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US A COVID-19 vaccine life cycle: from DNA to doses

13:30  07 february  2021
13:30  07 february  2021 Source:   usatoday.com

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On the evening of March 20, Chaz Calitri was getting ready to start in on his family's Friday night pizza-making tradition when his boss called.

diagram: Vaccine production © Veronica Bravo Vaccine production

The pharmaceutical giant Pfizer had decided to make a vaccine to fight COVID-19, the new disease caused by the novel coronavirus spreading with frightening speed in the U.S. The factory Calitri ran in Kalamazoo, Michigan, would play a key role in getting it made.

"I was really excited," he told USA TODAY. "I've been working in pharmaceutical manufacturing for almost 40 years and I've never been on a project like this."

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His facility would be responsible for the last few production steps in a vaccine that could help quell the pandemic and save lives.

Reality, however, soon sunk in. It normally takes years to devise a manufacturing process and develop a new vaccine or drug. He'd been given mere months. The vaccine formula wasn't even finalized.

"I sat down on the couch a half hour later and I was horrified," Calitri said. "My head was spinning."

During the last 10 months, Calitri and his peers at a handful of other drug companies have managed to pull off what they would have considered impossible a year ago: producing tens of millions of doses of a novel vaccine.

And he and others at Pfizer are on the verge of cutting production time for their vaccine nearly in half – from 110 to 60 days.

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Although Americans are clamoring for more vaccine, people who understand the manufacturing process are amazed at how quickly so many doses have been made.

"Vaccine manufacturing is an endeavor where an almost infinite combination of things have to work perfectly," said Prashant Yadav, a health care supply chain expert at the Center for Global Development, an international think-tank that aims to reduce poverty.

a factory next to a building: Plasmid manufacturing suite at Pfizer's Chesterfield, Missouri, site. © Photo provided by Pfizer Plasmid manufacturing suite at Pfizer's Chesterfield, Missouri, site.

There's variability in the raw materials, the microorganisms needed to grow vaccine products, the conditions of the culture in which those microorganisms are grown, and more, Yadav said. "It is science with established principles, but sometimes is more idiosyncratic than art."

The two vaccines rolling out across the country since late December have made the vaccine development and production process look easy.

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Moderna had a vaccine ready to be tested in people in just over two months. Pfizer, which partnered with a German company, BioNTech, had a 44,000-person clinical trial finished before Thanksgiving.

The two teams, both of which use a technology called mRNA, have delivered more than 59 million doses to the federal government since Dec. 11.

But the vaccine development and manufacturing process doesn't always go smoothly.

Merck, another pharmaceutical giant, dropped out of the race recently when its early vaccine candidates failed to live up to their promise.

And AstraZeneca, which is collaborating on a vaccine with Oxford University in England, has stumbled a few times. In a global trial, effectiveness figures were muddied by giving some participants a different vaccine dose. Not enough older people were included to make it clear whether they'd be protected.

Now, the company is struggling to meet its production commitments in Europe, because starting up a factory in Belgium proved harder than anticipated.

"People don’t understand, manufacturing vaccines is extremely complicated," AstraZeneca CEO Pascal Soriot said at a recent news conference. "It’s not like (making) orange juice."

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All the competitive COVID-19 vaccine manufacturers have been pushing to produce more doses faster. But no matter how much engineers like Calitri have worked to shave weeks, days and hours off the vaccine-making process, it still takes time.

For Pfizer-BioNTech, a batch can make anywhere from 1 to 3 million doses of vaccine per production run, which the company says will soon take just 60 days.

The time per batch from start to finish was originally about 110 days, but as engineers learn how to make the process more efficient, the company thinks it will get down to just 60 days per batch.

Still, vaccine arriving at hospitals and clinics today comes from batches started just before Halloween.

Even at the current 110 days, Pfizer's COVID-19 vaccine production time is more than two months faster than that of the influenza vaccine. The Salk polio vaccine takes a full 18 months to make, said Robert Van Exan, a 40-year vaccine industry veteran who now does consulting out of Ontario, Canada.

More than half of the production time for Pfizer's COVID-19 vaccine is devoted to testing and quality assurance – making sure the resulting product, at each stage is safe, pure and exactly the same as the tested vaccine that proved effective.

Vaccines are given to healthy people, so companies must err on the side of caution, Van Exan said.

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“We don’t have recalls," he said. "Nothing problematic could get out the door because it’s such a strict regulatory process.”

Both the end product and the production process are heavily regulated by the Food and Drug Administration, said Dr. Paul Offit, director of the Vaccine Education Center at Children's Hospital of Philadelphia.

"When the FDA licenses a vaccine, they license the building, they license the product and they license the process," he said. "The vaccine is the process."

Most of the companies haven't been forthcoming about their vaccine manufacturing process. Moderna has not publicly revealed details.

But Pfizer executives opened their doors virtually to USA TODAY to walk through the painstaking and time-consuming process of making a messenger RNA (mRNA) vaccine.

For Pfizer, this takes place in three distinct phases in three places: Chesterfield, Missouri; Andover, Massachusetts; and Kalamazoo, Michigan.

While it might seem inefficient to use separate, specialized facilities for each of the steps, it’s a common practice in the pharmaceutical industry.

“We used the facilities that were best suited to each of these independent operations,” said Margaret Ruesch, Pfizer’s vice president for worldwide research and development, based at the Andover plant.

Birth of a vaccine: Chesterfield, Missouri

Pfizer-BioNTech's American vaccine is born in Chesterfield, Missouri, not far from St. Louis, where the raw ingredients begin the process of becoming a vaccine.

It starts with circular snippets of DNA called plasmids. These carry the genetic material that code for the notorious spike protein on the surface of SARS-CoV-2, the virus that causes COVID-19. The virus uses the spike to hook on to cells so it can infiltrate them and reproduce.

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The DNA is made in large vats, said Christine Smith, vice president of Pfizer's division of BioTherapeutics Pharmaceutical Sciences Medicinal Sciences. These hold hundreds of gallons of an amber-colored solution containing specially designed E. coli bacteria.

Using a process called biosynthesis, these bacteria churn out trillions of the DNA plasmids over the course of two weeks.

When completed, the solution goes through a purification process – akin to straining spaghetti through a colander – that removes everything but the microscopic loops of DNA.

Next, the loops are straightened out, or "linearized,"  using enzymes to cut the circles. The lines of DNA in the now-clear solution are then packed into special high-tech bags about the size of a grocery bag and frozen to minus 112 F for storage.

Pfizer must vet the bag producer and check every lot that comes in, so it can verify they meet federal manufacturing guidelines. The bags can’t fail, because each contains the building blocks of the COVID-19 vaccine.

Then come days of checking and quality assurance in which the DNA material is tested to ensure it meets the strict requirements of the vaccine. There can be nothing extraneous in the purified mixture and the DNA strands have to all be exact copies.

Once the DNA templates have passed the necessary tests, the frozen bags of active ingredient are placed in specially-designed containers and shipped 1,200 miles away to Pfizer’s Andover plant.

Turning DNA into RNA: Andover, Massachusetts

In Andover, the lines of DNA are transcribed into messenger RNA, the “mRNA” in the name of the vaccine technology and what makes the vaccines unique.

In a cell, RNA acts like a "messenger" carrying the instruction of the DNA to the part of the cell where a protein is made. In this case, it is encoded with the message to churn out the distinctive SARS-CoV-2 spike protein.

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In effect, it enables the body to produce its own vaccine.

The body's immune system can "see" these foreign proteins and begins creating antibodies to fight them. That way when a person is exposed to COVID-19, their immune system will already know how to fight it off and they will be protected.

In a highly technical process, the linear strands of DNA are turned into RNA in 40-liter (10-gallon) vessels full of enzymes and chemicals over the course of three to four days, said Ruesch.

“That one 40-liter batch, depending on sampling and things like that, can make up to 10 million doses of vaccine,” she said.

All this happens in an extremely high-tech manufacturing suite. The air is filtered, the equipment constantly tested and all employees wear head-to-toe cleanroom coveralls to ensure nothing is introduced into the vaccine as it’s made.

Currently the Andover plant runs two batches a week, but it is gearing up to add more in 2021.

“We’ve added an additional suite, sort of a twin to the current one, so we can double our production. We’ll move from two to four or possibly five batches in 2021 and that will enable us to meet our growth targets for the year,” Ruesch said.

At that point, it will be able to produce enough mRNA for 40 million doses per week.

The Pfizer manufacturing site in Kalamazoo, Michigan. where the company’s COVID-19 vaccine is filled into vials. The vials are then stored at minus 114 F in ultracold freezers prior to shipping. © Photo provided by Pfizer The Pfizer manufacturing site in Kalamazoo, Michigan. where the company’s COVID-19 vaccine is filled into vials. The vials are then stored at minus 114 F in ultracold freezers prior to shipping.

As the mRNA is being made in Massachusetts, samples are constantly taken and tested. Detailed records are kept and reviewed by Pfizer’s quality assurance team and can be accessed by the FDA to ensure the plant is maintaining necessary standards.

Next the mRNA must be separated from the liquid it was created in and the excess chemicals used to make it. At this stage, it is less spaghetti and more dried angel hair pasta because it’s thinner – though it's all microscopic, of course.

Most of the purified mRNA is packed in the grocery bag-sized packages and frozen. The rest undergoes a second period of intense testing to ensure product quality. Only lots that pass stringent quality assurance tests can be sent on to the next phase.

Add fat, fill and finish: Kalamazoo, Michigan

This is where the frozen mRNA is turned into a vaccine and vials are filled for distribution.

The process happens in Building 41 at Pfizer’s enormous Kalamazoo, Michigan plant.

The COVID-19 vaccine uses most of the 1 million-square-foot building as it goes from start to finish. Three shifts of 30 to 40 people work 24 hours a day, seven days a week. The lines are continuously staffed, and didn't stop for the holidays.

Just to get into the formulation portion of the plant, workers must first change into scrubs, then enter the facility and completely strip down, donning an aseptic gown and finally gear that resembles space suits.

“Very few people go in there. They’re all monitored environmentally because we’re controlling those conditions very stringently,” said Calitri, vice president of Operations for Sterile Injectables for the United States and the European Union.

a man preparing food in a kitchen: Workers at Pfizer's manufacturing site in Kalamazoo, Michigan, fill buckets with dry ice that will be poured into thermal shipping containers holding the COVID-19 vaccine. The thermal shippers are used to ship vaccines from Pfizer plants to their intended destinations at the required subzero temperature. © Photo provided by Pfizer Workers at Pfizer's manufacturing site in Kalamazoo, Michigan, fill buckets with dry ice that will be poured into thermal shipping containers holding the COVID-19 vaccine. The thermal shippers are used to ship vaccines from Pfizer plants to their intended destinations at the required subzero temperature.

This is all to protect the purity of the vaccine. Any impurity would render the whole batch worthless, setting back the company and leaving millions of people waiting for promised shots.

During the encapsulation process, the fragile strands of mRNA are enclosed in tiny balls of fat known as lipid nanoparticles. This makes them stable enough to travel from the syringe into the bloodstream and then into cells before they dissolve.

Without the balls of fat the vaccine would disintegrate before it could deliver its payload. It's a bit like enclosing M&Ms in candy coating so they melt in your mouth, not in your hands.

For that to happen, the lipids, which is the chemical name for fats, are diluted with ethanol and then fed together with the mRNA into about 100 specially-produced hockey puck-sized mixers, using "a maze of piping,” Calitri said.

The perfectly functional but less-than-optimal layout is one example of how quickly things needed to be put together. One giant mixer would have been easier to operate, but there wasn't time to design one and get it made.

When the vaccine is ready to go into vials, it is thawed and sent into a high-speed vial filling machine, which puts a precise amount into six-dose vials about the size of a thimble.

The entire process, manufacturing of the vaccine and the fill and finish into vials, takes just three days.

The vials move to an inspection line where they are checked to make sure they are pure and don't leak. Those that pass go to packaging and then back into the subzero freezer.

Quality control and testing take weeks. Each lot of vaccine is tested to ensure product quality – identity, potency, purity and safety. During this time the vials are also packaged and labeled.

When orders come in from the federal government, and the packages are put into specially-designed thermal shipping boxes, 50 pounds of dry ice is poured on top to keep them cold enough and they're shipped out to the states. This takes between one and two days.

Workers remove COVID-19 vaccine kept in ultracold refrigerators at Pfizer's manufacturing site in Kalamazoo. © Photo provided by Pfizer Workers remove COVID-19 vaccine kept in ultracold refrigerators at Pfizer's manufacturing site in Kalamazoo.

Seven batches are in process at any one time, so there’s always one ready for fill and finish, Calitri said.

Pfizer is on track to produce the 200 million doses it promised the U.S. government by March but hopes to have more available as engineers improve systems on the fly.

In Kalamazoo, they've already doubled batch sizes, so another vial filling line needs to be added. That's in the works. To encase more of the mRNA in the vital fat layer, pre-fab formulation suites have been built in Texas and will be delivered to the plant next week.

"I'm really proud that we've been able to get to this place," Calitri said. "When you get everybody pulling in the same direction with the same goal, it's like magic. Stuff really can happen fast."

Contact Elizabeth Weise at eweise@usatoday.com and Karen Weintraub at kweintraub@usatoday.com.

Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input.

This article originally appeared on USA TODAY: A COVID-19 vaccine life cycle: from DNA to doses

US vaccine drive complicated by 1st, 2nd dose juggling act .
The U.S. has entered a tricky phase of the COVID-19 vaccination effort as providers try to ramp up the number of people getting first shots while also ensuring a growing number of others get second doses just when millions more Americans are becoming eligible to receive vaccines. The need to give each person two doses a few weeks apart vastly complicates the country’s biggest-ever vaccination campaign. And persistent uncertainty about future vaccine supplies fuels worries that some people will not be able to get their second shots in time.

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