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The Dangerous Irrationality of How Indian Regulators Classify Substandard Drugs

The Dangerous Irrationality of How Indian Regulators Classify Substandard Drugs

Photo: Volodymyr Hryshchenko/Unsplash

  • Last year, at least 13 children died after drinking poisoned cough syrup made by a Himachal-Pradesh-based drug manufacturer.
  • The incident was shocking: the culprit was a licensed manufacturer that had been around for more than ten years, not a fly-by-night operator.
  • For such a tragedy to happen, the manufacturer would have had to ignore ‘good manufacturing practices’. That they were able to was the symptom of a deeper rot.

Bengaluru: Last year, at least 13 Indian children died after drinking poisoned cough syrup made by a Himachal-Pradesh-based drug manufacturer named Digital Vision.

The incident was shocking: the culprit was a licensed manufacturer that had been around for more than ten years, not a fly-by-night operator. That is, the manufacturer had been under the watch of Himachal Pradesh’s state drug regulators, subject to routine inspections, and still managed to produce a botched drug.

The adulteration couldn’t have occurred unless the manufacturer had violated multiple laws. Diethylene glycol, the poison that had made its way into the cough syrup, is a well-known pharmaceutical adulterant. Preventing contamination with this chemical isn’t rocket science. It only requires a manufacturer to adhere to a system of checks and balances, called ‘Good Manufacturing Practices’ – which also happens to be a legal obligation for all drug-makers in the country.

For such a tragedy to happen, the manufacturer would have had to ignore this system – not once or twice but repeatedly.

There were ample signs that Digital Vision was, in fact, ignoring the system. As this correspondent recently reported, state drug regulators had found the firm’s drugs to be substandard at least 19 times before the diethylene glycol tragedy occurred. Why then did the Himachal Pradesh regulator, in whose jurisdiction the firm is located, not anticipate the tragedy?

There are two reasons.

The first is that all state drug regulators, including that of Himachal Pradesh, are heavily underfunded, while also being driven by perverse incentives to promote the pharmaceutical industry instead of protecting patients.

K.L. Sharma, former secretary to the Union health ministry between 2014 and 2017, documented these problems well in his recent book, Healing the Pharmacy of the World.

The result of this under-resourcing is that regulators can’t conduct the sort of inspections required to identify violations of ‘Good Manufacturing Practices’.

The second problem – partly a consequence of the first – is that state drug regulators have been taking a soft stance towards substandard drugs that place pharmaceutical-industry growth before patient interests.

To understand how this algorithm is driven by industry interests, we need to understand what a ‘standard’ drug is.

Broadly speaking, a regulatory text called a pharmacopoeia defines a standard drug in any country. For oral tablets, this text imposes the following key specifications: the content of active ingredient in the drug must match that on the label, with minimal variation (for many drugs, the acceptable variation is within 90-110% of the labelled amount). The drug must dissolve and disintegrate at a specified rate. Finally, the amount of impurities in the drug must not exceed predetermined limits.

Any drug that doesn’t meet these criteria is labelled a substandard drug. In India, its manufacturer is punishable with imprisonment for at least one year and a fine of at least Rs 20,000 under the Drugs and Cosmetics Act 1940.

But state drug regulators routinely treat dissolution, disintegration and impurity failures as minor compared to content failures. And even vis-à-vis the latter, there is no uniformity. Kerala will prosecute the maker of a substandard drug only if the active ingredient[footnote]The biologically active agent in the substance[/footnote] drops below 70%. For Karnataka, this line is 50%, while it is 30% for Maharashtra and zero for Gujarat.

Meanwhile, dissolution, disintegration and impurity failures are almost never prosecuted.

The reason? Since the 1990s, several Indian state regulators have been arguing that the Drugs and Cosmetics Act 1940 is too stringent with its punishments for substandard drugs, and that prosecuting every drug would throttle the industry. So, they said, some drug quality specifications had to be prioritised over others.

Second, out of content, dissolution, disintegration and impurity specifications, regulators believed that content assays were the easiest to comply with. This is why content assays are considered more important than others when it comes to penalising a firm.

Why a pharmacopoeia has quality specs other than content

Most of us can readily grasp why the content of active ingredients matters to medicine quality. After all, drug regulators license medicines after pharmaceutical firms have shown that a specific dose of the active ingredient treats an illness. This means the firm is obligated to to sell the same dose. Anything lesser or more than this dose could be ineffective or toxic.

But there is a reason why pharmacopoeias have tests for a medicine’s rate of dissolution, rate of disintegration and the levels of impurities as well. Unless a tablet disintegrates – i.e. breaks down into a powder – it won’t dissolve in the patient’s body, and thus fail to release its active ingredient. So a tablet containing the right dose may still be impotent if it doesn’t break down at the right time.

The pharmaceutical industry has known this fact since the beginning of the 20th century, with the Swiss pharmacopoeia being the first to require a disintegration test for compressed pastilles in 1907.

Regulators worldwide took a lot longer to fathom the importance of dissolution testing, however. The turning point for this specification came in the 1970s, when British doctors found that patients taking different brands of digoxin, a cardiac drug, had vastly varying blood levels of the medicine. This was despite the fact that all digoxin brands had the same content and similar disintegration rates.

Such unpredictable variations in digoxin are dangerous to patients, because this drug has a narrow therapeutic index. This means the blood level at which digoxin becomes toxic to the patient is not much higher than the treatment dose.  Eventually, scientists figured out that these differences were the result of some brands of the medicine dissolving faster in patients’ bodies than others.

The finding was a watershed moment that led to the US Pharmacopoeia introducing dissolution tests for the first time, in 1971. The Indian Pharmacopoeia did the same by 1985. Since then, dissolution testing has become a key quality specification for most solid-dose drug forms, like tablets and capsules.

Impurity tests also exist for a reason. The idea behind them is that, except the active ingredient and the fillers in a tablet, all else is of little use to the patient. Some of these superfluous extras can even be toxic. For example, an impurity in paracetamol tablets, called 4-aminophenol, can hurt the liver.

Even if impurities are not outright harmful, they can react with other chemicals in the drug and degrade the drug itself, Koduru V. Surendranath, a drug quality expert at the US Pharmacopoeia’s Hyderabad offices, said. This is why pharmacopoeias impose tight limits on impurities in most medicines.

The illogical Indian stance

Against this background, why did Indian drug regulators decide that dissolution, disintegration and impurity failures were minor?

A key reason behind this stance was a desire to spare both the pharmaceutical industry and already overburdened regulatory staff. If the manufacturer of every substandard drug was to be prosecuted, regulators believed the pharmaceutical industry would get choked. Understaffed regulatory agencies also wouldn’t be able to keep up with the court cases in such a situation, said D.R. Gahane, joint commissioner of the Maharashtra Food and Drug Administration.

According to Gahane, in most cases involving substandard drugs, the drug inspector who launches the prosecution has to be present at every judicial hearing. “Suppose I am an inspector, and I am filing five cases every year. After ten years, I will have fifty cases under me. Such a system would tremendously increase the workload on every inspector,” he said.

Such thinking led to the Drugs Consultative Committee, an advisory body comprising state drug regulators, recommending that the weapon of prosecution be used “sparingly”. The committee published two sets of guidelines, in 1996 and 2010, that suggest that regulators take manufacturers to court only when they can prove that the manufacturer intended to make a substandard drug.

The Drugs and Cosmetics Act itself says nothing about intent, treating all substandard drugs as offenses regardless of makers’ motivations.

Now, intent is hard to prove. After all, no one can read the manufacturer’s mind and whether they deliberately planned for their drugs to be defective. It was perhaps for this reason that state drug regulators interpreted the Drugs Consultative Committee’s guidelines in simplistic ways: they merely decided to prosecute the offenses they considered to be the worst.

But in picking the worst offenses, they kept industry interests and drug costs in mind – instead of quality.

For example, several regulatory officials told me that dissolution was considered a ‘minor’ offense because complying with this specification was technologically challenging. Hemant G. Koshia, commissioner of Gujarat’s Food and Drug Control Administration, said keeping up with dissolution standards is extremely hard, especially for certain dosage forms like enteric coated tablets [footnote]Enteric coated tablets are designed to resist the acidic stomach environment, so that the tablet could, for example, release its active ingredient in the intestine[/footnote]. Given these challenges, he suggested, prosecuting every manufacturer for dissolution failures was unfair.

Another common argument that regulators have advanced was that dissolution failures are often due to poor transportation and distribution conditions, instead of being the manufacturer’s fault directly.

“Nobody is manufacturing substandard drugs,” said M.P. George, who headed Kerala’s drugs control department until 2010. “But during transport, storage and handling, heat and humidity can cause the drugs to break down.”

Both George and Koshia were members of the Drugs Consultative Committee that gave the go-ahead to the body’s 2010 guidelines.

George also contended that given India’s hot and humid weather, and poor distribution infrastructure, substandard drugs were unavoidable. To solve this problem would mean manufacturers would have to invest in expensive packaging or distribution infrastructure, all of which would raise the prices of drugs to customers, he said.

“Who will bear the costs? Ultimately, it’s the people.”

But wouldn’t the increased cost be worth the better drug quality? According to George, it would be impossible to prioritise all aspects of drug quality equally while prosecuting firms.

Other regulators shared similar reasons for giving impurity failures the short shrift. Mainly, they said, manufacturers would find the high cost of testing for and controlling all impurities prohibitive.

An antiquated system that needs to change

While regulators deal with substandard drugs in a way that favours the industry, Indian patients are getting the short end of the stick.

Some regulatory officials’ claims don’t stand up to scientific scrutiny. For instance, dissolution failures don’t always happen due to storage conditions. A 2013 investigation by the UK’s Medicines and Healthcare-products Regulatory Agency into a dissolution failure for a hypothyroidism drug found the manufacturer’s own actions to be at fault.

There are other problems with the Drugs Consultative Committee’s 1996 and 2010 guidelines too. One of them is a requirement that state regulators establish ‘criminal intent’ before taking the manufacturer to court – even if the Drugs and Cosmetics Act itself requires no such thing.

This new demand dilutes the purpose of the Act because substandard drugs harm patients, whether the manufacturer means to do so or not, said Mahesh Zagade, a former head of the Maharashtra Food and Drugs Administration, who has been pushing for regulatory reform.

With the COVID-19 pandemic putting the spotlight on drug-quality issues in India, now may be an opportune time to overhaul this antiquated system. In September this year, the Centre set up a committee to redraft and modernise the Drugs and Cosmetics Act. The committee should also use this occasion to create a law that puts patient interests where they belong – above all else.

The reporting for this article was supported by a grant from the Thakur Family Foundation. The foundation did not exercise any editorial control over the contents of the article.

Priyanka Pulla is a science writer.

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