The file that keeps an ingredient maker's secrets

A filing cabinet designed so nobody has to share

When a company makes a finished medicine from someone else's ingredient, it needs to convince the regulator that the ingredient is made properly. The ingredient maker usually will not hand over how it does that.

A drug master file is the device that resolves the standoff. It is "a submission of information to the Food and Drug Administration by a person (the drug master file holder)" made for one of two purposes.

The first is straightforward. It lets the holder incorporate the information by reference into its own applications.

The second is the one that shapes this market. It lets the holder authorize other people to rely on the information to support their submissions "without the holder having to disclose the information to the person."

So a finished-product maker can build an application on manufacturing detail it has never read, because the regulator has the detail and the maker has permission to point at it.

The sentence that changes what a master file proves

The most useful line in the section is a disclaimer, and it sits in the same opening paragraph.

"FDA ordinarily neither independently reviews drug master files nor approves or disapproves submissions to a drug master file."

What happens instead is stated next. "the agency customarily reviews the information only in the context of an application" under the investigational or marketing application rules.

That has a direct consequence for how a claim should be read. Saying an ingredient has a master file on record describes a filing, not a review, and not a clearance.

The review, when it happens, is triggered by somebody else's application and is scoped to that application's needs.

A file that no application has ever pointed at may sit unexamined indefinitely, and nothing in the regulation suggests otherwise.

What can be in one

The section lists the kinds of information a master file may hold, and the list is narrower than people assume.

It covers "Drug substance, drug substance intermediate, and materials used in their preparation, or drug product".

It covers packaging materials.

It covers "Excipient, colorant, flavor, essence, or materials used in their preparation", which is the everything-else-in-the-vial category.

And it covers accepted reference information.

The first item in the numbered list is marked reserved, which is a small piece of regulatory archaeology visible in the current text.

Anything a person wants to submit that is not covered by those types requires a letter of intent to the master file staff first, after which the agency makes contact to discuss the proposed submission.

Permission is written, specific and revocable in practice

Pointing at someone else's file is not something a company can do unilaterally.

An application may incorporate all or part of a master file "if the holder authorizes the incorporation in writing."

The reference has to be precise. Each incorporation by reference must describe the incorporated material "by name, reference number, volume, and page number" of the file.

That precision is what makes the arrangement auditable. A reviewer can tell exactly which pages of which file an application is leaning on, even though the applicant cannot.

The file itself is required to be submitted in two copies, and any addition, change or deletion is submitted the same way, identifying the affected information by the same four descriptors.

The duty to tell everyone who is relying on you

Two housekeeping paragraphs turn out to be the ones with real consequences downstream.

The first is a notification duty. If the holder adds, changes or deletes any information in the file, "the holder shall notify in writing, each person authorized to reference that information."

So a change at the ingredient level is supposed to travel outward to every company whose application rests on it, even though those companies cannot see what changed.

The second is a register. The file is required to contain "a complete list of each person currently authorized to incorporate by reference any information in the file". It identifies by name, reference number, volume and page number what each of them may incorporate.

Where the holder limits an authorization to particular drug products, the list must name each product and its application number where known.

That list is the map of who depends on this ingredient information. It lives inside the file, which is not a public document.

How much of it can ever become public

The section ends by handing the disclosure question to other rules.

The public availability of data and information in a master file, including its availability to someone authorized to reference the file, is determined under the general disclosure part and under the application disclosure section.

Those rules are covered separately on this site, and they are restrictive by design.

The practical effect for a reader is that the underlying manufacturing detail behind an ingredient is generally not obtainable by asking. Its confidentiality is a feature of the system rather than a failure of it.

What can sometimes be established is the existence of a relationship, because the applications and listings built on top of a master file are more visible than the file itself.

Reading a supply chain claim against this

This mechanism sits directly under a claim readers see often: that an ingredient comes from a facility with a master file, or that a supplier is registered and filed.

Three things follow from the regulation, and none of them is reassurance about quality.

A master file exists because information is being withheld from the company using the ingredient. That is its designed purpose, stated in the section.

A master file is not ordinarily reviewed or approved on its own. It is looked at when an application needs it.

And the person telling you about it may not have seen its contents either, since the whole arrangement is built so they do not have to.

Two limits on this article. Only this section was read in full, plus the opening of the application disclosure section it points to. No master file, holder, authorization letter or supply chain claim was examined, so nothing here describes any actual ingredient or company.

Sources

Each document below is named as it names itself, with the date printed on that document rather than the day it was read.

1. Title 21 Code of Federal Regulations section 314.420, Drug master files, read in full — Electronic Code of Federal Regulations, Office of the Federal Register, March 2004
2. Title 21 Code of Federal Regulations section 314.430, Availability for public disclosure of data and information in an application or abbreviated application, read for the opening paragraphs on scope — Electronic Code of Federal Regulations, Office of the Federal Register, July 2023