WCC-PDA Dinner Meeting Changes and Comparability Elizabeth Leininger, PhD Vice President Regulatory Affairs and Quality Assurance, StemCells Inc 18 May 2006

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WCC-PDA Dinner Meeting Changes and
ComparabilityElizabeth Leininger, PhDVice
President Regulatory Affairs and Quality
Assurance, StemCells Inc18 May 2006

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Panelists

• Rob Frankenberg, PhD, PMP
• Sr. Project Manager, Bayer HealthCare, LLC
• Reed J. Harris
• Director, Late Stage Analytical Development,
  Genentech, Inc.
• Erik T. Fouts, PhD Associate Director,
  Manufacturing Sciences,
• BioMarin Pharmaceutical, Inc

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Product Development Stages
Basis for Approval

Post Approval
Discovery
Clinical (IND)
Pre-clinical
Phase 1 Phase 2 Phase 3
Safety
Efficacy
Consistency of Manufacture
Defined Product Profile
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Changes and Comparability

• Improvements, Optimizations Changes
• Cell line changes
• Source material
• Scale-up
• Process optimization
• Increase yields
• Facility changes
• Equipment changes
• Formulation
• Container closure systems
• Assay technology

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For Proposed Changes in CMC

• Determine impact on the products
• Identity, strength, quality, purity and potency
• As they relate to the
• SAFETY or EFFECTIVENESS of the product

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Comparability protocol
To demonstrate the lack of adverse effect

• Comprehensive Plan
• Describes the changes
• Specific tests and studies
• Analytical procedures
• Validation studies
• Acceptable limits

On the identity, strength, quality, purity or
potency of the product
As they may relate to the Safety or
Effectiveness of the product
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Comparability Protocols

• Not a requirement but
• FDAs review of the protocol
• Approve the protocol
• Potential reduced reporting category
• Facilitate implementation and reporting of the
  CMC changes
• Could result in moving a product into
  distribution sooner
• For products in development could result in
  completing clinical program sooner

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Development Stages and Comparability

• Changes will occur during the development of a
  process/product
• Natural growing pains
• Defining the process and product
• Scale-up
• Process optimization
• Changes will occur post Marketing Authorization

Post Approval
Clinical (IND)
Discovery
Pre-clinical
Phase 1 Phase 2 Phase 3
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Product Development Stages

Post Approval
Discovery
Clinical (IND)
Pre-clinical
Phase 1 Phase 2 Phase 3

• Validation and Conformance Lots

• Pilot Plant GLP Lots
• Animal safety studies

• Commercial lots

• Phase 1 GMP lot(s)

• Phase 2 GMP lot(s)

• Phase 3 GMP lot(s)

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3
4
changes
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1
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Product Development Stages

Post Approval
Discovery
Clinical (IND)
Pre-clinical
Phase 1 Phase 2 Phase 3
Product Characterization
Release assay, other assays, specifications,
stability
Process Characterization
Critical parameters, critical control points
Process Validation
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Considerations for Comparability

• Development stage
• Safety database
• Efficacy database
• Process knowledge
• Product knowledge

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Assessment of Comparability

• Based on understanding your product
  characteristics (structure/function/PK) and how
  these
• Relate to safety and efficacy
• Are impacted by critical control points in the
  manufacturing process
• Can be measure (define assays)

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Strategies for Comparability Studies

• Categories of changes
• Change with no impact on the quality criteria.
• Change with impact on the in process criteria,
  but not on the specifications.
• Change with impact on the quality of the product,
  specifications.
• Change with impact on quality and anticipated
  consequence on safety and efficacy.

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Quality Considerations

• Characterization studies
• Biological and physicochemical
• Impurity profiles
• Validated manufacturing process
• Batch-to-batch consistency
• Level of quality of the material used in clinical
  studies
• Release data
• Are the specs and in process criteria met?
• Stability data

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Basis for Comparability

• Analytical Methods/ Product Quality
• Animal Models
• In-vivo mechanism of action/potency
• Animal PK/PD
• Toxicology/Safety
• Clinical Trials
• Human PK/PD
• Safety
• Surrogate markers
• Efficacy

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LogisticsElements of Post Approval Changes

1. The Change (improvement, upgrade, modification,
   scale-up, etc.)
2. Development work
3. Manufacturing scale (pilot plant, GMP plant,
   under GMP?)
4. Comparability Protocol (change, justification,
   development work, specifications, product impact,
   characterization, stability, validation, format,
   sign-off, partner?)
5. FDA Review (under IND, pre-license application,
   pre-BLA/NDA meeting, during the BLA/NDA review)

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LogisticsElements of Post Approval Changes

1. Execution (GMP work, between campaigns, QC data,
   characterization data, validation/re-validation
   data)
2. Submission of report/ FDA review (post approval)
3. Time to market (CBE, CBE-30, Prior Approval)
4. Additional considerations (stockpile, evaluate
   risks to next GMP lots, notification to clients
   (CMOs), market at risk)

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Regulatory Guidance Documents

• CBER/CDER Guidance Demonstration of
  Comparability of Human Biological Products,
  Including Therapeutic Biotechnology-derived
  Products (04/01/1996)
• CBER/CDER Draft Guidance for Industry
  Comparability Protocols - Protein Drug Products
  and Biological Products CMC Information
  (9/3/2003)
• ICH Q5E Comparability of Biotechnological/Biologi
  cal Products Subject to Changes in their
  Manufacturing Process

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Questions for the Panel

• Summarize types of changes and development stage
  that required demonstration of comparability.
• 2. What made demonstration of comparability
  successful?
• 3. What did not work during demonstration of
  comparability?
• 4. What were the challenges with the assays used
  to demonstrate comparability? Which assays give
  valuable information, which assays should you
  stay away from?
• 5. Your recommendations on optimal time to
  introduce changes and up-front work required for
  demonstration of comparability.