N-nitroso-Duloxetine recall back in the news!

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Analytical Methods:

OMCL Network published NDSRIs Analytical Methods

The network of official medicines control laboratories (OMCL) published a series of analytical method for determination of nitrosamine drug substance-related impurities (NDSRIs) The German OMCL at the Landesamt für Gesundheit und Lebensmittelsicherheit (LGL) in Bavaria established the following methods: GC-MS/MS method for the determination of NTTP in sitagliptin/sitagliptin/metformin tablets LC-MS/MS method for the determination of N-nitroso-ramipril in ramipril tablets LC-MS/MS method for t…

Simple and Practical Method for the Quantitative High-Sensitivity Analysis of N-Nitroso Duloxetine in Duloxetine Drug Products Utilizing LC-MS/MS

Dr. Fukuda et al. from Towa Pharmaceutical Co., Ltd published a literature focusing on the testing method for N-nitroso duloxetine. Using LC-MS/MS they analyzed the trace amounts of NDSRIs by methanol extraction. https://pubs.acs.org/doi/10.1021/acsomega.4c00136 [image] You can check the Swissmedic method for Duloxetine. It is similar to Fukuda’s.

Duloxetine Impurity NDSRI

Hello All, anyone having experience working on NDSRIs of Duloxetine impurities like Nitroso Duloxetine Imp A, Nitroso Duloxetine Imp B, Nitroso Duloxetine Imp C, Nitroso Duloxetine Imp E and Nitroso Duloxetine Imp F.

Standards:

https://store.usp.org/product/1A04000

Limits:

AI for Nitroso-Duloxetine

Hello to everyone! Is anyone aware of Nitroso Duloxetine AI? I came across with an AI of 100ng/day. Is there any literature available? Thank you, Elena

Nitrosamines Published Limits -reference

[image] [Nitroso Fluoxetine] Based on above chemical similarity, AI for N-nitroso fluoxetine can be proposed as 100ng/day. @Yosukemino @Naiffer_Host @Diego_HM can you please provide input and guidance

Examining the Use of Surrogates in Combination with The Carcinogenic Potency Categorization Approach when Establishing Acceptable Intake Limits of N-Nitrosamine Impurities

Now the poster presented in SOT is available on the MutiCASE page. https://multicase.com/wp-content/uploads/2024/03/SOT2024_Poster1.pdf#new_tab According to Dr. Saiakhov, 21%(1,617) of 7,679 nitrosamines are classified as Cat.1 by CPCA. For 48%(790) of Cat.1 nitrosamine (1,617), the surrogate with the AI limit of 100 ng/day is supported by the software QSAR Flex. NNK and NTHP are mainly assigned as the surrogates. N-nitroso duloxetine and NNORT, N-nitroso-nortriptyline are shown as examples. R…

Nitrosamine impurities in medicines (presented at the ARCS Annual Conference 2024)

Dr. Helen Hughes from TGA presented at the ARCS Annual Conference. https://www.tga.gov.au/presentations/nitrosamine-impurities-medicines [image] I am interested in this slide. Nitrosamine A is likely to have the same molecular weight as N-Nitroso-Fluoxetine. I could not find a different surrogate with a TD50 of 0.537mg/kg/day.

Quantum Mechanical Assessment of Nitrosamine Potency -Pub

Follow-up paper: Estimation of Acceptable Daily Intake Values based on Modeling and In Vivo Mutagenicity of NDSRIs of Fluoxetine, Duloxetine and Atomoxetine - ScienceDirect Calculate C-N bond stretching frequency of the diazonium metabolite of the nitrosamine (measure for the bond dissociation energy and thus diazonium reactivity and thus likelihood of DNA alkylation) Build correlation with published TD50 data of justifiable analogues Calculate C-N bond stretching frequency for the NDSRI stud…

AI for Nitroso-Duloxetine

Hello to everyone! Is anyone aware of Nitroso Duloxetine AI? I came across with an AI of 100ng/day. Is there any literature available? Thank you, Elena

AMES Testing:

Optimizing the detection of N-nitrosamine mutagenicity in the Ames test -Pub

Dr. Heflich et.al from FDA published the literature on optimizing the Ames test. Highlights 12 small molecule nitrosamines and 17 NDSRIs were assessed for mutagenicity in the Ames test Different test protocols were evaluated for their effect on assay sensitivity. A combination of TA1535 and WP2 uvrA(pKM101) was able to detect all mutagenic nitrosamines In general, preincubations with 30% S9 produced higher mutagenic responses than 10% S9 In general, hamster liver S9 produced hig…

Recalls:

Nationwide recall of duloxetine

According to the article, Duloxetine Delayed-Release Capsules were recently recalled due to the presence of N-nitroso-duloxetine. The recalled medication was manufactured by Towa Pharmaceutical in Europe and distributed nationwide in the United States. 7,100 bottles were recalled so far. The amount of N-nitroso-duloxetine was above the proposed interim limit(600 ng/day) and FDA set risk as Class II. https://www.accessdata.fda.gov/scripts/ires/?Product=210449

FDA - Updated information on recommended AI for NDSRIs (23/Feb/2024) - Tables 2 & 3

According to the article, duloxetine capsules were recalled at a retail level. This recall was initiated due to the presence of N-nitroso-duloxetine above the interim limit. Duloxetine capsules distributed by Breckenridge Pharmaceutical, Inc. have been recalled

https://www.tga.gov.au/news/safety-alerts/safety-advisory-duloxetine