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2.4.1.2 Question 1.2

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What are the expectations for evaluation of the mutagenic potential for an impurity where the amount of impurity is less than or equal to 1 mg daily dose?	In the context of ICH M7, (quantitative) structure activity relationships ((Q)SARs) are considered an appropriate initial evaluation of mutagenic potential of an impurity at a daily dose of ≤1 mg. When a structural alert is identified, a follow‐up in vitro evaluation (e.g. bacterial reverse mutation assay) could be conducted, or the impurity could be controlled by TTC. Negative results in either evaluation would classify the impurity under Class 5. The result of the bacterial reverse mutation assay overrules the (Q)SAR prediction. Additionally, impurities should not be assigned to Class 5 based solely on the absence of structural alerts by visual evaluation alone. There is an expectation that structural alert assessment will be conducted using (Q)SAR prediction.

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Answer

What are the expectations for evaluation of the mutagenic potential for an impurity where the amount of impurity is less than or equal to 1 mg daily dose?

In the context of ICH M7, (quantitative) structure activity relationships ((Q)SARs) are considered an appropriate initial evaluation of mutagenic potential of an impurity at a daily dose of ≤1 mg. When a structural alert is identified, a follow‐up in vitro evaluation (e.g. bacterial reverse mutation assay) could be conducted, or the impurity could be controlled by TTC. Negative results in either evaluation would classify the impurity under Class 5. The result of the bacterial reverse mutation assay overrules the (Q)SAR prediction. Additionally, impurities should not be assigned to Class 5 based solely on the absence of structural alerts by visual evaluation alone. There is an expectation that structural alert assessment will be conducted using (Q)SAR prediction.

The main point made in this Q&A is that (Q)SAR analysis is necessary in order to determine if an impurity has an alert for mutagenicity, and visual evaluation alone (which was conventional prior to the implementation of ICH M7) is currently not acceptable. Here again the emphasis is on the Ames test as the proper assay to perform in case testing is desired, and the results from this test overrule any (Q)SAR prediction.

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