FORMULATION AND ANALYTICAL DEVELOPMENT FOR LOW …€¦ · FORMULATION AND ANALYTICAL DEVELOPMENT...

FORMULATION ANDANALYTICALDEVELOPMENT FORLOW-DOSE ORAL DRUGPRODUCTS

Edited By

JACK ZHENGPharmaceutical Sciences R&D, Lilly Research Labs, Eli Lilly and Company

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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


7.2 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


8.2 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


9.2 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


10.2 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


11.2 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


12.2 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


14.2 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


Acknowledgments 341

References 342

15 CLEANING VERIFICATION FOR HIGHLY POTENTCOMPOUNDS 345Brian W. Pack


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


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


16.2 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


17.2 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

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