The chemistry, manufacturing and controls (CMC) section of a gene therapy IND
Post on 23-Mar-2016
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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
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
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
Complexity of a gene therapy manufacturing process
Growth factors
Donor-derived PBMCs CD34+
cells
Retroviral vector
Transduced CD34+ cells
CD34+ selection
Fibronectin coated flask
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)
Presentation outline• Components used in product
manufacture
• Final product testing and characterization
• Good manufacturing practices (GMPs)
Components used to manufacture the product
• Vector• Cells• Banking system
– Master cell bank (MCB)– Master viral bank (MVB)
• Reagents
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
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
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)
Master cell bank characterization
• Identity– Examples:
• Isoenzyme• Karyotype• Short tandem repeat (STR) profiling
• Viability• Stability
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
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
Final Product Testing
• Goals:– Safety– Product characterization– Product lot consistency
• List all of your:– Release tests– Test methods– Acceptance criteria (specifications)
Final product testing: safety
• Sterility
• Mycoplasma
• Endotoxin
• Adventitious Virus – In vitro virus– Replication competent virus
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
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
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
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
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?
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
• 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
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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