FDA examines solvent used in production process.
Recalls of valsartan, the API found in Novartis’ blood-pressure treatment, Diovan, and its generic descendant valsartan, have underscored vulnerabilities in the way that the pharmaceutical industry assesses and manages global supply-chain risks.
The recalls were initiated in the United States and European Union in July 2018 after N-nitrosodimethylamine (NDMA) was found in API used to manufacture generic angiotensin receptor blockers (ARBs). The nitrosamine, classified as a probable carcinogen, was found in active ingredients manufactured by Zhejiang Huahai
Pharmaceutical Company, an API supplier in China, and a number of generic products using it were removed from pharmacy shelves.
The FDA released analytical methods for detecting the contaminant in August 2018. Later, regulators in Germany found low levels of another nitrosamine, N-nitrosodiethylamine (NDEA), in one batch of losartan manufactured in India by Hetero Labs.
Zhejian Huahai had also detected NDEA in some lots of its valsartan API and alerted the FDA; subsequent testing by the FDA confirmed its presence in several lots of valsartan API and in three lots of valsartan sold by Torrent Pharmaceuticals (3), that used that API. Now the FDA is looking into more “sartan” products including candesartan, irbesartan, losartan, and olmesartan.
In fact, over the past couple of weeks, nearly 90 lots of Losartan potassium tablets made by Hetero Labs in India and distributed by Camber Pharmaceuticals were recalled Thursday due the discovery of trace amounts of N-Nitroso N-Methyl 4-amino butyric acid (NMBA), a probable carcinogen.
The science behind this problem points to a change in solvents used to get a higher yield of the active ingredient.
According to Derek Lowe, a Ph.D. medicinal chemist who has spent years working on preclinical drug discovery in the pharmaceutical industry, “ZHP themselves appear to have introduced a cheaper, higher-yielding route using just sodium azide and zinc chloride in an aprotic solvent like DMF (here’s what seems to be the patent on that route). The excess azide is consumed at the end of the process using sodium nitrite – but nitrite under acidic conditions will give you some nitrous acid, and nitrous acid will react with secondary amines to give you N-nitrosoamines. That would seem to be the root of the problem.” (Click to read Dr. Lowe’s entire commentary: https://blogs.sciencemag.org/pipeline/archives/2019/01/04/the-sartan-contamination-story)
Since so many patients are on these ARB’s, it makes sense that the FDA would examine all of them to see if the same problems exist. To date, there have been no recalls or testing planned for eprosartan, telmisartan, or the last branded ARB, azilsartan (Edarbi). This may have something to do with where they are manufactured or the solvents that they are using.
Diabetes In Control will keep you updated as this story progresses.