The OGD got back to business right away after the government reopened by publishing the final guidance titled Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use: Guidance for Industry (here). The issue of changing pH-adjuster ingredients for the purposes of creating a generic formulation of a parenteral, ophthalmic, or otic generic that differs from the reference listed drug upon which the generic is relying has been a thorny issue since the passage of Hatch-Waxman; it is further complicated by the final implementing regulations for that legislation.
The guidance document, which is now final (it was originally published as a draft in 2022), outlines use of the waiver provisions contained in 21 CFR 314.99(b) and states that “an applicant may ask FDA to waive under this section any requirement that applies to the applicant under 314.92 through 314.99.” As we all know, pH adjusters were not included in the list of exception excipients in the regulations for differences in parenteral, ophthalmic, or otic ingredients (as further described in the guidance document cited above). Thus, certain changes in pH adjusters were not permitted to be made until the FDA decided that the waiver provisions could be applied to fix this situation.
Per the Federal Register Pre-Publication Notice, “Changes from the draft to the final guidance include recommendations for ANDA applicants to seek FDA feedback on a proposed approach for justifying a § 314.99(b) waiver request for a difference in pH adjuster, as well as in instances where the applicant also seeks to utilize a certain bioequivalence approach with a formulation that contains a Q1 or Q2 difference in pH adjuster. In addition, this [final] guidance includes information clarifying FDA’s obligations to maintain the confidentiality of trade secret and confidential commercial information when responding to questions regarding drug product formulations, and to distinguish the regulatory provisions for requesting waiver of a Q1 or Q2 difference in a pH adjuster from the provisions that support a request to waive submission of evidence of in vivo bioequivalence.”
The guidance discusses that, in certain circumstances, a change in the pH adjusters may be appropriate and describes the role of pH adjusters in product formulations; it further outlines when a Q1 or Q2 difference in pH adjuster may be appropriate. However, there may be instances where certain differences in pH adjusters may not be appropriate in an ANDA and these are also described in the final guidance.
The guidance also describes the type of information that should be considered in support of the waiver request. “FDA recommends that an ANDA applicant developing a proposed drug product intended for parenteral, ophthalmic, or otic use submit a controlled correspondence, requesting a formulation assessment of the proposed formulation as compared to the RLD formulation, before submission. If the response to the controlled correspondence indicates that the proposed formulation does not meet the inactive ingredient requirements applicable to the product, and the ANDA applicant believes that this failure to meet such requirements is due to a difference in pH adjuster(s) (e.g., the applicant wants to include a pH adjuster that is not included in the RLD), the ANDA applicant may consider submitting a § 314.99(b) waiver request to support the pH adjuster difference in its ANDA submission.” The FDA strongly recommends seeking the Agency’s input prior to submission of an application with a pH difference; however, an applicant can also seek the change in their ANDA submission without the FDA’s advice, but the risk there is obvious.
The guidance also includes information describing what information should be included in the waiver request and notes that the approach for establishing bioequivalence (BE) between the test and reference product may not fall under the BE waiver requirements at 21 CFR 314.94(a)(9)(iii) or (iv) for a difference in pH adjuster. In this case, the FDA suggests that the applicant contact the Agency to discuss the particular approach to establish BE for that particular drug product.
At least now sponsors have a defined avenue for making such changes, but please read the provisions of this guidance document carefully before moving forward with a product that is not Q1 and Q2 the same as the RLD in terms of pH adjusters.
