Drugs-From Discovery to Approval

362 Pages·2004·16.8 MB·English

by  Rick Ng

DRUGS
FROM DISCOVERY TO APPROVAL
DRUGS
FROM DISCOVERY TO APPROVAL
Rick Ng, Ph.D.
Biopharmaceutical Manufacturing Technology Centre
Singapore
@W IL EY-LISS
A JOHN WILEY &SONS, INC., PUBLICATION
Copyright 0 2004 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
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Library of Congress Cataloging-in-Publication Data:
Ng, Rick.
Drugs-from discovery to approval i Rick Ng
p. ; cm
Includes bibliographical references and index.
ISBN 0-471-60150-0 (alk. paper : cloth)
1. Drug development.
[DNLM: 1. Technology, Pharmaceutical. 2. Chemistry, Pharmaceutical.
3. Clinical Trials-methods. 4. Drug Approval-legislation &
jurisprudence. 5. Drug Approval-methods. 6. Drug Design. 7. Drug
Industry-methods. QV 778 N576d 20041 I. Title.
RM301.25 .NS 2004
6 IS'. 19-dc22
2003020804
Printed in the United States of America.
10 9 8 7 6 5 4 3
To
Cherry, Shaun and Ashleigh
CONTENTS
PREFACE xi
CHAPTER 1 Introduction 1
1.1 Aim of this Book 1
1.2 An Overview of the Drug Discovery and Development 2
Process
1.3 The Pharmaceutical Industry 5
1.4 Economics of Drug Discovery and Development 10
1.5 Trends in Drug Discovery and Development 11
1.6 Further Reading 13
CHAPTER 2 Drug Discovery: Targets and Receptors 15
2.1 Drug Discovery Processes 16
2.2 Medical Needs 16
2.3 Target Identification 18
2.4 Target Validation 25
2.5 Drug Interactions with Targets or Receptors 26
2.6 Enzymes 30
2.7 Receptors and Signal Transduction 32
2.8 Assay Development 39
2.9 Further Reading 40
CHAPTER 3 Drug Discovery: Small Molecule Drugs 43
3.1 Introduction 44
3.2 Irrational Approach 44
3.3 Rational Approach 50
3.4 Antisense Approach 67
3.5 Chiral Drugs 68
3.6 Closing Remarks 70
3.7 Further Reading 73
CHAPTER 4 Discovery: Large Molecule Drugs 75
Drug
4.1 Introduction 76
4.2 Vaccines 77
4.3 Antibodies 85
vii
Viii Contents
4.4 Cytokines 92
4.5 Hormones 97
4.6 Gene Therapy 99
4.7 Stem Cells 102
4.8 Further Reading 105
CHAPTER 5 Drug Development and Preclinical Studies 107
5.1 Introduction 108
5.2 Pharmacod ynamics 110
5.3 Pharmacokinetics 115
5.4 Toxicology 127
5.5 Animal Tests, In Vitro Assays and In Silico Methods 130
5.6 Formulations and Delivery Systems 132
5.7 Further Reading 138
CHAPTER 6 Clinical Trial 139
6.1 Definition of Clinical Trial 140
6.2 Ethical Considerations 140
6.3 Clinical Trials 144
6.4 Regulatory Requirements for Clinical Trials 147
6.5 Role of Regulatory Authorities 155
6.6 Gene Therapy Clinical Trial 156
6.7 Further Reading 156
CHAPTER Regulatory Authorities 159
7
7.1 Role of Regulatory Authorities 160
7.2 US Food and Drug Administration 161
7.3 European Agency for the Evaluation of Medicinal 166
Products
7.4 Japan’s Ministry of Health, Labour and Welfare 167
7.5 China’s State Drug Administration 168
7.6 Other Regulatory Authorities 169
7.7 Authorities other than Drug Regulatory Agencies 170
7.8 International Conference on Harmonization 171
7.9 World Health Organization 171
7.10 Pharmaceutical Inspection Cooperation Scheme 17 2
7.11 Further Reading 173
Contents
iX
CHAPTER 8 Regulatory Applications 175
8.1 Introduction 176
8.2 Food and Drug Administration 176
8.3 European Union 193
8.4 Japan 206
8.5 China 207
8.6 Further Reading 208
CHAPTER 9 Good Manufacturing Practice: Regulatory 211
Requirements
9.1 Introduction 212
9.2 United States 212
9.3 Europe 218
9.4 International Conference on Harmonization 218
9.5 Core Elements of GMP 222
9.6 Selected GMP Systems 232
9.7 The FDA's New cGMP Initiative 243
9.8 Further Reading 245
CHAPTER 10 Good Manufacturing Practice: Drug 247
Manufacturing
10.1 Introduction 248
10.2 GMP Manufacturing 250
10.3 GMP Inspection 252
10.4 Manufacture of Small Molecule APIs 259
10.5 Manufacture of Large Molecule APIs 267
10.6 Finished Dosage Forms 274
10.7 Further Reading 279
CHAPTER 11 Future Perspectives 281
11.1 Past Advances and Future Challenges 281
11.2 Small Molecule Pharmaceutical Drugs 282
11.3 Large Molecule Biopharmaceutical Drugs 285
11.4 Traditional Medicine 285
11.5 Individualized Medicine 287
11.6 Gene Therapy 288
11.7 Cloning and Stem Cells 289
11.8 Old Age Diseases and Aging 291
X Confenfs
11.9 Lifestyle Drugs 293
11.10 Performance-Enhancing Drugs 294
11.11 Chemical and Biological Terrorism 295
11.12 Transgenic Animal and Plants 297
11.13 Regulatory Issues 298
11.14 Intellectual Property Rights 299
11.15 Concluding Remarks 301
11.16 Further Reading 302
APPENDIX 1 History of Drug Discovery and Development 305
Al.l Early History of Medicine 305
A1.2 Drug Discovery and Development in the Middle Ages 308
A1.3 Foundation of Current Drug Discovery and 308
Development
A1.4 Beginnings of Modern Pharmaceutical Industry 309
A1.5 Evolution of Drug Products 310
A1.6 Further Reading 311
APPENDIX 2 Cells, Nucleic Acids, Genes and Proteins 313
A2.1 Cells 313
A2.2 Nucleic Acids 315
A2.3 Genes and Proteins 321
A2.4 Further Reading 326
APPENDIX 3 Selected Drugs and Their Mechanisms of Action 327
APPENDIX 4 Pharmacology/Toxicology Review Format 329
ACRONYMS 335
GLOSSARY 339
INDEX 347
PREFACE
This book is written as a basic framework to introduce the concepts and
processes from drug discovery to marketing approval by regulatory
authorities. It is particularly suitable for undergraduates pursuing courses in
medicine, pharmacy, science and life sciences. Professionals in the
pharmaceutical industry will find this book useful as a quick reference
guide.
There are eleven chapters:
Chapter 1 provides a snapshot about the drug discovery and
development processes, as well as the current status in the
pharmaceutical industry.
Chapter 2 describes the all-important steps in identifying disease
targets and receptors for drug interaction and intervention.
Chapter 3 explains the current technologies and methodologies for
discovering new small molecule drugs.
Chapter introduces the various large molecule drugs and the
4
methods for discovering and developing them.
Chapter 5 summarizes the steps for drug development and
preclinical tests.
Chapter 6 details the processes and conduct of clinical trials with
due respect for safety, risks and benefits.
Chapter 7 describes the major drug regulatory authorities in selected
countries such as the United States, European Union, Japan, China
and some international organizations.
Chapter 8 shows the basic procedures for applications to regulatory
authorities for clinical trials and drug marketing approvals.
Chapter 9 discusses the regulatory requirements for drug
manufacture, with selected examples.
Chapter 10 demonstrates the controls required to manufacture drugs
that meet the regulatory requirements.
Chapter 11 gives perspectives about the future events for drug
discovery and development.
Some background concepts are introduced in four appendices together
with acronyms and glossary.
xi