Huynh-Ba Pharmaceutical Stability Testing to Support Global Markets

1. Auflage 2009
ISBN: 978-1-4419-0889-6
Verlag: Springer-Verlag
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 266 Seiten

The International Conference of Harmonization (ICH) has worked on har- nizing the stability regulations in the US, Europe, and Japan since the early 1990s. Even though the Stability Guidelines Q1A (R2) was issued over a decade ago, issues surrounding this arena continue to surface as the principles described in the guideline are applied to different technical concentrations. As a result, the stability community has continued to discuss concerns and find ways of harmonizing regulatory requirements, streamlining practices, improving processes in order to bring safe and effective medical supplies to the patients around the world. In 2007, the American Association of Pharmaceutical Scientists (AAPS) Stability Focus Group organized two workshops – the Stability Workshop and the Degradation Mechanism Workshop. These meetings attracted many industry scientists as well as representatives from several regulatory agencies in the world to discuss important topics related to pharmaceutical stability practices. Recognizing the importance of documenting these discussions and with the permission of AAPS, I have worked with speakers to assemble a collection of 30 articles from presentations given at these two meetings, mainly the Stability Workshop. I trust that this book will be beneficial to all of you in providing guidance and up-to-date information for building quality stability programs. v Freedom of our mind is Mother of all inventions.

Autoren/Hrsg.

Huynh-Ba, Kim

Inhaltsverzeichnis

1;Huynh-Ba_Frontmatter.pdf;1
1.1;Anchor 1;5
1.2;Anchor 2;7
1.3;Anchor 3;8
1.4;Anchor 4;9
1.5;Anchor 5;13
2;Huynh-Ba_Ch01.pdf;16
2.1;Chapter 1;17
2.1.1;Introduction;17
2.1.1.1;1. Introduction;17
2.1.1.2;2. Background on the Stability Focus Group and the Workshop;17
2.1.1.2.1;2.1. Stability Focus Group;17
2.1.1.2.2;2.2. Background of the Workshop;17
2.1.1.3;3. Meeting Planning Committee;18
2.1.1.4;4. Introduction of this Volume;19
3;Huynh-Ba_Ch02.pdf;20
3.1;Chapter 2;21
3.1.1;Regulatory Perspectives on Product Stability;21
3.1.1.1;1. Introduction;21
3.1.1.2;2. During Product Development;22
3.1.1.2.1;2.1. Mechanism of Instability;22
3.1.1.2.2;2.2. Interactions with Excipients;23
3.1.1.2.3;2.3. Interactions with Packaging Materials;23
3.1.1.2.4;2.4. The Role of Manufacturing Process;23
3.1.1.3;3. Support a Marketing Application;24
3.1.1.4;4. Monitor Product Quality and Support Post-Approval Changes;24
3.1.1.5;5. Conclusion;24
3.1.1.6;Root;24
3.1.2;Reference;24
4;Huynh-Ba_Ch03.pdf;26
4.1;Chapter 3;26
4.1.1;Current International Harmonization Efforts;26
4.1.1.1;1. Introduction;26
4.1.1.2;2. Harmonization in Drug Regulation: Three Models;27
4.1.1.2.1;2.1. Populist Model: The Pan American Network for Drug Regulatory Harmonization (PANDRH);27
4.1.1.2.1.1;2.1.1. The Establishment of PANDRH;27
4.1.1.2.1.2;2.1.2. PANDRH Working Structure;28
4.1.1.2.2;2.2. International Conference on Harmonization;28
4.1.1.2.2.1;2.2.1. ICH Background;28
4.1.1.2.2.2;2.2.2 ICH Keys of Success;28
4.1.1.2.3;2.3. ICH Global Cooperation Group;29
4.1.1.2.3.1;2.3.1. Establishment of the Global Cooperation Group;29
4.1.1.3;3.3 Global Stability Testing Requirements: A Case Study in Models of Harmonization;29
4.1.1.4;4. Conclusion;32
4.1.1.5;Author Biography;33
5;Huynh-Ba_Ch04.pdf;34
5.1;Chapter 4;34
5.1.1;Update on the WHO Stability Guideline;34
5.1.1.1;1. Introduction;34
5.1.1.2;2. Basis for WHO International Guidelines;35
5.1.1.2.1;2.1. WHO Expert Committee;35
5.1.1.2.2;2.2. WHO Processes;35
5.1.1.2.3;2.3. WHO Partners;35
5.1.1.3;3. Update of WHO Guidelines;36
5.1.1.4;4. Key Recommendations on Stability Testing;37
5.1.1.5;5. Conclusion;38
5.1.2;References;38
6;Huynh-Ba_Ch05.pdf;40
6.1;Chapter 5;40
6.1.1;Development of a Regional Guideline for the Eastern Mediterranean Region;40
6.1.1.1;1. Historical Background;40
6.1.1.2;2. General Aspects of Medicine Stability;41
6.1.1.2.1;2.1. Educational Aspect;41
6.1.1.2.2;2.2. Operational Research;41
6.1.1.2.3;2.3. In-Use Study;42
6.1.1.3;3. Countries Situation;42
6.1.1.4;4. Draft Regional Guideline;42
6.1.1.5;5. Recommendations;44
6.1.1.5.1;5.1. Technical Recommendations;44
6.1.1.5.2;5.2. Other Recommendations;44
6.1.1.5.3;5.3. Storage Conditions;44
6.1.1.6;6. Conclusion;44
6.1.1.7;Anchor 18;44
6.1.2;References;45
7;Huynh-Ba_Ch06.pdf;47
7.1;Chapter 6;47
7.1.1;The Challenge of Diverse Climates: Adequate Stability Testing Conditions for India;47
7.1.1.1;1. India: The Country;47
7.1.1.2;2. Pharmaceutical Industry in India;47
7.1.1.3;3. Diverse Physical and Climatic Conditions in India;48
7.1.1.4;4. Calculation of Long-Term Stability Test Conditions for India by Risk-Based Approach;48
7.1.1.5;5. Suggested Revision of WHO’s Classification of Global Climatic Zones;52
7.1.1.6;6. Conclusion;53
7.1.1.7;Root;53
8;Huynh-Ba_Ch07.pdf;55
8.1;Chapter 7;55
8.1.1;Requirements for South East Asian Markets;55
8.1.1.1;1. Background;55
8.1.1.2;2. Harmonizing Stability Requirements for ASEAN Zone IV;55
8.1.1.2.1;2.1. Consideration on Storage Condition of ASEAN Zone IV;55
8.1.1.2.2;2.2. Harmonization Efforts;56
8.1.1.3;3. ASEAN Guideline on Stability Study of Drug Product;56
8.1.1.3.1;3.1. Testing Frequency;56
8.1.1.3.2;3.2. Storage Conditions;56
8.1.1.3.2.1;3.2.1. Solid Dosage Form;56
8.1.1.3.2.2;3.2.2. New Chemical Entity (NCE) Drug Products;57
8.1.1.3.2.3;3.2.3. Generics and Variation (MaV and MiV if appropriate) Products;57
8.1.1.3.2.4;3.2.4. Drug Product Intended for Storage in a Refrigerator;57
8.1.1.3.2.5;3.2.5. Drug Product Intended for Storage in a Freezer;57
8.1.1.3.3;3.3. Container Closure System;57
8.1.1.3.4;3.4. Different Stability Study from ASEAN Guideline;58
8.1.1.3.5;3.5. Labeling;58
8.1.1.4;4. ASEAN Position on Stability Studies in Global Environments;58
8.1.1.5;5. Conclusion;59
8.1.1.6;Author Biographies;59
9;Huynh-Ba_Ch08.pdf;61
9.1;Chapter 8;61
9.1.1;The Role of USP Monographs in Stability Testing;61
9.1.1.1;1. Introduction;61
9.1.1.1.1;1.1. United States Pharmacopeial Convention Facts: Who and What is USP?;61
9.1.1.1.2;1.2. USP Public Standards;62
9.1.1.2;2. Typical Monograph Procedures and Requirements;62
9.1.1.2.1;2.1. Definition with Proposed Limits;62
9.1.1.2.2;2.2. Identification Tests;62
9.1.1.2.3;2.3. Packages and Labeling;62
9.1.1.2.4;2.4. Other Procedures and Requirements;63
9.1.1.3;3. USP Monographs;63
9.1.1.4;4. Testing of Drug Products;63
9.1.1.4.1;4.1. Solid Oral Dosage Forms;63
9.1.1.4.2;4.2. Liquid Oral Dosage Forms;63
9.1.1.4.3;4.3. Parenteral Dosage Forms;63
9.1.1.5;5. Labeling;64
9.1.1.6;6. Identification;64
9.1.1.7;7. USP–NF General Chapters Related to Stability;65
9.1.1.7.1;7.1. Pharmaceutical Stability .;65
9.1.1.7.2;7.2. Validation of Compendial Methods .;65
9.1.1.7.3;7.3. Impurities in Official Articles .;65
9.1.1.8;8. Impurities and Degradants;65
9.1.1.9;9. Degradants in Dosage Form Monographs;66
9.1.1.10;10. Flexible Monographs;66
9.1.1.11;11. Examples of Flexible Monographs;66
9.1.1.11.1;11.1. Loratadine Drug Substance;66
9.1.1.11.2;11.2. Theophylline Extended-Release Capsules;67
9.1.1.11.3;11.3. Other Examples;67
9.1.1.12;12. USP Standards-Setting Process;67
9.1.1.12.1;12.1. USP–NF Monographs;67
9.1.1.12.2;12.2. Pending Monographs;68
9.1.1.12.3;12.3. Non-US Monographs;69
9.1.1.13;13. Summary;69
9.1.2;References;69
10;Huynh-Ba_Ch09.pdf;71
10.1;Chapter 9;71
10.1.1;Regulatory Requirements for Stability Testing of Generics;71
10.1.1.1;1. Introduction;71
10.1.1.2;2. Intrinsic Stability of a Drug Substance;72
10.1.1.3;3. Compatibility;72
10.1.1.4;4. Container Closure Attributes;72
10.1.1.5;5. Expedite ANDA Submission Review;73
10.1.1.6;6. Regulatory Requirement for Generic Submission;73
10.1.1.6.1;6.1. Stability Data;74
10.1.1.6.2;6.2. Batch Scale;74
10.1.1.7;7. Frequent Generic Related Issues;75
10.1.1.7.1;7.1. Extrapolation;75
10.1.1.7.2;7.2. Labeling;75
10.1.1.8;8. Conclusion;75
10.1.1.9;Author Biographies;75
11;Huynh-Ba_Ch10.pdf;77
11.1;Chapter 10;77
11.1.1;Stability Design for Consumer Healthcare Products;77
11.1.1.1;1. Stability Requirements for OTC Drug Products;77
11.1.1.2;2. Stability Requirements for Changes to Currently Marketed OTC Drug Products;79
11.1.1.3;3. Classification of Changes for OTC Drug Products;79
11.1.1.4;4. Conclusion;81
11.1.1.5;Author Biographies;81
12;Huynh-Ba_Ch11.pdf;84
12.1;Chapter 11;84
12.1.1;Challenges of Drug/Devices Pharmaceutical Products;84
12.1.1.1;1. Introduction;84
12.1.1.2;2. General Issues of Combination Products;84
12.1.1.2.1;2.1. Definition of Combination Products;84
12.1.1.2.2;2.2. Regulatory Process;85
12.1.1.2.3;2.3. Drug and Device Development and Approval Process;86
12.1.1.2.4;2.4. Review Jurisdiction for Combination Products;86
12.1.1.2.5;2.5. General CMC Issues for Combination Products;87
12.1.1.2.6;2.6. General Stability Issues;88
12.1.1.2.7;2.7. Legal Basis for Drug Stability Testing;88
12.1.1.3;3. Stability Issues for Combination Products;89
12.1.1.3.1;3.1. Stability Requirements for IDE and PMA;89
12.1.1.3.2;3.2. Stability Indicating Methods;90
12.1.1.3.3;3.3. Sample Size and Stability Testing;90
12.1.1.3.4;3.4. Timeline for Stability Studies;91
12.1.1.4;4. Conclusion;91
12.1.1.5;Author Biography;92
13;Huynh-Ba_Ch12.pdf;93
13.1;Chapter 12;93
13.1.1;Practical Challenges of Stability Testing of Nutraceutical Formulations;93
13.1.1.1;1. Introduction;93
13.1.1.2;2. Regulatory Challenges;94
13.1.1.2.1;2.1. Dietary Supplement Health and Education Act (DSHEA): The Act;94
13.1.1.2.2;2.2. Proposed Rule;94
13.1.1.2.3;2.3. The Final Rule;95
13.1.1.3;3. Compendial USP Challenges;95
13.1.1.3.1;3.1. Legal Authority of USP over Nutraceuticals/Dietary Supplements;95
13.1.1.3.2;3.2. Manufacturing Practices for Dietary Supplements: USP General Information Chapter .;96
13.1.1.3.3;3.3. USP Verified Program for Dietary Supplements;97
13.1.1.4;4. Analytical Methods/Technology Challenges;97
13.1.1.5;5. Formulation Related Challenges;98
13.1.1.6;6. Conclusions;98
13.1.1.7;Author Biography;99
14;Huynh-Ba_Ch13.pdf;100
14.1;Chapter 13;100
14.1.1;Setting Tolerances for Instrument Qualification;100
14.1.1.1;1. Introduction;100
14.1.1.2;2. Analytical Instrument Qualification Process;100
14.1.1.2.1;2.1. Design Qualification;101
14.1.1.2.2;2.2. Installation Qualification;101
14.1.1.2.3;2.3. Operational Qualification;101
14.1.1.2.4;2.4. Performance Qualification;101
14.1.1.3;3. Roles and Responsibilities;102
14.1.1.4;4. Software Validation;103
14.1.1.5;5. Change Control;103
14.1.1.6;6. Conclusion;103
14.1.1.7;Author Biographies;103
15;Huynh-Ba_Ch14.pdf;105
15.1;Chapter 14;106
15.1.1;The Concept of Quality-by-Design;106
15.1.1.1;1. Quality by Design: Introduction;106
15.1.1.2;2. Quality by Design: Implementation;107
15.1.1.3;3. Quality by Design: Benefits of The Desired State;109
15.1.1.4;4. Quality by Design: Implications for Stability Testing;109
15.1.1.5;Author Biography;111
15.1.2;References;110
16;Huynh-Ba_Ch15.pdf;112
16.1;Chapter 15;112
16.1.1;Forced Degradation and Its Relation to Real Time Drug Product Stability;112
16.1.1.1;1. Introduction;112
16.1.1.2;2. Background and Definitions;113
16.1.1.2.1;2.1. Foundation of Stability Testing;113
16.1.1.2.1.1;2.1.1. Relevant Conditions for Stress Testing Studies;113
16.1.1.3;3. Design of Studies;113
16.1.1.3.1;3.1. Conditions for Stress Testing to Predict Degradation;113
16.1.1.3.2;3.2. Predictive Oxidative Susceptibility Testing;114
16.1.1.3.2.1;3.2.1. Autoxidation;114
16.1.1.3.2.2;3.2.2. Peroxide-Mediated;115
16.1.1.3.2.3;3.2.3. Electron Transfer;115
16.1.1.3.3;3.3. Investigative Oxidative Susceptibility Testing;116
16.1.1.3.4;3.4. Drug Product Stress Testing;116
16.1.1.4;4. Using Quality-by-Design Concepts;116
16.1.1.4.1;4.1. Quality by Design (QbD) Principles;116
16.1.1.4.2;4.2. “Holes” in the Degradation Knowledge;117
16.1.1.4.3;4.3. “Degradation Design Space” Changes;118
16.1.1.5;5. Conclusion;119
16.1.1.6;Author Biography;121
16.1.2;References;119
17;Huynh-Ba_Ch16.pdf;122
17.1;Chapter 16;122
17.1.1;Low Level Impurities in Drug Substances and Drug Products and the Analytical Challenges in Identification and Quantitation;122
17.1.1.1;1. Introduction;122
17.1.1.2;2. Monitoring Low Level Impurities;123
17.1.1.2.1;2.1. Typical Techniques that are Used for Identification and Quantification;123
17.1.1.2.2;2.2. Impact of Stability;123
17.1.1.3;3. Genotoxic Impurities;124
17.1.1.3.1;3.1. Key Principles;124
17.1.1.3.2;3.2. PhRMA Position Paper and Staged TTC Approach;124
17.1.1.3.3;3.3. Proposed Qualification of Impurities;124
17.1.1.3.4;3.4. Scope of EMEA Guideline;125
17.1.1.4;4. Conclusion;126
17.1.1.5;Author Biography;126
18;Huynh-Ba_Ch17.pdf;127
18.1;Chapter 17;127
18.1.1;Stability of Repackaged Products*;127
18.1.1.1;1. Background;127
18.1.1.2;2. Ranitidine Hydrochloride Syrup;128
18.1.1.3;3. Phenytoin Sodium Suspension;130
18.1.1.4;4. Gabapentin Capsules;131
18.1.1.5;5. Furosemide Tablets;133
18.1.1.6;6. Metoprolol Tartrate Tablets;134
18.1.1.7;7. Conclusions;136
19;Huynh-Ba_Ch18.pdf;138
19.1;Chapter 18;138
19.1.1;Packaging-Induced Interactions and Degradation;138
19.1.1.1;1. Introduction;138
19.1.1.2;2. Overview/Results;140
19.1.1.2.1;2.1. Case I: Contamination by a Migratory Packaging Component;140
19.1.1.2.2;2.2. Case II: Reactivity with a Migratory Packaging Component;140
19.1.1.2.3;2.3. Case III: Reactivity of the Drug with Packaging Material;143
19.1.1.2.4;2.4. Case IV: Reactivity of the Drug Based Upon Packaging Defects or Packaging-Related Impurities;144
19.1.1.2.5;2.5. Further Examples;145
19.1.1.3;3. Summary;146
19.1.1.4;Author Biographies;147
19.1.2;References;147
20;Huynh-Ba_Ch19.pdf;148
20.1;Chapter 19;148
20.1.1;An Overview of Physical Stability of Pharmaceuticals;148
20.1.1.1;1. Introduction;148
20.1.1.2;2. Drug Substance;148
20.1.1.3;3. Excipients and Formulation;150
20.1.1.4;4. Manufacturing Processes;152
20.1.1.5;5. Container-Closure Systems;152
20.1.1.6;6. Distribution, Storage and In-use Physical Stability;153
20.1.1.7;7. Interplay Between Chemical and Physical Stability;154
20.1.1.8;8. Conclusion;154
20.1.1.9;Author Biography;155
20.1.2;References;155
21;Huynh-Ba_Ch20.pdf;156
21.1;Chapter 20;156
21.1.1;Stability of Split Tablets;156
21.1.1.1;1. Introduction;156
21.1.1.2;2. Materials and Method;157
21.1.1.2.1;2.1. Materials;157
21.1.1.2.2;2.2. Sample Preparation;158
21.1.1.2.3;2.3. Sample Analysis;158
21.1.1.3;3. Results;158
21.1.1.4;4. Conclusions;161
21.1.1.5;Root;162
21.1.2;References;162
22;Huynh-Ba_Ch21.pdf;164
22.1;Chapter 21;164
22.1.1;Temperature Monitoring During Shipment and Storage;164
22.1.1.1;1. Introduction;164
22.1.1.2;2. Global Monitoring;164
22.1.1.2.1;2.1. AstraZeneca’s Approach;165
22.1.1.3;3. Tools and Equipment Involved;166
22.1.1.3.1;3.1. The Tools to be Used;166
22.1.1.3.2;3.2. The Way of Using the Tools;166
22.1.1.3.3;3.3. Data Output;166
22.1.1.4;4. Evaluation of Temperature Excursions;166
22.1.1.4.1;4.1. Excursion Evaluation Step 1;167
22.1.1.4.2;4.2. Excursion Evaluation Step 2;167
22.1.1.5;5. Prevention of Temperature Excursions;167
22.1.1.5.1;5.1. Quality Systems;167
22.1.1.5.2;5.2. Understanding of the Supply Chain;168
22.1.1.5.3;5.3. Risk Assessment;168
22.1.1.6;6. Shipment Packing Examples;168
22.1.1.7;7. Conclusion;168
22.1.1.8;Author Biography;170
23;Huynh-Ba_Ch22.pdf;171
23.1;Chapter 22;171
23.1.1;Introducing a Science-Based Quality by Design Concept to Analytical Methods Development;171
23.1.1.1;1. Introduction;171
23.1.1.2;2. Material;172
23.1.1.3;3. Experimental Section;172
23.1.1.4;4. Results and Discussions;173
23.1.1.5;5. Conclusions;180
23.1.1.6;Author Biographies;181
23.1.2;References;180
24;Huynh-Ba_Ch23.pdf;182
24.1;Chapter 23;183
24.1.1;Optimizing Stability Data Package to Facilitate NDA/MAA Approval;183
24.1.1.1;1. Introduction;183
24.1.1.2;2. ICH Q1A Requirements;184
24.1.1.3;3. ICH Requirements: Alternate Stability Storage Conditions;185
24.1.1.3.1;3.1. Semi-Permeable Containers;185
24.1.1.3.2;3.2. Refrigerated Conditions;185
24.1.1.4;4. Reduced Stability Testing Design;186
24.1.1.5;5. Testing Considerations;187
24.1.1.6;6. ICH Requirements: Photostability;188
24.1.1.7;7. Additional Studies;189
24.1.1.8;8. Specifications;190
24.1.1.9;9. Stability Data Evaluation and Expiration Dating;191
24.1.1.10;10. ICH Requirements: Stability Commitment;192
24.1.1.11;11. Comparability Protocols;192
24.1.1.12;12. Stability Data Package;193
24.1.1.13;Author Biography;193
24.1.2;References;193
25;Huynh-Ba_Ch24.pdf;195
25.1;Chapter 24;195
25.1.1;Maximize Data for Post Approval Changes;195
25.1.1.1;1. Introduction;195
25.1.1.2;2. Regulatory Reporting Categories;196
25.1.1.3;3. Stability Study Designs;197
25.1.1.3.1;3.1. Case Study 1;198
25.1.1.3.2;3.2. Case Study 2;198
25.1.1.3.3;3.3. Case Study 3;199
25.1.1.4;4. Summary;200
25.1.1.5;Author Biography;201
26;Huynh-Ba_Ch25.pdf;202
26.1;Chapter 25;202
26.1.1;Use of Statistics to Establish a Stability Trend: Matrixing;202
26.1.1.1;1. Introduction;202
26.1.1.2;2. Statistical Designs;205
26.1.1.3;3. Analysis of Matrixed and Bracketed Designs;208
26.1.1.4;4. Prior Approval;208
26.1.1.5;Author Biography;208
27;Huynh-Ba_Ch26.pdf;209
27.1;Chapter 26;209
27.1.1;Setting Specifications for Drug Substances;209
27.1.1.1;1. Introduction;209
27.1.1.2;2. Developing Stability Testing Strategies Appropriate to the Stage of Development;210
27.1.1.3;3. Specific Tests to be Considered for APIs;211
27.1.1.3.1;3.1. Appearance;211
27.1.1.3.2;3.2. Solution Clarity;211
27.1.1.3.3;3.3. Turbidity;212
27.1.1.3.4;3.4. Identity;212
27.1.1.3.5;3.5. Solid form Identity;212
27.1.1.3.6;3.6. Particle Size;213
27.1.1.3.7;3.7. Assay;213
27.1.1.3.8;3.8. Water;213
27.1.1.3.9;3.9. Impurities;214
27.1.1.3.10;3.10. Solvents;214
27.1.1.3.11;3.11. Inorganic Impurities;214
27.1.1.3.12;3.12. Microbes and Endotoxins;215
27.1.1.3.13;3.13. Other Tests to be Considered;215
27.1.1.4;4. Stability Commitment Batches;215
27.1.1.5;5. Stability Studies Final Discussion;216
27.1.1.6;6. Relevant Guidelines not Referenced Directly;217
27.1.1.7;Root;217
27.1.2;References;217
28;Huynh-Ba_Ch27.pdf;219
28.1;Chapter 27;219
28.1.1;Setting Specifications for Drug Products;219
28.1.1.1;1. Introduction;219
28.1.1.2;2. Understand Critical Product Attributes;219
28.1.1.3;3. Understand Regulatory Requirements;221
28.1.1.4;4. Understand Process Capability;222
28.1.1.5;5. Understand Stability Trends;224
28.1.1.6;6. Summary;226
28.1.1.7;Author Biography;226
29;Huynh-Ba_Ch28.pdf;227
29.1;Chapter 28;227
29.1.1;Highlights of Investigating Out-of-Specifications Test Results;227
29.1.1.1;1. Introduction;227
29.1.1.2;2. Historical Considerations;228
29.1.1.2.1;2.1. The Barr Decision;228
29.1.1.2.2;2.2. Judge Wolin’s Legal Ruling-Issues;228
29.1.1.3;3. Scope of the OOS Guidance;228
29.1.1.3.1;3.1. Assessing OOS Test Results;228
29.1.1.3.1.1;3.1.1. System Performance Check Standard;228
29.1.1.3.1.2;3.1.2. Obvious Errors;229
29.1.1.3.2;3.2. Supervisor’s Responsibility;229
29.1.1.3.3;3.3. Responsibility of Laboratory Management;229
29.1.1.3.4;3.4. Root Cause Analysis;229
29.1.1.3.5;3.5. Laboratory Error and CAPA;229
29.1.1.4;4. Phases of Investigations;229
29.1.1.4.1;4.1. Phase 1 of the Investigation;229
29.1.1.4.2;4.2. Phase 2 of the Investigation;230
29.1.1.5;5. Review of Production;230
29.1.1.6;6. OOS Follow Up;231
29.1.1.6.1;6.1. Retesting;231
29.1.1.6.2;6.2. Reporting of Results;231
29.1.1.6.3;6.3. Case Studies;231
29.1.1.6.3.1;6.3.1. First Case Study;231
29.1.1.6.3.2;6.3.2. Second Case Study;232
29.1.1.6.3.3;6.3.3. Result Reporting;232
29.1.1.7;7. Outlier Test;232
29.1.1.8;8. Typical Number of Replicate Retests;232
29.1.1.9;9. Averaging the Results;233
29.1.1.10;10. Preventing OOS Results;233
29.1.1.10.1;10.1. Quality by Design;233
29.1.1.10.2;10.2. Analytical Method;233
29.1.1.10.3;10.3. Quality Systems;234
29.1.1.10.4;10.4. Stability Study;234
29.1.1.11;11. Conclusions;235
29.1.1.12;Author Biographies;235
29.1.2;Reference;235
30;Huynh-Ba_Ch29.pdf;236
30.1;Chapter 29;236
30.1.1;Strategies for Ensuring Regulatory and cGMP Compliance of Outsourced Stability Programs;236
30.1.1.1;1. Introduction;236
30.1.1.2;2. The Decision to Outsource;236
30.1.1.3;3. Choice of Vendor;237
30.1.1.4;4. The Startup Phase;238
30.1.1.5;5. Monitoring Ongoing Studies;239
30.1.1.6;6. Management of Change;240
30.1.1.7;7. Continuous Improvement;241
30.1.1.8;Author Biography;242
31;Huynh-Ba_Ch30.pdf;243
31.1;Chapter 30;243
31.1.1;Building and Developing of Relationships with Third Party Laboratories;243
31.1.1.1;1. Introduction;243
31.1.1.2;2. Current Pharmaceutical Industry Climate;244
31.1.1.3;3. Attitudes Towards Outsourcing and Contract Laboratory Services;244
31.1.1.4;4. Defining Relationships;245
31.1.1.5;5. Trust;246
31.1.1.6;6. Investment in the Relationship;246
31.1.1.7;7. Maintaining the Relationship and Avoiding the Pitfalls;247
31.1.1.8;Author Biography;248
32;Huynh-Ba_Ch31.pdf;249
32.1;Chapter 31;249
32.1.1;Outsourcing Stability Testing: A Tool for Resource and Risk Management;249
32.1.1.1;1. Introduction;249
32.1.1.2;2. Operating Environments;249
32.1.1.2.1;2.1. Regulatory Environment;249
32.1.1.2.2;2.2. Business Environment;250
32.1.1.3;3. Key Factors;251
32.1.1.4;4. Risk Assessment;252
32.1.1.5;5. Conclusion;253
32.1.1.6;Author Biography;253
33;Huynh-Ba_Backmatter.pdf;254