Читать книгу Mutagenic Impurities - Группа авторов - Страница 2
Table of Contents
Оглавление1 Cover
4 Preface
5 Section 1: The Development of Regulatory Guidelines for Mutagenic/Genotoxic Impurities – Overall Process 1 Historical Perspective on the Development of the EMEA Guideline and Subsequent ICH M7 Guideline 1.1 Introduction References 2 ICH M7 – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk 2.1 Introduction 2.2 ICH M7 2.3 Conclusions 2.4 Commentary on ICH M7 Questions and Answers References 3 Control Strategies for Mutagenic Impurities 3.1 Introduction 3.2 Assessment Process 3.3 Step 6 – Overall Risk Assessment 3.4 Further Evaluation of Risk – Purge (Spiking) Studies 3.5 Conclusion 3.6 Case Studies References
6 Section 2: In Silico Assessment of Mutagenicity 4 Use of Structure–Activity Relationship (SAR) Evaluation as a Critical Tool in the Evaluation of the Genotoxic Potential of Impurities 4.1 Introduction 4.2 (Q)SAR Assessment 4.3 Discussion 4.4 Conclusions Acknowledgments References 5 Evolution of Quantitative Structure–Activity Relationships ((Q)SAR) for Mutagenicity 5.1 Introduction 5.2 Pre ICH M7 Guideline 5.3 Post ICH M7 5.4 Expert Knowledge 5.5 Future Direction References
7 Section 3: Toxicological Perspective on Mutagenic Impurities 6 Toxicity Testing to Understand the Mutagenicity of Pharmaceutical Impurities 6.1 Introduction 6.2 In Vitro Genotoxicity Tests 6.3 In Vivo Mutation Assays 6.4 Conclusions References 7 Compound‐ and Class‐Specific Limits for Common Impurities in Pharmaceuticals 7.1 Introduction 7.2 Monograph Development 7.3 Derivation of the Compound‐specific Limit 7.4 Examples of Published Compound‐specific Limits 7.5 Class‐specific Limits 7.6 EMS Case Study and Updated Toxicity Analysis 7.7 Extractables and Leachables 7.8 Lhasa AI/PDE Database for Impurities 7.9 Conclusions and Future Directions 7.10 Acknowledgments References 8 Genotoxic Threshold Mechanisms and Points of Departure 8.1 Introduction to Genotoxic Dose Responses 8.2 Threshold Mechanisms 8.3 Conclusions References
8 Section 4: Quality Perspective on Genotoxic Impurities 9 Mutagenic Impurities – Assessment of Fate and Control Options 9.1 Introduction/Background 9.2 Reactivity 9.3 Solubility – Isolated Stages 9.4 Recrystallization 9.5 Volatility 9.6 Chromatography 9.7 Other Techniques 9.8 Overall Quantification of Risk 9.9 Alignment to ICH M7 – Control Options 9.10 Control Option Selection 9.11 Utilizing Mirabilis for a Purge Calculation References 10 N‐Nitrosamines 10.1 Background 10.2 Generation of N‐Nitrosamines 10.3 Article 31 10.4 Further Issues – Cross Contamination and Ranitidine 10.5 How to Assess the Risk Posed in Pharmaceuticals 10.6 Regulatory Guidance Pursuant to N‐Nitrosamines and its Implications 10.7 Way Forward Acknowledgments References 11 Conditions Potentially Leading to the Formation of Mutagenic Impurities 11.1 Problematic Reagent Combinations per Structural Alert 11.2 Miscellaneous 11.3 Mechanism and Processing Factors Affecting the Formation of N‐nitrosamines 11.4 Formation, Fate, and Purge of Impurities Arising from the Hydrogenation of Nitroarenes to Anilines 11.5 Mechanism and Processing Parameters Affecting the Formation of Sulfonate Esters – Summary of the PQRI Studies References 12 Strategic Approaches to the Chromatographic Analysis of Mutagenic Impurities 12.1 Introduction 12.2 Method Development and Validation 12.3 Analytical Equipment for Mutagenic Impurity Analysis 12.4 Alkyl Halides and Aryl Halides 12.5 Sulfonates 12.6 S‐ and N‐mustards 12.7 Michael Reaction Acceptors 12.8 Epoxides 12.9 Haloalcohols 12.10 Aziridines 12.11 Arylamines and Amino Pyridines 12.12 Hydrazines and Hydroxylamine 12.13 Aldehydes and Ketones 12.14 Nitrosamines 12.15 Nontarget Analysis of PMI/MIs 12.16 Conclusions Acknowledgements References 13 Analysis of Mutagenic Impurities by Nuclear Magnetic Resonance (NMR) Spectroscopy References 14 Addressing the Complex Problem of Degradation‐Derived Mutagenic Impurities in Drug Substances and Products 14.1 Introduction 14.2 Working Definitions 14.3 Challenges Associated with the Assessment of Risk Posed by (Potentially) Mutagenic Degradation Products 14.4 Risk Assessment Process for Mutagenic Degradants 14.5 Using Stress Testing to Select Degradation Products for Identification 14.6 Development Timeline Considerations 14.7 Developing Control Strategies for (Potential) Mutagenic Degradation Products 14.8 Risk Assessment Process Illustrated 14.9 Significance of the Risk of Forming Mutagenic Degradation Products 14.10 Degradation Reactions Leading to Alerting Structures in Degradation Products 14.11 N‐Nitrosamines: Special Considerations 14.12 Conclusions References
9 Index
