Manufacturing of Pharmaceutical Proteins: From Technology to Economy, 3rd Edition
- Length: 496 pages
- Edition: 3
- Language: English
- Publisher: Wiley-VCH
- Publication Date: 2022-03-01
- ISBN-10: 3527349472
- ISBN-13: 9783527349470
- Sales Rank: #0 (See Top 100 Books)
An expert, single-volume overview of the core processes and disciplines of biopharmaceutical production
In the newly revised Third Edition of Manufacturing of Pharmaceutical Proteins: From Technology to Economy, renowned chemical engineer Dr. Stefan Behme delivers a comprehensive text covering all aspects of biopharmaceutical manufacturing, including legal and regulatory considerations, production facility design, quality assurance, supply chain management, emerging market regulations, and cost control. Suitable as both a reference book and a training resource, this book extensively explores the impact of digital transformation on pharmaceutical protein manufacturers and includes a brand-new chapter dedicated to digitalization.
The distinguished author provides readers with practical understanding of the terminology and principles driving the various fields involved with biotechnological production, including operations, legal, finance, and IT. He also offers:
- A thorough introduction to biopharmaceutical production, including value creation, product types, and biological basics
- Comprehensive explorations of the technology of the manufacturing process and analytics
- Practical discussions of pharmacology and drug safety, quality assurance, and pharmaceutical law
- In-depth examinations of pharmaceutical protein production facilities, including facility design and the planning, construction, and commissioning of a manufacturing plant
Perfect for biotechnologists working in the pharmaceutical industry, Manufacturing of Pharmaceutical Proteins: From Technology to Economy will also earn a place in the libraries of pharmaceutical engineers seeking a one-stop reference for all aspects of biopharmaceutical production.
Cover Title Page Copyright Contents Preface to Third Edition Preface to First Edition List of Abbreviations Part I Introduction Chapter 1 Biopharmaceutical Production: Value Creation, Product Types, and Biological Basics Introduction 1.1 Role of Production in Pharmaceutical Biotechnology 1.1.1 Relationship Between Production and Development 1.1.2 Relationship Between Production and Marketing 1.2 Product Groups 1.2.1 Vaccines 1.2.2 Pharmaceuticals from Blood and Organs 1.2.3 Recombinant Therapeutic Proteins 1.2.4 Cell and Gene Therapeutics 1.2.5 Antibiotics 1.3 Basics of Biology 1.3.1 Cells and Microorganisms 1.3.1.1 Structure and Types of Cells 1.3.1.2 Metabolism 1.3.1.3 Reproduction and Aging 1.3.1.4 Viruses and Bacteriophages 1.3.1.5 Protein Biosynthesis 1.3.2 The Four Molecular Building Blocks of Biochemistry 1.3.2.1 Proteins 1.3.2.2 Nucleic Acids 1.3.2.3 Polysaccharides 1.3.2.4 Lipids Part II Technology Chapter 2 Manufacturing Process 2.1 Role of the Manufacturing Process in Biotechnology 2.2 Process Schematic and Evaluation 2.2.1 Drug Substance Manufacturing 2.2.2 Drug Product Manufacturing 2.2.3 Key Factors for Process Evaluation 2.3 Cell Bank 2.3.1 Expression Systems 2.3.2 Microbial Systems 2.3.2.1 Mammalian Systems 2.3.2.2 Transgenic Systems 2.3.3 Manufacturing and Storage of the Cell Bank 2.4 Fermentation 2.4.1 Basic Principles 2.4.1.1 Cell Growth and Product Expression 2.4.1.2 Comparison of Batch and Continuous Processes 2.4.1.3 Sterility and Sterile Technology 2.4.1.4 Comparison of Fermentation with Mammalian Cells and Microorganisms 2.4.2 Technologies and Equipment 2.4.2.1 Fermentation in Suspension Culture 2.4.2.2 Adherent Cell Cultures 2.4.2.3 Transgenic Systems 2.4.3 Raw Materials and Processing Aids 2.4.3.1 Nutrient Media 2.4.3.2 Water, Gases, and Other Processing Aids 2.4.4 Overview of Fermentation 2.5 Purification 2.5.1 Basic Principles 2.5.1.1 Basic Pattern of Purification 2.5.1.2 Types of Impurities 2.5.1.3 Principles of Separation Technologies 2.5.2 Technologies for Cell Separation and Product Isolation 2.5.2.1 Cell Separation 2.5.2.2 Cell Disruption, Solubilization, and Refolding 2.5.2.3 Concentration and Stabilization 2.5.3 Technologies for Final Purification 2.5.3.1 Chromatographic Processes 2.5.3.2 Precipitation and Extraction 2.5.3.3 Sterile Filtration and Virus Removal 2.5.4 Raw Materials and Processing Aids 2.5.4.1 Gels for Chromatography 2.5.4.2 Membranes for TFF 2.5.5 Overview of Purification 2.6 Formulation and Filling 2.6.1 Basic Principles 2.6.2 Freeze‐Drying 2.7 Labeling and Packaging Chapter 3 Analytics 3.1 Role of Analytics in Biotechnology 3.2 Product Analytics 3.2.1 Identity 3.2.2 Content 3.2.3 Purity 3.2.4 Activity 3.2.5 Appearance 3.2.6 Stability 3.2.7 Quality Criteria of Analytical Methods 3.2.8 Analytical Methods 3.2.8.1 Amino Acid Analysis 3.2.8.2 Protein Sequencing 3.2.8.3 Peptide Mapping 3.2.8.4 Protein Content 3.2.8.5 Electrophoresis 3.2.8.6 Western Blot 3.2.8.7 HCP Enzyme‐Linked Immunosorbent Assay (ELISA) 3.2.8.8 Analytical Chromatography 3.2.8.9 Infrared (IR) Spectroscopy 3.2.8.10 UV/Vis Spectroscopy 3.2.8.11 Mass Spectrometry 3.2.8.12 Glycoanalytics 3.2.8.13 PCR 3.2.8.14 DNA/RNA Sequencing 3.2.8.15 Endotoxins and Pyrogen Testing 3.2.8.16 Bioburden Test 3.2.8.17 Virus Testing 3.2.8.18 TEM 3.2.8.19 Circular Dichroism 3.2.8.20 Differential Scanning Calorimetry 3.3 Process Analytics 3.3.1 Fermentation 3.3.2 Purification 3.3.3 Formulation and Packaging 3.4 Environmental Monitoring 3.5 Raw Material Testing 3.6 Product Comparability Part III Pharmacy Chapter 4 Pharmacology and Drug Safety 4.1 Action of Drugs in Humans 4.1.1 Pharmacokinetics 4.1.2 Pharmacodynamics 4.1.2.1 Principles of Phenomenological Effects 4.1.2.2 Parameters of Drug Effects 4.2 Routes and Forms of Administration 4.3 Drug Study 4.3.1 Pre‐Clinical Study 4.3.2 Clinical Study 4.3.2.1 Phases of Clinical Studies 4.3.2.2 Design and Conduct of Clinical Trials 4.4 Path of the Drug from the Manufacturer to Patients 4.5 Drug Safety 4.5.1 Causes and Classification of Side Effects 4.5.2 Methods for Supervising Drug Safety (Pharmacovigilance) 4.5.3 Measures upon Incidence of Adverse Reactions Part IV Quality Assurance Chapter 5 Fundamentals of Quality Assurance 5.1 Basic Principles 5.2 Benefit of Quality Assurance Activities 5.3 Quality Management According to ISO 9000 5.3.1 Fields of Activity 5.4 Structure of Quality Management Systems 5.5 Quality Management System Components in the Pharmaceutical Area 5.5.1 Documentation 5.5.2 Failure Prevention and Correction 5.5.3 Responsibility of Management and Training of Personnel 5.5.4 Audits 5.5.5 External Suppliers 5.5.6 Contract Review 5.6 Quality Assurance in Development Chapter 6 Quality Assurance in Manufacturing 6.1 GMP 6.1.1 Personnel 6.1.2 Premises and Equipment 6.1.2.1 Measures to Avoid External Contamination 6.1.2.2 Measures to Avoid Cross‐Contamination and Product Confusion 6.1.3 Equipment Qualification 6.1.4 Process Validation 6.1.5 Computer Validation 6.1.6 Documentation 6.2 Operative Workflows under GMP Conditions 6.2.1 Product Release and Deviation Management 6.2.2 Changes in the Manufacturing Process 6.3 Production of Investigational Drugs A Case Study Part IV: Warning Letters by FDA Part V Pharmaceutical Law Chapter 7 Pharmaceutical Law and Regulatory Authorities 7.1 Fields of Pharmaceutical Law 7.2 Bindingness of Regulations 7.3 Authorities, Institutions, and Their Regulations 7.3.1 FDA 7.3.2 EMA 7.3.3 German Authorities 7.3.4 Japanese Authorities 7.3.5 Authorities of Growth Markets 7.3.5.1 China: National Medical Products Administration (NMPA) 7.3.5.2 Brazilian Agência Nacional de Vigilância Sanitária (National Health Surveillance Agency, ANVISA) 7.3.6 Other Important Institutions 7.3.6.1 US Pharmacopoeia 7.3.6.2 ICH 7.3.6.3 ISO 7.3.6.4 WHO 7.3.6.5 PIC/S 7.3.6.6 ISPE 7.3.6.7 PDA 7.4 Official Enforcement of Regulations 7.5 Drug Approval B Case Study Part V: Clinical Trials for Protein Products B.1 Mabthera®/Rituxan® B.2 Enbrel® B.2.1 Adult Patients with Rheumatoid Arthritis B.3 Remicade® Infliximab B.3.1 Adult Rheumatoid Arthritis B.4 Humira® 40 mg B.5 Lucentis® B.5.1 Treatment of Wet AMD B.6 Zaltrap® Part VI Production Facilities Chapter 8 Facility Design 8.1 Basic Principles 8.2 GMP‐Compliant Plant Design 8.2.1 Production Flow Diagram 8.2.2 Conceptual Plant Layout 8.2.2.1 Is the Facility Fit for the Intended Purpose? 8.2.2.2 Is the Facility cGMP Compliant? 8.2.2.3 Is the Facility Flexible? 8.2.2.4 Can the Facility Be Expanded? 8.2.2.5 Is It Possible to Separate the Core Process from the Support Functions? 8.2.2.6 Is the Plant Capacity Optimized and Are Synergies with Existing Facilities Used? 8.2.3 GMP Flow Analysis 8.2.4 Zoning Concept 8.3 Basic Concepts for Production Plants 8.3.1 Single‐ and Multiproduct Plants 8.3.2 Fractal and Integrated Configuration 8.3.3 Flexible and Fixed Piping 8.3.4 Steel Tanks and Disposable Equipment 8.4 Clean and Plant Utilities 8.4.1 Clean Utilities 8.4.1.1 Water 8.4.1.2 Clean Steam 8.4.1.3 Gases and Process Air 8.4.2 Plant Utilities 8.4.3 Waste Management 8.5 Equipment Cleaning 8.6 Clean Rooms 8.6.1 Separation of Zones by Clean Room Design 8.6.2 Finishing of Floors, Walls, and Ceilings 8.6.3 HVAC Installations 8.6.4 Qualification 8.7 Automation 8.8 QC Laboratories 8.9 Location Factors 8.9.1 Cost 8.9.2 Personnel 8.9.3 Permitting 8.9.4 Synergies with Existing Facilities or Units 8.9.5 Logistics 8.9.6 Know‐How and Intellectual Property Protection 8.9.7 Other Risks 8.9.8 Market Access 8.9.9 Language and Culture Chapter 9 Planning, Construction, and Commissioning of a Manufacturing Plant 9.1 Steps of the Engineering Project 9.1.1 Planning 9.1.2 Construction 9.1.3 Commissioning, Qualification, Validation 9.2 Project Schedules 9.3 Cost Estimates 9.4 Organization of an Engineering Project 9.4.1 Expert Groups Involved 9.4.2 Role and Selection of Contractors 9.4.3 Contracts and Scope Changes 9.5 Successful Execution of an Engineering Project 9.6 Legal Aspects of Facility Engineering 9.6.1 Health, Safety, and Environmental Law 9.6.2 Building Law Part VII Economy Chapter 10 Production Costs 10.1 Drug Life Cycle 10.2 Position of the Manufacturing Costs in the Overall Cost Framework 10.3 Basic Principles of Cost Calculation 10.3.1 Nominal Accounting – Actual Accounting 10.3.2 Cost Accounting – Profit and Loss Accounting 10.3.3 Direct Costs – Indirect Costs 10.3.4 Fixed Costs – Variable Costs 10.3.5 Relevant and Irrelevant Costs 10.3.6 Cost Type, Cost Center, and Cost Unit 10.4 Costs of Biotechnological Manufacturing Processes 10.4.1 Capital Costs 10.4.2 Operating Costs 10.5 Accounting Methods 10.5.1 Cost Accounting 10.5.2 Profit and Loss Accounting Chapter 11 Investments 11.1 Basic Principles 11.1.1 Investment Targets 11.1.2 Types of Investments 11.1.2.0 Classification According to the Object of Investment 11.1.2.0 Classification According to the Effect of Investment 11.1.2.0 Classification According to Other Criteria 11.1.3 Decision Processes 11.2 Value–Benefit Analysis 11.3 Investment Appraisal 11.3.1 Static Methods 11.3.1.1 Cost Comparison 11.3.1.2 Profit Comparison 11.3.1.3 Profitability Comparison 11.3.1.4 Static Payback Time 11.3.2 Dynamic Methods 11.3.2.1 Capital Value 11.3.2.2 Internal Rate of Return 11.3.2.3 Annuity 11.4 Dynamic Payback Time Chapter 12 Production Concept 12.1 Capacity Planning 12.2 Dilemma of In‐House Manufacturing 12.3 Aspects of Manufacturing Outsourcing 12.3.1 Types of Cooperation 12.3.2 Contractual Agreements 12.3.3 Technology Transfer 12.3.4 Time Schedules 12.4 Make‐or‐Buy Analysis 12.5 Process Optimization 12.5.1 Comparability of the Product 12.5.2 Operational Excellence 12.5.2.1 Lean Management 12.5.2.2 Six‐Sigma 12.6 Supply‐Chain Management 12.6.1 Security of Supply 12.6.2 Performance Management C Examples Part VII: Manufacturing Cost Calculation C.1 Introduction C.2 Basic Assumptions for Both Production Processes C.3 Step 1: Production of Product 1 in Dedicated Facility C.3.1 Cost Structure C.3.2 Product Costs C.3.3 Idle Costs C.3.4 Unit Price Based on Facility Usage C.4 Step 2: Addition of a Second Product C.4.1 Costs of Products C.4.2 Evaluation of Manufacturing Options Part VIII Production Organization and Digitalization Chapter 13 Organization of a Manufacturing Facility 13.1 Functional Setup of a Manufacturing Plant 13.2 Development of a Plant Organization 13.3 Organizational Charts and Cooperation Pathways 13.4 Cultural Aspects: The Human Factor Chapter 14 Digitalization 14.1 Operational and Digital Perspective 14.2 Digital Maturity 14.3 Integration and IT Architecture 14.4 Digital Transformation 14.5 Digital Applications in the GMP Environment References Index EULA
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