The bitter truth of drug death

Gambian authorities first observed unexplained deaths following a serious kidney injury in July 2022. Eventually, they found that children fell ill 3-5 days after consuming one of Maiden Pharma’s cough syrups. When Gambian officials sent 23 samples of the suspected drug for quality testing, results showed that batches of four Maiden Pharma brands contained high levels of diethylene glycol (DEG) and ethylene glycol, both deadly toxins that can cause harm to the human kidney. attack the tissues. The tragedy raises many questions. We try to answer some of them.

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Historically, more than a dozen cases of drugs contaminated with diethylene glycol have been documented. The first was the US Elixir Sulfanilamide case of 1937. A chemist at the US-based pharmaceutical firm, SE Massengil Company, designed a syrupy version of sulfanilamide, the first antibiotic given in tablet form. To do this, he dissolved the drug in diethylene glycol, which he didn’t know was lethal. More than 100 people died due to the consumption of this syrup.

Since then at least 15 cases of diethylene glycol contamination have been documented, of which five are from India. Most of these include drugs that contain either propylene glycol or glycerin, both of which are “excipients” used to provide flavor, form, or bulk to drugs. When mixed with diethylene glycol, they become lethal.

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

Regulators around the world, including India’s apex drug regulatory agency, the Central Drugs Standard Control Organization (CDSCO) and the country’s 36 regional regulators, enforce laws to prevent such incidents. These require a manufacturer to test propylene glycol or glycerin for diethylene glycol before any product can be manufactured.

Manufacturers are also required to follow certain precautions to ensure the safety and efficacy of their products. These are called Good Manufacturing Practices (GMPs), and are enshrined under Schedule M of the Drugs and Cosmetics Act, 1940.

What do we know about the case so far?

The CDSCO and the Food and Drug Administration (FDA) of Haryana, both of which were responsible for monitoring the quality of products sold in The Gambia, have so far shared very little concrete information.

The role of Haryana FDA is significant here as four adulterated cough syrups were manufactured at Maiden Pharma’s Sonipat plant. So, the license to operate the plant must have been granted by the Haryana FDA.

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

The Union Ministry of Health and Family Welfare initially sought to reassure Indian consumers about the safety of Maiden Pharma’s local products. In an October 6 press release, the ministry said the Haryana firm was exporting the adulterated brands only to The Gambia, and they were not sold in India. YK Gupta, member of the Standing National Committee on Medicines and Healthcare Products, told ANI that there is “not a chance” of adulteration in Maiden’s Indian cough syrup.

The claims of both Mantralaya and Gupta are dubious. Maiden Pharma’s website shows that even though the firm did not sell the four adulterated brands in India, it did sell similar formulations under other brand names. For example, the firm’s Macoff Baby Cough Syrup (which contains 2 mg chlorpheniramine maleate, 5 mg phenylephrine hydrochloride and 10 mg dextromethorphan hydrobromide) was sold only in The Gambia. But in India, the company sells Medellin cough syrup, which contains similar ingredients in similar quantities. If the firm manufactured the Gambian and Indian brands at the same time, both would be equally vulnerable to contamination.

In addition, many Indian products from Maiden Pharma contain propylene glycol. If DEG was mixed in the excipients, and if Maiden Pharma used adulterated batches in its Indian products as well, it would put Indian customers at risk.

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

In a show cause notice issued to the company, which has been seen by Mint, Haryana FDA said that the company has failed to enter the batch number in the quality report of raw materials such as propylene glycol and sorbitol. Despite being required to do so, the company did not conduct stability tests on the four brands. Most objectionable was the Haryana FDA’s observation that Maiden Pharma was not testing Propylene Glycol for DEG. But the question is, how did CDSCO and Haryana FDA give it the WHO-GMP certificate?

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

The Haryana-based firm did not respond to an email from Mint. Though its director Vivek Goel had told ANI on October 8 that the company could not comment on the ongoing investigation, it has followed all CDSCO and state regulatory protocols in the three decades of its existence.

Are the syrups sold in other countries?

The answer is complicated. While the ministry maintains that Maiden Pharma only exported four products to The Gambia, the company may have exported similar formulations to other countries under different brand names. If so, any country that has imported Maiden Pharma products should evaluate them for quality, especially if they contain propylene glycol.

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

It is also possible that The Gambia was the only country that distributed adulterated products. Sometimes, importing countries test a lot of incoming drugs before distributing them. This cannot be true of The Gambia. According to the BBC, The Gambia’s director of health services said the country “currently does not have a laboratory capable of testing whether the drugs are safe and therefore have to be sent abroad for testing.”

What will India do next?

In its October 6 press release, the health ministry said it was waiting for further data from the WHO to investigate the matter further. The data sought by India includes test results of adulterated batches (called “certificates of analysis”) and evidence that 66 deaths in The Gambia were caused by diethylene glycol and nothing else. Additionally, CDSCO is testing “control” samples of the syrup contained from Maiden Pharma’s plant, as well as samples of propylene glycol. A control is a sample from a batch already delivered in the market, which a manufacturer is required to retain by law to assist in such testing.

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

While the WHO did not explicitly specify what was being investigated, Gambian officials could establish the causal link in a number of ways. They could have conducted a case-control study comparing hospitalized patients with severe kidney injury to those without kidney injury to calculate whether the former group had consumed adulterated cough syrups. was more likely. One such study was conducted after a similar poisoning incident in Panama in 2006. If Gambian authorities find evidence of DEGs in blood or urine samples from affected children, it could also help establish that cough syrup was responsible for the illnesses.

How has India dealt with such cases in the past?

Five cases of infection have been reported in India, according to a new book, The Truth Pill, 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 Himachal Pradesh-based firm Digital Vision killed 13 children in Jammu and Kashmir and Baddi in Himachal Pradesh.

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

Like in the Maiden Pharma case, 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 at Digital Vision’s plant, questioning why the regulator had not shown them earlier. For example, Digital Vision did not purchase propylene glycol from a licensed pharmaceutical supplier, nor did it maintain a record of sending propylene glycol for quality testing before using it for manufacturing. Both can explain how the company’s products got adulterated.

What happened in the Digital Vision case?

India has a poor track record of checking adulterated drugs, punishing manufacturers and paying compensation to victims. Under the Drugs and Cosmetics Act, such manufacturers can be punished with imprisonment of not less than 10 years and a minimum fine. 10 lakhs. The Act also states that if adulteration leads to death, this fine can be used to pay compensation to the victim’s family.

This provision is rarely implemented for several reasons. First, poorly trained and equipped state regulators often fail to gather evidence to build a strong case against the accused. Second, even when regulators prosecute firms, court cases tend to last longer, meaning victims have to wait decades for any compensation.

In 1986, 14 patients died of DEG-contaminated glycerin at Jamsetji Jeejeebhoy Hospital in Mumbai. An investigation conducted by the then Bombay High Court judge Bakhtawar Lentin pointed to major illegalities by the manufacturers, suppliers, distributors of glycerin as well as the Maharashtra FDA. In response, the regulator canceled the licenses of manufacturers and suppliers. But the matter is still going on in the city’s Girgaum Metropolitan Magistrate Court. None of the 27 accused in the case have received any punishment under the Drugs and Cosmetics Act. A Maharashtra FDA official told Mint that neither the families of the victims have received any compensation.

In the 2020 Digital Vision case, Mint previously reported that the Himachal Pradesh drug regulator did not initiate legal proceedings against the firm until 2022, as it was struggling to gather sufficient evidence that the DEG in cough syrup caused the deaths. made. Such evidence could have come from autopsies of children, or from case-control studies, neither of which were commissioned by the FDA or CDSCO. The families of 13 dead children have not received any compensation from Digital Vision, which is still operating today.

Priyanka Pulla is a Bengaluru-based reporter covering health.