Mutagenic Impurities

1 Cover

2 Title Page

3 Copyright Page

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 Guideline1.1 Introduction References 2 ICH M7 – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk2.1 Introduction 2.2 ICH M7 2.3 Conclusions 2.4 Commentary on ICH M7 Questions and Answers References 3 Control Strategies for Mutagenic Impurities3.1 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 Impurities4.1 Introduction 4.2 (Q)SAR Assessment 4.3 Discussion 4.4 Conclusions Acknowledgments References 5 Evolution of Quantitative Structure–Activity Relationships ((Q)SAR) for Mutagenicity5.1 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 Impurities6.1 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 Pharmaceuticals7.1 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 Departure8.1 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 Options9.1 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 ‐Nitrosamines10.1 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 Impurities12.1 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 Products14.1 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

10 End User License Agreement

1 Chapter 1 Table 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 2 Table 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 the in 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 3 Table 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 investigate in vivo relevance of in vitro mutagens. Table 3.6 Summary of mutagenicity assessment for synthetic process to GW6415... Table 3.7 Purge predictions for ethyl bromoisobutyrate 2. Table 3.8 Purge predictions for hydroxylamine. Table 3.9 Purge predictions for alkyl chloride 8. Table 3.10 Proposed high‐level control summary table for potential MIs ethyl...

4 Chapter 4Table 4.1 Results where the two (Q)SAR methodologies were negative.Table 4.2 Results when the two methodologies are positive.Table 4.3 Results for conflicting results.Table 4.4 Results when there is an indeterminate prediction (IND = indetermi...Table 4.5 Results where at least one of the methodologies is out‐of‐domain.Table 4.6 Results showing the effect of using the probability score.

5 Chapter 6Table 6.1 Impurities classification with respect to mutagenic and carcinogen...Table 6.2 Tests to investigate the in vivo relevance of in vitro mutagens (po...Table 6.3 Description of bacterial strains commonly used for the bacterial r...

6 Chapter 7Table 7.1 Classes of mutagenic and/or carcinogenic impurities.Table 7.2 Examples of commonly searched toxicity databases.Table 7.3 LTL application to ICH M7 Class 1, 2, and 3 impurities.Table 7.4 Published compound‐specific limits.Table 7.5 Tests to investigate the in vivo relevance of in vitro mutagens (po...Table 7.6 Regulatory interim AIs for N ‐nitrosamine compounds.Table 7.7 EC SCCS tumor potency estimates for N‐ nitrosamines [61].Table 7.8 Carcinogenic potencies of selected N ‐nitrosamines.Table 7.9 Selected N ‐nitrosamines that were not carcinogenic when tested in a...Table 7.10 AI and PDE comparisons from different approaches for NDMA and NDE...Table 7.11 In vivo results for arylboronic acids and esters.Table 7.12 Genotoxic effects observed in 28‐day oral male gpt‐delta transgen...Table 7.13 EMS – details of carcinogenicity studies.Table 7.14 BMD estimates for EMS for the most sensitive sites in male gpt‐tr...