Nitrosamines are a class of chemicals that commonly occur as impurities in water, beverages, and foods (particularly in cured and grilled meats). Although nitrosamines are generally regarded to be carcinogenic, small amounts of exposure are not considered to be harmful. The acceptable U.S. intake limit for the nitrosamine known as NDMA (i.e., N-nitrosodimethylamine), for example, is less than one-ten millionth of a milligram (i.e., less than 100 nanograms) per day. Below the allowable intake level, NDMA is not expected to pose an appreciable cancer risk.
Since 2018, multiple drug products, including angiotensin receptor blockers (ARBs) and the histamine blocker ranitidine (commonly known as Zantac), have been recalled due to the presence of nitrosamines at unacceptable amounts.1 To help test these products for the presence of nitrosamines, CDER scientists have developed and publicly shared multiple methods,2 including gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-MS (LC-MS) technologies, specific for detecting and quantifying up to eight different nitrosamines in these drug products, even if present at amounts well below the allowable intake level.
Recently, the FDA was notified by international regulators of the presence of nitrosamines, particularly NDMA, in metformin, a widely used diabetes medication. Using the expertise gained in detecting nitrosamines in other products (e.g., ARBs and ranitidine), the FDA developed and validated two different and complementary methods to test for multiple nitrosamines in metformin products. Analysis with multiple complementary methods allows for the use of fundamentally different principles to investigate the same concept and assure dependable results. Initial testing by the FDA showed no NDMA at amounts above the level of concern in metformin products, but after the FDA released its testing results, a citizen petition, filed by a private testing laboratory, reported the detection of NDMA at higher amounts in metformin than those resulting from the FDA tests. The FDA moved quickly to determine the source of the discrepancy between the results of the private laboratory and those of the FDA.
The FDA learned that the private laboratory had relied on a single method (see below) that found the presence of NDMA above the allowable intake level (96 ng/day) in 16 of 38 tested metformin products. In comparison, the FDA used multiple methods, developed within CDER and validated appropriately for the examination of metformin products, to test the same 38 metformin products examined by the private testing laboratory that filed the citizen petition. The results of the CDER studies, which differ in important ways from the results of the private laboratory, have recently been published in a peer-reviewed journal.3 Notably, the FDA results indicated NDMA above the allowable intake level in only eight of the 38 products, and for those products in which it was detected, NDMA generally occurred at lower amounts than reported by the private laboratory. In addition to testing for NDMA within the 38 products, the CDER scientists used tests that could have detected seven other nitrosamine compounds but did not detect any. As a result of these tests, CDER recommended the recall of the eight extended-release metformin products that were found to have NDMA amounts above the acceptable intake limit.
To further investigate a potential cause of the discrepancies between results from the private laboratory and the CDER studies, the CDER scientists also reproduced the method used by the private laboratory. Indeed, the CDER scientists showed that another molecule in the drug product, called N,N-dimethylformamide (DMF), interfered with the measurement of NDMA and resulted in artificially elevated readings of NDMA in the tested metformin samples. More specifically, the private laboratory had relied on a mass spectrometry analysis that was not specific enough to distinguish the NDMA signal from the DMF signal, thereby resulting in inaccurate reporting of the amount of nitrosamine impurity. By contrast, the FDA instrumental resolution was suitable, allowing NMDA in the samples to be distinguished from DMF present in the product. DMF is a solvent commonly used in pharmaceutical manufacturing and can be present at low levels in certain drug products. DMF is potentially toxic when present at high levels, above permitted daily exposure limits. Although the methods used by the CDER scientists were not developed to quantify DMF specifically, they estimate that the levels of DMF in the tested metformin samples fall well below the level of concern to patients, as determined by current international standards.
The initial report of nitrosamine impurities in metformin products4 was of great concern to the FDA, and CDER immediately began investigations to evaluate the scientific and public health relevance of reported data from metformin testing. As demonstrated for other drug products (e.g., ARBs and ranitidine), regulatory mechanisms that culminate in product recalls must be based on accurate data and an evaluation of public health risk. The FDA is committed to making safe drugs available to patients who need them. Where recalls are enacted the agency needs to carefully weigh any action that might deprive patients of safe and effective medication. Therefore, CDER researchers apply multiple, complementary state-of-the art methods (i.e., “orthogonal” methods) that assure dependable results, so that regulatory decisions that may affect drug supply are made based on sound scientific data. One example of the FDA’s science- and risk-based approach is underscored by the CDER studies explored here. In this instance, the FDA was able to determine that eight of the 38 metformin products brought to its attention by a citizen petition contained more than the allowable intake level of NDMA, and as a consequence, only these eight extended-release metformin batches were recalled from the market, leaving other products to meet the demand of patients with diabetes who rely on this critical medicine.5 Furthermore, the work provides an important example of the necessity of accurate methods to industry or other laboratories performing similar studies.
The Spotlight series presents generalized perspectives on ongoing research- and science-based activities within CDER. Spotlight articles should not be construed to represent FDA’s views or policies.
1 FDA. Information about nitrosamine impurities in medications. (https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications) Accessed August 19, 2020.
2 FDA. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) method for the determination of NDMA in ranitidine drug substance and drug product. (https://www.fda.gov/media/130801/download) Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of NDMA in ranitidine drug substance and solid dosage drug product. (https://www.fda.gov/media/131868/download) liquid chromatography-high resolution mass spectrometry (LC-HRMS) method for the determination of NDMA in metformin drug substance and drug product. (https://www.fda.gov/media/134914/download) Accessed August 18, 2020.
3 Yang, J., Marzan, T.A., Ye, W. et al. A cautionary tale: Quantitative LC-HRMS analytical procedures for the analysis of N-nitrosodimethylamine in metformin. AAPS J 22, 89 (2020). https://doi.org/10.1208/s12248-020-00473-w
4 Valisure. Valisure citizen petition on metformin 2020. (https://www.valisure.com/wp-content/uploads/Valisure-FDA-Citizen-Petition-on-Metformin-v3.9.pdf) Accessed August 19, 2020.
5 CDER/FDA. Recalls, market withdrawals, & safety alerts FDA. (https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts) Accessed August 19, 2020.