Modern Pharmaceutical Industry: A Primer

345 Pages·2009·3.325 MB·English

by  Thomas M. Jacobsen, Albert I. Wertheimer

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MODERN
PHARMACEUTICAL
INDUSTRY
A PRIMER
EDITED BY
THOMAS M. JACOBSEN, PharmD, MS, RPh
Associate Director, Medical Affairs
ViroPharma Incorporated
ALBERT I. WERTHEIMER, PhD, MBA
Director, Center for Pharmaceutical Health Services Research
School of Pharmacy at Temple University
http://avaxho.me/blogs/ChrisRedfield
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especially important in the case of drugs that are new or seldom used.
Production Credits
Publisher: David Cella Composition: Achorn International
Associate Editor: Maro Gartside Cover Design: Kristin E. Parker
Production Manager: Julie Champagne Bolduc Cover Image: ©†Kamil Fazrin Rauf/ShutterStock, Inc.
Production Assistant: Jessica Steele Newfell Printing and Binding: Malloy, Inc.
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Library of Congress Cataloging-in-Publication Data
Modern pharmaceutical industry : a primer / [edited by] Thomas M.
Jacobsen, Albert I. Wertheimer.
p. cm.
Includes bibliographical references and index.
ISBN-13: 978-0-7637-6636-8 (casebound)
ISBN-10: 0-7637-6636-4 (casebound)
1. Drug development. 2. Pharmaceutical industry. I. Jacobsen, Thomas M. II. Wertheimer, Albert I.
[DNLM: 1. Drug Industry. 2. Drug Discovery. 3. Technology, Pharmaceutical. QV 736 M6896 2010]
RM301.25.M635 2010
615'.19—dc22
2009012593
6048
Printed in the United States of America
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This book is dedicated to my wife, Rebecca, and my children, Ryan, Matthew, and
Lauren, for it is their love and support that brings a project like this to fruition.
Also, for Mom and Dad—I wish you could have seen what I’ve accomplished.
––T. M. J.
To Joaquima and Lia, who permitted this endeavor at the expense of some family
activities, and to Bill Helfand who introduced me to the pharmaceutical industry.
––A. I. W.
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Brief Contents
CHAPTER1 ■ Drug Discovery: New Compounds 1
CHAPTER2 ■ Pharmaceutical Formulation 35
CHAPTER3 ■ Analytical Testing and Development 57
CHAPTER4 ■ Manufacturing and Production 75
CHAPTER5 ■ Ethics in Clinical Research 101
CHAPTER6 ■ Clinical Research 119
CHAPTER7 ■ Regulatory Affairs 131
CHAPTER8 ■ Medical Information 155
CHAPTER9 ■ Drug Safety and Pharmacovigilance 189
CHAPTER10 ■ Legal and Intellectual Property 203
CHAPTER11 ■ Sales and Marketing 215
CHAPTER 12 ■ Finance 231
v
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CHAPTER13 ■ Pharmacoeconomics and Outcomes Research 247
CHAPTER14 ■ Public Affairs 259
CHAPTER15 ■ Generic Drugs 269
CHAPTER16 ■ Over-the-Counter Drugs 281
CHAPTER17 ■ Future Industry Trends 295
vi Brief Contents
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Contents
Foreword xvii
Preface xix
About the Editors xxi
Contributors xxiii
CHAPTER 1 ■ Drug Discovery: New Compounds 1
Then and Now 1
Drug and Receptor 2
Modeling Molecules 2
Picturing Molecules 3
Picturing Interacting Molecules 4
Selection of Preferred Models 5
The Need for Crystals 6
The Double Helix and All That 6
Determining Nucleotide Sequences 7
From DNA to Protein 8
Converting DNA Sequences to Genomes 9
Structural Genomics 9
Genomes to Proteomes 11
Purifying Proteins and Growing Crystals 11
High-Throughput Systems for Growing Crystals 12
New and Novel Proteins 13
vii
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Fitting Drug to Receptor in Silico and Culling Misfits 14
High-Throughput Chemistry: Combinatorial Synthesis 16
■ A Combinatorial Example 17
High-Throughput Chemistry: Parallel Synthesis 18
Automated Cleanup 20
Product Characterization 20
Structural Genomics Leads to Structural Proteomics 21
Target Selection Through Structural Proteomics 21
High-Throughput Binding Studies 22
Assemble a Mouse 24
High-Throughput Screening: G-Protein-Coupled Receptors 25
■ Structure of G-Protein-Coupled Receptors 25 ■ Monitoring Transfection 27
Validating Target Receptors 28
References 30
CHAPTER 2 ■ Pharmaceutical Formulation 35
Preclinical/Preformulation Testing 35
Dosage Form Design: Choosing a Dosage Form 37
■ Formulation Basics 38 ■ Problem Formulations 40 ■ Degradation Issues 40
Stability Testing 41
■ Pilot Batches 42
Granulation 45
■ Drying 46 ■ Milling 47 ■ Blending 47 ■ Scale-Up 47 ■ Process
Validation 49 ■ General Concepts 50 ■ CGMP Regulations for Finished
Pharmaceuticals (The Current Codified CGMP Regulations, CFR Parts 210 and
211) 51 ■ Preliminary Considerations 52 ■ Elements of Process Validation 52
■ Documentation 54
Suggested Reading 55
CHAPTER 3 ■ Analytical Testing and Development 57
Method Development 57
Column Selection 58
Mode of Detection 58
Mobile Phase Selection 58
viii Contents
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Method Optimization 59
Effect of Buffer 59
Column-to-Column Equivalency 61
Effect of Temperature 61
Effect of Ion Pair Reagent 61
Definitions 67
Stability Testing 67
■ Drug Substance 67 ■ Drug Product 68 ■ Glossary of Terms for Analytical
and Method Development 69
Dissolution Test for Solid Dosage Forms 72
References 74
CHAPTER 4 ■ Manufacturing and Production 75
Active Pharmaceutical Ingredient (Drug Substance) 75
Manufacturing Equipment 76
Storage and Distribution 76
General Controls 77
Validation 78
Master Production Instructions 80
Batch Production Records 80
Finished Dosage Forms (Drug Product) 81
Description of the Manufacturing Process and Process Controls 82
Control of Excipients 83
Control of Drug Product 86
Container Closure Systems 88
Stability 90
Individual Dosage Forms 91
■ Solid Oral Dosage Forms 91
Parenterals 92
Ophthalmic Drug Products 95
Metered Dose and Dry Powder Drug Products 96
Topical Drug Products 97
Suggested Reading 98
Contents ix