Nitrocellulose blister material as a source of N-nitrosamine contamination of pharmaceutical drug products

Golob, Nejc; Grahek, Rok; Ross, Malcolm; Roškar, Robert

doi:10.1016/j.ijpharm.2022.121687

Cited by 18 publications

(9 citation statements)

References 18 publications

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“…In our case, as mentioned above, the NDMA content in the API was below the detection limit. In addition, nitrocellulose, which is considered to be a nitrosating agent, was not used in the packaging materials and inks used. Based on these two points, we considered the possibility of (a) an “API manufacturing process” to be unlikely and the possibility of (c) “during storage after formulation” to be small.…”

Section: Resultsmentioning

confidence: 99%

“…NDMA contamination of metformin has a significant impact on both patients and drug manufacturers. Pharmaceutical companies searched for the root cause to avoid NDMA contamination , and have reported that nitrite in excipients, − nitrite in water used in manufacturing, and nitrocellulose in packaging materials may be nitrosating agents. The conditions for the formation of nitroso amines have also been studied and reported. − …”

Section: Introductionmentioning

confidence: 99%

“…To elucidate the root cause of NDMA contamination, detailed data on metformin drug products manufactured at our Osaka and Yamagata factories in Japan were analyzed. It was found that no NDMA contamination was detected in the API and that the involvement of excipients, , water, and Press Through Pack (PTP) aluminum printing inks was considered small.…”

Section: Introductionmentioning

confidence: 99%

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N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO₂

Fukuda,

Kondo,

Fukumoto

et al. 2023

Org. Process Res. Dev.

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In 2019, N-nitrosodimethylamine (NDMA) exceeding the maximum allowable intake (96 ng/day) was detected in metformin drug products in Singapore, and since then, many of the drug products have been voluntarily recalled globally for the same reason. In our company, the analysis of the metformin drug products showed that small batches (1.9%) of products contained the excessive level of NDMA, so we investigated the root cause of NDMA formation. As a result, we found that dimethylamine (DMA) in the active pharmaceutical ingredient (API) used in the manufacturing process and nitrogen dioxide (NO 2 ) in the atmosphere had considerable influence on the formation of NDMA in metformin drug products. The results of a model experiment simulating a fluidized bed granulator also supported the hypothesis that atmospheric NO 2 introduced into the granulator Nnitrosated DMA in the API to form NDMA.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO₂

Fukuda,

Kondo,

Fukumoto

et al. 2023

Org. Process Res. Dev.

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“…Some studies suggested that these impurities are produced during the drug synthesis and/or during drug degradation, prompting further investigations into other pharmaceuticals, such as ranitidine medicines. , In the case of sartan medicines, the occurrence of NAs can be related to reagents and subproducts formed during the drug synthesis, as the use of azide salts and nitrous oxides in the tetrazole ring synthesis step. , Moreover, the use of N,N-dimethylformamide as solvent, and triethylamine as reagent in this synthesis can promote NAs formation as subproducts. In some cases, drug degradation can be related to the formation of new NAs, as indicated in ranitidine and nizatidine medicines. , FDA (U.S. Food and Drug Administration) observed that the content of N-nitrosodimethylamine (NDMA) increased with an expiration date of these medicines, thus the drug degradation might originate NAs. , Additionally, the European Medicine Agency reported that interaction between the medicine tablets and the lidding foils as packing material, such as nitrocellulose, might be a route of NAs formation …”

Section: Introductionmentioning

confidence: 99%

An Agile and Accurate Approach for N-Nitrosamines Detection and Quantification in Medicines by DART-MS

Batista Junior,

Bernardo,

Rocha

et al. 2024

J. Am. Soc. Mass Spectrom.

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N-nitrosamines (NAs) are prevalent mutagenic impurities in various consumer products. Their discovery in valsartan-containing medicines in 2018 prompted global regulatory agencies to set guidelines on their presence and permissible levels in pharmaceuticals. In order to determine the NAs content in medicines, efficient and sensitive analytical methods have been developed based on mass spectrometry techniques. Direct analysis in real time-mass spectrometry (DART-MS) has emerged as a prominent ambient ionization technique for pharmaceutical analysis due to its high-throughput capability, simplicity, and minimal sample preparation requirements. Thus, in this study DART-MS was evaluated for the screening and quantification of NAs in medicines. DART-MS analyses were conducted in positive ion mode, for both direct tablet analysis and solution analysis. The analytical performance was evaluated regarding linearity, precision, accuracy, limits of detection, and quantification. The DART-MS proved to be suitable for the determination of NAs in medicines, whether through direct tablet analysis or solution analysis. The analytical performance demonstrated linearity in the range from 1.00 to 200.00 ng mL −1 , limits of quantification about 1.00 ng mL −1 , precision and accuracy lower than 15%, and no significant matrix effect for six drug-related NAs. In conclusion, the DART-MS technique demonstrated to be an alternative method to determine NAs in medicines, aligning with the principles of green chemistry.

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“…10 The nitrocellulose blister materials used as key materials in printing primers, printing inks and over lacquers final product packaging are another source of NDMA. 6,11 Studies have shown that during the blistering process, nitrogen oxides (NOx) released from thermal decomposition of nitrocellulose can undergo the nitrosating process with secondary amines from printing inks. The trace level of NDMA permeates from the inner surface of the foil into tablets.…”

mentioning

confidence: 99%

Analysis of N‐nitrosodimethylamine in metformin hydrochloride products by high‐resolution accurate mass gas chromatography mass spectrometry

Kee

Zeng

et al. 2022

Rapid Comm Mass Spectrometry

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The high resolving power of the Orbitrap mass spectrometer in a highresolution accurate mass gas chromatography (HRAM-GC-MS) system provides greater selectivity and sensitivity for the identification and quantification of volatile analytes at low parts per billion (ppb) levels. Hence, it can be applied for the analysis of pharmaceutical impurities like N-nitrosodimethylamine (NDMA) in metformin hydrochloride products (METs).Methods: Different METs extracted by a dichloromethane/aqueous system were analyzed by HRAM-GC-MS under softer electron ionization (EI) at 30 eV. The accurate masses of NDMA and its internal standard NDMA-d6 were analyzed by full scan and targeted selected ion monitoring modes under 60 000 and 30 000 full width at half maximum at m/z 200, respectively. Data acquisition and processing were managed by Xcalibur and Trace Finder software, respectively.Results: Limits of detection (LOD) and quantification (LOQ) at 10 and 20 ng/g were achieved, which is below the allowed daily intake of 32 ng/g. The mass errors measured from experimental data were within ±2 ppm of the theoretical values over a period of a week. Sample analysis showed that 180 out of 212 samples (85%) were below LOD and 15 out of 212 samples (7 %) were within LOD and LOQ. Only 17 samples (8%) were found to be above LOQ, comprising one active pharmaceutical ingredient (API), five immediate-release METs and 11 extended-released METs. Amongst these, seven extended-release METs and one API exceeded the daily allowed intake, 32 ng/g. Conclusions:The validated method has been successfully applied for NDMA analysis in various forms of METs. The method is rather straightforward without an additional clean-up step. The scope can also be extended to other volatile impurities in finished pharmaceutical products. | INTRODUCTIONNitrosamines in pharmaceutical products were widely reported in 2019 with the finding of N-nitrosodimethylamine (NDMA) in angiotensin receptor blocker drugs. 1 This small compound has been classified as a probable human carcinogen by the International Agency for Research on Cancer. 2 Since then, there have been extensive collaborative studies carried out by regulatory agencies and pharmaceutical companies to determine the NDMA content in metformin hydrochloride products (METs) after being alerted by the United States Food and Drug Administration 3 and the European Medicine Agency. 4 METs have been used to treat patients with

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Nitrocellulose blister material as a source of N-nitrosamine contamination of pharmaceutical drug products

Cited by 18 publications

References 18 publications

N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO₂

N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO₂

An Agile and Accurate Approach for N-Nitrosamines Detection and Quantification in Medicines by DART-MS

Analysis of N‐nitrosodimethylamine in metformin hydrochloride products by high‐resolution accurate mass gas chromatography mass spectrometry

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Nitrocellulose blister material as a source of N-nitrosamine contamination of pharmaceutical drug products

Cited by 18 publications

References 18 publications

N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO2

N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO2

An Agile and Accurate Approach for N-Nitrosamines Detection and Quantification in Medicines by DART-MS

Analysis of N‐nitrosodimethylamine in metformin hydrochloride products by high‐resolution accurate mass gas chromatography mass spectrometry

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Product

Resources

About

N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO₂

N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO₂