In the UK this week there was a recall of the stomach acid reducing medicine Zantac by the MHRA due to unacceptably high levels of the impurity n-nitrosodimethylamine (NDMA). The active ingredient in Zantac, Ranitidine was found to be contaminated with the highly toxic and potentially carcinogenic impurity.
The recall by the MHRA followed recalls in the US and Canada during September 2019 over similar fears of the presence of high levels of NDMA in Zantac. During 2018, there had also been recalls of the angiotensin inhibitor drugs Valsartan, Losartan and Irbesartan due to high levels of NDMA and other N-nitrosoamine impurities.
In the case of Valsartan, the cause of the increased levels of NDMA was identified as a change in the manufacturing process brought in by the API manufacturers, which although approved by the FDA and EDQM in 2012, led to increases in the levels of NDMA present in the API.
Initially the presence of NDMA in Ranitidine was drawn to the attention of the FDA by the US pharmacy company Valisure. Although it was initially suggested that Valisure’s analysis method was the cause of the observed high levels of NDMA (they were using gas chromatography which exposed Ranitidine to high temperatures than the usual HPLC analysis method, causing degradation and formation of NDMA), it now appears there are genuine concerns about the presence of NDMA in the raw material and the potential for Rantidine to form NDMA once in the body or if disposed into the sewer system.
NDMA is an N-nitrosamine, a class of compounds that have shown to be carcinogenic in animal studies. The presence of N-nitrosamine impurities in pharmaceuticals and agrochemicals are strictly regulated and their presence and content is routinely tested for. For example the impurity N-Nitroso Glyphosate is tested for in herbicide Glyphosate.
Changes in manufacturing processes or a change in the sources of a raw material or intermediate can cause changes to the impurity profiles of the final product that can have a significant effects on the health of patients as well as a significant impact on a company’s commercial performance. Ranitidine (sold as Zantac) is one of the world’s most widely taken medications available over the counter in many countries. Although it has long been off-patent it is still sold by many of the leading global pharma companies including GSK, Merck, Boehringer Ingelheim, Strides Pharma Science Limited (Strides Shasun), Sun Pharma and Tocris Bioscience (R and D Systems). The removal of such a product from the market will lead to loss of revenues for the seller and a switch by patients to alternative medicines will lead to winners and losers on both sides.
The presence of NDMA in Ranitidine and other API’s has brought to into focus the risks that the impurities present in everyday medicines can present to the health of patients, even those impurities present at very low levels can be potentially dangerous for patients. The high toxicity of NDMA means that even small changes in the levels present in API’s can have a significant effect on the health risk to the people taking them.
This problem also shows the essential role that the identification and quantification of manufacturing and degradation impurities plays in protecting the health of patients.