CBER Presentation

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Common Challenges in Development of Cell and Gene Therapy Products

Well Characterized Biotechnology Pharmaceutical (WCBP) Symposium
1/28-29/2007

Mike Havert, Ph.D.
mike.havert@fda.hhs.gov
US Food and Drug Administration
Center for Biologics Evaluation and Research
Office of Cellular, Tissue, and Gene Therapies

Overview

  • Types of cell and gene therapy products
  • Regulatory expectations for product characterization and consistency
  • New analytical technology for characterizing emerging therapeutics

Products Regulated in OCTGT

  • Somatic cell therapies
  • Tumor Vaccines
  • Gene therapies
  • Xenotransplantation
  • Combination products
  • Devices used for cell/tissues
  • Unique assisted reproduction (ooplasm transfer)
  • Anti-idiotype antibodies
  • Tissue and tissue based products

Gene therapy products designed for.

  • Inherited disease
  • Acquired disease
    • Cancer
      • cytokines, immune modulators, tumor suppressor genes, suicide genes, oncolytic viruses
    • Wound healing / new vasculature / improve cell survival or function
      • growth factors, extracellular matrix, cell cycle regulators, signal transduction or anti-apoptotic molecules
    • Chronic infection
      • antisense or siRNA targeting virus

Vectors for delivery

vectors used in gene therapy clinical trials

Autologous cells transduced with vector

Autologous cells transduced with vector

Regulatory timeline

Regulatory timeline: preclinical, phase 1, phase 2, phase 3 phase 4 marketing

Preparing to submit an IND

How does a manufacturer know what test to use for their product?

  • Sponsor is free to use any scientifically valid test for in-process testing of product
  • For final product testing, if test method is not specified by biological product standards, sponsor can use any scientifically valid test (21 CFR 610)
  • It is also possible to use alternative tests to those prescribed by biological product standards
    • 21 CFR 610.9
  • Information on generally acceptable types of testing:
    • FDA Guidance documents
    • ICH Guidance documents
    • United States Pharmacopeia (USP)
    • Scientific literature, etc..

General Biological Products Standards

CFR Test
610.9 Alternative Methods
610.10 Potency
610.11 *General Safety
610.12 Sterility
610.13 Purity
610.14 Identity
610.15 Constituent Materials
610.30 **Mycoplasma
610.40 Communicable diseases

*Cellular Therapies are exempt
**Only required for cells that are cultured

Biologics Standards

Required Test Test Method Test Timing Specification
Sterility Specified Final Product Negative
Mycoplasma Specified Final Product Negative
Purity (pyrogenicity) Specified Final Product Pass
Identity Not Specified Final Product Product Specific
Potency Not specified Final Product Product Specific
Other tests Viability, Phenotype, etc.   Ensure safety and consistency

Identity

  • Verification that vial contents match the label
    • Develop identity assay specific for the product
    • Multiple active components in product?
      • The test methods should identify all of them
    • Distinguish the final product from other products made in the same facility

Potency Assay Wish List

  • Available for release
  • Consistent/validatable
  • Demonstrate product activity
  • Quantitative
  • Stability indicating
  • Demonstrate product consistency

Preparing for pivotal studies

Common challenges for Pivotal Studies

  • Product characterization
    • Lack of understanding of the product
    • Inability to ensure product consistency
  • Potency
    • Assay(s) is insufficient to determine biological activity
    • Assay(s) is not quantitative
    • Acceptance criteria are inadequate

Solution lies in preparation

  • Determine critical product characteristics and how they will be controlled
    • Identify and characterize therapeutic and inactive components
    • Identify and measure impurities and inactive components
  • Establish a meaningful potency assay
  • Refine procedures and acceptance criteria based on development experience
  • Make plans for potential comparability studies for new sites and unexpected process changes

Identifying critical attributes may involve new technology

  • New Technologies
    • Microarray, proteomics and others
  • May be useful for
    • Product development
      • Characterize complex products
      • Identify markers predictive of behavior
    • Lot release
      • Potency
      • Identity

Contact Information

Cell and Gene therapy product manufacturing questions
Mike Havert
mike.havert@fda.hhs.gov
301-827-5102

General CBER Issues
Office of Communication, Training & Manufacturers Assistance
Manufacturers Assistance and Technical Training Branch
Telephone: 800-835-4709 or 301-827-1800 E-mail: matt@cber.fda.gov
Internet: http://www.fda.gov/cber/manufacturer.htm

 
Updated: March 29, 2007