FDA Updates Investigation into Sartan Products; Notes Drug Shortages

By Patricia Van Arnum - DCAT Editorial Director

February 8, 2019

US Food and Drug Administration (FDA) Commissioner Scott Gottlieb and FDA’s Center for Drug Evaluation and Research Director Janet Woodcock issued a joint statement regarding the FDA’s ongoing investigation into impurities found in “sartan”-containing products, angiotensin II receptor blockers (ARBs) used as antihypertensive drugs. The review and investigation by the FDA dates back to 2018 of “sartan” products containing N-nitrosodimethylamine (NDMA) and N‑nitrosodiethylamine (NDEA), which are classified as probable human carcinogens and that were detected in some sartan medicines. The agency updated its review of the manufacturing processes used to make these products that contributed to these impurities and also noted that as a result of subsequent product recalls, certain sartan products face or potentially could face shortages. 

“We were deeply concerned when we learned about the presence of these impurities,” they said in a January 25, 2019 agency statement. “We immediately undertook a major operation to investigate and to identify the root causes for the presence of these impurities in some ARB drugs and to work with companies to address the risks that the impurities pose to patients,” they said in the statement.

While the FDA said that risk to patients is small, it is still assessing issues in the manufacturing processes of sartans to determine the cause of the impurities. “Our analysis of NDMA found that the risk to patients based on the maximum possible exposure appears to be small. That doesn’t diminish our concern and our determination to find out how these impurities occurred in the first instance,” they said in the statement. “We’re committed to implementing measures to prevent these impurities from occurring in the manufacturing process in the future. Our ultimate goal is to ensure that these impurities are not present in finished drug products, or their components (including active pharmaceutical ingredients, or API)….While we’re still investigating the root causes of the impurities, our ongoing effort has determined that the impurities may be generated when specific chemicals and reaction conditions are present in the manufacturing process of the drug’s API, and may also result from the reuse of materials, such as solvents.”

This issue first surfaced in the summer of 2018, when the FDA was informed that API manufactured by Zhejiang Huahai Pharmaceutical (ZHP), a Linhai, China-based pharmaceutical company, for some generic valsartan-containing medicines contained NDMA. Since then, the FDA and additional manufacturers of other ARB medicines have identified more cases of NDMA impurities as well as NDEA impurities. The FDA put the ZHP facility on import alert to stop all its API and finished drugs made using ZHP’s API from legally entering the US. The FDA also issued the company a Warning Letter outlining several manufacturing violations, including impurity control, change control and cross contamination from one manufacturing process line to another.

”Our investigation into ZHP’s process identified that a change made to the manufacturing process likely led to this impurity, and that the impurity went undetected by global regulators, including the FDA, for a period of time,” they said in the statement. “Before we undertook this analysis, neither regulators nor industry fully understood how NDMA or NDEA could form during this particular manufacturing process.” 

Since then, the FDA said it has worked with manufacturers of all ARB medicines to recall any product that poses a risk to patients. “Because of the way API is distributed in the supply chain, one source of contaminated API can impact multiple products,” they noted in the statement.

They further noted the challenges in detecting these impurities since their detection does not come up in conventional testing and inspection practices. "One challenge we’ve faced is that NDMA’s properties make it hard to detect in standard laboratory testing – the kind of testing results that are reviewed during a surveillance inspection,” they said in the statement. “In St. Louis, the FDA maintains one of the most advanced pharmaceutical laboratories of any regulatory agency in the world. As soon as we became aware of the presence of nitrosamine impurities in certain ARB medicines, we began collecting samples of all ARB API and medicines marketed in the US to test these products specifically for NDMA. More testing found NDEA, also a probable human carcinogen, in other valsartan products and other ARBs from different manufacturers.”

The FDA has posted lists of valsartan, losartan, and irbesartan products affected by recalls due to the impurities found in ARB products. As a result of these recalls, it says “valsartan products are in shortage, and we know that other types of products may fall into shortage soon.”

As a result, the FDA also evaluated safety data for NDMA and NDEA to determine interim acceptable intake levels for these impurities in the ARB class of medicines. “While consumers should limit exposure to NDMA and NDEA, these impurities exist in other ingested products, such as some charcoal grilled food items,” said Gottlieb and Woodcock in the agency statement. “And so, our goal is to balance the risk of patients ingesting low levels of the impurities (below the interim acceptable levels) for a short period of time with the risk that there is a shortage of certain ARBs, which may impact patients’ ability to access the medicine they need. “

In addition to noting potential shortages, the FDA also outlined its further investigative work into the manufacturing processes for sartans. “Now that these risks are identified, we’re applying what we’ve learned to the evaluation of similar manufacturing processes where we now know these risks could arise,” Gottlieb and Woodcock said in agency statement. “As part of this process, the FDA has identified specific factors in manufacturing processes that may contribute to the formation and presence of NDMA and NDEA. Through our investigation, we’re working to ensure that other manufacturing conditions don’t contribute to NDMA, NDEA, or related impurities in finished drug products. We’ll use the information we’ve learned about these impurities when reviewing applications, assessing manufacturing changes and conducting inspections. Now that they are aware that certain conditions result in the formation of nitrosamines, manufacturers using processes at risk for these impurities are expected to test for them to ensure that active ingredients and finished products are free of detectable levels of a nitrosamine impurities resulting in drug products that are safe for patients.”

In a related development, the European Medicines Agency outlined requirements for manufacturers to test for nitrosamine impurities in sartan products and interim testing requirements. 

Source: US Food and Drug Administration