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Cell Therapy – A Manufacturing Viewpoint

Cell Therapy – A Manufacturing Viewpoint. Anita Bate PhD Eden Biodesign. Cell Therapy of Cancer Symposium, Manchester Sunday 3 rd December 2006. Eden Biodesign. Operator of the National Biomanufacturing centre Consultancy Process Development GMP Manufacture

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Cell Therapy – A Manufacturing Viewpoint

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  1. Cell Therapy – A Manufacturing Viewpoint Anita Bate PhD Eden Biodesign Cell Therapy of Cancer Symposium, Manchester Sunday 3rd December 2006

  2. Eden Biodesign Operator of the National Biomanufacturing centre • Consultancy • Process Development • GMP Manufacture “Designing and developing valuable new medicines by the application of good science from day one”

  3. The key message • Begin with the end in mind! • Understand the process before you begin • Plan, Plan, Plan • Its all about Teamwork

  4. Presentation Overview • Outline of Product development • GMP Contract Manufacture- a users guide! • What is it & why does it cost so much • The goal of manufacturing • The ingredients of success – technical issues • Specific challenges for gene and cell therapy • Materials • Testing • Risk Mitigation

  5. Part 1 • Outline of Product Development

  6. 95% of all Investigational products do not progress to phase III trials Gene Therapy clinical trials by phase 2004-2006 Data from Journal of Gene Medicine 2004 and 2006

  7. CTA/IND CTA/IND Updates CTD Safety Efficacy Quality Phase I Pre-Clinical Phase II Manufacturing Phase III Small Scale Pilot scale Manufacturing Scale Analysis Validated Safety Testing Validated Safety, Identity, Purity, impurities Fully Validated In-process and Release Tests QUALITY RISK Product Development

  8. Part 2 • GMP Contract Manufacture- Overview

  9. What is GMP? • Patient Safety • Ensures High Quality Product • Safe • Pure • Effective • Right Identity • Right Strength • The quality of facilities are extreme! • Never-ending maintenance and testing

  10. Goal of manufacture • Two products • Product • A characterised and consistent product • A validated and reproducible process • With pre-determined acceptance criteria and specifications • Paper • Documented evidence to show that the product has been made to the correct standards

  11. Process Development Laboratory scale production process Cell culture and viral infection Cell lysis and clarification by centrifugation Gradient Centrifugation (x2) Dialysis Manufacturing scale production process Bulk Purified Virus Drug Product or Concentration/ Diafiltration – e.g. TFF Column Chromatography e.g. gel filtration Column Chromatography e.g. ion exchange Cell culture and viral infection Cell Lysis and filtration

  12. Part 3 • The keys to success – technical issues

  13. Animal/human Cell Line (GMP MCB) Vectors, nucleic acids etc (GMP MVSS/DNA) Technical Challenges Starting Materials Vector Manufacture Drug Substance Drug Product Patient Cells Patient Drug Product

  14. Cellular Therapy Paracetamol Paracetamol Immunoglobulin Immunoglobulin Predictability of clinical efficacy from physico-chemical and biological characteristics

  15. Aims of Analysis Product Characterisation QC Release Testing (specifications) Understand and define product (knowledge directed) To demonstrate the consistency and quality of product (quality directed)

  16. Starting Materials Cells Vector In-Process Drug Substance Drug Product Stability Comparability Product and Sample retention All possible tests All applicable tests Characterisation (‘well specified’) knowledge Product Release Safety Quality Efficacy Comparability How Much Analysis and When?

  17. Part 4 • Teamwork and Planning is most overlooked element but most vital of all

  18. Adeno-associated virus Adenovirus Adenovirus + Retrovirus Flavivirus Gene gun Herpes simplex virus Lentivirus Lipofection Listeria monocytogenes Measles virus Naked/Plasmid DNA Naked/Plasmid DNA + Adenovirus Newcastle disease virus Poliovirus Poxvirus Poxvirus + Vaccinia virus Recombinant Poxvirus Retrovirus RNA transfer Saccharomyces cerevisiae Salmonella typhimurium Semliki forest virus Simian virus 40 Vaccinia virus No CMO can be expert in every technology Array of Vectors used in Gene therapy Clinical Trials Journal of Gene Medicine 2006

  19. Technical transfer Knowledge, Methods, Safety information, Materials CommunicationTeam Approach Client CMO Knowledge, Methods, Safety information, GMP Materials, Quality Documentation

  20. Work with your outsource Partner • Start Early with realistic timelines • Knowledge and understanding • Get it wrong and risk backtrack of years • Planning/ Auditing /Technical agreement • Regular Communication • Team work • Person on site at critical phases of production. • Agree and sign off for critical documents • Keep an eye on the regulatory environment

  21. Part 6 • Conclusion !The keys to success

  22. How can we increase probability of success? • Plan, Plan, Plan • Effective Technical transfer of knowledge, production method and analytical tests • Develop process so that product can be made consistently • Manufacture to high quality • Characterisation and release of product • Work with your outsource partners • Engage with Regulatory Authorities Early

  23. So the message is • Begin with the end in mind!

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