Sustainable Risk Mitigation of Nitrosamine Impurities in Pharmaceutical Manufacturing

Nitrosamines are the most potent mutagens and carcinogens among the N-nitroso compounds. The unexpected detection of nitrosamines nowhere else but in extensively used drugs, notably ARBs, metformin, ranitidine and other long-term treatment medicines over the past ten years has caused a global awakening of regulators, widespread market recalls and a fundamental change in the pharmaceutical industry's risk assessment approach. It is believed that these impurities might come from the active pharmaceutical ingredients (APIs), the chemical processes, the excipients and the packaging materials or might even be a result of degradation during storage. Given that they are highly carcinogenic even at extremely low exposure levels, the authorities have set very low intake limits that are often within the nanogram-per-day range. In this paper, we will review through the entire nitrosamine spectrum in pharmaceuticals from their generation and underlying chemistry, drugs affected, mechanisms of toxicity, to reasons for their exceptional danger as well as current prevention and mitigation strategies. Analysis will mainly focus on risk-based approaches and analytical detection that ensure the safety of patients while not interrupting the supply of drugs.