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What The FDA’s Nitrosamine Impurity Guidance Means for Drug Manufacturers

It’s been over two years since carcinogenic nitrosamines were discovered in some widely used drugs. The discovery occurred in 2018 when the contaminant was found in active pharmaceutical ingredients in Valsartan, a blood pressure medication. Since then, the contaminant has been found in several other drugs taken by millions of people each year.

The Latest Update

In 2019, the contaminant was found in ranitidine medications (commonly known as Zantac) and Nizatidine. Almost immediately, the FDA requested the removal of all Ranitidine drugs from the market. Most recently, the agency announced levels of the carcinogen that are above its acceptable intake limit in metformin, a prescription drug used to control high blood sugar in patients with type 2 diabetes. 

After more than a year of numerous recalls and multiple warning letters, the FDA on September 1 released its guidance in Control of Nitrosamine Impurities in Human Drugs, which outlines in 24 pages how to detect and prevent unacceptable levels of nitrosamine impurities

What’s Inside The Guidance:

  • There appear to be several possible causes for the presence of nitrosamine impurities in drugs such as the general conditions related to the drug’s manufacturing process, the materials used in manufacturing, and the drugs’ chemical structure.
  • An “Acceptable Intake Limits” table for the nitrosamine impurities NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA is included for manufacturers to use as a reference when testing their drugs.
  • The FDA recommends manufacturers assess the risk of nitrosamine impurities in their drugs, conduct confirmatory testing when there is any risk for the presence of the carcinogen, and report changes implemented to prevent or reduce the contaminant.
  • The guidance specifies steps manufacturers should take to mitigate and prevent formation of nitrosamine impurities, including removal of quenching steps from the main reaction mixture, auditing the supply chain, careful monitoring for at-risk raw materials, and more.

What It Means For Manufacturers

With the FDA’s increased understanding of how nitrosamine impurities form in drugs, it now not only knows how to catch it, but also how to prevent it. And now that the guidance is available to drug manufacturers, they too will be expected to take the appropriate steps to catch and prevent the contaminant. The proof is in the agency’s words as it clearly states in the guidance, “drug manufacturers are responsible for mitigating these impurities.”

Expect the FDA to maintain its focus on the nitrosamine issue. If you’re a drug manufacturer, be prepared to prove the safety of your product or risk seeing an increase in recalls and litigation. The best thing you can do now is familiarize yourself with the guidance, treat the FDA’s recommendations as requirements, and follow the agency’s recommended remedial steps. Now that the FDA had laid out its position in writing, it’s your responsibility to prevent nitrosamine contamination before the agency’s investigators find it.

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