CPMPICH28395残留溶剂指南

Annexes to: CPMP/ICH/283/95 Impurities: Guideline for residual solvents & CVMP/VICH/502/99 Guideline on impurities: residual solventsCPMP/ICH/283/95 杂质：残留溶剂指南&CVMP/VICH/502/99 杂质指南：残留溶剂附录Introduction 概述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 2023 respectively.两份VICH 的残留溶剂指南：ICH Q3C 杂质：残留溶剂指南CPMP/ICH/283/95和 VICH GL18：杂质指南：兽药制剂、活性成分和辅料中的残留溶剂CVMP/VICH/502/99已经分别自1998 年 3 月和 2023 年 6 月开头使用多年了。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，现在要求对活性物质中 1 类和 2 类残留溶剂的质量标准需要进展进一步的澄清。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.同时也要求对制剂生产中使用的溶剂的残留问题进展清楚的阐述。Annex I: Specifications for class 1 and class 2 residual solvents in active substances附录 I：活性物质中 1 类和 2 类残留溶剂质量标准Specifications for class 1 solvents1 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”.在 ICH 和 VICH 的杂质指南：残留溶剂中，已经说明白“在药品/活性物质、辅料和人药/兽药生产中不应使用 1 类溶剂，由于其毒性无法承受，或者由于其对环境有巨大的影响。但是，假设在生产一种有显著疗效的药品时不能避开，则应掌握其水平在以下限度，否则应另行论证”。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).对于生产工艺中使用 1 类溶剂的论证可以是基于现行科学和技术学问，以及使用溶剂的步骤。例如，某个化学反响不能避开要使用 1 类溶剂，或只能使用 1 类溶剂来获得所需的纯度。假设1 类溶剂的使用是在生产工艺的较早步骤中，假设在适当的中间体中并不存在该溶剂残留，则是可以承受的例 如，傅-克反响。The maximum acceptable limit, in a suitable intermediate or in the final active substance, for a class 1 solvent, 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 limitsprescribed in the relevant aforementioned ICH/VICH guideline on impurities: residual solvents, unless otherwise justified (for example, by the benefit : risk ratio).在适当的中间体中或在最终活性物质中，不管是用作溶剂还是起始物料，不管是以副产物消灭，还是 在一种溶剂中消灭，1 类溶剂的最大可承受限度均应符合其在之前提到的ICH/VICH 指南杂质：残留溶剂中所规定的限度，否则应另行论证例如，依据利益-风险平衡。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.在全部状况下，假设测试的话，活性物质成品中的1 类溶剂含量应符合之前提到的指南中的要求。A class 1 solvents used as starting materials A 作为起始物料使用的 1 类溶剂Certain class 1 solvents, such as benzene and 1,2-dichloroethane, can be used as starting materials.有些特定的 1 类溶剂，如苯和 1,2-二氯乙烷可以用作起始物料。Indeed, the use of benzene as a starting material is unavoidable when benzene is a structural part of the active substance.事实上，假设苯环是原料药构造的一局部，使用苯作为起始物料是不行避开的。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).苯假设作为起始物料，一般用于格外早期的合成步骤，远远在关键起始物料之前。这是为什么在大多状况下，在生产工艺中并不会提到苯。因此假设另一个生产商可以引用一个从较后的工艺步骤开头的合成路线，而一个生产商描述的合成路线是从苯开头的，则该供给商不会被要求去除产品中的苯这里，不会提出访用该 1 类溶剂的问题。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.假设 1 类溶剂被用作起始物料，则需要对其残留进展常规掌握，可以是在适当的中间体中，也可以是在原料药成品中掌握。B class 1 solvents present as an impurity B 作为杂质消灭的 1 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响的副产物例如，格氏反响，当卤化苯镁用于水解生成苯，或会在另一种溶剂中存在，例如，甲苯或丙酮，众所周知，苯是其工艺杂质。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 1 类溶剂可能会存在于另一溶剂中例如含苯的甲苯或丙酮中，假设满足以下要求，则不需要对该 1 类溶剂进展常规检测，无论是在适当的中间体中，还是在原料药成品中：l 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 1 solvent. Thevolatility of both solvents in the drying processes must be taken into account when applying this argument;l 源溶剂中设定了 1 类溶剂的限度，在考虑最大可能的1 类溶剂污染状况下，该限度可以掌握使用得原料药中的该 1 类溶剂残留水平低于指南设定的水平。在运用该论据时必需考虑枯燥工艺中两种溶剂的挥发性。l 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 3 consecutive industrial scale batches;l 已经承受一个验证过的检验方法证明1 类溶剂在适当的中间体或原料药成品中不超过规定限度的30%。应供给连续 6 个中试批次或连续 3 个商业放大批次的支持性数据。l The specification for the originator solvent used includes a routinely performed test and limit for the class 1 solvent.l 所用的源溶剂中的质量标准包括了对该1 类溶剂的常规检测及限度。Specifications for class 2 solvents2 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.假设 2 类溶剂用作起始物料或溶剂，则应进展常规掌握，依据其所用的合成步骤，可以是在适当的中间体中，也可以是在原料药成品中进展掌握。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.原料药成品中 2 类溶剂的设定限度应符合前面提到的相关ICH/VICH 杂质指南：残留溶剂中的要求。A class 2 solvents used in the last step of the synthesis A 最终合成步骤使用的 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.在全部状况下，只要在合成最终步骤使用了2 类溶剂，则应对原料药成品进展常规掌握。B class 2 solvents used prior to the last step of the synthesis B 最终合成步骤前使用的 2 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.假设经过证明，在合成最终步骤之前使用的2 类溶剂不肯定要包括在制剂的质量标准中，可以在适当的中间体或在原料药药成品中进展掌握，2 类溶剂的含量应不超过前面提到的相关ICH/VICH 杂质指南：残留溶剂中设定的可承受限度的10%例如，乙腈 41ppm。假设检测，则 2 类溶剂在原料药成品中的含量应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.为了支持在原料药或在适当的中间体中对2 类溶剂不进展常规检测，应提交连续6 个中试批次或 3 连续 3 批商业放大批适当中间体或活性物质成品中2 类溶剂含量的结果。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.在拟对生产工艺进展变更时，生产商应考虑生产工艺变更对溶剂水平的影响，以及是否需要对工艺进展再验证。