如何读懂CEP?

发布日期:2018-05-28 08:18 字号:

1. Introduction概述
This document has been created with the intention ofclarifying the information to be concluded from a Certificate of suitability tothe Monographs of the European Pharmacopoeia (CEP) for Industry and theCompetent Authorities.
制订本文的目的是向企业和药监机构解释CEP证书上包括的信息。
Specifically, this document describes in detail theinformation conveyed on a CEP.
具体来说,本文详细解释了CEP所要传达的信息。
Marketing Authorisation (MA) applicants are advised toread existing guidance published by the Competent Authorities in their countries,or to contact them directly for advice, when using a CEP to replace therespective quality part of the CTD dossier related to that given source, or inany variation.
上市许可(MA)申报人在使用一份CEP替代CTD文档中指定来源相应的质量部分,或提交变更时,建议其阅读其所在国药监机构发布的现有指南,或直接联系获取建议。
Competent authorities may contact the EDQM if theyhave questions concerning the content of the CEP which prevent them performingthe evaluation of the MA application (MAA). If necessary, they may ask for theCEP assessment report.
药监机构如果对CEP内容有问题,可能阻碍其对MA申报(MAA)进行评审,可直接联系EDQM。必要时,他们亦可要求查看CEP评估报告。
CEPs are normally accepted in all countries which aremembers of the Ph. Eur. Convention. CEPs may be accepted in countries which arenot members of the Ph. Eur. Convention at the discretion of the authorities inthose countries.
欧洲药典委员会的所有成员国一般都接受CEP。非欧洲药典委员会成员国的国家可自行裁定是否接受CEP。
The regulatory basis for the CEP procedure is:
CEP程序的法规依据为:
―  Resolution AP-CSP(07) 1 “Certification of suitability to the monographs  of the European Pharmacopoeia” (available onthe EDQM website), adopted by the Public Health Committee (Partial Agreement)of the Council of Europe.
―  决议AP-CSP (07) 1“欧洲药典各论适应性证书”(EDQM官网上可找到),由欧洲理事会公众健康委员会(部分协定)采纳。
―  In the EU, EUDirectives 2001/82/EC and 2001/83/EC, as amended, of the European Council andof the Parliament on the Community code relating to medicinal products forhuman and veterinary use.
―  在EU,欧洲理事会和欧共体议会人兽药法:EU指令2001/82/EC和2001/83/EC及其修订案。
―  In the EU, NfG“Summary of Requirements for Active Substances in the Quality part of thedossier” (CHMP/QWP/297/97 Rev 1 corr & EMEA/CVMP/1069/02).
―  在EU,NfG“文档中质量部分里活性物质要求综述”(CHMP/QWP/297/97 Rev 1 corr & EMEA/CVMP/1069/02)。
This document should be read in conjunction with otherapplicable Certification Policy Documents and Guidelines.
本文应与其它适用的认证方针文件和指南一起解读。

2.  Aimand Scope of a CEP CEP证书的目的和范围
A CEP covering chemical purity and microbiological quality certifies, based on the specific data supplied by the manufacturer,that the quality of a substance can be suitably controlled by the Ph. Eur. monograph, i.e. that the quality of asubstance corresponds to the quality defined in the Ph. Eur. monograph.
CEP包括有化学纯度和微生物质量,它依据生产商提交的具体数据,证明某个物质的质量可以使用欧洲药典各论进行适当控制,即某个物质的质量对应着欧洲药典各论中所定义的质量。
Furthermore, as stated in EU Directives 2001/83/EC(Part I, section 3.2, paragraph 5) and 2001/82/EC (Part II, section C 1.1),where the substance “has been prepared by a method liable to leave impuritiesnot controlled in the respective Ph. Eur. monograph, these impurities  and their  maximum  tolerance limits  must  be declared  and  a suitable  test procedure must bedescribed”. The additional impurities (not included in the Ph. Eur.) and theiracceptable limits will be listed on the CEP and the analytical method will beappended to it so these impurities can be suitably controlled. These additionaltests and acceptance criteria supplement, as necessary, the monographs of thePh. Eur. for the control of this particular source of the substance.
另外,正如EU指令2001/83/EC(第I部第3.2节第5段)和2001/82/EC(第II部第C.1.1节)所说,如果该物质“所采用的生产方法并不控制EP各论中所列的杂质,这些杂质及其最大容许限度必须进行声明,必须描述一种适当的检测方法”。其它杂质(不包括在EP里的)及其可接受标准将列在CEP上,其分析方法将附在CEP后,使得这些杂质可以适当受控。这些其它杂质及其可接受标准在必要时补充了EP各论中对该物质特别来源的控制。
Biologicals are outside the scope of the CEP procedure(see also 4.3.6).
生物制品不在CEP程序范围内(也参见第4.3.6部分)。
Another type of CEP, for TSE risk, certifies that thesubstance complies with monograph 1483 of the Ph. Eur. “Products with risk oftransmitting agents of animal spongiform encephalopathies”, current editionincluding supplements. A TSE CEP does not certify that the quality of thesubstance is suitably controlled by a specific Ph. Eur. monograph.
另一种类型的CEP,TSE风险,认证的是该物质符合EP各论1483“具有TSE风险的产品”,当前的版本包括了增补内容。一份TSE CEP并不证明该物质的质量适合采用特定的EP各论进行适当控制。
A CEP does not certify that a specific batch orbatches of the substance covered by the CEP from a certain manufacturercomplies with the Ph. Eur. monograph and additional tests stated on therespective CEP. CEPs are not equivalent to batch release certificates and shallbe complemented by certificates of analysis demonstrating such batch-relatedcompliance.
CEP并不认证一个或多个特定的CEP所覆盖的物质批次说特定的生产商符合EP各论和相应CEP上所声明的其它检测。CEP并不等同于批放行证书,需要有批COA来补充证明该批次的符合性。
A CEP is not a GMP certificate: although when submitting a CEP application the manufacturer has to confirm that the substance covered by the CEP is produced according to GMP requirements, the CEP is granted following evaluation of data described in the submitted dossier. As acomplementary activity to dossier evaluation, the CEP procedure includes scopefor the performance of GMP inspections of sites involved in the manufacture ofthe respective substance. In line with the above-mentioned EU legislation, theselection of sites to be inspected is based on risk evaluation, which meansthat there is no routine inspection of all sites. As a consequence, a CEP maybe granted with, prior to or without an inspection of the manufacturing site being performed. A CEP, therefore, is neither equivalent to a GMP certificatenor does it replace it. In addition, the CEP may cover different types ofsubstance (e.g. active pharmaceutical ingredients or excipients) and theGMP/quality system which is applied by the company should be declared.
CEP并不是GMP证书:尽管在提交CEP申报资料时,生产必须确认其物质依GMP要求生产,但CEP的颁发是基于对所提交资料中数据的评估。作为对资料评估的补充,CEP程序包括了对相关物质生产所涉及现场的GMP检查。与上述EU法律相一致,对检查场所的选择是基于风险评估的,也就是说并不会对所有场所进行常规检查。因而,可能在没有对生产场所进行现场检查或在检查之前即颁发CEP。因此,一份CEP并不等同于一张GMP证书,也不能取代GMP证书。另外,CEP可能会覆盖不同类型的物质(例如,原料药或辅料),公司亦应声明公司采用了哪种GMP/质量体系。
For CEPs covering only the TSE risk, an appropriatequality system, such as ISO 9000 certification, HACCP or GMP, must beimplemented for monitoring the production process   and for batch delineation (i.e. definitionof  batch, separation of batches,cleaning between batches).
对于仅覆盖TSE风险的CEP,其公司必须实施适当的质量体系用于监测生产工艺和批界定(即,批定义、批拆分、批间清洁),如ISO 9000认证,HACCP或GMP。

3.  Typesof CEP CEP类型
There are several types of CEP, depending on the evaluation performed:
根据所实施的评估内容,CEP分为:
-   Certificatefor chemical purity and microbiological quality (“Chemical CEP”)
-   化学纯度和微生物质量证书(化学CEP)
-    Certificate for herbal drugs and herbal drug preparations (“Herbal CEP”)
-    草药和草药制品证书(草药CEP)
-     TSECertificate (“TSE CEP”)
-      TSE证书(TSE CEP)
Combined CEPs can also be granted, as follows:
也可能会颁发合并CEP如下:
-    Certificatefor chemical purity/microbiological quality and sterility
-     化学纯度/微生物质量和无菌证书
-      Doublecertificate (chemical + TSE)
-     双证(化学+TSE)
-      Doublecertificate (chemical + TSE) also covering sterility
-       双证(化学+TSE)也覆盖无菌
The contents of each type of CEP are described below.
每种类型的CEP内容在以下部分陈述。
For details of grades/subtitles, refer to “Subtitle”under section 4.3.1.
级别/子标题详细内容参见第4.3.1部分中“子标题”。
4.  Contentof a CEP CEP内容
4.1   CEP unique reference (valid for all types of CEP) CEP唯一索引号(对所有类型CEP有效)
The alphanumerical reference of a CEP consists of thefollowing three blocks:
一张CEP证书的索引号由以下三部分数字字母组成:
-    Unchanged root, linked to the number assigned to the original CEP application, composedof 12 characters: CEP procedure number + application year + chronologicalnumber, for example:
-    不变的根编号,它与对原始CEP申报资料的赋号相关联,由12位数字/字母组成:CEP(空格)4位申报年-3位流水号,例如:
CEP 2015-000
-     Variableparts of the reference:
-      变化的部分:
Quinquennial indicator,  which  indicates the  renewal  status of  the  CEP:  3characters, incremented five years after the original CEP is issued:
5年更新号:它表示CEP的更新状态:3位字符,在原始CEP颁发之后5年增加:
RX-
Revision indicator, which indicates the revisionstatus: 7 characters, incremented each time the CEP is revised:
修订标示,它显示修订状态:7位数字/字母,CEP每次修订时数字加1:
- RevXX
These three blocks together constitute the full CEPnumber of 22 characters:
这三个部分一起就组成了22位完整的CPE编号。
RX - CEP2015-000- Rev XX
4.2 CEP declaration of access (valid for all types of CEP) CEP授权书(对所有类型CEP有效)
In order to control the use of CEPs, the CEP holdershould authorise its customers to use a CEP in support of an MAA for aparticular product(s). For that, the CEP holder has to make a copy of theoriginal CEP and fill in the Declaration of access (“Box of access”) at the endof the CEP, including the name of the pharmaceutical company, the name of themedicinal product(s) and reference of the MA (where available). By signing thisbox, the CEP holder also certifies that no changes to the operations asdescribed in the CEP dossier have been made since the granting of the latestversion of the CEP.
为了控制CEP的使用,CEP持有人应授权其客户使用CEP支持具体产品的MAA。因此,CEP持有人必须复印一份原始CEP,填写CEP证书尾部的授权信部分(授权表),包括制药公司的名称、药品名称和MA的索引号(如有)。在此部分签名,则表示CEP持有人也证明自最新版本CEP颁发后其对CEP资料里的操作并无改变。
When a CEP has been revised/renewed, it is theresponsibility of the CEP holder to provide a copy to its customers.
当CEP修订/更新时,CEP持有人有义务向其客户提交一份副本。
It is possible to verify the validity status of a CEPat any time by searching the Certification Database on the EDQM websitewww.edqm.eu, under section “Certification of Suitability”.
通过登录EDQM官网,在“CEP证书”栏目下,搜索证书数据库即可随时核对CEP的有效性状态。
Note: only the CEP holder possesses the original CEPand can issue a valid (“true”) copy to its customers. The EDQM does not keepany original CEPs.
注:只有CEP持有人才拥有CEP正本,可以签发有效的副本给其客户(真实副本)。EDQM不保存任何CEP正本。
4.3   CEPstatements CEP声明
A number of statements are included on CEPs whichprovide transparency on the items that have/have not been considered during theassessment of the CEP application and provide useful additional information toCEP users (including Competent Authorities).
CEP里包括有大量声明,它为CEP申报评估中所未考虑的项目提供透明度,也为CEP用户提供一些有用的其它信息(包括药监机构)。
The statements vary depending on the type ofevaluation performed, as follows:
根据所进行的评估类型,这些声明分为以下几类:
4.3.1 Statements on a CHEMICAL CEP 化学CEP的声明
NOTE: CEPs may contain information which does notfully reflect the active substance specification submitted in the CEPapplication and on the certificates of analysis (some information not beingrelevant to demonstrate suitability/compliance with the Ph. Eur. monograph).The criteria used to decide whether or not to include specific information, suchas tests and limits, and to annex specific methods to the CEP are clarifiedbelow. It is thus important to keep in mind that the CEP frequently lists fewertests and limits than are included in the specification of the substance whichwas accepted by EDQM.
注:CEP可能含有一些信息,并未完全反映CEP申报资料中和检验报告书上的活性物质质量标准(一些信息与证明EP各论适用性/符合性并不相关)。用于决定是否包括特定信息的标准,如检测和限度,并作为CEP附录方法的标准说明如下。因此重点是要记住CEP通常列的测试和限度比EDQM所接受的物质质量标准中所包括的内容要少。
-  Subtitle(e.g. particle size, polymorphic form, sterile) 子标题(例如,颗粒度、多晶型、无菌)
The CEP applicant can request that a subtitle isincluded on the CEP, provided that the conditions laid down in theCertification policy document PA/PH/CEP (04) 1 “Content of the Dossier forChemical Purity and Microbiological Quality” (current version) are fulfilled.
如果符合认证政策文件PA/PH/CEP(04) 1 “化学纯度和微生物质量文档的内容”(现行版本)里列出的条件,CEP申报人可以要求在CEP里包括一个子标题。
Where a subtitle is requested by the CEP applicant,the acceptability of the requested subtitle is assessed within the CEPprocedure, and only if the subtitle is accepted by the EDQM is it included onthe CEP, together with the corresponding test(s) and limit(s) relative to thatparticular grade.
如果CEP申报人要求有一个子标题,CEP认证中心会评估该申请是否可接受,如果接受,则会在CEP上加上子标题,同时会有相应的测试和与颗粒级别有关的测试和限度信息。
The absence of a subtitle on the CEP means either thatthe characteristics related to a particular grade have not been accepted by theEDQM, even where data have been provided in the CEP dossier, or the CEPapplicant has not requested any subtitle.
CEP上没有子标题表示虽然申报人在CEP申报资料里已提交了这些数据,但是要么与颗粒度有关的特性未被EDQM接受,要么是CEP申报人并未申请此子标题。
If the method(s) used is/are not described in the Ph.Eur., the analytical method(s) used by the manufacturer is/are annexed to theCEP.
如果所用方法并未在EP里描述,则生产商所用的分析方法会被附在CEP后。
It is to be noted that grades such as “pyrogen-free”or “bacterial endotoxin-free” are only acceptable when this is stipulated underthe “Labelling” section of the specific Ph. Eur. monograph.
要注意的是象“无热源”或“无细菌内毒素”之类的级别只有在特定的EP各论“标签”部分里有规定时才会被接受。
In particular cases where the Ph. Eur. monographcovers different grades of a substance, it is possible to include thesedifferent grades in the subtitle of the CEP. However, different grades cannotbe covered by a single CEP if these different grades require different limitsand/or methods for the control of impurities. In such cases, separatecertificates will be required and the respective relevant grades will be statedin the subtitles (e.g. povidone, macrogol).
在特殊案例中,如果EP各论覆盖了不同级别的物质,则有可能在CEP子标题里包括这些不同级别。但是,如果不同级别需要有不同的杂质限度和/或方法,则同一张CEP并不能覆盖不同级别。在此情形中,需要申请单独的证书,在子标题里声明对应的级别(例如,聚维酮、聚乙二酮)。
A special subtitle case is “sterile” (see section4.3.3 “Statements on a CEP for a sterile substance”).
上述特殊子标题的案例是“无菌”(参见第4.3.3部分“CEP上无菌物质声明”)。
-    Sites场所
The sites declared in the CEP application are statedon the CEP, according to their respective roles and depending on the subtitlerequested for inclusion on the CEP:
在CEP申报资料里声明的场所会依其相应职责以及申报人要求放置子标题的申请列在CEP上:
The following sites are stated on a chemical CEP:
化学CEP上会写明以下场所:
-   CEPholder
-    CEP持有人
-     Substancemanufacturing site(s)
-      物质生产场所
-      Intermediatesmanufacturing site(s)
-      中间体生产场所
The following sites are only included if a specificsubtitle is requested (and accepted), and if not already listed on the CEP asthe substance manufacturer:
以下场所只有当申请特定子标题(并被接受),并且它未作为物质生产商列在CEP上时才会包括在CEP上
-     Site(s)performing the sterilisation steps
-      执行灭菌的场所
-      Site(s)performing any physical treatment (e.g. micronisation, milling, sieving,lyophilisation)
-     执行任何物理处理(例如,微粉、粉碎、过筛、冻干)的场所
CEPs granted before July 2013 might not cite allintermediate manufacturing sites. In this case, the CEP users need to requestmore detailed information from the CEP holder.
在2013年7月之前颁发的CEP证书可能并未写明所有中间体生产场所。在此情况下,CEP用户需要要求CEP持有人提供更多详细信息。
-     Compliancestatement  符合性声明
Statement by which the EDQM certifies that the qualityof the substance produced at the site(s) listed on the CEP (or its annexes) issuitably controlled by the corresponding Ph. Eur. monograph (current editionincluding supplements), supplemented by the test(s) stated on the CEP and theanalytical procedures included in the annex, where applicable. This means thatthe specification of the substance should include the tests from the Ph. Eur.monograph, together with the additional tests listed on the CEP.
通过此声明,EDQM证明CEP(及其附录)上所列场所生产的物质质量适用采用对应的EP各论进行控制(当前版本包括增补),适用时,CEP上所声明的附录测试和检验方法进行补充。这表示物质的质量标准应包括EP各论中的检测,加上CEP上所列的附加测试。
-      Impurities杂质
The assessment carried out at the EDQM during the CEPprocedure is performed taking into account the known use of an activesubstance. In particular, the maximal human daily dose (MDD) and the route(s) of administration of the alreadyapproved medicinal products in which the active substance is included are usedas a basis to establish acceptable limits for impurities not controlled by themonograph, as well as the options for controls in the case of residues ofmutagenic and elemental impurities.
EDQM在CEP认证程序中所做的评估考虑了已知的活性物质用途。尤其是将最大人体日给药剂量(MDD)和已批准的包括了活性物质的制剂给药途径作为建立不受各论控制的杂质可接受标准的基础,以及有诱变性和元素杂质残留时的控制方式。
Limits for “additional related substances” (those notalready mentioned in the Ph. Eur. monograph). Two cases are possible:
“其它有关物质”限度(在EP各论上未提及的那些“。可能有2种情形:
a)             Ifadditional related substances are present in the substance above the reportingthreshold set by the Ph. Eur. general monograph “Substances for pharmaceuticaluse (2034), and they are detected by the test for related substances of the Ph.Eur. monograph, these in-house impurities are stated on the CEP with specifiedlimits. Unspecified impurities (below the identification threshold) are notmentioned on the CEP and are automatically covered by the general limit forunspecified impurities.
如果有更多的有关物质出现在物质中,超出EP通论“药用物质”(2034)的报告阈值,并且用药典各论有关物质检测方法可检出时,在CEP上列出其特有的杂质以及指定的限度。非特定杂质(低于鉴定阈值)在CEP上不提及,由非特定杂质通用限度自动覆盖。
In this case no method is annexed to the CEP.
在此情形下,没有方法附在CEP后。
b)    Ifadditional related substances are present in the substance above the reportingthreshold set by the Ph. Eur. general monograph “Substances for pharmaceuticaluse (2034), and the Ph. Eur. monograph method is not suitable to control theseimpurities, they should be controlled by a validated in-house method and statedon the CEP (either with a specific limit or covered by the limit forunspecified impurities if found to be below the identification threshold).
如果有更多的有关物质出现在物质中,超出EP通论“药用物质”(2034)的报告阈值,并且药典各论有关物质检测方法不适合控制这些杂质时,则应采用一个经过验证的自建方法进行控制,在CEP上列出该方法(给定一个特定限度,或者如果发现其低于鉴定阈值时由非特定杂质覆盖)。
The in-house method is annexed to the CEP and isconsidered an additional method.
内控方法附在CEP后,作为附加方法。
In both cases (a and b), a limit for total impuritiesis also added if not stipulated in the specific Ph. Eur. monograph.
在上述2种情形中(a和b),总杂限度如果在EP各论里没有具体规定则也会增加。
Non-quantitative methods: 非定量方法
If the method for related substances in the Ph. Eur.monograph is a non-quantitative method (e.g. TLC with a general limit), the testfor related substances is replaced by a quantitative method which is annexed tothe CEP where it is indicated as replacing the Ph. Eur. method.
如果EP各论中有关物质方法是一个非定量方法(例如,只有通用限度的TLC),有关物质的检测可采用一个定量方法替代,该方法会附在CEP后,写明用它来替代EP方法。
Alternative methods: 替代方法
Manufacturers are free to use alternative methods tothose described in the Ph. Eur. monographs provided these methods are at leastequivalent to the Ph. Eur. methods; this has to be demonstrated in the CEPdossier and will be verified during the assessment of the CEP dossier. If themethods are cross-validated, and where the Ph. Eur. monograph is demonstratedas suitable to control the impurities present in the substance, the in-housemethods are not annexed to the CEP. In the event of doubt or dispute, the textsof the Ph. Eur. are authoritative.
生产商可以自由使用其它方法来替代EP各论里的方法,但替代方法要至少等同于EP方法。等同性可在CEP文档里证明,并在CEP文档审评期间进行核查。如果未交叉验证该方法,并且EP各论方法被证明适合于控制物质中出现的杂质,则内控方法不会附在CEP后。发生质疑或争议时,EP正文具有权威性。
Limit for unspecified impurities: 非特定杂质的限度
When the Ph. Eur. monograph of the substance for whicha CEP is granted does not include a general limit for unspecified impurities,according to the Ph. Eur. general monograph “Substances for pharmaceutical use”(2034), such a limit shall be introduced in the specification of the substanceand is included on the CEP. The limit is defined according to the MDD of thesubstance and is in line with the thresholds set by Ph. Eur. general monograph2034, unless the substance is out of the scope of this general monograph.
如果所颁发CEP的物质的EP各论并不包括非特定杂质的通用限度,则依EP通论“药用物质”(2034),此杂质应放在物质的质量标准中,并放在CEP上。应依据该物质的MDD制订其限度,并应符合EP通论 2034所设定的阈值,超出该通论范围的物质除外。
Genotoxic/mutagenic impurities: 基因毒性/诱变性杂质
Until 31 December 2015, the EMA “Guideline on thelimits of genotoxic impurities” (EMEA/CHMP/QWP/251344/2006) and the EMA“Questions and answers on the Guideline on the limits of genotoxic impurities”(EMA/CHMP/SWP/431994/2007 Rev. 3) were applied.
2015年12月31日,适用EMA“基因毒性杂质指南”(EMEA/CHMP/QWP/251344/2006)和EMA“基因毒性杂质指南问答”(EMA/CHMP/SWP/431994/2007Rev. 3)。
With effect from 1 January 2016, ICH guideline M7,adopted by the CHMP and issued as EMA/CHMP/ICH/83812/2013, is applied.
自2016年1月1日,ICH指南M7,由CHMP采纳并作为EMA/CHMP/ICH/83812/2013签发应用。
The above-mentioned guidelines do not apply tosubstances intended for veterinary use only. Consequently, the requirements ofthese guidelines are not taken into consideration during the assessment of CEPapplications for this type of substance.
上述指南并不适用于仅供兽用的物质。因此,在此类物质的CEP申报资料评估过程中不会考虑这些指南要求。
Where necessary, and in line with the requirements ofthe above-mentioned documents, genotoxic/mutagenic impurities are stated on theCEP together with the accepted limit and the corresponding analytical method.
必要时,与相述文件中要求保持一致,基因毒性/诱变杂质及其可接受限度和对应的分析方法会在CEP上声明。
-    Residualsolvents: 残留溶剂
Ph. Eur. general chapter 5.4 Residual Solvents isapplicable to the CEP procedure.
EP通则5.4残留溶剂适用于CEP程序。
The solvents that are stated on the CEP are thoselikely to be present in the substance, i.e. solvents used in the finalmanufacturing steps (regardless of their residual levels) and solvents that areused in earlier manufacturing steps which are not removed consistently by avalidated process and whose levels in the substance are above 10% of theconcentration (option 1) limit established by ICH Q3C (equal to the limits setby Ph. Eur. general chapter 5.4 Residual Solvents).
在CEP上声明的溶剂是可能出现在物质中的那些溶剂,即,用于最终生产步骤(无论是其残留水平如何)和用于较早生产步骤但不能经过验证的工艺持续清除,使得在物质中的水平高于ICH Q3C中指定浓度(等同于EP通则5.4残留溶剂中所设定限度)10%以上(方法1)的溶剂。
The limits for the residual solvents stated on the CEPare the manufacturer's proposed limits as accepted by the EDQM.
在CEP上声明的残留溶剂限度是生产商所提议并被EDQM接受的限度。
Some CEP holders may decide to test all solvents usedin the synthesis, including those demonstrated to be absent. In these cases,the CEP cites fewer solvents than are included in the CEP applicant’sspecification for the substance.
有些CEP持有人可能决定要检测用于合成的所有溶剂,包括那些被证明并无残留的溶剂。在此情形下,CEP引用的溶剂会少于CEP申报者的物质质量标准中所包括的溶剂。
Option 2 calculation for class 2 solvents: 2类溶剂的方法2计算
For class 2 solvents, any limit higher than that ofthe ICH Q3C Option 1 limit should be justified according to Option 2calculation. Option 2 allows use of the PDE (mg/day) according to the actualdaily dose of the active substance.
对于2类溶剂,任何高于ICHQ3C方法1的限度均应依方法2计算方法进行论证。方法2允许活性物质的实际日服用剂量使用PDE(mg/天)。
When Option 2 has been applied by the manufacturer ofthe substance for which the CEP is granted, this is made transparent on the CEPfor the users and should be considered in the frame of the MA assessment(further calculation of residual solvent levels may be required in the contextof the final use of the active substance).
如果物质生产商采用了方法2,则颁发CEP时会在CEP上写明让用户了解并在MA评估中进行考虑(在活性物质最终使用时可能需要进一步计算残留溶剂水平)。
Concerning class 3 solvents, in exceptional cases, higheramounts than those allowed by the ICH Q3C Option 1 limit (5000 ppm or 0.5%) mayalso be acceptable provided they are justified in relation to manufacturingcapability and GMP.
关于3类溶剂,在例外情形下,比ICHQ3C方法中的允许限度(5000ppm或0.5%)更高可能也会被接受,但需要与生产能力和GMP进行相关论证。
Control of class 3 solvents by Loss on drying test: 采用干燥失重项目控制3类溶剂
Where only class 3 solvents are likely to be presentin an active substance, a Loss on drying test may be used. If a Loss on dryingtest is already included in the Ph. Eur. monograph with a limit of not morethan 0.5%, this is reflected on the CEP with the names of the solvents used,and no method is annexed.
如果活性物质中只可能出现3类溶剂,可以使用干燥失重来控制。如果干燥失重项目已经包括在EP各论中,且限度为不超过0.5%,则在CEP上会写明所用溶剂名称,不附检测方法。
Where a mixture of class 2 and class 3 solvents islikely to be present in the active substance, and where a Loss on drying testwith a limit of not more than 0.5% is included in the Ph. Eur. monograph, allclass 3 solvents are normally stated on the CEP as being controlled by loss ondrying, even if the manufacturer controls them with a specific method, whileclass 2 solvents are stated as being controlled by a specific method (usuallygas chromatography).
如果在活性物质可能会出现2类和3类溶剂,且EP各论中干燥失重限度为不得过0.5%,即使生产商采用专用方法来控制,一般在CEP上会注明所有3类溶剂由干燥失重控制,而2类溶剂则声明采用专用方法控制(通常是气相色谱)。
Even if not described in the Ph. Eur. monograph, atest for loss on drying may be included in the specification of the activesubstance, performed as described in Ph. Eur. general chapter 2.2.32, with alimit of not more than 0.5%. In this case, this is stipulated on the CEP and nomethod description is annexed.
即使EP各论中并未描述,仍可在活性物质质量标准中放入干燥失重,按EP通则2.2.32所述方法检测,设定限度为不得过0.5%。在此情形下,会在CEP上指明,但不会附上检测方法。
Where the limit for loss on drying of the Ph. Eur.monograph is higher than 0.5%, the policy is that a specific test for residualsolvents should be included in the active substance specification. In thiscase, the names and limits for individual solvents are reported on the CEP andthe in-house method is annexed.
如果EP各论中干燥失重的限度高于0.5%,则原则上应在活性物质质量标准中放入残留溶剂的专用检测测试。在此情形下,单个溶剂的名称和限度会在CEP上报告,并附上内控方法。
Denaturants: 变性剂
If denaturants used in solvents are likely to becarried over to the active substance, a limit in the specification of theactive substance is expected, and such limits will be stated on the CEP.
如果溶剂中所用变性剂可能会残留在活性物质中,则要求在活性物质质量标准中设定其残留限度,CEP上面将写明此限度。
-               Useof water in the purification steps of the synthesis 合成精制步骤用水
The use of water in the purification step of thesynthesis is stated on the CEP.
合成精制步骤用水将在CEP上注明。
-    Qualityof water  水质
By default, the minimum acceptable quality of thewater used in the manufacture of an active substance for oral use is potablewater (cf. CPMP/CVMP NfG on quality of water for pharmaceutical use,CPMP/QWP/158/01 Revision & EMEA/CVMP/115/01 Revision). The quality of wateris stated on the CEP only when a particular grade/quality of an activesubstance is claimed (e.g. sterile).
口服用途活性物质生产用水水质默认最低可接受标准为饮用水(参考CPMP/CVMP NfG药用水质,CPMP/QWP/158/01 Revision &EMEA/CVMP/115/01 Revision)。只有当活性物质声明为特殊级别/质量时才会在CEP上声明的水质(例如,无菌)。
-    Residualmetal catalysts and reagents/elemental impurities 残留金属催化剂和试剂/元素杂质
Until August 2016, the EMEA/CHMP/SWP/4446/2000“Guideline on the Specification Limits for Residues of Metal Catalysts or MetalReagents” was applied (unless otherwise justified) for the evaluation ofcarryover of metal catalysts/reagents into the active substance.
2016年8月,EMEA/CHMP/SWP/4446/2000“金属催化剂或金属试剂残留限度质量标准指南”适用于金属催化剂/试剂在活性物质中的残留评估(另有论证者除外)。
Further calculation of residual metal levels might benecessary in the context of the final use of the drug substance.
在原料药最终使用情况下,可能需要进一步计算残留金属水平。
With effect from September 2016, ICH Guideline Q3D“Guideline for elemental impurities”, adopted by the CHMP and issued asEMA/CHMP/ICH/353369/2013, is applied to substances intended to be introduced inmedicinal products within the scope of ICH Q3D.
自2016年9月开始,ICH指南指南Q3D“元素杂质指南”由CHMP采纳并作为EMA/CHMP/ICH/353369/2013发布,适用于引入ICHQ3D范围内制剂的物质。
For affected CEPs, the information reported on the CEPconcerning elemental impurities will depend on the option chosen by the CEPapplicant, as follows:
受影响的CEP,会根据CEP申报者所选择的方法在该CEP上报告相关的元素杂质信息。具体如下:
a)             Ifa Risk Management Summary has been provided by the CEP applicant, the summaryis appended to the CEP, with the necessary information on the level ofcontamination of the substance, in order to implement the ICH Q3D  component approach to the finished medicinalproduct.
如果CEP申报者提交了一份风险管理综述,则该综述会附在CEP后,包括物质污染水平方面所必要的信息,以便制剂实施ICH Q3D组份法。
b)            If no risk assessment has been performed by the CEP applicant, elemental impuritiesclassified in ICH Q3D which are intentionally used in the process after theintroduction of the starting materials are stated on the CEP, regardless of thelevels found in the final substance. Alternatively, if no elemental impuritiesare intentionally added during the process, this is stated on the CEP.
如果CEP申报者并未执行风险评估,则在引入起始物料后的工艺中有意加入的ICH Q3D元素杂质会在CEP上声明,无论其在最终物质中所检出的水平如何。相反,如果在工艺中并未有意加入元素杂质,则也会在CEP上声明。
NOTE: the EDQM does not make a final decision oncompliance with ICH Q3D. This should be done within the context of the MAA forthe medicinal product in which the substance covered by the CEP is used.
注:EDQM并不做出是否符合ICHQ3D要求的最终决定。这是由使用CEP所覆盖物质的制剂MAA要做的事情。
Where necessary, the limit(s) proposed by the CEPapplicant (and accepted by  the EDQM) willbe stated on the CEP and the analytical method(s) will be annexed to it.
必要时,CEP申报人所提议(且被EDQM接受)的限度将在CEP上写明,并附上其分析方法。
The above-mentioned guidelines do not apply tosubstances intended for veterinary use only. Consequently, the requirements ofthese guidelines are not taken into consideration during the assessment of CEPapplications for this type of substance.
上述指南不适用于仅供兽用的物质。因此,在评估此类物质的CEP申报资料时不会考虑这些指南的要求。
-               Omittedtests 删除项目
Where the Ph. Eur. monograph includes a specific testfor a named compound (e.g. impurity, metal catalyst, reagent, solvent), but thecompound is not used during synthesis by the substance manufacturer or cannotbe present with the route of synthesis used, the Ph. Eur. test can be removedfrom the substance specification. This is clearly stated on the CEP.
如果EP各论包括有一个专用项目检测指定的化合物(例如,杂质、金属催化剂、试剂、溶剂),但这些化合物在合成中并未使用,也不会出现在合成所用路线中,则可以人物质质量标准中删除此项目。CEP上会载明此事。
-    Microbialquality 微生物质量
Only where the Ph. Eur. monograph indicates specificrequirements related to microbial quality for the manufacturing process (i.e.in the Production section of the Ph. Eur. monograph), is compliance to thisaspect assessed as part of the CEP procedure.
只有当EP各论为生产工艺指明与微生物有关的具体要求时(即,在EP各论的生产部分),此方面符合性才会作为CEP程序的一部分进行评估。
-    Containerclosure system 容器密闭系统
The packaging information is systematically assessedduring the CEP procedure, even when no retest period is requested by the CEPapplicant, and the full packaging material (immediate and outer) is describedon the CEP.
在CEP程序中会系统性地评估包装信息,即使CEP申报人并无复验期要求,在CEP上会描述所有包装材料(内包和外包)。
However, CEPs issued before 1 September 2011 might notinclude this information. This should be considered by the CEP users who needto request this information from the CEP holder.
但是,2011年9月1日之前签发的CEP上可能并未包括此类信息。CEP用户需要考虑到此,向CEP持有人要求此类信息。
-               Retestperiod 复验期
As stated in the EU Note for Guidance “Stabilitytesting of existing active substances and related finished products”(CPMP/QWP/122/02 and EMEA/CVMP/846/99), for active substances described in anofficial pharmacopoeial monograph (Ph. Eur. or the Pharmacopoeia of a EuropeanUnion Member State) which covers the degradation products, and for whichsuitable limits have been set but a retest period is not defined, results fromstability studies are not necessarily required, provided that the activesubstance complies with the pharmacopoeial monograph immediately prior to usein the finished product. This is why not all CEPs carry a retest period.
正如EU 指南注释“现有活性物质和相关制剂的稳定性测试”(CPMP/QWP/122/02 和EMEA/CVMP/846/99)中所述,对于官方药典各论中所述的活性物质(EP或欧盟成员国药典),如果覆盖了降解物并已设定了适当的标准,但并未定义复验期,则并不需要稳定性研究结果,只要该活性物质在用于制剂之前符合药典各论即可。这就是为什么并不是所有CEP都带有复验期的原因。
If a retest period is requested as part of the CEPapplication, stability data are assessed by the EDQM and a retest period forthe active substance is granted in line with the current EU requirements.
如果CEP申报资料申请了复验期,则EDQM会评审稳定性数据,并依据现行的EU要求批准该活性物质的复验期。
The granted retest period is stated on the CEPtogether with the packaging material and appropriate storage conditions if anyrestrictions apply. According to guideline CPMP/QWP/609/96 part B (Declarationof storage conditions) no declaration of specific storage condition means thatthe active substance is stable under climatic conditions for zone I/II (combinationof long-term and accelerated conditions).
批准的复验期会在CEP上写明,同时还会与明包材以及适当的存贮条件(如有限制。依据指南CPMP/QWP/609/96的B部分(存贮条件声明)无特定存贮条件声明表示活性物质在I/II气候带自然条件下是稳定的(长期和加速条件结合)。
-    Material ofhuman or animal origin used in the manufacture of the substance 物质生产中所用人体或动物来源物料
CEP applicants have to declare whether any material ofanimal or human origin is introduced in the production of the substance to becovered by the CEP (e.g. at the level of starting materials, reagents,additives, materials used in the media of fermentation processes). Thisdeclaration is not limited to TSE-risk materials.
CEP申报人必须声明,在否CEP所覆盖的物质在生产中引入的任何动物或人体来源的物料(例如,起始物料、试剂、添加剂、发酵工艺的培养基所用物料)。此声明不仅限于TSE风险物料。
The use of such material is made clear on the CEP inorder to alert the Competent Authorities to the possible need to address anyviral safety issues. Viral safety is not assessed at the EDQM, even if data areprovided.
此类物料的使用会在CEP上清楚载明以警示药监可能需要考虑是否有病毒安全问题。即使提供了数据,EDQM也不会评估病毒安全
If the substance involved is likely to present a TSErisk, the relevant TSE assessment is systematically carried out (see section4.3.5 “Statements on a TSE CEP”) and the relevant statement is included on theCEP (“double CEP”). In the absence of such a statement, users know that thesubstance does not pose any TSE risk.
如果所涉及的物质可能具有TSE风险,则会进行系统性的TSE相关评估(参见第4.3.5部分“TSE CEP上的声明”)并会在CEP上载明相关声明(双CEP)。如果没有此声明,则用户就知晓该物质并不具有任何TSE风险。
-   Productionsection 生产部分
Statements on a Ph. Eur. monograph under the heading“Production” draw attention to particular aspects of the manufacturing processbut are not necessarily comprehensive. They constitute instructions tomanufacturers. They may relate, for example, to source materials, to themanufacturing process itself and its validation and control, to in-processtesting or to testing that is to be carried out by the manufacturer on thefinal article, either on selected batches or on each batch prior to release.
EP各论里标题“生产”项下的声明引起对生产工艺特殊方面的注意,但并不一定是全面的。其中含有对生产方面的指导,可能与,例如,物料来源有关,可能与生产工艺本身及其验证和控制有关,可能与中控检测或生产商对最终产品要执行的检测有关,要么是在所选择的批次上,要么是在每个批次放行之前。
When the evaluation has considered the Productionrequirements, no statement will be added to the CEP.
如果评估已考虑到了生产要求,在CEP上不会载入任何声明。
In cases where the specific Production requirementsare out of the Certification scope (e.g. viral safety), a statement on the CEPmakes clear that compliance with the Production section of the Ph. Eur.monograph has to be addressed at the level of the MAA.
如果特定的生产要求超出了认证范围(例如病毒安全),则CEP上会有一个声明写清楚EP各论的生产部分符合性要在MAA层面进行讨论。
4.3.2       Statementson a CEP for API-mix API混合物CEP上的声明
A CEP application can only be accepted where there isa Ph. Eur. monograph which covers an API-mix (a mixture of a drug substance(API – active pharmaceutical ingredient) with excipients).
只有当API混合物(药用物质(API—活性药用成分)与辅料的混合物)录入EP各论时,EDQM才会接受该混合物的CEP申报资料。
The information which is included on the CEP in suchcases is dependent on the information included in the monograph, and the CEPreflects the Labelling section of the monograph. The CEP will supplement themonograph to provide transparency on the names and ranges of any excipientsused and, where an additive is used (e.g. antioxidant), the control method isannexed to the CEP.
在此情形下,CEP里所包括的信息取决于各论里包括的信息,并且CEP反映各论的标识部分。CEP会补充各论,提供关于所用辅料的名称和范围,如果使用了添加剂(例如,抗氧剂),则控制方法会附在CEP后。
The document PA/PH/CEP (16) 70 and the EMA Questionand Answer document (EMA/CHMP/CVMP/QWP/152772/2016) provide more information onthis subject.
文件PA/PH/CEP(16) 70和EMA问答文件(EMA/CHMP/CVMP/QWP/152772/2016)提供关于此专题的更多信息。
4.3.3       Statementson a CEP for a sterile substance 无菌物质CEP上的声明
A particular case of a combined CEP is one where thesubstance is claimed to be sterile and therefore the evaluation for chemicalpurity is complemented with an evaluation of sterility aspects. Thus, a“sterility CEP” does not exist on its own, but is always combined with thechemical purity evaluation. CEP applications must fulfil the conditions laiddown in the EDQM documents “Certificates of suitability for sterile activesubstances” (PA/PH/CEP/T0 (6) 13) and “Clarification on the acceptability ofCEP applications for sterile grade material” (PA/PH/CEP (08) 60).
合并CEP的特殊案例是物质被声明为无菌,因此无菌方面的评估将补充化学纯度的评估。因此,一份“无菌性CEP”并不单独存在,而总是与化学纯度评估一起。CEP申报资料必须符合EDQM文件“无菌原料药适用性证书”(PA/PH/CEP/T0(6) 13)和“无菌级别原料的CEP申报资料可接受度说明”(PA/PH/CEP(08) 60)中规定的条件。
When granted, the CEP for chemical purity andsterility includes, in addition to the statements for a Chemical CEP (asapplicable), the following statements related to sterility:
当颁发化学纯度和无菌性双证CEP时,除了化学CEP的声明外(适用时),以下声明与:
-  Thesubtitle “Sterile”
-   子标题“无菌”
-    Thequality of water in cases where water is used in the sterilisation steps
-    灭菌步骤用水时水质
-    Suitable  limits if  ethylene  oxide  or  ionising  radiation are  used  during sterilization
-     使用环氧乙烷或离子化辐射灭菌时适当限度
-      Residuallevels of solvents used during sterile filtration
-      无菌过滤中所用溶剂的残留水平
-       Thestatement: “The substance is sterile and shall comply with the relevant testfor sterility of the Ph. Eur.”
-     “物质无菌,且符合EP无菌性相关测试”声明
-     Thesterilisation method used
-      所用灭菌方法
-       Thestatement that the sterilisation process has been assessed and accepted
-      灭菌工艺经过评估并被接受的声明
-     Thecontrol of bacterial endotoxins if applicable
-      细菌内毒素控制(适用时)
4.3.4      Statementson a Herbal CEP 草药CEP上的声明
-      Subtitlefor extracts 提取物子标题
-       DrugExtract Ratio (DER): systematically included on CEPs for extracts granted afterMay 2012. It corresponds to the DER calculated on the genuine extract (extractwithout excipients).
-     药品提取率(DER):2012年5月之后颁发的提取物CEP上系统地包括此信息。它对应于原始提取物所计算的DER(无辅料的提取物)。
-     Sites 场所
-     CEPholder CEP 持有人
-     Substancemanufacturing site(s)-     物质生产场所
-     Intermediate(s)manufacturing site(s)-     中间体生产场所
-      Additionalsites might be included if necessary-    必要时可能包括的其它场所
-    Compliancestatement 符合性声明
Statement by which the EDQM certifies that the qualityof the substance produced at the site(s) listed on the CEP is suitablycontrolled by the corresponding Ph. Eur. monograph (current edition includingsupplements), supplemented by the test(s) mentioned on the CEP and theanalytical procedures given in the annex, where applicable. This means that thespecification of the substance includes the tests of the Ph. Eur. monographtogether with the additional tests listed on the CEP.
通过此声明,EDQM证明CEP上所列场所生产的物质质量适用采用对应的EP各论进行控制(当前版本包括增补),适用时,CEP上所声明的附录测试和检验方法进行补充。这表示物质的质量标准包括EP各论中的检测,加上CEP上所列的附加测试。
-    Residualsolvents 残留溶剂
Tests and limits for residual solvents are stated onthe CEP and the corresponding in- house method(s) are annexed.
残留溶剂的测试及其限度在CEP中注明,并附上相应的内控方法。
-   Extractionsolvent(s) 提取溶剂
The solvent(s) used to prepare the extract are statedon the CEP (e.g. ethanol 60% v/v).
用于制备提取物的溶剂会在CEP上注明(例如,乙醇60%v/v)。
-    Excipients辅料
The excipient(s) included in the extract and theirpercentage content are stated on the CEP.
提取物中所用辅料及其百分比含量会在CEP上注明。
If the extract does not include any excipients, thisis also made transparent on the CEP.
如果提取物并不包括任何辅料,也会在CEP上载明。
-     Retestperiod 复验期
If a retest period is requested as part of the CEPapplication, stability data are assessed by the EDQM and a retest period forthe active substance is granted in line with the current EU requirements. Thegranted retest period is stated on the CEP.
如果提交CEP申报资料时申请复验期,则EDQM会评估稳定性数据,并依现行EP要求批准活性物质的复验期。批准的复验期会在CEP上写明。
-   Containerclosure system 容器密闭系统
The full packaging material (immediate and outer) isdescribed on all Herbal CEPs.
在所有草药CEP中会描述全部包材(内包和外包)。
-     Materialof human or animal origin used in the manufacture of the product 产品生产中所用人体或动物来源物料
The use of such material in the manufacture of theproduct is made clear on the CEP.
产品生产中使用此类物料的情况会在CEP上清楚注明。
Statements on a TSE CEP TSE CEP上的声明
-    Subtitle子标题
The manufacturing process is included as a subtitle onthe CEP, where applicable (i.e. for gelatin).
适用时(例如明胶),生产工艺会作为子标题放在CEP上,
In addition, for CEPs covering several qualities ofthe same product, the product codes (having been described in the applicationand accepted by the EDQM) are stated in the subtitle.
此外,覆盖同一产品几个不同质量的CEP会在子标题上标明(在申报资料里描述并被EDQM接受的)产品代码。
-    Sites 场所
-    CEPholder  CEP持有人
-    Substancemanufacturing site(s) 物质生产场所
-    Compliancestatement 符合性声明
Statement by which the EDQM certifies that thesubstance produced at the site(s) listed on the CEP meets the criteriadescribed in the current version of the monograph “Products with risk oftransmitting agents of animal spongiform encephalopathies” (1483) of the Ph.Eur.
通过该声明,EDQM证明CEP上所列在该场所生产的该物质符合EP各论“具有TSE风险的产品”当前版本中所述的标准。
-    Country(ies)of origin of source materials 源物料原产地
The geographical origin of the animals used to sourcethe organs or tissues used in the manufacture of the substance is stated on theCEP.
CEP上所列物质生产中所用器官或组织来源动物的地理位置。
-    Natureof animal tissues used in manufacture 生产中所用动物组织属性
The type of tissues used in the manufacturing process(e.g. bovine blood, bovine tendons) is stated on the CEP.
用于CEP上所列物质生产的组织类型(例如,牛血、牛肌腱)。
-    Manufacturingprocess applied 所采用的生产工艺
Only when relevant for the safety of the product (e.g.gelatin).
只有当与产品安全有关时(例如明胶)
A double CEP (Chemical + TSE) will include thestatements from both types of CEP, where applicable.
双CEP(化学+TSE)将包括2种类型CEP上所有适用的声明。

相关内容

咨询色谱专家

 

欧系液相色谱工业标准的制定者

地址:河南·郑州市航海西路升龙国际二七中心7号楼A座21层

邮箱:info@aupos.cn 

电话:400-1158-566