Nitrosamines
Clarissa Chan, PharmD
Since 2018, blood pressure, diabetes, heartburn, and, most recently, smoking cessation medications have been recalled due to carcinogenic impurities called nitrosamines. Although trace amounts of these contaminants are typically found in water and foods like grilled and processed meats, exposure to higher-than-acceptable levels of nitrosamines for long periods of time may increase peoples’ risk of cancer.
Pfizer recently voluntarily recalled 12 lots of varenicline (Chantix) due to elevated amounts of a nitrosamine, N-nitroso-varenicline.
FDA indicated that while long-term ingestion of N-nitroso-varenicline may increase the risk of cancer in humans, there are no urgent risks to patients taking varenicline, and there have not been any adverse events associated with this recall.
“We continually gain new knowledge about drugs which allows us to identify and quickly address previously unknown risks to patients,” said Charles Kohler, press officer and spokesperson for FDA.
“When we identify drug quality lapses that pose potential risks for patients, we make every effort to react swiftly to resolve the problem, understand the issues, and provide our best recommendation to the public as quickly and accurately as possible,” said Kohler.
“FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area. We will continue to investigate and work to ensure these types of impurities do not exceed acceptable limits so that patients can continue taking their medicines without concern.”
Following are commonly asked questions regarding the recent nitrosamine contaminants in medications addressed by Kohler.
Why are these impurities just now being discovered?
Today, we have better testing methods than ever before, and we know what to look for in products’ chemical structures and manufacturing processes that may increase the risk of forming nitrosamines. Improved technology enables us to detect even trace amounts of impurities in drug products and may be why more products have been found to have low levels of nitrosamines. FDA has strict standards for safety, effectiveness, and quality, and is making every effort to help keep the U.S. drug supply safe. We also work closely with international drug regulatory agencies so that we leverage resources and testing done outside the U.S., which can help inform testing of the U.S. drug supply. As our investigations, research, and testing continues, along with the investigations done by other drug regulatory agencies, we may find low levels of nitrosamines in additional drugs.
Why are nitrosamines being found in drugs?
There are multiple reasons why nitros-amines can be present in drugs. FDA found the source of nitrosamines can be related to the drug’s manufacturing process, its chemical structure, or even its storage or packaging conditions. For example, in ranitidine products the impurity was found to increase over time and when stored at higher than room temperatures and may result in consumer exposure to unacceptable levels of this impurity. Nitrosamines can also be formed when foods and drugs are processed in the body.
Is testing for these impurities a mandatory part of the drug development process?
Manufacturers are responsible for understanding their processes, which includes preventing the presence of unacceptable impurities.
Manufacturers are also responsible for developing and using suitable methods to detect and limit unacceptable impurities, including any new impurities that may arise when they make changes to their manufacturing processes.
FDA has published testing methods that can be used by the industry to detect nitrosamine impurities. In collaboration with regulatory counterparts around the world, FDA has also set internationally-recognized acceptable daily intake limits for nitrosamines.
If drugs contain levels of nitros-amines above the acceptable daily intake limits, FDA recommends these drugs be recalled by the manufacturer, as appropriate, or not be released for distribution to the market. The agency is working with the industry to determine the source of these impurities, but there are multiple reasons nitrosamines can be present in medicines.
FDA published a guidance for industry, entitled “Control of N-Nitrosamine Impurities in Human Drugs.” This guidance recommends steps that manufacturers of active pharmaceutical ingredients and drug products should take to detect and prevent objectionable levels of nitrosamine impurities in pharmaceutical products.