Process Understanding E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 615

Veröffentlichungsjahr: 2011

Beschreibung

Process Understanding is the underpinning knowledge that allows the manufacture of chemical entities to be carried out routinely, robustly and to the required standard of quality. This area has gained in importance over the last few years, particularly due to the recent impetus from the USA`s Food and Drug Administration. This book covers the multidisciplinary aspects required for successful process design, safety, modeling, scale-up, PAT, pilot plant implementation, plant design as well the rapidly expanding area of outsourcing.

In discussing what process understanding means to different disciplines and sectors throughout a product`s life cycle, this handbook and ready reference reveals the factors important to the development and manufacture of chemicals. The book focuses on the fundamental scientific understanding necessary. for a smoother technical transfer between the disciplines, leading to more effective and effi cient process development and manufacturing. A range of case studies are used to exemplify and illustrate the main issues raised.

As a result, readers will appreciate that process understanding can deliver a real competitive advantage within the pharmaceuticals and fine chemicals industry. This book serves as an aid to meeting the stringent regulations required by the relevant authorities through demonstrable understanding of the underlying science.

Leseprobe

Table of Contents

Related Titles

Title Page

Copyright

Preface

List of Contributors

Chapter 1: Quality by Design

1.1 History

1.2 Defining Product Design Requirements and Critical Quality Attributes

1.3 The Role of Quality Risk Management in QbD

1.4 Design Space and Control Strategy

1.5 Quality Systems

References

Chapter 2: Route and Process Selection

2.1 Introduction

2.2 Route Evaluation

2.3 Factors to Consider

2.4 Route Selection

2.5 Process Selection

2.6 Summary

References

Chapter 3: Critical Stages of Safety Assessment in Process Design and Scale-Up

3.1 Reaction Safety Concepts

3.2 Pre-Laboratory Safety Studies

3.3 The Synergies of Safety and Optimization—Together

3.4 Establishing a Reliable Basis of Safety for Scale-Up

3.5 Flammability Hazards

3.6 Summary

References

Chapter 4: Understanding the Reaction

4.1 Introduction

4.2 Process Complexity

4.3 Topics for Data Acquisition

4.4 Reaction Profiles

4.5 Reaction Pictures

4.6 Ionic Equilibria and Reaction Selectivity

4.7 Kinetics

4.8 Catalyzed Processes

4.9 The Rate-Determining Step

4.10 Mixing in Chemical Reactors

4.11 Mixing Theory

4.12 Multiphase Processes

4.13 Mass Transfer Theory

4.14 Mass Transfer and Mixing Requirements in Multiphase Systems

4.15 Concepts of Structure and Scale for Equipment Selection

4.16 Conclusion

References

Chapter 5: Use of Models to Enhance Process Understanding

5.1 Introduction

5.2 The Process Characterization Elements of a Chemical Reaction

5.3 The Impact of Modeling

5.4 Understanding the Chemistry

5.5 Physical Rates (the Elements of Mass Transfer)

5.6 Summary and Outlook

References

Chapter 6: Scale-Up of Chemical Reactions

6.1 Introduction

6.2 Case Study – Batch Hydrogenation

6.3 Scale-Up of Stirred Tank Reactors (STRs)

6.4 Stirred Tank Scale-Up

6.5 Chemistry Effects in Scale-Up

6.6 Achieving Process Understanding for Reactor Scale-Up

6.7 Reactor Selection

6.8 Exploiting Process Understanding in Scale-Up

6.9 Conclusions

References

Chapter 7: Process Understanding – Crystallization

7.1 Introduction

7.2 Crystallization Processes

7.3 Batch Crystallization Techniques

7.4 Process Control of Crystallization

7.5 Analytical Techniques for Product Characterization

7.6 Conclusions

Acknowledgments

References

Chapter 8: Key Technologies and Opportunities for Innovation at the Drug Substance–Drug Product Interface

8.1 Introduction

8.2 Opportunities for Innovation

8.3 Crystallization

8.4 Selected Manufacturing Technologies at the Drug Substance–Drug Product Interface

8.5 Analytical Techniques

8.6 Conclusions

Acknowledgments

References

Chapter 9: Process Understanding Requirements in Established Manufacture

9.1 Introduction

9.2 The Status Quo

9.3 Risk and Reward

9.4 Terms and Definitions

9.5 Process Understanding Requirements

9.6 Method Development and Installation

9.7 Statistical Process Control

9.8 Automation

9.9 Conclusion

References

Chapter 10: Plant Design

10.1 Introduction

10.2 Developing Process Concept to Plant Concept

10.3 Regulations

10.4 Infrastructure Design

10.5 Portfolio Analysis and Asset Planning

Chapter 11: Contract Manufacture

11.1 Introduction

11.2 Why Contract?

11.3 The Contractor

11.4 The Client

11.5 Technology Transfer

11.6 What Makes a Good Technical Package?

11.7 Client Process Understanding

11.8 Case Studies

11.9 Winning and Delivering the Project

11.10 Project Timing

11.11 Challenges of Multiproduct Plant Scheduling against an Uncertain Background

11.12 Conclusion

Chapter 12: Whole Process Design

12.1 Process Understanding for Whole Process Design

12.2 Process Outcomes

12.3 Organization of the Design Activity

12.4 Risk and Uncertainty in WPD

12.5 Whole Process Representations

12.6 Decision Making in WPD

12.7 Summary

References

Index

Related Titles

Helmus, F. P.

Process Plant Design

Project Management from Inquiry to Acceptance

2008

ISBN: 978-3-527-31313-6

Bröckel, U., Meier, W., Wagner, G. (eds.)

Product Design and Engineering

Best Practices

2007

ISBN: 978-3-527-31529-1

Rao, S.

The Chemistry of Process Development in Fine Chemical and Pharmaceutical Industry

2007

ISBN: 978-0-470-31995-6

Zlokarnik, M.

Scale-up in Chemical Engineering

2006

ISBN: 978-3-527-31421-8

Vogel, G. H.

Process Development

From the Initial Idea to the Chemical Production Plant

2005

ISBN: 978-3-527-31089-0

Wiley-VCH (ed.)

Ullmann's Processes and Process Engineering

2004

ISBN: 978-3-527-31096-8

Koolen, J. L. A.

Design of Simple and Robust Process Plants

2001

ISBN: 978-3-527-29784-9

The Editor

Dr. Ian Houson

Giltech Limited

12 North Harbour Estate

Ayr KA8 8BN

United Kingdom

Cover

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.

© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

ISBN: 978-3-527-32584-9

ePDF: 978-3-527-63716-4

ePub: 978-3-527-63715-7

mobi: 978-3-527-63717-1

Preface

When I was asked to be the editor for a book on Process Understanding, I was delighted as it provided me with an opportunity to cover something that I have found challenging throughout my career as an industrial process development chemist. During my doctoral studies, I had specialized in one discipline and was encouraged to work very much on my own. However, when I started working in industry, I was suddenly being asked to work with a whole range of people and disciplines, often with no detailed knowledge of what they did. Then, as I gained experience, I learned that the other disciplines with whom I worked often have information that can be really helpful to me in the work I did (occasionally, I even had useful information for them!).

Even after 15+ years of working in active ingredients development and manufacture, I am still learning about what is important to other disciplines and how aspects of their work can really help me in the work I do. This book is a continuation of that learning and is intended to be relevant to both people who start new and experienced process technologists.

This book is not designed to be a detailed technical treatise on each of the subject areas, but to provide a valuable introduction to a range of subject areas that are vital to the successful development and manufacture of active chemical ingredients. The reader will be introduced to the areas that must be understood throughout the active ingredients lifecycle right from the route selection through to established manufacture. This book should help the reader understand what is important to other/all disciplines involved in the lifecycle, leading to improved interdisciplinary working, smoother technical transfer between disciplines, and more efficient process development and manufacture.

Process understanding is the underpinning knowledge that allows the manufacture of chemical entities to be carried out economically, sustainably, robustly, and to the required quality. This area has risen in importance in the last few years, particularly, with the recent impetus from the “Quality by Design” initiative from the US Food and Drug Administration. This move to a more science- and risk-based approach is already well entrenched in a number of fine chemicals companies and it is heartening to see fundamental scientific understanding being placed back at the core of process development and manufacture.

Many process development/scale-up books focus on specific products and tell you the story of one chemical entity. There is relatively little written about the general principles and underlying philosophy of what information was required to underpin the decisions made. This book will seek to provide a broad view of what process understanding means to different disciplines and gives readers the opportunity to think about what is important to other people/disciplines and stages throughout the product life cycle. This book will seek to show how process understanding is, not only necessary, but can also deliver a real competitive advantage within the pharmaceuticals and fine chemicals industry.

Although the authors were chosen primarily for their technical expertise, they have also been selected to provide a balanced view owing to their geographical spread and with a mix of academic and industry, pharmaceuticals, and fine chemicals backgrounds. It is hoped that the reader will benefit from such a breadth of experience. I have tried to include both established areas for process development such as safety and scale-up of equipment as well as examining some of the more emerging topics such as Quality by Design, semi-quantitative modeling, and outsourcing (contract manufacture).

And finally, I leave with you this thought ………

We know there are known knowns; there are things we know we know. We also know there known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns—the ones we don't know we don't know ….

12 February, 2002

Donald Rumsfeld, The Pentagon

The latter are the ones we should worry about and are why I agreed to be the editor of this book!

Acknowledgments

I would like to thank both Elke Masse and Stefanie Völk from Wiley WCH for their invaluable project management and assistance throughout the book preparation process. It goes without saying that this book could not have been written without the chapter authors and I am indebted to them for their enthusiasm, commitment and, ultimately, for the excellence of the chapters they have written. I would also like to thank the Britest staff and members for their valuable time and discussions, and for making it such a varied and interesting place to work in. And finally, I would like to thank my family for all their support and unstinting encouragement; especially my wife who, in the words of Alanis Morisette, is “My best friend with benefits.”

I hope that you enjoy reading this book as much as I have enjoyed putting it together!

October 2010

Ian Houson

List of Contributors

David J. Ager

DSM Pharmaceutical Chemicals

PMB 150 9650 Strickland Road Suite 103

Raleigh, NC 27615

USA

John Atherton

University of Huddersfield

Department of Applied Sciences

Queensgate

Huddersfield HDI 3DH

UK

Colm Campbell

BioMarin Europe Ltd.

29–31 Earlscourt Terrace

Dublin 2

Ireland

Leroy Cronin

University of Glasgow

School of Chemistry

Joseph Black Building

University Avenue

Glasgow G12 8QQ

UK

Mark J. Dickson

Morgan Sindall

Professional Services Ltd.

20 Timothys Bridge Road

Stratford Enterprise Park

Stratford-Upon-Avon

Warwickshire CV37 9NJ

UK

Wilfried Hoffmann

Pfizer Global Research & Development

Sandwich Laboratories

B530, IPC 533

Ramsgate Road

Sandwich CT13 9NJ

UK

Ian Houson

Giltech Limited

12 North Harbour Estate

Ayr KA8 8BN

UK

Dylan Jones

Genzyme Haverhill Operations

Technical Department

12 Rookwood Way

Haverhill

Suffolk CB9 8PB

UK

Brian Keaveny

Plant Director

Clarochem Ireland Limited

Damastown

Mulhuddart

Dublin 15

Ireland

Philip J. Kitson

University of Glasgow

School of Chemistry

Joseph Black Building

University Avenue

Glasgow G12 8QQ

UK

Vince McCurdy

Pfizer Inc.

558 Eastern Point Rd

Groton, CT 06340-5196

USA

Stephen Rowe

Chilworth Technology Ltd.

Beta House

Southampton Science Park

Southampton

Hampshire SO16 7NS

UK

Paul Sharratt

Institute of Chemical and Engineering Sciences (ICES)

1 Pesek Road

Singapore, 627833

Singapore

Mark J. H. Simmons

University of Birmingham

School of Chemical Engineering

Edgbaston

Birmingham B15 2TT

UK

E. Hugh Stitt

Johnson Matthey

Technology Centre

PO Box 1

Billingham TS23 1LB

UK

Mark Talford

10 Fern Grove

Whitehaven

Cumbria CA28 6RB

UK

Chick C. Wilson

University of Glasgow

School of Chemistry

Joseph Black Building

University Avenue

Glasgow G12 8QQ

UK

Steve Woolley

Shasun Pharma

Solutions Limited

Dudley Lane

Dudley

Cramlington

Northumberland NE23 7QG

UK

1

Quality by Design

Vince McCurdy

1.1 History

The pharmaceutical industry has been a highly regulated industry in the past for many good reasons [1]. While pharmaceuticals have greatly improved the mortality and morbidity rates, there is still some element of risk to the patients. These risks are greatly mitigated with the delivery of medicine at the appropriate purity, potency, delivery rate, and so on. While pharmaceutical regulations have clearly protected the population from much of the needless harm such as that incurred early in the twentieth century, there has been a concern more recently that overregulation may be associated with stifling innovation that can improve pharmaceutical quality even further [2] – innovation that has the potential to greatly improve the quality, cost, and time to market new and improved medicines. The twenty-first century began with the pharmaceutical industry using manufacturing technologies that have been employed since the 1940s and did not make significant changes in manufacturing process unless significant compliance or costs saving advantages could justify the high costs and long cycle time needed to gain approval. This often resulted in inefficient, overly expensive processes that were ultimately not in the best long-term interests of patients. As a result, the FDA (Food and Drug Administration) and other agencies around the world have embraced a new paradigm for regulation [3]. The “desired state” was to shift manufacturing from being empirical to being more science, engineering, and risk based. Another regulatory guidance that had major impact was the Process Analytical Technology (PAT) Guidance [9]. The continuous, real-time monitoring of manufacturing processes is a key enabler to achieve greater process control. Finally, the current Good Manufacturing Practices (cGMPs) for the Twenty-First Century Guidance acknowledged the undesired impact of good manufacturing practices (GMPs) on understanding manufacturing science and sought to set the framework for additional guidances that encouraged risk- and science-based understanding in exchange for more freedom to introduce innovations and improvements that will result in enhanced quality, cost, or timing.

Juran is often credited with introducing the concepts behind Quality by Design (QbD) [4]. Pharmaceutical QbD is a systematic approach to development that begins with pre-defined objectives and emphasizes product and process understanding based on sound science and quality risk management (ICH Q8R2). The holistic and systematic approach of QbD was relatively new to the pharmaceutical industry at the beginning of the twenty-first century. However, elements of QbD were certainly being applied across the industry long before then. QbD was put into practice in a big way with the advent of the FDA CMC pilot program in 2005. Nine companies participated in the program and eventually submitted regulatory filings based on a QbD framework [1, 2, 5, 6, 7]. Much was learned from these initial filings that help steer the industry and regulators toward a common vision for QbD. A comparison of the “current state” to the future “desired state” was succinctly summarized by Nasr in Table 1.1 [8].

Table 1.1 Comparison of the Current State to the Future Desired QbD State

AspectCurrent stateDesired QbD statePharmaceutical developmentEmpirical; typically univariate experimentsSystematic; multivariate experimentsManufacturing processLocked down; validation on three batches; focus on reproducibilityAdjustable within design space; continuous verification within design space; focus on control strategyProcess controlIn-process testing for go/no-go; offline analysisPAT utilized for feedback and feed forward in real timeProduct specificationPrimary means of quality control; based on batch dataPart of overall quality control strategy; based on product performanceControl strategyMainly by intermediate and end product testingRisk-based; controls shifted upstream; real-time releaseLifecycle managementReactive to problems and OOS; postapproval changes neededContinual improvement enabled within design space