ANDAs impurities in drug substances - Pharmanet

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 (point mutation, chromosomal aberration) a2. General toxicity studies (one species, min. 14 days, max. 90 days) b3. Other specific toxicity endpoint, as appropriateAdverse EffectsYesNoConsider additional testingor removal of impurityQualifiedaIf considered desirable, a minimum screen for genotoxic potential should be conducted. A study to detect pointmutations and one to detect chromosomal aberrations, both in vitro, are seen as an acceptable minimum 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 information andperformed in the species most likely to maximize the potential to detect the toxicity of an impurity. In general, aminimum duration of 14 days and a maximum duration of 90 days will be acceptable.J:\!GUIDANC\2452DFT.WPDJuly 21, 199813