The toxic drug impurity imperiling Indians

Relevance: The role of Central Drugs Standard Control Organization (CDSCO) in administering safe pharmaceutical drugs.

Synopsis: Detection of carcinogenic compounds in commonly used drugs has plunged the global pharma industry into crisis mode. India’s drug regulator has done little to protect citizens.

Background

Research has found that many drugs produced by global pharmaceutical industry have the presence of N-Nitroso-dimethylamine or NDMA. These contaminated drugs include ranitidine, tuberculosis drugs (rifampin and rifapentine), diabetes drugs (metformin and pioglitazone) and sartan group of blood pressure drugs.

What is N-Nitroso-dimethylamine or NDMA?

1. NDMA and many of its related compounds together called nitrosamines are strong carcinogens among animals, and likely have the same effect in humans.
2. Nitrosamines are often formed whenever so-called nitrosating agents (compounds containing oxidised nitrogen, for example) react with compounds called amines in an acidic environment.
3. The US, European Union and Australia prohibit sales of many popular drugs that can break down into a potent carcinogen like NDMA.

Risks associated with NDMA

• Through research, it was found that nitrosamines trigger cancers in multiple species. Epidemiological studies hinted strongly that nitrosamines were carcinogenic in humans too.
• One of the most challenging aspects of controlling nitrosamines in drugs is that they are toxic even at tiny levels.

Prevalence

Low levels of nitrosamines can be found in several everyday products and even natural resources such as air and water. Several foods have it, including cured meats, cheese and beer. Even drinking water can have it, as can the polluted air.

• In fact, some of the most potent toxins in tobacco smoke are nitrosamines. The World Health Organization (WHO) recommends an upper limit for NDMA in drinking water.

Steps taken by global regulators

Actions so far have included recalling and suspending sales of contaminated batches, widespread testing of samples, and the introduction of new quality control measures to prevent future contamination.

All these actions have happened in full public view, with the regulators sharing their decisions continuously with patients, doctors and manufacturers. For instance, In Canada, manufacturers are required to test samples from their batches multiple times during the drug’s shelf life, to make sure NDMA is below safe limits.

Further, in the US, the nitrosamine discoveries have led to lawsuits against the makers of ranitidine and sartans.

India’s reaction

Indian drug regulator, the Central Drugs Standard Control Organisation (CDSCO), has barely communicated with consumers over this issue. CDSCO currently doesn’t impose any standards for nitrosamines.

Since 2019, CDSCO has only directed state drug regulators to inform pharma companies to “verify their products” and to “take appropriate measures to ensure patient safety”.

• Directions issued do not ask companies to recall or suspend sales of their products if nitrosamine levels are high, nor to conduct risk assessments. It is also unclear if CDSCO independently tested Indian drug products for nitrosamines, instead of merely leaving it to manufacturers.
• In fact, the CDSCO’s four central drug-testing laboratories do not have the equipment required to do such tests. Recently, joint drugs controller of India, said these labs did not have instruments
  called Liquid Chromatography-High Resolution Mass Spectrometry systems (LC-HRMS) which are crucial for measuring nitrosamines.

Due to lack of any substantial directions from CDSCO, some firms have conducted recalls, but others continue to sell their products.

Way forward

When the US FDA learnt of NDMA in the tuberculosis drugs, rifampin and rifapentine, it took a temporary decision to increase the allowable level of NDMA in these drugs, because no alternative drugs were available for this deadly disease. And pulling them from the market immediately would have caused dangerous shortages.

CDSCO needs to make these decisions too. But there is no public record of the agency having weighed the risks and benefits of ranitidine, sartans, metformin or other contaminated drugs before allowing them to be sold freely. Nor is there any record of the agency testing these drugs.

This lack of communication has left many consumers with little faith in the agency.

Terms to know:

• CDSCO