ensuring product quality in gene transfer clinical trials stephanie simek ph.d. division of cellular...
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Ensuring Product Quality in Gene Ensuring Product Quality in Gene Transfer Clinical TrialsTransfer Clinical Trials
Stephanie Simek Ph.D.
Division of Cellular and Gene Therapies
OTRR/CBER/FDA
March 21, 2001
Regulation of Biological ProductsRegulation of Biological ProductsBased on Sound Science, Law and Public Based on Sound Science, Law and Public
Health ImpactHealth Impact
Review Research Surveillance
Policy Compliance
Regulations for Biological Products Regulations for Biological Products Title 21, Code of Federal RegulationsTitle 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 DocumentsGuidance 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Products, (Draft Guidance), CBER, June 1998.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 QualityHow 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
Phase I Phase II Phase IIIProductLicensePre-IND Phase IV
IND
Good
Manufacturing
Practices
Full GMP
21 CFR 210, 211
Product
Characterization
Step-wise Approach to Application of Regulatory Requirements
Full characterization
21 CFR 610
Phase III
Phase I
Phase II
Pre-clinical
Prior to Phase I : need product safety testing and basic characterization infoPrior to Phase I : need product safety testing and basic characterization info
QA &QC, Clinical Monitoring Program
Components Used in Manufacture of Product
Vector Cells
allogeneic & autologous cell components
Cell Bank System master cell bank/working cell bank master viral bank/working viral bank
Ancillary Product/Reagents growth 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 Virus
in 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 Virus
in 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 of Final Product formulation buffer excipients vector concentration/cell density storage
Final Product Testing Requirements
Demonstration of productsafety
Assessment of product characterization
Maintenance of product lot consistency
Final Product: Safety
Sterility Mycoplasma Endotoxin/Pyrogenicity Adventitious Virus
In vitro virus RCV
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)
DefinitionA 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
Growth factors
PBSC CD34+Selection
Retroviral Viral vector Flt-3,
CSF, Fibronectin
CD34+ transduction CD34+ expressing HSV tk
Anti-CD34+ MoAB
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: 301-827-1800http://www.fda.gov/cber/
E-mail: [email protected]