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Nitrosamine impurities in medicines

Overview of HSA's investigation of nitrosamine impurities in medicines

HSA has been closely monitoring international developments on the global issue of nitrosamine contamination in medicines. We are working closely with international regulatory agencies and product registrants to investigate the root causes of contamination and to identify the necessary measures to address the issue.

Background

In mid-2018, several blood pressure medicines were recalled globally due to the presence of the nitrosamine impurity, N-nitrosodimethylamine (NDMA). Since then, some other medicines have been found to contain NDMA or other nitrosamine impurities. The source of nitrosamines may be related to the manufacturing processes of the medicines or its chemical structure.

What are nitrosamine impurities?

Nitrosamines are environmental contaminants and can be found in food or the environment. For example, NDMA can be found in low levels in processed food (pickled vegetables, salted fish, processed meat products such as bacon and sausages).

There is no immediate risk associated with the use of medicines containing trace levels of nitrosamine impurities. In animal studies, exposure over a prolonged period to amounts of nitrosamine impurities that are much higher than usual human exposure has been reported to cause cancer in animals. Based on these animal studies, it is postulated that nitrosamines may cause cancer in humans.

A very conservative approach is used to set limits for these impurities in medicines. Acceptable levels of nitrosamines are set in nanograms (ng), i.e. one billionth of a gram, and is based on what is considered as reasonably safe if a patient continues to take the affected medicine every day for a lifetime of 70 years. Taking a medicine that contains nitrosamine impurities at or below the acceptable level is not expected to increase the risk of cancer.  

Patients are advised to speak to their doctor or healthcare professional if they have concerns about this issue, and should not stop the medicines which has been prescribed to them for their medical conditions on their own. Sudden stopping of the medicines may pose a greater health risk than the potential contamination with nitrosamine impurities.

What HSA is doing

Following the detection of the nitrosamine impurities in certain medicines marketed overseas, HSA conducted testing of the implicated medicines available in Singapore for the presence of these impurities. Necessary actions were also taken to stop the sale and supply or recall affected medicines that contained nitrosamines above the acceptable levels from the Singapore market:

As part of the regulatory approach to manage the issue, HSA has required product registrants to conduct assessments of their products for risk of nitrosamine contamination. Where risks of contamination are identified, companies are required to determine the source of the impurities, conduct testing on their products, remove products that pose safety risks from the Singapore market and make the necessary changes to mitigate the risk.

HSA will continue to investigate the issue and take the necessary actions to safeguard public health. Medicines that are recalled due to nitrosamine impurities are published under 'Announcements' - 'Product Recalls'.

 

Testing methods for the identification and determination of nitrosamine impurities in medicines

HSA has developed the below test methods for the identification and determination of nitrosamine impurities in medicines. These testing methods provide an option for the industry to detect nitrosamine impurities in medicines. These methods should be validated by users to ensure they are fit for their intended use.

Test methods

  1. N-Nitrosodimethylamine (NDMA)
  2. N-Nitrosodiethylamine (NDEA)
  3. N-ethyl-N-nitroso-2-propanamine (NEIPA)
  4. N-nitroso-di-isopropylamine (NDIPA)
  5. N-nitroso-di-n-butylamine (NDBA)
  6. N-nitroso-N-methylamino butyric acid (NMBA)
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