An ampoule of remdesivir is pictured at a news conference in Hamburg, Germany, April 2020. Photo: Ulrich Perrey/Pool via Reuters
- COVID-19 patients suffered debilitating side-effects after receiving multiple batches of remdesivir manufactured by Zydus Cadila, during India’s second wave.
- The incident demonstrated the laxity of drug regulators in responding to adverse events associated with drugs – especially injectable ones.
- Unfortunately, this incident wasn’t isolated: discussions with regulators and procurers suggest these agencies may have ignored many such incidents.
Bengaluru: In a recent report, this correspondent wrote about how Indian COVID-19 patients suffered unintended and debilitating side-effects after receiving multiple batches of remdesivir manufactured by Zydus Cadila, during India’s second wave.
The incident demonstrated the laxity of drug regulators in responding to adverse events associated with drugs – especially injectable ones.
But it also pointed to the significant shortcomings of states’ drug-procurement agencies. These procurers were the Rajasthan Medical Services Corporation, Maharashtra’s Haffkine Biopharmaceutical Corporation, the Uttar Pradesh Medical Supplies Corporation, the Bihar Medical Services & Infrastructure Corporation and the Gujarat Medical Services Corporation. They had purchased the remdesivir from Cadila – and had no functional pharmacovigilance systems to follow up on adverse-events.
Unfortunately, this Cadila incident – which may have been caused by contaminants called endotoxins – wasn’t an isolated one. Subsequent discussions with regulators and procurers suggest that these agencies have ignored similar incidents during the pandemic.
This correspondent learnt that when hospitals in Maharashtra reported similar adverse events following the use of remdesivir made by Hyderabad-based Hetero Healthcare, the state’s drug lab failed to investigate the incident in full. Multiple other states’ drug labs have also been frequently skipping endotoxin tests, which is a key quality test for injectable drugs.
Added to this, procurers, who typically test the drugs they purchase before distributing them to hospitals, have stopped doing so during the COVID-19 pandemic. This means that they can’t find and remove the supply of unsafe drugs before they reach patients.
The Hetero Healthcare case
In April 2021, there was an incident eerily similar to the Cadila one, but involving Hetero Healthcare’s remdesivir brand, Covifor. Around that time, several hospitals in Panvel, Navi Mumbai, Pune and Raigad reported that their patients were experiencing fever, chills, low SpO2 and low blood pressure after receiving Covifor from batch HCL21013.
When Hetero learnt about the issue, it told hospitals, stockists and institutions to stop using the drug immediately.
But here too, the Maharashtra regulator’s Mumbai lab repeated the mistakes that characterised the Cadila case. In the latter, the Uttar Pradesh Food Safety and Drug Administration (UPFSDA) and the Maharashtra Food and Drug Administration (MFDA) had skipped the crucial bacterial endotoxin test while evaluating Cadila’s remdesivir.
These endotoxins can cause the symptoms associated with Cadila’s drug – plus the test for endotoxins defines a key quality parameter for all injectable drugs.
So it was worrying that aside from omitting this test, the UPFSDA’s Lucknow lab and the MFDA’s Mumbai lab also concluded – misleadingly – that Cadila’s remdesivir was of standard quality.
And the same thing happened with HCL21013. According to a copy of the Mumbai lab’s test report, which this correspondent has seen, the lab conducted multiple quality tests but left out the one for endotoxins – and then concluded that the samples from HCL21013 batch were “of standard quality”.
The reason why the Mumbai lab skipped the test in Hetero Healthcare’s case is unclear, but points to arbitrariness in how the lab functions.
In the Cadila case, MFDA joint commissioner D.R. Gahane had a few reasons for the lab skipping the test: In May 2021, remdesivir was a proprietary drug in India, which meant that no country’s pharmacopoeia – including the Indian Pharmacopoeia – had common quality specifications for this drug. For such proprietary drugs, Schedule V of the Drugs and Cosmetics Act, India’s primary drug law, only requires that the drug comply with the quality specifications listed in the Indian Pharmacopoeia’s “general monograph” for the dosage form.
And because the Cadila remdesivir batch associated with adverse events in Maharashtra was sold as a powder [footnote]To be mixed with saline and sterile water before use[/footnote], Schedule V only mandated that the drug meet the Indian Pharmacopoeia’s general monograph for “powders for injection”, Gahane said. And, he added, this monograph lacked an endotoxin test.
But this reasoning fails to explain why the Mumbai lab didn’t test Hetero Healthcare’s remdesivir for endotoxins. HCL21013 was not sold as a powdered injectable but as a liquid. And the Indian Pharmacopoeia’s general monograph for liquid injectables does contain a test for endotoxins.
When asked about this, Gahane didn’t have an explanation but agreed that the skipping was a problem.
“We are asking the lab for clarification on why the endotoxin [test] wasn’t done,” he said. “We are of the opinion that it should have been done.”
Gahane also said that to explain the adverse events, the lab official had instead conducted a so-called abnormal toxicity test in both the Cadila and the Hetero cases. “The lab said that as they carried out the [abnormal] toxicity test, the endotoxin test wasn’t carried out.”
If correct, this statement suggests that the Mumbai lab personnel had a poor understanding of quality testing for injectable drugs. The abnormal toxicity test was developed in the 1940s and is outdated. It can’t reliably pick up on the presence of endotoxins, and is gradually being phased out from global pharmacopoeias for this and other reasons. For this test, lab personnel inject the drug into healthy mice and observe them for 24 hours. If the mice survive, the drug is deemed to have low levels of harmful toxins.
There are more reliable methods today to test for bacterial endotoxins. One, called a rabbit pyrogen test, involves injecting rabbits with the drug and monitoring them for temperature changes. This is the test the general monograph specifies for liquid injectables, such as Hetero’s Covifor.
A more sensitive version of this test is the limulus amoebocyte lysate test: the sample is combined with an extract from the blood cells of Atlantic horseshoe crabs (Limulus polyphemus). If the sample contains endotoxins, the combination coagulates[footnote]Becomes more viscous[/footnote].
The Mumbai lab should have performed one of these tests.
Worse, whatever the reasons the lab didn’t perform the tests, data published by the MFDA suggests it was only infrequently testing remdesivir for endotoxins.
When any Maharashtra lab tests a drug and finds it to be substandard, it publishes the test results on a website. A search for all remdesivir quality failures on this website between March 2020 and January 2022 – the period in which remdesivir was widely used in India – shows that of 20 substandard remdesivir samples, none failed the endotoxin test.
The only quality failures Maharashtra labs identified in this time were content and identification failures. An identification failure means remdesivir was missing from the injectable substance altogether; a content failure means the drug was present in lower quantities than the labelled amount.
Others may have been skipping endotoxin tests, too
In the Cadila case, the Maharashtra drug lab claimed to have followed the Indian Pharmacopoeia’s general monograph for powdered injectables to test the firm’s remdesivir. Even though its decision was seemingly supported by Schedule V of the Drugs and Cosmetics Act, it was nevertheless problematic.
Yet, the Maharashtra drug lab wasn’t the only one to rely on general monographs.
Leaning on the Indian Pharmacopoeia’s general monographs for quality tests is a bad strategy. When a specific monograph doesn’t exist, a general monograph is merely the minimum standard with which a proprietary drug must comply. This means general monographs typically do not list all the quality specifications relevant to a drug, and only serve broad pointers.
So when a firm wants to manufacture a proprietary drug, it will typically submit a more detailed list of quality specifications to the state drug regulator before it can receive its manufacturing license.
Consider the case of remdesivir itself. In May 2021, the Indian Pharmacopoeia had no monograph for powdered remdesivir yet, presumably because remdesivir entered widespread use only with the pandemic’s advent in early 2020. (And pharmacopoeias need time to develop monographs.)
By October 2021, the Indian Pharmacopoeia did introduce a specific monograph. This had multiple other tests, including for six impurities specific to remdesivir and which are missing in the general monograph.
So if any state lab is to test a proprietary drug, it has no option but to seek a detailed list of specifications from the manufacturer – which must have been vetted by the regulator in the manufacturer’s state.
Yet few state labs have such a policy. Lab personnel from the Kerala and Karnataka Drugs Control Departments told this correspondent they depended mainly on general monographs for proprietary drugs. The website on which the Gujarat Food and Drug Control Administration (FDCA) publishes its substandard results suggests it has a similar policy as well.
This is a dangerous strategy: it means that the testing in these states for proprietary drugs is routinely incomplete. And remdesivir was not the only proprietary drug used widely during the pandemic. Indian hospitals also used multiple other proprietary drugs, such as liposomal amphotericin B and tocilizumab – all of which would have been subjected to limited testing.
Procurers skipped quality tests
The Cadila incident also demonstrated that state procurement agencies had, and have, no functional pharmacovigilance systems in place. When doctors found that the drugs supplied by these procurers were causing adverse events, they often didn’t inform the procurers about this. And in the few instances where doctors did so, the procurer failed to inform the regulator or conduct its own investigation.
But subsequent discussions with these procurers revealed yet another failure. In their rush to disburse crucial COVID-management drugs during the pandemic, the procurers stopped testing these drugs before use altogether.
This was a marked departure from their usual policy. Typically, all procurers have systems in place to filter out unsafe drugs before they reach patients. These take the form of buying drugs only from manufacturers with proven track records and testing samples from select incoming batches.
For example, the Bihar Medical Services & Infrastructure Corporation (BMSICL) normally sends a sample from every batch to an accredited private lab for quality tests.
However, officials from BMSICL, the Rajasthan Medical Services Corporation Ltd and the Maharashtra’s Haffkine Biopharmaceutical Corporation said they relaxed this policy in the case of remdesivir.
Why did this happen? Parmeshwar Kognure, a medicine manager at Haffkine, said it was because they might have to wait for up to two months before receiving the results of the quality tests – and that this would delay distribution.
“It was an emergency period, and the [shelf life] of remdesivir was three months,” Kognure said. “We were in a hurry to use the drug.”
Haffkine also exempted other COVID-specific drugs, like injectable azithromycin, methylprednisolone, liposomal amphotericin B, low molecular weight heparin and tocilizumab, from quality tests.
Ironically, new drugs – especially injectables – are considered to be more likely to have quality issues. This is because manufacturers are only just coming to grips with the process of making these drugs and are more likely to slip up. At the same time, injectables need to be subjected to higher safety standards than oral drugs because they enter the bloodstream directly.
But state procurers seem to have ignored these concerns during the pandemic.
The takeaway
The systemic flaws exposed by the Cadila and Hetero cases should worry all Indian consumers. If multiple drug regulators and procurers failed to identify the cause of adverse events, there is no guarantee that similar incidents will not happen again.
In a functional drug regulatory system, things would have gone differently. All state regulators would have thoroughly investigated the adverse events, and identified the root cause – whether endotoxins or something else.
In fact, under Schedule M of the Drugs and Cosmetics Act, Cadila and Hetero are required to get to the bottom of every reported adverse event. And the Gujarat FDCA – the authority that granted both Cadila and Hetero their manufacturing licenses – would have monitored these investigations.
If the ultimate cause of the illnesses was defective drug products, such an investigation could have helped Cadila and Hetero correct the manufacturing failures that led to the defect. Bacterial endotoxin contamination, for example, is frequently linked to the use of unclean water. Second, the discovery of defective products would have allowed the Gujarat FDCA and other state regulators to sue both firms.
In contrast, nobody really knows what actually happened. The Gujarat FDCA did not answer any questions about either case – nor have any test reports pertaining to the implicated batches from both companies been published on the FDCA website. Ultimately, no one knows why so many recipients of remdesivir from two companies fell so seriously ill during the COVID-19 pandemic.
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.