Читать книгу Mutagenic Impurities - Группа авторов - Страница 77

Ahead of development of the guideline the question as to the relationship between guidelines pertaining to mutagenic impurities and ICH Q3A [5] was a considerable concern. These concerns centered on the issue of impurity qualification. For a marketed product, any impurity present at level >0.15% requires qualification. In addition to general toxicological qualification such an impurity requires qualification in terms of its genotoxic potential. It is of course obvious that ICH Q3A predates ICH M7 and indeed earlier regional guidelines; however, the question of genotoxic qualification remains. Of particular concern within this was, not only does ICH Q3A ask that consideration be given to conduct of assessment of mutagenic potential, but it also advises that an assessment of chromosomal activity be also considered.

Note 1 within ICH M7 addresses this specific concern. It states that no further qualification for mutagenic potential is required provided that an SAR assessment of mutagenic potential has been performed on any impurity present at levels either above or below those defined in ICH Q3A/Q3B. This includes the initial use of (Q)SAR tools to predict bacterial mutagenicity. Only in cases where the amount of the impurity exceeds 1 mg daily dose for chronic administration is further evaluation recommended. There seems little logic in the 1 mg limit; however, in reality this is unlikely to be regularly encountered in the context of reactive mutagenic impurities.

The other notes cover the following topics; Notes 2–6 each are examined as part of other detailed chapters.

 Note 2: Ames test – Good Laboratory Practice (GLP)

 Note 3: additional safety tests

 Note 4: compound‐specific limits – extrapolation of TD50 values

 Note 5: compound‐specific limits – class‐based limits – monofunctional alkyl halides

 Note 6: thresholded mechanisms

Note 7: derivation of LTL limits

The guideline provides a helpful table that aligns treatment type/disease area to the duration of treatment and hence the applicable durational limit. It should be noted that this is based on median duration not outliers. Many treatments involve multiple and complex patient groups making it impractical to establish the longest potential time small and often specialist subpopulations receive a medicine.