Who would have guessed that 21 CFR 314.94(a)(9)(iv) no longer applies to ophthalmics? You wouldn’t generally have expected it to just be cancelled – normally FDA must go through notice and comment, but apparently the FDA can make a regulation disappear by decree.
21 CFR 314(a)(9)(iv) states:
(iv)Inactive ingredient changes permitted in drug products intended for ophthalmic or otic use. Generally, a drug product intended for ophthalmic or otic use shall contain the same inactive ingredients and in the same concentration as the reference listed drug identified by the applicant under paragraph (a)(3) of this section. However, an applicant may seek approval of a drug product that differs from the reference listed drug in preservative, buffer, substance to adjust tonicity, or thickening agent provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product, except that, in a product intended for ophthalmic use, an applicant may not change a buffer or substance to adjust tonicity for the purpose of claiming a therapeutic advantage over or difference from the listed drug, e.g., by using a balanced salt solution as a diluent as opposed to an isotonic saline solution, or by making a significant change in the pH or other change that may raise questions of irritability.
Camargo’s client received feedback that their ANDA submission was not both qualitatively and quantitatively the same as the RLD and the ANDA could not be approved without reformulation or a BE study. In searching for justification, we found a PowerPoint presentationby Iain Margand, RPh, Sr. Regulatory Project Manager:
The first slide indicates that a ‘determination’ was made – by whom, when and how it is not stated and we find no Federal Register notice. But it appears that the determination was blanket – covering all ophthalmics. Note that changes must be submitted as a 505(b)(2).