g. Particular items within the IND, NDA, ANDA, DMF, and Export Application that are affected, if known.
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.
The description of the site should include acreage, actual site address, and a map showing its location with respect to the nearest city. An aerial photograph and a diagram of the site may be helpful.
A diagram of major production and processing areas is helpful for
understanding the operational layout. Major equipment should be described in terms of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique.
A diagram of major corporate organizational elements, with key manufacturing, quality control, and quality assurance positions highlighted, at both the manufacturing site and corporate headquarters, is also helpful.
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:
Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances.
Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application.
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:
Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application.
Guideline for Submitting Documentation for the Manufacture of and Controls for Drug Products
Guideline for Submitting Samples and Analytical Data for Methods Validation
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.\
Toxicological data on these materials would be included under this type of DMF, if not otherwise available by cross reference to another document.
IV. C.1.d.Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
Each additive should be identified and characterized by its method of manufacture, release specifications, and testing methods.
Toxicological data on these materials would be included under this type of DMF, if not otherwise available by cross reference to another document. 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.
An original and duplicate are to be submitted for all DMF submissions.
Drug Master File holders and their agents/representatives should retain a complete reference copy that is identical to, and maintained in the same chronological order as, their submissions to FDA.
IV. D.2.
The original and duplicate copies must be collated, fully assembled, and individually jacketed.
Each volume of a DMF should, in general, be no more than 2 inches thick. For multivolume submissions, number each volume. For example, for a 3 volume submission, the volumes would be numbered 1 of 3, 2 of 3, and 3 of 3.
IV. D.3.
U.S. standard paper size (8-1/2 by 11 inches) is preferred.
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. IV.D.4.
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.
Drug Master File submissions and correspondence should be addressed as follows:
Drug Master File Staff
Food and Drug Administration 5901-B Ammendale Rd. Beltsville, MD 20705-1266
IV.D.5.b. Delivery charges to the above address must be prepaid.
V. AUTHORIZATION TO REFER TO A DRUG MASTER FILE
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:
1. 2. 3. 4. 5. 6. 7. 8.
The date.
Name of DMF holder. DMF number.
Name of person(s) authorized to incorporate information in the DMF by reference. Specific product(s) covered by the DMF. Submission date(s) of 5, above.
Section numbers and/or page numbers to be referenced.
Statement of commitment that the DMF is current and that the DMF holder will comply with the statements made in it. 9. Signature of authorizing official.
10. Typed name and title of official authorizing reference to the DMF.
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.