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November 17, 2022 - FDA, Healthcare, Digital Health, Regulatory, Pharma

FDA Clarifies ANDA Active Ingredient Sameness Evaluation in Draft Guidance

life science blog post

On November 8, 2022, FDA issued a draft guidance document on Sameness Evaluations in an ANDA — Active Ingredients (“Draft Guidance”). In the Draft Guidance, FDA indicated that the active ingredient’s chemical form will generally be the entire molecule, but it may also encompass noncovalent derivatives. Importantly, the active ingredient can take a different physical form than the active ingredient in the reference listed drug (RLD), and FDA will not consider this as relevant in determining sameness. FDA also noted that the active ingredient in a drug product “may undergo a change in chemical form during drug product manufacture such that the active ingredient is converted to a different chemical form.” In such cases, FDA considers the converted chemical form to be the active ingredient, and ANDA filers should use the converted form, as present in the final dosage of the RLD, for comparison when demonstrating sameness.

Distinguishing Sameness Evaluation in Different Classes of Small Molecule Drugs

The Draft Guidance offers specific discussion on active ingredient sameness in synthetic peptides and complex mixtures. As to synthetic peptides, FDA noted that sameness can “generally be established through physicochemical characterization and biological evaluation,” and while compendial standards may be available for some peptides, FDA still recommends that ANDA applications conduct comparative testing of the generic peptide to the RLD. For complex mixtures, FDA “evaluates all relevant data in the ANDA and other relevant scientific information to determine whether an active ingredient of a complex mixture has been adequately characterized for the purposes of assessing active ingredient.” FDA noted that, while some complex mixtures may have multiple active ingredients, they will not be considered a fixed-drug combination product as they have not been intentionally combined. ANDA filers should characterize constituent components in the generic peptide in reference to the RLD by running multiple batches on both products under similar conditions, and then comparing the two. If the comparison test shows that the complex mixture contains a well-characterized component, “the [filer] should propose ranges for each molecule in common based on the comparative testing,” and provide explanation for why any differences are acceptable. As to other small molecule drugs, FDA encourages ANDA filers to review product-specific guidance documents, which may indicate how FDA will evaluate active ingredient sameness.

Active Ingredient Sameness Evaluations and Engaging with FDA

In the Draft Guidance, FDA reiterated its commitment to working with industry through the controlled correspondence process and pre-ANDA meetings to ensure that ANDA filers are utilizing an appropriate method to determine sameness. Interestingly, FDA doubled down on its commitment “to reduce, refine, and replace animal use in testing when feasible,” and FDA encouraged sponsors to consult with FDA as to whether there is an appropriate alternative method to test for equivalency. FDA also committed to updating guidance documents relevant to demonstrating sameness to reflect the appropriate methodology as informed by the evolution of scientific understanding and technology. Finally, FDA is seeking comment on the Draft Guidance, and with the request for comment closing on January 8, 2023, affected members of industry should consider working with counsel to file a comment sooner rather than later. 

Kai Mindick, a Law Clerk in our Austin office, contributed to the writing of this alert.