This handbook provides an in-depth review of information across the developmental spectrum of gene and cell therapy products. From introductory information to state-of-the-art technologies and concepts, the book provides insights into upstream processes such as vector design and construction, purification, formulation and fill/finish as well as delivery options. Planning steps for compliance with current good manufacturing practice (CGMP) to readiness for chemistry, manufacturing, and controls (CMC) are also discussed.This book wraps up with examples of successes and pitfalls addressed by experts who have navigated the multiple challenges that are part of any innovative endeavor.
Features
- It is intended as a one-stop resource for availability of state-of-the-art information related to cell and gene therapy products for researchers, scientists, management and other academic and research institutions.
- Provides the most up to date information on the development of gene therapy, from the technology involved to gene correction and genome editing.
- Discusses siRNA, mRNA, and plasmid manufacturing.
- Describes the importance of supplier-sponsor synergies on the path to commercialization.
- Diverse audience with a large number of individuals in the core technologies and supportive practices.
Author(s): Hazel Aranha, Humberto Vega-Mercado
Publisher: CRC Press
Year: 2023
Language: English
Pages: 371
City: Boca Raton
Cover
Half Title
Title Page
Copyright Page
Dedication
Table of Contents
Keywords
Preface
Author Biography
Contributors
Abbreviations
Chapter 1: History of Gene Therapy Products
Historical Timeline and Key Technological Advances
Key Historical Trials and Lessons Learned
Key Successes and Regulatory Approvals
Definition of Gene Therapy in the EU
Definition of GTMP in the US
References
Chapter 2: Gene Editing in Humans: How Bioethics Discussions Can Guide Responsible Research and Product Development
Introduction
Risk-Benefit Considerations
Bioethics Considerations in Genome Editing
Regulatory and Nonregulatory Discussions and Declarations
Concluding Comments
References
Chapter 3: Applying a Risk-Based Approach in the Development and Manufacture of Advanced Therapy Medicinal Products
Introduction
References
Chapter 4: Gene Therapy Products: Basics and Manufacturing Considerations
Introduction
Manufacturing Process
Quality Control
Final Remarks
References
Chapter 5: Cell Therapy Products: Basics and Manufacturing Considerations
Introduction
Manufacturing Process
Final Remarks
References
Chapter 6: Facility and Equipment Considerations
Introduction
Facility Design for Cell and Gene Therapy Products
Equipment Design Considerations
Contract Manufacturing Organizations
Supplier-Sponsor Synergies in Development of Cell and Gene Therapies
Final Remarks
References
Chapter 7: Analytical Methods for In-Process Testing and Product Release
Introduction
General Properties of a Typical CAR T Cell Product
Design
MoA and Mode of Action
CQAs
Novel CQA Discovery
General Considerations for the Control of Product Quality
Regulatory Expectations for Analytical Procedures
Development of Analytical Procedures
Control Strategy for Analytical Procedures
Documentation of Analytical Procedures in Regulatory Fillings
Types of Performance Attributes
Study Designs for the Evaluation of Performance Attributes
Robustness
Specificity
Attribute Specificity
Representative Material Specificity
Stability-Indicating Specificity
Accuracy
Precision
Sensitivity
Linearity
Range
Qualifications
Phase I
Phase II/III
Analytical Life Cycle Management during Clinical Development
Validations and Verifications
Analytical Life Cycle Management during Commercial
Managing Critical Instruments
Identifying and Managing Critical Reagents
Continued Performance Verification of Analytical Procedures
Sample Retention
Analytical Procedures
Transduction and Characterization of Integration
Control of Vector Dose during the Manufacture of a CAR T Cell Product
Control of Transduction
qPCR-based Analytical Procedures
Alternative Technology Platforms
Genome Editing and Characterization of Edited Cells
Genome Editing Technologies
Intended Genome Editing Outcomes
Unintended Genome Editing Outcomes
Identity
Purity and Characterization of Phenotype
General Considerations for Analytical Flow Cytometry Methods
Antibody Staining Panel Design
Critical Reagent Management
Critical Instruments
QC Flow Cytometry Methods
Method Development
Method Optimization
Method Robustness
Characterization Methods That Evaluate T Cell Phenotype and Cellular Impurities
Potency
Percent Viable Cells and VCC
Analytical Performance Requirements
Instrumentation and Critical Reagents
Analytical Development
Demonstrating Suitable for Its Intended Use
Strength
Biological Activities Relevant to the MoA and/or Mode of Action
Analytical Performance Requirements
Analytical Development
Instrumentation and Critical Reagents
Process-Related Impurities
Impurity Risk Assessment
Risk Assessment Approaches at Early Stages of Development or for Emerging Modalities/Novel Impurities
Impurity Methods Development Considerations and Key Impurity Method Platforms
Microorganisms, Pyrogens and Adventitious Agents
Sterility
Analytical Performance Requirements
Development of Alternative Analytical Procedures
Demonstrating Suitability for Its Intended Use
Mycoplasma
Analytical Performance Requirements
Development of Alternative Analytical Procedures
Demonstrating Suitability for Its Intended Use
Endotoxin
Development of Analytical Procedures
Demonstrating Suitability for Its Intended Use
Replication Competent Retrovirus
Analytical Performance Requirements
Analytical Development
Demonstrating Suitability for Its Intended Use
General CQAs
Container Content
Uniformity of Dosage Units
Container Closure Integrity
pH
Appearance (Visual Inspection)
References
Chapter 8: Validation, Verification and Qualification Considerations
Introduction
Facility and Equipment Qualifications
Environmental Monitoring and PQ
Process, Method, and Facility Changes
Process Validation Life Cycle
References
Chapter 9: Adventitious Agent Contamination Considerations during the Manufacture of Cell and Gene Therapy Products
Introduction
Risk Assessment and Quality Considerations in Adventitious Agent Contamination Control
Regulatory Approach to Adventitious Agent Contamination Control
Considerations in Adventitious Agent Contamination Control
Source and Raw Materials Controls
Input Materials
Raw Materials, Reagents and Components
Manufacturing Considerations
In-Process Testing
Conclusions
References
Chapter 10: Training Approaches to Build Cell and Gene Therapy Workforce Capacity
Cell and Gene Therapy Workforce Needs
Formal Education Pathways
Accreditation and Competency Frameworks
Short Courses
Conclusion
References
Chapter 11: How to Distribute Cell and Gene Therapies
Logistics Requirements of Cell and Gene Therapies – Demand of the Product
Time Criticality
Cryogenic Storage and Distribution
Chain of Custody
Genetically Modified Therapies
Regulatory Framework of Cell and Gene Therapy Logistics
Logistics for Time-Critical Products
Cryogenic Storage and Distribution
How to Assure Chain of Custody
Logistics of Genetically Modified Cell Therapies and Gene Therapies
Outlook
References
Chapter 12: Regulatory Compliance and Approval
General Considerations
Importance of cGMP in Product Manufacture
Structuring and Streamlining Your Regulatory Submission
Summary and Outlook
References
Chapter 13a: Regulatory Landscape in US, EU and Canada
Introductory Note
Regulation in the EU
Definitions
EU Regulatory Framework
Regulatory Oversight
Regulatory Tools
Approval Pathways
The Regulatory Framework in the US
Definitions
Regulatory Framework
Regulatory Oversight
Regulatory Tools
Approval Pathways
References
Chapter 13b: Regulatory Landscape in South America
Introduction: South America Pharmaceutical Medicines Market
Argentina’s Regulatory Background
Brazil Regulatory Background
Argentina Regulatory Framework on ATMP
Brazil’s Regulatory Framework on ATMP
References
Chapter 13c: Regulatory Landscape in Australia and New Zealand
Australia
Research Sector
Regulation of Therapeutic Goods
Registration of Prescription Medicines
Registration of Biologicals
Regulation of Genetically Modified Organisms
New Zealand
References
Chapter 13d1: Regulatory Landscape in Singapore
Introduction
CTGTPs in Singapore
Definition
Classification
Legislation
Regulatory Review
Product Consultation
Chemistry, Manufacturing and Controls
(Non-)clinical Requirements
Regulatory Pathway
Guidance Documents
Regulatory Registration Requirements and Process
Applicant
Application Route
Evaluation Route
Documentation
Application Process
Life Cycle Management – Variation Application (of a Registered CTGTP)
Fees and Turnaround Time
Clinical Trials
GMP Inspection of Manufacturers
Import, Manufacture and Wholesale of CTGTP
Dealer’s Licensing or Notification and Certification
Advertisement and Sales Promotion
Adverse Events Reporting
Product Defect Reporting
References
Chapter 13d2: Regulatory Landscape in Malaysia
Introduction
Regulatory Pathway for CTGTPs
Definition
Classification
Legislation
Regulatory Review
Pre-submission Meeting (PSM)
Chemistry, Manufacturing and Controls
(Non-)clinical Requirements
Regulatory Pathway
Guidance Documents
Regulatory Registration Requirements and Process
Applicant
Application Route
Evaluation Route
Documentation
Application Process
Lifecycle Management – Variation Application (of a Registered Class II CGTP)
Fees and Turnaround Time
Clinical Trials
GMP Inspection of Manufacturers
Import, Manufacture and Wholesale of CGTP
Dealer’s Licencing or Notification and Certification
Advertisement and Sales Promotion
Adverse Events Reporting
Product Defect Reporting and Recalls
References
Chapter 13e: Regulatory Landscape in China
Background
Administration of CGT Products in China
Relevant Authorities in China
Relevant Key Regulations in China
Registration Pathways of CGT Products in China
Communication Application for Consultation
Clinical Trial Application
Market Authorization Application
Application Document Requirements
Accelerated Procedures
Registration Fees
Post-market Requirements
Conditions Shown in the License
Adverse Events Reporting
Psur
Post-market Changes
Annual Report
Drug Recall
Others
Advertisement and Sales Promotion
Special Considerations for Overseeing CGT Products in China
Clinical Trial Management for Stem Cell Products
References
Chapter 13f: Regulatory Landscape in Japan
Background and History
Regulatory Body in Japan
ASRM
New Directions under ASRM
PMDA: Roles and Responsibilities
Standard and Priority Review
Accelerated or Conditional Approval
Breakthrough Therapy Designation
Cartagena Act for Gene Therapies
Conclusions
Websites
References
Chapter 13g: Regulatory Landscape in India
Introduction
Stem Cell Therapy Guidelines
Classification of Stem Cells
Review and Oversight Committees
Ethical Considerations
Scientific Considerations
Gene Therapy Guidelines
GTP
Classification of Gene Therapy
Review and Oversight Committees
Ethical Considerations
Responsibility of the Stakeholders
Scientific Considerations
Regulatory Process for Clinical Trial Approval and New Drug Approval
Conclusions
References
Chapter 14: Avoiding Pitfalls during Advanced Therapy Development
Introduction
Chemistry, Manufacturing and Control
Nonclinical Studies
Clinical Studies
Approval and Beyond
Conclusion
References
Chapter 15: Going Forward – Existing and Evolving Technologies (CRISPR, mRNA, siRNA)
Introduction
Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) – Historical Review and Future
mRNA – Historical Review and Future
siRNA – Historical Review and Future
Final Remarks
References
Glossary
Index
