Drug Master Files and their equivalents: how FDA, EMA, PMDA, Health Canada and TGA compare

A Drug Master File (DMF) and its regional equivalents solve one recurring problem in pharmaceutical registration: an active substance or component manufacturer needs to give a health authority the confidential manufacturing and quality detail required to assess a product, without handing that proprietary know-how to the marketing applicant who buys the material. Every major regulator has built a mechanism for this, but they differ in whether the file is formally registered and numbered, how it is split between an open and a confidential part, who transmits it to the authority, and whether a fee attaches. The five systems below are functionally similar but procedurally distinct, and those procedural details drive real timing and dossier-assembly decisions.

Terminology at a glance

Jurisdiction	Instrument	Formal registration / number?
FDA (US)	Drug Master File (DMF), Types I–V	Yes. FDA assigns a DMF number on administrative acceptance ²⁸
EMA / EU	Active Substance Master File (ASMF); Certificate of Suitability (CEP) as an alternative route	ASMF carries an EU ASMF reference number where available ¹³¹⁴; CEP issued by EDQM ¹⁷
PMDA (Japan)	Master File (MF) registration system	Yes. Voluntary registration with PMDA; MF registration certificate issued ⁷²
Health Canada	Master File (MF), five types	Yes. Health Canada assigns a Master File number on acceptance ¹⁰³¹⁰⁹
TGA (Australia)	DMF / Plasma Master File (PMF) / CEP referenced within the dossier	No TGA-owned master file registry or numbering scheme ⁶¹⁵³

FDA: a discretionary, numbered file reviewed only on reference

A US DMF is a submission that provides confidential detailed information about facilities, processes, or articles used in manufacturing, processing, packaging, and storing one or more human drugs ⁵³. It is not required by law or regulation, is filed solely at the holder's discretion, and is not a substitute for an IND, NDA, ANDA, or Export Application ⁵³. Critically, a DMF is never approved or disapproved on its own; FDA reviews it only when it is incorporated by reference in an application by an IND sponsor, NDA/ANDA applicant, Export Application applicant, or another DMF holder ²⁸⁵³.

FDA recognizes five types ²⁶⁵⁵⁵⁶:

Type I covers a manufacturing site, facilities, operating procedures and personnel, and was historically recommended for a person outside the US to assist FDA in on-site inspection ⁵⁵. (This type has since been retired in practice, but the type structure below reflects the guidance corpus.)
Type II covers a drug substance, drug substance intermediates and materials used in their preparation, or a drug product ²⁶⁵⁶. Bulk antibiotic drug substances are also filed as Type II ⁵⁶.
Type III covers packaging materials ²⁶.
Type IV covers an excipient, colorant, flavor, essence, or materials used in their preparation ²⁶.
Type V covers FDA-accepted reference information; FDA discourages using it for miscellaneous or duplicate content that belongs in Types I–IV ²⁶⁵⁴.

Authorization to reference. The applicant must obtain a Letter of Authorization (LOA) from the DMF holder, granting FDA authority to refer to the DMF during review ²⁶²⁸. The letter should be on the holder's letterhead, dated and signed, and should cite the holder's name, drug name, and DMF number; the incorporation by reference must be accompanied by a copy of the LOA ²⁶²⁸. Where a bulk drug substance comes from multiple sources, authorization is needed for each source ²⁶.

Confidentiality. Public availability of DMF information is governed by 21 CFR Part 20, 314.420(e), and 314.430 ²⁸. When FDA finds deficiencies, it discloses detail only to the DMF holder; the relying applicant is told only that more information is needed ²⁸.

Fee and completeness. Under GDUFA, a person who owns a Type II API DMF referenced on or after October 1, 2012 in a generic drug submission by an initial LOA is assessed a one-time DMF fee ²⁷. The fee is due on the earlier of the first generic submission referencing the DMF by initial LOA, or the date the holder requests the initial completeness assessment ²⁷. FDA strongly encourages filing a complete DMF and paying the fee at least six months before the ANDA or PAS that will rely on it ²⁷. On receipt, an original DMF is screened for minimum format and content; if administratively acceptable, FDA assigns a DMF number, and if not, it is returned without a number ²⁸.

Format. Not every DMF must be in eCTD. All Type III submissions are exempt (FDA still encourages PDF following the CTD structure), and certain Type II DMFs, for example those supporting a PET drug or solely supporting a noncommercial IND and held by academic, government, or nonprofit organizations, may qualify for a long-term eCTD waiver ¹⁴⁸¹⁵⁰. Where eCTD applies, it is the standard electronic format ¹⁴⁷¹⁴⁸.

EMA / EU: a two-part ASMF, with the CEP as a parallel route

The EU Active Substance Master File is a split-document system for a well-defined active substance. The Applicant's Part is the open part, included in Section 3.2.S of the CTD quality dossier ⁷⁸. The Restricted Part is the closed part of the active substance manufacturer, structured to Module 3.2.S with its own Quality Overall Summary ⁷⁸.

Responsibility for transmission sits with the applicant: the marketing authorisation applicant must ensure the complete ASMF (open plus closed part) is supplied to the authorities directly by the active substance manufacturer, in CTD format, timed to arrive around the same time as the MA application ⁷⁸. A Letter of Access must accompany the ASMF, with a copy placed in Annex 6.10 of Module 1 and addressed to the relevant authority ⁷⁸. The applicant's dossier records the ASMF holder/manufacturer details, the EU ASMF reference number where available, and the applicant part version and dates ¹³¹⁴.

The Certificate of Suitability (CEP), issued by EDQM, is an alternative route to document active substance quality where the substance is covered by a relevant European Pharmacopoeia monograph ¹⁷²². When a CEP is used, its information replaces the MA dossier sections that would otherwise describe manufacture and control of the active substance, and the manufacturer confirms in writing that the process has not been modified since the CEP was granted ¹⁷. The CEP is not the ASMF; it is a parallel documentation route, and the applicant should still have access to the open part (or equivalent) of the active substance information, including when a CEP is used ⁹¹⁰.

PMDA (Japan): a voluntary MF registration protecting registrant know-how

Japan's Master File system is a voluntary registration operated by PMDA to supply information needed for approval review while protecting the registrant's intellectual property and streamlining review ⁷⁰⁷²⁷⁹⁸¹. What can be registered is broad: drug substances, intermediates and product materials; new excipients and pre-mix excipients; materials for medical devices; materials for regenerative medical products (cells, media, additives); and containers/packaging materials ⁷². Notably, drugs used within medical devices, such as anticancer or immunosuppressant agents, are registered as drug substances rather than as device materials ⁷¹⁷⁸. Registered content typically includes manufacturing method and process control, quality control tests, specifications and test methods, stability data, and, for new excipients, non-clinical data, plus the manufacturing site named on the MF registration certificate ⁷².

Registrant and in-country agent. Domestic or foreign manufacturers of APIs and raw materials may register ⁷⁰. A foreign registrant must appoint a person with an address in Japan (an in-country management agent) to handle the registration application and must apply through that agent, and application forms and documents must be in Japanese ⁷⁰⁷³.

Authorization and information sharing. The system is designed so review-relevant information can be provided to the marketing authorization applicant without disclosing know-how ⁷⁰⁷². Rather than a single Western-style Letter of Access document, PMDA guidance emphasizes an information-sharing arrangement among the MF registrant, the in-country caretaker, and the MAH/applicant, with the scope of shared information agreed among them ⁷⁴⁷⁷. The registrant must notify affected applicants and approval holders in advance of changes to registered items, even minor ones ⁷⁴.

Review. MF applications, changes, and minor-change notifications are submitted to PMDA under prescribed procedures ⁷². The MF is used during approval review, and for cell- and tissue-based products can be used earlier, at clinical trial notification, confirmation, or face-to-face consultation stages when safety evaluation must be examined closely ⁷⁵.

Health Canada: five master file types, numbered before reference

Health Canada accepts master files as confidential references for information about processes or components used to manufacture, process, or package a drug, supporting drug submissions, DIN applications, and clinical trial applications for human and/or veterinary use ¹⁰⁵¹¹²¹¹⁷¹²⁰¹²³. The system is organized into five types ¹⁰²¹⁰⁷:

Type I: Active Substance Master Files (ASMFs), covering APIs, starting materials and intermediates for pharmaceuticals, and for biologics, bulk process intermediates, vaccine antigens, adjuvants (except alum), albumin (except as an excipient), and critical raw materials for radiopharmaceuticals or gene therapy vectors ¹⁰².
Type II: Container Closure System Master Files ¹⁰⁷.
Type III: Excipient Master Files, including excipients of biological origin, capsule shells, coatings, colourants, flavours, gelatin, alum, and growth media ¹⁰⁷.
Type IV: Dosage Form Master Files, covering dosage forms and drug product intermediates ¹⁰⁷.
Type V: Facilities and Equipment Master Files ¹⁰⁷¹¹⁸.

Filing and numbering. Master files are voluntary registrations filed directly with Health Canada by the MF holder or an authorized MF agent/third party, using Health Canada's Master File Application Form ¹⁰⁴¹¹²¹¹⁷. After acceptance, Health Canada assigns a Master File number, and sponsors should confirm the file has been received and numbered before relying on it ¹⁰³¹⁰⁹¹¹⁰¹¹².

Letter of Access and Canadian Agent. A Letter of Access signed by the MF holder is required before Health Canada will use the confidential part of the MF in support of a submission or CTA; it records that the applicant and holder agree the MF may be referenced during assessment, and copies of authorization letters go in Module 1 ¹³¹⁰⁹¹¹². For a CTA, the supporting DMF, its letter of access, and related fees should be submitted and accepted by Health Canada before the CTA is filed, with the letter of access citing the file and control number(s) referenced ⁴. If the holder uses a Canadian Agent, the holder (not the agent) must provide a letter authorizing the agent to act on its behalf ¹⁰⁶¹⁰⁹. Health Canada holds the MF in strict confidence, and reference to a master file is needed only where the requested information is third-party confidential and has not been provided to the sponsor directly ¹²³. The available guidance confirms that fees apply in the CTA context but does not enumerate MF-specific fee amounts ⁴¹²².

TGA (Australia): referenced within the dossier, no separate master file registry

Australia's approach is the outlier: TGA does not operate its own master file registration or numbering scheme, and does not treat DMFs as standalone confidential files that can simply be referenced without further action ⁶¹⁵³. Instead, active substance quality is documented primarily through the applicant's own quality section, with external support where the applicant's Module 3.2.S information alone is insufficient ¹⁵³.

Where external support is used, the applicant may rely on a DMF, a Plasma Master File (PMF), or an EDQM CEP ¹⁵³. The mechanics mirror the EU two-part model: the open part of the DMF must be included in Module 3.2.S of the dossier, while the restricted/closed part is supplied directly to TGA by the active substance manufacturer, not by the sponsor ⁶. The applicant should ensure the manufacturer's part of the DMF/PMF has reached TGA before lodging the application ⁶. For plasma-derived raw materials or excipients in new registrations, a PMF must be included in Module 3 or already approved by TGA ⁶.

Two obligations sit on the applicant. First, where the application references a third-party DMF, PMF, or a CEP, the applicant must include a declaration ⁶¹⁵³. Second, the applicant must establish a formal agreement with the API manufacturer requiring the manufacturer to communicate any change to the applicant and to TGA before any significant change to the drug substance; that agreement is independent of TGA ⁶. For variations involving a modified DMF/PMF/CEP, the document need not be resubmitted unless a new one is being provided or the sponsor changes ⁶¹⁵³.

Cross-cutting themes

Open part versus restricted part. The EU ASMF, Health Canada Type I ASMF, and the Australian DMF model all formalize a split between an open/applicant part that lives in the dossier and a restricted/closed part the applicant never sees ⁷⁸¹⁰²⁶. FDA's DMF and Japan's MF achieve the same confidentiality outcome by keeping the entire file with the authority and disclosing deficiencies only to the holder ²⁸⁷⁰⁷².

Who transmits the confidential part. In the EU and Australia, the active substance manufacturer sends the restricted part directly to the authority, and the applicant is responsible for making sure it arrives in time ⁷⁸⁶. In the US, Japan, and Canada, the holder files the master file with the authority independently and the applicant later points to it by number and letter ²⁸⁷²¹⁰³.

The letter of access is near-universal, but not identical. FDA, the EU, Health Canada, and Australia all rely on a Letter of Authorization / Letter of Access from the holder to unlock the confidential content for a specific application ²⁶⁷¹¹²⁶. Japan is the exception in form: PMDA guidance frames authorization as an information-sharing arrangement among the registrant, in-country agent, and applicant rather than a single access letter ⁷⁴⁷⁷.

Review only on reference. A consistent principle across FDA, the EU, Japan, and Health Canada is that the master file is not approved on its own; it is assessed in the context of, and to support, a referencing application, DIN application, or clinical trial application ²⁸⁷⁷⁵¹¹². Australia's model is the same in substance, since the DMF has no independent Australian registration and is assessed only through the product application ⁶¹⁵³.

Numbering and fees. FDA, Health Canada, and PMDA assign a formal master file number or registration on acceptance ²⁸¹⁰³⁷². FDA is distinctive in attaching a specific one-time GDUFA fee to Type II API DMFs referenced in generic submissions and encouraging payment well ahead of the referencing ANDA ²⁷. Australia assigns no master file number at all, relying instead on the dossier declaration and the manufacturer's direct submission ⁶¹⁵³.

Practical takeaway for dossier planning. The sequencing risk differs by region. In the US, Japan, and Canada, the file should be on record and numbered (and, for a US Type II API DMF, the fee paid) before the referencing application is filed ²⁷¹⁰³¹¹². In the EU and Australia, the applicant carries the burden of coordinating the manufacturer's direct submission of the restricted part to align with the marketing application ⁷⁸⁶. A reader planning a multi-region filing for the same active substance would want to confirm, per region, the current fee schedule, the accepted electronic format, and whether a CEP can substitute for a full master file, points that go beyond what the guidance summarized here settles definitively.

Drug Master Files and Global Equivalents: A Comparative Regulatory Overview Across FDA, EMA, PMDA, Health Canada, and TGA