FORMULATION ANDANALYTICALDEVELOPMENT FORLOW-DOSE ORAL DRUGPRODUCTS
Edited By
JACK ZHENGPharmaceutical Sciences R&D, Lilly Research Labs, Eli Lilly and Company
InnodataFile Attachment9780470386354.jpg
FORMULATION ANDANALYTICALDEVELOPMENT FORLOW-DOSE ORAL DRUGPRODUCTS
FORMULATION ANDANALYTICALDEVELOPMENT FORLOW-DOSE ORAL DRUGPRODUCTS
Edited By
JACK ZHENGPharmaceutical Sciences R&D, Lilly Research Labs, Eli Lilly and Company
Copyright # 2009 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada
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Library of Congress Cataloging-in-Publication Data:
Formulation and analytical development for low-dose oral drug products /[edited by] Jack Zheng.
p. ; cm.Includes bibliographical references and index.ISBN 978-0-470-05609-7 (cloth)
1. Drugs—Dose-response relationship. 2. Drugs—Dosage. 3. Oralmedication. 4. Drug development. I. Zheng, Jack.[DNLM: 1. Chemistry, Pharmaceutical—methods. 2. Administration, Oral.
3. Drug Evaluation, Preclinical—methods. 4. Drug Industry. QV 744 F7262008]RM301.8.F67 20086150.1—dc22
2009009573
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
http://www.copyright.comhttp://www.wiley.com/go/permissionhttp://www.wiley.com
Opportunities multiply as they are seized
—Sun Tsu
To my wonderful wife Lijuan and my talented children Karen and Allen fortheir love, encouragement, and support
CONTENTS
PREFACE xv
FOREWORD xix
CONTRIBUTORS xxi
1 AN OVERVIEW 1Jack Y. Zheng
1.1 The Drug Discovery and Development Process 21.2 Challenges and Strategies in Development of Low-Dose Drug Products 101.3 Summary 20Acknowledgments 20References 20
I CHALLENGES AND STRATEGIES IN FORMULATIONDEVELOPMENT OF ORAL LOW-DOSE DRUGPRODUCTS 23
2 CHALLENGES AND STRATEGIES IN FORMULATIONDEVELOPMENT OF ORAL SOLID LOW-DOSE DRUGPRODUCTS 25Jack Y. Zheng
2.1 Introduction 25
2.2 Current Regulatory Environment and its Impacton New Drug Product Development 28
2.3 Challenges in Developing Low-Dose Formulations 31
vii
2.4 Manufacturing Platforms for Low-Dose Drug Products 38
2.5 Use of Experimental Design in Formulation and Process Development 42
2.6 Containments 44
2.7 Summary 45
Acknowledgments 46
References 46
3 PARTICLE SIZE OF DRUG SUBSTANCE ANDPRODUCT CONTENT UNIFORMITY—THEORETICALCONSIDERATIONS 49Kevin C. Johnson
3.1 Introduction 49
3.2 Concept of Ideal Mixing 50
3.3 Ideal Mixing Model Comparison with the Yalkowsky andBolton Approach 56
3.4 Experimental Support of Model Assumptions 59
3.5 Analytical and Practical Considerations 61
References 62
4 DEVELOPMENT OF LOW-DOSE FORMULATIONS USINGFLUIDIZED BED GRANULATION 63J. Joe Zhou and Ralph Lipp
4.1 Introduction 63
4.2 Granulation Fundamentals 66
4.3 Theory of Fluidization 68
4.4 Formulation Development 72
4.5 Process Development 77
4.6 Summary 86
References 86
5 DEVELOPMENT OF LOW-DOSE SOLID ORALFORMULATIONS USING WET GRANULATION 89Ahmad Almaya
5.1 Introduction 89
5.2 Granulation Mechanisms 91
5.3 General Considerations on Wet Granulation 93
5.4 Advantages and Disadvantages of Wet Granulation 100
5.5 Use of Wet Granulation for Low-Dose Formulations 101
5.6 Process-Induced Form Changes in Wet Granulation 109
5.7 Concluding Remarks 111
References 112
viii CONTENTS
6 CHALLENGES IN DEVELOPMENT AND SCALE-UP OFLOW-DOSE DRUG PRODUCTS BY DRY GRANULATION:A CASE STUDY 117Mary T. Am Ende, Daniel O. Blackwood, Daniel S. Gierer, andChristopher P. Neu
6.1 Introduction 117
6.2 Dry Granulation Process—Pros and Cons 118
6.3 Overview of Dry Granulation Processes and Equipment Design 119
6.4 Challenges for Low-Dose Product Development and theirAssessment Methods 125
6.5 Case Study: Formulation Challenges for Low-Dose Products 128
6.6 Process Challenges During Dry Granulation Optimizationfor Low-Dose Products 140
6.7 Conclusions 154
Acknowledgments 155
References 155
7 DEVELOPMENT OF LOW-DOSE SOLID ORAL TABLETSUSING DIRECT COMPRESSION 159Jack Y. Zheng and Robert L. Ternik
7.1 Introduction 159
7.2 Advantages of Direct Compression 160
7.3 Challenges in Low-Dose Tablet Development Using Direct Compression 162
7.4 Formulation Development for Low-Dose Drug ProductsUsing Direct Compression 169
7.5 Manufacturing Process Development for Low-Dose Drug Products 187
7.6 Scale-Up for Blending Operation 196
7.7 Formulation Examples for Direct Compression 197
7.8 Conclusions 199
Acknowledgments 199
References 200
8 REDUCTION OF PARTICLE SIZE OF DRUG SUBSTANCEFOR LOW-DOSE DRUG PRODUCTS 205Christopher L. Burcham, Paul C. Collins, Daniel J. Jarmer,and Kevin D. Seibert
8.1 Introduction 205
8.2 Reduction of Particle Size of Drug Substance by Milling Technologies 207
8.3 Reduction of Particle Size of Drug Substance UsingCrystallization Technologies 216
8.4 Scale-Up Considerations 218
CONTENTS ix
8.5 Emerging Technologies and Future Directions 219
Acknowledgments 219
References 219
9 FUNCTION, QUALITY, AND REGULATIONS OFPHARMACEUTICAL EXCIPIENTS FOR ORAL SOLIDDOSAGE FORMS 223Jack Y. Zheng
9.1 Introduction 223
9.2 Classification of Pharmaceutical Excipients in Solid Dosage Forms 224
9.3 Physicochemical Attributes of Pharmaceutical Excipients 225
9.4 Regulatory Status and Excipient Quality 228
9.5 Summary 235
Acknowledgments 235
References 236
II CHALLENGES IN ANALYTICAL METHODDEVELOPMENT FOR ORAL LOW-DOSEDRUG PRODUCTS 239
10 ANALYTICAL METHOD DEVELOPMENT:CHALLENGES AND SOLUTIONS FOR LOW-DOSEORAL DOSAGE FORMS 241Beverly Nickerson, Reena M. Joseph, Charles Palmer,Alex M. Opio, and George H. Beresford
10.1 Introduction 241
10.2 Case Study 1: Drug Adsorption to Surfaces 242
10.3 Case Study 2: Challenges Due to Nondrug-Related Impurities 245
10.4 Case Study 3: HPLC Purity Method Development Challenges fora Fixed Combination Product Containing a Low-Dose ActiveIngredient and a High-Dose Active Ingredient 250
10.5 Case Study 4: Small Volume Dissolution Testing 255
10.6 Summary 261
Acknowledgments 261
References 261
11 IN VITRO DISSOLUTION TESTING AND METHODDEVELOPMENT 265Vivian A. Gray, Jack Y. Zheng, and Norman N. Sesi
11.1 Introduction 265
11.2 Overview of Dissolution Testing 265
x CONTENTS
11.3 Dissolution Method Development 271
11.4 Dissolution Method Development for Low-Dose OralDrug Products 275
11.5 Summary 279
References 280
12 ANALYSIS OF PHYSICAL TRANSFORMATION OFAPI DURING MANUFACTURE AND STORAGE 283Gregory A. Stephenson
12.1 Introduction 283
12.2 Discussion of Solid-State Forms 284
12.3 Monitoring Processing Steps 285
12.4 Measuring Transitions and Solid-Form Transformationsin the Low-Dose Tablet 287
12.5 Common Methods Used for Examination ofSolid Forms 289
12.6 Conclusions 305
References 306
13 PHYSICAL CHARACTERIZATION TESTSFOR DRUG SUBSTANCES USED INLOW-DOSE FORMULATIONS 309Ronald G. Iacocca
13.1 General Issues in the Physical Characterization ofMicronized Powders Used in Low-Dose Formulations 309
13.2 Particle Size Analysis 309
13.3 Specific Surface Area Analysis 320
13.4 Summary 323
References 323
14 AN EXCIPIENT LIBRARY APPROACH TO ANALYTICALDEVELOPMENT FOR LOW-DOSE, SOLID ORALDOSAGE FORM DRUG PRODUCTS 327Qing Chang, Lisheng Kang, Keri Varner, Joyce Bridges,Norman Sesi, and Margo Palmieri
14.1 Introduction 327
14.2 Importance of Excipient Absorbance Background toLow-Dose Impurity Analysis 328
14.3 Factors Affecting Excipient Absorbance Background 332
14.4 Use of Excipient Library 339
CONTENTS xi
14.5 Conclusions 341
Acknowledgments 341
References 342
15 CLEANING VERIFICATION FOR HIGHLY POTENTCOMPOUNDS 345Brian W. Pack
15.1 Introduction 345
15.2 Cleaning Validation vs Cleaning Verification 346
15.3 Acceptance Limit Calculations 347
15.4 Analytical Method Validation 352
15.5 General Analytical Techniques 361
15.6 Analytical Techniques for Low-Dose Compounds 364
15.7 Conclusions 376
Acknowledgments 377
References 377
III CONTAINMENT TECHNIQUES FOR HIGHLYPOTENT PHARMACEUTICAL COMPOUNDS 381
16 CONTAINMENT CHALLENGES AND STRATEGIESFOR POTENT COMPOUNDS IN THEPHARMACEUTICAL INDUSTRY 383Victoria Cathcart, Sarah Jones, and Beverly Nickerson
16.1 Introduction 383
16.2 Safe Exposure Control Levels—Bands, Limits, andHandling Guidance 384
16.3 The Hierarchy of Workplace Controls 389
16.4 Case Studies 397
16.5 Summary 403
Acknowledgments 403
References 403
17 SAMPLE HANDLING AND CONTAINMENT INANALYTICAL TESTING LABORATORIES 405David S. Pattavina, Nancy Sage, and Beverly Nickerson
17.1 Introduction 405
17.2 Sample Handling Considerations 406
17.3 Handling Potent Compounds in Standard Analytical Laboratories 407
xii CONTENTS
17.4 Handling Potent Compounds in a Containment Laboratory 411
17.5 Additional Considerations for Handling Potent Materials 426
17.6 Summary 427
Acknowledgments 428
References 428
IV REGULATORY CONSIDERATIONS IN THEDEVELOPMENT OF LOW-DOSE DRUGPRODUCTS 429
18 REGULATORY CONSIDERATIONS IN THE DEVELOPMENTOF LOW-DOSE SOLID ORAL DRUG PRODUCTS 431Ravi S. Harapanhalli
18.1 Introduction and Overview 431
18.2 Three-Pronged Approach to Low-Dose Formulations 433
18.3 Pharmaceutical Development Report 434
18.4 Facility Controls for Highly Potent Drugs 451
18.5 Conclusion 452
References 453
INDEX 455
CONTENTS xiii
PREFACE
In November 2005, I co-chaired a symposium entitled “Analytical and FormulationDevelopment Strategies, Challenges and Regulatory Considerations for Low-doseDrug Products” during the annual meeting of the American Association ofPharmaceutical Scientists. The goal of the symposium was to provide an overviewon development of low-dose drug products from the perspective of pharmaceutical,analytical, and regulatory sciences, including formulation design, process develop-ment, analytical method development, and regulatory considerations. The presentersincluded Dr Norm Sesi from Eli Lilly and Company, Dr Ravi Harapanhalli fromthe U.S. Food and Drug Administration, Dr Mary am Ende from Pfizer Inc., andDr Keith Hutchison from Capsugel, Division of Pfizer Inc. After the meeting, Iwas approached by John Wiley & Sons Inc. to discuss the publication of a bookon analytical and formulation development of low-dose drug products. As a pharma-ceutical scientist who has worked in product development for more than a decade, Iknow that product development scientists in the pharmaceutical industry and thegraduate students in the pharmacy schools will benefit from a book that collectsthe existing knowledge, techniques, and strategies in development of low-dosedrug products. After two years of diligent work, all contributors and the publisher,John Wiley& Sons Inc., have made the book available to our readers.
Formulation and Analytical Development for Low-Dose Oral Drug Productsfocuses on the key topics involved in the challenges and strategies in analytical,formulation, and regulatory perspectives for development of low-dose drug products.The book begins with eight chapters devoted to aspects of formulation and process
xv
development of low-dose drug products, including theoretical consideration ofparticle size of drug substance, micronization and physical characterization of drugsubstance, control of excipients, and different manufacturing platform technologies.Chapter 2 provides an overview of challenges and strategies in formulation develop-ment of low-dose drug products. Chapters 4–7 are concerned with formulation andprocess development of low-dose drug products. Commonly used manufacturingplatform technologies for low-dose drug products are discussed, such as high-shearwet granulation, fluid bed granulation, direct compression, and roller compaction.Chapters 3, 8, and 9 deal with drug substance, ranging from theoretical considerationof particle size according dose strengths, the methods for micronization of drugsubstance, and quality and functionality of pharmaceutical excipients.
Chapters 10–13 focus on challenges in analytical method development forlow-dose drug products, including physical characterization of the micronizedpowder and the solid state of API in dosage forms. Analytical issues related tolow-dose assay and impurities are discussed together with some specific casestudies. Chapter 11 provides guidance on how to run appropriate dissolutiontesting so that meaningful data can be obtained. Chapter 14 provides a particularlyinteresting perspective on how pharmaceutical excipients should be controlled inthe development of low-dose drug products and how an excipients library can helpformulation scientists select appropriate excipients for better control of productquality. There is also a chapter specifically addressing practical concerns inthe pharmaceutical industry with respect to cleaning verification of manufacturingequipment, illuminated by many examples.
The last section of the book is devoted to a few very important topics indevelopment of low-dose drug products, including regulatory perspectives andcontainment technologies used in analytical laboratories and manufacturing plants.I hope that this combination of topics will enable the readers to obtain a broadoverview on development of low-dose drug products.
I sincerely acknowledge the contributing authors of this book and thank them fortheir cooperation in the timely preparation of their specialized chapters, whichallowed me to produce a book that reflects state-of-the-art thinking in analyticaland formulation development of low-dose drug products. I would especially like tothank Drs Joe Zhou, Ralph Lipp, and Paul Collins for stepping in at the final hourand writing chapters on the fluid bed granulation technology and micronization ofdrug substance. Without these chapters, the book would have been incomplete.Also, I give my appreciation to Drs Gus Hartauer, Dave Maclaren, Ralph Lipp,Eugene Inman, Bret Huff, and Tom Verhoeven for their tremendous support andencouragement for my preparing this book. My sincerest thanks to Ms KarenBoleyn, a senior technical writer, for reviewing and making editorial correctionsfor several chapters in this book. Special thanks are expressed to Drs David Long,Tim Woznik, David Moeckly, Paul Sirois, James Wood, and Thirumala Kommurufor peer review of book chapters. Further, I would like to thank the editors at JohnWiley and Sons Inc., in particular Jonathan Rose, for his accessibility and helpfulness
xvi PREFACE
in all aspects of the book’s production. Finally, I would like to thank my wife Lijuan(Susan) and my talented children, Karen (a Yalie) and Allen, for their love, under-standing, and support in the time I have spent editing this book. Now I will havemore time for them upon the completion of this project.
JACK ZHENG, PH.D.
Indianapolis, Indiana
PREFACE xvii
FOREWORD
A few years ago, I sat in my office with Dr Jack Zheng as we discussed a technicallychallenging chemical stability issue we were having with a very-low-dose formu-lation of an early-phase clinical compound. There are unique challenges that adevelopment team faces with low-dose compounds delivered orally; in effect, weagreed that it would be extremely useful to generate an internal guidance leveragingour collective in-house knowledge in this area. Jack not only acted on that idea, buthas gone one better by recruiting a team of experienced scientists from multiplecompanies across the industry to author a book on this very topic.
At first glance, the thought of bringing forward a molecule with very low dosescan have an appealing upside. One specific benefit is seen in reduced quantities ofoften very expensive active pharmaceutical ingredient (API) needed during thevarious stages of the development process, as well as impact on COPS. While thisis definitely an advantage, this book clearly demonstrates that the hurdles presentin developing a low-dose product can quickly offset that advantage. Time andexpense can increase if the team does not robustly plan for and develop a formulation,manufacturing process, and analytical/API physical property control strategy toovercome those challenges. The most effective development plan in these casesarises from a multidisciplinary approach to bring to bear the best science and explora-tion of appropriate design space. This approach is reflected in the individual chaptersof this book, where specific technical areas such as in vitro dissolution testing,physical transformation and containment techniques are discussed, but in thecontext of the ultimate goal of developing a commercial product.
The development of low-dose formulations is certainly not new to the pharma-ceutical industry; one obvious example is the long-term clinical use of digoxintablets. However, with the introduction of new technologies to identify molecular
xix
targets and the use of high-throughput screening techniques to select structureswith increased selectivity and activity toward a given target, the trend has beentoward an ever-increasing amount of candidates dosed in the submilligramrange. The increase in candidates meeting this definition of low-dose, along withthe combination of increasing regulatory (e.g., impurity specifications) and technicalrequirements for such products, makes this book a valuable and timely contribution topharmaceutical sciences.
Recent estimates have approached $1.2 billion for the cost of development ofa new chemical entity into a commercial drug product (i.e., medicine). This bookis a systematic, technical collection on this relevant topic than can help lead toa more effective and efficient drug development process. I consider it to be awelcome addition to the library of all drug product developers involved in bringingnew therapies to patients.
KERRY “GUS” HARTAUER, PH.D.
Director—Pharmaceutical Sciences R&DEli Lilly and Company
xx FOREWORD
CONTRIBUTORS
AHMAD ALMAYA, PH.D., Pharmaceutical Sciences R&D, Lilly Research Labs, EliLilly and Company, Indianapolis, Indiana
H. GEORGE BERESFORD, Analytical Research & Development, DevelopmentScience & Technology, Global Research and Development, Pfizer, Inc., Groton,Connecticut
DANIEL O. BLACKWOOD, M.S., Pfizer Global Research & Development, Oral ProductsCenter of Emphasis, Pfizer, Inc., Groton, Connecticut
JOYCE BRIDGES, Analytical Sciences R&D, Lilly Research Labs, Eli Lilly andCompany, Indianapolis, Indiana
CHRISTOPHER L. BURCHAM, PH.D., Chemical Product R&D, Lilly Research Labs, EliLilly and Company, Indianapolis, Indiana
VICTORIA CATHCART, Scientific Safety, Global Operations Environmental Health &Safety, Pfizer, Inc., Groton, Connecticut
QING CHANG, PH.D., Analytical Sciences R&D, Lilly Research Labs, Eli Lilly andCompany, Indianapolis, Indiana
PAUL C. COLLINS, PH.D., Chemical Product R&D, Lilly Research Labs, Eli Lilly andCompany, Indianapolis, Indiana
MARY T. AM ENDE, PH.D., Pfizer Global Research & Development, Oral ProductsCenter of Emphasis, Pfizer, Inc., Groton, Connecticut
DANIEL S. GIERER, PH.D., Pfizer Global Research & Development, Oral ProductsCenter of Emphasis, Pfizer, Inc., Groton, Connecticut
VIVIAN A. GRAY, V. A. Gray Consulting, Inc., Hockessin, Delaware
xxi
RAVI S. HARAPANHALLI, PH.D., Branch V, Division of Pre-marketing Assessment andManufacturing Science, Office of New Drug Quality Assessment, Office ofPharmaceutical Science, Center for Drug Evaluation and Research. Food andDrug Administration, Silver Spring, Maryland
RONALD G. IACOCCA, PH.D., Analytical Sciences R&D, Lilly Research Labs, Eli Lillyand Company, Indianapolis, Indiana
DANIEL J. JARMER, PH.D., Chemical Product R&D, Lilly Research Labs, Eli Lilly andCompany, Indianapolis, Indiana
KEVIN C. JOHNSON, PH.D., Intellipharm, LLC, Niantic, Connecticut
SARAH JONES, Scientific Safety, Global Operations Environmental Health & Safety,Pfizer, Inc., Groton, Connecticut
REENA M. JOSEPH, Research Formulations, Research Science & Technology, GlobalResearch & Development, Pfizer, Inc., Groton, Connecticut
LISHENG KANG, PH.D., Pharmaceutical Sciences R&D, Lilly Research Labs, Eli Lillyand Company, Indianapolis, Indiana
RALPH LIPP, PH.D., Pharmaceutical Sciences R&D, Lilly Research Labs, Eli Lilly andCompany, Indianapolis, Indiana
CHRISTOPHER P. NEU, M.S., Pfizer Global Research & Development, Oral ProductsCenter of Emphasis, Pfizer, Inc., Groton, Connecticut
BEVERLY NICKERSON, PH.D., Analytical Research & Development, DevelopmentScience & Technology, Global Research & Development, Pfizer, Inc., Groton,Connecticut
ALEX M. OPIO, Analytical Research & Development, Development Science &Technology, Global Research & Development, Pfizer, Inc., Groton, Connecticut
BRIAN W. PACK, PH.D., Analytical Sciences R&D, Lilly Research Labs, Eli Lilly andCompany, Indianapolis, Indiana
CHARLES PALMER, Analytical Research & Development, Development Science &Technology, Global Research & Development, Pfizer, Inc., Groton, Connecticut
MARGO PALMIERI, PH.D., Analytical Sciences R&D, Lilly Research Labs, Eli Lillyand Company, Indianapolis, Indiana
DAVID S. PATTAVINA, Research Analytical, Research Science & Technology, GlobalResearch & Development, Pfizer Inc., Groton, Connecticut
NANCY SAGE, Chemical Research & Development, Development Science &Technology, Global Research & Development, Pfizer, Inc., Groton, Connecticut
KEVIN D. SEIBERT, PH.D., Chemical Product R&D, Lilly Research Labs, Eli Lilly andCompany, Indianapolis, Indiana
NORMAN SESI, PH.D., Elanco Animal Health, Eli Lilly and Company, Indianapolis,Indiana
xxii CONTRIBUTORS
GREGORY A. STEPHENSON, PH.D., Pharmaceutical Sciences R&D, Lilly ResearchLabs, Eli Lilly and Company, Indianapolis, Indiana
ROBERT L. TERNIK, PH.D., Pharmaceutical Sciences R&D, Lilly Research Labs, EliLilly and Company, Indianapolis, Indiana
KERI VARNER, Analytical Sciences R&D, Lilly Research Labs, Eli Lilly andCompany, Indianapolis, Indiana
JACK Y. ZHENG, PH.D., Pharmaceutical Sciences R&D, Lilly Research Labs, Eli Lillyand Company, Indianapolis, Indiana
J. JOE ZHOU, PH.D., Engineering Technology Center, Eli Lilly and Company,Indianapolis, Indiana
CONTRIBUTORS xxiii
CHAPTER 1
AN OVERVIEWJACK Y. ZHENGPharmaceutical Sciences R&D, Lilly Research Laboratories, Eli Lilly and Company,Indianapolis, IN 40285
U.S. law defines a drug as any substance, other than a food or device, either (1)intended for use in the diagnosis, cure, relief, treatment, or prevention of diseaseor (2) intended to affect the structure or function of the body. The mission ofpharmaceutical scientists is to continue developing safer and more effective newdrugs to conquer various human diseases. However, successfully developing newmedicines for patients requires significant collaboration of many interdisciplinarysciences, including:
† molecular biology;† medicinal chemistry;† pharmacology;† toxicology;† preformulation;† formulation;† clinical evaluation;† synthetic chemistry;† quality assurance/control;† regulatory affairs;† sales and marketing.
The objectives of formulation and analytical scientists are to develop new drugproducts for human use that are chemically and physically stable, bioavailableupon administration, manufacturable, cost-effective, elegant, and marketable.
Formulation and Analytical Development for Low-Dose Oral Drug Products. Edited by Jack ZhengCopyright # 2009 John Wiley & Sons, Inc.
1
Pharmacologically, a drug should demonstrate its ability to:
† target the intended site or receptor (selectivity);† remain attached to the receptor (affinity);† show its effectiveness (efficacy);† show its safety (adverse/side effects).
Ideally, a drug should be highly selective for its biological target, so that it haslittle or no effect on other physiological systems. The drug should also be verypotent and effective, so that low doses of drug substance can be used, even fordisorders that are difficult to treat. Finally, the drug should be administered orally,not only for patient compliance, but also for ease of production, distribution,and administration.
Drug product development is a process of transforming concept into reality. Theprocess is not only science, but also art. After selecting a new drug candidate, drugdevelopment moves from preclinical studies to critical clinical investigation, and thento various stages of clinical and commercial product development. A drug candidatecan become a drug product only when the compound is clinically efficacious andsafe, and the developed product is bioavailable and stable, produces the desiredpharmacological effects, and can be manufactured consistently with the identity,strength, quality, and purity it is represented to possess.
During development of an oral solid dosage form, dose strength is one of the criti-cal product attributes that may have a significant impact on formulation and analyticaldevelopment. Especially for a low-dose drug product, pharmaceutical scientists facegreat challenges in formulation, manufacture, analytical chemistry, and regulatoryrequirements.
This book addresses the challenges and strategies in developing low-dose oralsolid drug products (i.e., less than 1 mg per dose unit), and aids development scien-tists in improving research and development productivity with a scientific and struc-tured approach to product development. The information presented in the book isbased on the extensive experience of the contributors, all of whom are activelyworking in the pharmaceutical industry and/or regulatory agency and have gainedsignificant knowledge from their practical experience.
1.1 THE DRUG DISCOVERY AND DEVELOPMENT PROCESS
Drug discovery and development is a time-consuming and unpredictable process aswell as an expensive venture. Today the average cost to research and develop eachsuccessful drug is estimated to be somewhere between $1.2 billion and $1.5billion.1 The whole adventure is highly innovative, highly risky, highly regulated,and highly technology- and information-intensive. Typically, it takes 10–15 yearsto develop a safe and effective new medicine from the early stage of discoveryuntil the drug is available to treat patients.2 This process, as illustrated in Fig. 1.1,
2 AN OVERVIEW
is normally divided into two key phases: discovery and development. During thesephases, scientists have to:
† understand disease status, hypothesize “targets” that new drugs might be able toaffect, and validate the targets;
† discover the molecule(s) to interact with the target hypothesized;† assess the new compound (drug candidate) in the laboratory and clinic for safetyand efficacy;
† develop the right drug product/dosage form for the intended use;† gain regulatory approval and get the new drug into the hands of physicians andpatients.
1.1.1 The Discovery Phase
Before discovering any new drug, scientists strive to understand the disease needingtreatment and unravel the underlying cause of the condition. To do this, theyinvestigate:
† how the genes are altered;† how that alteration affects the proteins they encode;† how those proteins interact with each other in living cells;† how those affected cells change the specific tissue they are in;† how the disease affects the patient.
This knowledge is the critical foundation for hunting a new medicine and treatingthe disease.
In 2001, scientists completed the sequencing of the human genome. They foundthat the genome of Homo sapiens consists of 24 distinct chromosomes (22 autosomaland the sex-determining X and Y chromosomes). There are approximately 3 billion
Figure 1.1 New drug discovery and development process. (See color insert.)
1.1 THE DRUG DISCOVERY AND DEVELOPMENT PROCESS 3
DNA base pairs containing an estimated 20,000–25,000 genes.3,4 Each gene codesfor a protein, and these proteins carry out all the functions of the human body,laying out how it grows and works. These genes and proteins can also be involvedin disease. Hence, scientists are able to understand the inner workings of humandisease at both the tissue level and the molecular level.
Once scientists understand the underlying cause of a disease, they can select a“target” for a potential new drug. A target is generally a single molecule, such as agene or protein, which is involved in a particular disease state. Scientists call thisearliest step in drug discovery “target identification.”
After identifying a potential target, scientists must demonstrate that it actually isinvolved in the disease and that a drug can act on it. This process is called “targetvalidation.” Target validation is a crucial step in the drug discovery process thathelps scientists minimize research paths that look promising, but that ultimatelylead to dead ends. Target validation involves proving that DNA, RNA, or a proteinmolecule is directly involved in a disease process in vitro and in vivo, and that itcan be a suitable target for a new therapeutic drug. Scientists use several methodsto validate a target.
One type of target validation uses computer models. They are a fast, relativelycheap option for initial screening of both targets and potential drugs. The modelsusually focus on how the two types of candidate structures interact with eachother.5 Sense reversal is another route to target validation. It hinges on disruptinggene expression to reduce the amount of the corresponding protein, thereby identify-ing the physiological role of the target. Examples of this technique include geneknockouts, antisense technology, and RNA interference (RNAi).
One disadvantage of doing target validation at the genetic level, however, isthat many genes produce several different protein isoforms that can have subtly differ-ent functions. Post-translational modifications can also give protein variations. Toaddress these issues, a developing approach in target validation, proteomics, focuseson manipulating the activity of the potential target protein itself. Proteomics investi-gates and manipulates the protein make-up of a cell so it is easier to distinguish andtarget just one specific form of a protein.
In vivo target validation involves more complicated experiments in animal modelsof diseases.5 However, animal models for certain diseases, such as psychiatric ill-nesses, are extremely difficult to develop. The alternative is to use gene knockouts,in which genes are deleted or disrupted to halt their expression in vivo. This canbe a powerful method of predicting drug action. This method is based on the assump-tion that knocking out the gene for the potential target has the same effect as admin-istering a highly specific inhibitor of the target protein in vivo. Once the target isvalidated, it can then be used for screening potential new drug candidates.
Scientists screen thousands of compounds (either by synthesizing or choosingfrom libraries) to find a molecule, or “lead compound,” that may interact with thetarget to alter the disease course. De novo and high-throughput screening aremethods commonly used to find a lead compound.6,7 Promising lead candidatesare called “hits.” Hits go through a series of tests to provide an early assessment ofthe safety, efficacy, and pharmacokinetic properties.
4 AN OVERVIEW