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For any impurity identified as being potentially mutagenic (based on SAR evaluation) and assessed as having a high likelihood of carryover into the API, the next step is often to carry out in vitro safety testing.

If in vitro testing is selected, it is recommended that the synthesized or isolated impurity is tested for mutagenicity as an individual impurity. However, where this is impractical, then spiked samples or batches of material that contain elevated levels of the impurity of concern may be tested. The latter approach is not generally encouraged by regulatory authorities, and in such cases, an early dialogue with the relevant regulatory authority is recommended. In relation to the material quality, it is recommended to ensure the sample tested is as pure as is practically possible and is fully characterized in terms of the impurities present with the test sample. It is important to ensure that any result from subsequent testing is not confounded by the presence of trace impurities that may themselves elicit a response in the assay but would otherwise not be relevant to the route in which the (P)MI is being assessed. It is therefore important to fully characterize the test sample in terms of impurity profile with a specific emphasis on other potential mutagenic species that could be present, especially any used to synthesize the test sample.

ICH M7, Section 3 general principles, makes clear that the focus of the guideline is on deoxyribonucleic acid (DNA)‐reactive substances that have a potential to directly cause DNA damage when present at low levels leading to mutations and therefore, potentially causing cancer. It then states that to detect this type of mutagenic carcinogen a bacterial reverse mutation (mutagenicity), i.e. Ames test, has the necessary sensitivity and specificity.

A positive result in one or more of these tests is generally sufficient evidence to define the impurity as mutagenic, in which case it will be then necessary to adopt the appropriate TTC approach. Occasionally, a thresholded mechanism can be argued based on available safety data; this concept is examined in detail in Chapter 8. If an impurity is found to be negative, it is considered nonmutagenic (qualified for mutagenicity) and can then be treated as a normal impurity under ICH Q3A/B [13, 14].

The mutagenic potential of in vitro positive materials may be further evaluated in vivo, in order to look to establish the biological relevance of the in vitro findings (Table 3.5); this is highlighted in ICH M7, Note 3; and this is examined in detail in Chapter 6.