EMA Expands Contamination Investigation Into Other “Sartan” API Products

The European Medicines Agency (EMA) is evaluating four more “sartan” active pharmaceutical ingredients (APIs) in hypertension medicines marketed in the EU in addition to its ongoing investigation into impurities found in products containing the API, valsartan. The additional APIs are candesartan, irbesartan, losartan and olmesartan, which along with valsartan, are used in a class of medicines known as angiotensin-II-receptor antagonists (also known as “sartans”).

The EMA began its initial investigation into the “sartans” when the agency learned that Zhejiang Huahai Pharmaceuticals (ZHP), a Linhai, China-based pharmaceutical company, had detected N-nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA), two probable human carcinogens, in several batches of its valsartan API. The detection of these two impurities led to an EU-wide review of all valsartan medicines marketed in the EU. The review was subsequently extended to other “sartan” medicines when very low levels of NDEA were found in losartan made by Hetero Labs, a Hyderabad, India-headquartered pharmaceutical company.

Low levels of NDEA have now also been found in a third “sartan,” irbesartan, made by another Indian company, Aurobindo Pharma, a Hyderabad, India-headquartered generics and active pharmaceutical ingredients manufacturer. In October 2018, the European Directorate for the Quality of Medicines & HealthCare (EDQM) suspended Aurobindo Pharma’s Certificate of Suitability (CEP) to effectively stop the supply in the EU of medicines containing irbesartan from the company. In addition, national authorities in the EU are considering whether to recall medicines containing Aurobindo Pharma’s irbesartan from pharmacies as a precaution.

Additionally, EU authorities are placing Zheijiang Huahai under increased supervision following European and US inspections, which revealed weaknesses in quality management at the company’s Chuannan site in Linhai, China. The inspection findings included deficiencies in the way the company investigated impurities in its valsartan products and led EU authorities to issue a statement of non-compliance with GMP, prohibiting the use of its valsartan in EU medicines. This latest action means that EU authorities will supervise the manufacture of other active substances produced by Zhejiang Huahai more closely. Authorities will monitor corrective measures being implemented by the company on a regular basis and increase the frequency of inspections of the site. In addition, marketing authorization holders for EU medicines will be required to perform additional tests on all active substances supplied by Zhejiang Huahai.

The review into the presence of impurities in “sartans” and their potential effects in patients is ongoing. The EMA says it will continue working with national authorities, international partners, and EDQM and will provide updates as more information becomes available.

The review of valsartan medicines was triggered by the European Commission in July 2018 and was extended in September 2018 to include medicines containing candesartan, irbesartan, losartan and olmesartan. The review is being carried out by EMA’s Committee for Medicinal Products for Human Use (CHMP). The CHMP opinion will then be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU member states.

Source: European Medicines Agency




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