Food and Drug AdministrationCenter for Biologics Evaluation and Research
CMC Considerations for Stem Cell-based ProductsProducts
Donald W. Fink, Jr., Ph.D.Phone: (301) 827-5153( )
E-Mail: [email protected] of Cellular, Tissue and Gene TherapiesDivision of Cellular and Gene Therapies / FDADivision of Cellular and Gene Therapies / FDA
CIRM Regenerative Medicine Consortium and FDA Roundtableand FDA Roundtable
November 5, 2009
Presentation Overview Timeline FDA Activities – Pluripotent
Stem CellsStem Cells Stem Cell Biology Poses Regulatory
Challenges General Regulatory Approach General Regulatory Approach Key CMC Issues: Source Controls, Raw
M i l C ll B ki PMaterials, Cell Banking, Process Controls, Product Characterization
2 Early FDA Interaction: Pre-IND Meeting
FDA Activities TimelineFDA Activities Timeline
1998 2000 2001 2002 2008 20091998 2000 2001 2002 2008
CBER RESEARCH PROGRAM
OUTREACH: NIH Stem Cell Task Force / NAS / ISSCR / CIRM / ISCF / US UK Stem Cell Banks /
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ISSCR / CIRM / ISCF / US-UK Stem Cell Banks /Presentations / Book Chapters
Internal Human Embryonic Stem Cell Working Group
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Working Group
MOU Agreements: NINDS (2002) / NHLBI (2008)
Challenges Posed by StemChallenges Posed by Stem Cell Biology
U i P ti f St C llUnique Properties of Stem Cells
C bl f lf i lif ti Capable of self-renewing proliferation
Stem cells may be entirely unspecialized or y y ppossess restricted specialization potential, do not have tissue-specific structures or perform specialized functionsspecialized functions.
Unspecialized stem cells give rise to p gspecialized cells through differentiation.
ll f h b P h ll6
All of the Above Pose Challenges
Potential Product Risks Posed by Stem Cell BiologyCell Biology
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Developmental StagesE I fl
CharacterizationGene expression profile,
Exogenous InfluencesManufacturing Concerns
p p ,Antibodies, Enzymes, In vitro differentiation
Selfrenewal Commitment
TerminalDifferentiation
Lot ReleaseIdentityyPotencySafety
Viability
ManufacturingCell BanksFeeder Layers ViabilityFeeder LayersGrowth FactorsCell CharacterizationS i
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ScreeningDonors, Viruses, Genetic defects
General RegulatoryGeneral Regulatory Approach
Regulation of Cellular and Tissue-Based ProductsProducts
A tiered regulatory framework with the level of regulationproportional to the degree of riskproportional to the degree of risk
Provides greater flexibility intended to encourageinnovation in the field of cellular therapies
Risk determines level of regulationLower Risk – Premarket approval not required; for Control of C i bl Di th Ti R l ti A l S ti 361Communicable Disease the Tissue Regulations Apply: Section 361, PHS Act, 21 CFR Part 1271- Human Cells, Tissue and Cellular and Tissue-Based ProductsHigher Risk – Preapproval Required to demonstrate Safety and Efficacy: Section 351, PHS Act (Biologic); Section 505 Food, Drug and Cosmetic Act (Drug), Investigational New Drug Requirements
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( g), g g q– 21 CFR Part 312; Investigational Device Exemptions – 21 CFR Part 812.
Regulatory Framework:Goals
Prevent unwitting use of contaminated tissues with the potential for transmitting infectious disease
Prevent improper handling or processing that might contaminate or damage tissues
Ensure that clinical safety and effectiveness is demonstrated for cells and tissues that are highly processed used for purposes other than direct reprocessed, used for purposes other than direct re-placement, are combined with non-tissue components, or that have systemic effects.
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Key CMC IssuesKey CMC Issues
Product Development Stage and Review IssuesIssues
BLAPhase IIIPhase IIPhase IPreclinicalDevelopment
Qualification & Validation studies
Product characterization
Safety
Potency
Stage of product development serves to determine key i i ith f t b i i f d i
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review issues, with safety being a primary focus during all stages of development/clinical testing.
Developing Stem Cell-Based Product:Source Controls
Donor Eligibility Determination (DE): screening / testing of Evaluating Human Stem Cell Sources
g y ( ) g gdonors for relevant communicable disease - 21 CFR 1271, Subpart C: Donor Eligibility Final Rule EFFECTIVE DATE M 25 2005 (Ti R l Fi li d) EFFECTIVE DATE: May 25, 2005 (Tissue Rules Finalized) Anonymous/Directed gamete donors must have DE
determination performed based on screening/testing. DONOR SCREENING: review of relevant medical records
(history/exam) for risk factors, clinical evidence of relevant communicable disease agents
DONOR TESTING: required for evidence of relevant communicable disease infection, collection of test specimens within 7-days ± recovery of gametes.
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y y gNOTE: NIH Guidelines on Human Stem Cell Research do not require DE Determination
Developing Stem Cell-Based Product:Source Controls (cont)( )
Evaluating Human Stem Cell Sources
Assess whether intrinsic safety concerns exist based on their biological status as stem cells.g
Develop standardized criteria for accepting donor source materials to initiate production of a stem cell-based product.
Segregation and Tracking: traceability throughout the entire manufacturing process from donor source to final cellpreparation given to patients
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Chemistry, Manufacturing and Controls (CMC) Objectives for Cellular Products(CMC) Objectives for Cellular Products
Demonstrate capability of manufacturingDemonstrate capability of manufacturing process to reproducibly generate an investigational cellular product of definedinvestigational cellular product of defined quality intended for commercial distribution: Within and Between Clinical Trials Throughout the entirety of clinical/productg y p
development
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Achieving CMC Objectives: Control of Raw Materials QualityRaw Materials Quality
Manufacture of a cellular product of defined quality p q yrelies on thorough description, characterization, and testing beginning with:
(1) Source Materials(2) Reagents (3) Ingredients (4) Components used throughout the manufacturing
process.
Contingent upon developing a qualification program
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implemented during product development: applies to raw materials used to manufacture product.
Cell Banking System ConsiderationsSource Material
Expansion
MasterCell BankCell Bank
WorkingCell Bank
18Same level of testing not required for all stages of a multi-tiered cell bank.
Developing Stem Cell-Based Products:Manufacturing Process ControlsManufacturing Process Controls
St d di ti / ti i ti f t / i Critical Manufacturing Process Controls
Standardization/optimization of reagents/processing procedures, including in vitro differentiation protocols
In process/final product characterization and develop In-process/final product characterization and develop-ment of acceptance criteria. Controlling purity and impurities profiles of the final cellular g p y p p
product. Establish parameters to ensure product integrity. Identify characteristics that anticipate effectiveness and
adverse events: assess during preclinical testing. Develop analytical test methods to evaluate proposed
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Develop analytical test methods to evaluate proposed acceptance criteria for in-process intermediates and final product, demonstrate stability.
Developing Stem Cell-Based Product:Detailed CharacterizationDetailed Characterization
Multi-Parametric Approach: Examples of A l ti l T t
Morphologic evaluation / adherence
Analytical Tests
Morphologic evaluation / adherence
Detection of phenotype-specific cell surface ti (t l f f i i h t)antigens (tool for performing enrichment)
Unique molecular / biochemical markers
Gene and protein expression analysis (microarray / proteomics – useful for stability / identity)
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p y y)
Developing Stem Cell-Based Product:Detailed CharacterizationDetailed Characterization
Multi-Parametric Approach: Examples of A l ti l T t ( t)
C ll l h t fil t (t t /
Analytical Tests (cont)
Cellular phenotype profile assessment (target / non-target cell types)
Biologic activity assay potency
MHC/HLA expression- predicting immunologic p p g gcompatibility / anticipating immunogenicity
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Interacting with FDAInteracting with FDA
Developing a Stem Cell-Based Therapy:Early FDA Interaction
• Informal – Pre-pre IND Discussion: Generally CMC and Preclinical Topics
• Pre-IND / Type B – Formal Meeting Sponsors and CBER/FDA staff discuss product development
activities prior to submission of an Investigational New Drug application (IND): may touch on CMC, Preclinical and Clinical.
Represents a key juncture in the regulatory process Represents a key juncture in the regulatory process.
Rule of Thumb: Generally grant one Type B / pre-IND meeting prior to the submission of an IND: Exceptions do occur when
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p pcircumstances dictate. Follow-up communication/interaction is not uncommon.
When is the “Right Time” to Request a Pre-IND Meeting: CMC Perspective
• Directly correlated with the maturity of your cellular product development efforts.
• Should have developed standard procedures• Should have developed standard procedures that allow for reproducible product manufacturing: adequate cellular productmanufacturing: adequate cellular product characterization.
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When is the “Right Time” to Request a Pre-IND MeetingIND Meeting
REGULATORY ROADMAP: EARLY PHASE CLINICAL TRIALS
Discovery Discovery PhasePhase
Permission to Proceed to Early Phase Safety Study
Basic ResearchProof-of-Concept
Pre-INDDiscussio
n with FDA
OriginalIND
Submission
Phase Safety Study
What are your plans? Pre-submission Advice Early Phase Clinical Trial
Evaluation by FDA- 30 days
Demonstrate ability to manufacturebi l i h i “ f ” ( il f f
Pre-pre-INDInformal discus-
biologic that is “safe” (sterile, free ofadventitious agents and unwantedcontaminants)
Adequate product characterizationDemonstrate control of manufactur-
ing process- reproducibility
sions with FDA
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ing process- reproducibilityConducted adequately designed
preclinical studies to assess safety/ activity
Pre-IND Meeting : Examples of CMC TopicsTopics
Sourcing of Cellular Material - Adequate Donor Sourcing of Cellular Material Adequate Donor Testing/ Screening
Qualification of Raw Materials Reagents: use of Qualification of Raw Materials - Reagents: use of animal-derived reagents.
Establishing Cell Banks to Support Product Manufacturing: adventitious agent testing.
Adequate Characterization of Investigational CellularProduct: multi-parametric analytical testing, identity
d i iti fil t bilit26
and impurities profile, stability.
Pre-IND Meeting : Examples of CMC Topics (cont)Topics (cont)
In Process and Final Formulated Product Testing: In-Process and Final Formulated Product Testing: acceptance criteria and release testing (sterility, endotoxin, mycoplasma, identity, potency)., y p , y, p y)
Catheter / needle injection systems-reliably and reproducibly deliver targeted number of viable cells.p y g
Biocompatible cell scaffolds and matrices: tissue constructs
Encapsulation methodologies that prevent immunologic rejection while permitting release of
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g j p gbioactive materials from encapsulated cells (i.e. -islets, insulin)
Tips for a Productive Pre-IND Meeting
Be Prepared: Draft responses to questions in informa- Be Prepared: Draft responses to questions in informa-tional package communicated to sponsor prior to meeting (within 24-hrs)
Focus on the questions requiring additional discussion.
Avoid expending an excessive amount of time on any Avoid expending an excessive amount of time on any one topic/issue when there is a difference of opinion
Seek additional clarification and explanation when Seek additional clarification and explanation when there is uncertainty / request follow-up interaction if necessary.
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SUMMARY
Unique biological attributes of stem cells poseUnique biological attributes of stem cells pose significant regulatory challenges.
A tiered risk based regulatory framework is used for A tiered, risk-based regulatory framework is used for evaluation of investigational stem cell-based products.
Source controls, raw material quality, manufacturing process controls and detailed product characteriza-process controls, and detailed product characterization are pivotal to stem cell-based product development.
29 Early interaction with FDA encouraged.
SELECTED GUIDANCES• Guidance for FDA Reviewers and Sponsors: “Content and Review of
Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic C ll Th IND A li ti ”Cell Therapy IND Applications”
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Xenotransplantation/ucm092705.pdf
• Guidance for Industry: “Q5A Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin”
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G idances/ cm073454 pdfon/Guidances/ucm073454.pdf
• Guidance for Industry: “cGMP for Phase 1 Investigational Drugs”http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070273.pdf
• Guidance for Industry: Formal Meetings with Sponsors and Applicants for PDUFA Products”
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PDUFA Productshttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079744.pdf
REFERENCES
• Fink Jr, DW. “FDA Regulation of Stem Cell-Based Products.”SCIENCE 324:1662-1663 2009SCIENCE, 324:1662 1663, 2009.
• Moos Jr, M. “Stem Cell-Derived Products: an FDA Update.” Trends in Pharmacological Sciences, 29:591-593, 2008.
• DW Fink, Jr., and Bauer, SR. “Stem Cell-based Therapies: FDA Product and Preclinical Considerations.” In The Essentials of Stem C ll Bi l (S d Editi ) Ed R L J G h t B H DCell Biology (Second Edition). Ed. R Lanza, J Gearhart, B Hogan, D Melton, R Pedersen, J Thomson, E Thomas and I Wilmut; Elsevier Academic Press: Burlington, MA, pp. 619-630, 2009.
• CBER/FDA Cellular, Tissue and Gene Therapies Advisory Committee Meeting: “Cellular Therapies Derived from Human Embryonic Stem Cells Scientific Considerations for Pre-Clinical Safety Testing.” (April 10-11, 2008). T i t A il bl t
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Transcript Available at:
http://www.fda.gov/ohrms/dockets/ac/cber08.html#CellularTissueGeneTherapies
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