Current Published Literature
The contamination of valsartan and other sartans, Part 2: Untargeted screening reveals contamination with amides additionally to known nitrosamine impurities.
The recent incidences of contaminated valsartan drug products gave rise to review the suitability of current impurity profiling workflows. Researchers utilized a a generic untargeted approach allowed for the discrimination of different batches, different production sites, and differences after changes in the production process. This new untargeted approach applied revealed two new impurities in various sartans drug products: valeramide and N,N-dimethylvaleramide.
The contamination of valsartan and other sartans, Part 1: New findings
In July 2018 one of the bestselling antihypertensive agents valsartan, manufactured in China was found to be contaminated by the "probably carcinogenic" nitrosamine N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). Unfortunately, early measurements were performed by GC-MS or GC-MS/MS, which does not reach the sensitivity needed to find and quantitate trace levels of NDMA and NDEA. Though highly sensitive LC-MS/MS method with APCI ionization has been developed.
Short commentary on NDMA (N-nitrosodimethylamine) contamination of valsartan products.
After the guidance for the control of mutagenic impurities (ICH M72) was first introduced during 2014 many observers, across the pharmaceutical industry and various world-wide regulatory agencies had assumed that control of impurities in pharmaceuticals was a done deal. Robust processes to assess the possibility for mutagenic impurity formation (real and potential) were in place across industry. It was therefore surprising to many that in the middle of 2018, EMA (European Medicines Agency) announced it was “reviewing medicines containing valsartan drug substance supplied by Zhejianjg Huahai following the detection of an impurity”.
Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities.
This article reviews the potential gap area in current pharmaceutical industry practice that might have led to the NMDA and NDEA impurities escaping the drug manufacturer's and FDA's attention. Current industry practice which focuses on controlling the impurities above reporting threshold. ICH Q3A and FDA guidance on genotoxic and carcinogenic impurities needs to be integrated so that it begins by evaluating if the manufacturing process has the potential to generate toxic impurities. Such as step would help to determine the process was safe without the risk of generating mutagenic and carcinogenic impurities.
Mutagenic impurities: a done deal?
Most observers, in both industry and the various worldwide regulatory agencies, had thought that mutagenic impurities were a ‘done deal’ and reduced to practice. The mutagenic impurity guidance (ICH M71 ) had been first introduced in 2014 and subsequently updated at the beginning of 2017 (ICH M7(R1).
Valsartan recall: global regulatory overview and future challenges
In the world of regulatory sciences, such incidents are common and observed by many drug substance manufacturers during routine and stress testing and even after marketing of the product during real-time stability and post marketing analysis. National regulatory bodies should take immediate steps to ensure the provision of correct information to healthcare providers and the general public, which in this case seemed to be missing in various countries
Valsartan Induced Melanoma?! First Description in Medical Literature!
The content of probable carcinogens, such as NDMA or NDEA in the drug valsartan (ARBs), causes the product to be withdrawn from the market. We present a 70-year-old patient who has been on systemic therapy with a combined drug of amlodipine and valsartan since 2008 and only valsartan from 2015. It is proposed that the treatment with valsartan may have possibly triggered the development of melanoma.