the chemistry, manufacturing and controls (cmc) section of a gene therapy ind
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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: - PowerPoint PPT PresentationTRANSCRIPT
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Food and Drug AdministrationCenter for Biologics Evaluation and Research
The Office of Cellular, Tissue, and Gene Therapies Web Seminar Series
presents:
The chemistry, manufacturing and controls (CMC) section of a
gene therapy INDAndrew P. Byrnes, Ph.D.
Chief, Gene Transfer and Immunogenicity BranchDivision of Cellular and Gene Therapies
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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
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Examples of gene therapy products
1. Plasmid expressing an enzyme
2. AAV expressing a coagulation factor
3. T cells modified with a retrovirus to express a novel receptor
4. Bacterium expressing a tumor antigen
5. Oncolytic adenovirus expressing a cytokine
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Complexity of a gene therapy manufacturing process
Growth factors
Donor-derived PBMCs CD34+
cells
Retroviral vector
Transduced CD34+ cells
CD34+ selection
Fibronectin coated flask
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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)
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Presentation outline• Components used in product
manufacture
• Final product testing and characterization
• Good manufacturing practices (GMPs)
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Components used to manufacture the product
• Vector• Cells• Banking system
– Master cell bank (MCB)– Master viral bank (MVB)
• Reagents
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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
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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
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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)
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Master cell bank characterization
• Identity– Examples:
• Isoenzyme• Karyotype• Short tandem repeat (STR) profiling
• Viability• Stability
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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
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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
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Final Product Testing
• Goals:– Safety– Product characterization– Product lot consistency
• List all of your:– Release tests– Test methods– Acceptance criteria (specifications)
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Final product testing: safety
• Sterility
• Mycoplasma
• Endotoxin
• Adventitious Virus – In vitro virus– Replication competent virus
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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
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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
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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
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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
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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?
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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
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• 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
Summary
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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:[email protected] or 301-827-5102