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Regulatory Challenges in the Cell Preparation Facility
Adrian GeeCenter for Cell & Gene Therapy
Regulatory Challenges in the Cell Preparation Facility
Adrian GeeCenter for Cell & Gene Therapy
Overview
• Regulation of Cell Therapy products
• Current regulatory strategy
• Critical issues for regulatory compliance by Cell Preparation Facilities
• Required reporting
• Resources
Background
• FDA classifies Cell Preparation Facilities as drug manufacturers
• FDA required to ensure that drugs are safe and effective
• Initially applied existing drug regulations to cell therapy product manufacturing– products are Investigational New Drugs– manufacturing to comply with Good
Manufacturing Practices (GMP)
New Approaches
• Left “traditional” cell therapies unregulated– Bone Marrow Transplants– Peripheral Blood Progenitor Cell Transplants
• Resulted in new regulations in 2005
• Intended to address risk of communicable disease transmission
• Required manufacturing according to Good Tissue Practices
GMP or GTP?
• Regulations are NOT mutually exclusive• Primary regulatory strategy based on
perceived risk:– to donor– to product during manufacturing
• degree of ex vivo manipulation
– to recipient
• Most cell therapy products must be manufactured under GMP regulations
Regulatory Strategy
• Donor of cells assessed for eligibility– infectious disease testing– risk behavior assessment– not required for autologous products– use of ineligible donors acceptable under
Urgent Medical Need provision
• Manufacture using a controlled, reproducible and auditable process
Critical Areas
• Standard Operating Procedures
• Facility issues
• Training
• Quality
• Product Handling & Processing
• Product Release & Administration
Critical Areas
• Standard Operating Procedures– All aspects of operations: SOP for SOPs
– Appropriate document control• record of SOP release & implementation• staff review and training• updated annually• archived appropriately
Critical Areas
• Facility – annual FDA registration– environmental control– environmental monitoring– equipment: qualification, calibration, cleaning,
maintenance
– maintenance
Critical Areas
• Facility – supplies
• selection• release specifications, testing, management• vendor audits (visits or questionnaire)• water quality
– cleaning, maintenance– waste management– pest control
Critical Areas
• Training– job description– qualifications– initial training– annual retraining– annual training in GMP/GTP– assessment of aseptic technique– competency and proficiency records
Critical Areas
• Quality Program– error and deviation detection & reporting– corrective actions and follow-up– dealing with positive test results post-
administration– products prepared but not used– complaints from customers– audit program– annual quality report
Critical Areas
• Product receipt, release and return
• Product quarantine– for ineligible/pending eligibility– clearly identified area– appropriate labeling
• Product storage and expiration
• Product recall
Critical Areas
• Process controls
• Process validation– started at Phase 1– completed before Phase 3
• Labeling and label controls– correct product name– required language: Autologous use only etc.
– appropriate warnings: Reactive test for... etc.
Product Release• Certificate of Analysis
– identity– purity– potency
• Tests used – CFR compliant?• Sensitivity of testing method• Review of results • Released through QA• Appropriate labeling
Product Administration
• Prescription for administration
• Record of removal from inventory
• Appropriate cross-checks
• Record of additional manipulation and retesting
• Record and investigation of adverse reactions
Required Reporting
• Annual establishment registration
• Annual IND report
• Dear Cell/Gene Therapy letter response– all products manufactured– manufactured and not used
• Response to 483’s
• Documentation of SAEs
Resources
• FDA website– GMP and GTP regulations
• CBER website– Guidances
• Validation of sterility testing• Inspections
– Points to Consider– “What’s New at CBER” alerts– CBER presentations
Resources
• Professional Societies – ISCT– ISSCR– AABB– ICCBBA
• Accrediting Agencies– FACT– AABB– CAP
• Professional Standards– FACT– AABB– USP
• Consultants
Conclusions
• Cell Preparation Facilities are under regulatory scrutiny
• Regulations are still evolving– recent guidances for CMC sections &
pancreatic islets
• Ignorance cannot be used as an excuse
• Good faith efforts are appreciated
• Communication is essential
AcknowledgementsAcknowledgements
CAGT ColleaguesCAGT Colleagues
NHLBINHLBI
SCCTSCCT
PACTPACT
CAGT ColleaguesCAGT Colleagues
NHLBINHLBI
SCCTSCCT
PACTPACT