Answered: Six questions about cough syrup deaths linked to Haryana firm | Mint

Answered: Six questions about cough syrup deaths linked to Haryana firm

Gambian officials had first noticed unexplained deaths, following acute kidney injury, in July 2022. Photo: AFP
Gambian officials had first noticed unexplained deaths, following acute kidney injury, in July 2022. Photo: AFP

Summary

  • A deadly toxin found in syrup claimed lives of Indians too in the past. But manufacturers have rarely been punished.

BENGALURU : On 5 October 2022, the World Health Organisation (WHO) announced that four cough medicines, made by the Haryana-based manufacturer, Maiden Pharma, were suspected to have caused the deaths of 66 children in the West African nation, The Gambia. The brands—Promethazine Oral Solution, Kofexmalin Baby Cough Syrup, Makoff Baby Cough Syrup and Magrip N Cold Syrup—contained ingredients such as the anti-inflammatory drug paracetamol, and the anti-allergy drug chlorphenamine maleate.

Gambian officials had first noticed unexplained deaths, following acute kidney injury, in July 2022. Eventually, they found that the children fell ill 3-5 days after consuming one of Maiden Pharma’s cough syrups. When Gambian authorities sent 23 suspected medicine samples for quality testing, results showed that the batches of the four Maiden Pharma brands had high levels of diethylene glycol (DEG) and ethylene glycol, both of which are deadly toxins that attack human kidney tissue. The tragedy throws up several questions. We try and answer some of them.

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How does DEG get into medicines?

Historically, over a dozen cases of medicines contaminated with diethylene glycol have been documented. Among the first was the 1937 US Elixir sulfanilamide case. A chemist from the US-based pharmaceutical firm, S E Massengill Co, formulated a syrup version of sulfanilamide, an antibiotic previously administered in tablet form. To do so, he dissolved the drug in diethylene glycol, which he didn’t know was deadly. Over 100 people died after consuming this syrup.

Since then, at least 15 cases of diethylene glycol contamination have been documented till date, including five from India. Most of these involved medicines that contained either propylene glycol or glycerine, both “excipients" used to impart taste, form or bulk to medicines. When mixed with diethylene glycol, they become deadly.

Such adulteration occurs because diethylene glycol is similar in appearance and physical properties to propylene glycol and glycerine. It is also cheaper than pharma-grade propylene glycol and glycerine, leading unscrupulous manufacturers to dilute the ingredients with DEG.

Regulators across the world, including India’s apex drug regulatory agency, the Central Drugs Standard Control Organisation (CDSCO), and the country’s 36 regional regulators, enforce laws to prevent such incidents. These include requiring a manufacturer to test propylene glycol or glycerine for diethylene glycol before formulating any product with them.

Manufacturers are also required to follow a set of precautions to ensure the safety and efficacy of their products. These are called good manufacturing practices (GMP), and are enshrined under the Schedule M of the Drugs and Cosmetics Act, 1940.

What do we know so far about the case?

The CDSCO and Haryana’s food and drugs administration (FDA), both of which were responsible for overseeing the quality of products sold in The Gambia, have so far shared very little concrete information.

The Haryana FDA’s role is critical here because the four adulterated cough syrups were manufactured in Maiden Pharma’s Sonepat plant. So, the plant’s licence to operate would have been awarded by the Haryana FDA.

The CDSCO, too, was responsible for ensuring the quality of the products Maiden Pharma exported to The Gambia. Many importing countries require Indian manufacturers to provide a “WHO-GMP" certificate, an assurance that the plant is following practices recommended by the WHO. This set of GMP is widely known to be more stringent than India’s Schedule M and is awarded jointly in India by the CDSCO and the respective state regulator. Maiden Pharma had such a certificate, according to CDSCO’s website.

The Union ministry of health and family welfare initially sought to reassure Indian consumers of the safety of Maiden Pharma’s local products. In a 6 October press release, the ministry said the Haryana firm had been exporting the adulterated brands only to The Gambia, and that they weren’t sold in India. Y.K. Gupta, a member of the standing national committee on medicines and healthcare products, told ANI that Maiden’s Indian cough syrups “don’t have this possibility" of adulteration.

Both the ministry’s and Gupta’s claims are questionable. Maiden Pharma’s website shows that even though the firm didn’t sell the four adulterated brands in India, it sold the same formulations under other brand names. For instance, the firm’s Makoff baby cough syrup (which contains 2 mg of chlorpheniramine maleate, 5 mg of phenylephrine hydrochloride, and 10 mg of dextromethorphan hydrobromide) was sold only in The Gambia. But in India, the company sells Maidelin cough syrup, which contains the same ingredients in the same doses. If the firm manufactured the Gambian and Indian brands at the same time, both would be equally vulnerable to contamination.

Moreover, several of Maiden Pharma’s Indian products contain propylene glycol. If the excipient was adulterated with DEG, and if Maiden pharma used the adulterated batch in its Indian products too, this would put Indian customers at risk as well.

There are troubling indications that Maiden Pharma followed highly questionable manufacturing practices. After the WHO first communicated its concerns about the substandard drugs to CDSCO on 29 September, the Haryana FDA and the CDSCO inspected Maiden Pharma’s Haryana plant on 1 October. They identified major GMP violations.

In a showcause notice issued to the company, which Mint has viewed, the Haryana FDA noted that the company had failed to record batch numbers in the quality reports of raw materials like propylene glycol and sorbitol. Despite being required to do so, the company did not conduct stability tests on the four brands. Most incriminating was the Haryana FDA’s observation that Maiden Pharma had not been testing propylene glycol for DEG. But the question remains: How did CDSCO and the Haryana FDA award it a WHO-GMP certificate in the first place?

Following the showcause notice, Reuters reported on 12 October that the Haryana FDA had suspended manufacturing of all products at Maiden Pharma’s Sonepat plant. Maiden Pharma has not yet recalled any of its products in India, however.

The Haryana firm did not respond to an email from Mint. However, its director Vivek Goyal had told ANI on 8 October that while the company couldn’t comment on the ongoing investigation, it had followed all of CDSCO’s and the state regulatory protocols in over three decades of its existence.

Have the syrups been sold in other countries?

The answer is complicated. While the ministry says Maiden Pharma exported the four products only to The Gambia, the company may have exported the same formulation under other brand names to other countries. If so, any country which imported Maiden Pharma’s products must evaluate them for quality, especially if they contained propylene glycol.

Media reports from The Gambia indicate that the country’s health officials initially struggled to find a cause for the unexplained deaths and linked it to the consumption of cough syrup only later. Other countries that lack pharmacovigilance systems may fail to pick up on such adulteration, if health officials do not join the dots.

It is also possible that The Gambia was the only country that distributed the adulterated products. Sometimes, importing countries test incoming lots of medicine before distributing them. This may not have been true of The Gambia. According to the BBC, The Gambia’s health services director said the country “does not currently have a laboratory capable of testing whether medicines are safe and so they have to be sent abroad for checking."

What will India do next?

In its 6 October press release, the health ministry said it was waiting for more data from the WHO to investigate the case further. The data India asked for includes the results of the testing of the adulterated batches (known as “certificate of analyses") and evidence that the 66 deaths in The Gambia were caused by diethylene glycol and not something else. At the same, the CDSCO is also testing “control" samples of the implicated syrups, as well as samples of propylene glycol, from Maiden Pharma’s plant. A control is a sample from a batch already distributed in the market, which a manufacturer is required to retain by law to aid investigations such as this.

In an email to Mint on 10 October, a WHO spokesperson said that the certificate of analyses has now been shared with the CDSCO. “Investigations are ongoing to establish a causal link," he added.

While the WHO did not clarify exactly what investigations are being conducted, Gambian officials could establish this causal link in multiple ways. They could conduct a case-control study, in which hospitalized patients with acute kidney injury are compared to those without kidney injury to calculate whether the former group was more likely to have consumed the adulterated cough syrup. Such a study was conducted after a similar poisoning incident in Panama in 2006. If Gambian authorities find evidence of DEG in blood or urine samples from the affected children, this could also help in establishing that the cough syrup was responsible for the illnesses.

How has india dealt with such cases in the past?

India has seen five cases of contamination, according to The Truth Pill, a new book by public-health activist Dinesh Thakur and lawyer Prashant Reddy. The most recent incidents occurred between January 2020 and September 2020, when a cough syrup manufactured by the Himachal Pradesh-based firm, Digital Vision, killed 13 children in Jammu and Kashmir and Baddi in Himachal Pradesh.

After the children fell ill, and were admitted to Chandigarh’s Post Graduate Institute of Medical Education and Research, both the institute’s labs and CDSCO’s regulatory labs found DEG in the cough syrup.

Just like in the Maiden Pharma case, the CDSCO and the Himachal Pradesh Drug Regulatory Authority inspected the firm’s manufacturing facilities after the deaths were reported. Here too, the Himachal Pradesh drug regulator found major violations in Digital Vision’s plant, raising questions about why the regulator had not flagged these earlier. For instance, Digital Vision had not purchased the propylene glycol from a licensed pharmaceutical supplier, nor had it maintained a record of sending the propylene glycol for quality testing before using it for manufacture. Both could explain how the company’s products ended up being adulterated.

What happened in the digital vision case?

India has a poor track record of investigating adulterated drugs, punishing manufacturers and compensating victims. Under the Drugs and Cosmetics Act, such manufacturers can be punished with imprisonment of at least 10 years, and a fine of at least 10 lakh. The Act also says that if the adulteration leads to death, this fine may be used to compensate the victim’s family.

This provision is rarely implemented for multiple reasons. First, poorly trained and equipped state regulators frequently fail to collect evidence to build a strong case against the accused. Second, even when regulators prosecute firms, the court cases are long-drawn, meaning that victims have to wait decades for any compensation.

In 1986, 14 patients died in Mumbai’s Jamshetjee Jeejeebhoy Hospital after receiving DEG-contaminated glycerine. An investigation by then Bombay High Court judge, Bakhtawar Lentin, pointed at major illegalities by the manufacturer of the glycerine, suppliers, distributors, as well as the Maharashtra FDA. In response, the regulator cancelled the licences of the manufacturers and suppliers. But the case is still going on in the city’s Girgaun metropolitan magistrate court. None of the 27 accused in the case has received any punishment under the Drugs and Cosmetics Act. Nor have the families of the victims received any compensation, an official from the Maharashtra FDA told Mint.

In the 2020 Digital Vision case, Mint reported previously that the Himachal Pradesh drug regulator did not initiate legal proceedings against the firm until 2022, because it struggled to collect enough evidence that the DEG in the cough syrup had caused the deaths. Such evidence could have come from autopsies of the children, or a case-control study, neither of which the Himachal FDA, or the CDSCO, initiated. The families of the 13 deceased children have not received any compensation from Digital Vision, which continues to operate even today.

Priyanka Pulla is a Bengaluru-based reporter covering health.

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