TGA Laboratories testing of ranitidine medicines

Ranitidine is a medicine marketed in Australia and overseas to treat heartburn by reducing stomach acid. It is also used in the treatment and prevention of gastric reflux and ulcers.

In response to reports of contamination of ranitidine medicines with an impurity called N-nitrosodimethylamine (NDMA), which is associated with an increased risk of cancer, the TGA Laboratories have tested samples of these products currently marketed in Australia.

The purpose of this testing was to determine if NDMA was present in these medicines and to quantify the amounts present. The testing report is available below.

The report identifies batches tested that contained levels of NDMA above the internationally agreed limit of 0.3 parts per million (ppm) and those with levels below this limit. All products with levels of NDMA at or above 0.3 ppm have been recalled and removed from retailer shelves, while all batches with levels below 0.3 ppm are still available for sale.

The 0.3 ppm limit has been calculated in line with international guidance (ICH M7 guideline: Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk). This guideline was adopted by the TGA in 2016. The limit is derived from animal carcinogenicity data to ensure the additional risk from a genotoxic/carcinogenic impurity does not increase the life-time (70 year) risk of cancer for an individual by more than 1:100,000. The specific ppm limit is calculated from the acceptable daily intake of the impurity, adjusted for the maximum daily dose of the medicine.

The TGA reiterates the advice that the additional risk of cancer posed by the levels of NDMA identified to date in ranitidine products is considered to be very low. However, the TGA sets very high standards for safety in medicines and the levels of contamination observed through our laboratory testing are considered unacceptable. The TGA is also introducing new requirements for ranitidine products to ensure that they do not contain unacceptable levels of NDMA. Additionally, the TGA is considering suspending the registration for products which cannot demonstrate adequate safety and quality.

For further information about this issue, including information for consumers and health professionals, see the TGA's latest safety advisory.

Contamination of ranitidine medicines with the nitrosamine NDMA

TGA laboratory testing

Version 1.0, 22 October 2019

Ranitidine is a medicine marketed in Australia and overseas to treat heartburn by reducing stomach acid. It is also used in the treatment and prevention of gastric reflux and ulcers. Following international reports of contamination of ranitidine medicines with an impurity called N-nitrosodimethylamine (NDMA), the TGA published an alert on our website in September 2019, which was updated in October. NDMA belongs to a class of chemicals called nitrosamines and is classified as a probable human carcinogen.

As part of the TGA's response to this issue, the TGA Laboratories have tested samples of the ranitidine medicines available on the Australian market. The purpose of this testing was to determine if NDMA was present in these medicines and to quantify the amounts present.

Sponsors of ranitidine medicines on the Australian market provided batch samples for TGA testing. Ten sponsors provided samples of the 34 products of ranitidine medicines on the market. The TGA Laboratories analysed a selection of the batch samples provided by sponsors in order to assess the extent of the problem.

Results are reported as parts per million NDMA in the ranitidine active ingredient rather than as content per tablet. Thus, for example, a result of 1 ppm NDMA in a 300 mg ranitidine tablet corresponds to 300 nanograms of NDMA per tablet.

The TGA Laboratories adapted a publically available US Food and Drug Administration test method using LC-HRMS (liquid chromatography with high resolution mass spectrometric detection) to test for NDMA in the samples. This method has a limit of quantitation of 0.1 parts per million (ppm) NDMA, equivalent to 0.1 microgram of NDMA per gram of ranitidine active ingredient. There is an internationally agreed limit of 0.3 ppm NDMA in the ranitidine active ingredient.

A total of 135 batch samples of ranitidine medicines have being tested by the TGA Laboratories. The nitrosamine contents of the ranitidine batches tested are shown in the Tables below. All of the products with levels of NDMA at or above 0.3 ppm (Table 1) have been recalled and removed from pharmacy shelves. The batches of ranitidine products with levels of NDMA below the 0.3 ppm limit (Table 2) are still available for sale. Please note that NDMA values above 3 ppm are considered to be estimates only. The method does not give a fully linear response above 3 ppm, hence there is greater uncertainty associated with these higher results.

* Batch number and expiry date information is usually printed or embossed on the end flaps of the tablet cartons.

* Batch number and expiry date information is usually printed or embossed on the end flaps of the tablet cartons.