The Textbook of
`Pharmaceutical Medicine,
`Fourth Edition
`
`John P. Griffin
`John O' Grady,
`editors
`
`BMJ Books
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`The Textbook of
`Pharmaceutical
`Medicine
`Fourth edition
`
`Edited by
`
`John P Griffin BSc, PhD, MBBS, FRCP, FRCPath,
`FFPM
`Chairman, John Griffin Associates Ltd.
`Director, Pharmadiligence Ltd.
`Visiting Professor, University of Surrey Postgraduate Medical School
`Former Director, Association of the British Pharmaceutical Industry,
`London
`Formerly Professional Head of the Medicines Division, DHSS, London
`
`and
`
`John O’Grady MD, FRCP, FFPM, FBIRA, MRCPath
`Medical Director for Europe, Daiichi Pharmaceutical Co. Ltd., London
`Visiting Professor of Clinical Pharmacology, University of London
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`

`© BMJ Books 2002
`BMJ Books is an imprint of the BMJ Publishing Group
`
`All rights reserved. No part of this publication may be reproduced,
`stored in a retrieval system, or transmitted, in any form or by any
`means, electronic, mechanical, photocopying, recording and/or
`otherwise, without the prior written permission of the publishers.
`
`First published by BMJ Books in 2002
`BMA House, Tavistock Square,
`London WC1H 9JR
`
`All previous three editions were published by
`The Queen’s University of Belfast
`First edition published in 1993
`Second edition published in 1994
`Third edition published in 1998
`
`www.bmjbooks.com
`
`British Library Cataloguing in Publication Data
`A catalogue record for this book is available from the British Library
`
`ISBN 0 7279 1523 1
`
`Typeset by SIVA Math Setters, Chennai, India
`Printed and bound by MPG Books, Bodmin, Cornwall
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`

`Contents
`
`Contributors
`
`Preface
`
`Acknowledgements
`
`The editors
`
`Part I: Research and development
`
`1 Discovery of new medicines
`Anand S Dutta
`
`2 Pharmaceutical development
`Gavin Halbert
`
`3 Toxicity testing
`David J Tweats, M David C Scales
`
`4 Exploratory development
`John Posner
`
`5 Clinical pharmacokinetics
`Paul Rolan
`
`6 Clinical trials and good clinical practice
`Nigel Baber, John Sweatman
`
`7 Medical statistics
`Kenneth D MacRae
`
`8 Development of medicines: full development
`Alan G Davies, Peter D Stonier
`
`Part II: Medical department issues
`
`9 The medical department
`Darrall L Higson
`
`10 Medical marketing
`John H Young
`
`v
`
`viii
`
`ix
`
`x
`
`1
`
`3
`
`96
`
`128
`
`170
`
`214
`
`247
`
`358
`
`395
`
`421
`
`423
`
`436
`
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`CONTENTS
`
`11 Information and promotion
`D Michael Humphreys
`
`12 The supply of unlicensed medicines for particular patient use
`John O’Grady, Amanda Wearing
`
`13 Legal and ethical issues relating to medicinal products
`Christine H Bendall, Christopher JS Hodges
`
`14 The safety of medicines
`A Peter Fletcher, Susan Shaw
`
`Part III: Regulatory aspects
`
`15 The development of the control of human medicines in
`Europe from classical times to the year 2000
`John P Griffin, Rashmi R Shah
`
`16 Technical requirements for registration of pharmaceuticals
`for human use: the ICH process and the common
`technical document
`Patrick F D’Arcy, Dean WG Harron
`
`17 The regulation of drug products by the United States
`Food and Drug Administration
`Peter Barton Hutt
`
`18 The US FDA in the drug development, evaluation
`and approval process
`Richard N Spivey, Louis Lasagna, Judith K Jones,
`William Wardell
`
`19 Regulatory and clinical trial systems in Japan
`Yuichi Kubo, John O’Grady
`
`Part IV: Pharmacoeconomic and other issues
`
`20 Economics of healthcare
`Carole Bradley, Jane R Griffin
`
`21 Controls on NHS medicines prescribing and
`expenditure in the UK (a historical perspective)
`John P Griffin, Jane R Griffin
`
`Appendix 1: Declaration of Helsinki
`
`Appendix 2: Code of Practice for the Pharmaceutical Industry
`
`Index
`
`iv
`
`456
`
`491
`
`503
`
`532
`
`579
`
`581
`
`637
`
`653
`
`702
`
`719
`
`743
`
`745
`
`765
`
`787
`
`793
`
`859
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`Contributors
`
`Nigel Baber BSc MB FRCP FRCP(Ed) FFPM Dip Clin Pharmacol,
`Head Patient Safety Reclassification & Renewals, Medicines Control
`Agency, London UK
`
`Christine H Bendall, Arnold & Porter, London, UK
`
`Carole Bradley BSc(Hons) MSc, Manager, Health Economics and
`Reimbursement, Boehringer Ingelheim (Canada) Ltd, Burlington,
`Ontario, Canada
`
`Patrick F D’Arcy OBE BPharm PhD DSc FRPharmS CChem
`FRCS FPSNI, Formerly Emeritus Professor of Pharmacy, Queen’s
`University of Belfast, Northern Ireland
`
`Alan G Davies MBBS MRCP(UK) MD(Lond), Therapeutic Director,
`Kendle International Inc, Crowthorne, Berkshire UK
`
`Anand S Dutta PhD, Company Research Associate (retired), AstraZeneca,
`Macclesfield UK
`
`A Peter Fletcher MBBS PhD MFPM
`
`Jane R Griffin BA(Hons) MSc, Head, Health Economics and Outcomes
`Research, Boehringer Ingelheim UK Ltd, Bracknell, Berkshire UK
`
`John P Griffin BSc PhD MBBS FRCP FRCPath FFPM, John Griffin
`Associates Ltd, Welwyn, Hertfordshire UK
`
`Gavin Halbert BSc PhD CChem MRSC MRPharmS, Director, Cancer
`Research UK Formulation Unit, Department of Pharmaceutical Sciences,
`University of Strathclyde, Glasgow UK
`
`Dean WG Harron BSc PhD FRPharmS MPSNI, Professor, School of
`Pharmacy, The Queen’s University of Belfast, Northern Ireland
`
`Darrall L Higson MB ChB FFPM, Medical Director, Global Switch &
`Innovations, GlaxoSmithKline Consumer Healthcare, Uxbridge, Middlesex
`UK
`
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`CONTRIBUTORS
`
`Christopher JS Hodges MA (Oxon), CMS Cameron McKenna,
`London UK; Honorary Research Associate, New College, Oxford
`
`D Michael Humphreys MB ChB FFPM, Corporate Medical Advisor,
`Boehringer Ingelheim UK Ltd, Bracknell UK
`
`Peter Barton Hutt, Partner in law firm of Covington and Burling,
`Washington DC USA; Lecturer in Food and Drug Law, Harvard Law
`School; Former Chief Counsel to the US FDA
`
`Judith K Jones MD PhD, President, The Degge Group; President, The
`Pharmaceutical Education and Research Institute; Adjunct Professor of
`Pharmacology, Georgetown University, Washington DC USA
`
`Yuichi Kubo, Daiichi Pharmaceutical Co Ltd, Tokyo, Japan
`
`Louis Lasagna MD, Dean, Sackler School of Graduate Biomedical
`Sciences, Tufts University School of Medicine, Boston MA USA
`
`Kenneth D MacRae MA PhD MRCR(Hon) FIS, Formerly Professor of
`Medical Statistics, University of Surrey, Guildford UK
`
`John O’Grady MD FRCP FFPM FBIRA MRCPath, Medical Director
`for Europe, Daiichi Pharmaceutical Ltd, London UK
`
`John Posner BSc PhD MBBS FRCP FFPM, Independent Consultant
`in Pharmaceutical Medicine, John Posner Consulting, Beckenham, Kent
`UK
`
`Paul Rolan MBBS MD FRACP FFPM DCPSA, Medical Director,
`Medeval Ltd, Manchester UK
`
`M David C Scales LLM PhD FBiol FRCPath, Chief Scientific Officer,
`Strakan Pharmaceuticals, Galashiels, Scotland
`
`Rashmi R Shah BSc MB MD FRCP FFPM, Senior Medical Officer,
`Medicines Control Agency, London UK
`
`Susan Shaw BSc MBBS MRCPsych, Consultant Psychiatrist,
`Twickenham
`
`Richard N Spivey Pharm D PhD, Senior Vice President, Corporate
`Technology Policy, Pharmacia, Peapack, New Jersey USA
`
`Peter D Stonier BSc PhD MB ChB FRCP FRCPE FFPM, Medical
`Director, HPRU Medical Research Centre, University of Surrey, Guildford
`UK
`
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`CONTRIBUTORS
`
`John Sweatman BSc MPhil MIBiol FRQA, Consultant in Clinical
`Quality Assurance, Lightwater, Surrey UK
`
`David J Tweats BSc PhD FRCPath FIBiol, Vice President, Safety
`Assessment UK, Glaxo Smith Kline, Ware, Hertfordshire UK
`
`William Wardell MD PhD, President, Wardell Associates International,
`Princeton, New Jersey USA
`
`Amanda Wearing MA(Oxon), Solicitor, Arnold and Porter, London UK
`
`John H Young MBBS FRCP FRCPath FFPM, Medical Director,
`Merck Sharp Dohme Ltd, Hoddesdon, Hertfordshire UK
`
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`Preface
`
`The first edition of this book appeared in 1993 and was sold out in six
`months; the second edition was published in 1994 and the third edition in
`1998 and this edition has now also sold out. The fact that there has been such
`an enthusiastic uptake of this book is a tribute to the Faculty of
`Pharmaceutical Medicine of the Royal College of Physicians of the United
`Kingdom who have done so much to sponsor the discipline and give it a
`favourable and high profile and achieve specialist recognition. However, we
`are aware that the book has had a much wider audience than that for which
`it was initially written, namely those studying for the Diploma in
`Pharmaceutical Medicine of the Faculty. It is now the standard text used
`by courses in Pharmaceutical Medicine in Europe and the USA.
`This is the fourth edition of this textbook that it has been our pleasure to
`edit, and our task has been made easier by the dedication and enthusiasm
`of our contributors, by the fact that the book has been so well received by
`its intended readership and indeed by the wider audience it has attracted,
`and also by the feedback that they have provided. We hope that this edition
`will be as useful to its readers as the earlier editions and that the changes
`and revisions will have improved it.
`The success of the textbook has been in no small part due to our
`co-editor in the third edition Professor PF D’Arcy. Pat D’Arcy had decided
`on health grounds that he was unable to assist in the editing of this edition,
`but that he would like to revise the chapter he had contributed to the
`previous editions in collaboration with Dean Harron, with whom he had
`edited the proceedings of the first four ICH Conferences. Pat D’Arcy sadly
`died in September 2001 and he will be greatly missed by us, but we were
`pleased to have received his contribution to this book before he was so
`suddenly taken from us. We would therefore like to pay tribute to Pat for
`his past and present contribution to this textbook.
`In mid-April 2002, we were shocked to learn of the sudden death of
`Professor Ken MacRae who has written the statistical chapter for this book
`since its first edition; his expertise will be greatly missed. We would wish to
`extend our sympathies to the families of both Professor D’Arcy and
`Professor MacRae.
`
`John P Griffin
`John O’Grady
`
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`Acknowledgements
`
`We would like to thank all those who have contributed in any way to the
`production of this book, whether to the current fourth edition or previous
`editions. Especial thanks are extended to the authors, whether they have
`updated previous chapters or totally rewritten chapters. We would like to
`thank them for the quality and promptness of their contributions.
`We must also extend our thanks to our secretaries, Hazel Gunn and
`Judith Playford, whose help has been invaluable.
`Our appreciation to all the staff at BMJ Books who have guided this book
`from manuscript to final form must be recorded. In particular, we would
`like to thank Mary Banks and Christina Karaviotis for their help at all
`stages.
`Finally, we would like to thank the World Medical Association and the
`Association of the British Pharmaceutical Industry (ABPI) for permission
`to reproduce Appendices I and II respectively. We also wish to thank all
`those who have allowed material to be used and acknowledgement for all
`such help is recorded in the appropriate place in the text.
`
`John P Griffin
`John O’Grady
`
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`The editors
`
`Professor John P Griffin BSc PhD MB BS FRCP MRCS FRCPath
`FFPM qualified in medicine at the Royal London Hospital, where he
`was also in clinical practice. He was a lecturer in Physiology at King’s
`College, London and held the post of Head of Clinical Research at Riker
`Laboratories from 1967 to 1971. Professor Griffin joined the then
`Medicines Division of the Department of Health, now Medicines Control
`Agency (MCA) London, as a Senior Medical Officer, in 1971, and was
`subsequently appointed Medical Assessor to the Committee on Safety of
`Medicines. From 1977 to 1984, Professor Griffin was Senior Principal
`Medical Officer and Professional Head of Medicines Division as well as
`being Medical Assessor to the Medicines Commission. As Professional
`Head of Medicines Division he also attended the Scientific Sub-Committee
`of the Veterinary Products Committee of the Ministry of Agriculture, Food
`and Fisheries. During this time he was a member of the EC committee on
`Proprietary Medicinal Products and Chairman of the CPMP’s Working
`Party on Safety Requirements.
`From 1976 to 1984 John Griffin served on the Joint Formulary
`Committee of the British National Formulary, during which period the first
`eight issues of the current format were produced.
`John Griffin was the Director of the Association of the British
`Pharmaceutial Industry from 1984 to 1994. During this time he was a
`member of the Executive Board of the European Federation of
`Pharmaceutical Industries’ Associations and a council member of the
`International Federation of Pharmaceutical Industry Associations IFPMA.
`John Griffin chaired the ICH Safety Expert Working Group from 1988
`to 1994 and presented papers at ICH1 and ICH2 in the plenary sessions.
`Since June 1994 John Griffin has run his own independent consultancy
`company, which has provided independent and impartial advice to
`governments on the development of a pharmaceutical policy, to national
`trade associations and individual companies. John Griffin is Visiting
`Professor in Pharmaceutical Medicine at the University of Surrey, and is
`also Honorary Consultant Clinical Pharmacologist at the Lister Hospital in
`Hertfordshire, UK.
`Professor Griffin is on the Board of the Faculty of Pharmaceutical
`Medicine and Chairman of the Board of Examiners of the Faculty of
`Pharmaceutical Medicine of the Royal College of Physicians, and serves on
`the Task Force on Specialist Medical Training in Pharmaceutical
`
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`THE EDITORS
`
`Medicine. He served on a number of Royal College of Physicians
`London Working Parties including that on the “Development of Clinical
`Pharmacology and Therapeutics in a Changing World”.
`Professor Griffin is the author and co-author of over 250 publications on
`adverse drug reactions and iatrogenic disease, aspects of neurophysiology
`and clinical pharmacology and toxicology and drug regulation. Among his
`publications are the four following standard texts:
`Iatrogenic Diseases Oxford University Press, 1st ed. 1972, 3rd ed. 1986;
`jointly with Prof PF D’Arcy
`A Manual of Adverse Drug Interactions John Wright Bristol, 1st ed. 1975;
`Elsevier Press Amsterdam, 5th ed. 1997; jointly with Prof PF D’Arcy
`The Textbook of Pharmaceutical Medicine The Queen’s University of
`Belfast Press, 1st ed. 1993, 2nd ed. 1994
`Medicines, Research, Regulation and Risk The Queen’s University of
`Belfast Press, 1st ed. 1989, 2nd ed. 1992.
`Since 1991 he has been Editor in Chief of Adverse Drug Reactions and
`Toxicological Reviews, a peer-reviewed journal produced quarterly by
`Oxford University Press, which publishes in-depth assessments relating to
`drug and chemical safety issues.
`
`John O’Grady MD FRCP FFPM FBIRA MRCPath, after
`graduating in medicine, trained in general medicine and also in clinical
`pharmacology and therapeutics to achieve specialist registrations. He held
`medical appointments at the Radcliffe Infirmary in Oxford, Royal
`Postgraduate Medical School, Hammersmith Hospital, Hospital for
`Nervous Diseases Queen’s Square, London and St Bartholomew’s
`Hospital, London.
`Formerly Head of Clinical Pharmacology at Wellcome Reserch
`Laboratories, he was then made Medical Director at Rhone-Poulenc and
`Visiting Professor at the University of Cape Town, South Africa.
`Currently, he is a Medical Director for Europe, Daiichi Pharmaceuticals
`UK Ltd, a director of Imperial Cancer Research Technology Ltd, Visiting
`Professor of Clinical Pharmacology and Therapeutics at the University of
`Vienna, Austria, and Visiting Professor of Clinical Pharmacology,
`University of London.
`Professor O’Grady is Examiner to the Royal College of Physicians,
`Faculty of Pharmaceutical Medicine. He is a Fellow of the Royal Statistical
`Society and a member of the British Pharmacopoeia Commission.
`He has published widely in the field of medicine, in clinical
`pharmacology and therapeutics and in pharmaceutical medicine. He is
`editor of several books dealing with drug effects in man and with medicines
`and the law.
`
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`2: Pharmaceutical
`development
`
`GAVIN HALBERT
`
`2.1 Introduction
`The current vogue in drug discovery is the identification and validation of
`a pharmacological target, followed by high-throughput screening to
`identify suitable chemical motifs or lead molecules that interact with
`the target. These molecules may be further refined by combinatorial
`or traditional medicinal chemistry approaches linked with computer
`modelling of the target site. This will provide a compound or series of
`compounds that are designed to elicit a maximal response from a specific
`target receptor in in vitro tests. At this stage the candidate drug exists only
`as a powder in a “test tube”, or even maybe as a computer model, and is
`not in a state to benefit the ultimate end user, the patient. The drug is
`therefore formulated into a medicinal product that can be easily handled
`and administered by medical staff and patients. Such products may range
`from simple solutions through to transdermal patch delivery systems, the
`ultimate form depending on pharmacological, pharmaceutical and
`marketing considerations. All of these medicinal products or dosage forms
`will contain the drug plus a variety of additives or excipients whose role is
`to enhance product performance. It is therefore a general rule that patients
`are never administered a “drug” per se but rather a medicinal product that
`contains the drug.
`Pharmaceutical development of a medicinal product must retain the
`drug’s promising in vitro pharmacological activity and provide a predictable
`in vivo response. The marketed product must be stable, correctly packaged,
`labelled and easily administered, preferably by self-administration. The
`product must also be economical to manufacture on a large scale by a
`method that ensures product quality. In addition, development and eventual
`production processes must comply with the regulatory requirements of
`proposed market countries, and all development studies must be performed
`to acceptable levels of quality assurance.
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`PHARMACEUTICAL DEVELOPMENT
`
`Pharmaceutical development involves multiple skills, processes and
`stages and is therefore a large undertaking requiring extensive resources.
`The earlier pharmaceutical intervention occurs during development the
`better, to preclude, for example, the use of toxic solvents during manufacture
`or to employ computer models to determine potential bioavailability
`problems with candidate compounds. Changes introduced at later stages
`may necessitate costly retesting or delay product marketing and are best
`avoided. Development consists of several gross stages such as preformulation,
`formulation, toxicology and clinical trials, and, where possible, research is
`normally conducted in parallel in order to expedite the process. Because of
`drug diversity and the many possible approaches, there is no single optimum
`development model but the general stages presented in this chapter will
`be applied.
`For the majority of drugs, the initial formulation will be an injectable
`solution for basic pharmacology, pharmacokinetic and toxicology studies
`in animals or man to confirm in vitro activity. Other more complex
`formulations will follow as the research and pharmaceutical development
`programmes progress. The eventual range and type of formulations produced
`for a single drug will depend on the drug’s pharmacology and whether a
`local systemic action is required (Table 2.1). Some drugs can be administered
`by a variety of routes, resulting in several diverse formulations. Salbutamol,
`for example, is currently available in ten different formulations, excluding
`different doses and variations resulting from different manufacturers
`(Table 2.2).
`
`2.2 Preformulation
`Before product development studies are conducted, fundamental
`physicochemical information on the new chemical entity (NCE) or drug
`must be obtained.1,2 This provides valuable data to guide future work and
`initiates a sequence of specification setting exercises that define the drug’s
`boundaries for use. At early stages only limited drug supplies will be
`available and there may be competition between continuing pharmacology
`and early in vivo testing and preformulation studies. The utilisation of
`material has to be balanced to ensure that adequate information is obtained
`to determine future progress. For example, chemical purity and stability
`are important in both pharmacology and preformulation studies.
`
`2.2.1 Structure determination
`After synthesis it is important to determine the drug’s exact chemical
`structure. This will involve a variety of techniques such as mass spectrometry,
`nuclear magnetic resonance (H1 and C13), infrared and ultraviolet/visible
`spectrophotometry along with elemental analysis. This will confirm the
`
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`TEXTBOOK OF PHARMACEUTICAL MEDICINE
`
`Table 2.1 Basic information on common routes of administration.
`
`Route
`
`Advantages
`
`Disadvantages
`
`Product types
`
`Painful
`Self-administration
`unusual
`Requires trained
`personnel
`Expensive production
`processes
`
`Inappropriate during
`vomiting
`Potential drug
`stability problems
`Interactions with food
`Possible low
`availability
`Patient must be
`conscious
`Unpopular
`Inconvenient
`Erratic absorption
`Irritation
`
`Solutions, suspensions,a
`emulsions, implantsa
`
`Solutions, syrups,
`suspensions,
`emulsions, powders,
`granules, capsules,
`tablets
`
`Suppositories, enemas
`(solutions,
`suspensions,
`emulsions), foams,
`ointments, creams
`
`Taste
`Only suitable for low
`dose (high potency)
`drugs
`
`Tablets, mouthwashes
`
`Irritation
`Embarrassing
`Difficult technique
`
`Gases, aerosols
`(solutions,
`suspensions),
`powders
`
`Irritation
`Potent drugs only
`Absorption affected
`by site of application
`Hard to administer
`
`Solutions, lotions,
`sprays, gels,
`ointments, creams,
`powders, patches
`
`Inefficient
`Irritation
`Poor retention of
`solutions
`Inconvenient
`Erratic absorption
`Irritation
`
`Solutions, ointments,
`injections
`
`Creams, ointments,
`foams, tablets,
`pessaries
`
`Parenteral
`(injection)
`
`Oral
`
`Exact dose 100%
`compliance
`Suitable for
`unconscious patient
`Rapid onset, especially
`after intravenous
`administration
`
`Easy
`Convenient
`Acceptable
`Painless
`Self-administration
`possible
`
`Rectal
`
`Buccal
`
`Avoids problems of
`stability in
`gastrointestinal
`tract
`No first-pass
`metabolism
`Useful if oral
`administration is
`not possible
`Rapid onset of action
`No first-pass
`metabolism
`Dosage form
`recoverable
`Convenient
`Convenient
`Local or systemic
`effects
`No first-pass
`metabolism
`Transdermal Easy
`Convenient
`No first-pass
`metabolism
`Local or systemic
`effects
`Local action only
`
`Inhalation
`
`Eye
`
`Vaginal
`
`Local or systemic
`effects (hormones)
`No first-pass
`metabolism
`
`aNot for intravenous administration
`
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`Table 2.2 Salbutamol preparations available in the UK
`
`Route
`
`Form
`
`Product
`
`Manufacturer
`
`Strength
`
`PHARMACEUTICAL DEVELOPMENT
`
`Parenteral
`
`Solution
`
`Oral
`
`Solution
`Syrup
`Tablets
`Tablets
`(modified
`release)
`Capsules
`(modified
`release)
`
`Inhalation Metered dose
`inhaler
`
`Metered dose
`inhaler CFC
`free
`
`Powder for
`inhalation
`
`Nebuliser
`
`Injection
`Ventolin®
`injection
`Ventolin®
`Intravenous
`Infusion
`
`–
`Ventolin®
`–
`Volmax®
`
`Non-proprietary
`A&H
`
`A&H
`
`100 μg/ml
`50 μg/ml and
`500 μg/ml
`1 mg/ml
`
`Non-proprietary
`A&H
`Non-proprietarya
`A&H
`
`2 mg/5 ml
`2 mg/5 ml
`2 mg and 4 mg
`4 mg and 8 mg
`
`Ventmax®
`
`Trinity
`
`4 mg and 8 mg
`
`–
`
`Non-proprietaryb
`
`100 μg/inhalation
`
`3M
`
`Aerolin®
`Autohaler
`Easi-Breathe® A&H
`–
`Non-proprietary
`
`100 μg/inhalation
`
`100 μg/inhalation
`100 μg/inhalation
`
`Airomir®
`Autohaler
`Evohaler®
`Ventodisks®
`
`Accuhaler®
`Rotacaps®
`
`Asmasal®
`Clickhaler®
`Solution
`
`Nebules®
`
`Respirator
`solution
`
`3M
`
`A&H
`A&H
`
`A&H
`A&H
`
`Medeva
`
`Non-proprietaryc
`
`A&H
`
`A&H
`
`100 μg/inhalation
`
`100 μg/inhalation
`200 μg and
`400 μg/inhalation
`
`200 μg/inhalation
`200 μg and
`400 μg/inhalation
`95 μg/inhalation
`
`1 mg/ml and
`2 mg/ml
`1 mg/ml and
`2 mg/ml
`5 mg/ml
`
`From British National Formulary 40, September 2000. Liquid, tablet and powder
`preparations contain salbutamol as the sulphate salt; aerosols contain the free base.
`aFive manufacturer’s preparations available.
`bSix manufacturer’s preparations available.
`cFour manufacturer’s preparations available.
`
`99
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`Exhibit 2011 Page 16
`
`

`

`TEXTBOOK OF PHARMACEUTICAL MEDICINE
`
`medicinal chemist’s proposed structure and provide information useful in
`later stages such as analytical development.
`
`2.2.2 Analytical development
`An initial priority is to develop analytical methodology that detects the
`drug (main component), intermediate compounds carried over from
`synthesis and degradation products from chemical breakdown or
`instability. Paradoxically, these latter contaminants are of greater
`importance because their quantification, identification and control affect
`the quality of drug batches. In addition, chemical instability is more easily
`detected through an increased concentration of degradants than through
`decreased concentration of the main component. Methods are also
`required for quantification of other impurities such as residual solvents,
`catalyst residues and heavy-metal and microbial contamination. Further
`analytical tests will also be specified such as the general characteristics,
`colour, melting point, loss on drying and a basic identification method. The
`basic analysis of a new drug therefore necessitates the application of a full
`range of analytical techniques, all of which must be validated to a suitable
`level.3
`Drug assays are usually conducted using a specific chromatography
`or separative technique such as high-performance (or pressure) liquid
`chromatography (HPLC)4 or capillary zone electrophoresis (CZE).5,6
`These techniques ensure that the drug is separated from impurities and
`breakdown products, all of which can then be quantified. Development of
`these methods allows specifications to be set for the required percentage of
`the main component, usually 98 to 101% by weight, and limits for the
`tolerated level of impurities.7 If required, identification of the impurities
`and degradants will also be conducted. A reference sample will be retained
`and used as a standard for subsequent analysis. Simple ultraviolet/visible
`spectrophotometric analysis may suffice for some experiments such as
`solubility testing.
`It is common to find that early small-scale batches exhibit a higher or
`different purity or impurity profile to subsequent batches from large-scale
`production. As development progresses, the ability to synthesise the drug
`reproducibly must be determined so that impurity profiles are known and
`predictable and can be maintained within predetermined limits.
`
`2.2.3 Salt form
`The majority of NCEs synthesised are organic molecules of low
`molecular weight that are either weak acids or weak bases. There is
`therefore a choice between the free acid or base and a salt, with further
`complexity imposed by salt selection. The free acid or base does not
`normally possess an adequate aqueous solubility for the majority of
`applications and so salts are required. Since salt formation will occur
`
`100
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2011 Page 17
`
`

`

`PHARMACEUTICAL DEVELOPMENT
`
`during synthesis, the correct choice of salt at an early stage is critical. The
`non-steroidal anti-inflammatory drug fenoprofen is a derivative of
`2-phenylpropionic acid and the free acid exists as a viscous oil at room
`temperature.8 The potassium salt was found to be hygroscopic, the
`magnesium salt did not crystallise, and the aluminium salt was insoluble in
`water. Anhydrous sodium or calcium salts could not be obtained but the
`dihydrate salt was readily isolated. The sodium dihydrate was not stable
`and dehydrated at room temperature whereas the calcium dihydrate salt
`was stable up to 70°C (Table 2.3) and was therefore chosen for further
`development.
`
`2.2.4 Chemical stability
`The solid drug’s chemical stability will be examined under a range of
`different storage conditions and over varying periods of time, using the
`stability indicating assays described above. Chemical degradation occurs
`through four main routes:
`
`• hydrolysis resulting from the presence of H2O, H+ or OH−
`• oxidation
`• photolysis
`•
`catalysis by trace metals such as Fe2+, Cu2+.
`
`Hydrolysis and oxidation are the two main routes of degradation for the
`majority of drugs. Harmonised guidelines are available for new drugs9 but
`these specify only two conditions: long-term testing at 25 ± 2°C/60 ±
`5% relative humidity and accelerated testing at 40 ± 2°C/75 ± 5% relative
`humidity, which may not provide enough information to characterise
`degradation processes fully. To gain more information, testing at a range of
`temperatures from (depending upon stability) −80°C to 70°C, variable
`levels of relative humidity up to 90% and exposure to artificial or natural
`light (Table 2.4) may be conducted.10 Elevated temperatures, humidity
`and light deliberately stress the drug and induce rapid degradation.
`Determination of the physical chemistry of the degradation process will
`allow the extrapolation of results from short tests under stressed condition
`to provide estimates of shelf life in ambient environments (Figure 2.1). This
`will provide basic information on the conditions, processes and packaging
`that can be used to manipulate and store the drug safely. For example,
`hygroscopic drugs may require packaging with a desiccant in containers
`that prevent moisture ingress.
`Chemical stability studies will also be conducted on aqueous solutions of
`the drug at varying pHs and temperatures and in a variety of solvents,
`experiments that may be coupled with determination of solubility. This
`information is important for determining the shelf life of stock solutions for
`pharmacology testing and analytical assays.
`
`101
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2011 Page 18
`
`

`

`+6·3
`+9·3
`+36·5
`
`0
`–
`
`0
`
`+2·5
`+15·8
`
`–
`–
`
`0
`–
`
`–
`
`93
`
`–
`
`70
`
`Extremely hygroscopic
`
`+3·7
`
`–
`
`–
`–
`–
`–
`
`+2·9
`+0·4
`+12·5
`
`0
`
`0
`–
`
`–
`
`–
`
`+1·7
`+0·3
`+10·7
`
`–
`–
`
`0
`
`+0·5
`−11·4
`−0·5
`
`0
`–
`
`0
`
`–
`
`20
`
`–
`
`10
`
`2·5
`2·5
`>200
`>200
`0·1
`>200
`>200
`0·05
`
`O, oil; C, crystalline; A, amorphous.
`
`O
`C
`C
`C
`A
`A
`A
`–
`
`Dihydrate
`Anhydrous
`Dihydrate
`Anhydrous
`Dihydrate
`Dihydrate
`Unknown
`
`Ca2+
`Ca2+
`Na+
`Na+
`Al(OH)2+
`Mg2+
`K+
`Free acid
`
`Salt
`
`110
`
`–
`
`80
`
`
`
`––––
`
`40
`
`
`
`
`
`Relative humidity (%)
`
`60
`
`40
`
`Aqueous solubility
`
`(mg/ml)
`
`Melting point
`
`(°C)
`
`Form
`
`Hydration
`
`Weight change(%)
`
`Table 2.3Characteristics of fenoprofen salts
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2011 Page 19
`
`

`

`PHARMACEUTICAL DEVELOPMENT
`
`Table 2.4 Typical stress conditions used for the stability testing
`
`Test
`
`Stress
`
`Conditions
`
`Solution, chemical stability
`
`Heat and pH
`
`Solution, chemical stability
`Solution, chemical stability
`Solid, chemical stability
`
`Light
`Oxidation
`Heat and humidity
`
`Solid, moisture uptake
`
`Humidity
`
`pH 1, 3, 5, 7, 9, 11
`Ambient and elevated
`temperature
`Ultraviolet and white light
`Sparging with oxygen
`4 °C, 25 °C (60 and 75% RH),
`30 °C (70% RH), 40 °C
`(75% RH), 50 °C, 70 °C
`RHa: 30, 45, 60, 75, 90%
`Ambient temperature
`
`RH, relative humidity
`aProvided using saturated aqueous solutions of MgBr2, KNO2, NaBr, NaCl, KNO3
`respectively, or controlled humidity cabinets.
`
`25°C
`
`3.6
`
`3.2
` (K) × 10−3
`
`1T
`
`40°C
`
`100
`
`10
`
`Degradation rate constant
`
`1
`
`2.8
`
`50°C
`
`60°C
`
`70°C
`
`100
`
`200
`Time (days)
`
`300
`
`400
`
`100
`
`10
`
`Drug remaining (%)
`
`1
`
`0
`
`Figure 2.1 Accelerated stability testing. The percentage of drug remaining at
`elevated temperatures with time is measured (left) and the rate constants for the
`degradation reaction calculated. Using the Arrhenius relationship, a plot of the log
`of the rate constant against the reciprocal of absolute temperature of measurement
`yields a straight line (right). Extrapolation of the line permits calculation of the rate
`constant at lower temperatures and the prediction of shelf life.
`
`2.2.5 Physicochemical properties
`The drug’s physicochemical parameters are determined in order to provide
`essential information for interpreting subsequent studies and guiding
`formulation.11 Solubility in aqueous media of differing composition (for
`example buffers, physiological saline) and pH will be determined, along with
`a range of biocompatible organic solvents (for example, ethanol, propylene
`
`103
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2