A Practical GuidefreomCandidate Drug
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`Pharmaceutical
`Preformulation and
`Formulation
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`SelectoFgetealommere al Dosage Form
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`PHARMACEUTICAL
`PREFORMULATION
`AND
`FORMULATION
`
`A Practical Guide from
`Candidate Drug Selection to
`Commercial Dosage Form
`
`Mark Gibson
`Editor
`
`IHSfi Health Group
`
`An IHSfi GROUP Company
`
`Your Enterprise Solution to (cid:31)
`Global Healthcare Knowledge
`
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`disclaimer Page 1 Monday, June 9, 2003 12:22 PM
`
`Library of Congress Cataloging-in-Publication Data
`
`Catalog record is available from the Library of Congress
`
`This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with
`permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish
`reliable data and information, but the authors and the publisher cannot assume responsibility for the validity of all materials
`or for the consequences of their use.
`
`Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical,
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`No claim to original U.S. Government works
`Library of Congress Card Number 1-57491-120-1
`Printed in the United States of America 1 2 3 4 5 6 7 8 9 0
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`CONTENTS
`
`Preface
`
`Contributors
`
`1.
`
`Introduction and Perspective
`
`Mark Gibson
`
`Drug Development Drivers, Challenges, Risks and Rewards
`Current Trends in the Pharmaceutical Industry
`Lessons Learnt and the Way Forward
`Scope of the Book
`References
`
`2.
`
`3.
`
`PART I: Aiding Candidate Drug Selection
`Aiding Candidate Drug Selection:
`Introduction and Objectives
`
`Mark Gibson
`
`Stages of the Drug Discovery and Development Process
`Summary
`References
`
`Preformulation Predictions from Small Amounts of Compound
`as an Aid to Candidate Drug Selection
`Gerry Steele
`
`Initial Physicochemical Characterization
`Initial Solubility
`Initial Stability Investigations
`Crystallinity
`Crystal Morphology
`Hygroscopicity
`Salt Selection
`Methods for Evaluating Physicochemical Properties
`Concluding Remarks
`Acknowledgements
`References
`
`vii
`
`ix
`
`1
`
`2
`6
`8
`10
`11
`
`15
`
`15
`20
`20
`
`21
`
`22
`28
`34
`41
`46
`48
`49
`58
`87
`88
`88
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`iv
`
`4.
`
`Pharmaceutical Preformulation and Formulation
`
`Biopharmaceutical Support in Candidate Drug Selection
`Anna-Lena Ungell and Bertil Abrahamsson
`
`Drug Dissolution and Solubility
`Luminal Interactions
`Absorption/Uptake over the GI Membranes
`Models for Studying the Absorption Potential of Drugs
`Permeability Coefficients versus Fa
`In Vivo Techniques for Studies in Man
`Vehicles for Absorption Studies
`Functional Use of Absorption Models
`References
`
`PART II: Early Drug Development
`Early Drug Development: Product Design
`Mark Gibson
`
`5.
`
`The Importance of Product Design
`Product Design Considerations
`Concluding Remarks
`References
`
`6.
`
`Preformulation as an Aid to Product Design in Early Drug Development
`Gerry Steele
`
`Solid Dosage Forms
`Solution Formulations
`Freeze-Dried Formulations
`Suspensions
`Topical/Transdermal Formulations
`Inhalation Dosage Forms
`Compatibility
`References
`
`7.
`
`Biopharmaceutical Support in Formulation Development
`Bertil Abrahamsson and Anna-Lena Ungell
`
`In Vitro Dissolution
`Bioavailability Studies
`In Vitro/In Vivo Correlations
`Animal Models
`Imaging Studies
`References
`
`97
`
`100
`111
`117
`118
`134
`135
`139
`141
`143
`
`157
`
`157
`158
`173
`173
`
`175
`
`175
`196
`210
`214
`215
`217
`223
`228
`
`239
`
`241
`257
`269
`276
`279
`289
`
`PART III: From Product Design to Commercial Dosage Form
`Product Optimisation
`295
`
`8.
`
`Product Optimisation Purpose and Scope
`Excipient and Pack Optimisation Considerations
`
`Mark Gibson
`
`295
`296
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`Sources of Information
`Expert Systems
`Experimental Design
`Stability Testing
`Developing Specifications
`Process Design, Process Optimisation and Scale-Up
`Validation and Launch
`Acknowledgements
`References
`
`9.
`
`Parenteral Dosage Forms
`
`Joanne Broadhead
`
`Guiding Principles for Simple Parenteral Solutions
`Choice of Excipients
`Sterility Considerations
`Strategies for Formulating Poorly Soluble Drugs
`Strategies for Formulating Unstable Molecules
`Strategies for the Formulation of Macromolecules
`Liposomal Delivery Systems
`Sustained-Release Parenteral Formulations
`In Vitro and In Vivo Testing Methods
`Packaging of Parenteral Products
`Manufacturing of Parenteral Products
`Administration of Parenteral Products
`Parenteral Products and the Regulatory Environment
`References
`
`10.
`
`Inhalation Dosage Forms
`
`Paul Wright
`
`Lung Deposition
`Particle Sizing
`Dry Powder Inhalers
`Metered Dose Inhalers
`Nebulisers
`Standards
`Future
`References
`Bibliography
`
`11. Oral Solid Dosage Forms
`
`Peter Davies
`
`Powder Technology
`Powder Flow
`Mixing
`Compaction
`Solid Dosage Forms
`Tablets
`Hard Gelatin Capsules
`
`Contents
`
`v
`
`304
`305
`309
`313
`316
`319
`323
`327
`327
`
`331
`
`332
`334
`336
`336
`340
`342
`343
`343
`346
`347
`348
`350
`351
`353
`
`355
`
`356
`357
`361
`364
`372
`374
`375
`376
`378
`
`379
`
`381
`382
`388
`390
`403
`403
`441
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`vi
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`Pharmaceutical Preformulation and Formulation
`
`Soft Gelatin Capsules
`Summary
`References
`
`12. Ophthalmic Dosage Forms
`
`Mark Gibson
`
`Ocular Topical Drug Delivery Issues and Challenges
`Drug Candidate Selection
`Product Design Considerations
`Product Optimisation Considerations
`Processing Considerations
`Concluding Remarks
`References
`
`13. Aqueous Nasal Dosage Forms
`
`Nigel Day
`
`Nasal Anatomy and Physiology
`Formulation Selection Considerations
`Device Selection Considerations
`Regulatory Aspects
`Special Considerations for Peptide Nasal Delivery
`References
`Additional Reading
`
`14.
`
`Topical and Transdermal Delivery
`Kenneth A. Walters and Keith R. Brain
`
`The Skin and Percutaneous Absorption
`Drug Candidate Selection and Preformulation
`Formulation
`Concluding Remarks
`Bibliography
`References
`
`Index
`
`453
`455
`456
`
`459
`
`460
`464
`465
`473
`482
`486
`488
`
`491
`
`494
`496
`499
`506
`508
`511
`513
`
`515
`
`516
`534
`543
`567
`567
`569
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`PREFACE
`
`In my industrial career, I have gained broad experience working on many different pharma-
`ceutical development projects and dosage forms, spanning candidate drug selection through
`technology transfer to production and subsequent launch. With this background and with
`Gerry Steele’s encouragement and rich experience in preformulation studies, I planned a
`book that would emphasize what practical studies need to be undertaken, for what reasons
`and during what key stages of the drug development process. In addition to preformulation,
`I considered it essential to include biopharmaceutics (an area of emerging importance) as
`well as formulation aspects. I soon realized I could not commit the time to writing all the
`chapters in such a book, and, indeed, I considered the book would be more comprehensive by
`involving other contributors and adding their special knowledge and experiences.
`I am extremely grateful to all the contributors in this book, who have given up so much
`of their time to create their specialised chapters. I would specially like to thank Anna-Lena
`Ungell and Bertil Abrahammson for the two biopharmaceutics chapters, and also Jo Broad-
`head for stepping in at the final hour and writing the chapter on parenterals. Without these
`chapters, the book would have been incomplete.
`In the past few years, I have written internal company guidelines and given seminars ex-
`ternally on a logical approach to product development and technology transfer. This ap-
`proach emphasises the importance of starting development of an NCE with product design
`prior to commencing product and process optimisation, scale-up and technology transfer.
`Two people I would particularly like to thank for their input and support for these concepts
`are Gordon France and Mike Dey. This logical approach to ensure that products are devel-
`oped efficiently and moved speedily to market is part of my own contribution to the chapters
`in this book.
`Preparing this book took longer than anticipated, and it contains more pages than ex-
`pected. I have many vivid memories of one-finger typing on my laptop in airport lounges and
`hotel rooms and at home late in the evenings or on weekends. While my typing has become
`considerably faster, I hasten to add that I have progressed only to two-finger typing! I am in-
`debted to my secretarial support, particularly Hayley Pruden, who has much better typing
`skills than I, to complete the figures and tables for this book.
`
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`viii
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`Pharmaceutical Preformulation and Formulation
`
`This book should prove to be a useful guide to practitioners working in the pharmaceu-
`tical industry, including R&D scientists, technicians and managers. In the words of Francis
`Bacon (1561–1626):
`
`Some books are to be tasted, others to be swallowed, and some few to be
`chewed and digested: that is, some books are to be read only in parts; oth-
`ers to be read but not curiously; and some few to be read wholly, and with
`diligence and attention.
`
`I would like to think that this book might fit any of the above descriptions, depending on the
`reader’s need.
`Finally, I would like to thank my wife Alison for her love, understanding and support over
`the time I have spent preparing this book. Now that the book is finished, I should have more
`time to spend with her and my three children, Laura, Joanna and David.
`
`Mark Gibson
`May 2001
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`Contributors
`
`MARK GIBSON
`
`Mark Gibson, BPharm, PhD, CChem, MRSC, MRPharmS, is currently responsible for par-
`enteral and oral solid dosage form development at AstraZeneca R&D Charnwood, which is a
`division of AstraZeneca. His experience includes formulation and preformulation develop-
`ment, both as a bench scientist and a manger, at Cyanamid (Lederle) for six years, Fisons Par-
`maceuticals for six years, Astra Pharmaceuticals for four years and AstraZeneca for two years.
`He has worked on a variety of dosage forms and routes of delivery, including inhalation, oral,
`nasal, ophthalmic, parenteral and transdermal, resulting in some patents or marketable prod-
`ucts. Dr. Gibson is a member of the UK Academy of Pharmaceutical Sciences, the Parenteral
`Society and the Aerosol Society.
`
`BERTIL AB RAHAMSSON
`
`Bertil Abrahamsson, PhD, leads pharmaceutical and analytical research and development at
`AstraZeneca R&D Mölndal. His experience is in in vitro/in vivo correlations, in vitro dissolu-
`tion, in vivo imaging of dosage forms and drug absorption. Dr. Abrahamsson has published
`more than 20 articles in clinical pharmacology.
`
`KEITH R. BRAIN
`
`Keith Brain, BPharm, PhD, is head of the drug delivery research group at Cardiff Univer-
`sity. His major responsibilities are in molecular recognition research and skin research. He
`is also CEO of An-eX, a university-based spinoff company formed in 1988, which
`specialises in confidential contract research and development for international clients. He
`has organized several international conferences on skin research and workshops on molec-
`ular imprinting.
`
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`Pharmaceutical Preformulation and Formulation
`
`JOANNE BROADHEAD
`
`Joanne Broadhead, PhD, MRPharmS, manages a small team of formulation scientists at As-
`traZeneca R&D Charnwood in the development of solid and parenteral products. Her expe-
`rience includes two years as a formulation scientist for creative BioMolecules (Hopkinton,
`Mass., USA) prior to joining AstraZeneca in 1996. Dr. Broadhead is a member of the Ameri-
`can Association of Pharmaceutical Scientists, the Parenteral Drug Association and the Par-
`enteral Society.
`
`PETER DAVIES
`
`Peter Davies, BPharm, MRPharmS, PhD, is currently the formulation team leader in drug de-
`livery sciences at Roche Discovery Welwyn. At Roche for 18 years, his principal areas of in-
`terest are preformulation and formulation of solid dosage forms.
`
`NIGEL DAY
`
`Nigel H. Day, BSc, MSc, PhD, is a team manager in product development at AstraZeneca R&D
`Charnwood (formerly Fisons R&D and Astra Charnwood). He has wide experience in the de-
`velopment of solid, liquid and inhalation formulations. His professional experience includes
`a postdoctoral research fellowship at the University of Bradford and seven years in the Hoff-
`man-La Roche UK R&D Laboratories. Dr. Day is a member of the UK Academy of Pharma-
`ceutical Sciences.
`
`GERRY STEELE
`
`Gerry Steele, BSc, MSc, PhD, CChem, MRSC, is a team manager at AstraZeneca R&D Charn-
`wood. His research experience includes preformulation work and characterization and the
`surface rheology of phospholipid monolayers using photon correlation spectroscopy. Prior to
`joining AstraZeneca R&D Charnwood, he spent seven years with Fisons plc and a year at In-
`versesk Research International. Dr. Steele is a member of the Royal Society of Chemistry and
`the Academy of Pharmaceutical Scientists (of the Royal Pharmaceutical Society of Great
`Britain).
`
`ANNA-LENA UNGELL
`
`Anna-Lena Ungell, PhD, is associate director of DMPK and bioanalytical chemistry at
`AstraZeneca R&D Mölndal. She supports preclinical and pharmaceutical projects relating to
`absorption as well as the gastrointestinal absorption of drugs. Her experience includes ab-
`sorption models, mechanisms of drug absorption from the intestinal tract, substance evalua-
`tion and basic formulation development. Dr. Ungell has four patents and has written
`numerous research articles and reviews.
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`Contributors
`
`xi
`
`KENNETH A. WALTERS
`
`Kenneth A. Walters, PhD, is director of An-eX Analytical Services Ltd and an honorary lec-
`turer in pharmaceutical chemistry at the Welsh School of Pharmacy. His research interests are
`biological membrane penetration enhancement and retardation, particularly with respect to
`skin. He has experience at Fisons Pharmaceuticals, Eastman Pharmaceuticals (a division of
`Eastman Kodak Company) and Controlled Therapeutics Ltd. (Scotland). Dr. Walters has
`published many articles and reviews and has co-edited two volumes on skin penetration en-
`hancement and dermal toxicity. He is a charter member of the American Association of Phar-
`maceutical Scientists and also a member of the Society of Investigative Dermatology, the
`Controlled Release Society, the Society of Toxicology and the Society of Cosmetic Scientists.
`
`PAUL WRIGHT
`
`Paul Wright is an associate director within product development at AstraZeneca. He has in-
`halation development responsibilities at both the Charnwood (UK) site and the Lund (Swe-
`den) site. Mr. Wright has extensive experience in major respiratory dosage forms and is a
`committee member of several industry groups.
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`1
`
`Introduction and Perspective
`
`Mark Gibson
`AstraZeneca R&D Charnwood
`Loughborough, United Kingdom
`
`This book is intended to be a practical guide to pharmaceutical preformulation and formula-
`tion. It can be used as a reference source and a guidance tool for those working in the
`pharmaceutical industry or related industries, for example, medical devices and biophar-
`maceuticals, or anyone wanting an insight into this subject area. The information presented is
`essentially based on the extensive experiences of the editor and various other contributors
`who are all actively working in the industry and have learned “best practice” from their expe-
`riences.
`There are various excellent books already available which cover the theoretical aspects of
`different types of pharmaceutical dosage forms and processes. A variety of books are also
`available that focus on the drug development process, business, regulatory and project man-
`agement aspects. In my opinion, there has been a long-standing need for a pragmatic guide to
`pharmaceutical preformulation and formulation with an emphasis on what practical studies
`need to be undertaken, for what reasons and during what key stages of the drug development
`process. The important stages where preformulation, biopharmaceutics and formulation play
`a key role are candidate drug selection through the various stages of product development.
`This book has been written to try and address this need.
`A logical approach to product development is described in the book, with the key stages
`identified and the preformulation, biopharmaceutics and formulation activities and typical is-
`sues at each stage discussed. Wherever possible, the book is illustrated with real or worked
`
`1
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`2
`
`Pharmaceutical Preformulation and Formulation
`
`examples from contributors who have considerable relevant experience of preformulation,
`biopharmaceutics and formulation development.
`Jim Wells’ book on preformulation (Wells 1988) made a strong impact on trainees and
`pharmaceutical scientists (including myself) working in this field of the pharmaceutical in-
`dustry when it was introduced over 10 years ago. It describes the important concepts and
`methods used in preformulation with the underlying theory. To his credit, Wells’ book is still
`useful today, but sadly, the book is now out of print, and existing copies are hard to obtain. It
`also requires updating to include modern preformulation instrumental techniques which have
`emerged over the last decade, such as thermo gravimetric analysis (TGA), hot stage mi-
`croscopy (HSM), X-ray powder diffraction (XRPD), raman and infra-red spectroscopy and
`solid-state nuclear magnetic resonance (NMR), to name a few. These techniques can be used
`to provide valuable information to characterise the drug substance and aid formulation de-
`velopment using the minimal amounts of compound.
`Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug
`Selection to Commercial Formulation covers a wider subject area than just preformulation.
`Topics include biopharmaceutics, drug delivery, formulation and process development aspects
`of product development. The book also describes a logical and structured approach to the
`product development process, recommending at what stages appropriate preformulation, bio-
`pharmaceutics and formulation work is best undertaken.
`
`DRUG DEVELOPMENT DRIVERS,
`CHALLENGES, RISKS AND REWARDS
`
`It is important that the reader is aware of the nature of pharmaceutical research and develop-
`ment (R&D) in order to appreciate the importance of preformulation and formulation in the
`overall process.
`In simple terms, the objective of pharmaceutical R&D can be defined as “converting ideas
`into candidate drugs for development”, and the objective of product development defined as
`“converting candidate drugs into products for registration and sale”. In reality, these goals are
`extremely challenging and difficult to achieve because of the many significant hurdles a phar-
`maceutical company has to overcome during the course of drug development. Some of the
`major hurdles are listed in Table 1.1.
`The high risk of failure in drug discovery and development throughout the pharmaceu-
`tical industry statistically shows that, on average, only 1 in 5,000 to 1 in 10,000 compounds
`screened in research will reach the market (Tucker 1984). Of those that are nominated for de-
`velopment, the failure rate will vary from 1 in 5 to 1 in 10 compounds that will achieve regis-
`tration and reach the market-place. On top of that, there is a significant commercial risk from
`those that are marketed; only 3 out of 10 are likely to achieve a fair return on investment. The
`products which give poor return on investment are often the result of poor candidate drug se-
`lection (the compound does not have the desired properties of safety, selectivity, efficacy, po-
`tency or duration) and/or poor product development (the development programme does not
`establish the value of the product). The latter scenario should, and can be, avoided by careful
`assessment at the “product design” stage of development. Product design is discussed further
`in Chapter 5.
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`Introduction and Perspective
`
`3
`
`Table 1.1
`Major hurdles to successful product registration and sale.
`Requirements
`
`Activity
`
`Research
`
`Safety
`
`Clinical
`
`Drug process
`Pharmaceutical
`
`Regulatory
`Manufacturing
`
`Marketing/commercial
`
`Novel compound (patentable?)
`Novel biological mechanism (patentable?)
`Unmet medical needs
`Potent and selective
`High margin of safety
`Non-toxic (not carcinogenic, tetratogenic, mutagenic, etc.)
`Tolerable side-effects profile
`Efficacious
`Acceptable duration of action
`Bulk drug can be synthesised/scaled up
`Acceptable formulation/pack (meets customer needs)
`Drug delivery/product performance acceptable
`Stable/acceptable shelf-life
`Clinical trial process robust and can be scaled up
`Quality of data/documentation
`Manufacturable
`Able to pass pre-approval inspection
`Competitive
`Meets customer needs
`Value for money
`Commercial return
`
`To be successful and competitive, research-based pharmaceutical companies must ensure
`that new discoveries are frequently brought to the market to generate cash flow. This is re-
`quired to fund the next generation of compounds to meet the therapeutic needs of patients,
`and of course, to benefit the shareholders. This cycle of events is sometimes referred to as the
`“product life cycle” and is further illustrated in Figure 1.1.
`The costs of drug discovery and development to bring a New Chemical Entity (NCE) to
`the market are ever increasing. It is currently estimated that in excess of U.S. $500 million is
`required to recoup the costs of research, development, manufacturing, distribution, market-
`ing and sales. A significant proportion of this total is for the cost of failures, or in other words,
`the elimination of unsuccessful compounds. R&D expenditure for an NCE tends to increase
`substantially as the compound progresses from drug discovery research through the various
`clinical trial phases of development. The pivotal Phase III patient trials are usually the largest,
`involving thousands of patients, and hence the most expensive. To reduce development costs,
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`4
`
`Pharmaceutical Preformulation and Formulation
`
`Figure 1.1 Product life cycle.
`
`EXPLORATORY
`RESEARCH
`
`CANDIDATE
`SELECTION
`
`Candidate drug
`selected
`
`STRATEGIC
`RESEARCH
`
`Based on company
`strategy
`
`£/$
`Sales &
`profits
`
`Further market/medical needs
`new indications
`
`Further market/
`medical needs
`product line
`extensions
`
`MARKETING &
`COMMERCIAL
`
`Launch
`
`Regulatory
`submissions
`
`FULL
`DEVELOPMENT
`
`Safety and efficacy
`demonstrated
`
`
`
`
`EXPLORATORYEXPLORATORYEXPLORATORYEXPLORATORY
`
`
`
`DEVELOPMENTDEVELOPMENTDEVELOPMENTDEVELOPMENT
`
`Proof of concept
`demonstrated
`
`some companies selectively screen and eliminate compounds earlier in the drug development
`process based on results from small-scale, less expensive studies in man and progress fewer,
`more certain compounds to later clinical phases.
`In spite of the high risks and high costs involved, there is still a huge incentive for phar-
`maceutical companies to seek the financial rewards from successful marketed products, and
`especially from the phenomenal success of the rare “blockbuster” (reaching sales of ⬎1 billion
`U.S.$ per year). This can earn the company significant profits to reinvest in research and fund
`the product development pipeline.
`Another factor, the risk of delay to registration and launch, can also have a significant im-
`pact on the financial success of a marketed product. McKinsey & Company, a management
`consultancy, assessed that a product that is 6 months late to market will miss out on one-third
`of the potential profit over the product’s lifetime. In comparison, they found that a develop-
`ment cost overspend of 50 percent would reduce profits by just 3.5 percent, and a 9 percent
`overspend in production costs reduced profits by 22 percent (McKinsey & Co. 1991). The loss
`of product revenue is often due to competitor companies being first to market, capturing the
`market share and dictating the market price, in addition to the loss of effective patent life.
`Hence, the importance of accelerating and optimising drug discovery and development, and
`getting to the market first with a new therapeutic class of medicinal product, cannot be un-
`derestimated. The second product to market in the same class will usually be compared with
`the market leader, often unfavourably.
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`The average time from drug discovery to product launch is currently estimated to take
`10 to 12 years. Several factors may have contributed to lengthening development times over
`the years, including an increase in the preclinical phase to select the candidate drug, and also
`an increase in the duration of the clinical and regulatory period required for marketing ap-
`proval. Benchmarking studies show wide gaps between industry average or worst performance
`compared to what is achievable as best practice performance (Spence 1997). On average, the
`preclinical phase currently takes 4 to 6 years to complete, whereas the time from candidate
`drug nomination to regulatory submission takes on average 6 to 8 years, longer for treatments
`of chronic conditions. Most forward-looking pharmaceutical companies are aiming to reduce
`these times by re-evaluation and subsequently streamlining the development process, for ex-
`ample, by introducing more effective clinical programmes and more efficient data reporting
`systems, forward planning and conducting multiple activities in parallel. However, this, in
`turn, may put formulation development and clinical supplies on the critical path, with pres-
`sures to complete these activities in condensed time scales. Suggestions are offered through-
`out this book on how preformulation, biopharmaceutics and formulation can be conducted
`in the most efficient way to avoid delays in development times.
`Any reduction in the total time-frame of drug discovery to market should improve the
`company’s profitability. In a highly competitive market, product lifetimes are being eroded
`due to the pace of introduction of competitor products, the rapid introduction of generic
`products when patents expire and moves to “over-the-counter” (OTC) status. Successful phar-
`maceutical companies are focusing on strategies for optimum “product life cycle manage-
`ment” to maximise the early growth of the product on the market, sustain peak sales for as
`long as the product is in patent and delay the post-patent expiry decline for as long as possi-
`ble. This should maximise the return on investment during a product life cycle to enable the
`company to recover development costs and make further investments in R&D. Figure 1.2
`shows a classic cash flow profile for a new drug product developed and marketed. During de-
`velopment there is a negative cash flow, and it may be some time after launch before sales rev-
`enue crosses from loss to profit because of manufacturing, distribution and advertising costs.
`Profits continue to increase as the market is established to reach peak sales, after which sales
`decrease, especially after the primary patent expires and generic competition is introduced.
`Throughout the life span of a product, it is in a company’s interest to ensure the best
`patent protection in order to achieve the longest possible market exclusivity. Prior to the pri-
`mary patent expiring (normally for the chemical drug substance), it is imperative to introduce
`new indications, formulations, manufacturing processes, devices and general technology,
`which are patent protected, to extend the life of the product and maintain revenue. A patent
`generally has a term of about 20 years, but as development times are getting longer, there will
`be a limited duration of protection remaining once the product is marketed (the effective
`patent life). A comparison of effective patent life for pharmaceutical new chemical entities in
`various countries around the world shows the same downward trend between the 1960s and
`the 1980s (Karia et al. 1992; Lis and Walker 1988).
`Getting to the market quickly is a major business driving force, but this has to be balanced
`with the development of a product of the appropriate quality. There is a need to generate suf-
`ficient information to enable sound decisions on the selection of a candidate drug for devel-
`opment, as well as to develop dosage forms which are “fit for purpose” at the various stages of
`development. Anything more is wasting precious resources (people and drug substance),
`adding unnecessary cost to the programme and, more importantly, extending the development
`time. Perfect quality should not be the target if good quality is sufficient for the intended pur-
`pose. This can only be achieved if there is a clear understanding of the customer requirements.
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`Pharmaceutical Preformulation and Formulation
`
`Figure 1.2 Product life cycle management.
`CASH
`FLOW
`
`Primary patent expires
`
`Market
`penetration
`
`Research
`
`Development Launch
`
`Peak
`sales
`
`Increased competitor
`and generic products
`
`Market share held with line
`extensions
`
`No line extensions
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Increased
`development costs
`
`Manufacturing
`and launch costs
`
`Line extension
`development costs
`
`TIME
`(YEARS)
`
`+
`
`–
`
`For example, if a simple, non-optimised formulation with a relatively short shelf life is accept-
`able for Phase I clinical studies, any further optimisation or stability testing might be consid-
`ered wasteful, unless the data generated can be used later in the development programme.
`There can be a significant risk associated with doing a minimum development pro-
`gramme and cutting corners to fast track to market. Post-launch, the cost of a retrospective fix
`due to poor product/process design and/or development can be extremely high. The addi-
`tional financial cost from work in product/process redevelopment, manufacturing and vali-
`dation, technical support, regulatory and sales and marketing (due to a product recall) can
`easily wipe out the profit from an early launch. This can have several unpleasant knock-on ef-
`fects; it may affect the market share and the company’s relationship with the regulatory au-
`thorities, and its credibility with customers (both externally and internally within the
`company) may be threatened. These factors need to be taken in to account when planning pre-
`formulation/formulation studies which can directly influence the progress of a product to
`market and final product quality.
`
`CURRENT TRENDS IN THE PHARMACEUTICAL INDUSTRY
`
`Increasing competition and threats to the pharmaceutical industry with respect to maintain-
`ing continued sales growth and income mean that successful companies going forward will
`be those which have a portfolio of products capable of showing volume growth. However, to
`show volume growth innovative new products are required. The cost of drug discovery and
`development is escalating because there are no easy targets left and the cost of development
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`and the cost of goods sold is increasing. There have been several mergers and acquisitions of
`research-based pharmaceutical companies,