GUIDELINE FOR DRUG MASTER FILES
Center for Drug Evaluation and Research
Food and Drug Administration
Department of Health and Human Services
September 1989
For further information regarding the guideline please contact:
Food and Drug Administration
Center for Drug Evaluation and Research Office of Drug Evaluation I (HFD-100)
5600 Fishers Lane Rockville, Maryland 20857
TABLE OF CONTENTS
I. INTRODUCTION II. DEFINITIONS
III. TYPES OF DRUG MASTER FILES IV. SUBMISSIONS TO DRUG MASTER FILES
A. Transmittal Letters
1. Original Submissions 2. Amendments
B. Administrative Information
1. Original Submissions 2. Amendments
C. Drug Master File Contents
1. Types of Drug Master Files
a. Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel b. Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product c. Type III: Packaging Material
d. Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their
Preparation
e. Type V: FDA Accepted Reference Information
2. General Information and Suggestions
A. Environmental Assessment B. Stability
C. Format, Assembly, and Delivery
V. AUTHORIZATION TO REFER TO A DRUG MASTER FILE
A. Letter of Authorization to FDA
B. Copy to Applicant, Sponsor, or Other Holder
VI. PROCESSING AND REVIEWING POLICIES
A. Policies Related to Processing Drug Master Files B. Drug Master File Review
VII. HOLDER OBLIGATIONS
A. Notice Required for Changes to a Drug Master File
B. Listing of Persons Authorized To Refer to a Drug Master File C. Annual Update
D. Appointment of an Agent E. Transfer of Ownership
IX. CLOSURE OF A DRUG MASTER FILE
GUIDELINE FOR DRUG MASTER
FILES
I. INTRODUCTION
A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing,
packaging, and storing of one or more human drugs. The submission of a DMF is not required by law or FDA regulation. A DMF is submitted solely at the
discretion of the holder. The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug
Application (NDA), an Abbreviated New Drug Application (ANDA), another DMF, an Export Application, or amendments and supplements to any of these. A DMF is NOT a substitute for an IND, NDA, ANDA, or Export Application. It is not approved or disapproved. Technical contents of a DMF are reviewed only in connection with the review of an IND, NDA, ANDA, or an Export Application. This guideline does not impose mandatory requirements (21 CFR 10.90(b)). It does, however, offer guidance on acceptable approaches to meeting regulatory requirements. Different approaches may be followed, but the
applicant is encouraged to discuss significant variations in advance with FDA reviewers to preclude spending time and effort in preparing a submission that FDA may later determine to be unacceptable.
Drug Master Files are provided for in 21 CFR 314.420. This guideline is
intended to provide DMF holders with procedures acceptable to the agency for preparing and submitting a DMF. The guideline discusses types of DMF's, the information needed in each type, the format of submissions to a DMF, the administrative procedures governing review of DMF's, and the obligations of the DMF holder.
DMF's are generally created to allow a party other than the holder of the DMF to reference material without disclosing to that party the contents of the file. When an applicant references its own material, the applicant should reference the information contained in its own IND, NDA, or ANDA directly rather than establishing a new DMF.
II. DEFINITIONS
For the purposes of this guideline, the following definitions apply: II.1. Agency means the Food and Drug Administration.
II.2 Agent or representative means any person who is appointed by a DMF holder to serve as the contact for the holder.
II.3. Applicant means any person who submits an application or abbreviated application or an amendment or supplement to them to obtain FDA approval of a new drug or an antibiotic drug and any other person who owns an approved application (21 CFR 314.3 (b)).
II.4. Drug product means a finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (21 CFR 314.3 (b)).
II.5. Drug substance means an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient (21 CFR 314.3 (b)).
II.6. Export application means an application submitted under section 802 of the Federal Food, Drug, and Cosmetic Act to export a drug that is not approved for marketing in the United States.
II.7. Holder means a person who owns a DMF.
II.8. Letter of authorization means a written statement by the holder or
designated agent or representative permitting FDA to refer to information in the DMF in support of another person's submission.
II.9. Person includes individual, partnership, corporation, and association. (Section 201(e) of the Federal Food, Drug, and Cosmetic Act.)
II.10. Sponsor means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization (21 CFR 312.3 (b)).
III. TYPES OF DRUG MASTER FILES
There are five types of DMF's:
Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel Type II Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product Type III Packaging Material
Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
Type V FDA Accepted Reference Information
Each DMF should contain only one type of information and all supporting data. See Section IV.C of the guideline for more detailed descriptions of the kind of information desired in each type. Supporting information and data in a DMF can be cross referenced to any other DMF (see Part V).
IV. SUBMISSIONS TO DRUG MASTER FILES
Each DMF submission should contain a transmittal letter, administrative
information about the submission, and the specific information to be included in the DMF as described in this section.
The DMF must be in the English language. Whenever a submission contains information in another language, an accurate certified English translation must also be included.
Each page of each copy of the DMF should be dated and consecutively numbered. An updated table of contents should be included with each submission.
IV. A. Transmittal Letters
The following should be included:
IV. A.1. Original Submissions
a. Identification of submission: Original, the type of DMF as classified in Section III, and its subject.
b. Identification of the applications, if known, that the DMF is intended to
support, including the name and address of each sponsor, applicant, or holder, and all relevant document numbers.
c. Signature of the holder or the authorized representative. d. Typewritten name and title of the signer.
IV. A. 2. Amendments
a. Identification of submission: Amendment, the DMF number, type of DMF, and the subject of the amendment.
b. A description of the purpose of submission, e.g., update, revised formula, or revised process.
c. Signature of the holder or the authorized representative. d. Typewritten name and title of the signer.
IV. B. Administrative Information
Administrative information should include the following:
IV. B.1. Original Submissions
a. Names and addresses of the following: (1) DMF holder.
(2) Corporate headquarters.
(3) Manufacturing/processing facility. (4) Contact for FDA correspondence. (5) Agent(s), if any.
b. The specific responsibilities of each person listed in any of the categories in Section a.
c. Statement of commitment.
A signed statement by the holder certifying that the DMF is current and that the DMF holder will comply with the statements made in it.
IV. B2. Amendments
a. Name of DMF holder. b. DMF number.
c. Name and address for correspondence.
d. Affected section and/or page numbers of the DMF.
e. The name and address of each person whose IND, NDA, ANDA, DMF, or Export Application relies on the subject of the amendment for support.
f. The number of each IND, NDA, ANDA, DMF, and Export Application that relies on the subject of the amendment for support, if known.