—
`
`» Pharmaceutical
`Preformulationand
`Formulation
`
`~_
`
`A Practical Guidefrom Candidate Drug
`
`Selection to Commercial Dosage Form
`
`
`
`CELGENE 2063
`~~ Mark Gibsc
`CELGENE2063
`APOTEX v. CELGENE
`STEX v. CELGENE
`ial
`-— R2023-00512
`IPR2023-00512
`
`
`/.- —
`
`|
`
`

`

`PHARMACEUTICAL
`PREFORMULATION
`AND
`FORMULATION
`
`A Practical Guide from
`Candidate Drug Selection to
`Commercial Dosage Form
`
`Mark Gibson
`
`Editor
`
`IHS® Health Group
`
`Your Enterprise Solution to
`Global Healthcare Knowledge
`
`

`

`director of publications.
`
`[HS® Health Group publishes books focused upon applied technology and regulatory affairs
`impacting healthcare manufacturers worldwide. If you are considering writing or
`contributing to a book applicable to the pharmaceutical, biotechnology, medical device,
`diagnostic, cosmetic, or veterinary medicine manufacturing industries, please contact our
`
`Invitation to Authors
`
`Library of Congress Cataloging-in-Publication Data
`
`Pharmaceutical preformulation and formulation : a practical guide from candidate drug
`selection to commercial dosage form / Mark Gibson,editor.
`p.
`3; cm.
`Includes bibliographic references and index,
`ISBN 1-57491-120-1 (hard ; alk. paper)
`1. Drugs—Dosage forms.I. Gibson, Mark, 1957-
`{DNLM:1. Drug Compounding. 2. Biopharmaceutics—methods.3. Chemistry,
`Pharmaceutical—methods. 4. Dosage Forms. 5. Drug Evaluation. QV 778 P53535 2001]
`RS200 .P425 2001
`615'.14—dce21
`
`Commissioned in Europe by Sue Horwood of Medi-Tech. Publications, Storrington, England, on behalf
`of IHS” Health Group, Denver, Colorado, USA. General Scientific Advisor: Dr. Guy Wingate, UK Quality
`Manager, Computer Systems Compliance, Secondary Manufacturing, Glaxo Wellcome, Barnard Castle,
`
`England.
`
`2001016816
`
`10987654321
`
`ISBN: 1-57491-120-1
`Copyright © 2001 by IHS® Health Group. All rights reserved.
`
`All rights reserved. This book is protected by copyright. Nopart of it may be reproduced,stored in a retrieval
`system,or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or oth-
`erwise, without written permission from the publisher. Printed in the United States of America.
`Where a product trademark, registration mark, or other protected mark is madein the text, ownership
`of the mark remains with the lawful owner of the mark. No claim,intentional or otherwise, is made by ref-
`erence to any such marksin this book.
`While every effort has been made by IHS® Health Groupto ensure the accuracy ofthe information con-
`tained in this book,this organization accepts no responsibility for errors or omissions.
`
`IHS” Health Group
`15 Inverness Way East
`Englewood, CO 80112-5776, USA
`
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`Phone:
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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
`
`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
`
`15
`
`15
`20
`20
`
`21
`
`22
`
`28
`
`34
`
`4)
`46
`
`48
`49
`
`58
`
`87
`
`88
`
`88
`
`

`

`iv
`
`4.
`
`Pharmaceutical Preformulation and Formulation
`
`Biopharmaceutical Support in Candidate Drug Selection
`Anna-Lena Ungelf 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 F,
`In Vivo Techniques for Studies in Man
`Vehicles for Absorption Studies
`Functional Use of Absorption Models
`References
`
`PARTII: Early Drug Development
`
`5.
`
`Early Drug Development: Product Design
`Mark Gibson
`
`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
`4
`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 II!: From Product Design to Commercial Dosage Form
`
`8.
`
`Product Optimisation
`
`Mark Gibson
`
`Product Optimisation Purpose and Scope
`Excipient and Pack Optimisation Considerations
`
`295
`
`295
`296
`
`

`

`Sources of Information
`
`Expert Systems
`Experimental Design
`Stability Testing
`Developing Specifications
`Process Design, Process Optimisation and Scale-Up
`Validation and Launch
`
`Acknowledgements
`References
`
`Parenteral Dosage Forms
`
`Joanne Broadhead
`
`Guiding Principles for Simple Parenteral Solutions
`Choice of Excipients
`Sterility Cansiderations
`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 fn 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
`
`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
`
`

`

`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
`
`531
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`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
`methodsused in preformulation with the underlying theory. To his credit, Wells’ bookisstill
`useful today, but sadly, the book is now outof 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 powderdiffraction (XRPD), raman and infra-red spectroscopy and
`solid-state nuclear magnetic resonance (NMR), to namea 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 developmentaspects
`of product development. The book also describes a logical and structured approach to the
`product development process, recommendingat what stages appropriate preformulation,bio-
`pharmaceutics and formulation workis best undertaken.
`
`DRUG DEVELOPMENT DRIVERS,
`CHALLENGES, RISKS AND REWARDS
`
`It is important that the readeris 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 Re~D can be defined as “converting ideas
`into candidate drugs for development’, and the objective of product development defined as
`“converting candidate drugs into productsfor registration andsale”. In reality, these goals are
`extremely challenging anddifficult to achieve because of the manysignificant hurdles a phar-
`maceutical company has to overcome during the course of drug development. Someof the
`major hurdlesarelisted 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,thefailure rate will vary from 1 in 5 to 1 in 10 compoundsthat will achieve regis-
`tration and reach the market-place. On top ofthat, thereis a significant commercial risk from
`those that are marketed; only 3 out of10 arelikely to achieve a fair return on investment. The
`products which give poor return on investmentare often the result of poor candidate drug se-
`lection (the compound doesnot have the desired properties ofsafety, selectivity, efficacy, po-
`tency or duration) and/or poor product development (the development programmedoes not
`establish the value of the product). The latter scenario should, and can be, avoided bycareful
`assessmentat the “product design” stage of development. Product design is discussed further
`in Chapter5.
`
`

`

`Introduction and Perspective
`
`3
`
`Table 1.1
`Major hurdles to successful product registration and sale.
`
`
`Activity
`Requirements
`
`
`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-approvalinspection
`Competitive
`!
`Meets customer needs
`
`Value for money
`
`Commercial reture
`1ee
`
`To be successful and competitive, research-based pharmaceutical companies must ensure
`that new discoveries are frequently brought to the market to generate cash flow. Thisis re-
`quired to fund the next generation of compounds to meet the therapeutic needsofpatients,
`and of course, to benefit the shareholders. This cycle of events is sometimesreferred to as the
`“productlife cycle” andis further illustrated in Figure 1.1.
`Thecosts of drug discovery and developmentto bring a New Chemical Entity (NCE) to
`the marketare ever increasing. It is currently estimated that in excess of U.S. $500 million is
`required to recoupthecosts of research, development, manufacturing, distribution, market-
`ing andsales. A significant proportionofthis total is for the cost offailures, or in other words,
`the elimination of unsuccessful compounds. R&D expenditure for an NCEtendsto increase
`substantially as the compound progresses from drug discovery research through the various
`clinical trial phases of development. The pivotal PhaseIII patienttrials are usually the largest,
`involving thousands ofpatients, and hence the most expensive. To reduce developmentcosts,
`
`

`

`4
`
`Pharmaceutical Preformulation and Formulation
`
`
`
`Figure 1.1 Productlife cycle.
`
`
` STRATEGIC
`
`Further market/medical needs
`RESEARCH
`
`
`— newindications
` £/$
`
`
`Based on company
`Sales &
`
`
`strategy
`profits
` EXPLORATORY
`
`RESEARCH
`
`
`
`
`MARKETING &
`
`COMMERCIAL
`
`
`
`Further market/
`
`
`medical needs
`Launch
`
`
`— product line
`
`
`
`Regulatory
`CANDIDATE
`extensions
`
`
`submissions
` SELECTION
`
`
`
`FULL
`DEVELOPMENT
`
`
`Candidate drug
`
`selected
`
`
`
`EXPLORATORY
`DEVELOPMENT
`
`
`Safety andefficacy
`demonstrated
`
`Proof of concept
`demonstrated
`
`
`some companiesselectively screen and eliminate compoundsearlier in the drug development
`process based on results from small-scale, less expensive studies in man and progress fewer,
`more certain compoundstolaterclinical phases.
`In spite of the high risks and high costs involved,thereis still a huge incentive for phar-
`maceutical companiesto seek the financial rewards from successful marketed products, and
`especially from the phenomenalsuccessofthe rare “blockbuster”(reachingsales of >1 billion
`U.S.$ per year). This can earn the companysignificant profits to reinvest in research and fund
`the product developmentpipeline.
`Anotherfactor, 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 productthat is 6 monthslate to marketwill 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). Theloss
`of productrevenueis often due to competitor companiesbeing first to market, capturing the
`market share and dictating the market price, in addition to the loss of effective patentlife.
`Hence, the importanceof accelerating and optimising drug discovery and development, and
`getting to the marketfirst with a new therapeutic class of medicinal product, cannot be un-
`derestimated. The second product to market in the sameclass will usually be compared with
`the marketleader, often unfavourably.
`
`

`

`Introduction and Perspective
`
`5
`
`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 phaseto select the candidate drug, and also
`an increase in the duration of theclinical and regulatory period required for marketing ap-
`proval. Benchmarkingstudies show wide gaps between industry average or worst performance
`compared to whatis 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 moreeffective clinical programmes and moreefficient data reporting
`systems, forward planning and conducting multiple activities in parallel. However, this, in
`turn, may put formulation developmentandclinical supplies on the critical path, with pres-
`sures to complete these activities in condensed timescales. Suggestions are offered through-
`out this book on how preformulation, biopharmaceutics and formulation can be conducted
`in the mostefficient way to avoid delays in developmenttimes.
`Any reduction in the total time-frame of drug discovery to market should improve the
`company’s profitability. In a highly competitive market, productlifetimes are being eroded
`due to the pace of introduction of competitor products, the rapid introduction of generic
`products when patents expire and movesto “over-the-counter” (OTC) status. Successful phar-
`maceutical companies are focusing on strategies for optimum “productlife 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
`showsa classic cash flow profile for a new drug product developed ‘and marketed. During de-
`velopmentthereis a negative cash flow, and it may be sometimeafter launch beforesales rev-
`enuecrosses 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.
`Throughoutthe life span of a product, it is in a company’s interest to ensure the best
`patentprotection in order to achieve the longest possible market exclusivity. Prior to the pri-
`marypatent 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 thelife of the product and maintain revenue. A patent
`generally has a term of about20 years, but as developmenttimes are getting longer, there will
`be a limited duration of protection remaining once the product is marketed (the effective
`patentlife). A comparison ofeffective patentlife for pharmaceutical new chemicalentities 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 developmentof 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 whichare “fit for purpose”at the variousstages of
`development. Anything more is wasting precious resources (people and drug substance),
`adding unnecessary cost to the programmeand, more importantly, extending the development
`time. Perfect quality should notbethe target if good quality is sufficient for the intended pur-
`pose. This can only beachievedif there is a clear understanding of the customer requirements.
`
`

`

`6
`
`Pharmaceutical Preformulation and Formulation
`
`SeeEee
`
`Figure 1.2 Productlife cycle management.
`
`CASH
`Primary patent expires
`FLOW
`
`
`
`
`Increased competitor
`Peak
`and generic products
`Teae
`Market
`—_—
`
`
`
`penetration
`
`Development Launch
`(YEARS)
`
`
`15 20)
`Manufacturing
`Line extension
`and launch costs
`development costs
`
`sm Market share held with line
`extensions
`
`Noline extensions
`
`TIME
`
`
`
`
`Research
`
`development cost
`
`
`
`For example,if a simple, non-optimised formulation with a relatively short shelflife is accept-
`able for PhaseI clinical studies, any further optimisationorstability testing might be consid-
`ered wasteful, unless the data generated can beusedlater in the development programme.
`There can be a significant risk associated with doing a minimum development pro-
`grammeandcutting cornersto fast track to market. Post-launch,the costof 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, technica] support, regulatory and sales and marketing (due to a productrecall) 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) maybethreatened. These factors need to be taken in to account whenplanning pre-
`formulation/formulation studies which can directly influence the progress of a product to
`market andfinal product quality.
`
`CURRENT TRENDS IN THE PHARMACEUTICAL INDUSTRY
`
`Increasing competition andthreats to the pharmaceutical industry with respect to maintain-
`ing continued sales growth and income meanthat successful companies going forward will
`be those which havea portfolio of products capable of showing volume growth. However, to
`show volume growth innovative new products are required. The cost of drug discovery and
`developmentis escalating because there are no easy targets left and the cost of development
`
`

`

`Introduction and Perspective
`
`7
`
`and the cost of goodssoldis increasing. There have been several mergers and acquisitions of
`research-based pharmaceutical companies, and increased collaborations and inward licensing
`of products and technologies, in attempts to acquire new leads,to share costs, to reduce the
`time to licence and to maintain growth. Unfortunately, mergers and acquisitionsalso result
`in streamlining and job losses which improveefficiency and decrease overheadcosts at the
`same time.
`There is a changing trend in the nature of the candidate drug emerging from pharma-
`ceutical R&D, from a low molecular weight chemical to a more complex macromolecule (bi-
`ologicals), which can be a peptide, protein, enzyme,antibody, nucleic acid, genetic material or
`a multicomponentvaccine. Someof these compounds have been derived from biotechnolog-
`ical processes to produce biotechnological medicinal products that fight infection and disease.
`The U.S. Food and Drug Administration (FDA) and European Agency for the Evaluation of
`Medicinal Products (EMEA) havealready approved biotechnological medicinal products for
`anaemia,cystic fibrosis, growth deficiency, hepatitis and transplant rejection. Many more are
`being developed to treat cancer, human immunodeficiency virus (HIV) infections and ac-
`quired immunodeficiency syndrome(AIDS), multiple sclerosis and stroke. A majorchallenge
`to the formulator is to develop self-administered formulations to deliver macromolecules
`such as proteins and polypeptides into the body, for example, by the oralor inhalation route.
`More sophisticated drug delivery systems are being developed to overcomethe limita-
`tions of conventional formsof drug delivery systems(e.g., tablets and intravenous[IV] solu-
`tions), to overcome problemsof poor drug absorption, the non-compliance of patients and
`inaccurate targeting of therapeutic agents. One example of an emerging drug delivery tech-
`nology is the use of low-level electrical energy to assist the transport of drugsacross the skin
`in a process known aselectrophoresis. This method could beparticularly useful for the deliv-
`ery of peptides and proteins which are not adequately transported by passive transdermal
`therapy. The drug absorptionrate is very rapid and more controlled compared with passive
`diffusion across the skin. Another example is the improvementin inhaler technology to en-
`sure a moreefficient delivery to the lungs, with minimal drug deposition in the mouth and
`trachea. Theuse ofa breath-actuated aerosol is designed to c#ordinate drug delivery with the
`patient’s inhalation to achieve this. A third example is the use of bioerodable polymers that
`can be implantedor injected within the body to administer drugs from a matrix which can be
`formulated to degrade over a long duration from one day to six months, and do notrequire
`retrieval. Someof these specific delivery systems are explained in moredetail in later chapters
`of this book on the various dosage forms.
`Futuristic drug delivery systems are being developed which hopeto facilitate the trans-
`port of a drug with a carrier to its intended destination in the body and thenreleaseit there.
`Liposomes, monoclonalantibodies and modified viruses are being considered to deliver “Te-
`pair genes” by IV injection to target the respiratory epithelium in the treatmentofcystic fi-
`brosis. These novel drug delivery systems not only offer clear medical benefits to the patient
`but can also be opportunities for commercial exploitation, especially useful if a drug is ap-
`proaching the end ofits patentlife.
`There are pressures on the pharmaceutical industry which affect the way products are
`being developed. For example, there is a trend for more comprehensive documentation to
`demonstrate compliance with current Good Manufacturing Practice (CGMP) and Good Lab-
`oratory Practice (GLP) and to demonstrate that systems and procedures havebeenvalidated.
`The trend is for more information required for a regulatory submission, withlittle flexibility
`for changes once submitted. Therefore, the pressure is for a company to submit early and de-
`velop the product “right first time”.
`
`

`

`8
`
`Pharmaceutical Preformulation and Formulation
`
`In spite of efforts to harmonisetests, standards and pharmacopoeias,thereisstill diver-
`sity between the major global markets—Europe, the United States and Japan—which have to
`be taken in to accountin the design of preformulation and formulation programmes(Anony-
`mous 1993). This is discussed further in Chapter 5 on productdesign.
`Otherpressures facing the pharmaceutical industry are ofa political/economicalor envi-
`ronmental nature. Some governmentsare trying to contain healthcare costs by introducing
`healthcare reforms, which maylead to reducedprices andprofit margins for companies,orre-
`stricted markets where only certain drugs can be prescribed. Although the beneficial effect of
`drugs is not questioned in general, the pressure to contain the healthcare costs is acute.
`Healthcare costs are increasing partly because peopleare living longer and more treatments
`are available. This may influence the commercial price that can be obtained for a new prod-
`uct entering the marketand,in turn, the “cost of goods (CoG)target”. The industry average
`for the CoGtarget is 5 to 10 percent of the commercialprice with pressure to keepit as low as
`possible. This may impact on the choice andcost of raw materials, components and packag-
`ing for the product and the design and cost of manufacturing the drug and product.
`Environmental pressures are to use environmentally friendly materials in products and
`processes and to accomplish the reduction of waste emissions from manufacturing processes.
`A good exampleis the replacementof chlorofluorocarbons (CFCs) propellants in pressurised
`metered dose inhalers (pMDIs) with hydrofluorocarbons (HFAs). The production of CFCs in
`developed countries was banned by the Montreal Protocol (an international treaty) apart
`from “essential uses’, such as propellants in pMDIs, to reduce the damageto the earth’s ozone
`layer. However, there is increasing pressure to phase out CFCsaltogether. Thetransition from
`CFC to HFA products involves a massive reformulation exercise with significant technical
`challenges and costs for pharmaceutical companies involved in developing pMDIs, as de-
`scribed in Chapter 10 “Inhalation Dosage Forms”. However, this can be turned into a com-
`mercial opportunity for some companies which have developed patent-protected delivery
`systemsto extend the productlife cycle of their CFC pMDIproducts.
`
`LESSONS LEARNT AND THE WAY FORWARD
`
`To achieve the best chanceofa fast andefficient development programmeto bring a candi-
`date drug to market, several important messages can be gleaned from projects which have
`gonewell and from companies with consistently good track records.
`There are benefits for pharmaceutical developmentto get involved early with preclinical
`research during the candidate drugselection phase. This is to move away from an “over-the-
`wall” hand-over approachof the candidate drug to be developed from “research”to “develop-
`ment”. The drugselectioncriteria will be primarily based on pharmacological properties such
`as potency,selectivity, duration of action and safety/toxicology assessments. However,if all
`these factors are satisfactory and similar, there may be an important difference between the
`pharmaceutical properties of candidate drugs. A candidate drug with preferred pharmaceuti-
`cal properties, for example, good aqueous solubility, crystalline, nonhygroscopic and good
`stability, should be selected to minimise the challenges involved in developing a suitable for-
`mulation. This is discussed further in Chapter 2.
`Another importantfactoris good long-term planning,ideally from candidate drug nom-
`ination to launch, with consideration for the safety, clinical, pharmaceutical development,
`manufacturing operations and regulatory strategies involved to develop the product. Thereis
`a need for one central, integrated, companyproject plan that has been agreed on byall parties
`
`

`

`Introduction and Perspective
`
`9
`
`with a vested interest in the project. Needless to say, the plan should contain details ofactivi-
`ties, timings, responsibilities, milestones, reviews and decision points. Reviews and decision
`points are requiredat the end ofa distinct activity to ensure thatthe projectis still meetingits
`objectives and should progress to the next stage of development. However, these reviews
`should notcause any delays to the programme,rather, they shouldratify whatis already pro-
`gressing. The traditional sequential phases of product development (see Chapter 2) must be
`overlapped to accelerate the product to market. In reality, plans will inevitably change with
`time; they should be “living” documents which are reviewed and updated at regular intervals
`and then communicatedto all parties. There may be several more detailed, lower-level plans
`focusing on departmentalactivities, e.g., for pharmaceutical development, but these plans
`mustbe linked to the top level central project plan.
`Forward planning should provide the opportunity for a well thought out andefficient ap-
`proachto product development,identifying requirements up frontso as to avoid too much de-
`liberation and backtracking along the way. It also should providea visible communication tool.
`Good planningis supported by adopting a systematic and structured approach to prod-
`uct development. The development process can be broken down into several key defined
`stages—productdesign, process design, product optimisation, process optimisation, scale-up
`and so on. Eachstage will have inputs and outputs as shownin Figure 1.3, a simplified frame-
`workfor product development. The appropriate definition and requirementsat eachstage are
`described in Chapters 5 and8ofthis text.
`As product developmentcan take several years to complete,it is important to havean ef-
`fective document managementsystem in place to record the work. The primary reference
`source for recording experimental work will usually be a laboratory notebook. The work
`should be checked, dated and counter-signed to satisfy GLP and intellectual property re-
`quirements. Experimental protocols are sometimesuseful for defining programmesof work,
`
`
`Figure 1.3 Frameworkfor product development.
`
`>
`PLANNING / DOCUMENTATION
`@ Candidate Drug
`
`i
`
`Product
`
`Product Profile
`Critical Quality Parameters
`
`Peeeticn
`
`ae Quantitative Formula
`* Raw Material / Component Specifications
`
`Process
`
`Process Outline
`———-> Equipment / Facility Definition
`
`-
`=
`Scale-Upfor Clinical Trials
`
`In-Process Controls
`*
`* ProductSpecification
`Scale-Up for Commercial
`Production
`
`Process Validation
`NDA
`@Submission
`
`Manufacture Launch Stock
`
`Phase IV
`
`
`

`

`10
`
`Pharmaceutical Preformulation and Formulation
`
`explaining the rationale for the studies and defining the acceptance criteria. Whenthe studies
`are completed, the results can be reported with reference to the protocol and acceptancecri-
`teria. Laboratory notebooks are referenced in the protocols and reports so that the raw data
`can be retrieved in the event of an audit.
`At the completion of key stages of the work, summaryreports can be written, referencing
`all