Facts and Informations on Nitrosamines

Nitrosamine impurities are probable human carcinogens.
Nitrosamines (N-Nitrosodimethylamine [NDMA] and N-Nitrosodiethylamine [NDEA]), impurities containing Nitroso functional group.
NDMA is a common contaminant found in water and foods including cured and grilled meats, dairy products and vegetables.
Everyone is exposed to some level of NDMA on daily basis.
FDA and the international scientific community do not expect it to cause harm when ingested at low levels.
The FDA’s acceptable intake limit for NDMA in drug formulations is 96 nanograms per day.
Nitrosamine impurities may increase the risk of cancer if people are exposed to them above acceptable levels and over long periods of time, but a person taking a drug that contains nitrosamines at-or-below the acceptable daily intake limits every day for 70 years is not expected to have an increased risk of cancer.
The source of NDMA can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged.
Only limited impurity-specific toxicity data is available for NDMA and NDEA.
Due to their structural similarity, NDIPA, NEIPA, and NMBA are considered by international regulators to exhibit a toxicological profile like NDMA and NDEA.
Currently identified sources of nitrosamine impurities are listed below:
1.	Use of sodium nitrite (NaNO2), or other nitrosating agents, in the presence of secondary, tertiary amines or quaternary ammonium salts within the same or different process steps (if carry over can occur).
2.	Use of sodium nitrite (NaNO2), or other nitrosating agents, in combination with reagents, solvents and catalysts, which are susceptible to degradation to secondary or tertiary amines, within the same or different process steps (if carry over can occur).
3.	Use of contaminated raw materials in the API manufacturing process (e.g. solvents, reagents and catalysts).
4.	Use of recovered materials (e.g. solvents, reagents and catalysts), including recovery outsourced to third parties who are not aware of the content of the materials they are processing and routine recovery processes carried out in non-dedicated equipment.
5.	Use of contaminated starting materials and intermediates supplied by vendors that use processes or raw materials which may allow nitrosamine formation.
6.	Cross-contaminations due to different processes run on the same line and due to operator-related errors such as inadequate phase separations.
7.	Degradation processes of starting materials, intermediates and drug substances, including those induced by inherent reactivity in combination with carry-over of sodium nitrite (NaNO2), or other nitrosating agents. This could potentially occur also during finished product formulation or storage.
8.	Use of certain packaging materials.
Manufacturers are responsible for understanding their processes, which includes preventing the presence of unacceptable impurities. Manufacturers are also responsible for developing and using suitable methods to detect and limit unacceptable impurities, including any new impurities that may arise when they make changes to their manufacturing processes.