2011年度CEP首次申请审评中的十大缺陷中英文对照及个人看法和经验分享

笔者注：因为最近的手上的工作项目的缘故笔者查阅了这份由EDQM所发布的文件，觉得挺有价值的，于是便准备对其进行翻译以飨所需之人，查看网上发现了一篇由Zhulikou431完成的翻译稿，仔细阅读下来发现有少数地方翻译的不够准确，同时也为了更方便与很多国际注册初学者的需要，因此便重新翻译了一次，并加上了一些本人的工作经验和心得体会，如有不正确的地方还望大家更正。
Top ten deficiencies found after first assessment of new applicati** in 2011
+ d& {+ l# d7 ^% ]8 W; S0 p2011年度CEP首次申请审评中的十大缺陷(注意缺陷编号是完全根据原文来的，相同的原因是在统计的缺陷中相应的问题出现的次数一样，类似于并列排名)
This document is a summary of the main questi** resulting from the first assessment of new applicati** for Certificates of Suitability (CEP) for chemical purity. It is based on the content of a sample of 90 deficiency letters sent to applicants during the first months of 2011.
. J9 W7 G! V# m% i5 O本文件是纯化学类CEP**新申请首次审评中发现的问题的汇总，所发现的问题的是基于90封发给申请人的缺陷信样本中的内容。
From the data obtained, the average number of questi** for each application is 7, with the actual number of questi** ranging from 0 to 14. During the period of reference, 2 CEPs were granted after the first evaluation (out of 90 dossiers treated).
根据已有的数据显示每个CEP申请中发现的问题在0~14个之间，平均数是7。在本次考察基准期间（注：2011年度）（只）有2份申请是在首次审评之后就获得了CEP**（其他90份都是存在缺陷的）。
- F# K2 U, B3 O  X% p; R* gThe Top 10 most frequent questi** are listed below with recommendati** regarding EDQM requirements added. By including these recommendati**-together with the requirements  described in the EDQM Guideline “Content of the dossier for chemical purity” PA/PH/CEP (04) 1   (current version) which is available on our website-applicants can improve the quality of their  dossiers with a view to facilitating and speeding up the granting of their CEP.
下面列出了常见的十大问题并列出了根据EDQM要求所提供的建议，通过附加的这些建议并结合EDQM网站上的指南‘Content of the dossier for chemical purity” PA/PH/CEP (04) 1  ’(现行版)中的要求，申请者可以提高他们的申请材料的质量以达到促进和加快获得CEP**的目的。


译者注：其实下文中所提到的十大常见缺陷都在EDQM发布的指南中都有明确要求过，只是因为申请人的不在意、研究不充分或者心存侥幸而导致的缺陷信。
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1 w$ C9 p$ e4 n, Q# i) K& g; A3 OTOP 1 (3.2.S.2.3): Absence of discussion on the carry-over of impurities/by-products from key materials in the process:
缺少对来自于工艺中关键物料中的杂质/副产物传递的讨论
The impurities (related substances, solvents, catalysts) of the key materials of the process (starting materials, intermediates) should be described; their carry-over as well as the formation of by-products in the final substance should be discussed. In some cases, a scientific discussion   dem**trating/justifying the absence of impurities may replace analytical testing and batch   results. The European guidelines on residual solvents, genotoxic impurities and residues of metal catalysts should be used to support this discussion, as well as the Q &A published on EMA web-site dated July 2010 related to Harmonisation of Policies on Setting Specificati** for Potentially Genotoxic Impurities, Heavy metal Catalysts Residues and Class 1 Solvents Residues.
& {5 h3 R. [, b7 h1 E7 [  V$ Z（申请人）应该描述工艺过程中关键物料（起始物料、中间体）中的杂质（有关物质、溶剂、催化剂），同时还应该讨论这些杂质的传递以及在原料药中副产物的形成。在某些情况下可以用科学的讨论去替代分析测试以及批测试的结果来证明/论证了杂质的不存在。这样的讨论应该得到欧盟关于残留溶剂、基因毒性杂质和金属催化剂残留的指南以及2010年7月份EMA网站发布的相关问答‘Harmonisation of Policies on Setting Specificati** for Potentially Genotoxic Impurities, Heavy metal Catalysts Residues and Class 1 Solvents Residues’的支持。

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译者注：必须区别对待起始物料和一般物料，一般物料只需要提供质量标准和质量控制就可以了；而对于起始物料而言，必须对其合成过程中所（可能）产生的杂质、副产物等进行控制，并对这些杂质在后续API的合成过程中的传承进行适当的讨论和控制（必要的话）。
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6 ?+ `/ n: |3 {3 O$ C4 ], tTOP 2 (3.2.S.2.2) / (3.2.S.2.3): Proposed starting material not accepted:
申请人提议的起始物料不被认可；
$ X3 W  f3 }1 x* g' O$ {* gMore and more frequently, applicants propose short synthesis, with complex products proposed as starting materials in the application. This is generally not acceptable and the complex material is c**idered by the assessors as an intermediate in the synthesis.
9 c* [0 u+ s( {  N申请者在申请中越来越频繁的采用将一个复杂的产品作为起始物料短合成路线，而这通常是不被接受的，因为审评人会将该复杂物料视为是合成过程中的中间体。
( W9 n. v. M; ]7 r+ e1 jApplicants are reminded that the approved starting material is the starting point for GMP and variati**, and must be representative of the overall synthetic process and not just a late intermediate resulting in a shortened synthesis. The proposed starting material should be justified. Proposing a complex molecule as starting material may lead to a request for redefinition of the starting material further back in the synthesis.
+ f9 Z! \) g  q' o/ v' r' s需要提醒申请人的是被批准的起始物料是GMP和变更的起始点，它必须代表全部合成工艺，而不是采用一个靠后的中间体从而导致合成路线缩短。提议的起始物料必须是经过论证的，如果提议一个复杂的分子作为起始物料的话，可能会导致（申请人）被要求重新定义起始物料并将合成路线向前延伸。
The policy for definition of Starting Materials for APIs applied at EDQM is the following:
适用于EDQM的关于起始物料定义的政策：
—The proposed starting materials should generally not have a structure that is very close to that of the final substance in relative size and complexity (but will depend on the number of steps to the final active substance).
一般而言提议的起始物料不应该与原料药的结构相对分子量和复杂性方面很接近（但取决于原料药的合成步骤）。
! J7 ]- B9 A' r1 E$ k' M—Multiple synthesis steps should separate the starting material(s) and the active substance. A synthesis step is a step in the synthesis where covalent bonds are formed or broken. A process c**isting of only 1-2 steps is generally not sufficient to ensure full control of the quality of the final substance. Fewer steps may be acceptable in some cases, for example for simple molecules, or when the proposed starting material is the subject of a CEP.
& A2 F7 G( {; T% m在多个合成步骤中应该将起始物料和活性物质分离，一个合成步骤指的是在合成过程中存在共价键形成或断裂的步骤。
( g( {6 y+ C5 t8 R5 ]; z—The full description of the process should cover all the synthetic steps critical for safety (impurities) and/or efficacy; such as steps in which a genotoxic substance is used or formed, step contributing to the overall stereochemistry of the active substance or steps such as biocatalytic transformati**.
工艺的全面描述应该包括所有对安全性（杂质）和/或疗效很关键的合成步骤；这类步骤包括基因毒性物质使用或形成的步骤，对活性成分整体立体化学有影响的步骤，或者生物催化剂转化的步骤。
—Commercial availability is an insufficient justification to accept a starting material. Starting materials produced by custom synthesis and those available commercially are not accepted unless supported by additional criteria as described above.
) ?9 x& n" b, Y: E8 \商业可获得不是一个作为起始物料可接受的充足论证理由。除非提供上面所描述的额外标准，否则由定制合成和商业采购所得到的起始物料是不被接受的。
3 E, H7 F8 H% U7 W— It is the combination of the number of chemical synthetic transformation steps carried out under GMP and the control strategy applied to these steps, which provides assurance of quality of the active substance.
GMP条件下进行的多个化学合成转化步骤以及运用在这些步骤中的控制策略为活性物质的质量提供了保证；
2 Z! Z0 ~; M! U— The name and address of manufacturers of starting materials should be stated in the dossier.
: H* j: m4 {8 p' a4 J/ y8 ?; M申报材料中应该明确起始物料生产商的名字和地址；
# ^3 U; D2 M% k( H0 L2 @— In order to justify the specificati** of the starting material information on the manufacture of the starting material should be provided. This should include a flow diagram outlining enough   steps of the synthesis and information on the solvents, reagents and catalysts used during its synthesis.
应该提供起始物料生产方面的信息来证明起始物料的标准，这些信息应包括一个涵盖足够多合成步骤和使用的溶剂、试剂以及催化剂信息的流程图。
8 W1 Y! @7 Y5 _0 Y— Any declaration on GMP and/or on willingness to be inspected presented by starting material manufacturers will in effect have no influence on which substance will be accepted as an appropriate starting point for the part of the synthesis since GMP cannot be imposed for the manufacture of a starting material.
任何关于GMP的声明或者是起始物料生产商提供的愿意接受（官方）检查的声明事实上对什么物质应该被作为合成步骤的起点都不会有影响，因为GMP不能被强加到起始物料的生产中去。
0 o; m4 m+ S: s1 G$ b1 H— An appropriate control strategy should be proposed to ensure the robustness and c**istency of the manufacturing process.
! J% f; N, l$ }0 |: e应采用合适的控制策略来确保生产工艺的耐用性和稳定性。
When the assessors do not accept the proposed Starting Material(s) and a redefinition is asked for, suppliers of the proposed materials will thus become suppliers of intermediates and c**equently the relevant declarati** (compliance with GMP and willingness to be inspected) from these suppliers must be provided. This implies also that related updated CTD secti** are provided to reflect the finally approved route of synthesis (from the redefined starting material to the final substance).
当审评员不接受（申报材料中）推荐的起始物料将会要求（申请人）重新确定起始物料，这时原有的起始物料供应商就变成了中间体供应商，按照要求中间体供应商必须提供相关的声明（符合GMP的声明以及愿意接受检查的声明）。这也就意味中要提供更新后的CTD章节用来反映最终批准的合成路线（从重新确定的起始物料到最终的原料药）。

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( p% `9 y6 f; y" d译者注：起始物料的选择现在越来越受到重视，而且本身应该是一个非常复杂和科学的问题，必须经过合理的论证才能确定起始物料。起始物料的选择不一定是唯一的（同一个API相同的合成路线，不同的厂家可能会选择不同的起始物料），但一般有一个最起码的范围（一般默认的做法是从起始物料到最终的API应该至少有三步的共价键断裂/形成的反应）。另外起始物料是GMP监管的起点，因此起始物料的选择应该在满足官方要求的情况下尽可能的靠后，这样子既可以减少质量研究（主要是杂质的传递，合成步骤越多，质量研究越复杂）的工作量也可以减少GMP监管的成本。
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2 H7 H% Z. q& `" X7 g( j: W& r$ BTOP 2 (3.2.S.3.2): Genotoxic impurities:（基因毒性杂质/遗传毒性杂质）
Compliance with the CHMP Guideline on the Limits of Genotoxic Impurities, EMEA/CHMP/QWP/251344/2006 must be dem**trated for substances obtained by a manufacturing process not yet approved in Europe. A specific discussion as part of the overall discussion on impurities should be provided with regard to impurities with potential genotoxicity.
8 s* a  ~- Y4 l8 p$ q对于采用一个还没有被欧盟批准的制造工艺生产的物质来说必须要证明其符合‘CHMP Guideline on the Limits of Genotoxic Impurities, EMEA/CHMP/QWP/251344/2006’指南。对于存在潜在基因毒性的杂质的特定讨论应该作为（注册材料中）所提供的全部杂质讨论的一部分。
The Q&A (H) published on EMA website dated July 2010 related to Harmonisation of Policies on Setting Specificati** for Potentially Genotoxic Impurities, Heavy metal Catalysts Residues and Class 1 Solvents Residues should also be taken into account when setting specificati** for potentially genotoxic impurities. Limits for these impurities should be set either in a suitable intermediate or in the final substance.
在制定潜在基因毒性杂质的标准时应该将2010年7月份发布在EMA网站上的关于‘Harmonisation of Policies on Setting Specificati** for Potentially Genotoxic Impurities, Heavy metal Catalysts Residues and Class 1 Solvents Residues’的问答考虑进去。基因毒性杂质可以在适当的中间体或者原料药中控制。

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译者注: 基因毒性杂质方面的问题主要是对于基因毒性杂质的识别以及限度制定（对于没有明确PDE的基因毒性杂质可以按照ICH Q3C中提到的计算方式通过查找NOEL或NOAEL等资料来计算）；至于控制策略按照上文中提到的两个文件（EMA的指南和问答）就基本上足够了。


% {" Z7 `% @- O  T( t# RTOP 4 (3.2.S.4.4):  Absence of comparison of the quality of the final substance obtained with starting materials from different suppliers:
缺少对采用不同供应商的起始物料所生产的原料药质量的对比
A substance may be manufactured using starting materials from different suppliers, which should be specified in the CEP application. Where more than one supplier of starting materials(s) is used, a dem**tration should be provided that the quality of the final substance is equivalent whatever the source of starting material involved in the synthesis; batch analysis results from the substance manufactured from the different suppliers should be submitted to confirm that the impurity profile is identical.
% m. h+ f, q+ r7 W一个原料药可能采用来自于不同供应商提供的起始物料进行生产，这一点应该在CEP申请中明确。当起始物料的供应商超过一个以上的时候，（申请人）必须提供证明材料来证明不同的起始物料所得到的原料药的质量是等效的。应提供采用不同供应商提供的起始物料所生产的原料药的批分析结果来确认它们的杂质谱是相同的。

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- c+ ?0 q) d% f* ~! ~译者注: 采用不同供应商供应的起始物料是可以的，但是必须确认两种不同来源的起始物料得到的原料药质量是一样的，而且杂质谱也应该一样（为了做到这一点理论上要求不同的起始物料的厂家的合成路线和工艺都是一样的；但实际中可能经过恰当的科学评估来认定不同合成路线/工艺得到的起始物料的杂质谱是等同的）。


, G" A7 x. i+ _: R) T. _ TOP 5 (3.2.S.2.3): Incomplete specificati** for the declared starting materials:
6 d5 N* N  l4 y提议的起始物料的标准不完整
! W( T* R$ K9 W, h; j/ rThe specificati** of the declared starting materials are often not sufficient and fail to include suitable limits for relevant impurities/solvents/catalysts.
9 T& w, m9 K. n- v4 K- N（申请人）所提供的起始物料的标准经常是不充分的，其中缺少相关杂质/溶剂/催化剂的合适的限度。
Information on the synthesis of the starting materials (flow diagram) should be provided to support the description of the impurity profile and the proposed specification. The specification should    preferably include suitable limits for related substances (specified/unspecified, individual and total), reagents, solvents and catalysts as needed.
9 e( J9 j: A5 ?& T8 b应提供起始物料的合成信息（流程图）来支持（申报材料）中关于杂质谱和推荐的质量标准的描述。质量标准最好按照需要包含有关物质（特定杂质/非特定杂质，单个杂质和总杂），试剂，溶剂和催化剂的合适限度。

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译者注：不能把起始物料当做一般的物料仅仅检测一下含量/纯度、鉴别、单杂和总杂就认为可以了。起始物料的质量标准是基于对该物料的质量分析（工艺研究、杂质分析等）并结合工艺所需而定的，而一般物料则基本上是按照GMP要求并适当增加部分检测项目而来的。换句话说一般物料的标准更多的由API厂家自己自己决定，而起始物料的标准更多的是由起始物料的合成过程来定的；原则上一般物料是需要它有什么就检测什么项目，而起始物料是物料本身有什么我们就检测什么（结合需要适当调整控制策略）。

& w6 d2 S! i3 pTOP 6 (3.2.S.2.3): Absence of discussion for Class 1 solvent as con**inant of another solvent:
- j" @( n" d7 K3 u缺少对于那些作为其他溶剂污染物的一类溶剂的讨论
# ]0 p5 D2 ^& Q4 k# hSome solvents (e.g. acetone, toluene, ethanol, methanol, isopropanol, xylene, hexane and petroleum ether) may be con**inated with Class 1 solvents (e.g. benzene). Therefore, when these solvents are used in the manufacturing process of the final substance and in particular in the purification steps, potential residues of their con**inant in an intermediate or in the final substance should be addressed.
2 V) [( w9 e- C一些溶剂（例如丙酮、甲苯、乙醇、甲醇、异丙醇、二甲苯、己烷和石油醚）可能被一类溶剂（例如苯）所污染。因此当原料药生产工艺中使用到了这些溶剂，尤其是在纯化步骤使用到的时候，应该在中间体或者原料药中解决这些（一类溶剂）的潜在残留问题。
* i) [* v6 M6 yAccording to the European “Note for Guidance on Specificati** for Class 1 and Class 2 residual solvents in active substances, annex to the CPMP/ICH/283/95 Impurities:
, k: N& X7 a2 PGuideline for Residual Solvents & CVMP/VICH/502/99 Guideline on Impurities: Residual
Solvents”, 3 opti** may be used that support the absence of routine testing of the con**inant in the final substance.
可以根据EMA发布的‘Note for Guidance on Specificati** for Class 1 and Class 2 residual solvents   in active   substances,  annex  to   the  CPMP/ICH/283/95   Impurities:
Guideline for Residual Solvents & CVMP/VICH/502/99 Guideline on Impurities: Residual
3 n  i! Y# y$ d0 O& }Solvents’中的3个选择来支持不在原料药中对这些一类溶剂残留的日常检测的决定。
Compliance with this guideline should be dem**trated in the justification of the quality
6 x7 I* q8 U- Pof  the solvents  used  in  the  Impurities  section of  the  application. Where one of the 3 opti** is met and dem**trated in the application, a routine test for the Class I solvent in a suitable intermediate or in the final active substance is not required.
应该根据申请文件中杂质章节中关于使用溶剂的质量的论证来证明是否符合该指南。当3个选择中的某一个被证明是符合要求的，则不需要在合适的中间体或者是原料药中对（这些潜在的）一类溶剂进行控制。


译者注：工艺中所用溶剂可能携带的一类溶剂的残留问题现在越来越受到重视，本人就遇到过两次缺陷信中提到这个问题。目前的难点是在于不知道哪些溶剂中可能含有哪些一类溶剂（理论上应该根据溶剂的生产过程来分析，但实际中操作起来难度较大，因此一般都是把这些在相关官方发布的文件中提到的进行控制，而官方没有明确指出的则不进行讨论和控制），控制策略可以参考上文中提到的文件（主要分为在成品中控制和在中间体/源溶剂中控制，每批检测还是抽检或者不用纳入质量标准；不过从实践中来看最好是在源溶剂中控制，这是最科学也是对API厂商最有利的方式），尤其是Annex to 这份文件尤其有效。
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# @, }. r  \  ?6 F0 RTOP 6 (3.2.S.2.3): Incomplete specificati** for reagents/solvents:
试剂/溶剂的标准不完整
( E; d( v  n: y( |2 L3 PSpecificati** of all materials used during the synthesis should be given, and suitable purity tests should be introduced. Particular attention should be paid to the quality of solvents used during the final purification steps (including water); these materials should have adequate purity. The quality of water used during the manufacture of APIs should comply with the Note for Guidance on Quality of water for pharmaceutical use CPMP/QWP/158/01 Revision.
应该提供所有在合成中使用到的物料的标准，标准中应该包含合适的纯度测试。对于最后纯化步骤使用到的溶剂（包括水）的质量应给予格外的关注；这些物料应该具有足够的纯度。在API生产过程中使用到的谁的质量应该符合‘Note for Guidance on Quality of water for pharmaceutical use CPMP/QWP/158/01 Revision’。
0 G& _% D$ J: s; l- \* HIf applicable a suitable and reasonable mass balance should be observed between purity and impurities limits in the specification for the materials.
( T" Z* n6 {- l) o2 F; [3 Y' Y如果有可能的话，应该在物料质量标准中纯度和杂质限度之间观察到一个合适和合理的质量平衡。
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译者注：对于一般原辅料来说含量/纯度、外观和鉴别是基本检测项目，这里应该问题不大。个人来说不清楚为什么这一点也会是十大缺陷之一。

TOP 8 (3.2.S.2.4): Specificati** for key intermediate(s):
关键中间体的标准
: L  _. R9 }8 F) n$ @! cThe specificati** for the key intermediates are not detailed enough. A discussion on the potential impurities likely to arise from the process and their limits is expected. The need to take into account the impurities controlled in an intermediate in the discussion on the suitability of the monograph should not be forgotten.
' G" A6 Q4 C  B8 N: v8 c关键中间体中的质量标准不详细。（官方）期望（申请人）能够增加关于对生产工艺中可能出现的潜在杂质和限度的讨论。同时也不应忘记在对药典专论适用性讨论中将杂质控制考虑进去。
+ ~8 X. }! L8 K1 _3 |9 m1 g! A7 UWhen the proposed starting materials are not accepted by the assessors they should be re-defined as intermediates in the synthesis. As a result appropriate specificati** are expected for this intermediate.
& B( q- T. G/ @* c2 O' f2 R+ R7 \如果（申请人）提议的起始物料不被审评人接受的话，那么相应的起始物料应该被重新确定为合成过程中的中间体，此时就需要为这些中间体确立合适的标准。
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译者注：记住一点，所有的中间体而不只是关键中间体，都不是普通的原料；中间体的质量标准的制定（主要是杂质控制，控制哪些杂质，限度为多少）必须考虑杂质传递并结合整体控制策略而制定的。因此必须研究透、提供足够的数据。

TOP 9 (3.2.S.4.3): Absence of cross validation between PhEur and in-house method for the control of related substances:
) h$ ~4 e+ Y9 R& I- J9 L  I缺少用于相关物质控制的EP药典方法和内控方法之间的交叉验证
. ?5 S9 O! ?; c. p2 w9 l0 M& bAlternative methods may be used by the applicant, provided they have been shown to give equivalent results to those obtained with the ones of the monograph. Such methods should be described and their validation data given in the dossier. Where alternative methods are used they should be cross validated with reference to the Ph. Eur monograph’s method(s) and typical chromatograms should be provided. These methods will not be appended to the CEP if those of the monograph are c**idered appropriate to control the quality of the substance. To do so, results of testing the same batches with both methods, showing compliance with specificati** should be provided.
/ s0 Q( n% Q  ~! O- N申请人可以采用替代方法，如果替代的方法已经被证明可以获得跟药典专论中方法等效的结果的话。（申请人）需要在申报材料中描述这些替代方法并提供相应的验证数据。如果替代方法被采用的话，还需要在替代方法与EP专论方法之间进行交叉验证并提供替代方法的典型图谱。如果药典专论中的方法被认为是可以恰当的控制药品质量的话，那么相应的替代方法是不会附在CEP**上的。为了做到这些，（申请人）应该提供采用两种方对同一批样品检测的结果来证明质量标准的复合型。
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+ z# o, y/ t" {  v译者注：对于替代方法的问题本人遇到的较少，基本上都是按照EP专论的方法来的（不用再重新开发方法，专论方法经过简单的验证直接拿来就用省事）更多的是EP专论中的方法不能完全控制部分质量属性的时候，会增加某些检测方法（如元素杂质）；不过据本人了解，所谓的交叉验证不用太复杂，先对替代方法进行完全验证，然后提供数据证明两种方法的检测一致性（结果相同或无明显差异）就可以了。
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TOP 10 (3.2.S.4.3): Suitability of the monograph to control the impurity profile of the final substance:
/ ?8 R! ]# r- d4 J7 ]0 \9 p药典专论对于原料药中杂质谱控制的适用性
The suitability (or unsuitability) of the Ph.Eur. monograph to detect and limit all related substances present in the final substance should be dem**trated, even if a suitable in-house method is used   for their control. This discussion should also address how potential/actual impurities from the described route of synthesis are controlled. If the monograph method is not suitable to detect impurities, an additional method should be proposed for such impurities unless it can be dem**trated that they are absent.
2 Q' P' g. ^1 e& p; h必须证明EP药典专论对于原料药中存在的所有有关物质的检测和限制的适用性（或不适用性），即使有一个合适的内控方法能够对有关物质进行控制。这个讨论应该描述如何控制来自于合成路线中潜在的/实际的杂质。如果药典专论方法不适用于这一类杂质的测定的话，那么除非可以证明这类杂质不存在否则就应该提议额外一个额外的方法来控制它们。
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译者注：简单来说这个缺陷就是你所选择的方法必须要能够控制你们产品的质量，因为生产工艺的不同，甚至是合成路线的不同等原因，会造成申请人的产品的杂质谱并不一定和EP专论起草时的赞助人（sp**or）的一样，这个时候专论中的方法就不一定适合/能够控制完全控制申请人申请的产品。在杂质谱与药典专论杂质不一致的时候就需要讨论药典方法的适用性，必要的时候需要增加内控方法来对专论之外的杂质进行控制。比如说某个杂质X，在药典专论中没有提及，而申请人的工艺中又会产生这个杂质，这是就必须考虑药典方法的适用性了，必要的时候就需要增加内控方法来控制杂质X。
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  e8 g) K) f" M8 bTOP 10 (3.2.S.2.2): Absence of information related to the maximal batch size for the approved process:
缺少有关于批准工艺的最大批量的信息
The maximum batch size for which the manufacturer has acquired experience with the defined manufacturing method, and which should correspond to batches referred to in the dossier, should be stated. Where the substance has yet to be produced in commercial quantities (eg. only pilot scale batches manufactured) the CEP can be granted provided scale-up is reported to the EDQM via an appropriate notification. For a sterile product, an application for a variable and/or alternative batch size should be justified.
+ G1 L& ?7 f2 |! G" u3 e4 N/ t在申报材料中应该明确生产商在已经确定了生产方法并获得了生产经验的基础上所确定的最大批量，而且该批量应该与申报材料中所涉及到的批次的批量大小一样。对于那些还没有进行过商业规模生产的原料药也是可以获得CEP**的，只要（申请人）能够通过恰当的通知形式将放大生产的情况报告给EDQM。对于无菌类药品，提供的变更和/或者替代批量的申请需要得到论证。
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+ P" n! Z: I+ n8 f, A- S! P译者注：总的来说就是申请人所提供的申报材料中所涉及到的批次/数据都应该是来源于按照申报批量和工艺所实际生产的批次。不能用批量为30kg的批次得到的质量研究数据来证明批量为15kg或者60kg的产品的质量（除非是CEP**获得之后进行后续变更并得到官方的批准）。比如说某产品申请人的现行工艺是30kg，那么申请人所申报的批量应该就是30kg，申报材料中批分析等涉及到的批次的批量也应该是30kg，而不能是来源于曾经生产过的15kg批量的批次；如果后续因为需要而把批量从30kg扩大到60kg的话，那么需要通过变更提交官方审评，批准后就可以按照60kg批量进行生产；当然了也可以同时保留30kg和60kg两个不同的批量，但是需要跟官方明确。

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来源：网络博客的文章
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