The Azido Impurity – detecting a new peak?

The international spate of recalls caused by azido impurities in blood pressure products throughout 2021 has refocused attention on the importance of reliable laboratory safety testing.

Canada, France, Switzerland and the UK together saw dozens of batches of losartan or irbesartan medicines recalled over several months, after tests found the mutagenic impurity in them above the internationally agreed Threshold of Toxicological Concern (TTC).

The news was another headache for the global pharmaceutical industry, just as it was attempting to move on from the 2018 nitrosamine scandal – when numerous lots of sartans contaminated with N-Nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) were withdrawn from sale.

The Azido Impurity – also known as azidomethyl-biphenyl-tetrazole, or AZBT – is not part of the nitrosamine family. But nitrosamines and AZBT can both occur as by-products during the synthesis of sartan active pharmaceutical ingredients (APIs) with tetrazole rings. Both impurities are also classed as mutagens – or chemical substances that can cause a change in the DNA of a cell. NDMA has been labelled “an extremely potent carcinogen” by the US Environmental Protection Agency, while authorities state that long-term, above TTC, exposure to mutagens such as AZBT also “has the potential to increase the risk of cancer.”

The parallels between azido impurities and nitrosamines in sartans do not end there, however. In November 2019, the US Food and Drug Administration (FDA) warned an Indian producer of valsartan APIs about “several current good manufacturing practice deviations” – including inadequate record keeping and cleaning. The FDA also noted that the same firm was “subject of an ongoing global investigation into nitrosamine impurities in angiotensin II receptor blockers (ARBs) such as valsartan, losartan and irbesartan”. In an October 2021 report on the azido impurity recalls, Bloomberg stated that the FDA was investigating another Indian manufacturer - involved in the manufacture of valsartan APIs - about potentially cross-contaminating impurities in its production equipment. A Chinese third-party supplier was also implicated in the 2018 nitrosamine contamination scandal, reinforcing concerns about the quality of medicines manufactured in that country and about the overall reliability of the international pharmaceutical production process.

Regulators have responded to the azido- and nitrosamine-related recalls by ordering licence holders to review the safety of a wide range of products. The European Medicines Agency (EMA) told companies to check for NDMA and other nitrosamines in all of its drugs within six months, amid fears that the industry was facing a “much more general problem than simply the contamination of individual drugs or compounds.” The EMA’s executive director, Guido Rasi, added: “It is of paramount importance that we learn from our experience with sartans and take a proactive approach for other classes of medicines.” When the AZBT-contaminated sartans were first discovered in April last year, the Europe Directorate for the Quality of Medicine and Healthcare immediately ordered testing to ensure that APIs currently on the market did not exceed TTC and promising “actions (e.g. suspension)” if necessary.

Given the recent international focus on the safety of sartans medicines, it is more important than ever that the finished products pharmaceutical companies release onto the market are verifiably free from AZBT and other mutagenic impurities. Investing in reliable, high-quality reference standards not only gives laboratories confidence in their analytical results, but can help guarantee consumer safety, company reputation and the bottom line.

TRC has more than 40 years’ experience working through some of the most complex synthetic pathways to deliver you high quality research materials – including our popular AZBT impurity standards for valsartan, losartan and irbesartan. We can also offer a range of materials to aid your analysis of nitrosamine impurities, including NDMA, NDEA, NMEA and NDNPA - helping verify that your drug products comply with the relevant International Council for Harmonisation thresholds.

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