On September 16, 2014, the Office of Generic Drugs (OGD) posted its final Guidance on Refuse-to-Receive (RTR) Standards (here) and also published an ancillary draft Guidance entitled ANDA Submissions – Refuse To Receive Standards for Lack of Proper Justification of Impurity Limits (here) (which explains that proper justification for specified identified impurities above qualification thresholds and specified unidentified impurities and unspecified [unknown] impurities with limits above identification thresholds must be included in the ANDA or it will receive an RTR letter).

The Impurity Guidance provides examples of how one can justify such impurity limits:

(1) the observed impurity levels and proposed impurity limits do not exceed the level observed in the reference listed drug 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; or

(4) the observed impurity levels and proposed impurity limits do not exceed the level that has been adequately evaluated in toxicity studies.

This is consistent with past Guidance issued by OGD on the requirements for justification of impurity limits, but, in the past, OGD has not stated that if such justification is lacking, they will issue an RTR letter rather than handling the issue as a review issue.

The final RTR guidance does have some important changes from the draft that was issued in October 2013, some of which are outlined below:

  1. The new Guidance removes the reference to the internal ANDA Checklist, which has been noticeably removed from the CDER webpage.  The Checklist was the document that industry used to try to assure completeness of its submitted applications.  Apparently, OGD will be using officially issued guidance documents to provide the same information but not all in one place.  We know that some firms have challenged OGD on RTR issues based on the issue not being addressed in the checklist. Perhaps this can also explain the removal?
  2. An interesting point in the new Guidance appears to give applicants some ability to challenge RTR decisions in certain circumstances when it notes:  “[T]his guidance does not preclude the possibility that an ANDA applicant may be able to demonstrate, in particular circumstances, that the regulatory requirements for receiving an ANDA have been met even when, as described in this guidance, FDA would in the normal course find the application not sufficiently complete to permit a substantive review and refuse-to-receive it. “
  3. A big concession seen in the new Guidance is that for minor deficiencies (less than 10), OGD will allow 7 calendar days to respond instead of 5 business days cited in the draft guidance.  The industry was asking for 10 business days to respond.  But the footnote 16 indicates that if the due date falls a weekend or holiday then the next business day will be permitted.
  4. OGD removed the sections on citation of inappropriate reference listed drug/unfounded basis of submission without explanation.
  5. OGD removed the section on labeling deficiencies without explanation.
  6. The draft Guidance suggested that, with regards to inactive ingredients, that one method of qualification for ingredients that exceed the levels in the inactive ingredients database (IID) was the submission of pharmacology/toxicology information.  The final Guidance alludes to the fact that OGD might not have a final position on this issue when it states: “After additional consideration, FDA believes that this issue bears further evaluation, and the Agency is not prepared to offer its current thinking on this subject at this time. The Agency anticipates addressing this issue in a separate guidance.”
  7. OGD significantly revised the requirements for amount packaged for various dosage forms by removing examples and referring to other guidance documents.
  8. OGD provides additional clarification on the requirements for batch manufacture for transdermal systems.
  9. FDA backed off the requirement for submitting ALL case report forms for subjects in BE studies to require submission of 10% of randomly selected case report forms, but firms should also include all case report forms for patients eliminated from the analysis for any reason.
  10. The final Guidance also gives examples of some types of minor deficiencies.

It is clear that, based on reduced specificity in this Guidance and the removal of the ANDA checklist from the CDER web page, that OGD will be exercising its discretion in RTR determinations and will make decisions on a case-by-case basis.  Let’s see how this works out! This post is a summary of some of the important changes from the draft RTR guidance.  Please be certain to fully evaluate the entire Guidance to assure full clarity of OGD expectations.