impurities in new drug products

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Impurities in New Drug ProductsNotes on attachment 21 After identification, if the response factor is determined to differ significantlyfrom the original assumptions, it can be appropriate to re-measure the actualamount of the degradation product present and re-evaluate against thequalification threshold (see Attachment 1).2 To verify if a threshold is exceeded, a reported result has to be evaluatedagainst the thresholds as follows: when the threshold is described in %, thereported result rounded to the same decimal place as the threshold should becompared directly to the threshold. When the threshold is described in TDI,the reported result should be converted to TDI, rounded to the same decimalplace as the threshold and compared to the threshold e.g. an amount of 0.18%degradation level corresponds to a TDI of 3.4 mg impurity (absolute amount)which is then rounded down to 3 mg; so the qualification threshold expressedin TDI (3 mg) is not exceeded.10
Impurities in New Drug ProductsAttachment 3: Decision Tree for Identification and Qualification of aDegradation ProductIs degradationproduct greater thanidentificationthreshold c ?YesNoNo actionStructureidentified?YesAnyknown humanrelevant risks d ?YesReduce tosafe levelNoNoReduceto not more than(≤) identificationthreshold c ?NoYesNo furtheractionYesReduceto not more than(≤) qualificationthreshold c ?YesGreaterthan qualificationthreshold c ?NoNo actionNoConsider patient population and duration of useand consider conducting:• Genotoxicity studies (point mutation,chromosomal aberration) a• General toxicity studies (one species, usually14 to 90 days) b• Other specific toxicity endpoints, asappropriateReduce tosafe levelYesAnyclinicallyrelevant adverseeffects?NoQualified11
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