FDA guidance spells out acceptance criteria for synthetic peptide ANDAs

The US Food and Drug Administration (FDA) issued a final guidance on its criteria for accepting abbreviated new drug applications for synthetic peptide drugs of recombinant DNA (rDNA) origin.
 
The guidance is meant to spur the development of these complex drugs.  The agency also rejected industry calls to eliminate the impurity limit thresholds for accepting these submissions as abbreviated new drug applications (ANDAs).
 
The guidance, which finalizes 2017 draft version, should “facilitate the submission of ANDAs and the introduction of more generic medicines to the complex drug marketplace. Complex drugs have generally faced limited generic competition and often have higher prices.” (RELATED: FDA targets complex generic drugs with new draft guidance, Regulatory Focus, 2 October 2017)
 
Peptides are small polymers made up of 40 or fewer amino acids and are considered complex drugs, in part because some peptide products may vary in the length and sequence of their component amino acids, and also because the products often have accompanying impurities which may be difficult to characterize, according to a 2019 FDA Impact Story.
 
The finalized guidance covers five approved peptide drug products of rDNA origin: Glucagon, liraglutitide, nesiritide, teriparatide and teduglutide. FDA approved the first generic version of glucagon in December 2020 to treat severe hypoglycemia, or very low blood sugar, in diabetic patients.
 
According to an agency announcement, the document has been revised from the previous draft to add a flowchart in Appendix 1 that illustrates methods for evaluating peptide-related impurities, and also incorporates FDA’s final rule defining the term “biological product.” The final guidance also expands recommendations on assessing impurity profiles between the reference-listed drug and the proposed generic, and contains some minor clarifying edits.
 
According to the guidance, an ANDA for a generic version of a reference-listed peptide must show the drug is essentially the same as the reference-listed drug with respect to the active ingredient and impurities.
 
In terms of the active ingredient, FDA said it will accept ANDAs for these drugs if applicants can show that the proposed generic peptide “is characterized to show the sameness of the active ingredient to that of the reference-listed drug with respect to the primary sequence and physicochemical properties, secondary structure, oligomer and aggregation states and biological activity/function in in vitro or animal studies.”
 
The final guidance specifies that a generic should have have a specified peptide-related impurity level of no more than 0.5% of the drug substance. This level is consistent with the “small amount” of unspecified peptide impurities in reference-listed drugs (RLDs).
 
The final guidance emphasizes that the impurity profile, and not just the amount of impurities, is important in FDA’s consideration of whether to approve an ANDA for a proposed generic peptide: “Differences in impurities, particularly peptide-related impurities, may affect the safety or effectiveness of a peptide drug product as compared to the RLD,” wrote the agency in its introduction to the guidance.
 
Each peptide-related impurity that is found in both the proposed generic and the RLD should be present in equal or lower levels in the proposed generic synthetic peptide, according to the final guidance. Each new specified peptide-related impurity should be specified, and a justification should be provided why each such impurity would affect the proposed generic peptide’s safety or effectiveness, as compared to the RLD.
 
In the final guidance, FDA did not incorporate industry calls from the generic drug industry to eliminate the impurity threshold.
 
In a 17 December 2017 comment, the Association of Affordable Medicines called the 0.5% impurity limit “onerous” and said that the requirements would unnecessarily result in collecting large amounts of data.
 
The guidance states that potential ANDA applicants can submit a request to meet with the agency under FDA’s pre-ANDA program for product development assistance, pre-submission and mid-review cycle meetings for these products.
   
FDA peptide guidance