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[国际注册] DMF(Drug Master File,药物主文件)相关内容

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xiaoxiao 发表于 2018-9-9 16:30:08 | 显示全部楼层 |阅读模式

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下面DMF文件相关内容
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0 `0 |8 F! w3 i9 q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 % _$ {  ?4 `4 a  r7 k
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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 / R6 Q' Y: R+ M6 p/ W8 H; ]
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 + ?! v& r8 a0 O

6 r/ V# B8 M3 b) r- n4 j2 {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
# J  g7 u# U- }原料药申请FDA批准的基本程序:4 ]  g4 Z& N* I% G' B, I1 F6 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
4 [& @. s& \8 c% G" G9 V# B2.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( h. p6 [  O9 A  S5 v: I  r
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
) ?" A( p2 Z  @- M- D4.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 A7 p9 x* w, Q& e) f* k. W2 }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% w# g& B1 x+ S" r
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0 @! B2 F5 e* }7 R
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0 f# Z: F7 l8 H, H& M
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
0 {3 z7 x) k5 I7 [6 x6 K关于FDA批准( V/ H1 k3 E0 r+ O
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7 b  O! l- f5 A7 w3 {! F% W
    原料药通过美国FDA认证的步骤与途径:+ d% B8 Z& f1 v" F( j
    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。% X4 p7 z* d( m, A
    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
' w( }$ M5 o( w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
6 Y7 r$ w% `9 a$ v1、准备阶段
7 m+ ~; L! R  r8 Z5 T     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。
( n3 F0 w) ]4 F8 W4 s    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。
# s1 Y8 ^0 L/ Y) G* ], V6 D6 s) T2、DMF文件的编写和提交
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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) l/ V6 e  v+ z  {1 {# d" u
    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。
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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。$ ]  b$ X/ S6 N; N$ I

8 I7 x/ L! H4 N: |/ D3 rDMF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。) n3 Y8 Q, T, ?% ^1 O  r+ F
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FDA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。+ x, a7 C4 @  O9 B7 K
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6 ~1 p- g7 U  X- U, Z  y% T
    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
. H% E4 u' X8 d  l1 j* x, 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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FDA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 h9 \6 E& O! U/ q
    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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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)
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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; G( r+ `/ C& n; w

8 l! [1 P8 m3 ~! h' A* @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。

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) h. z4 ~/ _% H) k  @; v6 RFDA DMF基本信息,包括准入信格式: a  ^+ f) u9 I7 s
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
Guidance for Industry: ANDAs:  Stability Testing of Drug Substances and Products: Questions and Answers
. f' b/ y8 s2 b2 a* F/ VDRAFT GUIDANCE
! j8 r' K3 Q* Z5 n% g1 B5 o8 N! \8 @0 \" fhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM316671.pdf
Guidance for Industry: Generic Drug User Fee Amendments of
# Y, y7 p$ P. I* l+ H1 `) y6 F2012: Questions and Answers
) b8 {2 p: H  n: \DRAFT guidance
; H7 z5 I" Z% Nhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM316671.pdf
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


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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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  • “N” = Not an assigned number.  This can occur for a number of reasons, e.g., the holder withdrew the DMF during the administrative review or the DMF was transferred to another Center.


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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
Guideline for Drug Master Files (DMF guidance)  The version posted on the web is the current version.  Note that the address for submitting DMF documentation to the FDA in the Guidance has been superseded by the Beltsville address below. Please address questions regarding the DMF Guidance to dmfquestion@cder.fda.gov.
MORE INFORMATION ABOUT DMFs
and
CDER’s Small Business Assistance Office Webinar entitled “Drug Master Files (DMFs) under Generic Drug User Fee Amendments (GDUFA)” on February 11, 2013.
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.% L9 n; o0 u0 l/ J9 e  m
Category 2: Additional clarification of recommendations in the Guidance.6 L% H4 c' H/ `7 D
Category 3: New information for aspects of DMF filing that was not in effect when the Guidance was written.
4 F# E- p8 Y  J4 g! vCategory 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. y+ z+ e/ g! o# p" K/ O2 ?7 p
Center for Drug Evaluation and Research* ?8 J9 }+ U+ U9 y- K! G/ R- U
Central Document Room
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Drug Master File Staff4 s4 Y1 f2 ]' ?7 F* l- m0 G, K3 x3 }
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.
This address should be used when submitting electronic DMFs via disc.  See Electronic DMFs.
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/ `) M! Z# K1 Q  C  [
2. The holder sends a copy of the LOA to the authorized party (customer).
1 d. t; q  X6 S1 c& P3. 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
The list of DMFs that have passed the Completeness Assessment and are available for reference by ANDAs under GDUFA is available at http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM332875.pdf.
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)
To request a DMF Pre-Assigned Number, see “Requesting a Pre-Assigned Application number.”
Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application (Category 1)
The “Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application” cited in the DMF Guidance has been withdrawn.  DMFs may be submitted following the format recommended in the "Guidance for Industry  M4Q: The CTD - Quality" (CTD-Q) and the “Draft Guidance for Industry Submitting Marketing Applications According to the ICH-CTD Format —General Considerations” (CTD Guidance)
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.
DMFs in CTD format should follow the recommendations in the Appendix “Granularity” the ICH Harmonised Tripartite Guideline:  Organisation Of The Common Technical Document For The Registration Of Pharmaceuticals For Human Use:  M4. This supersedes the recommendation in the  DMF Guidance.
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.
DMF holders submitting DMFs for Sterile Manufacturing can consult the Manual of Policies and Procedures 5040.1:  Product Quality Microbiology Information in the Common Technical Document - Quality (CTD-Q)
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 information4 g0 Z" G6 N5 O
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.“2 @, Y* Q0 @2 n' f& M: \! B& J0 N

* H2 `/ Y( K% [) _. W4 e/ j! MSection 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 1.12.14 Environmental Analysis:  See Environmental Assessment
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)
According to the Draft Guidance for Industry: Submitting Debarment Certification Statements, DMF Holders are included in the category of “Persons whose services were used in any capacity in connection with the application” required under Section 306(k)(1) of the Food Drug and Cosmetic Act.  DMF holders may include a Debarment Certification statement in their DMF.
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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Separate 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 m# M& V' B$ @; ]7 a(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)
See relevant section in the DMF Guidance   If toxicology studies are submitted in the same DMF (in paper) as the CMC information, they should be in a separate volume or volumes, although it is preferable for holders to submit such information as a separate Type V DMF .  Toxicology studies in an electronic DMF for an excipient should be submitted in the appropriate module.  See also the “Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients”
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)
As specified in 21 CFR 314.420(a)(5), DMF holders wishing to submit a Type V DMF must obtain clearance from the FDA. Prospective Type V DMF holders should send their request to dmfquestion@cder.fda.gov, explaining the necessity for filing the information in a Type V DMF.  However, information regarding manufacturing site, facilities, operating procedures, and personnel for sterile manufacturing plants will be accepted without a request for prior clearance from FDA.  See Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products.  The Subject field should specify what the DMF covers i.e., Sterile Processing Facility.
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
      3 m4 ^9 v/ O) Z. ~
  • 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& Z: R& {3 V3 M; d; }6 p7 Z
  • Statement of Commitment) i: w0 ?) t( U
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/ g; j. M$ e, @# }8 J) E8 v
Original: 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 Authorization6 M. S, M& i+ j- e' A
  • 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 8 [5 e) p- q  u2 a( U; \
        ( z4 \4 I7 Y$ I  [& ^
        Subcategories under Administrative Category
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        • 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 Letter
          # I; z$ V& Z; @. u0 J7 o, L

        - D: j0 m* ]% c( Y3 e( b

      ( g: W# V$ g6 _( w

    / o' d, j: Z/ F! u' U+ V$ Y8 h
Note that a change in manufacturing address may require a change in Subject amendment.
  • Categories of Amendments (Supporting Documents) in Original Submission:
    • Category:  Quality/ e8 A+ J* j) p; ~5 A) z6 R1 \

      / w8 v5 @7 @+ C' Z1 e& WSubcategories under Quality Category (with corresponding CTD Sections, where applicable).
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      3 A* s  x4 B# }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.
      : A1 B( C' B! L6 B% e* b
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      • New item:  Additional item e.g. flavor added to a multi-item DMF
      • 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
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    • Category: Non-clinical
      • Non-clinical
      • Carcinogenicity Information5 O3 |+ \* R  m2 G$ p% w% }) P+ k

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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.9 z- ?6 y8 X7 Z. `1 m" M; q
    or
  • The submission state that an update will be submitted in the future
    2 T/ |: ~" l7 K# Gor
  • The submission does not contain the information specified below under an Annual Reports
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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)
As stated in 21 CFR 314.420(c)

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.
The FDA has published a Draft Guidance “Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (01/03/2013) regarding electronic submissions.  The Draft Guidance EXCLUDES DMFs.  However all DMF holders are encouraged to submit their DMFs in electronic form, including updating current paper DMFs.  Note that all applications to CDER, including DMFs that are submitted in electronic format are expected to be in ECTD format, unless a waiver is granted.   Waivers are not granted for DMFs.
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.
See also Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications. To make sure you have the most recent versions of the specifications referenced in this guidance please check Electronic Common Technical Document (eCTD).  All Letters of Authorization for electronic DMFs should specify that the DMF has been submitted 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.
% K1 p! ?8 F, L, _& @& ^' c, ]If 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./ X3 T: U2 V$ E1 m9 ?$ n
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.
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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.
    5 H! A. g8 n. V, H# i
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
Blue Binder 4 u5 m3 X' t0 f- y# \2 R7 `
Red Binder
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.
Note that the current Web site for completing containing the INSTRUCTIONS FOR COMPLETING FORM FDA 3794 (GENERIC DRUG USER FEE COVER SHEET) has been interpreted to mean that form 356h should be completed for DMFs.  Form 356h is not applicable to DMFs.
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)9 S4 P8 K! F+ ~/ B! u
The 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.
Cover Letter for Subsequent Amendments and Annual Reports (Not applicable to Holder Transfer, New Holder Acceptance, Holder Name Change, Letter of Authorization, and Closure Requests)
The following submissions do not require a Cover Letter

Holder Transfer
3 v& V% v* ]5 }, {% ^% M" s1 ONew Holder Acceptance, S" G2 W* ?2 q
Holder Name Change
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 楼主| xiaoxiao 发表于 2018-9-9 16:31:17 | 显示全部楼层
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FDA药物主文件DMF介绍, y; s( O) O. K8 w, m4 ^

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本文目录
       1、DMF简介
       1.1 FDA只对DMF做形式审查
       1.2 DMF类别) z& H0 U  i( Z* z0 K0 p( }  Y
         1.2.1.一类DMF--成品制剂企业
- z- ~5 O) \. [. z, d! c         1.2.2 .二类DMF--原料药物
1 W* e' M8 ?8 Q- T) e( @& L  V) b         1.2.3.三类DMF--包装材料
              1.2.4.四类DMF--药用辅料类
              1.2.5.五类DMF--其他
       1.3 FDA的DMF信息网站
       1.4 仿制药收费法案下FDA对DMF的一般要求; V/ r& [+ W) p, e# z6 a( a6 M
         1.4.1、DMF费  
         1.4.2、完整性审评(Completeness Assessment)  
         1.4.3、申报DMF的要点
. g/ z2 p' {9 c         1.4.4、DMF格式要求
4 r* {" A& J- O% n         1.4.5、DMF概述内容(Cover letter)/ O; ]3 E; e, R  {6 o0 L
         1.4.6、环境影响评价
) U' t$ d; B6 e1 }         1.4.7、DMF授权书
+ U' y9 p* M/ t8 n  T+ E4 _3 }         1.4.8、DMF用户名单
       2 DMF持有者职责# n! b( U- E3 p6 S/ N& d
       2.1 指定DMF驻美代理人/ V- J6 q3 U% k: t6 X* _" ^
       2.2 向用户提供授权书(LOA)
5 Y, D0 z0 }) e       2.3 向用户报告DMF变更
       2.4 DMF年度报告0 z) Y" E0 T! Z
       2.5 DMF转让
       2.6 DMF关闭


       1.DMF简介
3 _* g" c) x* _8 R4 h6 C3 G7 D       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作为一种参阅性资料在FDA中心档案室(Central Document Room,CDR)存档,用于一种或多种临床研究申请(IND)、创新药申请(NDA)、简化新药申请(ANDA)、出口申请、以及上述各种申请的修正和补充。DMF还可以作为其他DMF的参阅性文件,但作为这种用途的情况不是很多。
7 \( g" r! O- R+ v; K9 e: q       DMF持有者向FDA呈交DMF主要目的是支持用户向FDA提交的各种药品申请,而同时又不愿将其化学和生产流程的保密资料抄报用户。FDA对呈交的DMF资料进行存档处理,以备审查。这样,DMF持有者只需向用户提供授权书,授权FDA在评审用户的药品申请时,对所涉及的DMF进行全面考查。
! p% Y9 \% F5 o% t7 X9 P" x       DMF的另一特点是在FDA中心档案室存档的DMF可以支持所有使用该产品的用户,DMF持有者无须向每一用户重复提供资料。
$ E. X- m5 Q  _* f       2012出台的《仿制药收费法案》,要求在2012年10月1日后首次被仿制药引用的二类原料药DMF,需要缴纳DMF费,FDA对付费后的DMF作完整性审查(Completeness Assessment),此审查只检查资料的完整性,不审核具体内容,通过完整性审查后的DMF会被收录在'可被引用'列表中,并且FDA只会审评引用此列表中DMF的ANDA申请。1 y' ~6 Y" [' \) z8 d4 o
       1.1 FDA只对DMF做形式审查7 n* M5 D2 _" G5 J# @( p- Z' d
       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'。! Z4 S4 V# Q4 u! X1 ^& Q
       只有当DMF的用户向FDA申报制剂药品申请(IND、NDA、ANDA)及其修正或补充后,FDA才开始审查有关的DMF资料,即审查这些资料是否符合FDA的安全性及其他要求。因为DMF审查是由其用户的药品申报而引起关联性'审查',即在授权下因申报IND、NDA、ANDA而接受审查,因此DMF资料本身不存在'批准'与'不批准'的问题。
       FDA在审查中如发现DMF存在问题,FDA会向DMF持有者发函,指出欠缺之处,并同时通知药品申报者所参阅的DMF有欠缺。但FDA并不告知DMF的用户有关DMF欠缺的详细情况。对DMF的欠缺,FDA也仅仅是向DMF持有者指出而已,并不催促其改正。只要DMF存在问题,FDA是不会批准任何与其有关的药品申请的。因此,药品申报者为商业利益所迫,必然会积极地催促DMF持有者尽快改正欠缺,回复FDA。DMF持有者在改正欠缺并回复FDA后,还应立即通知用户已回复了FDA之事实,并注明回复日期。
       最常用的DMF是药物原料和制剂包装材料类。有些非药性成分如新颖的辅料也可以申报DMF在FDA备案。一般来说已在美国药典/国家处方集上的通用辅料的化学生产资料,FDA不再进行评审。
0 t# n5 z7 P' }  h3 P; H       此外,如果是非处方药(OTC)制剂,并已经被收录在FDA的OTC专论(OTC Monographs)管理系统内;只要OTC完全按照OTC专论标准生产和标签,制造商无须向FDA申请便可以直接将OTC药产品销往市场,(当然,OTC产品必须符合药品生产质量管理规范(GMP)、取得美国国家药品登记号(NDC)、以及进出口有关的法规要求),因此所涉及的药物及包装材料也不会涉及DMF的审查。例如,胃药雷尼替丁(Ranitidin)作为处方药上市要经过FDA审批,因此FDA要审查所用雷尼替丁的原料药DMF,以及所有包装资料的DMF。而抗组胺药马来酸吡拉明(Pyrilamine Maleate)作为OTC药上市则无须申报,原料药和包装材料的DMF亦无须评审。因此,对OTC制造商来说原料药和包装材料是否有DMF在FDA存档备案便不似处方药那样至关重要。
       FDA法规并不要求DMF的申报:事实上FDA并没有任何法规要求企业一定要申报DMF。DMF持有者完全可以不向FDA申报,而把有关化学生产资料(CMC)递交用户作为其药品申报资料的一部分申报FDA。但这种方式不仅要为每一用户提供同样的资料,更重要的是无法保护独特的生产机密,并且也不能减免《仿制药收费法案》中所要求的DMF费。
       在DMF用户的药品申报资料中(IND,NDA,ANDA申请及其补充和修正材料),FDA不要求申报者必须包含那些已经以DMF形式在FDA备了案的重复资料信息;由DMF持有者呈交一份授权书,允许FDA审查有关的DMF即可。在这方面上FDA比多数西方国家的药品管理权威机构显得更合理和更有效率。在加拿大和其他欧洲西方国家,尽管DMF资料已经备案,药品审批部门仍然要求药品申报资料中含有所参照DMF的非机密部分(Open Part)资料。这样,DMF持有者还必须向每一用户提供删除了机密部分的DMF资料。由于DMF持有者为用户提供资料的详细程度很难定义,对机密部分的解释也有所不同,常常是药品审批部门所要求的信息没有包含在给用户提供的资料中。由于审批部门向药品申报者索要,随即申报者向DMF持有者索要。而DMF持有者因怕生产机密流失不愿意提供详细内容,企业有时要花费许多时间和精力解释,因此有时会对药品审批时间上有所延误。FDA的药品法规管理虽然最严格,但也相对科学合理。这是因为FDA在制定政策中尽量考虑不增加企业的负担。
       很多情况下创新药申请的申报者自己拥有原料药DMF的知识产权,它在NDA中包括了全部的原料信息,因此不用申报二类(原料药)DMF。但包装材料和辅助内容广泛复杂,一般属其他公司所有,又很难包括在NDA里,所以一般都以DMF形式申报存档。
       1.2 DMF类别
       DMF根据内容划分为五类,各类DMF的要求在性质上有所不同。每次申报的DMF必须只含有单一类别的DMF资料及其支持数据,不可混合。
/ K1 F4 I" z: A9 X6 ~- Y3 I) y8 k       1.2.1.一类DMF--成品制剂企业
       一类DMF是制剂药厂信息,包括地点、厂房设施、操作规程、包装、测试以及雇员素质培训等详细情况。这类DMF的持有者一般是药品制剂生产者自身,即新药申请(NDA)、简化新药申请(ANDA)、以及修正(Amendments)和补充(Supplements)申请的持有者。$ \2 g) m, X% ]/ ?! B
       由于向FDA申报和不断更新DMF资料给企业带来了一定的负担,这类资料虽然对FDA进行药品批准前现场检察(PAI)和两年一度的例行GMP检察很有实际意义,检察员可以根据所报DMF资料进行有的放矢的现场核准,但这些资料并不对FDA药品评审员有直接的帮助。因此,在1993年被提议取消一类DMF后,经过与企业的反复商讨,FDA在1995年7月3日发布了通知,正式取消一类DMF。
       1.2.2 .二类DMF--原料药物
       二类DMF包括原料药物、原料药中间体、以及在制备中所用的材料、制剂、化学原料、合成工序、以及中间和最终产品质量控制等内容。这类DMF持有者也许和制剂生产者有组织机构关系,如纵向联合的跨国公司拥有自己的原料药生产企业,但更多情况下是原料药物生产企业为自己的产品向FDA申报DMF。
       1.2.3.三类DMF--包装材料
       三类DMF包括内容广泛的包装容器中各部件材料。内容之广,品种之多,部件之复杂以及生产过程差异之大等等,使药品申报者在申报中不可能包括包装材料,因此在FDA存档备案的DMF成为最佳选择。三类DMF持有者一般和药品申报者毫无关系,他们是独立的包装材料生产商。例如药品包装用的塑料瓶包装系统,塑料瓶制造商本身提交塑料瓶DMF,塑料材料本身由其他的供应商提供,形成了另一个DMF;塑料瓶所配的塑料盖又也许是另一个厂家的DMF,塑料盖内层的衬垫也各有各的DMF,通常属于不同的公司所有。如果塑料瓶或盖是有色的,所使用的色剂也有其生产商申报的DMF。( e( l" a' \0 I" E" O* B( V
       1.2.4.四类DMF--药用辅料类
       四类DMF包括辅料、色素、香精、调味料及其他添加剂等非药性成分。
2 s# u$ `4 F3 o) i       1.2.5.五类DMF--其他
       五类DMF包括FDA已接受的除化学生产控制(CMC)以外的资料,必须在FDA同意下方可申报。
       对于非临床数据资料和临床数据资料等,FDA并不鼓励采用第五类DMF形式申报。如果DMF持有者希望在该类DMF中介绍不符合以上第一至第四类定义的数据资料,申报者必须事先与FDA药物档案部门联系,递交一份意向书。随后,FDA便会与DMF持有者联系,讨论该持有者所提出的第五类DMF的上报内容。未经FDA商议不可擅自申报杂类DMF,否则会被退回。      
       1.3 FDA的DMF信息网站
       在FDA备案的DMF在逐年增多,但其中多数属于'非活跃'类,即在几年均未向FDA申报DMF年报或其他更新。截止2014年,在FDA备案的DMF总共有28696份,但其中活跃DMF为13836,仅占总数的48%。在活跃的DMF中,二类(原料药)占69%,三类(包装材料)占20%,四类(辅料)占9%,五类(其他)只有2%,可被引用的二类(原料药)DMF占17%。截止2014年底三季度,申报FDA的总数为28697份,其中活跃DMF为13836份(48%),二类DMF为9573份(活跃DMF的69%),三类DMF为2821份(活跃DMF的20%),四类DMF1211份(活跃DMF的9%),五类DMF231份(活跃DMF的2%),可被引用的二类(原料药)DMF2379份(活跃DMF的17%)。由此可见,申报FDA的DMF一般50%仍有活动,且二类DMF原料药约占总活跃DMF的2/3。值得一提的是,近年来由于诸多的创新药逐渐失去专利保护,仿制药的研发和上市导致了原料药DMF的增加。据统计,由印度公司申报的二类原料药DMF占活跃原料药DMF总数的1/3;2011年,印度上市和非上市制药公司向美国FDA提交了404份DMF。在2012年第一季度,这些公司提交了97份DMF。统计显示,2010年和2009年,印度制药公司总共向美国FDA分别提交了311份和271份DMF。
       FDA的DMF信息网站列出所有申报FDA的各类DMF清单,未缴费二类DMF,三类,四类和5类DMF列入总清单称为'DMF清单'(DMF Lists),交费后二类原料药同时列入'可被引用清单'(Availableto reference)。清单内容包括DMF登记号、DMF类别、备案日期、申报单位名称、DMF科目名称、以及DMF的更新状况等信息。所提供的DMF清单以微软的Excel和ASCII码两种格式提供,总清单每季度更新一次,可被引用二类DMF清单每周更新一次。FDA的这种绝对透明的信息提供,给予DMF用户极大的帮助。如果某公司宣称已向FDA申报了DMF,从FDA的DMF网站上便可以查证。查询网址如下:http://www.fda.gov/cder/dmf/: j8 f' Y4 e" G% k
  DMF状态:
/ ?& r; l) v7 G  ' 'A' = 活跃。指该DMF已经行政备案,并且没有关闭;
' C6 |5 F+ Y. A& C/ l) ?  ' 'I' = 失效。指该DMF已被所有人或者FDA关闭;0 i& c% c* _& z
  ' 'P' = 悬置。指该DMF正在形式审查
7 m7 ~8 N( @" ~. N  ' 'N' = 未分配DMF号- k! k# a- v! I( H7 R& V5 x8 Q
       1.4 仿制药收费法案下FDA对DMF的一般要求
       管理药物档案(DMF)系统对FDA来说是一项艰巨任务。历年来FDA对DMF管理系统不断地改进,目的是使FDA的政策和评审程序变得更加明确,并同时使企业双方(DMF持有者和药品申报者)更全面地了解自己的职责,同时也使企业和FDA双方之间的管理工作更加容易。由于DMF内容千变万化,对编写格式和内容,FDA只能提出原则性的要求和希望,对于二类和四类DMF,FDA推荐使用CTD格式,三类DMF也可以按CTD格式申报。
       1.4.1、DMF费
       为了加快仿制药的审评并减少企业的成本,FDA于2012年出台了仿制药收费法案,此法案要求二类原料药DMF必须缴纳一次性的DMF费,此费用可以是DMF所有人缴纳,也可以是DMF的用户缴纳,FDA会根据年度预算对DMF费作出一定的调整。2012年至2014年DMF费用如下表:
  • 2012.10.1至2013.9.30——$21,340
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  • 2013.10.1至2014.9.30——$31,460. h6 z5 I$ |! P- e$ L+ a+ p0 M
  • 2014.10.1至2015.9.30——$26,7207 i+ f+ C/ r4 @' w
          
    ; X$ c8 v( F3 D2 J+ \以下类型的DMF不需要缴纳DMF费:
    ' ?) M  c0 e, I& t

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         ★三类、四类和五类DMF;4 R; v" _8 u: W7 Z9 a8 U; @
         ★二类DMF:用于支持NDAs和INDs注册、原料药中间体、原料药中间体生产中用到的物料、制剂。
& e! W. J' [$ _9 l3 w- s6 N) q  k         1.4.2、完整性审评(Completeness Assessment)
       当二类原料药DMF所有人填写仿制药费用表(FDA表格 3794)并缴纳DMF费后,FDA将会对该DMF进行完整性审评,与全面的科学评估不同,完整性审评是为了确认DMF中的信息能否充分支持仿制药的注册,完整性审评的内容如下:
; l$ ]- A' k6 A7 h  ★ 该DMF的状态是否为活跃?) y( h0 e0 i/ s" v% z" R. x
  ★ 费用是否缴纳?
" `8 f- r, m5 z  ★ 该DMF是否以前被审评过?( d3 s$ t+ I& T* G& A
  ★ 该DMF是否只含一个活性物质?, e* S9 i5 i2 G8 p, X# {0 F, Z9 u
  ★ 该DMF中是否含有行政信息?
' [+ e4 `% f+ `, ^* q. R: n! f  ★ 该DMF中的是否含有进行全面科学审评所需的所有信息?
  A: g6 J* P- G4 |, o5 V  ★ 该DMF是否用英语书写?- Y7 s) V" h6 E# [, |- i
       对于进行全面科学审评所需的所有信息,FDA发布了'完整性审评清单',在清单中列出了进行完整性审评所需的所有信息。
         1.4.3、申报DMF的要点
       如果DMF申报资料在形式和管理要求上有较大的不完整或不合适,FDA药物档案管理人员会将申报资料退回DMF持有者,并附函件解释原因,退回的DMF不授予登记号。FDA的指导要点如下:6 K6 B3 c) y# h8 N# F
  ★提供DMF的概述、详细目录和索引以方便评审员的阅读和理解。* b: R% |8 d- G. ?3 m; [! L0 w* k
  ★应以文字形式解释DMF数据,而不是罗列数据和表格。
/ L  U# @9 M8 e, V3 D  ★标明用户所参阅的DMF章节,便于用户在药品申报资料中注明。5 T% M, _6 j+ Y, T
  ★在用户药品申请(NDA、ANDA等)申报之前呈交DMF。注意申报正确的DMF类型,并及时修正更新。
$ _- ?' v/ @, R% x$ q  ★DMF内容应尽量简洁,但原则上要满足用户药品申请所需要的评审信息。按照用户药品申请的特殊需求来撰写的DMF最有使用价值。
9 m# t. X, _; Y$ O3 d* w0 x2 d  ★可电话咨询不清楚的各种问题。
- k6 g- Z. L6 i( Y       FDA中心档案室(CDR)工作人员对其进行形式审查,确定在格式和内容上是否符合规定的要求。如有微小缺漏,DMF管理人员会向申报者发出形式欠缺通知。最常见的问题是缺少申报声明(Statement of Commitment)。被接受的DMF会被输进FDA的DMF数据库,指定一个DMF登记号,并向DMF持有者发出接收通知。如果在三周内没接到FDA的接受通知,DMF持有者可以电话形式向FDA询问。
6 }3 t/ S  ~9 z! a! @       1.4.4、DMF格式要求
       DMF必须使用英语。如果申报资料中含有其他语言信息,资料中必须包括经过公证的准确英语翻译。每份DMF都必须注明页数和日期,并包括详细的内容目录表。格式要求还包括如下:$ S" Q7 B! D. b4 M
  ★所有申报的DMF必须一式两份,正本和复本。DMF持有者及代理人还必须保留所申报的复本,并以申报的时间顺序维持DMF原始申报和修正申报。, ^: E0 `0 k9 ?# G8 @% s( _1 G
  ★每份DMF应该只含有单一类资料,不可混杂内容。
4 Y  A9 v! n3 y4 V3 P+ Z4 y  ★所有原始本和复本都必须经过校对、装订。每卷的厚度不应超过两英寸,并注明卷数。
" d) t( ~, k3 W0 C0 M3 Y# \% c: u  ★所有纸张是标准尺寸(8.5×11英寸)。个别表示场地蓝图、合成工艺图示等必须用超尺寸纸张时,应折叠并入标准卷。内容显示和装订应以不影响评审为基准。
  \. N3 g4 \. \) V- C  ★每份DMF申报资料必须附带一份概述,描述有关DMF申报的管理性信息以及所申报DMF的内容性质。
       目前FDA的DMF还可以通过电子提交的方式注册,但是只支持eCTD格式的电子注册,二类、三类和四类DMF都可以通过eCTD的形式提交;FDA推荐以电子形式提交DMF,当不作为强制性要求,以电子形式提交的DMF,在DMF清单中的主题部分会标注'ESUB'。$ A& q, S2 n9 q! W9 E. X
       1.4.5、DMF概述内容(Cover letter)
       DMF概述应包括如下内容:. v6 s- U6 W. f4 h
  ★确认申报类型:原始或补充修正申报、DMF类别(如是修正,注明DMF登记号)、以及申报科目;
& g; e# d3 e3 }% m2 s6 e  ★确认所支持的药品申报者(用户)名单,包括药品主办者或申报者名称、地址等;" n8 \9 v" p: ~: C# I+ Y' r  r
  ★行政管理性信息:DMF持有者名称和地址、法人组织总部、制造/加工设备场地、公司联系人、驻美国代理人、以及所列个人和团体的责任;
, i) V) Y* U2 s! J9 r4 V  ★承诺书:一份DMF持有者署名声明,确认DMF是现实的,且持有者将遵守DMF所述各项规程;$ Z1 X  v7 E# ~, y( W' {
       如果申报是修正的DMF,还应包括以下内容:8 M; C! B; A" F' q( L
  ★简述申报的(如:更新、改变配方、改变工艺或回复FDA申报等);9 b2 n) G% W1 ^) j# N5 r% L7 O* O
  ★ FDA欠缺通知的时间和通知者姓名;% d+ L1 @/ A2 r6 t9 W
  ★被修正的DMF章节、页数;8 U' U) e) u; {  [- G; ~! T
  ★受修正影响用户(药品申报公司)名单。& j1 U4 L  }0 a: r# O: Q
       1.4.6、环境影响评价
) |. L9 a/ i0 h8 a3 \. I& G       第二、三和四类DMF申报必须包括环境影响声明:声明在DMF产品/制造/加工中将遵守相应的环境保护法规。倘若必须递交完整详细的环境影响评价报告,请参考《联邦管理法》(21 CFR 25)'环境评价'一节。FDA指导文件《环境评价准则》(Environmental AssessmentGuidelines)有详细解释。  
       1.4.7、DMF授权书
$ `' C% o' _: U9 L( R       授权书,即Letter of Authorization(LOA)是由DMF持有者授权另一药品申请者,将DMF部分或全部内容以参阅形式纳入其药品申请(NDA、ANDA、IND等)资料中,以支持其药品申请有关材料的质量保证。授权书必须一式二份包括在DMF中。授权书中应描述所授权的特定厂商和特定产品。
       授权书内容包括:日期、DMF持有者名称、DMF登记号(如已知的话)、授权参阅的药品公司名称、DMF牵涉的特定产品名称(这点对包含了众多产品的庞大复杂的三类DMF特别重要)、所参阅的DMF章节页数、以及确认DMF是现实的,承诺将遵守DMF所述各项规程,授权人姓名、职称及签名。
       DMF持有者还必须将授权书复本呈交用户(药品申报者),由药品申请(IND,NDA和ANDA等)者包括在其申请中。如果药品申报者拥有DMF知识产权,即自己是DMF持有者,也应该在DMF中递交授权书,其内容与第三方DMF持有者的授权书无区别。FDA药品审评官员仅根据用户的复本向DMF档案室提取资料审查。2 H) z5 F5 X, A5 L' j- Y( c5 ^
       1.4.8、DMF用户名单
5 f% n- D# H7 m9 `+ {       联邦管理法(21 CFR 314.420 d)要求DMF包含一份用户名单,列出授权FDA参阅其DMF的所有药品申报公司。DMF持有者必须在每年向FDA申报的年报中更新此名单,并注明每个在年度年报中被撤销授权的参阅者。如果名单无变化,DMF持有者也应递交声明,说明用户名单与前一年度相同。


2 .  DMF持有者职责
       FDA在《药物档案准则》(Guidelinefor Drug Master Files)中明确指出了DMF持有者的职责。第一条就是及时申报DMF变更情况,包括对个别用户授权的情况改变。这种修正的申报必须一式两份,并详细告知改变所对应的原始DMF章节部分,包括卷数和页数。DMF持有者的职责还包括及时通知FDA其DMF持有者/厂商名称和地址的更改,驻美代理人变动等管理性信息。
       2.1 指定DMF驻美代理人
       虽然不是法定要求,但FDA强烈建议美国以外的DMF持有者指定在美国的代理人,以便于信息交流。美国境内的DMF持有者则不用指派代理人。
       代理人的职权范围应在代理人指派信上明确指出。应注意的是用'指派'(Appointment)而不要用'授权'(Authorization)。'授权'仅用于呈交FDA的授权书上。DMF的代理人不同于生产商注册(Registration)和药品登记(Listing)的代理人。当指派DMF驻美代理人时,DMF持有者应在指派信上明确描述代理人姓名、地址、职权范围(行政管理和/或科学技术)。
       2.2 向用户提供授权书(LOA)
       DMF持有者必须向用户提供一份授权书,允许FDA代表用户审查所存档的DMF资料。DMF用户的临床试验申请(IND)、新药申请(NDA)或仿制药简化新药申请(ANDA)资料必须要包括DMF授权书复本,否则不可通过药品申请的第一道关卡--资格审核。有时由于时间紧迫的关系,会出现DMF和药品申请(IND、NDA或ANDA)同时申报FDA的情况,而因DMF资料刚刚或同时在申报,还没有得到DMF登记号,因此授权书上无法提供DMF登记号。暂时性的解决办法是先在申报DMF时递交没有DMF登记号的授权书,注明主题、持有者名称和DMF申报日期。当获得登记号后再递交更新的授权书。
       2.3 向用户报告DMF变更
       DMF持有者必须及时通知用户(药品申报者)DMF的变更情况,包括技术和管理方面的改变信息。特别要强调的是,及时通知原料药DMF改变对用户来说事关重大。因为按照FDA规定,DMF的改变根据性质和产生的影响不同,有不同的申报级别,各级别对制剂的批准在时间上有很大区别。例如,对药品质量不存在潜在影响的改进可在年度报告中通知FDA,对产品有潜在影响的一般改进必须提前30天向FDA报告,而较大的改进则必须事前获得FDA允许后方可施行。因此DMF用户(药品申报者)需要一定的时间,根据DMF改变信息而作出相应的申报决策和生产计划。
       许多微不足道的小改进没有必要申报FDA或通知用户。如果是属于年报级别的改进,应包括在DMF年报里或申报修正,并通知用户年报性变化。如果是属于'已生效的变更'(CBE)级别或'预批准级补充'(PAS)级别的改进,DMF持有者应向FDA申报修正(Amendment),并通知用户修正类别。   在药品制剂被批准上市后所作的化学生产控制(CMC)改进被称为是'批准后变更'(Post Approval Change)。例如:辅料和组成(Ingredients and Composition)改变、生产和加工场地迁移、制造方法程序改进、产品规范改进、包装系统变更、标签改变、其他改变和多项改变等。
% E: u8 l- c  f8 G       FDA对批准后变更有严格详细的控制和申报程序规定。药品批准后变更的申报根据该参数变化对药品潜在影响程度的大小划分三类:主要变更、适当变更、和微小变更。
       2.4 DMF年度报告
       DMF持有者应每年通过驻美代理人向FDA递交一份DMF年度报告,列出所有授权参阅该DMF的公司名单。FDA每两到三年进行DMF复查。
       如果DMF持有者没有按照规定申报DMF年报,并报告所有DMF改变情况和更新用户名单,FDA并不对其进行追踪或督促。FDA仅仅是将DMF列入'不活跃类',甚至根据程序将其DMF关闭。其所涉及的药品申请将会受到延误。FDA此种做法是利用所涉及药品公司来牵制DMF持有者遵守法规。
       2.5 DMF转让: ^/ M% M" j& s  v+ i
       如果DMF 转让他人,原DMF持有者应向新持有者提供书面转让书,并发函通知FDA该所有权的转让。通知函上应注明生效日期、提供新持有者公司的名称和地点、以及转让方负责人姓名、职务、并签字。新的DMF持有者也应向FDA发函接受DMF的转让、更新DMF信息,并承诺履行所有前任DMF持有者的责任。
       2.6 DMF关闭
       当DMF持有者希望终止DMF时,应向FDA呈报说明终止理由的申请。申请上应声明已履行了所有DMF持有者责任。
       如果DMF没有更新,或没有按时递交年度报告,包括年度中的DMF改变情况和授权FDA评审的用户名单,FDA可以自行解决关闭DMF,但FDA会在关闭之前通知DMF持有者。应注意的是DMF持有者递交授权书(Letter of Authorization)不能算更新申报。
       原料药物的生产,无论是通过化学合成、发酵、或是分离,通常都始于粗原料;原料药的制造加工过程一般牵涉到极其复杂的化学反应和工序,变形到中间体,最后得到适用于人用药品的原料药。制造加工的过程中由于各种原因必然会使成品原料药中包含少量的各类杂质,影响药物的功效,甚至毒害集体。为保证药品的安全有效,药品监管部门必须对原料药的质量进行严格的控制。
       原料药供应商要解决的主要问题有:一是要遵从cGMP标准生产,二是要有DMF申报。对于准备进入国际市场的中国原料药企业来说,首先必须通过现行的药品生产质量管理规范(Current Good Manufacture Practice,cGMP)认证,这是医药产品进入国际市场的先决条件。中国企业国际GMP认证刚刚起步,目前中国执行的GMP认证,在概念和标准上与目前欧洲、美国、日本、加拿大等西方各国执行的GMP规范还存在一定的差距。一种原料药(API)的生产和经销要经过研发、小试、中试、工业生产、DMF申报、用户药品申请、以及产品上市后法规的遵守等一系列程序。原料药DMF文件(二类DMF文件)主要面对以下三类客户:专利药公司(品牌或创新药)、仿制药公司、以及小型医药研发公司。
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