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2.4.6.4 Question 6.4
ОглавлениеThe continuation of the text quoted above in Question 6.3 says the following (emphasis added): “A positive bacterial mutagenicity result would warrant further hazard assessment and/or control measures (Class 2 in table 1). For instance, when levels of the impurity cannot be controlled at an appropriate acceptable limit, it is recommended that the impurity be tested in an in vivo gene mutation assay in order to understand the relevance of the bacterial mutagenicity assay result under in vivo conditions. The selection of other in vivo genotoxicity assays should be scientifically justified based on knowledge of the mechanism of action of the impurity and expected target tissue exposure (Note 3). in vivo studies should be designed taking into consideration existing ICH genotoxicity Guidelines. Results in the appropriate in vivo assay may support setting compound specific impurity limits.”
| Question | Answer |
|---|---|
| Please clarify the rationale for the tests included under Note 3 as a follow‐up to investigate the in vivo relevance of Ames mutagen. | If an impurity is positive in the Ames test, an in vivo follow‐up test with mutagenic end point (mutagenicity) should be used. The other follow‐up tests outlined in Note 3 are also acceptable when scientific rationale is provided to support their use. For any of the above tests, adequate exposure should be demonstrated in line with ICH S2. |
Regulatory agencies expect a strong argument to overrule a positive Ames test. It is pertinent that the in vivo test(s) used to further investigate the relevance of the in vitro results be chosen correctly and that adequate exposure be demonstrated. A negative result in a transgenic mutation assay would normally be the strongest evidence to overrule a positive in vitro result, but this assay is relatively expensive and lengthy. Other assays are also acceptable, and often times a stakeholder will chose to combine several assays (e.g. Pig‐a assay, in vivo micronucleus assay, and Comet assay) to be absolutely certain that the impurity is nonmutagenic.
