Chemical Engineering in the Pharmaceutical Industry E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 2405

Veröffentlichungsjahr: 2011

Beschreibung

This book deals with various unique elements in the drugdevelopment process within chemical engineering science andpharmaceutical R&D. The book is intended to be used as aprofessional reference and potentially as a text book reference inpharmaceutical engineering and pharmaceutical sciences. Many of theexperimental methods related to pharmaceutical process developmentare learned on the job. This book is intended to provide many ofthose important concepts that R&D Engineers and manufacturingEngineers should know and be familiar if they are going to besuccessful in the Pharmaceutical Industry. These include basicanalytics for quantitation of reaction components- oftenskipped in ChE Reaction Engineering and kinetics books. In additionChemical Engineering in the Pharmaceutical Industryintroduces contemporary methods of data analysis for kineticmodeling and extends these concepts into Quality by Designstrategies for regulatory filings. For the current professionals,in-silico process modeling tools that streamlineexperimental screening approaches is also new and presented here.Continuous flow processing, although mainstream for ChE, is uniquein this context given the range of scales and the complex economicsassociated with transforming existing batch-plant capacity. The book will be split into four distinct yet related parts.These parts will address the fundamentals of analytical techniquesfor engineers, thermodynamic modeling, and finally provides anappendix with common engineering tools and examples of theirapplications.

Leseprobe

Contents

Cover

Title Page

Copyright

Preface

Contributors

Conversion Table

Part I: Introduction

Chapter 1: Chemical Engineering in the Pharmaceutical Industry: An Introduction

1.1 Pharmaceutical Development

1.2 Manufacturing

1.3 Summary

Acknowledgments

References

Chapter 2: Current Challenges and Opportunities in the Pharmaceutical Industry

2.1 Introduction

2.2 Industry-Wide Challenges

2.3 Opportunities for Chemical Engineers

2.4 Prospects for Chemical Engineers

Acknowledgments

References

Chapter 3: Chemical Engineering Principles in Biologics: Unique Challenges and Applications

3.1 Why are Biologics Unique from a Mass, Heat, and Momentum Transfer Standpoint?

3.2 Scale-Up Approaches and Associated Challenges in Biologics Manufacturing

3.3 Challenges in Large-Scale Protein Manufacturing

3.4 Specialized Applications of Chemical Engineering Concepts in Biologics Manufacturing

3.5 Conclusions

Acknowledgments

References

Chapter 4: Designing a Sustainable Pharmaceutical Industry: The Role of Chemical Engineers

4.1 Introduction

4.2 A Word on Sustainability

4.3 Green Chemistry and Green Engineering Principles

4.4 Chemical Engineers—Designing Sustainable Pharmaceutical Processes

4.5 Future Outlook

Acknowledgments

References

Chapter 5: Scientific Opportunities Through Quality by Design

Acknowledgment

References

Chapter 6: The Role of Chemical Engineering in Pharmaceutical API Process R&D

6.1 Introduction

6.2 Chemists and Chemical Engineers

6.3 Penicillin: A Chemical Engineering Achievement

6.4 Batch and Continuous Processing

6.5 Examples

6.6 Other Chemical Engineering Activities

References

Part II: Active Pharmaceutical Ingredient (API)

Chapter 7: Reaction Kinetics and Characterization

7.1 Introduction

7.2 Experimental Approaches

7.3 Reaction Modeling

7.4 Scale Sensitivity Assessment

7.5 Solid–Liquid Transport

7.6 Liquid–Liquid Transport

7.7 Gas–Liquid Transport

7.8 Leveraging the Advantages of Continuous Reactors

7.9 Conclusions

7.10 Questions

References

Chapter 8: Understanding Rate Processes in Catalytic Hydrogenation Reactions

8.1 Introduction

8.2 Solution Hydrogen Concentration During Hydrogenation Reactions, [H2]

8.3 Impact of kLa on Reaction Kinetics and Selectivity

8.4 Characterization of Gas–Liquid Mass Transfer Process

8.5 Characterization of Catalyst Reduction Process

8.6 Basic Scale-Up Strategy for Hydrogenation Processes

8.7 Summary

Acknowledgments

References

Chapter 9: Characterization and First Principles Prediction of API Reaction Systems

9.1 Introduction

9.2 Batch Processes with Homogeneous Reactions

9.3 Multiphase Batch Processes with Reactions

9.4 Fed-Batch Processes with Reactions

9.5 Application to Continuous Flow Systems

9.6 Equipment Characterization and Assessment

9.7 Model Verification Statistics

Symbols

References

Chapter 10: Modeling, Optimization, and Applications of Kinetic Mechanisms with OpenChem

10.1 Introduction

10.2 Description of the Example Mechanism

10.3 Mechanism Building and Analysis

10.4 Mechanism Calibration

10.5 Mechanism Application

10.6 Conclusion

Notation

References

Chapter 11: Process Safety and Reaction Hazard Assessment

11.1 Introduction

11.2 General Concepts

11.3 Studying the Desired Synthesis Reaction at Lab Scale

11.4 Scale-Up of the Desired Reaction

11.5 Studying the Decomposition Reaction at Lab Scale

11.6 Other Points to Consider

References

Chapter 12: Design of Distillation and Extraction Operations

12.1 Introduction to Separation Design by Distillation and Extraction

12.2 Design of Distillation Operations

12.3 Design of Extraction Operations

12.4 Appendix

References

Chapter 13: Crystallization Design and Scale-Up

13.1 Introduction

13.2 Crystallization Design Objectives and Constraints

13.3 Solubility Assessment and Preliminary Solvent Selection

13.4 Crystallization Kinetics and Process Selection

13.5 Understanding Crystallization Rate Processes: The Application of Solubility and Kinetics Data to Crystallization Modes

13.6 Batch Crystallization Scale-Up

References

Chapter 14: Scale-Up of Mixing Processes: A Primer

14.1 Introduction

14.2 Basic Approaches to Mixing Scale-Up

14.3 Other Considerations in Mixing Scale-Up

14.4 Common Mixing Equipment

14.5 Scale-Up of Chemical Reactions

14.6 CFD and Other Modeling Techniques

14.7 Symbols and Abbreviations

References

Chapter 15: Stirred Vessels: Computational Modeling of Multiphase Flows and Mixing

15.1 Engineering of Multiphase Stirred Reactors

15.2 Computational Modeling of Multiphase Stirred Reactor

15.3 Application to Engineering of Stirred Vessels

15.4 Summary and Path Forward

15.5 Symbols

References

Chapter 16: Membrane Systems for Pharmaceutical Applications

16.1 Introduction

16.2 Pervaporation in The Pharmaceutical Industry

16.3 Organic Solvent Nanofiltration in Pharmaceutical Industry

16.4 Nondispersive Membrane Solvent Extraction

16.5 Concluding Remarks

References

Chapter 17: Design of Filtration and Drying Operations

17.1 Introduction

17.2 Filtration

17.3 Drying

References

Chapter 18: The Design and Economics of Large-Scale Chromatographic Separations

18.1 Introduction

18.2 Key Design Elements

18.3 Fundamental Chromatographic Relationships

18.4 Chromatographic Adsorbent Chemistries and Basis of Retention

18.5 Operational Aspects

18.6 Equipment

18.7 Scale-Up

18.8 Design Space

18.9 Economics

18.10 Conclusions

18.11 Acknowledgments

References

Chapter 19: Milling Operations in the Pharmaceutical Industry

19.1 Introduction

19.2 Types of Milling and Mill Equipment

19.3 Safety and Quality Concerns

References

Chapter 20: Process Scale-Up and Assessment

20.1 Introduction

20.2 Drivers for Development/Risk Assessment

20.3 Unit Operations

20.4 Summary

References

Chapter 21: Scale-Up Dos and Don'ts

21.1 Introduction

21.2 Learning the Hard Way

21.3 Typical Scale-Up Issues

21.4 Purpose of This Chapter

21.5 Things to Do During Scale-Up

21.6 Things to Avoid During Scale-Up

21.7 Conclusions and Final Thoughts

References

Chapter 22: Kilo Lab and Pilot Plant Manufacturing

22.1 Introduction

22.2 Kilo Lab and Pilot Plant Facility Design

22.3 Operating Principles and Regulatory Drivers

22.4 Summary

Exercise

References

Chapter 23: Process Development and Case Studies of Continuous Reactor Systems for Production of API and Pharmaceutical Intermediates

23.1 Introduction

23.2 Benefits of Continuous Processing

23.3 Continuous Reactor and Ancillary Systems Considerations

23.4 Process Development of the Continuous Reaction

23.5 Scale-Up: Volumetric Versus Numbering-Up

23.6 Plant Operations

23.7 Case Study: Continuous Deprotection Reaction—Lab to Kilo Lab Scale-Up

23.8 Case Study: Continuous Production of A Cycloproponating Reagent

23.9 Integrated Continuous Processing in Pharma

23.10 Barriers to Implementation of Continuous Processing in Pharma

23.11 Summary

References

Chapter 24: Drug Solubility and Reaction Thermodynamics

24.1 Introduction

24.2 Solubility Prediction with COSMO-RS

24.3 Chemical Reactions in Solution

24.4 Conclusion and Outlook

24.5 Appendix

24.6 Abbreviations

24.7 Symbols

References

Chapter 25: Thermodynamics and Relative Solubility Prediction of Polymorphic Systems

25.1 Introduction

25.2 Methods

25.3 Results and Discussion

25.4 Application to An Estimation of Likely Impact on Drug Solubility by Unknown More Stable Form

25.5 Conclusion

25.5 A Appendix

25.5 B Appendix

25.8 Acknowledgments

References

Chapter 26: Toward a Rational Solvent Selection for Conformational Polymorph Screening

26.1 Introduction

26.2 Methods

26.3 Results and Discussion

26.4 Conclusions

Acknowledgments

References

Chapter 27: Molecular Thermodynamics for Pharmaceutical Process Modeling and Simulation

27.1 Introduction

27.2 Process Simulation and Molecular Thermodynamics

27.3 Future Developments

27.4 Aspen Technology's Process Development Solution

27.5 Conclusions

Acknowledgment

Appendix A: Solubility Modeling with Aspen Solubility Modeler

References

Chapter 28: The Role of Simulation and Scheduling Tools in the Development and Manufacturing of Active Pharmaceutical Ingredients

28.1 Introduction

28.2 Commercially Available Simulation and Scheduling Tools

28.3 Modeling and Analysis of an API Manufacturing Process

28.4 Uncertainty and Variability Analysis

28.5 Production Scheduling

28.6 Capacity Analysis and Production Planning

28.7 Summary

References

Part III: Analytical Methods and Applied Statistics

Chapter 29: Quality by Design for Analytical Methods

29.1 Introduction

29.2 Analytical Target Profile

29.3 Method Design

29.4 Method Evaluation

29.5 Method Control and LifeCycle Management

29.6 Conclusion

Acknowledgments

References

Chapter 30: Analytical Chemistry for API Process Engineering

30.1 Introduction

30.2 Use of Analytical Methods Applied to Engineering

30.3 Methods Used and Background

30.4 Things to Watch out for in LC and GC

30.5 Use of Multiple Analytical Techniques

30.6 Conclusion

References

Chapter 31: Quantitative Applications of NMR Spectroscopy

31.1 Introduction

31.2 One-Dimensional NMR Methods

31.3 Two-Dimensional NMR Methods

31.4 qNMR Spectroscopy

References

Chapter 32: Experimental Design for Pharmaceutical Development

32.1 Introduction

32.2 The Two-Level Factorial Design

32.3 Blocking

32.4 Fractional Factorials

32.5 Design Projection

32.6 Steepest Ascent

32.7 Center Runs

32.8 Response Surface Designs

32.9 Computer Generated Designs

32.10 Multiple Responses

32.11 Advanced Topics

References

Chapter 33: Multivariate Analysis for Pharmaceutical Development

References

Part IV: Drug Products

Chapter 34: Process Modeling Techniques and Applications for Solid Oral Drug Products

34.1 Introduction

34.2 Formulation Modeling

34.3 Process Modeling for Solid Oral Drug Product Processes

34.4 Summary

References

Chapter 35: Process Design and Development for Novel Pharmaceutical Dosage Forms

35.1 Introduction

35.2 Architecture and Formulation

35.3 Mechanism of Release

35.4 Process

35.5 Summary

35.6 Problems

35.7 Problem Solutions

Acknowledgment

References

Chapter 36: Design of Solid Dosage Formulations

36.1 Introduction

36.2 Understanding Drug Substance

36.3 Excipients

36.4 Drug–Excipient Compatibility Studies

36.5 Processing of Formulations

36.6 Tablet Formulation Design

36.7 Tablet Characteristics

36.8 Using Dissolution to Determine CQAs

36.9 Drug Product Stability

36.10 Process Operations and Scalability of Dosage Form

36.11 Conclusion

References

Chapter 37: Controlled Release Technology and Design of Oral Controlled Release Dosage Forms

37.1 Introduction

37.2 Development of Controlled Release Formulations in an Industrial Setting

37.3 Controlled Release Profiles and Mechanisms

37.4 Mathematical Equations for Drug Release from Controlled Release Dosage Forms

37.5 Case Study

37.6 Conclusions

References

Chapter 38: Design and Scale-Up of Dry Granulation Processes

38.1 Overview of the Dry Granulation Process

38.2 General Considerations for Roller Compaction Operations and Equipment

38.3 Material Behavior, Attribute Testing, and Process Sensors

38.4 Principles of Operation

38.5 Scale-Up of Roller Compaction

38.6 Summary

38.7 Symbols

References

Chapter 39: Wet Granulation Processes

39.1 Introduction

39.2 Mechanisms in Wet Granulation

39.3 Scale-Up

39.4 Future Directions

References

Chapter 40: Spray Atomization Modeling for Tablet Film Coating Processes

40.1 Introduction

40.2 Coating Formulations, Physical Properties, and Rheology Characterization

40.3 Spraying Process and Equipment

40.4 Droplet Size and Velocity Measurements

40.5 Mathematical Modeling of the Liquid Breakup: Average Droplet Size

40.6 Scale-Up of Atomization

40.7 Conclusions

40.8 Acknowledgments

References

Chapter 41: The Freeze-Drying Process: The Use of Mathematical Modeling in Process Design, Understanding, and Scale-Up

41.1 Introduction

41.2 Freezing Processes

41.3 Drying Processes

References

Chapter 42: Achieving a Hot Melt Extrusion Design Space for the Production of Solid Solutions

42.1 Introduction

42.2 Introduction to Solid Solutions

42.3 Risk Assessment

42.4 Achieving a Design Space

42.5 Conclusion

Acknowledgements

References

Chapter 43: Continuous Processing in Secondary Production

43.1 Introduction

43.2 Definitions

43.3 Review of Typical Unit Operations

43.4 Solid Dosage Unit Operation

43.5 Creams, Liquids, and Suspensions

43.6 Lyophilization

43.7 Novel Unit Operations

43.8 Why Consider Continuous Process for Drug Product Operations?

43.9 Implementation of Continuous Processes

References

Chapter 44: Pharmaceutical Manufacturing: The Role of Multivariate Analysis in Design Space, Control Strategy, Process Understanding, Troubleshooting, and Optimization

44.1 Introduction

44.2 The Nature of Process and Quality Data

44.3 Latent Variable Methods for Two-Way Matrices

44.4 Multivariate Statistical Process Control

44.5 Batch Process Monitoring

44.6 Multistage Operations: Multiblock Analysis

44.7 Process Control to Achieve Desired Product Quality

44.8 Other Applications of Latent Variable Methods

44.9 Quality by Design

44.10 Future Directions

Acknowledgment

References

Index

Copyright © 2011 John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Chemical engineering in the pharmaceutical industry : R&D to manufacturing / edited by David J. am Ende.

p. cm.

Includes index.

ISBN 978-0-470-42669-2 (cloth)

1. Pharmaceutical technology. 2. Biochemical engineering. 3. Chemical engineering. I. Ende, David J. am.

RS192.C525 2010

6150.19–dc22

2010013146

Contributors

Yuriy A. Abramov, Pfizer Global Research & Development, Pharmaceutical Sciences, Groton, CT, USA

Alberto Aliseda, Department of Mechanical Engineering, University of Washington, Seattle, WA, USA

David J. am Ende, Chemical R&D, Pfizer, Inc., Groton, CT, USA

Mary T. am Ende, Pharmaceutical Development, Pfizer Global Research & Development, Groton, CT, USA

Firoz D. Antia, Product Development, Palatin Technologies, Inc., Cranbury, NJ, USA

Leah Appel, Green Ridge Consulting, Bend, OR, USA

Simon J. Bale, Pfizer Global Research & Development, Sandwich, Kent, UK

Kimber L. Barnett, Pfizer Global Research & Development, Groton, CT, USA

Alfred Berchielli, Pharmaceutical Development, Pfizer worldwide Research & Development, Groton, CT, USA

Rahul Bharadwaj, Pharmaceutical Development, Pfizer Global Research & Development, Groton, CT, USA

Vivek Bhatnagar, Process Development, Amgen Inc.,West Greenwich, RI, USA

Kevin J. Bittorf, Formulation Development, Vertex Pharmaceuticals Inc., Cambridge, MA, USA

Alan D. Braem, Process Research & Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Chau-Chyun Chen, Aspen Technology, Inc., Burlington, MA, USA

Jennifer Chu, Pharmaceutical Sciences, Neurogen Corporation, Branford, CT, USA

Paul C. Collins, Eli Lilly & Co., Indianapolis, IN, USA

Eric M. Cordi, Chemical Research and Development, Pfizer Inc., Groton, CT, USA

Philip C. Dell'Orco, Chemical Development, Glaxo-SmithKline, King of Prussia, PA, USA

Wim Dermaut, Process Safety Center, API Small Molecule Development, Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium

Pankaj Doshi, Chemical Engineering and Process Division, National Chemical Laboratory, Pune, India

Elizabeth Fisher, Merck & Co., Inc., Rahway, NJ, USA

Salvador García-Muñoz, Pharmaceutical Development, Pfizer Global Research & Development, Groton, CT, USA

Imogen Gill, Pfizer Global Research & Development, Sandwich, Kent, UK

Timothy W. Graul, Pfizer Global Research & Development, Groton, CT, USA

James R. Hagan, GlaxoSmithKline, Sustainability and Environment, 1 Franklin Plaza, Philadelphia, PA, USA

Jason Hamm, Process Research & Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Melissa Hanna-Brown, Pfizer Global Research & Development, Sandwich, Kent, UK

Robert E. Hannah, GlaxoSmithKline, Sustainability and Environment, Philadelphia, PA, USA

Joe Hannon, Scale-up Systems Limited, Dublin, Ireland Karen P. Hapgood, Department of Chemical Engineering, Monash University, Clayton, VIC, Australia

José O. Jiménez, Intelligen, Inc., Amsterdam, The Netherlands

Concepción Jiménez-González, GlaxoSmithKline, Sustainability and Environment, Research Triangle Park, NC, USA

G. Scott Jones, Process Research & Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Matthew L. Jorgensen, Engineering Technologies, Chemical Research & Development, Pfizer Inc., Groton, CT, USA

Jeffrey P. Katstra, Formulation Development, Vertex Pharmaceuticals Inc., Cambridge, MA, USA

Stephen B. Kessler, Impact Technology Development, Lincoln, MA, USA

William Ketterhagen, Pharmaceutical Development, Pfizer Global Research & Development, Groton, CT, USA

Avinash R. Khopkar, Engineering Sciences, Dow Chemical International Private Ltd., Pune, Maharashtra, India

Andreas Klamt, COSMOlogic GmbH & Co. KG, Leverkusen, Germany and Institute of Physical and Theoretical Chemistry, University of Regensburg, Regensburg, Germany

Venkat Koganti, Pharmaceutical Development, Pfizer Global Research & Development, Pfizer, Inc., Groton, CT, USA

Alexandros Koulouris, A.T.E.I. of Thessaloniki, Thessaloniki, Greece

Theodora Kourti, GlaxoSmithKline, Pharma Launch and Global Supply, Global Functions

Joseph F. Krzyzaniak, Pfizer Global Research & Development, Pharmaceutical Sciences, Groton, CT, USA

Joseph L. Kukura, Global Science Technology and Commercialization, Merck & Co., Inc., Rahway, NJ, USA

Sourav Kundu, Process Development, Amgen Inc., West Greenwich, RI, USA

Pericles T. Lagonikos, Merck & Co., Union, NJ, USA

Thomas L. LaPorte, Process Research & Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Juan C. Lasheras, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA, USA

Carl LeBlond, Department of Chemistry, Indiana University of Pennsylvania, Indiana, PA, USA

Li Li, Merck & Co., Inc., West Point, PA, USA

James D. Litster, School of Chemical Engineering and Industrial & Physical Pharmacy, Purdue University, West Layafette, IN, USA

Frederick H. Long, Spectroscopic Solutions, LLC, Randolph, NJ, USA

Mike Lowinger, Merck & Co., Inc., West Point, PA, USA

Sumit Luthra, Pharmaceutical Development, Pfizer Global Research & Development, Pfizer, Inc., Groton, CT, USA

Brian L. Marquez, Pfizer Global Research & Development, Groton, CT, USA

Francis X. McConville, Impact Technology Development, Lincoln, MA, USA

Craig McKelvey, Merck & Co., Inc.,West Point, PA, USA

Robert Rahn McKeown, Chemical Development, GlaxoSmithKline, Research Triangle Park, NC, USA

Melanie Miller, Process Research & Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Saravanababu Murugesan, Process Research & Development, Bristol-Myers Squibb Co, New Brunswick, NJ, USA

Jason Mustakis, Chemical R&D, Pfizer, Inc., Groton, CT, USA

Roger Nosal, Global CMC, Pfizer, Inc., Groton, CT, USA

Charles J. Orella, Chemical Process Development and Commercialization, Merck & Co., Inc., Rahway, NJ, USA

Taeshin Park, RES Group, Inc., Cambridge, MA, USA

Naveen Pathak, Genzyme, Inc., Framingham, MA.

Edward L. Paul (Retired), Chemical Engineering R&D, Merck & Co., Inc., Rahway, NJ, USA

Klimentina Pencheva, Pfizer Global Research & Development, Pharmaceutical Sciences, Sandwich, Kent, UK

Demetri Petrides, Intelligen, Inc., Scotch Plains, NJ, USA

Michael J. Pikal, Pharmaceutics, School of Pharmacy, University of Connecticut, Storrs, CT, USA

Celia S. Ponder, GlaxoSmithKline, Sustainability and Environment, Research Triangle Park, NC, USA

Andrew Prpich, Pharmaceutical Development, Pfizer Global Research & Development, Groton, CT, USA

Tom Ramsey, Process Research & Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Vivek V. Ranade, Tridiagonal Solutions Private Ltd. and National Chemical Laboratory, Pune, Maharashtra, India

Tapan Sanghvi, Formulation Development, Vertex Pharmaceuticals Inc., Cambridge, MA, USA

Luke Schenck, Merck & Co., Inc., Rahway, NJ, USA

Richard L. Schild, Process Research & Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Kevin D. Seibert, Eli Lilly & Co., Indianapolis, IN, USA

Matthew Shaffer, Green Ridge Consulting, Bend, OR, USA

Praveen K. Sharma, Process Research & Development, Bristol-Myers Squibb Co, New Brunswick, NJ, USA

Joshua Shockey, Green Ridge Consulting, Bend, OR, USA

Charles Siletti, Intelligen, Inc., Mt. Laurel, NJ, USA

Brian Simpson, RES Group, Inc., Cambridge, MA, USA

Utpal K. Singh, Chemical Process R&D, Eli Lilly and Company, Chemical Product R&D, Indianapolis, IN, USA

Kamalesh K. Sirkar, Department of Chemical, Biological and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ, USA

Omar L. Sprockel, Biopharmaceutics Research and Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Howard J. Stamato, Biopharmaceutics Research and Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Gregory S. Steeno, Pfizer Global Research & Development, Groton, CT, USA

Andrew Stewart, Process Research & Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Yongkui Sun, Department of Process Research, Merck & Co., Inc., Rahway, NJ, USA

Jason T. Sweeney, Process Research & Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Jose E. Tabora, Process Research & Development, Bristol-Myers Squibb Co, New Brunswick, NJ, USA

Michael Paul Thien, Global Science Technology and Commercialization, Merck&Co., Inc., Rahway, NJ, USA

Avinash G. Thombre, Pharmaceutical Development, Pfizer Global Research & Development, Groton, CT, USA

John E. Tolsma, RES Group, Inc., Cambridge, MA, USA

Jean W. Tom, Process Research & Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Gregory M. Troup, Merck & Co., Inc.,West Point, PA, USA

Cenk Undey, Process Development, Amgen Inc., West Greenwich, RI, USA

Chenchi Wang, Process Research & Development, Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Martin Warman, Analytical Development, Vertex Pharmaceuticals Inc., Cambridge, MA, USA

Timothy J. Watson, Global CMC, Pfizer, Inc., Groton, CT, USA

James T. Wertman, Chemical Development, Glaxo-SmithKline, King of Prussia, PA, USA

Karin Wichmann, COSMOlogic GmbH & Co. KG, Leverkusen, Germany

R. Thomas Williamson, Roche Carolina, Inc., Florence, SC, USA

Xiao Yu (Shirley) Wu, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

Dimitrios Zarkadas, Chemical Process Development & Commercialization, Merck & Co., Inc., Union, NJ, USA

Mark Zell, Pfizer Global Research & Development, Pharmaceutical Sciences, Groton, CT, USA

Conversion Table

Preface

Chemical Engineering in the Pharmaceutical Industry is unique in many ways to what is traditionally taught in schools of chemical engineering. This book is therefore intended to cover many important concepts and applications of chemical engineering science that are particularly important to the Pharmaceutical Industry. There have been several excellent books written recently on the subjects of process chemistry in the pharmaceutical industry and separately on formulation development, but relatively little has been published specifically with a focus on chemical engineering.

The intention of the book is to highlight the importance and value of chemical engineering to the development and commercialization of pharmaceuticals covering active pharmaceutical ingredient (API) and drug product (DP) as well as analytical methods. It should serve as a resource for practicing chemical engineers as well as for chemists, analysts, technologists, and operations and management team members—all those who partner to bring pharmaceuticals successfully to market. The latter will benefit through an exposure to the mathematical and predictive approach and the broader capabilities of chemical engineers and also by the illustration of chemical engineering science as applied specifically to pharmaceutical problems. This book emphasizes both the need for scientific integration of chemical engineers with synthetic organic chemists within process R&D and the importance of the interface between R&D engineers and manufacturing engineers. The importance of analytical chemists and other scientific disciplines necessary to deliver pharmaceuticals to the market place is also emphasized with chapters dedicated to selected topics.

Although specific workflows for engineers in R&D depend on each company's specific organization, in general it is clear that, as part of a multidisciplinary team in R&D, chemical engineering practitioners offer value in many ways including API and DP process design, scale-up assessment from laboratory to plant, process modeling, process understanding, and general process development that ultimately reduces cost and ensures safe, robust, and environmentally friendly processes are transferred to manufacturing. How effective the teams leverage each of the various skill sets (i.e., via resource allocation) to arrive at an optimal process depends in part on the roles and responsibilities as determined within each organization and company. In general, it is clear that with increased cost pressures facing the pharmaceutical industry, including R&D and manufacturing, opportunities to leverage the field of chemical engineering science continue to increase. Indeed I have observed a significant increase in chemical engineering emphasis in API process development within Pfizer over the 15 years since I joined the company and especially in the past 5 years.

This book is divided into four main parts:

1. Introduction

2. Active Pharmaceutical Ingredient (API)

3. Analytical Methods and Applied Statistics

4. Drug Product (DP)

The introductory chapters span roles and opportunities for chemical engineering in small-molecule API, biologicals, drug products, as well as environmental sustainability and quality by design (QbD) concepts. The Active Pharmaceutical Ingredient part consists of 23 chapters covering chemical engineering principles applied to pharmaceutical specific unit operations (reaction engineering, crystallization, chromatography, filtration, drying, etc.) as well as pilot plant and scale-up manufacturing assessment chapters, including process safety. Process modeling promises to have significant payback as more in silico screening enables process design to be performed with fewer resources (for selection process conditions/optimization, solubility, distillation, and extraction design, etc.). Several chapters are devoted to process modeling with emphasis on several of the software tools currently available. The section on drug product includes formulation chapters as well as chapters highlighting unit operations specific to drug product (wet granulation, dry granulation, extrusion, controlled release, and lyophilization). In addition, process modeling within drug product chapter describes the various modeling approaches used to understand and predict performance of powder blending, mixing, tablet presses, tablet coating, and so on. The Analytical Methods and Applied Statistics part describes important topics on chemometrics, statistics, and analytical methods applied toward chemical engineering problems (e.g., material balance, kinetics, design of experiments, or quality by design for analytical methods).

The contributors were encouraged to provide worked out examples—so in most chapters a quantitative example is offered to illustrate key concepts and problem-solving approaches. In this way, the chapters will serve to help others solve similar problems.

There are many people to thank who made this work possible. First, I would like to thank all the contributors of this book. I also would like to thank my colleagues at Pfizer for writing many of the chapters and for my management (past and present) who encouraged and made this effort possible and who continue to encourage the role of chemical engineering in chemical R&D and pharmaceutical sciences.

Special thanks to my family (Mary, Nathan, Noah, and Brianna) for their support during the preparation of this book. Special thanks to Mary, not only for contributing two chapters to this book but also for her assistance in all phases of the project including the cover art. Finally, a special thanks to my parents for their encouragement to pursue chemical engineering in 1983 and their support through my attendance at the University of Iowa and Purdue University.

David J. am Ende, Ph.D.

Chemical R&DPfizer, Inc.Groton, CTJanuary 2010

Part I

Introduction

Chapter 1

Chemical Engineering in the Pharmaceutical Industry: An Introduction

Chemical R&D, Pfizer, Inc., Groton, CT, USA

Although recently several excellent books have been published geared toward process chemistry [1–3] or formulation development in the pharmaceutical industry [4], relatively little has been published specifically with a chemical engineering (ChE) focus. This book, therefore, is about chemical engineering applied to the process research, development, and manufacture of pharmaceuticals. Across the pharmaceutical industry, chemical engineers are employed in R&D through to full-scale manufacturing in technical and management capacities. The following chapters provide an emphasis on the application of chemical engineering science to process development and scale-up for active pharmaceutical ingredients (APIs), drug products (DPs), and biologicals including sections on analytical methods and computational methods. This chapter briefly highlights a few industry facts and figures, in addition to some of the challenges facing the industry, and touches on how ChE can contribute to addressing those challenges. Chapter 2 by Kukura and Thien provides further perspective on the challenges and opportunities in the pharmaceutical industry and the role of chemical engineering.

In general, pharmaceuticals are drug delivery systems in which drug-containing products are designed and manufactured to deliver precise therapeutic responses [5]. The drug is considered the “active,” that is, active pharmaceutical ingredient, whereas the formulated final drug is simply referred to as the drug product.

In the United States, federal and state laws exist to control the manufacture and distribution of pharmaceuticals. Specifically, the Food and Drug Administration (FDA) exists by the mandate of the U.S. Congress with the Food, Drug & Cosmetics Act as the principal law to enforce and constitutes the basis of the drug approval process [6]. Specifically in the United States, “The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health [7].”