Nitrosamine Impurities

History of Nitrosamine Impurities

In July 2018, USFDA has alerted healthcare professionals  to   withdraw the drug, valsartan, from the market due to the presence of   an impurity, N-nitrosodimethylamine (NDMA). This impurity is highly toxic and is considered as  a "probable human  carcinogen"  meaning it can cause cancer. 

Nitrosamines are classified by the ICH M7(R1) Guideline as Class 1 impurities, “known mutagenic carcinogens,” based on both rodent carcinogenicity and mutagenicity data

Other Nitrosamine Impurities

The investigation of NDMA in valsartan leads to the  detection of some more nitrosamine impurities in  drugs viz., N-nitrosodiethylamine (NDEA), N -nitrosodiisopropylamine (NDIPA), N – nitrosoethylisopropylamine (NEIPA), N -nitroso-N-methyl-4-aminobutyric acid (NMBA) etc.

Mechanism of Formation

Nitrosamines are formed when nitrites, which can be formed from nitrates, react with a secondary or tertiary amine to produce nitrosamine impurities.

Source of Nitrosamine Impurities

Raw materials

Use of sodium nitrite (NaNO2), or other nitrosating agents

Recovered solvents

Reagents, Catalysts

Manufacturing process

Water Quality

Primary Packing materials

Cleaning of Equipments

Nitrogen Gas etc.

Risk Assessment

To control the presence of these nitrosamine impurities in drugs, risk assessment of the sources shall be evaluated thoroughly through a checklist. APIC (Active Pharmaceutical Ingredients Committee) has provided a guidance document on risk assessment of nitrosamine impurities in API in detail.

Testing of Nitrosamine Impurities

Regulatory agencies are setting interim limits based on maximum daily intake and they're in the process of setting new limits which will be  below 1 ppm for some of the nitrosamine impurities.

Hence if the risk assessment indicate the possibility of any of these nitrosamine impurities in the drug manufacturing, confirmatory testing is mandatory.

Since these limits are ultra low levels, the detection and quantification of impurities is very challenging. Many applications are published by using highly sensitive equipments like GCMS, LCMS, HRMS etc. including methods provided by USFDA.

Nitrosamine Impurities



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