The world was waiting for any sign of hope in countering the COVID-19 pandemic when researchers released the first encouraging drips of data from a large clinical trial of the antiviral remdesivir last month. The drug, they said, reduced the time to recovery from COVID-19 by a few days — not enough to be branded a ‘cure’, but hopefully enough to relieve some pressure on overwhelmed health-care systems.
The discovery of remdesivir’s potential focused attention on the next problem facing the development of COVID-19 therapeutics: ramping up complex manufacturing processes to address a global pandemic. It is likely to be one of the biggest drug-making challenges the world has ever faced. Some of the therapies being tested against COVID-19 are novel and difficult to produce. Others — even if they are relatively simple compounds that have been in use for decades — face complications such as supply-chain weaknesses as drug-makers try to scale up production.
“A major rate-limiting step is going to be manufacturing,” says Ezekiel Emanuel, a bioethicist at the University of Pennsylvania in Philadelphia. “Getting up to hundreds of millions of doses is hard.”
Spectrum of drugs
Researchers are working furiously to test a wide variety of potential COVID-19 treatments. Those therapies span the gamut of complexity, from familiar generic medications such as the malaria drug hydroxychloroquine, to experimental small molecules like remdesivir, which was previously trialled against the Ebola virus. Scientists are also exploring antibody treatments that tamp down the body’s immune response when it becomes destructive, which happens in some critically ill coronavirus patients. And if the history of infectious disease is any guide, it will take a combination of drugs — each with a distinct, even if relatively minor, impact on the disease — to tame the novel coronavirus.
Each treatment will face different challenges when scaling up production, says Stephen Chick, who studies health-care management at INSEAD in Fontainebleau, France. “If it’s successful and the technology is then adopted, you need to be prepared to deliver,” says Chick. “And if you’re not, you’re in trouble.”
Remdesivir’s maker, Gilead Sciences in Foster City, California, has been working for months to scale up production of the compound, even before the latest data release. After the US Food and Drug Administration (FDA) authorized use of the drug for COVID-19 under emergency rules on 1 May, the company announced that it had reached out to drug manufacturers around the world to find ways of boosting production.
By then, Gilead had already been streamlining its manufacturing process — reducing the time to produce large batches of the drug from 9–12 months to 6–8 months — and searching for alternative sources for the rare chemicals needed to make it. (Gilead said that it could not disclose the raw materials that go into remdesivir.) The company has projected that it could make enough remdesivir to treat one million people by the end of the year, and potentially twice as many if it finds that lower doses of the drug are sufficient to reduce recovery time from COVID-19.
But it also warned that production of remdesivir relies on a complex chemical synthesis — with individual steps that can take weeks to perform — and could be derailed by shortages of key ingredients. Remdesivir is a molecule that is similar to the nucleotide building blocks the virus uses to copy its RNA genome. By imitating those building blocks, remdesivir blocks the enzyme that the coronavirus uses to replicate itself.
Gilead faces a particular challenge because it was not making large amounts of the drug when the pandemic started. But even for pharmaceuticals that are already produced in bulk — such as hydroxychloroquine and chloroquine — scaling up presents a significant problem, says David Simchi-Levi, an operations researcher at the Massachusetts Institute of Technology in Cambridge.
Over the past two decades, manufacturers in many different industries have been shifting to a ‘lean’ manufacturing model that reduces the amount of raw materials and finished product they keep in stock. “This was successful in terms of reducing costs,” Simchi-Levi says. “But it increased exposure to risk.”
In addition, companies have been seeking low-cost suppliers of raw materials in countries such as China and India. When a crisis such as a pandemic strikes, those countries may clamp down on exports of pharmaceutical ingredients to ensure availability to their own people.
Simchi-Levi and his colleagues’ research in the automotive industry shows that the riskiest links in the supply chain were providers of low-cost but crucial components that cost as little as US$0.10. The same could be true of the other industries including pharmaceuticals, he says, where there are already concerns about having enough glass vials to produce and distribute a vaccine, once one becomes available.
“If supply of these components is disrupted you have to stop the production line,” Simchi-Levi says. “And many companies don’t have a good enough understanding of their own supply chains to know who are the suppliers of their suppliers.”
For small-molecule drugs such as remdesivir or hydroxychloroquine, production broadly involves three stages. The first yields the active ingredient in the drug; the second modifies the drug to make it stable and readily absorbed by the body; and the third packages the drugs, for example into tablets or vials. All this takes place under the watchful eye of regulators, who periodically inspect facilities to ensure that quality and safety standards are maintained.
Relatively few sites are approved by regulators to make drugs, meaning that when one site fails an inspection — or when more facilities are needed to crank out higher volumes of a particular drug — it can be difficult to find a replacement. “That can be pretty significant,” says Simchi-Levi. “There’s high dependency on only a few sites for manufacturing.”
Production can be even more delicate for more complex therapies, such as proteins or antibodies. Researchers are hopeful that antibodies that block certain immune-system processes will help against COVID-19, by restraining the out-of-control immune responses. Genentech in South San Francisco, California, makes one such antibody, called tocilizumab (Actemra), which blocks the activity of an immune-system regulator called IL-6. Tocilizumab is already approved for use against some forms of arthritis, but if found to be useful against COVID-19, production would need to be vastly scaled up.
Antibody treatments such as tocilizumab are made in cells grown in culture, most often in Chinese hamster ovary cells . Antibodies are increasingly used to treat a range of diseases, from various forms of cancer to arthritis, and research has boosted production yields. About ten years ago, a manufacturer might expect to get less than 1 gram of antibody per litre of cell culture; now they typically extract 5 grams or more from the same volume, says Charles Christy, head of commercial solutions at the chemicals firm Lonza in Visp, Switzerland.
A 2,000-litre culture might produce enough antibody to fuel an early clinical trial, but drug-makers can scale up to as much as 20,000 litres of culture grown in giant steel vats to handle larger trials and commercialization.
Because antibody drugs are now such a large part of the pharmaceutical industry, there tend to be multiple suppliers for key reagents, Christy says. But you can always be blindsided, he says. “We and others are looking very hard at our supply chain.”
The industry found that out the hard way following the 2011 earthquake near Fukushima, Japan. Only a few factories in the world made the chemical polyethylene glycol for medicines, which can lengthen the time that some protein therapies remain stable in the blood. All were in Japan.
Tocilizumab has not yet been shown to help patients against COVID-19, but Genentech says that it has already increased its supply by 50% and is working to further raise capacity.
But even when companies work proactively to build supply, demand will almost certainly outstrip initial supplies of any compound found to be effective against COVID-19. That raises the spectre of determining who will be first to receive the treatments. Complaints have already surfaced about the allotment of remdesivir: Gilead donated its stocks of the drug to treat COVID-19, with about 40% — enough to treat 78,000 people — going to the United States. The US government has been distributing those vials to individual states, but some hospitals have complained about lack of access.
The company also announced this week that it had entered into agreements with five makers of generic drugs. Those manufacturers may produce remdesivir for distribution in 127 countries that have limited access to healthcare, without paying royalties to Gilead. The agreement will remain until the global health emergency ends, or another treatment or vaccine is found for COVID-19.
Concerns about access to pandemic medicines have arisen before, for example during the H1N1 outbreak in 2009, says Emanuel, when countries raced to stockpile the influenza drug Tamiflu. “It was a free-for-all,” he says.Those issues have never been fully addressed because the outbreak ended quickly. “People move on and no one stays around long enough to solve the problem,” Emmanuel says. “That will not happen here. We will be in this problem for a number of years.”
Nature 581, 247-248 (2020)