IPEC raises concerns over FDA guidance related to inactive ingredients

Based on the final Refuse-to-Receive (RTR) Standards Guidance for Industry related to ANDA submissions, IPEC says that “some information pertaining to inactive ingredients contradicts with ongoing long standing work between IPEC- Americas and key stakeholders from the Office of Generic Drugs Expert Working Group​.”

IPEC-Americas’ comments point out the “contradictory and ambiguous information contained in the various FDA guidance documents​,” which “can only create confusion for excipient manufacturers and ANDA sponsors​.”

More specifically, IPEC says it’s concerned that the FDA “has placed so much emphasis on current data captured in the IID [the current FDA Inactive Ingredients Database] which contains a lot of inaccurate, incomplete and missing information​.” IPEC claims the database has not been updated since October 2013 and that the agency has yet to clarify data requirements for inactive ingredients that exceed the IID level(s), which “creates ambiguity for the industry​.”

The final guidance notes that if an inactive ingredient “is determined to be a novel inactive ingredient for the corresponding route of administration of the drug product (unless it is a physical mixture of components found in the IID and within acceptable IID maximum levels), FDA will refuse-to-receive the ANDA​.”

But IPEC says it’s unclear to industry “just how the Agency defines novel inactive ingredient (i.e. novel excipients). Inactive ingredients with a long prior history of human exposure and safe use in related applications should not be viewed the same as a new chemical entity (NCE) and these excipient should not be subjected to an RTR​.”

IPEC also disagrees with the FDA that the use of an excipient that does not have precedence in the same route of delivery should always be viewed as high risk and subject to ANDA refusal. “Similarly, coprocessed excipients where each ingredient may have precedence of use in the IID should not be viewed as a novel excipient even though co-processed excipients are not simple physical mixtures of excipients​,” IPEC states.

Tox Studies​

The council also takes a position on toxicology studies related to excipient DMFs (drug master files), which seem to have been connected to some industry concerns recently. IPEC notes that the “details of these studies are considered confidential by excipient manufacturers and are not shared with their customers.” ​However, summaries of the studies “have not sufficiently met OGD filing reviewers’ standards recently, as demonstrated by the increased number of Refuse to File letters (due to insufficient safety data) received by pharmaceutical companies​.

“It is our belief that if detailed study information already exists in the excipient DMF, then the FDA OGD reviewer should be able to review a summary of safety study details along with a reference to the specific DMF version and section where the full study report(s) can be found rather than asking the sponsor to provide this information outside of the DMF system where confidentiality is no longer fully protected​,” IPEC says.