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.
Peter Kleinebudde, PhD, 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, PhD, 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, PhD, is Professor of Pharmaceutical Technology and Engineering at the Department of Pharmacy, University of Copenhagen, Denmark.
List of Contributors Preface Chapter 1 1.1 Introduction 1.2 Advantages of Continuous Manufacturing 1.3 Engineering Principles of Continuous Manufacturing Chapter 2 2.1 Introduction 2.2 Pharmaceutical solid dosage manufacturing processes 2.3 Mathematical modeling approaches 2.4 Unit operations models 2.5 Process control of continuous solid-based drug manufacturing 2.6 Summary 2.7 References Chapter 3 3.1 Introduction 3.2 Regulatory considerations 3.3 Quality/GMP considerations 3.4 Quality considerations for bridging existing batch manufacturing to continuous manufacturing 3.5 General regulatory references Chapter 4 4.1 Introduction 4.2 Micro Flow Technology 4.3 Multi-step synthesis of active pharmaceutical ingredients in micro flow 4.4 Larger scale syntheses 4.5 Current industrial applications 4.6 Conclusion and Outlook 4.7 References Chapter 5 5.1 Introduction 5.2. Principles of Crystallisation 5.3 Crystallisation Process Development 5.4 Continuous Crystallisers and Applications 5.5 Process Monitoring, Analysis and Control 5.6 Particle Characterisation 5.7 Concluding Remarks Chapter 6 6.1 Abstract 6.2 Introduction 6.3 Operation of fermentation systems 6.4 Continuous fermentation examples 6.5 Discussion 6.6 Conclusion 6.7 References Chapter 7 7.1. Background 7.2. Continuous upstream processing 7.3. Continuous downstream processing 7.4. Process integration and single use technology 7.5. Process monitoring and control 7.6. Process economics of continuous manufacturing 7.7. Conclusions 7.8. Acknowledgements 7.9. References Chapter 8 8.1 Introduction 8.2 Continuous wet-granulation using TSG 8.3 Components of high shear wet granulation in TSG 8.4 Material transport and mixing in a TSG 8.5 Granule size evolution during twin-screw granulation 8.6 Model-based analysis of twin-screw granulation 8.7 Towards generic twin-screw granulation knowledge 8.8 Strengths and limitations of TSG studies Chapter 9 9.1 Roller compaction 9.2 Main components of a roller compactor 9.3 Theory of powder densification in roller compaction 9.4 Experimental observations of pressure distribution from instrumented roller compactors 9.5 Off-line characterization of ribbon quality 9.6 In-line monitoring of roller compaction process 9.7 Formulative aspects of roller compaction 9.8 Roller compaction as a unit operation in continuous manufacturing 9.9 Process control of continuous roller compaction 9.10 Conclusions 9.11 References Chapter 10 10.1 Introduction 10.2 The Extruder 10.3 Feeding 10.4 Twin-screw extrusion 10.5 Operation Point 10.6 Downstream Processing 10.7 Continuous manufacturing with hot melt extrusion 10.8 Process Analytical Technology for hot melt extrusion 10.9 Process Integration into Computerized Systems 10.10 Conclusion 10.11 References Chapter 11 11.1 Industry Drivers for Continuous Processing: Competitive Advantages 11.2 Continuous Manufacturing in Bioprocessing 11.3 Continuous Manufacturing for Oral Solid Dosage Forms 11.4 The Pharmaceutical Supply Chain of the Future 11.5 Discussion 11.6 Conclusion Chapter 12 12.1 Introduction 12.2 Rough conceptual design 12.3 Material property screening 12.4 Characterizing Unit Operation using Actual Process Materials 12.5 Develop and Calibrate Unit Operation Models Including Process Materials 12.6 Develop an Integrated Model of an Open Loop System 12.7 Examine Open Loop Performance of the Process 12.8 Develop/fine tune PAT methods for appropriate unit ops 12.9 Implement open loop kit with PAT and IPCs enabled 12.10 Design of the control architecture 12.11 Develop integrated model of closed loop system 12.12 Implementation and Verification of the Control Framework 12.13 Characterize and verify closed performance 12.14 Conclusions Chapter 13 13.1 Introduction 13.2 Process Description 13.3 System Dynamics 13.4 Process Monitoring and Control 13.5 Outlook: opportunities for novel unit operations and system configurations 13.6 Summary and closing thoughts 13.7 References Chapter 14 14.1 Introduction 14.2 Technical-economic evaluation methodology 14.3 Conclusion Chapter 15 15.1 Introduction 15.2 Personalized Medicine 15.3 Flexible Dosing with Innovative Products 15.4 Future Health Care Scenario 15.5 References Chapter 16 16.1 Introduction 16.2 Inkjet (microdrop generation techniques) 16.3 Flexographic printing 16.4 Formulation approaches for inkjet and flexography 16.5 Process Control and Process Analytical Technology for continuous printing applications 16.6 From the lab-scale printing towards an industrial scale 16.7 3D printing/Additive manufacturing 16.8 References Chapter 17 17.1 Introduction 17.2 Background 17.3 Goals for the LDT program 17.4 Overview of liquid dispensing technology 17.5 LDT machine design details 17.6 Scale-Independence of the LDT Technology 17.7 Real-Time Release Potential 17.8 Occupational Health, Environmental and Cleaning Considerations 17.9 Conclusion 17.10 Acknowledgements REFERENCES Index