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
List of Tables
1 Chapter 1Table 1.1 Proposed allowable daily intakes (μg/day) for potential genotoxic ...Table 1.2 Acceptable limits for MIs based on duration of exposure.Table 1.3 EDQM decision table for use during elaboration or revision of mono...Table 1.4 Extracted text from ICH S9, Q&A document relating to MIs.
2 Chapter 2Table 2.1 Relationship between ICH S9 and ICH M7 [1] [9].Table 2.2 Impurities classification with respect to mutagenic and carcinogen...Table 2.3 Tests to investigate thein vivo relevance of in vitro mutagens (po...Table 2.4 Acceptable intakes for an individual impurity.Table 2.5 Acceptable total daily intakes for multiple impurities.Table 2.6 Purge values.Table 2.7 Examples of clinical use scenarios with different treatment durati...
3 Chapter 3Table 3.1 Acceptable intakes for an individual MI.Table 3.2 The Mueller five‐class classification scheme.Table 3.3 Purge factor calculation scoring system.Table 3.4 Relationship between purge factor ratios and regulatory reporting ...Table 3.5 Tests to investigatein vivo relevance of in vitro mutagens.