Transcript No Slide Title

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Products, (Draft Guidance), CBER, June 1998.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: [email protected]
[email protected]