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1.Introduction to Biotechnology Operations：Planning for Success1

Biotechnology Operations1

Marketing，Financial and Business Considerations for Development4

Product Development Planning7

Rationale for Product Development Planning7

Targeted Product Profile10

Product Development Plan16

Clinical Development Planning18

Project Management Planning19

Regulatory Planning20

Nonclinical Planning22

Biornanufacturing Planning23

Quality Control Planning24

Quality Systems and Quality Assurance Planning26

Additional Elements of Product Planning26

Summary of Planning for Success28

2.Project Management29

Project Management in Biotechnology29

Background of Project Management31

Project Management in Biotechnology32

Project Management Environment33

Project Objectives and Schedules35

Sociotechnical Considerations36

Participants in Project Management37

Project Management in Biotechnology Operations40

Establishing Project Management40

Work Breakdown Structure42

Forming a Project Team and Hands-On Project Management42

Communication and Feedback47

Team Dynamics47

Project Risk Assessment and Management50

Metrics and Tracking Progress51

Resources：Planning and Usage52

Human Factors in Project Management53

Project Completion55

Project Management with Contracts and Collaborations56

Tools for Effective Project Management57

Summary of Project Management in Biotechnology Development60

3.Regulatory Affairs61

The U.S.Food and Drug Administration：Law and Regulations for Biopharmaceuticals61

Historical Basis for FDA Regulation61

Regulatory Organization of FDA63

Food and Drug Law，Regulation and Guidance66

FDA-Regulated Products67

Biologics67

Drugs70

Medical Devices72

Combination Products72

Other Classes of Biotechnology Products and Their Review at the FDA73

Products for Veterinary Use73

Cosmetics，Food，Dietary Supplements，Homeopathic or Nutritional Products73

U.S.FDA Regulatory Information and Resources：Regulatory Intelligence75

Regulatory Operations for FDA Applications78

Regulatory Planning and the Regulatory Environment78

Risk versus Benefit78

Applications Seeking FDA Investigational Use or Marketing Approval80

Investigational Use Applications：Investigational New Drug （IND）Application81

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 Exemptions91

Generic Drugs and Biosimiliar or Follow-On Biologics93

Other Regulatory Activities94

Public Meetings and Advisory Committees94

Postmarketing Requirements and Activities96

Advertising and Promotion97

Summary on Regulatory Affairs Activities in Biotechnology Operations98

4.Regulatory Compliance99

Regulatory Compliance99

Quality Systems to Meet Regulatory Compliance99

Compliance and Quality Systems99

cGMPs：Current Good Manufacturing Practices for Manufacture and Quality Control100

cGLPs：Current Good Laboratory Practices for Nonclinical Lab Studies100

cGCPs：Current Good Clinical Practices for Clinical Studies102

Compliance for Biopharmaceuticals：Other Regulations of Importance104

Compliance for Import of Biopharmaceuticals into the United States104

Compliance for Medical Devices105

Inspection and Enforcement105

Inspections106

Enforcement Actions108

Product Liability110

Compliance with Non-FDA Regulations：International，National，State and Local110

International and Foreign National Regulatory Authorities for Medical Biotechnology Products110

Transporting Infectious or Otherwise Hazardous Materials114

Importing，Possessing or Transferring Controlled Biotechnology Materials116

Public Health Security and Bioterrorism Preparedness and Response Act of 2002118

Importation or Exportation of Biotechnology Products for the Purpose of Treatment of Diseases in Man119

Occupational Health and Safety120

Environmental Regulations in Biotechnology121

Genetically Modified Organisms or Molecules122

U.S.Regulatory Agencies Unified Biotechnology Web Site124

International Diligence in Biotechnology Operations124

Summary of Non-FDA Compliance125

5.Quality Systems127

Overview of Quality in Biotechnology127

History：Evolution of Quality Concepts and Practices128

Quality Systems Approach to Product Development130

Planning a Quality System132

Defining Objectives and Ensuring Management Support132

The Quality Manual133

The Quality Plan134

Hallmarks of Quality：Fundamental Criteria for Building Effective Quality Systems136

Management Responsibility137

Defined Quality System137

Quality by Design and Design Control138

Quality by Design138

Design Control139

Design Change143

Contractor，Vendor and Consultant Control143

Product Identification and Traceability146

Process Control146

Environmental Controls147

Inspection or Testing（Quality Control）147

Release of Material，Service or Product148

Change Control and Corrective or Preventive Actions149

Packaging and Labeling150

Preservation，Storage and Handling150

Servicing151

Customer Concerns and Adverse Event Reports151

Document Control151

Training151

Auditing152

Quality Assurance Unit152

Manage the Quality Assurance Function153

Control Documents and Manage the Documentation System154

Investigate Situations：Manage and Control Change156

Ensure Qualified and Trained Staff156

Perform Audits157

Initiate a Quality System for a Biotechnology Operation158

Unique and Effective Approaches to Quality Management160

Risk-Based Approaches to Quality Systems160

Total Quality Management（TQM）160

Six Sigma161

Quality Systems for Research161

Resolving Quality Issues or Problems162

Summary of Quality Systems163

6.Biomanufacture165

Overview of Biornanufacturing Requirements165

Design in Biomanufacture165

Technical Considerations for Biomanufacture169

Phases and Scale Up：The Biomanufacturing Life Cycle171

Raw Material Considerations175

Compliance and Quality in Biomanufacture：Current Good Manufacturing Practices176

Biomanufacturing Processes for Biotechnology Products179

Expression of Recombinant Proteins and Nucleic Acids179

Production of Recombinant Molecules from Expression Vectors179

Genes，Vectors and Host Cells180

Bacterial Cell Expression Systems182

Yeast Cell Expression Systems182

Mammalian or Insect Cell Expression Systems183

Production of Master Cell Banks and Working Cell Banks184

Biomanufacture of Recombinant Proteins186

Planning Production of a Recombinant Protein186

Upstream Process：Production by Bacterial or Yeast Cell Fermentation187

Upstream Process：Production by Mammalian or Insect Cell Culture190

Upstream Process：Recovery191

Downstream Process：Purification191

In-Process Testing and Analysis of Bulk Substance199

Production of Bacterial Plasmid DNA201

Production of Live Recombinant Organisms：Bacteria and Virus201

Production of Products Composed of Mammalian Somatic Cells or Tissues204

Production of Cellular Products Derived from Pluripotent （Stem）Cells204

Production of Biological Molecules by Transgenic Animals or Transgenic Plants206

Production of Biologically Active Lipids，Glycolipids and Complex Carbohydrates210

Production of Biologically Active Peptides212

Production of Combination Products：Biopharmaceutical with a Drug or Medical Device212

Final Product：Formulation Fill，Finish and Labeling214

Biomanufacturing Facilities，Utilities and Equipment218

Facility Design Considerations218

Facility and Utilities：A Controlled Environment219

Operation of Clean Work Areas for Biomanufacture221

Biomanufacturing Equipment222

Contract Manufacturing Options223

Validation of Biomanufacturing Facilities，Utilities，Equipment and Processes223

Summary of Biomanufacture226

7.Quality Control227

Quality Control Overview227

Define Product Attributes230

Analytical Methods Measure Attributes231

Traits of Analytical Methods231

Draft a Certificate of Analysis（Bulk Substance）232

Select Analytical Methods234

Develop Specifications242

Enter Test Results246

Certificate of Analysis for Drug Product246

In-Process Testing249

Analytical Methods250

Additional Analytical Tools and Concepts256

Quality Control of Cell Banks258

Samples and Sampling259

Analytical Controls and Reference Standards260

Test Failures，Out-of-Specification Results and Retesting261

Testing for Product Stability262

Quality Control Testing of Raw Materials266

Quality Control and the Manufacturing Environment269

Qualification，Validation and Verification of Analytical Methods269

Assay Validation270

Application of Statistics in Assay Performance and Validation274

Summary of Quality Control275

8.Nonclinical Studies277

Nonclinical Studies and Risk Assessment277

Biopharmaceutical Delivery，Pharmacokinetics and Pharmacodynamics279

Product Delivery to the Body279

Absorption，Distribution，Elimination and Metabolism （ADME）280

Absorption281

Distribution282

Metabolism and Biotransformation283

Excretion283

Pharmacokinetics and Pharmacodynamics283

Application of Pharmacokinetics and Pharmacodynamics in Biopharmaceutical Development289

Safety Assessment of Biopharmaceuticals291

Toxicology291

Design of a Safety Assessment Program292

In Vitro Screens：Surrogate Measures of Toxicity295

In Vivo Safety Testing of Biopharmaceuticals297

Animal Model Development297

Test Product Formulations，Routes of Delivery and Dosing Designs299

Protocols and Performance of Biopharmaceutical Safety Studies in Animals301

Elements of a Nonclinical Study Design302

Acute Toxicity Testing305

Subchronic and Chronic Toxicity Testing306

Reproductive，Developmental and Teratogenicity Toxicity Testing308

Carcinogenicity Testing310

Immunotoxicology310

Genetic Toxicology312

Tissue Binding or Local Tissue Tolerance313

Quality of Nonclinical Studies：Current Good Laboratory Practices314

Summary of Nonclinical Studies314

9.Clinical Trials317

Introduction to Clinical Trials317

Background of Clinical Research319

Introduction319

Historical Information on Clinical Trials320

Organization of Clinical Research321

Phases of Clinical Trials321

The Science of Clinical Research322

Quality in Clinical Research and Current Good Clinical Practices322

Clinical Development Planning323

Infrastructure for a Clinical Trial：Individuals，Documents and Investigational Product323

Design of Clinical Trials and the Clinical Protocol324

Human Subjects，Patients and Volunteers332

The Sponsor332

The Principal Investigator and His/Her Study Staff335

Institutional Review Boards（IRB）：Process of Informed Consent（IC）and IC Form336

Investigational Product339

Collection of Clinical Data：Case Report Forms and the Patient Diary339

Clinical Testing Laboratories340

Reporting Results of Clinical Trials：Clinical Summary Reports341

Clinical Trial Operations341

Activities Leading to a Clinical Trial342

Phase 1 Clinical Trial：First-Time-in-Man344

Clinical Pharmacology Studies of Biopharmaceuticals in Man345

Phase 2 Clinical Trial：Proof-of-Concept348

Phase 3 Clinical Trial：Therapeutic Confirmatory349

Phase 4 Clinical Study and REMS351

Clinical Trials for New Populations or Indications351

Global Clinical Trials352

Quality Systems for Clinical Trials：Current Good Clinical Practices353

Quality and cGCP in Clinical Trial Operations353

Integrity of Clinical Study Data and Documents355

Monitoring and Auditing Clinical Trials356

Ethical Behavior and the Well-Being of Clinical Trial Subjects356

Summary on Clinical Trials358

Glossary359

Additional Reading383

Practical Problems and Questions387

Index395