European Medicines Agency (EMA) announces that European Union (EU) authorities are placing the Chinese company Zheijiang Huahai under increased supervision following European and United States (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 good manufacturing practice (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 authorisation holders for EU medicines will be required to perform additional tests on all active substances supplied by Zhejiang Huahai.
In Jul 2018, the detection of impurities – N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) – in valsartan from Zhejiang Huahai led to an EU-wide review of all valsartan medicines. The review was subsequently extended to other ‘sartan’ medicines when very low levels of NDEA were found in losartan made by Hetero Labs in India.
Both NDMA and NDEA, which have not been found in any of Zheijiang Huahai’s other products, are classified as probable human carcinogens (substances that could cause cancers). A preliminary risk assessment for NDMA in valsartan indicated that the lifetime risk of cancer is low.
Low levels of NDEA have now also been found in a third sartan, irbesartan, made by another Indian company, Aurobindo Pharma. On 8 Oct 2018, the European Directorate for the Quality of Medicines & HealthCare (EDQM) suspended Aurobindo Pharma’s certificate of suitability to the monographs of the European Pharmacopoeia (CEP) effectively stopping the supply in the EU of medicines containing irbesartan from this company. National authorities in the EU are currently considering whether to recall medicines containing Aurobindo Pharma’s irbesartan from pharmacies as a precaution.
The review into the presence of impurities in sartans and their potential effects in patients is ongoing. EMA will continue working with national authorities, international partners and EDQM and will provide updates as more information becomes available.
Please refer to the following website in EMA for details:
http://www.ema.europa.eu/en/news/eu-authorities-take-further-action-ongoing-review-sartans-zheijiang-huahai-placed-under-increased
In Hong Kong, there are 253 registered pharmaceutical products containing valsartan (83 products), candesartan (19 products), irbesartan (64 products), losartan (70 products) and olmesartan (17 products). All products are prescription-only medicines.
Regarding impurities in valsartan, a public announcement was issued on 6 Jul 2018, and letters to inform local healthcare professionals were issued by the Department of Health (DH) on 6 Jul 2018, 9 Jul 2018, 25 Jul 2018 and 3 Aug 2018. Related news for the detection of impurities in sartan-containing products was also previously issued by various overseas drug regulatory authorities, and was posted on the Drug Office website since 6 Jul 2018, with the latest update posted on 6 Oct 2018.
In summary, there are four manufacturers, namely Zhejiang Huahai, Zhejiang Tianyu and Zhuhai Rundu in China and Hetero Labs Limited in India, reported to have detection of trace amounts of NDMA in the valsartan Active Pharmaceutical Ingredient (API) by various overseas drug regulatory authorities. The DH contacted the certificate holders of all registered valsartan products to follow up on the local impact regarding valsartan API produced by the above mentioned manufacturers.
For API produced by Zhejiang Huahai, there are 5 affected products (HK-61786, HK-61787, HK-61784, HK-61785 and HK-60794) marketed in Hong Kong. The DH instructed the certificate holders to recall all the products from the market as a precautionary measure on 6 Jul 2018, and the DH noted that all the recalls have been completed.
For API produced by Zhejiang Tianyu, amongst the registered pharmaceutical products containing valsartan, there is only one product namely Retoni Tablets 80mg (HK-65604) registered by Swiss Pharmaceutical Co Limited (Swiss Pharmaceutical) which has used API produced by Zhejiang Tianyu and is available in the local market. As confirmed with Swiss Pharmaceutical, the API was tested by the Taiwan Food and Drug Administration (TFDA) and the company has not received any notice from the TFDA for NDMA contamination. The DH collected samples of Retoni tablets for analysis and no NDMA was detected.
For API produced by Zhuhai Rundu and Hetero Labs Limited, the certificate holders confirmed that the valsartan products available in local market are not manufactured using API produced by Zhuhai Rundu or Hetero Labs Limited.
Regarding the announcements issued by various overseas drug regulatory authorities on the detection of the second impurity of NDEA in the valsartan API produced by Zhejiang Huahai, there should be no local impact as all valsartan products manufactured using API produced by Zhejiang Huahai have been recalled from the market.
Regarding the European Medicines Agency’s announcement on the detection of NDEA in losartan in the API produced by Hetero Labs Limited, and in irbesartan by Aurobindo Pharma in India, the DH has contacted the certificate holders of all registered candesartan, irbesartan, losartan and olmesartan products and will continue to follow up on the impact of NDEA impurities on the products available in the local market.
So far, the DH has received 14 cases of adverse drug reaction related to valsartan, candesartan, irbesartan, losartan and olmesartan. None of them are concluded to be related to the presence of NDMA and/or NDEA. The DH will keep vigilant on any further updates on the matter issued by overseas regulatory authorities.
Patients who are taking the above products should not stop taking the medicines, but should seek advice from their healthcare professionals as soon as possible for proper arrangement.
Ends/Tuesday, Oct 16, 2018
Issued at HKT 15:00
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