Nitrosamine Impurities Method Development & Validation

ESTIMATION OF NITROSAMINE IMPURITIES (NDMA, NDEA, NMBA, NIEPA, NDIPA, NDBA and NMPA, NDMA and NDEA Analysis in India) By LC-MS/MS

Nitrosamine Impurities in Metformin ER Tablet: Nitrosamines are organic compounds of the chemical structure R2N–N=O, where R is usually an alkyl group. The feature is a nitroso group (NO+) bonded to a deprotonated amine. Most nitrosamines are carcinogenic.
They are usually produced by the reaction of nitrous acid (HNO2) and secondary amines.
HONO + R2NH → R2N-NO + H2O

Nitrosamines are produced by the reaction of nitrites and secondary amines. Nitrites are used as food preservatives, e.g. cured meats. Secondary amines arise from the degradation of proteins (food).
Nitrite and nitrosamine intake are associated with the risk of gastric cancer and o esophageal cancer.

Some Nitrosamines are as follows:
NDMA i.e. N-nitrosodimethylamine
NDEA i.e. N-nitrosodiethylamine
NEIPA i.e. N-nitrosoethylIsopropylamine
NDIPA i.e. N-nitrosodiIsopropylamine
NMPA i.e. N-nitrosomethylphenylamine
NDBA i.e. N-nitrosodibutylamine
NMBA i.e. N-nitrosomethyl butyric acid

These impurities can come from FOOD, Water and Soil as well.

Nalanda Research Laboratories developed the analytical method to estimate the Nitrosamine impurities by LCMS/ MS and achieved the LOD & LOQ as follows:

Achieved LOD & LOQ at Nalanda Research Laboratories

Guidance to avoid nitrosamines in human medicines

In September 2019 EMA began a review under Article 5(3) of Regulation (EC) No 726/2004 to provide guidance to marketing authorization holders on how to avoid the presence of nitrosamine impurities in human medicines. As part of this review, the CHMP has requested marketing authorization holders for human medicines containing chemically synthesized active substances to review their medicines for the possible presence of nitrosamines and test all products at risk.

Nitrosamines EMEA-H-A5(3)-1490 – Information on nitrosamines for marketing authorization holders (PDF/100.46 KB)

Nalanda Research Laboratories Achieved LOQ 0.01ppm and the Actual concentration achieved is 0.001ppm for Nitrosamine Impurities

Interim Limits for NDMA, NDEA, and NMBA in Angiotensin II Receptor Blockers. (ARBs)

• 1 . The acceptable intake is daily exposure to a compound such as NDMA, NDEA, or NMBA that approximates a 1:100,000 cancer risk after 70 years of exposure.
• 2 . These values are based on a drug’s maximum daily dose as reflected in the drug label.
• 3 . FDA is temporarily not objecting to losartan with NMBA below 9.82 ppm remaining on the market.