The FDA 483 Heard Round The World
By Louis Garguilo, Chief Editor, Outsourced Pharma
For the first time in more than a decade writing editorials, I’ll focus on a specific 483 – actually two – received by a CDMO site.
It pains me to do so.
It pains me for a number of reasons, including something I believe ultimately true: No facility's operations are perfect; none immune from a lapse or error during its existence; a 483 in and of itself is not a condemnation.
As one biopharma executive put it, “I’ve seen facilities I thought were excellent receive a tough 483, and facilities I did not regard highly get clean inspection reports from the FDA.”
How CDMOs respond to each observation within a 483, and how they work with the FDA to successfully clear up issues, can demonstrate attitude, resolve, and capacity to improve.
It pains me because I once worked at a CDMO that had no citations after two decades of operations, but then received a 483 at a facility we purchased soon after we acquired it. Harsh judgements of our operations based on that reprimand would have been unfair, and unwarranted.
Yet despite these and other caveats, the overall industry reaction to this specific FDA issuance compels me to take this on.
For one thing, this facility has been implicated in the delay of a much-anticipated commercial launch.
Furthermore, in a number of columns, I have covered the Novo Holdings acquistion of Catalent assets – where the issues at hand have arisen.
To disregard this event would be unfair to readers, and a disappointing editorial oversight.
483s Have A Narrative
Catalyzing attention for this recent FDA observation is that it was the second 483 received at this facility in three years.
Not to drudge up past challenges, but in 2023 five observations were made in a 483 for Catalent’s Bloomington, Indiana site (prior to Novo Holding’s purchase). The observations were extensive, quickly summarized as:
- Quality Oversight
- Discrepancy Review
- Sterility Validation
- Process Control
- Lab Testing
- Equipment Cleaning
For customers to select this facility after these issues were cleared by with the FDA, would require, as one consultant told me, “a stringent and complete set of audits.”
“I’d have needed to see the CAPA [Corrective and Preventive Action] they had to implement were effective. If they weren’t, it would be hard to recommend this particular facility.”
Catalent has now received a second FDA Form 483 at this same Bloomington, Indiana, facility, after an inspection this summer.
Novo Holdings, as would be expected, has responded that it takes all observations seriously, and has “initiated a thorough review of our processes and procedures.”
The holding company says a comprehensive response will be implemented to address the Form 483 observations promptly and holistically.
Personally, I'd give them the benefit of the doubt, but here are the observations (again briefly) they'll have to address.
- Investigation of Records
- Sterility Procedures
- Environmental Monitoring
- Process Control
- Quality Oversight
In August, Regeneron CEO Len Schleifer (whose commercial launch of a drug is being impacted) reported that the company was confident in Novo’s ability to quickly resolve the issues.
But he also pointed out the inherent risk associated with outsourcing.
The Bloomington site, he wrote, produces medicines for the “vast majority of the top biopharmaceutical companies in the world,” and he wouldn’t be surprised if other drugs produced there were negatively impacted.
Should we, then, dwell on some form of condemnation for our reliance on biopharma outsourcing overall?
Some professionals would think it appropriate. Nobody I spoke to, though, while paying close attention to this situation, has intimated that.
In fact, I heard more about why it is we must always insist on the fundamentals of the (business and operational) practice of outsourcing development and manufacturing.
As one executive put it, “The best mitigation from challenges is rigorous quality and operational oversight at the CDMO by the sponsor.”
Other professionals mentioned a positive in this: the FDA in 2025 is doing its job just as it did in 2023.
That's a sigh of relief for those concerned with the new federal healthcare administration.
Judge Harshly But Fairly
No professional I canvassed hopes for less than a full recovery, shall we say, at the Catalent Bloomington site.
All hope repercussions for Regeneron and other customers (should they arise) are manageable and resolved as quickly as possible.
There but for the grace of God, go I. That is the thinking here.
Because as noted earlier, 483’s occur at reputable sites that have proven trustworthy.
“In this particular case,” noted one biotech executive, “you do have a site with a pretty long list in 2023, and another in 2025, with some of the same issues unresolved.”
However, she added, “it is certainly possible personnel and culture changes over the next several years improve things substantially.”
“It’s easy for us who aren’t using a site to say, ‘Well, I wouldn’t consider them,’” explains a biotech CEO. “But this is more about the companies who have commercial products being produced there. They have to make individual decisions.”
Should those existing customers have been more involved in the first place? That question raises others at drug sponsors:
How much more oversight do we need when working with reputable external partners? Are our own audit procedures lacking if the FDA was able to find so many issues, and we weren't?
Again, I do not detect some overall condemnation of outsourcing drug development and manufacturing as a business strategy, nor of any individual CDMO.
In some facets of consideration, we may actually have here a backhanded way to say we need more CDMOs with the capabilities similar to those in Bloomington – more competition in the marketplace.
I do hope I’ll never need to devote another column to a 483 at a CDMO.
The silver lining (if I may indulge), is the recognition of the novelty of this occurrence; an appreciation of the current FDA; and the understanding that sponsors must take responsibility for continuously verifying their drugs are being developed and produced as they should be.
483s say a lot about our industry, and as much about a customer’s outsourcing proclivity as a CDMO’s operations.
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Earlier from Chief Editor Louis Garguilo:
Novo Holdings Acquires Catalent, Shakes Up Outsourcing World
Novo Holdings Clarifies, But Competitors Circling Catalent
A Future Renaissance At Catalent? Employees Think So