FDA Issues Guidance for Controlling Nitrosamine Impurities

By Miranda Greenberg -

September 3, 2020

The US Food and Drug Administration (FDA) has issued guidance, Control of Nitrosamine Impurities in Human Drugs, for immediate implementation. The guidance recommends steps, including a comprehensive risk-assessment strategy and other actions that manufacturers can take to reduce or prevent the presence of nitrosamine impurities in their drugs.

The issue of nitrosamine impurities in certain active pharmaceutical ingredients (APIs) first emerged in 2018 with both the European Medicines Agency (EMA) and the FDA initiating investigations of nitrosamine impurities in certain “sartan”-containing APIs, used in anti-hypertensive and cardiovascular drugs, such as valsartan candesartan, irbesartan, losartan, and olmesartan. They later broadened those investigations into prescription and over-the-counter forms of ranitidine, a H2 (histamine-2) blocker used to decrease the amount of acid created by the stomach, as well as into metformin, a diabetes drug. These investigations led to certain product recalls as well.

Nitrosamines are classified as probable human carcinogens based on animal studies. They are present in some foods and water supplies and are not expected to cause harm when ingested at very low levels. Although several nitrosamine impurities were found in APIs, one nitrosamine, N-nitrosodimethylamine (NDMA), in particular was often cited. Given the risk that genotoxic substances, such as NDMA, may increase the risk of cancer if people are exposed to them above certain levels and over long periods of time, manufacturers have recalled drugs with NDMA levels higher than the FDA’s recommended acceptable intake levels.

The source of these impurities can be related to the drug’s manufacturing process, the materials used in manufacturing, the drugs’ chemical structure, or even the conditions in which drugs are stored or packaged. Under the FDA’s oversight, manufacturers are responsible for mitigating these impurities. The FDA’s guidance is intended to assist manufacturers in preventing unacceptable levels of nitrosamines in drugs.

The FDA’s guidance follows the issuance of a question-and-answer document by the EMA last month (August 2020) to provide guidance on risk evaluation and mitigation of nitrosamines impurities in APIs and finished products with new requirements coming into play in 2021.

Source: US Food and Drug Administration