Drug Master Files14

史上最全｜药物主文件DrugMasterFile（DMF）1、DMF一份较完整的DMF文件2、FDA指南：药物主文件（DMF）3、美、欧、中化药DMF资料要求对比4、DMF文件编制要求及重点内容分析5、原料药注册法规要求DMF解读6、美国FDA DMF list 3Q2019EXCEL7、DMF流程8、美国DMF目录及要求9、原料药出口DMF注册文件中的杂质研究10、美国DMF1.5 药物主文件1.5.1 DMF简介药物主文件，即Drug Master File (DMF)，是呈交FDA的存档待审资料，资料内容包括有关在制造、加工、包装、储存、批发人用药品活动中所使用的生产设施、工艺流程、质量控制及其所用原料、包装材料等详细信息。

DMF持有者向FDA呈交DMF主要目的是支持用户向FDA提交的各种药品申请，而同时又不愿将其化学和生产流程的保密资料抄报用户。

FDA对呈交的DMF资料进行存档处理，以备审查。

这样，DMF持有者只需向用户提供授权书，授权FDA在评审用户的药品申请时，对所涉及的DMF进行全面考查。

DMF的另一特点是在FDA中心档案室存档的DMF可以支持所有使用该产品的用户，DMF持有者无须向每一用户重复提供资料。

2012出台的《仿制药收费法案》，要求在2012年10月1日后首次被仿制药引用的二类原料药DMF，需要缴纳DMF费，FDA对付费后的DMF作完整性审查（Completeness Assessment），此审查只检查资料的完整性，不审核具体内容，通过完整性审查后的DMF会被收录在'可被引用'列表中，并且FDA只会审评引用此列表中DMF的ANDA申请。

1.5.1.1 FDA只对DMF做形式审查事实上FDA既不'审批'已备案的DMF资料，也不对DMF资料发表同意或不同意的观点。

DMF资料上交后仅是编号备案。

因此，在收到FDA'接收DMF通知'后，不要误认为呈交的DMF'通过了FDA审批'。

Master File System for Drug Substances, etc.1. Master File (MF) SystemMaster file (hereinafter referred to as “MF”) system for drug substances, etc. allows Japanese or foreign manufacturers of drug substances etc. to voluntarily register the data concerning the quality/manufacturing methods of their drug substances, etc. used for manufacture of drugs (pharmaceutical products) to the review authority.The registered data is quoted as the necessary information for an approval review of the drug (pharmaceutical product)in which the drug substance is used.Japanese or foreign drug manufacturers can register in MF by submitting the specified forms (application form for MF registration, application for change in registered items, minor change notification, etc.) to Pharmaceuticals and Medical Devices Agency (hereinafter referred to as “PMDA”) in accordance with the procedures described in the Enforcement Regulations for the Pharmaceutical Affairs Law (hereinafter referred to as “Regulations”). (See Article 72, 79, and 81 of the Regulations (*1); “Documents to be Submitted”.)Foreign manufacturers of drug substances, etc. can also apply for MF registration.In order to apply for MF registration, it is necessary for a foreign manufacturer to obtain a foreign manufacturer accreditation (*2) because the accreditation category, the accreditation number, and the date of accreditation of the foreign manufacturing site must be entered in the MF registration application form.In addition, when a foreign manufacturer applies for the accreditation and MF registration, the manufacturer codes for the foreign manufacturer and for the manufacturing site are required. Thus the both codes must be registered in advance.When a foreign manufacturer applies for MF registration, a person to undertake the duties concerning the relevant MF registration with an address within Japan (in-country caretaker of drug substances) shall be appointed (Article 72 of the Regulations).MF registration application form, notification, and other related documents shall be written in Japanese (Article 283 of the Regulations).(*1) The basic items related to MF registration are explained in “Guideline on Utilization of Master File for Drug Substances, etc.” (PFSB/ELD Notification No. 0210004, dated February 10, 2005) as well as in the related Articles of the Regulations.(*2) A manufacturer (foreign manufacturer) plans to manufacture drugs, medical devices, or quasi-drugs to be exported to Japan in the foreign country accredited under the Foreign Manufacturer Accreditation (Article 13-3 of the Pharmaceutical Affairs Law) can be accredited by the Minister of Health, Labour and Welfare. The accreditation is given to each manufacturing site according to the category.2. Items for MF Registration1) Drug substances, intermediates, and pharmaceutical product materials(materials of pharmaceutical products with special dosage form, etc.)However, the drug substances, intermediates and pharmaceutical product materials used in OTC drugs (excluding OTC drugs with new active ingredients) are not appropriate for registration in MF, as it is considered that their quality and safety are already established even in the existing specifications and test methods.2) New excipients and new pre-mix excipients with a different composition ratiofrom the existing ones3) Materials for medical devices4) Containers/packaging materialsOther than the above 1) to 4), country of origin and data on inspection/certification (including the new TSE data based on TSE Data Number) of bovine-derived raw-materials, and the items considered appropriate to quote their MF registration numbers under approval reviews can also be registered. MF registrations of the items in 3) “Materials for medical devices” and the items related to medical devices among 4) “Containers/packaging materials” are currently under consideration.3. MF Registration1) Items that can be registered in MFa) Name of drug substances, etc.b) Name of manufacturing site and other informationc) Information about ingredients and their quantity or nature of drugsubstances, etc.d) Manufacturing method, manufacturing process control, and quality controlteste) Specifications and test methodsf) Stability tests, storage method, and expiry dateg) Non-clinical study (mainly for new excipients)h) Information on safetyi) Category of license for manufacturing operation or accreditation of foreignmanufacturerj) Number of license for manufacturing operation or number and date of accreditation of foreign manufacturerk) Name and address of in-country caretaker if the applicant for the MF registration is manufacturing drug substances, etc, outside Japan2) Forms for MF registration informationAt the time of MF registration, PMDA checks whether it is written in the correct format, e.g., minimum required items are included or data (Module 3: in Englishor Japanese) is attached.MF registered items shall be regarded as a part of information which should be described in an approval application form and attached documents (“Data on Manufacturing Methods and Specifications/Test Methods”, “Data on Stability”, and “Data on Pharmacological Action”) for a drug (pharmaceutical product) and therefore, the MF registered items are also reviewed at the time of the approval review for the drug (pharmaceutical product) quoting the MF.3) Fee and submission of the application for MF registrationNo fee shall be charged for MF registration. When registering for MF, the registration application form and attached documents shall be submitted to Administration Division 1, Office of Review Administration, PMDA (see “Documents to be Submitted”).When a foreign drug manufacturer registers for MF, the cover page (seal) of application form can be completed with its name and address written in their own language and a handwritten signature of the representative is accepted instead of seal.Application form must be submitted with the handwritten signature of the representative of the foreign drug manufacturer. Application form with the signature and seal of their in-country caretaker is not acceptable. Documents such as “Application for change in registered items” and “Minor change notification” described in the following section shall also be handled in the same manner. In addition, “Replacement order” and the statement required for “Minor change notification” cannot be accepted with the signature and seal of the in-country caretaker.a) Application Form for MF RegistrationFor a new registration, application form for MF registration (addressed tothe Chief Executive of PMDA) prepared in duplicate (photocopy of the original sheet is not acceptable) using the Form No. 42 of the Regulations(Attachment 1 (PDF)), flexible disk (hereinafter referred to as “FD”), andattached documents to verify the registration items described under b) shallbe submitted.In addition, please note the followings when submitting the application form.•In the name of drug substance, etc. section, both of generic name and commercial name shall be stated.•Information that should be disclosed to the applicants or approval holders of drugs (pharmaceutical products) shall also be written in theregistration application form.•The data attached to the approval application of a drug substanceunder the previous Pharmaceutical Affairs Law can be reused for theMF registration application as the supporting data. However, pleasesubmit new information obtained after the approval of the drugsubstance under the previous law, or documents requested by thereview authority other than those already attached.•It is necessary to prepare the registration application form in FD.Please prepare the descriptions according to “Guidance on Handling ofApplications Submitted on Flexible Disk etc.” (PFSB/ELD NotificationNo. 0331023, dated March 31, 2005).•For the summary, etc. of the drug substance manufacturing methods;please refer to “Guideline for Descriptions on Application Forms forMarketing Approval of Drugs, etc. under the Revised PharmaceuticalAffairs Law” (PFSB/ELD Notification No. 0210001, dated February 10,2005).•For questions regarding the operation of the application software, please send your specific questions by fax or e-mail to Helpdesk (FAX:03-3507-0114, E-mail: fd_iyaku@pmda.go.jp).•If license for manufacturing operation or accreditation for the manufacturing site of the drug substance, etc. is in progress, MFregistration (issuance of the number) cannot be processed until thecertification/accreditation is obtained. Please allow enough time forapplication.b) Attached document (registration data)Data to be attached to the registration application form (registration data) shall be prepared by using the following forms.I) For pharmaceuticals excluding generic drugs and OTC drugs,Common Technical Document (hereinafter referred to as “CTD”)attached to “Guideline on Preparing Data Attached to ApplicationForm for Approval Application of Manufacture or Import of a NewPharmaceutical” (PFSB/ELD Notification No. 899, dated June 21,2001) shall be used.Submission of the data equivalent to Module 2 of CTD (Summary ofthe Attached Data) is not required at the time of MF registration. Thetiming of submission shall be instructed by PMDA reviewers in chargeof the approval review for the drug (pharmaceutical product).Electronic forms for MF registration shall comply with “ElectronicSpecifications on Common Technical Documents” (PFSB/ELDNotification No. 0604001, dated June 4, 2003 issued by Director ofEvaluation and Licensing Division, Pharmaceutical and Food SafetyBureau).II) For drug substances used in generic drugs, “Approval Application ofPharmaceuticals” (PFSB Notification No. 0331015, dated March 31,2005) shall be followed.III) OTC drugs and those among “New excipients and pre-mix excipients with a different composition ratio from the existing ones” and“Containers/packaging materials”, the drug substance used only forOTC shall follow the pattern specified in “Application for Approval ofNon-Prescription Pharmaceuticals” (PFSB Notification No. 0827003,dated August 27, 2003).4. Issuance and Publication of MF Registration CertificateAfter the registration, a MF registration certificate in the Form No. 43 of the Regulations and a duplicate of the registration application form shall be issued to the MF registrant. The registration certificate does not include any confidential information.At a later date, the MF registration number, registration date, date of the change in registered items, name and address of the registrant, the name of registered item, and the registration category will be posted in the PMDA homepage.5. Information to be Disclosed to Applicants and Approval Holders of Drugs(Pharmaceutical Products)Attachment 4 (PDF)describes the examples of the MF registered information to be disclosed to the applicants or approval holders of drugs (pharmaceutical products).The information that should be disclosed shall also be written in the registration application form. Applicants of drugs (pharmaceutical products) who quote the information registered in MF can include it in the approval application form for the marketing authorization.6. Changes in MF Registered Items1) If changes have to be made to registered items, an application for change inthe registered items or minor change notification shall be submitted. When changing the registered items, it is necessary for the MF registrant to discuss in advance with the approval holders of drugs (pharmaceutical products) who utilize the MF.Changes only in the attached documents cannot be filed.If the changes in the items in MF will substantially alter the nature of drug substances, etc., please note that a new MF registration form, not a change of registration must be submitted. In this case, for pharmaceutical products that use the relevant MF, it is necessary to submit a partial change approval application so that the newly registered MF can be quoted for these products.However, in case changes in the items are significant and the changed items are not regarded as being the same, the approval holders of pharmaceutical products should submit new approval application. Therefore, for significant changes, please consult with PMDA in advance.2) Application for changes in MF registrationa) Documents to be submittedWhen applying for changes in MF registration, submit an original sheet (forthe attention of Chief Executive of PMDA) and a duplicate sheet (photocopy of the original sheet is not acceptable) of the application forchange in the registered items in the Format No. 46 of the Regulations(Attachment 2 (PDF)), FD, table to compare the new and old items, originalregistration certificate, data concerning the content of the changes inregistered items, and the return envelope for the MF registration certificate.When making changes to items registered in MF, MF registrant shall enterin the column for remarks of application form for change in the registereditems in MF, the commercial name, the approval number, the name andaddress of the marketing authorization holders (the name and location ofthe main business sites if the licensed marketing approval holders arecorporate entities) for all pharmaceutical products that quote the relevantMF, as well as whether a partial change approval application or minorchange notification was applied for each of the drugs (pharmaceuticalproducts). They can be listed in a separate sheet (see “Documents to beSubmitted”).b) In-advance Notification to Approval Applicants of Drugs (PharmaceuticalProducts)When making changes to the registered items, MF registrant shall notify inadvance the applicants or approval holders of the drugs (pharmaceuticalproducts) who quote the MF. The approval holders of the drug (pharmaceutical product) are required to submit partial change approvalapplication or minor change notification depending on the content of thechange.c) Partial Change Approval Application for Drug (Pharmaceutical Product)If MF under change is quoted in the already approved drugs (pharmaceutical products), the approval holders of all these drugs (pharmaceutical products) are required to submit partial change approvalapplications in accordance with the application for change in the registereditems.Review for a change to the registered items commence only after all thepartial change applications for the necessary relevant drugs have beensubmitted. When these partial changes are approved, the MF registrationcertificate for the change with revised registration date, etc. will be issuedby PMDA.When making changes to the items in the MF, but the existing items are stillused for the already approved drugs, it shall be required to specify theitems. For example, when adding a manufacturing method, the MFregistrant shall be requested to number both of the existing and addedmanufacturing methods so that it can be specified that which manufacturing method is used for pharmaceutical products approved byquoting the MF. In this case, marketing authorization holders of drugs(pharmaceutical products) shall be required to submit partial changeapproval applications for the products with added items, and minor changenotifications for pharmaceutical products with existing items.3) Minor change notificationa) Scope of minor change notificationIf there is a minor change in the MF registered items, a minor changenotification in Form No. 47 of the Regulations (Attachment 3 (PDF)) shallbe submitted. The scope of the minor changes is other than those described below (Article 80 of the Regulations).I) Changes in the manufacturing methods, etc. affecting the nature,characteristics, performance, and safety of the drug substance, etc.II) Deletion of the items listed in the specifications and test methods or changes in the specificationIII) Changes in the inactivation or removal method for pathogenic factorsIV) The changes, other than those described in I) to III), which may affect the quality, efficacy, or safetyThe registrants shall judge personally whether or not the changes in theregistered items affect the quality, etc. of the products referring to “Guideline for Descriptions on Application Forms for Marketing Approval ofDrugs, etc. under the Revised Pharmaceutical Affairs Law” (PFSB/ELDNotification No. 0210001, dated February 10, 2005).For minor changes in the registered items, the MF registrant shall submit aminor change notification (1 original sheet), table to compare the new andold items, and statement indicating that the adequate validation andchange control have been performed to PMDA within 30 days after thechanges are made (after shipping the drug substance, etc. manufacturedwith the changes) (see “Documents to be Submitted”).When submitting the minor change notification, the MF registrant shallnotify and provide necessary information to the applicants and approvalholders of the drugs (pharmaceutical products) that utilize the MF.b) Handling of drugs (pharmaceutical products) related to minor changes inMF registered itemsBasically, approval holders are not required to file partial change approvalapplications for the drugs (pharmaceutical products) related to minor changes in the MF registered items. However, the approval holders areadvised to obtain the relevant information from the MF registrant accordingto the contract between them, etc.4) Simple consultation for MF registration applicationPMDA provides “Simple consultation” for the matters related to the MF registration application described in PSFB/ELD Notification No. 0210004, dated February 10, 2005 and PMDA Notification No. 1101014, dated November 1, 2005.If the drug (pharmaceutical product) for which “consulted MF” is a new drug, the consultation classification is “writing applications for new drugs”. For a generic drug, the classification is “generic drugs”.Examples of the consultation are as follows:•Whether or not the change is regarded as a partial change to manufacturing methods, etc. in the approval application or MF registrationapplication:a) Validity of the evaluation protocol performed for the changeb) Appropriateness of the judgment that the change imposes no obviousimpact on the quality based on the result of the test conductedaccording to the protocolc) Other items that require consultation when changing the section ofmanufacturing methods•Whether a significant change in the MF registered items is subject to a partial change approval application or a new application.5) Handling of drug substances, etc. registered using “abbreviated descriptions”PFSB/ELD Notification No. 0310002 dated March 10, 2005 states that the description of the drug substance for which the MF registration application filed by using “abbreviated descriptions” by March 31, 2005, shall be revised to the description suitable under the Revised Pharmaceutical Affairs Law (so-called “detailed descriptions”, without omission) by March 31, 2010. This change shall be made as “Application for change in registered items”. In this case, the data described in 3. 3) b) which verifies the items of the detailed description shall also be submitted.If the change in the “abbreviated descriptions” is not minor, the registered items shall be changed by submitting application for change in registered items. In this case, please describe concretely the change in the remarks section of the application form or attach a table to compare the new and old contents.In both cases, the application shall be prepared to ensure the registered items comply with the Revised Pharmaceutical Affairs Law.7. Approval Application and Approval Review for Drugs (PharmaceuticalProducts) that quote MF1) Approval application for drugs (pharmaceutical products) that quote MFa) When the MF registration is completedIn the manufacturing methods section of approval application form, enterthe name of the drug substance, etc., its MF registration number, latestissue date of the registration certificate, and the number of times theregistration certificate was revised. Enter “1” for the first registration, andadd 1 each time the registration is revised. However, the number does notchange for the minor change notification. If more than one manufacturingmethod is registered in one MF, also specify which method is used.Example: “… using the drug substance A (MF Registration Number:XXXXXXXXXX (YYYY/MM/DD, Version Number X of MF Registration),Method B) …”When applying for the approval of a drug (pharmaceutical product), a copyof the MF registration certificate and a copy of the contract with the MFregistrant for utilization of the MF shall be regarded as a part of documentsto be attached to the approval application form, such as “Data onManufacturing Methods and Specifications/Test Methods” and “Data onStability”.b) When the MF registration is not yet completedEven if the MF registration is not yet completed, if the MF registrationapplication has been submitted, approval application for a drug(pharmaceutical product) can be submitted, using the system receiptnumber assigned at the time of application, and indicating that “MFregistration is in progress” in the application form.When the MF registration is complete (registration number is issued),contact the Office of Review Administration immediately and request toreplace the approval application. The approval review for the drug(pharmaceutical product) will actually commence only after the approvalapplication concerning the MF number is replaced.2) Approval review for drugs (pharmaceutical products) that quote MFIn the approval review process for a drug (pharmaceutical product), if an inquiry regarding the quoted MF registered items is necessary, PMDA directly contacts the MF registrant (if the MF registrant is a foreign manufacturer, the inquiry will be made through the in-country caretaker).As a result of the review, if there are any changes to the registered items, the MF registrant is required to immediately submit application for change in the registered items or minor change notification. In the case of change in the registered items, PMDA issues the registration certificate related to the change at the time the related drug is approved. However, application for change in the registered items cannot be filed for changes only in the already submitted attached document.Depending on the registered item to be changed and its content (for example, when the change may affect the nature of the drug substance, etc.), a new MF registration application, not an application for change in the registered items, may have to be submitted.8. Duties of In-Country Caretakers for Drug Substances, etc.MF registration application forms, notifications, and other related documents have to be written in Japanese (Article 283 of the Regulations), and thus, in-country caretakers for drug substances, etc. play important roles in the related administration procedures.In the process of approval review for a drug (pharmaceutical product), PMDA may inquire about the MF registered items. If the MF registrant is a foreign manufacturer, PMDA will make the inquiry through its in-country caretaker without directly contacting the manufacturer. Thus the in-country caretaker shall act as the contact for the inquiries and be engaged in the related administrative procedures and control after the registration.In order to ensure the smooth operation of these duties, the in-country caretaker should fully discuss with the MF registrant so as to decide on important items in advance.It is possible to change in-country caretakers. Please submit a minor change notification if there is a change in the in-country caretaker.9. Transfer of RegistrationWhen transferring MF registration to a third party, the procedure specified in Article83 of the Regulations shall be taken. In the transferring procedure, it is necessaryto submit a copy of the contract between the transferor and transferee that specifies that the verification data for the registered items and all the documents relating to the registration. Statement indicating that there are no changes in the manufacturing site and other manufacturing technology, etc. is also required. Notifications etc. Related to MF System•“Guideline for Descriptions on Application Forms for Marketing Approval of Drugs, etc. under the Revised Pharmaceutical Affairs Law” (PFSB/ELD Notification No.0210001, issued by Director of Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, dated February 10, 2005)•“Guideline on Utilization of Master File for Drug Substances, etc.” (PFSB/ELD Notification No. 0210004, issued by Director of Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, dated February 10, 2005)•“Q&A on the Master File (MF) System, Part 1” (Administrative Notice issued by Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, dated July 28, 2005)•“Q&A on the Master File (MF) System, Part 2” (Administrative Notice issued by Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, dated December 20, 2005)Documents to be Submitted1) Application for Registration of MF for Drug Substance, etc. (RegistrationApplication) …Article 72 of the Enforcement Regulations of the Pharmaceutical Affairs Law• Application Form for Registration of Master File for Drug Substances, etc. (total of 2 sheets consisting of original and duplicate sheets: photocopy of the original sheet is not acceptable for the duplicate) (Attachment 1 (PDF))•FD or CD-R (containing the data prepared according to the FD application system, the same hereinafter).• Attached documents•Drugs (excluding generic drugs and OTC drugs): see PFSB Notification No.899 dated June 21, 2001•Generic drugs: see PFSB Notification No. 0331015 dated March 31, 2005• Return envelope for the registration certificate and the duplicate sheet of the application form2) Application for Changes in the Registered MF for Drug Substance, etc.(Application for changes in the registered items) …Article 79 of the Enforcement Regulations of the Pharmaceutical Affairs Law• Application Form for Change in Registered Master File for Drug Substance, etc.(total of 2 sheets consisting of original and duplicate sheets: photocopy of the original sheet is not acceptable for the duplicate) (Attachment 2 (PDF))•FD or CD-R•Attached documents (also required when changing from “abbreviated descriptions” to “detailed descriptions”)•Drugs (excluding generic drugs and OTC): see PFSB Notification No. 899, dated June 21, 2001•Generic drugs: see PFSB Notification No. 0331015, dated March 31, 2005• Return envelope for the registration certificate and the duplicate sheet of the registration application form•Original registration certificate•Others (comparison table for the old and new items, etc.)* Registration number of a MF registration certificate does not change as a result of the changes in the registered items. However, a new registration certificate will be issued due to the registration date change. Thus the registration certificate before the change (original) should be submitted.** Application for change in the registered items cannot be filed for the changes only in the already submitted attached document.3) Minor Change Notification for MF for Drug Substances, etc. (Minor changesin the registered items) …Article 81 of the Enforcement Regulations of the Pharmaceutical Affairs Law• Minor Change Notification for Master File for Drug Substances, etc. (1 original sheet) (Attachment 3 (PDF))•FD or CD-R•Attached document (if necessary)•Statement (to indicate adequate validation and change control have been performed)•Others (comparison table for the new and old items, etc.)* When a minor change notification is filed, the registration number of the MF registration certificate and the issuance date remain the same (a new registration certificate will not be issued).** Notification cannot be filed for the minor changes only in the already submitted attached document. Notification cannot be filed for matters other than those required under the instruction of PMDA while registration application or application for changes is in process.。

GUIDELINE FOR DRUG MASTER FILESCenter for Drug Evaluation and ResearchFood and Drug AdministrationDepartment of Health and Human ServicesSeptember 1989For further information regarding the guideline please contact:Food and Drug AdministrationCenter for Drug Evaluation and ResearchOffice of Drug Evaluation I (HFD-100)5600 Fishers LaneRockville, Maryland 20857TABLE OF CONTENTSI. INTRODUCTIONII. DEFINITIONSIII. TYPES OF DRUG MASTER FILESIV. SUBMISSIONS TO DRUG MASTER FILESA. Transmittal Letters1. Original Submissions2. AmendmentsB. Administrative Information1. Original Submissions2. AmendmentsC. Drug Master File Contents1. Types of Drug Master Filesa. Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnelb. Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Productc. Type III: Packaging Materiald. Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in TheirPreparatione. Type V: FDA Accepted Reference Information2. General Information and SuggestionsA. Environmental AssessmentB. StabilityC. Format, Assembly, and DeliveryV. AUTHORIZATION TO REFER TO A DRUG MASTER FILEA. Letter of Authorization to FDAB. Copy to Applicant, Sponsor, or Other HolderVI. PROCESSING AND REVIEWING POLICIESA. Policies Related to Processing Drug Master FilesB. Drug Master File ReviewVII. HOLDER OBLIGATIONSA. Notice Required for Changes to a Drug Master FileB. Listing of Persons Authorized To Refer to a Drug Master FileC. Annual UpdateD. Appointment of an AgentE. Transfer of OwnershipIX. CLOSURE OF A DRUG MASTER FILEGUIDELINE FOR DRUG MASTERFILESI. INTRODUCTIONA 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 DrugApplication (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. DEFINITIONSFor 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 FILESThere 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 ProductType III Packaging MaterialType IV Excipient, Colorant, Flavor, Essence, or Material Used in Their PreparationType V FDA Accepted Reference InformationEach 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 FILESEach 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 LettersThe following should be included:IV. A.1. Original Submissionsa. 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. Amendmentsa. 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 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 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. 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 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.g. Particular items within the IND, NDA, ANDA, DMF, and Export Application 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, and PersonnelA 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 ProductA 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 PreparationSummarize 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 ProductManufacturing 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 ProductsGuideline for Submitting Samples and Analytical Data for Methods 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 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 PreparationEach 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 InformationFDA 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 SuggestionsIV. C.2.a. Environmental AssessmentType 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. StabilityStability 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 DeliveryIV. 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 FDAIV.D.5.a.Drug Master File submissions and correspondence should be addressed as follows:Drug Master File StaffFood and Drug Administration5901-B Ammendale Rd.Beltsville, MD 20705-1266IV.D.5.b. Delivery charges to the above address must be prepaid.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 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. The date.2. Name of DMF holder.3. DMF number.4. Name of person(s) authorized to incorporate information in the DMF by reference.5. Specific product(s) covered by the DMF.6. Submission date(s) of 5, above.7. Section numbers and/or page numbers to be referenced.8. Statement of commitment that the DMF is current and that the DMF holder willcomply 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 HolderThe 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. PROCESSING AND REVIEWING POLICIESVI. A. Policies Related to Processing Drug Master FilesVI. 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.An original DMF submission will be examined on receipt to determine whether it meets minimum requirements for format and content. If the submission is administratively acceptable, FDA will acknowledge its receipt and assign it a DMF number.If the submission is administratively incomplete or inadequate, it will be returned to the submitter with a letter of explanation from the Drug Master File Staff, and it will not be assigned a DMF number.VI. B. Drug Master File ReviewA 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. HOLDER OBLIGATIONSAny change or addition, including a change in authorization related to specific customers, should be submitted in duplicate and adequately cross referenced to previous submission(s). The reference should include the date(s), volume(s), section(s), and/or page number(s) affected.VII. A. Notice Required for Changes to a Drug Master FileA 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 thesponsor/applicant to supplement or amend any affected application(s) as needed.VII. B. Listing of Persons Authorized To Refer to a Drug Master FileVII. 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.Any person whose authorization has been withdrawn during the previous year should be identified under a suitable caption.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 UpdateThe 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 AgentWhen 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 OwnershipTo transfer ownership of a DMF to another party, the holder should so notify FDA and authorized persons in writing. The letter should include the following:1. Name of transferee2. Address of transferee3. Name of responsible official of transferee4. Effective date of transfer5. Signature of the transferring official6. Typewritten name and title of the transferring official.The new holder should submit a letter of acceptance of the transfer and an update of the information contained in the DMF, where appropriate. Any change relating to the new ownership (e.g., plant location and methods) should be included.VIII. MAJOR REORGANIZATIONOF A DRUG MASTER FILEA holder who plans a major reorganization of a DMF is encouraged to submit a detailed plan of the proposed changes and request its review by the Drug Master File Staff. The staff should be given sufficient time to comment and provide suggestions before a major reorganization is undertaken.IX. CLOSURE OF A DRUG MASTER FILEA 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.The Agency may close a DMF that does not contain an annual update of persons authorized to incorporate information in the DMF by reference and a list of changes made since the previous annual report. The holder will be notified of FDA's intent to close the DMF.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)Center for Drug Evaluation and ResearchFood and Drug Administration5600 Fishers LaneRockville, MD 20857Copies of the Code of Federal Regulations (CFR) may be purchased from the following:Superintendent of DocumentsU.S. Government Printing OfficeWashington, D.C. 20402Back to Top Guidance PageDate updated: March 11, 2005Drug Master FilesImportant Guidance Information See belowIMPORTANT ADDRESS INFORMATIONPlease note that the current address for the Central Document Room for filing original DMFs and subsequent DMF documents is now:Food and Drug AdministrationCenter for Drug Evaluation and ResearchCentral Document Room5901-B Ammendale RoadBeltsville MD 20705-1266Submissions mailed to the old address will also be forwarded to the new address for a period of time. If you have previously submitted an original DMF or subsequent DMF document to the old address please DO NOT resubmit it to the new address.This site contains lists of Drug Master Files (DMFs) as well as information concerning submission of DMFs. See below for information regarding the current DMF Guideline.The list of DMFs is current as of September 30, 2005, through DMF 18781 Changes to the DMF activity status, DMF type, holder name, and subjects made since the last update of June 30, 2005 are included. The lists are updated quarterly.For people who downloaded the previous list (through DMF 18437, June 30, 2005) and do not wish to download the entire updated lists the following lists are available:1. New DMFs since the last list.2. A list of changes in DMF activity status, DMF type, holder name, and subject.The lists are available in Microsoft Excel and in ASCII (Tab-delimited). Please note that only ACTIVE DMFs have been sorted into different types.∙All DMFs∙Active DMFs∙Active Type II DMFs∙Active Type III DMFs∙Active Type IV DMFs∙Active Type V DMFs∙New DMFs since the last list∙ChangesThe types of DMFs are:∙Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable)∙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 InformationAll files zipped (2.7 MB) (updated 11/15/2005)“A” = Active“I” = Inactive“N” = Not an assigned number“P” = DMF Pending Filing Rev iewINACTIVATION AND RETIREMENT OF DMFsThe criteria for judging a DMF to be inactive include:1. The holder requested that the DMF be retired, closed, inactivated., or withdrawn2. DMFs filed before September 30, 2002 which have had no activity since they were filed or havehad no activity since September 30, 2002.Note that the status “Inactive” in the list does not distinguish between these two categories.According to the regulations regarding DMFs (21 CFR 314.420(c)),:“Any addition, change, or deletion of information in a drug master file (except the list required under paragraph (d) of this section) is required to be submitted in two copies and to describe by name, reference number, volume, and page number the information affected in the drug master file.”As discussed in the "Guideline for Drug Master Files" (September 1989), DMF holders should update their DMFs annually.FDA is in the process of sending “Overdue Notification Letters” (ONLs) to DMF holders that have not been updated in three years. If a DMF holder does not respond to this letter within 90 days, the DMF is retired and is unavailable for review.Some DMFs may be listed as inactive which are, in fact, still active. Every effort will be made to correct any errors.Please address ALL comments or questions regarding DMFs to dmfquestion@. All inquiries MUST have an entry in the "Subject" field of the e-mail. Due to concerns about viruses and the amount of "spam" received by this account, e-mails with subject fields containing meaningless text strings, only questions marks, or left blank will not be opened.Other inquiries unrelated to DMFs should go to druginfo@.GUIDANCESDMF Guideline The version posted on the web is the current version. No revision is planned for the immediate future. Please address question regarding the DMF Guideline to dmfquestion@.Type I DMFsType I DMFs are no longer accepted per a Final Rule published January 12, 2000 (65 FR 1776.) See Type V DMFs below.Holders of Type II, III, and IV DMFs should not place information regarding facilities, personnel or operating procedures in these DMFs. Only the addresses of the DMF holder and manufacturing site and contact personnel should be submitted.Type II DMFs。

DMF（Drug Master File,药物主文件）根据美国的联邦管理法规定，药品进入美国须向美国FDA申请注册并递交有关文件，化学原料药按要求提交一份药物管理档案(DMF)DMF是一份文件，是由生产商提供的某药品生产全过程的详细资料，便于FDA对该厂产品有个全面了解，内容包括：生产、加工、包装和贮存某一药物时所用的具体厂房设施和监控的资料，以确定药品的生产是通过GMP得到保证的DMF文件共有五种类型：I型，生产地点和厂房设施、人员；II型，中间体、原料药和药品；III型，包装物料；IV型，辅料、着色剂、香料、香精及其它添加剂；V型，非临床数据资料和临床数据资料国内原料药生产企业向FDA申报的DMF文件属于II型，申请文件的主要内容有：递交申请书、相关行政管理信息、企业的承诺声明、申请产品的物理和化学性质描述、产品生产方法详述、产品质量控制与生产过程控制、产品稳定性实验、包装和标签、标准操作规程、原材料及成品的贮存与管理、文件管理、验证、批号管理制度、退货及处理上报的DMF文件原件在FDA收到后经初审，如符合有关规定的基本要求，FDA就会发通知函并颁发给一个DMF登记号原料药申请FDA批准的基本程序：1．进行国际市场调研，摸清美国市场目前的销售情况，对市场发展趋势与走向做出正确的预测、分析和判断，选择好申请FDA批准的品种2．选择申请代理人和代理经销商，并签订委托协议书、签署委托书3．编写申请文件，原料药为DMF文件，由代理人完成申请文件终稿的编写并向FDA递交，取得DMF文件登记号4．FDA收到申请文件后，经初审合格后发通知函给申请人，并发给一个登记号，说明DMF文件持有人的责任和义务5．工厂按美国cGMP的要求进行厂房、设施设备的改造和并完善生产质量管理的各项软件和相关人员的强化培训6．应美国制剂生产厂家(即该原料药品的终端用户)的申请, FDA派官员到生产厂家按照FDA颁布的生产现场检查指南并对照已上报审核的DMF文件进行检查，FDA 官员在生产现场的基础上出具书面意见给生产厂家并向FDA报告检查结果7．FDA审核批准后将审核结果通知生产厂家并输入美国海关的管理系统，该原料药品即获准直接进入美国市场8．生产厂家每年向FDA递交一份DMF修改材料，一般情况下, 每2-3年可能要接受一次复查关于FDA批准按照美国联邦法规（Code of Federal Regulation）第210及第211条中的有关规定,任何进入美国市场的药品(包括原料药品)都需要首先获得FDA的批准, 而且所有有关药物的生产加工、包装均应严格符合美国cGMP的要求原料药通过美国FDA认证的步骤与途径：对于原料药来说，通过FDA批准主要有两个阶段，一是DMF文件的登记，要求递交的DMF文件对所申请的药品的生产和质量管理的全过程以及药品质量本身做一个详尽的描述FDA要为此文件保密，该文件是由FDA的药物评价及研究中心（Center for Drug Evaluation and Research, CDER）来审核。

1．介绍1) 名称：Drug Master File（药物主控档案）2）DMF的意义：美国的原料药管理同中国不同，不进行文号管理。

原料药厂家只需提供DMF(drug master file --生产及控制方面的资料)给FDA备案，当药品生产商采用该原料药生产制剂产品时再进行审查。

美国的ＤＭＦ文件库是全世界制剂厂家广泛参照的一个供应商资源库，所以几乎所有想让产品推向国际的原料药厂都进行DMF备案。

原料药若以合法的身份进入美国市场，必须获得FDA认可。

一般首先取得DMF登记号，这样，在制剂生产商向FDA提交注册申请资料时，原料药部分的资料可直接引用该原料药的DMF文件登记号，并且在现场检查时进行检查。

在FDA批准制剂申请之前，原料药生产企业必须通过FDA官员的现场检查。

现场检查的目的是确认原料药生产现场是否符合ICH Q7 GMP(同时也必须符合FDA技术上的一些特殊要求)；确认原料药生产现场是否与提交的DMF文件内容一致。

3）法规依据：FDA并不强制要求企业递交DMF文件。

相应内容也可以在制剂申请时进行提交。

2．程序1）按要求编写DMF文件。

2）递交DMF文件。

3）获得备案号。

3．原料药DMF的有关问题Q1 DMF文件的作用?A1提供的资料可用于支持新药申请（NDA）、简略新药申请（ANDA）等。

新药申请，适用于在美国首次上市的药品；简略新药申请，适用于仿制药的申请。

仿制药的简略新药申请大体与新药申请一样，但不必提供药理、毒理、临床等资料，重点是保证生物等效性。

Q2 DMF提交获得备案号如何维护？A2 DMF不是编好了一个版本，获得备案号后就一劳永逸了，它需要按客户的要求以及工艺和设施变更的情况不断地修改补充完善，重大的变更必须通知客户。

美国FDA要求，即使没有变更，每年也需要递交一份没有变更的声明。

4．我们提供的服务指导厂家准备DMF文件所要求的中文资料；翻译制作DMF英文文件；DMF文件的提交和与FDA的技术联络，回答FDA的有关问题；指导厂家准备生产现场，包括硬件和软件；提供现场检查迎检培训提供现场翻译对厂家进行ICH Q7 以及cGMP特定要求的专项培训。