Pharmaceutical Stability Testing to Support Global Markets (eBook)

Kim Huynh-Ba is the founder and Technical Director of Pharmalytik (www.pharmalytik.com). She has twenty two years of experience in various analytical areas of pharmaceutical development and a primary focus in stability sciences. Prior to Pharmalytik, she held positions in drug development at Astra Zeneca (formerly ICI Americas), DuPont Merck, DuPont Pharmaceuticals, Bristol Myers Squibb and Wyeth Vaccines. She has been advising pharmaceutical companies including companies operating under Consent Decree on harmonization and optimization of analytical best practices since 2001. In addition to her consulting activities, Kim is a short course instructor and organizer on topics ranging from cGMP compliance and quality issues to stability programs under sponsorship of global organizations such as American Chemical Society (ACS), American Association of Pharmaceutical Scientists (AAPS), Pittsburgh Conference, many other international training groups. She is the founder and past co-chair of the AAPS Stability Focus Group, and an active member of the Pharmaceutical Stability Discussion Group (PSDG). She serves on the Governing Board of Eastern Analytical Symposium (EAS). She currently is Chair of the AAPS APQ e-Learning Committee and the 2008 EAS Short Course Program. She is a member of USP's Prescription/Non-Prescription Stakeholder Forum and also USP Reference Standard Project Team. Kim Huynh-Ba is a recipient of the 2008 AAPS APQ Service Award and 2008 Recognition Award of AAPS Regulatory Section. She also received the 2001 DPCAA Leadership Award. Kim Huynh-Ba has authored numerous technical publications and book chapters. She is invited frequently to present at national and international conferences. She is the editor of the Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, which has been recognized as a practical reference book in the stability community.

Huynh-Ba_Frontmatter.pdf 1
Anchor 1 5
Anchor 2 7
Anchor 3 8
Anchor 4 9
Anchor 5 13
Huynh-Ba_Ch01.pdf 16
Chapter 1 17
Introduction 17
1. Introduction 17
2. Background on the Stability Focus Group and the Workshop 17
2.1. Stability Focus Group 17
2.2. Background of the Workshop 17
3. Meeting Planning Committee 18
4. Introduction of this Volume 19
Huynh-Ba_Ch02.pdf 20
Chapter 2 21
Regulatory Perspectives on Product Stability 21
1. Introduction 21
2. During Product Development 22
2.1. Mechanism of Instability 22
2.2. Interactions with Excipients 23
2.3. Interactions with Packaging Materials 23
2.4. The Role of Manufacturing Process 23
3. Support a Marketing Application 24
4. Monitor Product Quality and Support Post-Approval Changes 24
5. Conclusion 24
Root 24
Reference 24
Huynh-Ba_Ch03.pdf 26
Chapter 3 26
Current International Harmonization Efforts 26
1. Introduction 26
2. Harmonization in Drug Regulation: Three Models 27
2.1. Populist Model: The Pan American Network for Drug Regulatory Harmonization (PANDRH) 27
2.1.1. The Establishment of PANDRH 27
2.1.2. PANDRH Working Structure 28
2.2. International Conference on Harmonization 28
2.2.1. ICH Background 28
2.2.2 ICH Keys of Success 28
2.3. ICH Global Cooperation Group 29
2.3.1. Establishment of the Global Cooperation Group 29
3.3 Global Stability Testing Requirements: A Case Study in Models of Harmonization 29
4. Conclusion 32
Author Biography 33
Huynh-Ba_Ch04.pdf 34
Chapter 4 34
Update on the WHO Stability Guideline 34
1. Introduction 34
2. Basis for WHO International Guidelines 35
2.1. WHO Expert Committee 35
2.2. WHO Processes 35
2.3. WHO Partners 35
3. Update of WHO Guidelines 36
4. Key Recommendations on Stability Testing 37
5. Conclusion 38
References 38
Huynh-Ba_Ch05.pdf 40
Chapter 5 40
Development of a Regional Guideline for the Eastern Mediterranean Region 40
1. Historical Background 40
2. General Aspects of Medicine Stability 41
2.1. Educational Aspect 41
2.2. Operational Research 41
2.3. In-Use Study 42
3. Countries Situation 42
4. Draft Regional Guideline 42
5. Recommendations 44
5.1. Technical Recommendations 44
5.2. Other Recommendations 44
5.3. Storage Conditions 44
6. Conclusion 44
Anchor 18 44
References 45
Huynh-Ba_Ch06.pdf 47
Chapter 6 47
The Challenge of Diverse Climates: Adequate Stability Testing Conditions for India 47
1. India: The Country 47
2. Pharmaceutical Industry in India 47
3. Diverse Physical and Climatic Conditions in India 48
4. Calculation of Long-Term Stability Test Conditions for India by Risk-Based Approach 48
5. Suggested Revision of WHO’s Classification of Global Climatic Zones 52
6. Conclusion 53
Root 53
Huynh-Ba_Ch07.pdf 55
Chapter 7 55
Requirements for South East Asian Markets 55
1. Background 55
2. Harmonizing Stability Requirements for ASEAN Zone IV 55
2.1. Consideration on Storage Condition of ASEAN Zone IV 55
2.2. Harmonization Efforts 56
3. ASEAN Guideline on Stability Study of Drug Product 56
3.1. Testing Frequency 56
3.2. Storage Conditions 56
3.2.1. Solid Dosage Form 56
3.2.2. New Chemical Entity (NCE) Drug Products 57
3.2.3. Generics and Variation (MaV and MiV if appropriate) Products 57
3.2.4. Drug Product Intended for Storage in a Refrigerator 57
3.2.5. Drug Product Intended for Storage in a Freezer 57
3.3. Container Closure System 57
3.4. Different Stability Study from ASEAN Guideline 58
3.5. Labeling 58
4. ASEAN Position on Stability Studies in Global Environments 58
5. Conclusion 59
Author Biographies 59
Huynh-Ba_Ch08.pdf 61
Chapter 8 61
The Role of USP Monographs in Stability Testing 61
1. Introduction 61
1.1. United States Pharmacopeial Convention Facts: Who and What is USP? 61
1.2. USP Public Standards 62
2. Typical Monograph Procedures and Requirements 62
2.1. Definition with Proposed Limits 62
2.2. Identification Tests 62
2.3. Packages and Labeling 62
2.4. Other Procedures and Requirements 63
3. USP Monographs 63
4. Testing of Drug Products 63
4.1. Solid Oral Dosage Forms 63
4.2. Liquid Oral Dosage Forms 63
4.3. Parenteral Dosage Forms 63
5. Labeling 64
6. Identification 64
7. USP–NF General Chapters Related to Stability 65
7.1. Pharmaceutical Stability . 65
7.2. Validation of Compendial Methods . 65
7.3. Impurities in Official Articles . 65
8. Impurities and Degradants 65
9. Degradants in Dosage Form Monographs 66
10. Flexible Monographs 66
11. Examples of Flexible Monographs 66
11.1. Loratadine Drug Substance 66
11.2. Theophylline Extended-Release Capsules 67
11.3. Other Examples 67
12. USP Standards-Setting Process 67
12.1. USP–NF Monographs 67
12.2. Pending Monographs 68
12.3. Non-US Monographs 69
13. Summary 69
References 69
Huynh-Ba_Ch09.pdf 71
Chapter 9 71
Regulatory Requirements for Stability Testing of Generics 71
1. Introduction 71
2. Intrinsic Stability of a Drug Substance 72
3. Compatibility 72
4. Container Closure Attributes 72
5. Expedite ANDA Submission Review 73
6. Regulatory Requirement for Generic Submission 73
6.1. Stability Data 74
6.2. Batch Scale 74
7. Frequent Generic Related Issues 75
7.1. Extrapolation 75
7.2. Labeling 75
8. Conclusion 75
Author Biographies 75
Huynh-Ba_Ch10.pdf 77
Chapter 10 77
Stability Design for Consumer Healthcare Products 77
1. Stability Requirements for OTC Drug Products 77
2. Stability Requirements for Changes to Currently Marketed OTC Drug Products 79
3. Classification of Changes for OTC Drug Products 79
4. Conclusion 81
Author Biographies 81
Huynh-Ba_Ch11.pdf 84
Chapter 11 84
Challenges of Drug/Devices Pharmaceutical Products 84
1. Introduction 84
2. General Issues of Combination Products 84
2.1. Definition of Combination Products 84
2.2. Regulatory Process 85
2.3. Drug and Device Development and Approval Process 86
2.4. Review Jurisdiction for Combination Products 86
2.5. General CMC Issues for Combination Products 87
2.6. General Stability Issues 88
2.7. Legal Basis for Drug Stability Testing 88
3. Stability Issues for Combination Products 89
3.1. Stability Requirements for IDE and PMA 89
3.2. Stability Indicating Methods 90
3.3. Sample Size and Stability Testing 90
3.4. Timeline for Stability Studies 91
4. Conclusion 91
Author Biography 92
Huynh-Ba_Ch12.pdf 93
Chapter 12 93
Practical Challenges of Stability Testing of Nutraceutical Formulations 93
1. Introduction 93
2. Regulatory Challenges 94
2.1. Dietary Supplement Health and Education Act (DSHEA): The Act 94
2.2. Proposed Rule 94
2.3. The Final Rule 95
3. Compendial USP Challenges 95
3.1. Legal Authority of USP over Nutraceuticals/Dietary Supplements 95
3.2. Manufacturing Practices for Dietary Supplements: USP General Information Chapter . 96
3.3. USP Verified Program for Dietary Supplements 97
4. Analytical Methods/Technology Challenges 97
5. Formulation Related Challenges 98
6. Conclusions 98
Author Biography 99
Huynh-Ba_Ch13.pdf 100
Chapter 13 100
Setting Tolerances for Instrument Qualification 100
1. Introduction 100
2. Analytical Instrument Qualification Process 100
2.1. Design Qualification 101
2.2. Installation Qualification 101
2.3. Operational Qualification 101
2.4. Performance Qualification 101
3. Roles and Responsibilities 102
4. Software Validation 103
5. Change Control 103
6. Conclusion 103
Author Biographies 103
Huynh-Ba_Ch14.pdf 105
Chapter 14 106
The Concept of Quality-by-Design 106
1. Quality by Design: Introduction 106
2. Quality by Design: Implementation 107
3. Quality by Design: Benefits of The Desired State 109
4. Quality by Design: Implications for Stability Testing 109
Author Biography 111
References 110
Huynh-Ba_Ch15.pdf 112
Chapter 15 112
Forced Degradation and Its Relation to Real Time Drug Product Stability 112
1. Introduction 112
2. Background and Definitions 113
2.1. Foundation of Stability Testing 113
2.1.1. Relevant Conditions for Stress Testing Studies 113
3. Design of Studies 113
3.1. Conditions for Stress Testing to Predict Degradation 113
3.2. Predictive Oxidative Susceptibility Testing 114
3.2.1. Autoxidation 114
3.2.2. Peroxide-Mediated 115
3.2.3. Electron Transfer 115
3.3. Investigative Oxidative Susceptibility Testing 116
3.4. Drug Product Stress Testing 116
4. Using Quality-by-Design Concepts 116
4.1. Quality by Design (QbD) Principles 116
4.2. “Holes” in the Degradation Knowledge 117
4.3. “Degradation Design Space” Changes 118
5. Conclusion 119
Author Biography 121
References 119
Huynh-Ba_Ch16.pdf 122
Chapter 16 122
Low Level Impurities in Drug Substances and Drug Products and the Analytical Challenges in Identification and Quantitation 122
1. Introduction 122
2. Monitoring Low Level Impurities 123
2.1. Typical Techniques that are Used for Identification and Quantification 123
2.2. Impact of Stability 123
3. Genotoxic Impurities 124
3.1. Key Principles 124
3.2. PhRMA Position Paper and Staged TTC Approach 124
3.3. Proposed Qualification of Impurities 124
3.4. Scope of EMEA Guideline 125
4. Conclusion 126
Author Biography 126
Huynh-Ba_Ch17.pdf 127
Chapter 17 127
Stability of Repackaged Products* 127
1. Background 127
2. Ranitidine Hydrochloride Syrup 128
3. Phenytoin Sodium Suspension 130
4. Gabapentin Capsules 131
5. Furosemide Tablets 133
6. Metoprolol Tartrate Tablets 134
7. Conclusions 136
Huynh-Ba_Ch18.pdf 138
Chapter 18 138
Packaging-Induced Interactions and Degradation 138
1. Introduction 138
2. Overview/Results 140
2.1. Case I: Contamination by a Migratory Packaging Component 140
2.2. Case II: Reactivity with a Migratory Packaging Component 140
2.3. Case III: Reactivity of the Drug with Packaging Material 143
2.4. Case IV: Reactivity of the Drug Based Upon Packaging Defects or Packaging-Related Impurities 144
2.5. Further Examples 145
3. Summary 146
Author Biographies 147
References 147
Huynh-Ba_Ch19.pdf 148
Chapter 19 148
An Overview of Physical Stability of Pharmaceuticals 148
1. Introduction 148
2. Drug Substance 148
3. Excipients and Formulation 150
4. Manufacturing Processes 152
5. Container-Closure Systems 152
6. Distribution, Storage and In-use Physical Stability 153
7. Interplay Between Chemical and Physical Stability 154
8. Conclusion 154
Author Biography 155
References 155
Huynh-Ba_Ch20.pdf 156
Chapter 20 156
Stability of Split Tablets 156
1. Introduction 156
2. Materials and Method 157
2.1. Materials 157
2.2. Sample Preparation 158
2.3. Sample Analysis 158
3. Results 158
4. Conclusions 161
Root 162
References 162
Huynh-Ba_Ch21.pdf 164
Chapter 21 164
Temperature Monitoring During Shipment and Storage 164
1. Introduction 164
2. Global Monitoring 164
2.1. AstraZeneca’s Approach 165
3. Tools and Equipment Involved 166
3.1. The Tools to be Used 166
3.2. The Way of Using the Tools 166
3.3. Data Output 166
4. Evaluation of Temperature Excursions 166
4.1. Excursion Evaluation Step 1 167
4.2. Excursion Evaluation Step 2 167
5. Prevention of Temperature Excursions 167
5.1. Quality Systems 167
5.2. Understanding of the Supply Chain 168
5.3. Risk Assessment 168
6. Shipment Packing Examples 168
7. Conclusion 168
Author Biography 170
Huynh-Ba_Ch22.pdf 171
Chapter 22 171
Introducing a Science-Based Quality by Design Concept to Analytical Methods Development 171
1. Introduction 171
2. Material 172
3. Experimental Section 172
4. Results and Discussions 173
5. Conclusions 180
Author Biographies 181
References 180
Huynh-Ba_Ch23.pdf 182
Chapter 23 183
Optimizing Stability Data Package to Facilitate NDA/MAA Approval 183
1. Introduction 183
2. ICH Q1A Requirements 184
3. ICH Requirements: Alternate Stability Storage Conditions 185
3.1. Semi-Permeable Containers 185
3.2. Refrigerated Conditions 185
4. Reduced Stability Testing Design 186
5. Testing Considerations 187
6. ICH Requirements: Photostability 188
7. Additional Studies 189
8. Specifications 190
9. Stability Data Evaluation and Expiration Dating 191
10. ICH Requirements: Stability Commitment 192
11. Comparability Protocols 192
12. Stability Data Package 193
Author Biography 193
References 193
Huynh-Ba_Ch24.pdf 195
Chapter 24 195
Maximize Data for Post Approval Changes 195
1. Introduction 195
2. Regulatory Reporting Categories 196
3. Stability Study Designs 197
3.1. Case Study 1 198
3.2. Case Study 2 198
3.3. Case Study 3 199
4. Summary 200
Author Biography 201
Huynh-Ba_Ch25.pdf 202
Chapter 25 202
Use of Statistics to Establish a Stability Trend: Matrixing 202
1. Introduction 202
2. Statistical Designs 205
3. Analysis of Matrixed and Bracketed Designs 208
4. Prior Approval 208
Author Biography 208
Huynh-Ba_Ch26.pdf 209
Chapter 26 209
Setting Specifications for Drug Substances 209
1. Introduction 209
2. Developing Stability Testing Strategies Appropriate to the Stage of Development 210
3. Specific Tests to be Considered for APIs 211
3.1. Appearance 211
3.2. Solution Clarity 211
3.3. Turbidity 212
3.4. Identity 212
3.5. Solid form Identity 212
3.6. Particle Size 213
3.7. Assay 213
3.8. Water 213
3.9. Impurities 214
3.10. Solvents 214
3.11. Inorganic Impurities 214
3.12. Microbes and Endotoxins 215
3.13. Other Tests to be Considered 215
4. Stability Commitment Batches 215
5. Stability Studies Final Discussion 216
6. Relevant Guidelines not Referenced Directly 217
Root 217
References 217
Huynh-Ba_Ch27.pdf 219
Chapter 27 219
Setting Specifications for Drug Products 219
1. Introduction 219
2. Understand Critical Product Attributes 219
3. Understand Regulatory Requirements 221
4. Understand Process Capability 222
5. Understand Stability Trends 224
6. Summary 226
Author Biography 226
Huynh-Ba_Ch28.pdf 227
Chapter 28 227
Highlights of Investigating Out-of-Specifications Test Results 227
1. Introduction 227
2. Historical Considerations 228
2.1. The Barr Decision 228
2.2. Judge Wolin’s Legal Ruling-Issues 228
3. Scope of the OOS Guidance 228
3.1. Assessing OOS Test Results 228
3.1.1. System Performance Check Standard 228
3.1.2. Obvious Errors 229
3.2. Supervisor’s Responsibility 229
3.3. Responsibility of Laboratory Management 229
3.4. Root Cause Analysis 229
3.5. Laboratory Error and CAPA 229
4. Phases of Investigations 229
4.1. Phase 1 of the Investigation 229
4.2. Phase 2 of the Investigation 230
5. Review of Production 230
6. OOS Follow Up 231
6.1. Retesting 231
6.2. Reporting of Results 231
6.3. Case Studies 231
6.3.1. First Case Study 231
6.3.2. Second Case Study 232
6.3.3. Result Reporting 232
7. Outlier Test 232
8. Typical Number of Replicate Retests 232
9. Averaging the Results 233
10. Preventing OOS Results 233
10.1. Quality by Design 233
10.2. Analytical Method 233
10.3. Quality Systems 234
10.4. Stability Study 234
11. Conclusions 235
Author Biographies 235
Reference 235
Huynh-Ba_Ch29.pdf 236
Chapter 29 236
Strategies for Ensuring Regulatory and cGMP Compliance of Outsourced Stability Programs 236
1. Introduction 236
2. The Decision to Outsource 236
3. Choice of Vendor 237
4. The Startup Phase 238
5. Monitoring Ongoing Studies 239
6. Management of Change 240
7. Continuous Improvement 241
Author Biography 242
Huynh-Ba_Ch30.pdf 243
Chapter 30 243
Building and Developing of Relationships with Third Party Laboratories 243
1. Introduction 243
2. Current Pharmaceutical Industry Climate 244
3. Attitudes Towards Outsourcing and Contract Laboratory Services 244
4. Defining Relationships 245
5. Trust 246
6. Investment in the Relationship 246
7. Maintaining the Relationship and Avoiding the Pitfalls 247
Author Biography 248
Huynh-Ba_Ch31.pdf 249
Chapter 31 249
Outsourcing Stability Testing: A Tool for Resource and Risk Management 249
1. Introduction 249
2. Operating Environments 249
2.1. Regulatory Environment 249
2.2. Business Environment 250
3. Key Factors 251
4. Risk Assessment 252
5. Conclusion 253
Author Biography 253
Huynh-Ba_Backmatter.pdf 254