Wegovy weight-loss injection factory plagued by sterile-safety failures
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[July 27, 2023]
By Maggie Fick
LONDON (Reuters) - The factory that fills the self-injection pens for
booming weight-loss drug Wegovy has repeatedly breached U.S.
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 U.S. 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.
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.
Reuters is the first to report in detail on the quality-control issues
identified by the inspectors in their write-ups, the most recent FDA
reports on the Brussels factory.
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 U.S. 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 U.S. 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 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", adding that the
company had never said it was a mistake to partner with a specific
contract manufacturer. 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.
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A general view of the drug product
manufacturing laboratory in biologics and sterile injectables,
Catalent, in Brussels, Belgium June 27, 2023. REUTERS/Yves Herman
A spokesperson for U.S.-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.
(Reporting by Maggie Fick; Additional reporting by Vincent Flasseur;
Editing by Michele Gershberg and Pravin Char)
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