Review of common medicines used to treat hypertension – valsartan – due to detection of impurity, N-nitrosodimethylamine (NDMA), a probable human carcinogen! (Part III)
- 29 августа 2018
- active substance, API, cancer, carcinogen, CEP, detection, EDQM, FDA, final product, headspace GC/MS, Hetero Labs Limited, holder, human, hypertension, impurity, investigation, manufacturer, manufacturing, medicinal product, medicines, method, N-nitrosodimethylamine, NDMA, nitrosamine, OMCL, patient, process, quantification, recall, review, risk, suspension, Torrent Pharmaceuticals Limited, valsartan, Zhejiang Changming Pharmaceutical Co. Ltd., Zhejiang Huahai Pharmaceuticals, Zhejiang Tianyu Pharmaceutical Co. Ltd.,
The EDQM is continuing the investigations and actions which started in July 2018 to address the issue related to the detection of a nitrosamine (N-nitrosodimethylamine (NDMA)) in a source of active substance valsartan.
Following the complete review of the manufacturing information submitted in all Certificate of suitability (CEP) applications for valsartan and other structurally related active substances (e.g. losartan, olmesartan medoxomil, candesartan cilexetil), the EDQM has firstly contacted those CEP holders whose substances may present a contamination risk and has requested that they investigate and address the possible presence of NDMA. As a second step, all other holders of CEPs for these substances have been requested to evaluate their manufacturing process too and to confirm that their products do not present any risk of contamination.
The EDQM has been assessing the data received and is informing CEP holders by letter as soon as the evaluation of their data is completed. Based on the results, it seems that a limited number of sources of valsartan and other structurally related active substances may present a risk of contamination. Adequate measures and controls are being put in place to ensure the impurity is eliminated or reduced to an acceptable limit.
Following the suspension of the CEP on valsartan held by Zhejiang Huahai Pharmaceutical Co. Ltd, the EDQM has also decided to suspend the following Certificates (to check the current status of CEPs, please click here):
– CEP 2013-159/Valsartan held by Zhejiang Tianyu Pharmaceutical Co. Ltd.
– CEP 2016-069/Valsartan held by Hetero Labs Ltd.
– CEP 2014-162/Valsartan held by Zhejiang Changming Pharmaceutical Co. Ltd.
The decision was either triggered by the detection of some levels of NDMA in valsartan (albeit at much lower levels than those found in the active substance manufactured by the company Zhejiang Huahai), or as a precautionary measure in case insufficient information was received from the CEP holder or in case the CEP holder claimed that their product is not currently supplied to the market. The suspension of these CEPs is intended to reduce risks for the patients in all countries where the CEPs may be referred to, including beyond Europe. The EDQM’s international partner authorities and institutions have been informed accordingly.
Since the issue was identified, Official Medicines Control Laboratories (OMCLs) of the General European OMCL Network, which is coordinated by the EDQM, have also been involved in the activities. In the meantime, this Network has developed methods for the specific testing of nitrosamines in sartans on the basis of 2 different analytical principles. It established risk-based sampling plans and provided the first independent test results of batches of valsartan and related medicinal products to European authorities. The Network has also supported European authorities in evaluating the methods used by concerned companies to test their active substances.
On 20, 22 and 24 August 2018, FDA has updated again the list of valsartan products under recall to incorporate voluntary recall of valsartan-containing drug products, due to the detection of impurity N-nitrosodimethylamine (NDMA in the active pharmaceutical ingredient (API) manufactured by Zhejiang Huahai Pharmaceuticals, distributed in the U.S. by Torrent Pharmaceuticals Limited.
FDA recently learned Torrent used affected valsartan active pharmaceutical ingredient (API) manufactured by Zhejiang Huahai Pharmaceuticals. FDA testing confirmed NDMA in some Torrent products.
Additionally, FDA is releasing a gas chromatography-mass spectrometry (GC/MS) headspace method for manufacturers and regulators to detect and quantify NDMA in valsartan API and finished drug products. The agency is using this method to test potential NDMA-containing APIs and drug products. This method should be validated by the user if the resulting data are used to support a required quality assessment of the API or drug product, or if the results are used in a regulatory submission.
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 and Part II entries.
Source: EDQM, FDA