Exports of an Indian COVID-19 vaccine halted after WHO finds problems at manufacturing plant – Science

The World Health Organization (WHO) has raised unspecified concerns about the manufacturing of Covaxin, one of Indias home-grown COVID-19 vaccines. On 2 April, WHO said it had found problems during a March inspection of the production facilities of Bharat Biotech, the vaccines 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.

WHOs decision means U.N. 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 WHOs 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 Indias drug regulator, the Central Drugs Standard Control Organisation (CDSCO).

Covaxin is an inactivated vaccine; its main ingredient is killed SARS-CoV-2 particles. CDSCO gave it an accelerated approvalIndias version of an emergency use authorizationin January 2021, before Bharat Biotech had any efficacy 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 qualityat the companys plant. Bharat Biotech hadnt validated its method of inactivating SARS-CoV-2, ANVISA said, raising the possibility that the shot contained live virus, and hadnt assured the vaccines 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 hadnt 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 didnt 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 vaccines 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 2 April statement. Still, the spokesperson says, WHO is advising countries not to use remaining Covaxin doses.

Ocugen, Bharat Biotechs U.S. partner, has temporarily paused dosing in its U.S. phase 2/3 trial, as it evaluates WHOs statement.

For many countries in the low- and middle-income bracket, Covaxin was an easy-to-deploy shot because, unlike messenger RNA vaccines, it doesnt require storage at very low temperatures. But a Bharat Biotech spokesperson says WHOs decision will have little impact outside India because the company doesnt currently have any agreements with U.N. 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 WHOs 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 Indias national drug regulator, havent 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 hadnt asked Bharat Biotech to stop local sales as well.

The discrepancy between CDSCOs and WHOs 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, D.C. 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 industrys export credibility and for protecting the health of Indias population.

Update, 8 April, 10 a.m.: A statement from UNICEF has been added to this story.

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Exports of an Indian COVID-19 vaccine halted after WHO finds problems at manufacturing plant - Science