A Cautionary Tale: Quantitative LC-HRMS Analytical Procedures for the Analysis of N-Nitrosodimethylamine in Metformin

Abstract

A private testing laboratory reported in a Citizen Petition (CP) to FDA that 16 of 38 metformin drug products they tested had N-nitrosodimethyl amine (NDMA) amounts above the allowable intake (AI) of 96 ng/day. Because the FDA had been monitoring drugs for nitrosamines, orthogonal analytical procedures had been developed, validated and applied to detect the following nitrosamines in metformin drug products (if present): (i) NDMA (with a dedicated method) or (ii) NDMA (with a second confirmatory method), Nnitroso-diethylamine (NDEA), N-ethyl-N-nitroso-2-propanamine (NEIPA), N-nitrosodiisopropylamine (NDIPA), N-nitroso-din -propylamine (NDPA), N-nitrosomethylphenylamine (NMPA), N-nitroso-din -butylamine (NDBA) and N-nitroso-N-methyl-4-aminobutyric acid (NMBA). In contrast to the private laboratory results, FDA testing on the same set of 38 samples with orthogonal procedures observed amounts over the AI in only 8 of the 38 products and generally observed lower values than reported by the private testing laboratory. As described here, the investigation into the cause of the discrepancy revealed that N,N-dimethylformamide (DMF) can interfere with NDMA measurements. The data showed that the use of sufficient mass accuracy in the data acquisition and appropriate mass tolerance setting in the data processing to assure the selectivity of mass spectrometry measurements of NDMA in the presence of co-eluting DMF was necessary to prevent overestimation of the level of NDMA in metformin drug products. Overall, care should be taken to assure the necessary specificity in analytical procedures for adequate assessment of the nitrosamine level in drug products that also contain DMF or other potential interfering substances.

Empagliflozin Effectively Attenuates Olanzapine-Induced Body Weight Gain in Female Wistar Rats

“…However, metformin administration has shown serious gastrointestinal side effects resulting in discontinuation of the drug in approximately 5% patients (Rena et al, 2017;Siavash et al, 2017). More recently, FDA alerted clinicians and patients regarding the voluntary recalls of some extended-release (ER) dosage form of metformin drugs because of the presence of a cancer-causing agent N-nitrosodimethylamine (NDMA) above the acceptable intake limit (FDA, 2020;Yang et al, 2020). This encouraged the evaluation of other antidiabetic agents as adjunctive therapies to minimize antipsychotic-induced BWG.…”

Quality Testing of Difficult-to-Make Prescription Pharmaceutical Products Marketed in the US

“…Furthermore, the sampling for this study was completed prior to several of the FDA’s efforts to improve drug quality. 21 , 22 , 23 , 24 This study focused on prescription pharmaceuticals legally marketed in the US. The safety of counterfeit drugs or drugs purchased online cannot be guaranteed and may present consumers with a health risk from substandard products.…”

Advances in high‐resolution mass spectrometry applied to pharmaceuticals in 2020: A whole new age of information

“…In collaboration with pharmaceutical companies, the FDA developed, validated, and made publicly available a UHPLC‐HRMS method for the detection and quantitation of NDMA in metformin drug products 74 . Recently, high levels of NDMA above the acceptable limits were reported for 16 of 38 metformin products using this method by a private laboratory in a Citizen Petition file 75 . To confirm these findings, the FDA tested the 38 lots using three orthogonal methods with one being the same method used as the private laboratory, however, only 8 were found to be above the limit.…”