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The chemistry, manufacturing and controls (CMC) section of a gene therapy IND

The chemistry, manufacturing and controls (CMC) section of a gene therapy IND. Andrew P. Byrnes, Ph.D. Chief, Gene Transfer and Immunogenicity Branch Division of Cellular and Gene Therapies. What are gene therapy products?. Gene therapy products:

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The chemistry, manufacturing and controls (CMC) section of a gene therapy IND

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  1. The chemistry, manufacturing and controls (CMC) section of a gene therapy IND Andrew P. Byrnes, Ph.D. Chief, Gene Transfer and Immunogenicity Branch Division of Cellular and Gene Therapies

  2. What are gene therapy products? • Gene therapy products: • Are administered as nucleic acids, viruses or genetically-engineered microorganisms, and • Mediate effects via: • Transcription or translation of transferred genetic material, or • Integration into the genome • How are gene therapy products used? • To modify cells directly in patients, or • To modify cells in vitro that are then administered to patients

  3. Examples of gene therapy products • Plasmid expressing an enzyme • AAV expressing a coagulation factor • T cells modified with a retrovirus to express a novel receptor • Bacterium expressing a tumor antigen • Oncolytic adenovirus expressing a cytokine

  4. CD34+ selection Retroviral vector Growth factors Donor-derived PBMCs Fibronectin coated flask Transduced CD34+ cells CD34+ cells Complexity of a gene therapy manufacturing process

  5. Before you begin manufacturing… 2008 Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

  6. Presentation outline • Components used in product manufacture • Final product testing and characterization • Good manufacturing practices (GMPs)

  7. Components used to manufacture the product • Vector • Cells • Banking system • Master cell bank (MCB) • Master viral bank (MVB) • Reagents

  8. Vector • Description, history and details on derivation of construct • Vector diagram • Sequence analysis (from MVB) • Full sequence for vectors <40 kb • Vectors >40 kb: sequence inserts, flanking regions, modified regions • Description of unexpected sequences • Raw sequence data is not sufficient

  9. Cells • Cell substrate for production of vector • History, source, general characteristics • Cells used as cell therapies • Source • tissue and cell type • Collection procedure • mobilization, surgery, leukapheresis, devices used • Donor Eligibility • infectious disease screening & testing, 21 CFR 1271

  10. MCB and MVB safety testing • Sterility • Mycoplasma • Adventitious Virus • In vitro and in vivo adventitious virus assays • Bovine and porcine viruses • Not needed if reagents tested • For human cell lines: • Typically EBV, HBV, HCV, CMV, HIV 1&2, HTLV 1 & 2, B19 • For murine cell lines: • Typically mouse antibody production test, retroviruses • Replication-competent virus (for MVB)

  11. Master cell bank characterization • Identity • Examples: • Isoenzyme • Karyotype • Short tandem repeat (STR) profiling • Viability • Stability

  12. Reagents used in manufacturing • Tabulation of reagents • Final concentration • Vendor • Source (human, bovine, etc.) • Grade • e.g. licensed product, clinical grade, reagent grade • May need to provide details on reagent manufacturing • Certificates of Analysis • Cross reference letters • Qualification program • Safety testing and quality assessment

  13. Product Manufacturing • Vector production / purification • Describe all steps • e.g. cell growth, infection, harvest, purification, formulation, vialing, storage • Flowchart • Describe the formulation • Buffer components • Excipients • Product concentration • Storage

  14. Final Product Testing • Goals: • Safety • Product characterization • Product lot consistency • List all of your: • Release tests • Test methods • Acceptance criteria (specifications)

  15. Final product testing: safety • Sterility • Mycoplasma • Endotoxin • Adventitious Virus • In vitro virus • Replication competent virus

  16. Final product testing: characterization • Final product lot release testing • Concentration • Purity • e.g. residual cellular DNA, empty viral particles • Identity • e.g. restriction digest • Activity • e.g. infectious titer • Potency • e.g. transgene-specific protein expression • Cell viability (if a cell-based product) • Stability • Storage • Shipping • Compatibility with delivery devices

  17. Product characterization: why? • To demonstrate lot-to-lot consistency • To generate solid clinical data • For pivotal trials, characterization assays will need to be established with appropriate release limits • To show comparability after manufacturing changes

  18. Current Good Manufacturing Practices (cGMP) • Goals: • A product with defined and reproducible quality • Increased control of the manufacturing process as clinical trials advance • 2008 Guidance for Industry: CGMP for Phase 1 Investigational Drugs

  19. cGMPsQuality control • Quality (QC) Program • QC independent of production unit • Authority to accept or reject materials, lots, procedures and specifications • Prevent, detect, and correct deviations and failures

  20. cGMPsQuestions for phase I • Is the manufacturing process reproducible? • Do you have appropriate testing at critical steps? • Is there adequate control of the quality of the raw and source materials? • Are the records and record keeping systems adequate?

  21. cGMPsExamples for early development • Procedures to prevent contamination & cross-contamination • Aseptic processing • Facility and equipment cleaning and changeover • Tracking and segregation of patient-specific products • Methods qualification • Appropriate method specificity, sensitivity, reproducibility • Lack of interference • Process qualification of safety related processes • Removal of potentially dangerous impurities

  22. Summary • For a phase I submission, product safety is the focus of the CMC assessment • Freedom from microbes and adventitious agents • Safety-related characterization • Appropriate GMPs • Gene therapies and other complex biologics can be a challenge to characterize, and often require unique assays • Product control and process control should increase with clinical development

  23. Further information CBER guidance documents: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm If the webinar series and referenced websites leave you with unanswered questions: CBEROCTGTRMS@fda.hhs.gov or 301-827-5102

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