Cover -- Contents -- Preface -- 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 -- Appendix A Case Study Part 4: 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 Food and Drug Administration (CFDA) -- 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 -- Appendix B Case Study Part 5: Clinical Trials for Protein Products -- B.1 Mabthera®/Rituxan® -- B.2 Enbrel® -- B.3 Remicade® Infliximab -- B.4 Humira® 40 mg -- B.5 Lucentis® -- 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 -- 8.2.3 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.

11.1.3 Decision Processes.