The World Health Organization (WHO) has raised unspecified concerns about the manufacturing of Covaxin, one of India’s home-grown COVID-19 vaccines. On April 2, WHO said it had found problems during a March inspection of the production facilities of Bharat Biotech, the vaccine’s producer. WHO did not disclose the nature of the problems at the plant, which is located in Hyderabad, in Telangana state. But it said Bharat Biotech has agreed to stop exports of Covaxin and is “developing a corrective and preventive action plan.”
WHO’s decision means UN procurement agencies such as UNICEF can no longer supply countries with the vaccine. The agency has also asked countries that have authorized Covaxin to switch to other products. Just how widely the vaccine is used outside India is unclear, however.
In a Twitter statement posted 1 day before the WHO announcement, Bharat mentioned WHO’s inspection, but not the problems identified. It announced a “temporary slowing down” of Covaxin production because of decreasing demand and said the company would focus on maintenance and “process and facility optimization activities.” A Bharat Biotech spokesperson tells Science the company will continue to sell the vaccine in India, its biggest market, where some 309 million Covaxin doses have already been administered. To some scientists, that raises questions about vaccine production oversight by India’s drug regulator, the Central Drugs Standard Control Organization (CDSCO).
Covaxin is an inactivated vaccine; its main ingredient is killed SARS-CoV-2 particles. CDSCO gave it an accelerated approval — India’s version of an emergency use authorization — in January 2021, before Bharat Biotech had any efficiency estimates from its phase 3 trial, leading some scientists to accuse the Indian government of lax regulatory standards. A phase 3 trial published in July 2021 showed Covaxin had an efficacy of 77.8% in preventing symptomatic COVID-19, comparable to several vaccines approved in the United States and Europe.
Covaxin has run into trouble before: Following a March 2021 inspection, the Brazilian Health Regulatory Agency (ANVISA) said it had found several violations of good manufacturing practices (GMPs) —an umbrella term for actions manufacturers must take to ensure safety, efficacy, and quality — at the company’s plant. Bharat Biotech had not validated its method of inactivating SARS-CoV-2, ANVISA said, raising the possibility that the shot contained live virus, and had not assured the vaccine’s sterility and potency. In response, Brazil temporarily suspended a plan to import 20 million Covaxin doses; the deal fell through completely in July 2021 amid allegations of corruption and procurement irregularities.
According to a WHO spokesperson, ANVISA later told the agency that Bharat Biotech had addressed the deficiencies, and in November 2021, WHO awarded the vaccine an emergency use listing. The listing is a prerequisite for a vaccine to be supplied through the COVID-19 Vaccines Global Access Facility, an effort by WHO and two other organizations to provide doses to low- and middle-income countries, and a stamp of approval that helps member countries decide which vaccines to deploy.
But when WHO inspectors visited the plant between 14 and 21 March, they found several GMP deficiencies, some of which overlapped with those identified by ANVISA, according to the spokesperson. The company had changed its manufacturing process after its listing but had not communicated these changes to CDSCO and WHO for evaluation and validation.
Hans Meerburg, a Netherlands-based vaccine-quality consultant, says manufacturers are required to inform drug regulators of any major postapproval changes, because they can impact the safety, efficacy, or quality of the vaccine. “If not, the product may not comply with specifications, such as potency, or the absence of active material,” Meerburg says. Bharat Biotech did not respond to a question from Science on why it neglected to communicate the information.
The WHO spokesperson says a preliminary risk assessment by Bharat Biotech showed no indication that the vaccine’s risk-benefit ratio was altered. “The data, available to WHO, indicate the vaccine is effective and no safety concern exists,” the agency says in its April 2 statement. Still, the spokesperson says, WHO is advising countries not to use remaining Covaxin doses.
Ocugen, Bharat Biotech’s US partner, has temporarily paused dosing in its US phase 2/3 trial, as it “evaluates” WHO’s statement.
For many countries in the low- and middle-income bracket, Covaxin was an easy-to-deploy shot because, unlike messenger RNA vaccines, it does not require storage at very low temperatures. But a Bharat Biotech spokesperson says WHO’s decision will have little impact outside India because the company does not currently have any agreements with UN procurement agencies. (A UNICEF spokesperson confirms the agency does not have a contract with the company.) The spokesperson also says Bharat Biotech stopped selling Covaxin directly to many of the 25 countries that have authorized it under emergency licenses when, in April 2021, India paused vaccine exports because it was battling a massive COVID-19 wave.
CDSCO has stayed mum on WHO’s verdict. To some experts, its silence suggests the Indian regulator is not enforcing the same quality standards as WHO. “It concerns me that CDSCO, the custodian of public health as India’s national drug regulator, has not issued any statements yet on this issue,” said Jayanthi Vuppala, an independent GMP expert based in Hyderabad. CDSCO did not respond to a question from Science on why it hadn’t asked Bharat Biotech to stop local sales as well.
The discrepancy between CDSCO’s and WHO’s responses needs to be addressed because it creates confusion and could promote vaccine hesitancy, says Prashant Yadav, an expert in pharmaceutical supply chains at the Center for Global Development, a think tank based in Washington, DC “We need greater convergence on site inspections by the WHO and national regulatory authorities, ”Yadav says. “This is an important agenda… both for the Indian industry’s export credibility and for protecting the health of India’s population.”
Update, April 8, 10 am: A statement from UNICEF has been added to this story.