Serum Institute of India CEO Adar Poonawalla has urged US President Joe Biden to lift the embargo on export of raw materials needed to ramp up production of Covishield and Covovax, the Covid-19 vaccines it is making in India. A look at the embargo, the materials blocked and how this may impact vaccines produced for India and the world.
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So, what is the embargo?
Exports of critical raw materials used in the production of some Covid-19 vaccines have been blocked as a result of Biden’s decision to invoke the US Defense Production Act earlier this year. The 1950 Act was originally passed to help ensure supplies and equipment during the Korean War. Today, its scope extends beyond America’s military to cover natural hazards, terrorist attacks and other national emergencies. The Act empowers its President to order domestic businesses and corporations to prioritise federal contracts in such events, according to a report by the Congressional Research Service. Other provisions include conferring powers to the President to incentivise the domestic industry to ramp up production and supply of “critical” materials and goods.
Early on in the Covid-19 pandemic, then President Donald Trump had invoked the Act for purposes like increasing production of ventilators and limiting exports of medical supplies. After taking office this year, Biden invoked the powers of the Act on January 21 to ensure the availability of “critical” materials, treatments and supplies needed to combat the pandemic, including the resources necessary to “effectively” produce and distribute vaccines “at scale”. A White House briefing over a week later revealed that his administration intended to use provisions of this Act to ensure supplies of products crucial to making and administering the Pfizer and BioNTech vaccines. Last month, Biden once again announced that the Act was being invoked to ensure 24×7 manufacturing of the Johnson & Johnson vaccine. The government would also continue to use the Act to expedite “critical materials” in vaccine production, such as equipment, machinery and supplies.
This decision to ensure that companies on American soil divert their resources to meet the demands of the US population effectively blocks them from meeting export commitments. Mahima Datla, the managing director of Biological E, which is making the J&J vaccine in India as well as a protein subunit vaccine with Houston’s Baylor College of Medicine, had said US suppliers have told global clients that they may not be able to fulfil their orders because of the Act, as per a report in the Financial Times.
What are the raw materials blocked, and why are they important?
There is no comprehensive list of companies that have been called in to focus on vaccine production in the US, nor is there a list of all the raw materials that cannot be exported from the country as a result of invoking the Act. A typical vaccine manufacturing plant will use around 9,000 different materials, according to a report by the World Trade Organization. These materials are sourced from some 300 suppliers across some 30 countries. However, based on previous statements from the Biden Administration as well as vaccine company executives like Poonawalla, Dr Krishna Ella and Datla, the raw materials impacted will include those listed in the table alongside.
Which vaccines may be impacted as a result?
The US restrictions are expected to hit the output of major suppliers for the world. The continued restrictions may not only cause a fight for limited resources, but also delay regulatory clearances of some products, according to experts. Plastic bags, filters and cell culture media, especially, are relevant to most vaccines being made to tackle the Covid-19 pandemic. This includes vaccines like Covishield and Covovax, of which SII was expected to supply over a billion doses each this year.
Poonawalla has reportedly said the restrictions have halved the number of doses of Covovax that SII can stockpile. SII had earlier said the restrictions would not affect its current production of Covishield, but “may” impact “the scaling up of Covishield’s future capacity”.
The US Act seems to be impacting the ability of other Indian companies to make their Covid-19 vaccines in India. For instance, Dr Krishna Ella, the chairman and managing director of the Hyderabad-based Bharat Biotech that makes Covaxin, said late in March that the restrictions by the US “on some of the materials” have impacted supply logistics for vaccine makers.
“Actually, one of the raw materials we need to get, we are not able to get it from the US and Sweden,” he said. He did not specify these raw materials and whether they were used to make Covaxin.
Datla had earlier told the Financial Times that the US restrictions would not only make the scale-up for Covid vaccines “extremely difficult”, but would also hit the manufacturing of routine vaccines. Biological E is expected to make around a billion doses of the J&J vaccine as well as scale up its production of its recombinant protein vaccine with Baylor College to a billion doses over an unspecified time period. It is not clear how much of its production will be impacted at this stage, as the company is currently still testing the recombinant protein vaccine in India. A meeting among leaders of Quad nations US, India, Japan and Australia last month had also culminated in an agreement to support the company’s scale-up of production of the J&J vaccine.
Is the US the only supplier of these raw materials?
While some experts have said some capacity for specific input materials exists in other countries as well, the US does have the major contribution.
“The Johnson & Johnson vaccine is also an adenovirus vectored vaccine, and it (the company) has been told to work 24×7 to increase supply. Because of this, I can imagine that there will be a cutting off of supplies of materials used for cell cultures, which are important for other viral vector vaccines, inactivated vaccines and vaccines that are protein expression systems-based,” said Dr Gagandeep Kang, vice chair of the Coalition for Epidemic Preparedness Innovations (CEPI) and a professor at the Christian Medical College (CMC) in Vellore.
“Most of the equipment manufacturing is done in regions like Europe, but for plastics and the bulk of the reagents that we use in any laboratory, US companies are major suppliers. They may be made somewhere else, but they are by US-owned companies for the most part,” she said.
The sterile filters used for purification of the protein are majorly supplied by companies like New York-headquartered Pall Life Sciences and Merck Millipore, owned by Germany’s Merck but headquartered in Massachusetts. Major suppliers for the single-use bioreactor systems, which use disposable bags for cell culture and fermentation, include American multinational company Baxter Healthcare, Massachusetts-headquartered ThermoFisher and Cytiva.
However, Germany-headquartered Sartorius AG also provides such end-to-end disposable systems.
Cytiva-owned HyClone and Merck Millipore supply cell culture media and serums used in them, but these are also made by Germany’s CellGenix, India’s HiMedia and Switzerland’s Lonza Group AG–which also provides certain single-use packaging solutions for culture media, buffers and reagents.
Microcarriers are made by American companies like Pennsylvania’s VWR International and Cytiva as well as Germany’s Sartorius.
The US does not have a stronghold on all crucial raw materials. At least 50% of the required buffers and enzymes are imported “largely” from Western European countries like France, Germany, Switzerland and, to some extent, even Italy, said Syed S Ahmed, founder of TechInvention, a biotechnology company focused on making essential vaccines and biopharmaceuticals affordable and accessible in the developing world.
Dr Ella last month pointed out that products like thimerosal, used as a preservative in multi-dose vaccines, and beta propiolactone, used for inactivating viruses, are mainly imported from Germany.
Can’t Indian vaccine makers import from other countries?
Finding alternatives is difficult. According to the International Federation of Pharmaceutical Manufacturers and Associations, several of the components flagged by SII, Biological E and Bharat Biotech have also been reported as areas of concern by several other manufacturers around the world. These manufacturers already saw a surge in demand for these raw materials in the early days of the pandemic. Some of them already had to increase their output by around 50% to meet existing demands from the companies that placed early orders.
WTO trade statistics suggest that global exports of some particularly critical raw materials (including nucleic acids, amino acid phenols, acyclic amides, lecithins and sterols) grew by 49% in the first six months of 2020 to reach some US$ 15.5 billion in value.
Another problem is the complex regulatory processes that vaccine makers have to undergo for seeking approvals in different regions. “Since the process has been developed already, you don’t want to make too many changes to it. If you do, the regulator will have to know that changes have been made and that the changes do not impact the product,” a vaccine expert said.
Vaccine makers have increasingly relied on third parties for the timely supply of goods like raw materials, equipment, formulated drugs and packaging, critical product components and services. “Many of these goods are difficult to substitute in a timely manner or at all,” said AstraZeneca in its 2019 annual report.