Regulators around the world have paid close attention to the risk of nitrosamine contamination since a potential carcinogen, N-nitrosodimethylamine (NDMA), was found in batches of valsartan produced by Zhejiang Huahai Pharmaceutical last year. The regulatory investigations subsequently expanded to cover other drugs in the sartan class and contaminants related to NDMA.
Swissmedic recently improved its ability to protect patients from the contaminants by adopting an upgraded test method based on the use of gas chromatography–mass spectrometry. The regulator said the changes “further improve the sensitivity of testing for nitrosamine contamination,” adding that the test is more robust than its predecessor.
Using the new test, Swissmedic can detect NDMA in most sartans down to levels of three parts per billion (PPB). The sole exception is candesartan, an angiotensin II receptor antagonist developed by AstraZeneca. The test can only detect NDMA in that sartan down to six PPB.
Swissmedic’s test can also detect and quantify N-nitrosodiethylamine (NDEA), a substance related to NDMA that was found in batches of valsartan Zhejiang Huahai produced before changing its manufacturing process in 2012.
Applied to NDEA, the new test is even more sensitive. The test detects NDEA down to two PPB in all sartans except candesartan. The limit of detection for the AstraZeneca-developed sartan is three PPB.
While Swissmedic thinks NDMA and NDEA can feasibly be spotted at those low levels, higher concentrations need to be present to quantitatively detect the contaminants with a certain level of accuracy and precision. The limit of quantification of the test ranges from five to 20 PPB, depending on the contaminant and sartan involved.
The adoption of the improved test is part of a long-running effort by the Swiss regulator to get on top of the threat posed by contaminated sartans.
In July 2018, Swissmedic oversaw a recall of certain products that contain valsartan amid reports that some medicines were contaminated with a potentially carcinogenic impurity. Swissmedic followed up by testing samples of 10 valsartan-containing medicines that were outside of the scope of the recall.
Those tests found the sampled medicines were free from NMDA, enabling Swissmedic to move on to the assessment of other sartans. Late last year, Swissmedic revealed that it had found no evidence of contamination with NDMA in tests of more than 50 products that contained losartan, olmesartan, candesartan and irbesartan, active ingredients that have the tetrazole ring that makes valsartan susceptible to contamination.