Cell Therapy: cGMP Facilities and Manufacturing

Description

This new edition presents a fully-updated and expanded look at current Good Manufacturing Practice (cGMP) for cell therapy products. It provides a complete discussion of facility design and operation including details specific to cord blood banking, cell processing, vector production and qualification of a new facility. Several chapters cover facility infrastructure including cleaning and maintenance, vendor qualification, writing a Standard Operating Procedure, staff training, and process validation. The detailed and invaluable product information covers topics like labelling, release and administration, transportation and shipment, et al. Further chapters cover relevant topics like writing and maintaining investigational new drug applications, support opportunities in North America and the European Union, commercial cell processing and quality testing services, and financial considerations for academic GMP facilities. A chapter on future directions rounds out Cell Therapy: cGMP Facilities and Manufacturing making it essential reading for any cell therapy professional involved in the development, use, or management of this type of facility.  Preface Contents Part I: Regulatory Regulation of Cellular Therapy in the United States 1 Introduction 2 Regulatory Authority for Oversight of Cellular Therapy Products 3 Brief History of Cell Therapy Regulations 4 Definition of HCT/P 5 Determining Statutory Authority Applicable to an HCT/P 5.1 Minimal Manipulation 5.2 Homologous Use 6 Classification and Jurisdiction Assistance 7 HCT/Ps Regulated Solely Under Section 361 of the PHS Act 7.1 Reporting [21 CFR Subpart E] 7.1.1 Adverse Reaction Reports [§ 1271.30(a)] 7.1.2 Reports of HCT/P Deviations [§ 1271.30(b)] 7.2 Additional Labeling Requirements [21 CFR Subpart E] 7.3 FDA Inspections and Enforcement Actions [21 CFR Subpart F] 7.3.1 Enforcement Discretion 8 Requirements for HCT/Ps Regulated as Drugs, Biologics, and/or Medical Devices 8.1 Biologic Product Licensing 8.2 Investigational New Drug Application Regulations 8.3 Current Good Manufacturing Practices 8.4 Donor Eligibility and Good Tissue Practices 8.5 Registration and Listing 8.6 Enforcement Actions 9 Requirements of 21 CFR 1271 Applicable to All HCT/Ps, Including Registration and Listing, Good Tissue Practices, and Donor Eligibility Determination 9.1 HCT/P Establishment Registration and Listing 9.2 Good Tissue Practices 9.2.1 Quality Management Program [§ 1271.160] 9.2.2 Personnel [§ 1271.170] 9.2.3 Procedures [§ 1271.180] 9.2.4 Facilities [§ 1271.190] 9.2.5 Environmental Control and Monitoring [§ 1271.195] 9.2.6 Equipment [§ 1271.200] 9.2.7 Supplies and Reagents [§ 1271.210] 9.2.8 Recovery [§ 1271.215] 9.2.9 Processing and Processing Controls [§ 1271.220] 9.2.10 Process Changes [§ 1271.225] 9.2.11 Process Validation [§ 1271.230] 9.2.12 Labeling Controls [§ 1271.250] 9.2.13 Storage [§ 1271.260] 9.2.14 Receipt, Predistribution Shipment, and Distribution of an HCT/P [§ 1271.265] 9.2.15 Records [§ 1271.270] 9.2.16 Tracking [§ 1271.290] Complaint File [§ 1271.320] 9.3 Donor Eligibility, Screening, and Testing 9.3.1 Exemptions from Donor Eligibility Requirements 10 Special Considerations for Cord Blood 11 Gene Therapy Products 12 RMAT Designation 13 Conclusions References Regulatory Landscape and Emerging Trends in Advanced Therapy Manufacturing: An EU Perspective 1 The Legal Framework for ATMP Development and Manufacturing in the European Union (EU) 2 EU Versus US Legislative Frameworks: Identifying Commonalities and Differences 3 Process and Product Development: The Case of Chimeric Antigen Receptor (CAR) T Cells 3.1 Cellular Starting Material 3.2 Process Control Strategies 3.3 Off-the-Shelf Production 4 Automation in Cell and Gene Therapy Manufacturing 4.1 Automation Platforms 4.2 Automation of Process Monitoring 4.3 Opportunities Associated with Automation 5 Models of Distribution for Advanced Therapies Manufacturing 5.1 Advantages of Decentralized Manufacturing 5.2 Regulatory Expectations for Decentralized Manufacturing 6 Conclusions References Australian Cellular Therapy Regulations 1 Determination of a Biological 2 Types of Biologicals 3 Excluded Biologicals 4 Biologicals Regulated as a Therapeutic Good 5 Regulated Biologicals 6 Biological Classifications 6.1 Classification 6.1.1 Class 1 6.1.2 Class 4 6.1.3 Classes 2 and 3 7 Regulation of Autologous Human Cells and Tissue Products 7.1 Autologous Products 7.2 Regulation 7.3 Risk-Based Regulation 7.3.1 Excluded from TGA Regulation 7.3.2 Regulated by the TGA with Exemptions from Certain Requirements 7.3.3 Fully Regulated by the TGA 8 Manufacture of Biologicals and Human Cellular Therapy Products 9 Therapeutic Goods Orders 10 Special Access Schemes 10.1 SAS Category A 10.2 SAS Category B 10.3 SAS Category C 11 Clinical Trials 12 Genetically Modified Organisms 13 Quality Management System 14 Conclusions References Landscape for Regenerative Medicine Manufacturing in Japan 1 Introduction 2 RM Act: Regulations for Medical Therapies and Studies 3 PMD Act: Regulations for Products 4 Additional Regulations and Guidance Documents References GLP Regulations for Nonclinical Studies 1 Introduction 2 Elements of GLP 3 Nonclinical Studies Are Conducted to Support Clinical Trials 3.1 Toxicology Studies to Demonstrate Safety 3.2 Pharmacokinetics 3.3 Local Tolerance 3.4 Bioavailability 3.5 Genotoxicity 3.6 Carcinogenicity 3.7 Reproductive Toxicology 4 Stages of Development: Discovery to Clinical Trials 5 Research Protocol 6 Background/History 6.1 Biologics Control Act of 1902 and Its Revolution 6.2 Establishment of GLP 7 Why GLP Regulations Are Needed for Preclinical Studies 8 FDA’s Proposed Rules 8.1 History of Relevant FDA Documents: 1970–2017 9 The Fundamental Points of GLP 9.1 Rules 9.2 Characterization and Documentation 10 Regulatory Strategy 11 Conclusions References Ethical Considerations in Cell Therapy 1 Introduction 2 Operating Outside the Regulations 2.1 Finding the Loopholes, Promoting the Product 2.2 Posing as Clinical Trials 2.3 Trends Leading to the Popularity of Stem Cell Clinics: Patients’ Rights Movements 2.3.1 Right to Try 2.4 What’s the Harm of Unregulated Cell Therapies? 2.4.1 Physical Harm 2.4.2 Deception of Vulnerable Populations 2.4.3 Financial Risks 2.4.4 Harm to the Field of Regenerative Medicine 3 Operating Inside the Regulatory Framework 3.1 Is It Ready Yet? The Japanese Model 3.1.1 Ethical Issues False Impressions of Safety and Efficacy Products Are on the Market Too Soon, Presenting Safety Risks to Patients 3.2 The Experimental Arena: Ethical Considerations in Cell Therapy Clinical Trial Design 3.2.1 The Problem of the Comparator Group 3.2.2 Study Conduct and Withdrawal from Participation 4 Stem Cell Products: The Human Embryonic Stem Cell Vs. Induced Pluripotent Stem Cell Divide 5 Conclusions References Investigational New Drug Applications for Cell Therapy Products 1 Key Concepts 2 Introduction 3 History of Drug Development Regulation in the USA 4 The Drug Approval Process 4.1 Preclinical Testing 4.2 Investigational New Drug Application 4.3 Contents of IND 4.4 Amendment of IND 4.5 IND Submission 4.6 Inactivation, Withdrawal, and Termination of an IND 4.7 Phases of Clinical Trial 4.7.1 Phase I 4.7.2 Phase II 4.7.3 Phase III 4.8 Biological License Application/New Drug Application 4.8.1 Review of New Drug Application 4.9 Expanded Access to Investigational Drugs for Treatment Use 5 Right to Try 6 Cost of Using Investigational Drugs 7 Expedited Review for New Drugs 8 Phase IV Post-Marketing Surveillance 9 Risk Evaluation and Mitigation Strategies (REMS) 10 The Orphan Drug Act 11 Transparency of Drug Development 12 Institutional Reviews 12.1 Institutional Review Board/Institutional Ethics Committee 12.2 Scientific Review 12.3 Institutional Biosafety Committee 13 Conclusions References FDA Inspections 1 FDA Inspection Program 1.1 Inspection of Type 361 Product Manufacturing Establishments (cGTP) 1.2 Inspection of Type 351 Product Manufacturing Establishments (GMPs) 1.3 Establishment Inspection Reports (EIR) 2 EU Inspections 3 Behavior During a Regulatory Inspection 4 Complaints About FDA Inspections 5 FDA Pre-inspection Opportunities 5.1 Design Review 5.2 Pre-construction Review 5.3 Construction/Equipment Installation and Qualification Review 5.4 Pre-production Review 6 Conclusions References Commercialization of Investigational Cell Therapy Products 1 Introduction 2 Beginnings of Cell Therapy Commercialization 2.1 Epicel 2.2 Carticel 2.3 Sipuleucel-T 2.4 Remestemcel-L 2.5 Chimeric Antigen Receptor T Cells (CAR-T Cells) 2.6 Race to Regulatory Approval for Commercial CAR-T Therapies 3 Key Aspects of Cellular Therapy Commercialization 4 Challenges of Cellular Therapy Commercialization 5 Conclusions References Part II: Quality Systems The Meaning of Quality 1 Quality Principles and Concepts 2 Quality Management 2.1 Plan 2.2 Do 2.3 Check/Study 2.4 Act 3 Regulations and Standards 4 Quality Control 5 Quality Assurance 5.1 Audits 5.1.1 Types of Audits 5.1.2 Focused Audits 5.1.3 Process Audits 5.1.4 System Audits 5.2 Monitors and Indicators 6 Improvement 6.1 Error Management 6.2 Root Cause Analysis 7 Conclusions References Development and Maintenance of a Quality Program 1 Major Regulatory Requirements of a Quality Program 2 Development of a Quality Program 2.1 Initial Activities 2.2 Quality Plan SOPs 2.3 Procedure SOPs 3 The Quality Manual 4 Maintaining the Quality Program 4.1 Deviations 4.2 Audits and CAPA 4.3 Quality Meetings 4.4 Quality Agreements 4.5 Quality Reports 4.6 Accreditation 5 Problems Developing and Maintaining a Quality System 6 Conclusions References Quality Control of Cellular Therapy Products and Viral Vectors 1 Introduction 2 Quality Control (QC) of Somatic Cell Therapy Products 2.1 Microbiological Testing 2.1.1 Sterility 2.1.2 Mycoplasma 2.2 Adventitious Agent Testing 3 Identity Testing 4 Purity 4.1 Residual Contaminants 4.2 Endotoxin 5 Potency 6 Other Assays 6.1 General Safety Assay 6.2 Viability 6.3 Cell Dose 7 Product Stability 7.1 In-Process Stability Testing 7.2 Final Product Stability Testing 8 Quality Control for Manufacture of Viral Vectors 8.1 Master Cell Banks (MCB) 8.2 Working Cell Banks (WCB) 8.3 Master Viral Banks (MVB) 8.4 Working Viral Banks (WVB) 8.5 Final Vector Product 8.5.1 Process-Related Impurities 8.5.2 Product-Related Impurities 8.5.3 Testing of Vector Product [4] 8.5.4 Testing of Genetically Modified Cells 9 Stability Testing on Vector Intermediates and Final Products 10 Release of Products for Administration 11 Other Quality Control (QC) Responsibilities 12 Conclusions References Quality Management Software: Q-Pulse 1 Implementation of Q-Pulse 2 Q-Pulse 21 CFR Part 11 Compliance 3 Electronic Signatures 4 Q-Pulse Modules 4.1 Document Control Module 4.2 Document Revision 4.3 Review of Document Control Module 4.4 Training Module 4.5 Review of Training Module 4.6 Corrective and Preventative Action Module 4.7 Review of the Corrective and Preventative Action Module 4.8 Audit Module 5 Q-Pulse Validation 6 Q-Pulse Implementation 7 Conclusions Selection of Contract Manufacturing and Testing Organizations 1 Alternative Cell Processing Options 2 Contracts with Academic GMP Facilities 3 Contracts with Commercial Manufacturing Companies 4 Selection of Commercial Testing Companies 5 Conclusions References Part III: Facility Design Introduction: Facility Design 1 Design of a GTP Facility 2 Design of a GMP Facility 3 Design Features of Manufacturing Suites 4 Ancillary Areas 4.1 Materials Supply Rooms 4.2 Product Storage Areas 4.3 Janitor’s Closet 4.4 Waste Area 4.5 Quality Control (QC) Area 4.6 Quality Assurance (QA) Area 4.7 Document Storage 4.8 Desk Space 4.9 Meeting Area 5 GMP Certification 6 Conclusions References Design and Operation of a Multiuse GMP Facility at the City of Hope 1 CBG Organization 2 CBG Facility 2.1 Layout 2.2 Exterior Construction 2.3 Interior Construction 2.4 Walls 2.5 Floors 2.6 Ceilings 2.7 Paint 2.8 Doors 2.9 Windows 2.10 Lighting 2.11 Water Sprinklers 3 Critical Systems 3.1 Building Monitoring 3.2 Equipment Monitoring 3.3 Steam Supply 3.4 Electricity and Emergency Backup Systems 3.5 Heating, Ventilation, and Air Conditioning 3.6 Process Gas Supply System 3.7 Vacuum System 3.8 Storage Space 3.9 Cryostorage 4 Improvements 5 Conclusions Design of a Multiuse Acdamic GMP Facility at University of Miami 1 ISCI Organization 2 CRCMP Facility 2.1 Mission and Vision of CRCMP 2.2 Service Highlights 2.3 Accreditations 2.4 Objectives 2.5 Layout of the CRCMP Facility 2.5.1 Supporting Areas 2.5.2 Clean Room Area 2.5.3 Exterior Construction 2.5.4 Walls 2.5.5 Floors 2.5.6 Ceilings 2.5.7 Doors 2.5.8 Windows 2.5.9 Lighting 2.5.10 Fire Sprinklers 2.5.11 Americans with Disabilities Act (ADA) Compliance 3 Work Flow Within the CRCMP Facility 3.1 Personnel Flow 3.2 Reagent/Material Flow 3.2.1 The Cleanroom Laboratory Area 3.2.2 The Development Laboratory (DL) 3.3 Product Flow 3.4 Waste Flow 4 Critical Systems 4.1 Building Monitoring 4.2 Facility Monitoring 4.3 Equipment Management 4.4 Electricity and Emergency Backup Systems 4.5 Heating, Ventilation, and Air Conditioning (HVAC) 4.5.1 Classified Areas 4.5.2 Air Handling 4.5.3 Process Gas Supply System 4.5.4 Vacuum System 5 Conclusions References Design of a New Academic GMP Facility for Today and Beyond at the Dana-Farber Cancer Institute 1 Introduction 2 General Programmatic Considerations 3 Basic Ancillary Space Required to Support Cell Manufacturing 4 DFCI-Specific Strategic Considerations 5 FDA Type-C Review 6 Mechanical Systems 6.1 HVAC 6.2 Gasses and Liquid Nitrogen 6.3 Other Systems 7 Overall Design of the Connell and O’Reilly Families Cell Manipulation Core Facility: 2018 7.1 Stem Cell Therapy (SCT) Laboratory 7.2 Novel Cell Therapy Lab 8 Smith 11 Areas to Support GMP Cell Processing 9 Quality Control (QC): Cell Therapy Testing Lab 10 Methods Development Laboratory 11 Additional Shared Support Areas 12 Conclusions After 2 Years of Operation References Design and Licensure of an American Cord Blood Bank 1 History of Regulatory Requirements 2 Facility Selection and Design 2.1 General Description of MD Anderson Cord Blood Bank Facility 2.2 Access Control 2.2.1 MDACBB Facility Access Control 2.3 Heating, Ventilation, and Air Conditioning (HVAC) 2.4 Temperature and Humidity 2.5 Air Quality 2.6 Redundancy 2.6.1 MDACBB Heating, Ventilation, and Air Conditioning 2.7 Contamination Control 2.7.1 Facility 2.7.2 Equipment 2.7.3 Supplies 2.7.4 Personnel 2.7.5 MDACBB Cleaning/Sanitization Practice Facility Equipment Supplies Personnel 2.8 Containment Features 2.8.1 MDACBB Containment Features 3 Quality System 3.1 Establishing Quality Specifications 3.1.1 Product Specifications (HPC, Cord Blood) 3.1.2 In-process Specifications 3.1.3 MDACBB Cord Blood Specifications 3.1.4 Supplies and Reagent Specifications 3.1.5 MDACBB Supply Specifications 3.2 Vendor Qualification 3.2.1 MDACBB Vendor Qualification 3.3 Manufacturing Facility and Equipment Specifications 3.3.1 Specifications MDACBB Environmental Monitoring 3.3.2 Equipment Specifications 3.3.3 General Guidelines for Equipment Selection MDACBB Equipment Specifications 4 Validations 4.1 Process Validation 4.2 Methods Validation/Verification 4.2.1 MDACBB Validation Experience 5 Stability Program 5.1 Long-Term Stability (Pre-licensure) 5.2 Ongoing Stability (Post-licensure) 5.2.1 MDACBB Stability Program 5.2.2 Out-of-Specification (OOS) Results 6 Conclusions References Indiana University Vector Production Facility (IUVPF) 1 Background 2 Facility and Support Areas 3 Heating, Ventilation, and Air Conditioning (HVAC) Considerations 4 Maintaining Integrity of Vectors Manufactured by IUVPF 5 Lessons Learned 6 Conclusions References Qualification and Commissioning of a New GMP Facility 1 Qualification Plan 2 Initial Activities 2.1 Alarm Systems 2.2 Cleaning and Environmental Monitoring 2.3 Gas Supply 2.4 Equipment 2.5 Calibration 2.6 HVAC 2.7 Training 2.8 Gowning 2.9 Materials and Reagents 2.10 Validation 2.11 Documentation 3 Conclusions References Part IV: Facility Infrastructure Environmental Monitoring 1 Gowning for Monitoring 2 Monitoring Parameters 3 Selection of Sampling Locations 4 Center for Cell and Gene Therapy Risk Assessment (CAGT) 5 Monitoring Devices 5.1 Particle Counters 5.2 Viable Sampling Systems 6 CAGT Monitoring 6.1 Biological Safety Cabinet 6.1.1 Fallout Plates 6.1.2 Replicate Organism Detection and Counting (RODAC) Plates 6.2 Touch Plates 7 Data Management 8 Conclusions References GMP Facility Cleaning and Maintenance 1 Cleaning 1.1 Requirements and Definitions 1.2 Environmental Survey 1.3 Training of Cleaners 1.4 Disinfectants 1.5 Disinfectant Preparation 1.6 Equipment Used for Cleaning 1.7 Cleaning Frequency 1.8 Cleaning Methods 1.8.1 Two-Bucket Method for Floors, Walls, and Ceilings 1.8.2 Biological and Laminar Air Flow Cabinets 1.8.3 Worksurfaces and Cabinetry 1.8.4 Equipment and Tools 1.9 Waste Removal 2 Sources of Contaminants 2.1 Resistant Organisms 3 Environmental Monitoring 4 Common Cleaning Citations 5 Maintenance 5.1 Facility Maintenance 5.2 Equipment Maintenance 6 Conclusions References GMP Documentation 1 GMP Documentation Management Introduction 2 Standard Operating Procedures 2.1 Types of SOPs 2.2 Document Control 2.2.1 Numbering Systems for SOPs 2.3 Formatting and Content of SOPs 2.3.1 Purpose 2.3.2 Scope 2.3.3 Definitions 2.3.4 References 2.3.5 Health and Safety 2.3.6 Equipment and Materials 2.3.7 Procedure 2.3.8 Expected Endpoints 2.3.9 Attachments 2.4 Writing SOPs 3 Validation Plans 4 Document Approval 4.1 New SOPs 4.2 Revised SOPs 4.3 Retired SOPs 5 Document Distribution and Availability 6 Production Batch Records (PBR) 7 Training Documentation 8 Archival of SOPs 9 Annual Review 10 Conclusions Process Validation 1 Introduction 2 Definition of Terms 2.1 Process Validation 2.2 Process 2.3 Procedure Validation 2.4 Qualification 2.5 Verification 3 Process Validation 3.1 Process Design 3.2 Process Qualification 3.3 Continued Process Verification 4 The 2011 Guidance Document Vs the 1987 Guidance Document 5 Performing a Validation Study 5.1 Prospectively 5.2 Concurrently 5.3 Retrospectively 5.4 Revalidation 6 The Validation Plan 7 Conclusion References Equipment Qualification 1 Introduction 2 Qualification Procedures [2] 2.1 Design Qualification (DQ) 2.2 Installation Qualification (IQ) 2.3 Operational Qualification (OQ) 2.4 Performance Qualification (PQ) 3 Design Qualification 4 Installation Qualification 5 Operational Qualification 6 Performance Qualification 7 Requalification 8 Approval of Qualification 9 Conclusions References Vendor Qualification and Supply Management 1 Regulatory Requirements and External Standards 1.1 Establishing Your Program for Vendor Management and Supply Management 1.2 Qualification of Vendors and Service Providers 1.3 Supply Agreements, Quality Agreements/Contracts, and Change Notification 1.4 Monitoring and Tracking Supplier Performance 2 Pandemics, Supply Chains, and Disaster Mitigation Strategies 3 Selecting Supplies and Establishing Release Specifications 4 Evaluation, Testing, and Release 5 Issuance and Batch Traceability 6 Storage 7 Recalls and Product Advisories 8 Inventory Management 9 Expired Materials 10 Personnel 11 Conclusions References Staffing, Training, and Competency 1 Introduction 2 Analysis 3 Job Description 4 Training Regulations 5 Design of Training Program 6 The Adult Learner 7 E-Learning 8 Development 9 Implementation 10 Evaluation 11 Competence 12 Remediation 13 Recordkeeping 14 Conclusion References Part V: Product Management Product Accessioning, Tracing, and Tracking 1 General Requirements for Accessioning 2 Labels 2.1 Labeling During Manufacturing 2.2 Final Labels 3 Storage 4 Distribution and Administration 5 Shipment 6 Disposal 7 Conclusions References ISBT 128 in Labeling of Cellular Therapy Products 1 Introduction 2 Historical Perspective 3 Key Elements of ISBT 128 4 Uniqueness of Donor and Donation 5 Structured Standardized Terminology 6 Product Database and Product Description Codes 7 Data Structures 8 Role of ICCBBA and CTCLAG 9 Practical Considerations for the Implementation of ISBT 128 10 Conclusions References Product Processing, Manufacturing, and Administration 1 Regulatory Issues 2 Facility Design and Review 3 Reagents and Materials 4 Manufacturing Techniques 5 Culture Media 6 Manufacturing Validation 7 Changeover Procedures 8 In-Process Testing 9 Product Labeling 10 Finish and Fill 11 Cryopreservation 12 Long-Term Storage 13 Release Testing 14 Product Administration 14.1 Documentation 14.2 Cryopreserved Product Administration 14.3 Thawed and Fresh Product Administration 15 Conclusions References Transport and Shipment of Cellular and Gene Therapy Products 1 General Packaging Requirements 2 Transportation of Fresh Cells 2.1 General Packing Considerations for Fresh Cells (Fig. 1) 2.2 General Labeling Considerations 3 Shipment of Cryopreserved Products 3.1 Dry Shipper Qualification 3.2 Packaging of Frozen Shipments 3.3 Documentation Requirements for Cryopreserved Shipment 3.4 Shipping Companies for Cryopreserved Products 3.5 Action upon Receipt of Shipments 4 Transportation for Patient Administration 4.1 Cellular Therapy and Hematopoietic Products 4.2 Administration of Viral Vectors 5 Shipment of Viral Vectors 6 Conclusions References Regenerative Medicine: The Newest Cellular Therapy 1 Introduction 2 Tissue Engineering in Regenerative Medicine 2.1 Autologous 2.2 Allogeneic 2.3 Xenogeneic 3 Biomaterials 3.1 Acellular Tissue Matrix 3.2 Manufactured Scaffolds 4 Biomaterials Considerations 4.1 Level of Complexity in Regenerative Medicine Tissue Engineering 4.2 Extracellular Matrix: External Applications 4.3 Flat Organs 4.4 Hollow Organs 4.5 Solid Organs 5 Key Problems in Regenerative Medicine Therapies 5.1 Vascularity in Tissue-Engineered Structures 5.2 3D Bioprinting 5.3 Undeveloped Quality Control Metrics and Lack of Standards 5.3.1 Nondestructive Quality Testing 5.3.2 Potency Testing 5.4 Scaling Up 6 Future Promises in Regenerative Medicine 7 FDA and Regenerative Medicine 7.1 Initial Targeted Engagement for Regulatory Advice on CBER Products (INTERACT) Program 7.2 Regenerative Medicine Advanced Therapy (RMAT) Program 7.3 CBER Advanced Technologies Team (CATT) Program 7.4 Other FDA Guidance Documents 7.5 (PHS) Act 351 7.6 Twenty-First Century Cures Act (Cures Act) of 2016 8 Conclusions References Cellular Therapy Applications for COVID-19 1 Introduction 2 COVID Cellular Therapy 3 Biology of Cell Therapy for COVID-19 Pneumonia 4 Virology of Coronaviruses and Cytokine Release Syndrome in COVID-19 5 Effects of MSCs on the Immune System 6 Early-Stage Clinical Information 6.1 Mechanism for Cytokine Suppression 7 Pivotal Clinical Trials 8 Examples of Ongoing Pivotal Multicenter Clinical Trials 9 Expanded Access 10 Conclusions References Part VI: Professional Standards and Support Organizations Professional Standards for Cellular Therapy: The Foundation for the Accreditation of Cellular Therapy (FACT) 1 Historical Background 2 Recent Advances 3 FACT Standards for Immune Effector Cells 4 Standards 4.1 Standards Development 4.2 Current Standards 4.2.1 FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration 4.2.2 FACT Standards for Immune Effector Cells 4.2.3 NetCord-FACT International Standards for Cord Blood Collection, Processing, Testing, Banking, Selection, and Release 4.2.4 FACT Common Standards for Cellular Therapies 5 Accreditation 5.1 Types of Accreditation 5.1.1 Hematopoietic Cell Transplantation 5.1.2 Immune Effector Cell Accreditation 5.1.3 FACT Accreditation for Cord Blood Banks 5.1.4 Accreditation Under FACT Common Standards 6 Accreditation Process 7 Current Accreditation Statistics 8 Common Citations 9 International Expansion of Accreditation 9.1 FACT-JACIE International Stepwise Accreditation 9.1.1 FACT-SBTMO Accreditation in Brazil 9.1.2 FACT-India Working Group 10 Conclusions: Significance of FACT Accreditation References AABB Cell Therapy Standards 1 AABB: History and Evolution 2 Development and Evolution of Standards 3 Quality Systems Approach to Cellular Therapies 4 Transparency in Standards-Setting 5 Assessing Conformance to Standards 6 Accreditation 7 Validation of Assessments 8 AABB Cellular Therapies Certificate Program 9 Circular of Information for the Use of Cellular Therapy Products 10 ISBT 128 Labeling of Cellular Therapy Products 11 Technical Highlights of Each Edition 12 Conclusions References USP Standards for Cell-Based Therapies 1 Introduction: Why Standards for Cell-Based Therapies? 2 The United States Pharmacopeial Convention (USP) 3 The USP-NF “Book” of Standards 4 Evolution of Pharmacopeial Standards 5 A Public and Science-Based Approach to Standards Development 5.1 Volunteers Are at the Heart of the Standards-Setting Process 5.2 Developing Standards and Biologics 5.3 Physical Reference Standards 6 Standards Applicable to Cell-Based Therapies 6.1 USP ၆: Inaugural Cell Therapy Chapter in USP-NF 6.2 Revision of Chapter ၆ and the Creation of Chapter ၇ 6.3 Qualifications of Ancillary Materials Used in Manufacturing 6.4 From General to Specific Requirements: Standards for Ancillary Materials 6.5 Flow Cytometry: A Workhorse Technique in Cell-Based Therapy Applications 6.6 Cryopreservation of Cells 6.7 Sterility Assurance 6.8 Product-Specific Standards: Challenges and Opportunities 7 Importance of Standards and Need for Collaborative Efforts 8 The Path Forward and Future of Standards at the USP: Concept and Examples 9 Conclusions References The Role of the National Institute of Standards in Measurement Assurance for Cell Therapies 1 The Roles of NIST as the National Measurement Laboratory 2 Measurement Assurance and Standards for Cell-Based Therapies 2.1 The Role of Standards 2.2 Community Engagement 2.3 Assisting Measurement Assurance 3 Laboratory Technical Activities in Support of Cell-Based Therapies 3.1 Cell Counting 3.1.1 Importance of Cell Enumeration 3.1.2 Establishing a Performance Metric 3.1.3 Counting Viable and Non-viable Cells 3.2 Flow Cytometry 3.2.1 Challenges to Comparability 3.2.2 Equivalent Number of Reference Fluorophores 3.2.3 Quantifying Biomarkers 3.3 Quantitative Microscopy 3.3.1 Measurement Assurance in Imaging 3.3.2 Live Cell Imaging 3.3.3 Label-Free Imaging 3.3.4 Image Analysis and Machine Learning 3.4 Genomic Measurements and Gene Editing 3.4.1 Genome Editing Consortium 3.4.2 Genome in a Bottle Consortium 4 Conclusions References National Science Foundation Engineering Research Center for Cell Manufacturing Technologies (CMaT) 1 Introduction 2 Need for a Comprehensive, International Effort in Technology Development for Cell Manufacturing 3 Vision and Mission 4 Structure 4.1 Academic and Clinical Partnership 4.2 Industry Partners 4.3 Organizational and Management Structure 4.3.1 Management Structure Research Executive Committee 4.4 Student Leadership Council and Advisory Boards 4.4.1 Student Leadership Council 4.4.2 Scientific and Clinical Advisory Board 4.4.3 Workforce Development Advisory Board 4.4.4 Industry/Practitioner Advisory Board 4.4.5 Sustainability Advisory Board 5 Facilities 6 The Roadmaps 7 Harmonization and Standards Development 8 Workforce Development 9 Regional and CMaT-Wide Synergies 10 Innovation Ecosystem 11 Diversity and Inclusion 12 Conclusions References Financial Considerations for Academic GMP Facilities 1 Whether or Not to Build a cGMP Facility 2 What to Build 3 Operational Costs 4 Contract Manufacturing 5 Other Funding Sources 6 Conclusions References Governmental Support Opportunities for Cellular and Gene Therapies in the United States 1 Introduction 2 Federal Funding Agencies 2.1 National Institutes of Health (NIH) 2.1.1 NIH-Wide Programs 2.2 NIH Grants Process 2.3 Other Department of Human Health and Services Funding Organizations 2.4 National Science Foundation (NSF) 2.5 Department of Defense (DoD) 3 Federal Funding for Small Business Research 4 US Federal–Private Partnerships to Advance Cellular Therapy Manufacturing in the United States 4.1 The National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) 4.2 Advanced Regenerative Manufacturing Institute References Index