EMA残留溶剂指南附录

Annexes to:
CPMP/ICH/283/95 Impurities: Guideline for residual solvents
&
CVMP/VICH/502/99 Guideline on impurities: residual Solvents
EMA关于残留溶剂指南CPMP/ICH/283/95 杂质-残留溶剂指南和CVMP/VICH/502/99 杂质指南-残留溶剂的附录
Annex I: specifications for class 1 and class 2 residual solvents in active Substances
附录I：API中I类和II类残留溶剂质量标准
Annex II: residues of solvents used in the manufacture of finished products
附录II：制剂生产中使用溶剂的残留
Discussion at Quality Working Party 质量工作组讨论会议January 2003 to June 2004 2003.01~2004.06
Adoption by CVMP CVMP 采纳July 2004 2004.07
Adoption by CHMP CHMP 采纳July 2004 2004.07
Date for coming into operation 生效时间January 2005 2005.01
Rev. 01 Adoption by Quality Working Party 质量工作组采纳的01版本22 November 2012
2012.11.22
Rev. 01 Adoption by CVMP CVMP采纳的01版本7 February 2013 2013.02.07
Rev. 01 Adoption by CHMP CHMP采纳的01版本11 February 2013 2013.02.11
Rev. 01 Date for coming into operation 01版本生效1 March 2013 2013.03.01
Introduction
前言
The two (V)ICH residual solvents guidelines, ICH Q3C Impurities: Guideline for residual solvents (CPMP/ICH/283/95) and VICH GL18 Guideline on impurities: residual solvents in new veterinary medicinal products, active substances and excipients (CVMP/VICH/502/99), have been in operation for several years, since March 1998 and June 2001 respectively.
虽然ICH颁布的ICH Q3C 杂质: 残留溶剂指导原则 (CPMP/ICH/283/95) 和VICH GL18 杂质指导原则：兽用药、API和辅料(CVMP/VICH/502/99)中的残留溶剂这两个关于残留溶剂的指南分别从1998.03和2001.06就开始被采纳应用。

However, it has become evident that further clarification was required regarding the specifications for Class 1 and class 2 residual solvents in active substances.
但是从应用的实际情况来看，EMA觉得需要对API中I类和II类残留溶剂质量标准的问题进行澄清。

A clear interpretation of the issues regarding residues of solvents used in the manufacture of finished medicinal products, both human and veterinary, was also required.
EMA同时也认为需要对人用药和兽用药生产中的溶剂残留问题进行清楚的解释和说明。

Annex I: Specifications for class 1 and class 2 residual solvents in active substances
附录I：API中I类和II类残留溶剂质量标准
Specifications for class 1 solvents
I类溶剂质量标准
In both the ICH and VICH guidelines on impurities: residual solvents it is stated that “solvents in class 1 should not be employed in the manufacture of drug/active substances, excipients, and drug/veterinary medicinal products because of their unacceptable toxicity or their deleterious environmental effect. However, if their use is unavoidable in order to produce a drug/veterinary medicinal product with a significant therapeutic advance, then their levels should be restricted as shown…….., unless otherwise justified”.
因为I类溶剂的巨大的毒性或者对环境的危害性的原因，因此在ICH和VICH关于杂质-残留溶剂的指南中已经明确说明了
在制剂/API、药用辅料和人用药/兽用药生产中不应该使用I类溶剂；但如果在生产一种具有显著疗效的人用药/兽用药时而
不得不使用到I类溶剂的时候，那么除非有其他的解释，否则就应该将相应的I 类溶剂残留水平控制在指南中规定的限度……。

The justification for using a class 1 solvent as a solvent in a manufacturing process may be based on the current scientific and technical knowledge and the step in which this solvent is involved. For example, use of that class 1 solvent is unavoidable for the specific chemical reaction, or the desired purity profile can only be obtained by using that class 1 solvent. If a class 1 solvent is involved in a very early step of the manufacturing process and if the absence of this solvent is shown in a suitable intermediate, such an approach may be acceptable (for example, friedel crafts chemical reaction).
（生产商）可以根据现阶段的科学技术以及I类溶剂在实际生产中使用的步骤来对工艺中采用I类溶剂的情况进行解释和说明。

比如说某个化学反应必须要使用1类溶剂，或使用I类溶剂来获得所需的纯度。

如果只是在生产中较早的工艺步骤中使用到I类溶剂，而且这个溶剂可以在某个中间体之前被除尽的话，在这种情况下在工艺中使用I类溶剂是可以接受的（例如傅-克反应）。

The maximum acceptable limit, in a suitable intermediate or in the final active substance, for a class 1solvent, whether it is used as a solvent, a starting material, is present as a by-product, or it is present in a solvent, should comply with the limits prescribed in the relevant aforementioned ICH/VICH guideline on impurities: residual solvents, unless otherwise justified (for example, by the benefit-risk ratio).
除非有其他特别的合理解释（比如说效益风险比的考虑），否则不论是作为溶剂、起始原料、反应副产物还是其他溶剂携带的I类溶剂在中间体还是API中控制的限度都必须符合前面提到的ICH/VICH指南中对于残留溶剂规定的限度。

In all cases, the content of class 1 solvents in the final active substance should comply with the requirements of the relevant aforementioned Guideline, if tested.
任何存在I类溶剂测试的情况下API中I类溶剂的残留量都必须符合前面提到的指南中相应的要求。

A class 1 solvents used as starting materials
作为起始物料使用的I类溶剂
Certain class 1 solvents, such as benzene and 1,2-dichloroethane, can be used as starting materials.
Indeed, the use of benzene as a starting material is unavoidable when benzene is a structural part of the active substance.
某些特定的I类溶剂，如苯和1,2-二氯乙烷是可能被用作起始物料的。

实际上如
果苯环是API化学结构的一部分的话，那么在合成该API时，苯肯定是作为起始物料使用的。

Benzene, as a starting material, is commonly used in the very early steps of syntheses, well before the key starting material obtained. It is the reason why, in most cases benzene is not mentioned in the description of the manufacturing process. Therefore a manufacturer describing a synthesis starting from benzene should not be asked to eliminate it when another manufacturer could refer to a synthetic route starting from a later process step (where no questions related to the use of this class 1 solvent would be raised).
通常情况下当苯被当做起始物料使用的话，一般都是用在关键起始物料形成之前非常靠前的合成步骤中。

这是为什么在大多情况下苯的使用都不会在生产工艺体现的原因。

因此如果一个生产商A采用一个从苯开始进行合成的工艺会被另一个生产商B从该工艺后面步骤进行引用的话，那么对于生产商A来说，它不需要在生产中完全去除苯的残留。

（此时I类溶剂的使用是不会被质疑的）。

When class 1 solvents are used as starting materials they should be routinely controlled, either in a suitable intermediate or in the final active substance.
如果I类溶剂是被作为起始物料使用的话，那么必须在中间体或者API中对其进行常规控制。

B class 1 solvents present as an impurity
作为杂质出现的I类溶剂
Benzene in an active substance can be a by-product from a chemical reaction (for example, Grignard reaction, when phenylmagnesium halide used in excess is hydrolysed to yield benzene), or may arise from another solvent, for example, toluene or acetone where benzene is a known process impurity.
原料药中的苯可能会是化学反应的副产物（例如，格氏反应中过量的卤化苯镁会水解生成苯）；也可能由另一种溶剂携带，比如说苯是甲苯和丙酮合成过程中的工艺杂质。

Where a class 1 solvent might be present in another solvent (e.g. toluene or acetone containing benzene), a routine test for this class 1 solvent, on a suitable intermediate or on the final active substance, is not required when:
当某个I类溶剂作为潜在杂质存在于另一溶剂中（例如甲苯或丙酮含有的苯）时，如果满足以下要求，那么对于中间体
或者API中该I类溶剂残留是可以不必进行日常检测的：
The limit applied to the originator solvent is such that the class 1 solvent will be present in the active substance at levels below the limits set out in the guideline,
taking into account the maximum likely level of contamination of the class 1solvent. The volatility of both solvents in the drying processes must be taken into account when applying this argument;
在考虑了该源溶剂中I类溶剂存在最大可能污染的情况下，通过在API中控制源溶剂的方式就可以使得I类溶剂的在API中的含量低于指南中的限度的时候；不过在运用这一条论据的时候必须结合到这两种溶剂在烘干工艺中的挥发性。

It is demonstrated with a validated method that the class 1 solvent is not more than 30 % of the specified limit, in a suitable intermediate or in the final active substance. Supporting data should be presented on 6 consecutive pilot scale batches or 3consecutive industrial scale batches;
如果当采用一个经过验证的分析方法对6个连续的中试批次或者3个连续的商业批次的某个中间体或API进行I类溶剂残留量检测的结果都不大于指南中规定限度的30%的话。

The specification for the originator solvent used includes a routinely performed test and limit for the class 1 solvent.
当在含有I类溶剂的源溶剂质量标准中已经对该I类溶剂设定了限度并进行了日常检测的时候。

Specifications for class 2 solvents
2类溶剂质量标准
When class 2 solvents are used as starting materials or solvents, they should be normally routinely controlled either in a suitable intermediate or in the final active substance depending on the step(s) of the syntheses in which they are used.
当工艺中用到了II类溶剂的时候，那么必须根据其在工艺中具体使用到的步骤在适当的中间体或者是API中对其进行常规控制。

The limit set for class 2 solvents in the final active substance should comply with the requirements of the relevant aforementioned ICH/VICH guideline on impurities: residual solvents.
API中对II类溶剂的设定限度必须符合前面提到的相关ICH/VICH杂质指南中对残留溶剂的要求。

A class 2 solvents used in the last step of the synthesis
最后合成步骤使用的2类溶剂
In all cases where a class 2 solvent is used in the last step of a synthesis it should be routinely controlled in the final active substance.
在任何情况下，如果在合成最后步骤使用了2类溶剂，那么必须在API中对该
II类溶剂进行常规控制。

B class 2 solvents used prior to the last step of the synthesis
最后合成步骤之前使用的II类溶剂
Class 2 solvents used prior to the last step in the synthesis have not to be included in the drug substance specification if it has been demonstrated, on a suitable intermediate or on the final active substance, that the content of class 2 solvents is not more than 10 % of the acceptable concentration limit (e.g., acetonitrile 41 ppm) stated in the relevant aforementioned ICH/VICH guideline on impurities: residual solvents. If tested, the content of class 2 solvents in the final active substance should of course meet the requirements of the relevant aforementioned guideline.
如果能够证明在合成最后步骤之前使用的II类溶剂在某个中间体或者API中实际残留量不大于指南中对该II类溶剂规定限量的10%（比如说乙腈不大于41ppm）的话，那么可以在API中不对其进行控制。

如果在API中对II类溶剂进行检测的话，则其残留量必须符合前面所提到的相关指南要求。

To support the absence of a routine test for class 2 solvents in the final active substance or in the suitable intermediate, results of the content of class 2 solvents should be presented from 6 consecutive pilot scale batches or 3 consecutive industrial scale batches of the suitable intermediate or the final active substance.
如果想在API或中间体中不对II类溶剂进行常规检测的话，那么必须提交6个连续的中试批次或3个连续的商业批次的中间体或者API中II类溶剂的实际残留量数据。

Changes to manufacturing processes
生产工艺变更
When changes are proposed to a manufacturing process in which it has been demonstrated initially that a class 1 or class 2 solvent is below the defined threshold for routine testing, the manufacturer should consider the impact of manufacturing process changes on solvent levels and revalidate as necessary.
在生产商拟对生产工艺进行变更时应考虑生产工艺的变更对那些已经被证明了不需要进行常规检测的I类或II类溶剂残留水平的影响以及对工艺进行再验证的必要性（如有必要则需要对工艺进行再验证）。

Annex II: residues of solvents used in the manufacture of finished products
附录II：制剂生产中使用的溶剂残留
Justification for the use of organic solvents in the manufacture of finished products
制剂生产中使用有机溶剂的论证
Organic solvents can be used in the manufacture of medicinal products for different reasons.
在药品生产的过程中会因为各种原因而使用到有机溶剂。

For example:
比如说：
●as a granulation solvent for the manufacture of tablets;
在片剂生产中作为制粒溶剂
●as part of a tablet coating solution;
作为片剂包衣液的成分
●as a solvent for adhesives used in manufacture of transdermal patches;
作为透皮贴剂生产中的胶粘剂使用
●as a solvent for polymers used in manufacture of implants.
在移值体生产中作为聚合物使用
The justification and choice of solvents used in the manufacture of finished products should be included within the pharmaceutical development documentation. For example, ethanol can be proposed as a solvent for the granulation and/or for the coating solution if the drug substance is demonstrated to be very sensitive to moisture. Organic solvents seem to be unavoidable when certain polymers have to be introduced into the product manufacture. The use of a class 1 solvent in the manufacture of the finished product is not considered acceptable.
在制剂生产中对溶剂的使用的选择和论证必须写进研发文件中。

比如说如果制剂的API对水分比较敏感，那么就可以用乙醇作为制粒和/或包衣液的溶剂；即使为了在制剂生产中引入特定的聚合物而必须使用有机溶剂的话，那么也不能使用I类溶剂。

Specifications for finished products when organic solvents have been used
in their manufacture
针对在生产中使用了有机溶剂的制剂质量标准的制订
A test for organic residues of solvents that are used in the manufacture of finished products should be included in the product specifications. Process validation results are not considered to adequately justify the omission of such a test from the specifications, but they can be used to justify skip testing.
制剂的质量标准中必须包含有对制剂生产工艺中使用到的有机溶剂残留量的检测。

不能仅通过工艺验证的结果来作为在质量标准中省略残留溶剂检测的唯一依据，而仅能将其作为支持省略该检测的证据之一。

If class 3 solvents only are used, routine testing by loss on drying with a < 0.5% acceptance limit is acceptable when this test is appropriately validated for determination of the relevant solvent(s). Where residues of class 3 solvents cannot be reduced to this level and/or where class 2 solvents are used in the production, specific (chromatographic) techniques should be used.
如果只使用了III类溶剂而且可以通过干燥失重对其控制的话，那么可以通过将干燥失重限度设定为小于0.5%的方式来来控制III类溶剂的残留。

如果III类溶剂不能降低至该水平（＜0.5%）或着在生产中使用了II类溶剂的话，那么必须通过特定（色谱）方法溶剂的残留进行控制。