U.S. officials have run headlong into the limits of the Defense Production Act.
This article was published on Tuesday, February 23, 2021 in Kaiser Health News.
The U.S. government has invested billions of dollars in manufacturing, used a wartime act dozens of times to boost supplies and yet there's still not enough COVID vaccine on the way to meet demand — or even the government's own goals for national immunization.
President Joe Biden, in remarks at the National Institutes of Health this month, said the nation is "now on track to have enough supply for 300 million Americans by the end of July." But at the current rate of production, Pfizer and Moderna will miss their targets of providing at least 100 million doses each by the end of March, let alone 200 million more doses each has promised by July.
Moderna would need to more than double its vaccine production rate from January — when it made roughly 19 million doses — to meet its contractual obligations. Pfizer supplied 40 million vaccine doses by Feb. 17. It has roughly six weeks left to deliver the first 120 million doses it has promised.
Biden and officials from the two companies say they are rapidly expanding production capacity. But critics are lining up. They want to know whether the government did enough, fast enough, to guarantee that companies would meet the urgent challenges of the pandemic. As for the manufacturers bolstered by extraordinary sums of taxpayer money, why did they not share technology and know-how sooner, or move more quickly into strategic production partnerships?
Experts say it's complicated, noting that the output of raw materials and assembly lines can't be ratcheted up 10,000-fold at the push of a button — and that the effort thus far has been close to miraculous. They cite bottlenecks in at least three areas: the production of specialty lipids, fatty materials that are a primary component of the Moderna and Pfizer-BioNTech vaccines; the hundreds of millions of glass vials that hold the vaccine; and the sterile automated assembly lines where vaccine moves from bulk containers into vials before shipment.
U.S. officials have run headlong into the limits of the Defense Production Act, a Korean War-era law that allows the federal government to ramp up supplies of critical materials in times of national emergency. The vaccine manufacturing process relies on a complex supply chain, from sourcing raw materials and equipment to designing chemical processes, building production lines and hiring and training workers.
Also, experts note, no one knew which vaccines would prove effective.
"A year ago there was no commercial market for mRNA product. There was scientific research and pharma making small-volume clinical lots. Now we need billions of doses, in the space of a year. That's overloading the supply infrastructure," said Kevin Gilligan, a senior consultant with Biologics Consulting and a former official with the Biomedical Advanced Research and Development Authority, or BARDA, a federal agency created in 2006 to deal with pandemics and bioterrorism.
As of December, the Trump administration through its Operation Warp Speed initiative had obligated nearly $14 billion for vaccine development and manufacturing, including investments to expand U.S. capacity, according to a Government Accountability Office report in January. The administration invoked the Defense Production Act on at least 23 vaccine-related contracts, in part to prioritize the government's contracts over others, according to a KHN review of the federal contracts database, contracts obtained by the nonprofit group Knowledge Ecology International, GAO and government news releases.
They include the December contract that the Department of Health and Human Services signed with Pfizer for another 100 million doses, on top of the initial 100 million it committed to last summer. That contract, worth $1.95 billion, included DPA provisions to give the company priority access to raw materials and spare parts for factories, according to a former administration official.
The DPA has also been used in vaccine contracts with Moderna, Johnson & Johnson and other drug companies for hundreds of millions of doses. On top of that, the law has been invoked for at least 10 contracts with companies making needles or syringes. It's been used to require glass makers Corning and SiO2 Materials Science to prioritize vial production for vaccine production, and in contracts for aspects of manufacturing with companies like Emergent BioSolutions, Fujifilm Diosynth Biotechnologies and Grand River Aseptic Manufacturing.
Operation Warp Speed awarded Emergent BioSolutions $648 million last year to boost the manufacturing capacity it needed to enter agreements with Johnson & Johnson and AstraZeneca — worth at least $615 million and $261 million, respectively — to help make their vaccines. Grand River Aseptic Manufacturing won a $160 million award from BARDA and has contracted with Johnson & Johnson to fill vials and finish packaging of its single-shot COVID vaccine, which is expected to get emergency authorization from the Food and Drug Administration as soon as this month but will only have a few million doses available initially.
The Biden administration has expanded its use of the wartime act to prioritize equipment like filling pumps and filtration systems for Pfizer. "We told you that when we heard of a bottleneck on needed equipment, supplies or technology related to vaccine supply, that we would step in and help," Tim Manning, the White House official leading the administration's COVID supply efforts, said during a February press briefing.
Yet it can do only so much, according to medical supply chain experts. Prashant Yadav, a senior fellow at the Center for Global Development at Harvard University, said it could take months for the impact of that DPA action to be felt because of the time it takes to procure equipment and get it installed, with each step tightly regulated.
The U.S. is unlikely to get a meaningful bump in capacity "unless we think about co-production deals," in which a drug company agrees to manufacture a competitor's vaccine, said Tinglong Dai, an associate professor at Johns Hopkins University's Carey Business School.
So far, such arrangements have proliferated in Europe — which has less capacity to produce drugs than the United States does. Deals with other major vaccine manufacturers have been less common on the U.S. side of the pond.
"Though we have not partnered with, say, another large pharma for production, we have built strategic partnerships with a number of organizations that have been instrumental to our scaling up and meeting supply and commercialization plans," Moderna spokesperson Ray Jordan said in an email.
Moderna this month said that its manufacturing process would scale up rapidly in the coming weeks, that it would provide the U.S. between 30 million and 35 million doses in February and March and between 40 million and 50 million doses monthly from April to July. The company declined to elaborate on what made the boost possible.
Vaccine manufacturers long ago should have been sharing technology and expertise to boost production in the U.S. and Europe, and especially in developing countries, said James Love, director of Knowledge Ecology International, a nonprofit focused on patent rights.
"We've wasted about a year by not doing some of the obvious things," he said. "The rhetoric is that it's an emergency. But on the scale-up of manufacturing, you just don't see it."
It's not that simple, others say. "There wasn't any excess capacity available in the United States a year ago. Zero," Paul Mango, a former HHS official heavily involved in Operation Warp Speed, said regarding vaccines. "It's getting the equipment. It's quality control. It's getting the employees. People make it sound like this is easy. You can't just push 400 workers and say, go at it."
Each Pfizer-BioNTech or Moderna shot contains billions of lipid nanoparticles, each particle containing four lipids and a strand of the nucleic acid RNA, the five pieces assembled in a way that allows the RNA to enter our cells and create a particle that stimulates the immune system to defend against the COVID virus.
The lipids, which are made only in a handful of factories, have been a major supply problem. "No one has ever thought of a scenario where we would use lipid nanoparticle formulation for [billions of] doses," Yadav said. "We have not invented a process for doing lipid nanoparticles at scale."
Two of the lipids in the vaccine, cholesterol and DSCP, have long been used in industry to shape and buffer chemical formulations. A third lipid prevents the particles from clumping together. A fourth enables the lipid shell of the vaccine to fuse with human cells and, once inside the cell, to crack open so the RNA can move to a structure called a ribosome and make proteins that stimulate immunity.
All of these raw materials are produced under regulated conditions — in Massachusetts, Missouri, Colorado and Alabama by companies under license with Moderna, Pfizer or Acuitas Therapeutics, which was co-founded by Pieter Cullis, a University of British Columbia professor who is considered the grandfather of lipid nanoparticle technology.
Before the pandemic, these companies produced meager amounts for use in small clinical trials, laboratory experiments or in one licensed drug, patisiran, which is used to treat a rare genetic disease in about a thousand people worldwide. Now they are producing thousands of kilograms of the stuff, said Stefan Randl, a vice president at Evonik, a lipid maker. Evonik recently announced it would scale up production at two German sites, possibly in the second half of the year, to be used in the Pfizer-BioNTech vaccine. The company last year bought a U.S. lipid manufacturer in Alabama.
"All of a sudden the quantities had to be ramped up a thousand-fold or more," Randl said. "This is the biggest bottleneck."
Several elements of the vaccine, including lipids and enzymes used in making the mRNA, until recently were produced using animal products such as sheep's wool, said Andrew Geall, chief scientific officer at Precision NanoSystems, which designs equipment for mixing the mRNA and lipids. Animal products could cause contamination or disease, even in minute quantities, so manufacturers now use synthetic chemicals.
Luckily, the cosmetic industry — a major user of some of the same lipids used in the vaccines — has been switching from animal products in recent decades, noted Julia Born, an Evonik spokesperson.
Still, only a limited number of companies globally have expertise and facilities to make the lipids, said Thomas Madden, CEO and a co-founder of Acuitas, and they've all struggled to move from quantities produced in a laboratory to industrial-scale production. For instance, he said, hazardous solvents and chemicals used in laboratory procedures need to be avoided in industrial processes, where they could give rise to workplace safety issues.
"This is a hugely complex supply chain," Madden said. "Once you address a bottleneck at one point, you identify the next bottleneck in the process. It's a bit of a game of whack-a-mole."
Although it's not particularly difficult to make the lipids used in vaccines, it takes time to get FDA authorization of a facility that can make them in high quantities, said Cullis, the UBC professor. It would take two to three years to start such a factory from scratch, so instead, Moderna and Pfizer-BioNTech have been hooking up with existing manufacturers and getting them to convert to lipid production, he said.
Another bottleneck is "fill/finish" — getting the finished vaccine into vials or syringes so the shots can be shipped to customers. Vaccine filling lines require extremely high levels of efficiency and sterility, and few companies in the world have this capacity, said Mike Watson, former president of Valera, a Moderna subsidiary. Moderna has hired Catalent, a contract manufacturer that recently experienced delays that slowed the release of some doses, to fill and finish U.S. doses at its facility in Bloomington, Indiana. At least two other companies will do the same for Moderna's vaccine supply abroad.
In January, the French multinational Sanofi — whose own COVID vaccine has been delayed by poor performance in producing immunity — agreed to offer its fill/finish line in Germany for the Pfizer-BioNTech vaccine. That line isn't expected to be running until July.
In the U.S., the number of vaccine doses shipped to states has ticked up in recent weeks, partly because Pfizer said its five-dose vials actually provide six shots. Moderna is seeking FDA permission to add up to five doses to its 10-dose vials.
Pfizer has said it is manufacturing raw materials in St. Louis, the active ingredients for the vaccine in Andover, Massachusetts, and filling vials in Kalamazoo, Michigan.
CEO Albert Bourla, with Biden at his side in Kalamazoo on Friday, said the company added lipid production capabilities at plants in Michigan and Connecticut, as well as fill/finish lines in Kansas. He said it has significantly cut the average time it takes to make doses — from 110 days to 60 days.
"Today, during this meeting, the president challenged us to identify additional ways in which his administration could help us potentially accelerate even further the delivery of the full 300 million doses earlier than July," Bourla said. "The challenge is accepted, and we will try to do our best."
“We need billions of doses, in the space of a year. That's overloading the supply infrastructure.”
Kevin Gilligan, Biologics Consulting.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
Experts cite bottlenecks in at least three areas:
the production of specialty lipids, fatty materials that are a primary component of the Moderna and Pfizer-BioNTech vaccines;
the hundreds of millions of glass vials that hold the vaccine;
and the sterile automated assembly lines where vaccine moves from bulk containers into vials before shipment.