Production of one of the world’s most innovative vaccines begins in a small room, empty but for a workbench, a bottle rack and a bioreactor. Yet within two days, the 50-litre batch of genetic material made will be enough for 8m coronavirus jabs.
Six months ago, the 300 staff at this plant in the German city of Marburg had never worked with messenger ribonucleic acid, or mRNA. They developed cancer antibodies for Switzerland’s Novartis. Then BioNTech bought the plant to ramp up production of one of the handful of vaccines the world is counting on to end the pandemic.
Now, the entire team is trained in producing BNT162b, the first approved mRNA vaccine, made in partnership with US pharmaceuticals group Pfizer.
“Nobody has done this before,” said Valeska Schilling, BioNTech’s head of processing. “It was really motivating for us: we’re at the edge of science.”
Though the factory produces mRNA quickly, its technicians must go slow — they cannot disturb the calibrated filtered air that blows from ceiling to floor. They look like astronauts, dressed in blue suits and white anti-static boots. If you did not know they were on the frontier of nanomedicine, you might think they were dressed for a science-fiction film set.
This time, the scene is staged: BioNTech is showing journalists around the facility, so the mRNA manufacturing room is not completely sterile. The liquids in the bottles are just water — materials for the world’s most highly sought vaccine are too expensive to waste.
Manfred Brunen, head of manufacturing science and technology at the plant, said the real bottles of DNA templates and enzymes used to make mRNA do not look so different. “You’d see some swirls. That’s it,” he said. “Not very exciting.”
But the science is — as is the scale at which it operates.
The Marburg facility has a humble exterior: at just 1,800 sq m, it looks like a squat block of flats. Yet it is meant to produce about a quarter of the 2.5bn doses Pfizer and BioNTech pledged this year. By comparison, the building at Pfizer’s facility in Kalamazoo, Michigan, where the vaccine is made and bottled is more than 90,000 sq m.
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The Marburg factory’s size reflects how small mRNA-based medicine can be produced. Most conventional vaccines are made by growing a weakened virus either inside chicken eggs, meaning hundreds or thousands of sterilised eggs, or in cell cultures, inside large metal cylinders that look like those at a brewery.
A lot of research has gone into miniaturising vaccine production, said Anne Moore, a senior biochemistry lecturer at University College Cork, who specialises in vaccine development. But for vaccines using cell cultures, which is how the AstraZeneca and Johnson & Johnson vaccines are made, conventional methods are necessary.
When BioNTech came to Marburg, the staff stowed away the 2,500-litre steel vats once used for cell cultures — so tall they had staircases to reach the top.
RNA-based vaccines reproduce the genetic code of a pathogen — in this case, the coronavirus spike protein. The body’s cells then learn to produce antigens against it. Because it is molecular, substances can be manufactured on a far smaller scale. “It doesn’t mean mRNA vaccines can solve every disease but it’s working for coronavirus,” Moore said.
At Marburg, the vaccine is produced in four stages. It starts in one of two small rooms where technicians pour the bottles of DNA and enzymes into the bioreactors. This requires a specialised work bench, fitted with intense air filtering to ensure purity.
“It takes maybe eight to nine hours just to transfer everything into that bioreactor,” Brunen said. “Some steps must be performed at a very specific moment — so you start a reaction, then stop a reaction.”
Looking at the bioreactor, it is hard to fathom how sophisticated the process is. It looks like a steel drum fed with tubes and pumps, and lined with a giant plastic bag. Those specialised bags are in high demand by vaccine makers, so each one must be checked for leaks or damage.
Next, the substance is poured into drums that strain out the leftover “soup” of enzymes and DNA, leaving behind the mRNA.
Next, the purified mRNA is sent to four rooms, each fitted with identical steel vessels and pumps. The pumps “look like shoeboxes”, Schilling explained, adding: “This is where the magic happens.”
In order to enter a body’s cells without breaking down, mRNA has to be encased in fat droplets called lipid nanoparticles, just 0.1 micron in diameter. The pumps effectively “shoot” the RNA and lipids together.
It takes up to 13 days to formulate a batch. The more time-consuming part is testing: each batch needs a few weeks of analysis and quality control. This is also what uses most of the facility’s space — labs alone take up only one and a half floors.
Once approved, batches are shipped in refrigerated trucks to partner facilities around Europe for the “fill and finish” stage. The vaccine is checked again, then put into vials.
In normal times, setting up a new plant would take about a year. But Marburg staff and the German authorities got the facility approved in weeks. Regulators watched every step — they were eager to learn the technology, too, Schilling said.
Schilling is amazed how quickly her team has moved. But that is still not fast enough for her family and friends: “Everybody asks: how’s it going? Can you be faster?”