Impurity qualification requirements for drug-linkers related impurities used to generate antibody-drug conjugates

This position paper presents a science-based, holistic assessment of the toxicological risks posed by organic impurities in drug-linkers (D-L) used as intermediates in the production of Antibody-Drug Conjugates (ADCs) for oncology indications. The analysis outlined in this manuscript demonstrates that organic impurities present at levels at or below 1.0 % w/w in D-L intermediates are unlikely to result in adverse toxicological effects upon administration of the final ADC drug product. Due to the extremely low exposure (molar and weight) associated with 1.0 % w/w impurity level in the D-Ls, the authors propose to maintain the ICH Q3A criteria of not more than 1 mg/day limit however increase the qualification limit criteria for D-L related impurities from 0.15 % to 1.0 % w/w. Additionally, a methodology is introduced to assess the level of concern for non-conjugatable organic impurities, utilizing process-specific and ADC-specific factors to justify specifications for these impurities in D-L intermediates. Based on the minimal risk associated with D-L impurities at or below the discussed levels, the paper proposes a workflow for quality risk management of such impurities in D-Ls.