Formulation and Analytical Development for Low-Dose Oral Drug Products / Edition 1

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Developing and commercializing a low-dose oral drug product presents a number of hurdles that can quickly offset the drug's benefits. Written by a team of leading scientists in drug development, this book collects and synthesizes the knowledge, techniques, and strategies needed for developing low-dose drugs successfully. With this book's practical support, readers can overcome the hurdles at all stages in drug development, from formulation to manufacturing and control to regulatory compliance.
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Editorial Reviews

From The Critics
Reviewer: Joseph Boullata, PharmD (University of Pennsylvania College of Nursing)
Description: This welcome addition to books on dosage formulations has as its focus the challenging issue of developing and bringing to market oral drug products containing a low dose (< 1 mg) of active ingredient. These include widely used products such as oral contraceptives and thyroid hormone replacement.
Purpose: The objective is to provide a concise review of the development of low-dose drug products from pharmaceutical, analytical, and regulatory perspectives.
Audience: This book is written primarily for formulation scientists, analytical scientists, and regulatory specialists who will deal with low-dose oral drug products in industry or academia, as well as graduate students and postdoctoral fellows preparing for the field.
Features: Following an excellent overview chapter by the editor, the book is divided into four sections. The first section on formulation development provides detailed information on strategies dealing with particle size and process methods issues. The second section discusses analytical methods for low dose products given the challenges of such low quantities of active ingredient. The third section has two chapters on technology for containment related to the potency of the active ingredient. The last section includes a final chapter on regulatory considerations. Among the book's outstanding features are 97 tables, 74 figures, some color plates, and dozens of equations. Numerous formulation case studies are provided. The referencing format is not consistent across the chapters, but the 7-page index appears to be adequate. The contributors come predominantly from industry, and it is unfortunate not to have more from academia and regulatory bodies.
Assessment: This book is unique in its depth of coverage of the topic.
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Product Details

  • ISBN-13: 9780470056097
  • Publisher: Wiley, John & Sons, Incorporated
  • Publication date: 1/27/2009
  • Edition description: New Edition
  • Edition number: 1
  • Pages: 465
  • Product dimensions: 6.50 (w) x 9.60 (h) x 0.90 (d)

Meet the Author

Jack Zheng, PhD, is Research Advisor and Team Leader in the Pharmaceutical Sciences R&D Division of Eli Lilly and Company and Adjunct Professor at Beijing University. Dr. Zheng is the author of more than thirty articles and several book chapters. He has been invited to present his work at numerous national and international scientific meetings. He was involved in more than ten new drug product development and regulatory filing with the Food and Drug Administration.
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Table of Contents

Preface xv

Foreword xix

Contributors xxi

1 An Overview Jack Y. Zheng 1

1.1 The Drug Discovery and Development Process 2

1.2 Challenges and Strategies in Development of Low-Dose Drug Products 10

1.3 Summary 20

Acknowledgments 20

References 20

I Challenges and Strategies in Formulation Development of Oral Low-Dose Drug Products 23

2 Challenges and Strategies in Formulation Development of Oral Solid Low-Dose Drug Products Jack Y. Zheng 25

2.1 Introduction 25

2.2 Current Regulatory Environment and its Impact on New Drug Product Development 28

2.3 Challenges in Developing Low-Dose Formulations 31

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 and Product Content Uniformity - Theoretical Considerations Kevin C. Johnson 49

3.1 Introduction 49

3.2 Concept of Ideal Mixing 50

3.3 Ideal Mixing Model Comparison with the Yalkowsky and Bolton 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 Using Fluidized Bed Granulation J. Joe Zhou Ralph Lipp 63

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 Oral Formulations Using Wet Granulation Ahmad Almaya 89

5.1 Introduction 89

5.2 Granulation Mechanisms 91

5.3 General Considerations on Wet Granulation 93

5.4 Advantages and Disadvantages ofWet 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

6 Challenges in Development and Scale-Up of Low-Dose Drug Products by Dry Granulation: A Case Study Mary T. Am Ende Daniel O. Blackwood Daniel S. Gierer Christopher P. Neu 117

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 their Assessment Methods 125

6.5 Case Study: Formulation Challenges for Low-Dose Products 128

6.6 Process Challenges During Dry Granulation Optimization for Low-Dose Products 140

6.7 Conclusions 154

Acknowledgments 155

References 155

7 Development of Low-Dose Solid Oral Tablets Using Direct Compression Jack Y. Zheng Robert L. Ternik 159

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 Products Using 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 Substance for Low-Dose Drug Products Christopher L. Burcham Paul C. Collins Daniel J. Jarmer Kevin D. Seibert 205

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 Using Crystallization Technologies 216

8.4 Scale-Up Considerations 218

8.5 Emerging Technologies and Future Directions 219

Acknowledgments 219

References 219

9 Function, Quality, and Regulations of Pharmaceutical Excipients for Oral Solid Dosage Forms Jack Y. Zheng 223

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 Method Development for Oral Low-Dose Drug Products 239

10 Analytical Method Development: Challenges and Solutions for Low-Dose Oral Dosage Forms Beverly Nickerson Reena M. Joseph Charles Palmer Alex M. Opio George H. Beresford 241

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 for a Fixed Combination Product Containing a Low-Dose Active Ingredient 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 Method Development Vivian A. Gray Jack Y. Zheng Norman N. Sesi 265

11.1 Introduction 265

11.2 Overview of Dissolution Testing 265

11.3 Dissolution Method Development 271

11.4 Dissolution Method Development for Low-Dose Oral Drug Products 275

11.5 Summary 279

References 280

12 Analysis of Physical Transformation of Api During Manufacture and Storage Gregory A. Stephenson 283

12.1 1Introduction 283

12.2 1Discussion of Solid-State Forms 284

12.3 1Monitoring Processing Steps 285

12.4 1Measuring Transitions and Solid-Form Transformations in the Low-Dose Tablet 287

12.5 1Common Methods Used for Examination of Solid Forms 289

12.6 1Conclusions 305

References 306

13 Physical Characterization Tests for Drug Substances Used in Low-Dose Formulations Ronald G. Iacocca 309

13.1 1General Issues in the Physical Characterization of Micronized Powders Used in Low-Dose Formulations 309

13.2 1Particle Size Analysis 309

13.3 1Specific Surface Area Analysis 320

13.4 1Summary 323

References 323

14 An Excipient Library Approach to Analytical Development for Low-Dose, Solid Oral Dosage form Drug Products Qing Chang Lisheng Kang Keri Varner Joyce Bridges Norman Sesi Margo Palmieri 327

14.1 Introduction 327

14.2 Importance of Excipient Absorbance Background to Low-Dose Impurity Analysis 328

14.3 Factors Affecting Excipient Absorbance Background 332

14.4 Use of Excipient Library 339

14.5 Conclusions 341

Acknowledgments 341

References 342

15 Cleaning Verification for Highly Potent Compounds Brian W. Pack 345

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 Highly Potent Pharmaceutical Compounds 381

16 Containment Challenges and Strategies for Potent Compounds in the Pharmaceutical Industry Victoria Cathcart Sarah Jones Beverly Nickerson 383

16.1 Introduction 383

16.2 Safe Exposure Control Levels-Bands, Limits, and Handling 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 in Analytical Testing Laboratories David S. Pattavina Nancy Sage Beverly Nickerson 405

17.1 Introduction 405

17.2 Sample Handling Considerations 406

17.3 Handling Potent Compounds in Standard Analytical Laboratories 407

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 the Development of Low-Dose Drug Products 429

18 Regulatory Considerations in the Development of Low-Dose Solid Oral Drug Products Ravi S. Harapanhalli 431

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 Cosntrols for Highly Potent Drugs 451

18.5 Conclusion 452

References 453

Index 455

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