Risk Assessment and Control of N-Nitrosamines in Antibody–Drug Conjugates: Current Industry Practices

Abstract

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. Items covered include assessment methodology, identification and characterization of risks, control limits at the drug-linker intermediate and drug substance, and specific factors related to the ADC modality that can be considered. Simpler N-nitrosamines (e.g., NDMA) and more complex N-nitrosamine drug-linker-related impurities (NDLRIs) are discussed. Areas where there are greater or lesser degrees of consistency across companies are highlighted. The second paper builds on these survey results by presenting a comprehensive set of recommendations for the risk evaluation and control strategy of N-nitrosamine impurities in drug-linkers and ADCs. Taken together, these papers provide a perspective on the current state and encourage further development of scientifically sound approaches in this field.