1. Changes to methods or controls were not reported to FDA through a supplement to an approved [redacted]. (21 CFR 314.97(a) and 314.70(c)(6)(i))
...Investigators observed, in your [redacted] API, non-carcinogenic impurities of [redacted] and [redacted] at levels up to [redacted]% and [redacted]%, respectively, in residual solvent testing for [redacted] API batches. These impurities are present in drug substances at levels exceeding the [redacted] USP specification limit for Any other individual impurity (i.e. NMT [redacted]%). These impurity levels are also above the ICH Q3A(R2) reporting threshold for drug substance impurities.
Your Quality Unit failed to report to FDA these impurities, which were also above your internal reporting threshold limit of no more than [redacted]%. You updated the information in your Drug Master File (DMF) only after FDA investigators communicated during the inspection that you should be reporting all observed impurities above the reporting threshold.
In your response, you explained a “scheduled regulatory update skipped our attention.” In addition, you stated you would undertake an additional CAPA for controls of residual solvents. Your response is inadequate, as you did not commit to conduct a full review of all impurities observed in all your APIs above the reporting threshold and ensure that your DMFs and [redacted] are updated accordingly...