Table of Contents
1 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