FDA drafts guidance on ‘sameness’ evaluations for generic drugs

The US Food and Drug Administration (FDA) has released new draft guidance offering recommendations for applicants to prove sameness in active ingredients of abbreviated new drug application (ANDA) proposed generic drug products compared with the reference listed drug (RLD).

FDA defines an active ingredient as one “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.” An active ingredient “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,” the agency said.

Demonstrating that an active ingredient contained in a proposed generic drug product is the same as an RLD is required when submitting the product through ANDA. FDA recommended applicants use the same active ingredient in the proposed drug product and the RLD and “fully evaluate the potential for changes in or to the active ingredient during the manufacturing process.”

‘Flexible approach’ to demonstrating sameness

The ANDA applicant is required to demonstrate sameness between the active ingredient in the proposed drug and RLD to FDA with “sufficient information,” but applicants are also required to establish sameness for every active ingredient present in a combination drug product.

“FDA will refuse to approve an ANDA if the ANDA contains insufficient information to show that, among other things, the active ingredient of the proposed generic drug product is the same as that of the RLD,” FDA wrote.

What constitutes sufficient information is at the discretion of FDA, and there is no set amount or type of information that would demonstrate sameness in an ANDA applicant’s proposed drug product compared to an RLD, the agency said. While FDA said it has opted to pursue a “more flexible approach in assessing whether a proposed generic drug product contains the same active ingredient as that of the RLD,” they offered some general considerations to help ANDA applicants understand what FDA considers an active ingredient, several considerations for sameness in synthetic peptide and complex mixture drug products, and how they should characterize active ingredients for drug products.

In their view, FDA explained that an active ingredient’s chemical form is “the entire molecule, including those portions of the molecule that cause the drug to be an ester or salt.” FDA recommended ANDA applicants also consider noncovalent derivatives of the molecule like a complex, chelate, or clathrate to evaluate sameness. Active ingredients can also exist in different physical forms like polymorphs or co-crystals, they said.

“In general, differences in physical form will not prevent a prospective ANDA applicant from demonstrating active ingredient sameness between the active ingredient in the ANDA drug product and the RLD,” FDA wrote.

Using synthetic peptides as an example, FDA said ANDA applicants with a proposed generic synthetic peptide drug product could use physicochemical characterization and biological evaluation to demonstrate sameness with an RLD. “Although compendial standards may be available for some peptides for which an ANDA may be appropriate, it is recommended that applicants also perform comparative testing of the proposed generic synthetic peptide to the RLD,” they said.

In the case of complex mixtures, FDA said it examines all relevant evidence in an ANDA when evaluating sameness, and that orthogonal methods should be used to describe complex mixture components. “To support an active ingredient sameness determination for complex mixtures, we recommend that ANDA applicants characterize constituent components of the active ingredient in multiple batches of both the proposed generic drug product (test product) and reference product under similar conditions,” they explained.

For situations where an active ingredient undergoes a chemical change in a proposed generic drug product, “it is the converted chemical form of the active ingredient, as present in the finished dosage form of the RLD, that generally should be used for comparison when demonstrating active ingredient sameness,” FDA said.

FDA noted prospective ANDA applicants may request a meeting with the Office of Generic Drugs to review any methods for establishing sameness before submitting an application.

“As scientific understanding and technology evolve, FDA will continue to assist in and support the adequate characterization of an active ingredient so that prospective ANDA applicants may adequately demonstrate sameness,” the agency said.

Draft guidance

FDA drafts guidance on ‘sameness’ evaluations for generic drugs

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