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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