Impurities findings could enhance peptide drug safety

Generic peptide manufacturers could be aided by new research into identifying and controlling immunogenicity-associated impurities in generic drug products.

Preclinical immunogenicity assessment company EpiVax and R&D firm Cubrc worked with the US Food and Drug Administration (FDA) to evaluate whether peptide-related impurities may influence unwanted immune responses in generic teriparatide, an osteoporosis drug.

The recombinant peptide is one of the products highlighted in recent FDA guidance recommending assessment of immunogenicity risk for synthetic generics submitted under an abbreviated new drug application (ANDA).

Leveraging a series of different computational tools, the team combined in silico and in vitro approaches to evaluate peptide-related impurity risk.

This enabled investigators to identify multiple impurities with higher predicted immunogenic potential than the reference teriparatide sequence. The findings help improve the safety and availability of affordable generic products for clinical use.

Analysis supported these predictions, revealing enhanced HLA binding and T-cell responses for several impurities compared to teriparatide itself.

Notably, the team identified a potentially tolerogenic region within the teriparatide sequence that may reduce responses to teriparatide, but that could be disrupted by sequence changes in the impurities.

Mattei et al. noted while establishing active pharmaceutical ingredient (API) sameness “is a core regulatory requirement, impurities arising from manufacturing processes may introduce sequence changes with the potential to generate new ‘T-cell epitopes’”.

Dr Vibha Jawa, Chief Scientific Officer at EpiVax, said that overall, the research “highlights the power of combining robust computational and wet-lab methods to better understand and mitigate immunogenicity risks in generic peptide development”.

He concluded that the findings provide “a practical framework for developers navigating the FDA guidance on impurity assessment and highlight opportunities to strengthen peptide drug safety”.

The research was published in Frontiers in Immunology.