The sartan saga: Recapping the recalls
Recalls of ‘sartan’ drugs were on the rise earlier this year, with companies like Pfizer pulling drugs off the market, and regulatory agencies taking steps to mitigate the impurity issue.
As industry stakeholders shift focus to the potential cause of impurities we’re recapping the recalls and regulations of 2019:
2019 began with Taiwan’s Food and Drug Administration announcing the recall of 11 batches of blood pressure tablets from Siu Guan Chemical industries. The company recalled the medicines after it discovered impurities. The losartan used as an active ingredient was found to contain N-Nitrosodiethylamine (NDEA), which is classified as a probable carcinogen.
The US Food and Drug Administration (FDA) addressed the contamination and recalls in a statement noting that the impurities may be formed from the reuse of solvents during the manufacturing process.
In addition to addressing the possible cause, the FDA aimed to calm any fears over long-term use of the medicine and called the risk to patients “very small.”
Pfizer Japan recalled its high blood pressure drug Amvalo (valsartan amlodipine besilate) containing the active pharmaceutical ingredient (API) valsartan after possible carcinogenic impurities were found.
At the time, multiple drugs containing valsartan, losartan, and irbesartan were linked to recalls tied to the contamination of two possible carcinogens: N-Nitrosodimethylamine (NDMA) and NDEA.
Just a few days before Pfizer Japan recalled its product, the European Medicines Agency (EMA) concluded its investigation into ‘sartan’ medicines.
The EMA made a statement addressing the contaminations:
“It is now known that these impurities can form during the production of sartans that contain a specific ring structure known as a tetrazole ring under certain conditions and when certain solvents, reagents, or other raw materials are used.”
Three other substances that could potentially form during the synthesis of sartans were also investigated: N-nitrosoethylisopropylamine, N-nitrosodisopropylamine (DIPNA), and N-nitroso-N-methylamino butyric acid (NMBA).
At the time, the EMA announced that affected companies have a two-year transition period to make changes to the manufacturing of products, during which time temporary limits on the permissible levels will be applied.
Camber and Macleods voluntarily recalled losartan tablet lots after trace amounts of NDEA were found, in March 2019.
Based in Mumbai, Macleods’ tablets were manufactured by Hetero Labs in Hyderabad, India. Camber’s losartan tablets were also manufactured by the same company when the NMBA impurity was discovered in its product.
After numerous recalls of ‘sartan’ products in 2018 and new continued issues in 2019, the FDA approved a generic version of valsartan produced by Alkem Laboratories. The FDA prioritized the review of the drug’s application as a means to provide an additional supply of valsartan medication after the recalls.
The outgoing FDA Commissioner said at the time:
“We’ll continue to work with manufacturers so that more medicines like valsartan, that belong to a class of drugs called angiotensin II receptor blockers, can be approved that are free of nitrosamine impurities to continue to address the ongoing shortage.”
Shortly after the FDA approved the generic valsartan, Legacy Pharmaceutical Packaging recalled 40 lots of its repackaged losartan tablets at the consumer level.
Teva Pharmaceuticals recalled 35 lots of losartan tablets and Torrent Pharmaceuticals expanded its existing recall to include an additional 104 lot.
These recalls came after trace amounts of NMBA were found in both companies’ products. Hetero Labs produced the lots of the API for Torrent pharmaceuticals and Teva’s medicines.
Just a few days after the Teva and Torrent recall, the FDA issued a draft guidance on the process of voluntary recalls. The guidance encourages companies to be prepared for any potential recalls and focus on three key areas: Training, record keeping, and procedures.
The agency concluded its announcement with a statement on voluntary recalls:
“Collective efforts will help the agency to prevent further recalls and work quickly with companies to remove products from the market when an issue does arise.”
Valisure detected an additional potential carcinogen in a valsartan medication in June. The online pharmacy submitted a Citizen Petition to the FDA after it discovered trace amounts of dimethylformamide (DMF) in a valsartan medication. According to the WHO, DMF is considered a probable carcinogen.
The testing done by the pharmacy revealed that the levels of DMF in the medications were considered safe by the FDA, which permits up to 8,000,000 nanograms in daily exposure.
However, the pharmacy suggested that these levels were higher than those allowed for previously discovered probable carcinogens that prompted recalls like NDMA and NDEA.
NDMA has a daily limit of 96 nanograms and NDEA has a limit of 26.5 nanograms.
Valisure submitted a Citizen Petition:
“Given the increased risk to public safety, the concern of medical practitioners regarding DMF in pharmaceuticals, and the fact that the FDA did not amend the acceptable intake of DMF or take other appropriate action following the chemical’s reclassification to Group 2A status by WHO or IARC, Valisure seeks to utilize this Citizen Petition to bring these concerns directly to the attention of the commissioner and the FDA, and request that they take action.”
The Swiss Agency for Therapeutic Products revised the test it uses to assess contamination of sartan medicines.
The upgraded test method is based on the use of gas chromatography-mass spectrometry. The regulatory company stated that changes in testing “further improve the sensitivity of testing for nitrosamine contamination.”
According to the company, the new test can detect NDMA in most sartans down to levels of three parts per billion. Candesartan, another angiotensin II receptor antagonist from AstraZeneca can be tested with the upgraded system but levels of NDMA can other be detected down to six parts per billion. The test is even more sensitive to the impurity NDEA.
With regulatory agencies having concluded investigations into the cause of the impurities and recalls made, the industry seems to be poised to take on any challenges that may continue to arise with sartan products.
While it is unknown if the impurities will continue, the number of recalls of the valsartan and losartan have been few and far between as of late.