Pharma wrap: Ranitidine carcinogen impurity scare and rising problem of drug contamination

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The US Food and Drug Administration (USFDA) on September 13 said it had detected low level of a cancer-causing impurity in samples of commonly used heartburn or acidity medicine Ranitidine.

Ranitdine is sold by French drug maker Sanofi in US under the brand name Zantac. Patents of the drug expired long back and several generics are also in the US market.

The impurity or contaminant is a type of nitrosamine called N-nitrosodimethylamine, or NDMA.

NDMA is classified as a probable human carcinogen or a substance that could cause cancer. NDMA is water-soluble, yellow in colour and has little or no taste and odour.

The substance is a known environmental contaminant and is found in water and food, including meat, dairy products and vegetables.

While USFDA has so far not asked people to stop taking ranitidine, the agency has advised patients who wish to discontinue to consult their doctors about other treatment options.

The New York Times has reported that the agency’s announcement came on the same day that an online pharmacy, Valisure, petitioned the USFDA to request a recall of all products containing ranitidine, saying its own tests had revealed high levels of NDMA, above USFDA’s daily limit.

Valisure’s petition speculated that the source of NDMA was the result of the “inherent instability” of the ranitidine molecule, which can degrade under certain conditions, such as when it is digested, to create NDMA.

Incidentally, NDMA is the same contaminant that was found in some versions of blood-pressure drug carrying valsartan earlier that made drug regulators of US and Europe to order recalls of these drugs and go for surprise inspections.

How contaminants enter drug supply chain

The supply chain of drugs has become global. China supplies most of the key starting materials and active pharmaceutical ingredients to Indian companies. Indian firms then formulate it and export to other markets, besides consuming domesticcally.

It was found that the Valsartan API made by China’s Zhejiang Huahai Pharmaceuticals contained probable carcinogenic impurities NDEA and NDMA, in more than permissible limits.

Indian and other generic companies were allegedly importing this tainted API from Zhejiang Huahai Pharmaceuticals and formulating it without properly testing the materials.

The USFDA warning letter states that the contamination with nitrosamine impurities was an outcome of Zhejiang Huahai Pharmaceuticals efforts to "improve the manufacturing process, increase product yield, and lower production costs."

This is not just the case of Chinese companies. Indian drug makers too had to recall products from US and Europe markets. USFDA made surprise checks at the factories of Indian companies making sartans. In that process, Aurobindo Pharma too received a warning letter for three of its plants associated with Valsartans.

Given the cut throat competition in generic drug industry, and relentless focus to raise yield, cut costs and improve profits, companies at times tend to lose sight of the safety of their customers or patients. Most of the times this happens unintentionally.

What India is doing

India is not immune to contamination of drugs. We too are part of the global supply chain. During the sartans contamination, it was found that the batches of drugs contaminated with nitrosamine impurities were released into the Indian market.

Indian drug regulator’s position to deal with the situation ranged from outright denial, to keeping an eye on valsartans imports from China. However there were no significant recalls of any drug batches.

India already faces the problem of substandard and counterfeit drugs, the contamination could be a new problem. Given that we have a weak adverse event report system, it is even difficult for us to figure out cases of contamination.