Continuous Manufacturing of Pharmaceuticals

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.

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

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.