Valsartan: what caused the contamination?

After the recent supply shortages of medicinal products containing the API ibuprofen, there are now massive problems with Valsartan products.

What's known so far is that the API has been contaminated with N-nitrosodimethylamine (NDMA) during production. This concerns the deliveries by the Chinese manufacturer Zhejiang Huahai Pharmaceutical. A press release by the German Federal Institute for Drugs and Medical Devices (BfArM) states that the WHO's and EU's International Agency for Research on Cancer classified the substance as "potentially carcinogenic for humans".

But how exactly did this contamination occur, and since when does the problem exist? The authorities' press releases don't contain much information on that. The statements by Professor Dr Fritz Sörgel from the German "Institut für Biomedizinische und Pharmazeutische Forschung" (IBMP; engl: Institute for Biomedical and Pharmaceutical Research), which were being published in the online portal of "apotheke adhoc" (in German), are more informative. It seems like the contamination had been discovered by chance, which astonished Professor Sörgel.

apotheke adhoc previously reported (in German) that the Chinese manufacturer had already changed their manufacturing process in 2012(!). It appears like the production of tetrazole had been altered and N,N- dimethylformamide (DMF) had been used as a new solvent. An expert's statement to apotheke adhoc says that during the breakdown of DMF, small amounts of dimethylamine may develop. In the presence of nitrous acid, NDMA forms.

Could this have been prevented?

This is tough to say. In the course of a robust supplier qualification, it should be agreed that changes must be reported and possibly approved beforehand. This however sounds easier than it actually is since API manufacturers are seldom willing to disclose complete synthesis details. Nevertheless, customers should try to gain as much information as possible, especially about changes to the synthesis process. According to Professor Sörgel, a good chemist could have known about the possibility of contamination. It has to be viewed as highly critical that there had apparently been contaminations of Valsartan since 2012.

What can quality assurance units do now? Besides the initiated recall campaigns, deliveries should also be assessed retrospectively. The assessment of other active substances by the manufacturer is just as important. According to their website, there's a wide range of products, which are apparently distributed globally.