US-FDA-Control of Nitrosamine Impurities in Human Drugs

This guidance recommends steps manufacturers of APIs and drug products should take to detect and prevent unacceptable levels of nitrosamine  impurities in pharmaceutical products. The guidance also describes conditions that may introduce nitrosamine impurities. The recent unexpected finding of nitrosamine impurities, which are probable human carcinogens, in drugs such as angiotensin II receptor blockers (ARBs), ranitidine, nizatidine, and metformin, has made clear the need for a risk assessment strategy for potential nitrosamines in any pharmaceutical product at risk for their presence. This document revises the guidance of the same title issued in September 2020. 

The discovery of nitrosamines in some types of drug products led FDA and other international regulators to conduct a detailed analysis of these impurities in affected APIs and drug products.8, 9 Based on the Agency’s current understanding, this guidance discusses potential root causes of nitrosamine formation and advises API and drug product manufacturers that they should (1) conduct risk assessments of their approved or marketed products and products with pending applications, and (2) take appropriate actions to reduce or prevent the presence of nitrosamines in APIs and drug products.

Although nitrosamine impurities have been found in only some drug products, and batches of those products have been recalled when there were unacceptable levels10 of  these impurities, nitrosamine impurities might exist in other APIs and drug products due to use of vulnerable processes and materials that may produce nitrosamine impurities. Therefore, the recommendations made in this guidance apply to all chemically synthesized APIs. They also apply to drug products containing chemically synthesized APIs and to drug products at risk due to other factors described in this guidance (see sections II.B and C), and not just to the drug products that have  been identified in FDA announcements.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

Control of Nitrosamine Impurities in Human Drugs