20130320 EMA残留溶剂指南附录

20130320 EMA残留溶剂指南附录  

2014-11-06 18:50:08|  分类： EMA

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20 February 2013

CPMP/QWP/450/03 -Rev.1, EMEA/CVMP/511/03 -Rev.1

Committee for medicinal products for human use (CHMP)

Committee for medicinal products for veterinary use (CVMP)

Annexes to:

CPMP/ICH/283/95 Impurities: Guideline for residual solvents &

CVMP/VICH/502/99 Guideline on impurities: residual solvents

CPMP/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

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

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

Discussion at Quality Working Party	January 2003 to June 2004
Adoption by CVMP	July 2004
Adoption by CHMP	July 2004
Date for coming into operation	January 2005
Rev.01 Adoption by Quality Working Party	22 November 2012
Rev.01 Adoption by CVMP	7 February 2013
Rev.01 Adoption by CHMP	11 February 2013
Rev.01 Date for coming into operation	1 March 2013

质量工作组讨论	2003年1月至2004年6月
CVMP采纳	2004年7月
CHMP采纳	2004年7月
生效时间	2005年1月
质量工作组采纳版本01	2012年11月22日
CVMP采纳版本01	2013年2月7日
CHMP采纳版本01	2013年2月11日
版本01生效日期	2013年3月1日

Annexes to: CPMP/ICH/283/95 Impurities: Guideline for residual solvents & CVMP/VICH/502/99 Guideline on impurities: residual solvents

CPMP/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 2001 respectively.

两份（V）ICH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：新兽药制剂、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2001年6月开始使用多年了。

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行进一步的澄清。

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行清楚的阐述。

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 solvents

1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，已经说明了“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，因为其毒性无法接受，或者因为其对环境有巨大的影响。但是，如果在生产一种有显著疗效的药品时不能避免，则应控制其水平在以下限度……，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知识，以及使用溶剂的步骤。例如，某个化学反应不能避免要使用1类溶剂，或只能使用1类溶剂来获得所需的纯度。如果1类溶剂的使用是在生产工艺的较早步骤中，如果在适当的中间体中并不存在该溶剂残留，则是可以接受的（例如，傅-克反应）。

The maximum acceptable limit, in a suitable intermediate or in the final active substance, for a class 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 limits prescribed 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，不管是以副产物出现，还是在一种溶剂中出现，1类溶剂的最大可接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，根据利益-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.

在所有情况下，如果测试的话，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，如果苯环是原料药结构的一部分，使用苯作为起始物料是不可避免的。

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).

苯如果作为起始物料，一般用于非常早期的合成步骤，远远在关键起始物料之前。这是为什么在大多情况下，在生产工艺中并不会提到苯。因此如果另一个生产商可以引用一个从较后的工艺步骤开始的合成路线，而一个生产商描述的合成路线是从苯开始的，则该供应商不会被要求清除产品中的苯（这里，不会提出使用该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.

如果1类溶剂被用作起始物料，则需要对其残留进行常规控制，可以是在适当的中间体中，也可以是在原料药成品中控制。

B class 1 solvents present as an impurity

B 作为杂质出现的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应的副产物（例如，格氏反应，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，如果满足以下要求，则不需要对该1类溶剂进行常规检测，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. The volatility 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类溶剂污染情况下，该限度可以控制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。在运用该论据时必须考虑干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  已经采用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%。应提供连续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 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.

如果2类溶剂用作起始物料或溶剂，则应进行常规控制，根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行控制。

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.

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.

在所有情况下，只要在合成最后步骤使用了2类溶剂，则应对原料药成品进行常规控制。

B class 2 solvents used prior to the last step of the synthesis

B 最后合成步骤前使用的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.

如果经过证明，在合成最后步骤之前使用的2类溶剂不一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行控制，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接受限度的10%（例如，乙腈41ppm）。如果检测，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类溶剂不进行常规检测，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.

在拟对生产工艺进行变更时，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.

有机溶剂可能会因为不同的原因用于药品生产

For example: 例如

l  as a granulation solvent for the manufacture of tablets;

l  在片剂生产中作为制粒溶剂

l  as part of a tablet coating solution;

l  作为片剂包衣液的成分

l  as a solvent for adhesives used in manufacture of transdermal patches;

l  透皮吸收贴剂生产中作为溶剂的胶粘剂

l  as a solvent for polymers used in manufacture of implants.

l  在移值体生产中作为溶剂的聚合物

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.

在研发文件中要包括制剂生产中使用的溶剂的选择和论证。例如，如果原料药被证明对水分比较敏感，则乙醇可能被用作制粒和/或包衣液的溶剂，如果必须要在制剂生产中引入特定的聚合物，将不可避免会使用源溶剂。在制剂中生产中使用1类溶剂是不能被接受的。

Specifications for finished products when organic solvents have been used in their manufacture 制剂生产中使用了有机溶剂时其质量标准制订

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.

制剂中应包括有制剂生产中所使用的有机溶剂的检测。工艺验证结果不能作为质量标准中省略该项检测的充分证据，但可以用来论证周期检测。

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3类溶剂，可以在例行检测中使用LOD，可接受标准<0.5%来替代控制。当然，检测方法要进行适当验证，以证明相关的溶剂可以采用该方法来测定。如果3类溶剂不能降低至该水平和/或如果在生产中使用了2类溶剂，则应使用特定（色谱）技术。

来源：http://zhuyujiao1972.blog.163.com/blog/static/986947272014106650891/

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谢谢分享了，楼主辛苦