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Safeguarding patients from nitrosamine impurities in medicines
USP scientists and Expert Volunteers are helping to safeguard patients from unacceptable levels of nitrosamine impurities, probable or known human carcinogens, whose presence has recently been reported in widely used prescription and over-the-counter (OTC) medications. USP is providing tools and solutions to help drug manufacturers and regulators worldwide analyze, monitor, and control for nitrosamine impurities thereby strengthening the quality of the global medicines supply chain. These resources include a proposed new informational General Chapter on nitrosamine impurities, associated Reference Standards and on-demand educational webcasts.
Nitrosamine impurities have been detected in the following drug products, according to the U.S. Food and Drug Administration (FDA):
- Certain lots of valsartan, losartan, and irbesartan, angiotensin II receptor blockers used to treat high blood pressure and heart failure
- Ranitidine and nizatidine, histamine-2 (H2) blockers used to treat heartburn and other gastrointestinal conditions
- Certain metformin formulations, used to control high blood sugar in type 2 diabetes
- Rifampin and rifapentine, antibacterial drugs used to treat tuberculosis and other infections
The discovery of nitrosamine impurities in these drugs over the past two years has triggered major efforts by regulators and industry to reduce or eliminate their presence in the drug supply chain. The FDA has advised patients taking these prescription drugs to continue taking their medicine until their healthcare professional provides a different treatment option; and those taking the OTC medications to stop taking them and consider using other OTC products for their condition.(For updated information about these drugs, visit the FDA’s recalls, market withdrawals, and safety alerts web page.)
“Nitrosamine contamination is a global public health issue. USP is doing its part to engage with stakeholders, regulators and pharmacopeial partners around the world to develop strategies for nitrosamines control to help ensure the quality of medicines.”
—Jaap Venema, Ph.D., USP Chief Science Officer and Chair, USP Council of Experts
There are numerous pathways by which drug products can become contaminated with nitrosamines, which include formation during the manufacturing process for certain drug products. Nitrosamine impurities can originate from different sources such as active pharmaceutical ingredient synthesis, drug product manufacturing, or drug product degradation during storage. Changes in manufacturing and storage—however small they may seem—could have great impact on drug quality and, most importantly, on patients.
“It’s important for manufacturers to develop and validate analytical procedures and predictive approaches for identifying where in the supply chain impurities can emerge and to establish risk-based strategies so that patient safety and patient access remain protected.”
—Jaap Venema, Ph.D.
To help meet this critical challenge, USP has launched the following compendial solutions and USP resources.
Proposed USP General Chapter <1469> Nitrosamine Impurities
USP established the Nitrosamines Joint Subcommittee (JSC) in February 2020 to develop a roadmap for USP on nitrosamine topics and create public documentary standards.
Chaired by Mark Schweitzer, Ph.D., Global Head of Analytical Science and Technology at Novartis and General Chapters–Chemical Analysis (GCCA) Expert Committee (EC) member, the JSC comprises Expert Volunteers from industry who serve on the GCCA and Small Molecules ECs along with government liaisons from FDA. By September 2020, the JSC had proposed a new informational General Chapter <1469> Nitrosamine Impurities for public comment in Pharmacopeial Forum (PF) 46(5) [Sep.–Oct. 2020].
Proposed General Chapter <1469> aligns with current scientific and regulatory approaches to ensure the appropriate control of nitrosamine impurities in drug substances and drug products. It is the first step toward creation of robust public standards regarding nitrosamines in USP that help to ensure the quality and safety of the drug products. USP laboratory teams supported the development of <1469> by researching, evaluating, and identifying methods for monitoring these impurities. One of the most challenging issues was how to detect nitrosamines at extremely low levels in very different matrices, including drug substances, drug products, and solvents. To address this issue, USP scientists looked beyond traditional compendial methodologies and utilized more sensitive technologies such as mass spectrometry.
“General Chapter <1469> provides manufacturers with important information, tools, and approaches for evaluating and controlling nitrosamines in their products. For example, it provides performance criteria to assess the suitability of analytical procedures that manufacturers develop for monitoring nitrosamine levels.”
—Ed Gump, Ph.D., Vice President, Small Molecules
USP Reference Standards
USP released six new USP Nitrosamines Impurities Reference Standards, highly-characterized materials developed for use with the methods described in proposed <1469>, in July 2020. These Reference Standards are used as controls and in method validation to support the analysis and monitoring of nitrosamine impurities in the drug supply chain.
The portfolio of Reference Standards for nitrosamine impurities includes N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N-Nitrosodiisopropylamine (NDIPA), N-Nitrosodibutylamine (NDBA), N-Nitrosoethylisopropylamine (NEIPA), and N-Nitrosomethylaminobutyric Acid (NMBA).
As with all USP Reference Standards, nitrosamine impurities reference standards have been rigorously evaluated by USP’s collaborative process across multiple laboratories.
USP is committed to engaging global stakeholders that may be impacted by nitrosamines. USP offers on-demand webcasts, video tutorials, trainings, technical notes and other innovative tools that bring added-value to science-based USP Standards on nitrosamines. In India, for example, USP staff are conducting webinars and training sessions on proposed <1469> for regional pharmaceutical laboratory professionals and regulators.
One of the biggest challenges has been contextualizing the issue of nitrosamine impurities for those who don’t typically work in this area, says Kristi Muldoon Jacobs, Ph.D., Regulatory and Compendial Affairs Director and leader of the Nitrosamines Steering Committee, which coordinates and guides USP’s nitrosamine-related activities. “The key point is that chemicals are not all bad or good, it’s all about levels of control,” she says. “USP offers the tools and solutions needed to help ensure that nitrosamine impurities are controlled at acceptable levels.”