From The Editor | July 8, 2024

What's In Your DMF?


By Louis Garguilo, Chief Editor, Outsourced Pharma

Whats in the box-GettyImages-1455666173

Are relevant Drug Master Files (DMFs) at your CDMO in good order or fully under consideration as part of your upcoming new-drug submissions to the FDA or other agencies?

“I've lived with this on both sides of the fence, as an FDA official and at biopharma organizations,” says Ben Stevens, Director CMC Policy and Advocacy, GSK, and former  Branch Chief / Chemistry Reviewer at FDA.

“The process by which FDA reviews and scrutinizes DMFs, and the way those are evaluated in conjunction with new-drug applications in particular, can present confusion about the role of the CDMO in working with the teams submitting and actually maintaining the marketing application.”

Ben Stevens
Stevens and I produced a DMF primer in an earlier editorial. He now sets out some further, and intriguing, insights for readers.  

Three-Way Communication

“There are times, because the new-drug applicant doesn't have visibility into what's actually in the DMF, when the FDA has questions they need to ask directly of the DMF holder,” starts Stevens. That often means your CDMO.

For generics or certain materials, for example, he recalls times when DMF holders seemed shocked the FDA was calling. 

“In a few cases, the CMO didn't even have somebody who was able to act as an English-language translator to have the discussion with the FDA,” he says.  

Stevens is sympathetic to CMOs in most cases, but there’s no denying the problem they can cause for sponsors, who are ultimately responsible for getting all agency questions adequately answered.

“Many manufacturers are more accustomed to working with generics applications and common APIs. They’re not as aware of the differing areas of emphasis that comes, and the differences in the processes that occur, on the new-drug side.”

He offers some advice – to the providers:

“If I were a CDMO developing DMFs for use with innovator companies, I’d hold serious pre-alignment discussions to ensure we’ve appropriately captured all the elements within the NDA submission, and that DMFs are fully in line with that submission.

“For example, information in some DMFs may actually be in conflict with that included in the NDA, creating serious problems.”

At other times, facilities may be subject to pre-approval inspections (PAIs) because NDA applicants fail to register a facility that is listed in the DMF.

The onus of miscommunication is on CDMOs that are not proactive in verifying alignment with the NDA applicant – their customer.

CDMOs are in error to think the NDA-submitter is going to do all the CMC and related work, and if they do need something, they’ll reach out at that time.

This typically ends up with the CDMO getting agency questions they then scramble to answer in order to thwart delays, or even bigger issues.

“However,” says Stevens, “We can place blame only so much on the contract manufacturers. Guess who’s ultimately responsible to the agency?”  

Legacy DMFs

Some DMFs are held for the production of raw/starting materials or excipients, but the majority are Type 2 DMFs for actual drug substance – final API going into a commercial processes.

Says Stevens:

“In many of these cases, you are taking half of the commercial NDA’s CMC elements and essentially delegating that part of the dossier to the CDMO.”

Included are elements of process development, synthetic routes, starting materials and reagents, quality standards, analytical methods, final specifications, stability of the API, etc.

It’s also interesting to note that for existing DMFs, it’s up to the CDMO to decide which components are considered intellectual property, details of which they will not disclose.

Against that, sponsors on their end have to consider what details they must have disclosed for their applications.

“Not surprisingly,” says Stevens, “larger organizations won’t move forward with a certain CDMO unwilling to provide all the information deemed critical.”

But not all companies have the leverage of Big Pharma.

“I've worked with companies where I've had to guide them into what types of questions they should be asking, and what kind of information they absolutely need from CDMOs,” says Stevens.

But fundamental here is for sponsors to realize (a) all the information in a DMF is essentially proprietary and only reviewable by FDA, and (b) CDMOs carefully guard their IP to maintain competitive advantage.

You might approach two CDMOs who own DMFs for the manufacture of a specific material or API you need.

The first provides more details on their processes than the second, and with most other considerations relatively equal, that could be a deciding selection factor.

“It's definitely part of the discussion,” says Stevens.

“If I’m a part of your regulatory team, that would be a factor for me. It’s an aspect of your overall project risk you want insight into.”

If you approach a certain DMF holder that has been part of dozens of submissions to the FDA, and has a good track record, “you can feel more confident about how they're going to perform under your marketing application,” says Stevens.

However, he adds, it’s important to remember that DMFs are always viewed in the context of the application by which they are cross-referenced.

If it's a new DMF – never submitted/reviewed by the agency – there’s inherent risk. And that risk is elevated if the CDMO isn’t forthcoming about some details in the file.

Shoulders Of Giants

For most readers, the focus is on generating new IP, novel drugs, and innovative therapies.

Nonetheless, if CDMOs have in fact previously used their DMFs as part of other submissions, it is not easy, says Stevens, to gather legacy information.  

The FDA does issue public, final reports on NDA evaluations, but the CMC sections are heavily redacted.

“A reason for these redactions," says Stevens, "is because the agency has run into problems where information about a DMF was inadvertently captured in an NDA review, essentially violating some proprietary information.”

Lawsuits have been brought against the FDA because of this. And thus ... drug master files can feel like worlds onto themselves. 

A final analysis might suggest that unless you are utilizing your own facilities and  generating your own DMFs, these valuable files are authored, managed, and carefully guarded by your contract manufacturer – who tends to treat them as gold.

Work closely with manufacturers you trust, and work out beforehand any challenges with the CDMO providing you or the agencies requisite information in drug master files. 

And if it's the FDA, ensure the information can be communicated in English.