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BENGAURU : The story of how the Central Drugs Standard Control Organisation (CDSCO) and the Karnataka drugs control department (KDCD) together allowed the Kyasanur Forest Disease (KFD) vaccine to be manufactured with almost no oversight, for years, is one of incompetence, miscommunication and plain negligence.

To understand it fully, however, one needs to understand how India’s joint licensing system for human vaccines works.

The green signal

Both the CDSCO and the state regulator play roles in India’s joint licensing system, although the CDSCO’s part is more critical. This is because many state regulators do not have the expertise or infrastructure to evaluate the quality of vaccines. For instance, KDCD’s labs lack the ability to independently test the quality of the KFD vaccine. This is why CDSCO’s role matters.

Under the joint licensing system, when a manufacturer first wants to make a vaccine, they apply for a licence to the regulator of the state in which they are located. So, the Institute of Animal Health and Veterinary Biologicals (IAHVB) would have applied to the KDCD. At this point, the state regulator forwards the application to the CDSCO. This process is described in Rule 68-A of the Drugs and Cosmetics Act.

Graphic: Sarvesh Kumar Sharma
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Graphic: Sarvesh Kumar Sharma

CDSCO is then supposed to take multiple steps to ensure the vaccine is safe and effective: It evaluates clinical data, the method of manufacture, the quality control tests, and conducts physical inspections to evaluate the manufacturer’s compliance with good manufacturing practices (GMP).

It is only when the CDSCO ticks all these boxes that a representative from the CDSCO, called the Central Licence Approving Authority (typically the head of the CDSCO, the Drugs Controller General of India), signs the licence, and sends it to the state regulator. Next, a representative from the state regulator, called the State Licencing Authority, also signs the licence and sends it to the manufacturer.

Once the manufacturer has a licence, the CDSCO puts in place a so-called “lot-release" system, which it implemented in circa 2009. Under this system, a CDSCO lab, called the Central Drugs Laboratory (CDL) in Kasauli, Himachal Pradesh, evaluates every single batch of vaccine for quality, even after the licence is awarded.

Lot release

CDL Kasauli can choose to evaluate every batch in one of two ways: Either it directly tests a sample from the batch on all quality parameters, such as potency, or it evaluates the so-called “summary protocol" of the batch. This protocol is provided by the manufacturer, and contains a detailed account of the manufacturing process of the batch, from start to finish, including results of final quality testing.

Whatever CDL Kasauli’s preferred method of "lot release" for a particular vaccine, it ensures that CDSCO maintains tight control of the quality of all human vaccines received by Indians.

It is pertinent to note here that the ‘lot release’ system is not a requirement under the Drugs and Cosmetics Act. Instead, CDSCO implemented it so that Indian manufacturers could participate in the World Health Organisation’s (WHO) prequalification programme.

Under this programme, the WHO certifies the quality of vaccines from a particular manufacturer. However, the WHO doesn’t allow a manufacturer to participate in this programme, unless it is located in a country that is regulated by a “functional vaccine regulator". And in order to be deemed a “functional regulator", the CDSCO had to implement a "lot release" system, among other measures.

Renewals of licences

CDSCO and the state regulator follow a similar process while renewing licences, as they do while granting them. In other words, the manufacturer applies to the state regulator, after which the state regulator forwards the application to the CDSCO. Rule 68-A of the Drugs and Cosmetics Act says that after the CDSCO has satisfied itself with an inspection, the Central Licence Approving Authority signs the renewed licence. This means that the Drugs and Cosmetics Act doesn’t allow CDSCO to renew permissions without at least one inspection.

The renewed licence typically contains a product list, which contains all products the manufacturer is allowed to make. For IAHVB, this would include its animal vaccines, such as the sheep pox vaccine and the Ranikhet vaccine, as well as the human vaccine, KFD.

There are several caveats in this licensing process, however: If the CDSCO is not satisfied that the manufacturer is up to the mark, Rule 68-A says the Central Licence Approving Authority may reject the application, while conveying its reasons in writing.

Further, Rule 77 of the Drugs and Cosmetics Rules, a set of rules under the Drugs and Cosmetics Act, says that if a manufacturer applies for a licence renewal before the previous licence period has expired, or within six months of expiry, the licence is deemed to be in force unless the State Licencing Authority rejects it.

What happened in IAHVB’s case?

Documents viewed by Mint show that IAHVB’s first licence period for the KFD vaccine ended in December 2001. After this, the institute applied for a licence for the 2002-2006 period. However, IAHVB officials told Mint, they didn’t hear back from the KDCD. This was not uncommon, IAHVB scientist B M Chandranaik told Mint. “When we apply for a licence, they take a lot of time to process and validate it."

IAHVB didn’t stop manufacturing the vaccine at this point, though. Instead, it relied on Rule 77. Because it had applied for the licence prior to the expiry of the previous licence period, and because it hadn’t heard back from the KDCD, the institute assumed its licence was valid. “If the application is in the process of renewal, it is deemed to be in force," Chandranaik said.

This happened again in 2007, when the 2002-2006 licence period expired; in 2012, when the 2007-2011 licence period expired; and in 2017, when the 2012-2016 licence period expired. It kept applying for renewal every five years, even though it got no licence after 2001. To keep making the vaccine, IAHVB relied on Rule 77 again. In fact, it received a letter from the KDCD in 2008, assuring that its licence was still valid.

The actual licence documents arrived at IAHVB only in 2020, Chandranaik told Mint. The KDCD sent three licences at one go – for 2007-2011, 2012-2016, and 2017-2021. But that was hardly the biggest problem with these licences. The product list accompanying these licences contained only IAHVB’s veterinary vaccines, with the KFD human vaccine conspicuously struck out.

Confusingly, even though this suggested that the CDSCO and the KDCD had retrospectively rejected the KFD vaccine application, the licence didn’t provide any reasons for the cancellation in writing, as Rule 68-A requires. Further, Chandranaik said, the KDCD did not explicitly tell them to stop production.

So, IAHVB assumed the licence wasn’t cancelled. And they relied upon Rule 77 to continue making the vaccine.

Why were no licences renewed in 2002-2020?

Mint asked KDCD officials why they never sent any licence to IAHVB between 2002 and 2020. The officials said they were unable to access records from before 2008, and couldn’t answer questions pertaining to this period.

However, according to S Venkatesh, assistant drugs controller, KDCD, during the 2007-2011 licence period, CDSCO officials never came to inspect IAHVB’s facility. Since inspection was necessary to renew the license, KDCD couldn’t do anything, he said.

Venkatesh also added that IAHVB’s interpretation of Rule 77 was correct. So, the firm was within its rights to continue making the vaccine, even if KDCD didn’t send them the renewed licence. Mint asked how a manufacturer could be allowed to continue making vaccines without even a single inspection during its five-year licence period. Venkatesh didn’t answer.

For the 2012-2016 licence period, Venkatesh clarified that the CDSCO did inspect IAHVB’s facility twice, but found that the institute wasn’t complying with several GMP. Until IAHVB resolved these problems, the licence couldn’t be renewed, he explained. This was the reason the firm was denied a renewal, according to Venkatesh.

Finally, the CDSCO sent three licences only in 2018 to KDCD, after IAHVB satisfactorily resolved the GMP issues. However, Venkatesh says, CDSCO had struck out the name of the KFD vaccine. (It would take the Karnataka department two more years to send those licences to IAHVB.)

Mint reviewed the inspection reports from the 2012-2016 period, which were conducted jointly by CDSCO and KDCD inspectors. Interestingly, these reports note GMP violations pertaining to several of IAHVB’s animal vaccines, such as the enterotoxaemia vaccine. But they make no mention of the KFD vaccine, even though an assistant drugs controller, Raghuram Bhandary, from the Karnataka drugs control department was aware of the potency problems faced by IAHVB by then.

This raises questions about whether the CDSCO inspector even knew that IAHVB was making a human vaccine, or whether Bhandary ever informed CDSCO about the potency problems. Asked if CDSCO was informed about potency problems, Venkatesh said Bhandary had since retired, and the KDCD couldn’t answer questions on his behalf.

Why was the KFD vaccine’s name struck out?

 

Mint asked KDCD why the name of the KFD vaccine was struck out retrospectively from the list of licences from 2008 onwards.

Venkatesh and other officials argued that the striking out of the KFD vaccine didn’t mean a denial of licence, because the CDSCO hadn’t communicated any reasons for the rejection. Further, the officials said, when they wrote to the Drugs Controller General of India, V G Somani, asking why the vaccine was struck out, Somani was unable to clarify. “Somani Sir has to answer this question. But he hasn’t answered…He himself is confused," Bhagoji Khanapure, drugs controller of Karnataka, told Mint in September.

Somani did not respond to Mint’s queries either.

Khanapure’s interpretation was dubious. Mint independently confirmed that CDL Kasauli had never performed a lot-release on the KFD vaccine. Further, IAHVB’s name is missing from a list of all manufacturers of human vaccines in India since 2009, published on the CDSCO’s website.

VG Somani didn’t answer any of Mint’s questions.

The impact of CDSCO’s negligence

CDSCO’s oversight plays a critical role in ensuring vaccine quality and safety. For instance, when a recipient reports an adverse effect after vaccination, or quality issues with the vaccine, it is CDL Kasauli that tests the batch for quality. Mint came across at least two instances in which this didn’t happen, simply because CDSCO was nowhere in the picture.

In August 2019, a 12-year old girl collapsed within minutes of receiving the KFD vaccine in the Chikmagaluru district of Karnataka. She had to be rushed to the hospital, where she also developed rashes all over the body. She recovered fully within a day, as per the report on the adverse event filed by the Chikmagaluru medical officer. Mint learnt that the quality of this batch was never tested in response to the incident, either by IAHVB or VDL. And since CDL Kasauli was not aware of the existence of the vaccine, independent testing was impossible.

Then, in June 2022, officials from the National Centre for Disease Control, a Delhi-based institution that studies disease epidemiology, recovered a vial of substandard vaccine from a Shivamogga primary health centre. The vial had a clear suspension of particulate matter inside it, a quality failure. Mint reached out to Khanapure to ask if the Karnataka drugs control department planned to test the batch. Khanapure said there was no plan to do so, since his department had no facility to test the vaccine.

These incidents suggest that the CDSCO pharmacovigilance system, which keeps Indian vaccines safe, was completely missing for the KFD vaccine.

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