2021 FDA Science Forum
Pharmaceutical Analysis and Characterization of Nitrosamine Impurities Within Angiotensin II Receptor Blocker Drug Products
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Contributing OfficeCenter for Drug Evaluation and Research
Abstract
Introduction
Angiotensin II receptor blockers (ARBs) are a class of pharmaceutical drug products used to treat hypertension and congestive heart failure. On July 13, 2018, FDA issued a series of recalls for several lots of valsartan (an ARB) that contained the API originating from Zhejiang Huahai Pharmaceuticals. They were found to contain N-Nitrosodimethylamine (NDMA), a potent carcinogen. Other pharmaceutical drug products were later discovered to have nitrosamines contamination.
Methods
OTR scientists were asked by the FDA ARB Taskforce to develop a gas chromatography-mass spectrometer headspace method in August-2018 to analyze Valsartan drug products for an NDMA impurity at sub ppm levels. Three additional nitrosamine impurities were later identified: N-nitrosodiethylamine, N-Nitrosodiisopropylamine and N-ethyl-N-nitroso-2-propanamine. From a technical perspective, the structurally related nitrosamine analytes posed a significant analytical challenge and there were no analytical methods available as a starting point for the four analytes in combination. In January 2019, OTR scientists rapidly developed and validated a highly novel GC-MS-HS method to screen and analyze the four nitrosamine impurities and this method was implemented to provide the Agency a comprehensive analytical tool for its on-going Public Health response to the valsartan incident.
Results
Chromatographic separation was achieved in 24 mins with linearity of 0.05 ppm to 100 ppm and correlation coefficients for standard calibration curves were >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 effect and 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.
Conclusions
The regulatory impact of this work was significant and has provided FDA regulators with analytical tools to rapidly monitor ARB drug products as well as other related pharmaceutical drug products. These methods have been shared with regulators throughout the world. As result of the rapid implementation of new characterization methods, the Agency and its worldwide regulatory collaborators can more effectively address the response to the valsartan incident and other contaminated related pharmaceutical drug products.
