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Many are familiar with nitrosamine impurities, due to the widely publicized N-Nitrosodimethylamine (NDMA) contamination in over the counter (OTC) antacid medication, which led to wide-sweeping product recalls in 2019.

Companies must review all facets of their manufacturing and supply chain processes to ensure product quality and safety, and consumers need to take necessary steps to be informed, resulting in a greater understanding of the potential consequences and risks associated with the quality and safety of the medications and products they are consuming. Throughout this article, sources of nitrosamine impurities will be discussed, in addition to regulatory updates in and around nitrosamine impurities. Analytical methods employed in the identification of nitrosamine impurities and more will also be examined.

Sources of nitrosamine impurities

The interaction between secondary/tertiary amines and nitrites or oxides of nitrogen results in the formation of nitrosamines. These precursors of nitrosamines can be found in many products and materials, including frequently used solvents, reagents, pharmaceuticals, OTC products, foodstuffs, tobacco, cosmetic and personal care products, and more. A greater risk of nitrosamine formation, and therefore, contamination, has been linked to industrial processes, including the manufacturing of pharmaceuticals and rubber products. Rubber is frequently used within container-closure systems used for the storage of injectable drugs, and rubber is commonly found in both medical devices and inhalant drug delivery systems.

Oftentimes, when modifications are made to manufacturing processes to increase product yield, nitrosamine impurities can form as a result of the changes implemented. Raw materials, solvents, and product degradation have also been identified as sources of nitrosamine contamination. It is important to note that nitrosamines can arise throughout the various stages of the drug manufacturing process, including synthesis, purification, formulation, packaging, and/or storage. Even the slightest change can introduce impurities or increase levels of impurities present in a product beyond acceptable limits for exposure.

Regulatory updates and a review of nitrosamine impurities

In 2018, it was found that numerous lots of Valsartan, an angiotensin II receptor blocker (ARB), were contaminated with nitrosamines at levels above acceptable regulatory limits for exposure. Consequently, many doses of the medication were recalled due to the contamination. This led to a shortage of generic valsartan well into 2020, causing both patients and health care providers to turn to alternative medications that may not be as affordable, or more importantly, as effective, to treat existing health conditions.

A recall of all antacid products containing ranitidine was enacted in 2019 when lots of product were found to contain a nitrosamine impurity, specifically N-Nitrosodimethylamine (NDMA). The levels of NDMA in the recalled product were found to be nearly 10-fold higher than the .032 µg/g permissible level for ranitidine, which prompted regulatory agencies to enact an immediate product recall. The product recall and findings also resulted in heightened scrutiny regarding nitrosamine testing. Although studies have yet to show a causative effect, the wide-sweeping product recall has prompted multiple TV and radio advertisements stating law offices are searching for patients to join class-action lawsuits. As of 2020, ranitidine is no longer available for purchase in the US marketplace.

Still, more recently, NDMA impurities have been reported in certain extended-release formulations of Metformin, a medication widely prescribed for type 2 diabetes. The source of NDMA within some Metformin medications is still unknown, but the FDA has tightened the recall to eight specific lots of Metformin after reviewing test data which was generated with orthogonal methodology.

In late 2020, the FDA published guidance regarding the control of nitrosamine impurities, placing emphasis on recent product recalls and the manufacturing conditions which may generate nitrosamines. Furthermore, the Agency published analytical methodologies to encourage private labs, such as ÌìÃÀ´«Ã½, to assist the FDA in determining whether products contain nitrosamines, and to aid in the determination of the source(s) of nitrosamine contamination.

Employing analytical methodology and tools to identify nitrosamine impurities

Element has performed nitrosamine testing in accordance with the guidance published by the FDA. Our teams of expert scientists have also developed liquid chromatography with tandem mass spectrometry (LC-MS/MS) methods for nitrosamines in raw materials and process reagents used in the manufacturing of pharmaceuticals. These nitrosamine methods have also been set up on our Q Exactive Orbitrap system, enabling new levels of sensitivity.

It is important to note that nitrosamine impurities can be controlled with the implementation of robust quality control measures, including ensuring raw materials are thoroughly analyzed and characterized, in addition to making sure the entire pharmaceutical manufacturing process is traceable. This includes gaining a complete understanding of the excipient and active pharmaceutical ingredient (API) manufacturing processes. Any change in suppliers or processes should warrant an assessment of nitrosamine risk to avoid contaminations and product recalls, as seen with Valsartan and the other medications discussed throughout this article. In the absence of full traceability, rigorous testing can be employed to mitigate the risk of nitrosamine impurities in pharmaceuticals. Our understanding of nitrosamine formation and the ability to measure these substances has greatly increased since the first recall back in 2018. Yet, with expanded understanding and more robust analytical methodology and testing capabilities, additional instances of NDMA contamination may be uncovered, which may not have been identified previously.

Prevent NDMA impurities by partnering with a trusted CDMO

Partnering with a reputable lab with the proper expertise is crucial in understanding, identifying, and controlling potential nitrosamine impurities in pharmaceutical and over the counter (OTC) products. The partnering lab must have equipment capable of detecting nitrosamines at low parts per billion (ppb) levels of detection (LOD) in both drug products and substances. Element has the expertise, know-how, and equipment to solve even the most complex challenges, including nitrosamine impurities.