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

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