Introduction to Cellular cgmp Yen-Michael S. Hsu, MD, PhD, FCAP Assistant Professor of Pathology and Laboratory Medicine Assistant Director of Transfusion Medicine Assistant Director of Cellular Therapies Weill Cornell Medical College
Overview of Presentation What is current good manufacturing practice (cgmp)? Rules: regulations & accreditations How to stay compliant? Facility design & operation How to start an clinical trial with novel cell product? Summary 2
GMP World Wide Republic of China USA European Union India Japan Canada Taiwan 3
CAR-T on Magazine Cover 4
Examples of Novel Cellular Product under cgmp Manufacturing CAR-T» CD19 (ALL, CLL, MM, MCL)» Her2 (Glioblastoma, sarcoma)» CD30 (NHL)» CD22 (resistant/refractory ALL) CAR-NK» GD2 (Neuroblastoma) Allogeneic anti-viral Lymphocytes» AdV, EBV, CMV Hematopoietic Stem Cell Expansion» Cord blood» CD34-selected HSC» Small molecules/chemical 5
Why is cgmp Needed? 6
Origin & Purpose of cgmp 1938 Federal Food, Drug and Cosmetic Act Establish the minimum requirement» Drug preparation for human» Animal consumption Safety, Purity, Potency, Identity, and Stability OR 7
cgmp = Clean Room? 8
cgmp = A highly regulated system of practices by FDA 9
cgtp vs. cgmp in Cellular Therapy cgxp cgtp cgmp Purpose/Core requirements Prevent introduction/transmission/spread of communicable diseases Tractability & traceability Can manufacture HCT/P under Section 361 of the PHS Act Drug manufacturing standard Purity/Potency/Safety/Identify/Stability cgtp + DETAILED documentations Regulated under Section 351 of the PHS Act 10
351 vs. 361 Product Manufacturing Human Cells, Tissue, Tissues-based Product (HCT/P) AKA: 361 product Established in May 2005 Exempted from cgmp regulations ( 351 products) Examples Bone, ligament, skin, dura mater, heart valve, cornea Excluding Vascularized transplantable organ Whole blood & blood component Secreted or extracted product 11
361 Product Criteria 1. Minimal manipulation 2. Homologous use 3. No combination with cells or tissues 4. No systemic effect nor dependent on metabolic activity of living cells 12
Critical cgmp Elements Training & certification Processing control (SOP) Production control Equipment Facility Environmental monitoring Validation Management (QC/QA) DOCUMENTATION! 13
Regulatory Agencies for Biologics
Federal Agencies FDA (Food and Drug Administration) Public Health Service Act (initially to regulate biological products) Food, Drug, and Cosmetic Act (to regulate food, drug, and medical devices) Title 21 of Code of Federal Regulations (CFR) CBER (Center for Biologics Evaluation and Research) OCTGT (Office for Cellular, Tissue and Gene Therapies) Regulates HCT/Ps under sections 351 & 361 CDRH (Center for Devices and Radiological Health) CDER (Center for Drug Evaluation and Research) Monoclonal antibodies, therapeutic molecules (protein, cytokine, hormone, etc.) for in vivo functions 15
Clinical Laboratories Regulations State Regulations CLIA 88 16
Be Familiar with Laws & Regulations 21 CFR 211 s: cgmp 21 CFR 312: IND 21 CFR 600 s: Biologics 17
Cellular Therapy Accreditations AABB FACT 18
Systems Needed to Stay Legal Quality Assurance!
Risk-based QA Philosophy & Intent ASTM E2500-07 Risk based and science based approach Specification/design/verification of systems and equipment Provide capability to support consistent manufacturing that meets defined quality requirements. Subject Matter Experts (SMEs) Critical aspects of manufacturing systems to drive specification, design, and verification of facilities and equipment. 20
Scope of Quality Assurance Development requirement Specification Verification Acceptance/release Continuous improvement 21
Building a cgmp Facility
Facility Designs: Rule of Thumb Space & work flow to prevent mix-up Task and operation specific zone Facilitate cleaning, operation and maintenance Air flows from more clean to less clean User/Project specific requirements 23
cgmp Clean Room Space HVAC (HEPA filter) Lighting High purity gases Equipment Building management Cleanable surface Security system 24
ISO Classifications & Maintenance Class/(ISO Rating) Example of operation Class 100/ ISO 5 open manipulations (Biological Safety Cabinet) Aseptic operation Class 1000/ ISO 6 Class 10,000/ISO 7 Adjacent to Class 100 Equipment (centrifuge, incubator, close-systems) Class 100,000/ ISO 8 Surround Class 10,000 (moderate monitor/control) Equipment Material storage Prevent contamination & cross-contamination Reduce airborne and waterborne particles No street clothes (gowning) No sink (alcohol wipe) Segregation of materials and processes with tracking Aseptic techniques 25
Considerations During Designs Multidisciplinary or isolated? Starting material handling Control system Automation Open vs. close systems Product change-over Construction Staff operation Maintenance Safety Environmental issues Licensure or only IND 26
Facility Design Planning Facility programming/analysis (Feasibility study) Understanding and identifying problems Quantifying needs with summary Facility team/building department: building code Synthesis/design evaluation (Feasibility study) Developing solutions for problems Implementation (based on analysis and synthesis results) Action to deliver the solutions 27
Client/User Specifications Product type and specifications Stage of manufacturing Scale of manufacturing Material and personnel flows Efficiency and less error prone Researcher cgmp Director Open dialogues among all participants for goals and needs 28
Facility Design Flexibility Vs. Clean Room Advantage Disadvantage Modular Clean Space Lower cost Easier cleaning Easier monitoring Difficulty to scale up Less flexible to adapt protocol changes
Manufacturing Manufacturing SOPs Automations Product Change-over procedure 30
Cost & Schedule Realistic cost control (@programming phase) Interact to avoid duplication and stimulate comparison Budgets @start-up: Difficult to assess or project. Often based on historical cost data. Likely a moving target! 31
Pitfalls to Avoid During Planning Phase Lack of commitment to process Open to ideas and understanding of day-to-day operational issues Preconceived solutions Brainstorming, not brainwashing Fostering creativity and insights Narrow focus Unreasonable schedule Allow more time and expense Too much details 32
Facility Validation Validation master plan (did I remember everything?) User requirement specification Design qualification (will I be ok to start?) IQ/OQ/PQ Maintenance qualification (is everything taken cared?) 33
Facility Operation: Ready for FDA Inspection & Studies ALL cgmp components reviewed and validated Stay updated on FDA regulation changes Compliance of corrective/preventive actions Avoid unnecessary practice changes during peri-inspection period 34
Designing Clinical Trials Using Investigational Cellular Therapy Products Exciting but many cautions ahead
Phases of Clinical Trials Phase Purposes/Goals # participations Phase 0 Pharmacodynamics Pharmacokinetics ~10 Phase I Safety 20-100 Phase II Efficacy 100-300 Phase III Comparison 1000-2000 Phase IV Post-Marketing Study dependent 37
Investigational New Drug (IND) Regulatory pathway to conduct a clinical trial using a cell therapy (CT) product HCT/P not regulated under 21 CFR 1270.10 (Section 361 of PHS Act) Sponsor: Responsible for and initiate clinical investigation Investigator: Conducting and directing clinical trials and product administration Subject safety is Priority 38
Pre-IND Preparation/Meeting MOST CRITICAL! Pre-clinical testing Cell product manufacturing Cell product characterization Sponsor questions for FDA 39
Starting The IND Process Fulfill pre-ind meeting FDA response time: 30 days Complete Chemistry Manufacturing Control (CMC) Identification, safety, purity, and quality of product Variable depends the phase of the study Generating meaningful data for phase III study 40
Many Guidance Documents Available 41
Summary Patient safety should NEVER be compromised! Co-evolution of science & manufacturing. Sliding scale approach to meet cgmp requirements Endpoint testing alone Assure a quality product Facility design to meet current and future needs Reach the HIGHEST level & standard possible 42
References Adrian Gee. Cell Therapy cgmp Facilities and Manufacturing. New York, NY:Springer New York Dordrecht Heidelberg London, 2009. CFR Mini-Handbook. AABB. 2015 Edition. Cellular & Gene Therapy Guidances http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinforma tion/guidances/cellularandgenetherapy/ 43