Regulatory Open Forum

Dear Forum',

Need your support in the interpretation of ICH M7 guidance, If an API impurity has a structural alert in prediction software as Class 3, and In-vitro bacterial reverse mutation test study is to be conducted to evaluate mutagenic potential.

In such cases, can bacterial reverse mutation test be conducted with 'API (enriched with probable genotox impurity)' instead of 'isolated probable genotox impurity'.

Kindly advise. It would be a great help. Many thanks in advance.

Is there a reason that the impurity is not being isolated? Class 3 implies that it is structurally unrelated to the drug substance. If so, it should be feasible to isolate by chromatography, extraction, etc.

Regardless, Note 2 in the guidance (excerpt below) provides a path. It depends on how enriched it is. I would make sure that the drug substance itself would not be at a high enough concentration to interfere.

For impurities that are not feasible to isolate or synthesize or when compound quantity is limited, it may not be possible to achieve the highest test concentrations recommended for an ICH-compliant bacterial mutagenicity assay according to the current testing guidelines. In this case, bacterial mutagenicity testing could be carried out using a miniaturized assay format with proven high concordance to the ICH-compliant assay to enable testing at higher concentrations with justification.

Dear Forum',

Need your support in the interpretation of ICH M7 guidance, If an API impurity has a structural alert in prediction software as Class 3, and In-vitro bacterial reverse mutation test study is to be conducted to evaluate mutagenic potential.

In such cases, can bacterial reverse mutation test be conducted with 'API (enriched with probable genotox impurity)' instead of 'isolated probable genotox impurity'.

Kindly advise. It would be a great help. Many thanks in advance.

Dear Mr Scott

I appreciate you taking the time to provide inputs on below , further would the USFDA require a reason to perform studies using enriched API , if you could let us know more on miniaturized assay format.

Is there a reason that the impurity is not being isolated? Class 3 implies that it is structurally unrelated to the drug substance. If so, it should be feasible to isolate by chromatography, extraction, etc.

Regardless, Note 2 in the guidance (excerpt below) provides a path. It depends on how enriched it is. I would make sure that the drug substance itself would not be at a high enough concentration to interfere.

For impurities that are not feasible to isolate or synthesize or when compound quantity is limited, it may not be possible to achieve the highest test concentrations recommended for an ICH-compliant bacterial mutagenicity assay according to the current testing guidelines. In this case, bacterial mutagenicity testing could be carried out using a miniaturized assay format with proven high concordance to the ICH-compliant assay to enable testing at higher concentrations with justification.

Dear Forum',

Need your support in the interpretation of ICH M7 guidance, If an API impurity has a structural alert in prediction software as Class 3, and In-vitro bacterial reverse mutation test study is to be conducted to evaluate mutagenic potential.

In such cases, can bacterial reverse mutation test be conducted with 'API (enriched with probable genotox impurity)' instead of 'isolated probable genotox impurity'.

Kindly advise. It would be a great help. Many thanks in advance.