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  • Nitrosamine Impurities in Pharmaceuticals and Foods

    Nitrosamines are chemical compounds often found in foods, vegetables, rubber products, pharmaceutical products, and even in water at trace levels. Nitrites found in fertilizers result in nitrosamine in agriculture products e.g. cereals, rice, potatoes, and fruits. One and all are susceptible to some extent to nitrosamines.

    Nitrosamines (or more formally N-Nitrosamines) can form in food as a result of processing, and food preparation and have been found in several foodstuffs like meat products, cocoa, beer, processed fish, and other alcoholic beverages. Nitrosamines may also be present in various foods like processed vegetables, cooked meat, cereals, milk and dairy products, or fermented, spice foods and pickles. Some of the nitrosamines are carcinogenic and genotoxic.

    The European food safety authority (EFSA) published the public consultation on nitrosamines in food as a draft opinion. EFSA’s draft opinion evaluates the risks to public health related to the presence of nitrosamines in food.  As per a re-evaluation of the safety of nitrites and nitrates conducted in 2017, the experts of EFSA’s noticed high nitrosamine levels in meat products but did not have sufficient information to link these levels of nitrites deliberately added to food.

    Nitrosamines or N-nitroso compounds (NOCs) have been in the headlines for the last few years due to their presence in some of the pharmaceutical products and the results of the recall of the drugs as well. N-nitroso dimethylamine (NDMA) is highly potent carcinogenic and traces are detected commonly in foods and may be used as an indicator for the compound for the presence of nitrosamines.  N-nitroso dimethylamine (NDMA) or total nitrosamines in the United States have limits in barley malt, bacon, and malt beverages.  

    Nitrosamines contain nitro functional group (–NO) which forms when nitrates or nitrites in reaction with secondary or tertiary amines. The nitro group is related to mutagenicity and genotoxicity, which may be possible human carcinogens, based on the studies. The pre-clinical test study finding confirmed the evidence of their carcinogenicity. Due to this reason, nitrosamine content is not acceptable to regulatory agencies.

    FDA has declared a number of nitrosamines described below:

    Chemical NameAbbreviationAllowable Daily Intake
    N-Nitroso dimethyl amineNDMA96.0 ng/day
    N-Nitroso diethyl amineNDEA26.5 ng/day
    N-Nitroso di-isopropyl amineNDIPA26.5 ng/day
    N-Nitroso-ethyl iso-propylamineNEIPA26.5 ng/day
    N-Nitroso-N-methyl-4-aminobutyric acidNMBA96.0 ng/day
    Table-1: Provisional allowable daily intake limits for nitrosamine impurities

    Possible reasons for nitrosamine impurity formation

    1. Contamination from starting materials such as chemicals, solvents, catalysts, and other raw materials.
    2. Packaging materials are one of the reasons for nitrosamines in finished products. Imprinting inks based on nitrocellulose are the potential source of nitrites and azo pigments are another source of aromatic amines.
    3. Nitrates are used as a preservative in foods; amines are certainly derived from foodstuffs like meat products including cured meat, bacon, fish, etc.
    4. Nitroso di-methyl amine is formed in foods as an effect of the direct-fire drying process. 
    5. Nitrosamine impurities formed during the manufacturing processing of drug substances with some specific starting materials, raw materials, and intermediates.
    6. Secondary or tertiary amines are generated by degradation reactions due to the use of sodium nitrite (NaNO2) or other nitrating agents in combination with chemicals, reagents, solvents, and catalysts.
    7. Nitrosamine impurity formed due to incomplete reduction of sodium nitrite (NaNO2) or other nitrating agents in presence of secondary, tertiary amines or quaternary ammonium salts within the same or different step of the synthesis.
    8. Degradation of drug substance or drug product happened during the reaction with unreacted sodium nitrite or may be due to finished product formulation or storage.
    9. Use of contaminated raw materials such as recycled solvents, reagents, and catalysts which may carriage a risk of the presence of amines during recycling,
    10. The use of contaminated materials from vendors using processes that lead to the formation of nitrosamines or different manufacturing processes on a similar line.

    List of Drug Products Presence of Nitrosamine Impurities

    Following are the drug products that were recalled worldwide due to the presence of nitrosamine impurities:

    1. Valsartan, Candesartan, Irbesartan, Losartan and Olmesartan
    2. Pioglitazone
    3. Ranitidine
    4. Nizatidine
    5. Metformin

    Analytical Challenge

    Analysis of nitrosamines can be challenging because of their ultra-low levels in pharmaceuticals and food products. It may require the most sophisticated and most sensitive equipment to meet these limits, including, LC-MS-MS and GC-MS-MS systems. It needs a highly selective and sensitive method for the quantification of nitrosamines. The methods need to be validated to conform to their intended use.

    FAQ’s

    1. Which foods are nitrosamine found in?

    Nitrosamines can form in food as a result of processing and food preparation. Nitrosamines are found in several food items like meat products, cocoa, beer, processed fish, and other alcoholic beverages. Nitrosamines may also be present in various foods like processed vegetables, cooked meat, cereals, milk and dairy products, or fermented, spice foods and pickles.

    2. What is the source of nitrosamine in pharmaceuticals and its effect on humans?

    The source of Nitrosamines is from chemical reactions and also can form during the manufacturing process. Nitrosamines may increase the risk of cancer if exposed to people above acceptable levels and over a long period of time.  

    3. What foods are generally high in nitrosamines?

    Nitrosamines have been found in several types of foods such as cured meat products, cocoa, processed fish, beer, and other alcoholic beverages. Nitrosamines can also be present in other foods such as cooked meat, milk, cereals, processed vegetables, and dairy products, or fermented, pickled, and spiced foods.

    Reference:

    1. ICH Harmonised Guideline Assessment and Control Of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7(R1),
    2. Crews, C. (2019). The determination of N-nitrosamines in food. Quality Assurance and Safety of Crops & Foods,
    3. World. “Information Note Nitrosamine Impurities.” Who.int, World Health Organization: WHO, 20 Nov. 2019, www.who.int/news/item/20-11-2019-information-note-nitrosamine-impurities. Accessed 17 Feb. 2023.
    4. ‌Office. “Statement Alerting Patients and Health Care Professionals of NDMA Found in Samples of Ranitidine.” U.S. Food and Drug Administration, 2020, www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine. Accessed 17 Feb. 2023.
    5. OBSOLETE PLESE REFER to CHMP ASSESSMENT REPORT of ARTICLE 5 (3) REFERRAL on NITROSAMINES IMPURITIES in HUMAN MEDICINAL PRODUCTS and RELATED GUIDANCE Information on Nitrosamines for Marketing Authorisation Holders Request to Evaluate the Risk of the Presence of Nitrosamine Impurities in Human Medicinal Products Containing Chemically Synthesised Active Pharmaceutical Ingredients. 2019, www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-information-nitrosamines-marketing-authorisation-holders-obsolete_.pdf.
    6. P. Song, L. Wu and W. Guan, “Dietary Nitrates, Nitrites, and Nitrosamines Intake and the Risk of Gastric Cancer: A Meta-Analysis,” Nutrients 7(12), 9872–9
    7. “Public Consultation on Nitrosamines in Food: Draft Opinion Explained.” European Food Safety Authority, 12 Oct. 2022, www.efsa.europa.eu/en/news/public-consultation-nitrosamines-food-draft-opinion-explained. Accessed 17 Feb. 2023.
    8. Hamlet, C, Liang, L. (2017). An investigation to establish the types and levels of N-nitroso compounds (NOC) in UK consumed foods. Premier Analytical Services, 1-79
    9. ‌Office. “What to Know and Do about Possible Nitrosamines in Your Medication.” U.S. Food and Drug Administration, 2020, www.fda.gov/consumers/consumer-updates/what-know-and-do-about-possible-nitrosamines-your-medication. Accessed 17 Feb. 2023.