India’s cough syrup testing regime has a deadly blind spot

In October, Maharashtra’s drug inspectors visited a pharmaceutical company in Dombivli that makes cough syrups, among other medicines. What they found there was cause for alarm – the company had skipped testing an ingredient in the cough syrups for the presence of the deadly toxins, diethylene glycol and ethylene glycol.

Just a few days earlier, on October 5, the World Health Organization had linked the deaths of 70 children in The Gambia to four cough syrups exported by an Indian manufacturer, Maiden Pharmaceuticals.

Both, a parliamentary inquiry report of the Gambian government and an investigation by the World Health Organization, showed the presence of diethylene glycol and ethylene glycol – known to be potentially fatal – in the four cough syrups manufactured by Maiden Pharmaceuticals.

India’s experience with diethylene glycol poisoning has been equally tragic. Three years ago, 12 children in Jammu had died after being given cough syrup contaminated by diethylene glycol.

The most common route for diethylene glycol or ethylene glycol to enter cough syrups is through a basic ingredient – glycerine.

The deadly glycerine switch

When a paracetamol syrup, cough syrup or anti-cold syrup is manufactured, it needs a solvent to dissolve all its active ingredients, add sweetness and act as a lubricant. Active ingredients are the chemicals in a drug that make it effective. The solvent used could be glycerine or propylene glycol, a clear, faintly sweet and viscous liquid.

But not every kind of glycerine is suitable for use in cough syrup. Glycerine IP, or Indian pharmacopeia grade, is used in drugs and medicines, while industrial glycerine is used in chemicals and to make cosmetics.

“Glycerine that will be ingested has to be pharmacopeia grade, and one for external use can be industrial grade,” said Dushyant Bhamre, joint commissioner (drugs) of the Thane Food and Drugs Administration.

According to the good manufacturing practices framed by the World Health Organization and adopted by countries, a manufacturer must use glycerine IP to make a cough syrup since the industrial-grade variant can contain diethylene glycol and ethylene glycol.

“But industrial glycerine is cheaper,” said Ravi Menon, former drug controller in Kerala. “Many companies want economic benefits, they do not look at quality.” As a result, he said, the raw material is compromised through adulteration.

That can have lethal consequences. Diethylene glycol is colourless and odourless and tastes mildly sweet, making it difficult to distinguish from pharmacopoeia grade of glycerine. But it is toxic and can cause diarrhoea, altered mental status, acute kidney injury, and lead to death, especially if it is a child who is consuming it. Ethylene glycol can cause respiratory distress and affect the central nervous system.

To avoid both these impurities, a manufacturer has to test glycerine or propylene glycol before use through a technique called gas chromatography. Some manufacturers conduct this test in-house while others outsource it to a private laboratory. Menon said if the drug inspector finds these test records missing, they can even suspend or cancel the manufacturing licence, as the consequences of skipping this step can be fatal.

Maiden Pharmaceuticals, the Haryana firm whose cough syrups have been linked to the deaths in The Gambia, had missed the crucial step of testing propylene glycol before using it, or at least did not have records to prove so, according to an inspection carried out by the state drug controller in October last year.

It is clearly not an exception.

In their surprise visits in October, prompted by the deaths in The Gambia and the World Health Organization’s medical alert, Maharashtra officials found that four firms had skipped tests for diethylene glycol or ethylene glycol. At least three of the firms export syrups to other countries and all of them supply cough syrups to the domestic market.

The Maharashtra Food and Drug Administration ordered the four companies to shut down temporarily and issued them showcause notices.

But Maharashtra is among the better states when it comes to food and drug administration. The concern is that other states might not be as vigilant.

Joint commissioner Bhamre said that when a drug manufacturer procures raw materials, it must verify whether the vendor has a licence to sell pharmacopoeia-grade chemicals. “As per good manufacturing practices, a drug manufacturer should procure only from licensed suppliers,” Bhamre said.

But companies have been known to fall short of due diligence. In 1986, 14 patients died of renal failure at the JJ Hospital in Mumbai as the glycerine they were treated with was contaminated. The company had procured the glycerine from a vendor who had no licence to sell pharmacopoeia grade glycerine. Neither the hospital nor the supplier had verified the vendor’s credentials.

What inspections in Maharashtra found

The Maharashtra Food and Drug Administration inspected 84 oral liquid manufacturing units starting October 7. It found that one-fourth of them, or 21, did not follow good manufacturing practices. This included minor violations like poor record-keeping and major ones like skipping crucial tests. Four of them, like Maiden Pharmaceuticals, were not testing glycerine or propylene glycol for diethylene or ethylene glycol impurity.

“It shows the scale at which manufacturers flout production norms and play with the lives of people,” said Abhay Pande, president of All Food and Drug License Holders Foundation.

KL Sharma, former joint secretary in the Ministry of Health and Family Welfare, said, “Maharashtra is considered one of the better states when it comes to regulatory mechanism.” He added that if manufacturing units in Maharashtra are found flouting norms, the situation is likely to be replicated in other states across India.

In 2015-’16, the Central Drugs Standard Control Organisation and state drug controllers inspected over 200 drug manufacturing units. “We found compromises in most of them, 72% did not comply with good manufacturing practices and good laboratory practices under the Drugs and Cosmetics Act,” Sharma said. Only a minuscule number of units complied with all regulations, he added.

“Nothing seems to have changed since,” he said.

The Maharashtra officials found glaring missteps in four units – Glacier Pharmaceuticals in Amravati, Bhushal Chemical Private Limited in Badlapur, Asuwaldi Pharmaceuticals and Dortmund Laboratories, both in Dombivli.

In Asulwadi Pharmaceuticals in Dombivli, drug inspectors found that while the propylene glycol purchased was pharmacopoeia grade, the unit did not test it before use. On October 14, the authorities issued a stop-production notice and collected four samples of the syrup meant for export. A stop-production notice is issued in case of a serious violation.

Records seen by Scroll show that after Asulwadi Pharmaceuticals was asked to stop manufacturing, the Food and Drug Administration officers directed it to test the existing batch of propylene glycol and control samples of previous batches. If the tests were clear, it would be allowed to resume production. The company tested its samples in a private laboratory. It submitted the laboratory report and the authorities allowed it to resume production on October 21.

Separately, a showcause notice was issued to the company. “But we found that the manufacturer did not give a satisfactory response to the notice,” said assistant commissioner (drug) RP Chaudhari.

But even as late as January 1, authorities were yet to officially hand a licence suspension notice to Asulwadi Pharmaceuticals that would have penalised the unit by stopping production for 10 days. An official from the Food and Drugs Administration, who did not want to be identified, said the department is short staffed. “We have to prepare and send the notice to them,” the official said.

On October 13, the Maharashtra officials found that Dortmund Laboratories too had skipped the propylene glycol test. The two other firms – Bhushal Chemical Private Limited in Badlapur, and Glacier Pharmaceuticals in Amravati – did not test raw materials before use, officials said.

Dortmund Laboratories and Glacier Pharmaceuticals did not reply to an email query from Scroll on the drug officers’ findings, while Bhushal Chemical and Asulwadi Pharmaceuticals did not respond to phone calls.

“In all four cases, we will prosecute the manufacturer if their response to the showcause notice is not satisfactory,” said Bhushan Patil, the joint commissioner (drugs) in the Maharashtra Food and Drugs Administration.

But Patil points to a problem. The samples they collected from two of the four units inspected were sent for testing in October. “Two months later, the results have not come,” he told Scroll in the first week of January. “The labs are short-staffed and overburdened.”

The fault in the design

While good manufacturing practices demand that companies test the raw material for diethylene glycol before the production of cough syrups, what are the safeguards to ensure that medicine that has already been adulterated with the toxin does not find its way to the market?

Are cough syrups that are already being sold on the Indian market being randomly tested for the toxins?

Strangely, the answer is no. The reason: it is not in the rules.

While drug inspectors do sometimes check cough syrups being sold on the market to check if the drug has active ingredients in the right amounts, or if it contains fungi or other contaminants, it is not tested for diethylene glycol.

Haryana drug controller Manmohan Taneja said that is because the current Indian pharmacopoeia norms do not demand that drug officers test a finished product of cough syrup for diethylene and ethylene glycol. “We assume that the manufacturer is conducting this test as per law,” Taneja said.

Said Bhamre of the Thane Food and Drugs Administration, “Diethylene and ethylene glycol impurity is not supposed to be in a cough syrup. There are several other impurities that a drug must not have. We can’t test a sample for all such impurities.”

Need for centralised approach

On December 27, following the deaths of children in The Gambia, the Central Drugs Standard Control Organisation announced that it would inspect drug manufacturing units along with state regulators.

But not all states have stepped up vigilance. Haryana drug controller Taneja said they conducted a drive to inspect manufacturing units but “found no contravention”. Kerala stopped purchasing products from Maiden Pharmaceuticals but did not order a drive to inspect all cough syrup units while Gujarat took no action.

Sharma, former joint secretary in the health ministry, said India needs to move towards a centralised approach for drug regulation. “We have 37 drug regulators working in silos,” he said. “If one drug is found substandard, a centralised mechanism to prosecute the offender must be undertaken.”

Currently each state takes action, like suspension or a recall, within its jurisdiction and only informs the state where the manufacturing plant is located. The recall is not nationwide.

The Central Drugs Standard Control Organisation also tested 1,375 drugs and syrups and found that at least 5% of them were of substandard quality. VG Somani, drug controller general of India, did not respond to calls asking about the measures being taken to limit diethylene glycol poisoning after deaths in The Gambia and Uzbekistan.

In December, the Uzbekistan health ministry had said that 18 children in the country had died because of the side-effects of a cough syrup produced by an Indian pharmaceutical firm.

Sharma said the government’s inspection drive is a knee-jerk reaction. “Manufacturers look for shortcuts with fast selling products like cough syrups where the cost is lower,” said Sharma. “The drug regulators have to ensure robust manufacturing standards through regular inspections.”

This reporting was supported by a grant from the Thakur Family Foundation. Thakur Family Foundation has not exercised any editorial control over the contents of this article.