In January, Gilead Sciences wasn’t manufacturing more than a few doses of its experimental antiviral remdesivir. The drug wasn’t being studied in any major clinical trials. The company had enough on hand to treat 5,000 people.
A few months and the onset of one coronavirus pandemic later, demand for remdesivir is booming. A study run by the National Institute of Allergy and Infectious Diseases showed that patients with Covid-19 who were given the drug recovered faster than those who were given a placebo, the agency said this week. Regulators have not yet approved the drug — though an emergency authorization is reportedly imminent — but the company now stands in the position of having to scale up production of a drug that the whole world may want.
Gilead is working to meet the need. Already, it is up to 50,000 treatment courses, with a goal of having “multiple millions of treatment courses” by the end of the year, CEO Daniel O’Day told STAT Wednesday. Still, the realities of manufacturing pharmaceuticals limit how much a company can churn out and how fast that can be increased, experts say.
“We’re going to make sure that access is not an issue with this medicine,” O’Day told STAT. “This is a global pandemic. There should be no question about our ability to get medicine in the hands of patients.”
Making an intravenous drug like remdesivir is not a simple process. Filling a vial requires a whole lot of different pieces — many of which are made by other companies — coming together in a final product that has to be pure, sterile, and the same each time. It involves a series of chemical steps that are completed in a particular sequence and ends with a manual inspection of each vial, a process that is “both resource- and time-intensive, with some individual manufacturing steps taking weeks to complete,” Gilead wrote in a description of its efforts. Every aspect has to be performed under strict regulatory and safety rules to ensure the drug’s standards.
“You don’t just turn a dial and say, ‘Hey, we’re going to start making this,’” said Bernhardt Trout, a professor of chemical engineering at the Massachusetts Institute of Technology, who studies manufacturing technologies.
“It’s not just the active ingredient — there are additives,” Trout said. “Those have to be pharmaceutical grade and safe and tested. Every time you get an ingredient, you have to test that and make sure it falls within specifications. You have to analyze impurities. You have to have a quality control system. You have to then scale up your process to make millions of doses or whatever it is, and show that your process is robust because there are always variations.”
Gilead is also trying to ramp up manufacturing at a time when supply chains for raw materials have been threatened by the very pandemic the drug is trying to combat.
“Most raw materials and most active pharmaceutical ingredients are made in Asia, either in China or India,” said Greg Dombal, the president of the life-sciences-focused Halloran Consulting Group. “That supply chain spiders all the way across the world.”
Gilead has been preparing. It started building up production when it became clear in the early days of the pandemic that remdesivir might be effective against Covid-19. The company has tapped partners to make the drug as well. It’s been procuring raw materials and accelerated the manufacturing process from one that took nine to 12 months to complete to one that takes six to eight months.
“Immediately in January, when we knew there was even a possibility this medicine could be effective … we made the commitment as a company to say, this is too important,” O’Day said. “We have to make every investment that we can in the event that this works given the human need and the societal need here.”
Experts caution that remdesivir is not a quick cure. From the limited data that have been released, they say it appears to be a decent drug that sped improvement for some people, and one that, because it’s given intravenously over several days, will generally be reserved for people who have serious enough Covid-19 cases that they need hospital care. It’s not a simple pill that everyone with a mild coronavirus infection would be recommended to take.
Still, this is the first drug that’s been shown in a gold-standard, late-stage clinical trial to have any effect against the coronavirus, which has caused more than 3 million confirmed infections worldwide. Already, clinicians and families of seriously ill patients have been clamoring for access to the drug through clinical trials or expanded access programs. If and when regulators give it the green light to get on the market, people will demand it.
What may help stretch the supply of remdesivir was another piece of good news this week beyond the results of the NIAID-sponsored trial. In its own, separate study, Gilead found that people given remdesivir for five days did not show significantly different results than those given the drug for 10 days — suggesting the shorter course was adequate.
Being able to use a five-day regimen “could significantly expand the number of patients who could be treated with our current supply of remdesivir,” Merdad Parsey, Gilead’s chief medical officer, said in a statement Wednesday. “This is particularly important in the setting of a pandemic, to help hospitals and healthcare workers treat more patients in urgent need of care.”
Remdesivir as a compound is not particularly difficult to synthesize, experts said. But the challenge can be trying to turn on a dime to start making more of it than anticipated.
To some extent, manufacturing facilities can increase the hours that their equipment is running, for example, but there are strict rules for how often those machines have to be cleaned. The compounds have to be regularly assessed and analyzed to make sure they are hitting quality and safety benchmarks.
Scaling up also requires the companies that make all the individual components that go into a final product get on board. That extends from the vial makers to the labeling suppliers to the companies that make “excipients” — the components of a drug beside the active ingredient, which include compounds that help keep it stable or reduce the reactions when the drug is injected.
“It’s not just the company itself that needs to turn it up. It’s forecasting to suppliers and saying, ‘Hey, we’re going to have a significant increase in demand here,’” said John Stubenrauch, who has worked in the drug industry for more than two decades and is now senior vice president of operations at Immunomedics.
Big drug makers typically have more than one supplier for those components, Dombal said. But he added, “we build those in for fail safe, not for massive scale up.”
Scaling up quickly can be challenging because such situations will likely require finding other companies with plants that need to be retrofitted, which can be time consuming depending on the technology involved, according to David LaPre, a former Roche executive vice president and head of global pharma technical operations, who oversaw accelerated production of Tamiflu during the Avian flu in 2005.
To supplement what is certain to be worldwide demand, he noted that Gilead may want to consider doing what Roche did, which was to grant licenses to manufacturers in other countries, such as India, in order to supply the lesser-developed parts of the world. This approach, which Gilead has pursued with HIV drugs, took strain off the production system.
“If the stars are aligned you might find one or two plants where the capacity and process capability are a great fit,” LaPre said. “This would be the path of least resistance. A more likely scenario is a number of close fits which require some level of investments and/or retro-fitting.”
Matthew Herper and Ed Silverman contributed reporting.