Abstract:
This position study provides a science-based, holistic approach to evaluating the risks of nitrosamine presence in drug-linkers as intermediates toward antibody–drug conjugate (ADC) drug substances. The evaluation of 47 different ADC drug substances, which have a recommended dose available in the public domain, supports the conclusion that the chemically synthesized fragments of ADCs are unlikely to lead to nitrosamine presence in the final drug product. Hence, it can be concluded that for most ADCs there are few nitrosamine risks introduced by the drug-linkers and their impurities. An abbreviated workflow for quality risk management of nitrosamine in drug-linkers is therefore proposed.
The conclusion is as follows;
Even though vulnerable amines may be present in drug-linker and antibody intermediates of the ADC, nitrite is not typically used during ADC manufacturing processes, and if at all present, nitrite will be at a trace level.
Antibody–drug conjugates (ADCs) and N -nitrosamines are two topics that have seen a surge of interest in recent years. ADCs are increasingly prevalent as oncology therapeutics in clinical development and on the market. Concerns about the potential presence of N -nitrosamines in pharmaceutical products have led to increased regulatory scrutiny and implementation of robust control strategies by the industry. This article, the first in a two-part series, provides visibility into current industry practices for risk assessment and control of N -nitrosamines in ADCs with results and analysis from a benchmarking survey of member companies of the IQ Consortium.