[转载]FDA DMF指南_爱笑的squirrel_新浪博客

来自 : 新浪博客 发布时间：2021-03-25

A Drug Master File (DMF) is a submission to the Food and DrugAdministration (FDA) that may be used to provide confidentialdetailed information about facilities, processes, or articles usedin the manufacturing, processing, packaging, and storing of one ormore human drugs. The submission of a DMF is not required by law orFDA regulation. A DMF is submitted solely at the discretion of theholder. The information contained in the DMF may be used to supportan Investigational New Drug Application (IND), a New DrugApplication (NDA), an Abbreviated New Drug Application (ANDA),another DMF, an Export Application, or amendments and supplementsto any of these.

A DMF is NOT a substitute for an IND, NDA, ANDA, or ExportApplication. It is not approved or disapproved. Technical contentsof 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 CFR10.90(b)). It does, however, offer guidance on acceptableapproaches to meeting regulatory requirements. Different approachesmay be followed, but the applicant is encouraged to discusssignificant variations in advance with FDA reviewers to precludespending time and effort in preparing a submission that FDA maylater determine to be unacceptable.

Drug Master Files are provided for in 21 CFR 314.420. Thisguideline is intended to provide DMF holders with proceduresacceptable to the agency for preparing and submitting a DMF. Theguideline discusses types of DMF\'s, the information needed in eachtype, the format of submissions to a DMF, the administrativeprocedures governing review of DMF\'s, and the obligations of theDMF holder.

DMF\'s are generally created to allow a party other than the holderof the DMF to reference material without disclosing to that partythe contents of the file. When an applicant references its ownmaterial, the applicant should reference the information containedin its own IND, NDA, or ANDA directly rather than establishing anew DMF.

II. DEFINITIONSFor the purposes of this guideline, the following definitionsapply:

II.1.Agencymeansthe Food and Drug Administration.

II.2Agent orrepresentativemeans any personwho is appointed by a DMF holder to serve as the contact for theholder.

II.3.Applicantmeansany person who submits an application or abbreviated application oran amendment or supplement to them to obtain FDA approval of a newdrug or an antibiotic drug and any other person who owns anapproved application (21 CFR 314.3 (b)).

II.4.Drugproductmeans a finisheddosage form, for example, tablet, capsule, or solution, thatcontains a drug substance, generally, but not necessarily, inassociation with one or more other ingredients (21 CFR 314.3(b)).

II.5.Drugsubstancemeans an activeingredient that is intended to furnish pharmacological activity orother direct effect in the diagnosis, cure, mitigation, treatment,or prevention of disease or to affect the structure or any functionof the human body, but does not include intermediates used in thesynthesis of such ingredient (21 CFR 314.3 (b)).

II.6.Exportapplicationmeans anapplication submitted under section 802 of the Federal Food, Drug,and Cosmetic Act to export a drug that is not approved formarketing in the United States.

II.7.Holdermeansa person who owns a DMF.

II.8.Letter ofauthorizationmeans a writtenstatement by the holder or designated agent or representativepermitting FDA to refer to information in the DMF in support ofanother person\'s submission.

II.9.Personincludesindividual, partnership, corporation, and association. (Section201(e) of the Federal Food, Drug, and Cosmetic Act.)

II.10.Sponsormeansa person who takes responsibility for and initiates a clinicalinvestigation. The sponsor may be an individual or pharmaceuticalcompany, governmental agency, academic institution, privateorganization, or other organization (21 CFR 312.3 (b)).

III. TYPES OF DRUG MASTER FILESThere are five types of DMF\'s:

Type I Manufacturing Site, Facilities, Operating Procedures, andPersonnel

Type II Drug Substance, Drug Substance Intermediate, and MaterialUsed in Their Preparation, or Drug Product

Type III Packaging Material

Type IV Excipient, Colorant, Flavor, Essence, or Material Used inTheir Preparation

Type V FDA Accepted Reference Information

Each DMF should contain only one type of information and allsupporting data. See Section IV.C of the guideline for moredetailed descriptions of the kind of information desired in eachtype. Supporting information and data in a DMF can be crossreferenced to any other DMF (see Part V).

IV. SUBMISSIONS TO DRUG MASTER FILESEach DMF submission should contain a transmittal letter,administrative information about the submission, and the specificinformation to be included in the DMF as described in thissection.

The DMF must be in the English language. Whenever a submissioncontains information in another language, an accurate certifiedEnglish translation must also be included.

Each page of each copy of the DMF should be dated and consecutivelynumbered. An updated table of contents should be included with eachsubmission.

IV. A. Transmittal LettersThe following should be included:

IV. A.1. Original Submissionsa. Identification of submission: Original, the type of DMF asclassified in Section III, and its subject.

b. Identification of the applications, if known, that the DMF isintended to support, including the name and address of eachsponsor, applicant, or holder, and all relevant documentnumbers.

c. Signature of the holder or the authorized representative.

d. Typewritten name and title of the signer.

IV. A. 2. Amendmentsa. Identification of submission: Amendment, the DMF number, type ofDMF, 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 InformationAdministrative information should include the following:

IV. B.1. Original Submissionsa. 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 ofthe categories in Section a.

c. Statement of commitment.

A signed statement by the holder certifying that the DMF is currentand that the DMF holder will comply with the statements made in it.

IV. B2. Amendmentsa. 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 forsupport.

f. The number of each IND, NDA, ANDA, DMF, and Export Applicationthat relies on the subject of the amendment for support, ifknown.

g. Particular items within the IND, NDA, ANDA, DMF, and ExportApplication that are affected, if known.

IV. C. Drug Master File ContentsIV. C.1. Types of Drug Master FilesIV. C.1.a.Type I:Manufacturing Site, Facilities, Operating Procedures, andPersonnelA Type I DMF is recommended for a person outside of the UnitedStates to assist FDA in conducting on site inspections of theirmanufacturing facilities. The DMF should describe the manufacturingsite, equipment capabilities, and operational layout.

A Type I DMF is normally not needed to describe domesticfacilities, except in special cases, such as when a person is notregistered and not routinely inspected.

The description of the site should include acreage, actual siteaddress, and a map showing its location with respect to the nearestcity. An aerial photograph and a diagram of the site may behelpful.

A diagram of major production and processing areas is helpful forunderstanding the operational layout. Major equipment should bedescribed in terms of capabilities, application, and location. Makeand model would not normally be needed unless the equipment is newor unique.

A diagram of major corporate organizational elements, with keymanufacturing, quality control, and quality assurance positionshighlighted, at both the manufacturing site and corporateheadquarters, is also helpful.

IV. C.1.b.Type II: Drug Substance, Drug SubstanceIntermediate, and Material Used in Their Preparation, or DrugProductA Type II DMF should, in general, be limited to a single drugintermediate, drug substance, drug product, or type of materialused in their preparation.

IV. C.1.b.(1) Drug Substance Intermediates, Drug Substances, andMaterial Used in Their PreparationSummarize all significant steps in the manufacturing and controlsof the drug intermediate or substance. Detailed guidance on whatshould be included in a Type II DMF for drug substances andintermediates may be found in the following guidelines:

Guideline for Submitting Supporting Documentation in DrugApplications 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 ProductManufacturing procedures and controls for finished dosage formsshould ordinarily be submitted in an IND, NDA, ANDA, or ExportApplication. 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, theapplicant/sponsor should follow the guidance provided in thefollowing guidelines:

Guideline for the Format and Content of the Chemistry,Manufacturing, and Controls Section of an Application.

Guideline for Submitting Documentation for the Manufacture ofand Controls for Drug Products

Guideline for Submitting Samples and Analytical Data forMethods Validation

IV. C.1.c.Type III: Packaging MaterialEach packaging material should be identified by the intended use,components, composition, and controls for its release. The names ofthe suppliers or fabricators of the components used in preparingthe packaging material and the acceptance specifications shouldalso be given. Data supporting the acceptability of the packagingmaterial for its intended use should also be submitted as outlinedin the \"Guideline for Submitting Documentation for Packagingfor Human Drugs and Biologics.\"

Toxicological data on these materials would be included under thistype of DMF, if not otherwise available by cross reference toanother document.

IV. C.1.d.Type IV Excipient, Colorant,Flavor, Essence, or Material Used in Their PreparationEach additive should be identified and characterized by its methodof manufacture, release specifications, and testing methods.

Toxicological data on these materials would be included under thistype of DMF, if not otherwise available by cross reference toanother document.

Usually, the official compendia and FDA regulations for coloradditives (21 CFR Parts 70 through 82), direct food additives (21CFR Parts 170 through 173), indirect food additives (21 CFR Parts174 through 178), and food substances (21 CFR Parts 181 through186) may be used as sources for release tests, specifications, andsafety. Guidelines suggested for a Type II DMF may be helpful forpreparing a Type IV DMF. The DMF should include any othersupporting information and data that are not available by crossreference to another document.

IV. C.1.e.Type V: FDA Accepted Reference InformationFDA discourages the use of Type V DMF\'s for miscellaneousinformation, duplicate information, or information that should beincluded in one of the other types of DMF\'s. If any holder wishesto submit information and supporting data in a DMF that is notcovered by Types I through IV, a holder must first submit a letterof intent to the Drug Master File Staff (for address, see D.5.a. ofthis section). FDA will then contact the holder to discuss theproposed submission.

IV. C.2. General Information and SuggestionsIV. C.2.a. Environmental AssessmentType II, Type III, and Type IV DMF\'s should contain a commitment bythe firm that its facilities will be operated in compliance withapplicable environmental laws. If a completed environmentalassessment is needed, see 21 CFR Part 25.

IV. C.2.b. StabilityStability study design, data, interpretation, and other informationshould be submitted, when applicable, as outlined in the\"Guideline for Submitting Documentation for the Stability ofHuman Drugs and Biologics.\"

IV. D. Format, Assembly, and DeliveryIV. D.1.An original and duplicate are to be submitted for all DMFsubmissions.Drug Master File holders and their agents/representatives shouldretain a complete reference copy that is identical to, andmaintained in the same chronological order as, their submissions toFDA.

IV. D.2.The original and duplicate copies must be collated, fullyassembled, and individually jacketed.Each volume of a DMF should, in general, be no more than 2 inchesthick. For multivolume submissions, number each volume. Forexample, for a 3 volume submission, the volumes would be numbered 1of 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 12inches. However, it may occasionally be necessary to use individualpages 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 beopened for review without disassembling the jacket and refoldedwithout damage when the volume is shelved.

IV.D.4.

The agency\'s system for filing DMF\'s provides for assembly on theleft side of the page. The left margin should be at least threefourths of an inch to assure that text is not obscured in thefastened area. The right margin should be at least one half of aninch. The submitter should punch holes 8 1/2 inches apart in eachpage. See the page measurements shown in the following figure:

IV.D.5. Delivery to FDAIV.D.5.a.Drug Master File submissions and correspondence should be addressedas 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 beprepaid.

V. AUTHORIZATION TO REFER TO A DRUG MASTER FILEV. A. Letter of Authorization to FDABefore FDA can review DMF information in support of an application,the DMF holder must submit in duplicate to the DMF a letter ofauthorization permitting FDA to reference the DMF. If the holdercross references its own DMF, the holder should supply in a letterof authorization the information designated by items 3, 5, 6, 7,and 8 of this section. The holder does not need to send atransmittal letter with its letter of authorization.

The letter of authorization should include the following: