From The Editor | August 9, 2023

How A CDMO Should Communicate A Form 483


By Louis Garguilo, Chief Editor, Outsourced Pharma


I could have shortened the above headline to “How A CDMO Should Communicate.

But a 483 – forms issued at the conclusion of an FDA inspection when investigators have observed conditions that may constitute quality or other violations – is the perfect example to lend to a universal principle:

Whatever is transpiring at a CDMO that could impact customers should be communicated to those customers.  

CDMOs and the communication of 483s was a topic introduced by Francis Dumont, a 31-year veteran of Pfizer, during a recent discussion. (We’ll hear more from Dumont – recently retired from Pfizer – in upcoming editorials.)

I also reached out to others in the industry for their input, which follows Dumont’s retelling of his experiences, where we’ll begin.

Two 483 Experiences

Francis Dumont
1. Quiet As Crickets

“A prominent player in the CDMO manufacturing space making clinical trial drug product for us received a warning letter. The issue was not directly related to our product. We decided we would be patient, provide them some time to breathe, and take it from there.

However, from the beginning, there was a concerted lack of transparency on their part, even though we were working on a relatively high profile program – or maybe because of it.  We needed basic information to enable completion of our own risk assessment.

Their quality organization, surprisingly, was digging in its heels as far as providing any direct insights into what the situation was, and how it was being addressed. Dialogue was shutting down.

It may have been more reflective of the personnel we were dealing with, rather than a companywide attitude, but a significant contributing factor, I believe, is that this CDMO had been acquired by a larger entity relatively recently

Unfortunately, despite ultimately determining there would be no impact to our product, the experience led us to not schedule reloads at this supplier.

This happened about a decade ago, but that type of history survives.”

2. Sounding The Horns

“I had the opposite experience as well. Something negative in the regulatory space happened to one of our CDMOs. This time, there was a strong potential it could directly and negatively impact what we were doing there.

This CDMO acknowledged the depth of the situation upfront, quickly pulled together all relevant information, and reached out to us proactively.

We collaborated to help them get back in good standing with the agency. We were happy to help. They wanted our involvement. They didn't get defensive.”

Concludes Dumont:

“These were completely different experiences. Yes, I was sweating through both, but at least in the second case we were sweating together.

The success of our suppliers leads to our success. If we can’t even learn how we might help, or at least learn what a certain situation involves, it’s a no-win situation.”

Say What?

While always important, 483s can be minor and relatively easy to address. It’s rare that any facility with longevity will not at some point be advised of an area they need to improve.

And most 483s do not affect a large number of customers.

But some can.

An initial citation, when not accurately and openly addressed, can snowball to bigger issues with regulatory bodies – and for clients.

In all cases, sponsors need to know:

  • Can we be sure this citation is limited to a certain activity, equipment train, lab/facility?
  • Is the challenge more widespread – a sign of poor training/practices, quality systems or controls?
  • What are the plans of remediation, and how are they progressing?

We are not talking about coercing CDMOs into revealing so much as to impact any customer’s (or their own) IP or other confidentialities. (Unfortunately, the fear of which is often used by CDMOs as a reason for less divulgence to sponsors.)

Yes, 483s are made public by the FDA, and contain a fair amount of detail. But they are the starting point for sponsors to understand the challenges at the CDMO, and the impacts to their programs.

What Other’s Say

Roger Graben
Roger Graben, President of Vitruvias Therapeutics, and an  Outsourced Pharma Advisory Board member, says he’s had experiences similar to those described by Pfizer’s Dumont.

“Over and over,” he begins, “we find success with CDMOs who partner with us on every level, including on the outcome of inspections.

That an observation does not reference our product does not mean we are not impacted. An observation related to any major process or system, such as air handling, water, validation, data integrity and others affect every product at a facility.

The overall compliance status and attitude toward compliance is reflected in every part of an organization. I used to say when auditing, if on the initial tour of a facility the warehouse and machine shop is in disarray, later you’ll find the systems and records to be in disarray. 

And when we have a partner withholding information, it establishes a layer of distrust that grows with time.

On the other hand, we had a supplier experiencing what we thought was a very bad outcome. But they were open about it. We sent our most qualified person to the site at our expense for multiple trips to help them develop better systems. They gained a real respect for our expert, and even had him onsite for the next inspection, which went very well. It ended win-win for both parties.”

The CDMO Side

We’d be half-baked without including thoughts from the CDMO side.

Some CDMOs I reached out to decided they’d rather stay away from an editorial on 483s. I can understand the reluctance.

David Enloe
Others, including David Enloe, President and CEO, Societal CDMO, were willing to share their thoughts. 

“At the CDMOs I’ve led, I have always made sure we adopted a philosophy of complete - and timely - transparency. 

I always push back on the notion we are only a vendor. We should act as a true partner to our clients. Their pain is our pain and vice versa, and we share successes. I like to tell our clients, ‘We’re all in this soup together!’

Often after we’ve notified a client of FDA or other agency findings during an inspection, those clients offer support based on their experiences with similar issues.”

Enloe concludes for us: 

“Keep in mind that, while 483 observations may be given during a product-specific inspection, commitments to address those observations may very well impact the manufacture of other clients’ products. 

If we have agreed to modify the way we deal with Product X during fill/finish operations, that modification may impact the way we fill Product Y. Otherwise, we risk violating our commitment to the FDA to continuously improve our operations to ensure patient safety. At the end of the day, that is what the FDA is looking for. 

Bottom line for me: Clients appreciate being consulted and informed of these matters on a timely basis. Rarely, if ever, has a client left us due to an FDA 483 observation.”