原英文官网http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002907.pdf
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EMA/CHMP/SWP/431994/2007 Rev. 3
Committee for Medicinal Products for Human Use (CHMP)
人用药品委员会
Safety Working Party (SWP)
安全工作组
Questions and answers on the 'Guideline on the limits of genotoxic impurities'
关于“基因毒性杂质限度指南”的问答
/ _ C" u& s5 I C5 H( CAgreed by Safety Working Party (SWP) 安全工作组(SWP)一致同意 | September 2010 |
Adoption by CHMP 由CHMP采用 | 23 September 2010 |
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Keywords 关键词 | Impurities; Genotoxicity; Threshold of toxicological concern (TTC); Structure activity relationship (SAR) |
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Background 背景
The aim of this question-and-answer document is to provide clarification and harmonisation of the 'Guideline on the limits of genotoxic impurities' (EMEA/CHMP/QWP/251344/2006), published in 2006.
本问答文件的目的是对2006年出版的基因毒性杂质限度指南(EMEA/CHMP/QWP/251344/2006)进行相关内容统一和说明。
6 d! s8 T. W3 t4 ZQuestions and answers 问答
Question 1. The guideline does not need to be applied retrospectively to authorised products unless there is a specific cause for concern. What might constitute "a cause-for-concern" in terms of application to currently marketed products?
问题1:该指引并不要求对已批准销售的产品进行基因毒性杂质再评估,除非有一个特定的“重要原因”(cause-for-concern)。请问什么是“重要原因”?
6 `* v: b- X+ ?0 v; _9 e8 c; J2 fIf a manufacturing procedure for API remains essentially unchanged a re-evaluation with respect to the presence of potentially genotoxic impurities is generally not needed. However, new knowledge may indicate a previously unknown cause for concern. One example is the mesylate salt drug substances for which a few years ago, a concern regarding the potential for formation of genotoxic alkyl mesylates was raised. This concern resulted in the “Production Statement” requesting a specific evaluation of the potential for formation of these highly toxic products now included as part of the PhEur monographs for all the mesylates salts.
回答:如果原料药的生产过程基本上没有改变,就不需要对基因毒性杂质进行重新评价。但是,如果新知识表明有新原因时,例如几年前发现的甲磺酸盐药物可能形成甲磺酸烷基的基因毒性杂质,这需要进行基因毒性杂质的再评估,包括EP药典中收载的所有甲磺酸盐类产品,并出示“生产声明”。 ' j, b' I5 ^: Q' ]0 n) S5 Q# M( Q9 f
Question 2. The guideline indicates that it is necessary to reduce a known or suspected mutagenic impurity to as low as reasonably practicable (ALARP) even if the level is below the threshold of toxicological concern (TTC), i.e. in the decision tree ALARP considerations precede TTC considerations. If the level is already known to be below the TTC (which is a very conservative value), why is it necessary to reduce it even further? On a practical basis this would often involve developing analytical methods that have limits of quantitation around or below 1ppm level. The effort and resource this can take, and the possibility that it is not actually achievable, does not seem commensurate with the perceived risk.
问题2:该指引指出:即使按决策树程序其水平低于毒理学关注阈值(threshold of toxicological concern,TTC),也要尽可能地减少已知或未知的诱变杂质(mutagenic impurity)。如果已知其诱变杂质的水平低于TTC(TTC是一个非常保守的值),为什么要还进一步减少呢?实际上这还涉及定量限在1ppm左右的分析方法,可以这样做但可能没结果,这是否有必要呢?
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If the level of a mutagenic impurity is below the threshold of toxicological concern (equivalent to a clinical dose ≤1.5 μg/day) it is not necessary to apply ALARP considerations unless it is a structure of very high concern, e.g. N-nitroso, aflatoxins-like and azoxy-compounds.
回答:如果一个诱变杂质的水平低于毒理学关注阈值(相当于临床剂量≤1.5微克/天),就没有必要这样做。除非它具有一个高度关注的风险结构:如N -亚硝基,黄曲霉毒素类和氧化偶氮物就需要这样做。
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Question 3. The guideline states: “When a potential impurity contains structural alerts, additional genotoxicity testing of the impurity, typically in a bacterial reverse mutation assay, should be considered.”
i) If an impurity triggers a mutagenic structural alert, will a negative result in an Ames test on the impurity (conducted to regulatory acceptable standards) be sufficient to conclude that the compound is of no concern with respect to genotoxicity and no further ‘qualification’ studies will be required?
ii) Is the absence of a structural alert sufficient to show that the impurity is of no concern?
iii) Is it acceptable to control impurities with a structural alert by assuming they will be positive (without resorting to any testing) and ensuring the level remains below the appropriate TTC value?
问题3:该指引规定:“当一个潜在的杂质包含“警示结构”(structural alerts)时,应考虑用细菌突变试验对其杂质进行的基因毒性分析”。3 a8 Y6 B7 _, i* M5 i; F: B
i)如果一个杂质能诱发“警示结构”,该杂质的致突变试验(Ames)结果为阴性时,是否就足以得出结论:该化合物不属于关注的遗传毒性杂质?是否还需要进一步的确认研究?' e! c( Z- p6 L# t) u9 z
ii)“警示结构”不存在就足以说明不属于关注杂质呢?( A. i5 `1 E% l ^* p
iii)假设某杂质属于“警报结构”,但只要加以控制确保其杂质水平低于TTC,不进行常规检测是否可以接受?0 Z5 d! V( J, b( t. r- j) C. B
i) Yes, a negative Ames test (conducted to regulatory acceptable standards) will overrule a structural alert and no further studies would be required providing the level remains below ICH Q3A/B limits.
ii) Yes, the absence of a structural alert based on a well-performed assessment (e.g. through application of commonly used QSAR assessment software such as DEREK or MCASE) will be sufficient to conclude that the impurity is of no concern with respect to genotoxicity and no further ‘qualification’ studies or justification will be required.
iii) Yes, genotoxicity testing is not obligatory when a potential genotoxic impurity is controlled at the TTC level, unless it belongs to a class of very potent genotoxic carcinogens (N-nitroso and azoxy compounds, or a aflatoxin-like compound).
回答:, K5 ^& u1 ]1 f3 W
i)是的。只要按Q3A/B的要求做Ames试验显示阴性时,即可认定该杂质不属于“警报结构”,就不需要进一步确认研究。
' W6 o/ S& k. |, Gii)是的。通过仔细评估,如果“警报结构”不存在,即可认定“关注杂质”(concern impurity)不存在。通常这种评估常用构效关系的评估软件,如DEREK或MCASE软件。4 Z7 r o9 H1 v: v: ?- w4 e
iii)是的。当一个潜在的基因毒性杂质水平控制在TTC的水平时,就不强制要求进行基因毒性的常规检测,除非它具有非常强的基因毒性物质类(N -亚硝基化合物及偶氮化合物或黄曲霉毒类化合物)。
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Question 4. What would be an appropriate strategy to qualify a new impurity that arises during Phase III or with a commercial product? For example, would it be acceptable that a new unidentified impurity, discovered at the 0.05-0.09% range requires no action to be taken? Would an impurity discovered in the 0.10 to 0.15%, even if it triggers a structural alert, be fully qualified by testing the active ingredient containing this impurity in an Ames test?
问题4:什么是限定新杂质出现的适当战略(在三期临床阶段或商业批生产阶段)?,例如,下列战略是否可以接受?当发现一个新未知杂质在0.05-0.09%的范围就不需采取行动,在0.10至0.15%范围,即使它会诱导出“警示结构”,只要对含有这种杂质的成分进行Ames试验即可?
In line with the ICH guideline, no action is generally required for a new unidentified impurity found at levels below the ICH identification threshold. When an impurity is found above the ICH identification threshold, but below the qualification threshold, and the structure gives rise to a structural alert, this can be negated by carrying out an Ames test on the active ingredient containing the impurity as long as the impurity is present at a minimum concentration of 250 μg/plate (estimated detection limit for most relevant mutagens in Ames test, see Kenyon et al., Reg Tox & Pharm, 2007, 75-86). If the structure cannot be elucidated, then no action is generally required. Above the ICH qualification threshold, then the ICH guidance should be followed.
回答:出现新的低于鉴别阈值(identification threshold)的未知杂质时,ICH指南没有要求有任何行动;但是当高于鉴别阈值,低于确认阈(qualification threshold)并且可能成为“警示结构”时,并且该原料药中含该杂质的最小浓度为250μg/板(Ames方法的评估检测线,详见Kenyon et等,Reg Tox & Pharm, 2007, 75-86),就需要对含有这种杂质的活性成分进行Ames实验并成阴性。
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Question 5. The guideline states that “A TTC value higher than 1.5 μg /day may be acceptable under certain conditions e.g. short-term exposure….”. Is the CHMP in agreement with the principles of “staged TTC” dependent on the duration of clinical exposure, i.e. higher levels allowed for marketed drugs used to treat acute conditions, e.g. antibiotics. If ‘yes’, what levels would be acceptable?
问题5:该指引指出,“毒理学关注阈(TTC)值高于1.5微克/天,在一定条件下是可以接受的,例如短期接触….”,阶段性TTC与临床接触的持续时间有关,例如抗生素。如果是这样的话,什么是短期接触的可接受水平?
TTC values for genotoxic impurities above 1.5 μg /day will be treated on a case-by-case basis. For short-duration treatments, the acceptability of higher levels will be in line with the principles outlined in the CHMP’s answer to question 6.
回答:高于1.5 μg /天微克以上的基因毒性杂质的要逐案处理。对于短期治疗,更高水平的接受能力原则见问题6的回答。
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Question 6. The wording of the guideline implies that it is intended to cover an issue not covered specifically by ICH Q3A/B guidelines. The scope of the ICH guidelines does not include clinical development prior to NDA or MAA submission. However, experience across a range of pharmaceutical companies indicates that some regulatory authorities are applying the genotoxic impurity guideline during clinical development. In case the scope should include application to clinical development, can the CHMP advise on how genotoxic impurities should be controlled during the development stage?
问题6:该指引的措辞意味着它覆盖了ICH Q3A没有涉及的问题。ICH指南范围不包括NDA前的临床申请(或备忘录)。然而,实践表明,临床研发阶段涉及的基因毒性指南同样适合于注册法规要求。在研发阶段如何控制基因毒性杂质呢?
According to the scope of the guideline, it mainly applies to genotoxic impurities in “new active substances” which includes new active substances in both, MAA submissions as well as clinical trial applications. In fact, the CHMP Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in clinical trials (CHMP/QWP/185401/2004) states that “For impurities in IMPs, a justification that the product is safe for its intended use, considering the anticipated exposure of volunteers and patients, respectively, will be required.”, and further on “a brief justification of the specifications and acceptance criteria for impurities …… should be provided based on safety and toxicity data.”
The CHMP agrees with the use of a staged TTC concept during clinical development.
The acceptable limits for daily intake of genotoxic impurities are 5, 10, 20, and 60μg/day for a duration of exposure of 6-12 months, 3-6 months, 1-3 months, and less than 1 month, respectively. For a single dose an intake of up to 120 μg is acceptable. Compared to the proposal of a staged TTC in the Mueller et al (Reg Tox & Pharm, 2006, 44, 198–211) paper these values incorporate a dose rate correction factor of 2 to account for deviations from the linear
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| Duration of exposure |
Single dose | ≤1 month | ≤3 months | ≤6 months | ≤12 months |
Allowable daily intake | 120μg | 60μg | 20μg | 10μg | 5μg |
回答:根据该指南的范围,它主要适用于“新的活性物质”中的基因毒性杂质,包括临床申请和备忘录中提到的新活性物质和临床试验申请中提到的新活性物质。事实上,临床试验的化学品和药品质量文件要求指(CHMP/QWP/185401/2004)已经对IMP中的杂质对志愿者和患者的安全性提出过要求。要基于安全和毒性数据提供杂质的规格与接受标准。
CHMP认可在临床研发阶段采用TTC分段概念。
在临床研发时段,短期的TTC应符合下列要求。允许的日吸入量与接触时间关系见下表。
下面这些值都是考虑了单次校正因子为2后通过线性外推的模式来计算偏差得来的。
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单剂量 | ≤1个月 | ≤3个月 | ≤6个月 | ≤12个月 |
允许的日吸入量 | 120μg | 60μg | 20μg | 10μg | 5μg |
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Question 7. The guideline text implies that the indicated TTC value of 1.5 μg /day is a level that can be applied to each individual genotoxic impurity in a drug substance. Could this be confirmed?
问题7:按指引条款要求,意味着1.5微克/天的TTC值可适用于每一个原料药中的基因毒性杂质,请问这样的理解是否确切?
When more than one genotoxic impurity is present in the drug substance, the TTC value of 1.5 μg/day can be applied to each individual impurity only if the impurities are structurally unrelated.
In case of structural similarity, it can be assumed that the impurities act by the same genotoxic mode of action and have the same molecular target. and thus might exert effects in an additive manner. In such a situation, a limitation of the sum of the genotoxic impurities at 1.5 μg/day is recommended. This might be practically not achievable with reasonable efforts in particular when the maximum daily dose is very high and thus may demand application of lower group limits. Justifications should be made on a case-by-case basis taking into consideration issues such as:
回答:在原料药中存在一个以上的基因毒性杂质时,1.5微克/天TTC值对每一个结构不相关的杂质是适用的。在结构相似的情况下,基因毒性杂质的作用模式一致,并具有相同的分子靶向,在这种情况下,建议基因毒性杂质的总和为1.5微克/天。这可能不符合实际,特别是最大日剂量很高而且又要求按低限要求申报时。此时应根据下列因素逐案考虑:
l Maximum daily dose of the active substance;
l 原料药的每日最高剂量;
l Therapeutic indication;
l 治疗适应症;
l Step of the synthesis at which the genotoxic impurity(ies) arise;
l 产生基因毒性杂质的合成步骤;
l Capability of the manufacturing process (purification steps) to eliminate these impurities;
l 消除这些杂质生产纯化能力;
l Capability of the analytical procedure to control these impurities.
l 控制这些杂质的分析方法能力。
In cases where routine use of more powerful detection methods would be difficult, one could consider using such methods during development or testing of the first commercial batches, in order to demonstrate that the actual values are sufficiently below the TTC. In such a case, skip testing could be considered instead of routine testing, providing that the Competent Authorities, based on a risk assessment, consider the approach as acceptable. 在这种情况下将这种检测方法能力强的分析方法作为常规检测将是困难的,人们可以在开发过程或首次商业批生产中考虑使用这种分析方法,以充分证明其实际值低于TTC值。在这种情况下,使用风险评估的方法,定期检测而不是常规检测是可以接受的。
1 n7 X) J5 ^- FQuestion 8. The European Pharmacopoeia Commission Policy for dealing with potentially genotoxic impurities was issued in March 2008. This policy is to be applied during elaboration and revision of pharmacopoeial monographs. It provides very pragmatic guidance on how the CHMP guideline can be applied to active substances described in existing monographs. Can the same principles, as outlined within this policy, apply to established drug substances, which do not have pharmacopoeial monographs?
问题8:2008年3月欧洲药典委员会对具有潜在基因毒性杂质颁发过一个政策。这项政策将在制定和修订药典中得到应用。它提供了非常务实的一个政策来指导如何处理现行药典中收载的活性物质中存在的潜在基因毒性杂质。这些政策是否适用于没有收载到药典中的API吗?
+ X- [) O. J2 k) [, H' BYes. For active substances included in medicinal products authorized by the competent authorities before implementation of the CHMP guideline, the specifications as described in the dossier for marketing authorization should be followed. Action is needed only where there is study data demonstrating genotoxicity of the impurity. The existence of structural alerts alone is considered insufficient to trigger follow-up measures unless it is a structure of very high concern, e.g. N-nitroso, aflatoxins-like and azoxy-compounds. If a new synthetic route is used that may give rise to different potentially genotoxic impurities or to higher levels of previously recognized potentially genotoxic impurities then the situation should be discussed with the competent authority.
回答:是的。在这个指南执行前已批准的API是适用的。在注册申报文件中应递交相关的规格要求。只有当研究数据表明存在遗传毒性杂质时才需要采取行动,仅存在“警示结构”时不足以引发的后续措施,除非在出现一个高度关注的风险结构,例如:N -亚硝基,黄曲霉毒素类和氧化偶氮化合物。如果似使用新的合成路线,该合成路线可能引起潜在基因遗传毒性杂质出现或先前确认的潜在基因毒性杂质水平提高,这种情况应与主管机关进行讨论。( ], ~( A; Q6 o d2 O9 g. o
Question 9. What is a reasonable policy for setting specifications for potentially genotoxic impurities which are theoretical or actual impurities in a drug substance manufacturing process?
问题9:在原料药生产过程中,对于理论推测存在或实际存在的潜在基因毒性杂质质量标准的设定依据是什么?
Different possible scenarios can be identified and the applicable policies to be applied for each of them are described below:
回答:各种不同情形时的潜在基因毒性杂质质量标准可以依据下面的情况来进行设定:6 p8 H( x3 s" _3 q2 x, z8 [; y: _
Example 1 – A potential genotoxic impurity
例1:一个潜在基因毒性杂质
The definition for a potential genotoxic impurity is derived from the definition for “Potential impurity”: an impurity that theoretically can arise during manufacture or storage. It may or may not actually appear in the (new) drug substance (ICH Q3A, Glossary).
潜在基因毒性杂质的定义是基于“潜在杂质”的定义得来的。潜在杂质是指按照理论推测在生产或储存过程中可能产生的杂质。它可能在(新)原料药中存在,也可能不存在(ICH Q3A,术语)。: L2 u n/ U7 N8 x! r# F$ }/ G% X
If a potential genotoxic impurity is just a theoretical impurity i.e. based on theoretical considerations but not found in practice as demonstrated by studies during development of the manufacture, the impurity does not need to be included in the drug substance specification.
如果一个潜在基因毒性杂质仅仅是理论上推测存在,也就是说基于理论推测存在但生产中并未实际检测到(由生产工艺开发阶段的研究证实),则不需要将其列入到原料药的质量标准中。
Example 2 – A (potentially) genotoxic impurity actually formed or introduced prior to the final step of the synthesis
例2:合成最后一步前,实际生成或引入了一个(潜在)基因毒性杂质/ P7 f( H3 `, }# }: u( O- @! ?; V- P) a9 W
If a (potentially) genotoxic impurity is formed or introduced in a step before the final synthesis step, it is considered possible to not include this impurity in the drug substance specification if it is controlled by a suitable limit in a synthesis intermediate and if it is unambiguously demonstrated by analysis results (use of spiking experiments are encouraged) that presence of this impurity does not exceed 30 % of the limit, derived either from TTC or otherwise defined acceptable limit etc, in the drug substance. If these conditions are not fulfilled, this impurity has to be included in the drug substance specification and the test has to be carried out on a routine basis.
如果在最后一步合成前,实际生成或引入了一个(潜在)基因毒性杂质,可以不将其纳入原料药质量标准中,但是必须保证该杂质在合成中间体中有合理的控制限度并且在原料药检测结果中明确其含量不超过来源于TTC或其他认可标准的30%(推荐使用标准加入法检测原料药)。但是如果不能满足这些要求,就必须在原料药质量标准中进行日常检测。
Should a genotoxic impurity not be controlled at the intermediate stage, then the scenario of example 3 applies.
如果一个基因毒性杂质不可在中间阶段控制,那么适用例3情况。" M. R( d: J: Q; q1 b6 N& w
Example 3 - A (potentially) genotoxic impurity is formed or introduced in the last synthesis step
例3:最后一步合成中,实际生成或引入了一个(潜在)基因毒性杂质
If a (potentially) genotoxic impurity is formed or introduced in the final synthesis step, it should be included in the specifications. However, it is considered possible to apply skip 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 drug substance. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the drug substance specification is needed.
如果在最后一步合成中实际生成或引入了一个(潜在)基因毒性杂质,必须在原料药质量标准中控制该杂质。如果在原料药中该杂质的含量不超过TTC或其他认可标准的30%,可实行定期检测。至少要提交6批中试批或3批大生产的数据。如果不能满足这个要求,就必须在原料药质量标准中进行日常检测。
The following definitions apply: 以下为文件中涉及的定义
Genotoxic impurity: an impurity that has been demonstrated to be genotoxic in an appropriate genotoxicity test model, e.g. bacterial gene mutation (Ames) test.
基因毒性杂质:某种杂质在适当的基因毒性试验模式中表示为基因毒性,例如细菌基因诱变(Ames)试验
Potentially genotoxic impurity: an impurity that shows (a) structural alert(s) for genotoxicity but that has not been tested in an experimental test model. Here potentially relates to genotoxicity, not to the presence or absence of this impurity.
潜在基因毒性杂质:某种杂质其结构警示可能具有基因毒性,但未经过试验测试模式。这里潜在意指可能具有基因毒性,而不是指杂质的存在与否。
References 参考文献
M.O. Kenyon, J.R. Cheung, K.L. Dobo, W.W. Ku: An evaluation of the sensitivity of the Ames assay to discern low-level mutagenic impurities. Reg Tox & Pharm, 2007, 75-86.
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