Joint Session on the Relationship Between Impurities and Immunogenicity: Panel Discussion

There is limited regulatory guidance on acceptable levels of API-related impurities in drug substances during clinical testing. This presentation introduces a phase-appropriate, risk-based approach to evaluate the immunogenicity risk of impurities from an adaptive immune system perspective. The strategy presented considers the stage of development, indication, potential impact of unintended cross reactivity with endogenous proteins, dose, and frequency of dosing throughout development to inform chemistry manufacturing and control of inherent safety risks associated with API-related impurities. The elucidation of the actual sequences displayed for T cell surveillance by professional antigen presenting cells and the examination of the T cell proliferative potential of these sequences is used to characterize immunogenicity risk. The value of this approach and its novelty consist in framing the immunogenicity risk of the impurity in the context of both the immunogenicity potential of the API and dose level while also advocating for a shift from relative percentage to mass basis for impurity threshold considerations.