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Drug Master Files: Guidelines | FDA
Drug Master Files: Guidelines June 2014
For further information regarding the guideline please contact:
Office of Drug Evaluation I (HFD-100)
III. TYPES OF DRUG MASTER FILES
IV. SUBMISSIONS TO DRUG MASTER FILES
A. Transmittal Letters
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
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
D. Appointment of an Agent
E. Transfer of Ownership
IX. CLOSURE OF A DRUG MASTER FILE
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.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)).
There are five types of DMF's:
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).
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.
IV. A. Transmittal Letters
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.
IV. B. Administrative Information
Administrative information should include the following:
IV. B.1. Original Submissions
(1) DMF holder.
(2) Corporate headquarters.
(3) Manufacturing/processing facility.
(4) Contact for FDA correspondence.
(5) Agent(s), if any.
IV. B2. Amendments
IV. C. Drug Master File Contents
IV. C.1. Types of Drug Master Files
IV. C.1.a. Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel
A Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational layout.
A Type I DMF is normally not needed to describe domestic facilities, except in special cases, such as when a person is not registered and not routinely inspected.
IV. C.1.b.Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product
A Type II DMF should, in general, be limited to a single drug intermediate, drug substance, drug product, or type of material used in their preparation.
IV. C.1.b.(1) Drug Substance Intermediates, Drug Substances, and Material Used in Their Preparation
Summarize all significant steps in the manufacturing and controls of the drug intermediate or substance. Detailed guidance on what should be included in a Type II DMF for drug substances and intermediates may be found in the following guidelines:
IV. C.1.b.(2) Drug Product
Manufacturing procedures and controls for finished dosage forms should ordinarily be submitted in an IND, NDA, ANDA, or Export Application. If this information cannot be submitted in an IND, NDA, ANDA, or Export Application, it should be submitted in a DMF. When a Type II DMF is submitted for a drug product, the applicant/sponsor should follow the guidance provided in the following guidelines:
IV. C.1.c.Type III: Packaging Material
Each packaging material should be identified by the intended use, components, composition, and controls for its release. The names of the suppliers or fabricators of the components used in preparing the packaging material and the acceptance specifications should also be given. Data supporting the acceptability of the packaging material for its intended use should also be submitted as outlined in the "Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics."
IV. C.1.d.Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
Usually, the official compendia and FDA regulations for color additives (21 CFR Parts 70 through 82), direct food additives (21 CFR Parts 170 through 173), indirect food additives (21 CFR Parts 174 through 178), and food substances (21 CFR Parts 181 through 186) may be used as sources for release tests, specifications, and safety. Guidelines suggested for a Type II DMF may be helpful for preparing a Type IV DMF. The DMF should include any other supporting information and data that are not available by cross reference to another document.
IV. C.1.e.Type V: FDA Accepted Reference Information
FDA discourages the use of Type V DMF's for miscellaneous information, duplicate information, or information that should be included in one of the other types of DMF's. If any holder wishes to submit information and supporting data in a DMF that is not covered by Types I through IV, a holder must first submit a letter of intent to the Drug Master File Staff (for address, see D.5.a. of this section). FDA will then contact the holder to discuss the proposed submission.
IV. C.2. General Information and Suggestions
IV. C.2.a. Environmental Assessment
Type II, Type III, and Type IV DMF's should contain a commitment by the firm that its facilities will be operated in compliance with applicable environmental laws. If a completed environmental assessment is needed, see 21 CFR Part 25.
IV. C.2.b. Stability
Stability study design, data, interpretation, and other information should be submitted, when applicable, as outlined in the "Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics."
IV. D. Format, Assembly, and Delivery
IV. D.1.
IV. D.2.
The original and duplicate copies must be collated, fully assembled, and individually jacketed.
IV. D.3.
Paper length should not be less than 10 inches nor more than 12 inches. However, it may occasionally be necessary to use individual pages larger than standard paper size to present a floor plan, synthesis diagram, batch formula, or manufacturing instructions. Those pages should be folded and mounted to allow the page to be opened for review without disassembling the jacket and refolded without damage when the volume is shelved.
The agency's system for filing DMF's provides for assembly on the left side of the page. The left margin should be at least three fourths of an inch to assure that text is not obscured in the fastened area. The right margin should be at least one half of an inch. The submitter should punch holes 8 1/2 inches apart in each page. See the page measurements shown in the following figure:
IV.D.5. Delivery to FDA
IV.D.5.a.
IV.D.5.b. Delivery charges to the above address must be prepaid.
V. A. Letter of Authorization to FDA
Before FDA can review DMF information in support of an application, the DMF holder must submit in duplicate to the DMF a letter of authorization permitting FDA to reference the DMF. If the holder cross references its own DMF, the holder should supply in a letter of authorization the information designated by items 3, 5, 6, 7, and 8 of this section. The holder does not need to send a transmittal letter with its letter of authorization.
The letter of authorization should include the following:
V. B. Copy to Applicant, Sponsor, or Other Holder
The holder should also send a copy of the letter of authorization to the affected applicant, sponsor, or other holder who is authorized to incorporate by reference the specific information contained in the DMF. The applicant, sponsor, or other holder referencing a DMF is required to include a copy of the DMF holder's letter of authorization in the application.
VI. A. Policies Related to Processing Drug Master Files
VI. A.1.
Public availability of the information and data in a DMF is determined under 21 CFR Part 20, 21 CFR 314.420(e), and 21 CFR 314.430.
VI. A.2.
VI. B. Drug Master File Review
A DMF IS NEVER APPROVED OR DISAPPROVED.
The agency will review information in a DMF only when an IND sponsor, an applicant for an NDA, ANDA, or Export Application, or another DMF holder incorporates material in the DMF by reference. As noted, the incorporation by reference must be accompanied by a copy of the DMF holder's letter of authorization.
If FDA reviewers find deficiencies in the information provided in a DMF, a letter describing the deficiencies is sent to the DMF holder. At the same time, FDA will notify the person who relies on the information in the deficient DMF that additional information is needed in the supporting DMF. The general subject of the deficiency is identified, but details of the deficiency are disclosed only to the DMF holder. When the holder submits the requested information to the DMF in response to the agency's deficiency letter, the holder should also send a copy of the accompanying transmittal letter to the affected persons relying on the DMF and to the FDA reviewing division that identified the deficiencies. The transmittal letter will provide notice that the deficiencies have been addressed.
VII. A. Notice Required for Changes to a Drug Master File
A holder must notify each affected applicant or sponsor who has referenced its DMF of any pertinent change in the DMF (21 CFR 314. 420(c)). Notice should be provided well before making the change in order to permit the sponsor/applicant to supplement or amend any affected application(s) as needed.
VII. B. Listing of Persons Authorized To Refer to a Drug Master File
VII. B.1.
A DMF is required to contain a complete list of persons authorized to incorporate information in the DMF by reference [21 CFR 314.420(d)]. The holder should update the list in the annual update. The updated list should contain the holder's name, DMF number, and the date of the update. The update should identify by name (or code) the information that each person is authorized to incorporate and give the location of that information by date, volume, and page number.
VII. B.2.
VII. B.3.
If the list is unchanged on the anniversary date, the DMF holder should also submit a statement that the list is current.
VII. C. Annual Update
The holder should provide an annual report on the anniversary date of the original submission. This report should contain the required list as described in B.1., and should also identify all changes and additional information incorporated into the DMF since the previous annual report on the subject matter of the DMF. If the subject matter of the DMF is unchanged, the DMF holder should provide a statement that the subject matter of the DMF is current.
Failure to update or to assure FDA annually that previously submitted material and lists in the DMF remain current can cause delays in FDA review of a pending IND, NDA, ANDA, Export Application, or any amendment or supplement to such application; and FDA can initiate procedures for closure of the DMF (see Section IX).
VII. D. Appointment of an Agent
When an agent is appointed, the holder should submit a signed letter of appointment to the DMF giving the agent's name, address, and scope of responsibility (administrative and/or scientific). Domestic DMF holders do not need to appoint an agent or representative, although foreign DMF holders are encouraged to engage a U.S. agent.
VII. E. Transfer of Ownership
VIII. MAJOR REORGANIZATIONOF A DRUG MASTER FILE
A holder who wishes to close a DMF should submit a request to the Drug Master File Staff stating the reason for the closure. See Section IV.D.5.a for the address.
The request should include a statement that the holder's obligations as detailed in Section VII have been fulfilled.
Many of the guidelines referred to in the text and a current list of available guidelines may be obtained from the following:
Legislative, Professional, and Consumer Affairs Branch (HFD-365)
Copies of the Code of Federal Regulations (CFR) may be purchased from the following:
Date updated: March 11, 2005
All written comments should be identified with this document's docket number: FDA-2014-D-0397.