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The concentration system should be operated under aseptic conditions to maintain the sterility of the rhCollagen. Lab scale followed by pilot scale systems will be tested and compared. |
The various options will be evaluated based on the following criteria: • rhCollagen final concentration of 50 mg/ml • rhCollagen integrity • Scalability • Equipment and process suitability for aseptic processing. • Process efficiency |
Successful Outcome: • a selected system for further optimization • Meet specifications set in Exhibit E.2 • 10g of 50mg/ml post Work Package 2 rhCollagen • Critical Material Attributes report |
Work Package III: Process optimization The selected system will be further optimized including but not limited to: • Flow rate • Temperature • Pressure • Equipment sterilization • Aseptic processing |
Successful Outcome: • Scalable process to hundreds gr/batch at a recovery of at least 75% of intact 50 mg/ml rhCollagen • 50 mg/ml rhCollagen solution that meet the specifications set in Exhibit E.2. • Stability study on one batch will be initiated to set a provisional shelf life |
Work Package IV: Scale-up The scaled-up process equipment and clean environment set-up defined in the optimization phase will be purchased and installed. The equipment, methods and utilities will be validated (IQ/OQ) 2-3 engineering runs will be conducted to ensure the technical performance of the equipment and the ase... |
Successful Outcome: • Scaled up process ready for validation • Meet specifications set in Exhibit E.2 |
Work Package V: Process validation 3 PQ runs will be performed to validate the process and the product according to the specifications set in Exhibit E.2. The 3 batches will be tested for stability to set the shelf life of the 50 mg/ml sterile rhCollagen solution |
Successful Outcome: • Validated process and product meet specifications set in Exhibit E.2 • Shelf life of 12 months on one optimization batch (Work Package III). |
After completion of each package, samples of at least one batch will be provided by CollPlant to AbbVie for testing .in final formulation. |
Exhibit D Lyophilized Low Bioburden Project Development Plan |
Objective: The objective of this plan is to develop a scalable process for low bioburden, lyophilized rhCollagen. Timeline and budget will be added after AbbVie's approval to the plan. |
Source Material: Sterile rhCollagen, 3-20 mg/ml (TBD) in 1mM HCL or acetic acid (TBD) will serve as source material for lyophilization. |
Work Package I: Develop lyophilization cycle for concentrated rhCollagen. Sterile rhCollagen, 3-20mg/ml (TBD) will be the source for lyophilization. Lyophilization cycle will be developed and characterization of the lyophilized product will be determined. |
Successful Outcome: • Lyophilization cycle for concentrated rhCollagen and reconstitution protocol. Characterization of product • 10g of post Work Package 1 lyophilized rhCollagen • Critical Material Attributes report |
Work Package II: low bioburden lyophilized rhCollagen This Work Package will be done with the support of a sterilization expert consultant, Dr. Robert Tomaselli. A process will be designed including: 1. Filling of sterile concentrated rhCollagen into sterile Lyoguard tray 2. Lyophilization of the material based on the ... |
Successful Outcome: • A process for achieving a low bioburden lyophilized rhCollagen • Meet specifications set in Exhibit E.3 |
Work Package III: Process optimization The selected process design will be further optimized including but not limited to: • Concentration of starting material • Filling of Lyoguard trays • Lyophilization cycle • Reconstitution method |
Successful Outcome: • Scalable process to hundreds gr/batch at a recovery of at least 80% of collagen content. • Low bioburden, lyophilized rhCollagen solution that meet the specifications set in Exhibit E.3. • Stability study on one batch will be initiated to set a provisional shelf life |
Work Package IV: Scale-up The scaled-up process equipment and clean environment set-up defined in the optimization phase will be purchased and installed. The equipment, methods and utilities will be validated (IQ/OQ) 2-3 engineering runs will be conducted to ensure the technical performance of the equipment and the ase... |
Successful Outcome: • Scaled up process ready for validation • Meet specifications set in Exhibit E.3 |
Work Package V: Process validation 3 PQ runs will be performed to validate the process and the product according to the specifications set in Exhibit E.3 (concentration TBD). The 3 batches will be tested for stability to set the shelf life of the lyophilized, low bioburden rhCollagen solution |
Successful Outcome: • Validated process and product meet specifications set in Exhibit E.3 • Shelf life of 12 months on one optimization batch (Work Package III). |
After completion of each package, samples of at least one batch will be provided by CollPlant to AbbVie for testing.in final formulation. |
Exhibit E Specifications |
The following preliminary specifications refer to: 1. 20mg/ml rhCollagen Solution, sterile material 2. 50mg/ml rhCollagen Solution, sterile material 3. Lyophilized rhCollagen, low bioburden material |
A selection between 50mg/ml or lyophilized rhCollagen as the next phase following 20mg/ml Sterile rhCollagen Solution will be taken by AbbVie based on completion of a feasibility study as described in this Exhibit. |
The 20 mg/ml concentration requires development work as detailed in Exhibit B. The 50 mg/ml concentration requires development work detailed in Exhibit C. The lyophilized rhCollagen requires development work as detailed in Exhibit D. |
1. 20mg/ml, Sterile rhCollagen Solution |
Product Description 20mg/ml rhCollagen, is a solution at a nominal concentration of 20mg/ml recombinant human collagen type I in 10mM hydrochloric acid. The concentrated rhCollagen will be aseptically processed from Collage (sterile 3mg/ml rhCollagen solution) (described in Exhibit A). |
Minimum Batch Size: 35g Minimum Sample Size for AbbVie Confirmatory Testing: 3 batches of 20g |
Critical Material Attributes and proposed Release Criteria for 20mg/ml, Sterile rhCollagen Solution (pending development phase): The Critical Material Attributes will be defined on the Collage™ (3mg/ml sterile solution) and will be applicable for the 20mg/ml rhCollagen sterile solution. The following table describes on... |
Attribute Category Rational Method Acceptance criteria |
pH physico-chemical release spec pH meter 2.0 – 2.4 |
Identity (type I)(1) release spec western blot Type I Collagen |
Collagen Concentration release spec Sircol or Lowry > 20 mg/ml |
Collagen purity (type I)(1) release spec collagenase assay > 95 % Type I Collagen |
appearance (no visible particulate) release spec visual Clear, colorless liquid |
Rate of Fibrillogenesis biofunctional release spec fibrillogenesis assay >70% |
Sterility microbiological release spec USP <71> No growth |
Endotoxins release spec LAL < 0.25 EU/mg |
heavy metals(1) Process-related impurities (first production phase) release spec ICP-MS or USP<231> < 5 ppm |
(1)Per results of the rhCollagen source (SPEC 0301) |
• If necessary, the attribute section will be subject to changes upon AbbVie approval. Once completed, some of the tests can be added to the release criteria upon AbbVie request. |
• Stability (physicochemical and microbiological) of the sterile material must be demonstrated based on ICH guidelines on stability (Q1A) for storage in the fridge i.e. Long term storage conditions 5°C ± 3°C for the intended shelf life Selection of the batches, packaging selection, specifications and testing frequency ... |
• For development purpose, 12 months stability results on the 3 validation batches of the 20mg/ml and 2 years obtained on the 3 validation batches of the 3mg/ml. |
Shelf life and stability test results should support packaging and storage for commercial purposes for the requirements below: |
• Packaging: 20mg/ml rhCollagen Solutions are filled into specific packaging for aseptic product, with various volumes i.e. 10 to 1000ml. • The parties will agree in the Definitive Agreement on the packaging specification. • Storage: 20mg/ml rhCollagen Solutions should be stored between 2 and 8oC and should not be froz... |
2. 50mg/ml, Sterile rhCollagen Solution |
Product Description 50mg/ml rhCollagen, is a solution at a nominal concentration of 50mg/ml recombinant human collagen type I in 10mM hydrochloric acid. The concentrated rhCollagen will be aseptically processed from Collage™ (sterile 3mg/ml rhCollagen solution) (described in Exhibit A). |
Minimum Batch Size: 35g Minimize Sample Size for AbbVie Confirmatory Testing: 3 batches of 10g |
Critical Material Attributes and proposed Release Criteria for 50mg/ml, Sterile rhCollagen Solution (pending development phase): The Critical Material Attributes will be defined on the Collage™ (3mg/ml sterile solution) and will be applicable for the 50mg/ml rhCollagen sterile solution. The following table describes on... |
Attribute Category Rational Method Acceptance criteria |
pH physico-chemical release spec pH meter 2.0 – 2.4 |
Identity (type I)(1) release spec western blot Type I Collagen |
Collagen Concentration release spec Sircol or Lowry > 50 mg/ml |
Collagen purity (type I)(1) release spec collagenase assay > 95 % Type I Collagen |
appearance (no visible particulate) release spec visual Clear, colorless liquid |
Rate of Fibrillogenesis biofunctional release spec fibrillogenesis assay >70% |
Sterility microbiological release spec USP <71> No growth |
Endotoxins release spec LAL < 0.25 EU/mg |
heavy metals(1) Process-related impurities (first production phase) release spec ICP-MS or USP<231> < 5 ppm |
(1)Per results of the rhCollagen source (SPEC 0301) |
• If necessary, the attribute section will be subject to changes upon AbbVie approval. Once completed, some of the tests can be added to the release criteria upon AbbVie request. |
• Stability (physicochemical and microbiological) of the sterile material must be demonstrated based on ICH guidelines on stability (Q1A) for storage in the fridge i.e. Long term storage conditions 5°C ± 3°C for the intended shelf life Selection of the batches, packaging selection, specifications and testing frequency ... |
• For development purpose, 12 months stability results on the validation batches of the 50mg/ml. |
Shelf life and stability test results should support packaging and storage for commercial purposes for the requirements below: |
• Packaging: 50mg/ml rhCollagen Solutions are filled into specific packaging for aseptic product, with various volumes i.e. 10 to 1000ml. • The parties will agree in the Definitive Agreements on the packaging specification. • Storage: 50mg/ml rhCollagen Solutions should be stored between 2 and 8oC and should not be fro... |
3. Lyophilized rhCollagen |
Product Description Lyophilized cake of recombinant human collagen type I. The lyophilized rhCollagen will be processed from sterile rhCollagen solution obtained in Exhibit A.1 or E.1 |
Minimum Batch Size: 10g Minimize Sample Size for AbbVie Confirmatory Testing: 3 batches of 10g |
Critical Material Attributes and proposed Release Criteria for lyophilized rhCollagen, low bioburden (pending development phase): TBC |
The Critical Material Attributes will be defined on the Collage™ (3mg/ml sterile solution) and will be applicable for the lyophilized rhCollagen low bioburden material. The following table describes only the release specifications related to the lyophilized rhCollagen low bioburden material. |
Attribute Category Rational Method Acceptance criteria |
Identity (type I)(1) physico-chemical release spec western blot Type I collagen |
Collagen Content release spec Sircol or Lowry X mg/dry weight (TBD) |
Moisture content release spec dry weight or oven Karl Fisher 5-10% |
Collagen purity (type I) (1) release spec collagenase assay > 95 % Type I Collagen |
appearance release spec visual White cake |
Rate of Fibrillogenesis biofunctional release spec fibrillogenesis assay >70% |
Endotoxins microbiological release spec LAL < 0.25 EU/mg |
heavy metals(1) Process-related impurities (first production phase) release spec ICP-MS or USP<231> < 5 ppm |
Total Aerobic Microbial Counts non -viral adventitious agents release spec USP <61> < 10 CFU/mg |
Total Yeast and Mold release spec USP <61> < 10 CFU/mg |
(1)Per results of the rhCollagen source (SPEC 0301) |
• If necessary, the attribute section will be subject to changes upon AbbVie approval. Once completed, some of the tests can be added to the release criteria upon AbbVie request. |
• Bioburden of the lyophilized material must be demonstrated and controlled. |
• Stability (physicochemical and microbiological) of the sterile material must be demonstrated based on ICH guidelines on stability (Q1A) for storage of raw material. Selection of the batches, packaging selection, specifications and testing frequency will be based on the ICH guidelines on stability and the stability pr... |
• For development purpose, 12 months stability results on the validation batches of the Lyophilized material. |
• Reconstituted solution from lyophilized material must have similar properties as the 20mg/ml, sterile rhCollagen solution (same acceptance criteria). |
Shelf life and stability test results should support packaging and storage for commercial purposes for the requirements below: |
• Packaging: Lyoguard tray • The parties will agree in the Definitive Agreements on the package specification. • Storage: Product should be stored at room temperature Shelf life: Product should be stable for at least 2 years under the designated storage conditions. |
A selection between 50mg/ml or lyophilized rhCollagen as the next phase following 20mg/ml Sterile rhCollagen Solution will be taken by AbbVie based on completion of a feasibility study. |
Feasibility study of the sterile, concentrated rhCollagen, 50 mg/ml: The feasibility phase refers to: • Completion of Work Package II described in Exhibit C |
Feasibility study of low bioburden, lyophilized rhCollagen: The feasibility phase refers to: • Completion of Work Package I described in Exhibit D • Tests results of the reconstituted solution from lyophilized material (compared to the 20mg/ml, sterile rhCollagen solution (same acceptance criteria except for sterility) |
Both feasibility studies can be run in parallel for a maximum period of time of 12 months. Selection of the option will be made by AbbVie 6 months after that period to include testing in final formulation. |
Schedule 1.26 CollPlant Patents |
Patent Name Application Number Priority Date Patent Status |
Collagen Producing Plants and Methods of Generating and Using Same WO2006/035442 09/2004 Granted: US, Europe, Mexico, Canada, Japan, Israel, Australia, Singapore, South Africa, New Zealand, India, Hong Kong, China, National Phase: Brazil |
Tobacco Transgenic Event and Methods for Detection and Use Thereof WO2020/026241 07/2018 PCT |
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