https://www.nature.com/articles/d41586-020-01367-9
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.
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.
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.
...In addition, companies have been seeking low-cost suppliers of raw materials in countries such as China and India....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. ...
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.
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.
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.
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