Beginning in August, a half-dozen researchers at a Pfizer lab in Massachusetts sat down with vials of experimental coronavirus vaccine to learn how to transform the “overfill” in every vial — an extra amount of liquid that is standard for injectable pharmaceuticals — into a precious sixth dose.
By Jan. 6, the work paid off.
Pfizer won approval from the Food and Drug Administration to say its vials contained six doses, instead of the five the agency had approved less than a month earlier with its Dec. 11 emergency authorization of the vaccine.
The shift gave regulatory approval for Pfizer to sell 20 percent more vaccine at a time of severe scarcity. It also permitted Pfizer to apply that additional dose to its government contracts.
But regulatory approval immediately collided with the fragilities of America’s medical supply chain and a shortage of equipment able to extract all six doses out of Pfizer’s vials.
The FDA approval of the bonus dose caught state regulators and health systems unprepared, creating a sudden demand for millions of specific syringes and adding to the confusion of the slow and uneven rollout of vaccines across the country.
The timeline outlined by two Pfizer executives to The Washington Post shows the company had been working on a solution to the sixth dose for months before hospital pharmacists independently discovered that each vial contained enough overfill for an extra shot.
The chain of events signals a lack of coordination between federal officials and the vaccine supplier that was first over the finish line, said Jesse Goodman, a former chief scientist at the FDA and the director of Georgetown University’s Center on Medical Product Access, Safety and Stewardship. He noted that health providers were able to extract extra vaccine from vials during the H1N1 pandemic in 2009, so it was a known strategy to stretch supplies.
“I think this could have been anticipated. … It’s one more thing that was lost in the woodwork during the vaccine response,” he said. “If this problem had been identified and surfaced as part of the planning effort for vaccination, rather than suddenly ramping up production of these things in the last month, this is something that could have been done six months ago.”
The disconnect between potential extra doses and a shortage of syringes is a prime example of how medical supply chain gaps have foiled U.S. efforts to maximize the flow of vaccine into arms. The government, manufacturers and distributors also are grappling with shortages, among other things, of raw ingredients for vaccines, the plastic bags that line fermentation tanks and “finish-fill” capacity to put batches of vaccine into vials.
“There is more than one bottleneck. When you are ramping up from zero to 400 million doses, there are challenges at each part of that supply chain that have to be addressed,” said Julie Swann, a professor of industrial and systems engineering at North Carolina State University.
Pfizer said it raised the issue of the sixth dose with the FDA in December, after it had secured its emergency authorization. Company officials said by then they had completed work investigating various syringe combinations for the extra shot and felt confident enough equipment could be found.
The FDA generally does not discuss its interactions with companies. A person familiar with the situation who was not authorized to speak publicly said the FDA first heard about the sixth dose in December, from health-care providers calling the agency saying they were getting six or even seven doses out of the vials and asking what to do with them.
Pfizer says it has now validated 35 syringe-needle combos to get six doses out of the vials.
“That obviously is very important for the pandemic. A dose that was wasted that was in the vial and thrown away … now that is not going to be the case,” Pfizer chief executive Albert Bourla told Bloomberg News last week. “People are instructed to also try to extract the sixth dose, and they have the means to do it.”
The addition of 20 percent more vaccine per vial will allow Pfizer to accelerate distribution in Europe and the United States. The company on Tuesday said it expects to earn $15 billion in coronavirus vaccine sales in 2021; it expects to produce 2 billion doses for global distribution but said it is not certain it will sell all of it before the end of the year.
In the United States, Pfizer has committed to distributing 120 million doses before the end of March; another 100 million that were expected by the end of June will now be available by the end of May, according to the company. The United States also has ordered another 100 million doses to be delivered by the end of summer.
“It is a great thing for everyone,” Bourla said. “It would be criminal if we can use six doses and we were throwing one [away] in a vaccine that could save lives right now.”
The new administration publicly identified a lack of special syringes to extract all Pfizer vaccine vials as a priority problem on Biden’s second day in office. By last week, Biden officials said they had scraped together enough of the syringes and needles from existing pandemic contracts to accompany all Pfizer shipments.
But reports of vaccinators lacking appropriate syringes for Pfizer shots persisted as recently as Friday, according to pharmacists, raising the prospect that Pfizer will get paid for an unknown number of doses that are still going to waste.
“I don’t know those [new syringes] are in the hands of the front lines yet. The conversations that I had were talking about mixed supplies in those kits,” said Michael Ganio, senior director of pharmacy practice and quality at the American Society of Health-System Pharmacists, citing a conversation he had with New Jersey hospital officials Friday.
Low-dead-space syringes minimize waste by eliminating gaps between the plunger and needle. Such syringes, which cost more than regular units, are typically used to preserve every drop of oncology drugs and other expensive medicines. They also are distributed by needle-exchange programs to combat blood-borne illness among drug users who share needles because they reduce the amount of blood retained in the needle and syringe assembly.
“There’s companies that can produce them, but I don’t know how long it’s going to take them to scale up to those kinds of numbers” needed for a global vaccination program, said William Zule, a senior fellow in health policy at the nonprofit research institute RTI International and an expert in HIV transmission via needle sharing.
Long-term shortages of the syringes could become a problem as suppliers scramble to meet demand that will rise into the hundreds of millions. The Department of Health and Human Services said last month that it had advised the FDA about the potential of a long-term shortage of the special injectors.
BD, the largest syringe manufacturer in the world, said last month that establishing new production lines to make more of the special equipment will not be a rapid process. Under a U.S. government contract, BD is expanding production of standard syringes at a plant in Nebraska, a process that began last year and is expected to be complete by the summer.
B. Braun and Smiths Medical, two other large manufacturers, declined to comment in detail on demand created by Pfizer. B. Braun said it does not make the low-dead-zone syringes in the United States and that its foreign affiliates lack capacity.
“We were unable to accommodate Pfizer’s request because our parent company’s subsidiary did not have capacity to produce the syringe sizes needed to administer the vaccine,” the company said in a statement.
The Pfizer executives said they did not seek FDA permission for six doses in the company’s emergency use authorization bid in December because they were concerned about the potential shortage of the special syringes.
They stuck with five to play it safe, they said.
“Coming out of the gate, we really had to design for the least common denominator. We couldn’t assume that everybody” had access to low-dead-space syringes, said Kevin Nepveux, the Pfizer vice president who oversees new product rollouts in the manufacturing division. “The worst position to be in would be to have a health-care provider who has six patients lined up, using standard components, and not be able to give all six a vaccine.”
Ultimately, the work of the Pfizer researchers testing a variety of needle-and-syringe combinations gave the company confidence that a sufficient supply of syringes exists to uniformly extract all vaccine from all vials shipped.
Part of the complexity is that there is no established standard for low-dead-space syringes, also known as low-dead-volume syringes.
Pfizer set its own threshold as it ran its tests: combinations of needles and syringes that could extract 0.3 milliliters of vaccine, a single dose, six times.
Standard syringes and needles typically contain 0.1 milliliter of waste after a drug is injected, which is why drug companies generally add “overfill” in the first place. In Pfizer’s case for five-dose vials, the overfill was more than 0.5 milliliters, or greater than one 0.3-milliliter dose.
As it set out to designate that small bit of fluid as another dose, Pfizer set the bar for low-dead-space needles and syringes at a maximum of 0.035 milliliters retained in the needle-syringe assembly. That saves 0.065 milliliters on each shot; multiplied by five, that’s more than enough for a dose.
“The concern is we didn’t quite know what is the global availability of the low-dead-space syringes, and we had to work with the vendors, and understand what is already in the market, and how can we partner with companies to increase their capacity,” said Nick Warne, Pfizer’s vice president of pharmaceutical research and development.
The work proved pivotal after Pfizer lowered expectations for vaccine production during 2020 and wrangled with the U.S. government over the pace of vaccine production.
In November, Pfizer said it would produce just half of the vaccine it expected by the end of last year, reducing its end-of-year target from 100 million doses to 50 million doses.
Then government officials expressed frustration with the pace of supply after Pfizer won its emergency use authorization in December; confusion mounted over smaller-than-expected shipments to states and contradictory statements about the availability of reserve stockpiles.
The sixth dose is not immediately counting against the Pfizer allocation provided to states, which is set around 4.3 million doses for the next three weeks, toward the total goal of 10.5 million doses per week (when combined with shots from Moderna, the other drugmaker with an authorized vaccine), according to officials familiar with the process who were not authorized to speak publicly.
If all places consistently extract the additional dose from the vials, which are now being sent in six-dose labels, the weekly allocation of Pfizer vaccine will amount to more than 5 million doses. The difference is consequential because Moderna has moved ahead of Pfizer in manufacturing, according to two officials, which is primarily what allowed the federal government to boost vaccine allocations for about three weeks.
Moderna has now joined Pfizer in a bid to get more vaccine per vial, although it is taking a different approach. A person with knowledge of Moderna’s request, who was not authorized to speak publicly, told The Washington Post that the company is asking the FDA to allow it to add five more doses of vaccine to vials that hold 10 doses, a bid to ease bottlenecks in the packaging process.
Moderna, which confirmed its plan this week, did not respond when asked if any of the additional doses would be converted from current overfill, or whether special syringes would be required to use all 15 doses. CNBC first reported Moderna’s request.
Isaac Stanley-Becker contributed to this report.
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