The FDA recently published “Sameness Evaluations in an ANDA – Active Ingredients,” a new draft guidance detailing recommendations for demonstrating sameness between the active ingredient in a proposed generic drug product and its reference listed drug (RLD), as required under the Federal Food, Drug, and Cosmetic Act (FD&C Act) and related regulations.

Background on sameness within the generic drug approval pathway

Under the 1984 Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Amendments), a generic drug application may rely on evidence showing that its referenced brand name drug (reference listed drug or RLD) is safe and effective to support market approval.

In order to qualify for such reliance, the generic drug sponsor must show that its product is the “same” as the RLD. By definition, “same as” means “identical in active ingredient(s), dosage form, strength, route of administration, and conditions of use, except that conditions of use for which approval cannot be granted because of exclusivity or an existing patent may be omitted.”[1] Additionally, the abbreviated new drug application (ANDA) sponsor must show that its product is bioequivalent to the RLD, meaning there is no significant difference between the RLD’s and generic drug’s rates and extent of absorption when administered at the same dose of the therapeutic ingredient under similar experimental conditions.

General considerations for determining the active ingredient

First, the Agency’s draft guidance offers general considerations to help ANDA applicants understand what FDA considers an active ingredient and discusses the need to “fully evaluate the potential for changes in or to the active ingredient during the manufacturing process.”

As noted in the guidance, the FDA maintains “broad discretion” to determine the sufficiency of information submitted to support a sameness argument in an ANDA. One possible approach to this determination is to consider whether the active ingredient in question meets the applicable pharmacopeial (USP) standard of identity. If no USP standard of identity exists, then the Agency recommends establishing identity, and, by extension, ingredient sameness, through appropriate analytical methods such as high-performance liquid chromatography or titration. In some cases, the FDA may prescribe additional standards to help determine sameness.

A drug product’s active ingredient is defined as “any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals” (21 CFR 210.3(b)(7)). The active ingredient, which “may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect,” is evaluated for sameness as it exists in the drug’s finished dosage form – for example, the tablet, capsule or solution which contains the drug substance. The definition covers the entire molecule, including portions that cause the drug to be an ester or salt. For the purposes of determining sameness, “noncovalent derivatives of the molecule,” such as complexes, chelates or clathrates, are also relevant.

According to the guidance, some active ingredients have multiple physical forms that differ in structure (eg, polymorphs or co-crystals). While these may pose unique regulatory challenges, the draft guidance states that differences in physical form will not prevent a prospective ANDA applicant from demonstrating active ingredient sameness between the generic drug product and the RLD.

Active ingredient sameness considerations in certain drug products

The draft guidance also provides several considerations for sameness with respect to synthetic peptide and complex mixture drug products.  For instance, an ANDA applicant proposing a generic synthetic peptide drug product could use “physicochemical characterization and biological evaluation” to demonstrate sameness with an RLD. The Agency recommends that applicants perform comparative testing for the proposed generic synthetic peptide to the RLD even if appropriate compendial standards are available for an ANDA.

As another example, the guidance discusses the FDA’s approach to evaluating sameness of proposed complex mixtures. In these cases, the FDA will consider the totality of relevant evidence submitted in an ANDA to determine whether the mixture’s active ingredient(s) have been properly characterized for purposes of assessing sameness, and the Agency further recommends that orthogonal methods be applied to describe components of the mixture – for example, using “multiple batches of both the proposed generic drug product (test product) and reference product under similar conditions.”

The guidance notes that the FDA has identified various categories of complex mixtures, including naturally derived mixtures with multiple components, synthetic polymers and synthetic or semi-synthetic mixtures. The Agency treats most of these complex mixtures as a single active ingredient due to the inability to distinguish each constituent component in the mixture that meets the definition of “active ingredient.”

However, if it is possible to distinguish more than one individual constituent component and its pharmacological effects, the FDA will treat each constituent component as a separate active ingredient. Although ANDAs for fixed-combination drug products also require a showing of sameness for every active ingredient present, the guidance states that they are distinct from complex mixtures as described here because separate active ingredients in a fixed-combination drug are intentionally combined so that each component makes a contribution to the claimed effects (defined at 21 CFR 300.50).

Thus, in order to support an active ingredient sameness determination, the FDA recommends that applicants of ANDAs for complex mixtures characterize components of the mixture using the multiple batch method. Additionally, the guidance suggests that sponsors “propose ranges for each molecule in common based on the comparative testing” and provide a justification for the ranges.

Characterization of the active ingredient in the drug product

Lastly, the draft guidance outlines how sponsors should characterize active ingredients for drug products, as well as provides a non-exhaustive list of active ingredient characterization examples.

The draft guidance notes that the chemical form of the active ingredient is typically the “same as the chemical form introduced at the start of drug product manufacture.” However, for a proposed generic drug product with an active ingredient that undergoes a chemical change during manufacture, the FDA will generally evaluate sameness based on the converted chemical form of the active ingredient, as present in the finished dosage form of the RLD.

The Agency goes on to note that, in the event that the chemical form(s) of the active ingredient do not appear in the drug product formulation in a “consistent or known manner,” the prospective applicant may contact the Office of Generic Drugs during product development, as the draft guidance may not specifically address how to demonstrate sameness under these unique circumstances.

Impact on generic drug ANDAs

Despite providing a great deal of color around the definition and characterization of “active ingredient,” the non-binding draft guidance nonetheless contains open-ended language that describes potential approaches without closing the door to other conceivable sameness evaluation methods the FDA may apply at its discretion. The FDA also encourages sponsors to review product-specific guidances for generic drug development, as these may also “include recommendations on how to demonstrate active ingredient sameness.” In addition, the FDA invites prospective ANDA applicants to request a meeting with the Office of Generic Drugs to discuss proposed methods for establishing sameness before submitting an ANDA, which may ultimately help streamline the application process.

Furthermore, the FDA recognizes in its draft guidance that, as science and technology continue to evolve, sponsors may be required to characterize and quantify the sameness of their potential generic drugs without applicable guidance. To address this issue, the Agency will need to continue revisiting the various ways prospective ANDA applicants may adequately demonstrate sameness.

The comment period is scheduled to close on January 9, 2023.  We will continue to monitor any further developments and provide timely updates on this topic. For information about this evolving FDA guidance, please contact your DLA Piper relationship partner, the author of this alert or any member of our FDA practice group.