The US Food and Drug Administration (FDA) has provided an update to the agency’s ongoing investigation surrounding voluntary recalls of multiple generic “sartan”-containing products, angiotensin II receptor blockers (ARBs), used to treat high blood pressure and heart failure, due to the presence of nitrosamine impurities, probable human carcinogens. This issue first surfaced in the summer of 2018, which led to the recall of certain valsartan products and other drugs with “sartan”-containing active pharmaceutical ingredients (APIs).

Scope of problem

To put the safety issues in context, the agency noted in an August 28, 2019 statement that it initially estimated that if 8,000 people took the highest valsartan dose (320 mg) containing N-nitrosodimethylamine (NDMA) from the recalled batches daily for four years, there may be one additional case of cancer over the lifetimes of those 8,000 people. “In reality, the vast majority of patients exposed to NDMA through ARBs received much smaller amounts of the impurity than this worst-case scenario, and, since not all ARBs are affected, it’s very likely that a patient taking an ARB for four years would not have always received one of the affected products,” said the agency in its statement.

The agency, noted however, that “[w]hile we know the number of patients taking ARB medicines, we do not know the exact number of patients impacted by these ARB recalls.” It said that “we estimate there were likely more drugs replaced due to recalls than necessary, which means more patients were impacted but not necessarily exposed to an impurity.” Based on the FDA’s current assessments, including lab testing, the agency has identified 43 ARB medications that have been determined not to contain any nitrosamine impurities.

Manufacturing actions

The FDA says it continues its analysis to better understand the root causes and how nitrosamine impurities may have formed in ARBs. For example, earlier this month (August 2019), the agency issued a Warning Letter for cGMP violations to Telangana, India-based Lantech Pharmaceutical, which acts as a contract solvent recovery facility for valsartan API manufacturing operations. In March 2019, the FDA determined that solvent recovered by the company contained N-nitrosodiethylamine (NDEA) and that Lantech had insufficiently assessed the risks associated with their processes and did not adequately investigate the impurities. The FDA later put Lantech on import alert in June 2019, preventing an API made using its recovered solvent from legally entering the US.

The FDA says it is working closely with global regulatory organizations, including the European Medicines Agency, Health Canada, and others to understand the full scope of this issue. The agencies collaborate on inspectional findings, laboratory testing methods and results, and assessments of root cause and impact. The FDA says it is incorporating what it has learned about the process risks that caused these impurities into its oversight of drug manufacturing, which includes how it assess applications and changes to applications, as well as enhancing its inspection coverage to evaluate the controls in place to prevent unacceptable levels of nitrosamine.

The FDA says it plans to adjust inspections of API sites to include enhanced evaluation of impurity controls, particularly when the manufacturing process may lead to the formation of a nitrosamine or when recycled raw materials can create unacceptable contamination. “In the past year, the agency has conducted multiple unannounced, for-cause inspections to evaluate the practices at various API manufacturers and to verify appropriate corrective actions to address the risk of nitrosamine contamination,” noted the agency in its August 2019 statement.  “We are also working to improve how companies submit manufacturing changes to the agency with the goal of further improving our review of the more than 5,000 quality-related application change requests (supplements) each year.”

In its August 2019 statement, the FDA noted that now that it knows some of the root causes of the nitrosamine impurity problem, it is using these findings to inform its evaluation of medicines other than ARBs. “We are testing samples of other drugs with similar manufacturing processes,” said the agency in its statement. “If we detect a problem, we will take appropriate action. In the meantime, we continue to work with ARB manufacturers to remove all affected drugs from the market, and we work with API manufactures to fix their processes so they do not distribute affected API to [a] drug product manufacturer.”

Source: US Food and Drug Administration