BIOTECHNOLOGY OPERATIONS PRINCIPLES AND PRACTICES SECOND EDITIONPDF电子书下载

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

The Targeted Product Profile 10

The Product Development Plan 16

Clinical Development Planning 18

Project Management Planning 19

Regulatory Planning 20

Nonclinical Planning 22

Biomanufacturing 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

Biotechnology and Project Management 29

Background of Project Management 31

Project Management Plan 32

The Project Management Environment 34

Project Objectives and Schedules 36

Sociotechnical Considerations 37

Participants in Project Management 37

Project Management in Biotechnology Operations 41

Establishing Project Management 41

The Work Breakdown Structure 42

Forming a Project Team and Hands-on Project Management 46

Team Dynamics 46

Communication and Feedback 49

Project Risk Assessment and Management 51

Metrics and Tracking Progress 53

Resources：Planning and Usage 54

Human Factors in Project Management 55

Project Completion 57

Project Management with Contracts and Collaborations 59

Virtual Teams 60

Tools for Effective Project Management 61

Summary of Project Management in Biotechnology Development 64

3.Regulatory Affairs 65

The U.S.Food and Drug Administration：Law and Regulations for Biopharmaceuticals 65

Historical Basis for FDA Regulation 65

Regulatory Organization of the FDA 66

Food and Drug Law，Regulation，and Guidance 71

FDA-Regulated Products 71

Biologics 72

Drugs 75

Medical Devices 76

Combination Products 77

Other Classes of Biotechnology Products and Their Review at the FDA 79

Products for Veterinary Use 79

Cosmetics，Food，Dietary Supplements，Homeopathic，or Nutritional Products 79

FDA Regulatory Information and Resources：Regulatory Intelligence 81

Regulatory Operations for FDA Applications 84

Regulatory Planning and the Regulatory Environment 84

Risk Versus Benefit 84

Applications Seeking FDA Investigational Use or Marketing Approval 87

Investigational Use Applications.The Investigational New Drug Application 89

Common Technical Document 91

Electronic Submission of a CTD 92

Marketing Applications：BLA and NDA 96

Medical Device Applications.510（k） and PMA 99

Special Documents，Pathways，or Exemptions 101

Generic Drugs and Biosimiliar or Follow-on Biologics 104

Other Regulatory Activities 105

Public Meetings and Advisory Committees 105

Postmarketing Requirements and Activities 107

Advertising and Promotion 108

Summary of Regulatory Affair Activities in Biotechnology Operations 109

References 111

4.Regulatory Compliance 113

Regulatory Compliance 113

Quality Systems to Meet Regulatory Compliance 113

Compliance and Quality Systems 113

Current Good Manufacturing Practices for Manufacture and Quality Control 114

Current Good Laboratory Practices for Nonclinical Laboratory Studies 117

Current Good Clinical Practices for Clinical Studies 117

Compliance for Biopharmaceuticals：Other Regulations of Importance 119

Compliance for Import of Biopharmaceuticals into the United States 119

Compliance for Medical Devices 120

Inspection and Enforcement 120

Inspections 121

Enforcement Actions 123

Product Liability 125

Compliance with Non-FDA Regulations：International，National，State，and Local 126

International and Foreign National Regulatory Authorities for Medical Biotechnology Products 126

Transporting Infectious or Otherwise Hazardous Materials 132

Importing，Possessing，or Transferring Controlled Biotechnology Materials 134

The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 136

Importation or Exportation of Biotechnology Products for the Purpose of Treatment of Diseases in Humans 137

Occupational Health and Safety 140

Environmental Regulations in Biotechnology 141

Genetically Modified Organisms or Molecules 142

International Diligence in Biotechnology Operations 144

Summary of Regulatory Compliance 146

Summary of Non-FDA Compliance 147

References 148

5.Quality Systems 149

Overview of Quality in Biotechnology 149

History：Evolution of Quality Concepts and Practices 150

Quality Systems Approach to Product Development 153

Planning a Quality System 156

Defining Objectives and Ensuring Management Support 156

The Quality Manual 156

The Quality Plan 157

Hallmarks of Quality：Fundamental Criteria for Building Effective Quality Systems 159

Management Responsibility 160

Defined Quality System 162

QbD and Design Control 163

Quality by Design 163

Design Control 164

Design Change 169

Contractor，Vendor，and Consultant Control 169

Product Identification and Traceability 171

Process Control 172

Environmental Controls 173

Inspection or Testing （Quality Control） 173

Release of Material，Service，or Product 174

Change Control and Corrective or Preventive Actions 175

Packaging and Labeling 176

Preservation，Storage，and Handling 176

Servicing 178

Customer Concerns and Adverse Event Reports 178

Document Control 178

Training 178

Auditing 179

The Quality Assurance Unit 180

Manage the Quality Assurance Function 181

Control Documents and Manage the Documentation System 182

Investigate Situations：Manage and Control Change 184

Ensure Qualified and Trained Staff 184

Perform Audits 185

Initiate a Quality System for a Biotechnology Operation 188

Unique and Effective Approaches to Quality Management 190

Risk-Based Approaches to Quality Systems 190

Total Quality Management 190

Six Sigma 191

Statistics in Quality Assurance 191

Quality Systems for Research 191

Resolving Quality Issues or Problems 192

Summary of Quality Systems 193

References 194

6.Biomanufacture 195

Overview of Biomanufacturing Requirements 195

Design in Biomanufacture 196

Technical Considerations for Biomanufacture 200

Phases and Scale-up：The Biomanufacturing Life Cycle 201

Raw Material Considerations 205

Compliance and Quality in Biomanufacture：Current Good Manufacturing Practices 207

Biomanufacturing Processes for Biotechnology Products 209

Expression of Recombinant Proteins and Nucleic Acids 209

Production of Recombinant Molecules from Expression Vectors 209

Genes，Vectors，and Host Cells 210

Bacterial Cell Expression Systems 212

Yeast Cell Expression Systems 213

Mammalian or Insect Cell Expression Systems 213

Production of Master Cell Banks and Working Cell Banks 216

Biomanufacture of Recombinant Proteins 217

Planning Production of a Recombinant Protein 217

Upstream Process：Production by Bacterial or Yeast Cell Fermentation 218

Upstream Process：Production by Mammalian or Insect Cell Culture 220

Upstream Process：Recovery 221

Downstream Process：Purification 222

In-Process Testing and Analysis of Bulk Substance 230

Production of Bacterial Plasmid DNA 231

Production of Live Recombinant Organisms：Bacteria and Virus 232

Production of Products Composed of Mammalian Somatic Cells or Tissues 234

Production of Cellular Products Derived from Pluripotent （Stem） Cells 236

Production of Biological Molecules by Transgenic Animals or Plants 238

Production of Biologically Active Lipids，Glycolipids，and Complex Carbohydrates 245

Production of Biologically Active Peptides 245

Production of Combination Products：Biopharmaceutical with a Drug or Medical Device 247

FP：Formulation，Fill，Finish，and Labeling 248

Biomanufacturing Facilities，Utilities，and Equipment 253

Facility Design Considerations 253

The Facility and Utilities：A Controlled Environment 254

Operation of Clean Work Areas for Biomanufacture 255

Biomanufacturing Equipment 257

Contract Manufacturing Options 257

Validation of Biomanufacturing Facilities，Utilities，Equipment，and Processes 259

Summary of Biomanufacture 261

References 262

7.Quality Control 263

Quality Control Overview 263

Definition of Product Attributes 265

Analytical Methods to Measure Attributes 266

Traits of Analytical Methods 267

Drafting a Certificate of Analysis （Bulk Substance） 267

Selection of Analytical Methods 270

Development of Specifications 277

Entering Test Results 282

Certificate of Analysis for Drug Product 282

In-Process Testing 285

Analytical Methods 286

Additional Analytical Tools and Concepts 295

Quality Control of Cell Banks 297

Samples and Sampling 298

Analytical Controls and Reference Standards 299

Test Failures，Out-of-Specification Results，and Retesting 300

Testing for Product Stability 302

Quality Control Testing of Raw Materials 308

Quality Control and the Manufacturing Environment 310

Qualification，Validation，and Verification of Analytical Methods 312

Application of Statistics in Assay Performance and Validation 317

Summary of Quality Control 318

References 319

8.Nonclinical Studies 321

Nonclinical Studies and Risk Assessment 321

Biopharmaceutical Delivery，Pharmacokinetics，and Pharmacodynamics 323

Product Delivery to the Body 323

Adsorption，Distribution，Elimination，and Metabolism （ADME） 325

Absorption 325

Distribution 325

Metabolism and Biotransformation 327

Excretion 328

Pharmacokinetics and Pharmacodynamics 328

Application of Pharmacokinetics and Pharmacodynamics in Biopharmaceutical Development 333

Safety Assessment of Biopharmaceuticals 336

Toxicology 336

Design of a Safety Assessment Program 337

In Vitro Screens：Surrogate Measures of Toxicity 340

In Vivo Safety Testing of Biopharmaceuticals 342

Animal Model Development 342

Test Product Formulations，Routes of Delivery，and Dosing Designs 344

Protocols and Performance of Biopharmaceutical Safety Studies in Animals 346

Elements of a Nonclinical Study Design 347

Nonclinical Safety Testing 351

Acute Toxicity Testing 351

Subchronic and Chronic Toxicity Testing 356

Reproductive，Developmental，and Teratogenicity Toxicity Testing 359

Carcinogenicity Testing 360

Immunotoxicology 361

Genetic Toxicology 363

Tissue Binding or Local Tissue Tolerance 367

Quality of Nonclinical Studies：Current Good Laboratory Practices 368

Summary of Nonclinical Studies 369

References 370

9.Clinical Trials 371

Introduction to Clinical Trials 371

Background of Clinical Research 373

Introduction 373

Historical Information on Clinical Trials 374

Organization of Clinical Research 375

Phases of Clinical Trials 375

The Science of Clinical Research 376

Quality in Clinical Research and Current Good Clinical Practices 377

Clinical Development Planning 377

Infrastructure for a Clinical Trial：Individuals，Documents，and Investigational Product 378

Design of Clinical Trials and the Clinical Protocol 378

Human Subjects，Patients，and Volunteers 388

The Sponsor 388

The Principal Investigator and His or Her Study Staff 391

Institutional Review Boards，the Process of IC，and IC Form 392

Investigational Product 394

Collection of Clinical Data：Case Report Forms and the Patient Diary 395

Clinical Testing Laboratories 396

Reporting Results of Clinical Trials：Clinical Summary Reports 397

Clinical Trial Operations 397

Activities Leading to a Clinical Trial 398

Phase 1 Clinical Trial：First-In-Human Study 400

Clinical Pharmacology Studies of Biopharmaceuticals in Human 404

Phase 2 Clinical Trial：Proof-of-Concept Study 405

Phase 3 Clinical Trial：Therapeutic Confirmatory 406

Phase 4 Clinical Study and Risk Evaluation and Mitigation Strategy 407

Clinical Trials for New Populations or Indications 408

Global Clinical Trials 409

Quality Systems for Clinical Trials：Current Good Clinical Practices 409

Quality and cGCP in Clinical Trial Operations 410

Integrity of Clinical Study Data and Documents 413

Monitoring and Auditing Clinical Trials 414

Ethical Behavior and the Well-Being of Clinical Trial Subjects 415

Summary on Clinical Trials 416

References 417

Additional Readings 419

Glossary 425

Appendix 451

Index 459