Richard Hatchett is, in his own words, one of the few people who have “made a career out of worrying about pandemics”. After the 2009 H1N1 influenza pandemic, the expert in responding to epidemics who was then a White House staffer, helped the US government establish pharmaceutical factories ready to be switched on to defend against a future health threat.
But one of these facilities, run by Emergent BioSolutions, has become a liability in the Covid-19 pandemic. Tens of millions of Johnson & Johnson doses were ruined after they were contaminated with the AstraZeneca vaccine. The regulator discovered unsanitary conditions and poorly trained staff. The production line was halted for more than 100 days.
“Somehow, in that process of needing to surge and scale up when the crisis hit, their quality systems and controls broke down and they were not able to deliver the thing they were created to deliver,” Hatchett says.
But pandemic worriers like Hatchett now finally have the ear of politicians.
When coronavirus first emerged, governments watched as shortages of basic medical supplies spread, and this year they have struggled with access to vaccines as countries that already had manufacturing facilities — including India, the US, and the EU — deployed export controls to prioritise vaccinating their own citizens.
Rattled by these experiences, many governments want to bring drug and vaccine manufacturing home. The UK has expanded capacity for the Valneva and Novavax shots, and is in talks with GlaxoSmithKline about preparedness projects. The EU is using development funds for rejuvenating the economy to expand pharma manufacturing capacity, and the White House has recommended major reforms. The African Union plans to expand vaccine manufacturing to 60 per cent of the continent’s needs by 2040.
Hatchett, now chief executive of the Coalition for Epidemic Preparedness Innovations, wants to make sure policymakers learn the right lessons. If they do, they could achieve Cepi’s ambition for facilities to create new shots within 100 days of a dangerous disease emerging, cutting the time it took for a Covid vaccine by two-thirds and stopping a pandemic while it is still an “incipient outbreak”.
However, the problems at the Emergent plant demonstrate that it is hard to create a back-up factory, ready for action, and even harder to devise a comprehensive plan for a new crisis.
Governments are learning just how complicated it is to create manufacturing facilities that can respond quickly and safely to a previously unknown disease. Moreover, there is also a risk that attempts to untangle the global supply chain could further entrench inequalities in vaccine supply, by concentrating capacity even more in the richest countries.
“My concern is that, as critical as it is that we expand capacity, it’s critical that we do it right,” Hatchett says. “I don’t think there’s a cookie cutter answer for every country or every capability.”
Complex supply chains
While travel restrictions during the pandemic have left many people stuck in one country, vaccine components and manufacturing equipment have been criss-crossing borders. Pfizer’s shot alone has 280 ingredients coming from 19 different countries.
When the UK was looking to secure a domestic supply of Covid-19 vaccines, one of its first stops was Valneva, a French vaccine maker with a factory in Livingston, Scotland. The government invested to scale up the manufacturing for a potential Covid-19 vaccine and future health crises. Thomas Lingelbach, Valneva’s chief executive, said it won the contract partly because it had “some home territory advantage”.
Yet even if the Valneva vaccine is approved in time to be used in a booster campaign, it will have to be shipped to Sweden first to be put into vials. “For now, we don’t see [export controls affecting production] as a risk. But it is certainly a risk, not necessarily today but maybe it can become a risk going forward,” he says, adding Valneva is looking for a “fill-and-finish” facility in the UK.
Valneva is far from alone: no vaccine is manufactured start-to-finish in one factory, or even in one country. Thomas Cueni, director-general of the International Federation of Pharmaceutical Manufacturers and Associations, says this complexity is why he does not expect a “dramatic, radical, relocalisation”. The industry would prefer governments to focus on bringing down trade barriers.
“It is quasi-impossible,” he says. “That is why you need free flow of goods and open trade.”
Experts fret that governments may end up picking the wrong technologies, or backing companies that can’t keep up with innovation. Before the Covid-19 vaccines became the first products using mRNA technology to be approved, no government had invested in idle capacity for mRNA.
Prashant Yadav, a supply chain expert at the Center for Global Development, says one of Emergent’s problems was it was probably using “yesteryear’s technology”.
“Unless someone invests in capacity that is highly flexible, with modules that can be reconstituted relatively quickly . . . the chance of not being in tune with the latest technology are extremely high,” he says.
Emergent did manage to produce 75m approved doses. The company said vaccine manufacturing is “an inherently complex process, with few facilities capable of doing so when the pandemic began” but admitted it did not go as planned.
“The American people should have high expectations of the partners its government chooses to help prepare them for disaster. We did not live up to expectations, including those we have set for ourselves,” it said. “However, we have learned some important lessons which are allowing us to improve our operations and, at the same time, strengthen America’s public health response for the future.”
Governments are considering how to keep factories warm by making other products in what some experts worryingly call the “inter-pandemic period”. Darrin Morrissey, chief executive of Ireland’s National Institute for Bioprocessing Research and Training, a government-backed effort to educate such skilled staff, says companies have not figured out how to keep facilities “semi-switched on” and enough employees, often specialist scientists, ready to go.
“The talent is an equally complex thing. If you are starting someone de novo, coming into biopharma, it is probably at least 12 months before they are fully operational,” he says.
Securing basic medicines
While delays and disruption to vaccine manufacturing have made headlines this year, governments are also concerned about bolstering supplies of simpler drugs, as surges in Covid-19 hospitalisations exposed how little they knew about supply chains.
France is pushing to reshore production of paracetamol, which was rationed in the crisis, and has a list of 30 generic drugs it would like to be made domestically. A recent White House report, calling for more investment in domestic generic medicine manufacturing, warned that at the height of the crisis in New York, hospitals fought each other to secure critical medicines every day.
Soumi Saha, vice-president of advocacy at Premier, which represents more than 4,000 US hospitals, says a lack of transparency means hospitals are now “panic buying” for the next phase of the pandemic.
“No one knows what is on US soil at any point in time,” she says. Saha adds that Premier has been “ringing alarm bells” on this issue for a decade. “We want to be really careful that we don’t forget what happened over the past 12 months and go back to the status quo,” she says.
The pharmaceutical industry believes one-off investments are unlikely to be enough, arguing governments have to be prepared to pay more for generic drugs that were often offshored to reduce costs.
Eric Edwards, chief executive of Phlow, a public benefit pharma company, which is dedicated to creating a reliable supply of medicines and a $354m US government contract to manufacture generics domestically, says the “race to the bottom” for 20 to 30 years had led to a situation where the “most important medicines” are barely, or not at all, profitable.
“This is a complex problem that has been created over a period of decades, not overnight,” he says.
A similar “reckoning” over prices is due in the EU, says Adrian van der Hoven, director-general of industry association Medicines for Europe. “The reality is that the prices are so extremely low here due to government policy,” he says. “It is difficult to maintain those factories we have in Europe.”
Some are putting their hopes in new, more nimble technologies. Kate Antrobus, chief investment officer at Univercells, says the solution to securing more vaccine and biologics manufacturing is simple: the “Ikea kitchen-style”, adaptable manufacturing facilities that the Belgian company has built to fit inside a shipping container. Founded after the H1N1 outbreak, she says Univercells is now seeing a “sea change” in how global health organisations and governments are thinking about production.
“Modular flexible manufacturing can deal with uncertainty, which is really what pandemic preparedness is all about,” she says.
While Big Pharma insists that scale matters, a new generation of companies is trying to provide smaller facilities that can be distributed around the world.
The most flexible vaccine technology yet is mRNA, because scientists can update the jabs and create new ones simply by inputting a new genetic code. BioNTech, which partnered with Pfizer on the Covid-19 vaccine, and the EU are working to create mRNA facilities in Africa, although they admit that the most technical stages will take about four years to implement. CureVac, another German biotech, is working with a unit of Tesla, the electric vehicle and clean energy company, on what it calls “vaccine printers”, small units that can create its mRNA shots.
However, mRNA has so far only been proven to work with Covid-19. Rahul Singhvi, co-founder and chief executive of Resilience, a new company that aims to improve manufacturing of advanced therapies, says it “is not going to be the answer for everything”.
“An ideal approach is a multi-modality, Swiss Army Knife type of facility,” he says. “Yet not everybody can afford something like that.”
Some global leaders are now realising that they bear some responsibility to help address the inequality of access to vaccines. The Biden administration is pushing US vaccine makers to support the creation of low cost manufacturing hubs to make their shots available more cheaply in the developing world. The World Health Organization has created an mRNA hub to expand the capacity of low and middle-income countries to make Covid-19 vaccines.
But both proposals are dependent on co-operation from the industry at a time when it is vehemently resisting a proposal to waive intellectual property rights with the aim of expanding access to vaccines in low and middle-income countries.
Whether slimmed down or Swiss Army Knife, factories will still rely on supplies of active pharmaceutical ingredients, about 80 per cent of which come from China and India. The US and the EU are looking at bringing more API manufacturing home, while also stockpiling APIs because the ingredients have longer shelf lives than finished products. Even these large economies may not be able to go it alone: the recent White House report suggests working with allies to ensure that together, their supplies are comprehensive.
Yadav, the Center for Global Development supply chain expert, suggests regulators should do “stress tests” on drug and vaccine manufacturing, like they do on banks.
“In pharma you could see similar scenarios: What if India or China’s supply were completely disrupted? Can you still supply and how would you do it?” he says. “That approach accomplishes the end goal without becoming too heavy-handed about insisting manufacturing must be done on US soil.”
Despite being a rare professional pandemic worrier, Hatchett says he does not yet know exactly what lessons need to be learned from Emergent’s blunders. But he believes the most important thing is that policymakers use this opportunity to start with a “blank sheet of paper”.
Leading one of the three backers of the Covax initiative to distribute vaccines to developing countries, he has seen the “terrible inequity” in how the Covid-19 shots have been distributed.
“Right now, manufacturing is concentrated in the US, Europe, India and in China, and those are all huge markets that will absorb a lot of vaccines before they will share any,” he says.
He believes there must be a “more equitable distribution of manufacturing capacity” and supports regional investments and a pandemic treaty or international framework where wealthier countries use their leverage with pharma companies to supply the world.
“Increasing aggregate investment is a good thing. But there is a potential downside,” he says. “We need to do everything we can to have it not result in increasing nationalism . . . but think about it as a layer of investment in collective security.”