The Challenge of CMC Regulatory Compliance for Biopharmaceuticals, 4th

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. 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 This book highlights the challenges facing quality assurance/quality control (QA/QC) in today's biopharmaceutical environment and presents the strategic importance and value generated by QA/QC for their involvement in control of manufacturing. It will put into perspective the need for a graded approach to QA/QC from early clinical trials through market approval.