FDA Not A Good FRAME for CDMO Inspections?
By Louis Garguilo, Chief Editor, Outsourced Pharma
Is the CDER-initiated Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) a good idea?
It dates to 2019, but as of this July the FDA has proposed a regulatory pathway allowing a distributed manufacturing establishment (DME) to operate as a single registrant covering multiple locations.
A way to look into this proposal is in the context of a potential real-world example – the challenges at the former-Catalent now-Novo Nordisk facility in Bloomington, Indiana, where today Novo operates it as both a CDMO and to produce its own products.
FRAME is a hub-and-spoke manufacturing concept. Catalent runs some 50 CDMO sites around the world; Novo about a dozen. Both could benefit from this new policy, with the Bloomington site providing a neat beginning to our analysis.
Before proceeding, though, let’s make four points:
- Bloomington is NOT a Catalent facility since its sale to Novo in December 2024, but quality challenges arose prior to that sale.
- As stipulated previously, Catalent is a name-brand CDMO with a good reputation, and counts as clientele biotechs and pharma from around the world.
- Aspersions are NOT being cast on Novo Nordisk, a pioneering Big Pharma that purchased the facility with the main intent of producing its phenomenal GLP-1 drugs.
- We are using this case study as a positive exploration of the FDA FRAME proposal.
Preamble now complete, to help us with a closer look at FRAME I again turn to David Grote of GrayMatter Partners.
E Pluribus Unum Facility
We can summarize the proposed regulation this way:
* The HUB – main facility operated by a manufacturing organization with these attributes:
- centralized quality organization
- Unified Pharmaceutical Quality System (UPQS)
- policies, procedures, lifecycle management, oversight
* The SPOKES – additional physically separate facilities similarly operated by the manufacturing organization:
- same drug(s) produced
- equivalent design and operations
- potentially added, removed or relocated
FDA labels the spokes as distributed manufacturing units (DMUs).
The proposal states these DMUs must be equivalent in design and operation, and under the control of the single quality organization at the hub.
The proposal primarily creates a single-establishment registration and regulatory framework.
However and crucial, this is not the establishment of a blanket rule stipulating that if the FDA inspected and approved Site A, therefore Sites B, C and D are similarly designated inspected and approved.
FDA is explicit that each DMU remains equivalent and in a state of control. I’ll assume this implies self-control locally with centralized oversight as the manufacturer demonstrates and maintains equivalency through its unified quality system, validation, monitoring and lifecycle management.
How is this done exactly?
There's some further guidance in the proposal, but for now the agency intends to issue additional guidance addressing the cGMP complexities of distributed manufacturing, including equivalency, UPQS controls and mobile units.
We are currently in the public commenting period on FRAME. But as a guiding philosophy, our industry is pushing for evaluating a control system rather than treating every location as an independent manufacturing universe.
And quality philosophy is where Grote is most focused.
One Inspection Good Enough?
“We really are talking about a quality culture and your philosophy of control,” says Grote. Using our present example, he asks, “How could this one site in Bloomington be different from the other Catalent sites? Was it in fact different?”
“Over the years, I’ve gained a positive impression of CDMOs overall, but I still go audit or do a facility visit, and I find some significant issues and concerns.”
Grote and I agree cGMP or not, stellar reputation or otherwise, no facility is perfect, and even the best end up with challenges, and 483s. (And if out of the 50 or so Catalent and dozen or so Novo sites, no lingering quality issues have been raised outside of Bloomington, that record is a very good one.)
But getting back to FRAME specifically, Grote says some of the concerns in Bloomington would most likely be “local in terms of, for example, an issue with mammalian hair.”
“If you also have a parallel manufacturing site in Germany, for example, you’re unlikely to have the same problem. It is a specific site-related challenge.
“Nonetheless,” Grote says, “there are much broader questions of your company’s controls around raw materials and personnel."
"How are all your sites taught to address it when somebody sees something wrong? How are investigations handled?
"This then extends to the higher levels of the organization and the corporate level.
“Yes, the industry is in favor of FRAME and DME. But this can’t be implemented in a way that reduces the level of scrutiny applied to quality systems at every single site. We can’t say definitively, but Bloomington is exactly the kind of case that might demonstrate where this policy needs to be wrapped in caution.”
CDMOs Will Benefit
Let’s end with a more generic example – a CDMO with five facilities using equivalent:
- manufacturing platform equipment
- processes and automation
- quality system and SOP architecture
- hiring and training system.
How much regulatory value is gained by the FDA (repeatedly) examining essentially the same manufacturing and quality operations at these five physical locations?
Many would agree the current system can be duplicative. But here’s the tradeoff:
It should be demanded of manufacturers that they perform a strenuous demonstration of capability to control all its own operations. In effect, the FDA says if you want the regulatory benefit of treating each site as a distributed establishment, prove you are worthy of it.
In our CDMO case, this should spur the performance of more and more stringent facility inspections.
Finally, consider this:
If a single location of a CDMO receives 483s or other citations, do those visit upon the entire network of facilities, and even imperil continuation as a DME?
This is where we realize the immense pressure that will come to bear on the professionals managing the Unified Pharmaceutical Quality System (UPQS).
Considered from another angle, the Quality organization at both the “corporate” and “facility” levels at CDMOs – and sponsors – would in practice elevate in position and power.
Come to think of it, that might be an attractive FRAME for our entire industry.