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下面DMF文件相关内容
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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
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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
+ C d) H( Z1 N. {6 X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 ) r6 C9 }, V$ K
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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3 F) l- o* L0 D, _, B
原料药申请FDA批准的基本程序： v( l1 ]9 B# l# F) h8 @1 X) r! t
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7 i" s% a/ i+ f& C
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
5 `; a0 \( ]; P( ]) D1 o3．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9 u9 S( M `2 `8 c7 l3 x1 A7 h
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
2 g, g5 A; e2 }3 ~/ @- K$ f5．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; m$ x4 S: M3 Y$ j
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
4 h6 L3 ]% h$ L3 Z# d( X7．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. Y- @" M' D/ @* _& k! H8 `4 n
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
9 P+ ~! {. p) X: } C' ]关于FDA批准# ^; ^+ f- {2 l" H
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
/ w, h0 e L) A: ~ 原料药通过美国FDA认证的步骤与途径：
8 d4 \. v2 b9 h4 e6 | Z 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。二是当DMF文件的登记已经完成，而且在美国的原料药品终端用户提出了申请以后，FDA官员对原料药物的生产厂家进行GMP符合性现场检查，通过对药品生产全过程的生产管理和质量管理状况的全面考察，做出该原料药生产企业的生产和质量管理能否确保所生产药品的质量的判断FDA在现场检查的基础上做出是否批准该原料药品在美国市场上市的决定。6 ?/ A; L) P, a7 p
为此, FDA公布了许多指导文件，其中主要有《药物管理档案指南》、《申请药物生产的文件指南》和《原料药物生产检查指南》等，用于指导生产厂家进行药物上市申请文件和准备接受FDA官员的现场检查
2 g/ T6 o$ |* q9 a: `若要通过FDA的检查，使自己的产品进入美国市场，必须经过两个大的步骤：即DMF的递交和FDA的现场检查两个阶段在此之前，还需做一些准备阶段的工作
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, ]* m6 |0 s$ _8 q# R6 H! ` 首先要对美国市场深入了解，分析，找准自己需要申请的品种，品种的选择非常重要，如果选对了品种（美国市场急切需要或美国客商非常感兴趣的品种）那么FDA的检查就不会拖很长的时间，而且比较容易通过检查，如果品种选得不好，可能会拖上7、8年FDA还不会来检查，更不要说通过了。! ] f4 D5 ^& t# ~0 h
其次，选择一个好的美国代理商，这样与FDA的沟通会非常及时、有效，而且好的代理商会推动FDA的检查工作，使检查工作日程加快。# N4 a3 D8 u+ r N" E" r0 [/ U) ?
2、DMF文件的编写和提交4 l- S0 e5 P* |$ m7 ^! I) y8 C
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DMF（Drug Master File,药物主文件）分为5类类型，其中第I型已于2000年7月12日取消一般原料药厂商需提供II型DMF，主要包括原料药、原料药中间体以及用于制剂或原材料的生产过程、操作方法等有关生产和管理的所有重要方法
! _: u$ \. p! e% A 尽管在FDA的某些指南（比如Guideline for Drug Master File）中可以找到相应的DMF中需提交的内容，这里还是建议在编写DMF时应聘请一些资深专家给予指导，以提高一次成功率因为DMF的书写有一定模式，一旦所提交的DMF模式不符或不完善，FDA会不停地要求你补充材料，直到满意为止。3 ~# i0 p* Z! Z; V+ x( F
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DMF编写应是实事求是，因为FDA现场检查会以企业提交的DMF作为检查的依据如果只是为了文件做得漂亮，而不顾实际情况，一旦FDA现场检查，企业就会遇到很多问题难以解决，最终导致现场检查不能通过。# ~* v! O/ D- P
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DMF必须用英文书写，如果呈报文件是以其它语言书写的，就必须附有正确的英文译文，连同授权信、副本一同交给美国代理商，由代理商交给FDA。# b' }7 C+ d9 b. {( W! l8 [7 f
" D6 ?, F+ H: }+ I) H* OFDA审阅DMF之后，若认为符合模式要求，则会给该DMF一个注册号，同时将该注册号通知美国代理商表明FDA已经收到了符合模式要求的DMF。) \" g% N3 f$ ^' {
3、FDA的现场检查
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FDA并不是接到DMF后就会准备对企业进行检查，只有当FDA接到新药申请（NDA）或简略新药申请（ANDA），涉及到企业的产品时，他才会指定人员仔细审查你的DMF内容，并作出检查计划一般说来，经过仔细审查DMF后，检查人员都会发现一些问题他们会向企业发信询问，要求企业明确回答此时，离FDA的现场检查已经为期不远了5 b+ G1 m2 g+ w3 U0 B
企业对FDA的问题做出明确回答以后，FDA会安排工作组排列检查日程检查小组和他们要检查的企业是随机安排的在确定检查日期之后，对于美国以外的生产企业，FDA会提前1个月通知企业内容包括检查员的人数，姓名，检查的时间和检查的品种，同时希望企业在他们检查时进行正常的生产作业，并保证关键人员在场（企业可以推迟检查日期，但不要拖太长时间，否则FDA会以为你根本没有准备），不能处在大修期间( V H `+ j8 i% F6 P( \
接到通知后，企业应全力以赴搞好现场管理工作，并且对自己的软件进行最后的查漏补缺同时，可以联系国外代理商，聘请国外的一些顾问公司进行预检查FDA是根据GMP并结合企业提交的DMF进行现场检查的，因此企业在此期间应严格遵守DMF和SOP
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5 i6 s) c! e/ Y2 u( A0 YFDA现场检查一般是非无菌原料药两个人检查34天，无菌原料药23个人检查57天现场检查有两种形式，一是从头开始，按操作顺序的先后进行检查，这种按产品生产流程的检查一般适用于一种产品另一种产品是按系统检查，适用于多个品种的检查现场检查时FDA会提出大量问题，并查看企业的文件和记录，对此，企业应一一明确回答，回答的问题要和实际情况相一致，且要于SOP相符合，不要欺瞒FDA检查官应该明确，FDA是来评估企业是怎样做的，他不是顾问，也不教你怎样做，所以，尽量将问题解释清楚，而不是问FDA的检查人员应该怎样做
8 R: t5 g- E* @3 b; C 最后，FDA会有半天时间进行总结，若有疑问或认为有些地方不符合GMP和DMF，他们会在483表上列出通常483表上的问题要我们在3周内列出详细的解释或整改计划并交FDA
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c' A; q! L7 w# @5 m当FDA对企业的483表回信进行审查，感到满意时，FDA会通知代理商，同意其使用我们的产品同时FDA会通知美国的贸易部门，准许进口我们的原料药（FDA不会给企业发GMP证书）( ?5 K3 c3 r) L+ w2 p& `9 J) z) f, g
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% ~8 R+ u5 R x% n: n; U经过以上几个步骤，企业的原料药已经成功进入美国市场，但需要指出的是，并不是通过检查之后就万事大吉了，企业从此更应严格按照GMP和DMF的要求运作：重大变更应通知FDA，DMF及时更新，同时FDA会至少每两年对企业复查一次2 l' x+ L- g0 B0 B
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FDA的要求并不是高不可攀只要企业严格遵守GMP，同时做好现场的检查准备，完全可以成功通过FDA认证，从而提高我国原料药生产企业的管理水平和市场竞争力，树立我国制药企业的新形象。8 k2 |4 k* ~4 l- [, H, k& K6 A
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FDA DMF基本信息，包括准入信格式5 o2 F' q: S: F A
Drug Master Files (DMFs)This site contains lists of Drug Master Files (DMFs) as well as information concerning submission of DMFs to the FDA’s Center for Drug Evaluation and Research (CDER). The list is updated quarterly, although there may be delays of up to a month. See below for information regarding the current Guideline for Drug Master Files (September 1989) (DMF Guidance). IMPORTANT NEW INFORMATION See recent Q&A postings on the CDER guidance page QUESTIONS OR COMMENTS ABOUT DMFs Please address ALL comments or questions regarding DMFs to dmfquestion@cder.fda.gov except for inquiries specifically related to DMFs filed under GDUFA. Questions related to DMFs submitted under GDUFA should be sent toAskGDUFA. All inquiries MUST have an entry in the "Subject" field of the e-mail that indicates what the e-mail is about and how it relates to DMFs. Due to concerns about viruses and the amount of "spam" received by this account, e-mails with subject fields that are blank or contain meaningless text strings or contain only question marks will not be opened. If the inquiry concerns a specific DMF, the DMF number should be in the subject field of the message. Other inquiries unrelated to DMFs should be sent to druginfo@fda.hhs.gov. Note that inquiries regarding the reporting category for a change in a DMf should be sent to the druginfo address.
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DMF LISTS The current list contains DMFs RECEIVED by December 31, 2013. However the submitted date is listed for each DMF. The list of DMFs is current as of December 31, 2013, through DMF 27829. Changes to the DMF activity status, DMF type, holder name, and subject made since the last update of September 30, 2013 are included. DMFs submitted in electronic format have “(ESUB)” in the Subject field. TYPES OF DMFs The 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 Information 8 F# r# t7 F( [& v
STATUS OF DMFS “A” = Active. This means that the DMF was found acceptable for filing, administratively, and has not been closed. “I” = Inactive. This means a DMF that has been closed, either by the holder or by the FDA. “P” = DMF Pending Administrative Filing review.
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Note that the status “C,” which meant that a DMF had passed the Completeness Assessment, has been removed and replaced with “A”, since the list of those DMFs is updated more frequently than this list of all DMFs. The list of DMFs that have passed the Completeness Assessment and are available for reference by ANDAs under GDUFA is available athttp://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM332875.pdf The status conveys no information about whether a DMF has been reviewed for technical content. Overdue Notification Letters: DMFs must be current at the time of review. 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.” The DMF Guidance recommends that DMF holders update their DMFs annually (see below under Annual Reports). In order to ensure that DMFs are current, FDA is in the process of sending “Overdue Notification Letters” (ONLs) to DMF holders for DMFs that have not had an Annual Report submitted in the past three years. If a DMF holder does not respond to this letter within 90 days with the submission of an Annual Report, the DMF may be closed by the FDA. Reactivating a Inactive (Closed) DMF An Inactive DMF can be returned to ACTIVE status only by submission of a REACTIVATION, which should contain a complete resubmission of the DMF, updated to meet current Guidances. GUIDANCES MORE INFORMATION ABOUT DMFs and The recommendations in the DMF Guidance are, in general, still applicable. However the information below provides additional information or clarification of the recommendations in the Guidance. This information provided below falls into four categories: Category 1: Recommendations which are no longer applicable due to changes in regulations or guidances.
h+ n; i5 R- w4 G+ aCategory 2: Additional clarification of recommendations in the Guidance.1 J/ O5 c8 S) L, e0 @" w) T& }, b
Category 3: New information for aspects of DMF filing that was not in effect when the Guidance was written.% L% a$ S) x7 E8 c( p! T2 M- k/ ?$ j3 X
Category 4: Information related to the Generics Drug User Fee Act (GDUFA) Address for Filing Original DMFs and All Subsequent DMF Documents (Category 3) Food and Drug Administration
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Central Document Room% e- q( p, D8 }$ i% |: }$ g
5901-B Ammendale Road
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Beltsville MD 20705-1266 All submissions to an existing DMF that is in paper must be submitted in two copies in paper to the address above. Submissions via e-mail are not accepted. Paper DMFs may be submitted printed on two sides. Review of DMFs (Category 3) A DMF is reviewed for Administrative content when it is received. This may take 2-3 weeks. If the DMF is acceptable from an administrative point of view an Acknowledgement Letter will be issued, notifying the holder of the DMF number. If it is not acceptable from an administrative point of view, the holder will be notified of what deficiencies need to be corrected. Type II DMFs to support ANDAs under GDUFA are subject to an initial “Completeness Assessment” under the conditions specified in the Draft Initial CA Guidance. All DMFs are subject to a complete review for technical information only when all of the following events occur: 1. The DMF holder submits a Letter of Authorization (LOA) in two copies (if a paper submission) to the DMF. This LOA should contain the DMF number
8 I, z U4 o! L0 E" S( |2. The holder sends a copy of the LOA to the authorized party (customer)./ W: H; u" v( q7 G) y( }0 J: C% G, D" I
3. The customer submits an application to the FDA that contains a copy of the LOA. GDUFA (Category 4) The Generics Drug User Fee Act (GDUFA) section of the Food and Drug Administration Safety and Innovation Act” (S.3187 )includes provisions for fees for DMFs, an initial completeness assessment , and communications with DMF holders. GDUFA applies only to Type II DMFs for drug substances (Active Pharmaceutical Ingredients (APIs)) used to support Abbreviated New Drug Applications (ANDAs). It does not apply to any other type of DMF or to Type II DMFs used to support NDA or INDs. See also the GDUFA Web site. See also the following Web sites DMFs that have passed the Adminstrative review (have an active status) and have had the user fee paid are placed in the queue for a Completeness Assessment depending on workload may take a number of weeks. Pre-assignment of DMF Numbers (Category 3) Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application (Category 1) Conversion to CTD Companies may convert an existing DMF in non-CTD format to CTD format. In such cases DMF holders are advised to submit an amendment containing all sections specified in the CTD format that are applicable to the material covered by the DMF. Each section should be complete and contain up-to-date information. For drug substances and excipients all sections of 3.2.S in Module 3 should be submitted. For drug products all sections of 3.2.P in Module 3 should be submitted. If there are any changes in the technical content of the DMF as a result of the reformatting, e.g. addition of new information, the cover letter for the new submission should specify what areas of technical information have been changed. Type III DMFs may be submitted in CTD format, treating the finished product as if it were a drug product. e.g. the Materials of construction would be in P.1, the finished packaging material release specification would be in P.5. For conversion of a paper DMF to electronic CTD format, see Electronic DMF. DMFs that cover multiple items e.g. Type III DMFs for components of container-closure systems or Type IV DMFs for flavors, can be submitted in CTD format. The technical information can be in Module 3, following the outline in the Drug Product Section. The different sections within 3.2.P. can be populated as appropriate. Each product e.g. different flavors, would have a different name e.g. 3.2.P.[Flavor 1], 3.2.P.[Flavor 2]. Information that is common to different products e.g. analytical procedures can be accessed by reference (or links in the case of an Electronic DMF) from the relevant section for that product e.g. 3.2.P.5.1 [Flavor 1] for specifications. It is not necessary to submit all Modules i.e. it is not necessary to submit Module 4 and 5. However all Sections within Module 3 should be submitted. Products manufactured at separate facilities do not need to be filed as separate sections unless the manufacturing processes are different. Note that the Draft Initial CA contains recommendations regarding the submission of DMFs for multiple processes. Module 1 should contain the following information; z$ D6 S! Q4 b. L
Section 1.2: Cover Letter, Statement of Commitment and Generic Drug User Fee Cover Sheet (3794), where applicable According to the DMF Guidance (Section IV.B.1.c), the Statement of Commitment is: “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.“
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& c. ~( E7 M8 z% ]) g! \7 B. WSection 1.3: Administrative Information 1.3.1 Contact/sponsor/Applicant information 1.3.1.1 Change of address or corporate name Can be used to supply addresses of DMF holder and manufacturing and testing facilities 1.3.1.2 Change in contact/agent Can be used to supply the name and address of contact persons and/or agents, including Agent Appointment Letter. Section 1.4: Reference Section 1.4.1 - Letter of Authorization (LOA) Submission by the owner of information, giving authorization for the information to be used by another. An Agent Appointment Letter is NOT an LOA and should not be called “Letter of Authorization” and should not be submitted in Section 1.4.1 1.4.2 - Statement of Right of Reference Submission by recipient of a Letter of Authorization with a copy of the LOA and statement of right of reference. Submitted in a DMF only when another DMF is referenced.: If a DMF holder references other DMFs a list of those DMFs can be provided in this section. This is not the same as the list of authorized parties to be provided in 1.4.3. 1.4.3 - List of authorized persons to incorporate by reference This list should be submitted in DMF annual reports.
Section 1.14: A copy of the label, where applicable. The language in the following sentence in the DMF Guidance, Section VII.B.1, has given rise to some confusion on the part of DMF holders. “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)].”
It does NOT mean a list of individuals within the DMF holder’s company who are authorized to submit information to the DMF. The language in the CFR is more explicit: “The drug master file is required to contain a complete list of each person currently authorized to incorporate by reference any information in the file, identifying by name, reference number, volume, and page number the information that each person is authorized to incorporate.” English Translations of DMF in a Foreign Language (Category2) FDA regulations (21 CFR.1(a)(1)) state: “If any part of the application is in a foreign language, an accurate and complete English translation shall be appended to such part.” The same is true for DMFs. Debarment Certification for DMF Holders (Category 3) TYPES OF DMFs Type I DMFs (Category 1) Type 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 general operating procedures in these DMFs. Only the addresses of the DMF holder and manufacturing site and contact personnel should be submitted. See Administrative Information in a DMF. Type II DMFs (Category 1) For Type II DMFs filed in CTD-Q format, Module 2 (QOS) is expected. Drug Substance Type II DMFs for drug substances may be submitted in the format for "Drug substance" in the "Guidance for Industry M4Q: The CTD - Quality".(Category 3) Drug Substance: See the current Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances. It is not necessary to include a Methods Validation Package (3.2.R.3). Methods Validation information should be submitted in Section 3.2.S.4.3. See also the ICH Guidance “Q11 Development and Manufacture of Drug Substances"
Note that GDUFA includes requirements for Type II DMFs for Active Pharmaceutical Ingredients (APIs). Drug Product: Type II DMFs for drug products may be submitted in the format for "Drug product" in the "Guidance for Industry M4Q: The CTD - Quality".(Category 3) Drug Product. See the Guideline For Submitting Supporting Documentation In Drug Applications For The Manufacture Of Drug Products. It is not necessary to include a Methods Validation Package (3.2.R.3). Methods Validation information should be submitted in Section 3.2.P.5.3.
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' E+ }: g5 `3 V8 p$ Z+ S5 M& FSeparate DMFs should be submitted for drug substances and drug products.
Active Pharmaceutical Ingredient (API) (Category 4) According to GDUFA “SEC. 744A. DEFINITIONS. For purposes of this part: (2) The term ‘active pharmaceutical ingredient’ means— (A) a substance, or a mixture when the substance is unstable or cannot be transported on its own, intended— (i) to be used as a component of a drug; and
3 F& o# h! u+ {: S. ?(ii) 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; or (B) a substance intended for final crystallization, purification, or salt formation, or any combination of those activities, to become a substance or mixture described in subparagraph (A)”
Type III DMFs (Category 1) A Manual of Policies and Procedures covering reviewer responsibilities for review of Type III DMFs has been implemented. MAPP 5015.5 CMC Reviews of Type III DMFs for Packaging Materials This MAPP instructs reviewers to look for information regarding many packaging materials in the application (IND, NDA, or ANDA) for the drug product that utilizes the packaging material before reviewing the DMF. Much of the information needed for review can be provided directly to the applicant for inclusion in the application, thereby avoiding the need to review the DMF. Type III DMFs may be submitted in CTD format, treating the finished product as if it were a drug product. e.g. the Materials of construction would be in P.1, the finished packaging material release specification would be in P.5. Type IV DMFs (Category 3) Note that, in keeping with the recommendation in the DMF Guidance, components of flavor mixtures should include a CFR citation, where applicable, in addition to any other reference, e.g. GRAS or FEMA references. Type V DMFs (Category 3) Administrative Information in a DMF (Category 3) The elements of the administrative information that should be in a DMF are: - The name and address of the holder
- The name and address of manufacturing facility
- For the contact person:
- Name
- Mailing Address
- Telephone number
- Fax number
- E-mail address- v" h# Q% J% ?5 h
- Statement of Commitment
- The name and address of the agent (if applicable)
- For the contact person at the agent (if applicable):
- Name
- Mailing Address
- Telephone number
- Fax number
- E-mail address
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The appointment of an Agent is optional. See discussion below under “Agents” Submission of Amendments, Annual Reports, and Letters of Authorization (Category 3) To facilitate processing of documents that are submitted to an existing DMF, please list the Submission Type and the Category/Subcategory of the Amendment (Supporting Document) in bold type in the header on the transmittal letter. See list below. More than one Submission Type/Category/Subcategory can be used but all should be listed. Example: If updated stability data is submitted at the same time as an Annual Report, the heading of the Cover Letter should state: Annual Report
' m+ J% w5 k$ D1 t! u6 }* HOriginal: Quality/Stability FDA’s database is structured as follows: Application: Submission Amendment (called "Supporting Document") in the database)
Amendments (Supporting Documents) are named by a Category and Subcategory For the Application Type “Drug Master File” the Submission Types are - Original: Information containing changes to technical information are filed in the “Original” submission. Note that a new DMF does not need a “Category” designation by the holder. See Categories and Subcategories below
- Annual Report: There are no Amendments (Supporting Documents) Categories, or Subcategories
- Letter of Authorization: There is only one Category with two Subcategories:
- Letter of Authorization
- Withdrawal of Authorization: \& P; K/ A% k* c- F9 b; _
- General Information (Reactivation, Closure Request, Administrative Information)
- Categories of Amendments (Supporting Documents) in General Information
- Category: Closure Request
- Category: Reactivation (Used only when a DMF has been Closed.)
- Category: Administrative
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Subcategories under Administrative Category
/ S3 ^+ n" L2 \5 l l% _3 `! e - change in the holder name
- change in holder address
- change in ownership of the DMF (either internal name change, or change in ownership)
- change in the agent name or address.
- change in the contact person at the holder or agent.
- change in the subject of the DMF.
- change in the type of DMF
- response to an Administrative Filing Letter9 J. v" [; z9 i
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Note that a change in manufacturing address may require a change in Subject amendment. - Categories of Amendments (Supporting Documents) in Original Submission:
- Category: Quality
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Changes to a Subsection e.g. changes in Control of Materials (S.2.3) not specifically listed below should be reported as the next level up e.g. should be reported as Manufacture Information S.2.
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- Controls Information (specifications) S.4 and P.5
- Dissolution Data (Usually applies to drug product only) P.5
- Facility Information (changes in manufacturing and or testing sites) S.2.1 and P.3.1
- Formulation Information (Usually applies to drug product only) P.1 and related sections
- Lot Release (batch analysis) S.4.4 and P.5.4
- Manufacture Information S.2 and P.3
- Microbiology Information
- New Strength (Usually applies to drug product only) P.1 and related sections
- Quality (Not covered by other subcategories)
- Packaging Information (Applies to packaging of the material that is the subject of the DMF e.g. plastic bags for packaging a bulk drug substance in a Type II DMF) S.6 and P.7
- Stability Information S.7 and P.8
- Response to Information Request
- Response to Deficiency Letter . B# k9 z- U; p7 X) _# u; M, x
- Category: Non-clinical
- Non-clinical
- Carcinogenicity Information
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A response to an Overdue Notice Letter (ONL) to retain activity of a DMF should be identified as an Annual Report and contain the information listed below for an Annual Report. Additional administrative and technical information may be included asamendments. Responses to ONLs will not be sufficient to keep the DMF in active status if they meet ANY of the following conditions: - The submission is not labeled as Annual Report.
! \) F4 `' j5 V7 Por - The submission state that an update will be submitted in the future
1 j0 K( M( M0 ] e6 j: T6 Gor - The submission does not contain the information specified below under an Annual Reports: f5 j7 ~6 w3 E1 R! B7 ~2 j" Q
FDA does not acknowledge, whether via e-mail or letter, any submission after the original DMF. Submissions that cover multiple DMFs should have a copy submitted for each DMF. When a change is made to one part of a DMF the entire DMF does not need to be resubmitted. For DMFs in CTD format, the entire changed “Document” (Section) should be submitted e.g. a change in the material used in the synthesis should be included in a resubmission of Section S.2.3. All submissions should be paginated within the submission. Pages that replace an already-numbered page from a previous submission should also contain the page number in the current submission (e.g. a page replacing Page 10 in the original submission may be page 14 in the new submission). For DMFs in CTD format, only the pages within the changed “Document” (Section) are subject to re-numbering. No pages are ever physically replaced in a DMF. REPORTING CHANGES TO A DMF (Category 2) “If the drug master file holder adds, changes, or deletes any information in the file, the holder shall notify in writing, each person authorized to reference that information. 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.”
The notification of the change should also include the date for the “information affected in the drug master file.” Paragraph (d) in the regulation refers to the list of authorized persons. There are no reporting categories for DMFs. All changes must be reported as amendments. The DMF holder should notify customers of the nature of the changes, providing as much detail as is consistent with the confidentiality agreement between the DMF holder and each customer, so that the customer can determine how to report the changes in their approved NDA or ANDA. See 21 CFR 314.70 and related Guidances. ELECTRONIC DMFs (Category 3) There is no requirement to file DMFs in electronic format. Paper DMFs will continue to be accepted. Because submission of a DMF in mixed formats (paper and electronic) can delay its review, DMF holders are encouraged to submit the entire DMF in electronic format and to submit all subsequent submissions electronically when they submit an electronic DMF, including conversion from paper. All electronic submissions must have an application number. For a new DMF, the holder must request a pre-assignednumber in order to populate in the US Regional.xml. If a DMF currently in paper format is being converted to electronic format, it is not necessary to request a pre-assigned number. The previously assigned number in 6-digit format should be used e.g. 1234 becomes 001234. The first submission in electronic format should be given the sequence number “0000.” A submission in electronic format should NOT be submitted to a paper DMF unless the entire DMF is submitted in electronic format. Once the DMF holder has made an electronic submission every subsequent submission should be in electronic format. The ECTD format provides the backbone for the submission and a guide as to where to place information. It is not necessary to submit all Modules i.e. it is not necessary to submit Module 4 and 5. All Sections within Module 3 should be submitted. However, Module 1 is required for all eCTD submissions, as it contains the necessary administrative information to identify the DMF. Electronic signatures are accepted for electronic DMFs. Electronic DMFs may be submitted either through the Gateway or by sending a disc (one copy) to the Central Document Room at the address provided above. LETTERS OF AUTHORIZATION (Category 2) All Letters of Authorization (LOAs) should be submitted in two copies to the DMF, if the DMF is in paper format. A copy of the LOA must then be sent by the DMF holder to the Authorized Party (company or individual authorized to incorporate the DMF by reference). Failure to submit the LOA to the DMF may result in a delay in review of the DMF. LOAs should specify the name of the specific item being referenced and the date of the submission of information about that item. The LOA should not be called a “Letter of Access.” An LOA is required even if the DMF holder is the same company as the authorized party. LOAs should NOT be submitted with original paper DMFs (unless the DMF has received a pre-assigned number) because the LOA should contain the DMF number. Therefore DMF holders should wait before submitting an LOA until they have received an acknowledgment letter containing the DMF number. It is not necessary to reissue LOAs if there have been no changes in the holder, authorized party, subject of the DMF or item referenced.
W6 T3 |/ a( X7 v0 e5 w1 r6 LIf the holder or authorized party changes names, whether this represents a change in ownership or not, new LOAs should be submitted to the DMF and copies sent to the authorized party. If a company has a Master File submitted to another Center in the FDA, e.g. a Biologics Master File (BB-MF) submitted to the Center for Biologics Evaluation and Research, the Letter of Authorization should be submitted to that Center rather than CDER. Note: The “Subject” field in the Letter Templates refers to the Subject of the DMF, not the Item within the DMF being referenced. The Item name should be included in the body of the letter. AGENTS (Category 2) There is no regulatory requirement for an agent for any DMF, foreign or domestic. An agent for DMF purposes is not the same as an agent for the purposes of the Drug Listing and Registration System. (DRLS). Holders should not include the name of the agent for Registration purposes in the DMF. Also note that in the US, the process of “Registration” applies ONLY to “registering” an establishment with the FDA. All “Agent Appointment Letters” for DMFs should be signed by the holder. FDA recommends that such letters include the phrase “appoint AGENT NAME as the agent for DMF” rather than “authorize AGENT NAME to act as the agent for DMF,” since the latter can be confused with a “Letter of Authorization.” Agents for DMF purposes are not required to be located in the United States, although this is recommended. An “Agent Appointment Letter” may be included in an original DMF. If possible, the word “Agent” should be used for the legal entity (whether a company or an individual) who is authorized to act on behalf of the DMF holder. The word “Representative” should be used for an individual who is employed by the Agent or Holder as the contact point for FDA. If a company acting as an Agent changes its name, FDA recommends that the DMF holder issue a new Agent Appointment Letter. A different agent can be appointed for different DMFs submitted by the same holder. HOLDER NAMES (Category 2) When the company that owns a DMF (DMF holder) changes its name, whether through sale of the company or simply achange in the company’s name, the DMF holder must notify FDA. See Section VII.E. in the DMF Guidance for further recommendations on the procedure for transferring ownership. A change in the name of a company for registration purposes under DRLS will not change the DMF holder name. When a DMF is transferred from one company to another, the original holder should submit an administrative amendment stating that they are TRANSFERRING the DMF to the new holder. The new holder should then submit an administrative amendment stating that they are ACCEPTING the DMF from the former holder.- R, D' d5 p5 Y+ y( F" {4 J- z4 M* f
If the DMF holder changes its name and there is no transfer of ownership, the holder may submit a single Holder Name Change amendment. A DMF holder is expected to retain a complete reference copy that is identical to, and maintained in the same chronological order as, their submissions to FDA (See Section IV.D.1 in the DMF Guidance). Therefore the old owner of the DMF is expected to transfer that copy to the new owner of the DMF. In general FDA expects the manufacturer to be the holder. If a manufacturer (Company A) of a MATERIAL wishes to have the DMF submitted by another company (Company B) and Company B wishes to act as the holder, the DMF should include statements from both companies that Company B takes full responsibility for all the information in the DMF and for all the processes and testing performed by the manufacturer. The title of the DMF which will appear on the list of DMFs will be “MATERIAL manufactured in LOCATION OF COMPANY A for COMPANY B.” If Company B changes its name to Company C, whether through an internal name change or a through sale of the company, the new holder should submit an Administrative Amendment/Subject Change requesting a change in the Subject to “MATERIAL manufactured in LOCATION OF COMPANY A for COMPANY C.” ANNUAL REPORTS (Category 2) According to the DMF Guidance, Annual Reports are NOT to be used to report changes in the DMF. However, as describedabove, an Annual Report can be submitted at the same time as other information. The Annual Report should contain (for Cover Letter see Templates below): 1. An administrative page containing the Administrative Information specified above (Administrative Information in a DMF) AND 2. One of the following - Date(s) of the amendment(s) reporting changes since the last Annual Report or the original DMF filing date, whichever is most recent.
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Or - A statement that no amendments have been submitted since the last Annual Report or the original DMF filing date, whichever is most recent." @ ^/ }4 ] j! s0 [ B' z$ D
AND 3. One of the following: - A complete list of all parties authorized to make reference to the DMF, identifying by name, reference number, volume, date, and page number the information that each person is authorized to incorporate by reference and the date of the LOA. ' |4 y! Q7 @5 v ?# f
Or - A statement that there are no Authorized Parties.
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AND 4. List of all parties whose authorization has been withdrawn Note that the DMF Guidance uses the terms “Annual Update” and “Annual Report” interchangeably. All submissions of Annual Reports should be labeled “Annual Report.” The term “Annual Update” should not be used. Note that the Annual Report should contain a COMPLETE list of Authorized Parties. BIOLOGICS MASTER FILES (Category 3) Master Files submitted in support of products regulated by the Center for Biologics Evaluation and Research (CBER) should be submitted as BB-MFs. See the CBER web site for the products regulated by CBER. BINDERS (Category 2) The “binders” are actually covers. These may be ordered from the U.S. Government Printing Office (GPO) Web site: http://bookstore.gpo.gov/ or by calling 202-512-1800 to speak with a GPO customer service representative. The binders may be obtained from another supplier, provided they meet the requirements specified on the GPO Web site. The direct links for online ordering are One copy of the DMF should use the blue cover and one should use the red cover. Fasteners must be obtained separately. Use 2 Piece Prong Fasteners, 8 1/2" Center to Center, 3 1/2" Capacity. Binders should be used for all subsequent submissions to FDA that are more than 10 pages. If a DMF is submitted using any other kind of binder, it should be a loose-leaf type of binder so that the pages can be removed and placed in FDA-approved binders. DMFs should not be submitted as “bound” books. FEES (Category 4) GDUFA requires DMF fees for Type II DMFs for drug substances (Active Pharmaceutical Ingredients (APIs)) used to support Abbreviated New Drug Applications (ANDAs). Since GDUFA does not apply to any other type of DMF or to Type II DMFs used to support NDA or INDs, there are no fees for these types of DMFs. FORMS (Category 2) Certain forms are required for submission of NDAs and INDs. However there are no forms required or available for DMFs, except for the forms discussed above under Binders and the Generic Drug User Fee Cover Sheet. The latter applies only to Type II DMF submitted to support ANDAs under GDUFA. CONFIDENTIALITY OF DMFs (Category 2) The public availability of the contents of DMFs is covered in 21 CFR 314.430(e). There are no “open” or “closed” parts of DMFs filed with the FDA. The decision as to how much information DMF holders share with their customers is a business decision between the parties involved and is not covered by FDA regulations or Guidances. All requests for information about DMFs beyond that provided in the tables above must be made through the CDER Freedom of Information Web site. FILING DMFs AND PATENT EXPIRATION AND EXCLUSIVITY ISSUES (Category 2) DMFs may be filed at any time. The Patent Expiration date and the Exclusivity Expiration dates listed in the Orange Book have no impact on DMF filing. The submission of Abbreviated New Drug Applications (ANDAs) that reference DMFs is subject to the regulations regarding filing of ANDAs. ENVIRONMENTAL ASSESSMENTS (Category 2) Since DMFs are neither approved nor disapproved, there is no need to file an Environmental Assessment. However the DMF should contain a commitment by the firm that its facilities will be operated in compliance with applicable environmental laws. REORGANIZATION OF A DMF (Category 1)
- g$ W' Q/ X- ~0 tThe advice in the Guidance does not apply. It is not necessary to consult with FDA before reorganizing a DMF. REQUEST FOR CLOSURE OF A DMF BY THE HOLDER (Category 2). It is not necessary to include a statement that "the holder's obligations as detailed in Section VII have been fulfilled," as recommended in the DMF Guidance. It is sufficient to include a statement that all of the parties authorized to reference the DMF have been notified that the DMF is being closed. LETTER TEMPLATES AND COVER LETTERS (Category 2) Note that a “Transmittal Letter” and a “Cover Letter” are the same thing. The following submissions do not require a Cover Letter Holder Transfer
% c9 h% w/ n: |, q; M* i# kNew Holder Acceptance
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Letter of Authorization, z( T/ N- B( b2 M
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Withdrawal of Authorization
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Drug Master File Letters
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