Earlier this month, nearly 70 children in The Gambia died, reportedly after consuming Indian-made cough syrups contaminated with toxic chemicals. Two years ago, doctors in Jammu came across similar cases of children dying of kidney failure after drinking cough syrup made by Digital Vision, a company based in Himachal Pradesh. Investigations revealed the presence of an industrial grade solvent – diethylene glycol (DEG) – in the drug. The solvent is not used for the manufacture of drugs and is toxic to humans. The adverse effects of DEG have been known to the pharmaceutical industry since 1937. Yet there have been at least five major cases of DEG poisoning in India since 1972.
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Five decades later, the World Health Organization (WHO) has again reported the presence of “unacceptable” levels of DEG and ethylene glycol in four cough syrups manufactured by Maiden Pharmaceuticals, based in Haryana, which exported medicines to the West African nation. The United Nations health body said the company did not provide any guarantees on the safety and quality of the products. With the WHO alert sparking an outcry, the Union Health Ministry asked Maiden Pharmaceuticals – a company with a tainted past – to halt all manufacturing activities. The government has also formed a panel of experts to investigate the whole episode and suggest a future course of action.
However, this is too little, too late, as the ministry is well aware of the deep-rooted evils of India’s drug regulatory systems. What the WHO’s red flag has done is shine the spotlight, once again, on the Central Medicines Standards Control Organization, which has been described as an ‘Augean stable’ by a panel. of legislators ten years ago. Pharmaceutical manufacturers reap the benefits of such an opaque system until an accident occurs, as happened recently in The Gambia.
When officials from the Haryana Food and Drug Administration inspected Maiden’s manufacturing plant in Sonipat following the WHO alert, they found several discrepancies in the records, due to which the quality of the material first could not be verified.
The company could not provide the batch numbers of the propylene glycol and sorbitol solution, as well as that of the sodium methylparaben to the drug inspectors, which prevented them from tracing the source of the chemicals and verifying their quality. The company did not check for contaminants such as DEG and ethylene glycol in the solvent. She also did not produce the ongoing test report of the products.
Experts are of the opinion that it is entirely possible for traders supplying the chemicals to mislabel DEG as propylene glycol or to adulterate propylene glycol with DEG, either to cut costs or to due to poor quality control measures. “The company may not be using pharmaceutical grade propylene glycol. If the company does not perform quality testing on the final product, it is doomed,” said S Srinivasan of All India Drug Action Network.
There are many other discrepancies in the quality controls of Maiden’s four products. Now pause and think of India’s over 10,000 pharmaceutical manufacturing units – of which over 2,000 are WHO’s Good Manufacturing Practice Standards (WHO-GMP) certified – owned by over 3,000 companies and the thousands of products they make every day. . How robust and reliable is the regulatory system to verify their quality?
In August 2013, during a routine investigation, drug inspectors in Tamil Nadu discovered that an anti-diabetic drug, Glipizide, was “not of standard quality”, as it did not actually contain Glipizide. Instead, the tablet contained another antidiabetic drug called Glibenclamide, which cannot be used as a substitute for Glipizide because the human body takes three to four hours longer to metabolize the drug. This puts people at serious risk because it increases the risk of hypoglycaemia in patients who unwittingly take one drug instead of another.
When inspectors checked the production plant – Alfred Berg and Co was the manufacturer – they found shocking shortcomings, including the lack of a separate quality assurance department. The most critical records documenting the manufacturing process were not accessible to drug inspectors, and in the records that were accessible, inspectors reported several discrepancies. A lawsuit filed against the company in December 2014 has yet to go to trial as of March 2022.
Maiden, Digital Vision and Alfred are not isolated examples. There are many such companies that produce “non-standard grade” (NSQ) drugs. Some of them may be taken off the market after quality testing, but many continue to thrive. Since some states including Kerala and Maharashtra have active drug administration, there are also lawsuits against NSQ drug producers. But in the absence of a centralized database, it is impossible to identify those still sold on the market.
“The whole quality control process is riddled with holes. We don’t think about quality from the design stage. We think about quality as an end product. How else would you explain the fact that the whole Baddi region in Himachal Pradesh has about 690 pharmaceutical manufacturing units, as a newspaper reports, but not a single functional HPLC (high performance liquid chromatography) machine to test their quality?” asks Dinesh Thakur, public health activist and founder of Citizens for Affordable, Safe and Effective Medicine, a nongovernmental organization.
The main obstacle to improving the quality of drug regulation is the existing legal and administrative structures of the Central Drug Standards Control Organization (CDSCO). Unlike other regulators like Telecom Regulatory Authority of India and Food Safety and Standards Authority of India, CDSCO has no statutory backing.
CDSCO operates as a subsidiary of the Directorate General of Health Services (DGHS). The Drug Controller General of India (DCGI), who heads the CDSCO, is a lower officer in the hierarchy and is responsible to the DGHS, the Health Secretary and the Minister of Health. In fact, the Ministry of Health’s drug regulatory division, headed by a secretary-level co-officer, wields more power, even though the division lacks technical knowledge and relies on CDSCO.
“Such an administrative setup is completely outdated and inconsistent with modern regulatory structures that have evolved after liberalisation,” Thakur wrote in a letter to the health ministry, suggesting changes to the regulatory system.
An effort to initiate change was made nine years ago when the Medicines and Cosmetics (Amendment) Bill 2013 was introduced in Parliament to establish a Central Medicines Authority as an independent body. The bill was drafted based on recommendations made by a 2003 committee headed by the then Director General of the Council for Scientific and Industrial Research, RA Mashelkar. But the bill was never debated in parliament and was eventually withdrawn.
Need for transparency
The weak regulatory system is also plagued by a lack of transparency and the complex distribution of regulatory powers among 38 authorities (one in each state and union territory, and CDSCO) without much oversight.
There is also no public database of trademark violations, inspections, and history. In the absence of such a system, it is impossible for a drug inspector in Assam to know whether a particular drug has been banned in Punjab. The Maharashtra Food and Drug Administration cannot raid a manufacturing plant in Himachal Pradesh as it has no jurisdiction, even though it is aware that NSQ drugs are being produced at the plant.
“The CDSCO must be transparent at all levels. Drug inspection reports must be made public and there must be a database in which the reports of the 28 testing laboratories are made available to the public. Besides, there needs to be a centralized authorization and inspection function,” says T Prashant Reddy, patent attorney and co-author, with Thakur, of The Truth Pill, a new title on the system of Indian pharmaceutical regulation. In the absence of such cross-linking, drugs banned in one state can easily be sold in another state.
The examples of poor regulatory standards in India are too many – from the approval of hundreds of irrational FDCs (fixed dose combinations) to the questionable approval of the locally developed Covid-19 vaccine, Covaxin. The extent of the rot in the approvals process was revealed a decade ago, when the Parliamentary Standing Committee on Health scrutinized CDSCO, inspecting records that had never before been made public.
The lawmakers’ investigation uncovered numerous skeletons hidden in the closet. The House panel cited several instances in which doctors located in different cities, thousands of miles away, wrote identical letters of recommendation. In one case, a Mumbai-based doctor wrote a letter of recommendation the same day he received the DCGI notice to comment on a proposal with 131 pages of scientific data to go through. In another instance, a CDSCO official instructed a pharmaceutical company to select experts, obtain their opinions, and forward them to the DCGI office for approval of an FDC that was not authorized in North America. North, Europe and Australia. All of these cases, according to the panel, show that “there is sufficient evidence on the record to conclude that there is a collusive link between drug manufacturers, certain CDSCO officials and certain medical experts.”
The parliamentarians made recommendations to fill these gaps. What the government did in response was superficial. The ‘Action Taken’ report, tabled by the government in April 2013, contained 29 pages of scathing remarks and observations by MPs on the Department of Health. “The ministry has amply demonstrated that it has neither an intention to cleanse the stables of CDSCO’s Augeas nor any concern for probity and the rule of law,” the deputies wrote.
A year later, the government led by Narendra Modi came to power with a promise of change. “But almost nothing has changed at CDSCO over the past seven years,” says an expert.
One of the consequences of the Maiden Pharma controversy was a formal notice served on Thakur and Reddy for having publicly declared that the CDSCO could not escape its responsibility in the Gambian episode. But we are not talking about the deep-rooted corrections that are needed in the Indian regulatory system to put its house in order.