Angiotensin II receptor blockers (ARBs), also known as angiotensin II receptor antagonists, AT1 receptor antagonists or sartans, are a class of pharmaceuticals used to treat hypertension, diabetic nephropathy and congestive heart failure. Recently, FDA issued a recall of all valsartan drug products (one of the sartans) that contained the active pharmaceutical ingredient (API) produced by Zhejiang Huahai Pharmaceuticals. The Office of Testing and Research at USFDA was asked to develop a comprehensive analytical method to analyze the nitrosamine impurities including N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA) and N-nitrosoethylisopropylamine (NEIPA), from valsartan drug substance and drug product. Headspace GC/MS method was developed using a DB-Wax fused silica capillary column and fully validated per the USP Category I for Assay and ICH Q2R1 guidance for linearity, accuracy, precision, recovery and stability. Deuterated internal standards, NDMA-d6 and NDEA-d4, were employed for the quantification of the impurities. For the analysis of nitroso impurities, the valsartan API or the drug product was placed in a 20 mL GC vial containing 4.5 mL of DMSO solvent and the internal standard solution mix. The chromatographic separation was achieved in 24 mins with linearity of 0.05 ppm to 100 ppm and Correlation coefficients for standard calibration curves were &gt;0.99. Intra- and inter-day accuracy and precision of all analytes in DMSO were found to be acceptable with RSD% ≤ 10% and accuracy ≥ 85%. Matrix selectivity was tested in two different lots of valsartan API and no interference signal was observed at the retention time of the analyte of interest. Method recovery and matrix effect were tested for all quality control standards in DMSO and 500 mg blank valsartan API and were found to be acceptable with average analytes recovery ≥ 10.4% and matrix effect ≤ 19.9%. The method has been successfully applied to valsartan API and drug product to detect and quantify possible contamination of nitrosamine compounds; NDMA, NDEA, NDIPA, and NEIPA.

Development, validation and implementation of a Headspace GC/MS method for screening and quantification of NDMA, NDEA, NDIPA and NEIPA impurities in valsartan drug substances and drug products

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.