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with a copy to: Marina Gofman Feler, Legal Counsel |
If to AbbVie, addressed to: Allergan Industrie S.A.S. Route de Promery, Zone Artisanale de Pre-Mairy, 74370 Pringy, France |
69 88878677_21 |
with a copy (which shall not constitute notice) to: AbbVie Inc. 1 North Waukegan Road North Chicago, Illinois 60064 United States Attention: Vice Chairman, External Affairs, Chief Legal Officer and Corporate Secretary |
If to APIL, addressed to: Allergan Pharmaceuticals International Limited Clonshaugh Industrial Estate, Coolock Dublin 17 Ireland |
with a copy (which shall not constitute notice) to: AbbVie Inc. 1 North Waukegan Road North Chicago, Illinois 60064 United States Attention: Vice Chairman, External Affairs, Chief Legal Officer and Corporate Secretary |
12.6 Export Clause. This Agreement is made subject to any restrictions concerning the export of products or technical information from the United States or other countries that may be imposed on the Parties from time to time. Each Party agrees that it will not export, directly or indirectly, any technical information a... |
12.7 Waiver; Non-Exclusion of Remedies. Any term or condition of this Agreement may be waived at any time by the Party that is entitled to the benefit thereof, but no such waiver shall be effective unless set forth in a written instrument duly executed by or on behalf of the Party waiving such term or condition. The wa... |
12.8 No Benefit to Third Parties. The covenants and agreements set forth in this Agreement are for the sole benefit of the Parties hereto and their successors and permitted assigns, and they shall not be construed as conferring any rights on any other Persons. |
70 88878677_21 |
12.9 Further Assurance. Each Party shall duly execute and deliver, or cause to be duly executed and delivered, such further instruments and do and cause to be done such further acts and things, including the filing of such assignments, agreements, documents, and instruments, as may be necessary or as the other Party ma... |
12.10 Severability. If any provision of this Agreement is held to be illegal, invalid, or unenforceable under any present or future law, and if the rights or obligations of either Party under this Agreement will not be materially and adversely affected thereby, (a) such provision shall be fully severable, (b) this Agre... |
12.11 Equitable Relief. CollPlant acknowledges and agrees that the restrictions, rights and obligations set forth in Article 2 - (Development; Right of First Negotiation) and Section 4.1 (Grant of Exclusive Rights to AbbVie) through Section 4.4 (Covenant Not to Sue), and each Party acknowledges and agrees that the rest... |
12.12 Entire Agreement; Amendments. This Agreement, together with the Schedules and Exhibits attached hereto and the Supply Agreement (once executed by the Parties), sets forth and constitutes the entire agreement and understanding between the Parties with respect to the subject matter hereof and all prior agreements, ... |
71 88878677_21 |
12.13 Relationship of the Parties. It is expressly agreed that CollPlant, on the one hand, and AbbVie, on the other hand, shall be independent contractors and that the relationship between the Parties shall not constitute a partnership, joint venture, or agency, including for all tax purposes. Neither CollPlant, on the... |
12.14 Headings; Construction; Interpretation. Headings and any table of contents used herein are for convenience only and shall not in any way affect the construction of or be taken into consideration in interpreting this Agreement. The language of this Agreement shall be deemed to be the language mutually chosen by th... |
72 88878677_21 |
12.15 Books and Records. Any books and records to be maintained under this Agreement by a Party or its Affiliates or Third Party Transferees shall be maintained in accordance with applicable Accounting Standards. |
12.16 English Language. This Agreement shall be written and executed in, and all other communications under or in connection with this Agreement shall be in, the English language. Any translation into any other language shall not be an official version thereof, and in the event of any conflict in interpretation between... |
12.17 Parties in Interest. Except as provided in Article 10 - (Indemnification; Insurance), all of the terms and provisions of this Agreement shall be binding upon, and shall inure to the benefit of and be enforceable solely by the Parties and their respective successors, heirs, administrators and permitted assigns and... |
12.18 Counterparts. This Agreement may be signed in counterparts, each and every one of which shall be deemed an original, notwithstanding variations in format or file designation which may result from the electronic transmission, storage and printing of copies from separate computers or printers. Facsimile signatures ... |
[Signature page to follow] |
[Signature Page to Development, Exclusivity and Option Products Agreement] |
IN WITNESS WHEREOF, and intending to be legally bound hereby, the Parties have caused this Agreement to be executed by their duly authorized representatives as of the Effective Date. |
CollPlant Ltd. By: Name: Title: |
Allergan Industrie S.A.S. By: Name: Title: |
Solely for the purpose of Section 2.3 (Right of First Negotiation for Option Products), Section 6.1 (Upfront Fee), Section 6.2 (Option Exercise Fee), Section 7.3.4 (Option Products) and the terms of Section 6.4 (Milestone Payments) through Section 6.7 (Royalty Adjustments) that specifically apply to APIL: Allergan Phar... |
Yehiel Tal Eran Rotem CEO Deputy CEO&CFO |
Exhibit A CollPlant Collagen |
The following preliminary specifications refer to: |
1. Collage™ - 3mg/ml rhCollagen Solution, sterile material |
Product Description 3mg/ml rhCollagen is a solution at a nominal concentration of 3mg/ml recombinant human collagen type I in 10mM hydrochloric acid. The rhCollagen solution will be aseptically processed. |
Minimum Batch Size: 50g |
Minimize Sample Size for AbbVie Confirmatory Testing: 3 batches of minimum batch size |
Proposed release criteria based on current specifications of Collage™ (3mg/ml, sterile rhCollagen solution) |
Attribute Category Rational Method Acceptance criteria |
pH physico-chemical release spec pH meter 2.0 – 2.4 |
Identity (type I) release spec western blot Type I Collagen |
Collagen Concentration release spec Sircol 2.5-3.5 mg/ml |
Collagen purity (type I) 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 Process-related impurities (first production phase) release spec ICP-MS or USP<231> < 5 ppm |
The above specifications will be tested by AbbVie to characterize the Collage™ that will be used to develop the rhCollagen products described in Exhibit E. |
Critical Material Attributes for Collage™ (3mg/ml, Sterile rhCollagen Solution (pending development phase)): |
The following Collage™ attributes have to be evaluated and, based on risk assessment, the Critical Material Attributes will be defined by CollPlant and AbbVie. 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... |
Attribute Category Rational Method Acceptance criteria |
Structural integrity of collagen trimer physico-chemical impact on function CD; fibrillation of collagen [TBD] |
pro hydroxylation potential impact on trimer formation; in solution hydrolysis aaa analysis; peptide map [TBD] |
lys hydroxylation aaa analysis; peptide map [TBD] |
pro hydroxyglycosylation aaa analysis; peptide map [TBD] |
lys hydroxyglycosylation aaa analysis; peptide map [TBD] |
COL-1/COL-2 ratio LC-UV; peptide map [TBD] |
truncation products Product-related impurities immunogenicity LC-MS [TBD] |
higher order species immunogenicity; impact on cross-linking SEC-UV/MALLS [TBD] |
HCP Process-related impurities (host plant) immunogenicity LC-MS/ ELISA [TBD] |
Proteases immunogenicity; product relates impurities LC-MS/ ELISA [TBD] |
plant DNA immunogenicity PCR [TBD] |
total monosaccharides GC-MS [TBD] |
secondary metabolites safety LC-MS [TBD] |
fertilisers* Process-related impurities (first production phase) safety [TBD] [TBD] |
pesticides* safety [TBD] [TBD] |
Solvents* safety [TBD] [TBD] |
DSP materials** safety [TBD] [TBD] |
hantaviruses*** viral adventitious agents safety [TBD] [TBD] |
minute virus of mice*** safety [TBD] [TBD] |
avian influenza virus*** safety [TBD] [TBD] |
hepatitis A virus*** safety [TBD] [TBD] |
*can be risk assessed based on plant growth control **can be risk assessed based on process understanding ***can be risk assessed based on controls in place to avoid crop contamination by pests |
• Stability (physicochemical and microbiological) of the sterile material must be demonstrated based on International Council for Harmonization (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 select... |
Packaging and Storage |
• Packaging: Collage™ (sterile 3mg/ml rhCollagen) Solutions are filled into specific packaging for aseptic product, with various volumes i.e. 1,000 to 20,000ml. • The parties will agree in the Definitive Agreements on the packaging specification. |
• Storage: Collage™ (sterile 3mg/ml rhCollagen) Solutions should be stored between 2 and 8oC and should not be frozen. |
Shelf life: Collage™ (sterile 3mg/ml rhCollagen) Solutions should be stable for at least 2 years from production date under the designated storage condition. |
Exhibit B Sterile 20 Project Development Plan |
Objective: The objective of this plan is to develop a scalable process for sterile, concentrated rhCollagen, 20 mg/ml. Timeline and budget will be added after AbbVie's approval to the plan. |
Source Material: The current Collage™ material (3 mg/ml rhCollagen source (SPEC 0301)) is filtered through 0.2µ sterile filter and filled into sterile PETG bottles. This step is performed under ISO 5 Laminar Flow Hood and yields a solution with low bioburden (mostly <1 CFU/ml). |
Work Package I: Sterility validation of the current Collage™ (3 mg/ml rhCollagen source (SPEC 0301)) • This Work Package will be done with the support of a sterilization expert consultant, Dr. Robert Tomaselli. • The current process will be validated according to ISO 13408-1 (Aseptic processing of health care products ... |
The sterile Collage™ (3mg/ml rhCollagen) will be the source for the sterile concentrated rhCollagen solution (20mg/ml). |
Work Package II: Concentration process feasibility study rhCollagen concentration to at least 20 mg/ml was demonstrated using the current Hollowfiber (HF) system (1 mm diameter). |
Different scalable concentration systems will be evaluated to reach a concentration of 20 mg/ml, including Hollowfiber with relatively wide diameter HF or a membrane type ultrafiltration or any other system that will be compatible with the high viscosity of the concentrated rhCollagen. |
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 20 mg/ml • rhCollagen integrity • Scalability • Equipment and process suitability for aseptic processing • Process efficiency |
Successful Outcome: • a selected system for further optimization. • rhCollagen integrity (such as Western Blot, collagenase assay and fibrillogenesis assay) |
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 80% of intact 20 mg/ml rhCollagen • 20 mg/ml rhCollagen solution that meet the specifications set in Exhibit E.1. • 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, utilities and methods will be validated (Installation Qualification (IQ)/Operational Qualification (OQ)) 2-3 engineering runs will be conducted to ensu... |
Successful Outcome: • Scaled up process ready for validation • Meet specifications set in Exhibit E.1 |
Work Package V: Process validation 3 Performance Qualification (PQ) runs will be performed to validate the process and the product according to the specifications set in Exhibit E.1 The 3 batches will be tested for stability to set the shelf life of the 20 mg/ml sterile rhCollagen solution |
Successful Outcome: • Validated process and product meet specifications set in Exhibit E.1 • 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 C Sterile 50 Project Development Plan |
Objective: The objective of this plan is to develop a scalable process for sterile, concentrated rhCollagen, 50 mg/ml. Timeline and budget will be added after AbbVie's approval to the plan. |
Source Material: Sterile Collagen, 3mg/ml per Work Package I in Exhibit B above. |
Work Package I: Sterility validation of the current Collage™ (3 mg/ml rhCollagen source (SPEC 0301)) • As described above in Exhibit B, Work Package I. |
Work Package II: Concentration process feasibility study rhCollagen concentration to at least 40 mg/ml was demonstrated using the current Hollowfiber (HF) system (1 mm diameter) and ceramic hollowfiber system (6 mm diameter). |
Different scalable concentration systems will be evaluated to reach a concentration of 50 mg/ml, including Hollowfiber with relatively wide diameter HF or a membrane type ultrafiltration or any other system that will be compatible with the high viscosity of the concentrated rhCollagen. |
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