EMEA基因毒性雜質限度指南

1、EMEA/CHMP/QWP/251344/2006 基因毒性雜質限度指南(中英文對照) London, 28 June 2006 CPMP/SWP/5199/02 EMEA/CHMP/QWP/251344/2006 The Europea n Age ncy for the Evaluatio n of Medici nal Products 歐洲共同體藥物評審委員會 (EMEA) COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE 人用藥品委員會 (CHMP) GUIDLINE ON THE LIMITS OF GENOTOXIC IMPURITIE

2、S 基因毒性雜質限度指南 DESCUSSION IN THE SAFETY WORKING June 2002-October 2002 PARTY 安全工作組之內(nèi)的討論 TRANSMISSION TO CPMP December 2002 CPMP傳遞 RELEASE FOR CONSULTATION December 2002 專家討論 DEADLINE FOR COMMENTS March 2003 建議收集最后期限 DISCUSSION IN THE SAFETY WORKING June 2003-February 2004 PARTY AND QUALITY WORKING PAR

3、TY 安全工作組和質量工作組之間的討論 TRANSMISSION TO CPMP 轉移給CPMP March 2004 RE-RELEASE FOR CONSULTATION 再次放行給顧問團 June 2004 DEADLINE FOR COMMENTS 收集意見的最后期限 December 2004 DISCUSSION IN THE SAFETY WORKING PARTY AND QUALITY WORKING PARTY 安全工作組和質量工作組之間的討論 February 2005-May 2006 ADOPTION BY CHMP 被CHMP采用 28 June 2006 DATE

4、 FOR COMING INTO EFFECT 生效日期 01Ja nuary 2007 KEYWORDS 關鍵詞 Impurities; Genotoxicity; Threshold of toxicological concern (TTC); Structure activity relationship (SAR) GUIDLINE ON THE LIMITS OF GENOTOXIC IMPURITIES 基因毒性雜質限度指南 TABLE OF CONTENTS 目錄 EXECUTIVE SUMMARY 內(nèi)容摘要3 .INTRODUCTION 介紹3 2. SCOPE 范圍3 3.

5、 LEGAL BASIS 法 律依據(jù)3 4. TOXICOLOGICAL BACKGROUND毒理學背景4 5. RECOMMENDATIONS 建議4 Geno toxic Compo unds With Sufficie nt Evide nee for a Threshold-Related Mecha nism 具有充分證據(jù)證明其閾值相關機理的基因毒性化合物 4 Geno toxic Compo unds Without Sufficie nt Evide nee for a Threshold-Related Mecha nism 不具備充分證據(jù)支持其閾值相關機理的基因毒性化合物 5

6、 Pharmaceutical Assessment 學評價5 Toxicological Assessme nt毒理學評價5 Application of a Threshold of Toxicological Concern 毒理學擔憂閾值應用 5 Decisi on Tree for Assessme nt of Acceptability of Geno toxic Impurities 基因毒性雜質可接受性評價決策樹 7 REFERENCES.參考文獻8 EXECUTIVE SUMMARY 內(nèi)容摘要 The toxicological assessme nt of geno tox

7、ic impurities and the determ in ati on of acceptable limits for such impurities in active substances is a difficult issue and not addressed in sufficient detail in the existing ICH Q3X guidances. The data set usually available for genotoxic impurities is quite variable and is the main factor that di

8、ctates the process used for the assessme nt of acceptable limits. In the absence of data usually needed for the application of one of the established risk assessment methods, . data from carcinogenicity Iong-term studies or data providing evidence for a threshold mecha nism of geno toxicity, impleme

9、 ntati on of a gen erally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed. A TTC value of 卩 g/day in take of a geno toxic impurity is con sidered to be associated with an acceptable risk (excess can cer risk of 1 in 100,000 over a lifetime） for most pharmac

10、euticals. From this threshold value, a permitted level in the active substa nee can be calculated based on the expected daily dose. Higher limits may be justified un der certa in con diti ons such as short-term exposure periods. 基因毒性雜質的毒理學評估和這些雜質在活性藥物中的可接受標準的測定是一件困難的 事情，并且在現(xiàn)有的ICH Q3X指南中也沒有詳細的規(guī)定?，F(xiàn)有的關

11、于基因毒性雜質的相關 數(shù)據(jù)是容易變化的，也是對雜質可接受標準如何進行評價的主要影響因素。如果缺少風險評 估方法所需要的數(shù)據(jù)，比如，致癌作用的長期研究數(shù)據(jù)，或為基因毒性的閥值提供證據(jù)的數(shù) 據(jù)，一般建議使用一般通用的被定義為毒理學關注的閾值（ TTC）的方法。一個* g/day 的 TTC值，即相當于每天攝入卩g的基因毒性雜質，被認為對于大多數(shù)藥品來說是可以接受的 風險（一生中致癌的風險小于十萬分之1）。按照這個閥值，可以根據(jù)這個預期的每日攝入量 計算出活性藥物中可接受的雜質水平。較高的臨界值可以在特定的條件下，如短期暴露周期 等，進行推算。 1. INTRODUCTION 介紹 A genera

12、l concept of qualification of impurities is described in the guidelines for active substances （Q3A, Impurities in New Active Substances） or medicinal products （Q3B, Impurities in New Medicinal Products）, whereby qualification is defined as the process of acquiring and evaluat ing data that establish

13、es the biological safety of an in dividual impurity or a give n impurity profile at the level（s） specified. In the case of impurities with a geno toxic pote ntial, determ in ati on of acceptable dose levels is gen erally con sidered as a particularly critical issue, which is not specifically covered

14、 by the existing guidelines. 在原料藥（Q3A）和藥物制劑（Q3B）的雜質指導原則中，雜質限度確定的依據(jù)包括各 個雜質的生物安全性數(shù)據(jù)或雜質在某特定含量水平的研究概況。而對于遺傳毒性雜質限度的 確定，通常都認為是特別關鍵的問題，但目前尚無相關的指導原則。 2. SCOPE 范圍 This Guideli ne describes a gen eral framework and practical approaches on how to deal with genotoxic impurities in new active substances. It also

15、 relates to new applications for existing active substa nces, where assessme nt of the route of syn thesis, process con trol and impurity profile does not provide reas on able assura nee that no new or higher levels of geno toxic impurities are in troduced as compared to products curre ntly authoris

16、ed in the EU containing the same active substa nee. The same also applies to variatio ns to exist ing Market ing Authorisati ons perta ining to the syn thesis. The guideli ne does, however, not n eed to be applied retrospectively to authorised products uni ess there is a specific cause for concern.

17、本指導原則闡述了如何處理新原料藥中遺傳毒性雜質的一般框架和實際方法。該指導原 則也適用于已有原料藥的新申請，如果其合成路線、過程控制和雜質研究尚無法確保不會產(chǎn) 生新的或更高含量的遺傳毒性雜質(與 EU目前批準的相同原料藥相比)。該指導原則同樣 適用于已上市原料藥有關合成方面的補充申請。除非有特殊原因，本指導原則不適用于已上 市的產(chǎn)品。 In the curre nt con text the classificati on of a compo und (impurity) as geno toxic in gen eral means that there are positive find

18、ings in established in vitro or in vivo genotoxicity tests with the main focus on DNA reactive substances that have a potential for direct DNA damage. Isolated in vitro findings may be assessed for in vivo releva nce in adequate follow-up test in g. In the abse nce of such in formatio n in vitro gen

19、o toxica nts are usually con sidered as presumptive in vivo mutage ns and carci nogens. 目前對于基因毒性雜質的分類主要是指：在以DNA反應物質為主要研究對象的體內(nèi)體 外試驗中，如果發(fā)現(xiàn)它們對 DNA有潛在的破壞性，那可稱之為基因毒性。如果有足夠的后 續(xù)試驗，可由單獨的體外試驗結果，對它的體內(nèi)關聯(lián)性進行評估。在缺乏這樣的信息時，體 外基因毒性物質經(jīng)常被考慮為假定的體內(nèi)誘變劑和致癌劑。 3. LEGAL BASIS 法規(guī)依據(jù) This guideli ne has to be read in conjun ct

20、i on with Directive 2001/83/EC (as ame nded) and all releva nt CHMP Guida nce docume nts with special emphasis on: 在閱讀該指南時有必要參考“Directive 2001/83/EC以及相關的CHMP指南文件，特別是 以下幾個指南： Impurities Testi ng Guideli ne: Impurities in New Drug Substa nces (CPMP/ICH/2737/99, ICHQ3A(R) Note for Guida nce on Impuriti

21、es in New Drug Products (CPMP/ICH/2738/99, ICHQ3B (R) Note for Guida nce on Impurities: Residual Solve nts (CPMP/ICH/283/95) Note for Guida nce on Geno toxicity: Guida nce on Specific Aspects of Regulatory Geno toxicity Tests for Pharmaceuticals (CPMP/ICH/141/95, ICHS2A) Note for Guida nce on Geno t

22、oxicity: A Sta ndard Battery for Geno toxicity Testi ng of Pharmaceuticals (CPMP/ICH/174/95, ICHS2B) 4. TOXICOLOGICAL BACKGROUND毒理學背景 Accordi ng to curre nt regulatory practice it is assumed that (in vivo) geno toxic compo unds have the pote ntial to damage DNA at any level of exposure and that such

23、 damage may lead/c on tribute to tumour developme nt. Thus for geno toxic carc inogens it is prude nt to assume that there is no discer nible threshold and that any level of exposure carries a risk. 根據(jù)目前的研究實踐，具有(體內(nèi))遺傳毒性的化合物在任何暴露量下都有可能對DNA 產(chǎn)生損傷，而這種損傷可能會引發(fā)腫瘤。因此，對于遺傳毒性致癌物質，應謹慎認為不存在 明確的閾值，任何暴露量下都存在風險。 H

24、owever, the existe nee of mecha ni sms lead ing to biologically mea nin gful threshold effects is in creas in gly ack no wledged also for geno toxic eve nts. This holds true in particular for compo unds in teract ing with non-DNA targets and also for pote ntial mutage ns, which are rapidly detoxifie

25、d before coming in to con tact with critical targets. The regulatory approach to such chemicals can be based on the ide ntificatio n of a critical no-observed-effect level (NOEL) and use of un certa inty factors. 然而，對于一些遺傳毒性事件，其產(chǎn)生生物學意義的閾值效應的機理正越來越為人所了 解。對于非DNA靶點的化合物和潛在致突變劑更是如此，因為它們在與關鍵靶點接觸前就 已經(jīng)去毒化了。

26、對于這些化合物，研究的基礎可以是確定關鍵的未觀察到影響的劑量(NOEL) 和米用不確定因子。 Even for compounds which are able to react with the DNA molecule, extrapolation in a linear manner from effects in high-dose studies to very low level (huma n) exposure may not be justified due to several protective mechanisms operating effectively at l

27、ow doses. However, at present it is extremely difficult to experime ntally prove the existe nee of threshold for the geno toxicity of a give n mutage n. Thus, in the abse nee of appropriate evide nee support ing the existe nee of a threshold for a genotoxic compound making it difficult to define a s

28、afe dose it is necessary to adopt a eon cept of a level of exposure that carries an acceptable risk. 即使對能與DNA分子發(fā)生反應的化合物，由于低劑量時有多種有效的保護機制存在， 而不能將高劑量下的影響以線性方式外推到很低的(人)暴露水平。不過，目前要用實驗方 法證明某誘變劑的遺傳毒性閾值仍然非常困難。所以，在缺乏恰當?shù)淖C據(jù)支持遺傳毒性閾值 存在的情況下，確定安全劑量很困難，因此非常有必要采用一個可接受風險的暴露水平概念。 5. RECOMMENDATIONS 建議 As stated in t

29、he Q3A guideline, actual and potential impurities most likely to arise during synthesis, purification and storage of the new drug substanee should be identified, based on a sound seie ntifie appraisal of the chemical react ions invo Ived in the syn thesis, impurities associated with raw materials th

30、at could con tribute to the impurity profile of the new drug substa nee, and possible degradation products. This discussion can be limited to those impurities that might reas on ably be expected based on kno wledge of the chemical reacti ons and con diti ons invo Ived. Guided by existi ng geno toxic

31、ity data or the prese nee of structural alerts, pote ntial geno toxic impurities should be identified. When a potential impurity contains structural alerts, additional geno toxicity test ing of the impurity, typically in a bacterial reverse mutatio n assay, should be eonsidered (Dobo et al. 2006, M

32、ller et ali2006). While according to the Q3A guideline such studies can usually be eon ducted on the drug substa nee containing the impurity to be eon trolled, studies using isolated impurities are much more appropriate for this purpose and highly recomme nded. 正如Q3A指導原則所述，根據(jù)合理的化學反應機理分析，在新的原料藥合成、純化和

33、貯 存過程中很有可能產(chǎn)生實際的和潛在的雜質。依據(jù)現(xiàn)有的可能引起遺傳毒性的結構”數(shù)據(jù) 庫，潛在的遺傳毒性雜質應能被確認。如果潛在的雜質含有可引起遺傳毒性的結構單元，該 雜質應考慮進行遺傳毒性試驗(一般是細菌回復突變試驗)(Dobo等，2006)。雖然Q3A指 導原則認為這些研究采用含有那些需控制雜質的原料藥進行是可行的，但用分離出來的雜質 進行這些研究更恰當，也是高度推薦的方法。 For determ in ati on of acceptable levels of exposure to geno toxic care inogens eon siderati ons of possible

34、 mecha ni sms of acti on and of the dose-resp onse relati on ship are importa nt comp onen ts. Based on the above considerations genotoxic impurities may be distinguished into the following two classes: 根據(jù)以上論述，遺傳毒性雜質可以歸納成以下兩類： -Geno toxic compo unds with sufficie nt (experime ntal) evide nee for a t

35、hreshold-related mecha nism 有充分閾值相關機理證據(jù)(實驗)的遺傳毒性化合物 -Geno toxic compo unds without sufficie nt (experime ntal) evide nee for a threshold-related mecha nism 無充分閾值相關機理證據(jù)（實驗）的遺傳毒性化合物 Geno toxic Compo unds With Sufficie nt Evide nee for a Threshold-Related Mecha nism 具有充分證據(jù)證明其閾值相關機理的基因毒性化合物 Examples of

36、mecha ni sms of geno toxicity that may be dem on strated to lead to non-I in ear or thresholded dose-resp onse relati on ships in clude in teracti on with the spin dle apparatus of cell division leading to aneuploidy, topoisomerase inhibition, inhibition of DNA synthesis, overloading of defe nee mec

37、ha ni sms, metabolic overload and physiological perturbati ons .in duct ion of erythropoeisis, hyper- or hypothermia). 非線性或閾值明確的劑量效應關系的遺傳毒性機理包括：與細胞分化過程中紡錘體相互 作用；拓撲異構酶抑制；DNA合成抑制；過度的防御機制；代謝過度和生理性干擾(如誘 導紅血球生成，高體溫和低體溫)。 For (classes of) compo unds with clear evide nee for a thresholded geno toxicity, ex

38、posure levels which are without appreciable risk of geno toxicity can be established accord ing to the procedure as outlined for class 2 solvents in the Q3C Note for Guidance on Impurities: Residual Solvents. This approach calculates a “ Permitted Daily Exposure ” (PDE), which is derived from the NO

39、EL, or t lowestobserved effect level (LOEL) in the most releva nt (ani mal) study using“ un certa inty fac (UF). 有明確遺傳毒性閾值的化合物，不產(chǎn)生遺傳毒性風險的暴露水平可以被確定，方法可參 照Q3C“雜質指導原則”中二類溶劑的限度確定方法。該方法可計算每日最大允許暴露量” (PDE)，數(shù)據(jù)來源于 不確定因數(shù)”動物研究中的NOEL (未觀察到效果的最低水平)或觀 察到效果的最低水平(LOEL )。 Geno toxic Compo unds Without Sufficie nt E

40、vide nce for a Threshold-Related Mechanism不具備充分證據(jù)支持其閾值相關機理的基因毒性化合物 The assessme nt of acceptability of geno toxic impurities for which no threshold mecha ni sms are identified should include both pharmaceutical and toxicological evaluations. In general, pharmaceutical measureme nts should be guided

41、by a policy of con trolli ng levels to“ a reas on ably practicable” (ALARP prin ciple), where avoid ing is not possible. Levels con sidered being con siste nt with the ALARP prin ciple follow ing pharmaceutical assessme nt should be assessed for acceptability from a toxicological point of view (see

42、decisi on tree & followi ng sectio ns). 對于此類遺傳毒性雜質，研究應包括藥學和毒理學評估?？傊绻s質無法避免，藥 學方面的控制應遵循 合理可行的最低限量”原則(ALARP原則)。符合ALARP原則的雜質 水平再經(jīng)毒理學方面的進一步評估，以驗證其合理性(見決策樹和以下章節(jié))。 Pharmaceutical Assessment 藥學評價 A specific discussion -as part of the overall discussion on impurities (see Q3A(R)should be provided in the a

43、pplication with regard to impurities with potential genotoxicity. 申請材料應提供關于潛在遺傳毒性雜質的特別討論資料(見 Q3A (R)。 A rati on ale of the proposed formulati on/manu facturi ng strategy should be provided based on available formulati on opti ons and tech no logies. The applica nt should highlight, withi n the chemi

44、cal process and impurity profile of active substa nee, all chemical substa nces, used as reage nts or prese nt as in termediates, or side-products, known as geno toxic an d/or carc inogenic . alkylat ing age nts). 需要根據(jù)現(xiàn)在的配方選擇和技術， 提供證明所選的配方/生產(chǎn)策略合理性的證據(jù)。申請人 應在合成工藝和雜質研究部分重點指出所有的化學物質，包括用到的試劑、中間體、副產(chǎn)物， in

45、term： 哪些是已知遺傳毒性和/或致癌性物質(如烷化劑)。 More gen erally, react ing substa ncesnd substa nces which show“ alerti ng structure ” of genotoxicity which are not shared with the active substance should be considered (see . Dobo et al. 2006). Pote ntial alter natives which do not lead to geno toxic residues in the

46、 final product, should be used if available. 值得關注的是，雖然有些含有可能引起遺傳毒性的結構” (alerting structure)的反應試 劑與最終活性物質并沒有共同結構，但也要考慮它們的遺傳毒性(see . Dobo et al. 2006).如 果有可能，應該對它們進行一些替代研究，以使最終產(chǎn)品中不會引入基因毒性殘留。 A justificati on n eeds to be provided that no viable alter native exists, i ncludi ng alter native routes of s

47、ynthesis or formulations, different starting materials. This might for instance include cases where the structure, which is resp on sible for the geno toxic an d/or carci nogenic pote ntial is equivale nt to that n eeded in chemical syn thesis . alkylati on react ion s). 需要提供充分的論證來說明沒有可行的替代方法存在，包括可替

48、代的合成路線或配方， 不同的起始物料等。比如，應證明具有遺傳毒性和/或致癌性的結構在化學合成中(如烷化反 應)是必需的。 If a geno toxic impurity is con sidered to be un avoidable in a drug substa nce, tech ni cal efforts . purification steps) should be undertaken to reduce the content of the genotoxic residues in the final product in complia nee with safety

49、 n eeds or to a level as low as reas on ably practicable (see safety assessme nt). Data on chemical stability of reactive in termediates, reacta nts, and other comp onents should be in cluded in this assessme nt. 如果遺傳毒性雜質在原料中不可避免，則應該采取適當?shù)募夹g(如純化步驟)降低該雜 質的含量，以滿足安全性要求，或符合合理可行的最低限量”原則(見安全評估)。藥學評 估還應包括反應

50、中間體、反應物和其它組件等的化學穩(wěn)定性研究。 Detectio n an d/or qua ntificati on of these residues should be done by state-of-the-art an alytical tech niq ues. 應該使用比較先進的分析檢測技術來檢測和量化這些殘留的雜質。 Toxicological Assessme nt 毒理學評價 The impossibility of defi ning a safe exposure level (zero risk con cept) for geno toxic carci nogen

51、s without a threshold and the realizatio n that complete elim in ati on of geno toxic impurities from drug substa nces is ofte n un achievable, requires impleme ntati on of a con cept of an acceptable risk level, . an estimate of daily huma n exposure at and below which there is a n egligible risk t

52、o huma n health. 鑒于在沒有明確閾值的前提下定義安全暴露水平(零風險)是不可能的，且從原料藥中 完全除去遺傳毒性雜質經(jīng)常是很難做到的，所以有必要提出一個可接受風險水平” (acceptable risk leve)的概念，比如估算一個 每日最大暴露量”值，低于該暴露量時就可以 忽略其對人體健康的風險。 Procedures for the derivatio n of acceptable risk levels are con sidered in the Appe ndix 3 of the Q3C Note for Guidance on Impurities: Resi

53、dual Solvents for Class 1 solvents. However, these approaches require availability of adequate data from Ion g-term carci nogeni city studies. 對于可接受風險水平的推導過程請參見Q3C (雜質指南注釋：一類溶液殘留)中的附件 三。然而，應用這些方法必須有足夠多的長期致癌性研究數(shù)據(jù)。 In most cases of toxicological assessme nt of geno toxic impurities on ly limited data

54、from in vitro studies with the impurity . Ames test, chromosomal aberration test) are available and thus established approaches to determ ine acceptable in take levels cannot be applied. Calculati on of “ safety multiples ” from in vitro data . Ames test) are con sidered in appropriate for justifica

55、ti on of acceptable limits. Moreover, n egative carci nogeni city and geno toxicity data with the drug substa nee containing the impurity at low ppm levels do not provide sufficie nt assura nee for sett ing acceptable limits for the impurity due to the lack of sensitivity of this testing approach. E

56、ven pote nt mutage ns and carc inogens are most likely to remai n un detected whe n tested as part of the drug substa nee, . at very low exposure levels. A pragmatic approach is therefore n eeded which recog ni ses that the prese nee of very low levels of geno toxic impurities is not associated with

57、 an un acceptable risk. 大多數(shù)情況下，遺傳毒性雜質的毒理學評估只是局限于雜質的體外研究(如Ames試驗， 染色體畸變試驗)，但這些方法并不適用于確定雜質可接受的攝入水平。也就是說，根據(jù)體 外數(shù)據(jù)(如Ames試驗)計算雜質的 安全倍數(shù)(safety multiples)”、進而確定可接受的限度， 是不合適的。此外，用含有較低(ppm級)雜質水平的原料藥研究其致癌性和遺傳毒性，即 使得出陰性結果也不足以確保該雜質限度的合理性，因為這種試驗方法缺少必要的靈敏度。 有些具有很強致突變性和致癌性物質與原料藥一起進行試驗時，因為在非常低的暴露水平情 況下，很有可能因為低于檢測限而無

58、法檢出。所以，如果認識到含量非常低的遺傳毒性雜質 不存在不可接受的風險”(unacceptable risl)，那么可以采取實用的方法來控制該雜質。 Applicati on of a Threshold of Toxicological Concern毒理學相關的閾值應用 A threshold of toxicological concern (TTC) has bee n developed to defi ne a com mon exposure level for any unstudied chemical that will not pose a risk of signifi

59、cant carcinogenicity or other toxic effects (Mu nro et al. 1999, Kroes and Kozia nowski 2002). This TTC value was estimated to be 卩 g/pers on/day. The TTC, orig in ally developed as a“ threshold of regulatio n” a food contact materials (Rulis 1989, FDA 1995) was established based on the analysis of

60、343 carci nogens from a carc inogenic pote ncy database (Gold et al. 1984) and was repeatedly con firmed by evaluati ons expa nding the database to more tha n 700 carc inogens (Munro 1990, Cheesema n et al. 1999, Kroes et al. 2004). The probability distribution of carcinogenic potencies has been use