NAVIGATING NITROSAMINES: ORIGIN, DETECTING, ANALYSING AND REGULATING IMPURITIES IN PHARMACEUTICALS

Abstract

N-nitrosamines are carcinogenic impurities mostly found in groundwater, treated water, foods, beverages, and consumer products like processed meats, alcoholic beverages, cosmetics, and cigarette smoke. The recent discovery of N-nitrosamines in pharmaceutical products and subsequent recalls pose a significant health risk to patients. Nitrosamine impurities in drug products have emerged as a critical concern in pharmaceuticals, prompting extensive scrutiny from regulatory agencies and stakeholders. Initial investigation by the regulatory agency identified Active Pharmaceutical Ingredient (API) as a source of contamination. To avoid carcinogenic and mutagenic effects in patients relying on these medications, authorities have established specific guidelines in risk assessment scenarios and proposed control acceptable limits for nitrosamine impurities in pharmaceuticals. This review provides a thorough Carcinogenicity of Nitrosamine impurities, Historical background examination of the occurrence, formation mechanisms, addresses of Nitrosamines, and associated risks of nitrosamines in drug formulations. Nitrosation pathways and possible root causes of nitrosamine formation in pharmaceuticals are discussed. The review also gives an understanding of the General Quality Risk management process, Techniques for Measuring nitrosamine impurities, with control strategies as directed by the regulatory authorities, and how to avoid them in Pharmaceutical Drug Products. With this the review also points to the most prominent drug product recalls from the market with multiple lots. The review contains the challenges faced by manufacturers in risk assessment, i.e. impurity generation, stability of impurity, and its recovery are the pain areas. Moreover, the regulatory landscape governing nitrosamine impurities is explored, encompassing recent guidelines from major regulatory bodies such as the FDA, EMA and Health Canada and impact of recent developments related to nitrosamine on the pharmaceutical industry.