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  • Nitrosamine Impurity: A Regulatory Perspective

    The Regulatory agency announced that Nitrosamine impurities N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) are said to be present in generic drug substances and drug products, especially in angiotensin II receptor blockers (ARBs) and belong to a family of analog compounds referred to as the sartans. Further FDA and EMA investigation also led to the detection of these Nitrosamine impurities in Pioglitazone and the low level of NDMA impurity found in Metformin.

    Food Drug Administration (FDA)

    The U.S. Food and Drug Administration is investigating several potentially cancer-causing substances, called nitrosamines, recently found in some drugs, including those used to treat elevated blood pressure, heartburn, acid reflux, and diabetes. Some of these drugs from certain manufacturers – including angiotensin II receptor blockers (ARBs), Ranitidine, Nizatidine, and Metformin – have been recalled because of nitrosamine impurities

    Most recently, the FDA announced that its testing showed levels of nitrosamine N-Nitrosodimethylamine (NDMA) in some samples of the extended-release (ER) formulation of the diabetes medicine Metformin that exceed the agency’s acceptable intake limit. The agency is also asking all manufacturers of ER versions of Metformin to evaluate their risk of excessive NDMA and to test at-risk products before each batch is released onto the U.S. market. If testing shows NDMA above the acceptable intake limit, the manufacturer should inform the agency and should not release the batch to the U.S. market.

    The FDA continues to work with manufacturers to investigate the source of nitrosamines in drug products and whether they are at a level that may constitute risks to human health. Some nitrosamines may increase the risk of cancer if people are exposed to them above acceptable levels and over long periods of time. People taking drugs that contain NDMA at or below the acceptable intake limits every day for 70 years are not expected to have an increased risk of cancer. FDA has also published validated methods to detect and quantify NDMA and NDEA impurities in all ARB drug substances and some drug products.

    European Medicines Agency (EMA) 

    The European medicines regulatory has issued recommendations on impurities in medicines following the conclusion of an exercise to draw on lessons learned from the presence of nitrosamines in a class of blood pressure medicines known as sartans. The guidelines aim to explain the responsibilities of companies involved in the manufacture of medicines and amend guidance on controlling impurities and good manufacturing practice and also cover the management of impurities once detected communication with patients and healthcare professionals and international cooperation.

    Regulators in the EU first became aware that they were present in some sartan medicines in mid-2018 and this led to immediate regulatory action, including the recall of medicines and measures to stop the use of active substances from certain manufacturers. A review by EU in April 2019, established the sources of nitrosamines and set out new manufacturing requirements for sartans. Although the exercise focused on nitrosamines in sartans, the recommendations will help reduce the risk of impurities being present in other medicines and ensure that regulators are better prepared to manage cases of unexpected impurities in the future.

    In September 2019, EMA launched an Article 5(3) procedure to provide additional guidance to companies that make and market medicines in the EU and the procedure which will provide the key scientific opinion on the presence of nitrosamine impurities in human medicines containing chemically synthesized active substances. Reviewing practices on the basis of experience is one of the ways the authorities in the EU ensure that medicines in the EU are of the highest quality. EU authorities will continue working closely with the European Directorate for the Quality of Medicines & HealthCare and international partners and will take necessary measures to protect and reassure patients.

    Other Regulatory Agency

    Therapeutic Goods Administration (TGA) of Australia advised in a public notice that it has introduced requirements for sponsors of  ‘sartan’  blood pressure medicines to take measures to avoid the presence of  N-nitrosamine impurities in medicines and implement rigorous testing of their medicines to identify the presence of any  N-nitrosamine impurities. The TGA  will provide a two-year transition period (2019-2021)  to allow sponsors to review and if make necessary changes to their manufacturing processes and to implement adequate testing methods. 

    During the transition period, sponsors must inform the TGA if they identify the presence of N-nitrosamine compounds in their medicines. Changes to manufacturing processes and/or controls if needed should be lodged as a ‘category 3’ request under section 9D (3) of the Therapeutic Goods Act 1989 (the Act). The TGA Laboratories has adapted a publically available US-FDA test method. 

    Health Canada continues to work closely with international regulatory partners including the FDA and the EMA to share information and coordinate efforts on inspections,  risk assessments, and public communications. Health Canada has provided a method that has been developed to detect and quantify the Nitrosamine impurities NDMA and NDEA in angiotensin II receptor blockers (ARBs).

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    • U. S. Food and Drug Administration update (Feb 6, 2020), what to know and do about possible nitrosamines in your medication,
    • Tabrez Shaikh et al., (2020) Nitrosamine Impurities in Drug Substance and Drug Products. Journal of Advances in Pharmacy Practices (2582-4465), 2(I), 48-57.
    • Heads of Medicines agencies,
    • Therapeutic Goods Administration (TGA), n-nitroso compounds in sartans blood pressure medicines, available at

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