FDA and EMA Broaden Review of Impurities in API Manufacturing

By Patricia Van Arnum - DCAT Editorial Director

September 17, 2019

The FDA and the European Medicines Agency (EMA) are expanding their scope of investigation to evaluate other active pharmaceutical ingredients (APIs) that contain nitrosamine impurities, an issue that first surfaced last year with “sartan”-APIs, such as valsartan. How is this impacting the review of API manufacturing processes?

Additional API detected with nitrosamine impurities

Last week (September 13, 2019), the FDA reported that it found that some medicines with the API, ranitidine, a H2 (histamine-2) blocker used in over-the-counter and prescription drugs to decrease the amount of acid created by the stomach, contain the nitrosamine impurity, N-nitrosodimethylamine (NDMA), which is classified as a probable human carcinogen. This marks a second API class with detection of nitrosamine impurities. Last year (2018), the FDA began investigating NDMA and other nitrosamine impurities, such as N‑nitrosodiethylamine (NDEA) and N-nitroso-N-methyl-4-aminobutyric acid (NMBA), which are classified as probable human carcinogens that were detected in some blood-pressure and heart-failure medicines, specifically angiotensin II receptor blockers (ARBs) in “sartan”-containing drugs. This issue of nitrosamine impurities in sartan-containing drugs first surfaced in the summer of 2018, which led to company recalls and/or further investigation by both the FDA and European Medicines Agency (EMA) of drugs containing valsartan and other drugs with “sartan” APIs, including candesartan, irbesartan, losartan, and olmesartan.

The FDA’s report that it had found nitrosamine impurities in non-sartan APIs is a result of an ongoing investigation by the FDA and other regulatory agencies, such as the EMA, Health Canada, and others, in trying to determine the root causes of the nitrosamine impurities. In an update provided last month (August 2019), the FDA said the agencies are collaborating 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 impurities. FDA said 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.

As part of that process, the FDA noted in its August update that it now knows some of the root causes of the nitrosamine impurity problem and that it is using these findings to inform its evaluation of medicines other than sartan-containing products. “We are testing samples of other drugs with similar manufacturing processes,” said the agency in its August 2019 statement. “If we detect a problem, we will take appropriate action.”

Following that update, the FDA reported its findings of nitrosamine impurities in ranitidine. The FDA said it is working with international regulators and industry partners to determine the source of this impurity in ranitidine. “The agency is examining levels of NDMA in ranitidine and evaluating any possible risk to patients,” said the FDA in its September 13, 2019 statement. “The FDA will take appropriate measures based on the results of the ongoing investigation. The agency will provide more information as it becomes available.” The FDA noted the initial levels of nitrosamine impurities in ranitidine is at low levels. “Although NDMA may cause harm in large amounts, the levels the FDA is finding in ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods,” said the FDA in its statement.

EMA to provide guidance on nitrosamine impurities

In keeping with its investigation, the European Medicines Agency (EMA) is seeking to broaden its scope by providing guidance of nitrosamine impurities in APIs. Last week (September 13, 2019), the EMA’s Executive Director Guido Rasi asked the EMA’s Committee for Medicinal Products for Human Use to provide guidance for avoiding the presence of nitrosamine impurities in human medicines containing chemically synthesized active substances.

“It is of paramount importance that we learn from our experience with sartans and take a proactive approach for other classes of medicines,” said Rasi in a September 13, 2019 EMA statement.

Like the FDA, the EMA first initiated in 2018 its investigation on nitrosamine impurities found in sartan-containing medicines, which lead to a recall of several products and a review by the European Union (EU), which set strict new manufacturing requirements for these medicines. Earlier this year (January 2019), the EMA recommended that companies making sartan blood-pressure medicines review their manufacturing processes so that they do not produce nitrosamine impurities. Companies were given a transition period to make any necessary changes, during which strict temporary limits on levels of these impurities were applied. After this period, companies will have to demonstrate that their sartan products have no quantifiable levels of these impurities before they can be used in the EU. These recommendations follow EMA’s review of NDMA and NDEA impurities that were detected in some sartan medicines. The EMA noted that for the vast majority of sartan medicines, impurities were either not found or were present at very low levels.

Since then, the EMA reports that a nitrosamine impurity has been detected in a few batches of pioglitazone, an API used as a diabetes treatment, from one company and in batches of ranitidine. An EU-wide review of ranitidine has been initiated. The review of ranitidine medicines was initiated on September 12, 2019 at the request of the European Commission. The review will be carried out by the Committee for Medicinal Products for Human Use (CHMP), which will adopt an opinion. The opinion will then be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU member states.

Drawing on work already carried out with the EMA’s Coordination Group for Mutual Recognition and Decentralised Procedures-Human (CMDh), the EMA says they will now provide guidance on avoiding presence of nitrosamine impurities to marketing authorization holders in the EU, which they should consider alongside their knowledge of the manufacturing processes of their products.

The EMA says that the CHMP will also evaluate all 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. In addition, the committee will consider whether to provide guidance for medicines other than those containing chemically synthesized active substances.