Yes, you heard me right; after years of problems caused by those pesky pH adjusters, there is a way around the regulations (and by the way this avenue has always been available for the Agency to utilize). In a pre-publication of the Federal Resister (here), the FDA says “an ANDA applicant for a drug product intended for parenteral, ophthalmic, or otic use who seeks to use a pH adjuster(s) that is Q1 or Q2 different from the RLD may ask the Agency to waive the inactive ingredient requirements at § 314.94(a)(9)(iii) or (iv) for the pH adjuster(s).” This applies to parenteral, ophthalmic and otic products.
Such changes were previously deemed reasons to refuse to approve an ANDA for the reasons outlined in the FR notice cited above. The requirement for inactive ingredients to be the same is not a requirement of the FFDCA legislation, but the regulatory framework to implement the legislation provided the FDA’s acknowledgement that, in some instances, differences in inactive ingredients could cause a product to be unsafe. For those of you that have been around since the regulations first published in the form of a Proposed Rule, you know that for parenteral, ophthalmic and otic products, the FDA identified in the regulations what lovingly became to be known as “exception excipients” as those inactive ingredients that could be changed and may be found acceptable to the FDA with justification (i.e., if they had been used in other approved products for the same route of administration at levels that did not exceed the proposed levels in an ANDA product). For instance, for a parenteral product, a firm could make a change in preservative, buffer, or antioxidant from the Q1 and Q2 requirements; however, pH adjusters were not listed as one of the permitted “exception excipients” under the regulations for parenteral (nor for that matter for ophthalmic or otic products). FDA decided universally that a change in pH adjuster from that of the reference listed drug would on its face raise questions of safety and possible effectiveness of the product and thus preclude approval. However, after years of experience and constant clamoring from the generic industry the Agency recognized that perhaps such changes may not be a basis for refusal to approve.
The FR notice states:
“Under § 314.99(b) (21 CFR 314.99(b)), however, an applicant may ask FDA to waive any requirement that applies to the applicant under §§ 314.92 through 314.99 (21 CFR 314.92 through 314.99). Such a request under § 314.99(b) must comply with the requirements at 21 CFR 314.90. FDA may grant a § 314.99(b) waiver if the Agency finds one of the following: (1) the applicant’s compliance with the requirement is unnecessary for the Agency to evaluate the ANDA or compliance cannot be achieved; (2) the applicant’s alternative submission satisfies the requirement; or (3) the applicant’s submission otherwise justifies a waiver.” “Thus, an ANDA applicant for a drug product intended for parenteral, ophthalmic, or otic use who seeks to use a pH adjuster(s) that is Q1 or Q2 different from the RLD may ask the Agency to waive the inactive ingredient requirements at § 314.94(a)(9)(iii) or (iv) for the pH adjuster(s).” The ANDA must (of course) meet all other regulatory requirements.
So, mark this date in history as the FDA found a way around the regulation by applying another regulation that has existed for decades. Now, how is that for a timely solution! I am sure that sponsors of parenteral, ophthalmic, or otic products welcome this day. However, after reviewing the draft guidance document, just because a waiver request is made is no guarantee that the ANDA will be approved. The guidance explains how the application should address any difference, whether it be Q1 or Q2 and the degree of difference. It also addresses what additional comparative data should be addressed in the application. FDA continues to suggest a controlled correspondence (CC) to determine Q1 and Q2 similarity but notes the CC is not an appropriate vehicle to request the 314.99(b) waiver. The waiver will only be considered in the ANDA after submission. Read the guidance carefully as it has specific examples to help you better understand the Agency thinking on this issue. The FDA draft guidance announced in the FR notice can be found here.