Annexes to:CPMP/ICH/283/95 Impurities: Guideline for residual solvents&CVMP/VICH/502/99 Guideline on impurities: residual SolventsEMA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 2003.01~2004.06Adoption by CVMP CVMP 采纳July 2004 2004.07Adoption by CHMP CHMP 采纳July 2004 2004.07Date for coming into operation 生效时间January 2005 2005.01Rev. 01 Adoption by Quality Working Party 质量工作组采纳的01版本22 November 20122012.11.22Rev. 01 Adoption by CVMP CVMP采纳的01版本7 February 2013 2013.02.07Rev. 01 Adoption by CHMP CHMP采纳的01版本11 February 2013 2013.02.11Rev. 01 Date for coming into operation 01版本生效1 March 2013 2013.03.01Introduction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 solventsI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。