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 Implementation178179180181182183184185186187188189190191192193194195196197198199200201202203204205206which the <strong>impurities</strong> need to be controlled. For unidentified <strong>impurities</strong>, the procedure used andassumptions made <strong>in</strong> establish<strong>in</strong>g the level of the impurity should be clearly stated. Unidentified<strong>impurities</strong> <strong>in</strong>cluded <strong>in</strong> the specification should be referred to by some appropriate qualitativeanalytical descriptive label (e.g., "unidentified A," "unidentified with relative retention of 0.9").F<strong>in</strong>ally, a general acceptance criteria of not more than 0.1 percent for any unspecified impurityshould be <strong>in</strong>cluded.Acceptance criteria should be set no higher than the level that can be justified (see the ImpuritiesDecision Tree for generic <strong>drug</strong>s, Attachment I) either by comparative studies or genotoxicitystudies, and unless such data <strong>in</strong>dicate otherwise, no lower than the level achievable by themanufactur<strong>in</strong>g process and the analytical capability. In other words, where there is no safetyconcern, impurity acceptance criteria should be based on data generated on actual batches of the<strong>drug</strong> substance allow<strong>in</strong>g sufficient latitude to deal with normal manufactur<strong>in</strong>g and analyticalvariation, and the stability characteristics of the <strong>drug</strong> substance. Although normal manufactur<strong>in</strong>gvariations are expected, significant variation <strong>in</strong> batch-to-batch impurity levels may <strong>in</strong>dicate thatthe manufactur<strong>in</strong>g process of the <strong>drug</strong> substance is not adequately controlled and validated.In summary, the <strong>drug</strong> substance acceptance criteria should <strong>in</strong>clude, where applicable, acceptancecriteria for:! Organic Impurities:! Each specified identified impurity! Each specified unidentified impurity at or above 0.1 percent! Any unspecified impurity, with a limit of not more than 0.1 percent! Total <strong>impurities</strong>! Residual Solvents! Inorganic ImpuritiesA summation of assay value and impurity levels generally may be used to obta<strong>in</strong> mass balance forthe test sample. The mass balance need not add to exactly 100 percent because of the analyticalerror associated with each analytical procedure. The summation of impurity levels plus the assayvalue may be mislead<strong>in</strong>g, for example, when the assay procedure is nonspecific (e.g.,potentiometric titrimetry) and the impurity level is relatively high.J:\!GUIDANC\2452DFT.WPDJuly 21, 19987