The Challenge of CMC Regulatory Compliance for Biopharmaceuticals

by John Geigert

Overview

"The greater our knowledge increases, the more our ignorance unfolds. " U. S. President John F. Kennedy, speech, Rice University, September 12, 1962 My primary purpose for writing this book was much more than to provide another information source on Chemistry, Manufacturing & Controls (CMC) that would rapidly become out of date. My primary purpose was to provide insight and practical suggestions into a common sense business approach to manage the CMC regulatory compliance requirements for biopharmaceuticals. Such a common sense business approach would need (1) to be applicable for all types of biopharmaceutical products both present and future, (2) to address the needs of a biopharmaceutical manufacturer from the beginning to the end of the clinical development stages and including post- market approval, and (3) to be adaptable to the constantly changing CMC regulatory compliance requirements and guidance. Trying to accomplish this task was a humbling experience for this author! In Chapter 1, the CMC regulatory process is explained, the breadth of products included under the umbrella ofbiopharmaceuticals are identified, and the track record for the pharmaceutical and biopharmaceutical industry in meeting CMC regulatory compliance is discussed. In Chapter 2, while there are many CMC commonalities between biopharmaceuticals and chemically-synthesized pharmaceuticals, the significant differences in the way the regulatory agencies handle them are examined and the reasons for why such differences are necessary is discussed. Also, the importance of CMC FDA is stressed.

Product Details

ISBN-13:	9781461348047
Publisher:	Springer US
Publication date:	09/25/2012
Edition description:	Softcover reprint of the original 1st ed. 2004
Pages:	350
Product dimensions:	7.01(w) x 10.00(h) x 0.03(d)

About the Author

John Geigert is President of BioPharmaceutical Quality Solutions, which specializes in providing CMC regulatory strategy consulting for the biopharmaceutical and biologic industry. Dr. Geigert has over 35 years of CMC industrial experience and leadership in the biopharmaceutical industry. Dr. Geigert has served on the PDA Board of Directors, co-chaired the PDA Biotech Advisory Board and served as an expert member of the USP Biotechnology Committee. Dr. Geigert has written extensively for the Regulatory Affairs Professional Society (RAPS) Focus (What Senior Management Needs to Know About CMC Regulatory Compliance for Biotech Products (Aug-Nov 2009, 4-part series) and Demystifying CMC Regulatory Strategy (Sept 2011-Mar 2012, 4-part series)).

Table of Contents

	List of Tables	xix
	List of Figures	xxiii
Chapter 1	Biopharmaceutical CMC Regulatory Compliance: What is It?
1.	Defining Our Terms	1
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 Umbrella	3
2.1.	Recombinant DNA-Derived Proteins	3
2.2.	Monoclonal Antibodies	5
2.3.	Gene Therapy	7
2.4.	Animal/Plant Transgenics	8
2.5.	Rapid Pace of Biopharmaceutical Development	8
3.	Regulatory Development of Biopharmaceuticals	9
3.1.	The Drug Development Process	9
3.2.	Regulatory Agency Review	10
3.2.1.	U.S. FDA	10
3.2.2.	EMEA	11
4.	CMC Regulatory Compliance Track Record	13
4.1.	Drugs and Biologics	13
4.2.	Biopharmaceuticals	14
Chapter 2	Are Biopharmaceuticals Really Different?
1.	Perception or Reality?	17
1.1.	Five Questions Frequently Asked	18
1.2.	Bottom Line Question	18
2.	Regulatory Agencies Speak	18
2.1.	U.S. FDA	19
2.2.	EMEA	20
2.3.	ICH	20
3.	Three Unique CMC Challenges for Biopharmaceuticals	21
3.1.	The Use of Living Recombinant Organisms	21
3.2.	The Products Themselves	22
3.3.	The Impact of the Manufacturing Process	22
4.	CMC Meetings with the FDA Take on Greater Importance	23
4.1.	CMC Communication with FDA is Critical	25
4.2.	Preparing for the CMC Meeting	26
4.3.	Pre-IND Meeting	27
4.4.	End of Phase 2 (EOP2) Meeting	29
4.3.	Pre-BLA/NDA Meeting	31
5.	What About CMC Meetings with EMEA?	33
6.	Biopharmaceuticals Need to be Treated Differently	34
Chapter 3	Developing the Corporate CMC Regulatory Compliance Strategy
1.	Three Key Elements for a Complete CMC Strategy	35
1.1.	Element 1: The Broad CMC Scope Must Be Considered	36
1.2.	Element 2: Any Unique CMC Issues Must Be Addressed	37
1.3.	Element 3: Must Meet Minimum CMC Regulatory Requirements	38
2.	The Minimum CMC Continuum	39
3.	Minimum CMC Requirements for Clinical Development	40
3.1.	An Overview	40
3.2.	Phase 1	46
3.3.	Phase 2 and 3	47
4.	Full CMC Requirements for Dossier Filing	48
4.1.	Comparison of BLA/NDA and CTD CMC Formats	49
4.2.	Adequate Resources Required to Compile the Full CMC Dossier	51
4.3.	Quality of CMC Content Present in Dossier is Critical	52
5.	'Case-By-Case' CMC Strategy Specifics	54
Chapter 4	Can't Ignore cGMPs
1.	Not Optional	57
1.1	What are 'cGMPs'?	57
1.2	Three main GMP questions	58
2.	GMPs for Everything	59
2.1.	For Finished Drug Products	59
2.2.	Required for APIs Also	63
2.3.	Extra GMPs for Biopharmaceuticals	66
3.	Where in the Manufacturing Process Should GMP Begin?	68
4.	When During Clinical Development Should GMP Begin?	70
4.1.	API Clinical Trial Materials	70
4.2.	Drug Product Clinical Trial Materials	73
5.	Consequences of Not Following GMPs	73
5.1.	Issues with Market Approved Biopharmaceuticals	74
5.2.	Issues During Clinical Development	77
5.3.	How to Avoid GMP Difficulties with the FDA	78
6.	Strategic CMC Tips for GMP Compliance	80
Chapter 5	Recombinant Source Material: Master/Working Banks
1.	Needed: Reliable, Continuous, Stable Genetic Source	83
1.1.	Three Primary CMC Concerns for Banks	84
1.2.	Genetic Construction of a Bank	85
2.	So Many Hosts to Choose From	88
2.1.	Bank Terminology	88
2.2.	Choosing the Host	89
2.2.1.	Drivers to Reach a Decision	89
2.2.2.	Why Choose Recombinant Cells?	90
2.2.3.	Why Bioengineered Animals or Plants?	91
3.	CMC Guidance on Preparation of a Bank	92
3.1.	Accurate and Thorough Description of Preparation	92
3.1.1.	Recombinant Cell Banks	93
3.1.2.	Transgenic Banks	95
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 Bank	100
4.	CMC Guidance on Characterization of a Bank	101
4.1.	Appropriate and Sufficient Characterization	102
4.1.1.	Six Key Elements for a Thorough Characterization	102
4.1.2.	Recombinant Cell Bank Characterization	103
4.1.3.	Example of Characterization of a Bacterial Cell Bank	105
4.1.4.	Example of Characterization of a Mammalian Cell Bank	106
4.2.	How Much Characterization and When?	107
4.3.	Critical Concern for Virus Safety in Banks	109
4.4.	Minimizing the Risk of TSEs	111
5.	A Successful CMC Strategy for Banks	113
Chapter 6	Production: Expansion of the Recombinant Organism and Expression of the Biopharmaceutical
1.	Goals: Identity, Capacity and Consistency	115
1.1.	Two Major CMC Regulatory Concerns for Production	116
1.2.	Need for High and Consistent Expression of the Biopharmaceutical	116
1.3.	What is a 'Production Process'?	117
1.3.1.	Types of Bioreactors for Cell-Based Production	118
1.3.2.	Harvesting Procedures for Biopharmaceuticals	119
1.4.	Production Processes Familiar to the FDA	119
2.	Adequate Description of the Production Process	122
2.1.	During Clinical Development	122
2.1.1.	Phase 1 IND Submission	122
2.1.2.	Phase 2 IND Submission	124
2.1.3.	Phase 3 IND Submission	124
2.2.	Preparing the BLA/NDA Submission	125
3.	Validation of a Cell-Based Production Process	128
3.1.	When Should Validation of the Production Process Occur?	129
3.2.	Five Major Areas Involved in Validation of the Production Process	130
3.2.1.	The Production Facility, Utilities and Process Equipment	130
3.2.2.	Monitoring of Growth Parameters	132
3.2.3.	In-Process Controls	133
3.2.4.	Genetic Stability	136
3.2.5.	Cleaning Validation	137
3.3.	Final Comments on Process Validation	140
4.	Additional Production Controls and Concerns	140
4.1.	Cell-Based Production Processes	140
4.1.1.	Cell Culture Media Acceptance Criteria	141
4.1.2.	Avoidance of Animal- and Human-Derived Raw Materials	141
4.1.3.	Containment of the Recombinant Organism	144
4.1.4.	Contamination Control for Aseptic Processing Operations	144
4.2.	Gene Therapy Production Processes	146
4.2.1.	Control of the Cells	146
4.2.2.	RAC Review and Approval of the Production Process	148
4.3.	Transgenic Animal Production Processes	149
4.3.1.	Production Controls	149
4.3.2.	Protecting the Gene Pool	151
4.4.	Transgenic Plant Production Processes	151
4.4.1.	'Pharming' Controls	152
4.4.2.	USDA/APHIS Protecting the Gene Pool	155
5.	What Can Go Wrong	157
6.	Strategic CMC Tips for Production	158
Chapter 7	Purification of the Biopharmaceutical
1.	Goals: Purity, Recovery and Consistency	161
1.1.	Two Major CMC Regulatory Concerns for Purification	162
1.2.	Need for High Recovery of a Pure Product	162
1.3.	What is a 'Purification Process'?	163
1.3.1.	Physical Separations Methods for Biopharmaceuticals	164
1.3.2.	Chromatographic Purification Methods for Biopharmaceuticals	165
1.4.	Purification Processes Familiar to the FDA	167
2.	Adequate Description of the Purification Process	169
2.1.	During Clinical Development	170
2.1.1.	Phase 1 IND Submission	170
2.1.2.	Phase 2 IND Submission	171
2.1.3.	Phase 3 IND Submission	172
2.2.	Preparing the BLA/NDA Submission	172
3.	Facility and Utility Concerns	174
3.1.	Design and Operation	175
3.2.	Environmental Monitoring	176
4.	Purification Process Validation	177
4.1.	When Should Purification Validation Occur?	177
4.2.	Process Validation Concerns for a Chromatographic Step	178
4.3.	Process Validation Concerns for a Filtration Step	182
5.	In-Process Controls	183
6.	Process-Related Impurity Profile	185
7.	Viral Safety Evaluation	188
7.1.	General Study Design	189
7.2.	Justification of the Choice of Viruses	191
7.3.	Calculation of Virus Reduction Factors	193
7.4.	Virus Safety Calculation	195
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 Processes	197
9.	What Can Go Wrong	197
10.	Strategic CMC Tips for Purification	199
Chapter 8	Biopharmaceutical Drug Product Manufacturing
1.	Three Basic CMC Regulatory Concerns	201
2.	Formulation of a Biopharmaceutical	203
2.2.	Formulations Familiar to FDA	203
2.3.	Chemical Modification of API Prior to Formulation	205
3.	Biopharmaceutical Manufacturing Processes	206
4.	Adequate Description of the Manufacturing Process	208
4.1.	During Clinical Development	209
4.1.1.	Phase 1 IND Submission	209
4.1.2.	Phase 2 IND Submission	210
4.1.3.	Phase 3 IND Submission	211
4.2.	BLA/NDA Submission	212
5.	Adequate Control Over the Manufacturing Process	213
5.1.	Regulatory Requirements for Market Approved Products	214
5.2.	Regulatory Expectations During Clinical Development	216
6.	What Can Go Wrong	217
7.	Strategic CMC Tips for Drug Product Manufacturing	218
Chapter 9	Physicochemical/Biological Analysis of the Biopharmaceutical Product
1.	A Challenging Analysis	222
1.1.	Goals: Consistent, Safe, Potent and Pure Product	222
1.2.	Relationship Between Product Characterization and QC Testing	223
2.	Unraveling the Molecular Properties	224
2.1.	Molecular Variants for DNA	224
2.2.	Molecular Variants for Proteins	224
2.3.	Plethora of Analytical Methods Available For Proteins	226
3.	Characterization of Biopharmaceuticals	229
3.1.	Regulatory Expectations During Clinical Development	229
3.1.1.	Phase 1 IND Submission	229
3.1.2.	Phase 2 IND Submission	230
3.1.3.	Phase 3 IND Submission	230
3.2.	Regulatory Expectations for the BLA/NDA Submission	231
3.3.	Full Characterization of Recombinant Proteins and Monoclonal Antibodies	232
3.3.1.	What is 'Full' Characterization?	232
3.3.2.	Host-Dependent Glycosylation	236
3.3.3.	Host-Dependent Impurities	237
3.3.4.	Impact of Molecular Variants on Biological Activity	238
3.4.	Characterization of a Gene Therapy Biopharmaceutical	239
3.5.	Applying the Minimum CMC Continuum to Characterization	240
4.	Release Testing and Specifications	241
4.1.	Regulatory Expectations During Clinical Development	241
4.1.1.	Phase 1 IND Submission	241
4.1.2.	Phase 2 IND Submission	242
4.1.3.	Phase 3 IND Submission	242
4.2.	Regulatory Expectations for the BLA/NDA Submission	243
4.3.	Appropriate Release Test Methods	244
4.3.1.	Not All Release Testing is at API or Drug Product Stage	244
4.3.2.	Elimination of Release Testing by Process Validation	245
4.3.3.	Test Method Parameters Required for Release: Proteins	246
4.3.4.	Test Method Parameters Required for Release: DNA Vectors	250
4.4.	The Bioassay--Absolute Requirement for a Biopharmaceutical	252
4.5.	Test Method Validation--How Much and When?	253
4.5.1.	Regulatory Expectations for Test Method Validation	254
4.5.2.	Assay Qualification During Clinical Development	256
4.5.3.	Applying the Minimum CMC Continuum to Test Method Validation	257
4.6.	The Art of Setting a Specification	258
4.6.1.	Development of a Specification	258
4.6.2.	Release Versus Shelf-Life Specifications	261
4.6.3.	Are There Required Purity/Impurity Limits?	261
4.6.4.	Strategic CMC Tips for Setting Specifications	263
5.	Biopharmaceutical Stability and Expiration Dating	266
5.1.	Regulatory Expectations During Clinical Development	267
5.1.1.	Phase 1 IND Submission	267
5.1.2.	Phase 2 IND Submission	267
5.1.3.	Phase 3 IND Submission	268
5.2.	Regulatory Expectations for the BLA/NDA Submission	270
5.3.	Stability-Indicating Test Methods	272
5.4.	Setting an Expiration Date	274
5.5.	How Much Change is Acceptable?	277
5.6.	Applying the Minimum CMC Continuum to Stability	278
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