本人翻译的EMA关于API中基因毒性,金属杂质和残留溶剂的标准

llb1978

1. What is a reasonable policy forsetting specifications for potentially genotoxic impurities which aretheoretical or actual impurities in a drug substance manufacturing process? HJune 2012

1. 什么是设定潜在基因毒性杂质（原料药生产工艺中理论或实际的杂质）标准的基本原则？人用药品，2012年6月

Different possible scenarios can beidentified and the applicable policies to be applied for each of them aredescribed below:

不同的可能情况可被划分，并且不同的适用原则对应于下面描述的各个情况：

Example 1 – A potential genotoxicimpurity

举例1—潜在基因毒性杂质

The definition for a potentialgenotoxic impurity is derived from the definition for 'potential impurity': animpurity that theoretically can arise during manufacture or storage. It may ormay not actually appear in the (new) drug substance (ICH Q3A, glossary).

潜在基因毒性杂质的定义起源于“潜在杂质”的定义：理论上可能在生产中或贮藏中出现的杂质，它可能会或不会实际存在于（新）原料药中（ICH Q3A，术语）。

If a potential genotoxic impurity isjust a theoretical impurity i.e. based on theoretical considerations but notfound in practice at any key stage in the manufacturing process as demonstratedby studies during development of the manufacture, the impurity does not need tobe included in the drug substance specification or a specification of anintermediate.

如果潜在基因毒性杂质仅是理论杂质，即：基于理论考虑但在生产开发研究中证明生产工艺的任何关键阶段均不会发现，则该杂质不需要包含在原料药的标准或中间体的标准中。

Example 2 – A (potentially)genotoxic impurity actually formed or introduced prior to the final step of thesynthesis

举例2—在合成最后一步前形成或引入（潜在）基因毒性杂质

If a (potentially) genotoxicimpurity is formed or introduced in a step before the final synthesis step, itis considered possible to not include this impurity in the drug substancespecification if it is controlled by a suitable limit in a synthesisintermediate and if it is unambiguously demonstrated by analysis results (useof spiking experiments are encouraged) that presence of this impurity does notexceed 30 % of the limit, derived either from threshold of toxicologicalconcern (TTC) or otherwise defined acceptable limit etc., in the drugsubstance.

如果在最后合成步骤前产生或引入了（潜在）基因毒性杂质，假如在合成中间体中控制在适当的限度并且通过分析结果（鼓励使用加样试验）明确地证明该杂质在原料药中不超过限度（由毒理学关注阈值（TTC）或明确的可接受限度推导出）的30%，则认为原料药标准中可以不包含该杂质。

It is considered possible to applyskip testing if the level of the impurity in a synthesis intermediate does notexceed 30% of the limit, derived from either TTC or otherwise definedacceptable limit etc, in the intermediate. Data should be presented for atleast 6 consecutive pilot scale or 3 consecutive production scale batches.If this condition is not fulfilled, a routine test in the intermediate isneeded. If the impurity exceeds 30% of the limit, derived either from TTC orotherwise defined acceptable limit etc., in the drug substance the impurity hasto be included in the drug substance specification and the test has to becarried out on a routine basis.

如果合成中间体中的杂质水平不超过限度（由毒理学关注阈值（TTC）或确定的可接受限度等推导出）的30%，则认为可以使用跳跃检测，至少具有6个连续中试批或3个连续生产批的数据，如果不满足这些条件，则需要对中间体进行例行检测。如果原料药中该杂质超过限度（由毒理学关注阈值（TTC）或明确的可接受限度等推导出）的30%，则原料药标准中必须包含该杂质，并且应进行例行检测。

Should a genotoxic impurity not becontrolled at the intermediate stage, then the scenario of example 3 applies.

如果在中间体阶段没有基因毒性杂质需要控制，则适应举例3的情况。

Example 3 - A (potentially)genotoxic impurity is formed or introduced in the last synthesis step

举例3—在合成最后一步形成或引入（潜在）基因毒性杂质

If a (potentially) genotoxicimpurity is formed or introduced in the final synthesis step, it should beincluded in the specifications. However, it is considered possible to applyskip testing if the level of the impurity does not exceed 30% of the limit,derived from either TTC or otherwise defined acceptable limit etc., in the drugsubstance. Data should be presented for at least 6 consecutive pilot scale or 3consecutive production scale batches. If this condition is not fulfilled, aroutine test in the drug substance specification is needed.

如果在最后合成步骤形成或引入（潜在）基因毒性杂质，则应包含于质量标准中。然而，如果原料药中该杂质不超过限度（由毒理学关注阈值（TTC）或明确的可接受限度等推导出）的30%，则认为可以使用跳跃检测，至少具有6个连续中试批或3个连续生产批的数据，如果不满足这些条件，则原料药标准中需要包含例行检测。

Definitions:

定义：

For the purpose of these questionsand answers, the following definitions apply:

下列定义适用于这些问答：

· Genotoxic impurity: an impurity that has been demonstrated to be genotoxic in an appropriategenotoxicity test model, e.g. bacterial gene mutation (Ames) test.

· 基因毒性：在适宜的基因毒性检测模型（如：细菌基因突变（Ames）检测）中证明是基因毒性的杂质。

· Potentially genotoxic impurity: an impurity that shows (a) structural alert(s) for genotoxicity but thathas not been tested in an experimental test model. Here potentially relates togenotoxicity, not to the presence or absence of this impurity.

· 潜在基因毒性杂质：显示有基因毒性结构性警示但未经过实验检测模型检测的杂质，此处的“潜在”与基因毒性相关，与该杂质的存在与否无关。

2. In order to harmonise thepolicies to be applied for setting specifications for genotoxic impurities andheavy-metal-catalyst residues, what are reasonable policies to be applied whensetting specifications for heavy-metal-catalyst residues? H June 2012

llb1978

2. 为了协调应用于设定基因毒性杂质和重金属催化剂残留标准的原则，在为重金属催化剂残留设定标准时应用什么原则是合理的？人用药品，2012年6月

In order to harmonise the policy forsetting specifications for metal residues with that for setting specificationsfor genotoxic impurities, some clarifications of the interpretation of sections4.5 and 4.6 of the heavy-metal-catalyst guideline (EMEA/CHMP/SWP/4446/2000)are given below.

为了将金属残留设定标准与基因毒性杂质的设定标准的原则相互协调，对重金属催化剂指南(EMEA/CHMP/SWP/4446/2000)中第4.5和4.6项的解释进行阐明如下：

Since it is the class-1 metals thatare the most toxic metals with permitted daily exposures (PDEs) that approachthe level of the threshold of toxicological concern (TTC) applied for genotoxicimpurities, it seems reasonable that class-1 metals are the prime focus forharmonisation with the policy for genotoxic impurities while class-2 and 3 metalscould be treated similarly but somewhat less strictly.

因为1类金属是最毒的金属，其允许日暴露量（PDE）接近于基因毒性杂质的毒理学关注阈值（TTC）的水平，所以协调1类金属与基因毒性杂质的原则是合理的，而2类和3类金属用与其相似的方式但要相对宽松对待。

Example 1 – A class-1 metal is notused or suspected to be present in a synthesis process

举例1—1类金属未使用或不怀疑存在于合成工艺中

Metals are not expected to be formedin synthesis processes. Only if deliberately introduced or suspected to bepresent for other reasons, residues of metals can be expected. If not used orsuspected to be present, the metal does not need to be included in the drugsubstance specification or a specification of an intermediate.

合成工艺中不会形成金属，除非故意引入或其他原因怀疑存在，则可能有金属残留。如果未使用或不怀疑存在，原料药标准或中间体标准中不需要包含金属检测。

Example 2 – A class-1 metal is formedor introduced prior to the final step of the synthesis

举例2—在合成最后一步前形成或引入1类金属

If a class-1 metal is introduced ina step before the final synthesis step, it is considered possible to notinclude this metal in the drug substance specification if it is controlled by asuitable limit in a synthesis intermediate and if it is unambiguouslydemonstrated by analysis results that the presence of this metal does notexceed 30% of the guideline limit in the drug substance.

如果在最后合成步骤前产生或引入了1类金属，如果在合成中间体中控制在适当的限度并且通过分析结果明确地证明该杂质在原料药中不超过指南限度的30%，则认为原料药标准中可以不包含该金属。

It is considered possible to applyskip testing if the level of the class-1 metal in a synthesis intermediate doesnot exceed 30% of the guideline limit in the intermediate. Data should bepresented for at least 6 consecutive pilot scale or 3 consecutive productionscale batches. If this condition is not fulfilled, a routine test in theintermediate is needed. If the class-1 metal exceeds 30% of the guideline limitin the drug substance the impurity has to be included in the drug substancespecification and the test has to be carried out on a routine basis.

如果合成中间体中的1类金属水平不超过指南限度的30%，则认为可以使用跳跃检测，至少具有6个连续中试批或3个连续生产批的数据，如果不满足这些条件，则需要对中间体进行例行检测，如果原料药中该1类金属超过指南限度的30%，则原料药标准中必须包含该杂质，并且应进行例行检测。

Should a class-1 metal not becontrolled at the intermediate stage, then the scenario of example 3 applies.

如果在中间体阶段没有1类金属需要控制，则适应举例3的情况。

Example 3 – A class-1 metal isintroduced in the last synthesis step

举例3—在合成最后一步形成或引入1类金属

If a class-1 metal is introduced inthe final synthesis step, it should be included in the specifications. However,it is considered possible to apply skip testing if the level of the metal doesnot exceed 30% of the guideline limit in the drug substance. Data should bepresented for at least 6 consecutive pilot scale or 3 consecutive productionscale batches. If this condition is not fulfilled, a routine test in the drugsubstance specification is needed.

如果在最后合成步骤形成或引入1类金属，则应包含于质量标准中。然而，如果原料药中金属不超过指南限度的30%，则认为可以使用跳跃检测，至少具有6个连续中试批或3个连续生产批的数据，如果不满足这些条件，则原料药标准中需要包含例行检测。

llb1978

3. In order to harmonise thepolicies to be applied for setting specifications for genotoxic impurities andclass-1 solvent residues, what are reasonable policies to be applied whensetting specifications for class-1 solvent residues? H June 2012

3. 为了协调应用于设定基因毒性杂质和1类残留溶剂标准的原则，在为1类溶剂残留设定标准时应用什么原则是合理的？人用药品，2012年6月

In order to harmonise the policy forsetting specifications for class-1 solvents with that for settingspecifications for genotoxic impurities, some clarifications of theinterpretation of annex I to the residual solvents guideline(CPMP/ICH/283/96 / CVMP/VICH/502/99): Specifications for class 1 and class 2residual solvents in active substances (CPMP/QWP/450/03 / EMEA/CVMP/511/03)are given below.

为了将1类溶剂的设定标准与基因毒性杂质设定标准的原则相互协调，对残留溶剂指南 (CPMP/ICH/283/96/ CVMP/VICH/502/99) 附件I：原料药中1类和2类溶剂标准(CPMP/QWP/450/03 / EMEA/CVMP/511/03)中的解释进行阐明如下：

Since it is the class-1 solventsthat are most toxic solvents and have permitted daily exposures (PDEs) thatapproach the level of the threshold of toxicological concern (TTC) applied forgenotoxic impurities, it seems reasonable that clas- 1 solvents are the focusfor harmonisation with the policy for genotoxic impurities.

因为1类溶剂是最毒的溶剂，其允许日暴露量（PDE）接近于基因杂质的毒理学关注阈值（TTC）的水平，所以协调1类溶剂与基因毒性杂质的原则是合理的。

Example 1 – A class-1 solvent is notused or suspected to be present in a synthesis process

举例1—1类溶剂未使用或不怀疑存在于合成工艺中

If a class-1 solvent is just apotential impurity, not used directly or found in practice as demonstrated bystudies during development of the manufacture, the class-1 solvent does notneed to be included in the drug substance specification or a specification ofan intermediate.

如果1类溶剂仅是潜在的杂质，未直接使用或通过生产开发过程的研究明确实际不存在则原料药标准或中间体标准中不需要包含该1类溶剂。

Example 2 – A class-1 solvent isformed or introduced prior to the final step of the synthesis

举例2—在合成最后一步前形成或引入1类溶剂

If a class-1 solvent is formed orintroduced in a step before the final synthesis step, it is considered possibleto not include this solvent in the drug substance specification if it iscontrolled by a suitable limit in a starting material or synthesis intermediateand if it is unambiguously demonstrated by analysis results that the presenceof this solvent does not exceed 30% of the guideline limit in the drugsubstance.

如果在最后合成步骤前产生或引入了1类溶剂，如果在合成中间体控制在适当的限度并且通过分析结果明确地证明该杂质在原料药中含量不超过指南限度的30%，则认为原料药标准中可以不包含该溶剂。

It is considered possible to applyskip testing if the level of the solvent in a synthesis intermediate does notexceed 30% of the guideline limit in the intermediate. Data should be presentedfor at least 6 consecutive pilot scale or 3 consecutive production scalebatches. If this condition is not fulfilled, a routine test in the intermediateis needed. If the solvent exceeds 30% of the guideline limit in the drugsubstance the solvent has to be included in the drug substance specificationand the test has to be carried out on a routine basis.

如果合成中间体中的1类溶剂水平不超过指南限度的30%，则认为可以使用跳跃检测，至少具有6个连续中试批或3个连续生产批的数据，如果不满足这些条件，则需要对中间体进行例行检测。如果原料药中该1类溶剂超过指南限度的30%，则原料药标准中必须包含该溶剂，并且应进行例行检测。

Should a class-1 solvent not becontrolled at the starting material or intermediate stage, then the scenario ofexample 3 applies.

如果在中间体阶段没有1类溶剂需要控制，则适应举例3的情况。

Example 3 – A class-1 solvent isformed or introduced in the last synthesis step

举例3—在合成最后一步有1类溶剂形成或引入

If a class-1 solvent is formed orintroduced in the final synthesis step, it should be included in thespecifications. However, it is considered possible to apply skip testing if thelevel of the solvent does not exceed 30% of the guideline limit in the drugsubstance. Data should be presented for at least 6 consecutive pilot scale or 3consecutive production scale batches.

如果在最后合成步骤形成或引入1类溶剂，则应包含于质量标准中。然而，如果原料药中溶剂不超过指南限度的30%，则认为可以使用跳跃检测，但至少具有6个连续中试批或3个连续生产批的数据。

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llb1978

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