DMFs And CDMOs: Surprises At The Regulatory Intersection

By Louis Garguilo, Chief Editor, Outsourced Pharma

An integral FDA touchstone with CDMOs are drug master files (DMFs). Don’t let ramifications from that contact take you by surprise.

That DMF intersection between your CDMO and the FDA mostly occurs when submitting the CMC (chemistry, manufacturing and controls) section for your drug or therapy application.

Many sponsors regard the possession of certain DMFs as a key component in the selection of a  CDMO.

These external partners holding previously registered DMFs support your overall "development and manufacturing control strategy," says Ben Stevens, Director CMC Policy and Advocacy at GSK. Thus “FDA updates and policies can impact CDMOs and your programs.”

Stevens knows this firsthand.

He previously served at FDA as a Branch Chief and Chemistry Reviewer. “We were reviewing and managing a huge amount of DMFs,” he says.

With valuable assistance from Stevens, I’ve put together a primer and a deeper dive (part two) into the subject of DMFs.

ABCs Of DMFs

Most simply stated, a Drug Master File is a recipe, often “owned” and meticulously adhered to at a specific development and manufacturing facility.

DMFs may be utilized to produce anything from starting materials and precursors to APIs, drug substances, and finished dosage forms.

For the most part, DMFs are voluntarily submitted to the FDA for future reference, and can then be cross-referenced during any IND or NDA where the material made utilizing the instructions in the DMF is involved.

Stevens notes the EMA has an Active Substance Master File (ASMF), more limited in scope to the creation of active substances, but currently there’s legislation to make this designation more like the FDA’s DMF.

Of course, calling a DMF a “recipe” is a bit delimiting; more precisely, these are comprehensive documents containing detailed information on all aspects of processing or manufacturing a pharmaceutical ingredient.

However, Stevens clarifies, FDA does not actually ‘approve’ DMFs. The agency reviews them in the context of a submitted NDA or IND. DMFs are deemed "adequate" or "inadequate" under the review of the referring submission.

Submitting a DMF to the FDA – be it via a biopharma sponsor or contract facility directly – allows for the providing of sensitive confidential information about the quality, safety, processes, and efficacy of manufactured materials without disclosing it to the public or other partners.

Volunteering By The Numbers

Above I stated the submission of DMFs is voluntary.

CDMOs volunteer because they benefit by having a DMF at the ready when customers who plan to submit INDs or NDAs to the regulatory agency need materials to be quickly and reliably produced.

On the other side, sponsors may take into consideration the existence of DMFs for critical materials, and a history of “adequate” reviews of which by FDA assessors, as part of their criteria for selecting CDMOs.

A new drug developer can verify if a CDMO has a currently valid DMF by requesting the CDMO provide the number assigned the DMF by the FDA.

This six-digit number allows the agency to streamline organization and tracking of DMF submissions. Today, this is always done via an electronic Common Technical Document (eCTD) format, which manufacturers use when submitting applications for DMFs.

Assigned numbers can be cross-referenced by prospective or current CDMO clients directly via the FDA (see: List of Drug Master Files (DMFs) | FDA).

However, says Stevens, take into consideration that the FDA does not explicitly indicate whether the DMF has in the past been found adequate or inadequate for certain IND or NDA submissions.

The prospective client has to get that info directly from the CDMO.

Finally, if a contract manufacturer does not already hold a DMF for the production of certain materials, the initial submission of a DMF is usually a tactical and strategic decision by both the sponsor and the CDMO. Timing is important, of course.  

Basic DMF Knowledge

DMFs are considered highly confidential documents containing intellectual property (IP) and other proprietary information about the way certain facilities manufacture and process materials.

DMFs include detailed information about:

• the facilities where the materials or products are created, processed, packed and/or stored; as well as
• technical details regarding the manufacturing process to ensure compliance with regulatory standards.

And at the risk of repeating, this allows the FDA to revew and approve (or deny) INDs or NDAs that cross-reference the DMF for safety, quality, and efficacy without disclosing this information to the public or the sponsor/applicant.

Our DMF bottom line when outsourcing development and manufacturing is to include at least some level of investigation into:

1. the existence of and current DMFs at your prospective (or current) service provider;
2. their track record with relevant past DMF submissions;
3. what will be needed for new DMF submissions as part of your CMC application – and the timing of which.

A tardy or incomplete DMF submission to the FDA might delay the review process for your drug approval or changes. Delays can impact the overall timeline for regulatory approval and may result in setbacks in bringing a drug to market or implementing changes to an existing drug product.

More positively, consider it this way:

An existing DMF, or the timely and thorough submission and approval of a new one associated with your development and manufacturing, is actually a path to safely and efficiently creating an approvable, high-quality product.

So don’t let a drug master file trip up your manufacturing.