FWQRC, GMP, Life Sciences, Pharma

NDMA-Genotoxic Impurity

Hello Readers!!!

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Today’s discussion is about the hottest topic in the pharmaceutical industry, where many industries producing the Ranitidine and Valsartan drugs recalled the batches from the MARKET due to the presence of this impurity in the drug above the acceptance criteria.

First of all, What is NMDA and NDEA impurity?
N-Nitrosodimethylamine (NDMA), also known as dimethylnitrosamine (DMN) and N-nitrosodiethylamine, the member N-nitrosoamine class is a semi-volatile organic chemical, produced as a byproduct in chemical synthesis or as a whole.

A bit more about NDMA & NDEA impurities.

NDMA

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NDEA

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Numerous studies were conducted in vitro in bacterial and mammalian cells, there has been overwhelming evidence that NDMA is not only a mutagenic but also clastogenic. The NDMA impurity increased the frequencies of gene mutations, chromosomal damage, sister chromatid exchange, and unscheduled DNA synthesis in a wide variety of cell types including human and rodent cells.

The evidence of genetic effects has also been observed in in vivo studies. Clastogenic effects (e.g., micronuclei, sister chromatid exchange, chromosomal aberrations) in, bone marrow cells, spleen cells and peripheral blood lymphocytes, as well as in oesophageal, kidney cells have been observed in rodents (rats, mice, or hamsters) administered NDMA either orally or by intraperitoneal injection.
Evidence of genotoxicity (e.g., chromosomal aberrations, micronuclei, gene mutation,DNA strand breaks) has also been observed in the offspring of hamsters and mice.

How does it reacts with the human body?
NDMA is metabolized by CYP2E1 enzyme in the liver, which hydroxylates one methyl group. The resulting hydroxymethyl nitrosamine is unstable and decomposes to formaldehyde, which is also used to quantify the metabolic rate and methane-diazonium-ion, which methylates DNA and protein or reacts with water to methanol. The electrophilic intermediates produced by metabolic activation of nitrosamines, react rapidly with cellular nucleophiles and target for carcinogens during tumor initiation.

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The discussion about the NDMA impurities has been conversed previously.

  • In ICH M4 guideline “ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK”- Dated March 31, 2017.

  • World Health Organization Guidelines for Drinking-Water Quality, 3rd edition including 1st and 2nd addenda, 2008.

The topic is not only limited to Ranitidine and Valsartan drugs but it is applicable to all the drugs. All the drug substances should be assessed for the NDMA impurity and necessary controls should be taken.

Lets not wait for the regulatory authorities to take action upon the manufacturers. It is the Pharmaceutical manufacturers responsibility to deliver the right drugs to ensure the patient safety…

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