1 / 28

Ensuring Product Quality in Gene Transfer Clinical Trials

Explore guidelines and procedures to maintain product quality in gene therapy clinical trials. Learn about regulatory requirements, manufacturing processes, testing protocols, and more.

laniers
Download Presentation

Ensuring Product Quality in Gene Transfer Clinical Trials

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Ensuring Product Quality in Gene Transfer Clinical Trials Stephanie Simek Ph.D. Division of Cellular and Gene Therapies OTRR/CBER/FDA March 21, 2001

  2. Review Research Surveillance Policy Compliance Regulation of Biological ProductsBased on Sound Science, Law and Public Health Impact

  3. 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)

  4. 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 • Guidance for Industry: Stability Testing of Drug Substances and Drug Products, (Draft Guidance), CBER, June 1998.

  5. How to Ensure Product Quality • Components used in Product Manufacture • Product Testing and Characterization • Control of Manufacturing Process • cGMP Practices • In process controls

  6. 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.

  7. Stages in Product Development IND Product License Phase I Phase II Phase III Phase IV Pre-IND

  8. Phase I Phase II Step-wise Approach to Application of Regulatory Requirements Full characterization 21 CFR 610 ProductCharacterization Full GMP 21 CFR 210, 211 Good Manufacturing Practices Phase III Pre-clinical QA &QC, Clinical Monitoring Program Prior to Phase I : need product safety testing and basic characterization info

  9. 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

  10. Vector • Description, history, and detailed derivation of construct • Vector diagram • Sequence analysis

  11. 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

  12. 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)

  13. Master Cell Bank (cont.) • Characterization • Karyology/Morphology • Isoenzyme • Tumorgenicity • Other • Viability

  14. Working Cell Bank • Safety • Sterility • Mycoplasma • In vitro Adventitious virus • Characterization • Isoenzyme • Morphology

  15. 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

  16. Master Virus Bank • Characterization • Identity • sequence of vector & restriction map • Activity /Expression • transgene specific protein expression • other • Titer

  17. 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

  18. Product Manufacturing • Vector Production/Purification • Ex Vivo Modified Cells • method of collection/processing • ex vivo modification procedure • other modifications (irradiation) • final harvest

  19. Product Manufacturing (cont.) • Formulation of Final Product • formulation buffer • excipients • vector concentration/cell density • storage

  20. Final Product Testing Requirements • Demonstration of product safety • Assessment of product characterization • Maintenance of product lot consistency

  21. Final Product: Safety • Sterility • Mycoplasma • Endotoxin/Pyrogenicity • Adventitious Virus • In vitro virus • RCV

  22. Final Product: Characterization • Identity • restriction map, structural characterization • Activity • transgene specific • Titer • Purity • cell substrate DNA, RNA, & protein

  23. Final Product Characterization (cont) • Potency • required by phase II • Stability • Development of Lot Release Specifications

  24. Control of Manufacturing Process • Cell bank characterization • Master viral bank characterization • Final product characterization • Lot release tests and specifications • Ancillary products

  25. 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

  26. Ex Vivo Transduced CD34+ Cells Expressing HSV tk Anti-CD34+ MoAB Retroviral Viral vector Growth factors Flt-3, CSF, Fibronectin CD34+ expressing HSV tk PBSC CD34+ Selection CD34+ transduction

  27. Summary • Step-wise Approach to Regulatory Requirements • Safety Testing Requirements • Control of Manufacturing Process • cGMP Practices Ensure a safe and Quality Product

  28. 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.GOVDOC-LIST@A1.CBER.FDA.GOV

More Related