The discovery of carcinogenic chemicals in routinely prescribed medications has thrown the worldwide pharmaceutical business into disarray. Meanwhile, the Indian drug regulator has done very little to safeguard citizens. Recalls and sales of tainted batches have been halted in other parts of the world as a result of the findings. Pharma business in India, on the other hand, has been left unchecked.

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Suspension of ranitidine 

Because the ranitidine molecule may break down into a powerful carcinogen called N-Nitroso-dimethylamine, or NDMA, sales of this popular medication are prohibited in the United States, the European Union, and Australia. Manufacturers in Canada are obliged to test samples from their batches several times during the drug's shelf life to ensure that NDMA levels are within acceptable limits.

Ranitidine sales were suspended in several countries in 2020, and this is only one aspect of a much larger problem that has gripped the global pharmaceutical business. The issue started in June 2018, when the European Medicines Agency (EMA) discovered that batches of valsartan, a medication used to treat high blood pressure, had dangerously high amounts of NDMA.

In the three years since, the European agency and regulators from a number of other countries, including the US Food and Drug Administration (US FDA), Health Canada, and Australia's Therapeutic Goods Administration, have discovered not only NDMA but a number of other related compounds in a variety of drugs.

Ranitidine, two TB medicines known as rifampin and rifapentine, two diabetic drugs known as metformin and pioglitazone, and several blood pressure drugs known as the sartan group, including valsartan, losartan, and irbesartan, are among the tainted pharmaceuticals.

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Nitrosamine issue in India

Many Indian consumers of the impacted medicines were unaware of the nitrosamine issue. This is because the Indian drug regulator, the Central Medicines Standard Control Organisation (CDSCO), rarely engaged with customers during the worldwide upheaval, except to make infrequent assertions to the media that Indian drugs were unaffected by the nitrosamine problem.

CDSCO, on the other hand, does not seem to have done anything behind the scenes. Since the beginning of 2019, the CDSCO has only issued two brief and basic communications to state drug regulators, requesting that they notify pharmaceutical firms to "check their goods" and "take necessary steps to guarantee patient safety".

If nitrosamine levels are excessive, these briefings do not require businesses to recall or stop sales of their goods, nor do they require risk evaluations. Additionally, it is unknown if CDSCO independently evaluated Indian medicinal goods for nitrosamines, rather than relying on producers. The Indian pharmaceutical sector has been left to fester in the absence of any guidance from the national regulator.

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Nitrosamines are a kind of contaminant that has been around for a long time

Despite the fact that nitrosamines have only been a source of concern for the pharmaceutical business for three years, their oncogenic risk has been recognised for over sixty years. After automotive workers exposed to the chemical developed liver cirrhosis, two scientists in Surrey, England, started researching the health consequences of NDMA in the mid-1950s. Following that, the researchers discovered that rats fed NDMA for many months grew liver cancers.

The discovery sparked a flurry of studies with numerous related nitrosamines, including N-Nitrosodiethylamine (NDEA) and N-Nitrosomethylaminobutyric acid (NMBA), which have molecular structures that are quite similar. Scientists had examined over 200 nitrosamines in animals by the mid-1990s, and 85 per cent of them were shown to cause cancer in various species. Human studies strongly suggested that nitrosamines were carcinogenic as well.

Because low amounts of nitrosamines are present in the environment, this was terrible news. It's found in cured meats, cheeses, and beer, among other things. It may be found in drinking water and contaminated air. In fact, nitrosamines are among the most powerful poisons found in cigarette smoke. Given the risks, some brewers have devised methods to minimise NDMA production, while the World Health Organisation advises an NDMA limit in drinking water.

Despite their widespread use, nitrosamines have never been on the pharmaceutical industry's radar. There have been isolated instances of medication contamination in the 1970s, and NDMA was discovered in a now-banned painkiller called aminophenazone. Scientists have also discovered that some chemicals occurring in the human stomach called nitrites may react with medications to produce nitrosamines. However, since many food sources may generate much higher amounts of nitrosamines in the stomach, authorities did not consider them to represent a significant danger to consumers, according to a pharmacotoxicology specialist. He said, “Until the finding of NDMA residues in valsartan, the prevailing view among industry and authorities was that N-nitrosamines were unlikely to be found as pharmaceutical contaminants on a regular basis."

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Controversies

The valsartan controversy started in July 2019, when the European Medicines Agency discovered that an active pharmaceutical ingredient (API) for this medication, produced by Zhejiang Huahai in China, had very high amounts of NDMA. Drugmakers usually purchase API from companies like Zhejiang, add so-called 'excipients,' which stabilise and bulk up the medicine, and then offer it to customers as a tablet, syrup, or injection.

The discovery led the European authority to look into how NDMA got into Zhejiang's API and to issue a recall for any medicines that contained it. Similar measures were taken by other authorities, notably the US Food and Drug Administration. At the same time, authorities started looking for similar nitrosamines in recalled medicines.

They discovered not just NDMA in valsartan from other companies, but also NDEA and NMBA in other sartans within a few months. The nitrosamine drama was just getting started. Following these results, Valisure, a private pharmacy in the US state of California, began testing samples of the medicines it sold for nitrosamines. The company stated in September 2019 that it has discovered NDMA in a totally different medication called ranitidine. Ranitidine was eventually removed off the market by every manufacturer, including many Indian ones.

Furthermore, one manufacturer discovered NDMA in its pioglitazone; others found NDMA in their metformin preparations, and some detected nitrosamines in rifampicin and rifapentine (anti-tuberculosis drugs).

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How did the manufacturers of these medicines go so long without seeing that they included carcinogens?

All of these medications have extensive experience in their respective therapeutic areas. Since the 1990s, doctors have prescribed valsartan, losartan, and irbesartan to manage high blood pressure.

In 1981, a company began selling ranitidine under the trade name Zantac. Metformin was first synthesised in the year 1922. After all, drug regulations in every country compel producers to be aware of and strictly regulate contaminants in their products. After two years of research, authorities have some answers. In general, nitrosamines are produced when nitrosating substances (nitrogen compounds, for example) combine with amines in an acidic environment. And they're common chemical building components.

A non-profit that sets pharmaceutical quality standards, the United States Pharmacopoeia, claims tiny molecules are widespread. Water and pharmaceutical excipients frequently include nitrites, while many solvents contain amines.

In this light, the valsartan incident makes sense. The medication was initially created and produced until 2011-12 when its patent in the USA and Europe expired. It also modified its production method to reduce costs and increase output. When Zhejiang introduced new reagents and solvents, the substances sodium nitrite and the solvent dimethylformamide were combined in the same step.

According to EMA documents, dimethylformamide likely degraded to dimethylamine. This subsequently interacted with sodium nitrite to produce NDMA. Other sartan producers seem to have used Zhejiang's method, but with various amines and nitrosating agents, resulting in other nitrosamines.

Other contamination pathways existed. Instead, the sodium nitrite seems to have been left on the plant equipment as a consequence of inadequate cleaning following earlier stages. The nitrosamine was sometimes carried over between stages. Insidiously, one company discovered nitrosamines in the pill blister pack lidding foil. The foil was nitrocellulose, and the ink used to print on it was amine-based. When the packaging was sealed with heat, the final product was transferred to tablets.

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The perspective of the Indian regulator

By 2020, many worldwide authorities concluded that the nitrosamine issue was not limited to the few tainted medicines discovered so far. If these compounds can get into sartans, ranitidine, metformin, and pioglitazone, they can get into other drugs. As a result, they pushed for universal quality control standards.

In September 2020, FDA requested all pharmaceutical companies supplying the US to assess the risk of contamination during synthesis, storage, or delivery. This job was due in March 2021. To avoid nitrosamine formation, the producer must modify the synthetic method or maintain its levels below permissible limits. For manufacturers that cannot do this, frequent batch testing is required.

Unlike the Indian drug regulator CDSCO, whose activities are obscure. This is perplexing since the medicines marketed in India are likely to be synthesised in the same way as those sold in the US and Europe. However, the CDSCO claims that Indian medicines, such as sartans or ranitidine, are exempt to global issues.

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Legal actions

The nitrosamine findings triggered litigation against ranitidine and sartans manufacturers in the USA. Thousands of ranitidine users say the medication caused cancer and are suing the company that invented it, as well as two other generic manufacturers. In sartans cases, Indian companies are sued too.

Addressing the nitrosamine issue would not be simple for the CDSCO or Indian businesses. Initially, detecting contamination is technically challenging, and once detected, authorities must determine whether to recall promptly. This depends on the drug's importance and if alternatives exist. When the FDA discovered NDMA in the TB medicines rifampin and rifapentine, it temporarily increased the allowed amount of NDMA in these treatments since no other options were available.

And removing them from the market too soon would have created shortages. The availability of alternatives, such as famotidine, prompted the suspension of ranitidine sales. CDSCO must also decide. Nobody knows whether the FDA evaluated the dangers and advantages of ranitidine, sartans, metformin, and other tainted medicines before authorising their free sale. Neither has the agency tested these medicines. This poor communication has harmed the agency's reputation.

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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising super specialist from New Delhi.