Each year for the past three years, there have been about 50 new molecular medicines approved by the United States Food & Drug Administration (FDA), of which approximately 25% were new biopharmaceuticals. Over 200 recombinant proteins, monoclonal antibodies, antibody drug conjugates, fusion proteins, and Fab fragments are now in the marketplace in both the United States of America (USA) and European Union (EU). There are also now over 60 biosimilars available for all major classes of recombinant proteins and monoclonal antibodies. In addition, gene therapies using genetically engineered viruses and genetically engineered cells are now in the marketplace, and continually growing. This degree of change is reflected in the over 400 CMC regulatory compliance references listed in this book that were either issued or updated since the release of the third edition. Deficiencies in biopharmaceutical CMC regulatory compliance rarely result in termination of a product, but in can readily cause months if not years of delay in initiating clinical trials, or advancing clinical development stages, or even market approval.
In summary, this book:
- Updates real-world CMC deficiency examples with current examples;
- Addresses current FDA and EMA requirements and expectations for CMC regulatory compliance;
- Now includes CMC regulatory compliance for the new gene-based biopharmaceuticals.
Author(s): John Geigert
Edition: 4
Publisher: Springer
Year: 2023
Language: English
Pages: 596
City: Cham
Preface
Reference
Acknowledgments
Contents
List of Figures
List of Tables
Abbreviations
Chapter 1: Biopharmaceutical Landscape
1.1 Introduction
1.2 What’s in a Name
1.2.1 Terms: ‘Biologic’ and ‘Biological’
1.2.2 Terms: ‘Biopharmaceutical’ and ‘rDNA-Derived’
1.2.3 Terms: ‘ATMP’ and ‘CGTP’
1.3 Diversity of the Biopharmaceutical Product Landscape
1.3.1 1st Wave – Recombinant Proteins
1.3.2 2nd Wave – Monoclonal Antibodies
1.3.3 3rd Wave – Biosimilars
1.3.4 Transitioning to the ‘Fourth Wave’ of Biopharmaceuticals
1.3.5 4th Wave – Gene Therapy-Based Biopharmaceuticals
References
Chapter 2: Regulatory Pathways Impacting Biopharmaceuticals
2.1 Different Regulatory Pathways
2.2 Navigating United States Regulation for Biopharmaceuticals
2.2.1 Food, Drug, & Cosmetic (FD&C) Act
2.2.2 Public Health Services (PHS) Act
2.2.3 Similarity in CMC Regulatory Requirements Between the Two FDA Laws
2.2.4 Significant Differences in CMC Regulatory Requirements Between the Two FDA Laws
2.2.4.1 Commercial Batch-to-Batch Biologic Product Release
2.2.4.2 21 CFR 610.14 Identity Testing of Commercial Biologic Drug Product After Labeling
2.2.4.3 ‘Bioqualifier’ Suffix Added to Assigned INN for Commercial Biologics
2.2.5 CDER, CBER and CDRH
2.3 Navigating the European Union Regulation for Biopharmaceuticals
2.3.1 NCA Review and Approval During Clinical Development
2.3.2 EMA Review and Approval at Market Approval
2.3.3 CMC Regulation Differences Between EMA and FDA for Biopharmaceuticals
2.4 Embrace the CMC Regulatory Compliance Complexity
References
Chapter 3: Differences in CMC Regulatory Compliance: Biopharmaceuticals Versus Chemical Drugs
3.1 Regulatory Authorities Agree
3.2 Four Major CMC Regulatory Compliance Differences
3.2.1 Difference: Due to Type of Starting Material
3.2.1.1 Keep ‘Alive’
3.2.1.2 Keep ‘Happy’
3.2.1.3 Keep ‘Healthy’
3.2.2 Difference: Due to Inconsistency of Manufactured Product
3.2.3 Difference: Due to Complexity of Molecular Structure
3.2.3.1 Molecular Structure Complexity of Protein-Based Biopharmaceuticals
3.2.3.2 Molecular Structure Complexity of Vector-Based Biopharmaceuticals
3.2.3.3 Molecular Structure Complexity of Transduced Patient Cell Biopharmaceuticals
3.2.4 Difference: Biosimilars Are Not ‘Bio-Generics’
3.2.4.1 Generic Chemical Drugs
3.2.4.2 Biosimilar Biopharmaceuticals
3.3 The Times Are Changing
References
Chapter 4: Risk Management of the Minimum CMC Regulatory Compliance Continuum
4.1 Strategic Risk Management Is Essential
4.2 Minimum CMC Regulatory Compliance Continuum
4.3 Three Interactive CMC Regulatory Compliance Components
4.3.1 CMC Regulatory
4.3.1.1 CMC Content to Be Submitted – Regulatory Authority Guidance
4.3.1.2 CMC Content – Risk-Based and Clinical Stage-Appropriate
4.3.2 cGMPs
4.3.2.1 GMPs Required by Regulatory Authorities
4.3.2.2 GMPs – Risk-Based and Clinical Stage Appropriate
4.3.3 Quality System
4.3.3.1 Quality System Required by Regulatory Authorities
4.3.3.2 Quality Unit Independence from Manufacturing
4.3.3.3 Critical Importance of Training
4.3.3.4 Quality Unit Flexibility – Market-Approval vs Clinical Development
4.3.4 Industry Embracing the Three Interactive Regulatory Components
4.3.5 Consequences of Inadequate Senior Management Support
4.4 QbD/QRM Risk-Based Approach
4.4.1 Quality Target Product Profile (QTPP)
4.4.2 Critical Quality Attribute (CQA)
4.4.3 Critical Process Parameter (CPP)
4.4.4 Control Strategy (CS)
4.4.5 Design Space for Biopharmaceuticals
4.5 Limitations of Risk-Based CMC Regulatory Compliance
References
Chapter 5: Ever-Present Threat of Adventitious Agent Contamination
5.1 Risk-Managing the Ever-Present Threat
5.2 Adventitious Prions
5.2.1 Prion Risk Assessment
5.2.2 Prion Risk Control
5.2.2.1 Raw Materials/Excipients: Animal- or Human-Derived
5.2.2.2 Starting Material: Transgenic Animal Manufacture of Recombinant Proteins
5.2.2.3 Starting Material: Allogeneic Genetically Modified Donor Cells
5.2.3 Necessity of Ongoing Prion Risk Review
5.3 Adventitious Viruses
5.3.1 Virus Risk Assessment
5.3.2 Virus Risk Control
5.3.2.1 Raw Materials: Animal-Derived – FBS and Trypsin
5.3.2.2 Starting Material: Patient/Donor Cells for Ex Vivo Gene Therapy
5.3.2.3 Cell Culture Manufacturing Process: Protein-Based Biopharmaceuticals
5.3.2.3.1 Low Risk Viral Contamination Cell Lines – Bacteria, Yeast, Plant Cells
5.3.2.3.2 High Risk Viral Contamination Cell Lines – Insect, Animal, Human Cells
5.3.2.3.3 Complementary Virus Control: Absence in the Recombinant Production Cell Line
5.3.2.3.4 Complementary Virus Control: Testing at the Appropriate Manufacturing Stage
5.3.2.3.5 Complementary Virus Control: Clearance Capacity of the Purification Process
5.3.2.4 Cell Culture Manufacturing Process: Viral Vector Biopharmaceuticals
5.3.2.5 Cell Culture Transduction/Expansion: Genetically Modified Patient Cells
5.3.3 No Room for Complacency with Adventitious Virus
5.4 Adventitious Mycoplasma
5.4.1 Mycoplasma Risk Assessment
5.4.2 Mycoplasma Risk Control
5.4.2.1 Two Complementary Mycoplasma Controls: Erecting Barriers and Testing
5.4.2.2 Test Methods Available for Mycoplasma Detection
5.4.2.3 Cell Culture Manufacturing Process: Protein-Based Biopharmaceuticals
5.4.2.4 Cell Culture Manufacturing Process: Viral Vector Biopharmaceuticals
5.4.2.5 Cell Transduction/Expansion Patient Cells: Genetically Modified Patient Cells
5.4.3 CMC Strategy Tip: Improvements Sometimes Lead to Other Problems
5.5 Adventitious Bacteria/Fungi
5.5.1 Bacteria/Fungi Risk Assessment
5.5.2 Bacteria/Fungi Risk Control
5.5.2.1 Two Complementary Bacteria/Fungi Controls: Erecting Barriers and Testing
5.5.2.2 Test Methods Available for Bacterial/Fungi Detection
5.5.2.3 Bacteria/Fungi Control: Protein-Based Biopharmaceuticals
5.5.2.4 Bacteria/Fungi Control: Gene Therapy-Based Biopharmaceuticals
5.5.2.5 Message Received
5.5.3 CMC Strategy Tip: Not All Discoveries Have Been Made Yet
5.6 ‘Not Detected’ Is Not Confirmation of Absence
References
Chapter 6: Starting Materials for Manufacturing the Biopharmaceutical Drug Substance
6.1 In the Beginning
6.2 Starting Material for Recombinant Proteins and Monoclonal Antibodies
6.2.1 Development Genetics – Steps Prior to Cell Banking
6.2.2 Importance of Documenting Development Genetics
6.2.3 Importance of the Single Clone
6.2.4 CGMPs for Manufacture and Maintenance of Cell Banks
6.2.5 Characterization of Recombinant Cell Banks
6.2.6 Recombinant Cell Bank Myth Busting
6.2.7 Meeting CMC Regulatory Compliance for Cell Bank Starting Materials
6.3 Starting Materials for Gene Therapy-Based Biopharmaceuticals
6.3.1 Development Genetics
6.3.2 CGMPs Versus ‘Principles of GMP’
6.3.3 CMC Information on Starting Materials in Regulatory Submissions
6.3.3.1 Starting Materials: rAAV Viral Vector for In Vivo Gene Therapy
6.3.3.2 Starting Materials: Manufacture of Genetically Modified Patient Cells (Using rLV)
6.3.3.3 Starting Materials: mRNA to Be Used in Gene Therapy
6.3.3.4 Starting Materials: Genome Editing
6.3.4 Planning for the Logistical Challenges
References
Chapter 7: Upstream Production of the Biopharmaceutical Drug Substance
7.1 At the Start of the DS Manufacturing Process
7.2 Upstream Cell Culture Production of Recombinant Proteins and Monoclonal Antibodies
7.2.1 Assembling the rProtein/mAb Upstream Production Process
7.2.1.1 Expression Systems for Recombinant Protein/Monoclonal Antibody Production
7.2.1.2 Mode of Bioreactor Operations
7.2.2 Applying the Minimum CMC Regulatory Compliance Continuum
7.2.3 Genetic Instability During Production of Protein-Based Drug Substances
7.2.4 Meeting CMC Regulatory Compliance for Upstream Production
7.3 Upstream Cell Culture Production of Viral Vectors
7.3.1 Assembling the Viral Vector Production Process
7.3.1.1 Cell Culture Process
7.3.1.2 Transient Transfection with Recombinant DNA Plasmids
7.3.1.3 Viral Particle Harvest
7.3.1.4 Resources for a More in-Depth Comparison Between AAV and LV Production
7.3.2 Applying the Minimum CMC Regulatory Compliance Continuum
7.3.3 Genetic Instability During Production of Viral Vectors
7.3.4 Meeting CMC Regulatory Compliance for Upstream Production
7.4 Upstream Production of Genetically Modified Patient Cells
7.4.1 Assembling the Transduction Process
7.4.1.1 Selection and Activation of Collected Patient Cells
7.4.1.2 Transduction of Selected Patient Cells with Recombinant Lentivirus Vector
7.4.1.3 Resources for a More in-Depth Understanding of the Transduction Process
7.4.2 Applying the Minimum CMC Regulatory Compliance Continuum
7.4.3 Meeting CMC Regulatory Compliance for Upstream Production
7.5 Upstream IVT Production of Non-Viral Vector (mRNA)
7.5.1 Assembling the Non-Viral mRNA Production Process
7.5.2 Meeting CMC Regulatory Compliance for Upstream Production
7.6 Looking into the Future
References
Chapter 8: Downstream Purification of the Biopharmaceutical Drug Substance
8.1 At the End of the DS Manufacturing Process
8.2 Downstream Purification of Recombinant Proteins and Monoclonal Antibodies
8.2.1 Assembling the rProtein/mAb Downstream Purification Process
8.2.1.1 Harvest Step – The Link Between Production and Purification
8.2.1.2 Chromatographic Systems for Proteins
8.2.1.3 Filtration Systems for Proteins
8.2.1.4 The Downstream Purification Process
8.2.2 Applying the Minimum CMC Regulatory Compliance Continuum
8.2.3 Value/Limitation of Reduced-Scale Purification Studies
8.2.4 Meeting CMC Regulatory Compliance for Downstream Purification
8.3 Downstream Purification of Viral Vectors
8.3.1 Assembling the Viral Vector Downstream Purification Process
8.3.1.1 Chromatographic and Filtration Systems for Viral Vectors
8.3.1.2 The Downstream Purification Process
8.3.1.3 Resources for a More In-Depth Comparison Between AAV and LV Purification
8.3.2 Applying the Minimum CMC Regulatory Compliance Continuum
8.3.3 Value/Limitation of Reduced-Scale Purification Studies
8.3.3.1 Meeting CMC Regulatory Compliance for Downstream Purification
8.4 Downstream Purification of Transduced Patient’s Cells
8.5 Downstream Purification of Non-viral mRNA
8.5.1 Assembling the Non-viral Vector Downstream Purification Process
8.5.2 Meeting CMC Regulatory Compliance for Downstream Purification
8.6 Can We Speed Up Filling in the Knowledge Gap
References
Chapter 9: Manufacturing the Biopharmaceutical Drug Product
9.1 The Drug Product Manufacturing Process
9.2 Conjugation of the Purified Protein Drug Substance
9.2.1 Antibody-Drug Conjugates (ADCs)
9.2.2 PEGylation
9.3 Formulation
9.3.1 Formulation of Recombinant Proteins & Monoclonal Antibodies
9.3.2 Formulation of Gene Therapy Viral Vectors
9.3.3 Formulation of Genetically Modified Patient Cells
9.3.4 Formulation of mRNA Non-viral Vector
9.3.5 Formulation Changes – Tread Carefully
9.4 The Container Closure System
9.4.1 Close Encounters Not Wanted: Product – Container-Closure Interactions
9.4.2 Applying the Minimum CMC Regulatory Compliance Continuum
9.4.3 Combination Products
9.5 Stringent Aseptic Processing During the Filling/Sealing Process
9.5.1 Sterile Formulated Bulk Drug
9.5.2 Aseptic Filling/Sealing Process Step
9.6 Applying the Minimum CMC Regulatory Compliance Continuum
9.7 Meeting CMC Regulatory Compliance for Drug Product Manufacturing
References
Chapter 10: Complex Process-Related Impurity Profiles
10.1 Is It a Process-Related Impurity?
10.2 Process-Related Impurities Based on Manufacturing Process Type
10.2.1 Recombinant Proteins and Monoclonal Antibodies
10.2.1.1 DS Upstream Production
10.2.1.2 DS Downstream Purification
10.2.1.3 Conjugation of DS
10.2.1.4 DP Formulation
10.2.1.5 Impurities from Filling/Sealing of the Drug Product
10.2.1.6 Applying the Minimum CMC Regulatory Compliance Continuum
10.2.2 Viral Vectors
10.2.2.1 Sources of Process-Related Impurities
10.2.2.1.1 Starting Materials
10.2.2.1.2 Upstream Production Process
10.2.2.1.3 Downstream Purification Process
10.2.2.1.4 Formulation, Container Closure System, DP Filling/Sealing Process
10.2.2.2 Applying the Minimum CMC Regulatory Compliance Continuum
10.2.3 Genetically Modified Patient Cells
10.2.3.1 Sources of Process-Related Impurities
10.2.3.1.1 Starting Materials
10.2.3.1.2 Upstream Production Process
10.2.3.1.3 Downstream Purification Process
10.2.3.1.4 Formulation, Container Closure System, DP Filling/Sealing
10.2.3.2 Applying the Minimum CMC Regulatory Compliance Continuum
10.2.4 mRNA Non-Viral Vector
10.2.4.1 Sources of Process-Related Impurities
10.2.4.1.1 Starting Materials
10.2.4.1.2 Upstream Production Process
10.2.4.1.3 Downstream Purification Process
10.2.4.1.4 Formulation, Container Closure System, DP Filling/Sealing Process
10.2.4.2 Applying the Minimum CMC Regulatory Compliance Continuum
10.3 Specific Process-Related Impurities
10.3.1 Residual DNA
10.3.1.1 Recombinant Proteins and Monoclonal Antibodies
10.3.1.2 Viral Vectors
10.3.1.3 Measuring Residual Host Cell DNA
10.3.1.4 Measuring Residual Plasmid or Viral Seed DNA in Transfected/Transduced Cells
10.3.2 Residual Host Cell Proteins (HCPs)
10.3.2.1 Recombinant Proteins and Monoclonal Antibodies
10.3.2.2 Viral Vectors
10.3.2.3 Measuring Residual Host Cell Proteins
10.3.3 Residual Endotoxin – LAL and LER
10.3.4 Leachables
10.3.4.1 Highest Risk of Leachables for Biopharmaceuticals
10.3.4.2 Applying the Minimum CMC Regulatory Compliance Continuum
10.4 Unknown Unknowns
References
Chapter 11: Seemingly Endless Biomolecular Structural Variants
11.1 Is It a Biomolecular Structural Variant?
11.2 Recombinant Proteins and Monoclonal Antibodies
11.2.1 Origin of the Protein Variants in the Manufacturing Process
11.2.1.1 Starting Material
11.2.1.2 DS Upstream Production
11.2.1.3 DS Downstream Purification → DP Filling/Sealing
11.2.2 Structural Variants Due to the Nature of Proteins
11.2.3 Totality of Possible Biomolecular Structural Variants
11.2.4 Applying the Minimum CMC Regulatory Compliance Continuum
11.3 Viral Vectors
11.3.1 Sources of Biomolecular Structural Variants
11.3.1.1 Starting Materials
11.3.1.2 DS Upstream Production
11.3.1.3 DS Downstream Purification → DP Filling/Sealing Process
11.3.2 Issue of Empty Capsids
11.3.3 Applying the Minimum CMC Regulatory Compliance Continuum
11.4 Genetically Modified Patient Cells
11.4.1 Sources of Biomolecular Structural Variants
11.4.1.1 Starting Materials
11.4.1.2 DS Upstream Production
11.4.1.3 DS Downstream Purification → DP Filling/Sealing
11.4.2 VCN – Not Too Much, Not Too Little
11.4.3 Applying the Minimum CMC Regulatory Compliance Continuum
11.5 mRNA Non-Viral Vector
11.6 Variants – A Journey, Not a Destination
References
Chapter 12: Indispensable Potency (Biological Activity)
12.1 Is It Active?
12.2 Importance of the Potency Assay
12.2.1 Characterization
12.2.2 QC Batch-to-Batch Release
12.2.3 QC Stability Program
12.2.4 Product Comparability After Manufacturing Process Changes
12.2.5 Demonstration of Biosimilarity
12.3 Measurement of Biological Activity for Biopharmaceuticals
12.3.1 Bioassay
12.3.2 Surrogate Assay
12.3.3 Assay Matrix
12.4 Applying the Minimum CMC Regulatory Compliance Continuum
12.5 Missing the Target
References
Chapter 13: Biopharmaceutical Critical Quality Attributes
13.1 Appearance
13.1.1 Common Descriptors of Appearance
13.1.2 Intrinsic Visible Particles
13.2 Identity
13.2.1 Difference in Identity Between Chemical Drugs and Biopharmaceuticals
13.2.2 Regulatory Guidance on Identity
13.2.3 Meeting the Criteria
13.3 Purity/Impurities
13.3.1 What Is Purity for a Biopharmaceutical?
13.3.2 Regulatory Guidance on Purity/Impurities
13.4 Potency
13.5 Quantity
13.5.1 Common Descriptors of Quantity
13.5.2 Regulatory Guidance on Quantity
13.5.3 Measurement of Quantity
13.6 Safety
13.6.1 Safety from Adventitious Agents
13.6.2 Replication Competent Virus
13.7 General
13.8 Compiled Tables of CQAs for Different Biopharmaceutical Types
13.8.1 FDA Released CQA Test Results
13.8.2 Project A-Gene
13.8.3 Project A-Cell
13.8.4 mRNA (USP)
References
Chapter 14: The Art of Setting Biopharmaceutical Specifications – Release and Shelf-Life
14.1 What Is a Specification?
14.1.1 Connections Between Testing Categories
14.1.2 Specifications – Only as Reliable as the Test Method Used
14.2 Setting Release Specifications
14.2.1 Spec Linkages
14.2.2 Approaches to Setting Specs
14.2.3 A Time for Everything – Including Statistics
14.3 Setting Shelf-Life Specifications
14.3.1 Stability Assessment – A Regulatory Requirement
14.3.2 Key Basics of the Stability Program
14.4 In-Use Guidance for the Administered Drug
14.5 Applying the Minimum CMC Regulatory Compliance Continuum
14.5.1 Minimum … Continuum Applied to Release Specifications
14.5.1.1 Initiation of Clinical Development Stage (FIH)
14.5.1.2 Later Clinical Development Stage (Pivotal Clinical Studies)
14.5.1.3 Seeking Market Approval Stage
14.5.1.4 Interim Regulatory Specification – Post-market Commitment
14.5.2 Minimum … Continuum Applied to Shelf-Life Specifications
14.5.2.1 Initiation of Clinical Development (FIH)
14.5.2.2 Later Clinical Development Stage (Pivotal Clinical Studies)
14.5.2.3 Seeking Market Approval Stage
14.6 Release Specification Limits – Required Versus Recommended
14.6.1 Required Regulatory Release Specification Limits
14.6.2 Recommended Release Specification Limits
14.7 Need to Get This Right the First Time
References
Chapter 15: The Challenge of Demonstrating Biopharmaceutical Product Comparability
15.1 Manufacturing Process Change Is Inevitable
15.1.1 Process Change – Anytime and Anywhere
15.1.2 Process Change – Should Be Value-Added
15.1.3 Process Change – ICH Q5E Adapted for all Biopharmaceutical Types
15.1.4 The Comparability Study Must Address Three Risk-Based Concerns
15.2 Level of Risk Due to Stage of Clinical Development When Change Is Planned
15.3 Level of Risk Due to Nature (Type, Extent, Location) of Planned Process Change
15.3.1 Assigning Risk Levels to Proposed Manufacturing Process Changes
15.3.2 Risk Levels for Recombinant Proteins and Monoclonal Antibodies
15.3.2.1 Manufacturing Process Changes During Clinical Development
15.3.2.2 Manufacturing Process Changes Post-Market Approval
15.3.3 Risk Levels for Viral Vectors and Genetically Modified Patient Cells
15.3.3.1 Manufacturing Process Changes During Clinical Development
15.3.3.2 Manufacturing Process Changes Post-Market Approval
15.3.4 Established Conditions (ECs)
15.4 Level of Risk Due to Residual Uncertainty Still Remaining
15.5 PACMPs – Comparability ‘Contracts’
15.6 Clear Communication – Comparability Missteps Not Allowed
References
Chapter 16: Strategic CMC-Focused Interactions with Regulatory Authorities
16.1 CMC Regulatory Compliance Strategy – Teamwork Required
16.2 Clinical Development Milestones – Opportunities for CMC Strategy Discussions
16.2.1 FDA’s Encouragement for Milestone Meetings
16.2.1.1 PDUFA Meeting Opportunities
16.2.1.2 BsUFA Meeting Opportunities
16.2.2 EMA’s Encouragement for Scientific Meetings
16.3 Expedited Clinical Development – Opportunities for Additional Discussions
16.4 Securing a CMC Strategy-Focused Meeting
16.4.1 PDUFA Meetings with FDA
16.4.1.1 Request the Meeting
16.4.1.2 Timely Prepare the Meeting Package
16.4.2 BsUFA Meetings with FDA
16.4.3 Scientific Advice Meetings with EMA
16.5 Defending the CMC Strategy During the BLA/MAA Review
16.5.1 FDA BLA Review Process
16.5.1.1 BLA Initial Review
16.5.1.2 Conduct (and Complete) BLA Review
16.5.1.3 Wrap-Up Activities
16.5.2 EMA MAA Review Process
16.5.2.1 Step 2: Decision on Need for cGMP Compliance Inspection
16.5.2.2 Step 7: Day 120 List of Questions (LoQ)
16.5.2.3 Step 11: Day 180 List of Outstanding Questions (LoOQ)
16.5.2.4 Wrap-Up Activities
16.6 Why So Many Problems with Biopharmaceutical CMC Strategy?
16.7 Biopharmaceutical CMC Regulatory Compliance Strategy Future
References
Index
