The Challenge of CMC Regulatory Compliance for Biopharmaceuticals / Edition 1

The Challenge of CMC Regulatory Compliance for Biopharmaceuticals / Edition 1

by John Geigert

ISBN-10: 0306480409

ISBN-13: 9780306480409

Pub. Date: 12/31/2003

Publisher: Springer-Verlag New York, LLC

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.


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.

Product Details

Springer-Verlag New York, LLC
Publication date:
Edition description:
Older Edition
Product dimensions:
0.94(w) x 7.00(h) x 10.00(d)

Table of Contents

List of Tablesxix
List of Figuresxxiii
Chapter 1Biopharmaceutical CMC Regulatory Compliance: What is It?
1.Defining Our Terms1
1.1.What is a 'Biopharmaceutical'?2
1.2.What is 'CMC'2
1.3.What is 'CMC Regulatory Compliance'?3
2.Under the Biopharmaceutical Umbrella3
2.1.Recombinant DNA-Derived Proteins3
2.2.Monoclonal Antibodies5
2.3.Gene Therapy7
2.4.Animal/Plant Transgenics8
2.5.Rapid Pace of Biopharmaceutical Development8
3.Regulatory Development of Biopharmaceuticals9
3.1.The Drug Development Process9
3.2.Regulatory Agency Review10
3.2.1.U.S. FDA10
4.CMC Regulatory Compliance Track Record13
4.1.Drugs and Biologics13
Chapter 2Are Biopharmaceuticals Really Different?
1.Perception or Reality?17
1.1.Five Questions Frequently Asked18
1.2.Bottom Line Question18
2.Regulatory Agencies Speak18
2.1.U.S. FDA19
3.Three Unique CMC Challenges for Biopharmaceuticals21
3.1.The Use of Living Recombinant Organisms21
3.2.The Products Themselves22
3.3.The Impact of the Manufacturing Process22
4.CMC Meetings with the FDA Take on Greater Importance23
4.1.CMC Communication with FDA is Critical25
4.2.Preparing for the CMC Meeting26
4.3.Pre-IND Meeting27
4.4.End of Phase 2 (EOP2) Meeting29
4.3.Pre-BLA/NDA Meeting31
5.What About CMC Meetings with EMEA?33
6.Biopharmaceuticals Need to be Treated Differently34
Chapter 3Developing the Corporate CMC Regulatory Compliance Strategy
1.Three Key Elements for a Complete CMC Strategy35
1.1.Element 1: The Broad CMC Scope Must Be Considered36
1.2.Element 2: Any Unique CMC Issues Must Be Addressed37
1.3.Element 3: Must Meet Minimum CMC Regulatory Requirements38
2.The Minimum CMC Continuum39
3.Minimum CMC Requirements for Clinical Development40
3.1.An Overview40
3.2.Phase 146
3.3.Phase 2 and 347
4.Full CMC Requirements for Dossier Filing48
4.1.Comparison of BLA/NDA and CTD CMC Formats49
4.2.Adequate Resources Required to Compile the Full CMC Dossier51
4.3.Quality of CMC Content Present in Dossier is Critical52
5.'Case-By-Case' CMC Strategy Specifics54
Chapter 4Can't Ignore cGMPs
1.Not Optional57
1.1What are 'cGMPs'?57
1.2Three main GMP questions58
2.GMPs for Everything59
2.1.For Finished Drug Products59
2.2.Required for APIs Also63
2.3.Extra GMPs for Biopharmaceuticals66
3.Where in the Manufacturing Process Should GMP Begin?68
4.When During Clinical Development Should GMP Begin?70
4.1.API Clinical Trial Materials70
4.2.Drug Product Clinical Trial Materials73
5.Consequences of Not Following GMPs73
5.1.Issues with Market Approved Biopharmaceuticals74
5.2.Issues During Clinical Development77
5.3.How to Avoid GMP Difficulties with the FDA78
6.Strategic CMC Tips for GMP Compliance80
Chapter 5Recombinant Source Material: Master/Working Banks
1.Needed: Reliable, Continuous, Stable Genetic Source83
1.1.Three Primary CMC Concerns for Banks84
1.2.Genetic Construction of a Bank85
2.So Many Hosts to Choose From88
2.1.Bank Terminology88
2.2.Choosing the Host89
2.2.1.Drivers to Reach a Decision89
2.2.2.Why Choose Recombinant Cells?90
2.2.3.Why Bioengineered Animals or Plants?91
3.CMC Guidance on Preparation of a Bank92
3.1.Accurate and Thorough Description of Preparation92
3.1.1.Recombinant Cell Banks93
3.1.2.Transgenic Banks95
3.2.Why Does The FDA Want So Much CMC Documentation?98
3.3.When is Full CMC Documentation Needed?99
3.4.What If CMC Documentation is Missing?100
3.5.Don't forget GMPs During Preparation of the Bank100
4.CMC Guidance on Characterization of a Bank101
4.1.Appropriate and Sufficient Characterization102
4.1.1.Six Key Elements for a Thorough Characterization102
4.1.2.Recombinant Cell Bank Characterization103
4.1.3.Example of Characterization of a Bacterial Cell Bank105
4.1.4.Example of Characterization of a Mammalian Cell Bank106
4.2.How Much Characterization and When?107
4.3.Critical Concern for Virus Safety in Banks109
4.4.Minimizing the Risk of TSEs111
5.A Successful CMC Strategy for Banks113
Chapter 6Production: Expansion of the Recombinant Organism and Expression of the Biopharmaceutical
1.Goals: Identity, Capacity and Consistency115
1.1.Two Major CMC Regulatory Concerns for Production116
1.2.Need for High and Consistent Expression of the Biopharmaceutical116
1.3.What is a 'Production Process'?117
1.3.1.Types of Bioreactors for Cell-Based Production118
1.3.2.Harvesting Procedures for Biopharmaceuticals119
1.4.Production Processes Familiar to the FDA119
2.Adequate Description of the Production Process122
2.1.During Clinical Development122
2.1.1.Phase 1 IND Submission122
2.1.2.Phase 2 IND Submission124
2.1.3.Phase 3 IND Submission124
2.2.Preparing the BLA/NDA Submission125
3.Validation of a Cell-Based Production Process128
3.1.When Should Validation of the Production Process Occur?129
3.2.Five Major Areas Involved in Validation of the Production Process130
3.2.1.The Production Facility, Utilities and Process Equipment130
3.2.2.Monitoring of Growth Parameters132
3.2.3.In-Process Controls133
3.2.4.Genetic Stability136
3.2.5.Cleaning Validation137
3.3.Final Comments on Process Validation140
4.Additional Production Controls and Concerns140
4.1.Cell-Based Production Processes140
4.1.1.Cell Culture Media Acceptance Criteria141
4.1.2.Avoidance of Animal- and Human-Derived Raw Materials141
4.1.3.Containment of the Recombinant Organism144
4.1.4.Contamination Control for Aseptic Processing Operations144
4.2.Gene Therapy Production Processes146
4.2.1.Control of the Cells146
4.2.2.RAC Review and Approval of the Production Process148
4.3.Transgenic Animal Production Processes149
4.3.1.Production Controls149
4.3.2.Protecting the Gene Pool151
4.4.Transgenic Plant Production Processes151
4.4.1.'Pharming' Controls152
4.4.2.USDA/APHIS Protecting the Gene Pool155
5.What Can Go Wrong157
6.Strategic CMC Tips for Production158
Chapter 7Purification of the Biopharmaceutical
1.Goals: Purity, Recovery and Consistency161
1.1.Two Major CMC Regulatory Concerns for Purification162
1.2.Need for High Recovery of a Pure Product162
1.3.What is a 'Purification Process'?163
1.3.1.Physical Separations Methods for Biopharmaceuticals164
1.3.2.Chromatographic Purification Methods for Biopharmaceuticals165
1.4.Purification Processes Familiar to the FDA167
2.Adequate Description of the Purification Process169
2.1.During Clinical Development170
2.1.1.Phase 1 IND Submission170
2.1.2.Phase 2 IND Submission171
2.1.3.Phase 3 IND Submission172
2.2.Preparing the BLA/NDA Submission172
3.Facility and Utility Concerns174
3.1.Design and Operation175
3.2.Environmental Monitoring176
4.Purification Process Validation177
4.1.When Should Purification Validation Occur?177
4.2.Process Validation Concerns for a Chromatographic Step178
4.3.Process Validation Concerns for a Filtration Step182
5.In-Process Controls183
6.Process-Related Impurity Profile185
7.Viral Safety Evaluation188
7.1.General Study Design189
7.2.Justification of the Choice of Viruses191
7.3.Calculation of Virus Reduction Factors193
7.4.Virus Safety Calculation195
7.5.Worth All the Trouble and Cost?196
7.6.When Should the Viral Clearance Studies Be Performed?196
8.Purification Controls for Gene Therapy Processes197
9.What Can Go Wrong197
10.Strategic CMC Tips for Purification199
Chapter 8Biopharmaceutical Drug Product Manufacturing
1.Three Basic CMC Regulatory Concerns201
2.Formulation of a Biopharmaceutical203
2.2.Formulations Familiar to FDA203
2.3.Chemical Modification of API Prior to Formulation205
3.Biopharmaceutical Manufacturing Processes206
4.Adequate Description of the Manufacturing Process208
4.1.During Clinical Development209
4.1.1.Phase 1 IND Submission209
4.1.2.Phase 2 IND Submission210
4.1.3.Phase 3 IND Submission211
4.2.BLA/NDA Submission212
5.Adequate Control Over the Manufacturing Process213
5.1.Regulatory Requirements for Market Approved Products214
5.2.Regulatory Expectations During Clinical Development216
6.What Can Go Wrong217
7.Strategic CMC Tips for Drug Product Manufacturing218
Chapter 9Physicochemical/Biological Analysis of the Biopharmaceutical Product
1.A Challenging Analysis222
1.1.Goals: Consistent, Safe, Potent and Pure Product222
1.2.Relationship Between Product Characterization and QC Testing223
2.Unraveling the Molecular Properties224
2.1.Molecular Variants for DNA224
2.2.Molecular Variants for Proteins224
2.3.Plethora of Analytical Methods Available For Proteins226
3.Characterization of Biopharmaceuticals229
3.1.Regulatory Expectations During Clinical Development229
3.1.1.Phase 1 IND Submission229
3.1.2.Phase 2 IND Submission230
3.1.3.Phase 3 IND Submission230
3.2.Regulatory Expectations for the BLA/NDA Submission231
3.3.Full Characterization of Recombinant Proteins and Monoclonal Antibodies232
3.3.1.What is 'Full' Characterization?232
3.3.2.Host-Dependent Glycosylation236
3.3.3.Host-Dependent Impurities237
3.3.4.Impact of Molecular Variants on Biological Activity238
3.4.Characterization of a Gene Therapy Biopharmaceutical239
3.5.Applying the Minimum CMC Continuum to Characterization240
4.Release Testing and Specifications241
4.1.Regulatory Expectations During Clinical Development241
4.1.1.Phase 1 IND Submission241
4.1.2.Phase 2 IND Submission242
4.1.3.Phase 3 IND Submission242
4.2.Regulatory Expectations for the BLA/NDA Submission243
4.3.Appropriate Release Test Methods244
4.3.1.Not All Release Testing is at API or Drug Product Stage244
4.3.2.Elimination of Release Testing by Process Validation245
4.3.3.Test Method Parameters Required for Release: Proteins246
4.3.4.Test Method Parameters Required for Release: DNA Vectors250
4.4.The Bioassay--Absolute Requirement for a Biopharmaceutical252
4.5.Test Method Validation--How Much and When?253
4.5.1.Regulatory Expectations for Test Method Validation254
4.5.2.Assay Qualification During Clinical Development256
4.5.3.Applying the Minimum CMC Continuum to Test Method Validation257
4.6.The Art of Setting a Specification258
4.6.1.Development of a Specification258
4.6.2.Release Versus Shelf-Life Specifications261
4.6.3.Are There Required Purity/Impurity Limits?261
4.6.4.Strategic CMC Tips for Setting Specifications263
5.Biopharmaceutical Stability and Expiration Dating266
5.1.Regulatory Expectations During Clinical Development267
5.1.1.Phase 1 IND Submission267
5.1.2.Phase 2 IND Submission267
5.1.3.Phase 3 IND Submission268
5.2.Regulatory Expectations for the BLA/NDA Submission270
5.3.Stability-Indicating Test Methods272
5.4.Setting an Expiration Date274
5.5.How Much Change is Acceptable?277
5.6.Applying the Minimum CMC Continuum to Stability278
6.What Can

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