What are nitrosamines?

Nitrosamines, or more correctly N-nitrosoamines, refer to any molecule containing the nitroso functional group. These molecules are of concern because nitrosamine impurities are probable human carcinogens (a substance capable of causing cancer in living tissue). Although they are also present in some foods and drinking water supplies, their presence in medicines is even so considered unacceptable.

Background

Nitrosamines are chemical compounds classified as probable human carcinogens on the basis of animal studies. 

EU regulators first became aware of nitrosamines in medicines in July 2018 when nitrosamine impurities, including N-nitrosodimethylamine (NDMA), were detected in blood pressure medicines known as ‘valsartans’.

There is a very low risk that nitrosamine impurities at the levels found in medicines could cause cancer in humans.

What is Valsartan :

Valsartan is an Angiotensin II Receptor Blocker (ARB) and belongs to a family of analogue compounds commonly referred to as the sartans.

Further nitrosamine impurities were subsequently detected in other medicines belonging to the sartan family, including: N-nitrosodiethylamine (NDEA), N -nitrosodiisopropylamine (NDIPA), N -nitrosoethylisopropylamine (NEIPA) and N -nitroso-N-methyl-4-aminobutyric acid (NMBA).

More recently, nitrosamine impurities have been reported in pioglitazone and ranitidine containing products.

Why are they Present :

The formation of nitrosamines is generally only possible when secondary or tertiary amines react with nitrous acid. Nitrous acid itself is unstable but can be formed in situ from nitrites (NO2) under acid conditions.

In the case of the sartan compounds, most contain a tetrazole ring and formation of this tetrazole ring employs the use of sodium nitrite. Coincidently the solvents employed either were amines, or contained traces of amines, and this likely afforded the observed NDMA and NDEA. The origins of NDMA content in batches of ranitidine currently remains unclear.

However, during on-going investigations it was also concluded that the possibility for nitrosamine impurity content was broader than simply the concurrent presence of nitrites and amines in the synthesis of the active pharmaceutical ingredient (API).

Evidence suggests that sources of nitrites or amines as unintentional contaminants of starting materials, reagents and solvents – such as dimethylamine in the common solvent dimethyl formamide (DMF) – may also provide circumstances in which nitrosamines may form. The carryover of nitrites or amines from subsequent steps may also afford opportunities for formation.

Contamination from External factors :

Notably, contamination from external sources has been identified as a source of nitrosamine content. In particular, contamination from the use of recycled materials and solvents that already contain levels of nitrosamines. A cited example of this involves the use of recycled DMF, which is quenched with sodium nitrite to destroy residual azide as part of the recovery process. Furthermore, the recycling of materials and solvents is often outsourced to third parties who may not implement adequate controls in view of the content of the materials they are processing.

So during Risk Assessment of Nitrosamine impurities in Finished products we have to considered the below factors for sources of contamination (But not limited to).

a) API may contain Nitrosamine impurities- which may be carried forward to Finished product.

b) Excipients may contain Nitrosamine impurities- which may be carried forward to Finished product.

c) The incompatibility/ reactivity of the raw materials (APIs and Excipients) used in finished product formulation may lead to formation of Nitrosamine impurities.

d) Purified Water may be contaminated by nitrosamine impurities.

e) Manufacturing process may lead to formation of Nitrosamine Impurities due to the use of sodium nitrite, other nitrites, recycled reagents or solvents.

f) Equipment surface may add nitrosamine impurities during processing of the product and same shall be carried forward to finished product

g) Primary packing materials in which drug products are packed

h) The air supplied to the processing cubicle may carry nitrosamine impurity contamination to the product

i) The compressed air supplied to the processing equipments may carry nitrosamine impurity contamination to the product

These broader concerns have prompted the European Medicines Agency (EMA) to request that Marketing Authorisation Holders (MAHs) of all Finished Pharmaceutical Products (FPPs) conduct risk assessment to determine the risk of nitrosamine presence during the manufacturing of Human medicines.

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