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  • Nitrosamine Impurities Trace in Metformin

    Metformin is a prescription drug broadly used alone or in combination with other medicines to treat type 2 diabetes. Metformin is widely used as an oral anti-diabetic drug. According to the World Health Organization (WHO), metformin is considered an essential medicine.

    A recent investigation of traces of nitrosamine impurities in metformin

    The Regulatory agency announced traces of nitrosamine present in generic drug substances and drug products, further FDA and EMA investigations also led to the detection of nitrosamine impurities in low levels of NDMA impurity in Metformin. FDA has been investigating nitrosamines’ presence in drug products and late 2019 became aware of NDMA in some metformin products in other countries.

    The Regulatory authorities started testing to determine whether the metformin supply in the U.S. was at risk as part of the ongoing investigation into nitrosamine impurities across medication types. In February 2020, they identified very low levels of NDMA in some of the samples but at that time no FDA-tested sample of metformin exceeded the acceptable intake limit for NDMA.

    The FDA would continue with its ongoing testing of metformin and other medications, if any levels of NDMA or other impurities were pointed out then prompt action would be taken. Recently the FDA alerted patients and healthcare professionals about the recall of extended-release (ER) metformin, the recalls of the lot may contain N-nitroso dimethylamine (NDMA) above the acceptable intake limit. FDA has published a recalled metformin list which includes the details about metformin products that have been recalled.

    In addition, National authorities and EMA are also assessing the effect of recent tests which found NDMA in some EU batches of metformin medicines used for diabetes, and test results on metformin in the EU are being awaited. In line with earlier advice patients should continue taking their metformin medicines as usual.

    Methods for the determination of various nitrosamines in sartans with tetrazole ring, ranitidine, and metformin have been developed by the Official Medicines Control Laboratories and are also available for reference on the EDQM (European Directorate for the Quality of Medicines & Healthcare website these may serve as starting point for the development and validation of analytical methods for the testing of other APIs and FPs.    

    Lab testing for the analysis of NDMA in metformin

    FDA continues to look into the presence of the NDMA (N-Nitrosodimethylamine) impurity in metformin approved for sale in the U.S. The testing by FDA has found NDMA in certain lots of ER (extended-release) metformin and recommends companies recall lots with levels of NDMA above the acceptable intake limit of 96 nanograms per day.

    FDA is also collaborating with international regulators to share testing results for metformin. For reference, consuming up to the acceptable daily intake limit, 0.096 micrograms (96 nanograms), of NDMA per day is considered reasonably safe for human ingestion based on lifetime exposure. NDMA may increase the risk of cancer if people are exposed to it above the acceptable level and over a long period but a person taking a drug that contains NDMA at-or-below the acceptable daily intake limit every day for 70 years is not expected to have an increased risk of cancer.

    The testing method has been published by FDA to furnish an option for the regulators and industry to detect NDMA impurities in metformin drug products and drug substances.

    (LC-HRMS): Liquid Chromatography-High Resolution Mass Spectroscopy method for the determination of NDMA in metformin drug product and drug substance, this method is used to quantitate N-nitroso-di-methylamine (NDMA) impurities in metformin drug substance and drug products.

    According to Liquid Chromatography-High Resolution Mass Spectroscopy (LC-HRMS), the method was developed and validated by the agency to determine the level of NDMA in metformin drug substances and drug products to assist the ongoing investigations. LC-HRMS method was developed and validated following the ICH Q2 (R2) for the detection and quantification of NDMA in metformin drugs.

    LC-ESI-HRMS: Liquid Chromatography-Electrospray Ionization-High Resolution Mass Spectrometry method for the determination of nitrosamine impurities in metformin drug product and drug substance.

    LC-ESI-HRMS method was developed and validated in conformance with ICH Q2 (R1) for the quantification and detection of eight nitrosamine impurities, including N-nitroso-diethylamine (NDEA), N-nitroso-dimethylamine (NDMA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso-diisopropylamine (NDIPA), N-ethyl-N-nitroso-2-propanamide (NEIPA). N-nitroso-methylphenylamine(NMPA) and N-nitroso-di-n-butylamine (NDBA), N-nitroso-di-n-propylamine (NDPA).

    FAQs:

    What are the impurities in Metformin as per USFDA?

    LC-ESI-HRMS method was developed and validated in conformance with ICH Q2 (R1) for the detection and quantification of eight nitrosamine impurities including NDEA, NDMA, NMBA, NDIPA, NEIPA, NMPA, NDBA, and NDPA.

    Which drugs contain nitrosamines?

    The regulatory agencies studied the details regarding the presence of nitrosamine in some of the APIs and drug products. Some of the drugs including angiotensin II receptor blockers (ARBs), Ranitidine, Nizatidine, and Metformin have been recalled because of nitrosamine impurities.

    What are the testing methods FDA has published as an option for the regulators and industry to detect NDMA impurities?

    FDA has published the testing method to furnish an option for the industry and regulators to detect NDMA impurities in metformin drug products and drug substances.
    LC-HRMS: a method for the detection of NDMA in metformin drug substance and drug Product. LC-ESI-HRMS: a method for the measurement of amounts of nitrosamine impurities (total 08) in metformin drug products and drug substances.

    What is the impurity found in metformin?

    Metformin is a medication used to treat type 2 diabetes by lowering blood sugar levels. It is generally considered safe and effective, but there have been concerns about the presence of impurities in some metformin products. In particular, there have been reports of low levels of a potential carcinogen called N-Nitrosodimethylamine (NDMA) in some metformin products.

    References:

    1. FDA alerts on nitrosamine impurity findings in metformin, available at https://www.fda.gov/news-events/
    2. European medicines agency, available at https://www.ema.europa.eu/en/news/update-nitrosamines-eu-medicines
    3. Laboratory analysis of metformin products, available at https://www.fda.gov/drugs
    4. Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5(1):6.
    5. WHO. WHO model list of essential medicines – 22nd list, 2021.World Health Organization; 2021. p. 66.
    6. https://www.fda.gov/drugs/drug-safety-and-availability/search-list-recalled-metformin-products
    7. https://www.fda.gov/media/134914/download
    8. https://www.fda.gov/media/138617/download
    9. https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-marketing-authorisation-holders/applicants-chmp-opinion-article-53-regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinal-products_en.pdf