Australia Finds ‘Unacceptable’ Levels Of NDMA In 80% of Ranitidine Batches
Executive Summary
Testing carried out by Australia's drug agency on batches of 34 ranitidine products marketed by 10 different sponsors has found high levels of NDMA contamination in the vast majority of cases. The agency is now considering tightening its oversight of all ranitidine drugs sold in Australia.
Australia’s Therapeutic Goods Administration says the levels of potential carcinogen N-nitrosodimethylamine (NDMA) its testing has identified in ranitidine heartburn remedies are “unacceptable” leading the agency to withdraw numerous products from sale.
Prompted by US Food and Drug Administration and European Medicines Agency warnings about potential ranitidine contamination in September, the TGA tested 135 batch samples of ranitidine drugs (from 34 products) sold in Australia by 10 different sponsors. The tested products included both OTC and prescription presentations of ranitidine.
The testing identified 109 batches, or 81% of the total, that contained levels of NDMA above the internationally agreed limit of 0.3 parts per million (ppm).
The most contaminated product was Alphapharm Pty Ltd’s RANI 2 ranitidine 150mg (as hydrochloride) tablet blister pack, with one batch found to contain 14ppm NDMA, over 46-times above the 0.3ppm limit.
Batches of ranitidine drugs marketed by all 10 of the sponsors were found to contain levels of NDMA in breach of the 0.3ppm limit.
Just 26 batches had an acceptable level of NDMA, according to the TGA, all of which were marketed by either Arrow Pharma Pty Ltd or Sandoz Pty Ltd.
Of the 34 products tested, all but one – RANITIDINE SANDOZ ranitidine 50mg/5mL (as hydrochloride) concentrated injection ampoules – had a level of contamination above the limit in at least one batch.
Used FDA Testing Method
Explaining its testing process, the regulator said its TGA Laboratories branch had analysed a selection of the batch samples provided by sponsors in order to assess the extent of the problem.
TGA Laboratories had adapted a US FDA test method using LC-HRMS (liquid chromatography with high resolution mass spectrometric detection) to test for NDMA in the samples, the agency explained. This method had a limit of quantitation of 0.1ppm NDMA, equivalent to 0.1 microgram of NDMA per gram of ranitidine active ingredient.
Noting that the method did not give a fully linear response above 3 ppm, TGA said NDMA values greater than this were considered to be estimates only.
Products Recalled, Greater Oversight To Follow
As a result of these tests, TGA said it had recalled all products with levels of NDMA at or above 0.3ppm while all batches with levels below 0.3 ppm are still available for sale.
New requirements for ranitidine products would soon be introduced, the agency noted, to ensure that they did not contain unacceptable levels of NDMA.
Additionally, the TGA is considering suspending the registration for products which cannot demonstrate adequate safety and quality.
While the additional risk of cancer posed by the levels of NDMA identified to date in ranitidine products was considered to be very low, TGA said it set “very high standards for safety in medicines.”
In the US, the FDA is continuing to use liquid chromatography-mass spectrometry testing to detect and quantify NDMA in ranitidine. Earlier this month the agency said that its "early, limited testing has found unacceptable levels of NDMA in samples of ranitidine." (Also see "Testing Ranitidine With Too Much Heat Could Generate NDMA, FDA Says" - HBW Insight, 2 Oct, 2019.)
Meanwhile in Europe, the EMA has launched a review of ranitidine but is yet to publish any initial findings. Separate from that review, the EMA has asked marketing authorization holders to review all products containing chemically synthesized active pharmaceutical ingredients for the possible presence of nitrosamines and test all products at risk. (Also see "EMA Tells Firms To Evaluate OTCs For Carcinogenic Nitrosamines" - HBW Insight, 27 Sep, 2019.)