FDA Requirements for the Approval of GLP-1 Generic Peptide Injections

Introduction

The success of GLP-1 (glucagon-like peptide-1) receptor agonists, such as semaglutide (31-amino acids) and tirzepatide (39 amino acids), in treating type 2 diabetes and aiding weight loss has generated significant interest among generic drug substance and product manufacturers. Many of these manufacturers are actively developing generic versions of these peptides in anticipation of upcoming patent expirations. Several abbreviated new drug applications (ANDAs) for semaglutide have already been submitted for approval in the EU and China, where patent exclusivity is expected to expire soon. Notably, the approval requirements in these regions differ from those of the FDA.

This whitepaper explores the FDA’s requirements for the approval of generic GLP-1 peptide injections, with a focus on critical studies and other key considerations. The requirements outlined for GLP-1 generic peptide injections are also applicable to other generic peptide injections.

FDA Requirements for Generic Injectable Peptides

Abbreviated New Drug Application (ANDA)

Only synthetic peptides qualify for the Abbreviated New Drug Application (ANDA) pathway for generic product approval. Peptide drugs manufactured using recombinant DNA (rDNA) technology do not qualify for the ANDA pathway and must follow the new drug application (NDA) route.

Therapeutic Equivalence and API Sameness

A fundamental requirement for the approval of a generic peptide injection product is the demonstration of therapeutic equivalence to the reference listed drug (RLD), which consists of pharmaceutical equivalence and bioequivalence, to ensure comparable therapeutic effects and safety profile, as outlined in the 2021 FDA guidance[1] for generic peptide products. As with other injectable solutions, bioequivalence is considered self-evident and may qualify for a biowaiver, if they are qualitatively and quantitatively (Q1/Q2) identical to the RLD. Pharmaceutical equivalence can be demonstrated by meeting the FDA’s active pharmaceutical ingredient (API) sameness criteria. For generic peptide injection products, API sameness requires that they have the same primary, secondary, tertiary, and have equal or lower levels of aggregates compared to the RLD. In addition, generic peptide injection products must demonstrate comparable bioactivity, immunogenicity and purity levels to the RLD.

Comparative Studies

The most critical element in the approval process for a generic peptide injection is the adequacy of the comparative study, which is a study to evaluate the generic product against the RLD across several key areas, as outlined below.

Key Elements of Comparative Studies

Samples for Comparative Studies: The 2021 FDA guidance does not clearly specify the number of batches required, other than stating that a statistically valid number of batches should be evaluated. However, it is common practice to use a minimum of three batches for both the generic product and the RLD. The three batches of generic peptide drug product must be manufactured using at least two different batches of the drug substance. Comparative studies should be conducted at time points close to batch release and near the end of shelf life. Therefore, sourcing the RLD is a crucial and often rate-limiting step, as obtaining representative RLD batches is necessary for these comparisons. Careful planning and coordination of the generic product samples and RLD samples are essential for successful comparative studies. While samples stored at accelerated conditions may be used as supporting data, these data will not replace the use of aged samples near the end of shelf-life. Additionally, the manufacturing process used to produce the generic peptide product samples for comparative studies should be representative of the process proposed in the ANDA.
Structural Similarity: Structural analysis is crucial for peptides, which are considered complex drug substances. The therapeutic activity of GLP-1 receptor agonists peptides can be affected by subtle changes in their structure. Therefore, comparative structural studies should assess the following:
- Primary structure: the amino acid sequence of the peptide.
- Secondary structure: folding patterns, such as alpha-helices and beta-sheets.
- Tertiary structure: the overall three-dimensional conformation of the peptide.
- Aggregates: interactions between peptide subunits or aggregation propensity.

Applicants for a generic peptide product should select, develop and validate appropriate orthogonal analytical methods to conduct these comparative studies.

Peptide-Related Impurity Profile: The impurity profile of the generic peptide product should be comparable to that of the RLD. Impurities present in the generic product must not exceed the levels found in the RLD. New impurities at levels greater than 0.5% are not acceptable. For any new impurities between 0.10% and 0.5% that are either absent in the RLD or present at higher levels than in the RLD, a justification must be provided to demonstrate that the impurity does not impact the product’s safety, efficacy or immunogenicity potential. All impurities equal to or above 0.10% must be identified and characterized.
Immunogenicity Risk Mitigation: Anevaluation of the innate immune response must be performed on the fully formulated DP and the RLD. An adaptive immunogenicity response assessment must be performed for any new or peptide-related impurities at levels ≥ 0.10% and ≤ 0.5% and are higher than the RLD.
Role of DMF in API Comparative Studies: The ANDA applicant may rely on a DMF to provide comparative data on the primary structure and physicochemical properties of the generic peptide API relative to the API in the RLD. Therefore, it is essential that the ANDA applicant carefully reviews the DMF comparative data in the DMF to ensure its quality and the adequacy of the data, and to verify API sameness between the generic product and the RLD.

How ELIQUENT Life Sciences Can Help

FDA guidance is always a good starting point, but there are areas in the guidance that are ambiguous and open to interpretation. As a result, many generic peptide ANDA submissions faced delays due to common deficiencies.

At ELIQUENT Life Sciences, our team of experts brings extensive industry development experience and FDA review expertise in generic peptide drug products. We assist ANDA applicants in navigating the gray areas not clearly defined in FDA guidance. We provide strategic development advice to accelerate timelines and reduce costs, conduct gap assessments, draft controlled correspondence and preANDA meeting package, prepare or review ANDA dossiers, and support responses to information requests during the ANDA review process.

Because we understand FDA expectations, we effectively assist applicants in preparing submission dossier that are clear, accurate, and logically structured, and ensure the documents are properly formatted with correct English grammar. These elements help avoid confusion for regulatory reviewers and facilitate the approval process for not just ANDA but for NDA and BLA submissions.

[1] ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin, May 2021, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/andas-certain-highly-purified-synthetic-peptide-drug-products-refer-listed-drugs-rdna-origin.