A vial, a vaccine and hopes for slowing a pandemic — how a shot comes to be

The country appears to be on track to have two remarkably effective coronavirus vaccines available before year’s end — the one from Kalamazoo, made by Pfizer and its German partner BioNTech, and another from biotech company Moderna. Both are proving to be more than 90 percent effective in clinical trials so far.

But the next phase of this race will depend on the herculean task of producing these tiny vials of vaccine at a vast scale nearly overnight and distributing millions of doses without wasting any. Getting a vaccine into people’s arms is a meticulously choreographed high-wire act that must not falter at any juncture, and distribution looms as among the most daunting challenges. Basic questions remain to be resolved: Which hospitals or pharmacies will receive, store and administer the doses? Who will get first crack at receiving them?

And at the end, everything depends on those vials.

Following the path of a single dose of the coronavirus vaccine produced by Pfizer and BioNTech — from raw ingredients to deep-freeze in Kalamazoo to the people seeking protection — reveals the brute-force engineering challenge that lies ahead. Even as the scientific endeavor has notched historic successes, equally ambitious manufacturing timelines have slipped, a reflection of the magnitude of the challenge. This summer, executives projected having 100 million doses by the end of the year; now they are racing to produce half that amount.

“If you would ask me 10 months ago if an effective vaccine could be developed, then my answer would be, ‘We have to try it, but I don’t know,’ ” said Ugur Sahin, chief executive of BioNTech, the German firm that invented the vaccine technology and partnered with Pfizer for its expertise in bringing medical products to market. “The vaccine supply is not a matter of uncertainty. It’s a matter of execution.”

The vials must be transported and stored at extreme, subarctic temperatures, far below the chilling capabilities of standard equipment in medical offices, pharmacies and even many hospitals. Pfizer opted to use its own GPS-tracked, suitcase-sized coolers — “thermal shippers” — rather than rely on wholesalers that typically distribute drugs. Each shipper needs 50 pounds of dry ice pellets, so Pfizer is building its own dry ice factory.

The company must coordinate shipments of doses so they arrive before or in tandem with a separate box full of syringes, needles and the other accoutrements of vaccination. And manufacturing, transport and immunization will have to go seamlessly not once, but twice, because the regimen requires a booster shot to offer full protection. Pfizer executives predict the company will be able to produce 1.3 billion doses of its vaccine by the end of 2021.

Pharmaceutical manufacturing is a lot like cooking a recipe that must turn out perfect each time, said Rebecca Sheets, a regulatory expert and consultant at Grimalkin Partners, a firm that provides advice to the vaccine and biologics industry. A menu that worked as an intimate dinner for two cannot feed the world overnight, and the industry standard is to increase production by gradual, tenfold increments, in effect trying a dinner party for 20 before a banquet for 200.

“They’re trying to do in three months what might take three years,” Sheets said. “What they’re doing is really a Manhattan Project.”

From ‘bench scale’ to the masses

On a Friday night in mid-March, Chaz Calitri, Pfizer’s vice president of operations, got a call at home in Collegeville, Pa. His boss told him that Pfizer’s chief executive, Albert Bourla, had decided to launch on a coronavirus vaccine, and Kalamazoo — a 2,000-acre, 80-building campus in Michigan that Calitri oversees — was going to be key to the effort.

Calitri has worked in pharmaceutical manufacturing for 39 years, running a round-the-clock operation that churns out drugs for the world. But this was a daunting proposition. Typically, to take something made at a laboratory bench and turn it into a high-quality, mass-produced pharmaceutical product would take a year of experiments and equipment design. Bourla wanted it done in months.

“My head was spinning,” Calitri said. “It was only done at a bench scale, and we want 100 million doses by the end of the year, and 1.3 billion doses by next year — and we didn’t really have a process.”

Calitri moved to an apartment in Kalamazoo, leaving his family in Pennsylvania, and got to work.

The federal government has invested billions of dollars to ease the financial risk of vaccine development, to make sure there is no hesitation to spend money building a product before anyone knows if it works. Pfizer partnered with BioNTech in March and decided not to seek government help to underwrite research and development, instead spending $2 billion of its own cash. The companies then entered a contract to sell 100 million doses to the government for $1.95 billion — but getting paid only if they succeed.

At the core of Pfizer and BioNTech’s vaccine is a powerful but fundamentally transient and unstable genetic material called messenger RNA, ensconced in lipid nanoparticles — tiny fat bubbles. The messenger RNA encodes the blueprint for the hallmark spiky proteins that stud the surface of the coronavirus and, once inside a person’s body, it instructs cells to build replicas of the spike. Those harmless versions teach the immune system to recognize the real thing — in essence, turning the human body into a vaccine factory.

The technology has never been used in an approved medical product. That means Pfizer and BioNTech are inventing the recipes — and tinkering with them to increase the output at almost the same time.

From St. Louis to Kalamazoo

The first ingredients are manufactured far from the Kalamazoo freezer farm, in a pilot plant in St. Louis — a manufacturing facility that develops the first run of new products. The pilot plant is outfitted with large vats for growing cells, along with centrifuges and other laboratory equipment — and a curated library of cells that can be used to produce materials for drugs, including a coronavirus vaccine.

Step one is to generate lots of genetic material.

Scientists use a buzz of electricity to create holes in the cellular skin of E. coli bacteria to let a ring of DNA slip in, carrying the blueprint for the coronavirus spike protein. Those cells grow in large stainless steel vats, allowing the bacteria — and the DNA blueprint of the spike protein inside — to multiply over about four days. At the end of the process, scientists kill and break open the cells, using a purification process that takes about a week and a half to strain out a ring of DNA, called a plasmid, that codes for the spike protein.

To make sure the ring of DNA has a discernible beginning and end, scientists cut it to create a readable snippet. Then they portion about a gram into clear bottles and freeze them to ship to plants in Andover, Mass., and Germany.

The numerous quality checks — which can be one of the most time-consuming parts of the manufacturing process — begin at this early stage and occur with every batch and ingredient.

“Just with the sheer volume here and the cadence needed, we’re pretty much testing continuously,” said Aparna Deora, senior director of quality control, stability and microbiology at Pfizer.

A gamut of tests are run on samples to ensure that the materials and the final product are pure, potent and free of contaminants. Such testing is a critical but abstruse part of drug development that’s invisible to the general public, but Deora said her parents now pepper her with questions about her job, and a cafeteria worker recently told her that making lunch for her group makes him feel like he’s part of the vaccine campaign.

Moving to the next phase of manufacturing without delays is so important that the scientists have resorted at times to using the company jet and helicopter to make special deliveries, giving frozen bottles of DNA a VIP trip.

“What we’re doing here is completely aligned with what is going on in Andover and what’s going on in Germany. The cadence of manufacturing is linked,” said Paul Mensah, who leads the bioprocess research and development and drug substance supply group at Pfizer. “We’ve used the company jet on one day’s notice to come and pick up the [DNA] plasmid and fly to Germany to deliver it.”

In Andover and Germany, scientists take the line of DNA and put it in an incubator with genetic building blocks to create messenger RNA.

The scientists then fill a special plastic bag with the purified messenger RNA and freeze it down. Each bag, about the size of a large shopping bag, contains enough for about 5 million to 10 million doses of vaccine. In Andover, the bag is hung on a special frame for handling and put on trucks to Kalamazoo.

The bags aren’t defrosted until everything is ready, because once they are, a clock starts ticking — the product has to be formulated and refrozen in under 72 hours, or it is wasted.

The messenger RNA is combined with the lipid nanoparticles using a specialized piece of equipment and readied to be put in vials. This, Calitri, said, is currently the bottleneck in the process in Kalamazoo. It’s where, if there hadn’t been a pandemic, the company would have designed larger-scale machinery to optimize output instead of just replicating the existing process. It’s much like a caterer who wouldn’t bake 100 pizzas in a home oven, but instead would build a bigger oven.

Once the vaccine has been formulated, it is handed over to the filling team, which currently runs two lines — the fastest of which can fill nearly 600 vials a minute. Those vials are then put in the boxes and frozen to minus-70 degrees Celsius, or minus-94 Fahrenheit.

If Pfizer receives the regulatory green light, its freezer farm will become a distribution center, the pizza boxes submerged under 50 pounds of dry ice and sent to points of vaccination, which will be determined by states but could include locations such as hospitals or pharmacies. By the end of the year, Pfizer anticipates sending thousands of shipments each day from Kalamazoo and a second freezer farm in Pleasant Prairie, Wis.

Upon arrival, the thermal shippers must be refreshed with dry ice or the vials must be transferred to ultra-low-temperature freezers. The specifications are exacting if the vials stay in the shippers — the cooler is not to be opened more than twice a day, must be refreshed with dry ice every five days and is designed to be used for 15 days. The vials can stay at refrigerator temperatures for five days before their contents degrade.

“We have a real opportunity to get this right, and a real opportunity for this to be mass chaos,” said Soumi Saha, senior director of advocacy at Premier, the group purchasing organization and supply consultancy for 4,000 hospitals.

The ultracold storage requirement for the vaccine will add a wrinkle to an unprecedented vaccination campaign. Rolling out such a vaccine in the developed world will be challenging; doing so in the developing world could be nearly impossible. The next phase of vaccine production involves creating a more stable freeze-dried version and expanding production capabilities, for example, by finally building those bigger pizza ovens that could make formulation go faster.

Throughout the vaccine effort, government officials have projected hopeful timelines about when doses will be available: High-risk people may be able to get vaccines in the first months of next year, the rest of the population later in the spring and summer. Beneath those projections is a labyrinthine scientific and industrial process, with each node — hundreds of people’s work — coming together to bring the world closer to ending the pandemic.

“There’s a lot of times in this industry, you work on something that you know someone — a family member or friend” affected by a disease, said Pamela Siwik, vice president of Pfizer Global Supply. “In this case, it’s the world.”