NDMA impurity in valsartan and other pharmaceutical products: Analytical methods for the determination of N-nitrosamines

Parr, Maria Kristina; Joseph, Jan Felix

doi:10.1016/j.jpba.2018.11.010

Cited by 119 publications

(66 citation statements)

References 168 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NDMA and other nitrosamines are common contaminants in low amounts in foods, beverages, cosmetics, water, tobacco products, and consumer goods (1)(2)(3)(4). In 2018, observations of NDMA and NDEA in angiotensin receptor blocker drugs (ARBs) led to recalls of batches of products which had unacceptable amounts of nitrosamines (5,6). Since the ARB nitrosamine impurities were discovered, there have been additional drugs found to contain nitrosamines in the parts-per-million (ppm or ng/mg) to parts-per-billion (ppb or pg/mg) range (e.g., ranitidine in 2019, metformin in 2020 (7)) each with unique properties in terms of the route and source of their presence.…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Marzan

et al. 2020

AAPS J

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Yang

Marzan

et al. 2020

AAPS J

View full text Add to dashboard Cite

show abstract

“…Recently, NDMA and other NAs, e.g., N-nitrosodiethylamine (NDEA), have been detected in several pharmaceuticals, including sartans (valsartan, losartan, and candesartan) and raniditine [12,13]. The detection of the NDMA impurity was incidental and happened while performing other tests [14]. Improvement in the analytical techniques enabled the detection of NAs concentrations as low as 1 ng/L [15].…”

Section: Introductionmentioning

confidence: 99%

N-Nitrosodimethylamine Contamination in the Metformin Finished Products

2020

View full text Add to dashboard Cite

A GC–MS/MS method with EI ionization was developed and validated to detect and quantify N-nitrosodimethylamine (NDMA) and seven other nitrosamines in 105 samples of metformin tablets from 13 different manufactures. Good linearity for each compound was demonstrated over the calibration range of 0.5–9.5 ng/mL. The assay for all substances was accurate and precise. NDMA was not detected in the acquired active pharmaceutical ingredient (API); however, NDMA was detected in 64 (85.3%) and 22 (91.7%) of the finished product and prolonged finished product samples, respectively. European Medicines Agency recommends the maximum allowed limit of 0.032 ppm in the metformin products. Hence, 28 finished products and 7 pronged dosage products were found to exceed the acceptable limit of daily intake of NDMA contamination. The implications of our findings for the testing of pharmaceutical products are discussed.

show abstract

“…Since the valsartan and losartan products produced by several pharmaceutical companies were proven to contain potential contamination with carcinogenic nitrosamine impurities, namely, N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and N-nitroso-N-methyl-4-aminobutyric acid (NMBA) ( Fig. 1), FDA has recalled them since July 2018 (Parr and Joseph 2019).…”

Section: Introductionmentioning

confidence: 99%

Development of a sensitive and stable GC-MS/MS method for simultaneous determination of four N-nitrosamine genotoxic impurities in sartan substances

Liu¹,

Xie²,

Mai

et al. 2021

J Anal Sci Technol

View full text Add to dashboard Cite

Recently, N-nitrosamines have been unexpectedly found in generic sartan products. Herein, we developed a sensitive and stable GC-MS/MS method with multiple reactions monitoring mode for the simultaneous determination of four N-nitrosamines in sartan substances, namely, N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosodibutylamine, and N-nitrosodiisopropylamine. The conditions of gas chromatography and mass spectrometry were optimized. The method was validated according to the International Council for Harmonization guidelines in terms of sensitivity, linearity, accuracy, precision, specificity, and stability. The limits of detection of N-nitrosamines in sartan substances ranged from 0.002 to 0.150 ppm, and the corresponding limits of quantification were in the range of 0.008-0.500 ppm, which met the sensitivity requirements for the limits set by the Food and Drug Administration of the United States. The internal standard curve of four N-nitrosamines showed good linearity of regression coefficients over 0.99. The recoveries of N-nitrosamines in selected sartan drugs ranged from 87.68 to 123.76%. The intraday and interday relative standard deviation values were less than 9.15%. Therefore, this proposed method exhibited good sensitivity and precision, high accuracy, and fast analysis speed, which provide a reliable method for quality control of N-nitrosamines in sartan products.

show abstract

NDMA impurity in valsartan and other pharmaceutical products: Analytical methods for the determination of N-nitrosamines

Cited by 119 publications

References 168 publications

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

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

N-Nitrosodimethylamine Contamination in the Metformin Finished Products

Development of a sensitive and stable GC-MS/MS method for simultaneous determination of four N-nitrosamine genotoxic impurities in sartan substances

Contact Info

Product

Resources

About