如何提交ASMF

如何提交ASMF？

24. How should I submit an active-substance master file (ASMF)? Rev. August 2014

我应该如何提交一份ASMF文件？2014年4月，修订悉锋

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000020.jsp&mid=WC0b01ac0580022713#

Annex I to Directive 2001/83/EC describes the concept of an open and closed Active Substance Master File (ASMF) and specifies that:

指令2001/83/EC附录1中描述了ASMF公开部分和保密部分的概念，特别指明：

“For a well-defined active substance, the active substance manufacturer or the applicant may arrange for the:

“对于一个其性策已界定良好的活性物质，活性物质生产商或制剂申报人可以安排：”

i) Detailed description of the manufacturing process 详细的生产工艺描述

ii) Quality control during the manufacture, and 生产过程中的质量控制

iii) Process validation 工艺验证

to be supplied in a separate document directly to the competent authorities by the manufacturer of the active substance as an Active Substance Master File.

放在一个单独的文件中，由活性物质的生产商作为一份ASMF直接提交给相应药监当局

In this case, the manufacturer shall, however, provide the applicant with all of the data, which may be necessary for the latter to take the responsibility for the medicinal product…”

在这种情况下，生产商应向申报人提交所有之后申报人对药品承担责任所必须的数据

It should be emphasized that the concept of the ASMF shall only apply to a well-defined active substance and cannot be used for excipients, finished products and biological active substances. The information related to excipients, finished products and biological active substances shall be provided within the Marketing Authorisation Application (MAA) by the applicant.

要强调的是，ASMF的概念仅适用于性质已良好界定的活性物质，不适用于辅料、制剂和生物活性物质睁衡晌。与辅料、制剂和生物类活性物质拦数相关的信息应在MAA中由申报人提交。

In case an application under the Centralised Procedure includes the submission of an Active Substance Master File (previously referred to as European Drug Master File (EDMF)), applicants should be aware of the fact that, as mentioned in the Guideline on Active Substance Master File Procedure (CPMP/QWP/227/02), an ASMF consists of 2 parts:

如果采用了集中审评程序提交申报资料，包括ASMF（之前称为EDMF）提交，则申报人要明白，正如ASMF程序指南 (CPMP/QWP/227/02)中提到的，一份ASFM包括2个部分：

l An ASMF Applicant’s Part, also referred to as Open Part, which shall be at the disposal of the applicant.

l 一个ASMF申请人部分，也称为公开部分，应由申报人处理

l An ASMF Restricted Part, also referred to as Closed Part, which is a confidential document closed to the applicant.

l 一个ASMF受控部分，也称为保密部分，它是不对申报人公开的一份保密文件

Both parts need to be separated and follow the structure of the Module 3.2.S of the CTD.

两个部分需要分开，根据CET模块3.2.S的结构编写。

The content requirements as described in the above mentioned Guideline should be followed.

应遵守上述指南中所述的内容要求。

It is necessary for the applicant and the ASMF holder to liaise to ensure that the ASMF including all necessary documents are synchronized to arrive at ideally the same time as the planned MAA to be submitted by the applicant, although an interval of some days may be allowed. Note that the marketing authorisation application cannot be validated until all the necessary documents are received in a satisfactory form. This also applies to the ASMF-related responses to Day 120 LoQ and Day 180 LoOI. Applicants should be aware that the procedure cannot re-start until the responses from the ASMF holder are received by the Agency.

申报人和ASMF持有人应取得联系，保证ASMF包括所有必需的文件，并与计划的MAA提交时间同步到达药监当局，当然前后数天的差异是允许的。要注意的是，在所有必须的文件被收到，且格式符合要求之前，药监部门不能对上市许可申报进行核查。这也适用于与ASMF相关的120天LOQ和180天LOOI回复。申报人应明白只有在药监当局收到ASMF持有人的回复后，该程序才会重新开始。

Non applicability of ASMF concept to biological active substances

生物类活性物质不适用ASMF概念

Further to clarifications from the European Commission on the interpretation of Directive 2001/83/EC as amended, and the subsequent announcement in the October 2004 CHMP Monthly report, the ASMF concept is not acceptable for biological medicinal products.

欧盟委员会关于指令2001/83/EC的解释的澄清以外，在2004年10月CHMP月报中又进行了宣布，ASMF概念被用于生物类药品是不可接受。

The characterisation and determination of biological active substances requires not only a combination of physico-chemical and biological testing, but also extensive knowledge of the production process and its control.

生物类活性物质的特性和检测不仅要求复合的理化和生物类检测，还需要有大量的生产工艺及其控制的知识。

The MAH/applicant for a biological medicinal product could therefore not comply with the requirement to ‘take responsibility for the medicinal product’ without having full and transparent access to these quality-related data. The use of an ASMF would prevent such access, and should therefore not be allowed for biological active substances.

没有全面和透明的质量标准数据前提下，生物类药品MAH/申报人无法符合“承担药品责任”的要求。使用一份ASMF将阻止申报人获得这些资料，因此ASMF不能允许用于生物类活性物质。

In addition, active substances, which are present in certain medicinal products such as vaccines or cell therapy medicinal products, do not fit with the concept of a ‘well-defined’ active substance.

此外，活性物质，如果出现在例如疫苗或细胞治疗药品中，不满足“良好界定”的活性物质的概念。

Non applicability of ASMF concept of open and closed parts to Vaccine Antigen Master File (VAMF) and Plasma Master File (PMF)

公开部分和保密部分的ASMF概念不适用于疫苗主文件（VAMF）和血浆主文件（PMF）

The concept of the ASMF does not apply to blood derived medicinal products and vaccine antigens. In this context, the manufacturer can submit a PMF or a VAMF.

ASMF概念不适用于血液制品和疫苗抗原。在这种情况下，生产商可以提交PMF或VAMF。

Regarding the VAMF, the legislation specifies that the VAMF holder cannot differ from the MAH/applicant for the concerned medicinal product: there is hence no rationale for an open /closed parts system.

关于VAMF，法律指骨出VAMF持有人必须与MAH/相关药品申报人相同，因此没有理由采用公开/保密部分系统。

For VAMF linked MAs, if a particular MAH name and address are not identical to the name and address of the proposed VAMF certificate holder, a relevant declaration should be provided attached to the application form, stating that the MA applicant and the MAH belong to the same mother group of companies, which share the same data package.

对于与MA相关连的VAMF，如果特定的MAH名称和地址不同于所提交的VAMF证书持有人名称和地址，则应提交相关的声明附于申报表中，说明MA申报人和MAH持有的属于同一个集团，可以共享相同的数据包。

For the PMF the legislation specifies that where the MAH/applicant differs from the holder of the PMF, the PMF shall be made available to the MAH/applicant for submission to the competent authority.

对于PMF，法规说明如果MAH/申报人不同于PMF持有人，则MAH/申报人应可以获取PMF提交给药监当局。

根据不同国家和地区对注册程序的规定和DMF的编写要求不同，DMF大致分为两种，一种是欧洲共同体国家所要求的DMF（简写为EDMF），也称作ASMF (活性物质主文件）；一种是美国FDA所要求的。前一种要求重点介绍产品的工艺质量控制、杂质和稳定性研究等方面的资料和数据衫森嫌；后一种DMF被细分为五类，在EDMF基础上，尚需介绍生产厂的厂房、设施、人员、GMP管理、或手机构和职责等方面的内容。当然，现在只有后四类，第一类不再有效。

在欧共体，DMF是办理市场销售许可证的一部分。药品要在欧共体或销售国家药品管理局申报一套资料，办理市场销售许可证。当药品所用的活性成份（即原料药）的供应商改变时，同上办理。而DMF是申报资料的重要部分。不按要求提供DMF，就不能把所生产的产品销售到该国家。

在美国，虽然FDA没在正式文件中规定出口到美国的原料厂家必须上报DMF资料，但实际上大家都在做，而且美国FDA也发表了编写DMF文件的指南。若该原料药被用做处方药的成分时，则美国FDA一定派员对生产厂家进行检查，以确定该厂的生产是否与上报资料所述相符，是否是按美国CGMP（现行GMP）要求进行。鉴于欧共体和美国对进口原料药的严格的管理春差，编写一份符合要求的DMF文件对促进原料药的出口是至关重要的。

CE是欧盟强制性认证

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