1.Introduction to Biotechnology Operations：Planning for Success 1
Biotechnology Operations 1
Marketing，Financial and Business Considerations for Development 4
Product Development Planning 7
Rationale for Product Development Planning 7
Targeted Product Profile 10
Product Development Plan 16
Clinical Development Planning 18
Project Management Planning 19
Regulatory Planning 20
Nonclinical Planning 22
Biornanufacturing Planning 23
Quality Control Planning 24
Quality Systems and Quality Assurance Planning 26
Additional Elements of Product Planning 26
Summary of Planning for Success 28
2.Project Management 29
Project Management in Biotechnology 29
Background of Project Management 31
Project Management in Biotechnology 32
Project Management Environment 33
Project Objectives and Schedules 35
Sociotechnical Considerations 36
Participants in Project Management 37
Project Management in Biotechnology Operations 40
Establishing Project Management 40
Work Breakdown Structure 42
Forming a Project Team and Hands-On Project Management 42
Communication and Feedback 47
Team Dynamics 47
Project Risk Assessment and Management 50
Metrics and Tracking Progress 51
Resources：Planning and Usage 52
Human Factors in Project Management 53
Project Completion 55
Project Management with Contracts and Collaborations 56
Tools for Effective Project Management 57
Summary of Project Management in Biotechnology Development 60
3.Regulatory Affairs 61
The U.S.Food and Drug Administration：Law and Regulations for Biopharmaceuticals 61
Historical Basis for FDA Regulation 61
Regulatory Organization of FDA 63
Food and Drug Law，Regulation and Guidance 66
FDA-Regulated Products 67
Biologics 67
Drugs 70
Medical Devices 72
Combination Products 72
Other Classes of Biotechnology Products and Their Review at the FDA 73
Products for Veterinary Use 73
Cosmetics，Food，Dietary Supplements，Homeopathic or Nutritional Products 73
U.S.FDA Regulatory Information and Resources：Regulatory Intelligence 75
Regulatory Operations for FDA Applications 78
Regulatory Planning and the Regulatory Environment 78
Risk versus Benefit 78
Applications Seeking FDA Investigational Use or Marketing Approval 80
Investigational Use Applications：Investigational New Drug （IND）Application 81
Marketing Applications：Biologics License Application（BLA）and New Drug Application（NDA） 86
Medical Device Applications：510（k）and Premarket Approval （PMA） 89
Special Documents，Pathways or Exemptions 91
Generic Drugs and Biosimiliar or Follow-On Biologics 93
Other Regulatory Activities 94
Public Meetings and Advisory Committees 94
Postmarketing Requirements and Activities 96
Advertising and Promotion 97
Summary on Regulatory Affairs Activities in Biotechnology Operations 98
4.Regulatory Compliance 99
Regulatory Compliance 99
Quality Systems to Meet Regulatory Compliance 99
Compliance and Quality Systems 99
cGMPs：Current Good Manufacturing Practices for Manufacture and Quality Control 100
cGLPs：Current Good Laboratory Practices for Nonclinical Lab Studies 100
cGCPs：Current Good Clinical Practices for Clinical Studies 102
Compliance for Biopharmaceuticals：Other Regulations of Importance 104
Compliance for Import of Biopharmaceuticals into the United States 104
Compliance for Medical Devices 105
Inspection and Enforcement 105
Inspections 106
Enforcement Actions 108
Product Liability 110
Compliance with Non-FDA Regulations：International，National，State and Local 110
International and Foreign National Regulatory Authorities for Medical Biotechnology Products 110
Transporting Infectious or Otherwise Hazardous Materials 114
Importing，Possessing or Transferring Controlled Biotechnology Materials 116
Public Health Security and Bioterrorism Preparedness and Response Act of 2002 118
Importation or Exportation of Biotechnology Products for the Purpose of Treatment of Diseases in Man 119
Occupational Health and Safety 120
Environmental Regulations in Biotechnology 121
Genetically Modified Organisms or Molecules 122
U.S.Regulatory Agencies Unified Biotechnology Web Site 124
International Diligence in Biotechnology Operations 124
Summary of Non-FDA Compliance 125
5.Quality Systems 127
Overview of Quality in Biotechnology 127
History：Evolution of Quality Concepts and Practices 128
Quality Systems Approach to Product Development 130
Planning a Quality System 132
Defining Objectives and Ensuring Management Support 132
The Quality Manual 133
The Quality Plan 134
Hallmarks of Quality：Fundamental Criteria for Building Effective Quality Systems 136
Management Responsibility 137
Defined Quality System 137
Quality by Design and Design Control 138
Quality by Design 138
Design Control 139
Design Change 143
Contractor，Vendor and Consultant Control 143
Product Identification and Traceability 146
Process Control 146
Environmental Controls 147
Inspection or Testing（Quality Control） 147
Release of Material，Service or Product 148
Change Control and Corrective or Preventive Actions 149
Packaging and Labeling 150
Preservation，Storage and Handling 150
Servicing 151
Customer Concerns and Adverse Event Reports 151
Document Control 151
Training 151
Auditing 152
Quality Assurance Unit 152
Manage the Quality Assurance Function 153
Control Documents and Manage the Documentation System 154
Investigate Situations：Manage and Control Change 156
Ensure Qualified and Trained Staff 156
Perform Audits 157
Initiate a Quality System for a Biotechnology Operation 158
Unique and Effective Approaches to Quality Management 160
Risk-Based Approaches to Quality Systems 160
Total Quality Management（TQM） 160
Six Sigma 161
Quality Systems for Research 161
Resolving Quality Issues or Problems 162
Summary of Quality Systems 163
6.Biomanufacture 165
Overview of Biornanufacturing Requirements 165
Design in Biomanufacture 165
Technical Considerations for Biomanufacture 169
Phases and Scale Up：The Biomanufacturing Life Cycle 171
Raw Material Considerations 175
Compliance and Quality in Biomanufacture：Current Good Manufacturing Practices 176
Biomanufacturing Processes for Biotechnology Products 179
Expression of Recombinant Proteins and Nucleic Acids 179
Production of Recombinant Molecules from Expression Vectors 179
Genes，Vectors and Host Cells 180
Bacterial Cell Expression Systems 182
Yeast Cell Expression Systems 182
Mammalian or Insect Cell Expression Systems 183
Production of Master Cell Banks and Working Cell Banks 184
Biomanufacture of Recombinant Proteins 186
Planning Production of a Recombinant Protein 186
Upstream Process：Production by Bacterial or Yeast Cell Fermentation 187
Upstream Process：Production by Mammalian or Insect Cell Culture 190
Upstream Process：Recovery 191
Downstream Process：Purification 191
In-Process Testing and Analysis of Bulk Substance 199
Production of Bacterial Plasmid DNA 201
Production of Live Recombinant Organisms：Bacteria and Virus 201
Production of Products Composed of Mammalian Somatic Cells or Tissues 204
Production of Cellular Products Derived from Pluripotent （Stem）Cells 204
Production of Biological Molecules by Transgenic Animals or Transgenic Plants 206
Production of Biologically Active Lipids，Glycolipids and Complex Carbohydrates 210
Production of Biologically Active Peptides 212
Production of Combination Products：Biopharmaceutical with a Drug or Medical Device 212
Final Product：Formulation Fill，Finish and Labeling 214
Biomanufacturing Facilities，Utilities and Equipment 218
Facility Design Considerations 218
Facility and Utilities：A Controlled Environment 219
Operation of Clean Work Areas for Biomanufacture 221
Biomanufacturing Equipment 222
Contract Manufacturing Options 223
Validation of Biomanufacturing Facilities，Utilities，Equipment and Processes 223
Summary of Biomanufacture 226
7.Quality Control 227
Quality Control Overview 227
Define Product Attributes 230
Analytical Methods Measure Attributes 231
Traits of Analytical Methods 231
Draft a Certificate of Analysis（Bulk Substance） 232
Select Analytical Methods 234
Develop Specifications 242
Enter Test Results 246
Certificate of Analysis for Drug Product 246
In-Process Testing 249
Analytical Methods 250
Additional Analytical Tools and Concepts 256
Quality Control of Cell Banks 258
Samples and Sampling 259
Analytical Controls and Reference Standards 260
Test Failures，Out-of-Specification Results and Retesting 261
Testing for Product Stability 262
Quality Control Testing of Raw Materials 266
Quality Control and the Manufacturing Environment 269
Qualification，Validation and Verification of Analytical Methods 269
Assay Validation 270
Application of Statistics in Assay Performance and Validation 274
Summary of Quality Control 275
8.Nonclinical Studies 277
Nonclinical Studies and Risk Assessment 277
Biopharmaceutical Delivery，Pharmacokinetics and Pharmacodynamics 279
Product Delivery to the Body 279
Absorption，Distribution，Elimination and Metabolism （ADME） 280
Absorption 281
Distribution 282
Metabolism and Biotransformation 283
Excretion 283
Pharmacokinetics and Pharmacodynamics 283
Application of Pharmacokinetics and Pharmacodynamics in Biopharmaceutical Development 289
Safety Assessment of Biopharmaceuticals 291
Toxicology 291
Design of a Safety Assessment Program 292
In Vitro Screens：Surrogate Measures of Toxicity 295
In Vivo Safety Testing of Biopharmaceuticals 297
Animal Model Development 297
Test Product Formulations，Routes of Delivery and Dosing Designs 299
Protocols and Performance of Biopharmaceutical Safety Studies in Animals 301
Elements of a Nonclinical Study Design 302
Acute Toxicity Testing 305
Subchronic and Chronic Toxicity Testing 306
Reproductive，Developmental and Teratogenicity Toxicity Testing 308
Carcinogenicity Testing 310
Immunotoxicology 310
Genetic Toxicology 312
Tissue Binding or Local Tissue Tolerance 313
Quality of Nonclinical Studies：Current Good Laboratory Practices 314
Summary of Nonclinical Studies 314
9.Clinical Trials 317
Introduction to Clinical Trials 317
Background of Clinical Research 319
Introduction 319
Historical Information on Clinical Trials 320
Organization of Clinical Research 321
Phases of Clinical Trials 321
The Science of Clinical Research 322
Quality in Clinical Research and Current Good Clinical Practices 322
Clinical Development Planning 323
Infrastructure for a Clinical Trial：Individuals，Documents and Investigational Product 323
Design of Clinical Trials and the Clinical Protocol 324
Human Subjects，Patients and Volunteers 332
The Sponsor 332
The Principal Investigator and His/Her Study Staff 335
Institutional Review Boards（IRB）：Process of Informed Consent（IC）and IC Form 336
Investigational Product 339
Collection of Clinical Data：Case Report Forms and the Patient Diary 339
Clinical Testing Laboratories 340
Reporting Results of Clinical Trials：Clinical Summary Reports 341
Clinical Trial Operations 341
Activities Leading to a Clinical Trial 342
Phase 1 Clinical Trial：First-Time-in-Man 344
Clinical Pharmacology Studies of Biopharmaceuticals in Man 345
Phase 2 Clinical Trial：Proof-of-Concept 348
Phase 3 Clinical Trial：Therapeutic Confirmatory 349
Phase 4 Clinical Study and REMS 351
Clinical Trials for New Populations or Indications 351
Global Clinical Trials 352
Quality Systems for Clinical Trials：Current Good Clinical Practices 353
Quality and cGCP in Clinical Trial Operations 353
Integrity of Clinical Study Data and Documents 355
Monitoring and Auditing Clinical Trials 356
Ethical Behavior and the Well-Being of Clinical Trial Subjects 356
Summary on Clinical Trials 358
Glossary 359
Additional Reading 383
Practical Problems and Questions 387
Index 395