CONTROL OF NITROSAMINE IMPURITIES IN HUMAN DRUGS: A GUIDANCE FOR INDUSTRY

The unexpected discovery of nitrosamine impurities, potent genotoxic carcinogens, in various drug products prompted global regulatory action. This guidelines summarizes the key updates in the US FDA's September 2024 Revision 2 guidance, "Control of Nitrosamine Impurities in Human Drugs." The guidance expands its scope beyond well-known small-molecule nitrosamines (e.g., NDMA, NDEA) to include Nitrosamine Drug Substance-Related Impurities (NDSRIs), which are unique to specific APIs and can form during drug product manufacture or storage. The guidelines recommended three-step mitigation strategy: (1) conduct risk assessments for all chemically synthesized APIs and drug products, (2) perform confirmatory testing using sensitive, validated methods if a risk is identified, and (3) report changes to applications or Drug Master Files (DMFs). The guidelines will describe root causes of formation, acceptable intake (AI) limit determination strategies, and updated implementation timelines, emphasizing a deadline of August 1, 2025, for NDSRI confirmatory testing and changes. Furthermore, it will highlight novel mitigation strategies for NDSRIs. This overview provides a critical resource for industry professionals to ensure compliance and safeguard the global drug supply.