The Vaccine Issue

Source: Becton, Dickinson & Co.

Without Vials and Needles, a Virus Vaccine Is Just a Formula

Making sure the world will have enough vials, hypodermics, and adjuvants.

When you’re planning a large vaccine drive, predictability is vital. The immunization campaign that allowed India to eradicate polio in 2014, for example, worked methodically through the country’s populace of hundreds of millions of children, backed by a bank of knowledge about how the virus behaved, what the vaccine’s properties were, and where new cases could be found. Such factors dictate not only how much vaccine is manufactured but also the production of a host of ancillaries: chemical additives such as adjuvants; hypodermics, glass vials, rubber stoppers, and other parts of an injection kit; and storage equipment such as deep freezers. Without this gear, a vaccine is just a fine formula, a cure in search of its disease.

Bloomberg Businessweek cover image for issue dated Aug. 17, 2020.
▲ Featured in Bloomberg Businessweek, Aug. 17, 2020. Subscribe now.
Photo Illustration by 731; Getty Images (9); Alamy (4)

Nothing about Covid-19 has been predictable, though. When the quest for a vaccine began early this year, moments after the new coronavirus’s genes were sequenced and posted online, the prospects were so unclear that some governments postponed preparations for vaccine delivery. In a whistleblower complaint, Rick Bright, then the director of the U.S. Biomedical Advanced Research and Development Authority (Barda), wrote that his agency had estimated as far back as January that the country would need from 650 million to 850 million needles and syringes for a Covid-19 vaccination drive. The Strategic National Stockpile held just 15 million at the time, and Bright kept hearing that other countries, aware that scientists were predicting a 12- to 18-month timeline for the release of a vaccine, were buying up stocks of syringes and needles from the U.S. Yet the American government didn’t place its first order for needles and syringes until May 1, he told Congress.

When a vaccine is finally approved for manufacture, the rush to stock up on ancillary products will be unprecedented. Across the world, according to Simone Blayer, who oversees vaccine process development for Path, a public health nonprofit based in Seattle, “we’re looking at probably 2 to 4 billion doses to be deployed in the first quarter.” No one knows what kind of vaccine will succeed, how it will need to be stored, where it will be administered first, how many doses a person will need—or, indeed, whether we’ll even have a vaccine at all. If and when we do, manufacturers of vaccine ancillaries, accustomed to sedate and reliable cycles of demand, will have to meet a near-­instantaneous clamor for their products.

• Vials
A brief appreciation of borosilicate glass

Low-filled SCHOTT Vials with crimp neck.
Source: Schott AG

The invention of borosilicate glass is part of corporate lore at Schott AG. In 1880 the German chemist Otto Schott, a window maker’s son, set about experimenting with glass, trying to fulfill the stringent needs of a telescope observatory in the town of Jena. Methodically he worked his way through the then-new periodic table, adding one element after another to glass mixes and testing the results. Boron, until then, had been used mostly in detergent, but it turned out to make glass containers more resistant to temperature changes and far less reactive to the chemicals they held. 

I asked Fabian Stöcker, Schott’s vice president for global strategy and innovation, what makes borosilicate glass so different from the glass out of which I’ve just taken a sip of water. “That glass of water you’re holding—it’s a soda-lime glass,” he says. If it held a more potent chemical, he explains, small particles of glass would gradually leach into the liquid. That doesn’t happen with borosilicate glass, making it ideal for containing drugs and vaccines, which must avoid contamination. Schott makes long glass tubes out of borosilicate mixes—7% to 13% boron, the rest mostly silicon dioxide—at four melting facilities: two in Germany and one each in India and Brazil. The company is the world’s largest manufacturer of medical borosilicate. “Around the world, roughly 25 billion injections every year—or 1,200 a second—are drawn out of vials made with our borosilicate glass,” Stöcker says. About 11 billion of these are vials made by Schott itself; the rest are made by other vial manufacturers to whom Schott sells its borosilicate tubes. 

In the early weeks of the pandemic, vaccine developers still couldn’t forecast the kind of vials they’d need, but as prospects grew brighter and clearer, a tide of inquiries came Schott’s way. To commission and test all-new factories, Stöcker says, would have taken a couple of years. Instead, Schott freed up manufacturing capacity in its existing factories, giving over more and more production lines to vials. The company had already planned to invest €320 million ($376 million) across its operations, including for plant machinery; it ordered still more machines as vaccine development progressed. “We can supply vials for 2 billion vaccine doses, when the time comes,” Stöcker says. 

Several challenges of physics and logistics remain. The final step in the process of vaccine manufacturing is known as the “fill and finish,” in which vaccines and other chemicals are piped into vials, which are then sealed and checked. Many plants today can fill and finish tens of thousands of vaccine doses per hour, but when the immediate need is for billions of doses, even the fastest robotic filling arm can be too slow. For this reason, says Blayer at Path, the first wave of vaccines will likely have multiple doses in each vial. And the urgency of the demand may mean these multiple-dose vials won’t contain preservatives, which normally have to undergo extensive testing to ensure the chemicals don’t react adversely. In that case, Blayer says, “all the doses in a vial will have to be used up six or so hours after the vial has been opened, according to WHO [World Health Organization] requirements.” An analyst at investment adviser Evercore Inc. also warned in April that the glass industry will face shortages of the kind of high-purity sand that goes into borosilicate glass, though Stöcker insists Schott isn’t expecting a sand crunch. 

Bright warned the U.S. government early in the pandemic that all the borosilicate tubes on the global market were either sold out or spoken for. It wasn’t until May, when the U.S. government finally began to prepare for a vaccine, that it tried to secure a supply. Barda has invested $204 million in Corning Inc. to expand its production of glass vials, and the government is also trying to secure alternatives to the classic vial in its attempt to make up for lost time. A company in Connecticut, ApiJect Systems Corp., has received $138 million to make 100 million prefillable plastic syringes by the end of the year. Another company, SiO2 Materials Science in Auburn, Ala., manufactures a patented vial out of plastic coated with a thin layer of glass. It looks just like a glass vial but is stronger and won’t be affected by sand shortages, according to Lawrence Ganti, the company’s chief business officer. In June, after extensive presentations to Barda and the U.S. Department of Defense, SiO2 won a $143 million investment to accelerate its production—from 14 million vials to 120 million by December. “Basically they’ve called dibs on our entire production, should they need it,” Ganti says.

Camera inspection of Schott vials.
▲ Camera inspection of Schott vials.
Source: Schott AG

If you went to the SiO2 campus in Auburn, he adds, you’d see “our first 165,000-square-foot plant, with people running around in cleanrooms, wearing PPE bunny suits, and just down the road, diggers and machinery that are building a second plant. We’re having to hire like crazy.” (By July, SiO2 had started work on a third plant.) Every kind of vial has to undergo stability testing with vaccine candidates to make certain the container and its contents don’t react with each other. Ganti says SiO2 has been conducting this testing with Moderna Inc. and three other vaccine developers.

In June, Schott’s chairman, Frank Heinricht, told Reuters he’d rejected requests from pharma companies to reserve stocks of vials in advance, lest Schott end up committing a major supply to a vaccine developer that fails to bring its product to market. The company has instead forged agreements with a number of big companies—“hot tickets,” as Stöcker calls them—that are working on Covid-19 vaccines, so its newly added capacity can best support production. “Then, in case one of them gets to make the successful vaccine,” Stöcker says, “we are ready and there.”

• Adjuvants
Moving beyond soapbark to target the coronavirus

Soapbark tree (Quillaja saponaria), which is native to the country of Chile, used as the raw material in Agenus Biotech adjuvant.
▲ The soapbark tree is the raw material for Agenus’s adjuvant.
Source: Agenus Inc.

On a Zoom call, Garo Armen playacts with his hands the role of an adjuvant in a vaccine. “Say you have a gun, a very accurate gun, and you point it at the target you want to hit,” says Armen, CEO of the biotechnology company Agenus Inc., based near Boston. He mimes cocking a pistol with the fingers of one hand and aims it at the other. The gun is a vaccine, and the target is a particular kind of immune response roused by the vaccine. “Now, maybe your bullet doesn’t have enough energy to reach the target, and it drops away before the target. That extra energy needed is provided by the adjuvant.” 

More precisely, the adjuvant is a secondary chemical that acts alongside the vaccine to provoke the right kind of immune response and ensure the response has “memory”—that it can be stirred up again even if a pathogen invades the body years down the line. The first adjuvant was discovered by accident, by a French veterinarian named Gaston Ramon who gave horses diphtheria shots in which he’d mixed one or the other of a range of substances: breadcrumbs, tapioca, agar. For decades thereafter, the only notable adjuvants licensed for human vaccines were salts of aluminum, which could be produced cheaply and plentifully; they goosed inoculations against hepatitis, tetanus, and diphtheria. Only in the 1990s did biotech labs such as Agenus find and develop complex new approaches. Agenus’s flagship adjuvant, QS-21, rides inside GlaxoSmithKline Plc’s shingles vaccine. The addition helps make the vaccine effective in more people and for longer periods of time, Armen says. “Even eight or nine years out, we haven’t seen any decline in efficacy.”

Not every vaccine requires an adjuvant, but many of the Covid-19 vaccines under development are using one in trials. In theory, adjuvants can shrink the volume of vaccine needed in each dose, which would ease the pressure on manufacturers. They can also boost the effects of vaccines in older adults, who’ve been disproportionately affected by Covid-19 and whose immune systems are difficult to stimulate. The effectiveness of flu vaccines, for comparison, wanes in people over age 65, even though these shots frequently come “adjuvanted”; in 2018-19 they were effective in just 12% of this age group, vs. 25% for people 18 to 49. In May, GlaxoSmithKline announced it would manufacture 1 billion units of its AS03 adjuvant, which has worked with pandemic flu vaccines, to supply multiple developers of Covid vaccines around the world. 

Twenty years ago, a sudden demand for adjuvants could only have been filled by aluminum salts. The newer options are more refined and take better aim at the immune system, according to Armen. To demonstrate, he pulls open a drawer in his desk and takes out a flip phone. “Would you use one of these today?” he says. “No. So why would you use aluminum salts?” 

The new adjuvants, however, until very recently had to be distilled from natural sources, which took time, patience, and abundant supplies. The active ingredient in QS-21 comes from the soapbark tree, which grows in the mountains of Chile; its bark has to be harvested in the southern summer, turned into a slurry, and processed. Squalene, another new adjuvant, is derived from shark liver oil. To obtain 1 billion doses “would take a lot of sharks, and a lot of hunting, for a long time,” says John Melo, CEO of Amyris Inc., a biotech company based in Emeryville, Calif.

Now, biotechs are finding ways to synthesize these compounds. Armen says that Agenus has been working on multiplying cells in bioreactors and that in a couple of years he expects to be able to turn out vast quantities of QS-21 without needing a steady harvest of Chilean bark. Amyris has been testing and validating its version of squalene, made by fermenting raw sugarcane in Brazil and then processing that product in American factories, for the past two years. When the pandemic started, it was “close to market-ready,” Melo says. In July, Amyris had already committed to deliver 10 tons of squalene adjuvant—1 billion 10-milligram doses—by the end of the year to a major pharmaceutical company for its coronavirus vaccine candidate. 

Brazil sugarcane fields, sugarcane used in Amyris's version of squalene.
▲ Brazilian sugarcane is used in Amyris’s version of squalene.
Source: Amyris Inc.

I ask Melo what would happen to all that squalene if the search for a vaccine failed. He’s sure it would still be used—if not in a coronavirus vaccine, then in a flu shot. “It’ll have a home, definitely,” he says. The real issue is to have more squalene ready to go if a compatible coronavirus vaccine made by another company proves successful. “What makes it hard is that, right now, I don’t think anyone can predict which the winning vaccine will be.”

• Hypodermics
Building toward billions of ouchies

The world’s largest manufacturer of injection devices is Becton, Dickinson & Co., which sold its first syringe in 1897. Imported from France and costing $2.50, the original was an all-glass model at a time when others were made either of hard rubber or of glass and metal combined. Today, Becton Dickinson factories are spread across the U.S., Europe, and Asia, helping the company earn revenue last year of $17.3 billion. In the U.S., the largest manufacturer of Becton Dickinson’s syringes is a plant in Columbus, Neb., and its needles chiefly come from a factory in Canaan, Conn. Troy Kirkpatrick, a spokesperson for the company, won’t specify how many of each the company makes in a typical year but says it’s “in the billions in the U.S. alone.”

Hypodermics maker Becton Dickinson says it can handle large orders—as long as it has advance notice.
▲ Hypodermics maker Becton Dickinson says it can handle large orders—as long as it has advance notice.
Source: Becton, Dickinson & Co.

When I spoke with Kirkpatrick on the phone in June, he was at home; Becton Dickinson’s headquarters in Franklin Lakes, N.J., hadn’t reopened yet. But the company’s plants were all running, by and large. It helped, he says, that Becton Dickinson has factories in China, which saw the coronavirus first; as the pandemic spread westward, its factories in Europe and America were able to implement the lessons the company had learned. Employees had their temperature taken when they arrived; the shop floor was cleaned even more than usual. Some product lines, such as for catheters and artery balloons, had to be put on hiatus, Kirkpatrick says, because hospitals were so focused on Covid-19 they’d stopped performing elective surgeries and nonemergency procedures. 

Most modern syringes are extrusion-molded out of polypropylene resin and then packed in blister film and medical-grade paper. Needles are milled from stainless steel—the hollow tubes sealed along their sides by lasers, pressed to thinness in a die, and then ground to a sharp point. The raw materials for both products are common and widely available, according to Kirkpatrick. “We haven’t seen any issues in these supply chains, so we aren’t worried about that currently,” he says. “The bigger risk, I think, is, do we have enough of an understanding of the kinds of volumes that are going to be needed six or seven months from now?”

If the Trump administration were to order 300 million hypodermic injection sets, Becton Dickinson could do that. “Obviously it helps that our baseline is in the billions,” Kirkpatrick says. “But it isn’t like we can flip a switch and do it overnight.” He expresses concern that some officials haven’t been planning ahead. “One government that has thought about this already is the Canadian government, which has ordered 38 million needles and syringes from us. That’s enough to inoculate their entire population with one dose,” he says. “But others seem to be thinking that this is down the road a bit, and that they have the luxury of waiting. We’re talking to them and trying to break that myth.”

BD Injection Device.
▲ Becton Dickinson says vaccine makers need to be clear about what volume of vaccine they’ll need to inject.
Source: Becton, Dickinson & Co.

At the time Kirkpatrick and I spoke, Becton Dickinson was in talks with the U.S. government. “We’re trying to say: ‘Look, if you’re looking at potential vaccines that may be ready, say, at the beginning of next year, you need to place your orders now,’ ” he says. “Otherwise, even we can’t make hundreds of millions or billions of syringes in a matter of months without sacrificing all sorts of other products that are used for non-Covid purposes.” On July 8, Barda agreed to invest $42 million in ramping up Becton Dickinson’s manufacturing in Nebraska and to purchase 50 million needles and syringes; two weeks later, the U.S. ordered an additional 140 million, and Canada an additional 37 million. 

These orders notwithstanding, Becton Dickinson could well set about expanding its production capacity only for no vaccine to materialize. Purely from a business perspective, this scenario doesn’t trouble Kirkpatrick much; the U.S. government will pay for the equipment well in advance, and if no vaccine materializes, the needles and syringes will go into the national stockpile for future use. The priority is for manufacturers to get involved early in the planning process. Not all hypodermics are the same, and syringe and needle makers need to know the nature of the vaccine before they begin production. “Do you need 1 milliliter, or 10 milliliters, or something in between?” Kirkpatrick asks. This is why companies are pressing for quick decisions. “Cranking up production is fine, but cranking up production of what, specifically?” he says. “We can’t guess what types of syringes you’ll need at the last minute.” 

More On Bloomberg