Today, FDA reissued the Guidance for Industry: Abbreviated New Drug Application Submissions-Refuse to Receive for Lack of Justification of Impurity Limits, but the word “Proper” was removed from its title.  The title of the previous version read Abbreviated New Drug Application Submissions- -Refuse to Receive for Lack of Proper Justification of Impurity Limits (emphasis added).

While the Guidance document (here) itself is essentially the same, FDA notes that the review of the justification submitted in the application is a matter for the technical review of the ANDA.  But FDA emphasizes there must be a justification that is consistent with the ICH guidance on impurities and that appears in the ANDA, otherwise the deficiencies may be serious enough to cause the FDA to Refuse-to-Receive (RTR) the ANDA.  FDA goes on to say:

“Specifically, these deficiencies include: (1) Failing to provide justification for proposed limits for specified identified impurities in drug substances and drug products that are above qualification thresholds; (2) failing to provide justification for specified unidentified impurities that are above identification thresholds; and (3) proposing limits for unspecified impurities (e.g., any unknown impurity) that are above identification thresholds.”

The justification is required to address any of these issues and the FDA has expectations as to what information may be necessary to justify exceeding any limits, including, but not limited to:

(1) the observed impurity levels and proposed impurity limits do not exceed the level observed in the reference listed drug (RLD) product;
(2) the impurity is a significant metabolite of the drug substance;
(3) the observed impurity levels and proposed impurity limits are adequately justified by the scientific literature;
(4) the observed impurity levels and proposed impurity limits do not exceed the level that has been adequately evaluated in toxicity studies.

Impurity issues, including setting appropriate limits, have been an ongoing problem for applicants and in many instances, still cause review problems in the ANDA that result in multiple ANDA review cycles.  In this instance, FDA is reminding applicants of the requirement to provide a justification commensurate with the limits they propose at time of filing an ANDA or a supplement for a new strength of a product to avoid the application receiving an RTR letter.