Mutagenic Impurities - Группа авторов

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3.6 Summary of mutagenicity assessment for synthetic process to GW6415...Table 3.7 Purge predictions for ethyl bromoisobutyrate2.Table 3.8 Purge predictions for hydroxylamine.Table 3.9 Purge predictions for alkyl chloride8.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 thein 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 thein vivo relevance of in vitro mutagens (po...Table 7.6 Regulatory interim AIs forN‐nitrosamine compounds.Table 7.7 EC SCCS tumor potency estimates forN‐nitrosamines [61].Table 7.8 Carcinogenic potencies of selectedN‐nitrosamines.Table 7.9 SelectedN‐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...

      7 Chapter 8Table 8.1 BMD CI and PDE calculated usingin vivo mutation and cancer bioassa...

      8 Chapter 9Table 9.1 Potential general reactivity classes.Table 9.2 Examples of scavenging resins and their application.Table 9.3 Purge factor scoring system.Table 9.4 Examples of published purge values – predicted compared with measu...Table 9.5 Relationship between Purge Factor ratios and Regulatory Reporting ...Table 9.6 Data to support a regulatory submission that applies the ICH M7 Co...Table 9.7 High‐level control summary table for potential mutagenic impuritie...Table 9.8 Detailed purge calculations for an impurity.Table 9.9 Sample results from expert elicitations [18].Table 9.10 Experimental reactivity protocol.Table 9.11 Experimentally derived purge factors for oxidation of boronic aci...Table 9.12 Specified impurities for Camicinal (GSK962040).Table 9.13 Summary of mutagenic impurity assessment from Camicinal (GSK96204...Table 9.14 Summary of purge rationales for PMIs7 and 13 from the Camicinal r...

      9 Chapter 10Table 10.1 Initial events relating to Sartan contamination in mid‐2018.Table 10.2 Nitrite results for common excipients in drug product formulation...Table 10.3N‐Nitroso‐4‐phenylpiperidine in tablets from the direct compression an...Table 10.4 Nitrosamine sources from elastomeric cure accelerators.Table 10.5 Timescales for Article 31 process.Table 10.6 Safety Limits for commonly observed M Nitrosamines – part 1Table 10.7 Conclusions drawn in relation to all areas covered by the Article...Table 10.8 Nitrosamines and their interim limits.Table 10.9 Adjusted interim limits for impurities present in medicinal produ...Table 10.10 Most significant changes and their implications of the question ...

      10 Chapter 11Table 11.1 Measured kinetic and thermodynamic constants involving sulfonate ...

      11 Chapter 12Table 12.1 Typical alkyl halide and aryl halide analytes.Table 12.2 Sulfonate and sulfate ester target compounds.Table 12.3 Validation results for sulfonate ester analysis by derivatization...Table 12.4 SelectedS‐ and N‐mustard target analytes.Table 12.5 Selected Michael reaction acceptor target analytes.Table 12.6 Validation results for Michael reaction acceptor analysis by SHS‐...Table 12.7 Selected epoxide target analytes.Table 12.8 Figures of merit for 2D‐GC‐MS analysis of haloalcohols and glycid...Table 12.9 Selected aziridine target analytes.Table 12.10 Selected target analytes for arylamine and aminopyridine analysi...Table 12.11 Retention times, selected SIM ions, and recovery for arylamines ...Table 12.12 Selected hydrazine target analytes.Table 12.13 Selected aldehyde target analytes.Table 12.14 Retention times, SIM ions, and recovery for aldehydes spiked in ...Table 12.15N‐nitrosamine target compounds.Table 12.16 Selected ions for HR‐MS detection ofN‐nitrosamines using GC‐EI‐M...Table 12.17 Selected ions for LC‐HRAM MS or LC‐MS/MS analysis ofN‐nitrosamin...

      12 Chapter 13Table 13.1 Sensitivity of common spin‐1/2 nuclei.Table 13.2 Some examples of1H and 19F chemical shifts.Table 13.3 Concentration sensitivity of some example probe designs at differ...Table 13.4 Signal to noise in one hour assuming it is possible to pulse ever...Table 13.5 Choice of selective experiment pulse sequence.Table 13.6 ICH validation requirements.Table 13.7 Calculated ppm levels and recoveries from a selective experiment ...Table 13.8 TFNB recoveries.Table 13.9 Epoxide (7) and chlorohydrin (8) recoveries.

      13 Chapter 14Table 14.1 Peaks are selected for identification based on meeting Criteria 1...Table 14.2 Rate of degradation (relative to 25 °C) assuming an Arrhenius kin...Table 14.3 Number of days at specified temperatures calculated for a “kineti...Table 14.4 Proposed identification thresholds for major degradation products...Table 14.5 Reactions leading to the production of a mutagenicity alerting st...Table 14.6 Degradation reactions leading to the production of a mutagenic al...Table 14.7 Degradation reactions leading to the products of a mutagenic aler...Table 14.8 Degradation reactions leading to the production of a mutagenic al...Table 14.9 Degradation reactions leading to the production of a mutagenic al...Table 14.10 Degradation reactions leading to the production of a mutagenic a...

      List of Illustrations

      1 Chapter 2Figure 2.1 EDAC.Figure 2.2 Interrelationship between degradant classes.Figure 2.3 Potential sources of mutagenic impurities.Figure 2.4 Decision matrix when evaluating two in silico predictions.

      2 Chapter 3Figure 3.1 Proposed process flow for MI risk assessment for a pharmaceutical...Figure 3.2 (P)MI purge factor decision tree for use under ICH M7.Figure 3.3 Identified (I) and reasonably predicted (RP) impurities within GW...Figure 3.4 Synthetic process to GW641597X.Figure 3.5 1H NMR of Stage 1a product 3.Figure 3.6 1H NMR of Stage 4b product crude GW641597X.Figure 3.7 Nitrosamine formation pathways from Et3N and DMF.Figure 3.8 Process map of candesartan synthesis.Figure 3.9 Breakdown of purge assignments for Et3N in the Stage 2 workup pro...Figure 3.10 Purge calculation summary for Et3N.Figure 3.11 Purge calculation summary for DMF.Figure 3.12 Purge calculation summary for DMA and DEA.Figure

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