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A comprehensive look at existing technologies and processes for continuous manufacturing of pharmaceuticals
As rising costs outpace new drug development, the pharmaceutical industry has come under intense pressure to improve the efficiency of its manufacturing processes. Continuous process manufacturing provides a proven solution. Among its many benefits are: minimized waste, energy consumption, and raw material use; the accelerated introduction of new drugs; the use of smaller production facilities with lower building and capital costs; the ability to monitor drug quality on a continuous basis; and enhanced process reliability and flexibility. Continuous Manufacturing of Pharmaceuticals prepares professionals to take advantage of that exciting new approach to improving drug manufacturing efficiency.
This book covers key aspects of the continuous manufacturing of pharmaceuticals. The first part provides an overview of key chemical engineering principles and the current regulatory environment. The second covers existing technologies for manufacturing both small-molecule-based products and protein/peptide products. The following section is devoted to process analytical tools for continuously operating manufacturing environments. The final two sections treat the integration of several individual parts of processing into fully operating continuous process systems and summarize state-of-art approaches for innovative new manufacturing principles.
* Brings together the essential know-how for anyone working in drug manufacturing, as well as chemical, food, and pharmaceutical scientists working on continuous processing
* Covers chemical engineering principles, regulatory aspects, primary and secondary manufacturing, process analytical technology and quality-by-design
* Contains contributions from researchers in leading pharmaceutical companies, the FDA, and academic institutions
* Offers an extremely well-informed look at the most promising future approaches to continuous manufacturing of innovative pharmaceutical products
Timely, comprehensive, and authoritative, Continuous Manufacturing of Pharmaceuticals is an important professional resource for researchers in industry and academe working in the fields of pharmaceuticals development and manufacturing.
As rising costs outpace new drug development, the pharmaceutical industry has come under intense pressure to improve the efficiency of its manufacturing processes. Continuous process manufacturing provides a proven solution. Among its many benefits are: minimized waste, energy consumption, and raw material use; the accelerated introduction of new drugs; the use of smaller production facilities with lower building and capital costs; the ability to monitor drug quality on a continuous basis; and enhanced process reliability and flexibility. Continuous Manufacturing of Pharmaceuticals prepares professionals to take advantage of that exciting new approach to improving drug manufacturing efficiency.
This book covers key aspects of the continuous manufacturing of pharmaceuticals. The first part provides an overview of key chemical engineering principles and the current regulatory environment. The second covers existing technologies for manufacturing both small-molecule-based products and protein/peptide products. The following section is devoted to process analytical tools for continuously operating manufacturing environments. The final two sections treat the integration of several individual parts of processing into fully operating continuous process systems and summarize state-of-art approaches for innovative new manufacturing principles.
* Brings together the essential know-how for anyone working in drug manufacturing, as well as chemical, food, and pharmaceutical scientists working on continuous processing
* Covers chemical engineering principles, regulatory aspects, primary and secondary manufacturing, process analytical technology and quality-by-design
* Contains contributions from researchers in leading pharmaceutical companies, the FDA, and academic institutions
* Offers an extremely well-informed look at the most promising future approaches to continuous manufacturing of innovative pharmaceutical products
Timely, comprehensive, and authoritative, Continuous Manufacturing of Pharmaceuticals is an important professional resource for researchers in industry and academe working in the fields of pharmaceuticals development and manufacturing.
A comprehensive look at existing technologies and processes for continuous manufacturing of pharmaceuticals
As rising costs outpace new drug development, the pharmaceutical industry has come under intense pressure to improve the efficiency of its manufacturing processes. Continuous process manufacturing provides a proven solution. Among its many benefits are: minimized waste, energy consumption, and raw material use; the accelerated introduction of new drugs; the use of smaller production facilities with lower building and capital costs; the ability to monitor drug quality on a continuous basis; and enhanced process reliability and flexibility. Continuous Manufacturing of Pharmaceuticals prepares professionals to take advantage of that exciting new approach to improving drug manufacturing efficiency.
This book covers key aspects of the continuous manufacturing of pharmaceuticals. The first part provides an overview of key chemical engineering principles and the current regulatory environment. The second covers existing technologies for manufacturing both small-molecule-based products and protein/peptide products. The following section is devoted to process analytical tools for continuously operating manufacturing environments. The final two sections treat the integration of several individual parts of processing into fully operating continuous process systems and summarize state-of-art approaches for innovative new manufacturing principles.
* Brings together the essential know-how for anyone working in drug manufacturing, as well as chemical, food, and pharmaceutical scientists working on continuous processing
* Covers chemical engineering principles, regulatory aspects, primary and secondary manufacturing, process analytical technology and quality-by-design
* Contains contributions from researchers in leading pharmaceutical companies, the FDA, and academic institutions
* Offers an extremely well-informed look at the most promising future approaches to continuous manufacturing of innovative pharmaceutical products
Timely, comprehensive, and authoritative, Continuous Manufacturing of Pharmaceuticals is an important professional resource for researchers in industry and academe working in the fields of pharmaceuticals development and manufacturing.
As rising costs outpace new drug development, the pharmaceutical industry has come under intense pressure to improve the efficiency of its manufacturing processes. Continuous process manufacturing provides a proven solution. Among its many benefits are: minimized waste, energy consumption, and raw material use; the accelerated introduction of new drugs; the use of smaller production facilities with lower building and capital costs; the ability to monitor drug quality on a continuous basis; and enhanced process reliability and flexibility. Continuous Manufacturing of Pharmaceuticals prepares professionals to take advantage of that exciting new approach to improving drug manufacturing efficiency.
This book covers key aspects of the continuous manufacturing of pharmaceuticals. The first part provides an overview of key chemical engineering principles and the current regulatory environment. The second covers existing technologies for manufacturing both small-molecule-based products and protein/peptide products. The following section is devoted to process analytical tools for continuously operating manufacturing environments. The final two sections treat the integration of several individual parts of processing into fully operating continuous process systems and summarize state-of-art approaches for innovative new manufacturing principles.
* Brings together the essential know-how for anyone working in drug manufacturing, as well as chemical, food, and pharmaceutical scientists working on continuous processing
* Covers chemical engineering principles, regulatory aspects, primary and secondary manufacturing, process analytical technology and quality-by-design
* Contains contributions from researchers in leading pharmaceutical companies, the FDA, and academic institutions
* Offers an extremely well-informed look at the most promising future approaches to continuous manufacturing of innovative pharmaceutical products
Timely, comprehensive, and authoritative, Continuous Manufacturing of Pharmaceuticals is an important professional resource for researchers in industry and academe working in the fields of pharmaceuticals development and manufacturing.
Über den Autor
Editors
Peter Kleinebudde is Professor for Pharmaceutical Technology at Heinrich-Heine-University Duesseldorf, Germany, and Vice-Dean of the Faculty of Mathematics and Natural Sciences. His main research area is development, production and characterization of solid dosage forms.
Johannes Khinast is Professor of Chemical and Pharmaceutical Engineering and Head of the Institute of Process and Particle Engineering at the Graz University of Technology, Austria.
Jukka Rantanen is Professor of Pharmaceutical Technology and Engineering at the Department of Pharmacy, University of Copenhagen, Denmark.
Inhaltsverzeichnis
About the Editors xvii
List of Contributors xix
Series Preface xxv
Preface xxvii
1 Continuous Manufacturing: Definitions and Engineering Principles 1
Johannes Khinast and Massimo Bresciani
1.1 Introduction 1
1.1.1 Definition of Continuous Manufacturing 1
1.1.2 Continuous Manufacturing in the Pharmaceutical Industry 2
1.1.3 Our View of Continuous Manufacturing 3
1.1.4 Regulatory Environment 8
1.2 Advantages of Continuous Manufacturing 8
1.2.1 Flexibility 8
1.2.2 Effect on the Supply Chain 8
1.2.3 Agility and Reduced Scale-up Efforts 9
1.2.4 Real-Time Quality Assurance and Better Engineered Systems 9
1.2.5 Decentralized Manufacturing 10
1.2.6 Individualized Manufacturing 10
1.2.7 Reduced Floor Space and Investment Costs 10
1.2.8 More Efficient Chemistries 10
1.2.9 Societal Benefits 11
1.3 Engineering Principles of Continuous Manufacturing 11
1.3.1 Pharmaceutical Unit Operations 11
1.3.2 Fundamentals of Process Modeling 15
1.3.3 Balance Equations for Mass, Species, Energy and Momentum 16
1.3.4 Residence Time Distribution 20
1.3.5 Classical Reactor Types as a Basis for Process Understanding 21
1.3.6 Process Control, Modeling and PAT 24
1.3.7 Scale-Up 26
1.3.8 Dimensioning 27
1.4 Conclusion 28
References 30
2 Process Simulation and Control for Continuous Pharmaceutical Manufacturing of Solid Drug Products 33
Marianthi Ierapetritou, M. Sebastian Escotet-Espinoza and Ravendra Singh
2.1 Introduction 33
2.1.1 Scope and Motivation 33
2.1.2 Process Simulation 34
2.1.3 Process Control 36
2.2 Pharmaceutical Solid Dosage Manufacturing Processes 38
2.2.1 Overview 38
2.2.2 Continuous Manufacturing Processes 38
2.2.3 Continuous Process Equipment 39
2.3 Mathematical Modeling Approaches 44
2.3.1 First Principle "Mechanistic" Models 44
2.3.2 Multi-dimensional Population Balance Models 44
2.3.3 Engineering or Phenomenological Models 46
2.3.4 Empirical and Reduced Order Models 47
2.4 Unit Operations Models 48
2.4.1 Feeders 48
2.4.2 Blenders (Mixers) 56
2.4.3 Tablet Press 63
2.4.4 Roller Compactor 67
2.4.5 Wet Granulation 71
2.4.6 Drying 75
2.4.7 Milling/Co-milling 76
2.4.8 Flowsheet Modeling 77
2.5 Process Control of Continuous Solid-based Drug Manufacturing 81
2.5.1 Process Control Basics 83
2.5.2 Control Design of Continuous Pharmaceutical Manufacturing Process 84
2.6 Summary 93
Acknowledgments 94
References 94
3 Regulatory and Quality Considerations for Continuous Manufacturing 107
Gretchen Allison, Yanxi Tan Cain, Charles Cooney, Tom Garcia, Tara GooenBizjak, Oyvind Holte, Nirdosh Jagota, Bekki Komas, Evdokia Korakianiti,Dora Kourti, Rapti Madurawe, Elaine Morefield, Frank Montgomery, MohebNasr, William Randolph, Jean-Louis Robert, Dave Rudd and Diane Zezza
3.1 Introduction 108
3.2 Current Regulatory Environment 108
3.3 Existing Relevant Regulations, Guidelines, and Standards Supporting Continuous Manufacturing 108
3.3.1 ICH Guidelines 108
3.3.2 United States Food and Drug Administration Guidances 109
3.3.3 US FDA Guidance on Process Validation 109
3.3.4 American Society for Testing and Materials Standards 109
[...]opean Union Guidelines 110
3.4 Regulatory Considerations 110
3.4.1 Development Considerations for Continuous Manufacturing 111
3.4.2 Special Considerations for Control Strategy in Continuous Manufacturing 112
3.4.3 Stability Considerations for Continuous Manufacturing 114
3.5 Quality/GMP Considerations 115
3.5.1 Pharmaceutical Quality Systems 115
3.5.2 Batch Release 115
3.5.3 Startup and Shutdown Procedures 116
3.5.4 State of Control: Product Collection and In-process Sampling 117
3.5.5 Process Validation and CPV 117
3.5.6 Material Traceability in Continuous Manufacturing 119
3.5.7 Handling of Raw Material and In-process Material 119
3.5.8 Detection and Treatment for Non-conformity 119
3.5.9 Personnel Procedures and Training 120
3.5.10 Material Carry-over 120
3.5.11 Material Diversion 120
3.5.12 Production Floor Product Monitoring 121
3.5.13 Raw Material Variability 121
3.5.14 Cleaning Validation 121
3.5.15 Equipment Failure 122
3.6 Quality Considerations for Bridging Existing Batch Manufacturing to Continuous Manufacturing 122
3.6.1 Physicochemical Equivalence Considerations 123
3.6.2 Bioequivalence Considerations 123
3.7 Glossary and Definitions 123
3.7.1 Batch Definition 123
3.7.2 21CFR 210.3 124
3.7.3 CFR 211 124
3.7.4 ICH Q7 124
3.7.5 ICH Q10 124
3.8 General Regulatory References 124
3.8.1 cGMP Guidance 125
4 Continuous Manufacturing of Active Pharmaceutical Ingredients via Flow Technology 127
Svetlana Borukhova and Volker Hessel
4.1 Introduction 127
4.2 Micro Flow Technology 128
4.2.1 Micromixing 129
4.2.2 Flow Reactors 130
4.2.3 Reaction Activation Tools 130
4.2.4 Downstream Processing 139
4.2.5 Process Analytical Technology and Automation 142
4.3 Multi-step Synthesis of Active Pharmaceutical Ingredients in Micro Flow 150
4.3.1 Aliskiren 151
4.3.2 Artemisinin 151
4.3.3 Ibuprofen 153
4.3.4 Gleevec 154
4.3.5 Nabumetone 155
4.3.6 Quinolone Derivative as a Potent 5HT1B Antagonist 155
4.3.7 Rufinamide 155
4.3.8 Thioquinazolinone 156
4.4 Larger-scale Syntheses 156
4.4.1 Hydroxypyrrolotriazine (Bristol-Myers-Squibb) 156
4.4.2 2,2-Dimethylchromenes (Bristol-Myers-Squibb) 156
4.4.3 Fused-Bycyclic Isoxazolidines (Eli Lilly and Company) 158
4.4.4 7-Ethyltryptophol on the Way to Etodolac 158
4.4.5 6-Hydroxybuspirone (Bristol-Myers-Squibb) 159
4.5 Current Industrial Applications 160
4.6 Conclusion and Outlook 161
References 162
5 Continuous Crystallisation 169
Cameron Brown, Thomas McGlone and Alastair Florence
5.1 Introduction 169
5.2 Principles of Crystallisation 173
5.2.1 Supersaturation 173
5.2.2 Nucleation and Growth 176
5.2.3 Conservation Equations 180
5.3 Crystallisation Process Development 180
5.4 Continuous Crystallisers and Applications 185
5.4.1 Mixed Suspension Mixed Product Removal 186
5.4.2 MSMPR Cascade 193
5.4.3 Plug Flow Reactors 198
5.4.4 Impinging Jet 206
5.4.5 Microfluidics 207
5.5 Process Monitoring, Analysis and Control 207
5.5.1 Process Monitoring and Analysis 207
5.5.2 Crystallisation Control Strategies 211
5.6 Particle Characterisation 213
5.7 Concluding Remarks 215
References 217
6 Continuous Fermentation for Biopharmaceuticals? 227
L. Mears, H. Feldman, F.C. Falco, C. Bach, M. Wu, A. Nørregaard and K.V. Gernaey
6.1 Introduction 227
6.1.1 Definition of Fermentation 227
6.1.2 Production of Biopharmaceuticals 228
6.1.3 Structure of Chapter 228
6.2 Operation of Fermentation Systems 229
6.2.1 Comparison of Different Cultivation Systems 229
6.2.2 Monitoring of Continuous Fermentation Processes 232
6.2.3 Control of Continuous Fermentation Processes 234
6.3 Continuous Fermentation Examples 238
6.3.1 Continuous Ethanol Fermentation 238
6.3.2 Continuous Lactic Acid Fermentation 239
6.3.3 Single Cell Protein Production 240
6.4 Discussion 241
6.5 Conclusions 243
References 244
7 Integrated Continuous Manufacturing of Biopharmaceuticals 247
Alois Jungbauer and Nikolaus Hammerschmidt
7.1 Background 247
7.1.1 Current Status of Manufacturing of Biopharmaceuticals 247
7.1.2 Challenges to Developing Continuous Processes 249
7.1.3 Rationale for Continuous Biomanufacturing 250
7.2 Continuous Upstream Processing 251
7.2.1 Cell Lines and Cell Line Stability 251
7.2.2 Perfusion Reactor 252
7.2.3 Cell Retention Devices 252
7.2.4 Chemostat and Turbidostat 254
7.2.5 Overview of Products Produced by Continuous Upstream Processing 254
7.3 Continuous Downstream Processing 257
7.3.1 Overview of Unit Operations 257
7.3.2 Continuous Centrifuges 257
7.3.3 Continuous Filtration 258
7.3.4 Continuous Chromatography 260
7.3.5 Continuous Precipitation 263
7.3.6 Continuous Formulation 266
7.4 Process Integration and Single Use Technology 266
7.4.1 Disposable Bioreactors 268
7.4.2 Disposable Unit Operations in Downstream Processing 268
7.4.3 Full Process Train 270
7.5 Process Monitoring and Control 270
7.6 Process Economics of Continuous Manufacturing 274
7.7 Conclusions 275
Acknowledgments 276
References 276
8 Twin-screw Granulation Process Development: Present Approaches, Understanding and Needs 283
A. Kumar, K.V. Gernaey, I. Nopens and T. De Beer
8.1 Introduction 283
8.2 Continuous Wet-granulation using a TSG 284
8.3 Components of High Shear Wet Granulation in a TSG 287
8.4 Material Transport and Mixing in a TSG 287
8.4.1 Granulation Time in a TSG 288
8.4.2 Mixing in a TSG 291
8.5 Granule Size Evolution During Twin-screw Granulation 294
8.5.1 Granule Size and Shape Dynamics in a TSG 295
8.5.2 Link Between RTD, Liquid Distribution and GSD in a TSG 295
8.6 Model-based Analysis of Twin-screw Granulation 298
8.6.1 Modelling RTD in a TSG 298
8.6.2 Tracking GSD in a TSG using PBM 300
8.7 Towards Generic Twin-screw Granulation Knowledge 302
8.7.1 Regime Map Approach 303
8.7.2 Particle-scale Simulation using DEM 305
8.8 Strengths and Limitations of the Current Approaches in TSG Studies 307
8.9 Glossary 308
References 309
9 Continuous Line Roller Compaction 313
Ossi Korhonen
9.1 Roller Compaction 313
9.2 Main Components of a Roller Compactor 313
9.3 Theory of Powder Densification in Roller Compaction 315
9.4 Johanson Model 317
9.5 Modified Johanson Model 319
9.6 Experimental Observations of Pressure Distribution from Instrumented Roller Compactors 322
9.7 Off-line Characterization of Ribbon Quality 324
9.8 In-line Monitoring of Roller Compaction Process 326
9.9 Formulative Aspects of Roller Compaction 328
9.10 Roller Compaction as a Unit Operation in Continuous Manufacturing 330
9.11 Process Control of Continuous Roller Compaction 332
9.12 Conclusions 333
References 334
10 Continuous Melt Extrusion and Direct Pelletization 337
Stephan Laske, Theresa Hörmann, Andreas Witschnigg, Gerold Koscher, Patrick Wahl, Wen Kai Hsiao and Johannes Khinast
10.1 Introduction 337
10.2 The Extruder 338
10.3 Feeding 341
10.3.1 Solid...
List of Contributors xix
Series Preface xxv
Preface xxvii
1 Continuous Manufacturing: Definitions and Engineering Principles 1
Johannes Khinast and Massimo Bresciani
1.1 Introduction 1
1.1.1 Definition of Continuous Manufacturing 1
1.1.2 Continuous Manufacturing in the Pharmaceutical Industry 2
1.1.3 Our View of Continuous Manufacturing 3
1.1.4 Regulatory Environment 8
1.2 Advantages of Continuous Manufacturing 8
1.2.1 Flexibility 8
1.2.2 Effect on the Supply Chain 8
1.2.3 Agility and Reduced Scale-up Efforts 9
1.2.4 Real-Time Quality Assurance and Better Engineered Systems 9
1.2.5 Decentralized Manufacturing 10
1.2.6 Individualized Manufacturing 10
1.2.7 Reduced Floor Space and Investment Costs 10
1.2.8 More Efficient Chemistries 10
1.2.9 Societal Benefits 11
1.3 Engineering Principles of Continuous Manufacturing 11
1.3.1 Pharmaceutical Unit Operations 11
1.3.2 Fundamentals of Process Modeling 15
1.3.3 Balance Equations for Mass, Species, Energy and Momentum 16
1.3.4 Residence Time Distribution 20
1.3.5 Classical Reactor Types as a Basis for Process Understanding 21
1.3.6 Process Control, Modeling and PAT 24
1.3.7 Scale-Up 26
1.3.8 Dimensioning 27
1.4 Conclusion 28
References 30
2 Process Simulation and Control for Continuous Pharmaceutical Manufacturing of Solid Drug Products 33
Marianthi Ierapetritou, M. Sebastian Escotet-Espinoza and Ravendra Singh
2.1 Introduction 33
2.1.1 Scope and Motivation 33
2.1.2 Process Simulation 34
2.1.3 Process Control 36
2.2 Pharmaceutical Solid Dosage Manufacturing Processes 38
2.2.1 Overview 38
2.2.2 Continuous Manufacturing Processes 38
2.2.3 Continuous Process Equipment 39
2.3 Mathematical Modeling Approaches 44
2.3.1 First Principle "Mechanistic" Models 44
2.3.2 Multi-dimensional Population Balance Models 44
2.3.3 Engineering or Phenomenological Models 46
2.3.4 Empirical and Reduced Order Models 47
2.4 Unit Operations Models 48
2.4.1 Feeders 48
2.4.2 Blenders (Mixers) 56
2.4.3 Tablet Press 63
2.4.4 Roller Compactor 67
2.4.5 Wet Granulation 71
2.4.6 Drying 75
2.4.7 Milling/Co-milling 76
2.4.8 Flowsheet Modeling 77
2.5 Process Control of Continuous Solid-based Drug Manufacturing 81
2.5.1 Process Control Basics 83
2.5.2 Control Design of Continuous Pharmaceutical Manufacturing Process 84
2.6 Summary 93
Acknowledgments 94
References 94
3 Regulatory and Quality Considerations for Continuous Manufacturing 107
Gretchen Allison, Yanxi Tan Cain, Charles Cooney, Tom Garcia, Tara GooenBizjak, Oyvind Holte, Nirdosh Jagota, Bekki Komas, Evdokia Korakianiti,Dora Kourti, Rapti Madurawe, Elaine Morefield, Frank Montgomery, MohebNasr, William Randolph, Jean-Louis Robert, Dave Rudd and Diane Zezza
3.1 Introduction 108
3.2 Current Regulatory Environment 108
3.3 Existing Relevant Regulations, Guidelines, and Standards Supporting Continuous Manufacturing 108
3.3.1 ICH Guidelines 108
3.3.2 United States Food and Drug Administration Guidances 109
3.3.3 US FDA Guidance on Process Validation 109
3.3.4 American Society for Testing and Materials Standards 109
[...]opean Union Guidelines 110
3.4 Regulatory Considerations 110
3.4.1 Development Considerations for Continuous Manufacturing 111
3.4.2 Special Considerations for Control Strategy in Continuous Manufacturing 112
3.4.3 Stability Considerations for Continuous Manufacturing 114
3.5 Quality/GMP Considerations 115
3.5.1 Pharmaceutical Quality Systems 115
3.5.2 Batch Release 115
3.5.3 Startup and Shutdown Procedures 116
3.5.4 State of Control: Product Collection and In-process Sampling 117
3.5.5 Process Validation and CPV 117
3.5.6 Material Traceability in Continuous Manufacturing 119
3.5.7 Handling of Raw Material and In-process Material 119
3.5.8 Detection and Treatment for Non-conformity 119
3.5.9 Personnel Procedures and Training 120
3.5.10 Material Carry-over 120
3.5.11 Material Diversion 120
3.5.12 Production Floor Product Monitoring 121
3.5.13 Raw Material Variability 121
3.5.14 Cleaning Validation 121
3.5.15 Equipment Failure 122
3.6 Quality Considerations for Bridging Existing Batch Manufacturing to Continuous Manufacturing 122
3.6.1 Physicochemical Equivalence Considerations 123
3.6.2 Bioequivalence Considerations 123
3.7 Glossary and Definitions 123
3.7.1 Batch Definition 123
3.7.2 21CFR 210.3 124
3.7.3 CFR 211 124
3.7.4 ICH Q7 124
3.7.5 ICH Q10 124
3.8 General Regulatory References 124
3.8.1 cGMP Guidance 125
4 Continuous Manufacturing of Active Pharmaceutical Ingredients via Flow Technology 127
Svetlana Borukhova and Volker Hessel
4.1 Introduction 127
4.2 Micro Flow Technology 128
4.2.1 Micromixing 129
4.2.2 Flow Reactors 130
4.2.3 Reaction Activation Tools 130
4.2.4 Downstream Processing 139
4.2.5 Process Analytical Technology and Automation 142
4.3 Multi-step Synthesis of Active Pharmaceutical Ingredients in Micro Flow 150
4.3.1 Aliskiren 151
4.3.2 Artemisinin 151
4.3.3 Ibuprofen 153
4.3.4 Gleevec 154
4.3.5 Nabumetone 155
4.3.6 Quinolone Derivative as a Potent 5HT1B Antagonist 155
4.3.7 Rufinamide 155
4.3.8 Thioquinazolinone 156
4.4 Larger-scale Syntheses 156
4.4.1 Hydroxypyrrolotriazine (Bristol-Myers-Squibb) 156
4.4.2 2,2-Dimethylchromenes (Bristol-Myers-Squibb) 156
4.4.3 Fused-Bycyclic Isoxazolidines (Eli Lilly and Company) 158
4.4.4 7-Ethyltryptophol on the Way to Etodolac 158
4.4.5 6-Hydroxybuspirone (Bristol-Myers-Squibb) 159
4.5 Current Industrial Applications 160
4.6 Conclusion and Outlook 161
References 162
5 Continuous Crystallisation 169
Cameron Brown, Thomas McGlone and Alastair Florence
5.1 Introduction 169
5.2 Principles of Crystallisation 173
5.2.1 Supersaturation 173
5.2.2 Nucleation and Growth 176
5.2.3 Conservation Equations 180
5.3 Crystallisation Process Development 180
5.4 Continuous Crystallisers and Applications 185
5.4.1 Mixed Suspension Mixed Product Removal 186
5.4.2 MSMPR Cascade 193
5.4.3 Plug Flow Reactors 198
5.4.4 Impinging Jet 206
5.4.5 Microfluidics 207
5.5 Process Monitoring, Analysis and Control 207
5.5.1 Process Monitoring and Analysis 207
5.5.2 Crystallisation Control Strategies 211
5.6 Particle Characterisation 213
5.7 Concluding Remarks 215
References 217
6 Continuous Fermentation for Biopharmaceuticals? 227
L. Mears, H. Feldman, F.C. Falco, C. Bach, M. Wu, A. Nørregaard and K.V. Gernaey
6.1 Introduction 227
6.1.1 Definition of Fermentation 227
6.1.2 Production of Biopharmaceuticals 228
6.1.3 Structure of Chapter 228
6.2 Operation of Fermentation Systems 229
6.2.1 Comparison of Different Cultivation Systems 229
6.2.2 Monitoring of Continuous Fermentation Processes 232
6.2.3 Control of Continuous Fermentation Processes 234
6.3 Continuous Fermentation Examples 238
6.3.1 Continuous Ethanol Fermentation 238
6.3.2 Continuous Lactic Acid Fermentation 239
6.3.3 Single Cell Protein Production 240
6.4 Discussion 241
6.5 Conclusions 243
References 244
7 Integrated Continuous Manufacturing of Biopharmaceuticals 247
Alois Jungbauer and Nikolaus Hammerschmidt
7.1 Background 247
7.1.1 Current Status of Manufacturing of Biopharmaceuticals 247
7.1.2 Challenges to Developing Continuous Processes 249
7.1.3 Rationale for Continuous Biomanufacturing 250
7.2 Continuous Upstream Processing 251
7.2.1 Cell Lines and Cell Line Stability 251
7.2.2 Perfusion Reactor 252
7.2.3 Cell Retention Devices 252
7.2.4 Chemostat and Turbidostat 254
7.2.5 Overview of Products Produced by Continuous Upstream Processing 254
7.3 Continuous Downstream Processing 257
7.3.1 Overview of Unit Operations 257
7.3.2 Continuous Centrifuges 257
7.3.3 Continuous Filtration 258
7.3.4 Continuous Chromatography 260
7.3.5 Continuous Precipitation 263
7.3.6 Continuous Formulation 266
7.4 Process Integration and Single Use Technology 266
7.4.1 Disposable Bioreactors 268
7.4.2 Disposable Unit Operations in Downstream Processing 268
7.4.3 Full Process Train 270
7.5 Process Monitoring and Control 270
7.6 Process Economics of Continuous Manufacturing 274
7.7 Conclusions 275
Acknowledgments 276
References 276
8 Twin-screw Granulation Process Development: Present Approaches, Understanding and Needs 283
A. Kumar, K.V. Gernaey, I. Nopens and T. De Beer
8.1 Introduction 283
8.2 Continuous Wet-granulation using a TSG 284
8.3 Components of High Shear Wet Granulation in a TSG 287
8.4 Material Transport and Mixing in a TSG 287
8.4.1 Granulation Time in a TSG 288
8.4.2 Mixing in a TSG 291
8.5 Granule Size Evolution During Twin-screw Granulation 294
8.5.1 Granule Size and Shape Dynamics in a TSG 295
8.5.2 Link Between RTD, Liquid Distribution and GSD in a TSG 295
8.6 Model-based Analysis of Twin-screw Granulation 298
8.6.1 Modelling RTD in a TSG 298
8.6.2 Tracking GSD in a TSG using PBM 300
8.7 Towards Generic Twin-screw Granulation Knowledge 302
8.7.1 Regime Map Approach 303
8.7.2 Particle-scale Simulation using DEM 305
8.8 Strengths and Limitations of the Current Approaches in TSG Studies 307
8.9 Glossary 308
References 309
9 Continuous Line Roller Compaction 313
Ossi Korhonen
9.1 Roller Compaction 313
9.2 Main Components of a Roller Compactor 313
9.3 Theory of Powder Densification in Roller Compaction 315
9.4 Johanson Model 317
9.5 Modified Johanson Model 319
9.6 Experimental Observations of Pressure Distribution from Instrumented Roller Compactors 322
9.7 Off-line Characterization of Ribbon Quality 324
9.8 In-line Monitoring of Roller Compaction Process 326
9.9 Formulative Aspects of Roller Compaction 328
9.10 Roller Compaction as a Unit Operation in Continuous Manufacturing 330
9.11 Process Control of Continuous Roller Compaction 332
9.12 Conclusions 333
References 334
10 Continuous Melt Extrusion and Direct Pelletization 337
Stephan Laske, Theresa Hörmann, Andreas Witschnigg, Gerold Koscher, Patrick Wahl, Wen Kai Hsiao and Johannes Khinast
10.1 Introduction 337
10.2 The Extruder 338
10.3 Feeding 341
10.3.1 Solid...
Details
| Erscheinungsjahr: | 2017 |
|---|---|
| Fachbereich: | Allgemeines |
| Genre: | Chemie |
| Rubrik: | Naturwissenschaften & Technik |
| Medium: | Buch |
| Seiten: | 640 |
| Inhalt: | 620 S. |
| ISBN-13: | 9781119001324 |
| ISBN-10: | 1119001323 |
| Sprache: | Englisch |
| Einband: | Gebunden |
| Redaktion: |
Kleinebudde, Peter
Khinast, Johannes Rantanen, Jukka |
| Herausgeber: | Peter Kleinebudde/Johannes Khinast/Jukka Rantanen |
| Hersteller: |
Wiley
John Wiley & Sons |
| Maße: | 251 x 174 x 38 mm |
| Von/Mit: | Peter Kleinebudde (u. a.) |
| Erscheinungsdatum: | 05.09.2017 |
| Gewicht: | 1,092 kg |
Über den Autor
Editors
Peter Kleinebudde is Professor for Pharmaceutical Technology at Heinrich-Heine-University Duesseldorf, Germany, and Vice-Dean of the Faculty of Mathematics and Natural Sciences. His main research area is development, production and characterization of solid dosage forms.
Johannes Khinast is Professor of Chemical and Pharmaceutical Engineering and Head of the Institute of Process and Particle Engineering at the Graz University of Technology, Austria.
Jukka Rantanen is Professor of Pharmaceutical Technology and Engineering at the Department of Pharmacy, University of Copenhagen, Denmark.
Inhaltsverzeichnis
About the Editors xvii
List of Contributors xix
Series Preface xxv
Preface xxvii
1 Continuous Manufacturing: Definitions and Engineering Principles 1
Johannes Khinast and Massimo Bresciani
1.1 Introduction 1
1.1.1 Definition of Continuous Manufacturing 1
1.1.2 Continuous Manufacturing in the Pharmaceutical Industry 2
1.1.3 Our View of Continuous Manufacturing 3
1.1.4 Regulatory Environment 8
1.2 Advantages of Continuous Manufacturing 8
1.2.1 Flexibility 8
1.2.2 Effect on the Supply Chain 8
1.2.3 Agility and Reduced Scale-up Efforts 9
1.2.4 Real-Time Quality Assurance and Better Engineered Systems 9
1.2.5 Decentralized Manufacturing 10
1.2.6 Individualized Manufacturing 10
1.2.7 Reduced Floor Space and Investment Costs 10
1.2.8 More Efficient Chemistries 10
1.2.9 Societal Benefits 11
1.3 Engineering Principles of Continuous Manufacturing 11
1.3.1 Pharmaceutical Unit Operations 11
1.3.2 Fundamentals of Process Modeling 15
1.3.3 Balance Equations for Mass, Species, Energy and Momentum 16
1.3.4 Residence Time Distribution 20
1.3.5 Classical Reactor Types as a Basis for Process Understanding 21
1.3.6 Process Control, Modeling and PAT 24
1.3.7 Scale-Up 26
1.3.8 Dimensioning 27
1.4 Conclusion 28
References 30
2 Process Simulation and Control for Continuous Pharmaceutical Manufacturing of Solid Drug Products 33
Marianthi Ierapetritou, M. Sebastian Escotet-Espinoza and Ravendra Singh
2.1 Introduction 33
2.1.1 Scope and Motivation 33
2.1.2 Process Simulation 34
2.1.3 Process Control 36
2.2 Pharmaceutical Solid Dosage Manufacturing Processes 38
2.2.1 Overview 38
2.2.2 Continuous Manufacturing Processes 38
2.2.3 Continuous Process Equipment 39
2.3 Mathematical Modeling Approaches 44
2.3.1 First Principle "Mechanistic" Models 44
2.3.2 Multi-dimensional Population Balance Models 44
2.3.3 Engineering or Phenomenological Models 46
2.3.4 Empirical and Reduced Order Models 47
2.4 Unit Operations Models 48
2.4.1 Feeders 48
2.4.2 Blenders (Mixers) 56
2.4.3 Tablet Press 63
2.4.4 Roller Compactor 67
2.4.5 Wet Granulation 71
2.4.6 Drying 75
2.4.7 Milling/Co-milling 76
2.4.8 Flowsheet Modeling 77
2.5 Process Control of Continuous Solid-based Drug Manufacturing 81
2.5.1 Process Control Basics 83
2.5.2 Control Design of Continuous Pharmaceutical Manufacturing Process 84
2.6 Summary 93
Acknowledgments 94
References 94
3 Regulatory and Quality Considerations for Continuous Manufacturing 107
Gretchen Allison, Yanxi Tan Cain, Charles Cooney, Tom Garcia, Tara GooenBizjak, Oyvind Holte, Nirdosh Jagota, Bekki Komas, Evdokia Korakianiti,Dora Kourti, Rapti Madurawe, Elaine Morefield, Frank Montgomery, MohebNasr, William Randolph, Jean-Louis Robert, Dave Rudd and Diane Zezza
3.1 Introduction 108
3.2 Current Regulatory Environment 108
3.3 Existing Relevant Regulations, Guidelines, and Standards Supporting Continuous Manufacturing 108
3.3.1 ICH Guidelines 108
3.3.2 United States Food and Drug Administration Guidances 109
3.3.3 US FDA Guidance on Process Validation 109
3.3.4 American Society for Testing and Materials Standards 109
[...]opean Union Guidelines 110
3.4 Regulatory Considerations 110
3.4.1 Development Considerations for Continuous Manufacturing 111
3.4.2 Special Considerations for Control Strategy in Continuous Manufacturing 112
3.4.3 Stability Considerations for Continuous Manufacturing 114
3.5 Quality/GMP Considerations 115
3.5.1 Pharmaceutical Quality Systems 115
3.5.2 Batch Release 115
3.5.3 Startup and Shutdown Procedures 116
3.5.4 State of Control: Product Collection and In-process Sampling 117
3.5.5 Process Validation and CPV 117
3.5.6 Material Traceability in Continuous Manufacturing 119
3.5.7 Handling of Raw Material and In-process Material 119
3.5.8 Detection and Treatment for Non-conformity 119
3.5.9 Personnel Procedures and Training 120
3.5.10 Material Carry-over 120
3.5.11 Material Diversion 120
3.5.12 Production Floor Product Monitoring 121
3.5.13 Raw Material Variability 121
3.5.14 Cleaning Validation 121
3.5.15 Equipment Failure 122
3.6 Quality Considerations for Bridging Existing Batch Manufacturing to Continuous Manufacturing 122
3.6.1 Physicochemical Equivalence Considerations 123
3.6.2 Bioequivalence Considerations 123
3.7 Glossary and Definitions 123
3.7.1 Batch Definition 123
3.7.2 21CFR 210.3 124
3.7.3 CFR 211 124
3.7.4 ICH Q7 124
3.7.5 ICH Q10 124
3.8 General Regulatory References 124
3.8.1 cGMP Guidance 125
4 Continuous Manufacturing of Active Pharmaceutical Ingredients via Flow Technology 127
Svetlana Borukhova and Volker Hessel
4.1 Introduction 127
4.2 Micro Flow Technology 128
4.2.1 Micromixing 129
4.2.2 Flow Reactors 130
4.2.3 Reaction Activation Tools 130
4.2.4 Downstream Processing 139
4.2.5 Process Analytical Technology and Automation 142
4.3 Multi-step Synthesis of Active Pharmaceutical Ingredients in Micro Flow 150
4.3.1 Aliskiren 151
4.3.2 Artemisinin 151
4.3.3 Ibuprofen 153
4.3.4 Gleevec 154
4.3.5 Nabumetone 155
4.3.6 Quinolone Derivative as a Potent 5HT1B Antagonist 155
4.3.7 Rufinamide 155
4.3.8 Thioquinazolinone 156
4.4 Larger-scale Syntheses 156
4.4.1 Hydroxypyrrolotriazine (Bristol-Myers-Squibb) 156
4.4.2 2,2-Dimethylchromenes (Bristol-Myers-Squibb) 156
4.4.3 Fused-Bycyclic Isoxazolidines (Eli Lilly and Company) 158
4.4.4 7-Ethyltryptophol on the Way to Etodolac 158
4.4.5 6-Hydroxybuspirone (Bristol-Myers-Squibb) 159
4.5 Current Industrial Applications 160
4.6 Conclusion and Outlook 161
References 162
5 Continuous Crystallisation 169
Cameron Brown, Thomas McGlone and Alastair Florence
5.1 Introduction 169
5.2 Principles of Crystallisation 173
5.2.1 Supersaturation 173
5.2.2 Nucleation and Growth 176
5.2.3 Conservation Equations 180
5.3 Crystallisation Process Development 180
5.4 Continuous Crystallisers and Applications 185
5.4.1 Mixed Suspension Mixed Product Removal 186
5.4.2 MSMPR Cascade 193
5.4.3 Plug Flow Reactors 198
5.4.4 Impinging Jet 206
5.4.5 Microfluidics 207
5.5 Process Monitoring, Analysis and Control 207
5.5.1 Process Monitoring and Analysis 207
5.5.2 Crystallisation Control Strategies 211
5.6 Particle Characterisation 213
5.7 Concluding Remarks 215
References 217
6 Continuous Fermentation for Biopharmaceuticals? 227
L. Mears, H. Feldman, F.C. Falco, C. Bach, M. Wu, A. Nørregaard and K.V. Gernaey
6.1 Introduction 227
6.1.1 Definition of Fermentation 227
6.1.2 Production of Biopharmaceuticals 228
6.1.3 Structure of Chapter 228
6.2 Operation of Fermentation Systems 229
6.2.1 Comparison of Different Cultivation Systems 229
6.2.2 Monitoring of Continuous Fermentation Processes 232
6.2.3 Control of Continuous Fermentation Processes 234
6.3 Continuous Fermentation Examples 238
6.3.1 Continuous Ethanol Fermentation 238
6.3.2 Continuous Lactic Acid Fermentation 239
6.3.3 Single Cell Protein Production 240
6.4 Discussion 241
6.5 Conclusions 243
References 244
7 Integrated Continuous Manufacturing of Biopharmaceuticals 247
Alois Jungbauer and Nikolaus Hammerschmidt
7.1 Background 247
7.1.1 Current Status of Manufacturing of Biopharmaceuticals 247
7.1.2 Challenges to Developing Continuous Processes 249
7.1.3 Rationale for Continuous Biomanufacturing 250
7.2 Continuous Upstream Processing 251
7.2.1 Cell Lines and Cell Line Stability 251
7.2.2 Perfusion Reactor 252
7.2.3 Cell Retention Devices 252
7.2.4 Chemostat and Turbidostat 254
7.2.5 Overview of Products Produced by Continuous Upstream Processing 254
7.3 Continuous Downstream Processing 257
7.3.1 Overview of Unit Operations 257
7.3.2 Continuous Centrifuges 257
7.3.3 Continuous Filtration 258
7.3.4 Continuous Chromatography 260
7.3.5 Continuous Precipitation 263
7.3.6 Continuous Formulation 266
7.4 Process Integration and Single Use Technology 266
7.4.1 Disposable Bioreactors 268
7.4.2 Disposable Unit Operations in Downstream Processing 268
7.4.3 Full Process Train 270
7.5 Process Monitoring and Control 270
7.6 Process Economics of Continuous Manufacturing 274
7.7 Conclusions 275
Acknowledgments 276
References 276
8 Twin-screw Granulation Process Development: Present Approaches, Understanding and Needs 283
A. Kumar, K.V. Gernaey, I. Nopens and T. De Beer
8.1 Introduction 283
8.2 Continuous Wet-granulation using a TSG 284
8.3 Components of High Shear Wet Granulation in a TSG 287
8.4 Material Transport and Mixing in a TSG 287
8.4.1 Granulation Time in a TSG 288
8.4.2 Mixing in a TSG 291
8.5 Granule Size Evolution During Twin-screw Granulation 294
8.5.1 Granule Size and Shape Dynamics in a TSG 295
8.5.2 Link Between RTD, Liquid Distribution and GSD in a TSG 295
8.6 Model-based Analysis of Twin-screw Granulation 298
8.6.1 Modelling RTD in a TSG 298
8.6.2 Tracking GSD in a TSG using PBM 300
8.7 Towards Generic Twin-screw Granulation Knowledge 302
8.7.1 Regime Map Approach 303
8.7.2 Particle-scale Simulation using DEM 305
8.8 Strengths and Limitations of the Current Approaches in TSG Studies 307
8.9 Glossary 308
References 309
9 Continuous Line Roller Compaction 313
Ossi Korhonen
9.1 Roller Compaction 313
9.2 Main Components of a Roller Compactor 313
9.3 Theory of Powder Densification in Roller Compaction 315
9.4 Johanson Model 317
9.5 Modified Johanson Model 319
9.6 Experimental Observations of Pressure Distribution from Instrumented Roller Compactors 322
9.7 Off-line Characterization of Ribbon Quality 324
9.8 In-line Monitoring of Roller Compaction Process 326
9.9 Formulative Aspects of Roller Compaction 328
9.10 Roller Compaction as a Unit Operation in Continuous Manufacturing 330
9.11 Process Control of Continuous Roller Compaction 332
9.12 Conclusions 333
References 334
10 Continuous Melt Extrusion and Direct Pelletization 337
Stephan Laske, Theresa Hörmann, Andreas Witschnigg, Gerold Koscher, Patrick Wahl, Wen Kai Hsiao and Johannes Khinast
10.1 Introduction 337
10.2 The Extruder 338
10.3 Feeding 341
10.3.1 Solid...
List of Contributors xix
Series Preface xxv
Preface xxvii
1 Continuous Manufacturing: Definitions and Engineering Principles 1
Johannes Khinast and Massimo Bresciani
1.1 Introduction 1
1.1.1 Definition of Continuous Manufacturing 1
1.1.2 Continuous Manufacturing in the Pharmaceutical Industry 2
1.1.3 Our View of Continuous Manufacturing 3
1.1.4 Regulatory Environment 8
1.2 Advantages of Continuous Manufacturing 8
1.2.1 Flexibility 8
1.2.2 Effect on the Supply Chain 8
1.2.3 Agility and Reduced Scale-up Efforts 9
1.2.4 Real-Time Quality Assurance and Better Engineered Systems 9
1.2.5 Decentralized Manufacturing 10
1.2.6 Individualized Manufacturing 10
1.2.7 Reduced Floor Space and Investment Costs 10
1.2.8 More Efficient Chemistries 10
1.2.9 Societal Benefits 11
1.3 Engineering Principles of Continuous Manufacturing 11
1.3.1 Pharmaceutical Unit Operations 11
1.3.2 Fundamentals of Process Modeling 15
1.3.3 Balance Equations for Mass, Species, Energy and Momentum 16
1.3.4 Residence Time Distribution 20
1.3.5 Classical Reactor Types as a Basis for Process Understanding 21
1.3.6 Process Control, Modeling and PAT 24
1.3.7 Scale-Up 26
1.3.8 Dimensioning 27
1.4 Conclusion 28
References 30
2 Process Simulation and Control for Continuous Pharmaceutical Manufacturing of Solid Drug Products 33
Marianthi Ierapetritou, M. Sebastian Escotet-Espinoza and Ravendra Singh
2.1 Introduction 33
2.1.1 Scope and Motivation 33
2.1.2 Process Simulation 34
2.1.3 Process Control 36
2.2 Pharmaceutical Solid Dosage Manufacturing Processes 38
2.2.1 Overview 38
2.2.2 Continuous Manufacturing Processes 38
2.2.3 Continuous Process Equipment 39
2.3 Mathematical Modeling Approaches 44
2.3.1 First Principle "Mechanistic" Models 44
2.3.2 Multi-dimensional Population Balance Models 44
2.3.3 Engineering or Phenomenological Models 46
2.3.4 Empirical and Reduced Order Models 47
2.4 Unit Operations Models 48
2.4.1 Feeders 48
2.4.2 Blenders (Mixers) 56
2.4.3 Tablet Press 63
2.4.4 Roller Compactor 67
2.4.5 Wet Granulation 71
2.4.6 Drying 75
2.4.7 Milling/Co-milling 76
2.4.8 Flowsheet Modeling 77
2.5 Process Control of Continuous Solid-based Drug Manufacturing 81
2.5.1 Process Control Basics 83
2.5.2 Control Design of Continuous Pharmaceutical Manufacturing Process 84
2.6 Summary 93
Acknowledgments 94
References 94
3 Regulatory and Quality Considerations for Continuous Manufacturing 107
Gretchen Allison, Yanxi Tan Cain, Charles Cooney, Tom Garcia, Tara GooenBizjak, Oyvind Holte, Nirdosh Jagota, Bekki Komas, Evdokia Korakianiti,Dora Kourti, Rapti Madurawe, Elaine Morefield, Frank Montgomery, MohebNasr, William Randolph, Jean-Louis Robert, Dave Rudd and Diane Zezza
3.1 Introduction 108
3.2 Current Regulatory Environment 108
3.3 Existing Relevant Regulations, Guidelines, and Standards Supporting Continuous Manufacturing 108
3.3.1 ICH Guidelines 108
3.3.2 United States Food and Drug Administration Guidances 109
3.3.3 US FDA Guidance on Process Validation 109
3.3.4 American Society for Testing and Materials Standards 109
[...]opean Union Guidelines 110
3.4 Regulatory Considerations 110
3.4.1 Development Considerations for Continuous Manufacturing 111
3.4.2 Special Considerations for Control Strategy in Continuous Manufacturing 112
3.4.3 Stability Considerations for Continuous Manufacturing 114
3.5 Quality/GMP Considerations 115
3.5.1 Pharmaceutical Quality Systems 115
3.5.2 Batch Release 115
3.5.3 Startup and Shutdown Procedures 116
3.5.4 State of Control: Product Collection and In-process Sampling 117
3.5.5 Process Validation and CPV 117
3.5.6 Material Traceability in Continuous Manufacturing 119
3.5.7 Handling of Raw Material and In-process Material 119
3.5.8 Detection and Treatment for Non-conformity 119
3.5.9 Personnel Procedures and Training 120
3.5.10 Material Carry-over 120
3.5.11 Material Diversion 120
3.5.12 Production Floor Product Monitoring 121
3.5.13 Raw Material Variability 121
3.5.14 Cleaning Validation 121
3.5.15 Equipment Failure 122
3.6 Quality Considerations for Bridging Existing Batch Manufacturing to Continuous Manufacturing 122
3.6.1 Physicochemical Equivalence Considerations 123
3.6.2 Bioequivalence Considerations 123
3.7 Glossary and Definitions 123
3.7.1 Batch Definition 123
3.7.2 21CFR 210.3 124
3.7.3 CFR 211 124
3.7.4 ICH Q7 124
3.7.5 ICH Q10 124
3.8 General Regulatory References 124
3.8.1 cGMP Guidance 125
4 Continuous Manufacturing of Active Pharmaceutical Ingredients via Flow Technology 127
Svetlana Borukhova and Volker Hessel
4.1 Introduction 127
4.2 Micro Flow Technology 128
4.2.1 Micromixing 129
4.2.2 Flow Reactors 130
4.2.3 Reaction Activation Tools 130
4.2.4 Downstream Processing 139
4.2.5 Process Analytical Technology and Automation 142
4.3 Multi-step Synthesis of Active Pharmaceutical Ingredients in Micro Flow 150
4.3.1 Aliskiren 151
4.3.2 Artemisinin 151
4.3.3 Ibuprofen 153
4.3.4 Gleevec 154
4.3.5 Nabumetone 155
4.3.6 Quinolone Derivative as a Potent 5HT1B Antagonist 155
4.3.7 Rufinamide 155
4.3.8 Thioquinazolinone 156
4.4 Larger-scale Syntheses 156
4.4.1 Hydroxypyrrolotriazine (Bristol-Myers-Squibb) 156
4.4.2 2,2-Dimethylchromenes (Bristol-Myers-Squibb) 156
4.4.3 Fused-Bycyclic Isoxazolidines (Eli Lilly and Company) 158
4.4.4 7-Ethyltryptophol on the Way to Etodolac 158
4.4.5 6-Hydroxybuspirone (Bristol-Myers-Squibb) 159
4.5 Current Industrial Applications 160
4.6 Conclusion and Outlook 161
References 162
5 Continuous Crystallisation 169
Cameron Brown, Thomas McGlone and Alastair Florence
5.1 Introduction 169
5.2 Principles of Crystallisation 173
5.2.1 Supersaturation 173
5.2.2 Nucleation and Growth 176
5.2.3 Conservation Equations 180
5.3 Crystallisation Process Development 180
5.4 Continuous Crystallisers and Applications 185
5.4.1 Mixed Suspension Mixed Product Removal 186
5.4.2 MSMPR Cascade 193
5.4.3 Plug Flow Reactors 198
5.4.4 Impinging Jet 206
5.4.5 Microfluidics 207
5.5 Process Monitoring, Analysis and Control 207
5.5.1 Process Monitoring and Analysis 207
5.5.2 Crystallisation Control Strategies 211
5.6 Particle Characterisation 213
5.7 Concluding Remarks 215
References 217
6 Continuous Fermentation for Biopharmaceuticals? 227
L. Mears, H. Feldman, F.C. Falco, C. Bach, M. Wu, A. Nørregaard and K.V. Gernaey
6.1 Introduction 227
6.1.1 Definition of Fermentation 227
6.1.2 Production of Biopharmaceuticals 228
6.1.3 Structure of Chapter 228
6.2 Operation of Fermentation Systems 229
6.2.1 Comparison of Different Cultivation Systems 229
6.2.2 Monitoring of Continuous Fermentation Processes 232
6.2.3 Control of Continuous Fermentation Processes 234
6.3 Continuous Fermentation Examples 238
6.3.1 Continuous Ethanol Fermentation 238
6.3.2 Continuous Lactic Acid Fermentation 239
6.3.3 Single Cell Protein Production 240
6.4 Discussion 241
6.5 Conclusions 243
References 244
7 Integrated Continuous Manufacturing of Biopharmaceuticals 247
Alois Jungbauer and Nikolaus Hammerschmidt
7.1 Background 247
7.1.1 Current Status of Manufacturing of Biopharmaceuticals 247
7.1.2 Challenges to Developing Continuous Processes 249
7.1.3 Rationale for Continuous Biomanufacturing 250
7.2 Continuous Upstream Processing 251
7.2.1 Cell Lines and Cell Line Stability 251
7.2.2 Perfusion Reactor 252
7.2.3 Cell Retention Devices 252
7.2.4 Chemostat and Turbidostat 254
7.2.5 Overview of Products Produced by Continuous Upstream Processing 254
7.3 Continuous Downstream Processing 257
7.3.1 Overview of Unit Operations 257
7.3.2 Continuous Centrifuges 257
7.3.3 Continuous Filtration 258
7.3.4 Continuous Chromatography 260
7.3.5 Continuous Precipitation 263
7.3.6 Continuous Formulation 266
7.4 Process Integration and Single Use Technology 266
7.4.1 Disposable Bioreactors 268
7.4.2 Disposable Unit Operations in Downstream Processing 268
7.4.3 Full Process Train 270
7.5 Process Monitoring and Control 270
7.6 Process Economics of Continuous Manufacturing 274
7.7 Conclusions 275
Acknowledgments 276
References 276
8 Twin-screw Granulation Process Development: Present Approaches, Understanding and Needs 283
A. Kumar, K.V. Gernaey, I. Nopens and T. De Beer
8.1 Introduction 283
8.2 Continuous Wet-granulation using a TSG 284
8.3 Components of High Shear Wet Granulation in a TSG 287
8.4 Material Transport and Mixing in a TSG 287
8.4.1 Granulation Time in a TSG 288
8.4.2 Mixing in a TSG 291
8.5 Granule Size Evolution During Twin-screw Granulation 294
8.5.1 Granule Size and Shape Dynamics in a TSG 295
8.5.2 Link Between RTD, Liquid Distribution and GSD in a TSG 295
8.6 Model-based Analysis of Twin-screw Granulation 298
8.6.1 Modelling RTD in a TSG 298
8.6.2 Tracking GSD in a TSG using PBM 300
8.7 Towards Generic Twin-screw Granulation Knowledge 302
8.7.1 Regime Map Approach 303
8.7.2 Particle-scale Simulation using DEM 305
8.8 Strengths and Limitations of the Current Approaches in TSG Studies 307
8.9 Glossary 308
References 309
9 Continuous Line Roller Compaction 313
Ossi Korhonen
9.1 Roller Compaction 313
9.2 Main Components of a Roller Compactor 313
9.3 Theory of Powder Densification in Roller Compaction 315
9.4 Johanson Model 317
9.5 Modified Johanson Model 319
9.6 Experimental Observations of Pressure Distribution from Instrumented Roller Compactors 322
9.7 Off-line Characterization of Ribbon Quality 324
9.8 In-line Monitoring of Roller Compaction Process 326
9.9 Formulative Aspects of Roller Compaction 328
9.10 Roller Compaction as a Unit Operation in Continuous Manufacturing 330
9.11 Process Control of Continuous Roller Compaction 332
9.12 Conclusions 333
References 334
10 Continuous Melt Extrusion and Direct Pelletization 337
Stephan Laske, Theresa Hörmann, Andreas Witschnigg, Gerold Koscher, Patrick Wahl, Wen Kai Hsiao and Johannes Khinast
10.1 Introduction 337
10.2 The Extruder 338
10.3 Feeding 341
10.3.1 Solid...
Details
| Erscheinungsjahr: | 2017 |
|---|---|
| Fachbereich: | Allgemeines |
| Genre: | Chemie |
| Rubrik: | Naturwissenschaften & Technik |
| Medium: | Buch |
| Seiten: | 640 |
| Inhalt: | 620 S. |
| ISBN-13: | 9781119001324 |
| ISBN-10: | 1119001323 |
| Sprache: | Englisch |
| Einband: | Gebunden |
| Redaktion: |
Kleinebudde, Peter
Khinast, Johannes Rantanen, Jukka |
| Herausgeber: | Peter Kleinebudde/Johannes Khinast/Jukka Rantanen |
| Hersteller: |
Wiley
John Wiley & Sons |
| Maße: | 251 x 174 x 38 mm |
| Von/Mit: | Peter Kleinebudde (u. a.) |
| Erscheinungsdatum: | 05.09.2017 |
| Gewicht: | 1,092 kg |
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