DMF指南.doc

GUIDELINE FOR DRUG MASTER FILESDMF文件指南GUIDELINE FOR DRUG MASTER FILES药物主文件（DMF）指南Center for Drug Evaluation and Research药物评估及研究中心Food and Drug Administration美国食品药品管理局Department of Health and Human Services卫生福利部September 19891989年9月For further information regarding the guideline please contact:有关详细资料请联系：Food and Drug Administration美国食品药品管理局Center for Drug Evaluation and Research药物评估及研究中心Office of Drug Evaluation I (HFD-100)药物评审委员会I （HFD-100）5600 Fishers LaneRockville, Maryland 20857(301-827-7310 )Note: This Guideline was prepared by Dr. Arthur Shaw, Food and Drug Administration, for a Course offered by the Center for Professional Advancement in March of 1994. There have been no changes in the text from the printed version of the Guideline. However the text has been reformatted to reduce the number of pages. The Table of Contents reflects the new pagination. The old pagination is noted in the Guideline.备注：该指南印刷版本由专业促进中心于1994年3月提供方案，由食品药品管理局阿瑟肖博士起草完成。该指南在内容上没有对原版做任何变动，只是对文本进行重新排版，减少了文本的页数。这从目录上可以反映出来，本文对原印刷版本的页码进行了加注。TABLE OF CONTENTS目 录I. INTRODUCTION /介绍II. DEFINITIONS /定义III. TYPES OF DRUG MASTER FILES /药物主文件类型IV. SUBMISSIONS TO DRUG MASTER FILES /申报DMF文件A. Transmittal Letters /申报信Original Submissions /原件Amendments /修订B. Administrative Information /行政管理信息Original Submissions /原件Amendments /修订C. Drug Master File Contents/DMF内容1. Types of Drug Master Files /DMF类型a. Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel 第一类：生产地点，厂房设施，操作程序以及人员b.Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product 第二类：原料药，原料药中间体，及原料药/中间体制备过程中采用的材料，或药品c. Type III: Packaging Material 第三类：包装材料d. Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation 第四类：赋形剂，着色剂，调味剂，香精或制备过程中采用的材料。e. Type V: FDA Accepted Reference Information 第五类：FDA 公认的参考信息2. General Information and Suggestions/通用信息和建议a. Environmental Assessment /环境评估b. Stability/稳定性D. Format, Assembly, and Delivery/规格形式，装配和输送V. AUTHORIZATION TO REFER TO A DRUG MASTER FILE /DMF参考授权A. Letter of Authorization to FDA /致FDA的授权信B. Copy to Applicant, Sponsor, or Other Holder /致申请方，赞助商或其他持有者的副本VI. PROCESSING AND REVIEWING POLICIES/过程与评审方针A. Policies Related to Processing Drug Master Files /DMF文件相关方针B. Drug Master File Review/DMF评审 VII. HOLDER OBLIGATIONS/DMF持有者义务A. Notice Required for Changes to a Drug Master File DMF需要进行变更时予以通知B. Listing of Persons Authorized To Refer to a Drug Master File 列出授权参考DMF文件的人员C. Annual Update/年度更新D. Appointment of an Agent/指定代理商E. Transfer of Ownership/所有权转换IX. CLOSURE OF A DRUG MASTER FILE/DMF/文件的密封I. INTRODUCTION/介绍A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs. The submission of a DMF is not required by law or FDA regulation. A DMF is submitted solely at the discretion of the holder. The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), another DMF, an Export Application, or amendments and supplements to any of these.DMF文件为向FDA申报的保密资料，用于提供生产、加工、包装和贮存一种或多种人用药所采用的厂房设施、生产过程及各种物料的详细信息。DMF文件只是持有人为谨慎起见申报给FDA的，而非法律和FDA法规的硬性要求。DMF用来对临床研究申请（IND），新药申请（NDA），仿制药简化申请（ANDA），另一DMF文件，出口申请或对以上的修订和补充提供支持信息。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.DMF文件不能替代IND、NDA、ANDA或出口申请，不存在对DMF批准与否的问题。只是在审查IND、NDA、ANDA或出口申请时，才将DMF的技术内容结合起来加以审查。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. 本指南非为强制性要求（美国联邦法规21卷第10.90（b）部分），但确实提供了达到法规要求的可接受方法。申请人可以采用各种不同的方法，但建议在申报DMF文件前与FDA评审员就重大的改动进行讨论，避免由于编写的DMF资料不符合FDA要求而浪费时间和精力。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 DMFs, the information needed in each type, the format of submissions to a DMF, the administrative procedures governing review of DMFs, and the obligations of the DMF holder.美国联邦法规21卷第314.420部分对DMF进行了规定。本指南为DMF持有者提供FDA可以接受的准备及申报DMF文件的程序，内容涉及DMF文件的分类、每种类型需要的信息、DMF文件申报的格式、控制DMF文件审核的管理程序以及DMF持有者的义务和职责。DMFs 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.通常DMF文件被一方而不是持有者用作参考资料。如果要引用自己的资料，申请方应直接引用自己在IND, NDA或ANDA中包含的信息，而不是创建新的DMF文件。II. DEFINITIONS/定义For the purposes of this guideline, the following definitions apply: 本指南采用以下定义：II.1. Agency means the Food and Drug Administration. 机构Agency指食品和药品管理局。II.2 Agent or representative means any person who is appointed by a DMF holder to serve as the contact for the holder. 代理商或代理人指DMF持有者指定的联系人。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). 申请方指申报申请或简化申请及其修订或补充，以获得FDA对一种新药或者抗生素类药品批准的人员，也指拥有已获准申请（美国联邦法规21卷）的任一人员。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). 药品指制剂成品，如片剂、胶囊或溶液剂等，一般含有一种原料药，但不一定只含有一种原料药，并与一种或多种其他成分结合在一起（美国联邦法规21卷第314.3(b)部分）。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). 原料药指某种活性成分，在疾病的诊断、治疗、缓解或防治中提供药理活性或其他直接效果，或者对人体的结构或某种功能起作用，但不包括这种成分合成过程中采用的中间体（美国联邦法规21卷第314.3(b)部分）。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. 出口申请指在联邦食品、药品和化妆品法案第802章的规定下申报的申请，请求出口未被批准在美国销售的药品。II.7. Holder means a person who owns a DMF. 持有者指拥有DMF的个体。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 persons submission. 授权信指经持有者或其指定代理的书面声明，允许FDA查阅DMF的资料，作为对另一人申报文件的支持。II.9. Person includes individual, partnership, corporation, and association. (Section 201(e) of the Federal Food, Drug, and Cosmetic Act.) 个体包括个人，合作对象，企业和协会（联邦食品、药品和化妆品法案第201章第e部分）。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). 主办者指负责并发起新药临床研究的个体。主办者可以是一个个人或药厂，政府机构，研究所，私人组织或其它组织（美国联邦法规21卷第312.3(b)部分）。III.TYPES OF DRUG MASTER FILES DMF文件的分类There are five types of DMFs:DMF文件分五种类型：Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel 第一类：生产地点，厂房设施，操作规程及人员Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product 第二类：原料药，原料药中间体，及原料药/中间体制备过程中采用的材料，或药品Type III: Packaging Material第三类：包装材料Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation 第四类：赋形剂，着色剂，调味剂，香精或制备过程中采用的其它材料。Type V: FDA Accepted Reference Information 第五类：FDA 承认的参考资料*Original Page 6*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).每一DMF只应包含一类资料及其全部的支持性数据。每种类型需要的信息种类详细说明见本指南第IV章第C部分。DMF文件的支持资料和数据可以和任何其它DMF文件互相引用（见第V章）。IV. SUBMISSIONS TO DRUG MASTER FILES DMF文件申报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. 每一申报的DMF文件应包括一份申报信，与申报有关的行政管理信息以及本章提及的DMF应包含的具体信息。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.DMF必须用英文书写。如果申报的文件中含其它语言书写的资料，则必须包括一份准确的已证明的英文翻译件。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.DMF的每份复印件的每页均应注明日期和顺序编号。每次申报都应附有一份更新后的现在使用目录。IV. A. Transmittal Letters 申报信The following should be included:应包括以下内容：IV. A.1. Original Submissions 1MDF原件a. Identification of submission: Original, the type of DMF as classified in Section III, and its subject. 申报的特定标志：原件，DMF类型（按照第III章进行分类）和题目。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. 如果已知DMF用来证实申请书，就要列出特定标志，包括主办者、申请人或持有者的姓名和地址、以及所有相关文件的编号。c. Signature of the holder or the authorized representative. 持有者或授权代表签名d. Typewritten name and title of the signer. 签名人姓名和职务（打印）IV. A. 2. Amendments 2DMF修订件a. Identification of submission: Amendment, the DMF number, type of DMF, and the subject of the amendment. 申报的特定标志：修订件，DMF编号，DMF类型及修订的题目。b. A description of the purpose of submission, e.g., update, revised formula, or revised process. 本次申报目的说明：如，更新，修改配方或工艺过程c. Signature of the holder or the authorized representative. 持有者或授权代表签名d. Typewritten name and title of the signer. 签名人姓名和职务（打印）IV. B. Administrative Information 行政管理情况Administrative information should include the following: 行政管理情况应包括以下内容：IV. B.1. Original Submissions 1DMF原件a.Names and addresses of the following: 下列姓名和地址：(1) DMF holder./DMF持有者(2) Corporate headquarters./企业总部(3) Manufacturing/processing facility./生产/加工工厂(4) Contact for FDA correspondence./同FDA的联系方式(5) Agent(s), if any./代理，如果有的话b. The specific responsibilities of each person listed in any of the categories in Section a. 上述条目列出的每一个体的具体职责c. Statement of commitment. /承诺声明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.声明并附持有者签名，证明该DMF是最新版本，并且DMF持有者保证遵守声明所述内容。IV. B2. Amendments 2DMF修订件a. Name of DMF holder. / DMF持有者b. DMF number./DMF编号c. Name and address for correspondence./通信名称和地址d. Affected section and/or page numbers of the DMF./DMF文件中与修订有关的章节和/或页码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. 依靠DMF修订内容支持的有关IND、NDA、ANDA、DMF或出口申请的所有个体的名称和地址。f. The number of each IND, NDA, ANDA, DMF, and Export Application that relies on the subject of the amendment for support, if known. 需要DMF修订内容支持的有关IND、NDA、ANDA、DMF或出口申请的编号（如果已知）。g. Particular items within the IND, NDA, ANDA, DMF, and Export Application that are affected, if known. 受到修订影响的IND、NDA、ANDA、DMF或出口申请的详细条款（如果已知）。IV. C. Drug Master File Contents DMF内容IV. C.1. Types of Drug Master Files/DMF文件类型IV. C.1.a. Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel 第一类：生产地点，厂房设施，操作规程和人员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.第一类DMF建议用于美国国外的个体，帮助FDA对其生产厂房设施进行现场检查。DMF应说明生产地点、设备生产能力和生产布局。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. 第一类DMF一般不用来说明美国国内的厂房设施，除非在特殊情况下，比如某一个体没有注册而且没有接受常规检查。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.生产地点说明应该包含面积、实际地址以及表明该地点与最近城市之间关系的地图。采用空中鸟瞰图或生产地点的图表有一定帮助。提供一张主要生产加工区的图表有助于了解生产布局。主要设备应说明其生产能力、应用范围和位置。除非该设备比较新颖或者独特，否则一般不需要对其构造和模型进行说明。准备一张生产地点和企业总部的主要组织结构图也很有帮助，图中应突出关键生产、质量控制和质量保证的地位。IV. C.1.b.Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product 第二类：原料药，原料药中间体，及原料药/中间体制备过程中采用的材料，或药品。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.第二类一般局限于一种药物中间体、原料药、药品或原料药/中间体制备过程中采用的材料。IV. C.1.b.(1) Drug Substance Intermediates, Drug Substances, and Material Used in Their Preparation/原料药中间体，原料药和原料药/中间体制备过程中采用的材料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:概述药物中间体或原料药生产和控制过程中的所有重要步骤。第二类DMF中针对原料药和中间体应包含的内容详见以下指导方针：Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances.用于原料药生产申请的支持文件申报指南Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application. 申请中的化学、生产和控制部分的格式及内容指南IV. C.1.b.(2) Drug Product/药品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:一般来说IND，NDA，ANDA或出口申请中应对制剂成品的生产过程和控制进行说明。如果不能在上述申请中进行说明，则应在DMF中进行说明。如果第二类DMF的申报用于某种药品，那么申请人/主办者应遵守以下指导方针：Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application. 申请中的化学、生产和控制部分的格式及内容指南Guideline for Submitting Documentation for the Manufacture of and Controls for Drug Products 药品生产和控制文件申报指南Guideline for Submitting Samples and Analytical Data for Methods Validation方法验证样品和分析数据申报指南IV. C.1.c.Type III: Packaging Material/包装材料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.每种包装材料都应根据其预期用途、组分、成分和发放控制进行鉴别。还应说明制备包装材料所用组分的供应商或生产单位的名称及其验收标准。说明包装材料能否接受用于预期用途的支持性数据也应按照“人用药和生物制剂文件申报指南”的要求进行申报。IV. C.1.d.Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation/赋形剂，着色剂，调味剂，香精或制备过程中采用的其它材料Each additive should be identified and characterized by its method of manufacture, release specifications, and testing methods.每种添加剂的生产方法、放行标准和测试方法应进行鉴别和定性。Toxicological data on these materials would be included under this type of DMF, if not otherwise available by cross reference to another document.此类DMF包括这些材料的毒理学数据，或者通过交叉引用另一个文件得到。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. 通常采用法典和FDA有关色素添加剂（美国联邦法规21卷第70至80部分），直接食品添加剂（美国联邦法规21卷第170至173部分）、非直接食品添加剂（美国联邦法规21卷第174至178部分）以及食品（美国联邦法规21卷第181至186部分）的资料作为放行检验、规格和安全性的资料来源。第二类DMF指南的内容可能对准备第四类DMF文件有帮助。DMF还应包括其它不能交叉引用于另一文件的支持性资料和数据。IV. C.1.e.Type V:FDA Accepted Reference Information/FDA接受的参考资料FDA discourages the use of Type V DMFs for miscellaneous information, duplica