Handbook of Stability Testing in Pharmaceutical Development (eBook)

Kim Huynh-Ba is Technical Director of Pharmalytik. She has over 20 years of experiences in various analytical areas of pharmaceutical development, especially in Stability Sciences. She has involved with several projects harmonizing or optimizing analytical best practices in several companies, including those are under Consent Decree. Ms. Huynh-Ba has authored numerous technical publications and book chapters. She is a frequent invited speaker at national and international conferences. She has conducted several training courses on stability compliance and quality issues for American Chemical Society, American Association of Pharmaceutical Scientists, Pharmaceutical Training Institute, Eastern Analytical Symposium since 2001. She is the founder of AAPS Stability Focus Group and actively involved with Pharmaceutical Stability Discussion Group. She is an active member of ACS, AAPS, PSDG, ASQ, POMA and serves in the Governing Board of Eastern Analytical Symposium (EAS). In my professional career as a pharmaceutical scientist, I have been involved with several aspects of the drug development process from pre-IND to commercial and, somehow, I usually found myself coming back to a stability related issue. Stability area seems to draw my utmost interest because in my day-to-day work, my opportunities involved more than one product, and none of the issues was the same. Each situation posed challenges that usually required an exercise of judgment, an understanding of regulations, knowledge of science, a grasp of compliance, and an appreciation of common practices. Since early 2000, I have also been involved with several training opportunities and I struggled to find good, concise, practical resources, one of which I can just hand to a new scientist who wishes to gain more understanding of stability sciences. In addition, I encountered the same questions posted over and over on different stability best practices discussion forums. As a book lover, I also have a good collection of technical books. Unfortunately, most of the stability related books are outdated. In addition, many of these materials are theoretical and do not contain much practical information. I understand that the pharmaceutical industry during this period is quite volatile, and guidelines are changing rapidly while regulatory agencies are working closely with the pharmaceutical industry to accommodate these changes; however, the fundamental information continues to remain quite the same as current Good Manufacturing Practices (cGMP) continues to be the standard industry practice. Therefore, I hope to assemble a practical handbook to fill this void.

Preface 6
Editorial Notes 8
Acknowledgments 9
Contents 10
Contributors 12
Introduction 15
Contents 15
1.1 Stability 15
1.2 Drug Development Process 16
1.3 Introduction of this Handbook 18
1.4 Conclusion 20
Reference 20
Stability Regulations 21
Critical Regulatory Requirements for a Stability Program 22
Contents 22
2.1 Stability Role in the Drug Development Process 23
2.2 Types of Stability Studies 24
2.3 Scientific Principles of Stability Testing 26
2.4 Review of cGMP Stability Requirements 28
2.5 Review of Part 211.160 – Laboratory Controls 30
2.6 Part 211.165 – Testing and Release for Distribution 30
2.7 Part 211.194 – Laboratory Records 31
2.8 Conclusion 31
References 32
Understanding ICH Guidelines Applicable to Stability Testing 33
Contents 33
3.1 Introduction 34
3.2 Development of ICH Stability Guidelines 34
3.3 Status of FDA Draft Guidance (Contributed by Robert Seevers) 37
3.4 Summary of Q1A(R2) Guidance 39
3.5 Special Stability Studies 45
3.6 Mean Kinetic Temperature 46
3.7 Conclusion 52
References 52
Global Stability Practices 54
Contents 54
4.1 The Concept of Climatic Zones 55
4.2 Calculating the Probability of Failure 56
4.3 Climatic Data 58
4.4 Equations 59
4.5 WHO Stability Guideline 62
4.6 Regional Stability Guidelines 64
4.7 Global Stability Testing Protocols 98
References 101
Post-approval Changes – Stability Requirements and Regulations 103
Contents 103
5.1 Evaluating Proposed Changes 104
5.2 Types of Changes and Filing Requirements – US 106
5.3 Types of Changes and Global Filing Requirements 107
5.4 Stability Requirements for Various Types of Changes – US 109
5.5 Multiple Changes and Changes that Affect Multiple Products 119
5.6 Comparability Protocols 121
5.7 Pharmaceutical Development Considerations 121
5.8 Conclusion 122
References 123
Web Addresses 124
Understanding and Predicting Pharmaceutical Product Shelf-Life 125
Contents 125
6.1 Introduction 126
6.2 Factors Determining Pharmaceutical Product Shelf-Life 126
6.3 Drug Instability with Time 131
6.4 Accelerating Aging 134
6.5 Precision 142
6.6 Prediction of Stability in Packaged Product 143
6.7 Concluding Comments 145
References 145
Additional Resources 145
StabilityMethodologies and Best Practices 146
Development of Stability Indicating Methods 147
Contents 147
7.1 Introduction 148
7.2 ICH Guidelines and Other Worldwide Regulatory Guidance/Pharmacopeias for Method Development and Validation 149
7.3 Forced Degradation Studies 149
7.4 Stability Indicating HPLC Method Development 159
7.5 Conclusion 166
References 167
Method Validation and Transfer 170
Contents 170
8.1 Analytical Method Validation 171
8.2 Validation Parameters 172
8.3 Re-validation 181
8.4 Method Validation with Stage of Development 181
8.5 Technology Transfer 183
8.6 Analytical Method Transfer 183
8.7 Regulatory Requirements 191
8.8 Method Transfer Example 191
8.9 Conclusion 193
References 194
Overview of USP-NF Requirements for Stability Purposes 196
Contents 196
9.1 General Introduction to USP 197
9.2 General Discussion of Requirements for Stability 201
9.3 Conclusion 206
References 206
Non-chromatographic Methods to Support Stability Program 207
Contents 207
10.1 Appearance Testing 208
10.2 FTIR Spectroscopic Testing 213
10.3 Moisture Testing 214
10.4 Residual Solvents Analysis in Pharmaceutical API and Excipients 217
10.5 pH 218
10.6 Weight Variation and Fill Volume/Delivery Volume 219
10.7 Tablet and Capsule Physical Tests 221
10.8 Content Uniformity 222
10.9 Disintegration 223
10.10 UV/Vis Spectroscopy 223
10.11 Density/Specific Gravity 224
10.12 Melting Point 224
10.13 Particulate Matter in Parenterals and Intravenous (IV) Solutions 224
10.14 Dissolution 225
10.15 Conclusion 227
References 227
Vibrational Spectroscopic Methods for Quantitative Analysis 228
Contents 228
11.1 Introduction 228
11.2 Overview of Vibrational Spectroscopy and Equipment 229
11.3 Chemometrics and Multivariate Analysis 233
11.4 Equipment Qualification 239
11.5 Method Validation 241
11.6 Conclusion 244
References 244
Impact of Solid-State Characteristics to the Physical Stability of Drug Substance and Drug Product 246
Contents 246
12.1 Introduction 247
12.2 Solid-State Characteristics and Physical Stability of Drug Substance 247
12.3 Physical Stability of Drug Products 256
12.4 Conclusion 263
References 263
Evaluation of Stability Data 267
Contents 267
13.1 Data Evaluation and Trending 268
13.2 Investigation of Out-of-Specification (OOS) Results 273
13.3 Setting Specifications and Stability Data 279
13.4 Preparation of Stability Reports 281
13.5 Conclusions 286
References 287
Qualification, Calibration, and Maintenance of Stability Chambers 288
Contents 288
14.1 Introduction 289
14.2 Chamber Size 289
14.3 Chamber Specifications 291
14.4 Chamber Qualification 292
14.5 Chamber Calibration 296
14.6 Preventative Maintenance and Chamber Back-Up 297
14.7 Monitoring and Alarm System 298
14.8 Photo-stability 298
14.9 Excursions 304
14.10 Conclusion 305
Stability Operation Practices 306
Contents 306
15.1 Introduction 307
15.2 Development of SOPs 307
15.3 Training Program 312
15.4 Stability Protocols (ICH and Global) 313
15.5 Bracketing and Matrixing 317
15.6 Annual Product Review 322
15.7 Conclusions 323
References 323
Other Stability Programs 324
Combination Products/Drugs in Devices 325
Contents 325
16.1 Introduction 326
16.2 Available Guidance and Regulatory Framework 326
16.3 Stability Strategies for Drug in Device Combination Products 330
16.4 Nasal Spray and Inhaled Products 335
16.5 Pen Injectors 342
16.6 Drug Eluting Stents 344
16.7 Implantable Systems 345
16.8 Transdermal Products 345
16.9 Leachables Studies 346
16.10 Bracketing/Matrixing 347
16.11 Storage Orientation 347
16.12 Temperature Cycling 348
16.13 Transportation Studies 348
16.14 Commercial Stability Commitment 350
16.15 Conclusion 350
References 350
Stability Studies for Biologics 354
Contents 354
17.1 What Are Biologics? 355
17.2 Biologics Versus Small Molecules 356
17.3 Common Degradation Pathways for Proteins 357
17.4 Other Stability Considerations 359
17.5 The ICH Q5C Guideline 361
17.6 Specification Setting 367
17.7 Stability for Process Changes 368
17.8 Summary and Conclusion 368
References 369
List of Abbreviations 371
Index 375