A Science-Based Proposal for the Identification Threshold of Organic Impurities in Drug–Linker Intermediates Used to Produce Antibody–Drug Conjugates

Abstract

Abstract The identification threshold for organic impurities in drug–linker (D–L) intermediates used to manufacture antibody–drug conjugates (ADCs) remains undefined in the current regulatory landscape. Building on our previously established 1.0% w/w qualification threshold, we propose a science-based identification threshold of 0.25% w/w, derived through the simultaneous application of four independent quantitative criteria to a data set of 47 clinical-stage ADCs. The four criteria are (1) maintenance of a >200-fold safety margin relative to both the ICH Q3A allowable daily intake of 1.0 mg/day and the practical worst-case exposure from conventional small-molecule APIs; (2) preservation of a 5-fold safety-factored benchmark relative to the internal threshold of toxicological concern (iTTC) of 25 nmol/day for parenteral exposure; (3) maintenance of cumulative exposure below one-fifth of the ICH M7 acceptable lifetime dose of 38.3 mg over five years of dosing; and (4) a 1:4 identification-to-qualification ratio, more conservative than precedents for small molecules, peptides, and oligonucleotides. The convergence of these constraints uniquely defines 0.25% w/w as the value simultaneously satisfying all criteria, enabling efficient pharmaceutical development while ensuring patient safety across all oncological ADC indications. The proposed value is intended as a class-wide threshold. Higher product-specific thresholds, including 0.5% w/w and, where scientifically justified, values up to 1.0% w/w, may be considered when product-specific exposure calculations demonstrate compliance with the applicable criteria.