Nitrosamine Drug Substance-Related Impurities (NDSRIs) in Pharmaceuticals: Formation, Mitigation Strategies, and Emphasis on Mutagenicity Risks

Abstract

Objectives: To investigate the formation, detection, mutagenicity, and control strategies of nitrosamine drug substance-related impurities (NDSRIs) in pharmaceutical formulations, emphasizing regulatory compliance, risk mitigation, and the establishment of acceptable intake (AI) limits for enhanced drug safety.

Methods: This study reviews the NDSRI formation and mutagenicity assessment methods, including in silico, in vitro, and in vivo assays. It also explores mitigation strategies and approaches for determining AI limits.

Results: The findings indicate that NDSRIs are primarily formed through the nitrosation of APIs containing amine groups, with key risk factors including reactive functional groups and interactions between drugs and excipients. Mutagenicity evaluation revealed that while in silico and in vitro assays provide initial insights, in vivo assays offer more comprehensive and biologically relevant data by capturing complex metabolic processes and systemic interactions. Effective mitigation strategies, such as optimizing the manufacturing conditions and using nitrosation inhibitors, are crucial in reducing NDSRI formation. Approaches like the carcinogenic potency categorization (CPCA) and read-across methods are proposed for determining AI limits, facilitating safer exposure thresholds and supporting regulatory compliance.

Conclusion: A multifaceted approach is vital for managing NDSRIs in pharmaceuticals. Comprehensive mutagenicity testing, especially in vivo assays, provides biologically relevant insights into NDSRI-associated risks. Implementing control strategies and, determining AI limits are key to minimizing exposure. Strengthening regulatory frameworks and industry practices improves drug safety, quality, and public health protection.

Keywords: Acceptable intake; Mutagenic impurities; Mutagenicity; NDSRI; Nitrosamines.