USP launches new standards, tools for detecting and controlling nitrosamine impurities in drug supply chain

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Predictive, risk-based approaches needed to address unsafe impurity levels

Rockville, MD, July 9, 2020 – USP has announced the release of six new Reference Standards to support manufacturers and regulators in analyzing and monitoring potentially harmful nitrosamine impurities in the drug supply chain.

  • N-Nitrosodimethylamine (NDMA) (1 mg/mL in methanol)
  • N-Nitrosodiethylamine (NDEA) (1 mg/mL in methanol)
  • N-Nitrosodiisopropylamine (NDIPA) (1 mg/mL in methanol)
  • N-Nitrosodibutylamine (NDBA) (1 mg/mL in methanol)
  • N-Nitrosoethylisopropylamine (NEIPA) (1 mg/mL in methanol)
  • N-Nitrosomethylaminobutyric acid (NMBA) (1 mg/mL in acetonitrile)

In September 2020, USP will also propose for public comment a new United States Pharmacopeia—National Formulary general chapter standard to provide guidance on assessing materials for nitrosamine presence, establishing control strategies for these impurities and ensuring the performance of analytical procedures to monitor nitrosamine levels in drug products.

Starting in 2018, nitrosamine impurities were found to be present in some angiotensin II receptor blockers used to treat high blood pressure and heart failure. Depending on the levels and extent of exposure to this class of chemical compounds, nitrosamines have the potential to cause cancer. Nitrosamine impurities have since been found in ranitidine and metformin, leading to major recalls and efforts by regulators and industry worldwide to reduce or eliminate the presence of these impurities in the drug supply.

“Nitrosamine impurities can originate from different sources such as during active pharmaceutical ingredient synthesis, drug product formulation, degradation, or storage,” according to Jaap Venema, Ph.D., USP’s Chief Science Officer. “Changes in manufacturing and storage—however small they may seem—could have great impacts on drug quality and, most importantly, on patients. It’s important for manufacturers to develop validated methods and predictive approaches for where in the supply chain impurities can emerge and to establish risk-based strategies so that patient safety remains protected. With these six reference standards as well as the forthcoming general chapter, we are confident that we are providing modern and useful tools to address this critical issue.”

Focused on predictive tools and approaches, USP established a body of volunteer experts to develop the nitrosamines general chapter. Comprised primarily of industry experts with extensive experience in impurities and drug manufacturing, the USP Nitrosamines Joint Subcommittee represents a wide range of scientific perspectives. “As USP volunteers, we are called upon to utilize our best personal, professional, and scientific judgment to benefit public health by developing public quality standards,” said Mark Schweitzer, Ph.D., Global Head of Analytical Science and Technology at Novartis and Chair of USP’s Nitrosamines Joint Subcommittee.

The subcommittee also includes representatives from the U.S. Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines & HealthCare, which is responsible for drug quality standards in the European Pharmacopeia. Given the widespread global use of the medicines which have been found to contain nitrosamine impurities, the USP and the European Pharmacopoeia will continue to work on convergence and to ensure that their public quality standards for regulators and industry are harmonized.

USP’s new nitrosamine Reference Standards can be used by manufacturers to test their own materials against methods in USP’s general chapter. The Reference Standards may also be used with methods provided by U.S. FDA and other regulators as well as those developed by manufacturers in-house. As with all USP Reference Standards, the nitrosamine Reference Standards are highly-characterized and have been rigorously evaluated by USP’s collaborative process across multiple laboratories.

In August, USP will be launching a new USP Education webinar, “The ICH Q3 Impurity and the M7 Mutagenic Impurities Guidelines.” Designated as an “ICH Recognized Training Program”, this webinar will address the application of the International Conference on Harmonization Guidelines for Q3-A, B, C, D and M7 for controlling organic, inorganic and solvent impurities and the development of strategies for dealing with actual and potential impurities most likely to arise during synthesis, purification, manufacturing, and storage of drug substances and drug products.

USP will also be participating in a Pharmaceutical Technology Editors’ Series webinar, “Genotoxic Impurities and Drug Quality: Lessons from the Nitrosamine Contamination Crisis,” on July 14, 2020.

For additional information on USP’s standards, tools and webinars related to nitrosamines, visit

About USP
U.S. Pharmacopeia (USP) is an independent, nonprofit, scientific organization that sets quality standards for medicines, dietary supplements and food ingredients worldwide. USP’s quality standards are enforceable in the United States by the Food and Drug Administration and integrated into law in more than 40 countries. These standards, which are continuously developed and revised by more than 800 volunteer experts in science, industry, healthcare and academia, are also used in more than 150 countries. Learn more at