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Review of common medicines used to treat hypertension – valsartan – due to detection of impurity, N-nitrosodimethylamine (NDMA), a probable human carcinogen! (Part V)

  • 3 октября 2018
  • active substance, APCI-UHPLC-MS/MS, API, cancer, candesartan, carcinogen, CEP, drug product, EDQM, EMA, FDA, formation, GMP, headspace GC/MS, Hetero Labs Limited, HPLC-UV, human, hypertension, import alert, impurity, inspection, intermediate, irbesartan, losartan, MAH, manufacturer, manufacturing, manufacturing site, marketing authorisation holders, medicinal product, medicines, method, N-nitrosodimethylamine, NDEA, NDMA, nitrosamine, non-compliance, N‑nitrosodiethylamine, olmesartan, OMCL, patient, process, recall, review, risk, sartans, specific ring structure, statement, suspension, test, tetrazole, valsartan, Zhejiang Huahai Pharmaceuticals,

ASE Pharma Solutions



The European Medicines Agency (EMA) is expanding its review of impurities in valsartan following the detection of very low levels of N-nitrosodiethylamine (NDEA) in another active substance, losartan, made by Hetero Labs in India.

As a result of the detection of this impurity by German authorities, the review will now include medicines containing four other ‘sartans’, namely

– candesartan

(to check CEP holders and current status of CEP, please click here),

– irbesartan

(to check CEP holders and current status of CEP, please click here),

– losartan

(to check CEP holders and current status of CEP, please click here) and

– olmesartan

(to check CEP holders and current status of CEP, please click here).

Like valsartan, these active substances have a specific ring structure (tetrazole) whose synthesis could potentially lead to the formation of impurities such as NDEA (NDEA was detected in some of the recalled valsartan products). Other medicines of the class which do not have this ring are not included in the review.

Both NDEA and a related compound N-nitrosodimethylamine (NDMA) are classified as probable human carcinogens (substances that could cause cancer). How these impurities came to be present during the manufacture of sartans is yet to be fully established and is being evaluated in the ongoing review.

patient nd doctor


Based on the trace amounts of NDEA seen so far in one batch of losartan from Hetero Labs, there is no immediate risk to patients. Patients are therefore advised not to stop taking losartan or other sartan medicines without speaking to their doctor.

Further tests are required to determine the extent of the contamination and whether impurities are present in sartan medicines above levels that can be considered acceptable.

An inspection by EU authorities in collaboration with EDQM has found that Zhejiang Huahai did not comply with Good Manufacturing Practice (GMP) in the manufacture of valsartan at the Chuannan site in Linhai, China.


As a result, a statement of non-compliance for the manufacture of valsartan has been issued and the site is no longer authorised to produce valsartan (and its intermediates) for EU medicines. This means that marketing authorisation holders in the EU are prohibited from using valsartan from the site for the production of medicines.

This action comes after product recalls and the subsequent suspension of the company’s CEP for valsartan in July 2018.

The latest European inspection, which focused on the manufacture of valsartan and was completed in September 2018, found several weaknesses at Zhejiang Huahai, including deficiencies in the way the company investigated the presence of NDMA and another impurity N-nitrosodiethylamine (NDEA) in its valsartan products.

The non-compliance statement, which applies only to the manufacture of valsartan, is available here.

EMA and national authorities in the EU are now actively considering all available evidence, including the outcomes of the European and US inspections, as part of the ongoing process of evaluating the Zhejiang Huahai manufacturing site. This will determine what further EU action may be required for other active substances produced by the site.



OMCLs release three methods for determination of NDMA in sartans:

GC analysis+analyst

the method established by the Irish OMCL in Galway – the PALG method is based on Headspace-GC-MS (single quad) and applicable to the determination of NDMA in Active Pharmaceutical Ingredients (API) and corresponding powdered tablets of the sartan group,

the method established by the French OMCL in Montpellier – the ANSM method uses HPLC-UV as general analytical principle for the determination of NDMA in valsartan (API and drug product),

the method established by the German OMCL in Karlsruhe – the CVUA Karlsruhe method is based on APCI-UHPLC-MS/MS and applicable to the detection and quantitative determination of NDMA in valsartan drug products.



FDA placed Zhejiang Huahai Pharmaceuticals on import alert on September 28, 2018, to protect U.S. patients while the active pharmaceutical ingredient (API) manufacturer fully determines how impurities were introduced into its API and remediates its quality systems. The import alert stops all API made by ZHP and finished drug products made using ZHP’s API from legally entering the United States. FDA’s action follows a recent inspection at ZHP’s facility.

FDA reminds manufacturers that it is their responsibility to develop and use suitable methods to detect impurities, including when they make changes to their manufacturing processes. If a manufacturer detects new or higher levels of impurities, they should fully evaluate the impurities and take action to ensure the product is safe for patients.

We have already informed on our website about the ongoing review of valsartan medicines due to the detection of impurity N-nitrosodimethylamine (NDMA) as well as suspensions of CEPs by EDQM in Part I, Part II, Part III and Part IV entries.

Sources: EMA, EDQM, FDA