In July 2018, health authorities became aware for the first time of the presence of N-nitrosodimethylamine (NDMA), a nitrosamine impurity, in products containing valsartan. This drug is an angiotensin II receptor antagonist that belongs to a family of analogous compounds commonly called sartans.
Subsequently, nitrosamine impurities were detected in medicines containing sartans: N-nitrosoethylisopropylamine (NEIPA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), and N-nitroso-N-methyl-4-aminobutyric acid (NMBA).
More recently, the presence of such impurities has also been reported in medicinal products containing pioglitazone and ranitidine.
So what actually are the nitrosamines?
According to the Life Sciences Consulting Services in NJ, Nitrosamines are molecules that contain a nitrous functional group and are of concern because their impurities could be carcinogenic to humans. Although they can be found in some foods and in the drinking water supply, their presence in a drug is considered unacceptable.
How do they actually form?
In general, nitrosamines are formed only when a tertiary or secondary amine reacts with nitrous acid. Although this acid is unstable, it can be formed from nitrites (NO2) in an acid medium. Most sartans contain a tetrazole ring, which requires sodium nitrite to form. Coincidentally, the solvents used were amines or contained amine residues, which could explain the presence of NDMA and NDEA. However, the source of the NDMA found in some batches of ranitidine is not known with certainty.
However, in the studies in this regard, which are still ongoing, it was concluded that the presence of nitrosamine impurities could be due to causes other than the reaction between nitrites and amines during the synthesis of an active principle.
The data obtained also seem to indicate that the nitrosamines would have been formed from starting materials, solvents and reagents fortuitously contaminated with nitrites or amines (for example, due to the presence of dimethylamine in dimethylformamide, a commonly used solvent).
Similarly, nitrites or amines could have been transferred in later stages. Specifically, possible contamination from external sources, such as solvents and recycled materials containing nitrosamines, has been noted.
What should authorization holders do and overcome the risk?
It is important to bear in mind that these other mechanisms, to varying degrees, do not specifically affect a certain product, but could occur in products that would otherwise not be at risk of containing nitrosamines. This happens, for example, with cross-contamination. This broader concern has led the European Medicines Agency (EMA) to request marketing authorization holders of all types of finished pharmaceutical products to carry out assessments to determine the risk that these products contain nitrosamines.
Marketing Authorization holders have six months to carry out the risk assessment. If a risk factor is detected, MA holders should undertake further investigations. As soon as possible, but at the latest within three years, all contamination should be removed.
License holders should follow the following step-by-step plan:
Assess the possibility that nitrosamines are present in each affected drug.
Prioritize reviews of drugs that have a higher risk of containing nitrosamines. Take into account the CHMP results obtained when evaluating sartans.
Inform the competent authorities of the results of your risk assessment.
Test all products that pose a risk of containing nitrosamines.
When nitrosamines are detected, report it to the appropriate authorities.
Make the necessary changes in the MA.
On the other hand, the FAMHP (Federal Agency for Medicines and Health Products) and the EMA (European Medicines Agency) recommend that patients continue to use their drugs normally, not to interrupt their treatment, and in case of doubt to contact their attending physician, pharmacist or Life Sciences Consulting Services in NJ.
Nitrate and nitrite are compounds that occur naturally in the human body and certain foods. They are also added to some processed foods to extend their shelf life. They can be converted to nitric oxide, dilate blood vessels, and lower blood pressure. They can also improve physical performance. The reason for this improvement in physical performance occurs due to nitrates enhancing the effectiveness of mitochondria. Mitochondria are the parts of cells that produce energy.
However, the preparation of nitrates or nitrite at high temperatures can lead to the formation of nitrosamines, which are carcinogens that pose a health hazard. Today's processed foods contain less nitrite because strict rules require manufacturers to limit the amount. You can check the label carefully when buying processed meat to find products with limited or no nitrate additives, which reduces the risk of exposure to nitrosamines.
How nitrosamine impurities cause damage to the health?
If people are exposed to nitrosamine contaminants for longer than acceptable levels and are exposed to them for a long time, it will increase the risk of cancer. However, a person taking a nitrosamines-containing drug intake limits every day for 70 years is not expected to have an increased risk of cancer.
And how to control nitrosamine impurities?
Due to the potential serious public health risks, it is necessary to identify and control harmful impurities in substances. During use, contamination of pharmaceutical ingredients or finished products may delay product approval and lead to a product recall, resulting in business interruption, regulatory investigations, and corrective action.
The nitrosamine impurities crisis has prompted regulatory agencies around the world to strengthen control of the drug manufacturing process. In the future, this increased monitoring may lead to the discovery of nitrosamine impurities in other drugs. Therefore, manufacturers need to understand which drugs can produce nitrosamines, how much nitrosamine impurities are formed, and how to control nitrosamines so that they do not exist at levels that may be harmful to patients.
The bottom line
The complex and global nature of the pharmaceutical supply chain requires greater care, transparency, and cooperation between manufacturers and regulators around the world to protect patient safety. Collaboration between the department and other stakeholders, as well as effective tools for the detection and control of contaminants, will help patients’ access safe drugs with expected therapeutic benefits.
In clinical studies, it has been verified that supplementing the diet with foods rich in nitrates produces a reduction in blood pressure and an improvement in vascular function, but its effect, at least direct, on cardiac pathologies is not yet clear.