Guest Author: Phil Koerner, PhD.
The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have recently announced that they are conducting investigations into certain ranitidine drug products used to treat heartburn. The investigation includes the brand-name drug Zantac®, after it was found to contain low levels of the nitrosamine impurity N-nitrosodimethylamine (NDMA), while the levels found were reportedly lower than those previously found in some heart medicines.
The FDA and EMA are working with international regulators and industry partners to determine the source of the NDMA impurity found in ranitidine. The FDA and EMA are evaluating the data to assess whether patients using ranitidine are at any risk from NDMA and will provide information about this as soon as it is available. In the meantime, caution is being exercised as Sandoz has halted distribution of its generic versions of Zantac, and other generic versions have also been recalled in Europe and Canada.
Over-the-counter ranitidine is approved to prevent and relieve heartburn associated with acid ingestion and sour stomach. Prescription ranitidine is approved for multiple indications, including treatment and prevention of ulcers of the stomach and intestines and treatment of gastroesophageal reflux disease. Ranitidine medicines are available over-the-counter and through prescription and widely used to reduce the production of stomach acid in patients to prevent and relieve heartburn associated with acid ingestion and sour stomach, and for the treatment and prevention of stomach ulcers, and gastroesophageal reflux. This adds to the on-going saga of N-nitrosamine impurities found in drug products, dating back to June 2018, when reports of NDMA and other nitrosamines such as N-nitrosodiethylamine (NDEA) and N-Nitroso-N methyl-4-aminobutyric acid (NMBA) were first reported at low levels in multiple generic angiotensin II receptor blocker (ARB) medicines used to treat high blood pressure and heart failure. These reports of low-level nitrosamines in ‘sartan’ drugs have resulted in the voluntary recall of some ‘sartans’ and increased testing of these medicines by both the EMA and FDA. Additionally, low levels of NDMA were also found in a few batches of pioglitazone, a diabetes medicine, manufactured by Hetero Labs in India.
NDMA and other nitrosamines are classified as probable human carcinogens (i.e. substances that could cause cancer), based on results from laboratory tests. Nitrosamines, such as NDMA and NDEA, are also commonly found in grains, cured meats, beer, tobacco and drinking water, and most people are exposed to them daily in very small amounts. However, the presence of nitrosamines in medicines is largely avoidable, but despite the relatively low risk they pose to patients, their presence is not acceptable. It should be noted that EMA and FDA continue to look for the presence of other nitrosamine impurities in medicines.
Before June 2018, NDMA and NDEA were not among the impurities identified in sartan medicines and were therefore not detected with routine testing. The EMA has now established 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, and other raw materials are used. In addition, it is possible that impurities were present in some sartans because manufacturers had inadvertently used contaminated equipment or reagents in the manufacturing process. Recently FDA has identified a contract solvent recovery facility India (Lantech Pharmaceuticals Limited) for valsartan active pharmaceutical ingredient (API) manufacturing operations. FDA determined, upon inspection of this facility, that solvent recovered by the company contained N-Nitrosodiethylamine (NDEA) and that the company had failed to control and monitor procedures used to recover solvents to ensure that they met appropriate standards before reuse.
While the goal is to have no quantifiable nitrosamine impurities in sartans, the EMA has set temporary limits for NDMA and NDEA impurities at 96.0 ng and 26.5 ng, respectively, based on the maximum daily intake for each impurity derived from animal studies. Dividing these interim limits by the maximum daily dose (mg) for each active substance gives the limit in parts per million (ppm). For example, if the maximum daily dose for a medicine such as valsartan is 320 mg, then the limit for NDMA is ca. 0.300 ppm.
Companies must now take measures to avoid the presence of these impurities and carry out rigorous testing of their products. Testing during a two-year transition period will allow companies to make the necessary changes to their manufacturing processes and to put in place testing procedures that are capable to detect the smallest amounts of these impurities in their products. After the transition period, companies must exclude the presence of even lower levels of NDEA or NDMA in their products (< 0.03 parts per million).
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