Abstract

NITROSAMINE DRUG SUBSTANCE-RELATED IMPURITIES: COMPARATIVE FDA AND EMA REGULATORY FRAMEWORKS, ANALYTICAL CHALLENGES, AND SUPPLY IMPLICATIONS

Purva Pawar, Dhaval Desai, Piyush Modi*, Jigneshkumar Modasiya

Abstract

Nitrosamine drug substance-related impurities (NDSRIs) became a significant global concern after nitrosamines were found in angiotensin receptor blockers and other medicines. Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) aim to reduce patient exposure to these potentially harmful impurities, but they differ in their legal authority, how they set acceptable intake (AI) limits, implementation timelines, reporting requirements, and flexibility. This review examines how the FDA and EMA currently manage NDSRI control, covering their legal foundations, how they set AI limits, assess structure-activity relationships, use the Carcinogenic Potency Categorization Approach (CPCA), conduct confirmatory testing, handle regulatory submissions, and manage products throughout their lifecycle. It also covers analytical method development, supply chain effects, and new mutagenicity testing methods, such as transgenic rodent assays and error-corrected next-generation sequencing. The review finds that FDA guidance allows product-specific flexibility when patient access is at risk. In contrast, the EMA uses a more formal process via the Committee for Medicinal Products for Human Use (CHMP) Article 5(3) opinion. Greater harmonization, better compound-specific data, and improved analytical and toxicological tools could help make global standards more consistent and protect access to important medicines.

Keywords: Acceptable Intake; CPCA; EMA; FDA; NDSRI; Regulatory harmonization.