Among other requirements, an ANDA must contain information to show that the active ingredient of the proposed generic drug product is the “same as” that of the RLD. FDA’s regulations provide that the term “same as” means, among other things, “identical in active ingredient(s).” Although typically a relatively straightforward task, ensuring that a generic drug product has the same active ingredient as the RLD can involve difficult scientific and regulatory issues. The draft guidance provides general guidelines for evaluating active ingredient sameness and also addresses specific situations that raise complicated issues, such as synthetic peptides, complex mixtures, and chemical conversions.

Chemical [not physical] form integral to determining active ingredient

The draft guidance provides general recommendations on establishing the identity of an active ingredient for the purpose of demonstrating active ingredient sameness. Consistent with longstanding agency policy, FDA says it generally considers the chemical form of an active ingredient to be the entire molecule, including those portions of the molecule that cause the drug to be an ester or salt. For the evaluation of sameness, the identity of the active ingredient may also encompass noncovalent derivatives (e.g., a complex, chelate, or clathrate) of the molecule as it exists in the drug product (i.e., in the finished dosage form) (see below).

As FDA has previously indicated, the draft guidance says that the same active ingredient can exist in more than one physical form, such as polymorphs or co-crystals. FDA writes that “[i]n general, differences in physical form will not prevent a prospective ANDA applicant from demonstrating active ingredient sameness.” For example, in earlier guidance discussing polymorphism and sameness, FDA explained that while a polymorphic form can affect drug product stability and bioequivalence, differences in the physical form alone do not result in a different active ingredient.

Active ingredient evaluation for a complex, clathrate, chelate, and carbohydrate

The draft guidance clarifies that generally, a complex, clathrate, or chelate will be considered part of the active ingredient only if it “is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease associated with the approved use of the drug product.” For example, with respect to solid oral dosage forms (e.g., orally disintegrating tablets), the draft guidance indicates that an excipient that forms a weak complex through ionic interactions to mask an unpleasant taste generally would not be considered part of the active ingredient.

In addition, carbohydrates used to form complexes with the active ingredient in order to stabilize the active ingredient, facilitate bulk processing of the active ingredient, and enable the manufacture of the drug product generally would not be considered part of the active ingredient, the draft guidance specifies. If the entire carbohydrate complex is necessary for the product to function in the intended therapeutic manner, however, then the complexed carbohydrate would be considered part of the active ingredient.

Comparative testing recommended for generic synthetic peptides

Under the agency’s framework, a peptide is any amino acid polymer composed of 40 or fewer amino acids, as compared to a protein. FDA says it considers appropriate for submission in an ANDA certain highly purified synthetic peptides that reference a previously approved synthetic peptide drug product or a peptide of rDNA origin. FDA explains that the sameness of the active ingredient of a proposed generic synthetic peptide product can generally be established through physicochemical characterization and biological evaluation. The draft guidance recommends that applicants perform comparative testing of the proposed generic synthetic peptide to the RLD, including using orthogonal analytical methods to characterize the following properties:

• Primary sequence and physicochemical properties
• Secondary structure
• Oligomer/aggregation states
• Biological activities (by in vitro or animal studies).

For complex mixtures, active ingredient identity may depend on characterization of components

For an active ingredient in a complex mixture, FDA evaluates all relevant data in the ANDA and other relevant scientific information to determine whether the active ingredient has been adequately characterized for the purposes of assessing sameness. Like synthetic peptides, the draft guidance recommends orthogonal methods to characterize components of the complex mixture and says FDA will consider the totality of evidence.

In most instances, FDA explains, complex mixtures are treated as a single active ingredient “because it is not possible to distinguish each and every specific constituent component in the complex mixture 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.” However, where it is possible to identify each and every constituent component in the mixture, the draft guidance specifies that FDA “generally will treat each constituent component as a separate active ingredient.” Therefore, to support an active ingredient sameness determination for complex mixtures, FDA recommends that ANDA applicants characterize constituent components of the active ingredient in multiple batches of both the proposed generic drug product and the reference product under similar conditions. FDA further advises that, to the extent a complex mixture contains well-characterized components, applicants propose ranges for each molecule in common based on the comparative testing, and provide a justification and/or rationale for acceptability of any component differences between the test product and the reference product.

Finished dosage form used for sameness comparisons

In certain circumstances, an active ingredient undergoes a change in chemical form during drug product manufacture such that the active ingredient is converted to a different chemical that is present as the active ingredient in the RLD drug product. The draft guidance states that in these cases, FDA will use the converted chemical form of the active ingredient, as present in the finished dosage form of the RLD, for comparison when demonstrating active ingredient sameness. FDA makes a point to urge careful analysis of chemical changes that might be occurring between designated drug substances and what ends up in the finished dosage form. An ANDA applicant generally should refer to the approved RLD labeling to gain an understanding of the chemical form of the active ingredient in the approved drug product. FDA also acknowledges that there may be ambiguity as to the chemical form of an active ingredient compared to the description in the RLD labeling, and the ANDA applicant will need to complete additional investigations and provide related information for the sameness evaluation (e.g., comparative testing and scientific rationale).

Product-specific guidances should be consulted

FDA further advises in the draft guidance that prospective ANDA applicants should review product-specific guidances for generic drug development, which may include recommendations on how to demonstrate active ingredient sameness. For example, in certain situations, FDA recommends pharmacodynamic data to support a demonstration of active ingredient sameness and to adequately characterize an active ingredient. FDA notes that prospective ANDA applicants may submit controlled correspondence to or request a pre-ANDA meeting with the Office of Generic Drugs to discuss their proposed methods for demonstrating sameness.

FDA seeks comments on this draft guidance by January 9, 2023. If you have any questions on the draft guidance, wish to submit a comment, or have questions on sameness in active ingredients more generally, please contact any of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.

Authored by Gary Veron, Bryan Walsh, Deborah Cho, and Jason Conaty