Scaling up remdesivir amid the coronavirus crisis

Now, with cases worldwide at nearly 2.5 million, scrutiny of data coming out of clinical trials of the drug has reached fever pitch. When the health-focused news site Stat posted a story based on leaked video of a University of Chicago clinician talking optimistically about remdesivir’s possible effectiveness, it didn’t just prop up Gilead’s stock price; it lifted the entire stock market.

With each new anecdote, whether about an individual patient or a hunch from a doctor running a trial, the pressure on Gilead mounts. If any of the five late-stage clinical studies underway show that remdesivir works, Gilead will need to make a lot of it, and fast.

Gilead declined interview requests, but C&EN talked with manufacturing experts with experience in scaling up drugs amid crises to understand the challenge Gilead faces and how fast the firm—or any company developing a drug that might be effective against COVID-19—could reasonably meet demand. Past situations provide some guidance, though all concede that none of them matches the level of urgency being felt now.

Drug manufacturing today is like a bucket brigade, explains Princeton University chemist Paul Reider, who previously held chemistry leadership positions at Amgen and Merck & Co. One supplier sends raw materials to another, which uses those basic chemicals to do the first step in the synthesis of a molecule—say, creating a simple side chain. The result gets passed on to another company in the brigade, which performs the next step, and so on. Two or more of those bucket lines might converge to put together the now-complex pieces into the final molecule.

Roche, which licensed Tamiflu from Gilead in 1996, also was able to expand its internal capacity while at the same time building an external supply chain. Between 2005 and 2007, Roche ended up providing roughly 200 million courses of Tamiflu for government stockpiles around the globe.

But over the past 15 years, drug companies have scaled back their internal capacity. “People don’t recognize how many pieces are touched” by a vast network of contract manufacturing partners around the globe, says James Bruno, president of the consulting firm Chemical and Pharmaceutical Solutions. And “if one of those pieces fails,” it creates a bottleneck that is felt down the entire bucket brigade.

Gilead typically outsources the synthesis of its drugs through late-stage intermediates, performing the last critical steps in-house. And while it says it is trying to increase its own capacity, its first step was likely “to quickly scan the globe as to who has the right capability that can be brought to bear,” LaPre says.

The social-distancing guidelines and travel restrictions needed to combat the coronavirus pandemic impose unprecedented challenges for managers trying to execute a manufacturing plan, experts say.

“What I would do, which is what we did, is take a small team and lock them in a conference room and say, ‘We’re not leaving until this is done,’” LaPre says. But that can’t be done today, he acknowledges, and “it gets difficult to do after you’ve been on Zoom for a few hours.”

Technology transfer, or the process of teaching a partner how to do a difficult chemical step at scale, is particularly hard under current conditions. “You don’t just dump the technology over the fence,” Princeton’s Reider says. Typically, an internal expert “will go live someplace out of a suitcase for weeks at a time” while making sure a contract manufacturer is performing a synthetic step properly.

“Gilead is really good at doing this,” says Reider, who has consulted for Gilead on projects that predate remdesivir. In fact, some of Gilead’s current process development and manufacturing team helped out while Roche scaled up Tamiflu, he notes.

Others agree that the company is well prepared to tackle the crisis. “They’ve lived through a couple of these spikes before with their antivirals,” Bruno notes.

Other drugmakers face similar manufacturing challenges. Beyond the dozens of firms with drugs that were developed for other diseases and now are being tested against COVID-19, many are working at a furious pace to start trials of antivirals tailored to coronaviruses.

Pfizer, for one, recently announced it is working on a new antiviral that it hopes to put into clinical studies by the third quarter. Even though the compound has yet to be tested in humans, the company is doing extensive work on the manufacturing route—work typically done much later in the drug development process.

“We’re working with external CROs [contract research organizations] in terms of producing the raw and clinical materials, and also have colleagues in-house working on optimizing the chemistry and synthetic route,” says Charlotte Allerton, head of medicine design at Pfizer. The goal is to have an efficient route for producing large-scale quantities of the active ingredient ready to go if it proves to be effective.

“Right now,” LaPre says, “if you have something that’s promising, if you haven’t already done so, you should at least be conducting a tabletop exercise to figure out: What are we going to do to meet the high end of the potential demand? It doesn’t cost anything to cook up a plan.”