Methods to be employed in molecular design, impurity qualification, toxicological and environmental risk assessment (ERA).

A computational toxicology assessment should be performed using QSAR (Quantitative structure–activity relationship) methodologies that predict the outcome of a bacterial mutagenicity assay. Two QSAR prediction methodologies that complement each other should be applied. One methodology should be expert rule-based and the second methodology should be statistical-based.

QSAR models utilizing these prediction methodologies should follow the validation principles set forth by the Organisation for Economic Co-operation and Development (OECD). (18) The outcome of any computer system-based analysis should be reviewed with the use of expert knowledge in order to provide additional supportive evidence on relevance of any positive or negative prediction and to elucidate underlying reasons in case of conflicting results.

The absence of structural alerts from two complementary QSAR methodologies (expert rule-based and statistical) is sufficient to conclude that the impurity is of no concern, and no further testing is required (Class 5 in Table 1).