The contamination of valsartan and other sartans, part 1: New findings

Abstract

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), followed by the detection of N-nitrosodiethylamine (NDEA) by us and others soon after. Our work also revealed that two additional non-nitrosamine contaminations valeramide (VLA) and N,N-dimethylvaleramide (VLA-DEM) were present in sartan tablets. Early measurements by others and us 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. A highly sensitive LC-MS/MS method with APCI ionization was developed to detect and quantitate NDMA, NDEA, VLA and VLA-DIM in 152 sartan tablets from 8 structurally different sartan molecules. Good linearity for each compound could be demonstrated over calibration ranges in the lower nanograms. The assay for all substances was accurate and precise. With this method, a LLOQ of 0.00026 ppm for NDMA and 0.00013 ppm for NDEA could be achieved. NDMA, NDEA, VLA and VLA-DIM were found in 21 (13.8%), 9 (5.9%), 13 (8.6%) and 7 (4.6) % of the tablets, respectively. In addition, one candesartan product was found contaminated with NDEA. The implications of our findings for the testing of pharmaceutical products are discussed.

Keywords: API; Contamination; EMA; FDA; GC–MS; High sensitivity; LC–MS/MS; N,N-dimethylvaleramide; NDEA; NDELA,NMEA; NDMA; NDPA; NDiPA; NPip; Nitrosamines; Sartans; Tablets; Valeramide; Validation.