cellular therapy products (ppt - 349kb)
TRANSCRIPT
Food and Drug AdministrationCenter for Biologics Evaluation and Research
The Office of Cellular, Tissue, and Gene Therapies Web Seminar Series
presents:
Cellular Therapy Products
Keith Wonnacott, PhDChief, Cellular Therapies Branch
Division of Cellular and Gene Therapies
Office of Cellular, Tissue, and Gene Therapies
Presentation Outline
• Introduction • Tips and references for IND preparation• Manufacturing information to put in an
IND– Starting Material and Reagents– Product Manufacturing– Product Testing and Characterization – Product Stability
• Summary and concluding remarks
I. Introduction
I. Introduction Somatic Cell Therapy Defined
• “autologous, allogeneic, or xenogeneic cells that have been propagated, expanded, selected, pharmacologically treated, or otherwise altered in biological characteristics ex vivo to be administered to humans and applicable to the prevention, treatment, cure, diagnosis or mitigation of disease or injuries”
• October 14, 1993. 58 FR 53248• Do not meet the criteria in 21 CFR 1271.10 to
be regulated solely under PHS Act section 361 and regulations under 21 CFR 1271
I. Introduction
• Stem cells and stem cell-derived products– hematopoietic, mesenchymal, embryonic,
umbilical cord blood, etc• Cancer vaccines and immunotherapies
– E.g., dendritic cells, activated T lymphocytes (TIL, LAK), B lymphocytes, monocytes, cancer cells chemically modified or unmodified
Examples of cellular therapies
• Pancreatic islets• Chondrocytes• Keratinocytes• Hepatocytes• Xenotransplantation products• Combination Products• Gene therapy modified cells
I. IntroductionMore examples of cellular therapies
OPPORTUNITIES• Cells are dynamic. They migrate,
proliferate, differentiate, and respond to their environment in vitro and in vivo
• Multiple cell types and mechanisms of action can be involved
• Therapeutic outcome can be curative and permanent– Repair, replace, regenerate
I. IntroductionCell therapy opportunities
I. Introduction
CHALLENGES• No terminal sterilization• Limited shelf life (due to cell viability)• Small lot size/limited sample volume• Limited availability of starting material for
process, product, and test method development
• Patient to patient variability and cellular heterogeneity
Cell therapy challenges
II. IND Preparation
II. IND Preparation
• Learn and follow the regulations• Know what’s in your product• Be data driven and include the relevant
data in your submission• Present your information clearly and
concisely. Tables, figures, and flow-charts can be very helpful.
• Provide complete, well-organized, and internally consistent information
Helpful hints
II. IND PreparationSelected regulations for cell therapyRegulation DescriptionHCT/Ps Tissue rules intended to
prevent the spread of infectious disease
21 CFR 1271
Biologics Biologics product testing standards21 CFR 600
Drugs IND requirementsCurrent good manufacturing practices
21 CFR 31221 CFR 211
II. IND PreparationExamples of topics covered in guidance• CMC content and format for cell therapy• Donor Eligibility• CGMP for Phase 1• Potency• Aseptic Processing• Cell Banking• Stability• Process and test method validation
III. Product Manufacturing
Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs) 4/9/2008
III. Product Manufacturing
• Choose an appropriate cell source– Know the history, if applicable– Determine appropriate screening and
testing for autologous and allogeneic donors
– Minimize variability where possible
Cell source
III. Product Manufacturing
AUTOLOGOUS• Donor eligibility determination not required• However, labeling requirements may apply
– “NOT EVALUATED FOR INFECTIOUS SUBSTANCES” (21 CFR Part 1271.90 (b)(2))
– “FOR AUTOLOGOUS USE ONLY” (21 CFR Part 1271.90 (b)(1))
• Processing shown not to support propagation of infectious agents
Cell Source - Autologous
III. Product Manufacturing Cell Source - AllogeneicALLOGENEIC• Donor screening and testing required
– Screened and tested per 21 CFR Part 1271 – Sample timing for DE testing
• Within 7 days of cell harvest/collection• Except peripheral blood stem/progenitor cells
or bone marrow up to 30 days before recovery 21 CFR1271.80(b)
III. Product Manufacturing
• HIV-1 (antigen and NAT)• HIV-2• HCV (antigen and NAT)• HBV (surface & core Ag)• Syphilis
• HTLV-1• HTLV-2• CMV
All Leukocyte rich
Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) - 8/8/2007
Cell Source - Required Donor Testing
III. Product Manufacturing Cell Source – Cell Banks• Master Cell Bank
– In vivo, in vitro, and human virus testing (and potentially animal virus testing)• CMV, HIV-1 & 2, HTLV-1 & 2, EBV, HBV,
HCV, B19– Bacterial, fungal, mycoplasma,
endotoxin– Identity, purity, and activity testing
III. Product Manufacturing
• Working Cell Bank– In vitro virus testing– Bacterial, fungal, mycoplasma,
endotoxin– Limited identity testing
Cell Source – Working Cell Bank
ICH Guidance on Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin - 9/24/1998
III. Product Manufacturing Components/Reagents/Excipients• Reagent table
– Source, supplier, grade, concentration• Qualification program
– Qualify reagent suitability (performs as expected)
– Ensure reagent quality • Establish specifications for safety, purity,
potency or reference a master file• Approve each new lot of reagents through
in-house testing or review and verification manufacturer testing (COA)
III. Product Manufacturing• Choose a robust manufacturing process
– Establish standard operating procedures (SOPs)• Do performance runs to ensure process consistency• Establish procedures to prevent:
– Product mix-ups– Product cross-contamination
• Qualify procedures for safety– killing of tumorigenic cells, viral clearance, absence of
replication competent virus, removal of unwanted residuals, etc.
Guidance for Industry: CGMP for Phase 1 Investigational Drugs - 7/15/2008
Procedures
III. Product Manufacturing
• Tracking of all products from the donor to the consignee or final disposition, and from consignee or final disposition to donor (21 CFR 1271.290(b))
• Appropriate patient identifiers and procedures to prevent product mix-ups
• Procedures in place to ensure product segregation
Procedures - Tracking
III. Product Manufacturing
• Establish adequate facility and equipment performance standards and monitoring plans– Ensure aseptic environment for cell processing
through design and monitoring– Use closed systems where possible– Use disposable equipment and process aids
Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing -- Current Good Manufacturing Practice - 9/29/2004
Facilities
III. Product Manufacturing
• Written procedures for ensuring manufacturing oversight– Review and approval of procedures, testing,
acceptance criteria– Release/rejection of lots– Investigating manufacturing deviations
• Prevent, detect, and correct deficiencies• QC recommended to be independent of
production• Audit procedures and schedule
Quality systems
IV. Product Testing
IV. Product Testing
• Provide meaningful insight into process and product quality
• Contribute to the safety and quality of the final product
In process testing
IV. Product Testing
• Needs to be performed on the final product, not intermediate
• All relevant tests should be performed • Establish meaningful measures of
sterility, identity, purity, and potency
Final product testing
IV. Product Testing
• Define critical product attributes• Define and monitor/control all cell
types present in the product• Establish proper specifications
– Ensure the safety and consistency of product lots
– Base acceptance criteria on experience– Agree with current FDA standards
Product characterization
IV. Product Testing
• Methods – Must be adequate to assess safety – Must include aerobic, anaerobic, and fungal– 610.12 or USP <71> generally accepted– Alternative methods possible under 21 CFR
610.9 • Method Qualification
– Bacteriostasis and fungistasis data required if antibiotics are used in culture
Sterility Testing
IV. Product Testing Microbiological Testing – Rapid Release• Product may be released before 14 day
culture on final product if:– In-process test (48-72 hr) is negative at
time of release– Rapid method, such as Gram stain, is
negative– Final product testing is initiated– Sterility failure plan is in place to ensure
appropriate action and reporting
IV. Product Testing Mycoplasma• Testing should be done after pooling of
cultures but before washing• Recommend rapid method (PCR or other) If
unable to have results of culture based assay prior to administration (21 CFR 610.9 applies)
Draft Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals 7/12/1993
IV. Product Testing Identity Testing• Distinguish from other products
processed in same facility• Ensure labeling is accurate• May also help to characterize the
product– Distinguish between the multiple cell lines
used– Define product composition through
phenotypic analysis
IV. Product Testing Purity Testing• Freedom from extraneous material in the
finished product, whether or not harmful (21 CFR 600.3(r))
• Residuals contaminants– Reagents not intended to be in the product– Unwanted cellular subsets
• Pyrogenicity/Endotoxin– Rabbit pyrogen method required (21 CFR 610.13),
LAL is an alternative method (21 CFR 610.9 applies)
IV. Product Testing Potency Testing• The word potency is interpreted to mean the
specific ability or capacity of the product…to effect a given result. 21 CFR 600.3 (s)
• A quantitative biological assay or correlated to a quantitative biological assay
Draft Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products - 10/9/2008
IV. Product Testing Other Tests• General Safety
– Cellular therapy products are exempt• Viability
– Generally >70% – If not, data showing dead cells do not
affect safety• Cell number/dose
– Minimum, maximum?
IV. Product Testing
• Inappropriate timing of sample collection
• Unacceptable or unqualified test method
• Inadequate description of test method• Inadequate specification• Test not performed
Common Problems
V. Product Stability
V. Product Stability Stability Testing• Required for IND (21 CFR 312.23(a)(7)(ii))
– Data generated at appropriate time and conditions– Minimally will cover time period proposed for
clinical trial– Method, sampling times, temperature, assays
• Should cover shipping, storage, and holding of cells at all phases of manufacturing
• Stability at later phases designed to collect data to support final formulation and dating period
Summary
• Cellular therapies pose unique opportunities and challenges
• CMC information should ensure quality of:– Starting Material and Reagents– Product Manufacturing– Product Testing and Characterization – Product Stability
• Many additional resources are available
Thank you for your attention.