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Moderna's COVID-19 vaccine is expected to become the second to get the Food and Drug Administration's green light. A decision could come within days.

But compared with pharmaceutical giant Pfizer, which was granted emergency use authorization last week, upstart Moderna doesn't have a track record when it comes to mass production.

FDA panel recommends Moderna's COVID-19 vaccine for emergency use

Pfizer makes hundreds of medicines and vaccines and operates at least 40 manufacturing facilities registered with the FDA around the world. Despite being founded a decade ago, Moderna has never had a product win FDA approval. And it only has one factory registered with the FDA — and the registration occurred just this week.

"As the CEO I am always thinking about the next game, and the next game is manufacturing," Moderna's 

 “Technology Review.” "This is a big week at the FDA. But I am not worried about the EUA [emergency-use authorization], because the data is the data. I am worried about making more product."

So how will Moderna make the 200 million doses it has contracted to provide the federal government for $3.2 billion by the end of June? A big part of the answer is outsourcing production to contract manufacturers that will make the vaccine on Moderna's behalf.

Moderna is ultimately responsible for making sure the vaccine is made in compliance with regulations, and the FDA periodically inspects facilities around the world to make sure they are up to snuff. Still, the use of multiple companies to help make and package the vaccine stretches the supply and production chain and could add some risk to fulfillment of orders.

Vice President Mike Pence traveled to Bloomington, Ind., on Tuesday to tour Catalent, a contract manufacturing facility expected to help produce millions of Moderna coronavirus vaccines in the coming weeks and months. Catalent is probably the biggest drugmaker you've never heard of. It has dozens of factories around the world and makes more than 70 billion doses of all kinds of drugs each year. The company's facility in Pence's home state is working with Moderna on filling vials with the vaccine and preparing them for distribution.

"Two-thousand people of this facility are working tirelessly to deliver on that promise, volunteering for a production shift over Thanksgiving, over Christmas," 

Catalent president and COO Alessandro Maselli

 told Pence during a discussion after the tour. "Because everybody understands the mission we are on at this facility."

Catalent is processing 500,000 doses per day, but the factory is hoping to ramp up to a million doses a day to fulfill its contractual obligations and deliver 100 million doses by the end of March, 

Denis Johnson, Catalent Bloomington's general manager

It's a big job, but Catalent and the other contract manufacturers have long histories of doing it.

"There are no fly-by-night new manufacturing facilities that are being set up to make these products by definition, because there are only so many manufacturers who could make these products to begin with," says Rena Conti, a health economics professor at Boston University whose research includes the pharmaceutical supply chain. "And many of them are known. They've been making vaccines for the U.S. population for a very long time and have a proven safety record and quality record."

Still, FDA inspectors visited Catalent's Bloomington facility in October 2019, and found that it had problems with making sure sterile products weren't contaminated with bacterial or fungal particles. Inspectors also wrote that the facility had problems storing pharmaceuticals at the right temperature and humidity levels.

That could mean problems for the quality of the plant's products, Conti says.

"There were production and process control failures that make it possible that the product itself is not what it purports to be," Conti says. "So the safety identity, the strength, the quality or the purity of the product that is being manufactured may not meet the specifications or the attestation the company is making to the U.S. public that the product is what it says it is. So this is quite serious."

However, the findings didn't result in more serious punitive steps by the FDA, which can include formal warning letters and, in rare cases, injunctions and product seizures.

At the time, of course, the Catalent facility wasn't working on coronavirus vaccines. But 

that it would be helping Moderna make its vaccine in June of this year. In September, the Indiana facility received another visit from the FDA.

Inspectors again found that the employees weren't following rules to prevent microbial contamination. For example, employees weren't making sure sterile forceps didn't touch non-sterile surfaces, and they didn't follow rules around sanitizing gloved hands in certain situations involving vials and syringes.

By itself, the finding is fixable. It's a simple lapse in training, says 

Dinesh Thakur, a former drug company executive turned whistleblower

. The fact that Catalent didn't appear to have fixed its microbial contamination procedures a year earlier is what bothers him.

"These are easy to fix," says Thakur, who raised the alarm about quality-control problems at generics drugmaker Ranbaxy, resulting in a 

2013 guilty plea and a $500 million settlement

. "This is like, you know, within a week, you can try and get this thing wrapped up properly."

He called it "really concerning." "If you're told in 2019 to fix it, you have a year to fix it and we have to make the same observation another time? Then that would cause me to become a little concerned."

Catalent spokesperson Chris Halling told NPR in an email that the facility was able to resolve its findings and satisfy the FDA in 2019 and 2020.

"The Agency's latest Establishment Inspection Report (EIR) does not reflect that it was a repeat finding of the earlier observation, and relates to a different concern for a process in a different part of the facility.

Catalent takes its responsibility to comply with CGMPs [Current Good Manufacturing Practices] extremely seriously, and hosts hundreds of audits each year, including those by customers, the U.S. FDA, and other global regulatory bodies. The company utilizes regulators' observations as a means to continuously improve its operations and to assure ongoing compliance to all appropriate standards.

Catalent is on track to manufacture and package 20 million doses of Moderna's vaccine candidate by the end of this month, and the facility in Bloomington, IN, is ramping up production to supply another 100 million doses in the first quarter of 2021. Globally, the company is working on more than 75 Covid-19-related programs including antivirals, vaccines and treatments."

Moderna declined to comment, and suggested NPR speak with officials with the FDA and Operation Warp Speed, the more than $12 billion federal effort to make a vaccine widely available in record time. Operation Warp Speed has committed spending $4.1 billion on researching and developing the Moderna vaccine as well as buying 100 million doses to be delivered by the end of March and another 100 million to be delivered by the end of June.

Operation Warp Speed didn't respond to requests for comment, and the FDA said it typically doesn't comment on "compliance matters."

Catalent is filling vials and getting them ready to send around the country, but other facilities are responsible for making the mRNA, the key substance at the heart of the vaccine, that Catalent puts in those vials.

Another well-known contract manufacturing company, Lonza, 

that it is working with Moderna to make its coronavirus vaccine drug substance. Lonza is using two sites: one in Portsmouth, N.H., and another in Visp, Switzerland, and was aiming to complete the first batches by late October and early November, respectively.

Following an FDA inspection in February 2018, Lonza's plant in Portsmouth did not receive a document detailing observations called a 

, implying inspectors mostly liked what they saw.

Lonza spokesperson Sanna Fowler says it was also inspected in October 2020, and has an "exemplary track record" with the FDA and international regulatory bodies that conduct similar inspections. "The FDA have used the Portsmouth site as a training site for their inspectors, given its high standards," she wrote in an email to NPR. "Should the FDA decide an inspection of the Moderna facility is required, we are of course ready to receive them."

The other Lonza facility's inspection wasn't as spotless. In October 2019, FDA inspectors found problems with microbial control during certain plant processes. They also found inadequacies in the way the plant measured impurities like toxins released by bacteria. The facility has received several 483s in recent years as well as

, meaning the FDA twice detained drug product shipments for being out of compliance.

To do work on the Moderna vaccine, Lonza is setting up operations in "a new premises" in Visp, Switzerland, rather than using its existing facility there, Fowler says. She points out that although the FDA has found problems at its existing facility, they didn't result in a warning letter from the agency. Instead the inspectors' findings were "successfully resolved." She says the import refusals were the results of problems further up the supply chain, rather than because of problems at the Lonza plant.

Furthermore, the Moderna vaccine substance the new Swiss that facility makes won't be bound for the United States, according to Fowler. Instead, it will go to the European Union and Canada, for example.

Moderna has said that it's using a relatively new facility in Norwood, Mass., to make the vaccine.

"The vast majority of the U.S. production will be done in Massachusetts," Moderna co-founder Noubar Afeyan told 

NPR member station WGBH News in a Dec. 1 story.

Although the facility was built in 2018, it wasn't registered with the FDA until this week and has never been inspected, records show. Typically, new facilities need to be inspected before the agency will allow their products to be released.

"While the design of the facility is based on current standards for biotechnology facilities, it has not been reviewed or pre-approved by any regulatory agency, nor has the facility been inspected by any regulatory agency such as the FDA," the company wrote in a 

"We have only recently begun producing drug substance and drug product at the MTC [Moderna Technology Center] for our preclinical and clinical use," the filing continues. "We could incur delays in implementing the full operational state of the facility, causing delays to clinical supply or extended use of third-party service providers, resulting in unplanned expenses. In constructing the MTC facility, we have incurred substantial expenditures, and expect to incur significant additional expenditures in validating and operating the facility in the future."

The FDA doesn't speak publicly about specific compliance matters except with the firms involved. However, agency spokesperson Alison Hunt said that the FDA regularly interacts with manufacturers to help resolve regulatory compliance issues when they crop up, and it has a number of tools to accomplish this.

When the FDA is weighing whether to grant emergency use authorization of a COVID-19 vaccine, it takes manufacturing into account, she wrote in an email to NPR.

"FDA expects manufacturers to submit sufficient data to ensure the quality and consistency of the vaccine product," Hunt wrote. "FDA uses available tools and information, including records reviews, site visits, on-site investigations and previous compliance history to assess compliance with current good manufacturing practice (cGMP) requirements."

You can contact NPR pharmaceuticals correspondent Sydney Lupkin at 

Health

COVID-19

Sydney Lupkin

Author

Despite being founded a decade ago, Moderna has never had a product make it to market. And the company registered its first factory with the Food and Drug Administration just this week.

How will Moderna meet the demand for its COVID-19 vaccine?

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