PremiumIn 2019, Asha’s toddler son had a bout of illness. The three-year old would frequently vomit while at the day-care facility he attended, and refuse to eat lunch. Asha, who works at a medical-diagnostic chain in Mumbai, approached her trusted paediatrician. His investigations revealed that the child had gastroesophageal reflux disease—a condition in which stomach acid travels up the food pipe, causing pain and nausea.
The paediatrician prescribed a commonly used drug for this condition, a syrup of the acid-blocker ranitidine. The brand name was Rantac Syrup, and it is sold by JB Chemicals, one of India’s largest manufacturers of the drug. After a two-week course, Asha’s son seemed to get better. But the reflux kept coming back, and Asha says doctors freely prescribe Rantac Syrup whenever kids have nausea. Just last month, when her son, now five years old, had fever and nausea, he got the same prescription again.
Unknown to Asha, however, ranitidine sales are either suspended or tightly circumscribed in several countries today. The USA, the European Union and Australia prohibit sales of this popular drug because the ranitidine molecule can break down into a potent carcinogen called N-Nitroso-dimethylamine or NDMA. In Canada, manufacturers are required to test samples from their batches at multiple times during the drug’s shelf life, to make sure NDMA is below safe limits.
The suspension of ranitidine sales in multiple countries, which happened in 2020, is just one part of a much bigger crisis that has engulfed the global pharmaceutical industry. The crisis first crept up in June 2018, when the European drug regulator, the European Medicines Agency (EMA), learnt that batches of a drug used to treat high blood pressure, called valsartan, had dangerously high levels of NDMA. In the three years since, the European agency and regulators of several other countries, including the US Food and Drug Administration (US FDA), Health Canada and Australia’s Therapeutic Goods Administration, have discovered not just NDMA, but several other related compounds in a variety of drugs. These contaminated drugs include ranitidine, two tuberculosis drugs called rifampin and rifapentin, two diabetes drugs called metformin and pioglitazone, and several of the so-called sartan group of blood pressure drugs, including valsartan, losartan and irbesartan.
The findings were deeply troubling for consumers because NDMA and many of its related compounds—together called nitrosamines—are strong carcinogens among animals, and likely have the same effect in humans. And the discoveries of nitrosamines in so many drugs suggested that contamination could be widespread. This realisation has sent EMA, US FDA and other regulators scrambling to control nitrosamine levels in drugs. Actions so far have included recalling and suspending sales of contaminated batches, widespread testing of samples, and the introduction of sweeping 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.
Yet, many Indian users of the affected drugs, like Asha, never learnt about the nitrosamine problem. This is because, all through the global turmoil, the Indian drug regulator, the Central Drugs Standard Control Organisation (CDSCO), barely communicated with consumers, except to make occasional claims to media outlets that Indian drugs were untouched by the nitrosamine issue.
In fact, CDSCO doesn’t seem to have done much behind the scenes either. Since 2019, CDSCO head V.G. Somani has only sent two short and rudimentary communiques to state drug regulators, asking them to inform pharma companies to “verify their products" and to “take appropriate measures to ensure patient safety". These communiques 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. Responding to questions from Mint, S. Eshwar Reddy, joint drugs controller of India, said these labs did not have instruments called Liquid Chromatography-High Resolution Mass Spectrometry systems (LC-HRMS) or Liquid Chromatography-Tandem Mass Spectroscopy systems (LC-MS-MS), both of which are crucial for measuring nitrosamines. It is possible that CDSCO conducted such testing in private labs, but neither Somani, nor Reddy answered questions on whether this was ever done.
Yet another possibility is for state drug regulators to conduct their own testing. But officials from the drug control department of Kerala, Maharashtra and Telangana told Mint that their labs did not have LC-HRMS and LC-MS-MS systems either, while a Gujarat drug department official said their lab had LC-MS-MS, but no LC-HRMS.
In the absence of any cues from the central regulator, the Indian pharmaceutical industry has been left to its own devices. Some firms have conducted recalls, but others continue to sell their products. Out of four makers of ranitidine that Mint contacted, only GlaxoSmithkline said it had stopped supplying ranitidine in India, as well as internationally. When asked if it ever recalled its products, a spokesperson from JB Chemicals, the maker of the Rantac brand, said the CDSCO didn’t ask it to do so. To a question on whether the firm was testing its products for nitrosamines, the spokesperson said JB Chemicals was “working on monitoring and limiting nitrosamines to the acceptable levels", but that the risk of NDMA in ranitidine was “negligible".
Two other sellers of ranitidine in India, Torrent Pharma and Zydus Cadila, did not respond to questions.
Nitrosamines—an old impurity
Even though nitrosamines became a bugbear for the pharma industry only three years ago, their carcinogenic potential has been known for over sixty years. In the mid-fifties, two scientists in Surrey, England, began studying the health effects of NDMA after automobile- workers exposed to the chemical developed liver cirrhosis. In subsequent experiments, the scientists showed that when rats ate NDMA over several months, they developed liver tumours.
The findings triggered a rash of experiments with dozens of related nitrosamines, such as N-Nitrosodiethylamine (NDEA) and N-Nitrosomethylaminobutyric acid (NMBA)—all of which have similar chemical structures. By the mid-nineties, scientists had tested over 200 nitrosamines in animals, and found 85% of them to trigger cancers in multiple species. Epidemiological studies hinted strongly that nitrosamines were carcinogenic in humans too.
This was decidedly bad news because low levels of nitrosamines are everywhere in the environment. Several foods have it, including cured meats, cheeses and beer. Even drinking water can have it, as can polluted air; in fact, some of the most potent toxins in tobacco smoke are nitrosamines. Given the health hazards, some beer makers have developed ways to reduce NDMA formation, while the World Health Organisation recommends an upper limit for NDMA in drinking water.
Despite their pervasiveness, nitrosamines were never big on the pharma industry’s radar before. Isolated cases of drug contamination did occur—in the seventies, a now-banned pain-killer called aminophenazone was found to have NDMA. Scientists have also found that some compounds called nitrites that are present in the human stomach can react with medicines to form nitrosamines. But regulators did not consider them to be a major risk to consumers, because several dietary sources can produce even greater levels of nitrosamines in the stomach, said Edward Snodin, a UK-based pharmacotoxicology expert. “Until the discovery of NDMA residues in valsartan, the general perception by industry and regulators was that N-nitrosamines were unlikely to be encountered on a regular basis as pharmaceutical impurities," he added.
The valsartan episode began in July 2019, when the European Medicines Agency learnt that an active pharmaceutical ingredient (API) for this drug, made by a Chinese manufacturer called Zhejiang Huahai, contained very high levels of NDMA. Drug-makers typically buy API from firms like Zhejiang, add so-called ‘excipients’—which make the drug stable and give it bulk—and sell it to consumers in the form of a tablet, syrup or injection.
The finding prompted the European regulator to investigate how NDMA got into the Zhejiang’s API, and to recall all drugs containing it. Other regulators, including the US FDA, followed up with similar actions. At the same time, the regulators also began scanning recalled drugs for related nitrosamines.
Within a few months, they had found not only NDMA in valsartan from other firms, but also NDEA and NMBA in other sartans, to boot. The implicated manufacturers included India’s Hetero Drugs, Aurobindo Pharma, Dr Reddy’s Laboratories and several more.
The nitrosamine saga was only beginning. Prompted by these findings, a private pharmacy in the US state of California, called Valisure, had begun testing samples from the drugs it was selling for nitrosamines. In September 2019, the firm announced that it had found NDMA in a completely unrelated drug—ranitidine. Eventually, ranitidine from every manufacturer, including several Indian ones, was pulled from the shelves.
Meanwhile, Hetero Drugs found NDMA in its pioglitazone; multiple Indian firms, including Lupin Pharma, Sun Pharma and Marksans Pharma found NDMA in their metformin formulations; and another set of firms, including Sanofi and Macleods, found nitrosamines called 1-methyl-4-nitosopiperazine (MNP) and 1-cyclopentyl-4-nitrosopiperazine (CPNP) in the tuberculosis drugs rifampicin and rifapentine.
All these drugs are veterans in their respective therapeutic fields. Doctors have used valsartan, losartan and ibesartan to treat high blood pressure since the nineties. Glaxosmithkline commercialised ranitidine, under the brand name Zantac, in 1981. Metformin was synthesized in 1922.
So, how did the makers of these drugs miss carcinogens in them for so long? After all, the drug laws everywhere require manufacturers to know the impurities in their medicines and to control them tightly. What went wrong?
Many routes, many risks
Two years of investigative work later, regulators have some answers. Generally speaking, nitrosamines are often formed whenever so-called nitrosating agents (compounds containing oxidised nitrogen, for example) react with compounds called amines in an acidic environment. And these chemical building blocks are commonplace. “They're ubiquitous," says Edwin Gump, the vice president of the small molecules department at the United States Pharmacopoeia, a non-profit that sets quality standards for medicines. Nitrosating agents called nitrites are often present in water or the excipients used in the pharma industry, and many of the solvents used for manufacturing contain amines.
Against this context, the valsartan episode becomes clearer. The drug was originally synthesized by Swiss firm Novartis, which manufactured it until 2011-12, when its patent on the drug expired in the USA and Europe. That year, Zhejiang Huahai began supplying generic versions of the API, and changed its manufacturing process to cut costs and improve yields. It was then that Zhejiang introduced new reagents and solvents, which resulted in the compound sodium nitrite and the solvent dimethylformamide coming together in the same step.
Documents from the EMA say the dimethylformamide likely broke down to dimethylamine, an amine. This then reacted with the sodium nitrite, a nitrosating agent, to form NDMA. Other sartan makers seem to have adopted variations of Zhejiang’s process, with different amines and different nitrosating agents, resulting in other nitrosamines forming.
There were other contamination routes too. In the case of pioglitazone, the sodium nitrite and dimethylformamide weren’t even present in the same step; instead the sodium nitrite seems to have been left over on the plant equipment as a result of poor cleaning-up after previous steps. In other cases, fully formed nitrosamine was carried over across multiple steps. More insidiously, one firm found the source of nitrosamines to be the lidding foil on the tablet blister pack. This foil was made of nitrocellulose, a nitrosating agent, while the ink used to print on it had amines. Both reacted, and the end product was transferred to tablets when the package was sealed with heat.
The good news is that each of these routes of contamination can be eliminated. Sartans can be manufactured without bringing nitrites and amines together, equipment can be cleaned, and nitrocellulose packaging can be replaced. Which is why the story of ranitidine is the most worrying of all: in its case the nitrosating agent and the amine seem to exist within the ranitidine molecule itself.
This fact had somehow been missed by GlaxoSmithkline and generic drugmakers for years. But after Valisure found NDMA in the drug, subsequent investigations revealed that the ranitidine itself was degrading slowly on pharmacy shelves, especially when exposed to heat or light, to form NDMA. This happened even when fresh ranitidine batches had no NDMA, suggesting that it wasn’t the drug synthesis that was the culprit, as with valsartan. In fact, when the Australian drug regulator tested samples from the market, it found that tablets closer to expiry dates were likely to have more NDMA, sometimes as high as 7 ppm. This is 21 times the limit regulators consider safe.
The knowledge of the inherent instability of ranitidine prompted the FDA, EMA and TGA to suspend sales of drug altogether by 2020, instead of merely recalling contaminated batches, like with sartans or metformin. According to David Light, the CEO of Valisure, “With ranitidine, it’s not a manufacturing issue. It’s an issue of the drug falling apart."
Can the forty-year old acid blocker ever make a comeback? Some argue that as long as manufacturers are able to keep NDMA levels much below 0.32 ppm in fresh batches, shorten the shelf life, and control temperature during storage, it may be possible to continue using ranitidine. But as of now, the drug is unavailable in multiple countries, and regular users have been asked to switch to alternatives like famotidine.
In India, it continues to be prescribed and sold without any warning, however.
The risk of NDMA
One of the most challenging aspects of controlling nitrosamines in drugs is that they are toxic even at vanishingly small levels. And the instruments sensitive enough to detect such trace amounts, such as LC-HRMS, weren’t widely available until recently (See accompanying article).
The US FDA-mandated daily upper limit of 0.096 micrograms is what regulators call a ‘virtually safe dose’—a concept used to set upper limits for carcinogens like NDMA for which there is no safe threshold. In other words, virtually safe dose enters the picture when data suggests that a carcinogen is not absolutely safe at any dose. Still, because it may be impossible to limit its levels to zero, the virtually safe dose is a practical alternative. It is calculated such that when 100,000 people consume a virtually safe dose of a carcinogen for seventy years, one extra case of cancer is likely to be seen among them. The idea is that this rate is acceptable to society, because it is lower than typical background cancer rates.
The drug batches recalled globally in the last three years were higher than the virtually safe dose for NDMA, sometimes by a little, and sometimes by a mile. Valsartan from Zhejiang Huahai was the worst offender, with 75.4 micrograms per gram in some batches. This means that people taking the full dose of this drug – 320 mg – would have been exposed to 24 micrograms of NDMA per day. Based on this, the EMA calculated that if 5,000 patients took the full dose for the six years it was available in Europe, there would be one excess case of cancer, clearly an unacceptable level. FDA data shows the NDMA doses in drugs from some Indian companies was fairly high, if not as high as Zhejiang. For instance, one of Torrent Pharma’s batches had up to 11 micrograms of NDMA in a 320 mg tablet, 114 times the virtually safe dose.
The Indian regulator’s stance
By the year 2020, several global regulators had come to the conclusion that the nitrosamine problem was unlikely to be restricted to the few contaminated drugs identified so far. If these chemicals could creep unexpectedly into sartans, ranitidine, metformin or pioglitazone, they could get in elsewhere, too. This led to them pushing for sweeping quality control requirements from all manufacturers.
In September 2020, FDA asked all pharmaceutical manufacturers supplying to the USA to evaluate the risk that their drug could be tainted either during synthesis, or during storage and distribution. This task had to be completed by March 2021. If a risk was identified (for instance, a manufacturing step in which a nitrite or an amine came together), the manufacturer must alter the synthetic route to either prevent the nitrosamine from forming, or keep its levels below acceptable limits. If this isn’t possible, the manufacturer must test final product batches regularly.
In contrast, the Indian drug regulator CDSCO’s actions have been highly opaque. This is puzzling because the drugs that Indian firms sell domestically are likely to be manufactured by the same synthetic routes as those sold in the USA and Europe. Yet, CDSCO has made the puzzling claim that Indian drugs, whether sartans or ranitidine, are untouched by the problems sweeping the globe.
Mint asked a few Indian sartan and metformin manufacturers, which recalled their products in the USA and Europe, if they did the same with contaminated batches in India. A spokesperson from Aurobindo Pharma, which recalled losartan and Irbesartan in the USA, didn’t respond to a question about recalls in India, but said only that the firm’s sales for these products in India were negligible, and that they met all CDSCO standards. CDSCO currently doesn’t impose any standards for nitrosamines.
Dr Reddy’s Labs, Sun Pharma, Torrent Pharma, Hetero Labs and Zydus Cadila did not answer questions about nitrosamine contamination and steps taken to protect Indian consumers. Rajiv Desai, the global quality head at Lupin Ltd, said that the firm recalled a batch of valsartan from the Indian market, but didn’t do the same for its metformin extended-release tablets. In July 2020, the firm had recalled all metformin extended-release batches from the US, after the US FDA found some to have high nitrosamine levels.
State drug regulators also haven’t done much on this front. DR Gahane, the joint commissioner of Maharashtra Food and Drug Administration, said the response of drug manufacturers in the state to the CDSCO’s two communiques, asking them to “verify their products", was poor. Several firms had claimed then that they did not have the LC-HRMS or LC-MS-MS systems to conduct testing, he explained. Further, Maharashtra’s own state lab lacks this equipment, and it had conducted no testing either.
Hemant Koshia, the commissioner of Gujarat’s Food and Drug Administration, where multiple ranitidine manufacturers are located, said that API manufacturers in the states were meeting European standards. Asked how this was possible, given that Europe had suspended ranitidine sales, he said he wasn’t aware of the development. He added that the state lab only had LC-MS-MS, but no LC-HRMS, making it difficult to test for nitrosamines.
K J John, drug controller of Kerala, confirmed that the state lacked the facilities to test for nitrosamines, and had not done so since 2018. While the current joint director of the Telangana Drugs Control Administration didn’t respond to Mint’s questions, B Venkateshwarlu, who retired as joint director in January 2021, said the state lacked testing facilities.
Class action lawsuits
In the USA, the nitrosamine discoveries have snowballed into lawsuits against the makers of ranitidine and sartans. Thousands of ranitidine users now claim that the prolonged use of the drug gave them cancer, and are demanding damages from not only from the firm that first synthesized ranitidine, Glaxosmithkline, but also generics makers such as Torrent Pharma and Cadila. In the case of sartans too, names of Indian firms appear in lawsuits.
But back home, the story is different. Asha says she never heard about the NDMA issue. She is surprised, and plans to ask her paediatrician to change the drug. While Asha’s toddler only took ranitidine on two occasions, other Indians have taken it for years together. Rashmi*, a 37-year old resident of Bengaluru, says she has been on the drug on and off since her teenage years. When news of recalls first broke out in 2019, she dismissed it as a problem afflicting only a few batches. “I didn’t realise Zantac has been removed from several markets," she says.
To be sure, responding to the nitrosamine problem isn’t going to be easy for the CDSCO or for Indian firms. First, it is technologically complex to detect contamination (see accompanying story). And after a drug is found to be contaminated, regulators must decide whether to recall immediately. This decision is based on multiple factors, including how critical the drug is, and whether alternatives are available. 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. In ranitidine’s case, the decision to suspend sales was driven by the availability of alternatives, such as famotidine.
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. Asha was surprised to learn about the global nitrosamine developments, but wasn’t surprised that CDSCO hadn’t done much about them. “I know how callous regulatory bodies are," she says. She just wishes her paediatrician, who she trusts a lot more, had known better.
(Name changed to protect privacy)
Priyanka Pulla is a Bangalore-based reporter covering health. Her reporting on Covid-19 is supported by a grant from the Thakur Family Foundation. The Foundation exerts no editorial influence on her work.
