Stem Cell Production: Processes, Practices and Regulations

Description

This book examines the technologies and processes for the development and commercial production of stem cells according to cGMP guidelines. The initial chapter of the book discusses the therapeutic potentials of stem cells for the treatment of various diseases, including degenerative disorders and genetic diseases. The book then reviews the recent developments in the cultivation of stem cells in bioreactors, including critical cultural parameters, possible bioreactor configuration and integrations of novel technologies in bioprocess developmental stages. The book also introduces microscopic, molecular, and cellular techniques for characterization of stem cells for regulatory approvals. Further, it describes optimal cell transporting conditions to maintain cell viability and properties. Further, it summarizes characterization strategies of clinical grade stem cells for stem cell therapy. This book is an invaluable contribution to having an academic and industrial understanding with respect to R&D and manufacturing of clinical grade stem cells. Preface Acknowledgements Contents About the Editor 1: Stem Cell Therapy: Significance and Applications of Stem Cell Products in Tissue Engineering and Regenerative Medicine 1.1 Tissue Engineering and Regenerative Medicine (TERM) 1.2 Biomaterial Scaffolds as Essential Factors for the Success of TERM 1.3 Stem Cells and Their Products as Essential Factors for the Success of TERM 1.4 Clinical Application of Stem Cells Therapy in TERM 1.4.1 Cardiovascular System 1.4.2 Lungs 1.4.3 Nerves 1.4.4 Bone 1.4.5 Cartilage 1.4.6 Tendon/Ligaments 1.4.7 Liver 1.4.8 Urinary System 1.4.9 Cornea 1.4.10 Skin 1.5 Future Perspective of Stem Cells and Their Products in TERM References 2: GLP Requirements of Stem Cells 2.1 Laboratory Design 2.1.1 Key Consideration in Planning and Design 2.1.1.1 Budget 2.1.1.2 Space 2.1.1.3 Type and Scope of Work Biosafety Requirement for Tissue Culture Labs 2.1.1.4 Major Equipment 2.2 Major Functional Areas 2.2.1 Tissue Culture Laboratory 2.2.2 Quarantine Laboratory 2.2.3 Quality Control Laboratory 2.2.4 Microscopy Laboratory 2.3 Personnel 2.4 Freezer Rooms 2.5 Storage Areas 2.6 Information Technology 2.7 Key Construction Considerations 2.7.1 Engineering Controls 2.7.2 HVAC 2.7.3 Electrical Capacity and Routing 2.7.4 Interior Finishes 2.7.5 Tissue Culture Area 2.7.6 Quality Control Laboratory 2.7.7 Quarantine Laboratory 2.7.8 Storage 2.8 Equipment 2.8.1 Tissue Culture Laboratory 2.8.2 Biosafety Cabinets 2.8.3 CO2 Incubators 2.8.4 Pipettes 2.8.5 Vacuum Flask 2.8.6 Water Bath 2.8.7 Low Speed Centrifuge 2.8.8 Microscopy 2.8.8.1 Phase Contrast Microscope 2.8.8.2 Dissecting Microscope 2.8.9 Storage 2.8.10 Quality Control Laboratory 2.8.10.1 RT-PCR 2.8.10.2 Flow Cytometer 2.8.10.3 Fluorescent Microscope 2.8.10.4 Confocal Microscope 2.8.11 Quarantine Laboratory 2.8.11.1 Class II Biosafety Cabinet 2.8.11.2 CO2 Incubator 2.8.11.3 Phase Contrast Microscope 2.8.11.4 Water Bath 2.8.11.5 Low Speed Centrifuge 2.8.11.6 Pipettes 2.8.11.7 Aspiration/Vacuum Flask 2.9 Quality Control 2.9.1 Reliable Techniques 2.9.2 Validated Reagents 2.9.3 Quality PSCs 2.9.4 Checklist for Confirming Quality 2.10 Approvals 2.10.1 Typical Institutional Review 2.10.1.1 Stem Cell Research Oversight Committee (SCRO) 2.10.1.2 Institutional Review Board (IRB) 2.10.1.3 Biosafety Committee Review (IBC) 2.10.1.4 Institutional Animal Committee (IACUC) References 3: Current Good Manufacturing Practice (cGMP) Facility and Production of Stem Cell 3.1 General Regulation for CGTP 3.2 What Is cGMP? 3.2.1 Primary Aspect in cGMP 3.3 Quality Management System in Good Manufacturing Practice 3.4 Quality System 3.5 Quality Assurance and Quality Control 3.6 Document Preparation and Control 3.7 Facility Design and Construction 3.8 Facility Management 3.9 Environmental Control and Monitoring 3.10 Equipment and Maintenance in cGMP Facility 3.11 Calibration and Performance Check Procedures 3.12 Process, Personnel and Waste Flow 3.13 Cleaning 3.14 Quality Control Requirement for Stem Cell Therapy Products 3.15 Selection of Critical Material 3.15.1 Selection and Evaluation of Donor Suitability 3.15.2 Raw Materials Qualification 3.15.3 Master Cells Stock 3.16 Production Protocol 3.17 Validation 3.18 Process Validation 3.18.1 Media Fill Validation 3.18.2 Material Validation/Use Test 3.18.3 Dry Run 3.19 Equipment and Facility Validation 3.20 Quality Control Testing and Release of the MSCs 3.21 Personnel Training and Competency 3.22 Regulatory Requirement Process 3.23 Ethics, Legal and Social Issues in Stem Cell Research 3.24 Unapproved Stem Cell Therapy 3.25 Risk, Limitation and Adverse Effects Associated with Stem Cell Therapy 3.26 Conclusion and the Way Forward References 4: Global Regulatory Frameworks and Quality Standards for Stem Cells Therapy and Regenerative Medicines 4.1 Introduction 4.2 International Regulatory Framework for Stem Cell and Regenerative Medicine 4.2.1 Europe 4.3 India 4.4 China´s Rules 4.5 Africa 4.6 United States of America 4.6.1 Regenerative Therapy Guidelines 4.6.2 FDA Ends Their Discretionary Period and Is Focusing on Unscrupulous Providers 4.6.3 Risk-Based Regulatory Tiers for Regenerative Therapies 4.6.4 Lowest-Tier Products 4.6.5 Middle-Tier Products 4.6.6 Minimal Manipulation 4.6.7 Structural Versus Non-structural Cells, Tissues 4.6.7.1 Homologous Use 4.6.8 Highest-Tier Products 4.6.9 Opinion of Stakeholders About FDA Framework 4.7 Japan 4.8 Korea, South 4.8.1 South Korea Released New Law on Advanced Regenerative Medicine and Advanced Biopharmaceuticals 4.9 Australia 4.9.1 Access to the Provision of Cell Treatment to Patients 4.9.2 Reporting Adverse Events 4.9.3 Important Risks to Consider 4.9.4 Advertising 4.9.5 Other Regulatory Oversight 4.10 Canada 4.11 United Arab Emirates 4.12 Kingdom of Saudi Arabia 4.13 Israel 4.14 Quality Standards for Regenerative Medicine 4.15 Conclusion References 5: Stem Cell Bioreactors: Design, Structure, and Operation of Stem Cell Bioreactors 5.1 Introduction 5.2 Bioreactors and Its Application 5.3 Types of Bioreactors 5.3.1 Continuous Stirred Tank Bioreactors 5.3.2 Bubble Column Bioreactors 5.3.3 Airlift Bioreactors 5.3.4 Fluidized Bed Bioreactors 5.3.5 Packed Bed Bioreactors 5.3.6 Photo-Bioreactors 5.4 Design of Bioreactors 5.5 Function and Operation of Bioreactors 5.5.1 Culture Condition 5.5.2 Temperature Monitoring During Culture 5.5.3 pH Monitoring During Culture 5.5.4 Addition of Nutrients During Culture 5.5.5 Providing Air During Culture 5.5.6 Monitoring Pressure During Culture 5.6 Application of Bioreactors in Stem Cells Production 5.6.1 Induced Pluripotent Stem Cell Expansion 5.7 Future Prospects in the Advances of Bioreactors References 6: Stem Cell Production: Processes, Practices, and Regulation 6.1 Introduction 6.2 Types of Cell Used as Cell Therapy Medicinal Products: An Overview 6.2.1 Immune Cells 6.2.2 Cells for Regenerative Medicine 6.2.3 Cell Types for Different Approaches 6.3 Cell Sources 6.4 Cell Culture and Expansion 6.4.1 Cell Isolation and Purification Methods 6.4.2 Isolation of MSCs 6.4.3 Limbal Stem Cells Isolation 6.4.4 Treg Isolation 6.4.5 MPhis Isolation 6.4.6 iPSCs Isolation 6.5 Culture Media 6.6 Cell Expansion, Activation, and Differentiation 6.6.1 Immune Cells 6.6.2 Cells for Regenerative Medicine 6.7 Closed Culture Systems 6.8 Cryopreservation 6.9 Conclusions References 7: Upscaling of Clinical Grade Stem Cell Production: Upstream Processing (USP) and Downstream Processing (DSP) Operations of C... 7.1 Introduction 7.2 Background 7.2.1 Atomic to Organismic Level 7.2.2 Stem Cell Production 7.2.2.1 Categories of Stem Cells 7.2.2.2 Main Sources of Stem Cells 7.3 Upscaling of Clinical Grade Stem Cell Production 7.4 Upstream Processing (USP) Operations of Cell Expansion 7.4.1 Upstream Processing Areas, Systems, and Equipment 7.4.2 Clean in Place and Steam in Place Systems 7.4.3 Cell Isolation and Cell Culture 7.4.4 Cell Proliferation and Expression 7.4.5 Cell Banking 7.5 Downstream Processing (DSP) Operations of Cell Expansion 7.6 Harvest 7.7 Detachment 7.8 Separation 7.9 Washing and Concentration Steps 7.10 Regulatory Requirements References 8: Characterization of Clinical-Grade Stem Cells: Microscopic, Cellular, Molecular, and Functional Characterization of Stem Ce... 8.1 FDA Regulations and Recommendations for Cell Therapy Product Characterization 8.2 Characterization Strategies for Cell Therapy Products 8.2.1 Identity 8.2.2 Potency Assays 8.2.3 Reference Materials and Controls 8.2.4 Genome Stability 8.3 Mesenchymal Stem Cell Characterization 8.3.1 Identity 8.3.1.1 Morphology 8.3.1.2 Molecular Markers 8.3.1.3 Multilineage Differentiation 8.3.2 Purity 8.3.3 Viability 8.3.4 Proliferation 8.3.5 Potency 8.3.5.1 Immunoactivity 8.3.5.2 Angiogenic Assays 8.4 Human Pluripotent Stem Cell Characterization 8.4.1 Identity 8.4.1.1 Morphology 8.4.1.2 Molecular Markers 8.4.1.3 Multilineage Differentiation 8.4.2 Viability 8.4.3 Proliferation 8.4.4 Potency 8.5 Neural Stem Cell Characterization 8.5.1 Identity 8.5.1.1 Morphology 8.5.1.2 Molecular Markers 8.5.1.3 Multilineage Differentiation 8.5.2 Viability 8.5.3 Proliferation 8.5.4 Potency 8.6 Hematopoietic Stem Cell Characterization 8.6.1 Identity 8.6.1.1 Morphology 8.6.1.2 Molecular Markers 8.6.2 HLA Typing 8.6.3 Viability 8.6.4 Colony-Forming Cell Assays References 9: Stem Cell Safety and Sterility Testing: A Promising Approach in Regenerative Medicine 9.1 Introduction 9.1.1 Stem Cells 9.2 Stem Cells as Therapeutic Agents 9.3 Types of Stem Cells for Tissue Regeneration 9.4 Impediments and Ethical Concerns with Stem Cell-Based Therapies: How to Perpetuate Stem Cells Safety and Sterility 9.5 Stem Cells Safety 9.5.1 Types and Sources of Contamination and Their Characteristics 9.5.2 Microbial and Viral Contamination: Methods for Detection and Eradication 9.6 Sterility in Stem Cell Culture 9.6.1 Tests and Guidelines for Sterility Testing 9.7 Impact of Contamination in Cell 9.8 Methods to Maintain Sterility 9.9 Conclusion References 10: Stem Cells Storage, Packaging, and Transportation 10.1 Introduction 10.2 Classification of Stem Cells 10.3 Storage and Biopreservation of Stem Cells 10.3.1 Cryopreservation 10.3.2 Chilled Storage 10.3.3 Ambient Temperature Pausing 10.4 Stem Cell Transportation and Packaging 10.5 Cryopreservation 10.5.1 Advantage 10.5.2 Disadvantage 10.5.3 Demand 10.6 Chilled Storage 10.6.1 Advantage 10.6.2 Disadvantage 10.6.3 Demand 10.7 Ambient Temperature Pausing 10.7.1 Advantage 10.7.2 Disadvantage 10.7.3 Demand 10.8 Prospects 10.9 Challenges References 11: Stem Cell Clinical Trials and Stem Cell Market 11.1 Introduction 11.2 Haematopoietic Stem Cells 11.3 Mesenchymal Stem Cells (MSC) 11.4 Limbal Stem Cells (LSC) 11.5 Neural Stem Cells 11.6 Stem Cell Clinical Trials for Diverse Indications 11.7 Cancer 11.8 Clinical Trials in Heart Diseases 11.9 Clinical Trials to Treat Neurodegenerative Diseases 11.10 Clinical Trials in Spinal Cord Injury 11.11 Clinical Trials in Cerebral Palsy 11.12 Clinical Trials of Stem Cells for Treatment of Diabetes 11.13 Clinical Trials of Stem Cells for Treatment of Eye Disorders 11.14 Clinical Trials of Stem Cells for Infectious Diseases 11.15 Challenges of Stem Cell Clinical Trials and Therapy 11.16 Stem Cell Market References