Details

Manufacturing of Pharmaceutical Proteins

From Technology to Economy
3. Aufl.

von: Stefan Behme
133,99 €
Verlag:	Wiley-Blackwell (WB)
Format:	EPUB
Veröffentl.:	09.12.2021
ISBN/EAN:	9783527833801
Sprache:	englisch
Anzahl Seiten:	496

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Beschreibungen

Titelbeschreibung

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: <ul><li>A thorough introduction to biopharmaceutical production, including value creation, product types, and biological basics</li> <li>Comprehensive explorations of the technology of the manufacturing process and analytics</li> <li>Practical discussions of pharmacology and drug safety, quality assurance, and pharmaceutical law</li> <li>In-depth examinations of pharmaceutical protein production facilities, including facility design and the planning, construction, and commissioning of a manufacturing plant</li></ul> 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.

Inhaltsverzeichnis

Preface to Third Edition xvii Preface to First Edition xix List of Abbreviations xxi Part I Introduction 1 1 Biopharmaceutical Production: Value Creation, Product Types, and Biological Basics Introduction 3 1.1 Role of Production in Pharmaceutical Biotechnology 3 1.1.1 Relationship Between Production and Development 6 1.1.2 Relationship Between Production and Marketing 8 1.2 Product Groups 10 1.2.1 Vaccines 12 1.2.2 Pharmaceuticals from Blood and Organs 12 1.2.3 Recombinant Therapeutic Proteins 13 1.2.4 Cell and Gene Therapeutics 13 1.2.5 Antibiotics 16 1.3 Basics of Biology 16 1.3.1 Cells and Microorganisms 16 1.3.1.1 Structure and Types of Cells 17 1.3.1.2 Metabolism 19 1.3.1.3 Reproduction and Aging 21 1.3.1.4 Viruses and Bacteriophages 22 1.3.1.5 Protein Biosynthesis 23 1.3.2 The Four Molecular Building Blocks of Biochemistry 25 1.3.2.1 Proteins 25 1.3.2.2 Nucleic Acids 29 1.3.2.3 Polysaccharides 30 1.3.2.4 Lipids 31 Part II Technology 33 2 Manufacturing Process 35 2.1 Role of the Manufacturing Process in Biotechnology 35 2.2 Process Schematic and Evaluation 37 2.2.1 Drug Substance Manufacturing 38 2.2.2 Drug Product Manufacturing 40 2.2.3 Key Factors for Process Evaluation 41 2.3 Cell Bank 43 2.3.1 Expression Systems 43 2.3.2 Microbial Systems 44 2.3.2.1 Mammalian Systems 45 2.3.2.2 Transgenic Systems 46 2.3.3 Manufacturing and Storage of the Cell Bank 46 2.4 Fermentation 48 2.4.1 Basic Principles 48 2.4.1.1 Cell Growth and Product Expression 49 2.4.1.2 Comparison of Batch and Continuous Processes 50 2.4.1.3 Sterility and Sterile Technology 53 2.4.1.4 Comparison of Fermentation with Mammalian Cells and Microorganisms 55 2.4.2 Technologies and Equipment 56 2.4.2.1 Fermentation in Suspension Culture 56 2.4.2.2 Adherent Cell Cultures 57 2.4.2.3 Transgenic Systems 60 2.4.3 Raw Materials and Processing Aids 61 2.4.3.1 Nutrient Media 61 2.4.3.2 Water, Gases, and Other Processing Aids 62 2.4.4 Overview of Fermentation 63 2.5 Purification 64 2.5.1 Basic Principles 65 2.5.1.1 Basic Pattern of Purification 65 2.5.1.2 Types of Impurities 68 2.5.1.3 Principles of Separation Technologies 71 2.5.2 Technologies for Cell Separation and Product Isolation 73 2.5.2.1 Cell Separation 73 2.5.2.2 Cell Disruption, Solubilization, and Refolding 74 2.5.2.3 Concentration and Stabilization 75 2.5.3 Technologies for Final Purification 80 2.5.3.1 Chromatographic Processes 81 2.5.3.2 Precipitation and Extraction 89 2.5.3.3 Sterile Filtration and Virus Removal 90 2.5.4 Raw Materials and Processing Aids 91 2.5.4.1 Gels for Chromatography 91 2.5.4.2 Membranes for TFF 93 2.5.5 Overview of Purification 94 2.6 Formulation and Filling 96 2.6.1 Basic Principles 96 2.6.2 Freeze-Drying 98 2.7 Labeling and Packaging 99 3 Analytics 103 3.1 Role of Analytics in Biotechnology 103 3.2 Product Analytics 105 3.2.1 Identity 107 3.2.2 Content 107 3.2.3 Purity 109 3.2.4 Activity 109 3.2.5 Appearance 112 3.2.6 Stability 112 3.2.7 Quality Criteria of Analytical Methods 114 3.2.8 Analytical Methods 115 3.2.8.1 Amino Acid Analysis 116 3.2.8.2 Protein Sequencing 116 3.2.8.3 Peptide Mapping 117 3.2.8.4 Protein Content 117 3.2.8.5 Electrophoresis 118 3.2.8.6 Western Blot 120 3.2.8.7 HCP Enzyme-Linked Immunosorbent Assay (elisa) 122 3.2.8.8 Analytical Chromatography 123 3.2.8.9 Infrared (IR) Spectroscopy 125 3.2.8.10 UV/Vis Spectroscopy 125 3.2.8.11 Mass Spectrometry 126 3.2.8.12 Glycoanalytics 127 3.2.8.13 Pcr 127 3.2.8.14 DNA/RNA Sequencing 128 3.2.8.15 Endotoxins and Pyrogen Testing 129 3.2.8.16 Bioburden Test 130 3.2.8.17 Virus Testing 130 3.2.8.18 Tem 131 3.2.8.19 Circular Dichroism 131 3.2.8.20 Differential Scanning Calorimetry 131 3.3 Process Analytics 132 3.3.1 Fermentation 132 3.3.2 Purification 133 3.3.3 Formulation and Packaging 134 3.4 Environmental Monitoring 135 3.5 Raw Material Testing 137 3.6 Product Comparability 138 Part III Pharmacy 141 4 Pharmacology and Drug Safety 143 4.1 Action of Drugs in Humans 144 4.1.1 Pharmacokinetics 145 4.1.2 Pharmacodynamics 149 4.1.2.1 Principles of Phenomenological Effects 149 4.1.2.2 Parameters of Drug Effects 150 4.2 Routes and Forms of Administration 152 4.3 Drug Study 153 4.3.1 Pre-Clinical Study 155 4.3.2 Clinical Study 157 4.3.2.1 Phases of Clinical Studies 157 4.3.2.2 Design and Conduct of Clinical Trials 160 4.4 Path of the Drug from the Manufacturer to Patients 162 4.5 Drug Safety 164 4.5.1 Causes and Classification of Side Effects 165 4.5.2 Methods for Supervising Drug Safety (Pharmacovigilance) 167 4.5.3 Measures upon Incidence of Adverse Reactions 168 Part IV Quality Assurance 171 5 Fundamentals of Quality Assurance 173 5.1 Basic Principles 173 5.2 Benefit of Quality Assurance Activities 174 5.3 Quality Management According to ISO 9000 175 5.3.1 Fields of Activity 176 5.4 Structure of Quality Management Systems 178 5.5 Quality Management System Components in the Pharmaceutical Area 180 5.5.1 Documentation 180 5.5.2 Failure Prevention and Correction 181 5.5.3 Responsibility of Management and Training of Personnel 186 5.5.4 Audits 186 5.5.5 External Suppliers 187 5.5.6 Contract Review 188 5.6 Quality Assurance in Development 189 6 Quality Assurance in Manufacturing 191 6.1 Gmp 191 6.1.1 Personnel 196 6.1.2 Premises and Equipment 198 6.1.2.1 Measures to Avoid External Contamination 198 6.1.2.2 Measures to Avoid Cross-Contamination and Product Confusion 201 6.1.3 Equipment Qualification 203 6.1.4 Process Validation 206 6.1.5 Computer Validation 208 6.1.6 Documentation 209 6.2 Operative Workflows under GMP Conditions 210 6.2.1 Product Release and Deviation Management 211 6.2.2 Changes in the Manufacturing Process 213 6.3 Production of Investigational Drugs 216 Appendix A Case Study Part IV: Warning Letters by FDA 219 Part V Pharmaceutical Law 223 7 Pharmaceutical Law and Regulatory Authorities 225 7.1 Fields of Pharmaceutical Law 225 7.2 Bindingness of Regulations 226 7.3 Authorities, Institutions, and Their Regulations 227 7.3.1 Fda 228 7.3.2 Ema 230 7.3.3 German Authorities 233 7.3.4 Japanese Authorities 234 7.3.5 Authorities of Growth Markets 235 7.3.5.1 China: National Medical Products Administration (nmpa) 236 7.3.5.2 Brazilian Agência Nacional de Vigilância Sanitária (National Health Surveillance Agency, ANVISA) 236 7.3.6 Other Important Institutions 236 7.3.6.1 US Pharmacopoeia 236 7.3.6.2 Ich 237 7.3.6.3 Iso 237 7.3.6.4 Who 237 7.3.6.5 Pic/s 237 7.3.6.6 Ispe 239 7.3.6.7 Pda 239 7.4 Official Enforcement of Regulations 239 7.5 Drug Approval 241 Appendix B Case Study Part V: Clinical Trials for Protein Products 243 B.1 Mabthera® /Rituxan ® 243 B.2 Enbrel® 244 B.2.1 Adult Patients with Rheumatoid Arthritis 244 B.3 Remicade® Infliximab 245 B.3.1 Adult Rheumatoid Arthritis 245 B.4 Humira® 40 mg 246 B.5 Lucentis® 247 B.5.1 Treatment of Wet AMD 247 B.6 Zaltrap® 247 Part VI Production Facilities 249 8 Facility Design 251 8.1 Basic Principles 251 8.2 GMP-Compliant Plant Design 254 8.2.1 Production Flow Diagram 256 8.2.2 Conceptual Plant Layout 257 8.2.2.1 Is the Facility Fit for the Intended Purpose? 259 8.2.2.2 Is the Facility cGMP Compliant? 259 8.2.2.3 Is the Facility Flexible? 259 8.2.2.4 Can the Facility Be Expanded? 260 8.2.2.5 Is It Possible to Separate the Core Process from the Support Functions? 260 8.2.2.6 Is the Plant Capacity Optimized and Are Synergies with Existing Facilities Used? 261 8.2.3 GMP Flow Analysis 261 8.2.4 Zoning Concept 264 8.3 Basic Concepts for Production Plants 267 8.3.1 Single- and Multiproduct Plants 270 8.3.2 Fractal and Integrated Configuration 271 8.3.3 Flexible and Fixed Piping 273 8.3.4 Steel Tanks and Disposable Equipment 274 8.4 Clean and Plant Utilities 275 8.4.1 Clean Utilities 275 8.4.1.1 Water 275 8.4.1.2 Clean Steam 282 8.4.1.3 Gases and Process Air 282 8.4.2 Plant Utilities 283 8.4.3 Waste Management 285 8.5 Equipment Cleaning 286 8.6 Clean Rooms 288 8.6.1 Separation of Zones by Clean Room Design 289 8.6.2 Finishing of Floors, Walls, and Ceilings 291 8.6.3 HVAC Installations 292 8.6.4 Qualification 293 8.7 Automation 293 8.8 QC Laboratories 295 8.9 Location Factors 295 8.9.1 Cost 295 8.9.2 Personnel 296 8.9.3 Permitting 296 8.9.4 Synergies with Existing Facilities or Units 296 8.9.5 Logistics 297 8.9.6 Know-How and Intellectual Property Protection 297 8.9.7 Other Risks 297 8.9.8 Market Access 297 8.9.9 Language and Culture 298 9 Planning, Construction, and Commissioning of a Manufacturing Plant 299 9.1 Steps of the Engineering Project 299 9.1.1 Planning 300 9.1.2 Construction 301 9.1.3 Commissioning, Qualification, Validation 303 9.2 Project Schedules 306 9.3 Cost Estimates 307 9.4 Organization of an Engineering Project 309 9.4.1 Expert Groups Involved 309 9.4.2 Role and Selection of Contractors 310 9.4.3 Contracts and Scope Changes 310 9.5 Successful Execution of an Engineering Project 314 9.6 Legal Aspects of Facility Engineering 315 9.6.1 Health, Safety, and Environmental Law 316 9.6.2 Building Law 317 Part VII Economy 319 10 Production Costs 321 10.1 Drug Life Cycle 321 10.2 Position of the Manufacturing Costs in the Overall Cost Framework 325 10.3 Basic Principles of Cost Calculation 327 10.3.1 Nominal Accounting – Actual Accounting 327 10.3.2 Cost Accounting – Profit and Loss Accounting 328 10.3.3 Direct Costs – Indirect Costs 328 10.3.4 Fixed Costs – Variable Costs 329 10.3.5 Relevant and Irrelevant Costs 330 10.3.6 Cost Type, Cost Center, and Cost Unit 331 10.4 Costs of Biotechnological Manufacturing Processes 332 10.4.1 Capital Costs 333 10.4.2 Operating Costs 335 10.5 Accounting Methods 338 10.5.1 Cost Accounting 338 10.5.2 Profit and Loss Accounting 347 11 Investments 351 11.1 Basic Principles 352 11.1.1 Investment Targets 352 11.1.2 Types of Investments 353 11.1.3 Decision Processes 355 11.2 Value–Benefit Analysis 359 11.3 Investment Appraisal 360 11.3.1 Static Methods 364 11.3.1.1 Cost Comparison 364 11.3.1.2 Profit Comparison 365 11.3.1.3 Profitability Comparison 365 11.3.1.4 Static Payback Time 365 11.3.2 Dynamic Methods 365 11.3.2.1 Capital Value 366 11.3.2.2 Internal Rate of Return 366 11.3.2.3 Annuity 367 11.4 Dynamic Payback Time 367 12 Production Concept 369 12.1 Capacity Planning 369 12.2 Dilemma of In-House Manufacturing 372 12.3 Aspects of Manufacturing Outsourcing 375 12.3.1 Types of Cooperation 376 12.3.2 Contractual Agreements 377 12.3.3 Technology Transfer 382 12.3.4 Time Schedules 384 12.4 Make-or-Buy Analysis 385 12.5 Process Optimization 387 12.5.1 Comparability of the Product 387 12.5.2 Operational Excellence 390 12.5.2.1 Lean Management 391 12.5.2.2 Six-Sigma 392 12.6 Supply-Chain Management 396 12.6.1 Security of Supply 398 12.6.2 Performance Management 401 Appendix C Examples Part VII: Manufacturing Cost Calculation 405 C. 1 Introduction 405 C. 2 Basic Assumptions for Both Production Processes 405 C. 3 Step 1: Production of Product 1 in Dedicated Facility 405 C.3. 1 Cost Structure 406 C.3. 2 Product Costs 407 C. 3 Idle Costs 407 C.3.4 Unit Price Based on Facility Usage 407 C.4 Step 2: Addition of a Second Product 408 C.4.1 Costs of Products 409 C.4.2 Evaluation of Manufacturing Options 410 Part VIII Production Organization and Digitalization 413 13 Organization of a Manufacturing Facility 415 13.1 Functional Setup of a Manufacturing Plant 416 13.2 Development of a Plant Organization 416 13.3 Organizational Charts and Cooperation Pathways 421 13.4 Cultural Aspects: The Human Factor 424 14 Digitalization 427 14.1 Operational and Digital Perspective 428 14.2 Digital Maturity 435 14.3 Integration and IT Architecture 440 14.4 Digital Transformation 444 14.5 Digital Applications in the GMP Environment 446 References 451 Further Reading 451 Biotechnology General 451 Fermentation 452 Purification 452 Aseptic Filling and Lyophilization 452 Bioanalytics 452 Regulatory 453 Pharmacy and Clinical Development 453 Quality and Validation 453 Good Manufacturing Practice 454 Facility Design 454 Clean Rooms 454 Project Management 454 Engineering 454 Economy 455 Weblinks 455 Index 457

Autorenportrait

Stefan Behme, PhD, has held several positions within the pharma and biotech industry over the last 20 years with Bayer AG and former Schering AG, Germany. Trained as chemical engineer, his industrial assignments included: managing healthcare investment projects in Germany and the US, biotech manufacturing operations, strategic sourcing of finished pharmaceuticals, and quality assurance in one of the world’s largest drug manufacturing facilities. In parallel he has been passing on his knowledge to students of the Universities of Dortmund (Germany) and Berlin as lecturer for GMP-aspects of biopharmaceutical manufacturing and general life science manufacturing processes. In 2009 he published the first edition of the book “Manufacturing of Pharmaceutical Proteins: from Technology to Economy”, which has developed into a popular reference and was followed by a further expanded edition in 2015.

Back cover copy

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: <ul><li>A thorough introduction to biopharmaceutical production, including value creation, product types, and biological basics</li> <li>Comprehensive explorations of the technology of the manufacturing process and analytics</li> <li>Practical discussions of pharmacology and drug safety, quality assurance, and pharmaceutical law</li> <li>In-depth examinations of pharmaceutical protein production facilities, including facility design and the planning, construction, and commissioning of a manufacturing plant</li></ul> 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.