What FDA's Complete Response Letters (CRL) Say About Outsourcing

By Louis Garguilo, Chief Editor, Outsourced Pharma

As most readers know, the FDA embraced “radical transparency” by publishing more than 200 Complete Response Letters (CRL) for drug and biologics applications submitted between 2020 and 2024.

Hooray for the FDA; good for all drug developers hard at work today.

Good for developers because we can identify certain patterns in the CRLs across application types and services to help us learn how to outsource better.

And we can do this without calling out particular sponsors – or CDMOs.

Confirmation, Not Surprise

Of the intel we can gain from these CRLs, none will surprise you.

Generally, the stop signs to approvals are set at the intersections of substandard (or suboptimal) quality, and manufacturing deficiencies often encompassing processing flaws.

There are facility-inspection failures of all kinds, and the widest category is CMC data gaps or incongruities.

For all innovators reliant on CDMOs, this is a massive regulatory feedback. It demonstrates the need for rigorous due diligence when selecting your CDMO, and then continuous monitoring of all conditionals and data throughout a project's lifecycle.

It’s not enough to simply learn as much as possible about an external partner. Sponsors must discern whether in fact that CDMO is the exceptional option – an organization with talent and capabilities tailored to your program and goals.

We are not being naïve in having stated this. At the same time, we do acknowledge  no facility, no partnership is perfect. Moreover, at times CDMO options are limited, particularly for emerging biotechs with less outsourcing leverage.

Nonetheless, when you stack these CRLs on top of each other, we can’t avoid the suggestion that you, shall we say, opt for the optimal:

Strive to adhere to fundamental best practices, such as tech-transferring efficiently; managing skillfully; communicating constantly; and more colloquially, just keeping your eye on the outsourcing ball.

Sponsors should:

• Re-evaluate when you reach pivotal points of processing; when there are moves to new equipment or facilities; or if there are changes in human resources.
• Continuously ask yourself if the CDMO is operating as an extension of your organization; support them so they can do so. 

How serious is this for our entire industry?

Analysis from William Blair, a global partnership providing advisory services, strategies, and solutions, estimates that in 2024, 85% of small biopharma companies outsourced API production, and 77% outsourced finished dose manufacturing.

What’s that tell us?

When CRLs are issued – although final responsibility lands on the sponsors’ shoulders – they increasingly trace root causes to activity at or data derived from your CDMO.

Areas Of Most Concern?

An AI-generated review of the CRLs suggests manufacturing-related issues were not evenly distributed across product types.

The most often cited were for injectables, “biologics and complex modalities.”

Analysis suggests that nearly 75% of CRLs concerned specific manufacturing challenges, the dominant theme in these non‑approvals.

Scenario types were related to inspectional deficiencies, process validation failures, container‑closure incompatibility, and control strategy inadequacies.

Complicating matters is a proportional relationship: the more complex the drug or therapy, the deeper the reliance on CDMOs, and the more inherent challenges those CDMOs face.

Today, complex modalities demand more than CDMO capabilities; they require a more exacting CDMO skillset and execution excellence.

Without that level of competency, the CDMO risks faltering – often through common occurrences such as a degree of process drift that reveal some cGMP shortfall, as much as due to the actual science/technology behind the drug substance and product.

There is the example of an oncology developer whose application was rejected after the FDA’s inspection of (a globally renown facility) uncovered unresolved manufacturing deficiencies.

In this particular case, FDA stated it had identified concerns regarding the reliability of data generated at the CDMO’s facility; the adequacy of the proposed drug could not be determined at that time to support licensure.

An important point here: The product was later approved.

CRLs are not the end of the road, but those check engine signs that require you pull over and perform remediations.

A motto to live by is be as discerning as the FDA before they arrive.  

Reputation cannot pass FDA inspections. Nor can the best peer recommendations resolve the risks associated with external facilities – even the best.

A Focus On PAIs

In our regulatory environment, the Pre-Approval Inspection (PAI) is a critical type of inspection conducted by the FDA and other global regulatory bodies.

The primary goal of a PAI is to confirm that a manufacturing site listed in an application can consistently produce safe and effective drugs, and that the data in the application is accurate.

Keys to the PAI are:

• Readiness for Commercial Manufacturing: Assesses if the facility's quality system is sufficient for commercial production.
• Conformance to Application: Checks if manufacturing and analytical methods match the application description.
• Data Integrity Audit: Reviews data to ensure accuracy and that all relevant information was submitted.

And be certain if there is cause, the FDA will issue a CRL after a PAI.

On Final Inspection

In all cases, attitudes matter.

Treat the FDA as an organization helping to ensure you and your CDMO’s houses are in cGMP order, so to speak, so you can commercialize safe and effective drugs – your ultimate goal.

To take advantage of this positive CRL dump, at the least take up these stances.

• Bolster tech‑transfer protocols. Every project slides into a CDMO differently. The good news is that CRLs highlight what could have been preventable failures from early on.
• CDMOs should highlight successful track records to potential clients, but never rest on laurels. New projects always present new challenges.
• Remain proactive in the preparation for all audits. This requires full transparency and communication between sponsor and external partners, as well as with the auditing regulatory body.

The FDA CRL archive is more than a transparency milestone. It's a public reflecting pool showing where your systems may falter, where vigilance is most needed, and how to avoid future disruptions.