PROBLEM STATEMENT
On December 2022, the central Asian country of Uzbekistan’s government claimed that 18 kids died after ingesting cough medicine made by Indian pharmaceutical company Marion Biotech.[12] “To date, 18 out of 21 children with acute respiratory disease have died as a result of taking Doc-1 Max syrup manufactured by the Indian company Marion Biotech Pvt Ltd,” as per report from Health Ministry of Uzbekistan. “It was found that the deceased children, before admission to hospital treatment, took this drug at home for 2–7 days 3–4 times a day, 2.5–5 ml, which exceeds the standard dose of the drug for children.”[2] A similar incidence happened in Gambia, where 70 children death were linked to ingestion of cough syrup.[3] The initial report linked these deaths to unacceptable levels of diethylene glycol and ethylene glycol in cough syrups. However, deaths due to contamination from diethylene glycol are nothing new.
Previous reports of these occurrences came from India, the US, Bangladesh, Panama, and Nigeria.[4] In 2021, the Food and Drug Administration (FDA) issued the warning to an Indian state company’s tainted cough syrup that caused 12 youngsters to lose their lives in an Indian state in 2021.[5] These deaths were also related to the cough syrup’s high diethylene glycol content. The medicine was then taken off the market by the state administration in all other states where it had been promoted.[5]
WHY THIS HAPPENED, THAT IS, WHETHER THERE WAS ANY CONTAMINATION TO THE FORMULATION?
In October, the WHO discovered ethylene glycol (EG) and diethylene glycol (DEG) in four samples of cough syrup manufactured in India and classed them as contaminates.[6] DEG and EG are toxic to humans and can be lethal if swallowed, according to the WHO. These two toxic chemicals may cause gastroneurological symptoms like nausea, vomiting, diarrhea, dysuria, headache, altered sensorium, and acute tubular necrosis, which may result in death.[7]
Historically, it was a similar incident that led to enactment of stricter laws to check poor manufacturing practices. Strict restrictions governing manufacturing methods in the US were enacted as a result of a similar occurrence that occurred in 1937 and resulted in the deaths of more than 100 people there. This incident is known as the “sulfanilamide elixir incident.” The problem arose because DEG, a good solvent, sweet-tasting, and reasonably priced substance, was used to mix sulfanilamide, a highly bitter-tasting medicine, in order to taste-mask the elixir formulation for use in children.
DEG (72 percent w/v) was selected as a vehicle in the formulation because there was a dearth of knowledge about the toxicity of excipients, which are frequently utilized formulation ingredients.[8] The following year, the US Congress passed the 1938 Federal Food, Drug, and Cosmetic (FD and C) Act, mandating safety evaluations prior to the release of new drugs. The 1938 law transformed the FDA from a law enforcement agency to a regulatory agency responsible for overseeing the safety evaluation of new drug products. This was also the initial step toward the widespread implementation of good manufacturing practice (GMP).
Both DEG and EG, as solvents in liquid pharmaceuticals, are impermissible adulterants according to the National Centre for Biotechnology Information (NCBI) in the United States.[9] Experts assert that producers occasionally replace commercial grade versions of nontoxic solvents like glycerine or propylene glycol to the solvents that may contain DEG and EG and cause contamination.[8] Acute kidney failure due to acute tubular necrosis, which develops between 8 and 24 hours following exposure to fatal levels of a drug is the primary cause of mortality in poisoning cases. If they do not receive treatment, symptoms can escalate to multisystem failure in 2 to 7 days.[7] These recurring disasters [Table 1] highlight the gaps in implementation of the worldwide regulation of commonly used drugs, including control of manufacturing facilities and supply chains, particularly those producing goods for underdeveloped nations that lack the means to monitor the safety of pharmaceuticals.[10]
WAS THERE ANY ISSUE WITH THE MANUFACTURING OR QUALITY CHECK?
To answer this question, we need to understand the current situation of Indian pharmaceutical industry and its regulation first. The issue with medication production and regulation has long existed. In India, Central Drugs Standard Control Organization (CDSCO) is the regulatory body under the Ministry of Health and Family Welfare that is in charge of setting standards for drugs, approving clinical trials, monitoring the quality of drugs imported into the nation, and coordinating the efforts of State Drug Control Organizations by offering professional guidance in an effort to achieve uniformity in the enforcement of drug laws.
The CDSCO has done well with this, creating rules for clinical trial conduct under the New Drug and Clinical Trial Rule of 2019, introducing audio-visual consent, and being the first nation to create a formula for clinical trial compensation for expeditious case closure. But it has not been up to date with guidelines for manufacturing practices especially with the problem of generic drugs which has mushroomed in country.[11] The existence of multiple brands for one product is one of the major problems with pharmaceutical product regulation in India. The agencies may have granted license to manufacture and sell to any company that can demonstrate that its product is bioequivalent to the standard pharmaceuticals due to the widespread demand of the nation.
The fact that the pharmaceutical companies market their drugs under distinctive names, the so-called branded generics, has made things more difficult. This is unlike many other countries (US, UK) where unique name is restricted to the innovator company and all other manufacturers sell their product as generic name. With so many different formulations, it becomes difficult to monitor the quality of these products.
For example, on search of dextromethorphan in CIMS, around 543 products of various brands appear containing dextromethorphan alone or in combination with other drugs. Most of them are combination drugs with active ingredients having phenylephrine, chlorpheniramine, or others. Regulation of such huge volume of products is an impossible task.[121314]
However, it is crucial to recognize that the issues within the Indian drug regulatory framework extend beyond corruption, which was the main focus of the Lentin Commission in 1988. There is also a problem with regulatory design. This encompasses various issues such as a lack of transparency in regulations and the overly complicated distribution of regulatory powers across India.
The regulatory powers are divided among 38 authorities spread across each state and union territory, in addition to the CDSCO operating under the union government.[10]
For instance, inspection reports of pharmaceutical facilities are not accessible to the public, making it impossible to assess whether drug inspectors are effectively carrying out their duties. Furthermore, the jurisdictional problem arises due to each state and union territory having its own drug controller responsible for issuing manufacturing licenses. This often leads to a lack of information sharing and coordination among them.
Interstate investigations become extremely challenging because a drug inspector from one state, such as Maharashtra FDA, cannot enter and inspect a drug facility in another state like Himachal Pradesh (HP) without being accompanied by a drug inspector from the HP Drug Control Administration. However, the HP Drug Control Administration has its own reasons for not permitting such inspections, primarily driven by the state government’s desire to maintain Himachal Pradesh as a pharmaceutical manufacturing hub.[10]
These flaws collectively contribute to catastrophic events like the deaths of young children. As a country known as “the developing world’s pharmacy,” India’s regulatory failures impact not only its citizens but also the citizens of its trading partners. There are other issues as well, such as drug regulation being a policy matter that lies at the intersection of regulatory science and public law, which are not particularly popular among the general public or politicians.
Another concern is the difficulty in measuring and explaining the harm caused to patients as a result of poor regulatory policies and ineffective practices. The consequences of an inadequate drug regulation system are similar to climate change—linkages are not immediately visible, and the harm to public health is not easily quantifiable. However, it is undoubtedly causing harm.
Therefore, it is crucial to overhaul the regulations governing the Indian pharmaceutical industry.[10]
CONCLUSION
India is the biggest supplier of generic medicines worldwide. The pharmaceutical industry in India is the world’s third largest by volume and fourteenth largest by value. In 2019–20, the total yearly revenue of pharmaceuticals was 289,998 crore rupees.
The pharmaceutical industry currently generates approximately 1.72 percent of the nation’s gross domestic product.[10] The recent events have made a considerable dent in its image. To continue to be a leader of world pharmacy, it needs to bring the required reforms by taking appropriate measures to meet the highest standard. Otherwise, it will lead to erosion of trust and may lead to decline of its market capitalization to its competitors.
Despite the challenges, if the issue raise were solved, it has the potential to grow more to help fulfil the global demand of safe and efficacious medicines.
RECOMMENDATIONS AND WAY FORWARD
In our opinion, there is a need to bring reforms at regulatory levels to bring down the number of available brands to one digit; it will help to closely monitor these pharmaceutical products. The problem is not limited to cough medication, and limiting the number of products will help utilize the resources more effectively.
The Indian pharmaceutical companies are leading manufactures of the world. They provide generic medicine to several countries including USA, UK, and Africa. The Indian pharmaceutical companies need in addition United States Food and Drug Administration (USFDA) approval of manufacturing plants before being approved for supply to USA.
These plants undergo regular monitoring for quality to meet the standards. These regulations are not applied to the plants which do not supply to USA. Similar inspection, monitoring, and assessment are required to determine the compliance of the facilities across all manufacturing plants.
Any medicines including cough syrups for sale should be approved by competent authorities. Governments should allot adequate and trained regulators, have to assign resources to inspect manufacturers, increase market surveillance, and take action where required.
Conflicts of interest
There are no conflicts of interest.