The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have provided updates of their respective investigations into the detection of certain nitrosamine impurities regarded as probable human carcinogens in ranitidine, an over-the-counter (OTC) and prescription drug. The FDA is providing additional information on testing protocols, and the EMA is providing guidance on the steps that companies should take for detecting nitrosamines impurities in all chemically synthesized active pharmaceutical ingredients (APIs).

Following a report last month (September 2019) by the FDA of the detection of nitrosamine impurities in the API, ranitidine, the agency has provided an update to report that it is continuing to test ranitidine products from multiple manufacturers and is assessing the potential impact on patients who have been taking ranitidine. Ranitidine is an H2 (histamine-2) blocker used in OTC and prescription drugs, including the brand-name drug, Zantac, to decrease the amount of acid created by the stomach.

In addition, the agency has asked manufacturers of ranitidine to conduct their own laboratory testing to assess levels of N-nitrosodimethylamine (NDMA) in their ranitidine products and to send samples of ranitidine products to the FDA to be tested by its scientists.

In its update issued October 2, 2019, the FDA said it observed the testing method used by a third-party laboratory using higher temperatures.The higher temperatures generated very high levels of NDMA from ranitidine products because of the test procedure. The FDA had published the method for testing angiotensin II receptor blockers (ARBs) for nitrosamine impurities in “sartan” APIs, such as valsartan and other sartan APIs, which have been the subject of recalls and investigation dating back to 2018. The FDA says that method is not suitable for testing ranitidine because heating the sample generates NDMA.

FDA recommends using a liquid chromatography/high resolution mass spectroscopic (LC-HRMS) testing protocol to test samples of ranitidine. FDA says its LC-HRMS testing method does not use elevated temperatures and has shown the presence of much lower levels of NDMA in ranitidine medicines than those reported by the third-party laboratory. The FDA noted that international regulators using similar liquid chromatography–mass spectrometry (LC-MS) testing methods have also shown the presence of low levels of NDMA in ranitidine samples.

The FDA says it will test ranitidine oral solution products and has begun testing samples of other H2 blockers and proton-pump inhibitors to help inform this ongoing investigation. To date (as of October 2, 2019), the agency’s early, limited testing has found unacceptable levels of NDMA in samples of ranitidine. The agency says it will provide more information as it becomes available.

EMA outlines testing protocol for nitrosamine impurities in APIs

The EMA’s Committee for Medicinal Products for Human Use (CHMP) is requesting as a matter of precaution that marketing authorization holders for human medicines containing chemically synthesized active substances review their medicines for the possible presence of nitrosamines and test all products at risk.

A notice to this effect is being sent out to marketing authorization holders with information on the actions they should take. A questions-and-answers document is also available on the EMA’s website. The EMA is advising companies that they should take into account the published guidance along with knowledge of the manufacturing processes for their products and all other relevant scientific evidence.

The EMA is advising that companies take the following steps:

• Evaluate the possibility of nitrosamines being present in every concerned medicine within six months;

• Prioritize evaluations, starting with medicines more likely to be at risk of containing nitrosamines;

• Take into account findings from CHMP’s review of sartans;

• Notify authorities of outcome of risk evaluations;

• Test products at risk of containing any nitrosamines;

• Immediately report detection of nitrosamines to authorities;

• Apply for necessary changes to marketing authorizations to address nitrosamine risk; and

• Complete all steps within three years and prioritize high-risk products.

The EMA says that although nitrosamines are not expected to form during the manufacture of the vast majority of medicines containing chemically synthesized active substances, it is important that all companies who have not already done so take appropriate precautionary measures, if necessary, in line with recommendations from the recently concluded review of sartans.

The EMA says it will continue working closely with national authorities, the European Directorate for the Quality of Medicines and HealthCare of the Council of Europe, and international partners to ensure that companies are taking appropriate measures to prevent nitrosamine impurities from being present in their products.

In the meantime, the EMA says that the CHMP will continue evaluating available scientific knowledge on the presence of nitrosamines in medicines and advise regulatory authorities on actions to take if companies find nitrosamines in their medicines.

The ongoing investigations by the FDA and the EMA come as several pharmaceutical companies have recalled products and retailers have suspended sales of ranitidine products (see story).

Source: FDA , European Medicines Agency