The use of novel excipients has potential to assist in the development of better final drug-product formulations for patients. However, drug-product manufacturers are hesitant to use novel excipients in product development because of the uncertainty of the expectations of the FDA and, ultimately, on the FDA’s acceptance of the new excipients in its development program. In December 2019, the FDA issued a Federal Register (FR) notice soliciting comments on a proposed pilot program for novel excipients. After review of the comments received in response, the Agency has decided to move forward with a limited pilot program. It is the FDA’s hope that novel excipients that move through the program would ultimately be found acceptable for use without further documentation, except obviously for quality attributes when used in a formulated product if used within the boundaries of the data submitted in response to the pilot program.
For purposes of this pilot program, the Agency defines a novel excipient as “any excipient that is not fully supported by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration.” Because of the resources needed to fulfil the pilot’s goals, the program will initially be limited in scope to excipients that “(1) have not been previously used in FDA-approved drug products, and (2) do not have an established use in food.”
There will be two phases for the program. The first phase will be an application for inclusion in the pilot where a summary of the general information and proposed study plan are provided to the Agency (as described in the FR notice here). If the FDA accepts the initial proposal to include the novel excipient into the pilot program, then phase two would be a comprehensive review of data to support the safe use of the novel excipient (again see the details in the FR notice cited above).
The criteria for initial selection were outlined by the Agency as:
- Potential public health benefit of the novel excipient (for example, excipients that may facilitate opioid‑abuse-deterrent formulations or excipients that may promote development of new therapies for serious and life-threatening diseases)
- Likelihood of the novel-excipient manufacturer’s ability to submit a complete package within the timeframe established in this Notice
- Overall potential of the novel excipient to meaningfully improve pharmacokinetic characteristics that may lead to novel drug development
Once accepted into the program, “[F]ull packages should be submitted through a Type V DMF or other master file no later than three months after notification that FDA has selected the proposal” for inclusion in the pilot. The FR notice provides a comprehensive outline of needed information for the full package.
While this pilot has the potential to provide an avenue for use of novel excipients with most of the “fear factor” taken out of the equation for proposed uses of the excipients by drug-product developers, its success will be decided by the drug manufacturers themselves, if choosing to use the excipients in their formulations. It took almost two years to announce the pilot after the first FR notice was issued. How long will it take until the program is off the ground and the Agency makes its first positive decision for one of the initial candidates? Will excipient manufacturers see enough potential sales of their novel ingredient to make the considerable investment in the pilot? Final Agency determinations will be relevant for new drugs and biologic products, but will the decision also be relevant to generics? Or will that only occur once the excipient is approved in an NDA or BLA? Only time will tell.