ANDAs impurities in drug substances - Pharmanet
ANDAs impurities in drug substances - Pharmanet
ANDAs impurities in drug substances - Pharmanet
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Draft-Not for ImplementationAttachment IIICH Decision Tree for Safety StudiesDecrease impurity levelbelow thresholdYesAbove ThresholdNoQualifiedYesNoStructure elucidated?YesYesToxicity documented andsufficient?NoRelated to others withknown toxicity?YesAcceptablejustification?NoConsider patient populationand duration of useNoYesQualifiedConsider need for:1. Genotoxicity studies (po<strong>in</strong>t mutation, chromosomal aberration) a2. General toxicity studies (one species, m<strong>in</strong>. 14 days, max. 90 days) b3. Other specific toxicity endpo<strong>in</strong>t, as appropriateAdverse EffectsYesNoConsider additional test<strong>in</strong>gor removal of impurityQualifiedaIf considered desirable, a m<strong>in</strong>imum screen for genotoxic potential should be conducted. A study to detect po<strong>in</strong>tmutations and one to detect chromosomal aberrations, both <strong>in</strong> vitro, are seen as an acceptable m<strong>in</strong>imum screen.bFor NDAs, if general toxicity studies are desirable, study(ies) should be designed to allow comparison ofunqualified to qualified material. The study duration should be based on available relevant <strong>in</strong>formation andperformed <strong>in</strong> the species most likely to maximize the potential to detect the toxicity of an impurity. In general, am<strong>in</strong>imum duration of 14 days and a maximum duration of 90 days will be acceptable.J:\!GUIDANC\2452DFT.WPDJuly 21, 199813