There are unique challenges in the formulation, manufacture, analytical chemistry, and regulatory requirements of low-dose drugs. This book provides an overview of this specialized field and combines formulation, analytical, and regulatory aspects of low-dose development into a single reference book. It describes analytical methodologies like dissolution testing, solid state NMR, Raman microscopy, and LC-MS and presents manufacturing techniques such as granulation, compaction, and compression. Complete with case studies and a discussion of regulatory requirements, this is a core reference for pharmaceutical scientists, regulators, and graduate students.
Table of Contents:
Preface xv
Foreword xix
Contributors xxi
1 An Overview 1
Jack Y. Zheng
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 25
Jack Y. Zheng
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 49
Kevin C. Johnson
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 63
J. 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 Oral Formulations Using Wet Granulation 89
Ahmad 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
6 Challenges In Development and Scale-Up of Low-Dose Drug Products By Dry Granulation: A Case Study 117
Mary T. Am Ende, Daniel O. Blackwood, Daniel S. Gierer, and Christopher 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 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 159
Jack 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 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 205
Christopher 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 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 223
Jack 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 Method Development For Oral Low-Dose Drug Products 239
10 Analytical Method Development: Challenges and Solutions For Low-Dose Oral Dosage Forms 241
Beverly 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 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 265
Vivian A. Gray, Jack Y. Zheng, and Norman N. Sesi
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 283
Gregory 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 Transformations in the Low-Dose Tablet 287
12.5 Common Methods Used for Examination of Solid Forms 289
12.6 Conclusions 305
References 306
13 Physical Characterization Tests For Drug Substances Used In Low-Dose Formulations 309
Ronald G. Iacocca
13.1 General Issues in the Physical Characterization of Micronized 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 Analytical Development For Low-Dose, Solid Oral Dosage Form Drug Products 327
Qing Chang, Lisheng Kang, Keri Varner, Joyce Bridges, Norman Sesi, and Margo Palmieri
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 345
Brian 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 Highly Potent Pharmaceutical Compounds 381
16 Containment Challenges and Strategies For Potent Compounds In The Pharmaceutical Industry 383
Victoria Cathcart, Sarah Jones, and Beverly Nickerson
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 405
David 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
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 431
Ravi 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
About 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.
