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Ensuring Product Quality in Gene Transfer Clinical Trials Stephanie Simek Ph.D. Division of Cellular and Gene Therapies OTRR/CBER/FDA March 21, 2001 Regulation of Biological Products Based on Sound Science, Law and Public Health Impact Review Policy Research Surveillance Compliance Regulations for Biological Products Title 21, Code of Federal Regulations Part 312 - Investigational New Drugs (INDs) and Part 314 - New Drug Application (NDA) Part 25 - Environmental Assessments Part 201, 202 - Labeling & Advertising Parts 210, 211 -Current Good Manufacturing Products (cGMPs) (FD&C Act) Parts 610 - General Biological Product Standards (PHS Act) Guidance Documents Application of Current Statutory Authorities to Cell And Gene Therapy Products, Federal register/Vol. 58,No.1997/Oct. 14, 1993. Guidance for Human Somatic Cell Therapy and Gene Therapy. CBER. March 1998. PTC in the Characterization of Cell Lines Used to Produce Biologicals, 1993. 58 FR 42974. ICH: Guidance on Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin, FR. Sept. 24, 1998, Vol. 63, No. 185. Guidance for Industry: Stability Testing of Drug Substances and Drug Products, (Draft Guidance), CBER, June 1998. How to Ensure Product Quality Components used in Product Manufacture Product Testing and Characterization Control of Manufacturing Process cGMP Practices In process controls DEFINITION Gene Therapy: The administration of genetic material to modify or manipulate the expression of a gene product or to alter the biological properties of living cells for therapeutic use. Cells may be modified ex vivo for subsequent administration to the subject or altered in vivo by gene therapy products given directly to the subject. Stages in Product Development IND Pre-IND Phase I Phase II Phase III Product License Phase IV Step-wise Approach to Application of Regulatory Requirements Full characterization 21 CFR 610 Full GMP 21 CFR 210, 211 Phase III Phase II Phase I Preclinical QA &QC, Clinical Monitoring Program Prior to Phase I : need product safety testing and basic characterization info Components Used in Manufacture of Product Vector Cells allogeneic Cell & autologous cell components Bank System master cell bank/working cell bank master viral bank/working viral bank Ancillary growth Product/Reagents factors, cytokines, MoAb Vector Description, history, and detailed derivation of construct Vector diagram Sequence analysis Cells Autologous and allogeneic cells Source (tissue and cell type) Collection procedure Donor screening allogeneic- use blood banking criteria autologous- don’t increase viral load or spread adventitious virus Master Cell Bank Safety Testing Sterility Mycoplasma Adventitious in Virus vitro and in vivo virus bovine and porcine viruses human cell lines: EBV, HBV, HCV, CMV, HIV 1&2, HTLV 1 & 2, B19, (others) Master Cell Bank (cont.) Characterization Karyology/Morphology Isoenzyme Tumorgenicity Other Viability Working Cell Bank Safety Sterility Mycoplasma In vitro Adventitious virus Characterization Isoenzyme Morphology Master Virus Bank Safety Testing Sterility Mycoplasma Adventitious in Virus vitro and in vivo virus bovine and porcine viruses human viruses: EBV, HBV, HCV, CMV, HIV 1&2, HTLV 1 & 2, B19, (others) murine -MAP RCV Master Virus Bank Characterization Identity sequence of vector & restriction map Activity /Expression transgene specific protein expression other Titer Other Reagents Used During Manufacture Tabulation of reagents used Final concentration Vendor Source (human, bovine, etc.) Licensed product, clinical grade, reagent grade Certificates of Analysis, cross reference letter Qualification program Product Manufacturing Vector Production/Purification Ex Vivo Modified Cells method of collection/processing ex vivo modification procedure other modifications (irradiation) final harvest Product Manufacturing (cont.) Formulation formulation of Final Product buffer excipients vector concentration/cell density storage Final Product Testing Requirements Demonstration of product safety Assessment of product characterization Maintenance of product lot consistency Final Product: Safety Sterility Mycoplasma Endotoxin/Pyrogenicity Adventitious In vitro virus RCV Virus Final Product: Characterization Identity restriction map, structural characterization Activity transgene specific Titer Purity cell substrate DNA, RNA, & protein Final Product Characterization (cont) Potency required by phase II Stability Development of Lot Release Specifications Control of Manufacturing Process Cell bank characterization Master viral bank characterization Final product characterization Lot release tests and specifications Ancillary products Current Good Manufacturing Practices (cGMP) Definition A set of current, scientifically sound methods, practices or principles that are implemented and documented during product development and production to ensure consistent manufacture of safe, pure and potent products Applies to both the manufacturing process and the facilities Ex Vivo Transduced CD34+ Cells Expressing HSV tk Anti-CD34+ MoAB PBSC CD34+ Selection Retroviral Viral vector CD34+ transduction Growth factors Flt-3, CSF, Fibronectin CD34+ expressing HSV tk Summary Step-wise Approach to Regulatory Requirements Safety Testing Requirements Control of Manufacturing Process cGMP Practices Ensure a safe and Quality Product CBER INFORMATION FAX: 301-827-3844 or 1-888-CBER-FAX PHONE: 301-827-1800 http://www.fda.gov/cber/ E-mail: CBER_INFO@A1CBER.FDA.GOV DOC-LIST@A1.CBER.FDA.GOV
