Cell Therapy A Manufacturing Viewpoint

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Cell Therapy A Manufacturing Viewpoint

• Anita Bate PhD
• Eden Biodesign

Cell Therapy of Cancer Symposium,
Manchester Sunday 3rd December 2006
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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

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The key message

• Begin with the end in mind!
• Understand the process before you begin
• Plan, Plan, Plan
• Its all about Teamwork

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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

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Part 1

• Outline of Product Development

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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
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Product Development
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Part 2

• GMP Contract Manufacture- Overview

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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

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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

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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. ion exchange
Column Chromatography e.g. gel filtration
Cell culture and viral infection
Cell Lysis and filtration
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Part 3

• The keys to success technical issues

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Technical Challenges
Starting Materials
Vector Manufacture
Drug Substance
Drug Product
Patient
Patient Cells
Drug Product
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Predictability of clinical efficacy from
physico-chemical and biological characteristics
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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)
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How Much Analysis and When?

• Starting Materials
• Cells
• Vector
• In-Process
• Drug Substance
• Drug Product
• Stability
• Comparability
• Product and Sample retention

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Part 4

• Teamwork and Planning is most overlooked element
  but most vital of all

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No CMO can be expert in every technology
Array of Vectors used in Gene therapy Clinical
Trials

• 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

Journal of Gene Medicine 2006
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Technical transfer
Knowledge, Methods, Safety information, Materials
CommunicationTeam Approach
Client
CMO
Knowledge, Methods, Safety information, GMP
Materials, Quality Documentation
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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

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Part 6

• Conclusion !The keys to success

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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

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So the message is

• Begin with the end in mind!