Immunogenicity of Generic Peptide Impurities: Current Orthogonal Approaches

Generic drugs have saved consumers billions of dollars in the United States. The demand for lower-cost and effective drugs, particularly for well-known peptide drugs like Ozempic and Wegovy (brand names for semaglutide), has resulted in a surge of generic drug development to address perceived shortages in the supply of the reference listed drugs (RLD). To address this demand for generics and expedite consumer access to lower-cost generic versions of approved drugs, the U.S. Food and Drug Administration (FDA) has developed an "Abbreviated New Drug Application" (ANDA) pathway that simplifies the generic drug review process and expands access to these much-needed medicines without compromising quality and safety standards. Guidelines for this pathway require sponsors to identify and characterize both process- and product-related impurities in drug formulations that differ in nature or concentration from the RLD. The ANDA pathway devotes specific attention to immunogenicity and recommends the use of orthogonal methods of assessment to demonstrate that a proposed generic drug is immunologically equivalent to its RLD and therefore suitable for submission via the ANDA pathway. In this perspective, we describe several orthogonal methods for immunogenicity risk assessment of generic peptide impurities and contrast these with other methods such as MHC-Associated Peptide Proteomics peptide elution (MAPPs) assays. Given their importance in the generic drug approval pathway, we have submitted the "PANDA^®" immunogenicity risk assessment methods as a 'model master file'.