The factory that fills the self-injection pens for booming weight-loss drug Wegovy has repeatedly breached US sterile-safety rules in recent years and staff have failed to perform required quality checks, a Reuters review of regulatory documents shows.

The breaches at Catalent, the Wegovy pen filler, were found by inspectors from the US Food and Drug Administration who visited the plant in Brussels in October 2021 and August 2022 to check on its compliance with manufacturing regulations, according to detailed FDA reports on the inspections, obtained by Reuters under freedom of information laws.

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There is no evidence that Catalent’s compliance failures resulted in harm to users of Wegovy.

However, the inspectors said the lapses at the plant – which fills syringes for pharmaceutical clients – represented the most serious form of violations, according to the reports, which show Catalent shut the facility down twice between the two inspections.

In November 2022, the FDA published a final decision on the findings that allowed the factory to remain open while it fixes the issues, which the agency didn’t deem a threat to public safety.

Wegovy-maker Novo Nordisk and its manufacturing partner Catalent have said publicly that shipments of the drug were delayed throughout 2022 as Catalent addressed problems raised by the two FDA inspections, without elaborating on what was found.

Novo is enjoying bumper sales of Wegovy, with millions of people injecting themselves with the drug to shed pounds since it was approved for the US in June 2021, and the Danish drugmaker has doubled in market value. Rivals are on the way, with a similar drug from Eli Lilly expected this year.

A Novo spokesperson said the company had communicated any manufacturing delays promptly in public announcements, and that by late 2022 it had met its US supply target. Catalent said it has a track record of providing high-quality production and that it corrects any compliance issues promptly. Both companies and the FDA declined to comment on the specific inspection findings.

The most serious findings unearthed by the FDA during its October 2021 visit involved air-filtration systems needed to maintain sterile conditions. Inspectors examining historical operational data found the system on one filling line at the plant had failed repeatedly between 2017 and 2021, leading to sterility being “compromised” in the area where drug products were being manufactured, the FDA documents say.

“Standard operating procedures are not followed or are deficient,” the report following the first inspection said.

The August 2022 inspection found new problems with air quality in sterile areas had cropped up since the first visit, according to the FDA Establishment Inspection Reports written after each visit. Inspectors on both visits found Catalent staff were not performing the required safety controls, with breaches including failing to regularly check that equipment was not contaminated with microbes.

The FDA reports do not say how many filling lines were inspected or what drugs were being manufactured on the lines examined. Four regulatory experts and two former FDA inspectors who reviewed the documents told Reuters the findings raised concerns about the safety of all manufacturing being done at the factory, including for Wegovy.

“Based on the FDA’s findings, I would be concerned about the sterility of the products made at this site,” said Susan Bain, an assistant professor of regulatory and quality sciences at the University of Southern California and former FDA inspector.

Compliance history

At a meeting with Novo executives in May, two investors out of a group of about five expressed concerns about the choice of Catalent as manufacturing partner, citing the contractor’s history of compliance issues with the FDA, according to one of the shareholders who was present.

The investor, who declined to be named due to the sensitivity of the matter, said Novo’s Chief Financial Officer Karsten Munk Knudsen had responded by saying that, in hindsight, the company may have made a mistake in choosing Catalent and was now tightly overseeing the firm’s filling operations of Wegovy in Brussels.

Novo spokesperson Ambre James-Brown told Reuters that, given the extraordinary demand for Wegovy, “it would have been good to have more capacity and thus, more than one facility for supplies.” James-Brown didn’t respond directly to queries about the concerns raised by investors in May and the CFO’s remarks, while Knudsen didn’t immediately respond to a request for comment.

A spokesperson for US-based Catalent said its facilities around the world produce more than 8,000 products and are subject to dozens of regulatory audits a year, and that the company “has a strong regulatory record in an industry of extraordinary complexity.” The spokesperson said production at the Brussels factory had been suspended “on occasion to conduct scheduled maintenance and to undertake corrective and preventative actions that address regulatory observations”. Catalent didn’t comment on whether Novo was closely overseeing its Wegovy operations.

The FDA said the agency “remains vigilant in addressing potential issues in the global supply chain” to maintain consumer confidence in medicine safety.

Steven Lynn, a former head of the FDA’s Office of Manufacturing and Product Quality who is now a regulatory compliance consultant, said the issues found with the factory’s air system in sterile areas were “troubling” but that the FDA wouldn’t hesitate to act if there was a clear safety threat.

“They expect compliance with the law, but will typically work with manufacturers if their immediate corrections mitigate the risk posed to public health, while giving them time to put their longer-term corrections in place,” Lynn said.

‘Any issue should be critical’

A dozen pharmaceutical manufacturing experts interviewed by Reuters stressed that the consequences of a sterility failure while filling drugs could be severe. Microbial contamination of drugs injected into the body, rather than swallowed, can be deadly, the people said – although the FDA inspectors didn’t report any signs of this sort of contamination at the Brussels factory.

According to the first FDA inspection report, Catalent staff had repeatedly classified the failures of the air-filtration system as “minor” in internal records at the plant.

David Talmage, vice president of education at the Parenteral Drug Association, which provides training on best practices for sterile manufacturing, said the area of the plant where the filter failures happened “is the most critical area of the sterile-manufacturing operation”, known as a Grade A zone.

“Any issue within that space should be major or critical,” said Talmage, speaking about filling factories in general.

In both visits, the FDA inspectors found Catalent staff had repeatedly failed to investigate why equipment was malfunctioning. They found the facility didn’t have adequate written procedures for performing tests to prevent microbial contamination during manufacturing.

The 2022 inspection found the factory didn’t have appropriate controls to ensure data files for quality-control instruments were protected from the risk of manipulation.

After each visit, the inspectors recommended the breaches found be classed “Official Action Indicated” – the most serious designation, which must be remedied by the manufacturer to avert enforcement action, such as seizure of drugs made there.

The final FDA decision in November 2022 deemed the lapses “Voluntary Action Indicated,” a less serious designation. The FDA declined to comment on why it didn’t ultimately classify the issues as OAI.

Blindsided by booming demand

Within months of launching Wegovy, Novo Nordisk was overwhelmed by demand in America, and told shareholders that its initial supply would not keep pace. The company said that it expected to be able to meet that demand in early 2022.

That forecast changed after Catalent shut down the Brussels plant following the FDA inspection in October 2021. From December that year and throughout 2022, Novo repeatedly pushed out the timeline for when the supply constraints would end.

In late December 2022, Novo announced all five dose strengths were available again in the United States. But in May this year, Novo said it would reduce by half the supply of “starter doses” – the three lowest-dose versions – for “some months” to ensure supply for existing patients.

In June, Catalent told investors the company needed “some more time” to address problems at the Brussels plant. The FDA website states there will be “limited availability through September 2023” of those three Wegovy formulations.

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