Details

Mutagenic Impurities


Mutagenic Impurities

Strategies for Identification and Control
1. Aufl.

von: Andrew Teasdale

190,99 €

Verlag: Wiley
Format: EPUB
Veröffentl.: 01.02.2022
ISBN/EAN: 9781119551256
Sprache: englisch
Anzahl Seiten: 544

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Beschreibungen

<p><b>Learn to implement effective control measures for mutagenic impurities in pharmaceutical development </b></p> <p>In <i>Mutagenic Impurities: Strategies for Identification and Control</i>, distinguished chemist Andrew Teasdale delivers a thorough examination of mutagenic impurities and their impact on the pharmaceutical industry. The book incorporates the adoption of the ICH M7 guideline and focuses on mutagenic impurities from both a toxicological and analytical perspective. </p> <p>The editor has created a primary reference for any professional or student studying or working with mutagenic impurities and offers readers a definitive narrative of applicable guidelines and practical, tested solutions. It demonstrates the development of effective control measures, including chapters on the purge tool for risk assessment. </p> <p>The book incorporates a discussion of N-Nitrosamines which was arguably the largest mutagenic impurity issue ever faced by the pharmaceutical industry, resulting in the recall of Zantac and similar drugs resulting from N-Nitrosamine contamination. </p> <p>Readers will also benefit from the inclusion of: </p> <ul> <li>A thorough introduction to the development of regulatory guidelines for mutagenic and genotoxic impurities, including a historical perspective on the development of the EMEA guidelines and the ICH M7 guideline </li> <li>An exploration of in silico assessment of mutagenicity, including use of structure activity relationship evaluation as a tool in the evaluation of the genotoxic potential of impurities </li> <li>A discussion of a toxicological perspective on mutagenic impurities, including the assessment of mutagenicity and examining the mutagenic and carcinogenic potential of common synthetic reagents </li> </ul> <p>Perfect for chemists, analysts, and regulatory professionals, <i>Mutagenic Impurities: Strategies for Identification and Control</i> will also earn a place in the libraries of toxicologists and clinical safety scientists seeking a one-stop reference on the subject of mutagenic impurity identification and control. </p>
<p>List of Contributors xix</p> <p>Preface xxi</p> <p><b>Section 1 The Development of Regulatory Guidelines for Mutagenic/Genotoxic Impurities – Overall Process </b><b>1</b></p> <p><b>1 Historical Perspective on the Development of the EMEA Guideline and Subsequent ICH M7 Guideline </b><b>3<br /></b><i>Andrew Teasdale</i></p> <p>1.1 Introduction 3</p> <p>1.1.1 CPMP – Position Paper on the Limits of Genotoxic Impurities –2002 4</p> <p>1.1.1.1 Scope/Introduction 4</p> <p>1.1.1.2 Toxicological Background 4</p> <p>1.1.1.3 Pharmaceutical (Quality) Assessment 4</p> <p>1.1.1.4 Toxicological Assessment 4</p> <p>1.1.2 Guideline on the Limits of Genotoxic Impurities – Draft June 2004 5</p> <p>1.1.3 PhRMA (Mueller) White Paper 6</p> <p>1.1.4 Finalized EMA Guideline on the Limits of Genotoxic Impurities – June 2006 8</p> <p>1.1.4.1 Issues Associated with Implementation 9</p> <p>1.1.4.2 Control Expectations for Excipients 11</p> <p>1.1.4.3 Control Expectations for Natural/Herbal Products 12</p> <p>1.1.4.4 Identification of Potential Impurities 12</p> <p>1.1.4.5 The Principle of Avoidance 12</p> <p>1.1.4.6 The ALARP Principle 14</p> <p>1.1.4.7 Overall 14</p> <p>1.1.5 SWP Q&A Document 14</p> <p>1.1.5.1 The Application of the Guideline in the Investigational Phase and Acceptable Limits for GIs Where Applied to Studies of Limited Duration 14</p> <p>1.1.5.2 Application of the Guideline to Existing Products 15</p> <p>1.1.5.3 Avoidance and ALARP 17</p> <p>1.1.5.4 ICH Identification Threshold and its Relation to MI Assessment 17</p> <p>1.1.6 FDA Draft Guideline 17</p> <p>1.1.7 Other Relevant Guidance 17</p> <p>1.1.7.1 Excipients 18</p> <p>1.1.8 Herbals 18</p> <p>1.1.9 ICH S9 18</p> <p>1.1.10 Conclusions 19</p> <p>References 19</p> <p><b>2 ICH M7 – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk </b><b>21<br /></b><i>Andrew Teasdale and Raphael Nudelman</i></p> <p>2.1 Introduction 21</p> <p>2.2 ICH M7 22</p> <p>2.2.1 Introduction 22</p> <p>2.2.2 Scope 22</p> <p>2.2.2.1 Established Products 22</p> <p>2.2.2.2 Anticancer Treatments 23</p> <p>2.2.2.3 Nature of Therapeutic Agent/Excipients 23</p> <p>2.2.3 General Principles 24</p> <p>2.2.4 Considerations for Marketed Products 25</p> <p>2.2.4.1 Post-approval Changes to Drug Substance, Chemistry, and Manufacturing Controls 26</p> <p>2.2.4.2 Post-approval Changes to Drug Product Chemistry, Manufacturing, and Controls 26</p> <p>2.2.4.3 Changes to the Clinical Use of Drug Products 26</p> <p>2.2.5 Other Considerations for Marketed Products 27</p> <p>2.2.6 Drug Substance and Drug Product Impurity Assessment 27</p> <p>2.2.6.1 Synthetic Impurities 28</p> <p>2.2.6.2 Degradation Products 28</p> <p>2.2.7 Hazard Assessment 29</p> <p>2.2.8 Risk Characterization 32</p> <p>2.2.8.1 Acceptable Intakes Based on Compound-specific Risk Assessments 32</p> <p>2.2.8.2 Acceptable Intakes for Class 2 and Class 3 Compounds 33</p> <p>2.2.8.3 Multiple Impurities 34</p> <p>2.2.8.4 Exceptions and Flexibility in Approaches 35</p> <p>2.2.9 Control Strategy 35</p> <p>2.2.9.1 Considerations for Control Approaches 37</p> <p>2.2.9.2 Considerations for Periodic Testing 37</p> <p>2.2.9.3 Control of Degradation Products 38</p> <p>2.2.10 Lifecycle Management 38</p> <p>2.2.11 Documentation 38</p> <p>2.2.11.1 Clinical Trail Applications 38</p> <p>2.2.11.2 Common Technical Document (Marketing Application) 39</p> <p>2.2.12 Other Aspects 39</p> <p>2.2.12.1 Relationship Between ICH M7 and ICH Q3A 39</p> <p>2.3 Conclusions 40</p> <p>2.4 Commentary on ICH M7 Questions and Answers 40</p> <p>2.4.1 Section 1 – Introduction 41</p> <p>2.4.1.1 Question 1.1 41</p> <p>2.4.1.2 Question 1.2 42</p> <p>2.4.1.3 Question 1.3 42</p> <p>2.4.1.4 Question 1.4 42</p> <p>2.4.2 Section 2 – Scope 43</p> <p>2.4.2.1 Question 2.1 43</p> <p>2.4.3 Section 3 – General Principles 43</p> <p>2.4.3.1 Question 3.1 44</p> <p>2.4.3.2 Question 3.2 44</p> <p>2.4.4 Section 4 – Considerations for Marketed Products 44</p> <p>2.4.4.1 Question 4.1 45</p> <p>2.4.5 Section 5 – Drug Substance and Drug Product Impurity Assessment 45</p> <p>2.4.6 Section 6 – Hazard Assessment Elements 45</p> <p>2.4.6.1 Question 6.1 45</p> <p>2.4.6.2 Question 6.2 46</p> <p>2.4.6.3 Question 6.3 47</p> <p>2.4.6.4 Question 6.4 48</p> <p>2.4.7 Section 7 – Risk Characterization 48</p> <p>2.4.7.1 Question 7.1 48</p> <p>2.4.7.2 Question 7.2 49</p> <p>2.4.7.3 Question 7.3 49</p> <p>2.4.7.4 Question 7.4 50</p> <p>2.4.7.5 Question 7.5 51</p> <p>2.4.8 Section 9 – Documentation 53</p> <p>References 55</p> <p><b>3 Control Strategies for Mutagenic Impurities </b><b>57<br /></b><i>Andrew Teasdale, Michael Burns, and Michael Urquhart</i></p> <p>3.1 Introduction 57</p> <p>3.2 Assessment Process 58</p> <p>3.2.1 General 58</p> <p>3.2.2 Step 1 – Evaluation of Drug Substance and Drug Product Processes for Sources of Potentially Mutagenic Impurities 60</p> <p>3.2.3 Step 2 – Structural Assessment 61</p> <p>3.2.4 Step 3 – Classification 61</p> <p>3.2.5 Step 4 – Assessment of Risk of Potential Carryover of Impurities 63</p> <p>3.2.6 Overall Quantification of Risk 63</p> <p>3.2.6.1 Predicted Purge Factor 64</p> <p>3.2.6.2 Required Purge Factor 65</p> <p>3.2.6.3 Purge Ratio 66</p> <p>3.2.6.4 High Predicted Purge 67</p> <p>3.2.6.5 Moderate Predicted Purge 67</p> <p>3.2.6.6 Low Predicted Purge 67</p> <p>3.2.6.7 ICH M7 Control Option 1, 2, or 3 67</p> <p>3.2.6.8 Step 5 – Further Evaluation 67</p> <p>3.2.6.9 Safety Testing 67</p> <p>3.2.7 Quantification of Level Present 68</p> <p>3.3 Step 6 – Overall Risk Assessment 69</p> <p>3.4 Further Evaluation of Risk – Purge (Spiking) Studies 70</p> <p>3.5 Conclusion 70</p> <p>3.6 Case Studies 71</p> <p>3.6.1 Case Study 1 – GW641597X 71</p> <p>3.6.1.1 Ethyl Bromoisobutyrate 2 73</p> <p>3.6.1.2 Hydroxylamine 74</p> <p>3.6.1.3 Alkyl Chloride 8 75</p> <p>3.6.1.4 Additional Evidence for the Purging of Ethyl Bromoisobutyrate and Alkyl Chloride 8 76</p> <p>3.6.2 Proposed ICH M7-aligned Potential Mutagenic Control Regulatory Discussion 78</p> <p>3.6.3 Case Study 2 – Candesartan 78</p> <p>References 84</p> <p><b>Section 2 In Silico Assessment of Mutagenicity </b><b>87</b></p> <p><b>4 Use of Structure–Activity Relationship (SAR) Evaluation as a Critical Tool in the Evaluation of the Genotoxic Potential of Impurities </b><b>89<br /></b><i>Catrin Hasselgren and Glenn Myatt</i></p> <p>4.1 Introduction 89</p> <p>4.2 (Q)SAR Assessment 90</p> <p>4.2.1 Looking-up Experimental Data 90</p> <p>4.2.2 (Q)SAR Methodologies 91</p> <p>4.2.2.1 Overview 91</p> <p>4.2.2.2 OECD Validation Principles 91</p> <p>4.2.3 Expert Rule-Based Methodology 92</p> <p>4.2.4 Statistical-Based Methodology 95</p> <p>4.2.5 Applying (Q)SAR Models 97</p> <p>4.2.6 Expert Review 98</p> <p>4.2.6.1 Overview 98</p> <p>4.2.6.2 Refuting a Statistical-Based Prediction 100</p> <p>4.2.6.3 Mechanistic Assessment 101</p> <p>4.2.6.4 Assessing Lack of Chemical Reactivity 101</p> <p>4.2.7 Class Assignment 103</p> <p>4.2.7.1 Overview 103</p> <p>4.2.8 Documentation 109</p> <p>4.3 Discussion 109</p> <p>4.4 Conclusions 110</p> <p>Acknowledgments 111</p> <p>References 111</p> <p><b>5 Evolution of Quantitative Structure–Activity Relationships ((Q)SAR) for Mutagenicity </b><b>115<br /></b><i>James Harvey and David Elder</i></p> <p>5.1 Introduction 115</p> <p>5.2 Pre ICH M7 Guideline 116</p> <p>5.3 Post ICH M7 117</p> <p>5.3.1 Evolution of (Q)SAR Platforms 117</p> <p>5.3.2 Robust Negative <i>In Silico </i>(Q)SAR Predictions 118</p> <p>5.3.3 Development of Composite (Q)SAR Models 119</p> <p>5.3.4 Expansion of Training Data Sets to Enhance the Predictive Power of (Q)SAR Tools 120</p> <p>5.3.5 Focused Data Sharing Initiatives on Specific Chemical Classes 120</p> <p>5.3.5.1 Understanding <i>In Vitro </i>Mechanisms Leading to Mutagenicity 121</p> <p>5.3.5.2 Shared Data, Shared Progress 122</p> <p>5.3.6 Novel Data Mining Approaches 125</p> <p>5.3.6.1 Case Study: Primary Aromatic Amines (PAAs) 125</p> <p>5.3.6.2 Case Study: Aromatic <i>N</i>-oxides 125</p> <p>5.4 Expert Knowledge 127</p> <p>5.5 Future Direction 129</p> <p>References 131</p> <p><b>Section 3 Toxicological Perspective on Mutagenic Impurities </b><b>137</b></p> <p><b>6 Toxicity Testing to Understand the Mutagenicity of Pharmaceutical Impurities </b><b>139<br /></b><i>Andrew Teasdale, John Nicolette, Joel P. Bercu, James Harvey, Stephen Dertinger, Michael O’Donovan, and Christine Mee</i></p> <p>6.1 Introduction 139</p> <p>6.2 <i>In Vitro </i>Genotoxicity Tests 141</p> <p>6.2.1 Background 141</p> <p>6.2.2 Bacterial Reverse Mutation or “Ames” Test 142</p> <p>6.2.3 Modifications to the Standard Ames Test 145</p> <p>6.2.3.1 Six-well Ames Assay 146</p> <p>6.2.4 Test Strategy 146</p> <p>6.3 <i>In Vivo </i>Mutation Assays 148</p> <p>6.3.1 <i>In Vivo Pig-a </i>Gene Mutation Assay 148</p> <p>6.3.2 Rodent Micronucleus Test 152</p> <p>6.3.3 Rodent “Comet” Assay 155</p> <p>6.3.4 Transgenic Rodent (TGR) Mutation Assay 155</p> <p>6.4 Conclusions 158</p> <p>Glossary 159</p> <p>References 160</p> <p><b>7 Compound-and Class-Specific Limits for Common Impurities in Pharmaceuticals </b><b>165<br /></b><i>Joel P. Bercu, Melisa J. Masuda-Herrera, Alejandra Trejo-Martin, David J. Snodin, Kevin P. Cross, George E. Johnson, James Harvey, Robert S. Foster, David J. Ponting, and Richard V. Williams</i></p> <p>7.1 Introduction 165</p> <p>7.2 Monograph Development 167</p> <p>7.2.1 Exposure to the General Population 167</p> <p>7.2.2 Mutagenicity/Genotoxicity 170</p> <p>7.2.3 Noncarcinogenic Effects 170</p> <p>7.2.4 Carcinogenic Effects 170</p> <p>7.2.5 Mode of Action (MOA) and Assessment of Human Relevance 171</p> <p>7.2.6 Toxicokinetics 171</p> <p>7.2.7 Regulatory/Published Limits 171</p> <p>7.3 Derivation of the Compound-specific Limit 171</p> <p>7.3.1 PoD Selection 172</p> <p>7.3.2 Limited Data Sets 172</p> <p>7.3.3 PDE Development 172</p> <p>7.3.4 AI Development 172</p> <p>7.3.5 Class-specific Limit 173</p> <p>7.3.6 Less than Lifetime (LTL) AIs 173</p> <p>7.4 Examples of Published Compound-specific Limits 173</p> <p>7.4.1 Mutagenic Carcinogens 173</p> <p>7.4.2 Nonmutagenic Carcinogens 176</p> <p>7.4.3 Mutagenic Noncarcinogens 176</p> <p>7.4.4 Nonmutagenic Compounds 176</p> <p>7.4.5 Mutagenic <i>In vitro </i>but not <i>In vivo </i>176</p> <p>7.4.6 Route of Administration-specific Limits 177</p> <p>7.5 Class-specific Limits 177</p> <p>7.5.1 Alkyl Chlorides 177</p> <p>7.5.2 Alkyl Bromides 178</p> <p>7.5.3 <i>N</i>-Nitrosamines 178</p> <p>7.5.3.1 Regulatory Limits for <i>N</i>-Nitrosamines 178</p> <p>7.5.3.2 Additional Proposed Limits for <i>N</i>-Nitrosamines 180</p> <p>7.5.3.3 <i>N</i>-Nitrosamine Exposure in the General Population 181</p> <p>7.5.3.4 Developing a Class-specific Limit for <i>N</i>-Nitrosamines 182</p> <p>7.5.4 Arylboronic Acids and Esters 193</p> <p>7.6 EMS Case Study and Updated Toxicity Analysis 196</p> <p>7.6.1 Potential for Human Exposure 196</p> <p>7.6.2 Mutagenicity/Genotoxicity 196</p> <p>7.6.3 Noncarcinogenic Effects 198</p> <p>7.6.4 Carcinogenicity 199</p> <p>7.6.5 Regulatory and/or Published Limits 199</p> <p>7.6.6 Permitted Daily Exposure 199</p> <p>7.7 Extractables and Leachables 202</p> <p>7.8 Lhasa AI/PDE Database for Impurities 203</p> <p>7.9 Conclusions and Future Directions 203</p> <p>Acknowledgments 204</p> <p>References 204</p> <p><b>8 Genotoxic Threshold Mechanisms and Points of Departure </b><b>213<br /></b><i>George E. Johnson, Shareen H. Doak, Gareth J.S. Jenkins, and Adam D. Thomas</i></p> <p>8.1 Introduction to Genotoxic Dose Responses 213</p> <p>8.1.1 The Linear Default Position for Genotoxic Carcinogens 213</p> <p>8.1.2 Theoretical Evidence for Rejecting the Linear Approach 214</p> <p>8.1.3 <i>In Vitro </i>Experimental Evidence for Threshold Mechanism 215</p> <p>8.1.4 In Vivo Evidence for Genotoxic Thresholds 218</p> <p>8.2 Threshold Mechanisms 221</p> <p>8.2.1 Statistical Assessment of Dose Response Data Sets 224</p> <p>8.2.2 Extrapolation from One Chemical to Another 224</p> <p>8.2.3 Extrapolation of Threshold Mechanisms and PoDs to Populations 225</p> <p>8.3 Conclusions 227</p> <p>References 227</p> <p><b>Section 4 Quality Perspective on Genotoxic Impurities </b><b>233</b></p> <p><b>9 Mutagenic Impurities – Assessment of Fate and Control Options </b><b>235<br /></b><i>Michael W. Urquhart, Andrew Teasdale, and Michael Burns</i></p> <p>9.1 Introduction/Background 235</p> <p>9.2 Reactivity 236</p> <p>9.2.1 Reactivity Classification 238</p> <p>9.3 Solubility – Isolated Stages 238</p> <p>9.4 Recrystallization 239</p> <p>9.4.1 Solubility – Liquid/Liquid Partitioning 239</p> <p>9.5 Volatility 241</p> <p>9.6 Chromatography 241</p> <p>9.7 Other Techniques 242</p> <p>9.7.1 Activated Charcoal 242</p> <p>9.7.2 Scavenger Resins 242</p> <p>9.8 Overall Quantification of Risk 243</p> <p>9.9 Alignment to ICH M7 – Control Options 244</p> <p>9.10 Control Option Selection 247</p> <p>9.10.1 Predicted Purge Factor 248</p> <p>9.10.2 Required Purge Factor 249</p> <p>9.10.3 Purge Ratio 249</p> <p>9.10.4 High Predicted Purge 250</p> <p>9.10.5 Moderate Predicted Purge 250</p> <p>9.10.6 Low Predicted Purge 250</p> <p>9.10.7 ICH M7 Control Option 1, 2, or 3 251</p> <p>9.10.8 Representative Data to be Supplied in Regulatory Submission Under an ICH M7 Control Strategy 251</p> <p>9.10.9 Summary of PMI Purging Across the Synthetic Route 251</p> <p>9.10.10 Details of Individual Impurity Purging Through the Subsequent Downstream Chemistry 253</p> <p>9.10.11 Development of a Knowledge Base Expert In Silico System 254</p> <p>9.10.12 Experimental Work to Assess Reactivity 257</p> <p>9.11 Utilizing Mirabilis for a Purge Calculation 259</p> <p>9.11.1 Utility of In Silico Predictions 260</p> <p>9.11.1.1 Case Study – Camicinal [38] 260</p> <p>References 266</p> <p><b>10 <i>N</i>-Nitrosamines </b><b>269<br /></b><i>Andrew Teasdale, Justin Moser, J. Gair Ford, and Jason Creasey</i></p> <p>10.1 Background 269</p> <p>10.2 Generation of <i>N</i>-Nitrosamines 270</p> <p>10.3 Article 31 273</p> <p>10.4 Further Issues – Cross Contamination and Ranitidine 275</p> <p>10.4.1 Article 5(3) and Associated Q&A Document 276</p> <p>10.5 How to Assess the Risk Posed in Pharmaceuticals 278</p> <p>10.5.1 Drug Substance 278</p> <p>10.5.1.1 Where do Nitrites Come Within Drug Substance Come From? 278</p> <p>10.5.1.2 What Other Sources Are There? 278</p> <p>10.5.1.3 Other Factors Associated with Drug Substance Synthesis 280</p> <p>10.5.2 Process to Assess Drug Substance-Related Risk 280</p> <p>10.5.3 Drug Product-Related Risk 282</p> <p>10.5.3.1 Related Risks of Contamination and Formation in Drug Products 282</p> <p>10.5.4 Container Closure Systems 289</p> <p>10.5.5 Elastomeric Components 291</p> <p>10.5.6 Nitrosamine Impurities in Biologics 293</p> <p>10.5.6.1 Active Substance 293</p> <p>10.5.6.2 The Water Used in Formulation Is Depleted in Nitrosating Agents 295</p> <p>10.5.6.3 Bioconjugated or Chemically Modified Products 295</p> <p>10.5.6.4 Excipients 296</p> <p>10.6 Regulatory Guidance Pursuant to <i>N</i>-Nitrosamines and its Implications 297</p> <p>10.6.1 Article 31 Process and Outcomes 297</p> <p>10.6.1.1 Article 31 Request 297</p> <p>10.6.2 Sartans Lessons Learnt Report 298</p> <p>10.6.2.1 Reflection on the Initial Section of the EMA Report 299</p> <p>10.6.3 Article 5(3) Report 299</p> <p>10.6.3.1 Quality 299</p> <p>10.6.3.2 Consideration for Analytical Method Development to Identify and Quantify <i>N</i>-Nitrosamines in Drug Substances and Medicinal Products 300</p> <p>10.6.3.3 Safety 301</p> <p>10.6.3.4 Conclusions 305</p> <p>10.6.4 EMA Question and Answer Document [6] 305</p> <p>10.6.4.1 Further Revision of the EMA Question and Answer Document 310</p> <p>10.6.5 FDA Guideline 310</p> <p>10.6.5.1 Introduction and Background 310</p> <p>10.6.5.2 Recommendations 310</p> <p>10.6.5.3 Acceptable Intakes (section III.A) 313</p> <p>10.6.5.4 Quality/Chemistry and Controls 314</p> <p>10.7 Way Forward 315</p> <p>Acknowledgments 316</p> <p>References 317</p> <p><b>11 Conditions Potentially Leading to the Formation of Mutagenic Impurities </b><b>321<br /></b><i>Lucie Lovelle, Andrew Teasdale, Ian Ashworth, Adrian Clarke, and Alan Steven</i></p> <p>11.1 Problematic Reagent Combinations per Structural Alert 323</p> <p>11.1.1 <i>N</i>-Nitroso Compounds (COC) 323</p> <p>11.1.1.1 Amines and Nitrosating Agents [10] 323</p> <p>11.1.1.2 Amine Derivatives and Nitrosating Agents 324</p> <p>11.1.1.3 Other 324</p> <p>11.1.2 Alkyl-azoxy Compounds (COC) 325</p> <p>11.1.2.1 Reduction [52–54] 325</p> <p>11.1.2.2 Oxidation 325</p> <p>11.1.2.3 Others 325</p> <p>11.1.3 Other N-O Compounds 326</p> <p>11.1.3.1 Reduction of Nitro Groups 326</p> <p>11.1.3.2 Oxidation of Amines and Hydroxylamines 326</p> <p>11.1.4 Nitration 326</p> <p>11.1.5 Other N-N Compounds [59, 60] 326</p> <p>11.1.6 Aflatoxin-like Compounds [62] (COC) 327</p> <p>11.1.7 Dioxin-like Compounds (Including Polychlorinated Biphenyls = PCBs) [63] 327</p> <p>11.1.8 Alkyl and Acyl Halides 327</p> <p>11.1.8.1 ROH + HCl → RCl + H2O 327</p> <p>11.1.8.2 Ether Opening with Halides 328</p> <p>11.1.9 Methyl Sulfoxides and Pummerer Rearrangement 328</p> <p>11.1.10 Acyl Chlorides Formation [82] 329</p> <p>11.1.11 Halogenation of Unsaturated Compounds 329</p> <p>11.1.12 Ammonium Salts (Hofmann Elimination) 329</p> <p>11.1.12.1 Alkyl Sulfonates [90] 329</p> <p>11.1.13 Epoxides and Aziridines [95–97] 330</p> <p>11.2 Miscellaneous 331</p> <p>11.2.1 B and P Based Compounds 331</p> <p>11.2.2 Formation of <i>N-</i>Methylol 331</p> <p>11.2.3 Acetamide 332</p> <p>11.2.4 Quinones and Quinone Derivatives 332</p> <p>11.2.5 Anilines [100] 332</p> <p>11.2.6 Michael Acceptors 333</p> <p>11.2.7 Others 333</p> <p>11.3 Mechanism and Processing Factors Affecting the Formation of <i>N</i>-nitrosamines 333</p> <p>11.3.1 Introduction 333</p> <p>11.3.2 Mechanisms of Amine Nitrosation 333</p> <p>11.3.2.1 Nitrosation of Secondary Amines 333</p> <p>11.3.2.2 Aqueous Nitrosation 334</p> <p>11.3.2.3 Nitrosation in Organic Solvents 336</p> <p>11.3.3 Nitrosation of Tertiary Amines 337</p> <p>11.3.3.1 Nitrosation of Quaternary Amines 337</p> <p>11.3.3.2 Nitrosation of Amine Oxides 338</p> <p>11.3.4 Sources of Nitrosating Agents 338</p> <p>11.3.4.1 Process Water 338</p> <p>11.3.4.2 Nitric Acid 339</p> <p>11.3.4.3 Atmospheric Sources 339</p> <p>11.3.4.4 Excipients Used in Drug Product Manufacture 340</p> <p>11.3.4.5 Nitrocellulose 340</p> <p>11.3.4.6 Nitrosating Agent Scavengers 340</p> <p>11.3.4.7 Removal of Nitrosamines 341</p> <p>11.4 Formation, Fate, and Purge of Impurities Arising from the Hydrogenation of Nitroarenes to Anilines 341</p> <p>11.4.1 Primary Reaction Mechanism 341</p> <p>11.4.2 Mass and Heat Transfer Effects 342</p> <p>11.4.3 Condensation Chemistry 344</p> <p>11.4.4 Factors Affecting Aryl Hydroxylamine Accumulation 346</p> <p>11.4.5 Aryl Hydroxylamine Control 347</p> <p>11.4.5.1 Use of Cocatalysts 347</p> <p>11.4.5.2 Physical Adsorption 348</p> <p>11.4.5.3 Kinetic Understanding Around Formation and Consumption 349</p> <p>11.4.5.4 Holistic Control of Impurity Profile 349</p> <p>11.4.6 Controlling Residual Nitroarene 351</p> <p>11.4.7 Specific Considerations of Alkyl Nitro Reductions 353</p> <p>11.4.8 Closing Comments on Hydrogenation of Nitroarenes to Anilines 353</p> <p>11.5 Mechanism and Processing Parameters Affecting the Formation of Sulfonate Esters – Summary of the PQRI Studies 353</p> <p>11.5.1 Introduction 353</p> <p>11.5.2 Reaction Mechanism 355</p> <p>11.5.3 Experimental Results 357</p> <p>11.5.3.1 Experimental Results from Study of the Ethyl Methanesulfonate (EMS) System 357</p> <p>11.5.3.2 Other Methanesulfonic Acid Systems 359</p> <p>11.5.3.3 Experimental Results from Study of the Isopropyl Methanesulfonate (IMS) System 360</p> <p>11.5.4 Experimental Results from Study of Toluenesulfonic (Tosic) Acid Systems 361</p> <p>11.5.4.1 Experimental Results from Study of the Ethyl Tosylate (ETS) System 362</p> <p>11.5.4.2 Kinetic Modeling 363</p> <p>11.5.4.3 Key Learnings and Their Implications for Process Design 365</p> <p>11.5.4.4 Processing Rules 366</p> <p>11.5.5 What About Viracept™? 366</p> <p>11.5.6 What About Other Sources of Sulfonate Esters? 367</p> <p>11.5.7 Potential for Ester Formation in the Solid Phase 368</p> <p>11.5.8 Conclusions 369</p> <p>References 369</p> <p><b>12 Strategic Approaches to the Chromatographic Analysis of Mutagenic Impurities </b><b>381<br /></b><i>Frank David, Gerd Vanhoenacker, Koen Sandra, Pat Sandra, Tony Bristow, and Mark Harrison</i></p> <p>12.1 Introduction 381</p> <p>12.2 Method Development and Validation 384</p> <p>12.3 Analytical Equipment for Mutagenic Impurity Analysis 385</p> <p>12.4 Alkyl Halides and Aryl Halides 388</p> <p>12.4.1 Method Selection 388</p> <p>12.4.2 Typical Conditions Used for Alkyl-and Aryl Halide Analysis by SHS-GC-MS and SPME-GC-MS 390</p> <p>12.4.2.1 Sample Preparation 390</p> <p>12.4.2.2 GC-MS Parameters 391</p> <p>12.4.3 Typical Results Obtained for Alkyl-and Aryl Halide Analysis by SHS-GC-MS and SPME-GC-MS 391</p> <p>12.5 Sulfonates 393</p> <p>12.5.1 Method Selection 393</p> <p>12.5.2 Typical Conditions Used for Sulfonate Analysis by Derivatization SHS-GC-MS 394</p> <p>12.5.2.1 Sample Preparation 395</p> <p>12.5.2.2 Synthesis of Deuterated Internal Standards 395</p> <p>12.5.2.3 GC-MS Parameters 395</p> <p>12.5.3 Typical Results Obtained Using Derivatization – SHS – GC-MS 395</p> <p>12.5.4 Confirmation Analysis by PTV-GC-MS 396</p> <p>12.6 <i>S</i>-and <i>N</i>-mustards 398</p> <p>12.6.1 Method Selection 398</p> <p>12.6.2 Typical Analytical Conditions for the Analysis of <i>N</i>-mustards by Derivatization – SPME-GC-MS 399</p> <p>12.6.2.1 Sample Preparation 399</p> <p>12.6.3 Typical Results for <i>N</i>-mustards by Derivatization – SPME-GC-MS 399</p> <p>12.7 Michael Reaction Acceptors 400</p> <p>12.7.1 Method Selection 400</p> <p>12.7.2 Typical Analytical Conditions for Michael Reaction Acceptors 400</p> <p>12.7.2.1 Sample Preparation 401</p> <p>12.7.2.2 Parameters for SHS-GC-MS 401</p> <p>12.7.2.3 Parameters for Liquid Injection and GC-MS with Back-flush 402</p> <p>12.7.3 Typical Results Obtained for Trace Analysis of Michael Reaction Acceptors 402</p> <p>12.7.3.1 SHS with PTV 402</p> <p>12.7.3.2 Liquid Injection GC-MS 403</p> <p>12.8 Epoxides 404</p> <p>12.8.1 Method Selection 404</p> <p>12.8.2 Typical Analytical Conditions for the Analysis of Volatile Epoxides by SHS-GC-MS 406</p> <p>12.8.2.1 Sample Preparation 406</p> <p>12.8.2.2 SHS-GC-MS Parameters 406</p> <p>12.8.3 Typical Results Obtained for Volatile Epoxides Using SHS-GC-MS 407</p> <p>12.9 Haloalcohols 407</p> <p>12.9.1 Method Selection 407</p> <p>12.9.2 Analytical Conditions for Trace Analysis of Halo-alcohols by Derivatization and Liquid Injection - 2DGC-MS 409</p> <p>12.9.2.1 Sample Preparation 409</p> <p>12.9.2.2 2D-GC-MS Parameters 410</p> <p>12.9.3 Typical Results for Analysis of Halo-alcohols by Derivatization and Liquid Injection - 2DGC-MS 410</p> <p>12.10 Aziridines 411</p> <p>12.10.1 Method Selection 411</p> <p>12.10.2 Typical Analytical Conditions for RPLC-MS and HILIC-MS Analysis of Aziridines 412</p> <p>12.10.2.1 Sample Preparation 412</p> <p>12.10.2.2 RPLC-MS Method Parameters 413</p> <p>12.10.2.3 HILIC-MS Method Parameters 413</p> <p>12.10.3 Typical Results Obtained for Aziridine Analysis Using RPLC and HILIC 413</p> <p>12.11 Arylamines and Amino Pyridines 414</p> <p>12.11.1 Method Selection 414</p> <p>12.11.2 Typical Analytical Conditions for Arylamines and Aminopyridines by RPLC-MSD 415</p> <p>12.11.2.1 Sample Preparation 415</p> <p>12.11.2.2 HPLC-MS Parameters 416</p> <p>12.11.3 Typical Results for Arylamines and Aminopyridines by RPLC-MSD 417</p> <p>12.12 Hydrazines and Hydroxylamine 419</p> <p>12.12.1 Method Selection 419</p> <p>12.12.2 Analytical Conditions for the Analysis of Hydrazines Using Derivatization and HPLC-MS 420</p> <p>12.12.2.1 Sample Preparation 421</p> <p>12.12.2.2 HPLC-MS Parameters 421</p> <p>12.12.3 Typical Results Obtained for Hydrazines Using Derivatization LC-MS 421</p> <p>12.13 Aldehydes and Ketones 423</p> <p>12.13.1 Method Selection 423</p> <p>12.13.2 Typical Analytical Conditions for Analysis of Aldehydes and Ketones by DNPH Derivatization, Followed by LC-MS Analysis 423</p> <p>12.13.2.1 Sample Preparation 424</p> <p>12.13.2.2 Derivatization Reagent Solution 425</p> <p>12.13.2.3 HPLC-MS Parameters 425</p> <p>12.13.3 Typical Results Obtained for Aldehyde Analysis by DNPH Derivatization – LC-MS 426</p> <p>12.14 Nitrosamines 426</p> <p>12.14.1 Method Selection 426</p> <p>12.14.2 Sample preparation for SHS-GC-MS Analysis (according to ref [85]) 428</p> <p>12.14.2.1 SHS-GC-MS Analysis [85] Sample Preparation 428</p> <p>12.14.2.2 GC-MS (HRAM-MS) Conditions 428</p> <p>12.14.2.3 UHPLC-MS Analysis 429</p> <p>12.14.2.4 Sample Preparation for Hydrophilic Samples (e.g. Metformin) 429</p> <p>12.14.2.5 Sample Preparation for Hydrophobic Matrices 430</p> <p>12.14.2.6 UHPLC Conditions 430</p> <p>12.14.2.7 HRAM-MS and MS/MS Conditions 430</p> <p>12.14.3 Typical Results Obtained for Volatile <i>N</i>-nitrosamines Using SHS-GC-MS 430</p> <p>12.14.4 Typical Results Obtained for <i>N</i>-nitrosamines Using LC-MS 431</p> <p>12.15 Nontarget Analysis of PMI/MIs 434</p> <p>12.16 Conclusions 435</p> <p>Acknowledgements 436</p> <p>References 436</p> <p><b>13 Analysis of Mutagenic Impurities by Nuclear Magnetic Resonance (NMR) Spectroscopy </b><b>439<br /></b><i>Andrew R. Phillips and Stephen Coombes</i></p> <p>13.1 Introduction to NMR 439</p> <p>13.2 Why Is NMR an Insensitive Technique? 439</p> <p>13.2.1 Nuclear Spin 439</p> <p>13.2.2 Boltzmann Distribution 440</p> <p>13.3 How Could NMR Be Used for Trace Analysis? 440</p> <p>13.3.1 Generating an NMR Spectrum 440</p> <p>13.3.2 Chemical Shift 442</p> <p>13.3.3 Scalar Coupling 443</p> <p>13.3.4 The Quantitative Nature of NMR 444</p> <p>13.3.5 Relaxation 445</p> <p>13.3.6 Summary 446</p> <p>13.4 What Can Be Done to Maximize Sensitivity? 446</p> <p>13.4.1 System Performance 447</p> <p>13.4.1.1 Field Strength 447</p> <p>13.4.2 Probe Performance 447</p> <p>13.4.2.1 Probe Design 447</p> <p>13.4.2.2 Probe Diameter 448</p> <p>13.4.2.3 Cryogenically Cooled Probes 448</p> <p>13.4.3 Substrate Concentration 449</p> <p>13.4.4 Molecular Weight Ratio 451</p> <p>13.4.5 Acquisition Time and Signal Averaging 451</p> <p>13.4.6 Number of Protons and Linewidth 453</p> <p>13.4.7 Resolution 455</p> <p>13.4.8 Dynamic Range 455</p> <p>13.4.8.1 Selective Excitation 458</p> <p>13.4.8.2 Shaped Pulses 458</p> <p>13.4.8.3 Quantification Using Selective Pulses 460</p> <p>13.4.8.4 Excitation Sculpting 461</p> <p>13.4.9 Limit Tests 461</p> <p>13.4.9.1 Method Development 462</p> <p>13.4.9.2 Validation 463</p> <p>13.4.9.3 Unresolved Signals 463</p> <p>13.4.9.4 Rapid Analysis 464</p> <p>13.4.10 Expanded Use of MI NMR Methodology 464</p> <p>13.4.11 Summary 464</p> <p>13.5 Case Studies 464</p> <p>13.5.1 Case Study 1 – An Aldehyde Functionalized MI 464</p> <p>13.5.2 Case Study 2 – Use of 19F NMR 466</p> <p>13.5.3 Case Study 3 – Epoxide and Chlorohydrin MIs 468</p> <p>13.5.4 Case Study 4 – Sulfonate Esters 469</p> <p>13.5.5 Case Study 5 – Limit Test for Poorly Resolved Signals 470</p> <p>13.5.6 Case Study 6 – Using NMR MI Methodology for Cleaning Validation 472</p> <p>13.6 Conclusion 473</p> <p>References 475</p> <p><b>14 Addressing the Complex Problem of Degradation-Derived Mutagenic Impurities in Drug Substances and Products </b><b>477<br /></b><i>Steven W. Baertschi and Andrew Teasdale</i></p> <p>14.1 Introduction 477</p> <p>14.1.1 Background 477</p> <p>14.2 Working Definitions 478</p> <p>14.3 Challenges Associated with the Assessment of Risk Posed by (Potentially) Mutagenic Degradation Products 479</p> <p>14.4 Risk Assessment Process for Mutagenic Degradants 479</p> <p>14.4.1 Stability-Related MRA Process Overview 479</p> <p>14.4.2 Stress Studies 480</p> <p>14.4.3 Accelerated Stability Studies 480</p> <p>14.4.4 Long-term ICH Stability Studies 481</p> <p>14.4.5 Deciding Which Products to Include in the MRA 481</p> <p>14.4.6 In Silico Tools for the Prediction of Potential Degradation Products 482</p> <p>14.5 Using Stress Testing to Select Degradation Products for Identification 482</p> <p>14.5.1 Approach 1: Criteria for Structure Identification After Observation in Accelerated and Long-term Stability Studies 483</p> <p>14.5.2 Approach 2: Criteria for Structure Identification Through Use of an Algorithm in Stress Testing Studies 483</p> <p>14.5.3 Approach 3: Structure Identification Through Use of Kinetic Equivalence and Scaled ICH Q3B Thresholds 485</p> <p>14.5.3.1 Kinetic Equivalence 485</p> <p>14.5.3.2 Scaled ICH Q3B Thresholds 486</p> <p>14.6 Development Timeline Considerations 487</p> <p>14.6.1 Drug Discovery Stage 487</p> <p>14.6.2 Preclinical to Phases 1/2 487</p> <p>14.6.3 Phase 3 to New Drug Application (NDA) Regulatory Submission 488</p> <p>14.6.4 Post-marketing/Line Extensions 488</p> <p>14.7 Developing Control Strategies for (Potential) Mutagenic Degradation Products 488</p> <p>14.7.1 Determining Relevancy of Potential Degradation Products and Developing Control Strategies for Actual Degradation Products 488</p> <p>14.7.2 Accelerated Stability (40 °C/75% RH Six months) or Kinetic Equivalent 489</p> <p>14.7.3 Photostability Studies 489</p> <p>14.7.4 Degradation Chemistry Knowledge 490</p> <p>14.8 Risk Assessment Process Illustrated 491</p> <p>14.8.1 Case Study #1: Molecule A 491</p> <p>14.8.2 Case Study #2: Galunisertib 492</p> <p>14.8.3 Case Study #3: Naloxegol 494</p> <p>14.8.4 Case Study #4: Selumetinib Side Chain 496</p> <p>14.9 Significance of the Risk of Forming Mutagenic Degradation Products 498</p> <p>14.9.1 Frequency of Alerting Structures in Degradation Products 498</p> <p>14.10 Degradation Reactions Leading to Alerting Structures in Degradation Products 499</p> <p>14.10.1 Frequency of Alerting Structures Giving Rise to Ames Positive Tests 503</p> <p>14.10.2 Mutagenic Degradation Products: Overall Predicted Frequency 503</p> <p>14.11 N-Nitrosamines: Special Considerations 503</p> <p>14.11.1 Evaluation of Potential Formation of N-Nitrosamines in Drug Product 504</p> <p>14.12 Conclusions 506</p> <p>References 507</p> <p>Index 513</p>
<p><b>Andrew Teasdale, PhD, </b>is a senior principal scientist with AstraZeneca and a member of ICH Q3C, Q3D, Q3E Expert working groups as well as an industry advisor to ICH M7. He received his doctorate in organic chemistry from Durham University. He is the inventor of the purge factor concept applied to risk assessment of mutagenic impurities and has authored over 30 papers on that subject.</p>
<p><b>Learn to implement effective control measures for mutagenic impurities in pharmaceutical development</b></p> <p>In <i>Mutagenic Impurities: Strategies for Identification and Control,</i> distinguished chemist Andrew Teasdale delivers a thorough examination of mutagenic impurities and their impact on the pharmaceutical industry. The book incorporates the adoption of the ICH M7 guideline and focuses on mutagenic impurities from both a toxicological and analytical perspective. <p>The editor has created a primary reference for any professional or student studying or working with mutagenic impurities and offers readers a definitive narrative of applicable guidelines and practical, tested solutions. It demonstrates the development of effective control measures, including chapters on the purge tool for risk assessment. <p>The book incorporates a discussion of N-Nitrosamines which was arguably the largest mutagenic impurity issue ever faced by the pharmaceutical industry, resulting in the recall of Zantac and similar drugs resulting from N-Nitrosamine contamination. <p>Readers will also benefit from the inclusion of: <ul><li>A thorough introduction to the development of regulatory guidelines for mutagenic and genotoxic impurities, including a historical perspective on the development of the EMEA guidelines and the ICH M7 guideline</li> <li>An exploration of in silico assessment of mutagenicity, including use of structure activity relationship evaluation as a tool in the evaluation of the genotoxic potential of impurities</li> <li>A discussion of a toxicological perspective on mutagenic impurities, including the assessment of mutagenicity and examining the mutagenic and carcinogenic potential of common synthetic reagents</li></ul> <p>Perfect for chemists, analysts, and regulatory professionals, <i>Mutagenic Impurities: Strategies for Identification and Control </i>will also earn a place in the libraries of toxicologists and clinical safety scientists seeking a one-stop reference on the subject of mutagenic impurity identification and control.

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