Mutagenicity assessment of five pharmaceutical impurities


A pharmaceutical company


A Competent Authority had asked a pharmaceutical company to prepare assessments of the potential mutagenicity/genotoxicity of five impurities in an API.

Project Goals

Bibra was asked to prepare critical evaluations of the genotoxicity/mutagenicity potential of these five substances. The focus of the ICH EMA M7 guidance is on DNA reactive mutagens as opposed to genotoxins generally (as the latter may operate by mechanisms that might have thresholds).


Literature searches identified sufficient information on one impurity to conclude that it is lacks mutagenic character. For the other four, reliable “read-across” analogues were found, and these showed no mutagenic character in screening tests. In general, all five lacked structural alerts for mutagenicity as per Toxtree and OECD Toolbox analysis. However, as two impurities fired at least one (Q)SAR alert, bibra assessed the health risk implications of patient exposure, on the health‑precautionary assumption that these might be genuine mutagens.

Project Outcome

Bibra was able to provide the client with robust assessments that showed that none of the five impurities was likely to be mutagenic. Even in the worst-case scenario (that future testing reveals mutagenic potential for two of the impurities), the estimated exposures were reassuringly low when compared with EMA/ICH TTC default figures for exposure to “unavoidable” mutagens in pharmaceuticals.

Project Leader

Pete Watts


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