Nitroso Amines

Several nitrosamines have been tested for carcinogenicity and have shown carcinogenic activities: N-nitroso dimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N-Nitroso-N-Methyl-4-aminobutyric acid (NMBA), N-Nitroso diethanol amine (NDELA), Nitroso morpholine (NMOR), N-nitroso-N-methyl-N-ethylamine, and N-Nitroso pyrrolidone (NPYR) being some of the well-known among these. The majority of sartan molecules have a tetrazole ring, which is formed using sodium nitrite. Coincidentally, the solvents used were either amines or had residues of amines, which likely contributed to the detected NDMA and NDEA. The origin of NDMA concentration in ranitidine batches is currently unknown.

Nitrosamines are a kind of carcinogen produced when secondary and tertiary amines, amides, carbonates, and urea derivatives react with nitrite or another nitrogenous molecule. Nitrosamine refers to a class of molecules containing a nitroso group linked to an amine (R1N (R2)-N=O). The compounds can be produced by nitrosating secondary, tertiary, or quaternary amines using nitrous acid. Under certain circumstances, nitrite salts can create nitrous acid, which reacts with an amine to form nitrosamine. Using nitrous acid to quench leftover azide (a reagent used in tetrazole ring synthesis or to introduce an azide functional group into a molecule) in the presence of precursor amines boosts nitrosamine production.

 Secondary amines can also be derived from amide solvents, which degrade under specific conditions. Over time and at high temperatures, N, N-dimethylformamide can degrade into dimethylamine, which can then react with nitrous acid to form NDMA. N-methyl pyrrolidone, N, N-dimethylacetamide, and N, N-dimethylacetamide all have comparable degradation processes, resulting in secondary amines that can react with nitrous acid to produce nitrosamine contaminants. Secondary amines can exist as impurities in amide solvents. N, N-dimethylformamide may contain impurities such as dimethylamine, which can react with nitrous acid to produce NDMA. API synthesis reagents, such as tertiary and quaternary amines, may include contaminants. Tertiary amines, such as triethylamine, have modest quantities of secondary amines, including dipropylamine and isopropyl ethylamine. Secondary and tertiary amines may be impurities or degradation products from quaternary amines.

Regulatory Actions:

Following an Article 31 review of sartans at risk of containing nitrosamine impurities (those with a tetrazole ring), manufacturers were asked to review and change their manufacturing processes to reduce nitrosamine impurities to the greatest extent practically possible. These adjustments will be implemented over a two-year transition period. Batches of products that exceed these limitations for a single contaminant or that contain both NDMA and NDEA are not permitted in the European Union. The European Pharmacopoeia is revising the drug substance monographs for the sartan series to include nitrosamine testing. In addition, the general monograph for APIs (General Monograph 2034) is being revised and will include suitable tests.

The USFDA tried to identify and recall drugs with levels that exceeded interim acceptable limits. The USFDA publishes a list of ARB products along with their nitrosamine content. The USFDA, like the EMA, emphasized that the hazards of abruptly terminating these treatments considerably outweigh the minor risk associated with continuing the pharmaceuticals with these contaminants.

More recently, the contaminant NDMA has been found in batches of ranitidine and nizatidine. Ranitidine drugs are frequently used to lower stomach acid production in people suffering from heartburn and stomach ulcers. They are available both over the counter and with a prescription. Regulatory agencies' reactions have varied. Some European national authorities, as well as Swiss medic and Health Canada, took preventive actions, recalling or suspending distribution of all ranitidine products until batch analysis revealed NDMA levels below safe limits. The EMA is examining existing data to establish whether patients using ranitidine are at risk from NDMA.

As a precaution, many companies have issued voluntary recalls of ranitidine products.

As a general measure, the EMA has recommended that all FPPs of MAHs assess the risk of nitrosamines being present in all goods containing chemically synthesized active components. Although nitrosamines are unlikely to arise during the production of the vast majority of medicines, the chance of cross-contamination or unintended introduction of amines and nitrites has encouraged businesses to conduct this precautionary review. These reviews are planned to be extensive in scope, covering all areas of the manufacturing process, including FPP production. The EMA has asked MAHs to complete this review within 6 months.

Recommendations

For sartan, ranitidine, and other products with positively identified nitrosamine content, regulatory agencies should take action:

• Verify the amounts of nitrosamine in the items on the market, whether through national testing facilities or self-declarations by suppliers. Appropriate testing procedures should be utilized.
• Request that the MAHs of these goods do risk assessments to identify the sources of nitrosamine contamination and establish limits to assure control of such impurities below acceptable levels.
• Request that MAHs make modifications to ensure that future levels of nitrosamines are essentially zero.

Investigations into the presence of nitrosamines have revealed that a comprehensive assessment of potential nitrosamine contamination in an FPP must go beyond whether amines and nitrites are utilized concurrently in the manufacture of the API. Manufacturers of all FPPs should evaluate their goods for any scenarios that may mistakenly result in nitrosamine content and take action to mitigate these hazards. The EU request to manufacturers includes a full summary of the variables to be examined. When nitrosamine levels exceed acceptable limits or more than one nitrosamine is detected, such products should not be sold. However, when taking this step, each national body must also consider the impact on patients if the product is no longer available. This includes establishing the availability of other brands or therapies in their market, as well as the clinical implications of discontinuing or switching to a different medication.