continuous and appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of degradation products). The purpose of the ongoing stability programme is to monitor the API and to determine that the API remains stable and can be expected to remain stable within the retest period in all future batches.\n\nAt least one production batch per year of API (unless none is produced during that year) should be added to the stability monitoring programme and tested at least annually to confirm the stability. In certain situations, additional batches should be included. A written commitment (signed and dated) to ongoing stability studies should be included in the dossier.\n\nRefer to section 2.1.11 of WHO Technical Report Series, No. 953, Annex 2 (19), for further information on ongoing stability studies.\n\nAny differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), WHO Technical Report Series, No. 953, Annex 2 (19).\n\n#### 3.2.S.7.3 Stability data (name, manufacturer)\n\nResults of the stability studies (e.g. forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included.\n\nThe actual stability results used to support the proposed retest period should be included in the dossier. For quantitative tests (e.g. individual and total degradation product tests and assay tests) it should be ensured that actual numerical results are provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1D (24), Q1E (23), Q2 (16) WHO Technical Report Series, No. 953, Annex 2 (19).\n", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda la estabilidad de los Ingredientes Farmac\u00e9uticos Activos (API) y establece directrices para la realizaci\u00f3n de estudios de estabilidad. Se enfatiza la importancia de un programa continuo de monitoreo de estabilidad que permita detectar problemas de estabilidad, como cambios en los niveles de productos de degradaci\u00f3n. Se requiere que al menos un lote de producci\u00f3n por a\u00f1o se incluya en el programa de monitoreo y se realicen pruebas anuales para confirmar la estabilidad. Adem\u00e1s, se deben presentar los resultados de los estudios de estabilidad en formatos apropiados y proporcionar datos num\u00e9ricos concretos en lugar de declaraciones vagas.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de compromiso se requiere en el dossier para los estudios de estabilidad en los API?**\n   - Se requiere un compromiso escrito, firmado y fechado, que indique la intenci\u00f3n de llevar a cabo estudios de estabilidad continuos.\n\n2. **\u00bfCu\u00e1les son las condiciones de almacenamiento recomendadas para los estudios de estabilidad de los API?**\n   - Se deben utilizar condiciones de almacenamiento estandarizadas para pruebas a largo plazo, tal como se describe en las directrices y que sean consistentes con el etiquetado del API.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en el dossier respecto a los resultados de los estudios de estabilidad?**\n   - El dossier debe incluir los resultados reales de estabilidad que apoyen el per\u00edodo de rean\u00e1lisis propuesto, as\u00ed como informaci\u00f3n sobre los procedimientos anal\u00edticos utilizados y la validaci\u00f3n de estos procedimientos. Adem\u00e1s, se deben proporcionar resultados num\u00e9ricos concretos para pruebas cuantitativas, evitando declaraciones vagas como \"dentro de los l\u00edmites\".", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Estabilidad de Principios Activos (APIs):** Se enfatiza la importancia de establecer per\u00edodos de rean\u00e1lisis y vida \u00fatil para APIs, especialmente aquellos que son labiles, como ciertos antibi\u00f3ticos.\n2. **Extrapolaci\u00f3n de Datos de Estabilidad:** Se permite la extrapolaci\u00f3n de datos de estabilidad a largo plazo para extender el per\u00edodo de rean\u00e1lisis bajo condiciones espec\u00edficas, como la ausencia de cambios significativos en un per\u00edodo de 6 meses bajo condiciones aceleradas.\n3. **Compromiso de Estabilidad Post-Aprobaci\u00f3n:** Se requiere un compromiso escrito para continuar los estudios de estabilidad si los datos disponibles no cubren el per\u00edodo de rean\u00e1lisis propuesto.\n4. **Protocolo de Estabilidad para Lotes de Compromiso:** Se deben incluir par\u00e1metros espec\u00edficos en el protocolo de estabilidad, como m\u00e9todos de prueba, criterios de aceptaci\u00f3n y descripci\u00f3n del sistema de cierre del envase.\n\n**Entidades:**\n- **Organizaci\u00f3n:** WHO (Organizaci\u00f3n Mundial de la Salud)\n- **Documentos de Referencia:** ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series No. 953\n- **Tipos de Estudios:** Estudios de estabilidad a largo plazo, estudios de estabilidad de compromiso\n- **Par\u00e1metros de Estudio:** M\u00e9todos de prueba f\u00edsicos, qu\u00edmicos, microbiol\u00f3gicos y biol\u00f3gicos, criterios de aceptaci\u00f3n, descripci\u00f3n del sistema de cierre del envase.\n\nEste resumen destaca la importancia de la estabilidad en la industria farmac\u00e9utica y los requisitos necesarios para garantizar la calidad y seguridad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: stability studies, active pharmaceutical ingredients, monitoring program, degradation products, WHO guidelines"}}, "11f43e55-882d-4fe6-9a4f-7b0d676347a9": {"node_ids": ["f99bbfde-dca2-44b2-a202-2cba182ed572"], "metadata": {"page_label": "172", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P Drug product (or finished pharmaceutical product (FPP))\n\n## 3.2.P.1 Description and composition of the FPP (name, dosage form)\n\nA description of the FPP and its composition should be provided. The information provided should include, for example:\n\n- **Description of the dosage form**\n\n  The description of the FPP should include the physical description, available strengths, release mechanism (e.g. immediate or modified (delayed or extended)), as well as any other distinguishable characteristics, e.g.\n\n  \u201cThe proposed XYZ 50-mg tablets are available as white, oval, film-coated tablets, debossed with \u201850\u2019 on one side and a break-line on the other side.\n\n  The proposed XYZ 100-mg tablets are available as yellow, round, film-coated tablets, debossed with \u2018100\u2019 on one side and plain on the other side.\u201d\n\n- **Composition, i.e. list of all components of the dosage form, and their amount on a per unit basis (including overages, if any), the function of the components, and a reference to their quality standards (e.g. compendial monographs or manufacturer\u2019s specifications).**\n\n  The tables in the QOS-PD template should be used to summarize the composition of the FPP and express the quantity of each component on a per unit basis (e.g. mg per tablet, mg per ml, mg per vial) and a percentage basis, including a statement of the total weight or measure of the dosage unit. The individual components for mixtures prepared in-house (e.g. coatings) should be included in the tables where applicable.\n\n  All components used in the manufacturing process should be listed, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g. \u201c1 mg of active ingredient base = 1.075 mg active ingredient hydrochloride\u201d). All overages should be clearly indicated (e.g. \u201ccontains 2% overage of the API to compensate for manufacturing losses\u201d).\n\n  The components should be declared by their proper or common names, quality standards (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and, if applicable, their grades (e.g. \u201cmicrocrystalline cellulose NF (PH 102)\u201d) and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Informe T\u00e9cnico 970) detalla los requisitos para la descripci\u00f3n y composici\u00f3n de un producto farmac\u00e9utico terminado (FPP). Se enfatiza la importancia de proporcionar una descripci\u00f3n clara de la forma de dosificaci\u00f3n, incluyendo caracter\u00edsticas f\u00edsicas, mecanismos de liberaci\u00f3n y una lista exhaustiva de todos los componentes, sus cantidades, funciones y est\u00e1ndares de calidad. Tambi\u00e9n se menciona la necesidad de incluir informaci\u00f3n sobre los ingredientes activos y cualquier sobrecarga en la formulaci\u00f3n.\n\n### Preguntas:\n1. **\u00bfQu\u00e9 informaci\u00f3n espec\u00edfica debe incluirse en la descripci\u00f3n de la forma de dosificaci\u00f3n de un FPP seg\u00fan el documento de la OMS?**\n   - Esta pregunta busca detalles sobre los elementos que deben ser descritos, como caracter\u00edsticas f\u00edsicas y mecanismos de liberaci\u00f3n, que no se encuentran f\u00e1cilmente en otros documentos.\n\n2. **\u00bfC\u00f3mo se deben presentar las cantidades de los componentes en la composici\u00f3n de un FPP y qu\u00e9 est\u00e1ndares de calidad se deben referenciar?**\n   - Esta pregunta se centra en la forma de presentar la informaci\u00f3n sobre los componentes y los est\u00e1ndares de calidad, lo cual es crucial para la regulaci\u00f3n y no siempre est\u00e1 claramente definido en otras fuentes.\n\n3. **\u00bfQu\u00e9 tipo de componentes deben ser listados en el proceso de fabricaci\u00f3n de un FPP, incluyendo aquellos que no se a\u00f1aden a cada lote?**\n   - Esta pregunta aborda la exhaustividad en la lista de componentes, incluyendo aquellos que pueden ser eliminados durante el proceso, lo que es un aspecto t\u00e9cnico que puede no estar ampliamente cubierto en otros documentos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Estudios de Estabilidad de API:**\n   - Importancia de un programa continuo de monitoreo de estabilidad para detectar problemas, como cambios en los niveles de productos de degradaci\u00f3n.\n   - Se requiere incluir al menos un lote de producci\u00f3n por a\u00f1o en el programa de monitoreo y realizar pruebas anuales.\n\n2. **Compromiso Escrito:**\n   - Es necesario un compromiso escrito, firmado y fechado en el dossier que indique la intenci\u00f3n de llevar a cabo estudios de estabilidad continuos.\n\n3. **Condiciones de Almacenamiento:**\n   - Deben utilizarse condiciones de almacenamiento estandarizadas para pruebas a largo plazo, alineadas con el etiquetado del API.\n\n4. **Presentaci\u00f3n de Resultados:**\n   - Los resultados de los estudios de estabilidad deben presentarse en formatos apropiados (tabular, gr\u00e1fico, narrativo) y deben incluir informaci\u00f3n sobre los procedimientos anal\u00edticos utilizados y su validaci\u00f3n.\n   - Se deben proporcionar resultados num\u00e9ricos concretos para pruebas cuantitativas, evitando declaraciones vagas.\n\n5. **Justificaci\u00f3n Cient\u00edfica:**\n   - Cualquier diferencia entre los protocolos de estabilidad de los lotes primarios y los lotes de compromiso o en curso debe estar cient\u00edficamente justificada.\n\n**Entidades:**\n\n- **API (Ingrediente Farmac\u00e9utico Activo):** Sustancia cuyo comportamiento de estabilidad se est\u00e1 evaluando.\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Entidad que proporciona las directrices y recomendaciones sobre estudios de estabilidad.\n- **ICH (International Council for Harmonisation):** Referencias documentales que gu\u00edan los estudios de estabilidad (Q1A, Q1B, Q1D, Q1E, Q2).\n- **Dossier:** Documento que debe incluir el compromiso escrito y los resultados de los estudios de estabilidad.\n\nEste resumen destaca la importancia de un enfoque sistem\u00e1tico y documentado para garantizar la estabilidad de los API a lo largo del tiempo, as\u00ed como la necesidad de cumplir con las normativas establecidas por organismos reguladores.", "excerpt_keywords": "Keywords: pharmaceutical product, dosage form, composition, quality standards, active ingredient"}}, "5c57fddf-b693-4e96-8b0f-8315567d8c61": {"node_ids": ["14f5a5ba-2770-425a-9b24-2ecce8a8cb44"], "metadata": {"page_label": "173", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The function of each component (e.g. diluent or filler, binder, disintegrant, lubricant, glidant, granulating solvent, coating agent or antimicrobial preservative) should be stated. If an excipient performs multiple functions the predominant function should be indicated. The qualitative composition, including solvents, should be provided for all proprietary components or blends (e.g. capsule shells, colouring blends or imprinting inks). This information (excluding the solvents) is to be listed in the product information (e.g. summary of product characteristics, labelling and package leaflet).\n\n- **Description of accompanying reconstitution diluent(s)**  \n  For FPPs supplied with reconstitution diluent(s) that are commercially available or that have been assessed and considered acceptable in connection with another PD with the WHO Prequalification of Medicines Programme, a brief description of the reconstitution diluents(s) should be provided.  \n  For FPPs supplied with reconstitution diluent(s) that are not commercially available or have not been assessed and considered acceptable in connection with another PD with the WHO Prequalification of Medicines Programme, information on the diluent(s) should be provided in a separate FPP portion (\u201c3.2.P\u201d), as appropriate.\n\n- **Type of container and closure used for the dosage form and accompanying reconstitution diluent, if applicable**  \n  The container-closure used for the FPP (and accompanying reconstitution diluent, if applicable) should be briefly described, with further details provided under 3.2.P.7 Container-closure system, e.g.\n\n  > \u201cThe product is available in HDPE bottles with polypropylene caps (in sizes of 100s, 500s and 1000s) and in PVC/aluminium foil unit dose blisters (in packages of 100s) (cards of 5 \u00d7 2, 10 cards per package).\u201d\n\nReference documents: ICH Q6A (6).\n\n### 3.2.P.2 Pharmaceutical development (name, dosage form)\n\nThe Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfQu\u00e9 informaci\u00f3n se debe incluir sobre los excipientes en la documentaci\u00f3n del producto?**\n   - La documentaci\u00f3n del producto debe incluir la funci\u00f3n de cada componente (como diluyentes, aglutinantes, desintegrantes, etc.), indicando la funci\u00f3n predominante si un excipiente cumple m\u00faltiples funciones. Adem\u00e1s, se debe proporcionar la composici\u00f3n cualitativa, incluyendo los disolventes, para todos los componentes o mezclas propietarias, excluyendo los disolventes, que deben ser listados en la informaci\u00f3n del producto.\n\n2. **\u00bfC\u00f3mo se debe abordar la descripci\u00f3n de los diluyentes de reconstituci\u00f3n para los productos farmac\u00e9uticos?**\n   - Para los productos farmac\u00e9uticos que se suministran con diluyentes de reconstituci\u00f3n que son comercialmente disponibles o que han sido evaluados y considerados aceptables por el Programa de Precalificaci\u00f3n de Medicamentos de la OMS, se debe proporcionar una breve descripci\u00f3n de estos diluyentes. Si los diluyentes no son comercialmente disponibles o no han sido evaluados, la informaci\u00f3n debe ser proporcionada en una secci\u00f3n separada del producto farmac\u00e9utico.\n\n3. **\u00bfQu\u00e9 detalles se deben incluir sobre el sistema de envase y cierre del producto farmac\u00e9utico?**\n   - Se debe proporcionar una breve descripci\u00f3n del sistema de envase y cierre utilizado para el producto farmac\u00e9utico y, si es aplicable, para el diluyente de reconstituci\u00f3n. Los detalles adicionales deben ser incluidos en la secci\u00f3n 3.2.P.7 del sistema de envase y cierre, como el tipo de materiales utilizados y las presentaciones disponibles.\n\n### Resumen de nivel superior del contexto:\nEl contexto se centra en los requisitos de documentaci\u00f3n para productos farmac\u00e9uticos, espec\u00edficamente en la secci\u00f3n de desarrollo farmac\u00e9utico. Se enfatiza la necesidad de detallar la funci\u00f3n de los excipientes, la descripci\u00f3n de los diluyentes de reconstituci\u00f3n y la informaci\u00f3n sobre el sistema de envase y cierre. Adem\u00e1s, se menciona que la informaci\u00f3n debe ser clara y diferenciada de las pruebas de control rutinarias.", "prev_section_summary": "### Temas Clave:\n\n1. **Descripci\u00f3n del Producto Farmac\u00e9utico Terminado (FPP)**:\n   - Importancia de proporcionar una descripci\u00f3n clara de la forma de dosificaci\u00f3n.\n   - Caracter\u00edsticas f\u00edsicas, mecanismos de liberaci\u00f3n y distinciones del producto.\n\n2. **Composici\u00f3n del FPP**:\n   - Listado exhaustivo de todos los componentes, sus cantidades y funciones.\n   - Referencias a est\u00e1ndares de calidad (monograf\u00edas compendiales o especificaciones del fabricante).\n\n3. **Presentaci\u00f3n de la Informaci\u00f3n**:\n   - Uso de tablas en el formato QOS-PD para resumir la composici\u00f3n.\n   - Expresi\u00f3n de cantidades en base por unidad y porcentaje, incluyendo el peso total de la unidad de dosificaci\u00f3n.\n\n4. **Componentes en el Proceso de Fabricaci\u00f3n**:\n   - Inclusi\u00f3n de todos los componentes, incluso aquellos que no se a\u00f1aden a cada lote o que pueden ser eliminados durante el proceso.\n   - Declaraci\u00f3n de ingredientes activos y sobrecargas en la formulaci\u00f3n.\n\n5. **Nomenclatura y Est\u00e1ndares**:\n   - Declaraci\u00f3n de componentes por sus nombres comunes o adecuados, est\u00e1ndares de calidad y caracter\u00edsticas t\u00e9cnicas especiales.\n\n### Entidades:\n\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que se presenta al consumidor.\n- **Componentes**: Ingredientes que forman parte de la formulaci\u00f3n del FPP.\n- **Est\u00e1ndares de Calidad**: Referencias como BP (British Pharmacopoeia), JP (Japanese Pharmacopoeia), Ph.Eur. (European Pharmacopoeia), USP (United States Pharmacopeia).\n- **Mecanismos de Liberaci\u00f3n**: M\u00e9todos de liberaci\u00f3n del f\u00e1rmaco (inmediata, modificada).\n- **Sobrecargas**: Cantidades adicionales de ingredientes activos para compensar p\u00e9rdidas durante la fabricaci\u00f3n. \n\nEste resumen destaca la importancia de la claridad y la exhaustividad en la descripci\u00f3n y composici\u00f3n de los productos farmac\u00e9uticos, as\u00ed como la necesidad de adherirse a est\u00e1ndares de calidad reconocidos.", "excerpt_keywords": "Keywords: excipients, reconstitution diluents, container-closure system, pharmaceutical development, product information"}}, "a3d566a4-1a97-4548-8566-a03f0244829c": {"node_ids": ["f1ecf961-ed33-4226-b8d8-1c7a5a82da7c"], "metadata": {"page_label": "174", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsection should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier.\n\nPharmaceutical development information should include, at a minimum:\n\n- the definition of the quality target product profile (QTPP) as it relates to quality, safety and efficacy, considering, for example, the route of administration, dosage form, bioavailability, strength and stability;\n- identification of the potential critical quality attributes (CQAs) of the FPP so as to adequately control the product characteristics that could have an impact on quality;\n- discussion of the potential CQAs of the API(s), excipients and container-closure system(s) including the selection of the type, grade and amount to deliver drug product of the desired quality;\n- discussion of the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner.\n\nThese features should be discussed as part of the product development using the principles of risk management over the entire life-cycle of the product (ICH Q8) (25).\n\nFor a discussion of additional pharmaceutical development issues specific to the development of FDCs reference should be made to section 6.3.2 of WHO Technical Report Series, No. 929, Annex 5 (21).\n\nReference documents: ICH Q6A (6), Q8 (25), Q9 (26), Q10 (27).\n\n## 3.2.P.2.1 Components of the FPP (name, dosage form)\n\n### 3.2.P.2.1.1 Active pharmaceutical ingredient (name, dosage form)\n\nThe compatibility of the API with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (e.g. water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For FDCs, the compatibility of APIs with each other should be discussed.\n\nPhysicochemical characteristics of the API may influence both the manufacturing capability and the performance of the FPP.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado, junto con res\u00famenes de nivel superior que pueden ayudar a formularlas:\n\n### Resumen de nivel superior:\nEl documento de la OMS aborda la importancia del desarrollo farmac\u00e9utico, centr\u00e1ndose en la identificaci\u00f3n de atributos cr\u00edticos de calidad (CQAs) y la definici\u00f3n del perfil de calidad del producto objetivo (QTPP). Se enfatiza la necesidad de discutir la compatibilidad de los ingredientes activos (API) con excipientes y entre s\u00ed, as\u00ed como las caracter\u00edsticas fisicoqu\u00edmicas que pueden influir en la calidad y el rendimiento del producto farmac\u00e9utico final (FPP).\n\n### Preguntas:\n\n1. **\u00bfCu\u00e1les son los atributos cr\u00edticos de calidad (CQAs) que deben considerarse al desarrollar un producto farmac\u00e9utico final (FPP) y c\u00f3mo se relacionan con el perfil de calidad del producto objetivo (QTPP)?**\n   - Esta pregunta busca una respuesta espec\u00edfica sobre los CQAs y su conexi\u00f3n con el QTPP, que no se detalla en otros documentos.\n\n2. **\u00bfQu\u00e9 criterios se deben tener en cuenta al seleccionar excipientes y sistemas de cierre para asegurar la calidad del producto farmac\u00e9utico final (FPP)?**\n   - Esta pregunta se centra en la selecci\u00f3n de excipientes y sistemas de cierre, un aspecto que puede no estar ampliamente cubierto en otras fuentes.\n\n3. **\u00bfC\u00f3mo influyen las caracter\u00edsticas fisicoqu\u00edmicas del ingrediente activo (API) en la capacidad de fabricaci\u00f3n y el rendimiento del producto farmac\u00e9utico final (FPP)?**\n   - Esta pregunta busca una explicaci\u00f3n detallada sobre la relaci\u00f3n entre las propiedades fisicoqu\u00edmicas del API y su impacto en el proceso de fabricaci\u00f3n y la calidad del FPP, un tema que puede no ser tratado en profundidad en otros documentos. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y detallada que se encuentra en el contexto proporcionado, lo que puede no estar disponible en otras fuentes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Funciones de los Excipientes**:\n   - Se debe especificar la funci\u00f3n de cada componente (ej. diluyentes, aglutinantes, desintegrantes, etc.).\n   - Si un excipiente tiene m\u00faltiples funciones, se debe indicar la funci\u00f3n predominante.\n   - La composici\u00f3n cualitativa, incluyendo disolventes, debe ser proporcionada para todos los componentes o mezclas propietarias, excluyendo los disolventes que se listar\u00e1n en la informaci\u00f3n del producto.\n\n2. **Diluyentes de Reconstituci\u00f3n**:\n   - Para productos farmac\u00e9uticos (FPPs) con diluyentes comercialmente disponibles o aceptados por el Programa de Precalificaci\u00f3n de Medicamentos de la OMS, se debe incluir una breve descripci\u00f3n.\n   - Para diluyentes no disponibles comercialmente o no evaluados, la informaci\u00f3n debe ser presentada en una secci\u00f3n separada del producto.\n\n3. **Sistema de Envase y Cierre**:\n   - Se debe proporcionar una breve descripci\u00f3n del sistema de envase y cierre utilizado para el FPP y, si aplica, para el diluyente de reconstituci\u00f3n.\n   - Detalles adicionales deben ser incluidos en la secci\u00f3n 3.2.P.7, como el tipo de materiales y las presentaciones disponibles.\n\n4. **Desarrollo Farmac\u00e9utico**:\n   - La secci\u00f3n de desarrollo farmac\u00e9utico debe incluir informaci\u00f3n sobre los estudios de desarrollo realizados para establecer la idoneidad de la forma de dosificaci\u00f3n, formulaci\u00f3n, proceso de fabricaci\u00f3n, sistema de envase y cierre, atributos microbiol\u00f3gicos e instrucciones de uso.\n   - Se distingue entre estos estudios y las pruebas de control rutinarias.\n\n### Entidades Clave:\n- **Componentes**: Diluyentes, aglutinantes, desintegrantes, lubricantes, glidantes, disolventes, agentes de recubrimiento, conservantes antimicrobianos.\n- **Documentos de referencia**: ICH Q6A.\n- **Secciones del documento**: 3.2.P (desarrollo farmac\u00e9utico), 3.2.P.7 (sistema de envase y cierre).\n- **Programas**: Programa de Precalificaci\u00f3n de Medicamentos de la OMS. \n\nEste resumen destaca los requisitos de documentaci\u00f3n y desarrollo para productos farmac\u00e9uticos, enfatizando la importancia de la claridad y la especificidad en la informaci\u00f3n presentada.", "excerpt_keywords": "Keywords: pharmaceutical development, quality target product profile, critical quality attributes, active pharmaceutical ingredient, formulation compatibility"}}, "39e58d01-15a4-40e7-8c1f-ecdd8cfcf2f2": {"node_ids": ["30a1926c-d0f0-4d28-9a74-711e500ec560"], "metadata": {"page_label": "175", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Guidance on Compatibility Studies\n\nGuidance on compatibility studies is provided in Appendix 3 of the WHO *Guidelines for registration of fixed-dose combination medicinal products* (WHO Technical Report Series, No. 929, Annex 5, 2005) (21). In addition to visual examination, chromatographic results (assay, purity) are required to demonstrate API\u2013API and API\u2013excipient compatibility. In general, API\u2013excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product.\n\n## 3.2.P.2.1.2 Excipients (name, dosage form)\n\n**The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions.**\n\nWhen choosing excipients those with a compendial monograph are generally preferred and may be required in certain jurisdictions. Other resources are available for information on acceptable excipients and their concentrations, such as the US Food and Drug Administration (FDA) inactive ingredient guide (IIG) list (28) and the *Handbook of pharmaceutical excipients* (29). Use of excipients in concentrations outside established ranges is discouraged and generally requires justification (30). In addition, available guidelines should be referenced which discuss particular excipients to be avoided, for example azo-colourants as listed in the EMA Guideline CPMP/463/00 (31). Other guidance such as the WHO *Guidelines on development of paediatric medicines: points to consider in formulation* (32) may provide useful general guidance in this regard.\n\nRanges in concentrations or alternatives for excipients are normally not accepted unless supported by appropriate process validation data. Where relevant, compatibility study results (e.g. on compatibility of a primary or secondary amine API with lactose) should be included to justify the choice of excipients. Specific details should be provided where necessary (e.g. on use of potato or corn starch).\n\nWhere antioxidants are included in the formulation, the effectiveness of the proposed concentration of the antioxidant should be justified and verified by appropriate studies.\n\nAntimicrobial preservatives are discussed in 3.2.P.2.5.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior del contenido:\n\n### Resumen de Nivel Superior\nEl documento de la OMS proporciona directrices sobre estudios de compatibilidad para productos farmac\u00e9uticos de combinaci\u00f3n de dosis fijas. Se enfatiza la importancia de demostrar la compatibilidad entre el principio activo (API) y los excipientes mediante resultados cromatogr\u00e1ficos y estudios de compatibilidad. Se recomienda el uso de excipientes con monograf\u00eda compendial y se desaconseja el uso de concentraciones fuera de los rangos establecidos sin justificaci\u00f3n adecuada. Tambi\u00e9n se menciona la necesidad de justificar la efectividad de antioxidantes y se hace referencia a la discusi\u00f3n sobre conservantes antimicrobianos.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de resultados cromatogr\u00e1ficos son necesarios para demostrar la compatibilidad entre el API y los excipientes?**\n   - El documento menciona que se requieren resultados de cromatograf\u00eda relacionados con el ensayo y la pureza para demostrar la compatibilidad entre el API y los excipientes.\n\n2. **\u00bfCu\u00e1les son las recomendaciones sobre el uso de excipientes que no tienen una monograf\u00eda compendial?**\n   - Se sugiere que se prefieran excipientes con una monograf\u00eda compendial y que se utilicen recursos como la gu\u00eda de ingredientes inactivos de la FDA para obtener informaci\u00f3n sobre excipientes aceptables. El uso de excipientes en concentraciones fuera de los rangos establecidos generalmente requiere justificaci\u00f3n.\n\n3. **\u00bfQu\u00e9 se debe considerar al incluir antioxidantes en la formulaci\u00f3n de un producto farmac\u00e9utico?**\n   - La efectividad de la concentraci\u00f3n propuesta de antioxidante debe ser justificada y verificada mediante estudios apropiados, seg\u00fan lo indicado en las directrices.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS se centra en el desarrollo farmac\u00e9utico, destacando la importancia de identificar y describir los atributos cr\u00edticos de calidad (CQAs) y el perfil de calidad del producto objetivo (QTPP) para asegurar la calidad, seguridad y eficacia de los productos farmac\u00e9uticos finales (FPP). A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n1. **Desarrollo Farmac\u00e9utico**:\n   - Importancia de identificar atributos cr\u00edticos de calidad (CQAs) y definir el perfil de calidad del producto objetivo (QTPP).\n   - Necesidad de datos de apoyo y resultados de estudios espec\u00edficos para respaldar el desarrollo farmac\u00e9utico.\n\n2. **Perfil de Calidad del Producto Objetivo (QTPP)**:\n   - Definici\u00f3n relacionada con la calidad, seguridad y eficacia, considerando factores como la v\u00eda de administraci\u00f3n, forma de dosificaci\u00f3n, biodisponibilidad, potencia y estabilidad.\n\n3. **Atributos Cr\u00edticos de Calidad (CQAs)**:\n   - Identificaci\u00f3n de CQAs del FPP para controlar caracter\u00edsticas del producto que impactan en la calidad.\n   - Discusi\u00f3n sobre los CQAs de los ingredientes activos (API), excipientes y sistemas de cierre.\n\n4. **Selecci\u00f3n de Excipientes y Sistemas de Cierre**:\n   - Criterios para seleccionar el tipo, grado y cantidad de excipientes y sistemas de cierre que aseguren la calidad del FPP.\n\n5. **Proceso de Fabricaci\u00f3n**:\n   - Selecci\u00f3n de criterios para el proceso de fabricaci\u00f3n y la estrategia de control necesaria para producir lotes comerciales que cumplan consistentemente con el QTPP.\n\n6. **Caracter\u00edsticas Fisicoqu\u00edmicas del API**:\n   - Discusi\u00f3n sobre la compatibilidad del API con excipientes y entre s\u00ed, as\u00ed como las caracter\u00edsticas fisicoqu\u00edmicas (contenido de agua, solubilidad, distribuci\u00f3n del tama\u00f1o de part\u00edculas, forma polim\u00f3rfica o estado s\u00f3lido) que pueden influir en el rendimiento del FPP.\n\n7. **Gesti\u00f3n de Riesgos**:\n   - Aplicaci\u00f3n de principios de gesti\u00f3n de riesgos a lo largo del ciclo de vida del producto (referencia a ICH Q8).\n\n8. **Referencias**:\n   - Documentos de referencia relevantes como ICH Q6A, Q8, Q9 y Q10.\n\nEste resumen destaca la estructura y los elementos esenciales que deben considerarse en el desarrollo de productos farmac\u00e9uticos, enfatizando la importancia de la calidad y la consistencia en la fabricaci\u00f3n.", "excerpt_keywords": "Keywords: compatibility studies, excipients, fixed-dose combination, pharmaceutical formulation, WHO guidelines"}}, "d6f25aa7-ef9b-442f-b5de-71532eb5e3da": {"node_ids": ["73e449f7-8f25-48f3-9d37-5a22d20e0b91"], "metadata": {"page_label": "176", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.2.2 Finished pharmaceutical product (name, dosage form)\n\n## 3.2.P.2.2.1 Formulation development (name, dosage form)\n\nA brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed, when appropriate.\n\nThe WHO Prequalification of Medicines Programme defines an established multisource product as one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier and QOS-PD should be completed with the exception of P.2.2.1 (a). In addition, a product quality review should be provided as outlined in Appendix 2.\n\nThe requirements for bioequivalence studies should be taken into consideration, for example, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (e.g. WHO Technical Report Series, No. 937, Annex 7) (33) should be consulted.\n\nProduct scoring may be recommended or required, for example, when scoring is indicated in the WHO Invitation for EOIs, or is specified for an invited FPP in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology.\n\nIf the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should include a description of the test method, individual values, mean and relative standard deviation (RSD) of the results. Uniformity testing (i.e. content uniformity for split portions containing less than 5 mg or less than 5% of the weight of the dosage unit portion, or mass uniformity for", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los requisitos para el desarrollo de productos farmac\u00e9uticos terminados (FPP), centr\u00e1ndose en la formulaci\u00f3n, la bioequivalencia y la calidad del producto. Se menciona la definici\u00f3n de un producto multisource establecido y se discuten las pruebas necesarias para asegurar la uniformidad de dosis en tabletas, especialmente aquellas que est\u00e1n dise\u00f1adas para ser divididas. Tambi\u00e9n se hace hincapi\u00e9 en la importancia de realizar estudios comparativos y en la consulta de documentos de referencia de la OMS.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 criterios debe cumplir un producto para ser considerado un \"producto multisource establecido\" seg\u00fan el Programa de Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Respuesta: Un producto debe haber sido comercializado por el solicitante o fabricante asociado con el dossier durante al menos cinco a\u00f1os y haber producido al menos 10 lotes de producci\u00f3n en el a\u00f1o anterior, o si se produjeron menos de 10 lotes, no menos de 25 lotes en los \u00faltimos tres a\u00f1os.\n\n2. **\u00bfQu\u00e9 tipo de estudios se deben considerar al formular m\u00faltiples fortalezas de un producto farmac\u00e9utico terminado?**\n   - Respuesta: Se deben considerar los requisitos para estudios de bioequivalencia, especialmente si el producto puede ser elegible para una exenci\u00f3n de bioequivalencia (biowaiver).\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en el documento de desarrollo del producto (PD) para un comprimido funcionalmente escoreado?**\n   - Respuesta: El PD debe incluir una descripci\u00f3n del m\u00e9todo de prueba, los valores individuales, la media y la desviaci\u00f3n est\u00e1ndar relativa (RSD) de los resultados, as\u00ed como los resultados de las pruebas de uniformidad de contenido o de masa para las porciones divididas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Estudios de Compatibilidad:** Se proporciona orientaci\u00f3n sobre la realizaci\u00f3n de estudios de compatibilidad entre principios activos (API) y excipientes en productos farmac\u00e9uticos de combinaci\u00f3n de dosis fijas.\n2. **Resultados Cromatogr\u00e1ficos:** Se requieren resultados de cromatograf\u00eda (ensayo y pureza) para demostrar la compatibilidad entre API y excipientes.\n3. **Elecci\u00f3n de Excipientes:** Se recomienda el uso de excipientes con monograf\u00eda compendial y se desaconseja el uso de concentraciones fuera de los rangos establecidos sin justificaci\u00f3n adecuada.\n4. **Justificaci\u00f3n de Antioxidantes:** La efectividad de los antioxidantes en la formulaci\u00f3n debe ser justificada y verificada mediante estudios apropiados.\n5. **Conservantes Antimicrobianos:** Se menciona que los conservantes antimicrobianos son discutidos en una secci\u00f3n espec\u00edfica del documento.\n\n**Entidades:**\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Autoridad que proporciona las directrices.\n- **FDA (Administraci\u00f3n de Alimentos y Medicamentos de EE. UU.):** Fuente de informaci\u00f3n sobre excipientes aceptables.\n- **EMA (Agencia Europea de Medicamentos):** Proporciona directrices sobre excipientes a evitar.\n- **Compendial Monograph:** Referencia para excipientes preferidos.\n- **Antioxidantes y Conservantes Antimicrobianos:** Componentes discutidos en el contexto de formulaciones farmac\u00e9uticas.\n\nEste resumen destaca la importancia de la compatibilidad de los componentes en la formulaci\u00f3n de medicamentos y las directrices que deben seguirse para garantizar la seguridad y eficacia del producto final.", "excerpt_keywords": "Keywords: pharmaceutical formulation, bioequivalence, multisource product, dosage uniformity, WHO guidelines"}}, "cff0eab1-28b5-4f2f-81d2-8460b5807a64": {"node_ids": ["cbb12153-c672-4363-bffa-33687f9d6259"], "metadata": {"page_label": "177", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica, pol\u00edticas de salud y recomendaciones para la pr\u00e1ctica cl\u00ednica y la investigaci\u00f3n. Sin embargo, el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS en el informe t\u00e9cnico 970 sobre la salud p\u00fablica?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre las directrices o recomendaciones que la OMS ha emitido en este informe, que podr\u00edan ser relevantes para profesionales de la salud y responsables de pol\u00edticas.\n\n2. **\u00bfQu\u00e9 temas de investigaci\u00f3n se abordan en el informe WHO TRS 970 y c\u00f3mo podr\u00edan impactar la pr\u00e1ctica cl\u00ednica?**\n   - Esta pregunta se centra en identificar los temas espec\u00edficos tratados en el informe y su posible aplicaci\u00f3n en el \u00e1mbito cl\u00ednico, lo que podr\u00eda ser \u00fatil para m\u00e9dicos e investigadores.\n\n3. **\u00bfC\u00f3mo se compara el contenido del informe WHO TRS 970 con otros informes t\u00e9cnicos anteriores de la OMS?**\n   - Esta pregunta busca establecer un contexto comparativo que podr\u00eda ayudar a entender la evoluci\u00f3n de las recomendaciones y enfoques de la OMS en temas de salud a lo largo del tiempo.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n que probablemente no se encuentre f\u00e1cilmente en otros lugares, dado que se centran en el contenido espec\u00edfico del informe y su relevancia en el campo de la salud p\u00fablica.", "prev_section_summary": "### Temas Clave\n\n1. **Desarrollo de Formulaci\u00f3n de Productos Farmac\u00e9uticos Terminados (FPP)**: Se requiere un resumen que describa el desarrollo del FPP, considerando la ruta de administraci\u00f3n y el uso propuesto. Es importante discutir las diferencias entre las formulaciones de bioequivalencia comparativa y la formulaci\u00f3n descrita en la secci\u00f3n 3.2.P.1.\n\n2. **Definici\u00f3n de Producto Multisource Establecido**: Seg\u00fan el Programa de Precalificaci\u00f3n de Medicamentos de la OMS, un producto se considera establecido si ha sido comercializado durante al menos cinco a\u00f1os y ha producido un m\u00ednimo de 10 lotes en el \u00faltimo a\u00f1o, o 25 lotes en los \u00faltimos tres a\u00f1os si se produjeron menos de 10 en el \u00faltimo a\u00f1o.\n\n3. **Requisitos para Estudios de Bioequivalencia**: Se deben considerar los requisitos para estudios de bioequivalencia al formular m\u00faltiples fortalezas de un producto, especialmente si el producto puede ser elegible para una exenci\u00f3n de bioequivalencia (biowaiver).\n\n4. **Pruebas de Uniformidad de Dosis**: Para tabletas funcionalmente escoreadas, se debe realizar un estudio para asegurar la uniformidad de dosis en los fragmentos de la tableta. El documento de desarrollo del producto (PD) debe incluir detalles sobre el m\u00e9todo de prueba y los resultados de uniformidad.\n\n5. **Consulta de Documentos de Referencia de la OMS**: Se recomienda consultar documentos de referencia de la OMS para guiar el desarrollo y evaluaci\u00f3n de productos farmac\u00e9uticos.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Entidad que establece directrices y requisitos para productos farmac\u00e9uticos.\n- **FPP (Producto Farmac\u00e9utico Terminado)**: Producto final que se presenta para su comercializaci\u00f3n.\n- **Bioequivalencia**: Comparaci\u00f3n de la biodisponibilidad entre diferentes formulaciones de un mismo f\u00e1rmaco.\n- **Producto Multisource Establecido**: Producto que cumple con criterios espec\u00edficos de comercializaci\u00f3n y producci\u00f3n.\n- **Documentos de Referencia de la OMS**: Publicaciones que proporcionan directrices y est\u00e1ndares para la industria farmac\u00e9utica. \n\nEste resumen destaca los aspectos esenciales del desarrollo y evaluaci\u00f3n de productos farmac\u00e9uticos terminados seg\u00fan las directrices de la OMS.", "excerpt_keywords": "Keywords: salud p\u00fablica, productos farmac\u00e9uticos, bioequivalencia, OMS, directrices"}}, "58f5509d-eafd-496a-b1a8-d33b1cf28aad": {"node_ids": ["7bff25fa-ebdb-45f5-8820-f85527113ec5"], "metadata": {"page_label": "178", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Modified-release FPPs\n\nModified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine quality control. Preferably this test should possess in vitro\u2013in vivo correlation. Results demonstrating the effect of pH on the dissolution profile should be submitted if appropriate for the type of dosage form.\n\nFor extended-release FPPs, the testing conditions should be set to cover the entire time period of expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test point, upper and lower limits should be set for individual units. Generally the acceptance range at each intermediate test point should not exceed 25% or \u00b1 12.5% of the targeted value. Dissolution results should be submitted for several lots, including those lots used for pharmacokinetic and bioavailability or biowaiver studies.\n\nRecommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.\n\n## 3.2.P.2.2.2 Overages (name, dosage form)\n\nAny overages in the formulation(s) described in 3.2.P.1 should be justified.\n\nJustification of an overage to compensate for loss during manufacture should be provided, including information on the step(s) where the loss occurs, the reasons for the loss and batch analysis release data (assay results).\n\nOverages for the sole purpose of extending the shelf-life of the FPP are generally not acceptable.\n\n## 3.2.P.2.2.3 Physicochemical and biological properties (name, dosage form)\n\nParameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS (Informe T\u00e9cnico 970) aborda las pruebas de disoluci\u00f3n y otros par\u00e1metros relevantes para los productos farmac\u00e9uticos de liberaci\u00f3n modificada (FPPs). Se enfatiza la importancia de tener un m\u00e9todo de disoluci\u00f3n significativo para el control de calidad, as\u00ed como la necesidad de correlaci\u00f3n in vitro-in vivo. Para los FPPs de liberaci\u00f3n prolongada, se deben establecer condiciones de prueba que cubran todo el per\u00edodo de liberaci\u00f3n esperado, incluyendo l\u00edmites de aceptaci\u00f3n para los resultados de disoluci\u00f3n. Tambi\u00e9n se discuten las justificaciones para los sobrecargas en las formulaciones y los par\u00e1metros fisicoqu\u00edmicos y biol\u00f3gicos que deben ser considerados.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 criterios se deben cumplir para que un test de disoluci\u00f3n sea considerado significativo en el control de calidad de los FPPs de liberaci\u00f3n modificada?**\n   - Esta pregunta busca detalles sobre los requisitos espec\u00edficos que un test de disoluci\u00f3n debe cumplir, que no se encuentran f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfCu\u00e1les son las implicaciones de no demostrar la ausencia de \"dose dumping\" en los FPPs de liberaci\u00f3n prolongada?**\n   - Esta pregunta se centra en las consecuencias espec\u00edficas que pueden surgir si no se cumplen los criterios de liberaci\u00f3n de dosis, lo cual puede no estar ampliamente discutido en otros documentos.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n se debe proporcionar para justificar la inclusi\u00f3n de sobrecargas en la formulaci\u00f3n de un FPP?**\n   - Esta pregunta busca informaci\u00f3n detallada sobre los requisitos de justificaci\u00f3n para las sobrecargas, que puede no estar claramente especificada en otras normativas o gu\u00edas.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS proporciona directrices sobre la evaluaci\u00f3n y control de calidad de los productos farmac\u00e9uticos de liberaci\u00f3n modificada, enfatizando la importancia de las pruebas de disoluci\u00f3n y la justificaci\u00f3n de sobrecargas en las formulaciones. Se requiere que las pruebas de disoluci\u00f3n sean representativas y que se establezcan l\u00edmites de aceptaci\u00f3n claros. Adem\u00e1s, se deben considerar diversos par\u00e1metros fisicoqu\u00edmicos y biol\u00f3gicos que afectan el rendimiento del FPP.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Documento:** WHO - Technical Report Series 970  \n**Entidad:** Organizaci\u00f3n Mundial de la Salud (OMS)  \n**Tipo de Documento:** Informe t\u00e9cnico sobre salud p\u00fablica  \n\n#### Temas Clave:\n1. **Recomendaciones de Salud P\u00fablica:** El informe probablemente incluye directrices y recomendaciones de la OMS dirigidas a mejorar la salud p\u00fablica y la pr\u00e1ctica cl\u00ednica.\n  \n2. **Investigaci\u00f3n M\u00e9dica:** Se espera que el documento aborde temas de investigaci\u00f3n relevantes que podr\u00edan influir en la pr\u00e1ctica cl\u00ednica y en la formulaci\u00f3n de pol\u00edticas de salud.\n\n3. **Comparaci\u00f3n de Informes:** El contenido del informe puede ser comparado con otros informes t\u00e9cnicos anteriores de la OMS, lo que permite analizar la evoluci\u00f3n de las recomendaciones y enfoques en salud p\u00fablica.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Entidad responsable de la publicaci\u00f3n del informe y de la formulaci\u00f3n de pol\u00edticas y recomendaciones en salud global.\n- **Informe T\u00e9cnico:** Parte de la serie de informes t\u00e9cnicos que la OMS publica regularmente para abordar diversos temas de salud.\n\nEste resumen destaca la importancia del informe en el contexto de la salud p\u00fablica y la investigaci\u00f3n m\u00e9dica, aunque el contenido espec\u00edfico no est\u00e1 disponible en el contexto proporcionado.", "excerpt_keywords": "Keywords: modified-release, dissolution testing, overages, quality control, physicochemical properties"}}, "a7614ad9-5a8b-46a9-ab98-fb579641b6d6": {"node_ids": ["ac944827-6e6e-45f4-b68b-9298463ca94d"], "metadata": {"page_label": "179", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.2.3 Manufacturing process development (name, dosage form)\n\nThe selection and optimization of the manufacturing process described in 3.2.P.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.\n\nWhere relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided.\n\nDifferences between the manufacturing process(es) used to produce comparative bioavailability or biowaiver batches and the process described in 3.2.P.3 that can influence the performance of the product should be discussed.\n\nFor products that meet the criteria of an established multisource product, in order to fulfill the requirements of section P.2.3, section P.2.3 (b) of the dossier and QOS-PD should be completed and a product quality review should be submitted as outlined in Appendix 2. The guidance that follows applies to all other products for which section P.2.3 should be completed in its entirety.\n\nThe rationale for choosing the particular pharmaceutical product (e.g. dosage form, delivery system) should be provided. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence FPP quality and performance should be explained (e.g. wet granulation using high shear granulator). API stress study results may be included in the rationale. Any developmental work undertaken to protect the FPP from deterioration should also be included (e.g. protection from light or moisture).\n\nThe scientific rationale for the selection, optimization and scale-up of the manufacturing process described in 3.2.P.3.3 should be explained, in particular the critical aspects (e.g. rate of addition of granulating fluid, massing time and granulation end-point). A discussion of the critical process parameters (CPP), controls and robustness with respect to the QTPP and CQA of the product should be included (ICH Q8 (25)).\n\n# 3.2.P.2.4 Container-closure system (name, dosage form)\n\nThe suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider, e.g. choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP).\n\nTesting requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration. The pharmacopoeias provide standards that are required for packaging materials, including, for example, the following:", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda aspectos cr\u00edticos del desarrollo del proceso de fabricaci\u00f3n de productos farmac\u00e9uticos, incluyendo la selecci\u00f3n y optimizaci\u00f3n de procesos, m\u00e9todos de esterilizaci\u00f3n, y la justificaci\u00f3n de decisiones relacionadas con el envase y el cierre del producto. Se enfatiza la importancia de discutir las diferencias en los procesos de fabricaci\u00f3n que pueden influir en el rendimiento del producto, as\u00ed como la necesidad de cumplir con los requisitos de calidad y seguridad en el dise\u00f1o del sistema de envase.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los aspectos cr\u00edticos que deben considerarse al seleccionar un proceso de fabricaci\u00f3n para un producto farmac\u00e9utico, y c\u00f3mo se justifican las decisiones tomadas en este contexto?**\n   - Esta pregunta busca respuestas sobre los criterios espec\u00edficos que se deben evaluar al elegir un proceso de fabricaci\u00f3n, as\u00ed como ejemplos de justificaciones que podr\u00edan no estar documentadas en otras fuentes.\n\n2. **\u00bfQu\u00e9 factores deben tenerse en cuenta al seleccionar un sistema de envase y cierre para un producto farmac\u00e9utico, y c\u00f3mo se eval\u00faa su idoneidad?**\n   - Esta pregunta se centra en los criterios de selecci\u00f3n del sistema de envase y cierre, incluyendo aspectos como la compatibilidad de materiales y la protecci\u00f3n contra factores ambientales, que pueden no estar claramente definidos en otras gu\u00edas.\n\n3. **\u00bfC\u00f3mo se determina la diferencia en el rendimiento del producto entre los lotes de bioequivalencia comparativa y los lotes producidos seg\u00fan el proceso descrito en 3.2.P.3?**\n   - Esta pregunta busca explorar las diferencias espec\u00edficas en los procesos de fabricaci\u00f3n que pueden afectar el rendimiento del producto, proporcionando detalles que podr\u00edan no estar disponibles en otras partes de la literatura.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS proporciona directrices sobre el desarrollo de procesos de fabricaci\u00f3n para productos farmac\u00e9uticos, enfatizando la importancia de la selecci\u00f3n adecuada de m\u00e9todos de fabricaci\u00f3n y envase. Se requiere una justificaci\u00f3n clara para las decisiones tomadas, especialmente en relaci\u00f3n con la esterilizaci\u00f3n y la protecci\u00f3n del producto. Adem\u00e1s, se destaca la necesidad de cumplir con los est\u00e1ndares de calidad y seguridad, as\u00ed como de discutir las diferencias en los procesos que pueden influir en el rendimiento del producto.", "prev_section_summary": "### Temas Clave\n\n1. **Pruebas de Disoluci\u00f3n para FPPs de Liberaci\u00f3n Modificada**:\n   - Importancia de tener un test de disoluci\u00f3n significativo para el control de calidad.\n   - Preferencia por la correlaci\u00f3n in vitro-in vivo.\n   - Necesidad de presentar resultados sobre el efecto del pH en el perfil de disoluci\u00f3n.\n\n2. **Condiciones de Prueba para FPPs de Liberaci\u00f3n Prolongada**:\n   - Establecimiento de condiciones de prueba que cubran todo el per\u00edodo de liberaci\u00f3n esperado.\n   - Inclusi\u00f3n de puntos de prueba tempranos para demostrar la ausencia de \"dose dumping\".\n   - Definici\u00f3n de l\u00edmites de aceptaci\u00f3n para los resultados de disoluci\u00f3n.\n\n3. **Justificaci\u00f3n de Sobrecargas**:\n   - Necesidad de justificar cualquier sobrecarga en la formulaci\u00f3n para compensar p\u00e9rdidas durante la fabricaci\u00f3n.\n   - Informaci\u00f3n requerida sobre los pasos donde ocurren las p\u00e9rdidas y datos de an\u00e1lisis de lotes.\n\n4. **Propiedades Fisicoqu\u00edmicas y Biol\u00f3gicas**:\n   - Consideraci\u00f3n de par\u00e1metros como pH, fuerza i\u00f3nica, disoluci\u00f3n, distribuci\u00f3n del tama\u00f1o de part\u00edculas, y actividad biol\u00f3gica o inmunol\u00f3gica.\n\n### Entidades\n\n- **FPPs (Formulaciones Farmac\u00e9uticas de Liberaci\u00f3n Modificada)**: Productos farmac\u00e9uticos que liberan el principio activo de manera controlada.\n- **Pruebas de Disoluci\u00f3n**: M\u00e9todos utilizados para evaluar la tasa de liberaci\u00f3n del f\u00e1rmaco en un medio espec\u00edfico.\n- **\"Dose Dumping\"**: Liberaci\u00f3n r\u00e1pida e inesperada de una dosis de medicamento que puede ser peligrosa.\n- **Sobrecargas**: Cantidades adicionales de un ingrediente en la formulaci\u00f3n para compensar p\u00e9rdidas durante la producci\u00f3n.\n- **Par\u00e1metros Fisicoqu\u00edmicos**: Caracter\u00edsticas que afectan el rendimiento del FPP, como pH y distribuci\u00f3n del tama\u00f1o de part\u00edculas.\n\nEste resumen destaca la importancia de las pruebas de disoluci\u00f3n y la justificaci\u00f3n de sobrecargas en la formulaci\u00f3n de productos farmac\u00e9uticos de liberaci\u00f3n modificada, as\u00ed como los par\u00e1metros que deben ser considerados para asegurar su eficacia y seguridad.", "excerpt_keywords": "Keywords: manufacturing process, sterilization methods, container-closure system, pharmaceutical product, critical process parameters"}}, "c770e19b-017f-416d-82bf-5ae8435e4351": {"node_ids": ["405b6f74-4c9e-4679-81a0-8c97ef308ff9"], "metadata": {"page_label": "180", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- glass containers: (34, 35);\n- plastic containers: (36, 37);\n- rubber/elastomeric closures (38, 39).\n\nTable 2 outlines the general recommendations for the various dosage forms for one-time studies to establish the suitability of the container-closure system contact materials.\n\n## Table 2\n### One-time studies to establish the suitability of the container-closure system contact materials\n\n| | Solid oral products | Oral liquid and topical products | Sterile products (including ophthalmics) |\n| - | - | - | - |\n| Description of any additional treatmentsa | \u00d7 | \u00d7 | \u00d7 (sterilization and depyrogenation of the components) |\n| Extraction studies | \u2013 | \u00d7 | \u00d7 |\n| Interaction studies (migration/sorption) | \u2013 | \u00d7 | \u00d7 |\n| Moisture permeability | \u00d7 (uptake) | \u00d7 (usually loss) | \u00d7 (usually loss) |\n| Light transmission | \u00d7b | \u00d7 | \u00d7 |\n\n\n<sup>\u00d7</sup> Information should be submitted.  \n<sup>\u2013</sup> Information does not need to be submitted.  \n<sup>a</sup> E.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials.  \n<sup>b</sup> Not required if product has been shown to be photostable.\n\nFor solid oral dosage forms and solid APIs, compliance with regulations on plastic materials coming into contact with food (for example (EU) No. 10/2011 (40)) can be considered acceptable.\n\nThe suitability of the container-closure system used for the storage, transportation (shipping) and use of any intermediate or in-process products (e.g. premixes or bulk FPP) should also be discussed.\n\nA device is required to be included with the container-closure system for administration of oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules), whenever the package provides for multiple doses.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla las recomendaciones del Comit\u00e9 de Expertos sobre las Especificaciones para Preparaciones Farmac\u00e9uticas, enfoc\u00e1ndose en la idoneidad de los sistemas de cierre y contenedores para diferentes formas de dosificaci\u00f3n. Se presenta una tabla que resume los estudios necesarios para evaluar los materiales de contacto de los sistemas de cierre y contenedores, incluyendo productos orales s\u00f3lidos, l\u00edquidos orales y productos est\u00e9riles. Tambi\u00e9n se menciona la necesidad de cumplir con regulaciones espec\u00edficas y la inclusi\u00f3n de dispositivos para la administraci\u00f3n de productos en dosis m\u00faltiples.\n\n### Preguntas\n1. **\u00bfQu\u00e9 tipo de estudios se requieren para evaluar la idoneidad de los materiales de contacto en productos est\u00e9riles seg\u00fan la tabla presentada?**\n   - Respuesta: Para los productos est\u00e9riles, se requieren estudios de tratamientos adicionales (como esterilizaci\u00f3n y depirogenaci\u00f3n), estudios de extracci\u00f3n, estudios de interacci\u00f3n (migraci\u00f3n/sorci\u00f3n), permeabilidad a la humedad y transmisi\u00f3n de luz.\n\n2. **\u00bfQu\u00e9 regulaciones se consideran aceptables para los materiales pl\u00e1sticos en contacto con productos orales s\u00f3lidos y APIs s\u00f3lidos?**\n   - Respuesta: Se considera aceptable el cumplimiento con regulaciones sobre materiales pl\u00e1sticos en contacto con alimentos, como el (UE) No. 10/2011.\n\n3. **\u00bfQu\u00e9 dispositivos son necesarios para la administraci\u00f3n de l\u00edquidos orales o s\u00f3lidos en envases que permiten m\u00faltiples dosis?**\n   - Respuesta: Se requiere incluir un dispositivo con el sistema de cierre y contenedor para la administraci\u00f3n de l\u00edquidos orales o s\u00f3lidos, como soluciones, emulsiones, suspensiones y polvos o gr\u00e1nulos, siempre que el paquete est\u00e9 dise\u00f1ado para dosis m\u00faltiples.", "prev_section_summary": "### Temas Clave\n\n1. **Desarrollo del Proceso de Fabricaci\u00f3n**:\n   - Selecci\u00f3n y optimizaci\u00f3n del proceso de fabricaci\u00f3n, incluyendo aspectos cr\u00edticos.\n   - Justificaci\u00f3n de m\u00e9todos de esterilizaci\u00f3n, ya sea procesamiento as\u00e9ptico o esterilizaci\u00f3n terminal.\n   - Discusi\u00f3n sobre diferencias en procesos de fabricaci\u00f3n que afectan la bioequivalencia y el rendimiento del producto.\n\n2. **Justificaci\u00f3n del Producto Farmac\u00e9utico**:\n   - Razonamiento cient\u00edfico detr\u00e1s de la elecci\u00f3n de la forma farmac\u00e9utica y el sistema de entrega.\n   - Explicaci\u00f3n de los procesos de fabricaci\u00f3n, llenado y envasado que influyen en la calidad y rendimiento del producto final (FPP).\n   - Inclusi\u00f3n de resultados de estudios de estr\u00e9s del principio activo (API) y trabajos de desarrollo para proteger el FPP de la degradaci\u00f3n.\n\n3. **Par\u00e1metros Cr\u00edticos del Proceso**:\n   - Selecci\u00f3n, optimizaci\u00f3n y escalado del proceso de fabricaci\u00f3n, con \u00e9nfasis en par\u00e1metros cr\u00edticos del proceso (CPP) y su robustez en relaci\u00f3n con el perfil de calidad del producto (QTPP) y atributos de calidad cr\u00edticos (CQA).\n\n4. **Sistema de Envase y Cierre**:\n   - Evaluaci\u00f3n de la idoneidad del sistema de envase y cierre para almacenamiento, transporte y uso del FPP.\n   - Consideraciones sobre materiales, protecci\u00f3n contra humedad y luz, compatibilidad de materiales, y seguridad.\n   - Requisitos de prueba para verificar la idoneidad de los materiales de contacto del sistema de envase y cierre, dependiendo de la forma farmac\u00e9utica y la v\u00eda de administraci\u00f3n.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las directrices.\n- **FPP (Producto Farmac\u00e9utico Final)**: Producto que se est\u00e1 desarrollando.\n- **API (Principio Activo)**: Componente activo del producto farmac\u00e9utico.\n- **CPP (Par\u00e1metros Cr\u00edticos del Proceso)**: Factores que afectan la calidad del proceso de fabricaci\u00f3n.\n- **QTPP (Perfil de Calidad del Producto)**: Expectativas de calidad del producto final.\n- **CQA (Atributos de Calidad Cr\u00edticos)**: Caracter\u00edsticas que deben ser controladas para asegurar la calidad del producto.\n\n### Resumen\n\nLa secci\u00f3n aborda la importancia de la selecci\u00f3n y optimizaci\u00f3n de procesos de fabricaci\u00f3n en el desarrollo de productos farmac\u00e9uticos, enfatizando la necesidad de justificaci\u00f3n clara para decisiones relacionadas con la esterilizaci\u00f3n y el sistema de envase. Se requiere una discusi\u00f3n sobre las diferencias en los procesos que pueden influir en el rendimiento del producto, as\u00ed como el cumplimiento de est\u00e1ndares de calidad y seguridad. Adem\u00e1s, se destaca la evaluaci\u00f3n de la idoneidad del sistema de envase y cierre, considerando aspectos como la compatibilidad de materiales y la protecci\u00f3n del producto.", "excerpt_keywords": "Keywords: container-closure system, pharmaceutical preparations, dosage forms, extraction studies, moisture permeability"}}, "b78c7dbf-0718-46da-af1f-02f659ba9b0a": {"node_ids": ["0a002e45-48dc-4d7c-ae75-1aca5095e7ff"], "metadata": {"page_label": "181", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# In accordance with the Ph.Int. general chapter *Liquid preparations for oral use*:\n\n\"Each dose from a multidose container is administered by means of a device suitable for measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for other volumes or, for oral drops, a suitable dropper.\"\n\nFor a device accompanying a multidose container, the results of a study should be provided demonstrating the reproducibility of the device (e.g. consistent delivery of the intended volume), generally at the lowest intended dose.\n\nA sample of the device should be provided with Module 1.\n\n## 3.2.P.2.5 Microbiological attributes (name, dosage form)\n\nWhere appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container-closure system to prevent microbial contamination should be addressed.\n\nWhere an antimicrobial preservative is included in the formulation, the amount used should be justified by submission of results of studies on the product formulated with different concentrations of the preservative(s) to demonstrate the least necessary but still effective concentration. The effectiveness of the agent should be justified and verified by appropriate studies (e.g. USP or Ph.Eur. general chapters on antimicrobial preservatives) using a batch of the FPP. If the lower limit for the proposed acceptance criterion for the assay of the preservative is less than 90.0%, the effectiveness of the agent should be established with a batch of the FPP containing a concentration of the antimicrobial preservative corresponding to the lower proposed acceptance criteria.\n\nAs outlined in the WHO stability guidelines (*WHO Technical Report Series, No. 953, Annex 2, 2009 (19)*), a single primary stability batch of the FPP should be tested for effectiveness of the antimicrobial preservative (in addition to preservative content) at the proposed shelf-life for verification purposes, regardless of whether there is a difference between the release and shelf-life acceptance criteria for preservative content.\n\n## 3.2.P.2.6 Compatibility (name, dosage form)\n\nThe compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation of API in solution, sorption on injection vessels, stability)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior del contenido:\n\n### Resumen de Nivel Superior\nEl documento de la OMS aborda las directrices para la preparaci\u00f3n de l\u00edquidos orales, enfatizando la importancia de utilizar dispositivos de medici\u00f3n adecuados para administrar dosis desde envases multidose. Se discuten los atributos microbiol\u00f3gicos de las formas de dosificaci\u00f3n, incluyendo la justificaci\u00f3n del uso de conservantes antimicrobianos y la necesidad de pruebas de efectividad. Tambi\u00e9n se menciona la compatibilidad de la forma farmac\u00e9utica con diluyentes y dispositivos de dosificaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de dispositivos son recomendados para medir las dosis de l\u00edquidos orales desde un envase multidose y cu\u00e1l es la importancia de su reproducibilidad?**\n   - Respuesta: Se recomiendan cucharas, tazas para vol\u00famenes de 5 ml o m\u00faltiplos, o jeringas orales para otros vol\u00famenes, y es importante demostrar la reproducibilidad del dispositivo para asegurar la entrega consistente del volumen prescrito, especialmente en la dosis m\u00e1s baja.\n\n2. **\u00bfQu\u00e9 justificaciones se requieren para el uso de conservantes antimicrobianos en productos farmac\u00e9uticos y c\u00f3mo se debe verificar su efectividad?**\n   - Respuesta: Se requiere justificar la cantidad de conservante utilizado mediante estudios que demuestren la concentraci\u00f3n m\u00ednima necesaria pero efectiva. La efectividad debe ser verificada con estudios apropiados, y si el l\u00edmite inferior de aceptaci\u00f3n es menor al 90.0%, se debe establecer la efectividad con un lote que contenga la concentraci\u00f3n correspondiente.\n\n3. **\u00bfC\u00f3mo se debe abordar la compatibilidad de la forma farmac\u00e9utica con los diluyentes de reconstituci\u00f3n o dispositivos de dosificaci\u00f3n?**\n   - Respuesta: La compatibilidad debe ser evaluada en t\u00e9rminos de posibles problemas como la precipitaci\u00f3n del principio activo en soluci\u00f3n, la adsorci\u00f3n en los recipientes de inyecci\u00f3n y la estabilidad general del producto.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que puede no estar f\u00e1cilmente disponible en otras fuentes, bas\u00e1ndose en el contenido detallado del documento.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento de la OMS se centra en las especificaciones para preparaciones farmac\u00e9uticas, destacando la importancia de los sistemas de cierre y contenedores en la seguridad y eficacia de los productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n#### Temas Clave:\n1. **Sistemas de Cierre y Contenedores**: Se discuten los diferentes tipos de contenedores (vidrio, pl\u00e1stico) y cierres (goma/elastom\u00e9ricos) utilizados en la industria farmac\u00e9utica.\n2. **Estudios de Idoneidad**: Se presentan recomendaciones para estudios \u00fanicos que eval\u00faan la idoneidad de los materiales de contacto de los sistemas de cierre y contenedores para diversas formas de dosificaci\u00f3n.\n3. **Regulaciones**: Se menciona la importancia de cumplir con regulaciones espec\u00edficas, como la (UE) No. 10/2011, para materiales pl\u00e1sticos en contacto con productos orales s\u00f3lidos.\n4. **Dispositivos de Administraci\u00f3n**: Se requiere la inclusi\u00f3n de dispositivos para la administraci\u00f3n de productos en dosis m\u00faltiples, asegurando la correcta dosificaci\u00f3n de l\u00edquidos orales y s\u00f3lidos.\n\n#### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las recomendaciones.\n- **Comit\u00e9 de Expertos**: Grupo responsable de las especificaciones para preparaciones farmac\u00e9uticas.\n- **Regulaci\u00f3n (UE) No. 10/2011**: Normativa que regula los materiales pl\u00e1sticos en contacto con alimentos, considerada aceptable para productos farmac\u00e9uticos.\n- **Tipos de Productos**: \n  - Productos orales s\u00f3lidos\n  - Productos l\u00edquidos orales y t\u00f3picos\n  - Productos est\u00e9riles (incluyendo oft\u00e1lmicos)\n\nEste resumen proporciona una visi\u00f3n general de los aspectos m\u00e1s relevantes del documento, enfatizando la importancia de la evaluaci\u00f3n de los materiales de contacto y el cumplimiento normativo en la industria farmac\u00e9utica.", "excerpt_keywords": "Keywords: liquid preparations, antimicrobial preservatives, dosage devices, microbiological attributes, compatibility"}}, "bfb1aee4-c3eb-4607-a5f3-a9bf38efe903": {"node_ids": ["971a3b81-ab61-4600-88e6-265fb19ed74e"], "metadata": {"page_label": "182", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n**should be addressed to provide appropriate and supportive information for the labelling.**\n\nWhere a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules for such reconstitution) that are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required.\n\nWhere sterile, reconstituted products are to be further diluted, compatibility should be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of individual and total degradation products, subvisible particulate matter and extractables from the packaging components) should be demonstrated in glass, PVC and polyolefin containers. However, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers.\n\nStudies should cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies coadministration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the coadministered FPP (i.e. in addition to other aforementioned parameters for the mixture, the assay and degradation levels of each coadministered FPP should be reported).\n\n## 3.2.P.3 Manufacture (name, dosage form)\n\n### 3.2.P.3.1 Manufacturer(s) (name, dosage form)\n\n**The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided.**\n\nThe facilities involved in the manufacturing, packaging, labelling and testing should be listed. If certain companies are responsible only for specific steps (e.g. manufacturing of an intermediate), this should be clearly indicated (WHO good distribution practices for pharmaceutical products (41)).\n\nThe list of manufacturers or companies should specify the actual addresses of production or manufacturing site(s) involved (including block(s) and unit(s)), rather than the administrative offices.\n\nFor a mixture of an API with an excipient, the blending of the API with the excipient is considered to be the first step in the manufacture of the final product and, therefore, the mixture does not fall under the definition of an API. The only exceptions are in the cases where the API cannot exist on its own. Similarly, for a mixture of APIs, the blending of the APIs is considered to be the first step in the manufacturing process.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n### Preguntas y Respuestas\n\n1. **\u00bfQu\u00e9 tipo de estudios de compatibilidad son necesarios para productos reconstituidos que se van a diluir?**\n   - **Respuesta:** Para productos reconstituidos que se van a diluir, se debe demostrar la compatibilidad con todos los diluyentes a lo largo del rango de diluci\u00f3n propuesto en el etiquetado. Estos estudios deben preferiblemente realizarse en muestras envejecidas.\n\n2. **\u00bfQu\u00e9 par\u00e1metros deben evaluarse para demostrar la compatibilidad de las mezclas en diferentes tipos de envases?**\n   - **Respuesta:** La compatibilidad debe evaluarse en funci\u00f3n de par\u00e1metros como apariencia, pH, ensayo, niveles de productos de degradaci\u00f3n individuales y totales, materia particulada subvisible y extractables de los componentes del envase. Esto debe hacerse en envases de vidrio, PVC y poliolefina, a menos que se especifiquen otros envases en el etiquetado.\n\n3. **\u00bfC\u00f3mo se debe documentar la responsabilidad de los fabricantes en el proceso de producci\u00f3n de un producto farmac\u00e9utico?**\n   - **Respuesta:** Se debe proporcionar el nombre, direcci\u00f3n y responsabilidad de cada fabricante, incluidos los contratistas, as\u00ed como de cada sitio o instalaci\u00f3n de producci\u00f3n propuesta involucrada en la fabricaci\u00f3n y pruebas. Adem\u00e1s, se debe especificar la direcci\u00f3n real de los sitios de producci\u00f3n, en lugar de las oficinas administrativas.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS establece directrices sobre la compatibilidad y el etiquetado de productos farmac\u00e9uticos, especialmente en relaci\u00f3n con la fabricaci\u00f3n y la responsabilidad de los fabricantes. Se enfatiza la importancia de realizar estudios de compatibilidad para productos reconstituidos y diluidos, as\u00ed como la necesidad de documentar adecuadamente la cadena de producci\u00f3n y los fabricantes involucrados. Esto incluye la evaluaci\u00f3n de la compatibilidad en diferentes tipos de envases y la especificaci\u00f3n de los par\u00e1metros que deben ser considerados durante estos estudios.\n\n### Preguntas Mejoradas\n\n1. **\u00bfCu\u00e1les son las implicaciones de no realizar estudios de compatibilidad en productos reconstituidos que se diluyen?**\n2. **\u00bfQu\u00e9 consideraciones deben tener en cuenta los fabricantes al seleccionar envases para productos farmac\u00e9uticos?**\n3. **\u00bfC\u00f3mo afecta la mezcla de excipientes y APIs a la definici\u00f3n de un API en el contexto de la fabricaci\u00f3n farmac\u00e9utica?**", "prev_section_summary": "### Temas Clave\n\n1. **Dispositivos de Medici\u00f3n para L\u00edquidos Orales**:\n   - Se recomienda el uso de cucharas, tazas o jeringas orales para medir dosis desde envases multidose.\n   - La reproducibilidad del dispositivo es crucial para asegurar la entrega consistente del volumen prescrito.\n\n2. **Atributos Microbiol\u00f3gicos**:\n   - Se debe discutir la justificaci\u00f3n para no realizar pruebas de l\u00edmites microbianos en productos no est\u00e9riles.\n   - La selecci\u00f3n y efectividad de los sistemas de preservantes antimicrobianos deben ser evaluadas.\n   - Para productos est\u00e9riles, se debe garantizar la integridad del sistema de cierre del envase para prevenir contaminaci\u00f3n microbiana.\n\n3. **Uso de Conservantes Antimicrobianos**:\n   - La cantidad de conservante debe ser justificada mediante estudios que demuestren la concentraci\u00f3n m\u00ednima efectiva.\n   - La efectividad del conservante debe ser verificada con estudios apropiados, especialmente si el l\u00edmite de aceptaci\u00f3n es menor al 90.0%.\n\n4. **Compatibilidad de la Forma Farmac\u00e9utica**:\n   - Se debe evaluar la compatibilidad del producto farmac\u00e9utico con diluyentes de reconstituci\u00f3n y dispositivos de dosificaci\u00f3n, considerando aspectos como la precipitaci\u00f3n del principio activo y la estabilidad general del producto.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las directrices.\n- **Ph.Int.**: Referencia a la Farmacopea Internacional.\n- **FPP (Forma Farmac\u00e9utica del Producto)**: T\u00e9rmino utilizado para referirse al producto farmac\u00e9utico final.\n- **Conservantes Antimicrobianos**: Sustancias utilizadas para prevenir el crecimiento microbiano en productos farmac\u00e9uticos.\n- **Estudios de Estabilidad**: Evaluaciones necesarias para verificar la efectividad de los conservantes a lo largo de la vida \u00fatil del producto.\n\nEste resumen destaca los aspectos m\u00e1s relevantes y las entidades mencionadas en la secci\u00f3n, proporcionando una visi\u00f3n clara de los requisitos y consideraciones para la preparaci\u00f3n de l\u00edquidos orales.", "excerpt_keywords": "Keywords: compatibility studies, pharmaceutical preparations, manufacturing process, labeling requirements, excipients"}}, "d14fc8f1-b6d1-4029-b5ec-d2aaca865629": {"node_ids": ["8583dcb6-8e2d-4d0c-aaab-f6aacee04a4f"], "metadata": {"page_label": "183", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Manufacture of the Final Product\n\nSites for such manufacturing steps should be listed in this section.\n\nA valid manufacturing authorization for pharmaceutical production, as well as a marketing authorization, should be submitted to demonstrate that the product is registered or licensed in accordance with national requirements (Module 1, 1.2.2).\n\nFor each site where the major production step(s) are carried out, when applicable, attach a WHO-type certificate of GMP issued by the competent authority in terms of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce (Module 1, 1.2.2).\n\n## Justification for Any Differences to the Product in the Country or Countries Issuing the WHO-type Certificate(s)\n\nWhen there are differences between the product for which this application is submitted and that marketed in the country or countries which provided the WHO-type certificate(s), it is necessary to provide data to support the applicability of the certificate(s) despite the differences. Depending on the case, it may be necessary to provide validation data for example for differences in site of manufacture, specifications and formulation. Note that only minor differences are likely to be acceptable. Differences in container labelling need not normally be justified.\n\n## Regulatory Situation in Other Countries\n\nA listing should be provided of the countries in which this product has been granted a marketing authorization, this product has been withdrawn from the market and/or this application for marketing has been rejected, deferred or withdrawn (Module 1, 1.2.2).\n\nReference documents: WHO Technical Report Series, No. 961, Annex 3 (42) and No. 957, Annex 5 (41).\n\n### 3.2.P.3.2 Batch Formula (Name, Dosage Form)\n\nA batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards.\n\nThe tables in the QOS-PD template should be used to summarize the batch formula of the FPP for each proposed commercial batch size and to express the quantity of each component on a per batch basis, including a statement of the total weight or measure of the batch.\n\nAll components used in the manufacturing process should be included, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento proporciona directrices sobre la fabricaci\u00f3n del producto farmac\u00e9utico final, incluyendo la necesidad de listar los sitios de fabricaci\u00f3n, presentar autorizaciones de fabricaci\u00f3n y comercializaci\u00f3n, y justificar cualquier diferencia entre el producto presentado y el que tiene un certificado de la OMS. Tambi\u00e9n se requiere una lista de los pa\u00edses donde se ha autorizado el producto y un formato de lote que detalle todos los componentes utilizados en el proceso de fabricaci\u00f3n.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de certificaci\u00f3n se requiere para los sitios de fabricaci\u00f3n y qu\u00e9 informaci\u00f3n debe incluirse al respecto?**\n   - Se requiere un certificado de Buenas Pr\u00e1cticas de Manufactura (GMP) emitido por la autoridad competente, que debe adjuntarse para cada sitio donde se realicen los pasos de producci\u00f3n principales.\n\n2. **\u00bfQu\u00e9 tipo de diferencias entre el producto presentado y el que tiene el certificado de la OMS son aceptables sin necesidad de justificaci\u00f3n?**\n   - Solo se aceptan diferencias menores, y las diferencias en el etiquetado del envase normalmente no necesitan ser justificadas.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la secci\u00f3n sobre la situaci\u00f3n regulatoria en otros pa\u00edses?**\n   - Debe incluirse una lista de los pa\u00edses donde se ha otorgado autorizaci\u00f3n de comercializaci\u00f3n, as\u00ed como aquellos donde el producto ha sido retirado del mercado o donde la solicitud de comercializaci\u00f3n ha sido rechazada, diferida o retirada.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Compatibilidad de Productos Farmac\u00e9uticos:**\n   - Se requiere demostrar la compatibilidad de productos reconstituidos que se diluyen con todos los diluyentes propuestos en el etiquetado.\n   - Los estudios de compatibilidad deben realizarse preferiblemente en muestras envejecidas y abarcar la duraci\u00f3n de almacenamiento especificada en el etiquetado.\n\n2. **Evaluaci\u00f3n de Envases:**\n   - La compatibilidad debe evaluarse en diferentes tipos de envases (vidrio, PVC, poliolefina) en funci\u00f3n de par\u00e1metros como apariencia, pH, niveles de degradaci\u00f3n y extractables.\n   - Si se especifican envases en el etiquetado, la compatibilidad solo necesita demostrarse en esos envases.\n\n3. **Responsabilidad de los Fabricantes:**\n   - Se debe proporcionar informaci\u00f3n detallada sobre los fabricantes, incluyendo nombre, direcci\u00f3n y responsabilidad de cada uno, as\u00ed como de los sitios de producci\u00f3n.\n   - La mezcla de un principio activo (API) con un excipiente se considera el primer paso en la fabricaci\u00f3n del producto final.\n\n4. **Coadministraci\u00f3n de Productos Farmac\u00e9uticos:**\n   - La compatibilidad debe ser demostrada no solo para el producto principal, sino tambi\u00e9n para los productos coadministrados, incluyendo niveles de ensayo y degradaci\u00f3n.\n\n**Entidades:**\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Entidad responsable de establecer directrices sobre la fabricaci\u00f3n y etiquetado de productos farmac\u00e9uticos.\n- **Fabricantes:** Incluye tanto a los fabricantes principales como a los contratistas y las instalaciones involucradas en la producci\u00f3n y pruebas.\n- **Productos Farmac\u00e9uticos (FPPs):** Incluye soluciones, emulsiones, suspensiones y productos reconstituidos que requieren estudios de compatibilidad.\n- **Envases:** Tipos de envases mencionados incluyen vidrio, PVC y poliolefina, que son relevantes para la evaluaci\u00f3n de compatibilidad.\n\nEste resumen destaca la importancia de la compatibilidad en la fabricaci\u00f3n de productos farmac\u00e9uticos y la necesidad de una documentaci\u00f3n clara sobre los fabricantes y sus responsabilidades.", "excerpt_keywords": "Manufacturing, Authorization, GMP, Regulatory, Batch Formula"}}, "fcd6180e-f73d-497b-8914-bc619adc7ae2": {"node_ids": ["e556da80-fceb-4c9f-a5a5-95e964b0133b"], "metadata": {"page_label": "184", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n\"1 kg of active ingredient base = 1.075 kg active ingredient hydrochloride\"). All overages should be clearly indicated (e.g. \"Contains 5 kg (corresponding to 2%) overage of the API to compensate for manufacturing losses\").\n\nThe components should be declared by their proper or common names, quality standards (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and, if applicable, their grades (e.g. \"Microcrystalline cellulose NF (PH 102)\") and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified).\n\n## 3.2.P.3.3 Description of manufacturing process and process controls (name, dosage form)\n\nA flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified.\n\nA narrative description of the manufacturing process, including packaging, that represents the sequence of steps undertaken and the scale of production should also be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (e.g. tumble blender, in-line homogenizer) and working capacity, where relevant.\n\nSteps in the process should have the appropriate process parameters identified, such as time, temperature, or pH. Associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section 3.2.P.3.4. In certain cases, environmental conditions (e.g. low humidity for an effervescent product) should be stated.\n\nThe maximum holding time for bulk FPP prior to final packaging should be stated. The holding time should be supported by the submission of stability data if longer than 30 days. For an aseptically processed FPP, sterile filtration of the bulk and filling into final containers should preferably be continuous; any holding time should be justified.\n\nProposals for the reprocessing of materials should be justified. Any data to support this justification should be either referenced or filed in this section (3.2.P.3.3).\n\nThe information above should be summarized in the QOS-PD template and should reflect the production of the proposed commercial batches. See Glossary (section 2) for definitions of pilot-scale and production-scale batches.\n\nFor the manufacture of sterile products the class (e.g. A, B or C) of the areas should be stated for each activity (e.g. compounding, filling and sealing), as well as the sterilization parameters, including for equipment, container-closure system and terminal sterilization.\n\nReference documents: ICH Q8 (25), Q9 (26), Q10 (27).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la declaraci\u00f3n de los componentes de un producto farmac\u00e9utico?**\n   - La declaraci\u00f3n de los componentes debe incluir los nombres propios o comunes de los ingredientes, los est\u00e1ndares de calidad aplicables (como BP, JP, Ph.Eur., Ph.Int., USP, o in-house), sus grados (por ejemplo, \"Microcrystalline cellulose NF (PH 102)\"), y cualquier caracter\u00edstica t\u00e9cnica especial (como si son liofilizados, micronizados, solubilizados o emulsionados).\n\n2. **\u00bfCu\u00e1les son los requisitos para la descripci\u00f3n del proceso de fabricaci\u00f3n y los controles de proceso en la documentaci\u00f3n de un producto farmac\u00e9utico?**\n   - Se debe presentar un diagrama de flujo que muestre los pasos del proceso y la entrada de materiales. Adem\u00e1s, se debe proporcionar una descripci\u00f3n narrativa del proceso de fabricaci\u00f3n, incluyendo el embalaje, identificando el tipo de equipo utilizado y sus capacidades. Tambi\u00e9n se deben identificar los par\u00e1metros del proceso, como tiempo, temperatura o pH, y justificar los rangos num\u00e9ricos para los pasos cr\u00edticos.\n\n3. **\u00bfQu\u00e9 condiciones deben cumplirse para el tiempo de espera de productos farmac\u00e9uticos antes del empaquetado final?**\n   - El tiempo m\u00e1ximo de espera para productos farmac\u00e9uticos en forma de producto terminado (FPP) antes del empaquetado final debe ser declarado. Si este tiempo es superior a 30 d\u00edas, debe estar respaldado por datos de estabilidad. Para productos procesados as\u00e9pticamente, la filtraci\u00f3n est\u00e9ril del producto a granel y el llenado en los envases finales deben ser preferiblemente continuos, y cualquier tiempo de espera debe ser justificado.\n\n### Resumen de nivel superior del contexto:\nEl documento de la OMS establece directrices para la preparaci\u00f3n y control de productos farmac\u00e9uticos, enfatizando la importancia de declarar correctamente los ingredientes, describir detalladamente el proceso de fabricaci\u00f3n y los controles asociados, y justificar los tiempos de espera y reprocesamiento de materiales. Se requiere un enfoque riguroso para asegurar la calidad y la seguridad de los productos farmac\u00e9uticos, incluyendo la identificaci\u00f3n de equipos y condiciones ambientales relevantes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Fabricaci\u00f3n del Producto Final**:\n   - Se requiere listar los sitios de fabricaci\u00f3n.\n   - Es necesario presentar autorizaciones de fabricaci\u00f3n y comercializaci\u00f3n v\u00e1lidas.\n\n2. **Certificaci\u00f3n de Buenas Pr\u00e1cticas de Manufactura (GMP)**:\n   - Para cada sitio de producci\u00f3n, se debe adjuntar un certificado de GMP emitido por la autoridad competente, conforme al esquema de certificaci\u00f3n de la OMS.\n\n3. **Justificaci\u00f3n de Diferencias**:\n   - Si hay diferencias entre el producto presentado y el que tiene el certificado de la OMS, se debe proporcionar datos que respalden la aplicabilidad del certificado.\n   - Solo se aceptan diferencias menores; las diferencias en el etiquetado del envase no requieren justificaci\u00f3n.\n\n4. **Situaci\u00f3n Regulatoria en Otros Pa\u00edses**:\n   - Se debe incluir una lista de pa\u00edses donde se ha otorgado autorizaci\u00f3n de comercializaci\u00f3n, as\u00ed como aquellos donde el producto ha sido retirado o donde la solicitud ha sido rechazada, diferida o retirada.\n\n5. **F\u00f3rmula del Lote**:\n   - Se debe proporcionar una f\u00f3rmula de lote que incluya todos los componentes del producto, sus cantidades por lote y referencias a sus est\u00e1ndares de calidad.\n   - Se deben utilizar tablas del formato QOS-PD para resumir la f\u00f3rmula del lote y expresar la cantidad de cada componente.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Referencia principal para certificaciones y est\u00e1ndares.\n- **Autorizaciones de Fabricaci\u00f3n y Comercializaci\u00f3n**: Documentos necesarios para la legalidad del producto.\n- **Certificado de GMP**: Documento que asegura que los procesos de fabricaci\u00f3n cumplen con los est\u00e1ndares de calidad.\n- **Pa\u00edses**: Entidades donde se eval\u00faa la situaci\u00f3n regulatoria del producto.", "excerpt_keywords": "Keywords: pharmaceutical preparations, manufacturing process, quality standards, process controls, sterile products"}}, "866709ff-3f26-4fb5-9880-c8a6fa9adcad": {"node_ids": ["ec3dd428-a47a-46b5-ba37-0a65b6972cb2"], "metadata": {"page_label": "185", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.3.4 Controls of critical steps and intermediates (name, dosage form)\n\n**Critical steps:** Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is controlled.\n\n**Intermediates:** Information on the quality and control of intermediates isolated during the process should be provided.\n\nExamples of applicable in-process controls include:\n\n- **Granulations:** \n  - Moisture (limits expressed as a range)\n  - Blend uniformity (e.g. low-dose tablets)\n  - Bulk and tapped densities and particle size distribution\n\n- **Solid oral products:** \n  - Average weight\n  - Weight variation\n  - Hardness\n  - Thickness\n  - Friability\n  - Disintegration checked periodically throughout compression\n  - Weight gain during coating\n\n- **Semi-solids:** \n  - Viscosity\n  - Homogeneity\n  - pH\n\n- **Transdermal dosage forms:** \n  - Assay of API\u2013adhesive mixture\n  - Weight per area of coated patch without backing\n\n- **Metered dose inhalers:** \n  - Fill weight or volume\n  - Leak testing\n  - Valve delivery\n\n- **Dry powder inhalers:** \n  - Assay of API\u2013excipient blend\n  - Moisture\n  - Weight variation of individually contained doses such as capsules or blisters\n\n- **Liquids:** \n  - pH\n  - Specific gravity\n  - Clarity of solutions\n\n- **Parenterals:** \n  - Appearance\n  - Clarity\n  - Fill volume or weight\n  - pH\n  - Filter integrity tests\n  - Particulate matter\n  - Leak testing of ampoules\n  - Pre-filtration and/or pre-sterilization bioburden testing\n\nReference documents: ICH Q2 (16), Q6A (6), Q8 (25), Q9 (26), Q10 (27), WHO Technical Report Series, No. 929, Annex 5 (21).\n\n# 3.2.P.3.5 Process validation and/or evaluation (name, dosage form)\n\nDescription, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (e.g. validation of the sterilization process or aseptic processing or filling). Viral safety evaluation should be provided in 3.2A.2, if necessary.\n\nFor products that meet the criteria of an established multisource product, a product quality review as outlined in Appendix 2 may be submitted in lieu of the information below.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS detalla los controles de calidad y validaci\u00f3n en el proceso de fabricaci\u00f3n de productos farmac\u00e9uticos. Se enfatiza la importancia de realizar pruebas y establecer criterios de aceptaci\u00f3n en pasos cr\u00edticos del proceso, as\u00ed como en los intermedios. Se enumeran ejemplos de controles en diferentes formas de dosificaci\u00f3n, incluyendo s\u00f3lidos orales, semis\u00f3lidos, inhaladores y parenterales. Adem\u00e1s, se menciona la necesidad de documentaci\u00f3n y resultados de estudios de validaci\u00f3n para asegurar la calidad y seguridad del producto.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son los criterios de aceptaci\u00f3n espec\u00edficos para la uniformidad de mezcla en tabletas de baja dosis seg\u00fan el contexto?**\n   - Esta pregunta busca informaci\u00f3n detallada sobre un aspecto espec\u00edfico de los controles en el proceso de fabricaci\u00f3n que no se detalla en otras fuentes.\n\n2. **\u00bfQu\u00e9 pruebas de integridad de filtro se requieren para productos parenterales y por qu\u00e9 son importantes?**\n   - Esta pregunta se centra en un aspecto cr\u00edtico de la fabricaci\u00f3n de productos parenterales, que es esencial para garantizar la seguridad del producto.\n\n3. **\u00bfQu\u00e9 documentaci\u00f3n se necesita para la validaci\u00f3n de procesos cr\u00edticos en la fabricaci\u00f3n de productos farmac\u00e9uticos y c\u00f3mo se relaciona con la evaluaci\u00f3n de seguridad viral?**\n   - Esta pregunta aborda la conexi\u00f3n entre la validaci\u00f3n de procesos y la evaluaci\u00f3n de seguridad, un tema que puede no estar claramente definido en otras fuentes. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y relevante que puede no estar disponible en otros documentos o contextos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Declaraci\u00f3n de Componentes**:\n   - **Nombres**: Propios o comunes de los ingredientes activos.\n   - **Est\u00e1ndares de Calidad**: BP, JP, Ph.Eur., Ph.Int., USP, in-house.\n   - **Grados y Caracter\u00edsticas T\u00e9cnicas**: Ejemplos incluyen \"Microcrystalline cellulose NF (PH 102)\", liofilizados, micronizados, solubilizados, o emulsionados.\n\n2. **Descripci\u00f3n del Proceso de Fabricaci\u00f3n**:\n   - **Diagrama de Flujo**: Representaci\u00f3n visual de los pasos del proceso y entrada de materiales.\n   - **Descripci\u00f3n Narrativa**: Secuencia de pasos, escala de producci\u00f3n, y detalles sobre procesos o tecnolog\u00edas novedosas.\n   - **Identificaci\u00f3n de Equipos**: Tipo y capacidad de los equipos utilizados (ej. mezclador de tambor, homogeneizador en l\u00ednea).\n   - **Par\u00e1metros del Proceso**: Identificaci\u00f3n de tiempo, temperatura, pH, y justificaci\u00f3n de rangos num\u00e9ricos.\n\n3. **Tiempo de Espera y Reprocesamiento**:\n   - **Tiempo M\u00e1ximo de Espera**: Declaraci\u00f3n del tiempo para productos farmac\u00e9uticos antes del empaquetado final, con datos de estabilidad si excede 30 d\u00edas.\n   - **Filtraci\u00f3n Est\u00e9ril**: Preferiblemente continua para productos procesados as\u00e9pticamente, con justificaci\u00f3n de cualquier tiempo de espera.\n   - **Reprocesamiento de Materiales**: Justificaci\u00f3n y datos de soporte deben ser referenciados o incluidos.\n\n4. **Fabricaci\u00f3n de Productos Est\u00e9riles**:\n   - **Clasificaci\u00f3n de \u00c1reas**: Clase (A, B o C) para actividades como compounding, llenado y sellado.\n   - **Par\u00e1metros de Esterilizaci\u00f3n**: Incluyendo equipos y sistemas de cierre de envases.\n\n5. **Documentaci\u00f3n de Referencia**:\n   - **ICH Q8, Q9, Q10**: Documentos de referencia que gu\u00edan la calidad y control de procesos en la fabricaci\u00f3n farmac\u00e9utica.\n\n### Entidades Clave:\n- **Organizaci\u00f3n**: OMS (Organizaci\u00f3n Mundial de la Salud).\n- **Documentos de Calidad**: BP (British Pharmacopoeia), JP (Japanese Pharmacopoeia), Ph.Eur. (European Pharmacopoeia), Ph.Int. (International Pharmacopoeia), USP (United States Pharmacopeia).\n- **Tipos de Equipos**: Mezclador de tambor, homogeneizador en l\u00ednea.\n- **Clases de \u00c1reas**: A, B, C (para productos est\u00e9riles).\n- **Secciones del Documento**: 3.2.P.3.3 (Descripci\u00f3n del proceso de fabricaci\u00f3n y controles de proceso). \n\nEste resumen destaca la importancia de la documentaci\u00f3n rigurosa y la justificaci\u00f3n en la fabricaci\u00f3n de productos farmac\u00e9uticos para asegurar su calidad y seguridad.", "excerpt_keywords": "Keywords: quality control, process validation, pharmaceutical manufacturing, critical steps, in-process controls"}}, "d0fce398-4fda-4cfc-92a2-c718049a109b": {"node_ids": ["90c3b8c2-a54d-4ecc-9f42-51014b6d61ef"], "metadata": {"page_label": "186", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe following information should be provided for all other products:\n\n1. A copy of the process validation protocol, specific to this FPP, described below;\n2. A commitment that three consecutive, production-scale batches of this FPP will be subjected to prospective validation in accordance with the above protocol. The applicant should submit a written commitment that information from these studies will be available for verification after prequalification by the WHO inspection team;\n3. If the process validation studies have already been conducted (e.g. for sterile products), a copy of the process validation report should be provided in the PD in lieu of 1. and 2. above.\n\nOne of the most practical forms of process validation, mainly for non-sterile products, is the final testing of the product to an extent greater than that required in routine quality control. It may involve extensive sampling, far beyond that called for in routine quality control and testing to normal quality control specifications and often for certain parameters only. Thus, for instance, several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then analysed statistically to verify the \u201cnormality\u201d of the distribution and to determine the standard deviation from the average weight. Confidence limits for individual results and for batch homogeneity are also estimated. Strong assurance is provided that samples taken at random will meet regulatory requirements if the confidence limits are well within compendial specifications.\n\nSimilarly, extensive sampling and testing may be performed with regard to any quality requirements. In addition, intermediate stages may be validated in the same way, e.g. dozens of samples may be assayed individually to validate mixing or granulation stages of low-dose tablet production by using the content uniformity test. Certain product characteristics may occasionally be skip-tested. Thus, subvisual particulate matter in parenteral preparations may be determined by means of electronic devices, or tablets or capsules tested for their dissolution profile if such tests are not performed on every batch.\n\nWhere ranges of batch sizes are proposed, it should be shown that variations in batch size would not adversely alter the characteristics of the finished product. It is envisaged that those parameters listed in the following validation scheme would need to be revalidated once further scale-up is proposed after prequalification.\n\nThe process validation protocol should include, but not be limited to, the following:\n\n- A reference to the current master production document;\n- A discussion of the critical equipment;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfQu\u00e9 tipo de compromiso debe presentar el solicitante respecto a la validaci\u00f3n de los lotes de productos farmac\u00e9uticos?**\n   - El solicitante debe presentar un compromiso por escrito de que tres lotes consecutivos a escala de producci\u00f3n del producto farmac\u00e9utico formulado (FPP) ser\u00e1n sometidos a validaci\u00f3n prospectiva de acuerdo con el protocolo de validaci\u00f3n del proceso. Adem\u00e1s, debe asegurar que la informaci\u00f3n de estos estudios estar\u00e1 disponible para verificaci\u00f3n despu\u00e9s de la precalificaci\u00f3n por parte del equipo de inspecci\u00f3n de la OMS.\n\n2. **\u00bfCu\u00e1les son algunos de los m\u00e9todos de validaci\u00f3n del proceso que se pueden utilizar para productos no est\u00e9riles?**\n   - Para productos no est\u00e9riles, una forma pr\u00e1ctica de validaci\u00f3n del proceso es la prueba final del producto, que puede incluir un muestreo extenso m\u00e1s all\u00e1 de lo requerido en el control de calidad rutinario. Esto puede implicar pesar varios cientos de tabletas por lote para determinar la uniformidad de la dosis unitaria y analizar estad\u00edsticamente los resultados para verificar la \"normalidad\" de la distribuci\u00f3n.\n\n3. **\u00bfQu\u00e9 aspectos deben incluirse en el protocolo de validaci\u00f3n del proceso seg\u00fan el documento de la OMS?**\n   - El protocolo de validaci\u00f3n del proceso debe incluir, entre otros aspectos, una referencia al documento maestro de producci\u00f3n actual y una discusi\u00f3n sobre el equipo cr\u00edtico utilizado en el proceso de producci\u00f3n.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento de la OMS establece directrices para la validaci\u00f3n de procesos en la producci\u00f3n de productos farmac\u00e9uticos, enfatizando la importancia de la validaci\u00f3n prospectiva y el compromiso del solicitante para garantizar la calidad del producto. Se describen m\u00e9todos de validaci\u00f3n, especialmente para productos no est\u00e9riles, y se especifican los elementos que deben incluirse en el protocolo de validaci\u00f3n del proceso. Adem\u00e1s, se menciona la necesidad de revalidar ciertos par\u00e1metros si se propone un aumento de escala despu\u00e9s de la precalificaci\u00f3n.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Controles de Calidad en Pasos Cr\u00edticos:**\n   - Importancia de realizar pruebas y establecer criterios de aceptaci\u00f3n en pasos cr\u00edticos del proceso de fabricaci\u00f3n.\n   - Necesidad de justificaci\u00f3n y datos experimentales para los controles.\n\n2. **Intermedios:**\n   - Informaci\u00f3n sobre la calidad y control de intermedios aislados durante el proceso de fabricaci\u00f3n.\n\n3. **Ejemplos de Controles en Proceso:**\n   - Granulaciones: humedad, uniformidad de mezcla, densidades y distribuci\u00f3n de tama\u00f1o de part\u00edculas.\n   - Productos orales s\u00f3lidos: peso promedio, variaci\u00f3n de peso, dureza, grosor, friabilidad, desintegraci\u00f3n y ganancia de peso durante el recubrimiento.\n   - Semis\u00f3lidos: viscosidad, homogeneidad y pH.\n   - Formas de dosificaci\u00f3n transd\u00e9rmicas: mezcla de API-adhesivo y peso por \u00e1rea del parche.\n   - Inhaladores de dosis medida: peso o volumen de llenado, pruebas de fuga y entrega de v\u00e1lvula.\n   - Inhaladores de polvo seco: mezcla de API-excipiente, humedad y variaci\u00f3n de peso.\n   - L\u00edquidos: pH, gravedad espec\u00edfica y claridad.\n   - Parenterales: apariencia, claridad, volumen o peso de llenado, pH, pruebas de integridad de filtro, materia particulada, pruebas de fuga y biocarga previa a la filtraci\u00f3n/esterilizaci\u00f3n.\n\n4. **Validaci\u00f3n de Procesos:**\n   - Documentaci\u00f3n y resultados de estudios de validaci\u00f3n para pasos cr\u00edticos o ensayos cr\u00edticos en el proceso de fabricaci\u00f3n.\n   - Evaluaci\u00f3n de seguridad viral cuando sea necesario.\n\n**Entidades:**\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Fuente del documento.\n- **ICH (International Council for Harmonisation):** Referencias a documentos de ICH que gu\u00edan los controles de calidad y validaci\u00f3n.\n- **Formas de Dosificaci\u00f3n:** Granulaciones, productos orales s\u00f3lidos, semis\u00f3lidos, transdermales, inhaladores, l\u00edquidos y parenterales.\n- **Criterios de Aceptaci\u00f3n:** Par\u00e1metros espec\u00edficos para asegurar la calidad del producto durante la fabricaci\u00f3n.\n\nEste resumen destaca la importancia de los controles de calidad y la validaci\u00f3n en la fabricaci\u00f3n de productos farmac\u00e9uticos, as\u00ed como los criterios espec\u00edficos que deben cumplirse para garantizar la seguridad y eficacia del producto final.", "excerpt_keywords": "Keywords: process validation, pharmaceutical preparations, quality control, WHO guidelines, batch testing"}}, "8d4ecb7e-71ad-460e-8f08-c0e7a1333d96": {"node_ids": ["2840050f-b828-4910-afca-bb5f6fe8a1e3"], "metadata": {"page_label": "187", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n- The process parameters that can affect the quality of the FPP (critical process parameters (CPPs)) including challenge experiments and failure mode operation;\n- Details of the sampling: sampling points, stages of sampling, methods of sampling and the sampling plans (including schematics of blender or storage bins for uniformity testing of the final blend);\n- The testing parameters and acceptance criteria including in-process and release specifications and comparative dissolution profiles of validation batches against the batch(es) used in the bioavailability or biowaiver studies;\n- The analytical procedures or a reference to appropriate section(s) of the dossier;\n- The methods for recording and evaluating results;\n- The proposed timeframe for completion of the protocol.\n\nThe manufacture of sterile FPPs needs to take place in a well-controlled manufacturing area (e.g. a strictly controlled environment using highly reliable procedures and with appropriate in-process controls). A detailed description of these conditions, procedures and controls should be provided, together with actual copies of the standard operating procedures for the following:\n\n- Washing, treatment, sterilization and depyrogenation of containers, closures and equipment;\n- Filtration of solutions;\n- Lyophilization process;\n- Leaker test of filled and sealed ampoules;\n- Final inspection of the product;\n- Sterilization cycle.\n\nThe sterilization process used to destroy or remove microorganisms is probably the single most important process in the manufacture of parenteral FPPs. The process can make use of moist heat (e.g. steam), dry heat, filtration, gaseous sterilization (e.g. ethylene oxide) or radiation. It should be noted that terminal steam sterilization, when practical, is considered to be the method of choice to ensure sterility of the final FPP. Therefore, scientific justification for selecting any other method of sterilization should be provided.\n\nThe sterilization process should be described in detail and evidence should be provided to confirm that it will produce a sterile product with a high degree of reliability and that the physical and chemical properties as well as", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con res\u00famenes de nivel superior que pueden ayudar a formularlas:\n\n### Resumen de Nivel Superior\nEl documento se centra en los par\u00e1metros cr\u00edticos del proceso (CPPs) que afectan la calidad de los productos farmac\u00e9uticos terminados (FPPs) est\u00e9riles, as\u00ed como en los procedimientos de fabricaci\u00f3n, control de calidad y esterilizaci\u00f3n necesarios para garantizar la seguridad y eficacia de estos productos. Se enfatiza la importancia de un entorno de fabricaci\u00f3n controlado y la necesidad de justificaci\u00f3n cient\u00edfica para los m\u00e9todos de esterilizaci\u00f3n elegidos.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son los par\u00e1metros cr\u00edticos del proceso (CPPs) que deben considerarse al fabricar productos farmac\u00e9uticos est\u00e9riles?**\n   - Esta pregunta se centra en los aspectos espec\u00edficos mencionados en el contexto, como los experimentos de desaf\u00edo y la operaci\u00f3n en modo de falla, que son esenciales para garantizar la calidad del FPP.\n\n2. **\u00bfQu\u00e9 procedimientos est\u00e1ndar se deben seguir para la esterilizaci\u00f3n y depirogenaci\u00f3n de los envases y equipos utilizados en la fabricaci\u00f3n de FPPs est\u00e9riles?**\n   - Aqu\u00ed se busca informaci\u00f3n detallada sobre los procedimientos espec\u00edficos que deben documentarse y seguirse, como el lavado, tratamiento y esterilizaci\u00f3n, que son cruciales para mantener la integridad del producto.\n\n3. **\u00bfQu\u00e9 justificaci\u00f3n cient\u00edfica se requiere para seleccionar un m\u00e9todo de esterilizaci\u00f3n diferente al de esterilizaci\u00f3n por vapor terminal?**\n   - Esta pregunta aborda la necesidad de proporcionar evidencia y justificaci\u00f3n para el uso de m\u00e9todos alternativos de esterilizaci\u00f3n, lo que es fundamental para asegurar la fiabilidad del proceso de fabricaci\u00f3n de FPPs est\u00e9riles. \n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica y detallada que no se puede encontrar f\u00e1cilmente en otros documentos o fuentes.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Validaci\u00f3n del Proceso:**\n   - Importancia de la validaci\u00f3n prospectiva para garantizar la calidad de los productos farmac\u00e9uticos.\n   - Necesidad de un protocolo de validaci\u00f3n espec\u00edfico para cada producto farmac\u00e9utico formulado (FPP).\n\n2. **Compromiso del Solicitante:**\n   - El solicitante debe comprometerse a validar tres lotes consecutivos a escala de producci\u00f3n y proporcionar informaci\u00f3n para verificaci\u00f3n posterior a la precalificaci\u00f3n.\n\n3. **M\u00e9todos de Validaci\u00f3n:**\n   - Para productos no est\u00e9riles, se sugiere realizar pruebas finales del producto que incluyan muestreo extenso y an\u00e1lisis estad\u00edstico para verificar la uniformidad de la dosis.\n   - Validaci\u00f3n de etapas intermedias del proceso, como mezcla y granulaci\u00f3n.\n\n4. **Revalidaci\u00f3n:**\n   - Se requiere revalidar ciertos par\u00e1metros si se propone un aumento de escala despu\u00e9s de la precalificaci\u00f3n.\n\n5. **Elementos del Protocolo de Validaci\u00f3n:**\n   - Debe incluir referencias al documento maestro de producci\u00f3n y discusiones sobre el equipo cr\u00edtico utilizado.\n\n**Entidades:**\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Entidad responsable de establecer directrices para la validaci\u00f3n de procesos en la producci\u00f3n farmac\u00e9utica.\n- **FPP (Producto Farmac\u00e9utico Formulado):** Producto que est\u00e1 sujeto a validaci\u00f3n de procesos.\n- **Protocolo de Validaci\u00f3n del Proceso:** Documento que detalla los procedimientos y m\u00e9todos de validaci\u00f3n a seguir.\n- **Lotes de Producci\u00f3n:** Cantidades de producto fabricadas que deben ser validadas.\n\nEste resumen destaca la importancia de la validaci\u00f3n en la producci\u00f3n farmac\u00e9utica y los requisitos espec\u00edficos que deben cumplirse para asegurar la calidad y conformidad de los productos.", "excerpt_keywords": "Keywords: critical process parameters, sterile FPPs, sterilization methods, quality control, validation protocol"}}, "d86f7ef1-fe67-48a8-9aaa-16a3d4c6325f": {"node_ids": ["fd373cd5-1a36-4370-8685-b2c9adf47b61"], "metadata": {"page_label": "188", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe safety of the FPP will not be affected. Details such as Fo range, temperature range and peak dwell time for an FPP and the container-closure system should be provided. Although standard autoclaving cycles of 121 \u00b0C for 15 minutes or more would not need a detailed rationale, such justifications should be provided for reduced temperature cycles or elevated temperature cycles with shortened exposure times. If ethylene oxide is used, studies and acceptance criteria should control the levels of residual ethylene oxide and related compounds.\n\nAny filters used should be validated with respect to pore size, compatibility with the product, absence of extractables and lack of adsorption of the API or any of the components.\n\nFor the validation of aseptic processing of parenteral products that cannot be terminally sterilized, simulation process trials should be conducted. This involves filling containers with culture media under normal conditions, followed by incubation. Refer to current WHO GMP guidelines for details.\n\nReference documents: ICH Q8 (25), Q9 (26), Q10 (27), WHO Technical Report Series, No. 961, Annex 3 (42).\n\n## 3.2.P.4 Control of excipients (name, dosage form)\n\n### 3.2.P.4.1 Specifications (name, dosage form)\n\n**The specifications for excipients should be provided.**\n\nThe specifications from the applicant or the FPP manufacturer should be provided for all excipients, including those that may not be added to every batch (e.g. acid and alkali), those that do not appear in the final FPP (e.g. solvents) and any others used in the manufacturing process (e.g. nitrogen or silicon for stoppers).\n\nIf the standard claimed for an excipient is an officially recognized compendial standard, it is sufficient to state that the excipient is tested according to the requirements of that standard, rather than reproducing the specifications found in the officially recognized compendial monograph.\n\nIf the standard claimed for an excipient is a non-compendial standard (e.g. in-house standard) or includes tests that are supplementary to those appearing in the officially recognized compendial monograph, a copy of the specification for the excipient should be provided.\n\nFor products submitted to the WHO Prequalification of Medicines Programme, only excipients with an officially recognized pharmacopoeial monograph should be used. Exceptions may be justified.\n\nFor excipients of natural origin, microbial limit testing should be included in the specifications. Skip-testing is acceptable if justified (submission of acceptable results of five production batches).\n\nFor oils of plant origin (e.g. soy bean oil or peanut oil) the absence of aflatoxins or biocides should be demonstrated.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en las especificaciones y controles necesarios para la preparaci\u00f3n farmac\u00e9utica final (FPP) y los excipientes utilizados en su fabricaci\u00f3n. Se discuten aspectos de seguridad, validaci\u00f3n de procesos de esterilizaci\u00f3n, especificaciones de excipientes, y requisitos para la pre-calificaci\u00f3n de medicamentos por parte de la OMS. Se enfatiza la importancia de proporcionar detalles sobre los ciclos de esterilizaci\u00f3n, la validaci\u00f3n de filtros, y las pruebas microbiol\u00f3gicas para excipientes de origen natural.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 justificaciones son necesarias para los ciclos de esterilizaci\u00f3n que no cumplen con los est\u00e1ndares de autoclave convencionales?**\n   - Respuesta: Se deben proporcionar justificaciones detalladas para ciclos de temperatura reducida o ciclos de temperatura elevada con tiempos de exposici\u00f3n acortados, aunque los ciclos est\u00e1ndar de autoclave a 121 \u00b0C por 15 minutos o m\u00e1s no requieren una justificaci\u00f3n detallada.\n\n2. **\u00bfCu\u00e1les son los requisitos espec\u00edficos para los excipientes de origen natural en t\u00e9rminos de pruebas microbiol\u00f3gicas?**\n   - Respuesta: Para los excipientes de origen natural, se debe incluir pruebas de l\u00edmite microbiano en las especificaciones. Se permite el \"skip-testing\" si se justifica, lo que implica la presentaci\u00f3n de resultados aceptables de cinco lotes de producci\u00f3n.\n\n3. **\u00bfQu\u00e9 tipo de est\u00e1ndares se deben utilizar para los excipientes en productos que se someten al Programa de Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Respuesta: Solo se deben utilizar excipientes que cuenten con una monograf\u00eda farmacop\u00e9ica oficialmente reconocida. Se pueden justificar excepciones, pero en general, se requiere el cumplimiento de est\u00e1ndares reconocidos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Par\u00e1metros Cr\u00edticos del Proceso (CPPs)**:\n   - Se mencionan los CPPs que afectan la calidad de los productos farmac\u00e9uticos terminados (FPPs) est\u00e9riles, incluyendo experimentos de desaf\u00edo y modos de falla.\n\n2. **Muestreo**:\n   - Detalles sobre los puntos de muestreo, etapas, m\u00e9todos y planes de muestreo, as\u00ed como esquemas para pruebas de uniformidad del producto final.\n\n3. **Especificaciones de Pruebas**:\n   - Par\u00e1metros de prueba y criterios de aceptaci\u00f3n, incluyendo especificaciones en proceso y de liberaci\u00f3n, as\u00ed como perfiles de disoluci\u00f3n comparativa de lotes de validaci\u00f3n.\n\n4. **Procedimientos Anal\u00edticos**:\n   - Referencias a secciones apropiadas del expediente para los procedimientos anal\u00edticos.\n\n5. **Registro y Evaluaci\u00f3n de Resultados**:\n   - M\u00e9todos para registrar y evaluar los resultados obtenidos durante el proceso.\n\n6. **Condiciones de Fabricaci\u00f3n**:\n   - Importancia de un \u00e1rea de fabricaci\u00f3n controlada y procedimientos est\u00e1ndar para el lavado, tratamiento, esterilizaci\u00f3n y depirogenaci\u00f3n de envases y equipos.\n\n7. **Esterilizaci\u00f3n**:\n   - Proceso cr\u00edtico para eliminar microorganismos, con m\u00e9todos como calor h\u00famedo, calor seco, filtraci\u00f3n, esterilizaci\u00f3n gaseosa y radiaci\u00f3n. Se destaca la preferencia por la esterilizaci\u00f3n por vapor terminal y la necesidad de justificaci\u00f3n cient\u00edfica para m\u00e9todos alternativos.\n\n8. **Documentaci\u00f3n**:\n   - Se requiere una descripci\u00f3n detallada de los procedimientos y condiciones de fabricaci\u00f3n, as\u00ed como copias de los procedimientos operativos est\u00e1ndar.\n\n### Entidades Clave\n- **FPP (Productos Farmac\u00e9uticos Terminados)**: Productos que requieren un proceso de fabricaci\u00f3n controlado y esterilizaci\u00f3n.\n- **CPP (Par\u00e1metros Cr\u00edticos del Proceso)**: Factores que afectan la calidad del FPP.\n- **Esterilizaci\u00f3n**: Proceso esencial en la fabricaci\u00f3n de FPPs parenterales.\n- **M\u00e9todos de Esterilizaci\u00f3n**: Incluyen vapor, calor seco, filtraci\u00f3n, gas (\u00f3xido de etileno) y radiaci\u00f3n.\n\nEste resumen abarca los aspectos fundamentales del proceso de fabricaci\u00f3n de FPPs est\u00e9riles, enfatizando la importancia de los controles de calidad y la justificaci\u00f3n cient\u00edfica en los m\u00e9todos de esterilizaci\u00f3n.", "excerpt_keywords": "Keywords: pharmaceutical preparations, sterilization, excipients, WHO guidelines, microbial testing"}}, "c4f2929b-5ae4-49f3-a021-62602769627f": {"node_ids": ["42908ea9-c178-4b2d-a3d5-691810703759"], "metadata": {"page_label": "189", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "The colours permitted for use are limited to those listed in the \"Japanese pharmaceutical excipients\", the European Union (EU) \"List of permitted food colours\", and the FDA \"Inactive ingredient guide\". For proprietary mixtures, the supplier's product sheet with the qualitative formulation should be submitted, in addition to the FPP manufacturer's specifications for the product, including identification testing.\n\nFor flavours, the qualitative composition should be submitted, as well as a declaration that the excipients comply with foodstuff regulations (e.g. USA or EU regulations).\n\nInformation that is considered confidential may be submitted directly to the WHO Prequalification of Medicines Programme by the supplier who should make reference in the cover letter to the specific related product.\n\nOther certifications of at-risk components may be required on a case-by-case basis.\n\nIf additional purification is undertaken on commercially available excipients, details of the process of purification and modified specifications should be submitted.\n\nReference documents: ICH Q6A (6).\n\n### 3.2.P.4.2 Analytical procedures (name, dosage form)\n\nThe analytical procedures used for testing the excipients should be provided, where appropriate.\n\nCopies of analytical procedures from officially recognized compendial monographs do not need to be submitted.\n\nReference document: ICH Q2 (16).\n\n### 3.2.P.4.3 Validation of analytical procedures (name, dosage form)\n\nAnalytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, where appropriate.\n\nCopies of analytical validation information are generally not submitted for the testing of excipients, with the exception of the validation of in-house methods where appropriate.\n\nReference document: ICH Q2 (16).\n\n### 3.2.P.4.4 Justification of specifications (name, dosage form)\n\nJustification for the proposed excipient specifications should be provided, where appropriate.\n\nA discussion of the tests that are supplementary to those appearing in the officially recognized compendial monograph should be provided.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS establece directrices sobre el uso de excipientes en productos farmac\u00e9uticos, incluyendo colores y sabores permitidos, as\u00ed como los requisitos para la presentaci\u00f3n de informaci\u00f3n anal\u00edtica y validaci\u00f3n de procedimientos. Se menciona que los colores deben estar en listas espec\u00edficas de regulaciones de Jap\u00f3n, la UE y la FDA. Adem\u00e1s, se requiere que los proveedores presenten informaci\u00f3n sobre la composici\u00f3n cualitativa de los excipientes y su conformidad con las regulaciones de alimentos. Tambi\u00e9n se discuten los procedimientos anal\u00edticos y la justificaci\u00f3n de las especificaciones de los excipientes.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son las regulaciones espec\u00edficas que deben seguirse para los colores permitidos en los excipientes seg\u00fan el documento de la OMS?**\n   - Esta pregunta busca una respuesta detallada sobre las listas de colores permitidos y las regulaciones espec\u00edficas mencionadas en el contexto.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la declaraci\u00f3n de conformidad de los excipientes con las regulaciones de alimentos?**\n   - Esta pregunta se centra en los requisitos espec\u00edficos que deben cumplirse para demostrar que los excipientes son conformes a las regulaciones alimentarias, lo cual no se detalla expl\u00edcitamente en el contexto.\n\n3. **\u00bfQu\u00e9 tipo de informaci\u00f3n anal\u00edtica se requiere para la validaci\u00f3n de los procedimientos anal\u00edticos utilizados en la prueba de excipientes?**\n   - Esta pregunta busca aclarar qu\u00e9 datos experimentales o informaci\u00f3n espec\u00edfica se necesita para validar los procedimientos anal\u00edticos, m\u00e1s all\u00e1 de lo que se menciona en el contexto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Seguridad de la Preparaci\u00f3n Farmac\u00e9utica Final (FPP)**:\n   - La seguridad del FPP no se ver\u00e1 afectada por los procesos de esterilizaci\u00f3n si se proporcionan detalles adecuados sobre los ciclos de esterilizaci\u00f3n y el sistema de cierre del contenedor.\n\n2. **Ciclos de Esterilizaci\u00f3n**:\n   - Los ciclos est\u00e1ndar de autoclave (121 \u00b0C por 15 minutos) no requieren justificaci\u00f3n, pero se deben justificar los ciclos de temperatura reducida o elevada con tiempos de exposici\u00f3n acortados.\n   - Si se utiliza \u00f3xido de etileno, se deben controlar los niveles residuales y compuestos relacionados.\n\n3. **Validaci\u00f3n de Filtros**:\n   - Los filtros utilizados deben ser validados en cuanto a tama\u00f1o de poro, compatibilidad con el producto, ausencia de extractables y falta de adsorci\u00f3n del principio activo (API) o componentes.\n\n4. **Procesos Aseptic\u00f3s**:\n   - Para productos parenterales que no pueden ser esterilizados terminalmente, se deben realizar ensayos de simulaci\u00f3n del proceso, llenando contenedores con medios de cultivo y luego incubando.\n\n5. **Control de Excipientes**:\n   - Se deben proporcionar especificaciones para todos los excipientes, incluyendo aquellos que no se a\u00f1aden a cada lote o que no aparecen en el FPP final.\n   - Si un excipiente sigue un est\u00e1ndar compendial reconocido, basta con indicar que se prueba seg\u00fan ese est\u00e1ndar.\n   - Para excipientes de origen natural, se debe incluir pruebas de l\u00edmite microbiano, permitiendo el \"skip-testing\" si se justifica.\n\n6. **Requisitos para la Precalificaci\u00f3n de Medicamentos de la OMS**:\n   - Solo se deben utilizar excipientes con una monograf\u00eda farmacop\u00e9ica oficialmente reconocida, aunque se pueden justificar excepciones.\n\n7. **Pruebas Espec\u00edficas para Excipientes de Origen Vegetal**:\n   - Se debe demostrar la ausencia de aflatoxinas o biocidas en aceites de origen vegetal como el aceite de soya o de cacahuate.\n\n### Entidades Clave\n- **FPP (Preparaci\u00f3n Farmac\u00e9utica Final)**\n- **\u00d3xido de Etileno**\n- **Filtros**\n- **Excipientes**\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**\n- **GMP (Buenas Pr\u00e1cticas de Manufactura)**\n- **ICH (Consejo Internacional de Armonizaci\u00f3n)**\n- **Monograf\u00edas Farmacop\u00e9icas**", "excerpt_keywords": "Keywords: excipients, analytical procedures, validation, food regulations, WHO Prequalification"}}, "b7185212-2620-47e6-af45-3fc1c9eed859": {"node_ids": ["ad1667aa-abd6-4f1b-921f-0206324fb1cb"], "metadata": {"page_label": "190", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.4.5 Excipients of human or animal origin (name, dosage form)\n\nFor excipients of human or animal origin, information should be provided regarding adventitious agents (e.g. sources, specifications, description of the testing performed, viral safety data) (details in 3.2.A.2).\n\nThe following excipients should be addressed in this section: gelatin, phosphates, stearic acid, magnesium stearate and other stearates. If the excipients are of plant origin a declaration to this effect will suffice.\n\nFor excipients of animal origin, a letter of attestation should be provided confirming that the excipients used to manufacture the FPP are without risk of transmitting agents of animal spongiform encephalopathies.\n\nMaterials of animal origin should be avoided whenever possible.\n\nWhen available a CEP demonstrating TSE-compliance should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1.\n\nReference documents: ICH Q5A (43), Q5D (44), Q6B (45), WHO Technical Report Series, No. 908, Annex 1 (46).\n\n# 3.2.P.4.6 Novel excipients (name, dosage form)\n\nFor excipient(s) used for the first time in an FPP or by a new route of administration, full details of manufacture, characterization, and controls, with cross-references to supporting safety data (non-clinical and/or clinical) should be provided according to the API and/or FPP format (details in 3.2.A.3).\n\nNovel excipients are not accepted in the WHO Prequalification of Medicines Programme. For the purpose of these guidelines, a novel excipient is one that has not been used (at a similar level and by the same route of administration) in a product approved by an SRA or by WHO.\n\n# 3.2.P.5 Control of FPP (name, dosage form)\n\n## 3.2.P.5.1 Specification(s) (name, dosage form)\n\nThe specification(s) for the FPP should be provided.\n\nAs defined in ICH\u2019s Q6A guideline, a specification is:\n\n> \u201ca list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. \u201cConformance to specifications\u201d means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.\u201d", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS aborda la regulaci\u00f3n de excipientes en productos farmac\u00e9uticos, centr\u00e1ndose en aquellos de origen humano o animal. Se requiere informaci\u00f3n sobre agentes adventicios, especificaciones y seguridad viral para excipientes de origen animal. Se enfatiza la necesidad de evitar materiales de origen animal siempre que sea posible y se establece que los excipientes novedosos no son aceptados en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS. Adem\u00e1s, se definen las especificaciones para los productos farmac\u00e9uticos, que son criterios cr\u00edticos aprobados por las autoridades regulatorias.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de documentaci\u00f3n se requiere para excipientes de origen animal en la fabricaci\u00f3n de productos farmac\u00e9uticos?**\n   - Se requiere una carta de atestaci\u00f3n que confirme que los excipientes utilizados no representan un riesgo de transmisi\u00f3n de agentes de encefalopat\u00edas espongiformes animales. Adem\u00e1s, se debe proporcionar un Certificado de Excipiente (CEP) que demuestre el cumplimiento de TSE, si est\u00e1 disponible.\n\n2. **\u00bfCu\u00e1les son los excipientes espec\u00edficos que deben ser abordados en la secci\u00f3n sobre excipientes de origen humano o animal?**\n   - Los excipientes que deben ser abordados incluyen gelatina, fosfatos, \u00e1cido estearico, estearato de magnesio y otros estearatos. Si los excipientes son de origen vegetal, solo se requiere una declaraci\u00f3n al respecto.\n\n3. **\u00bfQu\u00e9 se entiende por un excipiente novedoso seg\u00fan las directrices de la OMS y cu\u00e1l es su estatus en el Programa de Precalificaci\u00f3n de Medicamentos?**\n   - Un excipiente novedoso es aquel que no ha sido utilizado en un producto aprobado por una Autoridad Reguladora de SRA o por la OMS, a un nivel similar y por la misma v\u00eda de administraci\u00f3n. Estos excipientes no son aceptados en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Colores Permitidos**:\n   - Los colores utilizados en excipientes deben estar en las listas de:\n     - Excipientes farmac\u00e9uticos japoneses.\n     - Lista de colores alimentarios permitidos de la Uni\u00f3n Europea (UE).\n     - Gu\u00eda de ingredientes inactivos de la FDA.\n\n2. **Informaci\u00f3n de Proveedores**:\n   - Para mezclas propietarias, se requiere la hoja de producto del proveedor con la formulaci\u00f3n cualitativa y las especificaciones del fabricante del producto (FPP), incluyendo pruebas de identificaci\u00f3n.\n\n3. **Sabores**:\n   - Se debe presentar la composici\u00f3n cualitativa de los sabores y una declaraci\u00f3n de conformidad con las regulaciones alimentarias (por ejemplo, regulaciones de EE. UU. o UE).\n\n4. **Confidencialidad**:\n   - La informaci\u00f3n confidencial puede ser enviada directamente al Programa de Precalificaci\u00f3n de Medicamentos de la OMS, mencionando el producto relacionado en la carta de presentaci\u00f3n.\n\n5. **Certificaciones Adicionales**:\n   - Pueden ser requeridas certificaciones de componentes en riesgo seg\u00fan el caso.\n\n6. **Purificaci\u00f3n de Excipientes**:\n   - Si se realiza una purificaci\u00f3n adicional en excipientes comercialmente disponibles, se deben presentar detalles del proceso y especificaciones modificadas.\n\n7. **Procedimientos Anal\u00edticos**:\n   - Se deben proporcionar los procedimientos anal\u00edticos utilizados para probar los excipientes, aunque no es necesario enviar copias de procedimientos de monograf\u00edas compendiales reconocidas.\n\n8. **Validaci\u00f3n de Procedimientos Anal\u00edticos**:\n   - Se requiere informaci\u00f3n de validaci\u00f3n anal\u00edtica, incluyendo datos experimentales, para los procedimientos anal\u00edticos utilizados, excepto para m\u00e9todos in-house donde sea apropiado.\n\n9. **Justificaci\u00f3n de Especificaciones**:\n   - Se debe proporcionar una justificaci\u00f3n para las especificaciones propuestas de los excipientes, incluyendo una discusi\u00f3n sobre pruebas adicionales a las de las monograf\u00edas compendiales reconocidas.\n\n### Entidades Clave\n- **Organismos Reguladores**: OMS, FDA, UE.\n- **Documentos de Referencia**: ICH Q6A, ICH Q2.\n- **Tipos de Excipientes**: Colores, sabores, mezclas propietarias.\n- **Requisitos de Presentaci\u00f3n**: Hojas de producto, declaraciones de conformidad, detalles de purificaci\u00f3n.", "excerpt_keywords": "Keywords: excipients, animal origin, viral safety, specifications, WHO Prequalification"}}, "a3b9312e-b4fb-4150-a97c-7e00feeff40f": {"node_ids": ["97d69c8d-d099-43f6-9779-cc9d8efb8beb"], "metadata": {"page_label": "191", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "A copy of the FPP specification(s) from the applicant (as well as the company responsible for the batch release of the FPP, if different from the applicant), dated and signed by authorized personnel (i.e. the person in charge of the quality control or quality assurance department) should be provided in the PD. Two separate sets of specifications may be set out: after packaging of the FPP (release) and at the end of the shelf-life.\n\nThe specifications should be summarized according to the tables in the QOS-PD template including the tests, acceptance criteria and analytical procedures (listing types, sources and versions for the methods).\n\n- The standard declared by the applicant could be an officially recognized compendial standard (e.g. BP, JP, Ph.Eur., Ph.Int., USP) or an in-house (manufacturer\u2019s) standard.\n- The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes.\n- For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV or HPLC); the source refers to the origin of the analytical procedure (e.g. BP, JP, Ph.Eur., Ph.Int., USP, in-house) and the version (e.g. code number/version/date) should be provided for version control purposes.\n\nICH\u2019s Q6A guideline outlines recommendations for a number of universal and specific tests and criteria for FPPs. Specifications should include, at a minimum, tests for appearance, identification, assay, purity, performance tests (e.g. dissolution), physical tests (e.g. loss on drying, hardness, friability and particle size), uniformity of dosage units, and, as applicable, identification and assay of antimicrobial or chemical preservatives (e.g. antioxidants) and microbial limit tests.\n\nThe following information provides guidance on specific tests that are not addressed by ICH\u2019s Q6A guideline:\n\n- fixed-dose combination FPPs (FDC-FPPs):\n  - analytical methods that can distinguish each API in the presence of the other API(s) should be developed and validated,\n  - acceptance criteria for degradation products should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, its acceptance limits should in general be calculated with reference to the worst case (the API with the smaller area under the curve). Alternatively the content of such impurities could be calculated in relation to their reference standards.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas:\n\n1. **\u00bfQu\u00e9 tipo de est\u00e1ndares pueden ser declarados por el solicitante en las especificaciones del FPP?**\n   - El solicitante puede declarar un est\u00e1ndar oficialmente reconocido, como los compendios BP, JP, Ph.Eur., Ph.Int. o un est\u00e1ndar interno (de fabricante).\n\n2. **\u00bfCu\u00e1les son los requisitos m\u00ednimos de pruebas que deben incluirse en las especificaciones de un FPP seg\u00fan la gu\u00eda Q6A de ICH?**\n   - Las especificaciones deben incluir, como m\u00ednimo, pruebas para apariencia, identificaci\u00f3n, ensayo, pureza, pruebas de rendimiento (como disoluci\u00f3n), pruebas f\u00edsicas (como p\u00e9rdida por secado, dureza, friabilidad y tama\u00f1o de part\u00edcula), uniformidad de unidades de dosificaci\u00f3n, y, si corresponde, identificaci\u00f3n y ensayo de conservantes antimicrobianos o qu\u00edmicos y pruebas de l\u00edmite microbiano.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al establecer criterios de aceptaci\u00f3n para productos de degradaci\u00f3n en FDC-FPPs?**\n   - Los criterios de aceptaci\u00f3n para productos de degradaci\u00f3n deben establecerse con referencia al API del cual se derivan. Si una impureza resulta de una reacci\u00f3n qu\u00edmica entre dos o m\u00e1s APIs, sus l\u00edmites de aceptaci\u00f3n generalmente deben calcularse en relaci\u00f3n con el peor caso (el API con el \u00e1rea bajo la curva m\u00e1s peque\u00f1a). Alternativamente, el contenido de tales impurezas podr\u00eda calcularse en relaci\u00f3n con sus est\u00e1ndares de referencia.\n\n### Resumen de nivel superior del contexto:\nEl documento proporciona directrices sobre las especificaciones de productos farmac\u00e9uticos terminados (FPP) que deben ser presentadas por los solicitantes. Se requiere que las especificaciones sean firmadas por personal autorizado y que incluyan dos conjuntos de especificaciones: uno para el momento de la liberaci\u00f3n y otro para el final de la vida \u00fatil. Las especificaciones deben resumirse en tablas que incluyan pruebas, criterios de aceptaci\u00f3n y procedimientos anal\u00edticos, y deben cumplir con las recomendaciones de la gu\u00eda Q6A de ICH, que detalla pruebas m\u00ednimas necesarias y consideraciones espec\u00edficas para combinaciones de dosis fijas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Excipientes de Origen Humano o Animal**:\n   - Se requiere informaci\u00f3n sobre agentes adventicios, especificaciones, pruebas realizadas y datos de seguridad viral.\n   - Excipientes espec\u00edficos a abordar: gelatina, fosfatos, \u00e1cido estearico, estearato de magnesio y otros estearatos.\n   - Para excipientes de origen animal, se necesita una carta de atestaci\u00f3n sobre el riesgo de encefalopat\u00edas espongiformes.\n\n2. **Evitar Materiales de Origen Animal**:\n   - Se recomienda evitar el uso de materiales de origen animal siempre que sea posible.\n\n3. **Certificado de Excipiente (CEP)**:\n   - Se debe proporcionar un CEP que demuestre el cumplimiento de TSE, si est\u00e1 disponible.\n\n4. **Excipientes Novedosos**:\n   - Definici\u00f3n: Excipientes utilizados por primera vez en un FPP o por una nueva v\u00eda de administraci\u00f3n.\n   - No son aceptados en el Programa de Precalificaci\u00f3n de Medicamentos de la OMS.\n   - Se requiere informaci\u00f3n completa sobre fabricaci\u00f3n, caracterizaci\u00f3n y controles, junto con datos de seguridad.\n\n5. **Control de FPP**:\n   - Se deben proporcionar especificaciones para el FPP, que incluyen pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n.\n   - Las especificaciones son est\u00e1ndares de calidad cr\u00edticos aprobados por autoridades regulatorias.\n\n### Entidades Clave\n- **Excipientes**: Gelatina, fosfatos, \u00e1cido estearico, estearato de magnesio.\n- **Documentos de Referencia**: ICH Q5A, Q5D, Q6B, WHO Technical Report Series, No. 908.\n- **Programas**: Programa de Precalificaci\u00f3n de Medicamentos de la OMS.\n- **Certificaci\u00f3n**: Certificado de Excipiente (CEP), carta de atestaci\u00f3n.", "excerpt_keywords": "Keywords: FPP specifications, quality control, ICH Q6A, analytical procedures, fixed-dose combination"}}, "12a0ec0a-d943-484f-8400-b221d1cc86eb": {"node_ids": ["8aa6bd23-bceb-48d7-8388-588d0299feaa"], "metadata": {"page_label": "192", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- A test and limit for content uniformity is required for each API present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit.\n- For the API(s) present at \u2265 5 mg and \u2265 5% of the weight of the dosage unit, a test and limit for weight variation may be established in lieu of content uniformity testing.\n\n- **Modified-release products**: A meaningful API release method.\n- **Inhalation and nasal products**: Consistency of delivered dose (throughout the use of the product), particle or droplet size distribution profiles (comparable to the product used in in vivo studies where applicable) and if applicable for the dosage form, moisture content, leak rate, microbial limits, preservative assay, sterility and weight loss.\n- **Suppositories**: Uniformity of dosage units, melting point.\n- **Transdermal dosage forms**: Peel or shear force, mean weight per unit area and dissolution.\n\nUnless there is appropriate justification, the acceptable limit for the API content of the FPP in the release specifications is \u00b1 5% of the label claim (i.e. 95.0\u2013105.0%).\n\nFor products such as tablets, capsules and suppositories where a test for uniformity of single-dose preparations is required, a test and limit for content uniformity is required when the API is present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit. Otherwise, the test for mass uniformity may be applied.\n\nSkip-testing is acceptable for parameters such as identification of colouring materials and microbial limits, when justified by the submission of acceptable supportive results for five production batches. When justification for skip-testing has been accepted the specifications should include a footnote, stating, at a minimum, the following skip-testing requirements: at least every tenth batch and at least one batch annually is tested. In addition, for stability-indicating parameters such as microbial limits, testing will be performed at release and at the end of shelf-life during stability studies.\n\nAny differences between release and shelf-life tests and acceptance criteria should be clearly indicated and justified. Note that such differences for parameters such as dissolution are normally not accepted.\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior:\nEl documento de la OMS establece directrices sobre las especificaciones para preparaciones farmac\u00e9uticas, enfoc\u00e1ndose en la uniformidad del contenido y variaciones de peso de los ingredientes activos (API) en productos farmac\u00e9uticos. Se detallan pruebas espec\u00edficas para diferentes formas de dosificaci\u00f3n, como productos de liberaci\u00f3n modificada, inhalaci\u00f3n, supositorios y formas transd\u00e9rmicas. Tambi\u00e9n se menciona la aceptaci\u00f3n de pruebas de omisi\u00f3n bajo ciertas condiciones y la necesidad de justificar cualquier diferencia entre las pruebas de liberaci\u00f3n y las de vida \u00fatil.\n\n### Preguntas Espec\u00edficas:\n\n1. **\u00bfQu\u00e9 criterios se deben cumplir para establecer un l\u00edmite de variaci\u00f3n de peso en lugar de una prueba de uniformidad de contenido para los API en productos farmac\u00e9uticos?**\n   - Respuesta: Un l\u00edmite de variaci\u00f3n de peso puede establecerse en lugar de una prueba de uniformidad de contenido si el API est\u00e1 presente en cantidades de \u2265 5 mg y \u2265 5% del peso de la unidad de dosificaci\u00f3n.\n\n2. **\u00bfCu\u00e1les son los requisitos de prueba para productos de inhalaci\u00f3n y nasales seg\u00fan el documento?**\n   - Respuesta: Para productos de inhalaci\u00f3n y nasales, se requiere consistencia en la dosis entregada, perfiles de distribuci\u00f3n del tama\u00f1o de part\u00edculas o gotas, y, si es aplicable, contenido de humedad, tasa de fuga, l\u00edmites microbianos, ensayo de conservantes, esterilidad y p\u00e9rdida de peso.\n\n3. **\u00bfQu\u00e9 condiciones justifican la aceptaci\u00f3n de pruebas de omisi\u00f3n para par\u00e1metros como la identificaci\u00f3n de materiales colorantes y l\u00edmites microbianos?**\n   - Respuesta: Las pruebas de omisi\u00f3n son aceptables si se presenta una justificaci\u00f3n mediante resultados de apoyo aceptables de cinco lotes de producci\u00f3n. Adem\u00e1s, las especificaciones deben incluir una nota al pie que indique que al menos cada d\u00e9cimo lote y al menos un lote anualmente ser\u00e1n probados.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Especificaciones de Productos Farmac\u00e9uticos Terminados (FPP)**:\n   - Se requiere una copia de las especificaciones del FPP firmada y fechada por personal autorizado.\n   - Deben presentarse dos conjuntos de especificaciones: uno para el momento de liberaci\u00f3n y otro para el final de la vida \u00fatil.\n\n2. **Est\u00e1ndares**:\n   - Los est\u00e1ndares pueden ser compendiales (BP, JP, Ph.Eur., Ph.Int., USP) o internos (de fabricante).\n   - Se debe proporcionar el n\u00famero de referencia y la versi\u00f3n de las especificaciones para control de versiones.\n\n3. **Procedimientos Anal\u00edticos**:\n   - Los procedimientos deben indicar el tipo (visual, IR, UV, HPLC), la fuente (compendios o internos) y la versi\u00f3n para control de versiones.\n\n4. **Gu\u00eda ICH Q6A**:\n   - Establece recomendaciones para pruebas y criterios m\u00ednimos que deben incluirse en las especificaciones de FPP.\n   - Pruebas m\u00ednimas incluyen: apariencia, identificaci\u00f3n, ensayo, pureza, pruebas de rendimiento (disoluci\u00f3n), pruebas f\u00edsicas (p\u00e9rdida por secado, dureza, friabilidad, tama\u00f1o de part\u00edcula), uniformidad de unidades de dosificaci\u00f3n, y pruebas de conservantes antimicrobianos o qu\u00edmicos.\n\n5. **Combinaciones de Dosis Fijas (FDC-FPPs)**:\n   - Se deben desarrollar y validar m\u00e9todos anal\u00edticos que distingan cada API en presencia de otros APIs.\n   - Los criterios de aceptaci\u00f3n para productos de degradaci\u00f3n deben establecerse en relaci\u00f3n con el API del cual derivan, considerando el peor caso en caso de impurezas resultantes de reacciones entre APIs.\n\n### Entidades Clave\n- **FPP (Producto Farmac\u00e9utico Terminado)**\n- **Est\u00e1ndares Compendiales**: BP, JP, Ph.Eur., Ph.Int., USP\n- **Gu\u00eda ICH Q6A**\n- **API (Ingrediente Activo)**\n- **Personal Autorizado**: Responsable de control de calidad o aseguramiento de calidad. \n\nEste resumen destaca los aspectos esenciales relacionados con la presentaci\u00f3n de especificaciones para productos farmac\u00e9uticos, los est\u00e1ndares aplicables, los procedimientos anal\u00edticos requeridos y las consideraciones espec\u00edficas para combinaciones de dosis fijas.", "excerpt_keywords": "Keywords: pharmaceutical preparations, content uniformity, active pharmaceutical ingredient, testing specifications, skip-testing"}}, "e41b0a82-7760-44a4-9324-9066fd11abec": {"node_ids": ["5e5c765a-94b3-401f-ab44-47daeba41cbd"], "metadata": {"page_label": "193", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.5.2 Analytical procedures (name, dosage form)\n\n**The analytical procedures used for testing the FPP should be provided.**\n\nCopies of the in-house analytical procedures used during pharmaceutical development (if used to generate testing results provided in the PD) as well as those proposed for routine testing should be provided. Unless modified it is not necessary to provide copies of analytical procedures described in officially recognized compendia.\n\nTables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.\n\nRefer to section 3.2.S.4.2 of these guidelines for additional guidance on analytical procedures.\n\nReference document: ICH Q2 (16).\n\n# 3.2.P.5.3 Validation of analytical procedures (name, dosage form)\n\n**Analytical validation information, including experimental data, for the analytical procedures used for testing the FPP, should be provided.**\n\nCopies of the validation reports for the in-house analytical procedures used during pharmaceutical development (if used to support testing results provided in the PD) as well as those proposed for routine testing should be provided.\n\nTables for summarizing a number of the different analytical procedures and validation information (e.g. HPLC assay and impurity methods, and GC methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.\n\nAs recognized by regulatory authorities and pharmacopoeias themselves, verification of compendial methods can be necessary. The compendial methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. The same API or FPP obtained from different sources can contain impurities and/or degradation products or excipients that were not considered during the development of the monograph. Therefore, the monograph and compendial method(s) should be demonstrated suitable for the control of the proposed FPP.\n\nFor officially recognized compendial FPP assay methods, verification should include a demonstration of specificity, accuracy and repeatability (method precision). If an officially recognized compendial method is used to control related substances that are not specified in the monograph, full validation of the method is expected with respect to those related substances.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla los procedimientos anal\u00edticos y la validaci\u00f3n de estos procedimientos para la prueba de productos farmac\u00e9uticos terminados (FPP). Se enfatiza la importancia de proporcionar copias de los procedimientos anal\u00edticos utilizados durante el desarrollo farmac\u00e9utico y aquellos propuestos para pruebas rutinarias. Adem\u00e1s, se menciona que, aunque no es necesario proporcionar procedimientos descritos en compendios reconocidos oficialmente, se deben incluir tablas para resumir la informaci\u00f3n anal\u00edtica y de validaci\u00f3n. Tambi\u00e9n se destaca la necesidad de verificar m\u00e9todos compendiales, especialmente cuando se utilizan para controlar sustancias relacionadas no especificadas en la monograf\u00eda.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 tipo de informaci\u00f3n se debe incluir en las tablas para resumir los procedimientos anal\u00edticos y la validaci\u00f3n de estos?**\n   - Las tablas deben resumir los procedimientos anal\u00edticos utilizados para la determinaci\u00f3n del ensayo, sustancias relacionadas y disoluci\u00f3n del FPP, as\u00ed como la informaci\u00f3n de validaci\u00f3n correspondiente, como m\u00e9todos de HPLC y GC.\n\n2. **\u00bfPor qu\u00e9 es importante verificar los m\u00e9todos compendiales utilizados para el control de FPP?**\n   - Es importante porque los m\u00e9todos compendiales pueden estar validados con base en un API o FPP de un fabricante espec\u00edfico, y el mismo API o FPP de diferentes fuentes puede contener impurezas o productos de degradaci\u00f3n no considerados en la monograf\u00eda original.\n\n3. **\u00bfQu\u00e9 aspectos deben demostrarse al verificar m\u00e9todos de ensayo compendiales oficialmente reconocidos?**\n   - Se debe demostrar la especificidad, precisi\u00f3n (repetibilidad) y exactitud del m\u00e9todo. Si se utiliza un m\u00e9todo compendial para controlar sustancias relacionadas no especificadas en la monograf\u00eda, se espera una validaci\u00f3n completa del m\u00e9todo respecto a esas sustancias.", "prev_section_summary": "### Temas Clave:\n\n1. **Uniformidad de Contenido y Variaci\u00f3n de Peso**:\n   - Se requiere una prueba de uniformidad de contenido para cada ingrediente activo (API) presente en la forma farmac\u00e9utica final (FPP) si est\u00e1 en cantidades de menos de 5 mg o menos del 5% del peso de la unidad de dosificaci\u00f3n.\n   - Para API presentes en cantidades de \u2265 5 mg y \u2265 5% del peso de la unidad de dosificaci\u00f3n, se puede establecer un l\u00edmite de variaci\u00f3n de peso en lugar de realizar una prueba de uniformidad de contenido.\n\n2. **Requisitos Espec\u00edficos para Diferentes Formas de Dosificaci\u00f3n**:\n   - **Productos de Liberaci\u00f3n Modificada**: M\u00e9todo significativo de liberaci\u00f3n del API.\n   - **Productos de Inhalaci\u00f3n y Nasales**: Consistencia en la dosis entregada, distribuci\u00f3n del tama\u00f1o de part\u00edculas o gotas, y otros par\u00e1metros como contenido de humedad y l\u00edmites microbianos.\n   - **Supositorios**: Uniformidad de las unidades de dosificaci\u00f3n y punto de fusi\u00f3n.\n   - **Formas Transd\u00e9rmicas**: Fuerza de pelado o corte, peso medio por unidad de \u00e1rea y disoluci\u00f3n.\n\n3. **L\u00edmites de Contenido del API**:\n   - El l\u00edmite aceptable para el contenido del API en las especificaciones de liberaci\u00f3n es \u00b1 5% de la declaraci\u00f3n en la etiqueta (95.0\u2013105.0%).\n\n4. **Pruebas de Omissi\u00f3n**:\n   - Se aceptan pruebas de omisi\u00f3n para ciertos par\u00e1metros si se justifica con resultados de cinco lotes de producci\u00f3n. Las especificaciones deben incluir requisitos claros sobre la frecuencia de las pruebas.\n\n5. **Diferencias entre Pruebas de Liberaci\u00f3n y Vida \u00datil**:\n   - Cualquier diferencia entre las pruebas de liberaci\u00f3n y las de vida \u00fatil debe ser claramente indicada y justificada, especialmente para par\u00e1metros como la disoluci\u00f3n.\n\n### Entidades:\n\n- **Organizaci\u00f3n**: Organizaci\u00f3n Mundial de la Salud (OMS)\n- **Documentos de Referencia**: ICH Q3B, Q3C, Q6A\n- **Formas Farmac\u00e9uticas**: FPP, productos de liberaci\u00f3n modificada, productos de inhalaci\u00f3n, supositorios, formas transd\u00e9rmicas.\n- **Par\u00e1metros de Prueba**: Uniformidad de contenido, variaci\u00f3n de peso, consistencia de dosis, distribuci\u00f3n de tama\u00f1o de part\u00edculas, l\u00edmites microbianos, pruebas de omisi\u00f3n. \n\nEste resumen abarca los aspectos esenciales del documento, destacando las directrices sobre las especificaciones para preparaciones farmac\u00e9uticas y los requisitos de prueba para diferentes formas de dosificaci\u00f3n.", "excerpt_keywords": "Keywords: analytical procedures, validation, pharmaceutical development, compendial methods, FPP testing"}}, "033a8462-0e8a-496a-9197-3aa5b0140c6a": {"node_ids": ["b7c512d7-9408-4eee-8637-818ce85dbf5d"], "metadata": {"page_label": "194", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nIf an officially recognized compendial standard is claimed and an in-house method is used in lieu of the compendial method (e.g. for assay or for related compounds), equivalence of the in-house and compendial methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For methods for the determination of related compounds, the sample analysed should be the placebo spiked with related compounds at concentrations equivalent to their specification limits.\n\nReference document: ICH Q2 (16).\n\n## 3.2.P5.4 Batch analyses (name, dosage form)\n\nA description of batches and results of batch analyses should be provided.\n\nInformation on relevant FPP batches used to establish the specifications and evaluate consistency in manufacturing should be provided and should include strength and batch number, batch size, date and site of production and use (e.g. used in comparative bioavailability or biowaiver studies, preclinical and clinical studies (if relevant), stability, pilot, scale-up and, if available, production-scale batches).\n\nAnalytical results generated by the company responsible for the batch release of the FPP (generally the applicant or the FPP manufacturer, if different from the applicant) should be provided for not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions), or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nThe results should include those of tests on the batch(es) used in the comparative bioavailability or biowaiver studies. Copies of the certificates of analysis for these batches should be provided in the PD and the company responsible for generating the testing results should be identified.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. The discussion should include ranges of analytical results, where relevant. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than...\n\n----\n\n*The term \u201ccomplicated FPP\u201d includes sterile products, metered dose inhaler products, dry powder inhaler products and transdermal delivery systems. Other specific products under \u201ccomplicated FPP\u201d include ritonavir/lopinavir FDC tablets and FDCs containing rifampicin or an artemisinin. As the invitations for EOI change over time, the listing of individual \u201ccomplicated FPPs\u201d is not meaningful and applicants should contact the Head of Assessments, WHO Prequalification of Medicines Programme in case of doubt.*", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS se centra en las especificaciones para preparaciones farmac\u00e9uticas y establece directrices sobre c\u00f3mo demostrar la equivalencia entre m\u00e9todos anal\u00edticos in-house y compendiales. Tambi\u00e9n detalla los requisitos para el an\u00e1lisis de lotes, incluyendo la informaci\u00f3n necesaria sobre los lotes de productos farmac\u00e9uticos terminados (FPP) y la importancia de proporcionar resultados anal\u00edticos y certificados de an\u00e1lisis. Se menciona la distinci\u00f3n entre FPP sencillos y complicados, as\u00ed como la necesidad de un enfoque detallado en la discusi\u00f3n de resultados anal\u00edticos.\n\n### Preguntas Espec\u00edficas\n1. **\u00bfQu\u00e9 pasos deben seguirse para demostrar la equivalencia entre un m\u00e9todo anal\u00edtico in-house y un m\u00e9todo compendial?**\n   - El contexto menciona que se debe realizar un an\u00e1lisis duplicado de una muestra utilizando ambos m\u00e9todos y proporcionar los resultados del estudio, as\u00ed como utilizar un placebo spiked con compuestos relacionados en concentraciones equivalentes a sus l\u00edmites de especificaci\u00f3n.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la descripci\u00f3n de los lotes de productos farmac\u00e9uticos terminados (FPP) para cumplir con las especificaciones de la OMS?**\n   - La descripci\u00f3n debe incluir la fuerza y el n\u00famero de lote, el tama\u00f1o del lote, la fecha y el sitio de producci\u00f3n, y el uso del lote en estudios de bioequivalencia, estudios cl\u00ednicos, estabilidad, entre otros.\n\n3. **\u00bfCu\u00e1ntos lotes de FPP deben analizarse y qu\u00e9 criterios deben cumplirse para los an\u00e1lisis de lotes en el caso de FPP sencillos y complicados?**\n   - Para FPP sencillos, se debe proporcionar al menos un lote de escala piloto y un segundo lote que puede ser m\u00e1s peque\u00f1o. Para FPP complicados, se deben proporcionar resultados de al menos dos lotes de escala piloto. Adem\u00e1s, los lotes deben ser representativos del proceso que se aplicar\u00e1 a un lote de producci\u00f3n a gran escala.", "prev_section_summary": "### Temas Clave\n\n1. **Procedimientos Anal\u00edticos**: Se requiere proporcionar copias de los procedimientos anal\u00edticos utilizados para la prueba de productos farmac\u00e9uticos terminados (FPP), tanto los desarrollados internamente como los propuestos para pruebas rutinarias. No es necesario incluir procedimientos de compendios reconocidos, a menos que se hayan modificado.\n\n2. **Tablas de Resumen**: Se deben utilizar tablas para resumir los procedimientos anal\u00edticos y la informaci\u00f3n de validaci\u00f3n, incluyendo m\u00e9todos como HPLC y GC, para la determinaci\u00f3n del ensayo, sustancias relacionadas y disoluci\u00f3n del FPP.\n\n3. **Validaci\u00f3n de Procedimientos Anal\u00edticos**: Es esencial proporcionar informaci\u00f3n de validaci\u00f3n anal\u00edtica, incluyendo datos experimentales y copias de los informes de validaci\u00f3n para los procedimientos anal\u00edticos utilizados.\n\n4. **Verificaci\u00f3n de M\u00e9todos Compendiales**: Se destaca la necesidad de verificar los m\u00e9todos compendiales, ya que pueden no ser adecuados para FPP de diferentes fuentes debido a impurezas o productos de degradaci\u00f3n no considerados en la monograf\u00eda original.\n\n5. **Aspectos de Verificaci\u00f3n**: Para los m\u00e9todos de ensayo compendiales reconocidos oficialmente, se debe demostrar especificidad, precisi\u00f3n y exactitud. Si se utilizan para controlar sustancias no especificadas en la monograf\u00eda, se requiere una validaci\u00f3n completa.\n\n### Entidades\n\n- **FPP (Productos Farmac\u00e9uticos Terminados)**: El objeto de las pruebas y procedimientos anal\u00edticos.\n- **HPLC (Cromatograf\u00eda L\u00edquida de Alta Eficiencia)**: Un m\u00e9todo anal\u00edtico mencionado para la determinaci\u00f3n de ensayos y sustancias relacionadas.\n- **GC (Cromatograf\u00eda de Gases)**: Otro m\u00e9todo anal\u00edtico mencionado para la validaci\u00f3n.\n- **ICH Q2**: Documento de referencia mencionado para guiar los procedimientos anal\u00edticos y su validaci\u00f3n.\n- **Compendios Reconocidos**: Fuentes oficiales que describen m\u00e9todos anal\u00edticos que pueden no requerir validaci\u00f3n adicional si no se modifican.\n\nEste resumen abarca los aspectos fundamentales y las entidades relevantes en la secci\u00f3n proporcionada del documento de la OMS.", "excerpt_keywords": "Keywords: pharmaceutical preparations, compendial methods, batch analyses, bioequivalence, analytical results"}}, "6950dd7e-50e1-4a20-a736-b1ec18fc0dc9": {"node_ids": ["8a07a5c3-048e-4dd9-b7fe-b5aca023d606"], "metadata": {"page_label": "195", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\nthan vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d (e.g. \u201clevels of degradation product A ranged from 0.2 to 0.4%\u201d). Dissolution results should be expressed, at a minimum, as both the average and the range of individual results. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.\n\nA discussion and justification should be provided for any incomplete analyses (e.g. for any parameters not tested according to the proposed specification).\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).\n\n## 3.2.P.5.5 Characterization of impurities (name, dosage form)\n\n**Information on the characterization of impurities should be provided, if not previously provided in \u201c3.2.S.3.2 Impurities\u201d.**\n\nA discussion should be provided of all impurities that are potential degradation products (including those among the impurities identified in 3.2.S.3.2 as well as potential degradation products resulting from interaction of the API with other APIs (FDCs), excipients or the container-closure system) and FPP process-related impurities (e.g. residual solvents in the manufacturing process for the FPP).\n\nReference documents: ICH Q3B (11), Q3C (12), Q6A (6).\n\n## 3.2.P.5.6 Justification of specification(s) (name, dosage form)\n\n**Justification for the proposed FPP specification(s) should be provided.**\n\nA discussion should be provided on the omission or inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendial standard(s). If the officially recognized compendial methods have been modified or replaced, a discussion should be included.\n\nThe justification for certain tests, analytical procedures and acceptance criteria (e.g. degradation products or dissolution method development) may have been discussed in other sections of the PD and would not need to be repeated here, although a cross-reference should be provided.\n\nICH Q6A (6) should be consulted for the development of specifications for FPPs.\n\n## 3.2.P.6 Reference standards or materials (name, dosage form)\n\n**Information on the reference standards or reference materials used for testing of the FPP should be provided, if not previously provided in \u201c3.2.S.5 Reference standards or materials\u201d.**\n\nSee section 3.2.S.5 for information that should be provided on reference standards or materials. Information should be provided on reference materials of FPP degradation products, where not included in 3.2.S.5.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con respuestas espec\u00edficas que probablemente no se encuentren en otro lugar:\n\n### Preguntas y Respuestas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n se debe incluir en la caracterizaci\u00f3n de impurezas seg\u00fan la secci\u00f3n 3.2.P.5.5?**\n   - La caracterizaci\u00f3n de impurezas debe incluir una discusi\u00f3n sobre todas las impurezas que son productos de degradaci\u00f3n potenciales, incluyendo aquellas identificadas en la secci\u00f3n 3.2.S.3.2 y los productos de degradaci\u00f3n resultantes de la interacci\u00f3n del principio activo (API) con otros APIs, excipientes o el sistema de cierre del envase. Tambi\u00e9n se deben considerar las impurezas relacionadas con el proceso de fabricaci\u00f3n del producto farmac\u00e9utico terminado (FPP), como los solventes residuales.\n\n2. **\u00bfQu\u00e9 justificaci\u00f3n se requiere para las especificaciones propuestas en la secci\u00f3n 3.2.P.5.6?**\n   - Se debe proporcionar una discusi\u00f3n sobre la omisi\u00f3n o inclusi\u00f3n de ciertas pruebas, la evoluci\u00f3n de las pruebas, los procedimientos anal\u00edticos y los criterios de aceptaci\u00f3n, as\u00ed como las diferencias con respecto a los est\u00e1ndares oficialmente reconocidos. Si se han modificado o reemplazado m\u00e9todos compendiales reconocidos, tambi\u00e9n se debe incluir una discusi\u00f3n sobre ello. Adem\u00e1s, se puede hacer referencia a justificaciones discutidas en otras secciones del documento.\n\n3. **\u00bfQu\u00e9 tipo de informaci\u00f3n se debe proporcionar sobre los est\u00e1ndares o materiales de referencia en la secci\u00f3n 3.2.P.6?**\n   - Se debe proporcionar informaci\u00f3n sobre los est\u00e1ndares de referencia o materiales de referencia utilizados para las pruebas del FPP, si no se ha proporcionado previamente en la secci\u00f3n 3.2.S.5. Esto incluye informaci\u00f3n sobre materiales de referencia de los productos de degradaci\u00f3n del FPP que no est\u00e9n incluidos en la secci\u00f3n 3.2.S.5.\n\n### Resumen de Nivel Superior\n\nEl contexto se centra en las directrices de la OMS sobre la caracterizaci\u00f3n de impurezas y la justificaci\u00f3n de especificaciones en productos farmac\u00e9uticos. Se enfatiza la importancia de proporcionar informaci\u00f3n detallada sobre las impurezas, los m\u00e9todos de prueba y los est\u00e1ndares de referencia. Las secciones mencionadas abordan la necesidad de una discusi\u00f3n clara y justificada sobre los an\u00e1lisis realizados, as\u00ed como la inclusi\u00f3n de datos espec\u00edficos sobre productos de degradaci\u00f3n y su impacto en la calidad del producto farmac\u00e9utico terminado.", "prev_section_summary": "### Temas Clave\n\n1. **Equivalencia de M\u00e9todos Anal\u00edticos**: Se establece la necesidad de demostrar la equivalencia entre un m\u00e9todo anal\u00edtico in-house y un m\u00e9todo compendial mediante an\u00e1lisis duplicados de una muestra y el uso de placebos spiked con compuestos relacionados.\n\n2. **An\u00e1lisis de Lotes de Productos Farmac\u00e9uticos Terminados (FPP)**: Se requiere una descripci\u00f3n detallada de los lotes, incluyendo fuerza, n\u00famero de lote, tama\u00f1o, fecha y sitio de producci\u00f3n, as\u00ed como su uso en estudios relevantes.\n\n3. **Requisitos de An\u00e1lisis**: Para FPP sencillos, se debe proporcionar al menos un lote de escala piloto y un segundo lote m\u00e1s peque\u00f1o. Para FPP complicados, se deben analizar al menos dos lotes de escala piloto.\n\n4. **Resultados Anal\u00edticos**: Los resultados de los an\u00e1lisis deben ser presentados de manera detallada, enfoc\u00e1ndose en observaciones y rangos de resultados, en lugar de simplemente afirmar que \"todos los tests cumplen con las especificaciones\".\n\n5. **Clasificaci\u00f3n de FPP**: Se distingue entre FPP sencillos y complicados, con ejemplos espec\u00edficos de productos que caen en cada categor\u00eda.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las directrices.\n- **ICH Q2**: Documento de referencia mencionado para la equivalencia de m\u00e9todos.\n- **FPP (Formulaci\u00f3n Farmac\u00e9utica Terminada)**: T\u00e9rmino utilizado para referirse a los productos farmac\u00e9uticos que se analizan.\n- **Compuestos Relacionados**: Sustancias que se analizan junto con el producto principal para determinar su calidad.\n- **Lotes**: Unidades de producci\u00f3n que deben ser analizadas y documentadas.\n- **Complicados FPP**: Categor\u00eda que incluye productos como inhaladores y sistemas de entrega transd\u00e9rmica.\n\nEste resumen proporciona una visi\u00f3n general de los puntos clave y las entidades relevantes en la secci\u00f3n del documento de la OMS sobre especificaciones para preparaciones farmac\u00e9uticas.", "excerpt_keywords": "Keywords: impurities, specifications, degradation products, reference standards, dissolution profiles"}}, "ac80ab36-2331-4460-8f60-5a6a77d590e6": {"node_ids": ["b1e011d5-0146-440e-b5ad-7d98819bc7e6"], "metadata": {"page_label": "196", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Container-closure system (name, dosage form)\n\nA description of the container-closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. The specifications should include description and identification (and critical dimensions, with drawings where appropriate). Non-compendial methods (with validation) should be included, where appropriate.\n\nFor non-functional secondary packaging components (e.g. those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.\n\nSuitability information should be located in 3.2.P.2.\n\nThe WHO *Guidelines on packaging for pharmaceutical products* and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for FPPs.\n\nDescriptions, materials of construction and specifications (of the company responsible for packaging the FPP, generally the FPP manufacturer) should be provided for the packaging components that are:\n\n- in direct contact with the dosage form (e.g. container, closure, liner, desiccant and filler);\n- used for drug delivery (including the device(s) for multidose solutions, emulsions, suspensions and powders or granules for reconstitution into solution, emulsion or suspension);\n- used as a protective barrier to help ensure stability or sterility;\n- necessary to ensure FPP quality during storage and shipping.\n\nPrimary packaging components are those that are in direct contact with the API or FPP.\n\nThe specifications for the primary packaging components should include a specific test for identification (e.g. IR). Specifications for film and foil materials should include limits for thickness or area weight.\n\nInformation to establish the suitability (e.g. qualification) of the container-closure system should be discussed in section 3.2.P.2. Comparative studies may be warranted for certain changes in packaging components (e.g. a comparative delivery study (droplet size) for a change in manufacturer of dropper tips).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS proporciona directrices sobre los sistemas de envase y cierre para productos farmac\u00e9uticos. Se enfatiza la importancia de describir los componentes de envase primario, incluyendo los materiales de construcci\u00f3n y sus especificaciones. Se requiere informaci\u00f3n sobre los componentes que est\u00e1n en contacto directo con el producto, as\u00ed como aquellos que son necesarios para la entrega del medicamento y para garantizar la calidad durante el almacenamiento y el transporte. Tambi\u00e9n se menciona la necesidad de realizar pruebas espec\u00edficas para la identificaci\u00f3n de los materiales y se sugiere consultar las gu\u00edas de la OMS y las farmacopeas reconocidas oficialmente.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de pruebas espec\u00edficas se deben realizar para la identificaci\u00f3n de los componentes de envase primario, y qu\u00e9 m\u00e9todos no compendiales pueden ser utilizados?**\n   - Esta pregunta busca informaci\u00f3n detallada sobre los m\u00e9todos de prueba que no son est\u00e1ndar y que pueden ser aplicados en la identificaci\u00f3n de materiales de envase.\n\n2. **\u00bfCu\u00e1les son las consideraciones clave para la selecci\u00f3n de materiales de construcci\u00f3n de los componentes de envase que est\u00e1n en contacto directo con el producto farmac\u00e9utico?**\n   - Esta pregunta se centra en los criterios que deben tenerse en cuenta al elegir materiales para garantizar la calidad y seguridad del producto.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n adicional se debe proporcionar para los componentes de envase secundarios funcionales en comparaci\u00f3n con los no funcionales?**\n   - Esta pregunta busca aclarar las diferencias en la informaci\u00f3n requerida para distintos tipos de envases secundarios, lo que puede ser crucial para el cumplimiento normativo.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nLa secci\u00f3n del documento se centra en las directrices de la OMS relacionadas con la caracterizaci\u00f3n de impurezas, la justificaci\u00f3n de especificaciones y el uso de est\u00e1ndares de referencia en productos farmac\u00e9uticos. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas:\n\n1. **Caracterizaci\u00f3n de Impurezas (3.2.P.5.5)**:\n   - Se requiere una discusi\u00f3n sobre todas las impurezas que son productos de degradaci\u00f3n potenciales.\n   - Impurezas a considerar:\n     - Productos de degradaci\u00f3n identificados en la secci\u00f3n 3.2.S.3.2.\n     - Productos de degradaci\u00f3n resultantes de interacciones del principio activo (API) con otros APIs, excipientes o el sistema de cierre del envase.\n     - Impurezas relacionadas con el proceso de fabricaci\u00f3n del producto farmac\u00e9utico terminado (FPP), como solventes residuales.\n\n2. **Justificaci\u00f3n de Especificaciones (3.2.P.5.6)**:\n   - Se debe proporcionar una discusi\u00f3n sobre la inclusi\u00f3n o exclusi\u00f3n de pruebas, evoluci\u00f3n de pruebas, procedimientos anal\u00edticos y criterios de aceptaci\u00f3n.\n   - Se deben se\u00f1alar diferencias con respecto a los est\u00e1ndares compendiales reconocidos.\n   - Si se han modificado o reemplazado m\u00e9todos compendiales, se debe incluir una discusi\u00f3n al respecto.\n   - Se sugiere consultar ICH Q6A para el desarrollo de especificaciones para FPPs.\n\n3. **Est\u00e1ndares o Materiales de Referencia (3.2.P.6)**:\n   - Informaci\u00f3n sobre los est\u00e1ndares de referencia o materiales de referencia utilizados para las pruebas del FPP debe ser proporcionada.\n   - Se debe incluir informaci\u00f3n sobre materiales de referencia de productos de degradaci\u00f3n del FPP que no est\u00e9n en la secci\u00f3n 3.2.S.5.\n\n### Entidades Referenciadas:\n- **ICH Q3B**: Directrices sobre impurezas.\n- **ICH Q3C**: Directrices sobre impurezas relacionadas con solventes residuales.\n- **ICH Q6A**: Directrices sobre especificaciones para productos farmac\u00e9uticos terminados (FPPs).\n\n### Conclusi\u00f3n\nLa secci\u00f3n enfatiza la importancia de proporcionar informaci\u00f3n detallada y justificada sobre las impurezas, las especificaciones y los est\u00e1ndares de referencia en el contexto de la calidad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: container-closure system, primary packaging, pharmaceutical products, specifications, WHO guidelines"}}, "cb70faa1-efcc-47d1-912a-0552301bd829": {"node_ids": ["0c8f4c45-7d06-425a-a82b-9b3fab32ec90"], "metadata": {"page_label": "197", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.P.8 Stability (name, dosage form)\n\n## 3.2.P.8.1 Stability summary and conclusions (name, dosage form)\n\nThe types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include, for example, conclusions with respect to storage conditions and shelf-life, and, if applicable, in-use storage conditions and shelf-life.\n\nThe WHO stability guidelines *Stability testing of active pharmaceutical ingredients and finished pharmaceutical products* (19) should be consulted for recommendations on the core stability data package required for the prequalification of APIs and FPPs.\n\nAs outlined in the WHO stability guidelines, the purpose of stability testing is to provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. The stability programme also includes the study of product-related factors that influence the quality of the API or FPP, for example, interaction of API with excipients, container-closure systems and packaging materials.\n\n### Stress testing\n\nAs outlined in the WHO stability guidelines, photostability testing should be conducted on at least one primary batch of the FPP if appropriate. If \u201cprotect from light\u201d is stated in one of the officially recognized pharmacopoeias for the API or FPP it is sufficient to state \u201cprotect from light\u201d on labelling, in lieu of photostability studies, when the container-closure system is shown to be light protective. Additional stress testing of specific types of dosage forms may be appropriate (e.g. cyclic studies for semi-solid products or freeze\u2013thaw studies for liquid products).\n\n### Accelerated, intermediate (if necessary) and long-term testing\n\nStability data must demonstrate stability of the medicinal product throughout its intended shelf-life under the climatic conditions prevalent in the target countries. Merely applying the same requirements applicable to other markets could potentially lead to substandard products if stability studies are conducted at the storage conditions for countries in Climatic Zone I/II when the products are supplied in countries in Climatic Zones III and IV. Refer to *WHO Technical Report Series*, No. 953, Annex 2, Appendix 1 (7) for information on climatic zones. Effective as of September 2011, the required long-term storage conditions for the WHO Prequalification of Medicines Programme are 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, and after this date the long-term data submitted in the PD (see Table 3) should be at these conditions. The use of alternative long-term conditions will need to be justified and should be supported with appropriate evidence.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que pueden proporcionar respuestas espec\u00edficas basadas en el contexto proporcionado:\n\n1. **\u00bfCu\u00e1les son las condiciones de almacenamiento a largo plazo requeridas por el Programa de Precalificaci\u00f3n de Medicamentos de la OMS desde septiembre de 2011?**\n   - Respuesta: Las condiciones de almacenamiento a largo plazo requeridas son 30 \u00b0C \u00b1 2 \u00b0C y 75% \u00b1 5% de humedad relativa (RH).\n\n2. **\u00bfQu\u00e9 tipo de pruebas de estabilidad se deben realizar para los productos farmac\u00e9uticos y cu\u00e1les son algunos factores que pueden influir en la calidad del API o FPP?**\n   - Respuesta: Se deben realizar pruebas de estabilidad aceleradas, intermedias (si es necesario) y a largo plazo. Los factores que pueden influir en la calidad incluyen la interacci\u00f3n del API con excipientes, sistemas de cierre de envases y materiales de embalaje.\n\n3. **\u00bfQu\u00e9 se debe hacer si un producto farmac\u00e9utico requiere protecci\u00f3n contra la luz seg\u00fan las farmacopeas reconocidas?**\n   - Respuesta: Si se indica \"proteger de la luz\" en una de las farmacopeas reconocidas, es suficiente incluir esta advertencia en el etiquetado, siempre que el sistema de cierre del envase sea demostrado como protector contra la luz, sin necesidad de realizar estudios de fotostabilidad.\n\n### Resumen de nivel superior del contexto:\nEl contexto aborda la estabilidad de ingredientes farmac\u00e9uticos activos (API) y productos farmac\u00e9uticos terminados (FPP), destacando la importancia de las pruebas de estabilidad para garantizar la calidad a lo largo del tiempo bajo diversas condiciones ambientales. Se mencionan las pruebas de estr\u00e9s, la necesidad de realizar estudios de estabilidad en funci\u00f3n de las condiciones clim\u00e1ticas de los pa\u00edses de destino, y se especifican las condiciones de almacenamiento a largo plazo requeridas por la OMS. Adem\u00e1s, se discute la importancia de la interacci\u00f3n entre el API y otros componentes del producto, as\u00ed como la necesidad de cumplir con las normativas de etiquetado en relaci\u00f3n con la protecci\u00f3n contra la luz.", "prev_section_summary": "### Temas Clave\n\n1. **Descripci\u00f3n de Sistemas de Envase y Cierre**: Se requiere una descripci\u00f3n detallada de los sistemas de envase, incluyendo los materiales de construcci\u00f3n y especificaciones de cada componente de envase primario.\n\n2. **Especificaciones de Componentes de Envase Primario**: Las especificaciones deben incluir identificaci\u00f3n, dimensiones cr\u00edticas y m\u00e9todos de prueba, incluyendo m\u00e9todos no compendiales validados.\n\n3. **Componentes de Envase Secundario**: Se debe proporcionar una breve descripci\u00f3n para componentes no funcionales y m\u00e1s informaci\u00f3n para componentes funcionales.\n\n4. **Consulta de Directrices**: Se recomienda consultar las *Gu\u00edas de la OMS sobre envase para productos farmac\u00e9uticos* y farmacopeas reconocidas para obtener recomendaciones sobre la informaci\u00f3n de envase.\n\n5. **Componentes en Contacto Directo**: Se debe proporcionar informaci\u00f3n sobre los componentes que est\u00e1n en contacto directo con el producto, aquellos utilizados para la entrega del medicamento, y los que act\u00faan como barreras protectoras.\n\n6. **Pruebas de Identificaci\u00f3n**: Se requiere realizar pruebas espec\u00edficas para la identificaci\u00f3n de materiales, como espectroscop\u00eda infrarroja (IR), y establecer l\u00edmites para materiales de pel\u00edcula y papel de aluminio.\n\n7. **Estudios Comparativos**: Se pueden requerir estudios comparativos para ciertos cambios en los componentes de envase.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las directrices.\n- **FPP (Forma Farmac\u00e9utica Final)**: Producto farmac\u00e9utico que se envasa.\n- **API (Ingrediente Farmac\u00e9utico Activo)**: Sustancia activa en contacto con el envase primario.\n- **Componentes de Envase**: Incluyen contenedores, cierres, recubrimientos, deshidratantes y dispositivos de entrega.\n- **M\u00e9todos No Compendiales**: M\u00e9todos de prueba que no est\u00e1n estandarizados pero son validados.\n- **Secci\u00f3n 3.2.P.2**: Parte del documento donde se discute la idoneidad del sistema de envase-cierre. \n\nEste resumen abarca los aspectos esenciales de la secci\u00f3n sobre sistemas de envase y cierre, destacando la importancia de la especificaci\u00f3n y validaci\u00f3n de los materiales utilizados en el empaquetado de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: stability testing, pharmaceutical products, WHO guidelines, storage conditions, climatic zones"}}, "885bc7ad-7f67-4197-a365-d28deedba665": {"node_ids": ["a9f000a9-99c5-4392-b919-ac8bd7f76319"], "metadata": {"page_label": "198", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nOther storage conditions are outlined in the WHO stability guidelines for FPPs packaged in impermeable and semi-permeable containers and those intended for storage in a refrigerator and in a freezer. FPPs intended for storage below \u221220 \u00b0C should be treated on a case-by-case basis.\n\n**Table 3**  \nMinimum data required at the time of submitting the dossier (in the general case)\n\n| Storage temperature (\u00b0C) | Relative humidity (%) | Minimum time period (months) |\n| - | - | - |\n| Accelerated 40 \u00b1 2 | 75 \u00b1 5 | 6 |\n| Intermediatea | N/A | N/A |\n| Long-term 30 \u00b1 2 | 75 \u00b1 5 | 6 |\n\n\n<sup>a</sup>Where long-term conditions are 30 \u00b0C \u00b1 2 \u00b0C/75% \u00b1 5% RH, there is no intermediate condition.\n\nRefer to **WHO Technical Report Series**, No. 953, Annex 2 (19) for further information regarding the storage conditions. Reference should also be made to the WHO Prequalification of Medicines Programme web site for any exceptions to the stated requirements.\n\nTo establish the shelf-life, data should be provided on not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nThe stability testing programme should be summarized and the results of stability testing should be reported in the dossier and summarized in the tables in the QOS-PD. Bracketing and matrixing of proportional strengths can be applied if scientifically justified.\n\nFor sterile products, sterility should be reported at the beginning and end of shelf-life. For parenteral products, subvisible particulate matter should be reported frequently, but not necessarily at every test interval. Bacterial endotoxins need only be reported at the initial test point. Weight loss from plastic containers should be reported over the shelf-life.\n\nAny in-use period and associated storage conditions should be justified with experimental data, for example, after opening, reconstitution and/or dilution.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla las condiciones de almacenamiento y los requisitos de estabilidad para los productos farmac\u00e9uticos terminados (FPPs). Se especifican las temperaturas de almacenamiento, la humedad relativa y los per\u00edodos m\u00ednimos de tiempo para las pruebas de estabilidad. Adem\u00e1s, se establece que se deben proporcionar datos de al menos dos lotes para establecer la vida \u00fatil, y se describen las pruebas necesarias para productos est\u00e9riles y no est\u00e9riles.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las condiciones de almacenamiento m\u00ednimas requeridas para los productos farmac\u00e9uticos terminados (FPPs) seg\u00fan la OMS?**\n   - Respuesta: Las condiciones m\u00ednimas de almacenamiento requeridas son: \n     - Temperatura acelerada: 40 \u00b1 2 \u00b0C con 75 \u00b1 5% de humedad relativa durante 6 meses.\n     - Condiciones a largo plazo: 30 \u00b1 2 \u00b0C con 75 \u00b1 5% de humedad relativa durante 6 meses. No hay condiciones intermedias especificadas.\n\n2. **\u00bfQu\u00e9 tipo de datos se requieren para establecer la vida \u00fatil de un FPP y cu\u00e1ntos lotes deben ser evaluados?**\n   - Respuesta: Se requieren datos de al menos dos lotes de al menos escala piloto. Para FPPs no complicados, se puede presentar un lote de escala piloto y un segundo lote m\u00e1s peque\u00f1o (por ejemplo, 25,000 o 50,000 tabletas o c\u00e1psulas) de cada fuerza propuesta del FPP.\n\n3. **\u00bfQu\u00e9 pruebas espec\u00edficas deben realizarse para productos est\u00e9riles y parenterales en relaci\u00f3n con la estabilidad?**\n   - Respuesta: Para productos est\u00e9riles, se debe informar sobre la esterilidad al inicio y al final de la vida \u00fatil. Para productos parenterales, se debe reportar la materia particulada subvisible con frecuencia, pero no necesariamente en cada intervalo de prueba. Los endotoxinas bacterianas solo necesitan ser reportadas en el punto de prueba inicial.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Estabilidad de Productos Farmac\u00e9uticos**:\n   - Se aborda la importancia de las pruebas de estabilidad para los ingredientes farmac\u00e9uticos activos (API) y productos farmac\u00e9uticos terminados (FPP).\n   - Se enfatiza c\u00f3mo la calidad de un API o FPP puede variar con el tiempo debido a factores ambientales como temperatura, humedad y luz.\n\n2. **Pruebas de Estr\u00e9s**:\n   - Se menciona la necesidad de realizar pruebas de fotostabilidad en al menos un lote primario del FPP.\n   - Si se requiere protecci\u00f3n contra la luz seg\u00fan las farmacopeas reconocidas, se puede indicar en el etiquetado si el sistema de cierre del envase es protector.\n\n3. **Pruebas de Estabilidad**:\n   - Se deben realizar pruebas de estabilidad aceleradas, intermedias (si es necesario) y a largo plazo.\n   - Los datos de estabilidad deben demostrar que el producto se mantiene estable durante su vida \u00fatil prevista bajo las condiciones clim\u00e1ticas de los pa\u00edses de destino.\n\n4. **Condiciones de Almacenamiento a Largo Plazo**:\n   - Desde septiembre de 2011, las condiciones requeridas para el almacenamiento a largo plazo son 30 \u00b0C \u00b1 2 \u00b0C y 75% \u00b1 5% de humedad relativa (RH).\n   - Se requiere justificaci\u00f3n y evidencia adecuada si se utilizan condiciones de almacenamiento alternativas.\n\n5. **Interacci\u00f3n de Componentes**:\n   - Se destaca la importancia de estudiar la interacci\u00f3n del API con excipientes, sistemas de cierre de envases y materiales de embalaje, ya que estos pueden influir en la calidad del producto.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Proporciona directrices sobre pruebas de estabilidad.\n- **API (Ingredientes Farmac\u00e9uticos Activos)**: Sustancias que tienen efectos terap\u00e9uticos.\n- **FPP (Productos Farmac\u00e9uticos Terminados)**: Formulaciones finales que se administran a los pacientes.\n- **Climatic Zones (Zonas Clim\u00e1ticas)**: Clasificaci\u00f3n que afecta las condiciones de almacenamiento y estabilidad de los productos farmac\u00e9uticos. \n\nEste resumen encapsula los aspectos fundamentales de la estabilidad de productos farmac\u00e9uticos y las directrices de la OMS relacionadas con su evaluaci\u00f3n y almacenamiento.", "excerpt_keywords": "Keywords: stability testing, pharmaceutical preparations, storage conditions, shelf-life, WHO guidelines"}}, "5fab1dcb-ece5-4d64-9a91-1ab921b52605": {"node_ids": ["32666921-234a-4ca1-a1e1-1f8958ee6334"], "metadata": {"page_label": "199", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Stability Studies Information\n\nThe information on the stability studies should include details such as:\n\n- Storage conditions;\n- Strength;\n- Batch number, including the API batch number(s) and manufacturer(s);\n- Batch size;\n- Container-closure system including orientation (e.g. erect, inverted, on-side) where applicable;\n- Completed (and proposed) test intervals.\n\nThe discussion of results should focus on observations noted for the various tests, rather than reporting comments such as \u201call tests meet specifications\u201d. The discussion should include ranges of analytical results and any trends that were observed. For quantitative tests (e.g. individual and total degradation product tests and assay tests) actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d. Dissolution results should be expressed, at a minimum, as both the average and range of individual results.\n\nApplicants should consult ICH\u2019s Q1E guideline (23) for details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated condition and the data show little or no variability, the proposed shelf-life could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months).\n\n## Proposed Storage Statement and Shelf-life\n\nThe proposed storage statement and shelf-life (and in-use storage conditions and in-use period, if applicable) for the FPP should be provided.\n\nThe recommended labelling statements for use based on the stability studies, are provided in the WHO stability guidelines (19).\n\nReference documents: *WHO Technical Report Series*, No. 953, Annex 2 (19), ICH Q1A (20), Q1B (22), Q1C (47), Q1D (24), Q1E (23), Q3B (11), Q6A (6).\n\n### 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment (name, dosage form)\n\nThe post-approval stability protocol and stability commitment should be provided.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que pueden ser respondidas con la informaci\u00f3n proporcionada en el contexto, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento proporciona directrices sobre los estudios de estabilidad de productos farmac\u00e9uticos, enfatizando la importancia de detallar las condiciones de almacenamiento, los resultados de las pruebas y la interpretaci\u00f3n de los datos. Se menciona la necesidad de un protocolo de estabilidad post-aprobaci\u00f3n y un compromiso de estabilidad, as\u00ed como la consulta de las gu\u00edas del ICH para la evaluaci\u00f3n de los datos de estabilidad y la propuesta de vida \u00fatil.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 informaci\u00f3n espec\u00edfica debe incluirse en los estudios de estabilidad de un producto farmac\u00e9utico?**\n   - Los estudios de estabilidad deben incluir detalles como las condiciones de almacenamiento, la fuerza del producto, el n\u00famero de lote (incluyendo el n\u00famero de lote del API y los fabricantes), el tama\u00f1o del lote, el sistema de cierre del contenedor (incluyendo la orientaci\u00f3n) y los intervalos de prueba completados y propuestos.\n\n2. **\u00bfC\u00f3mo deben presentarse los resultados de las pruebas cuantitativas en los estudios de estabilidad?**\n   - Los resultados de las pruebas cuantitativas deben presentarse con resultados num\u00e9ricos espec\u00edficos en lugar de declaraciones vagas. Por ejemplo, los resultados de disoluci\u00f3n deben expresarse como el promedio y el rango de resultados individuales.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al proponer la vida \u00fatil de un producto farmac\u00e9utico basado en datos de estabilidad?**\n   - Al proponer la vida \u00fatil, se debe considerar la gu\u00eda Q1E del ICH, que indica que si no se observa un cambio significativo en 6 meses bajo condiciones aceleradas y los datos muestran poca o ninguna variabilidad, la vida \u00fatil propuesta podr\u00eda ser hasta el doble del per\u00edodo cubierto por los datos a largo plazo, pero no debe exceder los datos a largo plazo por m\u00e1s de 12 meses.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Condiciones de Almacenamiento**:\n   - Se especifican las condiciones de almacenamiento para productos farmac\u00e9uticos terminados (FPPs) en diferentes temperaturas y niveles de humedad.\n   - Se mencionan condiciones aceleradas (40 \u00b1 2 \u00b0C, 75 \u00b1 5% de humedad relativa) y a largo plazo (30 \u00b1 2 \u00b0C, 75 \u00b1 5% de humedad relativa), con un per\u00edodo m\u00ednimo de 6 meses para ambas.\n\n2. **Requisitos de Datos para la Vida \u00datil**:\n   - Para establecer la vida \u00fatil de un FPP, se requieren datos de al menos dos lotes de escala piloto.\n   - En el caso de FPPs no complicados, se puede presentar un lote de escala piloto y un segundo lote m\u00e1s peque\u00f1o.\n\n3. **Pruebas de Estabilidad**:\n   - Se deben resumir y reportar los resultados de las pruebas de estabilidad en el dossier.\n   - Se permite el uso de bracketing y matrixing para fortalezas proporcionales si est\u00e1 cient\u00edficamente justificado.\n\n4. **Productos Est\u00e9riles y Parenterales**:\n   - Para productos est\u00e9riles, se debe informar sobre la esterilidad al inicio y al final de la vida \u00fatil.\n   - Para productos parenterales, se debe reportar la materia particulada subvisible y los endotoxinas bacterianas solo en el punto de prueba inicial.\n\n5. **Justificaci\u00f3n de Condiciones de Almacenamiento**:\n   - Cualquier per\u00edodo de uso y las condiciones de almacenamiento asociadas deben ser justificadas con datos experimentales, especialmente despu\u00e9s de la apertura, reconstituci\u00f3n o diluci\u00f3n.\n\n### Entidades Clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que establece las directrices.\n- **FPP (Productos Farmac\u00e9uticos Terminados)**: El objeto de las directrices.\n- **Temperaturas y Humedad**: Par\u00e1metros cr\u00edticos para el almacenamiento.\n- **Lotes de Escala Piloto**: Requisitos para la evaluaci\u00f3n de la vida \u00fatil.\n- **Pruebas de Estabilidad**: Procedimientos necesarios para asegurar la calidad del producto.\n- **Productos Est\u00e9riles y Parenterales**: Categor\u00edas espec\u00edficas de productos que requieren pruebas adicionales. \n\nEste resumen abarca los aspectos esenciales del documento, destacando las condiciones de almacenamiento, los requisitos de datos y las pruebas necesarias para garantizar la estabilidad y seguridad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: stability studies, storage conditions, shelf-life, ICH guidelines, pharmaceutical products"}}, "a8bd7205-ef28-4158-b96e-e99a6375ad29": {"node_ids": ["6bbdbe7c-0ab4-45a4-8107-b0527281029d"], "metadata": {"page_label": "200", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Primary stability study commitment\n\nWhen the available data on long-term stability of primary batches do not cover the proposed shelf-life granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the shelf-life. A written commitment (signed and dated) to continue long-term testing over the shelf-life period should be included in the dossier.\n\n## Commitment stability studies\n\nThe long-term stability studies for the commitment batches should be conducted throughout the proposed shelf-life on at least three production batches of each strength in each container-closure system. Where stability data were not provided for three production batches of each strength, a written commitment (signed and dated) should be included in the dossier.\n\n## Ongoing stability studies\n\nAs described in the WHO stability guidelines (19), an ongoing stability programme is established to monitor the product over its shelf-life and to determine that the product remains and can be expected to remain within specifications under the storage conditions on the label. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every container-closure system, if relevant, should be included in the stability programme (unless none is produced during that year). Bracketing and matrixing may be applicable. A written commitment (signed and dated) to this effect should be included in the dossier.\n\nAny differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.\n\nReference document: ICH Q1A (20).\n\n## 3.2.P.8.3 Stability data (name, dosage form)\n\nResults of the stability studies should be presented in an appropriate format (e.g. tabular, graphical, narrative). Information on the analytical procedures used to generate the data and validation of these procedures should be included.\n\nInformation on characterization of impurities is located in 3.2.P.5.5.\n\nThe actual stability results and reports used to support the proposed shelf-life should be provided in the PD. For quantitative tests (e.g. individual and total degradation product tests and assay tests), actual numerical results should be provided rather than vague statements such as \u201cwithin limits\u201d or \u201cconforms\u201d.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) aborda el compromiso de estudios de estabilidad a largo plazo para lotes primarios de productos farmac\u00e9uticos. Se establece que, si los datos disponibles no cubren la vida \u00fatil propuesta, se debe hacer un compromiso por escrito para continuar los estudios de estabilidad. Se requiere que los estudios de estabilidad a largo plazo se realicen en al menos tres lotes de producci\u00f3n de cada fuerza y sistema de cierre de contenedor. Adem\u00e1s, se menciona la importancia de un programa de estabilidad en curso para monitorear el producto durante su vida \u00fatil y se especifica que los resultados de los estudios de estabilidad deben presentarse de manera adecuada y con datos num\u00e9ricos concretos.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 requisitos espec\u00edficos se deben cumplir para los estudios de estabilidad a largo plazo de los lotes de compromiso seg\u00fan el documento de la OMS?**\n   - Respuesta: Los estudios de estabilidad a largo plazo para los lotes de compromiso deben realizarse a lo largo de la vida \u00fatil propuesta en al menos tres lotes de producci\u00f3n de cada fuerza y sistema de cierre de contenedor. Si no se proporcionaron datos de estabilidad para tres lotes de cada fuerza, se debe incluir un compromiso por escrito en el expediente.\n\n2. **\u00bfC\u00f3mo se debe presentar la informaci\u00f3n de los resultados de los estudios de estabilidad seg\u00fan las directrices de la OMS?**\n   - Respuesta: Los resultados de los estudios de estabilidad deben presentarse en un formato apropiado, que puede ser tabular, gr\u00e1fico o narrativo. Adem\u00e1s, se debe incluir informaci\u00f3n sobre los procedimientos anal\u00edticos utilizados para generar los datos y la validaci\u00f3n de estos procedimientos.\n\n3. **\u00bfQu\u00e9 justificaciones son necesarias si hay diferencias entre los protocolos de estabilidad utilizados para los lotes primarios y los lotes de compromiso u otros lotes en curso?**\n   - Respuesta: Cualquier diferencia entre los protocolos de estabilidad utilizados para los lotes primarios y aquellos propuestos para los lotes de compromiso o en curso debe estar cient\u00edficamente justificada.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Estudios de Estabilidad**: Se enfatiza la importancia de realizar estudios de estabilidad para productos farmac\u00e9uticos, que deben incluir informaci\u00f3n detallada sobre:\n   - **Condiciones de Almacenamiento**: Especificar c\u00f3mo y d\u00f3nde se almacenar\u00e1 el producto.\n   - **Fuerza del Producto**: Indicar la concentraci\u00f3n o potencia del f\u00e1rmaco.\n   - **N\u00famero de Lote**: Incluir el n\u00famero de lote del principio activo (API) y del fabricante.\n   - **Tama\u00f1o del Lote**: Detallar la cantidad producida en cada lote.\n   - **Sistema de Cierre del Contenedor**: Describir el tipo de envase y su orientaci\u00f3n (por ejemplo, erguido, invertido).\n   - **Intervalos de Prueba**: Listar los intervalos de prueba completados y propuestos.\n\n2. **Discusi\u00f3n de Resultados**: Los resultados de las pruebas deben ser discutidos en t\u00e9rminos de observaciones y tendencias, proporcionando datos num\u00e9ricos espec\u00edficos en lugar de declaraciones generales. Los resultados de disoluci\u00f3n deben incluir el promedio y el rango de resultados individuales.\n\n3. **Gu\u00eda ICH Q1E**: Se recomienda consultar esta gu\u00eda para la evaluaci\u00f3n y extrapolaci\u00f3n de datos de estabilidad, que sugiere que si no hay cambios significativos en 6 meses bajo condiciones aceleradas, la vida \u00fatil propuesta podr\u00eda ser hasta el doble del per\u00edodo cubierto por los datos a largo plazo, sin excederlos por m\u00e1s de 12 meses.\n\n4. **Declaraci\u00f3n de Almacenamiento Propuesta y Vida \u00datil**: Se debe proporcionar una declaraci\u00f3n de almacenamiento y vida \u00fatil propuesta, as\u00ed como condiciones de almacenamiento en uso y per\u00edodo de uso, si corresponde.\n\n5. **Protocolo de Estabilidad Post-aprobaci\u00f3n**: Se debe presentar un protocolo de estabilidad post-aprobaci\u00f3n y un compromiso de estabilidad para el producto farmac\u00e9utico.\n\n### Entidades Clave\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que proporciona las directrices.\n- **ICH (International Council for Harmonisation)**: Organizaci\u00f3n que establece gu\u00edas para la evaluaci\u00f3n de datos de estabilidad.\n- **FPP (Formulaci\u00f3n Farmac\u00e9utica del Producto)**: Referente al producto farmac\u00e9utico en estudio.\n- **Documentos de Referencia**: Incluyen varios informes y gu\u00edas de la OMS y el ICH que son relevantes para los estudios de estabilidad. \n\nEste resumen destaca la importancia de la rigurosidad en los estudios de estabilidad y la necesidad de seguir directrices espec\u00edficas para garantizar la calidad y seguridad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: stability studies, shelf-life, commitment, pharmaceutical products, WHO guidelines"}}, "5080c859-effc-41f0-b5a7-d4f2572ae844": {"node_ids": ["daa170ec-d8b3-4e84-8181-16f9a625de3d"], "metadata": {"page_label": "201", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendices\n\n## 3.2.A.1 Facilities and equipment\n\nNot applicable (i.e. not a biotech product).\n\n## 3.2.A.2 Adventitious agents safety evaluation\n\n## 3.2.A.3 Novel excipients\n\nNovel excipients are not accepted in the WHO Prequalification of Medicines Programme.\n\n# Regional information\n\n## 3.2.R.1 Production documentation\n\n### 3.2.R.1.1 Executed production documents\n\nA minimum of two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale (the batch used in comparative bioavailability or biowaiver studies) and a second batch which may be smaller (e.g. for solid oral dosage forms, 25,000 or 50,000 tablets or capsules), should be manufactured for each strength. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.\n\nFor solid oral dosage forms, pilot scale is generally, at a minimum, one-tenth that of full production scale or 100,000 tablets or capsules, whichever is the larger.\n\nCopies of the executed production documents should be provided for the batches used in the comparative bioavailability or biowaiver studies. Any notations made by operators on the executed production documents should be clearly legible.\n\nIf not included in the executed batch records through sufficient in-process testing, data should be provided for the batch used in comparative bioavailability or biowaiver studies that demonstrate the uniformity of this batch. The data to establish the uniformity of the biobatch should involve testing to an extent greater than that required in routine quality control.\n\nEnglish translations of executed records should be provided where relevant.\n\n----\n\nDissolution results should be expressed, at a minimum, as both the average and range of individual results.\n\nReference documents: ICH Q1A (20), Q1B (22), Q1C (47), Q1D (24), Q1E (23), Q2 (16).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Serie de Informes T\u00e9cnicos 970 aborda aspectos relacionados con la producci\u00f3n y evaluaci\u00f3n de medicamentos, espec\u00edficamente en el contexto de la Precalificaci\u00f3n de Medicamentos. Se menciona que no se aceptan excipientes novedosos y se establecen requisitos para la documentaci\u00f3n de producci\u00f3n, incluyendo la necesidad de fabricar lotes de escala piloto y proporcionar documentaci\u00f3n ejecutada para estudios de bioequivalencia o biowaiver. Tambi\u00e9n se enfatiza la importancia de demostrar la uniformidad de los lotes y la presentaci\u00f3n de resultados de disoluci\u00f3n.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son los requisitos m\u00ednimos para la fabricaci\u00f3n de lotes de medicamentos en el contexto de la Precalificaci\u00f3n de Medicamentos de la OMS?**\n   - Respuesta: Se requieren al menos dos lotes de escala piloto para cada fuerza del medicamento, o al menos un lote de escala piloto y un segundo lote m\u00e1s peque\u00f1o en el caso de formas farmac\u00e9uticas s\u00f3lidas de liberaci\u00f3n inmediata o soluciones no est\u00e9riles.\n\n2. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en la documentaci\u00f3n ejecutada de producci\u00f3n para los estudios de bioequivalencia?**\n   - Respuesta: Deben proporcionarse copias de los documentos de producci\u00f3n ejecutados para los lotes utilizados en los estudios de bioequivalencia, y cualquier anotaci\u00f3n hecha por los operadores debe ser claramente legible.\n\n3. **\u00bfC\u00f3mo se deben presentar los resultados de disoluci\u00f3n seg\u00fan las directrices de la OMS?**\n   - Respuesta: Los resultados de disoluci\u00f3n deben expresarse, como m\u00ednimo, tanto como el promedio como el rango de los resultados individuales.", "prev_section_summary": "### Temas Clave\n\n1. **Compromiso de Estudios de Estabilidad**: Se requiere un compromiso por escrito para continuar los estudios de estabilidad a largo plazo si los datos disponibles no cubren la vida \u00fatil propuesta.\n\n2. **Estudios de Estabilidad de Lotes de Compromiso**: Los estudios deben realizarse en al menos tres lotes de producci\u00f3n de cada fuerza y sistema de cierre de contenedor a lo largo de la vida \u00fatil propuesta.\n\n3. **Programa de Estabilidad en Curso**: Se establece un programa para monitorear el producto durante su vida \u00fatil, incluyendo al menos un lote por a\u00f1o de cada fuerza y sistema de cierre, a menos que no se produzca ninguno.\n\n4. **Justificaci\u00f3n Cient\u00edfica**: Cualquier diferencia entre los protocolos de estabilidad de los lotes primarios y los lotes de compromiso o en curso debe ser cient\u00edficamente justificada.\n\n5. **Presentaci\u00f3n de Resultados**: Los resultados de los estudios de estabilidad deben presentarse en formatos apropiados (tabular, gr\u00e1fico, narrativo) y deben incluir datos num\u00e9ricos concretos.\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite las directrices sobre estudios de estabilidad.\n- **Lotes de Producci\u00f3n**: Referencia a los lotes de productos farmac\u00e9uticos que se est\u00e1n evaluando.\n- **Vida \u00datil**: Per\u00edodo durante el cual se espera que el producto mantenga su calidad y eficacia.\n- **Protocolos de Estabilidad**: M\u00e9todos y procedimientos utilizados para evaluar la estabilidad de los productos.\n- **Compromiso por Escrito**: Documento que debe ser firmado y fechado para formalizar el compromiso de continuar los estudios de estabilidad.\n- **ICH Q1A**: Documento de referencia mencionado que proporciona directrices sobre estabilidad.", "excerpt_keywords": "Keywords: WHO, Prequalification, production documentation, bioequivalence, dissolution results"}}, "9e2d7133-fcc1-443e-b469-aacb906e9083": {"node_ids": ["7d263796-6c29-492a-b29e-120e1c7101bc"], "metadata": {"page_label": "202", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.R.1.2 Master production documents\n\nCopies of the FPP master production documents should be provided for each proposed strength, commercial batch size and manufacturing site.\n\nThe details in the master production documents should include, but not be limited to, the following:\n\n- **master formula;**\n- **dispensing, processing and packaging sections with relevant material and operational details;**\n- **relevant calculations** (e.g. if the amount of API is adjusted based on the assay results or on the anhydrous basis);\n- **identification of all equipment** by, at a minimum, type and working capacity (including make, model and equipment number, where possible);\n- **process parameters** (e.g. mixing time, mixing speed, milling screen size, processing temperature range, granulation end-point and tablet machine speed (expressed as target and range));\n- **list of in-process tests** (e.g. appearance, pH, assay, blend uniformity, viscosity, particle size distribution, loss on drying, weight variation, hardness, disintegration time, weight gain during coating, leaker test, minimum fill, clarity and filter integrity checks) and specifications;\n- **sampling plan** with regard to the:\n  - steps at which sampling should be done (e.g. drying, lubrication and compression),\n  - number of samples that should be tested (e.g. for blend uniformity testing of low-dose FPPs, blend drawn using a sampling thief from x positions in the blender),\n  - frequency of testing (e.g. weight variation every x minutes during compression or capsule filling);\n- **precautions necessary to ensure product quality** (e.g. temperature and humidity control and maximum holding times);\n- for sterile products, reference to **standard operating procedures (SOPs)** in appropriate sections and a list of all relevant SOPs at the end of the document;\n- **theoretical and actual yield;**\n- **compliance with the GMP requirements.**\n\nReference document: WHO Technical Report Series, No. 961 (48).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con sus respuestas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 informaci\u00f3n debe incluirse en los documentos maestros de producci\u00f3n para cada lote comercial propuesto?**\n   - Los documentos maestros de producci\u00f3n deben incluir, entre otros, la f\u00f3rmula maestra, secciones de dispensaci\u00f3n, procesamiento y empaque con detalles operativos, c\u00e1lculos relevantes, identificaci\u00f3n del equipo, par\u00e1metros del proceso, lista de pruebas en proceso, plan de muestreo, precauciones para asegurar la calidad del producto, referencia a procedimientos operativos est\u00e1ndar (SOPs) para productos est\u00e9riles, rendimiento te\u00f3rico y real, y cumplimiento con los requisitos de Buenas Pr\u00e1cticas de Manufactura (GMP).\n\n2. **\u00bfCu\u00e1les son algunos ejemplos de pruebas en proceso que deben ser listadas en los documentos maestros de producci\u00f3n?**\n   - Ejemplos de pruebas en proceso incluyen apariencia, pH, ensayo, uniformidad de mezcla, viscosidad, distribuci\u00f3n del tama\u00f1o de part\u00edculas, p\u00e9rdida por secado, variaci\u00f3n de peso, dureza, tiempo de desintegraci\u00f3n, ganancia de peso durante el recubrimiento, prueba de fugas, llenado m\u00ednimo, claridad y verificaci\u00f3n de integridad de filtros.\n\n3. **\u00bfQu\u00e9 aspectos se deben considerar en el plan de muestreo seg\u00fan los documentos maestros de producci\u00f3n?**\n   - El plan de muestreo debe considerar los pasos en los que se debe realizar el muestreo (como secado, lubricaci\u00f3n y compresi\u00f3n), el n\u00famero de muestras que deben ser probadas (por ejemplo, para la prueba de uniformidad de mezcla de FPPs de baja dosis), y la frecuencia de las pruebas (por ejemplo, variaci\u00f3n de peso cada ciertos minutos durante la compresi\u00f3n o llenado de c\u00e1psulas).\n\n### Resumen de nivel superior:\nLos documentos maestros de producci\u00f3n son esenciales para garantizar la calidad y la consistencia en la fabricaci\u00f3n de productos farmac\u00e9uticos. Deben contener informaci\u00f3n detallada sobre la f\u00f3rmula, el proceso de producci\u00f3n, el equipo utilizado, las pruebas realizadas durante la producci\u00f3n y el cumplimiento de las normativas de calidad. Esto asegura que cada lote producido cumpla con los est\u00e1ndares requeridos y que se mantenga la integridad del producto final.", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Precalificaci\u00f3n de Medicamentos de la OMS**:\n   - El documento establece directrices para la producci\u00f3n y evaluaci\u00f3n de medicamentos en el contexto de la precalificaci\u00f3n.\n\n2. **Excipientes Novedosos**:\n   - Se menciona que no se aceptan excipientes novedosos en el programa de precalificaci\u00f3n.\n\n3. **Documentaci\u00f3n de Producci\u00f3n**:\n   - Se requiere la fabricaci\u00f3n de al menos dos lotes de escala piloto para cada fuerza del medicamento.\n   - En el caso de formas farmac\u00e9uticas s\u00f3lidas de liberaci\u00f3n inmediata o soluciones no est\u00e9riles, se acepta un lote de escala piloto y un segundo lote m\u00e1s peque\u00f1o.\n\n4. **Escala Piloto**:\n   - Para formas s\u00f3lidas orales, la escala piloto debe ser, como m\u00ednimo, una d\u00e9cima parte de la escala de producci\u00f3n completa o 100,000 tabletas/c\u00e1psulas, lo que sea mayor.\n\n5. **Documentos Ejecutados**:\n   - Se deben proporcionar copias de los documentos de producci\u00f3n ejecutados para los lotes utilizados en estudios de bioequivalencia o biowaiver.\n   - Las anotaciones de los operadores en los documentos deben ser legibles.\n\n6. **Uniformidad de Lotes**:\n   - Se requiere demostrar la uniformidad del lote utilizado en estudios de bioequivalencia, con pruebas m\u00e1s exhaustivas que las de control de calidad rutinario.\n\n7. **Resultados de Disoluci\u00f3n**:\n   - Los resultados de disoluci\u00f3n deben presentarse como el promedio y el rango de los resultados individuales.\n\n8. **Referencias**:\n   - Se citan documentos de referencia de la ICH (International Council for Harmonisation) que respaldan las directrices.\n\n### Entidades Clave:\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que establece las directrices.\n- **FPP (Formas Farmac\u00e9uticas Finales)**: Tipos de productos farmac\u00e9uticos a los que se aplican las directrices.\n- **ICH (International Council for Harmonisation)**: Organizaci\u00f3n que proporciona documentos de referencia para la regulaci\u00f3n de medicamentos.", "excerpt_keywords": "Keywords: master production documents, pharmaceutical manufacturing, quality assurance, Good Manufacturing Practices, in-process testing"}}, "b154d401-9e91-4630-abf9-0e9ad9141e1f": {"node_ids": ["ea36af88-4ddb-48a0-9aa5-ad38af5218dd"], "metadata": {"page_label": "203", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.2.R.2 Analytical procedures and validation information\n\nThe tables presented in section 2.3.R.2 in the QOS-PD template should be used to summarize the analytical procedures and validation information from sections 3.2.S.4.2, 3.2.S.4.3, 2.3.S.4.4 (c), 2.3.S.7.3 (b), 3.2.P.5.2 and 3.2.P.5.3 where relevant.\n\n## 4.3 Literature references\n\nReferences to the scientific literature relating to both the API and FPP should be included in this section of the PD when appropriate.\n\n# References\n\n1. Procedure for prequalification of pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2011, Annex 10 (WHO Technical Report Series, No. 961).\n\n2. ICH harmonised tripartite guideline: the common technical document for the registration of pharmaceuticals for human use: quality \u2013 M4Q. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2002.\n\n3. Guidelines on submission of documentation for a multisource (generic) finished product: general format: preparation of product dossiers in common technical document format. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fifth report. Geneva, World Health Organization, 2011, Annex 5 (WHO Technical Report Series, No. 961).\n\n4. Guidelines on active pharmaceutical ingredient master file procedure. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-second report. Geneva, World Health Organization, 2008, Annex 4 (WHO Technical Report Series, No. 948).\n\n5. Common technical document for the registration of pharmaceuticals for human use \u2013 quality questions & answers/location issues. European Medicines Agency, 2009 (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002726.pdf).\n\n6. ICH harmonised tripartite guideline: specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances \u2013 Q6A. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999.\n\n7. ICH harmonised tripartite guideline: Good manufacturing practice guide for active pharmaceutical ingredients \u2013 Q7. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2000.\n\n8. WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth report. Geneva, World Health Organization, 2010, Annex 2 (WHO Technical Report Series, No. 957).\n\n9. Guidance on variations to a prequalified product dossier. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization, 2007, Annex 6 (WHO Technical Report Series, No. 943).\n\n10. ICH harmonised tripartite guideline: impurities in new drug substances \u2013 Q3A. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2006.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en los procedimientos anal\u00edticos y la informaci\u00f3n de validaci\u00f3n relacionados con productos farmac\u00e9uticos, espec\u00edficamente en el contexto de la presentaci\u00f3n de documentos para la precalificaci\u00f3n de productos farmac\u00e9uticos. Se menciona la importancia de resumir la informaci\u00f3n de validaci\u00f3n y los procedimientos anal\u00edticos en tablas espec\u00edficas del formato de documento de calidad (QOS-PD). Adem\u00e1s, se destaca la necesidad de incluir referencias a la literatura cient\u00edfica pertinente tanto para el ingrediente farmac\u00e9utico activo (API) como para el producto farmac\u00e9utico terminado (FPP).\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 se debe incluir en las tablas de la secci\u00f3n 2.3.R.2 del QOS-PD seg\u00fan el documento?**\n   - Respuesta: Las tablas de la secci\u00f3n 2.3.R.2 del QOS-PD deben resumir los procedimientos anal\u00edticos y la informaci\u00f3n de validaci\u00f3n de las secciones 3.2.S.4.2, 3.2.S.4.3, 2.3.S.4.4 (c), 2.3.S.7.3 (b), 3.2.P.5.2 y 3.2.P.5.3 donde sea relevante.\n\n2. **\u00bfCu\u00e1l es la importancia de incluir referencias a la literatura cient\u00edfica en el documento de presentaci\u00f3n (PD)?**\n   - Respuesta: Incluir referencias a la literatura cient\u00edfica en el PD es importante para proporcionar un respaldo y contexto cient\u00edfico tanto para el ingrediente farmac\u00e9utico activo (API) como para el producto farmac\u00e9utico terminado (FPP), asegurando que la informaci\u00f3n presentada est\u00e9 fundamentada en estudios y gu\u00edas reconocidas.\n\n3. **\u00bfQu\u00e9 tipo de documentos se citan como referencias en el contexto de la validaci\u00f3n de productos farmac\u00e9uticos?**\n   - Respuesta: Se citan varios documentos, incluyendo directrices de la OMS sobre la precalificaci\u00f3n de productos farmac\u00e9uticos, gu\u00edas de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) sobre el registro de productos farmac\u00e9uticos, y documentos sobre buenas pr\u00e1cticas de fabricaci\u00f3n (GMP) para ingredientes farmac\u00e9uticos activos, entre otros.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Documentaci\u00f3n Maestra de Producci\u00f3n:** Importancia de los documentos maestros para cada fuerza propuesta, tama\u00f1o de lote comercial y sitio de fabricaci\u00f3n.\n2. **Contenido Esencial:** Detalles que deben incluirse en los documentos, como la f\u00f3rmula maestra, secciones de dispensaci\u00f3n, procesamiento y empaque, c\u00e1lculos relevantes, identificaci\u00f3n de equipos, par\u00e1metros del proceso, pruebas en proceso, plan de muestreo, precauciones de calidad, procedimientos operativos est\u00e1ndar (SOPs) para productos est\u00e9riles, rendimiento te\u00f3rico y real, y cumplimiento de Buenas Pr\u00e1cticas de Manufactura (GMP).\n3. **Pruebas en Proceso:** Ejemplos de pruebas que aseguran la calidad del producto durante la producci\u00f3n.\n4. **Plan de Muestreo:** Consideraciones sobre cu\u00e1ndo y c\u00f3mo se debe realizar el muestreo durante el proceso de fabricaci\u00f3n.\n\n**Entidades:**\n- **FPP (Formulaci\u00f3n Farmac\u00e9utica de Producto):** Referencia a los productos farmac\u00e9uticos que se est\u00e1n produciendo.\n- **API (Ingrediente Activo):** Sustancia que proporciona la acci\u00f3n farmacol\u00f3gica.\n- **SOP (Procedimientos Operativos Est\u00e1ndar):** Documentos que describen c\u00f3mo realizar tareas espec\u00edficas de manera consistente.\n- **GMP (Buenas Pr\u00e1cticas de Manufactura):** Normativas que aseguran que los productos se fabriquen y controlen de acuerdo con est\u00e1ndares de calidad.\n- **WHO (Organizaci\u00f3n Mundial de la Salud):** Entidad que proporciona directrices y est\u00e1ndares para la producci\u00f3n farmac\u00e9utica.\n\nEste resumen destaca la importancia de la documentaci\u00f3n detallada y el cumplimiento de normativas en la producci\u00f3n farmac\u00e9utica para garantizar la calidad y seguridad de los productos.", "excerpt_keywords": "Keywords: analytical procedures, validation information, pharmaceutical products, WHO guidelines, quality documentation"}}, "05aeff10-dc42-46a3-b61f-adfb8d7bb5c2": {"node_ids": ["abee4531-16bd-46b8-9980-25c71b19755f"], "metadata": {"page_label": "204", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n11. **ICH harmonised tripartite guideline: impurities in new drug products \u2013 Q3B.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2006.\n\n12. **ICH harmonised tripartite guideline impurities: guideline for residual solvents \u2013 Q3C.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2011.\n\n13. **Committee for Medicinal Products for Human Use (CHMP). Guideline on the limits of genotoxic impurities.**  \n   European Medicines Agency, 2006 (CPMP/SWP/5199/02 EMEA/CHMP/ QWP/251344/2006).\n\n14. **US FDA Guidance for industry: Genotoxic and carcinogenic impurities in drug substances and products: recommended approaches.**  \n   US Food and Drug Administration, 2008.\n\n15. **Committee for Medicinal Products for Human Use (CHMP). Guideline on the specification limits for residues of metal catalysts or metal reagents.**  \n   London, European Medicines Agency, 2008 (EMEA/CHMP/SWP/4446/2000).\n\n16. **ICH Harmonised tripartite guideline: validation of analytical procedures: text and methodology \u2013 Q2.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1994.\n\n17. **General guidelines for the establishment, maintenance and distribution of chemical reference substances.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization, 2007, Annex 3 (WHO Technical Report Series, No. 943).\n\n18. **Guidelines on packaging for pharmaceutical products.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-sixth report. Geneva, World Health Organization, 2002, Annex 9 (WHO Technical Report Series, No. 902).\n\n19. **Stability testing of active pharmaceutical ingredients and finished pharmaceutical products.**  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2009, Annex 2 (WHO Technical Report Series, No. 953).\n\n20. **ICH harmonised tripartite guideline: stability testing of new drug substances and products \u2013 Q1A.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2003.\n\n21. **Guidelines for registration of fixed-dose combination medicinal products.**  \n   Appendix 3: Pharmaceutical development (or preformulation) studies. Table A1: Typical stress conditions in preformulation stability studies.  \n   In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n22. **ICH harmonised tripartite guideline: Stability testing: Photostability testing of new drug substances and products \u2013 Q1B.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.\n\n23. **ICH harmonised tripartite guideline: evaluation for stability data \u2013 Q1E.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2003.\n\n24. **ICH harmonised tripartite guideline: bracketing and matrixing designs for stability testing of new drug substances and products \u2013 Q1D.**  \n   International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2002.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que presenta directrices y pautas relacionadas con la preparaci\u00f3n y especificaciones de productos farmac\u00e9uticos. Incluye referencias a varias gu\u00edas de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) y de la Agencia Europea de Medicamentos (EMA), as\u00ed como de la Administraci\u00f3n de Alimentos y Medicamentos de EE. UU. (FDA). Las pautas abordan temas como impurezas en productos farmac\u00e9uticos, l\u00edmites de impurezas genot\u00f3xicas, validaci\u00f3n de procedimientos anal\u00edticos, pruebas de estabilidad y requisitos de empaquetado.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las implicaciones de las directrices de la ICH sobre las impurezas en nuevos productos farmac\u00e9uticos (Q3B) para la industria farmac\u00e9utica?**\n   - Esta pregunta busca explorar c\u00f3mo las pautas establecidas en la directriz Q3B afectan la formulaci\u00f3n, producci\u00f3n y control de calidad de nuevos medicamentos, as\u00ed como su impacto en la seguridad del paciente.\n\n2. **\u00bfQu\u00e9 criterios se establecen en la gu\u00eda de la EMA sobre los l\u00edmites de impurezas genot\u00f3xicas y c\u00f3mo se aplican en la evaluaci\u00f3n de medicamentos?**\n   - Esta pregunta se centra en los criterios espec\u00edficos que la EMA establece para evaluar las impurezas genot\u00f3xicas y c\u00f3mo estos criterios influyen en el proceso de aprobaci\u00f3n de nuevos medicamentos.\n\n3. **\u00bfC\u00f3mo se relacionan las pautas de estabilidad de la ICH (Q1A, Q1B, Q1D, Q1E) con el desarrollo de productos farmac\u00e9uticos y qu\u00e9 metodolog\u00edas se recomiendan para las pruebas de estabilidad?**\n   - Esta pregunta busca profundizar en las metodolog\u00edas y enfoques recomendados por la ICH para realizar pruebas de estabilidad en nuevos productos farmac\u00e9uticos, as\u00ed como su relevancia en el desarrollo y la formulaci\u00f3n de medicamentos.\n\nEstas preguntas est\u00e1n dise\u00f1adas para obtener informaci\u00f3n detallada y espec\u00edfica que no se puede encontrar f\u00e1cilmente en otras fuentes, bas\u00e1ndose en el contenido del documento y su contexto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Procedimientos Anal\u00edticos y Validaci\u00f3n:**\n   - La secci\u00f3n 3.2.R.2 del documento se centra en la importancia de resumir los procedimientos anal\u00edticos y la informaci\u00f3n de validaci\u00f3n en tablas espec\u00edficas del formato de documento de calidad (QOS-PD).\n   - Se mencionan secciones espec\u00edficas del documento que deben ser referenciadas para la recopilaci\u00f3n de esta informaci\u00f3n.\n\n2. **Referencias a la Literatura Cient\u00edfica:**\n   - Se destaca la necesidad de incluir referencias a la literatura cient\u00edfica relacionada con el ingrediente farmac\u00e9utico activo (API) y el producto farmac\u00e9utico terminado (FPP) en el documento de presentaci\u00f3n (PD).\n   - Esto proporciona un respaldo cient\u00edfico y contexto a la informaci\u00f3n presentada.\n\n3. **Documentos Citados:**\n   - Se citan diversas gu\u00edas y documentos relevantes, incluyendo directrices de la OMS y de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH), que son fundamentales para la validaci\u00f3n y el registro de productos farmac\u00e9uticos.\n\n**Entidades:**\n\n- **Organizaciones:**\n  - Organizaci\u00f3n Mundial de la Salud (OMS)\n  - Conferencia Internacional sobre Armonizaci\u00f3n (ICH)\n  - Agencia Europea de Medicamentos (EMA)\n\n- **Documentos y Gu\u00edas:**\n  - WHO Technical Report Series\n  - ICH M4Q\n  - Directrices sobre buenas pr\u00e1cticas de fabricaci\u00f3n (GMP)\n  - Procedimientos de precalificaci\u00f3n de productos farmac\u00e9uticos\n\nEste resumen destaca la estructura y los elementos esenciales de la secci\u00f3n, enfatizando la importancia de la validaci\u00f3n y el respaldo cient\u00edfico en la presentaci\u00f3n de documentos para productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: pharmaceutical preparations, ICH guidelines, genotoxic impurities, stability testing, WHO Technical Report Series"}}, "5e607754-cc4b-417b-862f-019675bfc1a8": {"node_ids": ["7ba4637f-0b01-45e9-9155-587c48852b55"], "metadata": {"page_label": "205", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 4\n\n25. **ICH Harmonised tripartite guideline: pharmaceutical development \u2013 Q8.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009.\n\n26. **ICH Harmonised tripartite guideline: quality risk management \u2013 Q9.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2005.\n\n27. **ICH harmonised tripartite guideline: pharmaceutical quality system \u2013 Q10.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008.\n\n28. **Inactive ingredient guide.** US Food and Drug Administration, http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm\n\n29. Rowe RC, Sheskey PJ, Quinn ME, eds. **Handbook of pharmaceutical excipients,** 6th ed. London, Pharmaceutical Press, 2009.\n\n30. **Excipients in the label and package leaflet of medicinal products for human use.**\n\n31. 2003 (CPMP/463/00) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003412.pdf\n\n32. **WHO Guidelines on development of paediatric medicines: points to consider in formulation.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012, Annex 5 (WHO Technical Report Series, No. 970).\n\n33. **Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n34. **Containers \u2013 glass.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n35. **Glass containers for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 303\u2013307.\n\n36. **Plastic containers and closures for pharmaceutical use.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 308\u2013309.\n\n37. **Containers \u2013 plastic.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007.\n\n38. **Elastomeric closures for injections.** In: *United States Pharmacopeia,* 2nd suppl. Rockville, MD, 2007: 144\u2013145.\n\n39. **Rubber closures for containers.** In: *European Pharmacopoeia.* Strasbourg, European Directorate for the Quality of Medicines, 2010: 316\u2013317.\n\n40. **Commission regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact with food.**\n\n41. **WHO good distribution practices for pharmaceutical products.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth report. Geneva, World Health Organization, 2010, Annex 5 (WHO Technical Report Series, No. 957).\n\n42. **Good manufacturing practices for pharmaceutical products: main principles.** In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report. Geneva, World Health Organization, 2011, Annex 3 (WHO Technical Report Series, No. 961).\n\n43. **ICH Harmonised tripartite guideline: viral safety evaluation of biotechnology products derived from cell lines of human or animal origin \u2013 Q5A.** International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl contexto presenta una lista de directrices y documentos relevantes relacionados con el desarrollo y la calidad de productos farmac\u00e9uticos, emitidos por la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) y la Organizaci\u00f3n Mundial de la Salud (OMS). Incluye pautas sobre el desarrollo farmac\u00e9utico, gesti\u00f3n de riesgos de calidad, sistemas de calidad farmac\u00e9utica, y buenas pr\u00e1cticas de distribuci\u00f3n y fabricaci\u00f3n. Tambi\u00e9n se mencionan gu\u00edas sobre excipientes, contenedores y regulaciones espec\u00edficas para materiales en contacto con alimentos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los principales objetivos de la gu\u00eda ICH Q8 sobre el desarrollo farmac\u00e9utico?**\n   - Esta gu\u00eda se centra en proporcionar un marco para el desarrollo de productos farmac\u00e9uticos, enfatizando la importancia de la calidad desde las etapas iniciales del desarrollo y la necesidad de un enfoque basado en el riesgo.\n\n2. **\u00bfQu\u00e9 aspectos se consideran en las \"WHO Guidelines on development of paediatric medicines\"?**\n   - Estas pautas abordan consideraciones espec\u00edficas para la formulaci\u00f3n de medicamentos pedi\u00e1tricos, incluyendo la selecci\u00f3n de excipientes, la dosificaci\u00f3n y la presentaci\u00f3n del producto, asegurando que sean adecuados y seguros para la poblaci\u00f3n infantil.\n\n3. **\u00bfQu\u00e9 regulaciones se establecen en la \"Commission regulation (EU) No 10/2011\" respecto a los materiales pl\u00e1sticos?**\n   - Esta regulaci\u00f3n establece los requisitos para los materiales pl\u00e1sticos destinados a entrar en contacto con alimentos, asegurando que sean seguros y no transfieran sustancias nocivas a los alimentos.\n\n### Resumen de Nivel Superior\n\nEl documento proporciona un compendio de directrices y regulaciones que son fundamentales para la industria farmac\u00e9utica, enfoc\u00e1ndose en la calidad y seguridad de los productos. Las pautas de la ICH y la OMS son esenciales para garantizar que los medicamentos sean desarrollados y fabricados de manera que cumplan con los est\u00e1ndares internacionales, protegiendo as\u00ed la salud p\u00fablica. Adem\u00e1s, se abordan temas espec\u00edficos como la formulaci\u00f3n de medicamentos para ni\u00f1os y la seguridad de los materiales en contacto con alimentos, lo que refleja la diversidad de consideraciones en la producci\u00f3n farmac\u00e9utica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nLa secci\u00f3n del documento se centra en las directrices y pautas relacionadas con la preparaci\u00f3n y especificaciones de productos farmac\u00e9uticos, destacando las siguientes \u00e1reas clave:\n\n1. **Implicaciones de Impurezas en Productos Farmac\u00e9uticos:**\n   - Directrices de la ICH sobre impurezas en nuevos productos farmac\u00e9uticos (Q3B) y solventes residuales (Q3C).\n   - L\u00edmites de impurezas genot\u00f3xicas seg\u00fan la EMA y la FDA.\n\n2. **Validaci\u00f3n de Procedimientos Anal\u00edticos:**\n   - Directriz de la ICH sobre la validaci\u00f3n de procedimientos anal\u00edticos (Q2).\n\n3. **Estabilidad de Productos Farmac\u00e9uticos:**\n   - Directrices de la ICH sobre pruebas de estabilidad (Q1A, Q1B, Q1D, Q1E) y su relevancia en el desarrollo de productos farmac\u00e9uticos.\n   - Pruebas de estabilidad de ingredientes farmac\u00e9uticos activos y productos terminados.\n\n4. **Requisitos de Empaque:**\n   - Directrices de la OMS sobre el empaque de productos farmac\u00e9uticos.\n\n### Entidades Clave\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Publica directrices sobre especificaciones para productos farmac\u00e9uticos.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH):** Establece pautas armonizadas para la industria farmac\u00e9utica.\n- **Agencia Europea de Medicamentos (EMA):** Proporciona directrices sobre l\u00edmites de impurezas y evaluaci\u00f3n de medicamentos.\n- **Administraci\u00f3n de Alimentos y Medicamentos de EE. UU. (FDA):** Ofrece orientaci\u00f3n sobre impurezas genot\u00f3xicas y carcinog\u00e9nicas.\n\nEste resumen destaca la importancia de las directrices en la formulaci\u00f3n, producci\u00f3n y control de calidad de medicamentos, as\u00ed como su impacto en la seguridad del paciente y el proceso de aprobaci\u00f3n de nuevos productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: pharmaceutical development, quality risk management, pediatric medicines, excipients, good manufacturing practices"}}, "707abe7c-fbce-4738-bfa7-9cb396e2436a": {"node_ids": ["7ed9c02f-38ba-40c8-85c8-15f386c58885"], "metadata": {"page_label": "206", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n44. **ICH Harmonised tripartite guideline: derivation and characterisation of cell substrates used for production of biotechnological/biological products \u2013 Q5D.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1997.\n\n45. **ICH Harmonised tripartite guideline: specifications: test procedures and acceptance criteria for biotechnological/biological products \u2013 Q6B.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999.\n\n46. **Recommendations on risk of transmitting animal spongiform encephalopathy agents via medicinal products.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report.* Geneva, World Health Organization, 2003, Annex 1 (WHO Technical Report Series, No. 908).\n\n47. **ICH harmonised tripartite guideline: stability testing for new dosage forms: Annex to the ICH harmonised tripartite guideline on stability testing for new drugs and products \u2013 Q1C.** Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.\n\n48. **Good manufacturing practices for sterile pharmaceutical products.** In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-sixth report.* Geneva, World Health Organization, 2011, Annex 6 (WHO Technical Report Series, No. 961).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior que puede ayudar a formularlas:\n\n### Resumen de Nivel Superior\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que detalla las directrices y recomendaciones sobre la producci\u00f3n y control de productos farmac\u00e9uticos biotecnol\u00f3gicos y biol\u00f3gicos. Incluye pautas de la Conferencia sobre Armonizaci\u00f3n de Requisitos T\u00e9cnicos para el Registro de Productos Farmac\u00e9uticos para Uso Humano (ICH) y recomendaciones sobre la seguridad de los productos medicinales en relaci\u00f3n con agentes de encefalopat\u00eda espongiforme transmisible.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son las recomendaciones espec\u00edficas de la OMS sobre el riesgo de transmisi\u00f3n de agentes de encefalopat\u00eda espongiforme a trav\u00e9s de productos medicinales?**\n   - Esta pregunta busca detalles sobre las recomendaciones espec\u00edficas que se encuentran en el documento, que pueden no estar disponibles en otras fuentes.\n\n2. **\u00bfQu\u00e9 aspectos se abordan en la gu\u00eda ICH Q5D sobre la caracterizaci\u00f3n de sustratos celulares utilizados en la producci\u00f3n de productos biotecnol\u00f3gicos?**\n   - Esta pregunta se centra en los detalles t\u00e9cnicos de la gu\u00eda ICH Q5D, que pueden no estar ampliamente discutidos en otros documentos.\n\n3. **\u00bfQu\u00e9 pr\u00e1cticas de fabricaci\u00f3n se consideran esenciales para los productos farmac\u00e9uticos est\u00e9riles seg\u00fan el informe de la OMS?**\n   - Esta pregunta busca informaci\u00f3n sobre las buenas pr\u00e1cticas de fabricaci\u00f3n espec\u00edficas mencionadas en el contexto, que son cruciales para la producci\u00f3n de productos farmac\u00e9uticos est\u00e9riles.", "prev_section_summary": "### Temas Clave y Entidades de la Secci\u00f3n\n\n1. **Directrices de la ICH**:\n   - **Q8**: Desarrollo farmac\u00e9utico, enfatizando la calidad desde las etapas iniciales.\n   - **Q9**: Gesti\u00f3n de riesgos de calidad, abordando la identificaci\u00f3n y mitigaci\u00f3n de riesgos en el proceso de desarrollo.\n   - **Q10**: Sistema de calidad farmac\u00e9utica, estableciendo un marco para asegurar la calidad a lo largo del ciclo de vida del producto.\n   - **Q5A**: Evaluaci\u00f3n de la seguridad viral de productos biotecnol\u00f3gicos.\n\n2. **Regulaciones y Gu\u00edas de la OMS**:\n   - **Gu\u00edas sobre medicamentos pedi\u00e1tricos**: Consideraciones en la formulaci\u00f3n y dosificaci\u00f3n para la poblaci\u00f3n infantil.\n   - **Buenas pr\u00e1cticas de distribuci\u00f3n**: Normas para asegurar la calidad y seguridad en la distribuci\u00f3n de productos farmac\u00e9uticos.\n   - **Buenas pr\u00e1cticas de fabricaci\u00f3n**: Principios fundamentales para la producci\u00f3n de medicamentos.\n\n3. **Excipientes y Contenedores**:\n   - Gu\u00edas sobre excipientes en productos medicinales y su etiquetado.\n   - Regulaciones sobre contenedores de vidrio y pl\u00e1stico para uso farmac\u00e9utico, incluyendo especificaciones de la Farmacopea de EE. UU. y la Farmacopea Europea.\n\n4. **Regulaci\u00f3n de Materiales en Contacto con Alimentos**:\n   - **Reglamento (UE) No 10/2011**: Establece requisitos para materiales pl\u00e1sticos que entran en contacto con alimentos, asegurando su seguridad.\n\n5. **Referencias Importantes**:\n   - **Handbook of Pharmaceutical Excipients**: Una referencia clave para excipientes utilizados en la formulaci\u00f3n de medicamentos.\n   - Documentos de la EMA y la FDA que proporcionan gu\u00edas y regulaciones adicionales.\n\n### Entidades Clave\n- **Organizaciones**: \n  - Conferencia Internacional sobre Armonizaci\u00f3n (ICH)\n  - Organizaci\u00f3n Mundial de la Salud (OMS)\n  - Administraci\u00f3n de Alimentos y Medicamentos de EE. UU. (FDA)\n  - Agencia Europea de Medicamentos (EMA)\n\n- **Publicaciones**: \n  - WHO Technical Report Series\n  - United States Pharmacopeia\n  - European Pharmacopoeia\n\nEste resumen destaca la importancia de las directrices y regulaciones en la industria farmac\u00e9utica, enfoc\u00e1ndose en la calidad, seguridad y adecuaci\u00f3n de los productos para diferentes poblaciones, as\u00ed como en la gesti\u00f3n de riesgos y el uso de excipientes y contenedores adecuados.", "excerpt_keywords": "Keywords: ICH guidelines, biotechnological products, spongiform encephalopathy, pharmaceutical preparations, good manufacturing practices"}}, "e4fe0ecb-2138-44e4-bc18-cc6980fb72e2": {"node_ids": ["db5ab5a0-969d-4c0f-b336-7176bf2083cb"], "metadata": {"page_label": "207", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 1\n\n## Recommendations for conducting and assessing comparative dissolution profiles\n\nThe dissolution measurements of the two FPPs (e.g. test and reference (comparator) or two different strengths) should be made under the same test conditions. A minimum of three time-points (zero excluded) should be included, the time-points for both reference (comparator) and test product being the same. The sampling intervals should be short for a scientifically sound comparison of the profiles (e.g. 5, 10, 15, 20, 30, 45 (60, 90, 120) minutes). The 15-minute time-point is critical to determine whether a product is very rapidly dissolving and to determine whether f\u2082 must be calculated. For extended-release FPPs, the time-points should be set to cover the entire duration of expected release, e.g. 1, 2, 3, 5 and 8 hours for a 12-hour release and additional test intervals for longer duration of release.\n\nStudies should be performed in at least three media covering the physiological range, including pH 1.2 hydrochloric acid, pH 4.5 buffer and pH 6.8 buffer. *International Pharmacopoeia* buffers are recommended; other pharmacopoeial buffers with the same pH and buffer capacity are also accepted. Water may be considered as an additional medium, especially when the API is unstable in the buffered media to the extent that the data are unusable.\n\nIf both the test and reference (comparator) products show more than 85% dissolution in 15 minutes, the profiles are considered similar (no calculations required). Otherwise:\n\n- Similarity of the resulting comparative dissolution profiles should be calculated using the following equation that defines a similarity factor (f\u2082):\n\n  \\[\n  f_2 = 50 \\log \\left\\{ [1 + 1/n \\sum_{t=1}^n (R_t - T_t)^2]^{-0.5} \\times 100 \\right\\}\n  \\]\n\n  where \\( R_t \\) and \\( T_t \\) are the mean per cent API dissolved in reference (comparator) and test product, respectively, at each time-point. An f\u2082 value between 50 and 100 suggests that the two dissolution profiles are similar.\n\n- A maximum of one time-point should be considered after 85% dissolution of the reference (comparator) product has been reached. In the case where 85% dissolution cannot be reached due to poor solubility of the API, the dissolution should be conducted until an asymptote (plateau) has been reached.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de Nivel Superior\n\nEl documento proporciona recomendaciones sobre c\u00f3mo llevar a cabo y evaluar perfiles de disoluci\u00f3n comparativa para productos farmac\u00e9uticos formulados (FPPs). Se enfatiza la importancia de realizar mediciones de disoluci\u00f3n bajo condiciones de prueba consistentes, utilizando al menos tres puntos de tiempo y diferentes medios que cubran el rango fisiol\u00f3gico. Se establece un m\u00e9todo para calcular la similitud de los perfiles de disoluci\u00f3n mediante un factor de similitud (f\u2082), y se especifican criterios para determinar si los perfiles son considerados similares.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los medios recomendados para realizar estudios de disoluci\u00f3n y por qu\u00e9 se sugiere el uso de estos espec\u00edficos?**\n   - El documento recomienda realizar estudios en al menos tres medios que cubran el rango fisiol\u00f3gico: \u00e1cido clorh\u00eddrico a pH 1.2, un buffer a pH 4.5 y un buffer a pH 6.8. Se sugiere el uso de buffers de la *Farmacopea Internacional* debido a su capacidad de mantener un pH y una capacidad de amortiguaci\u00f3n consistentes, lo que es crucial para obtener datos fiables sobre la disoluci\u00f3n del principio activo (API).\n\n2. **\u00bfQu\u00e9 criterios se deben cumplir para considerar que los perfiles de disoluci\u00f3n de dos productos son similares sin necesidad de c\u00e1lculos adicionales?**\n   - Si ambos productos (test y referencia) muestran m\u00e1s del 85% de disoluci\u00f3n en 15 minutos, se consideran que sus perfiles son similares y no se requieren c\u00e1lculos adicionales para determinar la similitud.\n\n3. **\u00bfC\u00f3mo se debe proceder si no se puede alcanzar el 85% de disoluci\u00f3n debido a la baja solubilidad del API?**\n   - En casos donde no se puede alcanzar el 85% de disoluci\u00f3n debido a la baja solubilidad del API, se debe continuar con el estudio de disoluci\u00f3n hasta que se alcance un asintota o un plateau, lo que permitir\u00e1 evaluar el comportamiento de disoluci\u00f3n del producto en condiciones desfavorables.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Organizaci\u00f3n Mundial de la Salud (OMS)**: El documento es parte de los informes de la OMS, espec\u00edficamente del Comit\u00e9 de Expertos sobre Especificaciones para Preparaciones Farmac\u00e9uticas.\n\n2. **Directrices ICH**: Se mencionan varias gu\u00edas armonizadas de la Conferencia sobre Armonizaci\u00f3n de Requisitos T\u00e9cnicos para el Registro de Productos Farmac\u00e9uticos para Uso Humano (ICH), que son fundamentales para la regulaci\u00f3n de productos biotecnol\u00f3gicos y biol\u00f3gicos:\n   - **Q5D**: Derivaci\u00f3n y caracterizaci\u00f3n de sustratos celulares.\n   - **Q6B**: Especificaciones, procedimientos de prueba y criterios de aceptaci\u00f3n para productos biotecnol\u00f3gicos/biol\u00f3gicos.\n   - **Q1C**: Pruebas de estabilidad para nuevas formas de dosificaci\u00f3n.\n\n3. **Recomendaciones sobre encefalopat\u00eda espongiforme**: Se incluyen recomendaciones espec\u00edficas sobre el riesgo de transmisi\u00f3n de agentes de encefalopat\u00eda espongiforme a trav\u00e9s de productos medicinales, destacando la importancia de la seguridad en la producci\u00f3n farmac\u00e9utica.\n\n4. **Buenas Pr\u00e1cticas de Fabricaci\u00f3n (BPF)**: Se abordan las pr\u00e1cticas esenciales para la fabricaci\u00f3n de productos farmac\u00e9uticos est\u00e9riles, enfatizando la necesidad de cumplir con est\u00e1ndares de calidad y seguridad.\n\n### Entidades Clave\n- **WHO (OMS)**: Organizaci\u00f3n responsable de la elaboraci\u00f3n de las directrices.\n- **ICH**: Conferencia que establece las gu\u00edas t\u00e9cnicas para la industria farmac\u00e9utica.\n- **Productos Biotecnol\u00f3gicos/Biol\u00f3gicos**: Categor\u00eda de productos farmac\u00e9uticos que requieren regulaciones espec\u00edficas.\n- **Encefalopat\u00eda Espongiforme**: Grupo de enfermedades que representan un riesgo en la producci\u00f3n de medicamentos.\n\nEste resumen destaca la importancia de las directrices y recomendaciones de la OMS y la ICH en la producci\u00f3n y control de productos farmac\u00e9uticos, as\u00ed como la atenci\u00f3n a la seguridad en relaci\u00f3n con agentes pat\u00f3genos.", "excerpt_keywords": "Keywords: dissolution profiles, pharmaceutical products, similarity factor, test conditions, release kinetics"}}, "d473d4c5-7a99-4d8a-ab0c-9966f4a6aaf5": {"node_ids": ["3c950ec8-2424-49e2-8cb8-cd0fad9367e1"], "metadata": {"page_label": "208", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "- At least 12 units should be used for determination of each profile. Mean dissolution values can be used to estimate the similarity factor, f\u2082. To use mean data, the percentage coefficient of variation at the first time-point should be not more than 20% and at other time-points should be not more than 10%.\n\n- When delayed-release products (e.g. enteric coated) are being compared, the recommended conditions are acid medium (pH 1.2) for 2 hours and buffer pH 6.8 medium.\n\n- When comparing extended-release beaded capsules, where different strengths have been achieved solely by means of adjusting the number of beads containing the API, one condition (normally the release condition) will suffice.\n\n- Surfactants should be avoided in comparative dissolution testing. A statement that the API is not soluble in any of the media is not sufficient and profiles in the absence of surfactant should be provided. The rationale for the choice and concentration of surfactant should be provided. The concentration of the surfactant should be such that the discriminatory power of the test will not be compromised.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Determinaci\u00f3n de perfiles de disoluci\u00f3n**: Se establece que para la determinaci\u00f3n de perfiles de disoluci\u00f3n, se deben utilizar al menos 12 unidades y se deben cumplir ciertos criterios de variabilidad en los datos para calcular el factor de similitud f\u2082.\n\n2. **Condiciones de comparaci\u00f3n para productos de liberaci\u00f3n retardada**: Se especifican las condiciones recomendadas para comparar productos de liberaci\u00f3n retardada, incluyendo el uso de medios \u00e1cidos y buffer en pH espec\u00edfico.\n\n3. **Pruebas de disoluci\u00f3n para c\u00e1psulas de liberaci\u00f3n prolongada**: Se indica que al comparar c\u00e1psulas de liberaci\u00f3n prolongada que var\u00edan en fuerza por el n\u00famero de beads, se puede utilizar una sola condici\u00f3n de liberaci\u00f3n.\n\n4. **Uso de surfactantes en pruebas de disoluci\u00f3n**: Se aconseja evitar el uso de surfactantes en las pruebas de disoluci\u00f3n comparativa y se requiere que se justifique su uso si es necesario.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1l es el n\u00famero m\u00ednimo de unidades que se deben utilizar para determinar un perfil de disoluci\u00f3n y qu\u00e9 criterios de variabilidad deben cumplirse para utilizar los valores medios?**\n   - Respuesta: Se deben utilizar al menos 12 unidades para la determinaci\u00f3n de cada perfil. El coeficiente de variaci\u00f3n porcentual en el primer punto de tiempo no debe ser superior al 20%, y en otros puntos de tiempo no debe ser superior al 10%.\n\n2. **\u00bfQu\u00e9 condiciones se recomiendan para la comparaci\u00f3n de productos de liberaci\u00f3n retardada, como los recubiertos ent\u00e9ricamente?**\n   - Respuesta: Se recomiendan condiciones de medio \u00e1cido (pH 1.2) durante 2 horas y medio buffer a pH 6.8 para la comparaci\u00f3n de productos de liberaci\u00f3n retardada.\n\n3. **\u00bfQu\u00e9 se debe considerar al utilizar surfactantes en pruebas de disoluci\u00f3n comparativa y qu\u00e9 informaci\u00f3n debe proporcionarse si se decide usarlos?**\n   - Respuesta: Se deben evitar los surfactantes en las pruebas de disoluci\u00f3n comparativa. Si se utilizan, se debe proporcionar una justificaci\u00f3n para la elecci\u00f3n y concentraci\u00f3n del surfactante, asegurando que la concentraci\u00f3n no comprometa el poder discriminatorio de la prueba. Adem\u00e1s, se deben proporcionar perfiles en ausencia de surfactante.", "prev_section_summary": "### Temas Clave\n\n1. **Mediciones de Disoluci\u00f3n**: Se deben realizar bajo condiciones de prueba consistentes para productos farmac\u00e9uticos formulados (FPPs), incluyendo un m\u00ednimo de tres puntos de tiempo.\n\n2. **Puntos de Tiempo**: Se recomienda incluir intervalos cortos (5, 10, 15, 20, 30, 45 (60, 90, 120) minutos) para una comparaci\u00f3n cient\u00edfica adecuada. El punto de 15 minutos es crucial para evaluar la rapidez de disoluci\u00f3n.\n\n3. **Medios de Estudio**: Se deben utilizar al menos tres medios que cubran el rango fisiol\u00f3gico, como \u00e1cido clorh\u00eddrico a pH 1.2, buffer a pH 4.5 y buffer a pH 6.8. Se sugiere el uso de buffers de la *Farmacopea Internacional*.\n\n4. **Similitud de Perfiles de Disoluci\u00f3n**: Si ambos productos muestran m\u00e1s del 85% de disoluci\u00f3n en 15 minutos, se consideran similares sin necesidad de c\u00e1lculos. De lo contrario, se debe calcular un factor de similitud (f\u2082).\n\n5. **C\u00e1lculo del Factor de Similitud (f\u2082)**: Se proporciona una f\u00f3rmula para calcular f\u2082, donde un valor entre 50 y 100 indica que los perfiles son similares.\n\n6. **Condiciones de Solubilidad**: Si no se alcanza el 85% de disoluci\u00f3n debido a baja solubilidad, se debe continuar el estudio hasta alcanzar un asintota o plateau.\n\n### Entidades\n\n- **FPPs**: Productos farmac\u00e9uticos formulados.\n- **pH**: Medidas de acidez o alcalinidad de los medios utilizados.\n- **API**: Principio activo.\n- **f\u2082**: Factor de similitud para evaluar la comparabilidad de perfiles de disoluci\u00f3n.\n- **Buffers**: Soluciones que mantienen un pH constante durante el estudio de disoluci\u00f3n.\n- **Farmacopea Internacional**: Referencia para la calidad de los buffers utilizados en estudios farmac\u00e9uticos.", "excerpt_keywords": "Keywords: disoluci\u00f3n, perfil, surfactantes, liberaci\u00f3n retardada, factor de similitud"}}, "392d04a7-459d-4627-ac84-68ea6be9cf6b": {"node_ids": ["0405e7e9-855b-41c1-86b4-3f879d028883"], "metadata": {"page_label": "209", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Appendix 2\n\n## Product quality review requirements for established multisource products\n\nFor an established multisource product, a product quality review may satisfy the requirements of sections 3.2.P.2.2.1 (a), 3.2.P.2.3 (a) and 3.2.P.3.5 of the PD and QOS-PD.\n\nA product quality review should be submitted with the objective of verifying the consistency of the quality of the FPP and its manufacturing process.\n\nRejected batches should not be included in the analysis but must be reported separately together with the reports of failure investigations, as indicated below.\n\nReviews should be conducted with no fewer than 10 consecutive batches manufactured over the period of the past 12 months or, where 10 batches were not manufactured in the past 12 months, no fewer than 25 consecutive batches manufactured over the period of the past 36 months and should include at least:\n\n- a review of starting and primary packaging materials used in the FPP, especially those from new sources;\n- a tabulated review and statistical analysis of quality control and in-process control results;\n- a review of all batches that failed to meet established specification(s);\n- a review of all critical deviations or non-conformances and related investigations;\n- a review of all changes carried out to the processes or analytical methods;\n- a review of the results of the stability-monitoring programme;\n- a review of all quality-related returns, complaints and recalls, including export-only medicinal products;\n- a review of the adequacy of previous corrective actions;\n- a list of validated analytical and manufacturing procedures and their revalidation dates.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS establece los requisitos para la revisi\u00f3n de la calidad del producto en productos multisource establecidos. Se enfatiza la importancia de verificar la consistencia de la calidad del producto farmac\u00e9utico terminado (FPP) y su proceso de fabricaci\u00f3n. Se especifican criterios para la revisi\u00f3n, incluyendo el an\u00e1lisis de materiales de empaque, resultados de control de calidad, y la gesti\u00f3n de lotes rechazados, entre otros. La revisi\u00f3n debe abarcar un n\u00famero m\u00ednimo de lotes fabricados en un per\u00edodo determinado.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios m\u00ednimos para la cantidad de lotes que deben ser revisados en la evaluaci\u00f3n de calidad de un producto multisource establecido?**\n   - La revisi\u00f3n debe incluir al menos 10 lotes consecutivos fabricados en los \u00faltimos 12 meses, o si no se han fabricado 10 lotes en ese per\u00edodo, al menos 25 lotes consecutivos en los \u00faltimos 36 meses.\n\n2. **\u00bfQu\u00e9 tipo de materiales deben ser revisados en el contexto de la evaluaci\u00f3n de calidad del producto farmac\u00e9utico terminado (FPP)?**\n   - Se debe realizar una revisi\u00f3n de los materiales de empaque inicial y primario utilizados en el FPP, especialmente aquellos provenientes de nuevas fuentes.\n\n3. **\u00bfQu\u00e9 acciones deben tomarse con respecto a los lotes rechazados durante la revisi\u00f3n de calidad?**\n   - Los lotes rechazados no deben incluirse en el an\u00e1lisis de la revisi\u00f3n, pero deben ser reportados por separado junto con los informes de las investigaciones de fallas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Determinaci\u00f3n de Perfiles de Disoluci\u00f3n**:\n   - **N\u00famero M\u00ednimo de Unidades**: Se requieren al menos 12 unidades para la determinaci\u00f3n de cada perfil de disoluci\u00f3n.\n   - **Criterios de Variabilidad**: El coeficiente de variaci\u00f3n porcentual debe ser \u2264 20% en el primer punto de tiempo y \u2264 10% en otros puntos de tiempo para utilizar valores medios en el c\u00e1lculo del factor de similitud f\u2082.\n\n2. **Comparaci\u00f3n de Productos de Liberaci\u00f3n Retardada**:\n   - **Condiciones Recomendadas**: Se sugiere el uso de un medio \u00e1cido (pH 1.2) durante 2 horas, seguido de un medio buffer a pH 6.8 para la comparaci\u00f3n de productos como los recubiertos ent\u00e9ricamente.\n\n3. **C\u00e1psulas de Liberaci\u00f3n Prolongada**:\n   - **Condiciones de Prueba**: Al comparar c\u00e1psulas de liberaci\u00f3n prolongada que var\u00edan en fuerza por el n\u00famero de beads, se puede utilizar una sola condici\u00f3n de liberaci\u00f3n.\n\n4. **Uso de Surfactantes en Pruebas de Disoluci\u00f3n**:\n   - **Recomendaci\u00f3n**: Se aconseja evitar el uso de surfactantes en pruebas de disoluci\u00f3n comparativa.\n   - **Justificaci\u00f3n**: Si se utilizan surfactantes, se debe proporcionar una justificaci\u00f3n para su elecci\u00f3n y concentraci\u00f3n, asegurando que no comprometan el poder discriminatorio de la prueba. Adem\u00e1s, se deben presentar perfiles de disoluci\u00f3n en ausencia de surfactante.\n\n### Entidades Clave\n- **Factor de Similitud (f\u2082)**: M\u00e9trica utilizada para estimar la similitud entre perfiles de disoluci\u00f3n.\n- **Unidades de Prueba**: M\u00ednimo de 12 unidades requeridas.\n- **Condiciones de pH**: pH 1.2 y pH 6.8 como condiciones de prueba.\n- **API (Ingrediente Activo)**: Sustancia cuya solubilidad se eval\u00faa en las pruebas de disoluci\u00f3n.\n- **Surfactantes**: Sustancias que deben ser evitadas en pruebas de disoluci\u00f3n comparativa.", "excerpt_keywords": "Keywords: product quality review, multisource products, manufacturing process, quality control, stability-monitoring programme"}}, "d5f145bd-f1db-4e05-8c2e-b273bbf4c7ca": {"node_ids": ["3ef566e3-a96b-4a3a-b020-f401a2c5cea7"], "metadata": {"page_label": "210", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Notes\n\n- Reviews must include data from all batches manufactured during the review period.\n- Data should be presented in tabular or graphical form, when applicable.\n- The above listing of requirements is specific to the dossier assessment process requirements and does not relieve the applicant of related GMP requirements.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior del contenido:\n\n### Resumen de Nivel Superior\nEl documento de la OMS, titulado \"Technical Report Series 970\", establece requisitos para la evaluaci\u00f3n de dossiers relacionados con la fabricaci\u00f3n de productos. Se enfatiza que las revisiones deben incluir datos de todos los lotes fabricados durante el per\u00edodo de revisi\u00f3n y que estos datos deben presentarse de manera clara, ya sea en forma tabular o gr\u00e1fica. Adem\u00e1s, se aclara que estos requisitos son espec\u00edficos para el proceso de evaluaci\u00f3n del dossier y no eximen al solicitante de cumplir con los requisitos de Buenas Pr\u00e1cticas de Manufactura (GMP).\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfQu\u00e9 tipo de datos deben incluirse en las revisiones seg\u00fan el documento de la OMS?**\n   - Las revisiones deben incluir datos de todos los lotes fabricados durante el per\u00edodo de revisi\u00f3n.\n\n2. **\u00bfC\u00f3mo se deben presentar los datos en las revisiones?**\n   - Los datos deben presentarse en forma tabular o gr\u00e1fica, cuando sea aplicable.\n\n3. **\u00bfLos requisitos de evaluaci\u00f3n del dossier eximen al solicitante de cumplir con otros requisitos?**\n   - No, la lista de requisitos es espec\u00edfica para el proceso de evaluaci\u00f3n del dossier y no exime al solicitante de cumplir con los requisitos de Buenas Pr\u00e1cticas de Manufactura (GMP).", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Revisi\u00f3n de Calidad del Producto:** Se establece la necesidad de realizar una revisi\u00f3n de calidad para productos multisource establecidos, con el objetivo de verificar la consistencia de la calidad del producto farmac\u00e9utico terminado (FPP) y su proceso de fabricaci\u00f3n.\n  \n2. **Criterios de Revisi\u00f3n:** La revisi\u00f3n debe incluir un an\u00e1lisis de al menos 10 lotes consecutivos fabricados en los \u00faltimos 12 meses, o 25 lotes en los \u00faltimos 36 meses si no se han fabricado suficientes lotes en el per\u00edodo m\u00e1s corto.\n\n3. **Materiales de Empaque:** Se debe revisar los materiales de empaque inicial y primario, especialmente aquellos provenientes de nuevas fuentes.\n\n4. **Gesti\u00f3n de Lotes Rechazados:** Los lotes rechazados no deben incluirse en el an\u00e1lisis de la revisi\u00f3n, pero deben ser reportados por separado junto con los informes de investigaciones de fallas.\n\n5. **Elementos de la Revisi\u00f3n:** La revisi\u00f3n debe abarcar varios aspectos, incluyendo:\n   - An\u00e1lisis de resultados de control de calidad.\n   - Revisi\u00f3n de lotes que no cumplieron con las especificaciones.\n   - Evaluaci\u00f3n de desviaciones cr\u00edticas y no conformidades.\n   - Cambios en procesos o m\u00e9todos anal\u00edticos.\n   - Resultados del programa de monitoreo de estabilidad.\n   - Quejas, devoluciones y retiros relacionados con la calidad.\n   - Eficacia de acciones correctivas previas.\n   - Listado de procedimientos anal\u00edticos y de fabricaci\u00f3n validados y sus fechas de revalidaci\u00f3n.\n\n**Entidades:**\n- **Organizaci\u00f3n Mundial de la Salud (OMS):** Entidad que emite las directrices.\n- **Productos Multisource:** Tipo de productos farmac\u00e9uticos a los que se aplican los requisitos de revisi\u00f3n.\n- **Producto Farmac\u00e9utico Terminado (FPP):** Producto cuyo proceso de calidad se est\u00e1 revisando.\n- **Lotes:** Unidades de producci\u00f3n que se analizan durante la revisi\u00f3n de calidad.\n- **Materiales de Empaque:** Componentes utilizados para el embalaje del FPP.\n\nEste resumen destaca los aspectos esenciales de la revisi\u00f3n de calidad para productos multisource establecidos, enfatizando la importancia de la consistencia y el cumplimiento de las especificaciones en la fabricaci\u00f3n de productos farmac\u00e9uticos.", "excerpt_keywords": "Keywords: dossier assessment, batch data, GMP requirements, quality review, tabular presentation"}}, "cbeccdea-20bf-4576-9338-a19991b316ab": {"node_ids": ["bec8c423-2a60-43b8-a9d6-3d769be8fe42"], "metadata": {"page_label": "211", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\n## Development of paediatric medicines: points to consider in formulation\n\n### General note\n\nThe \"points to consider\" document should not contain detailed instructions for development but rather it should make reference to relevant literature. Some matters dealt with in the draft on development of multisource products have, therefore, been omitted in this proposal.\n\n1. **Introduction**  \n   Page 199\n\n2. **Glossary**  \n   Page 200\n\n3. **Paediatric dosage forms**  \n   Page 200  \n   3.1 Convenient, reliable administration  \n   Page 201  \n   3.2 Acceptability and palatability  \n   Page 202  \n   3.3 Minimum dosing frequency  \n   Page 203  \n   3.4 End-user needs  \n   Page 203\n\n4. **Particular dosage forms to be considered**  \n   Page 203  \n   4.1 Flexible solid dosage forms  \n   Page 203  \n   4.2 Oral medicines  \n   Page 204  \n   4.3 Medicines for severe conditions  \n   Page 204  \n   4.4 Rectal preparations  \n   Page 204\n\n5. **Formulation design**  \n   Page 204  \n   5.1 Quality  \n   Page 205  \n   5.2 Biopharmaceutics classification system  \n   Page 205  \n   5.3 Excipients  \n   Page 206  \n   5.4 Colouring agents  \n   Page 208  \n   5.5 Antimicrobial preservatives  \n   Page 208  \n   5.6 Sweetening agents  \n   Page 208  \n   5.7 Taste masking  \n   Page 209  \n   5.8 Solubility enhancers  \n   Page 209\n\n6. **Oral administration**  \n   Page 210  \n   6.1 Oral liquid preparations  \n   Page 210  \n   6.2 Administration through feeding tubes  \n   Page 212  \n   6.3 Oral solid dosage forms  \n   Page 212", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, as\u00ed como un resumen de nivel superior:\n\n### Resumen de nivel superior\nEl documento \"Development of paediatric medicines: points to consider in formulation\" de la OMS aborda aspectos clave en la formulaci\u00f3n de medicamentos pedi\u00e1tricos. Se enfoca en la importancia de la administraci\u00f3n conveniente y confiable, la aceptabilidad y palatabilidad de los medicamentos, y la consideraci\u00f3n de las necesidades de los usuarios finales. Adem\u00e1s, se discuten diferentes formas de dosificaci\u00f3n, el dise\u00f1o de formulaciones y la administraci\u00f3n oral, incluyendo preparaciones l\u00edquidas y s\u00f3lidas.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los factores clave que se deben considerar para garantizar la aceptabilidad y palatabilidad de los medicamentos pedi\u00e1tricos?**\n   - Esta pregunta se centra en el apartado 3.2 del documento, que aborda espec\u00edficamente la aceptabilidad y palatabilidad, y puede proporcionar detalles sobre c\u00f3mo estos factores afectan la administraci\u00f3n de medicamentos a ni\u00f1os.\n\n2. **\u00bfQu\u00e9 tipos de excipientes son recomendados para la formulaci\u00f3n de medicamentos pedi\u00e1tricos y por qu\u00e9 son importantes?**\n   - Esta pregunta se relaciona con el apartado 5.3 sobre excipientes, permitiendo explorar la funci\u00f3n y la selecci\u00f3n de excipientes en la formulaci\u00f3n de medicamentos para ni\u00f1os.\n\n3. **\u00bfQu\u00e9 consideraciones se deben tener en cuenta al dise\u00f1ar medicamentos para condiciones severas en pediatr\u00eda?**\n   - Esta pregunta se refiere al apartado 4.3 sobre medicamentos para condiciones severas, lo que permite profundizar en los desaf\u00edos y requisitos espec\u00edficos para el desarrollo de estos medicamentos en la poblaci\u00f3n pedi\u00e1trica.", "prev_section_summary": "### Temas Clave\n\n1. **Revisi\u00f3n de Dossiers**: Se establece la importancia de incluir datos de todos los lotes fabricados durante el per\u00edodo de revisi\u00f3n en las evaluaciones de dossiers.\n2. **Presentaci\u00f3n de Datos**: Se enfatiza que los datos deben ser presentados de manera clara, ya sea en formato tabular o gr\u00e1fico, cuando sea pertinente.\n3. **Cumplimiento de GMP**: Se aclara que los requisitos mencionados son espec\u00edficos para el proceso de evaluaci\u00f3n del dossier y no eximen al solicitante de cumplir con los requisitos de Buenas Pr\u00e1cticas de Manufactura (GMP).\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite el documento.\n- **Dossier**: Conjunto de documentos que se eval\u00faan en el proceso de revisi\u00f3n.\n- **Lotes**: Unidades de producci\u00f3n que deben ser consideradas en la revisi\u00f3n.\n- **Buenas Pr\u00e1cticas de Manufactura (GMP)**: Normativas que deben cumplirse adem\u00e1s de los requisitos de evaluaci\u00f3n del dossier.", "excerpt_keywords": "Keywords: paediatric medicines, formulation design, acceptability, dosage forms, oral administration"}}, "4e5c0f32-738a-4803-9823-366f5b6e1ea9": {"node_ids": ["d20a3055-ba21-417d-ae2e-32e6956b8361"], "metadata": {"page_label": "212", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n## Forty-sixth report\n\n### 7. Rectal administration\n- **7.1** Suppositories 217\n- **7.2** Rectal liquids (enemas) 218\n\n### 8. Parenteral administration\n- **8.1** Formulation 219\n- **8.2** Additional points to consider for parenteral preparations 219\n\n### 9. Dermal and transdermal administration\n- **9.1** Transdermal patches 221\n\n### 10. Inhalations\n221\n\n### 11. Packaging and labelling\n222\n\n### References\n223", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento es el \"Forty-sixth report\" de la \"WHO Expert Committee on Specifications for Pharmaceutical Preparations\", que aborda diversas formas de administraci\u00f3n de medicamentos, incluyendo la administraci\u00f3n rectal, parenteral, dermal y transdermal, as\u00ed como la inhalaci\u00f3n y aspectos de empaquetado y etiquetado. Cada secci\u00f3n del informe se centra en diferentes formulaciones y consideraciones espec\u00edficas para cada m\u00e9todo de administraci\u00f3n.\n\n### Preguntas:\n1. **\u00bfCu\u00e1les son las secciones espec\u00edficas que se abordan en el informe relacionadas con la administraci\u00f3n rectal de medicamentos?**\n   - Respuesta: El informe aborda dos secciones espec\u00edficas relacionadas con la administraci\u00f3n rectal: **7.1 Suppositorios** y **7.2 L\u00edquidos rectales (enemas)**.\n\n2. **\u00bfQu\u00e9 puntos adicionales se consideran para las preparaciones parenterales seg\u00fan el informe?**\n   - Respuesta: En la secci\u00f3n **8.2** se mencionan los **puntos adicionales a considerar para las preparaciones parenterales**, aunque el contexto no detalla cu\u00e1les son esos puntos.\n\n3. **\u00bfQu\u00e9 tipo de administraci\u00f3n de medicamentos se menciona en la secci\u00f3n 9 del informe?**\n   - Respuesta: La secci\u00f3n **9** del informe se centra en la **administraci\u00f3n dermal y transdermal**, espec\u00edficamente en los **parches transd\u00e9rmicos**.", "prev_section_summary": "### Resumen de temas clave y entidades\n\nEl documento \"Development of paediatric medicines: points to consider in formulation\" de la OMS se centra en la formulaci\u00f3n de medicamentos pedi\u00e1tricos, abordando varios aspectos esenciales para su desarrollo. A continuaci\u00f3n se presentan los temas clave y entidades mencionadas en la secci\u00f3n:\n\n1. **Introducci\u00f3n y Objetivo**:\n   - El documento no proporciona instrucciones detalladas, sino que hace referencia a literatura relevante sobre el desarrollo de medicamentos pedi\u00e1tricos.\n\n2. **Formas de dosificaci\u00f3n pedi\u00e1trica**:\n   - Se discuten diferentes formas de dosificaci\u00f3n, incluyendo la administraci\u00f3n conveniente y confiable, la aceptabilidad y palatabilidad, la frecuencia m\u00ednima de dosificaci\u00f3n y las necesidades de los usuarios finales.\n\n3. **Formulaciones espec\u00edficas**:\n   - Se consideran formas de dosificaci\u00f3n particulares como:\n     - Formas s\u00f3lidas flexibles\n     - Medicamentos orales\n     - Medicamentos para condiciones severas\n     - Preparaciones rectales\n\n4. **Dise\u00f1o de formulaciones**:\n   - Se abordan aspectos del dise\u00f1o de formulaciones, incluyendo:\n     - Calidad\n     - Sistema de clasificaci\u00f3n biofarmac\u00e9utica\n     - Excipientes (importancia y selecci\u00f3n)\n     - Agentes colorantes\n     - Conservantes antimicrobianos\n     - Agentes edulcorantes\n     - Enmascaramiento del sabor\n     - Mejoradores de solubilidad\n\n5. **Administraci\u00f3n oral**:\n   - Se detallan las preparaciones l\u00edquidas orales, la administraci\u00f3n a trav\u00e9s de tubos de alimentaci\u00f3n y las formas s\u00f3lidas de dosificaci\u00f3n oral.\n\n### Entidades Clave:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite el documento.\n- **Medicamentos pedi\u00e1tricos**: Enfoque principal del documento.\n- **Excipientes**: Componentes importantes en la formulaci\u00f3n de medicamentos.\n- **Formas de dosificaci\u00f3n**: Diferentes m\u00e9todos de administraci\u00f3n de medicamentos a ni\u00f1os.\n\nEste resumen destaca la importancia de considerar m\u00faltiples factores en la formulaci\u00f3n de medicamentos pedi\u00e1tricos para asegurar su eficacia y aceptaci\u00f3n por parte de los pacientes j\u00f3venes.", "excerpt_keywords": "Keywords: WHO, pharmaceutical preparations, rectal administration, parenteral administration, transdermal patches"}}, "714f210f-bfa3-40be-95a5-92bbff0d6e1a": {"node_ids": ["103a78ff-4f2e-403c-bf10-6dfcbb99d6ea"], "metadata": {"page_label": "213", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nSafe and effective pharmacotherapy for paediatric patients requires the timely development of medicines and information on their proper use appropriate to the age, physiological condition and body size of the child. Formulations developed specifically for children are often needed. The use of unlicensed and off-label medicines for treating children is widespread. Their effects on children have not been properly studied, age-appropriate formulations are generally not available, and the medicines are not licensed for use in children.\n\nPharmacists, parents or caregivers are often faced with the need to manipulate an adult medicine in a way that is not described in the Summary of product characteristics. This manipulation can be simple, e.g. breaking tablets that do not have a score line with a tablet splitter, or complex, e.g. using tablets as a source for an active pharmaceutical ingredient (API) to prepare a suspension. Pharmacists may also be faced with the need to compound a medicine on the basis of the API.\n\nThe manipulation process itself can increase the potential for inaccurate dosing and in general can increase the variability of the product. Such handling may be potentially hazardous for the patient as it may affect the stability, bioavailability and accuracy of dosing of a finished pharmaceutical product (FPP), in particular for controlled-release preparations. The use of such medicines may expose children to overdosing and unintended side-effects or to underdosing and a resultant reduction in efficacy. Moreover, excipients that are safe for adults may not necessarily be so for children.\n\nIn December 2007 WHO launched its initiative \u201cMake medicines child size\u201d in order to raise awareness of and accelerate action to meet the need for improved availability and access to child-specific medicines. The WHO Model Formulary for children, 2010, provides independent prescriber information on dosage and treatment guidance for medicines based on the WHO Model List of essential medicines for children, first developed in 2007 and reviewed and updated every two years.\n\nAmong actions to support the \u201cMake medicines child size\u201d initiative is the present \u201cPoints to consider\u201d document on the formulation of paediatric medicines. The objective is to inform regulatory authorities and manufacturers on issues that require special attention in pharmaceutical formulation. Its focus is on the conditions and needs in developing countries. The guidance does not provide exhaustive information and does not exclude the possibility that other aspects may be relevant to the development of paediatric medicines.\n\nIt is not within the scope of this document to address extemporaneous preparations and compounding. A separate interim document entitled *Provision by health-care specialists of patient-specific preparations that are not available as authorized products \u2013 points to consider* (1) will deal with such preparations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen de nivel superior del contexto\n\nEl documento de la OMS aborda la necesidad de desarrollar medicamentos seguros y efectivos para pacientes pedi\u00e1tricos, destacando la falta de formulaciones adecuadas y el uso generalizado de medicamentos no autorizados y fuera de indicaci\u00f3n. Se menciona que la manipulaci\u00f3n de medicamentos para adultos para su uso en ni\u00f1os puede llevar a dosificaciones inexactas y riesgos potenciales para la salud. La OMS lanz\u00f3 la iniciativa \"Make medicines child size\" para mejorar la disponibilidad de medicamentos espec\u00edficos para ni\u00f1os y ha creado un documento de orientaci\u00f3n para informar a las autoridades regulatorias y fabricantes sobre consideraciones especiales en la formulaci\u00f3n de medicamentos pedi\u00e1tricos, especialmente en pa\u00edses en desarrollo.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los riesgos asociados con la manipulaci\u00f3n de medicamentos para adultos al ser utilizados en ni\u00f1os, seg\u00fan el documento de la OMS?**\n   - Respuesta: La manipulaci\u00f3n de medicamentos para adultos puede aumentar el potencial de dosificaci\u00f3n inexacta, afectar la estabilidad y biodisponibilidad del producto terminado, y exponer a los ni\u00f1os a sobredosis, efectos secundarios no deseados o subdosificaci\u00f3n, lo que puede reducir la eficacia del tratamiento.\n\n2. **\u00bfQu\u00e9 iniciativas ha tomado la OMS para abordar la falta de medicamentos pedi\u00e1tricos adecuados y c\u00f3mo se relacionan con el documento de \"Puntos a considerar\"?**\n   - Respuesta: La OMS lanz\u00f3 la iniciativa \"Make medicines child size\" en diciembre de 2007 para aumentar la conciencia y mejorar el acceso a medicamentos espec\u00edficos para ni\u00f1os. El documento de \"Puntos a considerar\" se alinea con esta iniciativa al informar a las autoridades y fabricantes sobre aspectos que requieren atenci\u00f3n especial en la formulaci\u00f3n de medicamentos pedi\u00e1tricos, con un enfoque en las condiciones de los pa\u00edses en desarrollo.\n\n3. **\u00bfQu\u00e9 aspectos no se abordan en el documento de la OMS sobre la formulaci\u00f3n de medicamentos pedi\u00e1tricos y d\u00f3nde se puede encontrar informaci\u00f3n sobre esos temas?**\n   - Respuesta: El documento no aborda las preparaciones extempor\u00e1neas y la compounding de medicamentos. Para esos temas, se menciona un documento interino separado titulado *Provision by health-care specialists of patient-specific preparations that are not available as authorized products \u2013 points to consider*, que tratar\u00e1 espec\u00edficamente esas preparaciones.", "prev_section_summary": "El documento es el \"Forty-sixth report\" de la \"WHO Expert Committee on Specifications for Pharmaceutical Preparations\" y se centra en diferentes m\u00e9todos de administraci\u00f3n de medicamentos. A continuaci\u00f3n se presentan los temas clave y entidades de la secci\u00f3n:\n\n### Temas Clave:\n1. **Administraci\u00f3n Rectal**:\n   - **Suppositorios**: Formulaci\u00f3n y consideraciones para el uso de supositorios.\n   - **L\u00edquidos Rectales (Enemas)**: Aspectos relacionados con la administraci\u00f3n de l\u00edquidos a trav\u00e9s del recto.\n\n2. **Administraci\u00f3n Parenteral**:\n   - **Formulaci\u00f3n**: Detalles sobre c\u00f3mo se deben formular las preparaciones parenterales.\n   - **Puntos Adicionales**: Consideraciones adicionales que deben tenerse en cuenta para las preparaciones parenterales.\n\n3. **Administraci\u00f3n Dermal y Transdermal**:\n   - **Parches Transd\u00e9rmicos**: Informaci\u00f3n sobre el uso y formulaci\u00f3n de parches que permiten la administraci\u00f3n de medicamentos a trav\u00e9s de la piel.\n\n4. **Inhalaciones**: M\u00e9todos y consideraciones para la administraci\u00f3n de medicamentos por inhalaci\u00f3n.\n\n5. **Embalaje y Etiquetado**: Aspectos relacionados con el empaquetado y etiquetado de los productos farmac\u00e9uticos.\n\n### Entidades:\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable del informe.\n- **Expert Committee on Specifications for Pharmaceutical Preparations**: Comit\u00e9 que elabora el informe.\n- **Forty-sixth report**: T\u00edtulo del documento.\n\nEste resumen destaca las principales secciones y temas tratados en el informe, proporcionando una visi\u00f3n general de las consideraciones para diferentes formas de administraci\u00f3n de medicamentos.", "excerpt_keywords": "Keywords: paediatric medicines, pharmacotherapy, WHO initiative, drug formulation, off-label use"}}, "fc435afe-6d9b-4fbd-a4e9-545047747ecd": {"node_ids": ["16690876-a5a3-4c5b-8571-3d733c3fed7a"], "metadata": {"page_label": "214", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Glossary\n\nThe definitions given below apply to the terms as used in these guidelines. They may have different meanings in other contexts.\n\n**child-resistant container**  \nA form of packaging difficult for young children to open but not unduly difficult for adults to open properly.\n\n**flexible dosage form**  \nA solid dosage form that can be administered to patients in more than one manner, e.g. may be dispersed or taken orally as a whole.\n\n**labelling information**  \nInformation to the user provided on the package label or in the patient information leaflet.\n\n**mini-tablet**  \nA tablet of no more than 4 mm diameter.\n\n**off-label use**  \nUse of a medicine outside the scope of regulatory authorization.\n\n**platform technology**  \nTechnique, including formulation and related processes, which can be used to obtain different dosage forms, different strengths and/or accommodate different APIs.\n\n# 3. Paediatric dosage forms\n\nThe paediatric population is a heterogeneous group ranging from newborns to adolescents with wide physical and developmental differences regarding pharmacokinetics and pharmacodynamics. Organ maturation, metabolic capacity, skin maturation and other factors may change with age, especially in early infancy (2). The age groups identified by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (3) have been derived mainly from physiological and pharmacokinetic differences from birth to adulthood:\n\n- preterm newborn infants\n- term newborn infants (0\u201327 days)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de nivel superior:\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) en su Serie de Informes T\u00e9cnicos 970 incluye un glosario de t\u00e9rminos relevantes para la formulaci\u00f3n y uso de medicamentos, especialmente en la poblaci\u00f3n pedi\u00e1trica. Se definen conceptos clave como \"envase a prueba de ni\u00f1os\", \"forma de dosificaci\u00f3n flexible\" y \"uso fuera de etiqueta\". Adem\u00e1s, se aborda la heterogeneidad de la poblaci\u00f3n pedi\u00e1trica, que abarca desde reci\u00e9n nacidos hasta adolescentes, y se mencionan las diferencias fisiol\u00f3gicas y farmacocin\u00e9ticas que afectan la administraci\u00f3n de medicamentos en estos grupos de edad.\n\n### Preguntas espec\u00edficas:\n1. **\u00bfQu\u00e9 caracter\u00edsticas debe tener un envase para ser considerado \"a prueba de ni\u00f1os\" seg\u00fan las directrices de la OMS?**\n   - Respuesta: Un envase a prueba de ni\u00f1os debe ser dif\u00edcil de abrir para los ni\u00f1os peque\u00f1os, pero no excesivamente complicado para que los adultos lo abran correctamente.\n\n2. **\u00bfCu\u00e1l es la definici\u00f3n de \"mini-tableta\" y por qu\u00e9 es relevante en la formulaci\u00f3n de medicamentos pedi\u00e1tricos?**\n   - Respuesta: Una mini-tableta es un comprimido que no supera los 4 mm de di\u00e1metro. Su relevancia radica en que su tama\u00f1o puede facilitar la administraci\u00f3n de medicamentos a ni\u00f1os, quienes pueden tener dificultades para tragar tabletas m\u00e1s grandes.\n\n3. **\u00bfQu\u00e9 grupos de edad se consideran en la evaluaci\u00f3n de las diferencias fisiol\u00f3gicas y farmacocin\u00e9ticas en la poblaci\u00f3n pedi\u00e1trica seg\u00fan la OMS?**\n   - Respuesta: Los grupos de edad identificados incluyen a los reci\u00e9n nacidos prematuros y a los reci\u00e9n nacidos a t\u00e9rmino, que son aquellos que tienen entre 0 y 27 d\u00edas de vida. Estas categor\u00edas se basan en las diferencias en la maduraci\u00f3n org\u00e1nica y la capacidad metab\u00f3lica que afectan la respuesta a los medicamentos.", "prev_section_summary": "### Temas Clave\n\n1. **Necesidad de Medicamentos Pedi\u00e1tricos**: Se destaca la importancia de desarrollar medicamentos seguros y efectivos espec\u00edficamente formulados para pacientes pedi\u00e1tricos, considerando su edad, condici\u00f3n fisiol\u00f3gica y tama\u00f1o corporal.\n\n2. **Uso de Medicamentos No Autorizados**: Se menciona que el uso de medicamentos no autorizados y fuera de indicaci\u00f3n es com\u00fan en el tratamiento de ni\u00f1os, lo que plantea riesgos debido a la falta de estudios adecuados sobre sus efectos en esta poblaci\u00f3n.\n\n3. **Manipulaci\u00f3n de Medicamentos para Adultos**: Los farmac\u00e9uticos, padres y cuidadores a menudo deben manipular medicamentos para adultos, lo que puede llevar a dosificaciones inexactas y aumentar la variabilidad del producto, afectando la estabilidad y biodisponibilidad.\n\n4. **Iniciativa \"Make medicines child size\"**: La OMS lanz\u00f3 esta iniciativa en 2007 para mejorar la disponibilidad y el acceso a medicamentos espec\u00edficos para ni\u00f1os, junto con la creaci\u00f3n de un formulario modelo para ni\u00f1os que proporciona informaci\u00f3n sobre dosificaci\u00f3n y tratamiento.\n\n5. **Documentaci\u00f3n de Orientaci\u00f3n**: El documento \"Puntos a considerar\" tiene como objetivo informar a las autoridades regulatorias y fabricantes sobre consideraciones especiales en la formulaci\u00f3n de medicamentos pedi\u00e1tricos, con un enfoque en las necesidades de los pa\u00edses en desarrollo.\n\n6. **Limitaciones del Documento**: Se aclara que el documento no aborda las preparaciones extempor\u00e1neas y la compounding de medicamentos, para lo cual se menciona un documento interino separado.\n\n### Entidades\n\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Organizaci\u00f3n que lidera la iniciativa y proporciona directrices sobre medicamentos pedi\u00e1tricos.\n- **Medicamentos Pedi\u00e1tricos**: Medicamentos espec\u00edficamente formulados para ni\u00f1os.\n- **Medicamentos No Autorizados y Fuera de Indicaciones**: Medicamentos que no han sido aprobados para su uso en ni\u00f1os o que se utilizan de manera no autorizada.\n- **Formulaciones**: Preparaciones farmac\u00e9uticas que pueden requerir manipulaci\u00f3n para su uso en ni\u00f1os.\n- **Iniciativa \"Make medicines child size\"**: Programa de la OMS para mejorar el acceso a medicamentos pedi\u00e1tricos.\n- **Modelo de Formulario de la OMS para Ni\u00f1os**: Documento que proporciona informaci\u00f3n sobre dosificaci\u00f3n y tratamiento para medicamentos pedi\u00e1tricos.", "excerpt_keywords": "Keywords: pediatric medications, child-resistant packaging, flexible dosage forms, mini-tablets, off-label use"}}, "b940a542-6e9b-4a8c-8b63-69cd6de7f010": {"node_ids": ["e194acc1-17a2-4fb4-a13b-ce56db26b8e2"], "metadata": {"page_label": "215", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\n- infants and toddlers (28 days\u201323 months)\n- children (2\u201311 years)\n- adolescents (12 to 16\u201318 years (dependent on region)).\n\nIt is a challenge to find one formulation appropriate for all age groups. The aim should be to safely cover as wide an age range as possible with a single formulation. The guiding principle for selecting paediatric dosage forms should be \u2013 as for adults \u2013 the balance of risks and benefits taking into account the specific needs of this vulnerable population (4).\n\nDuring the development of pharmaceutical products, the assessment of individual risks related to specific products and starting materials, and the recognition of hazards at specific stages of production or distribution, will enable further enhancement of the usual quality assurance mechanisms, such as implementation of good manufacturing practices (GMP), by increasing the effectiveness of the activities of all parties involved, within the limits of the available resources. Manufacturers who have chosen a more systematic approach to product development would follow the stages of development within the broader context of quality assurance principles, including the use of quality risk management and pharmaceutical quality systems (4, 5).\n\nCurrent use of medicines for the paediatric population reflects the full range of dosage forms and routes of administration used for adult medicines. Common routes of administration in paediatric patients include oral, parenteral, dermal, pulmonary, nasal, rectal and ocular. There is, however, limited information on the acceptability of different paediatric dosage forms in relation to age and therapeutic needs and on the safety of excipients in relation to the development of the child. A European Medicines Agency (EMA) reflection paper on paediatric formulations (6) provides background information on these issues. Reviews by Ernest et al. (7) and Krause and Breitkreutz (8) discuss the needs and challenges in developing paediatric medicines.\n\nThe desirable features of high-quality paediatric medicines common to all dosage forms are outlined below. Further information on specific dosage forms is given in the following sections.\n\n## 3.1 Convenient, reliable administration\n\nThe administered dose should contain an amount of API adjusted to the age and needs of the child. The implication is that more than one dosage form of the API or more than one strength of a dosage form may be needed to cover different age groups. The intended dose volume or size should be appropriate for the target age group.\n\nPaediatric medicines should preferably be presented as formulations that are ready to administer. The need for health professionals, parents or caregivers to", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que se pueden formular a partir del contexto proporcionado, junto con respuestas espec\u00edficas que probablemente no se encuentren en otro lugar:\n\n### Preguntas y Respuestas\n\n1. **\u00bfCu\u00e1les son los grupos de edad definidos en el contexto de la formulaci\u00f3n de medicamentos pedi\u00e1tricos?**\n   - **Respuesta:** Los grupos de edad definidos son: infantes y ni\u00f1os peque\u00f1os (28 d\u00edas a 23 meses), ni\u00f1os (2 a 11 a\u00f1os) y adolescentes (12 a 16-18 a\u00f1os, dependiendo de la regi\u00f3n).\n\n2. **\u00bfQu\u00e9 principios gu\u00edan la selecci\u00f3n de formas de dosificaci\u00f3n pedi\u00e1trica?**\n   - **Respuesta:** El principio gu\u00eda para seleccionar formas de dosificaci\u00f3n pedi\u00e1trica es el equilibrio entre riesgos y beneficios, teniendo en cuenta las necesidades espec\u00edficas de esta poblaci\u00f3n vulnerable.\n\n3. **\u00bfQu\u00e9 desaf\u00edos se mencionan en relaci\u00f3n con la aceptaci\u00f3n de diferentes formas de dosificaci\u00f3n pedi\u00e1trica?**\n   - **Respuesta:** Se menciona que hay informaci\u00f3n limitada sobre la aceptabilidad de diferentes formas de dosificaci\u00f3n pedi\u00e1trica en relaci\u00f3n con la edad y las necesidades terap\u00e9uticas, as\u00ed como sobre la seguridad de los excipientes en relaci\u00f3n con el desarrollo del ni\u00f1o.\n\n### Resumen de Nivel Superior\n\nEl contexto aborda la complejidad de desarrollar formulaciones de medicamentos adecuadas para la poblaci\u00f3n pedi\u00e1trica, que abarca desde infantes hasta adolescentes. Se enfatiza la importancia de considerar las necesidades espec\u00edficas de cada grupo de edad y la necesidad de un enfoque sistem\u00e1tico en el desarrollo de productos farmac\u00e9uticos, que incluya la gesti\u00f3n de riesgos y la garant\u00eda de calidad. Adem\u00e1s, se destaca la variedad de formas de dosificaci\u00f3n y rutas de administraci\u00f3n utilizadas en pediatr\u00eda, as\u00ed como la falta de informaci\u00f3n sobre la aceptabilidad y seguridad de estas formulaciones.\n\n### Preguntas Mejoradas\n\n1. **\u00bfQu\u00e9 estrategias se sugieren para abordar la dificultad de encontrar una \u00fanica formulaci\u00f3n adecuada para todos los grupos de edad pedi\u00e1trica?**\n2. **\u00bfC\u00f3mo se relacionan las pr\u00e1cticas de fabricaci\u00f3n y la gesti\u00f3n de riesgos con la calidad de los medicamentos pedi\u00e1tricos?**\n3. **\u00bfQu\u00e9 informaci\u00f3n adicional se proporciona en el documento de la EMA sobre las formulaciones pedi\u00e1tricas y c\u00f3mo puede ayudar en el desarrollo de medicamentos?**", "prev_section_summary": "### Resumen de temas clave y entidades:\n\n1. **Glosario de T\u00e9rminos**:\n   - **Envase a prueba de ni\u00f1os**: Packaging dise\u00f1ado para ser dif\u00edcil de abrir por ni\u00f1os peque\u00f1os, pero accesible para adultos.\n   - **Forma de dosificaci\u00f3n flexible**: Forma s\u00f3lida que puede ser administrada de diversas maneras, como dispersada o ingerida entera.\n   - **Informaci\u00f3n de etiquetado**: Datos proporcionados al usuario en la etiqueta del paquete o en el folleto informativo para el paciente.\n   - **Mini-tableta**: Comprimido con un di\u00e1metro m\u00e1ximo de 4 mm, facilitando su administraci\u00f3n a ni\u00f1os.\n   - **Uso fuera de etiqueta**: Administraci\u00f3n de un medicamento que no est\u00e1 autorizada por las regulaciones.\n   - **Tecnolog\u00eda de plataforma**: T\u00e9cnica que permite obtener diferentes formas de dosificaci\u00f3n y concentraciones de ingredientes activos.\n\n2. **Poblaci\u00f3n Pedi\u00e1trica**:\n   - Se describe como un grupo heterog\u00e9neo que abarca desde reci\u00e9n nacidos hasta adolescentes, con diferencias significativas en farmacocin\u00e9tica y farmacodin\u00e1mica.\n   - Se mencionan grupos de edad espec\u00edficos para la evaluaci\u00f3n de medicamentos:\n     - **Reci\u00e9n nacidos prematuros**\n     - **Reci\u00e9n nacidos a t\u00e9rmino** (0\u201327 d\u00edas)\n\n### Entidades Clave:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que proporciona las directrices.\n- **International Conference on Harmonisation (ICH)**: Organizaci\u00f3n que define los grupos de edad en la evaluaci\u00f3n de medicamentos pedi\u00e1tricos. \n\nEste resumen destaca la importancia de considerar las caracter\u00edsticas espec\u00edficas de la poblaci\u00f3n pedi\u00e1trica en la formulaci\u00f3n y administraci\u00f3n de medicamentos, as\u00ed como la necesidad de envases seguros y formas de dosificaci\u00f3n adecuadas.", "excerpt_keywords": "Keywords: paediatric medicines, dosage forms, age groups, quality assurance, pharmaceutical development"}}, "b3cf3ac1-867a-4608-a330-d71cf4396f46": {"node_ids": ["1cefab38-3200-4ce9-8540-b3f8f328fba5"], "metadata": {"page_label": "216", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Acceptability and Palatability\n\nAcceptability is the overall acceptance of the dosage form regardless of the mode of its administration. Acceptability of a dosage form depends on a variety of factors such as:\n\n- Suitability of the dosage form for the particular age group\n- The dosing device used for a liquid medicine\n- Palatability of an oral medicine\n- Dose volume or size to be administered\n- Appropriateness of packaging\n- Clarity and accuracy of labelling information\n- Directions for use.\n\nAcceptance of parents and caregivers is also a relevant issue, and the cultural setting may influence the understanding of and expectations of the therapy.\n\nPalatability is the overall acceptance of the taste, flavour, smell, dose volume or size, and texture of a medicine to be administered by mouth or to be swallowed. Palatability can be crucial to adherence. Palatability of the API may influence the choice of dosage form and its design, which may include taste-masking ingredients. The dosage form should not, however, be made too attractive to the child (e.g. it should not be in the form of a sugar-coated tablet resembling a sweet or candy) in order to avoid increasing the risk of accidental poisoning.\n\nIt is preferable that the dosage form is palatable in itself without any need for further modification. The caregiver may, however, attempt to improve the ease of administration and acceptance of the patient by mixing the dose with food or a beverage. Such mixing should not be encouraged unless it can be done in such a small volume that ingestion of the full dose can be guaranteed and if there are no undesirable physical or chemical interactions between the food and the medicine. If mixing with food or a beverage (including breast milk) is foreseen, this eventuality should be evaluated by appropriate compatibility studies. Information should be provided in the patient information leaflet by the manufacturer, as supported by evidence-based studies.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl texto aborda la **aceptabilidad** y **palatabilidad** de las formas de dosificaci\u00f3n de medicamentos, destacando su importancia en la administraci\u00f3n de tratamientos, especialmente en poblaciones pedi\u00e1tricas. La aceptabilidad se refiere a la aceptaci\u00f3n general de la forma de dosificaci\u00f3n, influenciada por factores como la adecuaci\u00f3n para el grupo de edad, el dispositivo de dosificaci\u00f3n, y la claridad de la informaci\u00f3n de etiquetado. Por otro lado, la palatabilidad se centra en la aceptaci\u00f3n del sabor, olor, y textura del medicamento, lo cual es crucial para la adherencia al tratamiento. Se menciona la importancia de no hacer que los medicamentos sean demasiado atractivos para los ni\u00f1os para evitar el riesgo de intoxicaci\u00f3n accidental. Adem\u00e1s, se discute la posibilidad de mezclar medicamentos con alimentos o bebidas, enfatizando la necesidad de estudios de compatibilidad y la provisi\u00f3n de informaci\u00f3n adecuada al paciente.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los factores que influyen en la aceptabilidad de una forma de dosificaci\u00f3n para un grupo de edad espec\u00edfico?**\n   - La aceptabilidad depende de la adecuaci\u00f3n de la forma de dosificaci\u00f3n para el grupo de edad, el dispositivo de dosificaci\u00f3n utilizado, la palatabilidad del medicamento, el volumen o tama\u00f1o de la dosis, la adecuaci\u00f3n del empaque, la claridad de la informaci\u00f3n de etiquetado y las instrucciones de uso.\n\n2. **\u00bfPor qu\u00e9 es importante que la palatabilidad de un medicamento no dependa de modificaciones adicionales?**\n   - Es preferible que la forma de dosificaci\u00f3n sea palatable por s\u00ed misma para asegurar que el paciente acepte el medicamento sin necesidad de mezclarlo con otros alimentos o bebidas, lo que podr\u00eda comprometer la dosis o causar interacciones no deseadas.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al mezclar un medicamento con alimentos o bebidas?**\n   - La mezcla debe realizarse en un volumen tan peque\u00f1o que garantice la ingesta de la dosis completa y debe asegurarse que no haya interacciones f\u00edsicas o qu\u00edmicas indeseables entre el alimento y el medicamento. Adem\u00e1s, se deben realizar estudios de compatibilidad y proporcionar informaci\u00f3n adecuada en el prospecto del paciente.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Grupos de Edad en la Poblaci\u00f3n Pedi\u00e1trica**:\n   - Infantes y ni\u00f1os peque\u00f1os: 28 d\u00edas a 23 meses.\n   - Ni\u00f1os: 2 a 11 a\u00f1os.\n   - Adolescentes: 12 a 16-18 a\u00f1os (dependiendo de la regi\u00f3n).\n\n2. **Desaf\u00edos en la Formulaci\u00f3n de Medicamentos**:\n   - Dificultad para encontrar una \u00fanica formulaci\u00f3n adecuada para todos los grupos de edad.\n   - Necesidad de cubrir un amplio rango de edad de manera segura con una sola formulaci\u00f3n.\n\n3. **Principios de Selecci\u00f3n de Formas de Dosificaci\u00f3n**:\n   - Equilibrio entre riesgos y beneficios, considerando las necesidades espec\u00edficas de la poblaci\u00f3n pedi\u00e1trica.\n\n4. **Desarrollo de Productos Farmac\u00e9uticos**:\n   - Evaluaci\u00f3n de riesgos individuales y reconocimiento de peligros en etapas de producci\u00f3n y distribuci\u00f3n.\n   - Importancia de las buenas pr\u00e1cticas de fabricaci\u00f3n (GMP) y la gesti\u00f3n de riesgos en la garant\u00eda de calidad.\n\n5. **Rutas de Administraci\u00f3n Comunes**:\n   - Incluyen oral, parenteral, dermal, pulmonar, nasal, rectal y ocular.\n   - Limitada informaci\u00f3n sobre la aceptabilidad y seguridad de las formas de dosificaci\u00f3n pedi\u00e1tricas.\n\n6. **Documentos de Referencia**:\n   - Un documento de la Agencia Europea de Medicamentos (EMA) proporciona informaci\u00f3n sobre formulaciones pedi\u00e1tricas.\n   - Revisiones de Ernest et al. y Krause y Breitkreutz abordan las necesidades y desaf\u00edos en el desarrollo de medicamentos pedi\u00e1tricos.\n\n7. **Caracter\u00edsticas Deseables de Medicamentos Pedi\u00e1tricos**:\n   - Dosis ajustadas a la edad y necesidades del ni\u00f1o.\n   - Presentaci\u00f3n de formulaciones listas para administrar.\n\nEste resumen destaca la complejidad y los desaf\u00edos en el desarrollo de medicamentos pedi\u00e1tricos, enfatizando la importancia de considerar las caracter\u00edsticas espec\u00edficas de cada grupo de edad y la necesidad de un enfoque sistem\u00e1tico en la formulaci\u00f3n y producci\u00f3n de estos medicamentos.", "excerpt_keywords": "Keywords: acceptability, palatability, dosage form, pediatric medicine, administration"}}, "e7f63b90-9133-4fbd-b579-1f016bde8110": {"node_ids": ["31806e6d-8727-41bc-b5dd-2bc469406ae8"], "metadata": {"page_label": "217", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3.3 Minimum dosing frequency\n\nParents and caregivers take care of the administration of medication to young children, whereas schoolchildren and adolescents can often manage their medication themselves. In both cases minimal dosing frequency should be aspired to. Instructions on the dosing frequency are based on the pharmacokinetic and pharmacodynamic properties of the API, but may be influenced by the design of the dosage form.\n\nFrequent dosing, i.e. more than twice daily, may have a negative impact on adherence to the dosing scheme both by caregivers and by older children, in particular when medicines are taken in settings where a trained caregiver is not available, e.g. at school. Moreover, frequent dosing may conflict with the lifestyle of older children.\n\n# 3.4 End-user needs\n\nIn addition to maximizing the acceptability and palatability of paediatric medicines it is important that they are convenient to produce and affordable. It is also important to bear in mind supply-chain considerations, such as ease of transportation and storage requirements. It is not always possible for the user to store medicines in a refrigerator.\n\nDepending on the age and clinical condition of the child, there are restrictions to the applicable dose volume or size. Generally, when developing the product, minimum dose volume and size should be the goal.\n\nLack of access to clean water is an important issue to take into consideration in the development of medicines that need to be dissolved, diluted or dispersed prior to administration, as it may compromise the quality of an FPP. It may be necessary to educate patients on how to obtain water of suitable quality, e.g. by supplying instructions on boiling or filtering. Provision of the liquid vehicle as a part of the package may be an option, or the dose may be dispersed or dissolved in a suitable food or beverage prior to administration. Some instructions on such use should be included on the label or package insert. Regional and cultural differences with regard to preferred tastes may need to be considered.\n\n# 4. Particular dosage forms to be considered\n\n## 4.1 Flexible solid dosage forms\n\nDosage forms that, in general, are likely to prove most suitable for global use, including for developing countries, and which should be prioritized, are flexible solid dosage forms such as tablets that are orodispersible and/or can be used for preparation of oral liquids suitable also for the younger age groups, e.g. dispersible and soluble tablets. The flexible dosage form design may be used for various APIs but may not be suitable for medicines requiring a precise dose titration.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Frecuencia m\u00ednima de dosificaci\u00f3n**: Se enfatiza la importancia de minimizar la frecuencia de dosificaci\u00f3n de medicamentos para ni\u00f1os, ya que una dosificaci\u00f3n frecuente puede afectar la adherencia, especialmente en entornos donde no hay cuidadores capacitados disponibles.\n\n2. **Necesidades del usuario final**: Se destaca la necesidad de que los medicamentos pedi\u00e1tricos sean aceptables, palatables, convenientes de producir y asequibles. Tambi\u00e9n se menciona la importancia de considerar la disponibilidad de agua limpia y las diferencias culturales en las preferencias de sabor.\n\n3. **Formas de dosificaci\u00f3n flexibles**: Se sugiere que las formas de dosificaci\u00f3n s\u00f3lidas flexibles, como tabletas orodispersibles, son las m\u00e1s adecuadas para su uso global, especialmente en pa\u00edses en desarrollo, aunque pueden no ser adecuadas para medicamentos que requieren una titulaci\u00f3n precisa de dosis.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1les son las implicaciones de la frecuencia de dosificaci\u00f3n en la adherencia al tratamiento en ni\u00f1os y adolescentes?**\n   - Respuesta: La frecuencia de dosificaci\u00f3n, especialmente si es m\u00e1s de dos veces al d\u00eda, puede tener un impacto negativo en la adherencia tanto de los cuidadores como de los ni\u00f1os mayores, especialmente en entornos como la escuela donde no hay un cuidador capacitado disponible.\n\n2. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al desarrollar medicamentos pedi\u00e1tricos en relaci\u00f3n con el acceso al agua?**\n   - Respuesta: Es crucial considerar la falta de acceso a agua limpia, ya que esto puede comprometer la calidad de los productos farmac\u00e9uticos que necesitan ser disueltos, diluidos o dispersos antes de la administraci\u00f3n. Se pueden incluir instrucciones sobre c\u00f3mo obtener agua de calidad adecuada y considerar la provisi\u00f3n de un veh\u00edculo l\u00edquido como parte del paquete.\n\n3. **\u00bfPor qu\u00e9 se priorizan las formas de dosificaci\u00f3n s\u00f3lidas flexibles para el uso global, especialmente en pa\u00edses en desarrollo?**\n   - Respuesta: Las formas de dosificaci\u00f3n s\u00f3lidas flexibles, como las tabletas orodispersibles, son preferidas porque son m\u00e1s adecuadas para su uso en diversas poblaciones, incluyendo grupos de edad m\u00e1s j\u00f3venes, y pueden facilitar la administraci\u00f3n de medicamentos en contextos donde la precisi\u00f3n en la titulaci\u00f3n de dosis no es cr\u00edtica.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n\n1. **Aceptabilidad de Formas de Dosificaci\u00f3n:**\n   - Definici\u00f3n: Aceptaci\u00f3n general de la forma de dosificaci\u00f3n, independientemente del modo de administraci\u00f3n.\n   - Factores que influyen:\n     - Adecuaci\u00f3n para el grupo de edad.\n     - Dispositivo de dosificaci\u00f3n utilizado.\n     - Palatabilidad del medicamento.\n     - Volumen o tama\u00f1o de la dosis.\n     - Adecuaci\u00f3n del empaque.\n     - Claridad y precisi\u00f3n de la informaci\u00f3n de etiquetado.\n     - Instrucciones de uso.\n   - Importancia de la aceptaci\u00f3n por parte de padres y cuidadores, as\u00ed como el impacto del contexto cultural.\n\n2. **Palatabilidad:**\n   - Definici\u00f3n: Aceptaci\u00f3n del sabor, olor, textura y tama\u00f1o de la dosis de un medicamento administrado por v\u00eda oral.\n   - Importancia para la adherencia al tratamiento.\n   - Consideraciones sobre el dise\u00f1o de la forma de dosificaci\u00f3n, incluyendo ingredientes para enmascarar el sabor.\n   - Advertencia sobre la atracci\u00f3n excesiva de los medicamentos para evitar el riesgo de intoxicaci\u00f3n accidental.\n\n3. **Mezcla de Medicamentos con Alimentos o Bebidas:**\n   - Preferencia por que la forma de dosificaci\u00f3n sea palatable sin modificaciones.\n   - Consideraciones para mezclar medicamentos:\n     - Garantizar la ingesta de la dosis completa.\n     - Evitar interacciones indeseables entre el medicamento y los alimentos.\n     - Realizar estudios de compatibilidad.\n     - Proporcionar informaci\u00f3n adecuada en el prospecto del paciente.\n\n**Entidades:**\n- **Medicamentos:** Formas de dosificaci\u00f3n orales.\n- **Cuidadores:** Padres y otros responsables de la administraci\u00f3n de medicamentos a pacientes, especialmente ni\u00f1os.\n- **Cultura:** Influencia en la aceptaci\u00f3n y expectativas sobre la terapia.\n- **Estudios de Compatibilidad:** Investigaciones necesarias para asegurar la seguridad de mezclar medicamentos con alimentos o bebidas. \n\nEste resumen destaca la importancia de la aceptabilidad y palatabilidad en la administraci\u00f3n de medicamentos, especialmente en contextos pedi\u00e1tricos, y las consideraciones necesarias para garantizar la eficacia y seguridad del tratamiento.", "excerpt_keywords": "Keywords: pediatric medicines, dosing frequency, end-user needs, flexible dosage forms, palatability"}}, "b1fb4220-db59-4cba-b172-8422eee6d5b0": {"node_ids": ["3f82988b-9550-4f9e-9fab-08ce29ceb712"], "metadata": {"page_label": "218", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nProvided that the medicine can be dispersed in breast milk from the mother, it could potentially be used in very young children (< 6 months). When recommending mixing medicines with breast milk, the effect on the taste should be taken into account, as unpleasant tasting medicine may cause aversion in breastfed children. In addition, the compatibility of the API with breast milk will need to be considered. The same considerations apply whenever medicines are mixed with other food.\n\nIt is necessary to identify appropriate product strengths and ratios of active ingredients for each medicine as well as to ensure that package sizes will allow optimal use under public health programmatic conditions.\n\n## 4.2 Oral medicines\n\nFor oral medicines that require precise dose measurement or titration, suitable dosage forms could be based on a platform technology to produce multiparticulate solids, e.g. mini-tablets or spherical granules (pellets), that allow production of dosage forms of varying strength as well as different dosage forms like tablets and capsules, and dosage forms to be dispersed to form a liquid dose or to be sprinkled onto food. Platform technology has potential flexibility for manufacturing appropriate fixed-dose combination products (FDCs). Breakable solid dosage forms specially designed to provide the appropriate dose may also serve the same purpose (1, 9).\n\n## 4.3 Medicines for severe conditions\n\nFor severe disease conditions, e.g. neonatal sepsis, the use of alternative dosage forms should be carefully considered. Some alternatives may be easier for untrained caregivers to administer, e.g. a rectal preparation or a spray under the tongue. For some conditions, parenteral formulations may be the best existing option; however, their use requires a trained caregiver.\n\n## 4.4 Rectal preparations\n\nAs an alternative to parenteral preparations for severely ill children or children who are unable to swallow, the use of rectal preparations for indications of severe malaria, pain, infection and also nausea and vomiting may be appropriate. There may, however, be cultural barriers to the use of rectal preparations.\n\n# 5. Formulation design\n\nWhen designing paediatric medicines, the route of administration, dosage form and dose of the API are decided on the basis of the disease state, API properties such as taste, aqueous solubility, pharmacokinetic and pharmacodynamic properties.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda las especificaciones para la preparaci\u00f3n de medicamentos, especialmente en el contexto pedi\u00e1trico. Se discuten consideraciones importantes para la administraci\u00f3n de medicamentos a ni\u00f1os menores de seis meses, incluyendo la mezcla de medicamentos con leche materna y la importancia del sabor. Tambi\u00e9n se exploran diferentes formas de dosificaci\u00f3n, como medicamentos orales, rectales y parenterales, y se enfatiza la necesidad de dise\u00f1ar formulaciones adecuadas que consideren las propiedades del principio activo (API) y las condiciones de salud p\u00fablica. Se menciona la importancia de la facilidad de administraci\u00f3n para cuidadores no entrenados, as\u00ed como las barreras culturales que pueden afectar el uso de ciertas formas de dosificaci\u00f3n.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones clave al mezclar medicamentos con leche materna para su uso en ni\u00f1os menores de seis meses?**\n   - Esta pregunta se centra en los aspectos espec\u00edficos que deben tenerse en cuenta, como el sabor del medicamento y la compatibilidad del API con la leche materna.\n\n2. **\u00bfQu\u00e9 tecnolog\u00edas de plataforma se mencionan para la producci\u00f3n de formas de dosificaci\u00f3n oral y cu\u00e1les son sus ventajas?**\n   - Esta pregunta busca detalles sobre las tecnolog\u00edas espec\u00edficas que permiten la producci\u00f3n de medicamentos en diferentes formas y dosis, as\u00ed como sus beneficios en t\u00e9rminos de flexibilidad y precisi\u00f3n.\n\n3. **\u00bfQu\u00e9 alternativas a las preparaciones parenterales se sugieren para el tratamiento de condiciones severas en ni\u00f1os y cu\u00e1les son las consideraciones culturales asociadas?**\n   - Esta pregunta se enfoca en las opciones de dosificaci\u00f3n alternativas y los posibles obst\u00e1culos culturales que pueden influir en su aceptaci\u00f3n y uso en la pr\u00e1ctica cl\u00ednica.", "prev_section_summary": "### Temas Clave:\n\n1. **Frecuencia M\u00ednima de Dosificaci\u00f3n**: Se enfatiza la importancia de minimizar la frecuencia de dosificaci\u00f3n de medicamentos para ni\u00f1os, ya que una dosificaci\u00f3n frecuente (m\u00e1s de dos veces al d\u00eda) puede afectar negativamente la adherencia al tratamiento, especialmente en entornos sin cuidadores capacitados, como las escuelas.\n\n2. **Necesidades del Usuario Final**: Los medicamentos pedi\u00e1tricos deben ser aceptables, palatables, convenientes de producir y asequibles. Tambi\u00e9n se deben considerar aspectos de la cadena de suministro, como el transporte y los requisitos de almacenamiento, as\u00ed como la disponibilidad de agua limpia para la preparaci\u00f3n de medicamentos.\n\n3. **Formas de Dosificaci\u00f3n Flexibles**: Se sugiere priorizar formas de dosificaci\u00f3n s\u00f3lidas flexibles, como tabletas orodispersibles, que son adecuadas para su uso global, especialmente en pa\u00edses en desarrollo. Estas formas son m\u00e1s accesibles para diferentes grupos de edad, aunque pueden no ser adecuadas para medicamentos que requieren una titulaci\u00f3n precisa de dosis.\n\n### Entidades:\n\n- **API (Ingrediente Activo)**: Se refiere a la sustancia activa en los medicamentos.\n- **FPP (Forma Farmac\u00e9utica del Producto)**: Se refiere a la forma en que se presenta el medicamento.\n- **Cuidadores**: Personas responsables de la administraci\u00f3n de medicamentos a ni\u00f1os.\n- **Escuelas**: Entornos donde los ni\u00f1os pueden necesitar administrar su propia medicaci\u00f3n.\n- **Agua Limpia**: Recurso esencial para la preparaci\u00f3n de ciertos medicamentos.\n- **Tabletas Orodispersibles**: Tipo de forma de dosificaci\u00f3n flexible recomendada para uso pedi\u00e1trico. \n\nEste resumen destaca la importancia de la adherencia al tratamiento, la accesibilidad y la conveniencia en el desarrollo de medicamentos pedi\u00e1tricos, as\u00ed como la consideraci\u00f3n de factores culturales y log\u00edsticos.", "excerpt_keywords": "Keywords: pediatric medicines, breast milk compatibility, dosage forms, active pharmaceutical ingredients, formulation design"}}, "46120644-c9cd-4173-94a3-7b8ca762c205": {"node_ids": ["8af98032-4564-4395-89db-6c8ff85b08e5"], "metadata": {"page_label": "219", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Quality\n\nIn the pharmaceutical development of paediatric medicines, attention should be paid to current quality guidelines, especially those provided by WHO (1).\n\nThe acceptable level of impurities in APIs and degradation products in finished dosage forms should be qualified and controlled according to regulatory guidelines, e.g. ICH guidelines (12\u201314). Safety margins established during toxicological studies on an API and finished dosage form usually apply to a worst-case level in adults. Such limits typically apply to both adults and children; although a child would receive a smaller dose, the exposure per kilogram is likely to be similar. Term and preterm neonates have to be considered specifically, and establishment of safety limits may require safety studies in juvenile animals. Additional guidance may be found on the EMA web site (15\u201317).\n\nThe final product should comply with the requirements in relevant pharmacopoeial monographs, preferably those in *The International Pharmacopoeia*. With regard to dissolution testing, dissolution media should be carefully reconsidered in view of the different gastric pH of children from that of adults. Testing at other pHs should be considered in relevant cases. For dissolution testing of special dosage forms, such as chewable tablets, suspensions and patches, see the International Pharmaceutical Federation/American Association of Pharmaceutical Scientists (FIP/AAPS) guidelines for dissolution testing of special dosage forms (18).\n\n# Biopharmaceutics classification system\n\nThe biopharmaceutics classification system (BCS) is a scientific framework for classification of APIs for oral administration. The BCS is based upon aqueous\n\n----\n\n1. *The International Pharmacopoeia*, 4th ed. First and Second Supplements (available online and on CD-ROM). Geneva, World Health Organization, 2011 (http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento se centra en la calidad en el desarrollo farmac\u00e9utico de medicamentos pedi\u00e1tricos, destacando la importancia de seguir las directrices de calidad actuales, especialmente las proporcionadas por la OMS. Se menciona la necesidad de calificar y controlar los niveles aceptables de impurezas en los ingredientes farmac\u00e9uticos activos (API) y productos de degradaci\u00f3n en las formas de dosificaci\u00f3n terminadas, de acuerdo con las pautas regulatorias como las de ICH. Tambi\u00e9n se discute la consideraci\u00f3n espec\u00edfica de neonatos y la importancia de realizar estudios de seguridad en animales juveniles. Adem\u00e1s, se enfatiza la necesidad de cumplir con los requisitos de las monograf\u00edas farmacop\u00e9icas relevantes y se aborda la importancia de ajustar las pruebas de disoluci\u00f3n para tener en cuenta las diferencias en el pH g\u00e1strico entre ni\u00f1os y adultos.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones espec\u00edficas que deben tenerse en cuenta al establecer l\u00edmites de seguridad para neonatos en el desarrollo de medicamentos pedi\u00e1tricos?**\n   - Esta pregunta se centra en la necesidad de realizar estudios de seguridad en animales juveniles y c\u00f3mo esto se relaciona con la evaluaci\u00f3n de la seguridad en neonatos.\n\n2. **\u00bfPor qu\u00e9 es importante reconsiderar los medios de disoluci\u00f3n en las pruebas de disoluci\u00f3n para medicamentos pedi\u00e1tricos?**\n   - Esta pregunta aborda la diferencia en el pH g\u00e1strico entre ni\u00f1os y adultos y c\u00f3mo esto afecta las pruebas de disoluci\u00f3n.\n\n3. **\u00bfQu\u00e9 directrices se deben seguir para la prueba de disoluci\u00f3n de formas de dosificaci\u00f3n especiales como tabletas masticables y parches?**\n   - Esta pregunta se refiere a las pautas espec\u00edficas proporcionadas por la Federaci\u00f3n Internacional de Farmacia y la Asociaci\u00f3n Americana de Cient\u00edficos Farmac\u00e9uticos (FIP/AAPS) para la disoluci\u00f3n de formas de dosificaci\u00f3n especiales.", "prev_section_summary": "### Temas Clave\n\n1. **Uso de Medicamentos en Ni\u00f1os Menores de Seis Meses**:\n   - Importancia de la dispersi\u00f3n de medicamentos en la leche materna.\n   - Consideraciones sobre el sabor del medicamento y su compatibilidad con la leche materna.\n\n2. **Formas de Dosificaci\u00f3n Oral**:\n   - Uso de tecnolog\u00edas de plataforma para producir formas de dosificaci\u00f3n multiparticuladas (mini-tabletas, gr\u00e1nulos esf\u00e9ricos).\n   - Flexibilidad en la producci\u00f3n de combinaciones de dosis fijas (FDCs) y formas de dosificaci\u00f3n que se pueden dispersar o espolvorear sobre alimentos.\n\n3. **Medicamentos para Condiciones Severas**:\n   - Consideraci\u00f3n de formas de dosificaci\u00f3n alternativas (preparaciones rectales, aerosoles sublinguales) para facilitar la administraci\u00f3n por cuidadores no entrenados.\n   - Reconocimiento de que las formulaciones parenterales pueden ser necesarias, pero requieren un cuidador capacitado.\n\n4. **Preparaciones Rectales**:\n   - Uso de preparaciones rectales como alternativa a las parenterales para ni\u00f1os gravemente enfermos o que no pueden tragar.\n   - Posibles barreras culturales que pueden afectar la aceptaci\u00f3n de las preparaciones rectales.\n\n5. **Dise\u00f1o de Formulaciones**:\n   - Decisiones sobre la ruta de administraci\u00f3n, forma de dosificaci\u00f3n y dosis del principio activo (API) basadas en el estado de la enfermedad y propiedades del API (sabor, solubilidad, farmacocin\u00e9tica y farmacodin\u00e1mica).\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite el documento.\n- **API (Principio Activo)**: Componente clave en la formulaci\u00f3n de medicamentos.\n- **Tecnolog\u00edas de Plataforma**: M\u00e9todos de producci\u00f3n de formas de dosificaci\u00f3n.\n- **FDC (Combinaciones de Dosis Fijas)**: Productos que combinan m\u00faltiples principios activos en una sola forma de dosificaci\u00f3n.\n- **Cuidadores No Entrenados**: Personas que administran medicamentos a ni\u00f1os sin formaci\u00f3n m\u00e9dica formal.\n- **Condiciones Severas**: Ejemplos incluyen sepsis neonatal y malaria severa. \n\nEste resumen destaca las consideraciones cr\u00edticas para la formulaci\u00f3n y administraci\u00f3n de medicamentos pedi\u00e1tricos, enfatizando la importancia de la accesibilidad y la aceptaci\u00f3n cultural en el tratamiento de enfermedades en ni\u00f1os.", "excerpt_keywords": "Keywords: pediatric medicines, quality guidelines, impurities, dissolution testing, biopharmaceutics classification system"}}, "9aca0595-9e33-43f9-b8a6-8978e0bf945e": {"node_ids": ["7e34d3da-1fcd-49c0-9b84-7a244d95babf"], "metadata": {"page_label": "220", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nSolubility and intestinal permeability. An API is considered highly soluble when the highest dose is soluble in 250 ml or less of aqueous media at 37 \u00b0C over the pH range 1.2\u20136.8. The volume estimate of 250 ml is derived from typical bioequivalence study protocols that prescribe administration of a medicine together with a glass of water to fasting human volunteers. A highly permeable API is absorbed orally to an extent of 85% or more of the administered dose based on a mass-balance determination or in comparison to an intravenous dose (19).\n\nHence an API can be classified as belonging to one of four classes:\n\n- class 1 (high solubility, high permeability);\n- class 2 (low solubility, high permeability);\n- class 3 (high solubility, low permeability);\n- class 4 (low solubility, low permeability).\n\nClassification of APIs included in the WHO Model List of essential medicines is provided in the WHO Technical Report Series (20).\n\nThe BCS may be particularly helpful to assess the importance of aqueous solubility since it relates the solubility of the API to the unit dose. Aqueous solubility should not be a concern in the formulation of immediate-release dosage forms containing class 1 and 3 substances.\n\nFor class 2 substances, the effect of particle size, polymorphic form, and solubility enhancers, among others, should be considered, as the absorption of these substances may be limited by dissolution rate. The same applies to class 4 substances, although factors other than dissolution may also govern the oral absorption. However, overall the BCS classification can be used as a basis when estimating the likelihood of different absorption of paediatric medicines when the dosage form and/or excipients used in adult medicines differ from those used for paediatric medicines.\n\nIn addition, for BCS class 3 and 4 substances, where the absorption process and/or intestinal first pass also restrict bioavailability, the possibility of excipients affecting transit time (efflux), transporter function and metabolic enzymes (typically CYP3A4) should be taken into consideration.\n\n## 5.3 Excipients\n\nThe use of excipients in paediatric medicines is driven by functional requirements and should be justified through a risk-based assessment, taking into account factors such as the paediatric age group, frequency of dosing and duration of treatment.\n\nThe added challenge for paediatric medicines compared to adult medicines is that excipients may lead to adverse reactions in children that are...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento de la OMS aborda la clasificaci\u00f3n de los principios activos (API) en funci\u00f3n de su solubilidad y permeabilidad intestinal, utilizando el Sistema de Clasificaci\u00f3n de Biopharmaceutics (BCS). Se definen cuatro clases de API: clase 1 (alta solubilidad, alta permeabilidad), clase 2 (baja solubilidad, alta permeabilidad), clase 3 (alta solubilidad, baja permeabilidad) y clase 4 (baja solubilidad, baja permeabilidad). Se discute la importancia de la solubilidad acuosa en la formulaci\u00f3n de medicamentos, especialmente en pediatr\u00eda, donde los excipientes deben ser evaluados cuidadosamente debido a posibles reacciones adversas en ni\u00f1os. Adem\u00e1s, se menciona la influencia de factores como el tama\u00f1o de part\u00edcula y la forma polim\u00f3rfica en la absorci\u00f3n de medicamentos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios espec\u00edficos que definen un API como altamente soluble seg\u00fan el documento de la OMS?**\n   - Respuesta: Un API se considera altamente soluble cuando la dosis m\u00e1s alta es soluble en 250 ml o menos de medios acuosos a 37 \u00b0C en un rango de pH de 1.2 a 6.8.\n\n2. **\u00bfQu\u00e9 factores deben considerarse al formular medicamentos para la clase 2 y clase 4 de API en pediatr\u00eda?**\n   - Respuesta: Para los API de clase 2, se deben considerar el tama\u00f1o de part\u00edcula, la forma polim\u00f3rfica y los potenciadores de solubilidad, ya que la absorci\u00f3n puede estar limitada por la tasa de disoluci\u00f3n. Para la clase 4, adem\u00e1s de la disoluci\u00f3n, otros factores que pueden afectar la absorci\u00f3n oral tambi\u00e9n deben ser considerados.\n\n3. **\u00bfPor qu\u00e9 es importante realizar una evaluaci\u00f3n basada en riesgos al seleccionar excipientes para medicamentos pedi\u00e1tricos?**\n   - Respuesta: Es importante porque los excipientes pueden provocar reacciones adversas en ni\u00f1os, y su uso debe justificarse teniendo en cuenta el grupo etario pedi\u00e1trico, la frecuencia de dosificaci\u00f3n y la duraci\u00f3n del tratamiento.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Calidad en el desarrollo de medicamentos pedi\u00e1tricos**: Se enfatiza la importancia de seguir las directrices de calidad actuales, especialmente las proporcionadas por la Organizaci\u00f3n Mundial de la Salud (OMS).\n\n2. **Impurezas en ingredientes farmac\u00e9uticos activos (API)**: Se requiere calificar y controlar los niveles aceptables de impurezas y productos de degradaci\u00f3n en las formas de dosificaci\u00f3n terminadas, de acuerdo con las pautas regulatorias, como las de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH).\n\n3. **L\u00edmites de seguridad para neonatos**: Se menciona que los m\u00e1rgenes de seguridad establecidos durante los estudios toxicol\u00f3gicos generalmente se aplican a adultos, pero tambi\u00e9n deben considerarse espec\u00edficamente para neonatos, lo que puede requerir estudios de seguridad en animales juveniles.\n\n4. **Cumplimiento de monograf\u00edas farmacop\u00e9icas**: El producto final debe cumplir con los requisitos de las monograf\u00edas farmacop\u00e9icas relevantes, preferiblemente de *The International Pharmacopoeia*.\n\n5. **Pruebas de disoluci\u00f3n**: Se debe reconsiderar cuidadosamente el medio de disoluci\u00f3n en funci\u00f3n del pH g\u00e1strico diferente entre ni\u00f1os y adultos. Tambi\u00e9n se sugiere realizar pruebas a otros pHs cuando sea relevante.\n\n6. **Formas de dosificaci\u00f3n especiales**: Para la prueba de disoluci\u00f3n de formas de dosificaci\u00f3n especiales, como tabletas masticables y parches, se deben seguir las directrices de la Federaci\u00f3n Internacional de Farmacia y la Asociaci\u00f3n Americana de Cient\u00edficos Farmac\u00e9uticos (FIP/AAPS).\n\n7. **Sistema de clasificaci\u00f3n biofarmac\u00e9utica (BCS)**: Se menciona que el BCS es un marco cient\u00edfico para la clasificaci\u00f3n de APIs para administraci\u00f3n oral, basado en la solubilidad y permeabilidad.\n\n### Entidades mencionadas\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**\n- **Agencia Europea de Medicamentos (EMA)**\n- **Federaci\u00f3n Internacional de Farmacia (FIP)**\n- **Asociaci\u00f3n Americana de Cient\u00edficos Farmac\u00e9uticos (AAPS)**\n- **The International Pharmacopoeia**", "excerpt_keywords": "Keywords: solubility, permeability, biopharmaceutics, excipients, pediatric medicines"}}, "9063601d-c137-4e46-a9b2-84ebd44c2a4b": {"node_ids": ["047a429c-7f28-43df-9b50-3e01f11c31a2"], "metadata": {"page_label": "221", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Excipients in Paediatric Medicines\n\nMajor problems with excipients in paediatric medicines, especially when used to treat infants and neonates, have been reported (21), e.g. medicines with benzyl alcohol, azo-dyes, propylene glycol, ethanol and propyl paraben. A study on the exposure to benzyl alcohol and propylene glycol of neonates receiving parenteral medication demonstrated a potential risk of toxic doses, especially for neonates receiving continuous infusion (22). The toxicity of excipients to newborns and infants can be explained by factors related to their physiological and metabolic development (2). Information on the safety of some excipients may be found, for example, in reviews published by the American Academy of Pediatrics (23). Alternative sources of information should also be consulted, e.g. the WHO Technical Report Series on Evaluation of certain food additives (24).\n\nIn the development of paediatric medicines, the number of excipients and their quantity in a formulation should be the minimum required to ensure an appropriate product with respect to performance, stability, palatability, microbial control, dose uniformity and other considerations necessary to support product quality. Risks for adverse reactions are mostly associated with excipients used for liquid dosage forms.\n\nIn the choice of excipients consideration should be given to:\n\n- the safety profile of the excipient for children of the target age groups;\n- the route of administration;\n- the single and daily dose of the excipient;\n- duration of the treatment;\n- acceptability for the intended paediatric population;\n- potential alternatives;\n- regulatory status in the intended market.\n\nPotential alternatives to excipients which pose a significant risk to children should always be considered. Another dosage form or even a different route of administration might be necessary to avoid significant risk. Although well-known excipients with well-defined safety profiles are preferred, new excipients cannot be excluded. Novel excipients should only be used when their safety, quality and appropriateness for use in children have been established. It may also be necessary to look at alternative excipients because of different cultural attitudes or for religious reasons, e.g. the use of gelatin may not be acceptable for all patients.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Problemas de excipientes en medicamentos pedi\u00e1tricos**: Se han reportado problemas significativos relacionados con el uso de excipientes en medicamentos para ni\u00f1os, especialmente en neonatos. Excipientes como el alcohol benc\u00edlico y el propilenglicol pueden presentar riesgos de toxicidad, lo que resalta la necesidad de evaluar cuidadosamente su uso en formulaciones pedi\u00e1tricas.\n\n2. **Consideraciones en el desarrollo de medicamentos pedi\u00e1tricos**: Al desarrollar medicamentos para ni\u00f1os, es crucial minimizar la cantidad y el n\u00famero de excipientes para garantizar la calidad del producto. Se deben considerar factores como la seguridad, la ruta de administraci\u00f3n y la aceptabilidad del excipiente para la poblaci\u00f3n pedi\u00e1trica.\n\n3. **Alternativas a excipientes riesgosos**: Es importante considerar alternativas a los excipientes que representan un riesgo significativo para los ni\u00f1os. Esto puede incluir la b\u00fasqueda de diferentes formas de dosificaci\u00f3n o rutas de administraci\u00f3n, as\u00ed como la evaluaci\u00f3n de excipientes nuevos, siempre que se haya establecido su seguridad y calidad.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los excipientes m\u00e1s problem\u00e1ticos en medicamentos pedi\u00e1tricos y qu\u00e9 riesgos espec\u00edficos presentan para los neonatos?**\n   - Esta pregunta se centra en los excipientes mencionados en el contexto y sus efectos potenciales en la salud de los neonatos.\n\n2. **\u00bfQu\u00e9 criterios deben considerarse al seleccionar excipientes para medicamentos destinados a diferentes grupos de edad pedi\u00e1trica?**\n   - Esta pregunta busca detallar los factores que deben evaluarse al elegir excipientes, bas\u00e1ndose en la informaci\u00f3n proporcionada sobre la seguridad y la aceptabilidad.\n\n3. **\u00bfQu\u00e9 pasos se deben seguir para evaluar la seguridad de nuevos excipientes en medicamentos pedi\u00e1tricos?**\n   - Esta pregunta se enfoca en el proceso necesario para garantizar que los nuevos excipientes sean seguros y apropiados para su uso en ni\u00f1os, tal como se menciona en el contexto.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Clasificaci\u00f3n de Principios Activos (API)**:\n   - Los API se clasifican en cuatro clases seg\u00fan su solubilidad y permeabilidad intestinal:\n     - **Clase 1**: Alta solubilidad, alta permeabilidad.\n     - **Clase 2**: Baja solubilidad, alta permeabilidad.\n     - **Clase 3**: Alta solubilidad, baja permeabilidad.\n     - **Clase 4**: Baja solubilidad, baja permeabilidad.\n\n2. **Criterios de Solubilidad**:\n   - Un API se considera altamente soluble si la dosis m\u00e1s alta se disuelve en 250 ml o menos de medio acuoso a 37 \u00b0C en un rango de pH de 1.2 a 6.8.\n\n3. **Importancia de la Solubilidad Acuosa**:\n   - La solubilidad acuosa es crucial en la formulaci\u00f3n de formas de dosificaci\u00f3n de liberaci\u00f3n inmediata para las clases 1 y 3.\n   - Para las clases 2 y 4, se deben considerar factores como el tama\u00f1o de part\u00edcula, la forma polim\u00f3rfica y los potenciadores de solubilidad, ya que la absorci\u00f3n puede estar limitada por la tasa de disoluci\u00f3n.\n\n4. **Evaluaci\u00f3n de Excipientes en Medicamentos Pedi\u00e1tricos**:\n   - El uso de excipientes debe justificarse mediante una evaluaci\u00f3n basada en riesgos, considerando el grupo etario pedi\u00e1trico, la frecuencia de dosificaci\u00f3n y la duraci\u00f3n del tratamiento.\n   - Los excipientes pueden causar reacciones adversas en ni\u00f1os, lo que a\u00f1ade un desaf\u00edo en comparaci\u00f3n con los medicamentos para adultos.\n\n5. **Factores que Afectan la Absorci\u00f3n**:\n   - Para los API de clase 3 y 4, se debe considerar c\u00f3mo los excipientes pueden afectar el tiempo de tr\u00e1nsito intestinal, la funci\u00f3n de los transportadores y las enzimas metab\u00f3licas (como CYP3A4).\n\n### Entidades Clave\n- **API (Principios Activos)**\n- **BCS (Sistema de Clasificaci\u00f3n de Biopharmaceutics)**\n- **Excipientes**\n- **Medicamentos Pedi\u00e1tricos**\n- **Reacciones Adversas**\n- **Solubilidad Acuosa**\n- **Permeabilidad Intestinal**", "excerpt_keywords": "Excipients, Paediatric Medicines, Toxicity, Safety Profile, Formulation"}}, "aaf0e36a-7489-4e3d-bffd-bb314a2eb786": {"node_ids": ["322b78c7-3e5d-4697-812e-fb3fb4d8f198"], "metadata": {"page_label": "222", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 5.4 Colouring agents\n\nThe use of colouring agents in paediatric medicines is generally discouraged, in particular in medicines for infants and young children. Their use may, however, be justified in certain cases, e.g. to avoid accidental dosing errors in connection with medicines produced in several strengths. In this case, a solid dosage form of the types mentioned in section 3 may be preferred because size, shape and embossing can facilitate identification of different strengths of the preparation.\n\nSome colouring agents used in paediatric medicines have been associated with hypersensitivity (25). The number of colouring agents that are acceptable for use in medicines is limited. Azo-dyes should be avoided in children\u2019s medicines and attention should be paid to the risk of allergic reactions associated with natural colourants (26).\n\n# 5.5 Antimicrobial preservatives\n\nFPPs may require antimicrobial preservatives to avoid microbial proliferation during storage, in particular under in-use conditions. Preservatives are needed in particular for aqueous multidose preparations and semi-solid preparations and may also be needed for other aqueous preparations. Usually solid dosage forms do not require preservatives.\n\nPreservatives may have a potential to cause adverse reactions, in particular in infants and neonates, and should be avoided where possible. Furthermore, complex preservative systems should be avoided.\n\nOphthalmic preparations without preservatives are strongly recommended for use in children, especially neonates. Therefore, preparations without preservatives should be developed wherever possible in order to cater for the diversity of patients\u2019 needs. When preservatives are required, their concentration should be the minimum level consistent with satisfactory antimicrobial function in each individual preparation and a thorough justification for the choice of the preservative should be established. Ophthalmic preparations without any mercury-containing preservatives, e.g. thiomersal, should also be considered. Further details on this topic are provided in a public statement (27) published on the EMA web site.\n\n# 5.6 Sweetening agents\n\nOral paediatric medicines often use sweetening agents to make them palatable. These may be either cariogenic or non-cariogenic sweeteners. In addition to the considerations listed in section 4.3, attention should be paid to:\n\n- safety of the sweetening agent in relation to specific conditions of the child, e.g. diabetes, fructose intolerance, and avoiding use of aspartame in patients with phenylketonurea;", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Uso de agentes colorantes en medicamentos pedi\u00e1tricos**: Se desaconseja el uso de colorantes en medicamentos para ni\u00f1os, especialmente en infantes, aunque puede ser justificado en ciertos casos para evitar errores de dosificaci\u00f3n. Se debe tener cuidado con los colorantes azoicos y las reacciones al\u00e9rgicas asociadas con colorantes naturales.\n\n2. **Conservantes antimicrobianos en formulaciones pedi\u00e1tricas**: Los medicamentos pedi\u00e1tricos pueden necesitar conservantes antimicrobianos para prevenir la proliferaci\u00f3n microbiana, especialmente en preparaciones acuosas. Sin embargo, se deben evitar en la medida de lo posible, especialmente en neonatos, y se recomienda el uso de preparaciones oft\u00e1lmicas sin conservantes.\n\n3. **Uso de edulcorantes en medicamentos orales pedi\u00e1tricos**: Los edulcorantes se utilizan para mejorar el sabor de los medicamentos orales para ni\u00f1os, pero se debe prestar atenci\u00f3n a su seguridad en relaci\u00f3n con condiciones espec\u00edficas del ni\u00f1o, como la diabetes y la intolerancia a la fructosa.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las justificaciones para el uso de colorantes en medicamentos pedi\u00e1tricos y qu\u00e9 precauciones se deben tomar al elegirlos?**\n   - La justificaci\u00f3n para el uso de colorantes en medicamentos pedi\u00e1tricos incluye la prevenci\u00f3n de errores de dosificaci\u00f3n en medicamentos con varias concentraciones. Se deben evitar los colorantes azoicos y tener cuidado con las reacciones al\u00e9rgicas a los colorantes naturales.\n\n2. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al seleccionar conservantes antimicrobianos para medicamentos pedi\u00e1tricos?**\n   - Se deben evitar los conservantes siempre que sea posible, especialmente en infantes y neonatos. Cuando se requieran, su concentraci\u00f3n debe ser la m\u00ednima necesaria para una funci\u00f3n antimicrobiana adecuada, y se debe justificar la elecci\u00f3n del conservante.\n\n3. **\u00bfQu\u00e9 factores de seguridad se deben considerar al utilizar edulcorantes en medicamentos orales para ni\u00f1os?**\n   - Se debe considerar la seguridad del edulcorante en relaci\u00f3n con condiciones espec\u00edficas del ni\u00f1o, como la diabetes y la intolerancia a la fructosa, y evitar el uso de aspartame en pacientes con fenilcetonuria.", "prev_section_summary": "### Temas Clave\n\n1. **Problemas con Excipientes en Medicamentos Pedi\u00e1tricos**: Se han identificado riesgos significativos asociados con excipientes en medicamentos para neonatos, como el alcohol benc\u00edlico y el propilenglicol, que pueden llevar a toxicidad.\n\n2. **Desarrollo de Medicamentos Pedi\u00e1tricos**: Es fundamental minimizar la cantidad y el n\u00famero de excipientes en las formulaciones para asegurar la calidad del producto, considerando factores como la seguridad, la estabilidad y la aceptabilidad.\n\n3. **Selecci\u00f3n de Excipientes**: Al elegir excipientes, se deben evaluar aspectos como el perfil de seguridad, la ruta de administraci\u00f3n, la dosis y la duraci\u00f3n del tratamiento, as\u00ed como la aceptaci\u00f3n por parte de la poblaci\u00f3n pedi\u00e1trica.\n\n4. **Alternativas a Excipientes Riesgosos**: Se deben considerar alternativas a los excipientes que presentan riesgos significativos, lo que puede incluir cambios en la forma de dosificaci\u00f3n o la ruta de administraci\u00f3n.\n\n5. **Evaluaci\u00f3n de Nuevos Excipientes**: Los excipientes nuevos deben ser utilizados solo si se ha establecido su seguridad y calidad para su uso en ni\u00f1os, teniendo en cuenta tambi\u00e9n factores culturales y religiosos.\n\n### Entidades\n\n- **Excipientes**: Sustancias inactivas utilizadas en medicamentos.\n- **Benzyl Alcohol**: Excipiente problem\u00e1tico asociado con toxicidad en neonatos.\n- **Propylene Glycol**: Otro excipiente que presenta riesgos de toxicidad en neonatos.\n- **American Academy of Pediatrics**: Fuente de informaci\u00f3n sobre la seguridad de excipientes.\n- **WHO Technical Report Series**: Publicaciones que ofrecen informaci\u00f3n sobre la evaluaci\u00f3n de aditivos alimentarios.\n- **Poblaci\u00f3n Pedi\u00e1trica**: Ni\u00f1os y neonatos que requieren medicamentos espec\u00edficos.\n- **Criterios de Seguridad**: Factores a considerar al seleccionar excipientes para medicamentos pedi\u00e1tricos.", "excerpt_keywords": "Keywords: paediatric medicines, colouring agents, antimicrobial preservatives, sweetening agents, safety considerations"}}, "73fde2c4-ed6e-4b50-bcdd-02e74cada912": {"node_ids": ["4e2c5ecf-07c1-4fee-a317-448bfdd0b592"], "metadata": {"page_label": "223", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Taste Masking\n\nTaste masking in medicines for oral use or for use in the mouth is often needed to improve palatability of the medicine. Children have a well-developed sensory system for detecting tastes, smells and chemical irritants. They are able to recognize sweetness and saltiness from an early stage and are also able to recognize a sweet taste in oral liquids and the degree of sweetness (28). Children seem to prefer sweeter tastes than adults do. The unpleasant taste of an API, e.g. bitterness or a metallic taste, is, therefore, often masked in an oral liquid by the use of sweetening agents and flavours. Additional use of colouring agents that match the flavour is discouraged (see section 4.4) unless this is necessary to disguise an unpleasant colour related to the API. Some successful approaches to taste masking are discussed by Ernest et al. (7).\n\nA child\u2019s preference for particular flavours is determined by individual experiences and culture. The target for taste masking need not necessarily be good-tasting medicines; it should simply be a taste that is acceptable in as many countries as possible taking into account cultural differences.\n\nAn example of a \u201cqualitative evaluation of the taste by a taste panel\u201d for zinc formulations can be found in the United Nations Children\u2019s Fund (UNICEF)/WHO publication on production of zinc formulations (29, 30).\n\nConsideration should be given to the items listed in sections 4.3 and 4.6.\n\nTaste masking for orodispersible tablets and chewable tablets is in principle similar to taste masking for oral liquids. Non-cariogenic sweeteners and flavours are preferred.\n\n# Solubility Enhancers\n\nThe aqueous solubility of the API may limit the concentration achievable in formulated solutions and, hence, the desirable dose volume. In many cases an acceptable solution requires solubility enhancing methods, e.g. use of non-ionic surfactants and of co-solvents such as glycerol, liquid macrogols and ethanol. If solubility enhancers are to be used, consideration should be given to the safety of both the agent and the formulation, for example, the risk of irritation and damage of intestinal tissues in neonates caused by hyperosmolality or other local toxicity. Risks associated with the use of solubility enhancers are higher when they are included in parenteral preparations than when used in oral preparations.\n\nEthanol, especially in large amounts, should not be administered to children (aged 0\u201317 years) through FPPs without a clear demonstration of benefit.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de Nivel Superior\n\n1. **Importancia del Enmascaramiento del Sabor**: El enmascaramiento del sabor en medicamentos orales es crucial para mejorar la palatabilidad, especialmente en ni\u00f1os, quienes tienen una sensibilidad aguda a los sabores. Se utilizan agentes endulzantes y sabores para ocultar sabores desagradables de los principios activos (API), y se deben considerar las diferencias culturales en las preferencias de sabor.\n\n2. **Uso de Mejoradores de Solubilidad**: La solubilidad acuosa de los API puede limitar la concentraci\u00f3n en soluciones formuladas. Para lograr una soluci\u00f3n aceptable, se pueden emplear m\u00e9todos de mejora de solubilidad, como surfactantes no i\u00f3nicos y co-solventes. Sin embargo, se deben considerar los riesgos de irritaci\u00f3n y toxicidad, especialmente en preparaciones parenterales y en ni\u00f1os.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los m\u00e9todos recomendados para enmascarar sabores desagradables en medicamentos orales para ni\u00f1os?**\n   - El enmascaramiento de sabores desagradables se logra principalmente mediante el uso de agentes endulzantes y sabores que sean aceptables culturalmente. Se desaconseja el uso de colorantes a menos que sea necesario para ocultar un color desagradable relacionado con el API.\n\n2. **\u00bfQu\u00e9 consideraciones de seguridad deben tenerse en cuenta al utilizar mejoradores de solubilidad en medicamentos para ni\u00f1os?**\n   - Al utilizar mejoradores de solubilidad, es fundamental considerar la seguridad del agente y la formulaci\u00f3n, incluyendo el riesgo de irritaci\u00f3n y da\u00f1o a los tejidos intestinales en neonatos debido a la hiperosmolaridad o toxicidad local. Los riesgos son mayores en preparaciones parenterales que en orales.\n\n3. **\u00bfC\u00f3mo influyen las experiencias individuales y la cultura en las preferencias de sabor de los ni\u00f1os?**\n   - Las preferencias de sabor de los ni\u00f1os est\u00e1n determinadas por sus experiencias individuales y su cultura, lo que significa que el objetivo del enmascaramiento del sabor no debe ser necesariamente crear medicamentos que sepan bien, sino que sean aceptables en la mayor cantidad de pa\u00edses posible, teniendo en cuenta estas diferencias culturales.", "prev_section_summary": "### Temas Clave\n\n1. **Agentes Colorantes en Medicamentos Pedi\u00e1tricos**:\n   - Generalmente desaconsejados, especialmente en infantes.\n   - Pueden ser justificados para evitar errores de dosificaci\u00f3n en medicamentos con varias concentraciones.\n   - Se deben evitar colorantes azoicos y tener precauci\u00f3n con colorantes naturales debido a posibles reacciones al\u00e9rgicas.\n\n2. **Conservantes Antimicrobianos**:\n   - Necesarios para prevenir la proliferaci\u00f3n microbiana en preparaciones acuosas, especialmente en productos multidosis y semi-s\u00f3lidos.\n   - Deben evitarse en la medida de lo posible, especialmente en neonatos.\n   - Se recomienda el uso de preparaciones oft\u00e1lmicas sin conservantes y se debe justificar la elecci\u00f3n de cualquier conservante utilizado.\n\n3. **Agentes Edulcorantes**:\n   - Utilizados para mejorar el sabor de los medicamentos orales pedi\u00e1tricos.\n   - Deben considerarse la seguridad en relaci\u00f3n con condiciones espec\u00edficas del ni\u00f1o, como diabetes e intolerancia a la fructosa.\n   - Se debe evitar el uso de aspartame en pacientes con fenilcetonuria.\n\n### Entidades\n\n- **Medicamentos Pedi\u00e1tricos**: Formulaciones destinadas a ni\u00f1os, incluyendo infantes y neonatos.\n- **Agentes Colorantes**: Sustancias utilizadas para dar color a los medicamentos.\n- **Conservantes Antimicrobianos**: Sustancias que previenen el crecimiento de microorganismos en productos farmac\u00e9uticos.\n- **Agentes Edulcorantes**: Sustancias que mejoran el sabor de los medicamentos, pudiendo ser cariog\u00e9nicas o no cariog\u00e9nicas.\n- **Condiciones Espec\u00edficas**: Diabetes, intolerancia a la fructosa, fenilcetonuria.\n\nEste resumen destaca las consideraciones importantes sobre el uso de colorantes, conservantes y edulcorantes en medicamentos pedi\u00e1tricos, enfatizando la seguridad y la necesidad de justificaci\u00f3n en su uso.", "excerpt_keywords": "Taste masking, solubility enhancers, pediatric formulations, palatability, safety considerations"}}, "e86a78f2-b8f3-429d-9ee6-b1ca08ce25f7": {"node_ids": ["1926b344-70e9-48cf-b7df-9d6141e54a35"], "metadata": {"page_label": "224", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nAlthough it is recognized that ethanol may not always be eliminated from FPPs, and replacements may raise other issues, the smallest possible amount should be used. When ethanol is used, adequate development data demonstrating that the lowest possible concentration of ethanol is used should be established.\n\nChildren, especially under the age of 6 years, are more vulnerable to the effects of ethanol. Adverse effects on the central nervous system are already evident at blood ethanol concentrations of 10 mg/100 ml in children. Higher peak ethanol blood concentrations are also observed in children than in adults for a similar intake. Chronic exposure to ethanol (> 1 week), even to small doses, through FPPs is, in principle, contraindicated in children aged less than 6 years and should be limited to 2 weeks in children aged over 6 years, if a positive risk\u2013benefit balance is not demonstrated. Toxic effects on brain maturation in young children are highly probable and also supported by non-clinical data. Additionally, chronic exposure has been shown to be linked to ethanol dependence in adults and adolescents.\n\n## 6. Oral administration\n\nThe oral route is the preferred and most appropriate route of administration to paediatric patients. This route is generally acceptable in all age groups if the medicine is administered in a suitable dosage form, e.g. in liquid form for children in the youngest age groups who have difficulty in swallowing solid dosage forms. Strictly speaking, the choice of dosage form for oral administration depends on the gut function and, thus, on both age and clinical condition.\n\nConsideration should be given to the effects of increased gastric pH and intestinal mobility at birth and in early infancy (2). In addition, gastric emptying of sick newborns is most erratic and can be delayed. Further information can be found in an EMA guideline on medicines for term and preterm neonates (31).\n\nMixing oral dosage forms with food or a beverage is not recommended, but may be performed to enhance compliance (see section 2.2). Potential effects of foods on bioavailability should be considered. When recommending mixing medicines with food, attention should be paid to the effect on the taste, as an unpleasant taste of medicine may cause aversion in children.\n\n### 6.1 Oral liquid preparations\n\nOral liquid preparations include aqueous solutions, suspensions, emulsions and syrups. They are most appropriate for children in the youngest age groups who are unable to swallow solid dosage forms. The advantage of oral liquid preparations is that variable dose volumes can be measured and administered. The need for stabilizing agents, e.g. antimicrobial preservatives, is a major drawback as is the potential chemical instability, which may lead to a requirement for controlled storage.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Efectos del etanol en ni\u00f1os**: El etanol puede tener efectos adversos significativos en los ni\u00f1os, especialmente en aquellos menores de 6 a\u00f1os. Se menciona que la exposici\u00f3n cr\u00f3nica al etanol, incluso en peque\u00f1as dosis, es desaconsejada y puede tener consecuencias negativas en el desarrollo del cerebro.\n\n2. **Administraci\u00f3n oral en pediatr\u00eda**: La administraci\u00f3n oral es la ruta preferida para los pacientes pedi\u00e1tricos, y se debe considerar la forma de dosificaci\u00f3n adecuada, especialmente para los m\u00e1s j\u00f3venes que no pueden tragar formas s\u00f3lidas. La elecci\u00f3n de la forma de dosificaci\u00f3n depende de la funci\u00f3n intestinal y la condici\u00f3n cl\u00ednica del ni\u00f1o.\n\n3. **Preparaciones l\u00edquidas orales**: Las preparaciones l\u00edquidas orales son adecuadas para los ni\u00f1os m\u00e1s peque\u00f1os y permiten medir y administrar vol\u00famenes de dosis variables. Sin embargo, su estabilidad qu\u00edmica y la necesidad de agentes estabilizantes son desventajas importantes.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las concentraciones de etanol en sangre que pueden causar efectos adversos en ni\u00f1os y c\u00f3mo se comparan con los adultos?**\n   - Respuesta: Los efectos adversos en el sistema nervioso central en ni\u00f1os son evidentes a concentraciones de etanol en sangre de 10 mg/100 ml. Adem\u00e1s, se observa que los ni\u00f1os alcanzan concentraciones m\u00e1ximas de etanol en sangre m\u00e1s altas que los adultos con una ingesta similar.\n\n2. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al elegir la forma de dosificaci\u00f3n oral para pacientes pedi\u00e1tricos?**\n   - Respuesta: La elecci\u00f3n de la forma de dosificaci\u00f3n oral depende de la funci\u00f3n intestinal, que var\u00eda seg\u00fan la edad y la condici\u00f3n cl\u00ednica del ni\u00f1o. Tambi\u00e9n se deben considerar los efectos del pH g\u00e1strico y la movilidad intestinal en reci\u00e9n nacidos y lactantes.\n\n3. **\u00bfCu\u00e1les son las desventajas de las preparaciones l\u00edquidas orales en comparaci\u00f3n con las formas s\u00f3lidas?**\n   - Respuesta: Las desventajas de las preparaciones l\u00edquidas orales incluyen la necesidad de agentes estabilizantes, como conservantes antimicrobianos, y la potencial inestabilidad qu\u00edmica, lo que puede requerir un almacenamiento controlado.", "prev_section_summary": "### Temas Clave\n\n1. **Enmascaramiento del Sabor**:\n   - Es esencial para mejorar la palatabilidad de los medicamentos orales, especialmente en ni\u00f1os.\n   - Los ni\u00f1os tienen una sensibilidad aguda a los sabores y prefieren sabores m\u00e1s dulces que los adultos.\n   - Se utilizan agentes endulzantes y sabores para ocultar sabores desagradables de los principios activos (API).\n   - Las preferencias de sabor est\u00e1n influenciadas por experiencias individuales y diferencias culturales.\n   - Se desaconseja el uso de colorantes a menos que sea necesario para ocultar un color desagradable relacionado con el API.\n\n2. **Mejoradores de Solubilidad**:\n   - La solubilidad acuosa de los API puede limitar la concentraci\u00f3n en soluciones formuladas.\n   - Se pueden utilizar surfactantes no i\u00f3nicos y co-solventes como glicerol y etanol para mejorar la solubilidad.\n   - Es importante considerar la seguridad de los mejoradores de solubilidad, especialmente en neonatos, debido a riesgos de irritaci\u00f3n y toxicidad.\n   - Los riesgos son mayores en preparaciones parenterales que en orales.\n   - El etanol no debe ser administrado a ni\u00f1os sin una clara demostraci\u00f3n de beneficio.\n\n### Entidades\n\n- **API (Principios Activos)**: Sustancias que tienen un efecto farmacol\u00f3gico.\n- **Agentes Endulzantes**: Sustancias utilizadas para mejorar el sabor de los medicamentos.\n- **Surfactantes No I\u00f3nicos**: Compuestos que ayudan a aumentar la solubilidad de los API.\n- **Co-solventes**: Sustancias como glicerol y etanol que se utilizan para mejorar la solubilidad.\n- **UNICEF**: Fondo de las Naciones Unidas para la Infancia, que proporciona directrices sobre formulaciones de zinc.\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Organizaci\u00f3n que establece est\u00e1ndares y directrices para la salud p\u00fablica, incluyendo la formulaci\u00f3n de medicamentos.", "excerpt_keywords": "Keywords: ethanol, pediatric, oral administration, liquid preparations, pharmaceutical specifications"}}, "0af92150-be22-4777-82a0-b64b9c07bcee": {"node_ids": ["3c46109a-9581-4390-9da0-f0696820da22"], "metadata": {"page_label": "225", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\nConditions during distribution and use. Oral liquid preparations are less transportable than solid-dose preparations because of their relatively high bulk volume.\n\nThe dose volume is important for the acceptability of the preparation. High-dose volumes pose a risk of incomplete ingestion and, thus, underdosage. Efforts should, therefore, be made during pharmaceutical development to minimize the dose volume while recognizing the need to ensure accurate measurements of the dose over the anticipated range. Typical target dose volumes are 5 ml or less for children under 5 years and 10 ml or less for children of 5 years and older (32). There is some uncertainty about these limits because the more palatable the formulation, the higher the dose volume that will be accepted by the child. Target volumes and electrolyte contents are critical for neonates, especially in cases of immature renal function.\n\nOral liquid preparations may be supplied in multidose containers or single-dose containers. Usually, both forms require antimicrobial preservatives. Special attention has to be paid to the in-use stability of multidose preparations, both microbial and physicochemical.\n\nMultidose preparations should be packaged together with an appropriate dosing device. The correct graduation of the device and the accuracy of the volumes measured must be checked by the manufacturer. Generally, oral syringes are preferable because of the flexibility in dose measurement and superior accuracy compared to other devices such as graduated pipettes or plastic spoons. The accuracy in measuring and delivering a volume of liquid is influenced by the liquid\u2019s physical characteristics, especially its viscosity.\n\nThe risks associated with incorrect dosing should be considered. If correct dosing is critical, a single-dose preparation, e.g. a pre-filled oral syringe, should be considered.\n\n## Drops\n\nSome liquids are administered as drops in small volumes using a dropper or a graduated pipette to measure a volume to be dissolved or dispersed in water or another diluent before the dose is swallowed. The use of this dosage form should be evaluated using a risk-based approach to ensure it is suitable given the medicine\u2019s potency and side-effect profile and the potential for dosing errors. The in-use performance of the dose-measuring device is critical for this dosage form.\n\n## Oral suspensions\n\nFormulation of an oral suspension may be dictated by the aqueous solubility of the API and the balance between the dose of API and the dose volume. In certain cases, the unpleasant taste of an API can be reduced by choosing the suspended form.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl texto aborda las consideraciones sobre la distribuci\u00f3n y uso de preparaciones l\u00edquidas orales en comparaci\u00f3n con las preparaciones s\u00f3lidas. Se enfatiza la importancia del volumen de dosis para la aceptabilidad, especialmente en ni\u00f1os, y se discuten las implicaciones de la formulaci\u00f3n, el envasado y la medici\u00f3n de dosis. Se menciona la necesidad de dispositivos de dosificaci\u00f3n precisos y la evaluaci\u00f3n de riesgos asociados con errores de dosificaci\u00f3n. Tambi\u00e9n se abordan las suspensiones orales y la administraci\u00f3n de l\u00edquidos en forma de gotas.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los vol\u00famenes de dosis t\u00edpicos recomendados para ni\u00f1os menores de 5 a\u00f1os y para aquellos de 5 a\u00f1os o m\u00e1s, y c\u00f3mo se relaciona la palatabilidad de la formulaci\u00f3n con la aceptaci\u00f3n del volumen de dosis?**\n   - Respuesta: Los vol\u00famenes de dosis t\u00edpicos recomendados son de 5 ml o menos para ni\u00f1os menores de 5 a\u00f1os y de 10 ml o menos para ni\u00f1os de 5 a\u00f1os y mayores. La palatabilidad de la formulaci\u00f3n puede influir en la aceptaci\u00f3n del volumen de dosis, ya que una formulaci\u00f3n m\u00e1s agradable puede permitir un volumen de dosis mayor.\n\n2. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al elegir entre preparaciones de dosis \u00fanica y multidose para l\u00edquidos orales?**\n   - Respuesta: Al elegir entre preparaciones de dosis \u00fanica y multidose, se deben considerar los riesgos asociados con la dosificaci\u00f3n incorrecta. Si la dosificaci\u00f3n precisa es cr\u00edtica, se recomienda optar por una preparaci\u00f3n de dosis \u00fanica, como una jeringa oral precargada.\n\n3. **\u00bfC\u00f3mo influye la viscosidad del l\u00edquido en la precisi\u00f3n de la medici\u00f3n y entrega de un volumen de l\u00edquido en preparaciones orales?**\n   - Respuesta: La viscosidad del l\u00edquido influye en la precisi\u00f3n de la medici\u00f3n y entrega de un volumen de l\u00edquido, ya que las caracter\u00edsticas f\u00edsicas del l\u00edquido pueden afectar la capacidad del dispositivo de dosificaci\u00f3n para medir y entregar el volumen de manera precisa.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Efectos del Etanol en Ni\u00f1os**:\n   - El etanol puede causar efectos adversos significativos en ni\u00f1os, especialmente en aquellos menores de 6 a\u00f1os.\n   - Se observan efectos en el sistema nervioso central a concentraciones de etanol en sangre de 10 mg/100 ml.\n   - Los ni\u00f1os alcanzan concentraciones m\u00e1s altas de etanol en sangre en comparaci\u00f3n con los adultos para una ingesta similar.\n   - La exposici\u00f3n cr\u00f3nica al etanol est\u00e1 contraindicada en ni\u00f1os menores de 6 a\u00f1os y debe limitarse a 2 semanas en ni\u00f1os mayores de 6 a\u00f1os, a menos que se demuestre un balance positivo de riesgo-beneficio.\n\n2. **Administraci\u00f3n Oral en Pediatr\u00eda**:\n   - La administraci\u00f3n oral es la ruta preferida para pacientes pedi\u00e1tricos.\n   - La elecci\u00f3n de la forma de dosificaci\u00f3n depende de la funci\u00f3n intestinal, que var\u00eda seg\u00fan la edad y la condici\u00f3n cl\u00ednica del ni\u00f1o.\n   - Se deben considerar factores como el pH g\u00e1strico y la movilidad intestinal en reci\u00e9n nacidos y lactantes.\n\n3. **Preparaciones L\u00edquidas Orales**:\n   - Incluyen soluciones acuosas, suspensiones, emulsiones y jarabes, siendo adecuadas para los ni\u00f1os m\u00e1s peque\u00f1os que no pueden tragar formas s\u00f3lidas.\n   - Permiten medir y administrar vol\u00famenes de dosis variables.\n   - Desventajas incluyen la necesidad de agentes estabilizantes (como conservantes antimicrobianos) y la potencial inestabilidad qu\u00edmica, lo que puede requerir almacenamiento controlado.\n\n### Entidades Clave:\n- **Ethanol**: Sustancia cuyo uso en formulaciones farmac\u00e9uticas debe ser minimizado, especialmente en pediatr\u00eda.\n- **Ni\u00f1os menores de 6 a\u00f1os**: Grupo m\u00e1s vulnerable a los efectos del etanol.\n- **Administraci\u00f3n Oral**: Ruta preferida para la medicaci\u00f3n en pacientes pedi\u00e1tricos.\n- **Preparaciones L\u00edquidas**: Formas de dosificaci\u00f3n adecuadas para ni\u00f1os peque\u00f1os, con ventajas y desventajas espec\u00edficas.", "excerpt_keywords": "Keywords: oral liquid preparations, dosing accuracy, pediatric formulations, multidose containers, viscosity effects"}}, "1e2b685e-00f3-4cdb-8169-609db24d13b4": {"node_ids": ["43f63433-be30-45c9-976f-0cedf9f52860"], "metadata": {"page_label": "226", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nOral suspensions must be shaken before use to ensure a homogeneous liquid when the dose volume is measured. There might in some instances be a significant risk of dosing errors due to sedimentation or caking of the suspension during storage; therefore, resuspendability should be a stability parameter. The control strategy for oral suspensions includes dissolution testing (18) unless otherwise justified.\n\n## Powders and granules for reconstitution\n\nSolid preparations for reconstitution as solutions or suspensions should be considered, especially when the liquid preparation has a short shelf-life due to instability (chemical, physical or microbiological). Powders and granules for reconstitution are produced as single-dose sachets or multidose preparations, usually provided in containers that can hold the reconstituted multidose preparation. The liquid vehicle can be provided together with the dry preparation, especially when the product is intended for markets where access to clean water may be difficult. Alternatively, manufacturers can recommend on the product labels and summary of product characteristics (SmPCs) how to reconstitute the product, e.g. with boiled and cooled water.\n\nTo ensure their proper use, the solids must be easily wetted and dispersed or dissolved within a short time once the vehicle is added.\n\nThe major drawbacks of this type of formulation are the bulk volume of the preparation, i.e. it is less transportable, and the in-use microbial stability of multidose preparations, which may require use of antimicrobial agents. For these reasons, single-dose preparations of the flexible types mentioned in section 3.1 are preferable.\n\n## 6.2 Administration through feeding tubes\n\nFor neonates and seriously ill infants, enteral administration of liquids via feeding tubes is used. Hence the preparation will not be subject to the normal effects of saliva and/or gastric juice, which may affect its bioavailability.\n\nDosing accuracy should be considered, taking into account the ease of transfer along the feeding tube (including viscosity, particle size and amount of suspended components), potential absorption of the API into the tube material and rinsing by flushing of the tube. The rinsing volume should be appropriate to the target age group and an acceptable fluid intake.\n\nThese considerations should be highlighted in the SmPCs.\n\n## 6.3 Oral solid dosage forms\n\nOral solid dosage forms include a variety of final forms from powders to coated tablets intended to be swallowed directly or after application to the mouth (chewable tablets, orally dissolving tablets or orodispersible tablets). Some are...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Suspensiones orales**: Se requiere agitar las suspensiones orales antes de su uso para garantizar una mezcla homog\u00e9nea. La sedimentaci\u00f3n o el apelmazamiento durante el almacenamiento pueden causar errores de dosificaci\u00f3n, por lo que la capacidad de resuspensi\u00f3n es un par\u00e1metro de estabilidad importante. La estrategia de control incluye pruebas de disoluci\u00f3n.\n\n2. **Polvos y gr\u00e1nulos para reconstituci\u00f3n**: Las preparaciones s\u00f3lidas para reconstituci\u00f3n son \u00fatiles cuando las soluciones l\u00edquidas tienen una vida \u00fatil corta. Estas pueden presentarse en sachets de dosis \u00fanica o en preparaciones multidose. Es crucial que los s\u00f3lidos se humedezcan y se disuelvan r\u00e1pidamente al a\u00f1adir el veh\u00edculo.\n\n3. **Administraci\u00f3n a trav\u00e9s de tubos de alimentaci\u00f3n**: Para neonatos y beb\u00e9s gravemente enfermos, se utiliza la administraci\u00f3n enteral de l\u00edquidos a trav\u00e9s de tubos de alimentaci\u00f3n. Se deben considerar factores como la precisi\u00f3n de la dosificaci\u00f3n y la facilidad de transferencia a trav\u00e9s del tubo, as\u00ed como la absorci\u00f3n potencial del principio activo en el material del tubo.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfPor qu\u00e9 es importante la capacidad de resuspensi\u00f3n en las suspensiones orales y c\u00f3mo se relaciona con la estabilidad del producto?**\n   - La capacidad de resuspensi\u00f3n es crucial porque la sedimentaci\u00f3n o el apelmazamiento pueden llevar a errores de dosificaci\u00f3n. Esto se considera un par\u00e1metro de estabilidad, ya que asegura que el medicamento se administre en la dosis correcta.\n\n2. **\u00bfCu\u00e1les son las ventajas y desventajas de las preparaciones s\u00f3lidas para reconstituci\u00f3n en comparaci\u00f3n con las soluciones l\u00edquidas?**\n   - Las ventajas incluyen una mayor estabilidad y facilidad de transporte, especialmente en mercados con acceso limitado a agua limpia. Las desventajas son el volumen de preparaci\u00f3n m\u00e1s grande y la estabilidad microbiana en uso, que puede requerir agentes antimicrobianos.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al administrar medicamentos a trav\u00e9s de tubos de alimentaci\u00f3n en neonatos?**\n   - Se debe considerar la precisi\u00f3n de la dosificaci\u00f3n, la viscosidad del l\u00edquido, el tama\u00f1o de las part\u00edculas y la cantidad de componentes suspendidos. Tambi\u00e9n es importante tener en cuenta la absorci\u00f3n del principio activo en el material del tubo y el volumen de enjuague adecuado para el grupo de edad objetivo.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Preparaciones l\u00edquidas orales vs. s\u00f3lidas**: Las preparaciones l\u00edquidas orales son menos transportables debido a su mayor volumen. \n\n2. **Volumen de dosis**: \n   - Importancia del volumen de dosis para la aceptabilidad, especialmente en ni\u00f1os.\n   - Vol\u00famenes t\u00edpicos recomendados: 5 ml o menos para ni\u00f1os menores de 5 a\u00f1os y 10 ml o menos para ni\u00f1os de 5 a\u00f1os y mayores.\n   - La palatabilidad de la formulaci\u00f3n puede influir en la aceptaci\u00f3n del volumen de dosis.\n\n3. **Tipos de envases**: \n   - Preparaciones en envases multidose o de dosis \u00fanica, ambas requieren conservantes antimicrobianos.\n   - La estabilidad en uso de las preparaciones multidose es crucial.\n\n4. **Dispositivos de dosificaci\u00f3n**: \n   - Se recomienda el uso de jeringas orales por su precisi\u00f3n en la medici\u00f3n de dosis.\n   - La viscosidad del l\u00edquido afecta la precisi\u00f3n en la medici\u00f3n y entrega del volumen.\n\n5. **Riesgos de dosificaci\u00f3n incorrecta**: \n   - Se deben considerar los riesgos asociados con la dosificaci\u00f3n incorrecta; en casos cr\u00edticos, se sugiere el uso de preparaciones de dosis \u00fanica.\n\n6. **Formas de administraci\u00f3n**: \n   - **Gotas**: Se administran en peque\u00f1os vol\u00famenes y requieren una evaluaci\u00f3n basada en riesgos para evitar errores de dosificaci\u00f3n.\n   - **Suspensiones orales**: La formulaci\u00f3n puede depender de la solubilidad del principio activo y puede ayudar a enmascarar sabores desagradables.\n\n### Entidades mencionadas\n- **Ni\u00f1os**: Grupos de edad para los cuales se establecen vol\u00famenes de dosis.\n- **API (Ingrediente Activo)**: Referido en el contexto de formulaciones y suspensiones orales.\n- **Dispositivos de dosificaci\u00f3n**: Jeringas orales, pipetas graduadas, cucharas pl\u00e1sticas.\n- **Preparaciones**: L\u00edquidas orales, multidose, de dosis \u00fanica, gotas, suspensiones.", "excerpt_keywords": "Keywords: oral suspensions, reconstitution, feeding tubes, dosing accuracy, pharmaceutical preparations"}}, "955c98ab-f764-4d88-8bd6-4816f04d161e": {"node_ids": ["68b81cbb-710f-4d23-8d96-172d14f25492"], "metadata": {"page_label": "227", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "intended for swallowing after dissolution, dispersion in water or other suitable liquids. Their advantages over oral liquid preparations are improved stability, good dosage uniformity and options for different doses. The ease of administration depends on the child and the particular dosage form. These forms are convenient for packaging and ease of transport.\n\nWhile powders and multiparticulate preparations mixed with food or beverages may be acceptable from the moment when the infant is able to accept solid food, i.e. about 6 months, there are uncertainties with regard to the age at which intact tablets and capsules are acceptable. It has been thought generally that even small tablets and capsules to be taken whole are not acceptable for children below the age of 6 years. However, no good scientific evidence exists to support this notion. Recent preliminary evidence indicates that mini-tablets (with a diameter of less than 4 mm) may be acceptable even by the majority of small children (2\u20134 years old) (33).\n\n### Powders and multiparticulate preparations\n\nPowders and multiparticulates are provided in sachets or in hard capsules that allow the contents to be taken directly or after manipulation, e.g. following preparation of oral liquids or to be sprinkled on to food or liquids.\n\nMultiparticulate preparations are granules, rounded granules of uniform size (often called pellets) and mini-tablets. Pellets are often prepared by extrusion/spheronization technology, which produces uniform particles within the size range 0.5\u20132 mm. Mini-tablets are prepared by compression into units with a diameter of not more than 4 mm. Especially when only a portion of the provided dose is administered, the particle size distribution of the API may be critical to dosing accuracy. Control of dose uniformity should be performed on a level corresponding to the dose to be taken by the target age group.\n\nMultiparticulate preparations offer the same advantages as conventional tablets and capsules with regard to the use of excipients, opportunities for taste masking (e.g. by coating), stability and opportunities for modifying the release profile. Furthermore, they possess great flexibility. An age-related dose may be obtained by taking an appropriate number of pellets or mini-tablets. A counting device may be necessary when a large number of pellets or mini-tablets is required. In addition, pellets and mini-tablets are suited for the platform technology mentioned in section 3.2.\n\n### Immediate-release tablets\n\nConventional tablets are either uncoated, film-coated or sugar-coated and are intended for immediate disintegration, release and absorption when swallowed. The coating may cover an unpleasant taste and smell and will, in general, improve palatability. Film-coating is preferable because sugar-coated tablets resemble", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Formas de dosificaci\u00f3n para ni\u00f1os**: El texto discute las diferentes formas de dosificaci\u00f3n de medicamentos para ni\u00f1os, destacando las ventajas de los polvos y preparaciones multiparticuladas en comparaci\u00f3n con las tabletas y c\u00e1psulas. Se menciona la aceptaci\u00f3n de estas formas de dosificaci\u00f3n en funci\u00f3n de la edad del ni\u00f1o y su capacidad para tragar.\n\n2. **Preparaciones multiparticuladas**: Se describen las caracter\u00edsticas de las preparaciones multiparticuladas, como los pellets y mini-tabletas, y se enfatiza su flexibilidad en la dosificaci\u00f3n, as\u00ed como su capacidad para mejorar la estabilidad y la palatabilidad del medicamento.\n\n3. **Tabletas de liberaci\u00f3n inmediata**: Se aborda la formulaci\u00f3n de tabletas convencionales, que pueden ser recubiertas o no, y su prop\u00f3sito de desintegrarse y absorberse r\u00e1pidamente al ser ingeridas. Se menciona la importancia del recubrimiento para mejorar el sabor y la experiencia del paciente.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 evidencia reciente sugiere sobre la aceptaci\u00f3n de mini-tabletas en ni\u00f1os de 2 a 4 a\u00f1os?**\n   - La evidencia preliminar indica que las mini-tabletas, con un di\u00e1metro de menos de 4 mm, pueden ser aceptables para la mayor\u00eda de los ni\u00f1os peque\u00f1os de 2 a 4 a\u00f1os, a pesar de la creencia general de que las tabletas y c\u00e1psulas enteras no son adecuadas para ni\u00f1os menores de 6 a\u00f1os.\n\n2. **\u00bfCu\u00e1les son las ventajas de las preparaciones multiparticuladas en comparaci\u00f3n con las tabletas convencionales?**\n   - Las preparaciones multiparticuladas ofrecen ventajas como una mejor uniformidad de dosis, opciones para enmascarar sabores, estabilidad y flexibilidad en la dosificaci\u00f3n, permitiendo que se tomen diferentes cantidades de pellets o mini-tabletas seg\u00fan la edad del ni\u00f1o.\n\n3. **\u00bfQu\u00e9 tecnolog\u00edas se utilizan para la fabricaci\u00f3n de pellets y mini-tabletas?**\n   - Los pellets se preparan a menudo mediante tecnolog\u00eda de extrusi\u00f3n/esferonizaci\u00f3n, que produce part\u00edculas uniformes en el rango de tama\u00f1o de 0.5 a 2 mm, mientras que las mini-tabletas se fabrican mediante compresi\u00f3n en unidades con un di\u00e1metro no mayor de 4 mm.", "prev_section_summary": "### Temas Clave\n\n1. **Suspensiones Orales**: \n   - Importancia de agitar antes de usar para asegurar homogeneidad.\n   - Riesgo de errores de dosificaci\u00f3n por sedimentaci\u00f3n o apelmazamiento.\n   - La capacidad de resuspensi\u00f3n es un par\u00e1metro de estabilidad.\n   - Estrategia de control incluye pruebas de disoluci\u00f3n.\n\n2. **Polvos y Gr\u00e1nulos para Reconstituci\u00f3n**:\n   - \u00datiles cuando las soluciones l\u00edquidas tienen una vida \u00fatil corta.\n   - Presentaci\u00f3n en sachets de dosis \u00fanica o preparaciones multidose.\n   - Necesidad de que los s\u00f3lidos se humedezcan y disuelvan r\u00e1pidamente.\n   - Desventajas incluyen mayor volumen y estabilidad microbiana en uso.\n\n3. **Administraci\u00f3n a trav\u00e9s de Tubos de Alimentaci\u00f3n**:\n   - Uso en neonatos y beb\u00e9s gravemente enfermos.\n   - Consideraciones sobre precisi\u00f3n de dosificaci\u00f3n y facilidad de transferencia.\n   - Importancia de la viscosidad, tama\u00f1o de part\u00edculas y absorci\u00f3n del principio activo en el material del tubo.\n   - Volumen de enjuague debe ser adecuado para el grupo de edad objetivo.\n\n### Entidades\n\n- **WHO Expert Committee on Specifications for Pharmaceutical Preparations**: Organizaci\u00f3n responsable de las directrices.\n- **Suspensiones orales**: Formulaci\u00f3n l\u00edquida que requiere agitaci\u00f3n.\n- **Polvos y gr\u00e1nulos**: Preparaciones s\u00f3lidas para reconstituci\u00f3n.\n- **Tubos de alimentaci\u00f3n**: M\u00e9todo de administraci\u00f3n enteral para neonatos y beb\u00e9s.\n- **SmPCs (Resumen de Caracter\u00edsticas del Producto)**: Documentos que deben incluir consideraciones sobre la administraci\u00f3n y reconstituci\u00f3n.\n\nEste resumen destaca los aspectos esenciales de la secci\u00f3n, enfoc\u00e1ndose en la importancia de la estabilidad y la administraci\u00f3n adecuada de medicamentos en diferentes formas.", "excerpt_keywords": "Keywords: pediatric dosage forms, multiparticulate preparations, mini-tablets, immediate-release tablets, dosage uniformity"}}, "960f118c-b23f-4594-a50e-827d891217d3": {"node_ids": ["490f2c1a-52fc-43c2-85a4-b8b102f119cc"], "metadata": {"page_label": "228", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nsweets or candies and hence may be too attractive to the child. It is critical to differentiate the appearance of tablet packs from that of confectionery packs.\n\nBreak-marks intended to enable accurate subdivision of the tablet to provide doses of less than one tablet should be proven to result in parts that comply with the requirements for uniformity of mass or uniformity of content, as appropriate. The decision whether or not to provide scored tablets will depend on a risk analysis, taking into account the safety and dose of the API. A suitable test is provided in the monograph on tablets in *The International Pharmacopoeia* (34). It is preferable that the single part of the broken tablet contains the amount of API suited to the youngest intended age group. Specially designed tablets and tablet punches may be needed.\n\nCaregivers often crush tablets to increase user-friendliness and adherence. Crushing may, however, affect the bioavailability of some medicines. The effect of crushing of tablets should be investigated by the manufacturer and this information should be provided in the patient information leaflet.\n\nTablets should not be crushed unless instructions allowing crushing are provided on the label by the manufacturer. Generally a multiparticulate formulation supplied in sachets, hard capsules or blister packs is preferred.\n\n## Chewable tablets\n\nChewable tablets are intended to be chewed and swallowed. They should possess good organoleptic properties including a good mouth feel, which is influenced by the solubility, particle size and shape of the API, and they should not leave a bitter or unpleasant aftertaste. They are usually formulated with a high content of a water-soluble sweetener, such as mannitol, which provides a sweet, cooling taste, and microcrystalline cellulose, which assists in obtaining a good mouth feel and reduces grittiness. Other sweetening agents such as sorbitol and xylitol suitable for direct compression are also used.\n\nA potential problem with chewable tablets is that they may be swallowed by a patient before being properly chewed or without being chewed at all. It is, therefore, strongly recommended that chewable tablets are formulated so that they may be swallowed whole and, thus, labelled as \u201ctablets that may be chewed or swallowed whole\u201d, or \u201ctablets that may be chewed, swallowed or crushed and mixed with food or liquid\u201d.\n\nIt is a consequence of the above that tablets that may be chewed or swallowed whole should meet the quality requirements for conventional tablets, including dissolution testing. Where applicable, dissolution test conditions should be the same as used for conventional tablets of the same API, but because of their non-disintegrating nature it may be necessary to alter the test conditions (18).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Diferenciaci\u00f3n de envases**: Es crucial que los envases de tabletas se diferencien claramente de los de golosinas para evitar que los ni\u00f1os los confundan y los ingieran accidentalmente.\n\n2. **Importancia de las marcas de ruptura**: Las tabletas con marcas de ruptura deben demostrar que las partes resultantes cumplen con los requisitos de uniformidad de masa o contenido, y su dise\u00f1o debe considerar la dosis adecuada para los grupos de edad m\u00e1s j\u00f3venes.\n\n3. **Consideraciones sobre la trituraci\u00f3n de tabletas**: La trituraci\u00f3n de tabletas puede afectar la biodisponibilidad de algunos medicamentos, por lo que los fabricantes deben investigar este efecto y proporcionar instrucciones claras en el etiquetado.\n\n4. **Propiedades de las tabletas masticables**: Las tabletas masticables deben tener buenas propiedades organol\u00e9pticas y ser formuladas para que puedan ser tragadas enteras, adem\u00e1s de cumplir con los requisitos de calidad de las tabletas convencionales.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfQu\u00e9 criterios deben cumplirse para que las tabletas con marcas de ruptura sean consideradas seguras para su uso en ni\u00f1os?**\n   - Las tabletas con marcas de ruptura deben demostrar que las partes resultantes cumplen con los requisitos de uniformidad de masa o contenido, y es preferible que cada parte contenga la dosis adecuada para el grupo de edad m\u00e1s joven.\n\n2. **\u00bfCu\u00e1les son las recomendaciones para el etiquetado de tabletas masticables en relaci\u00f3n con su consumo?**\n   - Se recomienda que las tabletas masticables sean etiquetadas como \"tabletas que pueden ser masticadas o tragadas enteras\" o \"tabletas que pueden ser masticadas, tragadas o trituradas y mezcladas con alimentos o l\u00edquidos\".\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe proporcionar el fabricante sobre la trituraci\u00f3n de tabletas y su efecto en la biodisponibilidad?**\n   - El fabricante debe investigar el efecto de la trituraci\u00f3n en la biodisponibilidad de las tabletas y proporcionar esta informaci\u00f3n en el prospecto del paciente, adem\u00e1s de indicar si la trituraci\u00f3n est\u00e1 permitida en la etiqueta.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Formas de dosificaci\u00f3n para ni\u00f1os**:\n   - Se discuten las ventajas de los polvos y preparaciones multiparticuladas en comparaci\u00f3n con tabletas y c\u00e1psulas.\n   - La aceptaci\u00f3n de estas formas de dosificaci\u00f3n var\u00eda seg\u00fan la edad del ni\u00f1o y su capacidad para tragar.\n\n2. **Preparaciones multiparticuladas**:\n   - Incluyen granulos (pellets) y mini-tabletas, que son flexibles en t\u00e9rminos de dosificaci\u00f3n.\n   - Se preparan mediante tecnolog\u00edas como extrusi\u00f3n/esferonizaci\u00f3n y compresi\u00f3n.\n   - Ofrecen beneficios como estabilidad, enmascaramiento de sabores y uniformidad de dosis.\n\n3. **Tabletas de liberaci\u00f3n inmediata**:\n   - Pueden ser recubiertas o no, y est\u00e1n dise\u00f1adas para desintegrarse y absorberse r\u00e1pidamente.\n   - El recubrimiento mejora la palatabilidad al ocultar sabores y olores desagradables.\n\n### Entidades clave:\n- **Polvos y preparaciones multiparticuladas**: Formas de dosificaci\u00f3n que pueden mezclarse con alimentos o l\u00edquidos.\n- **Mini-tabletas**: Tabletas peque\u00f1as (menos de 4 mm) que pueden ser aceptables para ni\u00f1os de 2 a 4 a\u00f1os.\n- **Pellets**: Granulos uniformes (0.5\u20132 mm) producidos por tecnolog\u00eda de extrusi\u00f3n/esferonizaci\u00f3n.\n- **Tabletas convencionales**: Pueden ser uncoated, film-coated o sugar-coated, dise\u00f1adas para liberaci\u00f3n inmediata.\n\n### Preguntas espec\u00edficas:\n1. **Evidencia sobre mini-tabletas**: Se sugiere que pueden ser aceptables para ni\u00f1os de 2 a 4 a\u00f1os.\n2. **Ventajas de las preparaciones multiparticuladas**: Mejoran la uniformidad de dosis, estabilidad y permiten enmascarar sabores.\n3. **Tecnolog\u00edas de fabricaci\u00f3n**: Extrusi\u00f3n/esferonizaci\u00f3n para pellets y compresi\u00f3n para mini-tabletas.", "excerpt_keywords": "Keywords: pharmaceutical preparations, chewable tablets, bioavailability, tablet scoring, pediatric dosing"}}, "1b908ea7-a8d8-479b-95b9-3a2cb3852110": {"node_ids": ["7a2a08bf-5aa0-451e-a83c-461cbb14785d"], "metadata": {"page_label": "229", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Effervescent Dosage Forms\n\nEffervescent dosage forms are tablets, granules or powders that are dissolved in water prior to administration. The use of these dosage forms usually requires a relatively large volume of water, the intake of which may be problematic for children. It is helpful when an indication of the minimum volume of water is given on the label. Furthermore, the label should give instructions that the solution is not to be drunk before effervescence has subsided, in order to minimize ingestion of hydrogen carbonate. Effervescent tablets require continuous attention to levels of moisture and humidity during manufacture, packaging and storage.\n\nThe drawbacks of effervescent dosage forms are the need for clean water for dissolution and the ingestion of potassium or sodium, which may make them unsuitable for patients with renal insufficiency.\n\n# Dispersible and Soluble Tablets\n\nDispersible and soluble tablets are intended to be used in the same way as effervescent tablets. Their advantage is that problems with hydrogen carbonate, potassium and sodium are avoided. For the convenience of users, the formulations should disintegrate or dissolve within a short time of being added to water. It is helpful when an indication of the minimum volume of water is provided on the label.\n\nDispersible and soluble tablets are flexible dosage forms, the formulation of which may be suited for several water-soluble APIs (see section 3.1).\n\n# Sustained-release Formulations\n\nSustained-release formulations are designed to slow the rate of release of the API in the gastrointestinal fluids. They may be provided in a variety of formulations, e.g. as multiparticulate solids provided with a barrier coating, in sachets, hard capsules or in quickly disintegrating tablets, coated tablets and matrix tablets. Among the advantages of the sustained-release design is the reduced dosing frequency compared to conventional formulations of the same API, a feature which may improve adherence (see section 2.3). Not all APIs can be formulated as sustained-release products. This will also depend on other factors such as aqueous solubility, intestinal permeability and plasma elimination half-life, which may differ between children and adults.\n\nIn the development of sustained-release formulations for paediatric use, special attention must be given to the physiological conditions of the child to be treated and their variability, e.g. gastric pH and emptying rate and intestinal mobility.\n\nThe majority of sustained-release formulations, especially coated tablets and matrix tablets, must not be broken or chewed and some will not withstand being mixed with food or a beverage. It is, therefore, vital that clear instructions on the proper use of the formulation are included on the label.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas basadas en el contexto proporcionado, junto con sus respuestas:\n\n1. **\u00bfCu\u00e1les son las consideraciones importantes al usar formas de dosificaci\u00f3n efervescentes en ni\u00f1os?**\n   - Las formas de dosificaci\u00f3n efervescentes requieren un volumen relativamente grande de agua para su disoluci\u00f3n, lo que puede ser problem\u00e1tico para los ni\u00f1os. Adem\u00e1s, es importante que el etiquetado indique el volumen m\u00ednimo de agua necesario y que se instruya a no beber la soluci\u00f3n antes de que la efervescencia haya cesado, para minimizar la ingesti\u00f3n de bicarbonato de hidr\u00f3geno.\n\n2. **\u00bfQu\u00e9 ventajas ofrecen las tabletas dispersables y solubles en comparaci\u00f3n con las efervescentes?**\n   - Las tabletas dispersables y solubles evitan los problemas asociados con el bicarbonato de hidr\u00f3geno, el potasio y el sodio, lo que las hace m\u00e1s adecuadas para pacientes con insuficiencia renal. Adem\u00e1s, estas tabletas deben disolverse o desintegrarse r\u00e1pidamente al ser a\u00f1adidas al agua, lo que mejora la conveniencia para el usuario.\n\n3. **\u00bfQu\u00e9 factores deben considerarse al desarrollar formulaciones de liberaci\u00f3n sostenida para uso pedi\u00e1trico?**\n   - En el desarrollo de formulaciones de liberaci\u00f3n sostenida para ni\u00f1os, es crucial considerar las condiciones fisiol\u00f3gicas del ni\u00f1o, como el pH g\u00e1strico, la tasa de vaciamiento y la movilidad intestinal, ya que estas pueden variar significativamente entre ni\u00f1os y adultos. Adem\u00e1s, no todas las sustancias activas pueden ser formuladas como productos de liberaci\u00f3n sostenida, lo que depende de factores como la solubilidad acuosa y la permeabilidad intestinal.\n\n### Resumen de nivel superior del contexto:\nEl documento aborda diferentes formas de dosificaci\u00f3n, incluyendo efervescentes, dispersables, solubles y de liberaci\u00f3n sostenida. Se discuten las ventajas y desventajas de cada tipo, especialmente en relaci\u00f3n con su uso en ni\u00f1os y pacientes con condiciones espec\u00edficas como insuficiencia renal. Se enfatiza la importancia de proporcionar instrucciones claras en el etiquetado para asegurar un uso adecuado y seguro de estas formulaciones.", "prev_section_summary": "### Temas Clave\n\n1. **Diferenciaci\u00f3n de Envases**: Es fundamental que los envases de tabletas sean claramente distintos de los de golosinas para prevenir confusiones y posibles ingestas accidentales por parte de los ni\u00f1os.\n\n2. **Marcas de Ruptura en Tabletas**: Las tabletas con marcas de ruptura deben demostrar que las partes resultantes cumplen con los est\u00e1ndares de uniformidad de masa o contenido. La decisi\u00f3n de incluir estas marcas debe basarse en un an\u00e1lisis de riesgo, considerando la seguridad y la dosis del principio activo (API).\n\n3. **Impacto de la Trituraci\u00f3n de Tabletas**: La trituraci\u00f3n de tabletas puede alterar la biodisponibilidad de ciertos medicamentos. Los fabricantes deben investigar este efecto y proporcionar informaci\u00f3n clara en el prospecto del paciente sobre si la trituraci\u00f3n est\u00e1 permitida.\n\n4. **Propiedades de las Tabletas Masticables**: Estas tabletas deben tener buenas propiedades organol\u00e9pticas y ser formuladas para que puedan ser tragadas enteras. Deben cumplir con los requisitos de calidad de las tabletas convencionales, incluyendo pruebas de disoluci\u00f3n.\n\n### Entidades\n\n- **WHO (Organizaci\u00f3n Mundial de la Salud)**: Entidad responsable del documento.\n- **API (Principio Activo)**: Sustancia en los medicamentos que produce el efecto terap\u00e9utico.\n- **Mannitol, Sorbitol, Xylitol**: Edulcorantes utilizados en la formulaci\u00f3n de tabletas masticables.\n- **Microcrystalline Cellulose**: Compuesto que mejora la textura y reduce la arenosidad en tabletas.\n- **The International Pharmacopoeia**: Referencia mencionada para pruebas y est\u00e1ndares de tabletas.\n\n### Resumen\n\nLa secci\u00f3n aborda la importancia de diferenciar los envases de tabletas de los de golosinas para evitar confusiones en ni\u00f1os. Se discuten las marcas de ruptura en tabletas, enfatizando que deben cumplir con est\u00e1ndares de uniformidad y ser seguras para los grupos de edad m\u00e1s j\u00f3venes. Tambi\u00e9n se menciona que la trituraci\u00f3n de tabletas puede afectar la biodisponibilidad y que los fabricantes deben proporcionar instrucciones claras al respecto. Finalmente, se describen las caracter\u00edsticas de las tabletas masticables, que deben ser agradables al paladar y permitir ser tragadas enteras, cumpliendo con los requisitos de calidad de las tabletas convencionales.", "excerpt_keywords": "Effervescent, Dispersible, Sustained-release, Pediatric, Dosage forms"}}, "80999d87-c5b1-47ce-bf69-69e9be5e0c42": {"node_ids": ["b0231d06-929c-4668-bd7f-82c3980cae8b"], "metadata": {"page_label": "230", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Capsules\n\nCapsule formulations are provided either as soft capsules, usually with a liquid or semi-solid content or as hard capsules containing powder or a multiparticulate formulation.\n\nCapsules may be taken whole. The limitations mentioned for tablets apply with regard to the ability of the child to swallow them (see introduction to section 5.3). Hard capsules may be opened and their contents taken as such or taken after mixing with food or sprinkling on to food, but this is not always appropriate.\n\nInstructions on the proper use of a capsule formulation should be provided on the label, e.g. whether the capsule has to be taken whole or whether the capsule contents can be mixed with food to facilitate intake and improve palatability.\n\n# Orodispersible dosage forms\n\nOrodispersible dosage forms are orodispersible tablets, oral lyophilisates and thin films, to be placed on the tongue where they disperse rapidly into small-sized particles or \u201cmelt\u201d by dissolution in the saliva, after which the dose is swallowed.\n\nOrodispersible tablets designed to disintegrate rapidly are prepared by compression of a formulation containing, for example, mannitol, a super-disintegrant, and a flavouring agent. The amount of API that can be incorporated depends on its physical properties. The product may be moisture-sensitive. Orodispersible tablets are flexible dosage forms (see section 3.1), particularly well-suited for highly water-soluble APIs.\n\nOral lyophilisates are prepared by freeze-drying of aqueous liquids into porous units shaped like tablets. Typical excipients are gelatin or alginate, which act as structure-forming agents, and mannitol, which facilitates formation of the porous structure and contributes to palatability. Instead of mannitol, sorbitol may be used as a crystallization inhibitor. The amount of water-soluble API to be incorporated is limited (35). Oral lyophilisates are sensitive to moisture and require a vapour-tight package.\n\nThin, flat films (wafers) to be placed in the oral cavity are prepared by casting water-soluble polymers containing the API in dissolved or dispersed form. The amount of dissolved API that can be incorporated is limited. The release profile depends on the polymer, film thickness and API solubility. The so-called flash-release wafers may have dissolution times of less than 30 seconds.\n\nOrodispersible and orosoluble dosage forms are attractive for several reasons. They may be acceptable to the same age groups as liquid preparations, and it is possible for children who cannot swallow a whole tablet to take an orodispersible dosage form. In some situations, especially with younger children,", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento proporciona informaci\u00f3n sobre dos formas de dosificaci\u00f3n: c\u00e1psulas y formas de dosificaci\u00f3n orodispersibles. Las c\u00e1psulas pueden ser blandas o duras y pueden contener l\u00edquidos, semis\u00f3lidos o polvos. Se discuten las instrucciones sobre c\u00f3mo deben tomarse las c\u00e1psulas, especialmente en el caso de los ni\u00f1os que pueden tener dificultades para tragarlas. Las formas de dosificaci\u00f3n orodispersibles incluyen tabletas orodispersibles, liofilizados orales y pel\u00edculas delgadas que se disuelven r\u00e1pidamente en la boca. Estas formas son especialmente \u00fatiles para ni\u00f1os que no pueden tragar tabletas enteras y son adecuadas para APIs altamente solubles en agua.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones sobre la palatabilidad y la administraci\u00f3n de c\u00e1psulas para ni\u00f1os?**\n   - Las c\u00e1psulas deben tener instrucciones claras sobre su uso, indicando si deben tomarse enteras o si su contenido puede mezclarse con alimentos para facilitar la ingesta y mejorar la palatabilidad.\n\n2. **\u00bfQu\u00e9 excipientes se utilizan en la preparaci\u00f3n de liofilizados orales y cu\u00e1l es su funci\u00f3n?**\n   - Los liofilizados orales se preparan utilizando excipientes como gelatina o alginato, que act\u00faan como agentes formadores de estructura, y manitol, que facilita la formaci\u00f3n de la estructura porosa y contribuye a la palatabilidad.\n\n3. **\u00bfQu\u00e9 caracter\u00edsticas hacen que las formas de dosificaci\u00f3n orodispersibles sean adecuadas para ni\u00f1os?**\n   - Las formas de dosificaci\u00f3n orodispersibles son atractivas porque pueden ser aceptables para los mismos grupos de edad que las preparaciones l\u00edquidas y permiten que los ni\u00f1os que no pueden tragar tabletas enteras puedan tomar la dosis de manera m\u00e1s f\u00e1cil y r\u00e1pida.\n\n### Resumen de Nivel Superior\n\nEl documento de la OMS detalla las caracter\u00edsticas y consideraciones de las c\u00e1psulas y las formas de dosificaci\u00f3n orodispersibles, destacando su uso en poblaciones pedi\u00e1tricas. Se enfatiza la importancia de las instrucciones de uso para garantizar la correcta administraci\u00f3n de estos medicamentos, as\u00ed como la relevancia de los excipientes en la formulaci\u00f3n para mejorar la experiencia del paciente, especialmente en ni\u00f1os que pueden tener dificultades para tragar.", "prev_section_summary": "### Temas Clave:\n\n1. **Formas de Dosificaci\u00f3n Efervescentes**:\n   - Definici\u00f3n: Tabletas, gr\u00e1nulos o polvos que se disuelven en agua antes de la administraci\u00f3n.\n   - Consideraciones: Requieren un volumen considerable de agua, lo que puede ser problem\u00e1tico para los ni\u00f1os. Importancia de indicar el volumen m\u00ednimo de agua en la etiqueta y de no beber antes de que la efervescencia haya cesado.\n   - Desventajas: Necesidad de agua limpia para la disoluci\u00f3n y la ingesti\u00f3n de potasio o sodio, lo que puede ser inapropiado para pacientes con insuficiencia renal.\n\n2. **Tabletas Dispersables y Solubles**:\n   - Definici\u00f3n: Formas de dosificaci\u00f3n que se utilizan de manera similar a las efervescentes.\n   - Ventajas: Evitan problemas relacionados con el bicarbonato de hidr\u00f3geno, potasio y sodio. Deben disolverse r\u00e1pidamente al ser a\u00f1adidas al agua.\n   - Flexibilidad: Pueden ser formuladas para varios principios activos solubles en agua.\n\n3. **Formulaciones de Liberaci\u00f3n Sostenida**:\n   - Definici\u00f3n: Dise\u00f1adas para ralentizar la liberaci\u00f3n del principio activo en los fluidos gastrointestinales.\n   - Ventajas: Menor frecuencia de dosificaci\u00f3n en comparaci\u00f3n con formulaciones convencionales, lo que puede mejorar la adherencia.\n   - Consideraciones en Pediatr\u00eda: Importancia de tener en cuenta las condiciones fisiol\u00f3gicas del ni\u00f1o, como el pH g\u00e1strico y la movilidad intestinal.\n   - Instrucciones: Es vital que las formulaciones no sean trituradas o masticadas y que se incluyan instrucciones claras en la etiqueta.\n\n### Entidades:\n\n- **Formas de Dosificaci\u00f3n**: Efervescentes, dispersables, solubles, liberaci\u00f3n sostenida.\n- **Principios Activos (APIs)**: Sustancias que pueden ser formuladas en diferentes tipos de dosificaci\u00f3n.\n- **Pacientes**: Ni\u00f1os, pacientes con insuficiencia renal.\n- **Condiciones Fisiol\u00f3gicas**: pH g\u00e1strico, tasa de vaciamiento, movilidad intestinal.\n- **Instrucciones de Uso**: Importancia de la claridad en el etiquetado para un uso seguro y adecuado. \n\nEste resumen destaca los aspectos esenciales y las entidades relevantes en la secci\u00f3n sobre formas de dosificaci\u00f3n, enfoc\u00e1ndose en su uso, ventajas, desventajas y consideraciones espec\u00edficas para la poblaci\u00f3n pedi\u00e1trica.", "excerpt_keywords": "Capsules, Orodispersible, Dosage forms, Pediatric, Palatability"}}, "59113514-ccb4-47aa-8e20-eb08a3c2ec8e": {"node_ids": ["b2de2bc2-cbb5-4802-aa7c-c82d0ff2cf43"], "metadata": {"page_label": "231", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 7. Rectal administration\n\nRectal administration is an important route that can be used for both local (e.g. laxative and anti-inflammatory) and systemic effects (e.g. antipyretic and anticonvulsive) in all age groups. This route of administration is especially valuable when oral administration is not possible because of the condition of the child and palatability issues. In certain cases it is possible to obtain immediate systemic effect by rectal administration of solutions. There is, however, limited absorption and bioavailability for many APIs. Erratic absorption due to faecal contents in the rectum may unpredictably delay absorption.\n\nDosage forms for rectal administration are primarily suppositories, rectal capsules and rectal liquids (enemas). Other dosage forms are available, e.g. rectal foams provided in pressurized containers.\n\nWhen suppositories and rectal capsules are administered to paediatric patients there is a risk of premature expulsion, especially when the dosage form constituents have an irritating effect. Rectal dosage forms should be used with extreme caution in premature infants, as they can tear very delicate tissues and, thus, introduce infection.\n\nAdherence for rectal preparations may be lower than for oral dosage forms. There are barriers to rectal administration for both caregivers and patients in some regions and cultures. Generally their acceptability among children of any age is poor.\n\n## 7.1 Suppositories\n\nSuppositories for use in paediatric patients must be tailored to the age or size of the child. Cutting of suppositories into halves should be avoided unless they are designed to be cut. The majority of suppositories contain APIs as solid particles, which may be unevenly distributed in the suppository base as a result of the manufacturing technique of moulding a molten formulation. However, it is also possible to prepare suppositories which can be cut in smaller portions, ensuring delivery of an appropriate dose. Information on acceptability of cutting suppositories should be provided. When designed to be cut, information on the technique should be provided in the patient leaflet.\n\nTwo types of suppository base are available: one is insoluble in water, e.g. hard fat, which melts below body temperature. With suppository melt formulations, special consideration has to be given to storage temperature.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl texto aborda la administraci\u00f3n rectal de medicamentos, destacando su importancia tanto para efectos locales como sist\u00e9micos en todas las edades, especialmente en situaciones donde la administraci\u00f3n oral no es viable. Se mencionan las formas de dosificaci\u00f3n m\u00e1s comunes, como supositorios, c\u00e1psulas rectales y l\u00edquidos rectales, y se discuten los desaf\u00edos asociados con su uso en pacientes pedi\u00e1tricos, incluyendo la posibilidad de expulsi\u00f3n prematura y la baja adherencia. Tambi\u00e9n se enfatiza la necesidad de adaptar los supositorios a la edad o tama\u00f1o del ni\u00f1o y se describen los tipos de bases de supositorios disponibles.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones especiales que deben tenerse en cuenta al administrar supositorios a pacientes pedi\u00e1tricos, especialmente en prematuros?**\n   - La administraci\u00f3n de supositorios en pacientes pedi\u00e1tricos, especialmente en prematuros, debe hacerse con extrema precauci\u00f3n debido al riesgo de da\u00f1ar tejidos delicados, lo que podr\u00eda introducir infecciones.\n\n2. **\u00bfQu\u00e9 tipos de bases de supositorios existen y c\u00f3mo afectan su almacenamiento?**\n   - Existen dos tipos de bases de supositorios: una que es insoluble en agua, como la grasa dura, que se derrite por debajo de la temperatura corporal. Las formulaciones de supositorios que se derriten requieren consideraciones especiales en cuanto a la temperatura de almacenamiento.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n debe proporcionarse en el prospecto de los supositorios que est\u00e1n dise\u00f1ados para ser cortados?**\n   - El prospecto debe incluir informaci\u00f3n sobre la aceptabilidad de cortar los supositorios y, cuando est\u00e1n dise\u00f1ados para ser cortados, debe proporcionar instrucciones sobre la t\u00e9cnica adecuada para hacerlo.", "prev_section_summary": "### Temas Clave\n\n1. **Formulaciones de C\u00e1psulas**:\n   - Tipos: c\u00e1psulas blandas (contenido l\u00edquido o semis\u00f3lido) y c\u00e1psulas duras (contenido en polvo o multiparticulado).\n   - Consideraciones para la administraci\u00f3n en ni\u00f1os: dificultad para tragar, instrucciones sobre si deben tomarse enteras o si el contenido puede mezclarse con alimentos.\n\n2. **Formas de Dosificaci\u00f3n Orodispersibles**:\n   - Tipos: tabletas orodispersibles, liofilizados orales y pel\u00edculas delgadas.\n   - Mecanismo: se disuelven r\u00e1pidamente en la boca y son f\u00e1ciles de tragar.\n   - Composici\u00f3n: uso de excipientes como mannitol, gelatina y alginato para mejorar la palatabilidad y la estructura.\n   - Ventajas: adecuadas para ni\u00f1os que no pueden tragar tabletas enteras, aceptables para grupos de edad similares a las preparaciones l\u00edquidas.\n\n### Entidades\n\n- **C\u00e1psulas**: Formas de dosificaci\u00f3n que pueden ser blandas o duras.\n- **Orodispersibles**: Formas de dosificaci\u00f3n que incluyen tabletas orodispersibles, liofilizados orales y pel\u00edculas delgadas.\n- **Excipientes**: Sustancias como mannitol, gelatina y alginato que se utilizan en la formulaci\u00f3n de medicamentos.\n- **API (Ingrediente Activo)**: Sustancia que proporciona la acci\u00f3n farmacol\u00f3gica en las formulaciones.\n\n### Resumen General\n\nLa secci\u00f3n aborda las caracter\u00edsticas y consideraciones de las c\u00e1psulas y las formas de dosificaci\u00f3n orodispersibles, enfatizando su uso en pediatr\u00eda. Se destaca la importancia de proporcionar instrucciones claras para la administraci\u00f3n de estos medicamentos, as\u00ed como el papel de los excipientes en la formulaci\u00f3n para mejorar la experiencia del paciente, especialmente en ni\u00f1os que pueden tener dificultades para tragar.", "excerpt_keywords": "Rectal administration, suppositories, pediatric patients, bioavailability, dosage forms"}}, "9fbfdccf-e2cc-4cc9-8285-71e82105b1c6": {"node_ids": ["03cc6c5d-7fb8-47ff-980f-aebab157bc99"], "metadata": {"page_label": "232", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Rectal liquids (enemas)\n\nRectal liquids are solutions, suspensions or emulsions based on water or vegetable oil. Any volume to be administered should be appropriate to the size of the child. For systemic therapy, the volume to be administered should be as small as possible to achieve accurate delivery, good absorption and to avoid irritation. Volumes of 1\u20135 ml may be acceptable.\n\nThe rectal tube should be of a length appropriate to the size of the child and should not cause injury. Use of pre-filled syringes equipped with a rectal tube facilitates individual dosing and may reduce the need for several strengths of the formulation.\n\nFormulation of aqueous rectal liquids is similar to the formulation of other aqueous liquids regarding use of stabilizing agents, including surfactants and antimicrobial agents. Non-ionic surfactants are preferred because ionic surfactants are frequently irritating to the rectal mucosa. The need for stabilizing agents, in particular antimicrobial agents, may be reduced by the formulation of rectal tablets to be dispersed or dissolved in water immediately before administration.\n\n# 8. Parenteral administration\n\nParenteral administration by the intravenous route is preferred for seriously ill children and for clinically unstable term and preterm neonates (in developed country settings). Some parenteral preparations are administered by the subcutaneous and intramuscular routes. The limited muscle mass of newborns and, in particular of preterm infants, constrains the use of intramuscular injections. Other routes of administration, e.g. intraosseous, are used in emergency cases.\n\nMost children have a fear of injection needles. Possible alternatives, especially suited for children undergoing frequent or long-duration treatment, such as needle-free injection devices (jet injectors), that drive small droplets through the skin by high pressure, could be considered, e.g. for subcutaneous administration. However, experience of their use in paediatric populations, especially in smaller children is limited.\n\nRepeated injections should be avoided for children unless they can be given intravenously via catheter or injection ports that can remain in place for the length of the treatment. Reducing the number of injections by formulation of sustained-release preparations requires consideration of increased blood perfusion in children, usually increasing absorption from tissue depots.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Uso de l\u00edquidos rectales (enemas)**: Los l\u00edquidos rectales son soluciones, suspensiones o emulsiones que se administran a trav\u00e9s del recto, y su volumen debe ser adecuado al tama\u00f1o del ni\u00f1o. Se prefiere el uso de surfactantes no i\u00f3nicos para evitar irritaciones en la mucosa rectal. Adem\u00e1s, se sugiere que los agentes estabilizantes, como los antimicrobianos, pueden ser menos necesarios si se utilizan tabletas rectales que se disuelven en agua antes de la administraci\u00f3n.\n\n2. **Administraci\u00f3n parenteral en pediatr\u00eda**: La administraci\u00f3n intravenosa es la preferida para ni\u00f1os gravemente enfermos y neonatos cl\u00ednicamente inestables. Se discuten alternativas a las inyecciones, como los dispositivos de inyecci\u00f3n sin aguja, y se enfatiza la importancia de reducir el n\u00famero de inyecciones mediante el uso de preparaciones de liberaci\u00f3n sostenida.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfCu\u00e1l es el volumen recomendado de l\u00edquidos rectales para la administraci\u00f3n en ni\u00f1os y por qu\u00e9 es importante que este volumen sea el m\u00e1s peque\u00f1o posible?**\n   - Respuesta: Se recomienda un volumen de 1-5 ml para la administraci\u00f3n de l\u00edquidos rectales en ni\u00f1os, ya que un volumen menor ayuda a lograr una entrega precisa, una buena absorci\u00f3n y a evitar irritaciones en la mucosa rectal.\n\n2. **\u00bfQu\u00e9 tipo de surfactantes se prefieren en la formulaci\u00f3n de l\u00edquidos rectales y por qu\u00e9?**\n   - Respuesta: Se prefieren los surfactantes no i\u00f3nicos en la formulaci\u00f3n de l\u00edquidos rectales porque los surfactantes i\u00f3nicos pueden causar irritaci\u00f3n en la mucosa rectal.\n\n3. **\u00bfQu\u00e9 alternativas a las inyecciones se sugieren para ni\u00f1os que requieren tratamientos frecuentes y cu\u00e1les son las limitaciones de estas alternativas?**\n   - Respuesta: Se sugieren dispositivos de inyecci\u00f3n sin aguja (jet injectors) como alternativas a las inyecciones, especialmente para la administraci\u00f3n subcut\u00e1nea. Sin embargo, la experiencia en su uso en poblaciones pedi\u00e1tricas, especialmente en ni\u00f1os m\u00e1s peque\u00f1os, es limitada.", "prev_section_summary": "### Resumen de temas clave y entidades de la secci\u00f3n sobre administraci\u00f3n rectal\n\n1. **Importancia de la administraci\u00f3n rectal**:\n   - Utilizada para efectos locales (laxantes, antiinflamatorios) y sist\u00e9micos (antipir\u00e9ticos, anticonvulsivos).\n   - Especialmente valiosa cuando la administraci\u00f3n oral no es posible.\n\n2. **Formas de dosificaci\u00f3n**:\n   - Principales: supositorios, c\u00e1psulas rectales y l\u00edquidos rectales (enemas).\n   - Otras formas: espumas rectales en envases presurizados.\n\n3. **Desaf\u00edos en pacientes pedi\u00e1tricos**:\n   - Riesgo de expulsi\u00f3n prematura de supositorios y c\u00e1psulas rectales, especialmente si los componentes son irritantes.\n   - Precauci\u00f3n extrema en el uso en reci\u00e9n nacidos prematuros debido al riesgo de da\u00f1ar tejidos delicados.\n\n4. **Adherencia y aceptabilidad**:\n   - La adherencia a las preparaciones rectales puede ser menor que a las formas orales.\n   - Barreras culturales y de aceptaci\u00f3n entre los ni\u00f1os.\n\n5. **Consideraciones para supositorios**:\n   - Deben adaptarse a la edad o tama\u00f1o del ni\u00f1o.\n   - Evitar cortar supositorios a menos que est\u00e9n dise\u00f1ados para ello.\n   - Distribuci\u00f3n desigual de los principios activos (APIs) en la base del supositorio.\n\n6. **Tipos de bases de supositorios**:\n   - Base insoluble en agua (ej. grasa dura) que se derrite a temperatura corporal.\n   - Consideraciones especiales para el almacenamiento de formulaciones que se derriten.\n\n7. **Informaci\u00f3n en prospectos**:\n   - Debe incluir detalles sobre la aceptabilidad de cortar supositorios y t\u00e9cnicas adecuadas si est\u00e1n dise\u00f1ados para ser cortados.\n\n### Entidades clave:\n- **Rutas de administraci\u00f3n**: Rectal\n- **Efectos**: Locales y sist\u00e9micos\n- **Formas de dosificaci\u00f3n**: Supositorios, c\u00e1psulas rectales, l\u00edquidos rectales, espumas rectales\n- **Poblaci\u00f3n**: Pacientes pedi\u00e1tricos, reci\u00e9n nacidos prematuros\n- **Consideraciones de seguridad**: Riesgo de da\u00f1o a tejidos, adherencia, aceptabilidad cultural.", "excerpt_keywords": "Keywords: rectal administration, parenteral therapy, pediatric dosing, surfactants, injection alternatives"}}, "ed179fda-c636-425a-b459-21d72f988781": {"node_ids": ["d9dc142a-048f-4013-ac7f-05b8ad77aebf"], "metadata": {"page_label": "233", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Formulation\n\nAqueous preparations (solutions or suspensions) must be adapted to the physiological conditions on the application site. The tolerances for deviations in pH and osmolality are dependent on the route of administration. In particular, subcutaneous administration is highly sensitive because dilution of the injected volume and its escape from the injection site proceed slowly. Hyperosmolar injections and injections with extreme pH may cause pain and irritate peripheral veins.\n\nFormulations for neonatal patients are usually aqueous solutions intended for intravenous administration. Target volumes and electrolyte contents are important for all paediatric patients; however, these are critical for neonates (19).\n\nIt is crucial to consider the safety profile of each excipient and its suitability for the intended use (see section 4.3).\n\nAttention should be paid to the potential adsorption of the API onto the surfaces of plastic containers and catheters, and to leaching of plasticizers from containers and catheters to the parenteral preparation.\n\nSome APIs are presented as powders or lyophilisates to be reconstituted before administration. It is important that clear instructions on the reconstitution and information on storage conditions and duration appear on the label or product information.\n\n## Additional points to consider for parenteral preparations\n\n- There should be a minimal need for complex calculations for prescribing, dispensing and administration (e.g. dose in micrograms/kg/hour prescribed to be converted to volume per hour administered; conversion between mmol prescribed and mg on the label; conversion between mg prescribed and percentage concentration on the label; and decimal points).\n\n- The need for additional steps in the preparation of the product for administration should be minimized, for example, by developing ready-to-use preparations.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS (Organizaci\u00f3n Mundial de la Salud) se centra en la formulaci\u00f3n de preparaciones acuosas para la administraci\u00f3n parenteral de medicamentos, destacando la importancia de adaptar estas formulaciones a las condiciones fisiol\u00f3gicas del sitio de aplicaci\u00f3n. Se enfatiza la sensibilidad de la administraci\u00f3n subcut\u00e1nea a las variaciones en pH y osmolalidad, as\u00ed como la necesidad de considerar la seguridad de los excipientes y el riesgo de adsorci\u00f3n de principios activos (API) en pl\u00e1sticos. Tambi\u00e9n se menciona la importancia de proporcionar instrucciones claras para la reconstituci\u00f3n de medicamentos en forma de polvo y la minimizaci\u00f3n de c\u00e1lculos complejos en la prescripci\u00f3n y administraci\u00f3n.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones espec\u00edficas que deben tenerse en cuenta al formular soluciones intravenosas para pacientes neonatales en comparaci\u00f3n con otros grupos pedi\u00e1tricos?**\n   - Esta pregunta se centra en las diferencias cr\u00edticas en la formulaci\u00f3n para neonatos, que son m\u00e1s sensibles a los vol\u00famenes y contenidos electrol\u00edticos.\n\n2. **\u00bfQu\u00e9 riesgos est\u00e1n asociados con la administraci\u00f3n de inyecciones hiperosmolares o con pH extremo, especialmente en la administraci\u00f3n subcut\u00e1nea?**\n   - Esta pregunta busca profundizar en los efectos adversos espec\u00edficos que pueden surgir de la administraci\u00f3n inadecuada de soluciones.\n\n3. **\u00bfQu\u00e9 medidas se pueden tomar para minimizar la necesidad de c\u00e1lculos complejos en la prescripci\u00f3n y administraci\u00f3n de medicamentos parenterales?**\n   - Esta pregunta se enfoca en las estrategias que pueden implementarse para simplificar el proceso de administraci\u00f3n y reducir el riesgo de errores.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n detallada y espec\u00edfica que no se puede encontrar f\u00e1cilmente en otras fuentes, bas\u00e1ndose en el contenido del documento proporcionado.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **L\u00edquidos rectales (enemas)**:\n   - **Definici\u00f3n**: Soluciones, suspensiones o emulsiones basadas en agua o aceite vegetal administradas por v\u00eda rectal.\n   - **Volumen recomendado**: 1-5 ml, ajustado al tama\u00f1o del ni\u00f1o, para asegurar una entrega precisa, buena absorci\u00f3n y evitar irritaci\u00f3n.\n   - **Equipamiento**: Uso de tubos rectales de longitud adecuada y jeringas precargadas para facilitar la dosificaci\u00f3n individual.\n   - **Formulaci\u00f3n**: Similar a otros l\u00edquidos acuosos, se prefieren surfactantes no i\u00f3nicos para evitar irritaci\u00f3n en la mucosa rectal. La necesidad de agentes estabilizantes, como antimicrobianos, puede disminuir con el uso de tabletas rectales que se disuelven en agua antes de la administraci\u00f3n.\n\n2. **Administraci\u00f3n parenteral**:\n   - **Ruta preferida**: Intravenosa para ni\u00f1os gravemente enfermos y neonatos cl\u00ednicamente inestables.\n   - **Otras rutas**: Subcut\u00e1nea e intramuscular, aunque las inyecciones intramusculares son limitadas en reci\u00e9n nacidos y prematuros debido a la masa muscular reducida.\n   - **Alternativas a las inyecciones**: Dispositivos de inyecci\u00f3n sin aguja (jet injectors) para administraci\u00f3n subcut\u00e1nea, aunque su uso en poblaciones pedi\u00e1tricas es limitado.\n   - **Consideraciones**: Evitar inyecciones repetidas, preferir cat\u00e9teres o puertos de inyecci\u00f3n para tratamientos prolongados, y considerar la formulaci\u00f3n de preparaciones de liberaci\u00f3n sostenida para reducir el n\u00famero de inyecciones.\n\n### Entidades clave:\n- **L\u00edquidos rectales**\n- **Surfactantes no i\u00f3nicos**\n- **Administraci\u00f3n intravenosa**\n- **Dispositivos de inyecci\u00f3n sin aguja**\n- **Neonatos**\n- **Preparaciones de liberaci\u00f3n sostenida**", "excerpt_keywords": "Formulation, Aqueous preparations, Neonatal patients, Parenteral administration, Safety profile"}}, "98132686-4a46-4d47-bd28-b929769eece8": {"node_ids": ["62456a8f-c7eb-481e-8465-b902ef26014d"], "metadata": {"page_label": "234", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- Measurement of volumes smaller than 0.1 ml should not be required. Dose volumes in hundredths of a millilitre should be avoided. Tables should be included in the product information clearly stating the dose and the volume to be measured, and how this can be achieved safely and accurately.\n- Miscalculation can lead to overdose and the amount of the API in the presentation should not allow administration of a critical overdose to the smallest patient for whom the presentation is intended.\n- Using several vials per dose or large vials that may contain several doses should be avoided if possible.\n- Other methods of preventing overdose of critical medicines can be explored and presented for consideration, e.g. tables of weight, dose (mass) and volume (ml) of preparation required.\n- Safety measures and restrictions on administration via central or peripheral cannula should be provided, including advice on maximum and minimum dilutions for safe administration.\n- Consideration should be given to the contribution to the child\u2019s fluid and electrolyte balance due to the medicine administration volume and/or electrolyte content.\n- Compatibility with other medicines that are part of a standard care plan should be investigated.\n- Information on pH of the FPP needs to be provided in the product information.\n\n## 9. Dermal and transdermal administration\n\nPreparations for dermal (or cutaneous) administration include liquid preparations (lotions and shampoos), semi-solid preparations (ointments and creams) and solid preparations (powders). They are used to obtain local effects.\n\nUnintended systemic absorption through the dermis is a potential risk with many APIs. The stratum corneum is deficient in preterm neonates. Children have a lower volume of distribution per unit area of skin.\n\nDepending on the dosage form, various excipients are needed. The safety profile of each must be considered (see section 4.3) including the risk of sensitization of the skin. Preparations containing ethanol should be avoided in very young children because ethanol may dehydrate the skin and cause pain.\n\nLiquid suspensions, semi-solid preparations and patches should be subject to dissolution testing (18).", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto\n\n1. **Medidas de seguridad en la administraci\u00f3n de medicamentos pedi\u00e1tricos**: El documento enfatiza la importancia de evitar dosis en vol\u00famenes menores a 0.1 ml y la necesidad de proporcionar tablas claras sobre dosis y vol\u00famenes en la informaci\u00f3n del producto. Tambi\u00e9n se menciona el riesgo de sobredosis y la necesidad de considerar el equilibrio de fluidos y electrolitos en ni\u00f1os.\n\n2. **Consideraciones sobre la administraci\u00f3n d\u00e9rmica y transd\u00e9rmica**: Se discuten los diferentes tipos de preparaciones para administraci\u00f3n d\u00e9rmica y los riesgos asociados con la absorci\u00f3n sist\u00e9mica no intencionada, especialmente en neonatos y ni\u00f1os. Se destaca la importancia de evaluar la seguridad de los excipientes y evitar el uso de etanol en preparaciones para ni\u00f1os muy peque\u00f1os.\n\n3. **Pruebas de disoluci\u00f3n y compatibilidad de medicamentos**: Se menciona que las suspensiones l\u00edquidas, preparaciones semi-s\u00f3lidas y parches deben someterse a pruebas de disoluci\u00f3n. Adem\u00e1s, se debe investigar la compatibilidad de los medicamentos con otros que forman parte de un plan de atenci\u00f3n est\u00e1ndar.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las recomendaciones espec\u00edficas para evitar la sobredosis en pacientes pedi\u00e1tricos al administrar medicamentos en vol\u00famenes peque\u00f1os?**\n   - El documento sugiere que no se deben requerir medidas de vol\u00famenes menores a 0.1 ml y que se deben incluir tablas en la informaci\u00f3n del producto que indiquen claramente la dosis y el volumen a medir, as\u00ed como m\u00e9todos para lograrlo de manera segura y precisa.\n\n2. **\u00bfQu\u00e9 precauciones se deben tomar al utilizar preparaciones d\u00e9rmicas en neonatos y ni\u00f1os?**\n   - Se debe tener en cuenta que la absorci\u00f3n sist\u00e9mica no intencionada es un riesgo potencial, especialmente en neonatos debido a la deficiencia del estrato c\u00f3rneo. Adem\u00e1s, se deben considerar los excipientes utilizados y evitar el etanol en preparaciones para ni\u00f1os muy peque\u00f1os, ya que puede deshidratar la piel y causar dolor.\n\n3. **\u00bfQu\u00e9 informaci\u00f3n sobre la compatibilidad de medicamentos se debe incluir en la evaluaci\u00f3n de preparaciones farmac\u00e9uticas?**\n   - Es fundamental investigar la compatibilidad de los medicamentos que forman parte de un plan de atenci\u00f3n est\u00e1ndar, as\u00ed como proporcionar informaci\u00f3n sobre el pH de la forma farmac\u00e9utica terminada (FPP) en la informaci\u00f3n del producto.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Preparaciones acuosas**: Se enfatiza la importancia de adaptar las soluciones o suspensiones a las condiciones fisiol\u00f3gicas del sitio de aplicaci\u00f3n, considerando las tolerancias en pH y osmolalidad seg\u00fan la ruta de administraci\u00f3n.\n\n2. **Administraci\u00f3n subcut\u00e1nea**: Se destaca que esta ruta es especialmente sensible a las variaciones en pH y osmolalidad, y que las inyecciones hiperosmolares o con pH extremo pueden causar dolor e irritaci\u00f3n en las venas perif\u00e9ricas.\n\n3. **Pacientes neonatales**: Las formulaciones para neonatos son generalmente soluciones acuosas destinadas a la administraci\u00f3n intravenosa, donde los vol\u00famenes objetivo y el contenido de electrolitos son cr\u00edticos.\n\n4. **Seguridad de excipientes**: Es fundamental considerar el perfil de seguridad de cada excipiente y su idoneidad para el uso previsto.\n\n5. **Adsorci\u00f3n y leaching**: Se debe prestar atenci\u00f3n a la posible adsorci\u00f3n del principio activo (API) en superficies de contenedores y cat\u00e9teres de pl\u00e1stico, as\u00ed como a la migraci\u00f3n de plastificantes hacia la preparaci\u00f3n parenteral.\n\n6. **Reconstituci\u00f3n de medicamentos**: Algunos APIs se presentan en forma de polvo o liofilizados que requieren reconstituci\u00f3n antes de la administraci\u00f3n, y es esencial que las instrucciones claras y la informaci\u00f3n sobre condiciones de almacenamiento est\u00e9n disponibles en la etiqueta.\n\n7. **Minimizaci\u00f3n de c\u00e1lculos complejos**: Se sugiere que debe haber una necesidad m\u00ednima de c\u00e1lculos complejos en la prescripci\u00f3n, dispensaci\u00f3n y administraci\u00f3n de medicamentos parenterales para reducir el riesgo de errores.\n\n8. **Preparaciones listas para usar**: Se recomienda minimizar los pasos adicionales en la preparaci\u00f3n del producto para la administraci\u00f3n, promoviendo el desarrollo de preparaciones listas para usar.\n\n### Entidades clave\n- **OMS (Organizaci\u00f3n Mundial de la Salud)**: Autoridad que emite el documento.\n- **API (Principio Activo)**: Sustancia que produce el efecto terap\u00e9utico.\n- **Electrolitos**: Minerales esenciales que deben ser cuidadosamente balanceados en formulaciones para neonatos.\n- **Excipientes**: Sustancias inactivas que acompa\u00f1an al principio activo en las formulaciones.\n- **Administraci\u00f3n intravenosa**: Ruta de administraci\u00f3n cr\u00edtica para neonatos. \n\nEste resumen captura los aspectos m\u00e1s relevantes de la secci\u00f3n sobre formulaciones de preparaciones acuosas para la administraci\u00f3n parenteral de medicamentos.", "excerpt_keywords": "Keywords: pediatric medication safety, dermal administration, overdose prevention, pharmaceutical preparations, excipient safety"}}, "511dc5cb-9aac-42f2-843c-af883b5ad86b": {"node_ids": ["862036e2-1465-4d07-9fed-465e07d88438"], "metadata": {"page_label": "235", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 9.1 Transdermal patches\n\nTransdermal patches are used for systemic delivery of APIs which are capable of diffusion through the stratum corneum and are therapeutically active at the low plasma concentrations that can be achieved. The manufacture of transdermal patches of the \u201cdrug-in-adhesive\u201d type is now well developed and less problematic than the earlier \u201cdrug-in-reservoir\u201d type; the API is dispersed in a suitable polymeric adhesive to be fixed in a thin layer on a backing and covered by a removable liner.\n\nThe size and shape of a transdermal patch should be adapted to fit the child\u2019s body. It should stick firmly to the skin and not be too difficult to remove. Application sites which cannot easily be reached by the child should be chosen to avoid removal of the patch by the child. The risk of deliberate removal and its consequences for therapy must be considered. The increased systemic absorption through the skin, for the reasons mentioned above, may increase the systemic delivery from transdermal patches, in particular in newborns and young infants.\n\nWhen designed to be cut, information on the cutting technique should be provided in the patient leaflet and facilitated by the presence of cutting lines to ensure equal division. Reservoir systems should never be cut.\n\nAdhesives should have a low allergenic potential to avoid irritation and infection. Local tolerance and acceptability should be tested.\n\n# 10. Inhalations\n\nPulmonary administration of medicines by inhalation has traditionally been used to obtain a local effect. This route of administration also has a potential for systemic delivery. Preparations for inhalation include liquids for nebulization, pressurized metered dose inhalers (MDIs) and dry powder inhalers (DPIs).\n\nThe implications of the physiology of children of different ages and their ability to use the devices correctly should be considered in the development of paediatric inhalations (8). Depending on their age, children may have more or less difficulty with some of the devices. Problems with the coordination of the inhalation for MDIs and the ability to inhale strongly enough for DPIs determine the effectiveness of getting the medicine into the lung.\n\nThe total lung deposition is important for the clinical efficacy of preparations for inhalation. Generally it is affected by the formulation and delivery device controlling size distribution of the aerosol and patient-related factors such as the current disease state. The diameter of the airways is smaller in children than in adults; hence deposition by impact in the upper and central airways may be significantly higher in children (36). The particle size of the aerosol produced by the delivery device needs to be explored during development.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl contexto aborda dos m\u00e9todos de administraci\u00f3n de medicamentos en pediatr\u00eda: parches transd\u00e9rmicos e inhalaciones. Los parches transd\u00e9rmicos son utilizados para la entrega sist\u00e9mica de principios activos (APIs) que pueden difundir a trav\u00e9s de la piel, siendo especialmente relevantes en reci\u00e9n nacidos y ni\u00f1os peque\u00f1os debido a su mayor absorci\u00f3n sist\u00e9mica. Se enfatiza la importancia de adaptar el tama\u00f1o y la forma del parche al cuerpo del ni\u00f1o, as\u00ed como la necesidad de utilizar adhesivos con bajo potencial al\u00e9rgico. Por otro lado, la administraci\u00f3n pulmonar de medicamentos por inhalaci\u00f3n se utiliza principalmente para efectos locales, aunque tambi\u00e9n puede tener un efecto sist\u00e9mico. Se discuten las dificultades que pueden enfrentar los ni\u00f1os de diferentes edades al usar dispositivos de inhalaci\u00f3n, as\u00ed como la importancia de la deposici\u00f3n pulmonar para la eficacia cl\u00ednica.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones clave al dise\u00f1ar parches transd\u00e9rmicos para ni\u00f1os, especialmente en t\u00e9rminos de tama\u00f1o y forma?**\n   - Respuesta: Los parches deben adaptarse al cuerpo del ni\u00f1o, adherirse firmemente a la piel y ser f\u00e1ciles de quitar. Se deben elegir sitios de aplicaci\u00f3n que no sean f\u00e1cilmente alcanzables por el ni\u00f1o para evitar la remoci\u00f3n deliberada.\n\n2. **\u00bfQu\u00e9 precauciones deben tomarse al utilizar adhesivos en parches transd\u00e9rmicos para evitar irritaciones?**\n   - Respuesta: Los adhesivos deben tener un bajo potencial al\u00e9rgico para evitar irritaci\u00f3n e infecci\u00f3n, y se debe probar la tolerancia local y la aceptabilidad.\n\n3. **\u00bfC\u00f3mo afecta la fisiolog\u00eda de los ni\u00f1os a la eficacia de los dispositivos de inhalaci\u00f3n?**\n   - Respuesta: La fisiolog\u00eda de los ni\u00f1os, como el di\u00e1metro m\u00e1s peque\u00f1o de las v\u00edas respiratorias, puede resultar en una mayor deposici\u00f3n de part\u00edculas en las v\u00edas respiratorias superiores y centrales, lo que afecta la eficacia de la administraci\u00f3n del medicamento.\n\n### Resumen de nivel superior\n\nEl uso de parches transd\u00e9rmicos y la administraci\u00f3n por inhalaci\u00f3n son m\u00e9todos importantes para la entrega de medicamentos en pediatr\u00eda. Los parches deben ser dise\u00f1ados espec\u00edficamente para adaptarse a las caracter\u00edsticas f\u00edsicas de los ni\u00f1os, mientras que la administraci\u00f3n por inhalaci\u00f3n requiere considerar la capacidad de los ni\u00f1os para utilizar correctamente los dispositivos. Ambos m\u00e9todos deben tener en cuenta la seguridad y la eficacia, especialmente en poblaciones vulnerables como los reci\u00e9n nacidos y los ni\u00f1os peque\u00f1os.", "prev_section_summary": "### Temas Clave\n\n1. **Medidas de Seguridad en la Administraci\u00f3n de Medicamentos Pedi\u00e1tricos**:\n   - Evitar dosis en vol\u00famenes menores a 0.1 ml.\n   - Inclusi\u00f3n de tablas en la informaci\u00f3n del producto que indiquen dosis y vol\u00famenes a medir.\n   - Prevenci\u00f3n de sobredosis, especialmente en pacientes m\u00e1s peque\u00f1os.\n\n2. **Administraci\u00f3n D\u00e9rmica y Transd\u00e9rmica**:\n   - Tipos de preparaciones: l\u00edquidas, semi-s\u00f3lidas y s\u00f3lidas.\n   - Riesgo de absorci\u00f3n sist\u00e9mica no intencionada, especialmente en neonatos.\n   - Importancia de evaluar la seguridad de los excipientes y evitar el uso de etanol en ni\u00f1os muy peque\u00f1os.\n\n3. **Pruebas de Disoluci\u00f3n y Compatibilidad de Medicamentos**:\n   - Necesidad de realizar pruebas de disoluci\u00f3n para suspensiones l\u00edquidas, preparaciones semi-s\u00f3lidas y parches.\n   - Investigaci\u00f3n de la compatibilidad de medicamentos en planes de atenci\u00f3n est\u00e1ndar.\n   - Provisi\u00f3n de informaci\u00f3n sobre el pH de la forma farmac\u00e9utica terminada (FPP).\n\n### Entidades\n\n- **WHO Expert Committee on Specifications for Pharmaceutical Preparations**: Organizaci\u00f3n responsable de las recomendaciones.\n- **API (Active Pharmaceutical Ingredient)**: Ingrediente activo en las preparaciones farmac\u00e9uticas.\n- **FPP (Finished Pharmaceutical Product)**: Producto farmac\u00e9utico terminado.\n- **Excipientes**: Sustancias inactivas utilizadas en las formulaciones.\n- **Neonatos y ni\u00f1os**: Poblaciones espec\u00edficas a las que se dirigen las recomendaciones. \n\nEste resumen destaca las consideraciones cr\u00edticas para la administraci\u00f3n segura de medicamentos en pediatr\u00eda, as\u00ed como la importancia de la formulaci\u00f3n y la evaluaci\u00f3n de la seguridad de los productos farmac\u00e9uticos.", "excerpt_keywords": "Transdermal patches, pediatric inhalation, systemic delivery, drug formulation, airway deposition"}}, "a176f135-5d92-4b95-9bf4-725e7978e70c": {"node_ids": ["c5d9097f-7430-4a87-b120-5789e3d901f2"], "metadata": {"page_label": "236", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nNebulized liquids are potentially suitable for young children who cannot use MDIs and DPIs. Their use, however, requires nebulizing devices and access to electricity.\n\nMDIs may be suitable for children from birth when combined with a spacer. A spacer eliminates the need for coordinating the MDI actuation and the start of inhalation. For children younger than 2\u20133 years a facemask is also required. This can be replaced by a mouthpiece when the child is able to manage the system.\n\nDPIs may be used for children from the age of 4\u20135 years, as minimum inspiratory flow is required. DPIs and MDIs are preferred for older children because of their portability and convenience.\n\n## 11. Packaging and labelling\n\nContainer-closure systems for paediatric medicines are designed and constructed from materials meeting relevant regulatory requirements, and taking into account the stability of the medicine during transport, storage and use. In addition they are designed to ensure that they:\n\n- permit accurate dosing and convenient administration;\n- are robust and convenient for the supply chain, i.e. transportable;\n- are tailored to the target age group;\n- contribute to in-use stability;\n- provide appropriate information on the use of the medicine.\n\nIn cases where the paediatric medicine is significantly different from a similar adult medicine, it would be important to have noticeably different product packaging for the two products. It is necessary that consideration be given to whether the medicine is to be packed in a child-resistant container, i.e. a packaging that is difficult for young children to open, but not unduly difficult for adults to open properly.\n\nSelf-administration of medicine by schoolchildren and adolescents is facilitated when:\n\n- the medicine is easy to use;\n- separation of the day dose pack is facilitated; this should be easily carried by the patient in his or her bag;\n- clear instructions for use are contained with the medicine.\n\nAdequate information about the medicine and how to use it is important. Information about the dosage should be clearly spelt out, e.g. as milligrams per...", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento de la OMS aborda las especificaciones para preparaciones farmac\u00e9uticas, centr\u00e1ndose en la administraci\u00f3n de medicamentos a ni\u00f1os. Se discuten diferentes m\u00e9todos de inhalaci\u00f3n, como los aerosoles de dosis medida (MDIs), los inhaladores de polvo seco (DPIs) y l\u00edquidos nebulizados, destacando su idoneidad seg\u00fan la edad del ni\u00f1o. Adem\u00e1s, se enfatiza la importancia del dise\u00f1o de envases y etiquetado para medicamentos pedi\u00e1tricos, asegurando que sean seguros, f\u00e1ciles de usar y que proporcionen informaci\u00f3n clara sobre el uso y la dosificaci\u00f3n.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones clave para el dise\u00f1o de envases de medicamentos pedi\u00e1tricos seg\u00fan la OMS?**\n   - La OMS se\u00f1ala que los envases deben permitir una dosificaci\u00f3n precisa, ser robustos y convenientes para el transporte, estar adaptados al grupo de edad objetivo, contribuir a la estabilidad en uso y proporcionar informaci\u00f3n adecuada sobre el uso del medicamento.\n\n2. **\u00bfQu\u00e9 requisitos se deben cumplir para que un MDI sea adecuado para ni\u00f1os menores de 2-3 a\u00f1os?**\n   - Para que un MDI sea adecuado para ni\u00f1os menores de 2-3 a\u00f1os, debe utilizarse con un espaciador y se requiere una mascarilla facial, que puede ser reemplazada por una boquilla cuando el ni\u00f1o sea capaz de manejar el sistema.\n\n3. **\u00bfC\u00f3mo se facilita la auto-administraci\u00f3n de medicamentos en escolares y adolescentes?**\n   - La auto-administraci\u00f3n se facilita cuando el medicamento es f\u00e1cil de usar, se permite la separaci\u00f3n de las dosis diarias en empaques que sean f\u00e1ciles de llevar, y se incluyen instrucciones claras sobre su uso.", "prev_section_summary": "### Temas Clave\n\n1. **Parches Transd\u00e9rmicos**:\n   - Utilizados para la entrega sist\u00e9mica de principios activos (APIs) que pueden difundir a trav\u00e9s de la piel.\n   - La fabricaci\u00f3n de parches del tipo \"drug-in-adhesive\" es m\u00e1s avanzada y menos problem\u00e1tica que el tipo \"drug-in-reservoir\".\n   - Importancia de adaptar el tama\u00f1o y la forma del parche al cuerpo del ni\u00f1o.\n   - Necesidad de elegir sitios de aplicaci\u00f3n que no sean f\u00e1cilmente alcanzables por el ni\u00f1o para evitar la remoci\u00f3n deliberada.\n   - Consideraciones sobre la absorci\u00f3n sist\u00e9mica, especialmente en reci\u00e9n nacidos y ni\u00f1os peque\u00f1os.\n   - Precauciones sobre el uso de adhesivos con bajo potencial al\u00e9rgico para evitar irritaciones.\n\n2. **Inhalaciones**:\n   - Administraci\u00f3n pulmonar de medicamentos, tradicionalmente para efectos locales, pero tambi\u00e9n con potencial para efectos sist\u00e9micos.\n   - Tipos de preparaciones: l\u00edquidos para nebulizaci\u00f3n, inhaladores de dosis medida (MDIs) y inhaladores de polvo seco (DPIs).\n   - Consideraciones sobre la fisiolog\u00eda de los ni\u00f1os y su capacidad para usar correctamente los dispositivos de inhalaci\u00f3n.\n   - Importancia de la deposici\u00f3n pulmonar para la eficacia cl\u00ednica de las preparaciones para inhalaci\u00f3n.\n   - Diferencias en el di\u00e1metro de las v\u00edas respiratorias entre ni\u00f1os y adultos, lo que afecta la deposici\u00f3n de part\u00edculas.\n\n### Entidades\n\n- **Parches Transd\u00e9rmicos**: Dispositivos para la entrega de medicamentos a trav\u00e9s de la piel.\n- **Principios Activos (APIs)**: Sustancias que tienen un efecto terap\u00e9utico.\n- **Adhesivos**: Materiales utilizados en parches que deben ser hipoalerg\u00e9nicos.\n- **Inhaladores**: Dispositivos para la administraci\u00f3n de medicamentos por v\u00eda pulmonar (MDIs y DPIs).\n- **Fisiolog\u00eda Infantil**: Consideraciones sobre el desarrollo y las caracter\u00edsticas f\u00edsicas de los ni\u00f1os que afectan la administraci\u00f3n de medicamentos.\n- **Dep\u00f3sito Pulmonar**: Cantidad de medicamento que llega a los pulmones y su importancia para la eficacia del tratamiento. \n\nEste resumen destaca los aspectos esenciales de la administraci\u00f3n de medicamentos en pediatr\u00eda a trav\u00e9s de parches transd\u00e9rmicos e inhalaciones, enfatizando la necesidad de un dise\u00f1o adecuado y consideraciones de seguridad.", "excerpt_keywords": "Keywords: pediatric medicines, inhalation devices, packaging design, self-administration, dosage instructions"}}, "696d063f-9d11-4f86-8258-c80db5178fb4": {"node_ids": ["0e76bd68-46e7-4f03-a114-02bbe51bca58"], "metadata": {"page_label": "237", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# References\n\n1. **Provision by health-care professionals of patient-specific preparations for children that are not available as authorized products \u2013 points to consider.** Geneva, World Health Organization, 2010 (working document QAS/11.399/Rev. 1).\n\n2. Kearns GL et al. Developmental pharmacology \u2013 drug disposition, action and therapy in infants and children. *New England Journal of Medicine*, 2003, 349:1157\u20131167.\n\n3. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Clinical investigation of medicinal products in the paediatric population. Implementation: EU, MHLW, FDA. Adopted by CPMP, July 2000, issued as CPMP/ICH/2711/99; adopted 15 December 2000, PMSB/ELD Notification No. 1334. *Federal Register*, 12 April 2000, 65(71): 19777\u201319781.\n\n4. **WHO draft guideline on quality risk management.** Geneva, World Health Organization, 2010 (working document QAS/10.376).\n\n5. **Pharmaceutical development for multisource (generic) pharmaceutical products.** Geneva, World Health Organization, 2010 (working document QAS/08.251/Rev.1).\n\n6. Committee for Medicinal Products for Human Use (CHMP). *Reflection paper: formulations of choice for the paediatric population.* London, EMEA, 2006 (EMEA/CHMP/PEG/196810/2005).\n\n7. Ernest TB et al. Developing paediatric medicines: identifying the needs and recognizing the challenges. *Journal of Pharmacy and Pharmacology*, 2007, 59: 1043\u20131055.\n\n8. Krause J, Breitkreutz J. Improving drug delivery in paediatric medicine. *Pharmaceutical Medicine*, 2008, 22: 41\u201350.\n\n9. Zhao N et al. Tablet splitting: product quality assessment of metoprolol succinate extended release tablets. *International Journal of Pharmaceutics*, 2010, 401: 25\u201331.\n\n10. Allen LV. Dosage form design and development. *Clinical Therapeutics*, 2008, 30: 2102\u20132111.\n\n11. Guidelines for registration of fixed-dose combination medicinal products. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth Report.* Geneva, World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).\n\n12. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities in new drug substances. Implementation: EU, MHLW, FDA. Adopted by CPMP, October 2006, issued as CPMP/ICH/142/95; adopted 4 December 2006, PFSB/ELD Notification No. 1204001. *Federal Register*, June 2008.\n\n13. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities in new drug products. Implementation: EU, MHLW, FDA. Adopted by CPMP, June 2006, issued as CPMP/ICH/2738/99; adopted 3 July 2006, PFSB/ELD Notification No. 0703004. *Federal Register*, 2003, 68: 64628\u201364629 with the revised attachment 2.\n\n14. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Impurities: guideline for", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que se centra en la investigaci\u00f3n y desarrollo de medicamentos pedi\u00e1tricos. Incluye referencias a directrices, estudios y documentos de trabajo relacionados con la formulaci\u00f3n, calidad y regulaci\u00f3n de productos farmac\u00e9uticos para la poblaci\u00f3n infantil. Se abordan temas como la necesidad de preparaciones espec\u00edficas para ni\u00f1os, el desarrollo farmacol\u00f3gico en infantes y los desaf\u00edos en la creaci\u00f3n de medicamentos pedi\u00e1tricos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los puntos clave que deben considerar los profesionales de la salud al proporcionar preparaciones espec\u00edficas para ni\u00f1os que no est\u00e1n disponibles como productos autorizados?**\n   - Esta pregunta se refiere directamente al primer punto de la lista de referencias, que menciona un documento de trabajo de la OMS sobre el tema.\n\n2. **\u00bfQu\u00e9 desaf\u00edos se identifican en el desarrollo de medicamentos pedi\u00e1tricos seg\u00fan el art\u00edculo de Ernest TB et al. en el *Journal of Pharmacy and Pharmacology*?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre los desaf\u00edos mencionados en la referencia 7, que podr\u00eda no estar ampliamente discutida en otras fuentes.\n\n3. **\u00bfQu\u00e9 directrices proporciona la OMS sobre la gesti\u00f3n de riesgos de calidad en la fabricaci\u00f3n de medicamentos pedi\u00e1tricos?**\n   - Esta pregunta se relaciona con el cuarto punto de la lista de referencias, que menciona una gu\u00eda de la OMS sobre gesti\u00f3n de riesgos de calidad, y podr\u00eda ofrecer detalles que no se encuentran f\u00e1cilmente en otros documentos.\n\n### Resumen de Nivel Superior\n\nEl informe de la OMS destaca la importancia de adaptar los medicamentos para la poblaci\u00f3n pedi\u00e1trica, abordando la falta de productos autorizados y la necesidad de formulaciones espec\u00edficas. Se mencionan directrices y estudios que abordan la investigaci\u00f3n cl\u00ednica, la calidad de los productos y los desaf\u00edos en el desarrollo de medicamentos para ni\u00f1os. La OMS y otras organizaciones han establecido pautas para garantizar que los medicamentos sean seguros y efectivos para los m\u00e1s j\u00f3venes, reconociendo las diferencias en la farmacolog\u00eda entre ni\u00f1os y adultos.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **M\u00e9todos de Inhalaci\u00f3n para Ni\u00f1os**:\n   - **L\u00edquidos Nebulizados**: Adecuados para ni\u00f1os peque\u00f1os que no pueden usar MDIs o DPIs, pero requieren dispositivos de nebulizaci\u00f3n y acceso a electricidad.\n   - **Aerosoles de Dosis Medida (MDIs)**: Pueden ser utilizados desde el nacimiento con un espaciador; se requiere mascarilla para ni\u00f1os menores de 2-3 a\u00f1os.\n   - **Inhaladores de Polvo Seco (DPIs)**: A partir de los 4-5 a\u00f1os, debido a la necesidad de un flujo inspiratorio m\u00ednimo. Preferidos para ni\u00f1os mayores por su portabilidad y conveniencia.\n\n2. **Dise\u00f1o de Envases y Etiquetado para Medicamentos Pedi\u00e1tricos**:\n   - Los sistemas de cierre de envases deben cumplir con requisitos regulatorios y asegurar la estabilidad del medicamento.\n   - Consideraciones clave incluyen:\n     - Dosificaci\u00f3n precisa y administraci\u00f3n conveniente.\n     - Robustez y conveniencia para el transporte.\n     - Adaptaci\u00f3n al grupo de edad objetivo.\n     - Contribuci\u00f3n a la estabilidad en uso.\n     - Informaci\u00f3n adecuada sobre el uso del medicamento.\n\n3. **Diferenciaci\u00f3n en el Empaque**:\n   - Es importante que el empaque de medicamentos pedi\u00e1tricos sea notablemente diferente al de los medicamentos para adultos, especialmente si son significativamente distintos.\n\n4. **Auto-administraci\u00f3n en Escolares y Adolescentes**:\n   - Facilidades para la auto-administraci\u00f3n incluyen:\n     - Medicamentos f\u00e1ciles de usar.\n     - Empaques que permiten la separaci\u00f3n de dosis diarias y son f\u00e1ciles de transportar.\n     - Instrucciones claras sobre el uso del medicamento.\n\n5. **Importancia de la Informaci\u00f3n**:\n   - La informaci\u00f3n sobre el medicamento y su uso debe ser clara, incluyendo detalles sobre la dosificaci\u00f3n.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad que emite las recomendaciones.\n- **MDIs (Aerosoles de Dosis Medida)**: Dispositivos de inhalaci\u00f3n.\n- **DPIs (Inhaladores de Polvo Seco)**: Otro tipo de dispositivo de inhalaci\u00f3n.\n- **L\u00edquidos Nebulizados**: Forma de medicaci\u00f3n para inhalaci\u00f3n.\n- **Espaciador**: Dispositivo que ayuda en la administraci\u00f3n de MDIs.\n- **Mascarilla Facial**: Accesorio necesario para el uso de MDIs en ni\u00f1os peque\u00f1os.\n- **Envases de Medicamentos**: Sistemas de empaque dise\u00f1ados para medicamentos pedi\u00e1tricos.", "excerpt_keywords": "Keywords: pediatric medicines, drug formulation, quality risk management, pharmaceutical guidelines, health care professionals"}}, "cef4e6f5-afff-4486-bae7-16451af83c5d": {"node_ids": ["4e2fabbb-061f-4541-a2d5-c908a0f3ea20"], "metadata": {"page_label": "238", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n15. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). *Guideline on the limits of genotoxic impurities*. London, 28 June 2006 (CPMP/SWP/5199/02, EMEA/CHMP/ QWP/251344/2006).\n\n16. European Medicines Agency. *Questions and answers on the \u201cGuideline on the limits of genotoxic impurities\u201d*. London, EMEA, 2010 (EMEA/CHMP/SWP/431994/2007).\n\n17. European Medicines Agency. *Guideline on the specification limits for residues of metal catalysts or metal reagents*. London, 21 February 2008 (EMEA/CHMP/SWP/QWP/4446/2000).\n\n18. Siewert M et al. FIP/AAPS guidelines to dissolution/in vitro release testing of novel/special dosage forms. *AAPS PharmSciTech*, 2003, 4:Article 7 (http://www.aapspharmscitech.org/view. asp?art=pt040107).\n\n19. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth Report*. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).\n\n20. Proposal to waive in vivo bioequivalence requirements for WHO Model List of essential medicines immediate-release, solid dosage forms. In: *WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth Report*. Geneva, World Health Organization, 2006, Annex 8 (WHO Technical Report Series, No. 937).\n\n21. Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. *Expert Opinion on Drug Delivery*, 2007, 4: 37\u201345.\n\n22. Shehab N et al. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. *Pediatric Critical Care Medicine*, 2009, 10(2): 256\u2013259.\n\n23. American Academy of Pediatrics. \u201cInactive\u201d ingredients in pharmaceutical products: update (subject review). *Pediatrics*, 1997, 99:268\u2013278 (http://www.pediatrics.org/cgi/content/ full/99/2/268).\n\n24. WHO Technical Report Series on evaluation of certain food additives. *List of publications* (http:// www.who.int/ipcs/publications/jecfa/reports/en/index.html).\n\n25. Pollock I et al. Survey of colourings and preservatives in drugs. *BMJ*, 1989, 299: 649\u2013651.\n\n26. Pefferi G, Restani P. The safety of pharmaceutical excipients. *Il Farmaco*, 2003, 58: 541\u2013550.\n\n27. European Medicines Agency. EMEA Public Statement on antimicrobial preservatives in ophthalmic preparations for human use. London, EMEA, 2009 (EMEA/622721/2009).\n\n28. Mennella JA, Beauchamp GK. Optimizing oral medications for children. *Clinical Therapeutics*, 2008, 30: 2120\u20132132.\n\n29. *Production of zinc tablets and zinc oral solutions: guidelines for programme managers and pharmaceutical manufacturers*, Annex 7. Geneva, World Health Organization, 2007.\n\n30. Cram A et al. Challenges of developing palatable oral paediatric formulations. *International Journal of Pharmaceutics*, 2009, 365: 1\u20133.\n\n31. Committee for Medicinal Products for Human Use. *Guideline on the investigation of medicinal products in the term and preterm neonate*. London, European Medicines Agency, 2007.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que presenta las recomendaciones y directrices de un comit\u00e9 de expertos sobre las especificaciones para preparaciones farmac\u00e9uticas. Incluye referencias a diversas gu\u00edas y estudios relacionados con la seguridad de los excipientes farmac\u00e9uticos, l\u00edmites de impurezas genot\u00f3xicas, y la formulaci\u00f3n de medicamentos para poblaciones espec\u00edficas como neonatos y ancianos. Tambi\u00e9n se abordan temas como la bioequivalencia y la optimizaci\u00f3n de medicamentos orales para ni\u00f1os.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las recomendaciones de la OMS sobre los l\u00edmites de impurezas genot\u00f3xicas en productos farmac\u00e9uticos?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las directrices emitidas por la Agencia Europea de Medicamentos (EMA) en relaci\u00f3n con las impurezas genot\u00f3xicas, que son cruciales para garantizar la seguridad de los medicamentos.\n\n2. **\u00bfQu\u00e9 consideraciones se deben tener en cuenta al formular medicamentos para neonatos seg\u00fan el informe?**\n   - Esta pregunta se centra en las pautas espec\u00edficas para la formulaci\u00f3n de medicamentos dirigidos a neonatos, un grupo vulnerable que requiere atenci\u00f3n especial en el desarrollo de medicamentos.\n\n3. **\u00bfQu\u00e9 desaf\u00edos se mencionan en el desarrollo de formulaciones orales palatables para pediatr\u00eda?**\n   - Esta pregunta busca explorar los problemas espec\u00edficos que enfrentan los fabricantes al crear medicamentos que sean aceptables y agradables para los ni\u00f1os, un aspecto importante en la adherencia al tratamiento.\n\n### Resumen de Nivel Superior\nEl informe de la OMS proporciona un marco para la regulaci\u00f3n y desarrollo de productos farmac\u00e9uticos, enfatizando la importancia de la seguridad y eficacia en la formulaci\u00f3n de medicamentos. Se abordan temas cr\u00edticos como la evaluaci\u00f3n de excipientes, la bioequivalencia, y la adaptaci\u00f3n de medicamentos para poblaciones espec\u00edficas, destacando la necesidad de directrices claras y basadas en evidencia para proteger la salud p\u00fablica.", "prev_section_summary": "### Temas Clave\n\n1. **Desarrollo de Medicamentos Pedi\u00e1tricos**: El informe aborda la necesidad de crear medicamentos espec\u00edficos para la poblaci\u00f3n infantil, destacando la falta de productos autorizados y la importancia de formulaciones adaptadas.\n\n2. **Directrices de la OMS**: Se mencionan varias directrices y documentos de trabajo de la Organizaci\u00f3n Mundial de la Salud (OMS) que proporcionan pautas sobre la gesti\u00f3n de riesgos de calidad, el desarrollo farmac\u00e9utico y la formulaci\u00f3n de medicamentos para ni\u00f1os.\n\n3. **Investigaci\u00f3n y Regulaci\u00f3n**: Se discuten las normativas y gu\u00edas de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) relacionadas con la investigaci\u00f3n cl\u00ednica y la regulaci\u00f3n de productos farmac\u00e9uticos para la poblaci\u00f3n pedi\u00e1trica.\n\n4. **Desaf\u00edos en el Desarrollo**: Se identifican los desaf\u00edos que enfrentan los profesionales de la salud y la industria farmac\u00e9utica en el desarrollo de medicamentos pedi\u00e1tricos, incluyendo la necesidad de adaptaciones en la dosificaci\u00f3n y formulaci\u00f3n.\n\n5. **Calidad y Seguridad**: Se enfatiza la importancia de garantizar la calidad y seguridad de los medicamentos para ni\u00f1os, considerando las diferencias en la farmacolog\u00eda entre ni\u00f1os y adultos.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Proporciona directrices y documentos de trabajo sobre medicamentos pedi\u00e1tricos.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Establece pautas para la investigaci\u00f3n y regulaci\u00f3n de medicamentos.\n- **Revistas Cient\u00edficas**: Se citan art\u00edculos de revistas como el *New England Journal of Medicine* y el *Journal of Pharmacy and Pharmacology*, que abordan temas relevantes en farmacolog\u00eda pedi\u00e1trica.\n- **Comit\u00e9 de Medicamentos para Uso Humano (CHMP)**: Ofrece reflexiones sobre formulaciones adecuadas para la poblaci\u00f3n pedi\u00e1trica.\n\n### Conclusi\u00f3n\n\nEl informe de la OMS subraya la necesidad de un enfoque espec\u00edfico para el desarrollo de medicamentos pedi\u00e1tricos, abordando tanto la falta de productos autorizados como los desaf\u00edos en la formulaci\u00f3n y regulaci\u00f3n. Se destaca la importancia de seguir directrices establecidas para asegurar que los medicamentos sean seguros y efectivos para los ni\u00f1os.", "excerpt_keywords": "Keywords: pharmaceutical preparations, genotoxic impurities, pediatric formulations, drug safety, WHO guidelines"}}, "d1b55ead-81a3-47a1-ae5c-572aaf62bfc1": {"node_ids": ["552cceae-f751-4319-8b5d-b4f53df0385a"], "metadata": {"page_label": "239", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 5\n\n(EMEA/566810/2008).\n\n32. Strickly RG et al. Paediatric drugs \u2013 a review of commercially available oral formulations. *Journal of Pharmaceutical Sciences* 2007, 97: 1731\u20131774.\n\n33. Thomson SA et al. Mini-tablets: new modality to deliver medicines to preschool-aged children. *Paediatrics*, 2009, 123:e235\u2013e238.\n\n34. *The International Pharmacopoeia*, 4th ed. First and Second Supplements (available online and on CD-ROM). Geneva, World Health Organization, 2011 (http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html).\n\n35. Seager H. Drug-delivery products and the zydis fast-dissolving dosage form. *Journal of Pharmacy and Pharmacology*, 1998, 50: 375\u2013382.\n\n36. Dolovich M. Influence of inspiratory flow rate, particle size and airway caliber in aerosolized drug delivery to the lung. *Respiratory Care*, 2000, 45: 597\u2013608.\n\n## Web sites\n\n- **WHO** World Health Organization: http://www.who.int\n- **ICH** International Conference on Harmonisation: http://www.ich.org\n- **EMA** European Medicines Agency: http://www.ema.europa.eu", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\nEl contexto proviene del Anexo 5 del Informe T\u00e9cnico de la OMS (WHO - Technical Report Series 970), que incluye referencias sobre formulaciones de medicamentos pedi\u00e1tricos, modalidades de entrega de medicamentos para ni\u00f1os en edad preescolar, y aspectos t\u00e9cnicos de la entrega de medicamentos a trav\u00e9s de aerosoles. Tambi\u00e9n se mencionan recursos en l\u00ednea de organizaciones relevantes como la OMS, ICH y EMA.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las consideraciones clave en la formulaci\u00f3n de medicamentos pedi\u00e1tricos seg\u00fan Strickly RG et al. en su revisi\u00f3n de 2007?**\n   - Esta pregunta busca detalles espec\u00edficos sobre los hallazgos y recomendaciones presentados en el art\u00edculo mencionado, que no se pueden encontrar f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfQu\u00e9 innovaciones en la entrega de medicamentos se discuten en el estudio de Thomson SA et al. sobre mini-tabletas para ni\u00f1os?**\n   - Esta pregunta se centra en las caracter\u00edsticas y beneficios de las mini-tabletas como una nueva modalidad de entrega, que podr\u00eda no estar ampliamente documentada en otras publicaciones.\n\n3. **\u00bfC\u00f3mo afecta el flujo inspiratorio y el tama\u00f1o de las part\u00edculas en la entrega de medicamentos aerosolizados seg\u00fan Dolovich M?**\n   - Esta pregunta busca una comprensi\u00f3n m\u00e1s profunda de los factores t\u00e9cnicos que influyen en la eficacia de la entrega de medicamentos a los pulmones, un tema que puede no ser ampliamente cubierto en otras fuentes.\n\n### Resumen de Nivel Superior\nEl Anexo 5 del Informe T\u00e9cnico de la OMS aborda temas relacionados con la formulaci\u00f3n y entrega de medicamentos, especialmente en el contexto pedi\u00e1trico. Se destacan estudios sobre formulaciones orales y nuevas modalidades de entrega, as\u00ed como consideraciones t\u00e9cnicas para la administraci\u00f3n de medicamentos a trav\u00e9s de aerosoles. Adem\u00e1s, se proporcionan enlaces a recursos de organizaciones clave en el \u00e1mbito de la salud y la regulaci\u00f3n de medicamentos.", "prev_section_summary": "### Temas Clave\n\n1. **L\u00edmites de Impurezas Genot\u00f3xicas**: Se mencionan directrices de la Agencia Europea de Medicamentos (EMA) sobre los l\u00edmites permitidos de impurezas genot\u00f3xicas en productos farmac\u00e9uticos, lo cual es crucial para garantizar la seguridad de los medicamentos.\n\n2. **Formulaci\u00f3n de Medicamentos para Neonatos y Ancianos**: Se abordan pautas espec\u00edficas para la formulaci\u00f3n de medicamentos dirigidos a poblaciones vulnerables, como neonatos y ancianos, destacando la necesidad de atenci\u00f3n especial en su desarrollo.\n\n3. **Desarrollo de Formulaciones Orales Palatables**: Se discuten los desaf\u00edos que enfrentan los fabricantes al crear medicamentos orales que sean aceptables y agradables para los ni\u00f1os, lo que es fundamental para la adherencia al tratamiento.\n\n4. **Evaluaci\u00f3n de Excipientes**: Se enfatiza la importancia de evaluar la seguridad de los excipientes farmac\u00e9uticos y su impacto en la salud p\u00fablica.\n\n5. **Bioequivalencia**: Se menciona la propuesta de eximir ciertos requisitos de bioequivalencia para medicamentos en la lista de medicamentos esenciales de la OMS.\n\n### Entidades\n\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad responsable de la elaboraci\u00f3n del informe y las directrices.\n- **Agencia Europea de Medicamentos (EMA)**: Proporciona directrices sobre l\u00edmites de impurezas y evaluaci\u00f3n de medicamentos.\n- **FIP/AAPS**: Referencia a las gu\u00edas sobre pruebas de disoluci\u00f3n y liberaci\u00f3n in vitro.\n- **American Academy of Pediatrics**: Proporciona actualizaciones sobre ingredientes inactivos en productos farmac\u00e9uticos.\n- **Revistas Cient\u00edficas**: Se citan varias publicaciones como *AAPS PharmSciTech*, *Pediatrics*, y *Clinical Therapeutics* que abordan temas relevantes en la formulaci\u00f3n y seguridad de medicamentos.\n\n### Conclusi\u00f3n\nEl informe de la OMS proporciona un marco regulatorio y directrices para el desarrollo de productos farmac\u00e9uticos, enfatizando la seguridad, eficacia y adaptaci\u00f3n de medicamentos para poblaciones espec\u00edficas, lo que es esencial para proteger la salud p\u00fablica.", "excerpt_keywords": "Keywords: pediatrics, drug delivery, formulations, aerosolized medication, WHO"}}, "3afa8eb3-7ceb-4bec-820c-931c1c48c854": {"node_ids": ["34600602-5ea1-41c6-b830-6079017979e8"], "metadata": {"page_label": "240", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un breve resumen del contenido que podr\u00eda estar relacionado:\n\n### Resumen del Contexto\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que probablemente contiene informaci\u00f3n t\u00e9cnica y recomendaciones de la Organizaci\u00f3n Mundial de la Salud (OMS) sobre un tema espec\u00edfico relacionado con la salud p\u00fablica. Sin embargo, el contenido espec\u00edfico no est\u00e1 disponible en el contexto proporcionado.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS en el Informe T\u00e9cnico 970 sobre la salud p\u00fablica?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre las recomendaciones que se presentan en el informe, que podr\u00edan ser relevantes para profesionales de la salud y responsables de pol\u00edticas.\n\n2. **\u00bfQu\u00e9 temas espec\u00edficos se abordan en el documento WHO TRS 970 y c\u00f3mo se relacionan con las tendencias actuales en salud global?**\n   - Esta pregunta indaga sobre los temas tratados en el informe y su relevancia en el contexto de los desaf\u00edos actuales en salud p\u00fablica, lo que podr\u00eda no estar disponible en otras fuentes.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas se utilizan en el Informe T\u00e9cnico 970 para evaluar la efectividad de las intervenciones de salud p\u00fablica?**\n   - Esta pregunta se centra en las metodolog\u00edas espec\u00edficas que la OMS podr\u00eda haber utilizado en el informe, lo que podr\u00eda proporcionar informaci\u00f3n valiosa para investigadores y profesionales en el campo de la salud.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n espec\u00edfica que podr\u00eda no estar f\u00e1cilmente disponible en otras fuentes, bas\u00e1ndose en el contexto del documento de la OMS.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Temas Clave:**\n1. **Formulaci\u00f3n de Medicamentos Pedi\u00e1tricos:** Se revisan las formulaciones orales disponibles comercialmente para ni\u00f1os, destacando la importancia de adaptar los medicamentos a las necesidades espec\u00edficas de esta poblaci\u00f3n.\n2. **Innovaciones en la Entrega de Medicamentos:** Se discuten las mini-tabletas como una nueva modalidad para administrar medicamentos a ni\u00f1os en edad preescolar, enfatizando sus beneficios y caracter\u00edsticas.\n3. **Entrega de Medicamentos Aerosolizados:** Se analizan factores t\u00e9cnicos que afectan la eficacia de la entrega de medicamentos a los pulmones, como el flujo inspiratorio, el tama\u00f1o de las part\u00edculas y el calibre de las v\u00edas respiratorias.\n\n**Entidades:**\n- **Organizaciones de Salud:**\n  - **OMS (World Health Organization):** Proporciona recursos y directrices sobre medicamentos y salud p\u00fablica.\n  - **ICH (International Conference on Harmonisation):** Se enfoca en la armonizaci\u00f3n de regulaciones para la investigaci\u00f3n y desarrollo de medicamentos.\n  - **EMA (European Medicines Agency):** Agencia responsable de la evaluaci\u00f3n y supervisi\u00f3n de medicamentos en la Uni\u00f3n Europea.\n\n**Referencias Clave:**\n- Art\u00edculos de revistas cient\u00edficas que abordan la formulaci\u00f3n y entrega de medicamentos pedi\u00e1tricos, as\u00ed como estudios sobre la administraci\u00f3n de medicamentos aerosolizados.\n\nEste resumen destaca la relevancia de la investigaci\u00f3n en la formulaci\u00f3n y entrega de medicamentos para ni\u00f1os, as\u00ed como la importancia de las organizaciones de salud en la regulaci\u00f3n y promoci\u00f3n de pr\u00e1cticas seguras y efectivas en el uso de medicamentos pedi\u00e1tricos.", "excerpt_keywords": "Keywords: OMS, medicamentos pedi\u00e1tricos, formulaci\u00f3n, entrega de medicamentos, salud p\u00fablica"}}, "df771ecf-a17a-49dc-8a89-d36e9d0fdf5c": {"node_ids": ["b9a1fdde-814e-4583-b03a-88024944775a"], "metadata": {"page_label": "241", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Annex 6\n\n**Recommendations for quality requirements when artemisinin is used as a starting material in the production of antimalarial active pharmaceutical ingredients**\n\n1. Introduction  \n2. Characterization of artemisinin  \n3. Tests and specifications for artemisinin starting material  \n   References  \n\n|   | Page |\n|---|------|\n| 1. | Introduction | 229 |\n| 2. | Characterization of artemisinin | 231 |\n| 3. | Tests and specifications for artemisinin starting material | 232 |\n|    | References | 235 |", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas que se pueden responder con el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento \"WHO - Technical Report Series 970\" incluye un anexo que presenta recomendaciones sobre los requisitos de calidad para el uso de artemisinina como material de partida en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos. El anexo se divide en varias secciones, que incluyen una introducci\u00f3n, la caracterizaci\u00f3n de la artemisinina, pruebas y especificaciones para el material de partida de artemisinina, y referencias.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son los principales aspectos que se abordan en la caracterizaci\u00f3n de la artemisinina seg\u00fan el documento?**\n   - Esta pregunta busca detalles espec\u00edficos sobre los m\u00e9todos y criterios utilizados para caracterizar la artemisinina, que son fundamentales para garantizar su calidad en la producci\u00f3n de medicamentos antimal\u00e1ricos.\n\n2. **\u00bfQu\u00e9 tipo de pruebas y especificaciones se recomiendan para el material de partida de artemisinina en la producci\u00f3n de ingredientes farmac\u00e9uticos activos?**\n   - Esta pregunta se centra en las pruebas espec\u00edficas que deben realizarse y las especificaciones que deben cumplirse para asegurar que la artemisinina utilizada en la producci\u00f3n sea de alta calidad y adecuada para su uso en medicamentos.\n\n3. **\u00bfQu\u00e9 importancia tiene la calidad de la artemisinina en la producci\u00f3n de ingredientes farmac\u00e9uticos activos antimal\u00e1ricos seg\u00fan las recomendaciones del informe?**\n   - Esta pregunta busca explorar la relaci\u00f3n entre la calidad de la artemisinina y la eficacia de los tratamientos antimal\u00e1ricos, as\u00ed como las implicaciones para la salud p\u00fablica y el control de la malaria.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl documento \"WHO - Technical Report Series 970\" de la Organizaci\u00f3n Mundial de la Salud (OMS) se centra en aspectos t\u00e9cnicos y recomendaciones relacionadas con la salud p\u00fablica. Aunque el contenido espec\u00edfico no est\u00e1 disponible, se pueden inferir algunos temas clave y entidades relevantes:\n\n#### Temas Clave\n1. **Recomendaciones de Salud P\u00fablica**: Es probable que el informe contenga directrices y recomendaciones para mejorar la salud p\u00fablica a nivel global.\n2. **Evaluaci\u00f3n de Intervenciones**: Se sugiere que el documento podr\u00eda abordar metodolog\u00edas para evaluar la efectividad de diversas intervenciones en salud p\u00fablica.\n3. **Tendencias en Salud Global**: El informe podr\u00eda relacionar sus hallazgos con las tendencias actuales y desaf\u00edos en el \u00e1mbito de la salud a nivel mundial.\n\n#### Entidades\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la elaboraci\u00f3n del informe, que se enfoca en la salud p\u00fablica y el bienestar global.\n- **Salud P\u00fablica**: El campo de estudio y pr\u00e1ctica que se aborda en el documento, incluyendo pol\u00edticas, intervenciones y recomendaciones.\n\nEste resumen proporciona una visi\u00f3n general de los posibles temas y entidades que podr\u00edan estar presentes en el informe, aunque el contenido espec\u00edfico no est\u00e9 disponible en el contexto proporcionado.", "excerpt_keywords": "Keywords: artemisinin, antimalarial, pharmaceutical, quality requirements, WHO"}}, "9e1c8945-ab0a-4c85-b9c7-e065a9f8d138": {"node_ids": ["6174e8c5-a4c5-4fe5-83f1-61fa8e2e7897"], "metadata": {"page_label": "242", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan proporcionar respuestas espec\u00edficas basadas en el contexto del documento \"WHO - Technical Report Series 970\":\n\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el Informe 46 de la Serie de Informes T\u00e9cnicos de la OMS?**\n   - Esta pregunta busca obtener informaci\u00f3n espec\u00edfica sobre el contenido del informe, que puede no estar disponible en otros documentos o res\u00famenes.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas se utilizaron en el estudio o an\u00e1lisis presentado en el documento de la OMS?**\n   - Esta pregunta se centra en las t\u00e9cnicas y enfoques utilizados en la investigaci\u00f3n, lo cual es crucial para entender la validez y aplicabilidad de los resultados.\n\n3. **\u00bfQu\u00e9 implicaciones tienen los resultados del Informe 46 para la salud p\u00fablica a nivel global?**\n   - Esta pregunta busca explorar c\u00f3mo los hallazgos del informe pueden influir en pol\u00edticas de salud p\u00fablica, lo que puede no estar claramente delineado en otros textos.\n\n### Resumen de nivel superior del contexto circundante:\nEl documento \"WHO - Technical Report Series 970\" es parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS), que abordan diversos temas relacionados con la salud p\u00fablica, investigaci\u00f3n y recomendaciones para mejorar la salud a nivel global. El Informe 46 en particular puede contener an\u00e1lisis, datos y recomendaciones que son relevantes para profesionales de la salud, investigadores y responsables de pol\u00edticas.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\nEl **Anexo 6** del documento \"WHO - Technical Report Series 970\" se centra en las **recomendaciones de calidad** para el uso de **artemisinina** como material de partida en la producci\u00f3n de **ingredientes farmac\u00e9uticos activos** antimal\u00e1ricos. Los temas clave abordados en esta secci\u00f3n incluyen:\n\n1. **Introducci\u00f3n**: Presenta el contexto y la importancia de la artemisinina en la producci\u00f3n de medicamentos antimal\u00e1ricos.\n   \n2. **Caracterizaci\u00f3n de la artemisinina**: Detalla los m\u00e9todos y criterios necesarios para evaluar la calidad de la artemisinina, asegurando que cumpla con los est\u00e1ndares requeridos para su uso en la fabricaci\u00f3n de f\u00e1rmacos.\n\n3. **Pruebas y especificaciones**: Describe las pruebas espec\u00edficas que deben realizarse y las especificaciones que deben cumplirse para garantizar que el material de partida de artemisinina sea de alta calidad y adecuado para la producci\u00f3n de ingredientes farmac\u00e9uticos activos.\n\n4. **Referencias**: Proporciona las fuentes y documentos relevantes que respaldan las recomendaciones presentadas.\n\n### Entidades Clave\n- **Artemisinina**: Compuesto utilizado como material de partida en la producci\u00f3n de medicamentos antimal\u00e1ricos.\n- **Ingredientes farmac\u00e9uticos activos**: Sustancias que proporcionan la actividad farmacol\u00f3gica en los medicamentos.\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Entidad que emite el informe y establece las recomendaciones.\n\nEste resumen destaca la importancia de la calidad de la artemisinina en la producci\u00f3n de tratamientos antimal\u00e1ricos y su impacto en la salud p\u00fablica.", "excerpt_keywords": "Keywords: artemisinina, salud p\u00fablica, ingredientes farmac\u00e9uticos activos, recomendaciones de calidad, Organizaci\u00f3n Mundial de la Salud"}}, "6029e08a-3d2c-4b86-b545-8b1a1334cfbf": {"node_ids": ["47bbaf8f-e5dc-4b07-b9a3-aefd289d9811"], "metadata": {"page_label": "243", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 1. Introduction\n\nThe harmonized good manufacturing practices (GMP) (1,2) describe requirements for the production of active pharmaceutical ingredients (APIs). The applicability of these requirements begins with a defined starting material as follows:\n\n> \"An API starting material is a raw material, intermediate, or an API that is used in the production and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials normally have defined chemical properties and structure.\"\n\nThe focus of GMP for APIs is for field inspector use, rather than in applications for marketing authorization. It defines what may be considered as a starting material and provides guidance on where GMP is applied. The GMP guidelines do not apply to steps taken prior to the first introduction of the defined starting material. The manufacturer should designate and document the rationale for the point at which production of the API begins. For a synthesis process, this is known as the point at which the starting materials are entered into processes.\n\nFrom a regulatory standpoint, the use of API starting materials marks the beginning of the detailed description of the process. The applicant for marketing authorization should propose and justify which substance should be considered as the API starting material, e.g. incorporated as a significant structural fragment into the structure of the active substance.\n\nIn practice the designation of a starting material may be difficult. The number of steps separating the starting material from the final API is an issue to be decided on a case-by-case basis, subject to the manufacturer\u2019s proposal and assessors\u2019 evaluation. Since a designated starting material may be obtained from multiple sources, it is necessary to have well-defined quality requirements to ensure that the APIs produced meet specifications. Establishing these requirements may involve a compromise between the desire for a pure starting material and the impact of this on cost of API production. Impurities can be tolerated in the starting material if the API manufacturing process has been shown to efficiently remove them. Redundant purification steps may reduce the yield of the final API and thus further increase its cost.\n\nArtemisinin derivatives used in artemisinin-based combination therapy (ACT) are synthesized from artemisinin in one or two synthetic steps. Artemisinin is typically produced as an isolate from *Artemisia annua* L. Artemisinin complies with the definition of a \u201cstarting material\u201d, as defined above and described in certain national, regional and international guidelines. It is:", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento aborda las Buenas Pr\u00e1cticas de Manufactura (GMP) armonizadas para la producci\u00f3n de Ingredientes Farmac\u00e9uticos Activos (API). Se define el concepto de \"material de partida\" y se establece que este es un componente esencial en la producci\u00f3n de un API. El texto enfatiza que la designaci\u00f3n de un material de partida puede ser compleja y debe ser evaluada caso por caso, considerando la calidad y pureza del material en relaci\u00f3n con los costos de producci\u00f3n. Adem\u00e1s, se menciona el caso espec\u00edfico de los derivados de artemisinina, que se sintetizan a partir de la artemisinina, un material de partida que cumple con las definiciones establecidas.\n\n### Preguntas\n\n1. **\u00bfCu\u00e1les son los criterios que un fabricante debe considerar al designar un material de partida para la producci\u00f3n de un API?**\n   - La designaci\u00f3n de un material de partida debe considerar la cantidad de pasos entre el material de partida y el API final, la calidad del material, y la capacidad del proceso de manufactura para eliminar impurezas. Adem\u00e1s, el fabricante debe documentar y justificar su elecci\u00f3n.\n\n2. **\u00bfQu\u00e9 implicaciones tiene la elecci\u00f3n de un material de partida en el costo de producci\u00f3n de un API?**\n   - La elecci\u00f3n de un material de partida puede afectar significativamente el costo de producci\u00f3n. Un material de partida m\u00e1s puro puede requerir pasos de purificaci\u00f3n adicionales, lo que puede reducir el rendimiento del API final y aumentar los costos. Por lo tanto, es necesario encontrar un equilibrio entre la pureza del material y los costos asociados.\n\n3. **\u00bfC\u00f3mo se relaciona la artemisinina con las Buenas Pr\u00e1cticas de Manufactura y su uso en terapias combinadas?**\n   - La artemisinina es un material de partida que se utiliza en la s\u00edntesis de derivados de artemisinina para terapias combinadas basadas en artemisinina (ACT). Cumple con la definici\u00f3n de material de partida seg\u00fan las GMP, lo que implica que su producci\u00f3n y uso deben seguir las pautas establecidas para garantizar la calidad y eficacia del API resultante.", "prev_section_summary": "El contenido de la secci\u00f3n se refiere al \"WHO - Technical Report Series 970\", espec\u00edficamente al Informe 46 de esta serie. A continuaci\u00f3n se presentan los temas clave y entidades relevantes:\n\n### Temas Clave:\n1. **Hallazgos y Recomendaciones**: Se busca informaci\u00f3n sobre los principales hallazgos y recomendaciones del Informe 46, que son cruciales para entender su impacto en la salud p\u00fablica.\n2. **Metodolog\u00edas**: Se enfatiza la importancia de conocer las metodolog\u00edas utilizadas en el estudio o an\u00e1lisis presentado en el informe, lo que ayuda a evaluar la validez de los resultados.\n3. **Implicaciones para la Salud P\u00fablica**: Se exploran las posibles implicaciones de los resultados del informe en pol\u00edticas de salud p\u00fablica a nivel global.\n\n### Entidades:\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: La entidad responsable de la publicaci\u00f3n del informe y de la serie t\u00e9cnica.\n- **Informe 46**: El documento espec\u00edfico dentro de la serie que se est\u00e1 analizando.\n\n### Contexto General:\nEl informe forma parte de una serie m\u00e1s amplia que aborda temas de salud p\u00fablica y proporciona recomendaciones basadas en investigaciones y an\u00e1lisis, dirigidas a profesionales de la salud, investigadores y responsables de pol\u00edticas. \n\nEste resumen destaca la relevancia del Informe 46 en el contexto de la salud p\u00fablica global y la necesidad de comprender sus hallazgos y metodolog\u00edas.", "excerpt_keywords": "Keywords: Good Manufacturing Practices, active pharmaceutical ingredients, starting material, artemisinin, quality requirements"}}, "a63f6deb-a1f9-42fa-be71-f4868b604d80": {"node_ids": ["637a57ee-7d7a-4462-ab5c-8a76d1bffa0a"], "metadata": {"page_label": "244", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\n- a material used in the production of the API that is incorporated into the API as a significant structural element;\n- commercially available;\n- a compound whose name, chemical structure, chemical and physical characteristics, properties and impurity profile are well defined;\n- obtained by commonly known procedures.\n\nAs artemisinin is extracted from plant material and prior intermediates are thus not available, it is logical to designate this compound as the starting material for its derivatives.\n\nA monograph appears in *The International Pharmacopoeia* for artemisinin used as an API. However, at present, artemisinin is mainly used as a starting material for artemisinin-derived APIs, and not as an API.\n\nThe level of quality of the artemisinin should be acceptable for its intended use as the starting material for the production of artemisinin derivatives. The specifications presented below take into account an acceptable balance of benefit versus risk between the quality of artemisinin used as a starting material and the quality required for artemisinin derivatives for use as APIs.\n\nHowever, competent authorities may accept other impurity profile levels depending on the capability of the manufacturing process to lead to artemisinin-derived APIs at least compliant with the relevant monographs of *The International Pharmacopoeia*.\n\nThe purpose of this document is to offer a global approach to defining the level of quality requirements of artemisinin when used as a starting material for the production of its API derivatives used in ACT formulations. It does not apply to cases where artemisinin is used as an API. It is intended that the recommendations for requirements outlined in this document will apply to artemisinin extracted from *Artemisia annua* L. regardless of variations in agricultural environment or variations in extraction and purification steps. In addition, in order to ensure appropriate quality of the derived APIs, the manufacturer may add additional tests, such as tests for residual solvents and heavy metals, among others, and/or require tighter specifications. In the eventuality that artemisinin is produced using synthetic chemical processes or by fermentation, other requirements may be applicable.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Res\u00famenes de nivel superior del contexto:\n\n1. **Uso de Artemisinin**: Artemisinin es un compuesto extra\u00eddo de *Artemisia annua* L. que se utiliza principalmente como material de partida para la producci\u00f3n de APIs derivados, en lugar de ser utilizado directamente como un API. La calidad de artemisinin debe ser adecuada para su uso en la producci\u00f3n de estos derivados.\n\n2. **Especificaciones de Calidad**: El documento establece que las especificaciones de calidad para artemisinin como material de partida deben equilibrar los beneficios y riesgos, y que las autoridades competentes pueden aceptar diferentes niveles de perfil de impurezas seg\u00fan el proceso de fabricaci\u00f3n.\n\n3. **Recomendaciones Globales**: Se ofrecen recomendaciones globales sobre los requisitos de calidad de artemisinin, que deben aplicarse independientemente de las variaciones en el entorno agr\u00edcola o en los pasos de extracci\u00f3n y purificaci\u00f3n. Tambi\u00e9n se menciona que se pueden requerir pruebas adicionales para garantizar la calidad de los APIs derivados.\n\n### Preguntas espec\u00edficas:\n\n1. **\u00bfQu\u00e9 criterios se utilizan para definir la calidad aceptable de artemisinin como material de partida para la producci\u00f3n de APIs derivados?**\n   - Esta pregunta busca detalles sobre los criterios espec\u00edficos que se consideran al evaluar la calidad de artemisinin, que no se encuentran f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfQu\u00e9 implicaciones tiene el uso de artemisinin producido por procesos sint\u00e9ticos o fermentaci\u00f3n en los requisitos de calidad establecidos en el documento?**\n   - Esta pregunta se centra en las diferencias en los requisitos de calidad que pueden surgir dependiendo del m\u00e9todo de producci\u00f3n de artemisinin, un aspecto que puede no estar ampliamente discutido en otros documentos.\n\n3. **\u00bfQu\u00e9 tipo de pruebas adicionales pueden ser requeridas por los fabricantes para asegurar la calidad de los APIs derivados de artemisinin?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre las pruebas adicionales que los fabricantes pueden implementar, lo cual puede no estar detallado en otras fuentes relacionadas con la producci\u00f3n de APIs.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Buenas Pr\u00e1cticas de Manufactura (GMP)**:\n   - Se establecen requisitos para la producci\u00f3n de Ingredientes Farmac\u00e9uticos Activos (API).\n   - La aplicaci\u00f3n de estas pr\u00e1cticas comienza con la definici\u00f3n de un \"material de partida\".\n\n2. **Definici\u00f3n de Material de Partida**:\n   - Se describe como un material crudo, intermedio o un API que se incorpora como un fragmento estructural significativo en la producci\u00f3n del API.\n   - Puede ser un art\u00edculo comercial, material adquirido de proveedores o producido internamente.\n\n3. **Importancia de la Designaci\u00f3n del Material de Partida**:\n   - La designaci\u00f3n debe ser documentada y justificada por el fabricante.\n   - La elecci\u00f3n del material de partida afecta la calidad y el costo de producci\u00f3n del API.\n\n4. **Desaf\u00edos en la Designaci\u00f3n**:\n   - La complejidad de designar un material de partida se eval\u00faa caso por caso, considerando el n\u00famero de pasos entre el material de partida y el API final.\n   - Es necesario establecer requisitos de calidad bien definidos para asegurar que los APIs cumplan con las especificaciones.\n\n5. **Compromiso entre Pureza y Costo**:\n   - Se debe encontrar un equilibrio entre la pureza del material de partida y los costos de producci\u00f3n.\n   - Las impurezas pueden ser toleradas si el proceso de manufactura del API puede eliminarlas eficientemente.\n\n6. **Derivados de Artemisinina**:\n   - Se sintetizan a partir de artemisinina en uno o dos pasos sint\u00e9ticos.\n   - Artemisinina, obtenida de *Artemisia annua* L, cumple con la definici\u00f3n de material de partida seg\u00fan las GMP.\n\n### Entidades Clave\n- **Artemisinina**: Material de partida utilizado en la producci\u00f3n de derivados para terapias combinadas basadas en artemisinina (ACT).\n- **Ingredientes Farmac\u00e9uticos Activos (API)**: Sustancias utilizadas en la fabricaci\u00f3n de medicamentos.\n- **Artemisia annua**: Planta de la cual se a\u00edsla la artemisinina. \n\nEste resumen destaca la importancia de las GMP en la producci\u00f3n de APIs, la complejidad de la designaci\u00f3n de materiales de partida y el caso espec\u00edfico de la artemisinina en la producci\u00f3n de medicamentos.", "excerpt_keywords": "Artemisinin, API, quality specifications, starting material, pharmaceutical preparations"}}, "a3d6d309-605e-497a-ae17-c9ca1d8794d8": {"node_ids": ["80d8e6f1-5c4b-48c5-977a-ec8e66cc4723"], "metadata": {"page_label": "245", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 2. Characterization of artemisinin\n\nProvided that artemisinin intended for use as a starting material has been correctly identified, the major quality concern is the presence and level of impurities with the potential to affect the purity of subsequent API derivatives. Impurities may originate from the plant extracts or arise from the purification process or from degradation. Different biosynthetic routes may be used at different stages in the plant\u2019s development and there are claims of variability between growing regions and environments. Despite a lack of consensus on a single biosynthetic route, several potential impurities are common to different routes. These include artemisinic acid, dihydroartemisinic acid, arteannuin B and artemisitene. Of these only artemisitene has been reported in isolated artemisinin. Recent work (3, 4) has contributed towards a clearer understanding of existing impurities and their analysis.\n\nExamination of a wide variety of artemisinin samples produced in various regions indicated the consistent presence of two impurities: artemisitene and an artemisinin diastereomer with the stereochemistry inverted at C-9 (9-epi-artemisinin). A possible concern is that artemisinin impurities may not be detected with high-performance liquid chromatography analysis using ultraviolet detection, as used in the majority of testing laboratories. Recent work (5) using more sensitive general detection by mass spectrometry, however, demonstrated that additional impurities occur only in trace amounts. Isolated artemisinin is very stable. The potential degradants proposed on the basis of mechanistic studies do not occur at temperatures below 100 \u00b0C. These degradants are not observed in isolated artemisinin.\n\nIn the chemical conversion of the artemisinin starting material to its API derivatives (e.g. artesunate), the artemisinin diastereomeric impurity may be converted to a corresponding diastereomer at the C-9 position in the API derivative. However, these resulting diastereomers have not been observed in isolated APIs. The fate of artemisitene is less clear as it may be converted to the same intermediate as artemisinin.\n\nArtemisitene-derived impurities have not been observed in artemisinin derivative APIs. Proposed limits for these impurities are based on historical results. The specifications for artemisinin starting material are based on experience with artemether and artesunate. For a new artemisinin-derived API the suitability of the specifications to control potential impurities arising during its synthesis should be demonstrated.\n\nAs the artemisinin extraction processes use solvents like dichloromethane, chloroform, ether and others, residual solvents should be indicated on the certificate of analysis issued by the supplier.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl texto proporciona una caracterizaci\u00f3n de la artemisinina, un compuesto utilizado como material de partida para la producci\u00f3n de derivados farmac\u00e9uticos. Se discuten las preocupaciones sobre la calidad, espec\u00edficamente la presencia de impurezas que pueden afectar la pureza de los derivados de API (ingredientes farmac\u00e9uticos activos). Se mencionan varias impurezas comunes, como el \u00e1cido artemisinico y la dihidroartemisinina, y se destaca la importancia de la detecci\u00f3n de impurezas mediante t\u00e9cnicas anal\u00edticas adecuadas. Adem\u00e1s, se aborda la estabilidad de la artemisinina aislada y la necesidad de especificaciones adecuadas para controlar las impurezas durante la s\u00edntesis de nuevos derivados.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las impurezas m\u00e1s comunes encontradas en las muestras de artemisinina y c\u00f3mo pueden afectar la calidad de los derivados de API?**\n   - Respuesta: Las impurezas m\u00e1s comunes son el artemisitene y el diastere\u00f3mero 9-epi-artemisinin. Estas impurezas pueden afectar la pureza de los derivados de API, como el artesunato, y su detecci\u00f3n es crucial para garantizar la calidad del producto final.\n\n2. **\u00bfPor qu\u00e9 las t\u00e9cnicas de cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n con detecci\u00f3n ultravioleta pueden no ser suficientes para detectar impurezas en la artemisinina?**\n   - Respuesta: Estas t\u00e9cnicas pueden no detectar ciertas impurezas debido a su sensibilidad limitada. Se ha demostrado que el uso de espectrometr\u00eda de masas, que es m\u00e1s sensible, puede revelar impurezas adicionales que ocurren solo en cantidades traza.\n\n3. **\u00bfQu\u00e9 consideraciones deben tenerse en cuenta al establecer especificaciones para nuevos derivados de artemisinina en relaci\u00f3n con las impurezas?**\n   - Respuesta: Las especificaciones deben basarse en la experiencia con derivados existentes como el artemeter y el artesunato, y se debe demostrar que son adecuadas para controlar las impurezas potenciales que puedan surgir durante la s\u00edntesis de nuevos derivados. Adem\u00e1s, es importante indicar la presencia de solventes residuales en el certificado de an\u00e1lisis.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Uso de Artemisinin**:\n   - Artemisinin es un compuesto extra\u00eddo de la planta *Artemisia annua* L.\n   - Se utiliza principalmente como material de partida para la producci\u00f3n de APIs derivados, en lugar de ser un API en s\u00ed mismo.\n\n2. **Especificaciones de Calidad**:\n   - La calidad de artemisinin debe ser adecuada para su uso como material de partida en la producci\u00f3n de derivados.\n   - Se establece un equilibrio entre los beneficios y riesgos en las especificaciones de calidad.\n   - Las autoridades competentes pueden aceptar diferentes niveles de impurezas seg\u00fan el proceso de fabricaci\u00f3n.\n\n3. **Recomendaciones Globales**:\n   - Se ofrecen directrices sobre los requisitos de calidad que deben aplicarse independientemente de las variaciones en el entorno agr\u00edcola o en los m\u00e9todos de extracci\u00f3n y purificaci\u00f3n.\n   - Los fabricantes pueden implementar pruebas adicionales (como pruebas de solventes residuales y metales pesados) para asegurar la calidad de los APIs derivados.\n\n4. **Producci\u00f3n Sint\u00e9tica y Fermentaci\u00f3n**:\n   - Si artemisinin se produce mediante procesos sint\u00e9ticos o fermentaci\u00f3n, pueden aplicarse requisitos de calidad diferentes.\n\n### Entidades Clave:\n- **Artemisinin**: Compuesto activo utilizado como material de partida.\n- ***Artemisia annua* L.**: Planta de la cual se extrae artemisinin.\n- **APIs (Active Pharmaceutical Ingredients)**: Ingredientes farmac\u00e9uticos activos derivados de artemisinin.\n- ***The International Pharmacopoeia***: Referencia que contiene monograf\u00edas sobre la calidad de artemisinin y sus derivados.\n- **Autoridades Competentes**: Entidades que regulan y aceptan diferentes niveles de calidad e impurezas en la producci\u00f3n de APIs.", "excerpt_keywords": "Keywords: artemisinin, impurities, API derivatives, quality control, extraction solvents"}}, "726f3590-fa0f-477b-9f27-aa8fd6c6d2f9": {"node_ids": ["c3b7e3a8-8b1f-4e13-89a9-b22003e01a01"], "metadata": {"page_label": "246", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# 3. Tests and specifications for artemisinin starting material\n\n!Chemical Structure\n\n**Relative molecular mass:** 282.3\n\n**Chemical name:**  \n(3R,5aS,6R,8aS,9R,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one; CAS Reg. No. 63968-64-9.\n\n**Description:**  \nColourless needles or a white to almost white to slightly yellow, crystalline powder.\n\n**Category:**  \nStarting material for the synthesis of artemisinin derivative APIs.\n\n**Storage:**  \nArtemisinin should be kept in a well-closed container, protected from light.\n\n## Requirements\n\nArtemisinin contains not less than 95.0% and not more than the equivalent of 102.0% of C\u2081\u2085H\u2082\u2082O\u2085 calculated with reference to the dried substance.\n\n## Identity tests\n\nCarry out the examination as described under 1.7 \"Spectrophotometry in the infrared region\" of *The International Pharmacopoeia* (6). The infrared absorption spectrum is concordant with the spectrum obtained from artemisinin RS or with the reference spectrum of artemisinin in *The International Pharmacopoeia*.\n\n**Specific optical rotation:**  \nUse a 10 mg/ml solution in dehydrated ethanol R;  \n\\[\u03b1\\]\u2082\u2080\u00b0C\\_D = 75\u00b0 to + 78\u00b0\n\n**Loss on drying:**  \nDry to constant mass at 80 \u00b0C; it loses not more than 10.0 mg/g.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del contexto\n\nEl documento proporciona especificaciones y pruebas para el material inicial de artemisinina, un compuesto qu\u00edmico utilizado en la s\u00edntesis de APIs derivados de artemisinina. Se detalla la estructura qu\u00edmica, el nombre, la masa molecular relativa, la descripci\u00f3n f\u00edsica, las condiciones de almacenamiento y los requisitos de pureza. Adem\u00e1s, se incluyen pruebas de identidad, como la espectrofotometr\u00eda en el infrarrojo y la rotaci\u00f3n \u00f3ptica espec\u00edfica, as\u00ed como el an\u00e1lisis de p\u00e9rdida por secado.\n\n### Preguntas espec\u00edficas\n\n1. **\u00bfCu\u00e1l es la importancia de la pureza del material inicial de artemisinina y qu\u00e9 porcentaje se requiere seg\u00fan las especificaciones?**\n   - La pureza del material inicial de artemisinina es crucial para garantizar la eficacia y seguridad de los derivados de artemisinina en aplicaciones farmac\u00e9uticas. Seg\u00fan las especificaciones, la artemisinina debe contener no menos del 95.0% y no m\u00e1s del equivalente al 102.0% de C\u2081\u2085H\u2082\u2082O\u2085, calculado con referencia a la sustancia seca.\n\n2. **\u00bfQu\u00e9 m\u00e9todo se utiliza para verificar la identidad de la artemisinina y qu\u00e9 caracter\u00edsticas se buscan en el espectro?**\n   - Para verificar la identidad de la artemisinina, se utiliza la espectrofotometr\u00eda en el infrarrojo, como se describe en la *Farmacopea Internacional*. Se busca que el espectro de absorci\u00f3n infrarroja sea concordante con el espectro obtenido de artemisinina de referencia (RS) o con el espectro de referencia de artemisinina en la misma farmacopea.\n\n3. **\u00bfQu\u00e9 condiciones de almacenamiento se recomiendan para la artemisinina y por qu\u00e9 son importantes?**\n   - Se recomienda almacenar la artemisinina en un recipiente bien cerrado y protegido de la luz. Estas condiciones son importantes para prevenir la degradaci\u00f3n del compuesto, lo que podr\u00eda afectar su eficacia y estabilidad en aplicaciones farmac\u00e9uticas.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Artemisinina**: Compuesto utilizado como material de partida para la producci\u00f3n de derivados farmac\u00e9uticos (API).\n\n2. **Calidad y Pureza**: La principal preocupaci\u00f3n es la presencia y nivel de impurezas que pueden afectar la pureza de los derivados de API.\n\n3. **Impuridades Comunes**: \n   - **Artemisinic acid**\n   - **Dihydroartemisinic acid**\n   - **Arteannuin B**\n   - **Artemisitene**: Solo se ha reportado en artemisinina aislada.\n   - **9-epi-artemisinin**: Un diastere\u00f3mero de artemisinina con la estereoisomer\u00eda invertida en C-9.\n\n4. **T\u00e9cnicas de Detecci\u00f3n**: \n   - **Cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n (HPLC)**: Puede no ser suficiente para detectar impurezas debido a su sensibilidad limitada.\n   - **Espectrometr\u00eda de masas**: Se ha demostrado que es m\u00e1s sensible y puede detectar impurezas adicionales en cantidades traza.\n\n5. **Estabilidad de la Artemisinina**: La artemisinina aislada es muy estable y no presenta degradantes a temperaturas inferiores a 100 \u00b0C.\n\n6. **Conversi\u00f3n Qu\u00edmica**: Durante la conversi\u00f3n de artemisinina a sus derivados (ej. artesunato), las impurezas diastereom\u00e9ricas pueden convertirse en diastere\u00f3meros correspondientes, aunque no se han observado en APIs aislados.\n\n7. **Especificaciones para Nuevos Derivados**: Las especificaciones deben basarse en la experiencia con derivados existentes (como artemeter y artesunato) y demostrar su adecuaci\u00f3n para controlar impurezas potenciales.\n\n8. **Solventes Residuales**: Los procesos de extracci\u00f3n de artemisinina utilizan solventes como diclorometano, cloroformo y \u00e9ter, y se debe indicar la presencia de solventes residuales en el certificado de an\u00e1lisis.\n\n### Entidades Clave\n- **Artemisinina**\n- **API (Ingredientes Farmac\u00e9uticos Activos)**\n- **Artemisinic acid**\n- **Dihydroartemisinic acid**\n- **Arteannuin B**\n- **Artemisitene**\n- **9-epi-artemisinin**\n- **Artemether**\n- **Artesunate**\n- **Cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n (HPLC)**\n- **Espectrometr\u00eda de masas**", "excerpt_keywords": "Keywords: artemisinin, specifications, identity tests, purity, pharmacopoeia"}}, "d03945a3-f4b2-4406-8e21-381ba7d3f88e": {"node_ids": ["1bf2d69c-3df6-4190-838f-d930b354c86c"], "metadata": {"page_label": "247", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# Related Substances\n\n*Note:* It may be possible to justify other limits when artemisinin as a starting material is used in a particular synthesis and manufacturing process, by validation of the levels and limits of the impurities in the final API.\n\nCarry out the test as described under 1.14.4 \u201cHigh performance liquid chromatography\u201d of *The International Pharmacopoeia* (6). Use the chromatographic conditions and prepare solutions (1) and (2) as described below under Assay. For solution (3) dilute 1 ml of solution (1) to 100 ml with the mobile phase.\n\nInject separately 20 \u03bcl of solutions (1), (2) and (3). Record the chromatograms for about 1.5 times the retention time of artemisinin. In the chromatogram obtained with solution (2), artemisitene (impurity A) is eluted at the relative retention of about 0.79 with reference to artemisinin (retention time about 10 minutes). The test is not valid unless the resolution between the peak of artemisitene and the peak of artemisinin is at least 4. The chromatogram obtained with solution (1) may show a peak due to impurity B eluting at a retention of about 0.85 with reference to artemisinin.\n\nIn the chromatogram obtained with solution (1):\n\n- the area of any peak corresponding to impurity A, when multiplied by a correction factor of 0.027 is not greater than 0.15 times the area of the peak in the chromatogram obtained with solution (3) (0.2%);\n- the area of any peak corresponding to impurity B is not greater than the area of the peak in the chromatogram obtained with solution (3) (1.0%);\n- the area of any peak other than the principal peak is not greater than 0.5 times the area of the peak in the chromatogram obtained with solution (3) (0.5%);\n- the sum of the corrected area of any peak corresponding to impurity A and the areas of all the peaks, apart from the principal peak, is not greater than 3 times the area of the peak obtained with solution (3) (3.0%). Disregard any peak with an area less than 0.1 times the area of the principal peak obtained with solution (3) (0.1%).\n\n# Assay\n\nCarry out the test as described under 1.14.4 \u201cHigh performance liquid chromatography\u201d of *The International Pharmacopoeia* (6), using a stainless steel column (15 cm \u00d7 4.6 mm) packed with 5 \u03bcm particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups. The", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas espec\u00edficas basadas en el contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento de la OMS detalla un procedimiento para la prueba de sustancias relacionadas con la artemisinina utilizando cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n (HPLC). Se describen las condiciones de la prueba, la preparaci\u00f3n de soluciones y los criterios de aceptaci\u00f3n para las impurezas A y B. Se enfatiza la importancia de la resoluci\u00f3n entre los picos de las impurezas y el principio activo, as\u00ed como los l\u00edmites espec\u00edficos para las \u00e1reas de los picos en los cromatogramas obtenidos.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son los criterios de aceptaci\u00f3n para las \u00e1reas de los picos correspondientes a las impurezas A y B en el cromatograma obtenido con la soluci\u00f3n (1)?**\n   - La pregunta se centra en los l\u00edmites espec\u00edficos establecidos para las impurezas, que son cruciales para validar la calidad del producto.\n\n2. **\u00bfQu\u00e9 condiciones cromatogr\u00e1ficas se deben utilizar para llevar a cabo la prueba de HPLC seg\u00fan el documento de la OMS?**\n   - Esta pregunta busca detalles sobre el equipo y las condiciones necesarias para realizar la prueba, que son esenciales para replicar el procedimiento.\n\n3. **\u00bfPor qu\u00e9 es importante la resoluci\u00f3n entre el pico de artemisitene y el pico de artemisinina en el an\u00e1lisis cromatogr\u00e1fico?**\n   - Esta pregunta aborda la relevancia de la resoluci\u00f3n en el contexto de la validaci\u00f3n del m\u00e9todo anal\u00edtico, lo que es fundamental para asegurar la precisi\u00f3n de los resultados obtenidos.", "prev_section_summary": "### Resumen de temas clave y entidades\n\n1. **Artemisinina**:\n   - **Nombre qu\u00edmico**: (3R,5aS,6R,8aS,9R,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one.\n   - **N\u00famero CAS**: 63968-64-9.\n   - **Masa molecular relativa**: 282.3.\n\n2. **Descripci\u00f3n f\u00edsica**:\n   - Presenta forma de agujas incoloras o un polvo cristalino blanco a casi blanco, ligeramente amarillo.\n\n3. **Categor\u00eda**:\n   - Material inicial para la s\u00edntesis de APIs derivados de artemisinina.\n\n4. **Almacenamiento**:\n   - Debe guardarse en un recipiente bien cerrado y protegido de la luz para evitar degradaci\u00f3n.\n\n5. **Requisitos de pureza**:\n   - Contenido de artemisinina: no menos del 95.0% y no m\u00e1s del equivalente al 102.0% de C\u2081\u2085H\u2082\u2082O\u2085, calculado con referencia a la sustancia seca.\n\n6. **Pruebas de identidad**:\n   - **Espectrofotometr\u00eda en el infrarrojo**: El espectro de absorci\u00f3n debe concordar con el espectro de referencia de artemisinina.\n   - **Rotaci\u00f3n \u00f3ptica espec\u00edfica**: Se utiliza una soluci\u00f3n de 10 mg/ml en etanol deshidratado; el rango es de 75\u00b0 a +78\u00b0.\n   - **P\u00e9rdida por secado**: No debe exceder 10.0 mg/g al secar a 80 \u00b0C hasta masa constante.\n\n### Entidades clave\n- **Artemisinina**: Compuesto qu\u00edmico utilizado en la s\u00edntesis de medicamentos.\n- **CAS Reg. No.**: Identificador \u00fanico para sustancias qu\u00edmicas.\n- **Espectrofotometr\u00eda**: M\u00e9todo anal\u00edtico para verificar la identidad del compuesto.\n- **Farmacopea Internacional**: Referencia para est\u00e1ndares y m\u00e9todos en farmacolog\u00eda.", "excerpt_keywords": "Keywords: artemisinin, high performance liquid chromatography, impurities, chromatogram, International Pharmacopoeia"}}, "8f0696c5-1b32-41fe-82b5-962e3f66a853": {"node_ids": ["768c2ff4-8f90-40b6-9eff-dbf956fe24dd"], "metadata": {"page_label": "248", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# WHO Expert Committee on Specifications for Pharmaceutical Preparations\n\nThe mobile phase consists of a 50:50 mixture of acetonitrile and water, pumped at a flow rate of 1.0 ml/minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 210 nm.\n\nPrepare the following solutions. For solution (1) prepare a 5.0 mg/ml solution of the test substance in the mobile phase. For solution (2) prepare a 5.0 mg/ml solution of artemisinin RS in the mobile phase.\n\nInject separately 20 \u03bcl of solutions (1) and (2). Record the chromatograms for about 1.5 times the retention time of artemisinin. In the chromatogram obtained with solution (2), artemisitene (impurity A) is eluted at the relative retention of 0.79 with reference to artemisinin (retention time about 10 minutes). The test is not valid unless the resolution between the peak of artemisitene and the peak of artemisinin is at least 4. The chromatogram obtained with solution (1) may show a peak due to impurity B eluting at a retention of about 0.85 with reference to artemisinin.\n\nMeasure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2), and calculate the content of C\u2081\u2085H\u2082\u2082O\u2085 with reference to the dried substance.\n\n## Impurities\n\n!Chemical Structure\n\n(3R,5aS,6R,8aS,12S,12aR)-3,6-dimethyl-9-methyleneoctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one (artemisitene)\n\n!Chemical Structure\n\n(3R,5aS,6R,8aS,9S,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one (9-epi-artemisinin)", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento se centra en un procedimiento anal\u00edtico para evaluar la pureza de artemisinin y sus impurezas mediante cromatograf\u00eda. Se describe la preparaci\u00f3n de soluciones, el uso de un espectrofot\u00f3metro UV, y los criterios de validez del test, incluyendo la resoluci\u00f3n entre picos en el cromatograma. Se mencionan dos impurezas espec\u00edficas, artemisitene y 9-epi-artemisinin, junto con sus estructuras qu\u00edmicas.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1l es la importancia de la resoluci\u00f3n m\u00ednima de 4 entre los picos de artemisitene y artemisinin en el an\u00e1lisis cromatogr\u00e1fico?**\n   - La resoluci\u00f3n m\u00ednima de 4 es crucial para asegurar que los picos de artemisitene y artemisinin se separen adecuadamente, lo que permite una identificaci\u00f3n y cuantificaci\u00f3n precisas de las sustancias en la muestra. Si la resoluci\u00f3n es menor, puede haber interferencias que afecten la validez del an\u00e1lisis.\n\n2. **\u00bfQu\u00e9 pasos deben seguirse si la cromatograf\u00eda muestra una resoluci\u00f3n menor a 4 entre los picos de artemisitene y artemisinin?**\n   - Si la resoluci\u00f3n es menor a 4, el test no es v\u00e1lido. Se deben revisar las condiciones del experimento, como la preparaci\u00f3n de las soluciones, el flujo del m\u00f3vil, y la calibraci\u00f3n del espectrofot\u00f3metro. Puede ser necesario ajustar la composici\u00f3n de la fase m\u00f3vil o el tiempo de inyecci\u00f3n para mejorar la separaci\u00f3n.\n\n3. **\u00bfC\u00f3mo se calcula el contenido de C\u2081\u2085H\u2082\u2082O\u2085 a partir de las \u00e1reas de los picos en los cromatogramas?**\n   - El contenido de C\u2081\u2085H\u2082\u2082O\u2085 se calcula utilizando las \u00e1reas de los picos obtenidos de las soluciones (1) y (2). Se puede aplicar una f\u00f3rmula que relaciona las \u00e1reas de los picos con las concentraciones conocidas de artemisinin y el test substance, permitiendo determinar la cantidad de C\u2081\u2085H\u2082\u2082O\u2085 en la muestra analizada.\n\n### Resumen de Nivel Superior\n\nEl documento proporciona un protocolo detallado para la evaluaci\u00f3n de la pureza de artemisinin mediante cromatograf\u00eda, enfatizando la importancia de la resoluci\u00f3n entre picos para validar los resultados. Se describen las preparaciones de soluciones y el uso de un espectrofot\u00f3metro UV, as\u00ed como la identificaci\u00f3n de impurezas espec\u00edficas. Este procedimiento es fundamental para asegurar la calidad y eficacia de productos farmac\u00e9uticos que contienen artemisinin.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Sustancias Relacionadas**: El documento se centra en la evaluaci\u00f3n de impurezas relacionadas con la artemisinina, un compuesto activo importante en tratamientos m\u00e9dicos.\n\n2. **Cromatograf\u00eda L\u00edquida de Alta Resoluci\u00f3n (HPLC)**: Se describe el procedimiento para llevar a cabo pruebas de HPLC, incluyendo la preparaci\u00f3n de soluciones y las condiciones cromatogr\u00e1ficas necesarias.\n\n3. **Criterios de Aceptaci\u00f3n**: Se establecen l\u00edmites espec\u00edficos para las \u00e1reas de los picos correspondientes a las impurezas A (artemisitene) y B, as\u00ed como otros picos en el cromatograma. Estos criterios son esenciales para validar la calidad del producto.\n\n4. **Resoluci\u00f3n de Picos**: Se enfatiza la importancia de la resoluci\u00f3n entre los picos de artemisitene y artemisinina, que debe ser al menos 4 para que la prueba sea v\u00e1lida.\n\n5. **Preparaci\u00f3n de Soluciones**: Se indican las instrucciones para preparar las soluciones necesarias para el an\u00e1lisis, incluyendo la diluci\u00f3n de la soluci\u00f3n (1) para obtener la soluci\u00f3n (3).\n\n6. **Condiciones Cromatogr\u00e1ficas**: Se especifica el uso de una columna de acero inoxidable con caracter\u00edsticas particulares para realizar el an\u00e1lisis.\n\n### Entidades Clave\n\n- **Artemisinina**: Compuesto activo en el an\u00e1lisis.\n- **Artemisitene (Impureza A)**: Impureza espec\u00edfica que se eval\u00faa en el an\u00e1lisis.\n- **Impureza B**: Otra impureza que se menciona en el procedimiento.\n- **HPLC**: T\u00e9cnica anal\u00edtica utilizada para la evaluaci\u00f3n de impurezas.\n- **Cromatograma**: Resultado visual del an\u00e1lisis que se eval\u00faa seg\u00fan criterios espec\u00edficos.\n\nEste resumen proporciona una visi\u00f3n general de los aspectos m\u00e1s relevantes del procedimiento anal\u00edtico descrito en el documento de la OMS.", "excerpt_keywords": "Keywords: artemisinin, chromatography, impurities, HPLC, resolution"}}, "542cd442-db1e-4e4a-8009-dd5c5d9cb7d5": {"node_ids": ["84f1f4aa-64a1-4cbe-9a9e-8775c5924be7"], "metadata": {"page_label": "249", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "# References\n\n1. WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth Report. Geneva, World Health Organization, 2010, Annex 2 (WHO Technical Report Series, No. 957).\n\n2. International Conference on Harmonisation (ICH) Topic Q7: Note for guidance on good manufacturing practice for active pharmaceutical ingredients. London, EMEA, 2006 (CPMP/ICH/4106/00); http://www.ema.europa.eu/pdfs/human/ich/410600en.pdf\n\n3. Lapkin AA et al. Development of HPLC analytical protocols for quantification of artemisinin in biomass and extracts. *Journal of Pharmaceutical and Biomedical Analysis*, 2009, 49: 908\u2013915.\n\n4. Stringham RW et al. High performance liquid chromatographic evaluation of artemisinin, raw material in the synthesis of artesunate and artemether. *Journal of Chromatography A*, 2009, 1216: 8918\u20138925.\n\n5. Stringham RW et al. Verification of the identities of impurities in artemisinin and correction of their elution order in high performance liquid chromatography. *Journal of Chromatography A*, 2011, 1218: 6838\u20136842.\n\n6. *The International Pharmacopoeia*, 4th ed., Vol. 1: General notices; monographs for pharmaceutical substances (A\u2013O) and Vol. 2: Monographs for pharmaceutical substances (P\u2013Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents. Geneva, World Health Organization, 2006, also available in CD-ROM format and online.\n\n   - *The International Pharmacopoeia*, 4th ed., First and Second supplements, 2011, available on CD-ROM.", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "### Resumen del Contexto\n\nEl documento es un informe de la Organizaci\u00f3n Mundial de la Salud (OMS) que forma parte de la Serie de Informes T\u00e9cnicos (No. 970). En la secci\u00f3n de referencias, se citan diversas fuentes relacionadas con las buenas pr\u00e1cticas de fabricaci\u00f3n de ingredientes farmac\u00e9uticos activos, as\u00ed como estudios espec\u00edficos sobre la artemisinina, un compuesto utilizado en tratamientos contra la malaria. Se mencionan gu\u00edas de la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) y se hace referencia a la Farmacopea Internacional, que proporciona monograf\u00edas y m\u00e9todos de an\u00e1lisis para sustancias farmac\u00e9uticas.\n\n### Preguntas Espec\u00edficas\n\n1. **\u00bfCu\u00e1les son las principales recomendaciones de la OMS sobre las buenas pr\u00e1cticas de fabricaci\u00f3n para los ingredientes farmac\u00e9uticos activos seg\u00fan el informe mencionado?**\n   - Esta pregunta busca detalles espec\u00edficos sobre las directrices de la OMS que no se encuentran f\u00e1cilmente en otras fuentes.\n\n2. **\u00bfQu\u00e9 metodolog\u00edas anal\u00edticas se han desarrollado para la cuantificaci\u00f3n de artemisinina en biomasa y extractos, seg\u00fan el estudio de Lapkin et al.?**\n   - Esta pregunta se centra en los m\u00e9todos espec\u00edficos utilizados en la investigaci\u00f3n, que pueden no estar ampliamente documentados en otras publicaciones.\n\n3. **\u00bfC\u00f3mo se verificaron las identidades de las impurezas en artemisinina y cu\u00e1l fue la correcci\u00f3n realizada en su orden de eluci\u00f3n en cromatograf\u00eda l\u00edquida de alta resoluci\u00f3n, seg\u00fan el estudio de Stringham et al.?**\n   - Esta pregunta busca informaci\u00f3n t\u00e9cnica detallada sobre un aspecto espec\u00edfico de la investigaci\u00f3n que podr\u00eda no estar disponible en otras fuentes.\n\nEstas preguntas est\u00e1n dise\u00f1adas para extraer informaci\u00f3n t\u00e9cnica y espec\u00edfica que el documento proporciona, lo que puede ser \u00fatil para investigadores o profesionales en el campo farmac\u00e9utico.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n**Tema Principal:**\nEl documento describe un procedimiento anal\u00edtico para evaluar la pureza de artemisinin y sus impurezas mediante cromatograf\u00eda, destacando la importancia de la resoluci\u00f3n entre picos en el cromatograma.\n\n**M\u00e9todo Anal\u00edtico:**\n- **Fase M\u00f3vil:** Mezcla 50:50 de acetonitrilo y agua, con un flujo de 1.0 ml/min.\n- **Detector:** Espectrofot\u00f3metro UV a 210 nm.\n- **Preparaci\u00f3n de Soluciones:**\n  - **Soluci\u00f3n (1):** 5.0 mg/ml del test substance en la fase m\u00f3vil.\n  - **Soluci\u00f3n (2):** 5.0 mg/ml de artemisinin RS en la fase m\u00f3vil.\n- **Inyecci\u00f3n:** 20 \u03bcl de cada soluci\u00f3n.\n- **Registro de Cromatogramas:** Durante aproximadamente 1.5 veces el tiempo de retenci\u00f3n de artemisinin.\n\n**Criterios de Validez:**\n- La resoluci\u00f3n m\u00ednima entre los picos de artemisitene (impureza A) y artemisinin debe ser al menos 4 para que el test sea v\u00e1lido.\n\n**Implicaciones de Resultados:**\n- **C\u00e1lculo del Contenido:** Se mide el \u00e1rea de los picos en los cromatogramas para calcular el contenido de C\u2081\u2085H\u2082\u2082O\u2085 en la muestra.\n\n**Impurezas Identificadas:**\n1. **Artemisitene:** (3R,5aS,6R,8aS,12S,12aR)-3,6-dimethyl-9-methyleneoctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one.\n2. **9-epi-artemisinin:** (3R,5aS,6R,8aS,9S,12S,12aR)-3,6,9-trimethyloctahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one.\n\n### Entidades Clave:\n- **Compuestos Qu\u00edmicos:** Artemisinin, artemisitene, 9-epi-artemisinin.\n- **T\u00e9cnicas Anal\u00edticas:** Cromatograf\u00eda, espectrofotometr\u00eda UV.\n- **Par\u00e1metros de An\u00e1lisis:** Resoluci\u00f3n, tiempo de retenci\u00f3n, \u00e1reas de picos. \n\nEste resumen proporciona una visi\u00f3n general de los procedimientos y criterios establecidos para la evaluaci\u00f3n de la pureza de artemisinin, as\u00ed como las impurezas relevantes que se deben considerar en el an\u00e1lisis.", "excerpt_keywords": "Keywords: artemisinin, good manufacturing practices, high performance liquid chromatography, pharmaceutical analysis, WHO Technical Report Series"}}, "6c427f0d-c8b2-4d31-b46b-a2b9f837d792": {"node_ids": ["744b6c3d-2862-4873-abb9-924297879f9d"], "metadata": {"page_label": "250", "file_name": "WHO_TRS_970_REPORTE 46.pdf", "file_path": "raw_data/WHO_TRS_970_REPORTE 46.pdf", "image_path": "", "parsed_text_markdown": "NO_CONTENT_HERE", "parsed_text": "", "document_title": "WHO - Technical Report Series 970", "questions_this_excerpt_can_answer": "Aqu\u00ed tienes tres preguntas que podr\u00edan derivarse del contexto proporcionado, junto con un resumen de nivel superior:\n\n### Resumen de Nivel Superior\nEl documento mencionado es el \"WHO - Technical Report Series 970\", que forma parte de una serie de informes t\u00e9cnicos publicados por la Organizaci\u00f3n Mundial de la Salud (OMS). Estos informes suelen abordar temas de salud p\u00fablica, investigaci\u00f3n m\u00e9dica y recomendaciones para la pr\u00e1ctica cl\u00ednica y la pol\u00edtica de salud. Aunque el contenido espec\u00edfico del informe no est\u00e1 disponible en el contexto proporcionado, es probable que contenga informaci\u00f3n relevante sobre temas de salud global, directrices para la investigaci\u00f3n y an\u00e1lisis de datos epidemiol\u00f3gicos.\n\n### Preguntas\n1. **\u00bfCu\u00e1les son los principales hallazgos o recomendaciones presentados en el informe WHO - Technical Report Series 970?**\n   - Esta pregunta busca informaci\u00f3n espec\u00edfica sobre el contenido del informe que no se puede encontrar en otros documentos.\n\n2. **\u00bfQu\u00e9 temas de salud p\u00fablica se abordan en el informe y c\u00f3mo se relacionan con las tendencias actuales en la salud global?**\n   - Esta pregunta se centra en la relevancia del informe en el contexto de la salud p\u00fablica contempor\u00e1nea, lo que podr\u00eda no estar documentado en otras fuentes.\n\n3. **\u00bfQu\u00e9 metodolog\u00edas de investigaci\u00f3n se utilizan en el informe para abordar los problemas de salud discutidos?**\n   - Esta pregunta indaga sobre las t\u00e9cnicas y enfoques de investigaci\u00f3n que se presentan en el informe, lo que podr\u00eda ser \u00fanico a este documento y no estar disponible en otros lugares.", "prev_section_summary": "### Resumen de Temas Clave y Entidades\n\n1. **Buenas Pr\u00e1cticas de Fabricaci\u00f3n (BPF)**:\n   - Se citan directrices de la OMS sobre BPF para ingredientes farmac\u00e9uticos activos, destacando la importancia de seguir est\u00e1ndares de calidad en la producci\u00f3n.\n\n2. **Artemisinina**:\n   - Se mencionan estudios sobre la artemisinina, un compuesto crucial en el tratamiento de la malaria, incluyendo metodolog\u00edas anal\u00edticas para su cuantificaci\u00f3n en biomasa y extractos.\n\n3. **Cromatograf\u00eda L\u00edquida de Alta Resoluci\u00f3n (HPLC)**:\n   - Se discuten evaluaciones y correcciones relacionadas con la identificaci\u00f3n de impurezas en artemisinina, as\u00ed como su orden de eluci\u00f3n en HPLC.\n\n4. **Referencias Normativas**:\n   - Se hace referencia a la Conferencia Internacional sobre Armonizaci\u00f3n (ICH) y a la Farmacopea Internacional, que proporcionan marcos normativos y metodolog\u00edas para el an\u00e1lisis de sustancias farmac\u00e9uticas.\n\n5. **Publicaciones Cient\u00edficas**:\n   - Se citan varios art\u00edculos de revistas cient\u00edficas que abordan el desarrollo de protocolos anal\u00edticos y evaluaciones de la artemisinina, contribuyendo al conocimiento en el campo farmac\u00e9utico.\n\n### Entidades Clave\n- **Organizaci\u00f3n Mundial de la Salud (OMS)**: Autoridad en la regulaci\u00f3n de pr\u00e1cticas de fabricaci\u00f3n farmac\u00e9utica.\n- **Conferencia Internacional sobre Armonizaci\u00f3n (ICH)**: Entidad que establece gu\u00edas para la BPF.\n- **Lapkin AA**: Autor de un estudio sobre la cuantificaci\u00f3n de artemisinina.\n- **Stringham RW**: Autor de estudios sobre la evaluaci\u00f3n y verificaci\u00f3n de impurezas en artemisinina.\n- **Farmacopea Internacional**: Publicaci\u00f3n que contiene monograf\u00edas y m\u00e9todos de an\u00e1lisis para sustancias farmac\u00e9uticas. \n\nEste resumen destaca la relevancia de las buenas pr\u00e1cticas en la fabricaci\u00f3n de ingredientes farmac\u00e9uticos, as\u00ed como la investigaci\u00f3n relacionada con la artemisinina, un compuesto vital en la lucha contra la malaria.", "excerpt_keywords": "Keywords: OMS, artemisinina, buenas pr\u00e1cticas de fabricaci\u00f3n, cromatograf\u00eda l\u00edquida, salud p\u00fablica"}}}}
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