Glowienke, Susanne (2025) Impurity Qualification Requirements for Drug-Linkers Related Impurities Used to Generate Antibody-Drug Conjugates. Regulatory toxicology and pharmacology.

Abstract

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 conjugatable organic impurities present at levels at or below 1.0% w/w or 1 mg/day 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 DLs, the authors propose to maintain the ICH Q3A criteria of not more than 1 mg/day limit however increase the ICH Q3A qualification limit criteria from 0.15% to 1.0% w/w. Additionally, a methodology is introduced to assess the level of concern for non-conjugatable organic impurities, utilising 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.

Item Type:	Article
Date Deposited:	03 Feb 2026 00:45
Last Modified:	03 Feb 2026 00:45
URI:	https://oak.novartis.com/id/eprint/57484