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OMCL Combating nitrosamines

After medicinal products contaminated with nitrosamines had to be recalled just under two years ago, Swissmedic’s own laboratory – the Official Medicines Control Laboratory, or OMCL – developed its own, more sensitive test for detecting contamination. Below we take a closer look at several cases.

It is summer 2018, and the first report of substantial quantities of a nitrosamine – N-nitrosodimethylamine or NDMA – have been detected in valsartan, an active substance for reducing blood pressure, produced by a Chinese manufacturer is published. This is a clear breach of current international medicinal products regulations. It is also reason enough for Swissmedic to get involved, especially as the Chinese manufacturer never reported the genetically harmful impurities (see case 1 below).

The problem of quantity

The tolerated quantity of this genetically harmful substance is always dependent on the maximum daily dose and how long the medicine is used for. For NDMA in valsartan it is 0.3 ppm (parts per million) relative to the quantity of active substance for a lifelong dose of 300 mg daily. As Massimiliano Conti, Head of Swissmedic's laboratory explains, the challenge is therefore to find this tiny amount of contamination. “Swissmedic monitors the medicinal products market. That means that when we test samples, we have to be able to detect and identify the tiniest quantities of nitrosamine and know exactly what we’re looking for at this level.” Impurities are normally subject to limits of 0.1 percent of the active substance (approx. 1,000 ppm); however, this limit is very much lower if the impurity is genetically harmful. When testing for nitrosamines, that means using special analytical methods that are around 3,000 times more sensitive than normal techniques. Or, to take a practical example, when looking for impurities, we are normally looking for something in the order of 1 ml in a litre. In this case we are trying to find that millilitre in 33,000 litres – i.e. something the size of a tanker.

New test methods for nitrosamines in sartans

Sartans have antihypertensive and vasodilatory effects, and are used for the treatment of cardiovascular and kidney disease.

Following several cases of these carcinogenic nitrosamines being discovered in sartan-containing medicinal products, Swissmedic decided to develop a new test method of its own in its OMCL. Since then the laboratory has been testing sartans with a critical chemical structure. The aim is to be able to detect nitrosamine contamination even more sensitively. “We can use the new method to determine whether the quantity of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in valsartan and related sartans is above or below the safe limit”, says Massimiliano Conti, explaining the new approach to testing. “We had to use and validate a new analyser that is sensitive enough to carry out the measurement.”

What are nitrosamines?

Nitrosamines are genetically harmful, carcinogenic substances. They are found in water and beer, in food such as grilled meat and in cosmetics. The Federal Office of Public Health (FOPH) routinely tests products placed on the Swiss market. Swissmedic is responsible for testing the quality, safety and efficacy of medicinal products and verifies compliance with GMP (Good Manufacturing Practices) at all stages of production from active substance to finished product.

Case 1

Substantial quantities of NDMA

In summer 2018, Swissmedic experts were notified via the rapid alert system of nitrosamine contamination in the active substance valsartan. The Chinese manufacturer had not reported the case. Swissmedic reacted immediately, first establishing which products and manufacturers were affected. At the same time, an appropriate communication strategy was put in place. After consultations with the marketing authorisation holders, a recall of all affected valsartan preparations was ordered. At the same time Swissmedic published information for the public on its website. “We explained why the recall was taking place and told people not to simply stop taking the contaminated products, but to keep taking them and to consult a doctor at the first opportunity to ask for an alternative product”, says Massimiliano Conti, describing the procedure adopted at the time. The important thing was to prevent people panicking and reassure them that they could and should continue to take their medicines because treatment must not be stopped abruptly. The acute risk to health from uncontrolled discontinuation is much greater than the risk presented by nitrosamine contamination. Since sartan preparations worldwide were subsequently found to be contaminated, international cooperation and coordinated action became a key issue.

The effects

In November 2018, Swissmedic discovered another contaminated valsartan product. This time the impurity was NDEA. This discovery triggered a global recall of all finished products containing active substance from the affected manufacturer. “This was a story with far-reaching repercussions for us, especially as we only have just under 50 people in our lab. The FDA have a thousand, for example. Since then, the European Medicines Agency (EMA) has regularly invited Swissmedic to its meetings”, says Massimiliano Conti with a certain amount of pride. “Authorities are working together closely, and things are going extremely well.”

Case 2

Contamination in medicines containing ranitidine

In September 2019, medicinal products containing the active substance ranitidine were recalled in Switzerland because they contained traces of the nitrosamine NDMA (N-nitrosodimethylamine). Tests by Swissmedic's OMCL found that all ranitidine preparations authorised in Switzerland contained small quantities of the impurity in excess of the specified safety limit. There was no acute risk to health. Patients who had been prescribed one of the three recalled products were asked to see their doctor to discuss changing treatment.

Case 3

Contamination in medicines containing metformin

While testing metformin preparations for the treatment of type 2 diabetes in December 2019, Swissmedic's OMCL detected NDMA contamination in excess of the internationally tolerated safety level for medicinal products. At the same time, the Singapore national regulatory authority HSA found the impurity during tests of its own. Since antidiabetics containing this active substance are widely used, the extent and cause of the contamination had to be carefully investigated so that affected batches could be identified and recalled if necessary.

Conclusion

Thanks to smooth international cooperation on communication and laboratory analytics it was possible to deal with cases 2 and 3 not only much faster, but also with greater efficiency and effective coordination of activities. In addition, the analytical methods developed by the official laboratories were published and made available to marketing authorisation holders.