基因毒性雜質(zhì)限度指引轉(zhuǎn)載中英文

1、20060628 EMEA/CHMP/QWP/251344/2006 基因毒性雜質(zhì)限度指南（轉(zhuǎn)載中英文）Lon do n, 28 June 2006CPMP/SWP/5199/02EMEA/CHMP/QWP/251344/2006COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE人用藥品委員會(CHMP)GUIDLINE ON THE LIMITS OF GENOTOXIC IMPURITIES基因毒性雜質(zhì)限度指南DESCUSSION IN THE SAFETY WORKINGPARTY安全工作組之內(nèi)的討論June 2002-October 2002T

2、RANSMISSION TO CPMPCPMP傳遞December 2002RELEASE FOR CONSULTATION專家討論December 2002DEADLINE FOR COMMENTS建議收集最后期限March 2003DISCUSSION IN THE SAFETY WORKINGJune 2003-February 2004PARTY AND QUALITY WORKING PARTY安全工作組和質(zhì)量工作組之間的討論TRANSMISSION TO CPMP轉(zhuǎn)移給CPMPMarch 2004RE-RELEASE FOR CONSULTATION再次放行給顧問團(tuán)June 200

3、4DEADLINE FOR COMMENTS收集意見的最后期限D(zhuǎn)ecember 2004DISCUSSION IN THE SAFETY WORKINGPARTY AND QUALITY WORKING PARTY安全工作組和質(zhì)量工作組之間的討論February 2005-May 2006ADOPTION BY CHMP被CHMP采用28 June 2006DATE FOR COMING INTO EFFECT生效日期01Ja nuary 2007KEYWORDS關(guān)鍵詞Impurities; Genotoxicity; Threshold of toxicological (TTC); Str

4、ucture activity relationship (SAR)GUIDLINE ON THE LIMITS OF GENOTOXIC IMPURITIES基因毒性雜質(zhì)限度指南TABLE OF CONTENTS 目錄EXECUTIVE SUMMARY內(nèi)容摘要31. INTRODUCTION 介紹32. SCOPE 范圍33. LEGAL BASIS 法律依據(jù)34. TOXICOLOGICAL BACKGROUND毒理學(xué)背景45. RECOMMENDATIONS 建議45.1 Geno toxic Compo unds With Sufficie nt Evide nee for a Thr

5、eshold-Related Mecha nism具有充分證據(jù)證明其閾值相關(guān)機(jī)理的基因毒性化合物 45.2 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(guān)機(jī)理的基因毒性化合物.55.2.1 Pharmaceutical Assessme nt 藥學(xué)評價55.2.2 Toxicological Assessme nt 毒理學(xué)評價55.2.3 Applicatio n of a Threshold of Toxicological Co ncer

6、n 毒理學(xué)擔(dān)憂閾值應(yīng)用55.3 Decisi on Tree for Assessme nt of Acceptability of Geno toxic Impurities基因毒性雜質(zhì)可接受性評價決策樹7REFERENCES.參考文獻(xiàn)8EXECUTIVE SUMMARY 內(nèi)容摘要The toxicological assessme nt of geno toxic impurities and the determ in ati on of acceptablelimits for such impurities in active substances is a difficult is

7、sue 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 dictates the process used for the assessme nt of acceptable limits. In the absence of data usually needed for the applic

8、ation of one of the established risk assessme nt methods, i.e. data from carci nogeni city Ion g-term studies or data provid ing evide nce for a threshold mecha nism of geno toxicity, impleme ntati on of a gen erally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is p

9、roposed. A TTC value of 1.5 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 pharmaceuticals. From this threshold value, a permitted level in the active substa nce can be calculated based on th

10、e 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(zhì)的毒理學(xué)評估和這些雜質(zhì)在活性藥物中的可接受標(biāo)準(zhǔn)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(xì)的規(guī)定?，F(xiàn)有的關(guān)于基因毒性雜質(zhì)的相關(guān) 數(shù)據(jù)是容易變化的，也是對雜質(zhì)可接受標(biāo)準(zhǔn)如何進(jìn)行評價的主要影響因素。如果缺少風(fēng)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?yàn)榛蚨拘缘拈y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

11、Threshold of Toxicological Co ncern (TTC)的方法。一個“ 1.5ug/day的TTC值，即相當(dāng)于每天攝入1.5ug的基因毒性雜質(zhì)，被認(rèn)為對于大多數(shù)藥品 來說是可以接受的風(fēng)險(一生中致癌的風(fēng)險小于100000分之1)。按照這個閥值，可以根據(jù)這個預(yù)期的每日攝入量計算出活性藥物中可接受的雜質(zhì)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(jìn)行推算。1. INTRODUCTION 介紹A general concept of qualification of impurities is described in the guidelines for ac

12、tive 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 establishes the biological safety of an in dividual impurity or a give n impurity pro t

13、he level(s) specified. In the case of impurities with a geno toxic pote ntial, determ in atio n of acceptable dose levels is gen erally con sidered as a particularly critical issue, which is not specifically covered by the existing guidelines.在原料藥(Q3A)和藥物制劑(Q3B)的雜質(zhì)指導(dǎo)原則中，雜質(zhì)限度確定的依據(jù)包括各 個雜質(zhì)的生物安全性數(shù)據(jù)或雜質(zhì)在某

14、特定含量水平的研究概況。而對于遺傳毒性雜質(zhì)限度的確定，通常都認(rèn)為是特別關(guān)鍵的問題，但目前尚無相關(guān)的指導(dǎo)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 relates to new applications for existing active substa nces, where assessme nt of the ro

15、ute of syn thesis, process con trol and impurity pro 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 authorised in the EU containing the same active substa nee. The same also applies to variations to existin

16、g Marketing Authorisations pertaining to the synthesis. The guideli ne does, however, not n eed to be applied retrospectively to authorised products uni ess there is a specific cause for concern.本指導(dǎo)原則闡述了如何處理新原料藥中遺傳毒性雜質(zhì)的一般框架和實(shí)際方法。該指導(dǎo)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(zhì)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(zhì)(與EU目前批準(zhǔn)的相

17、同原料藥相比)。該指導(dǎo)原則同樣適用于已上市原料藥有關(guān)合成方面的補(bǔ)充申請。除非有特殊原因，本指導(dǎo)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 findings in established in vitro or in vivo genotoxicity tests with the main focus on DNA reactive substances th

18、at 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 geno 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(zhì)的分類主要是指：在以D

19、NA反應(yīng)物質(zhì)為主要研究對象的體內(nèi)體外試驗(yàn)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(yàn)，可由單獨(dú)的體外試驗(yàn)結(jié)果，對它的體內(nèi)關(guān)聯(lián)性進(jìn)行評估。在缺乏這樣的信息時，體 外基因毒性物質(zhì)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 cti on with Directive 2001/83/EC (as ame nded) and all releva nt CHMP Guida nce docume nts with special emphasis o

20、n:在閱讀該指南時有必要參考“Directive 2001/83/EC以及相關(guān)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 nee on Impurities in New Drug Products (CPMP/ICH/2738/99, ICHQ3B (R)Note for Guida nee on Impurities: Residual Solve nts (CPMP/ICH/

21、283/95)Note for Guida nee on Geno toxicity: Guida nee on Specific Aspects of Regulatory Geno toxicity Tests for Pharmaceuticals (CPMP/ICH/141/95, ICHS2A)Note for Guida nee on Geno toxicity: A Sta ndard Battery for Geno toxicity Testi ng of Pharmaceuticals (CPMP/ICH/174/95, ICHS2B)4. TOXICOLOGICAL BA

22、CKGROUND毒理學(xué)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 damage may lead/c on tribute to tumour developme nt. Thus for geno toxic care inogens it is prude nt to assume that ther

23、e is no discer nible threshold and that any level of exposure carries a risk.根據(jù)目前的研究實(shí)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(zhì)，應(yīng)謹(jǐn)慎認(rèn)為不存在 明確的閾值，任何暴露量下都存在風(fēng)險。However, the existe nee of mecha ni sms lead ing to biologically mea nin gful threshold effects is in creas in gly ack no wle

24、dged 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 detoxified before coming into eon tact with critical targets. The regulatory approach to such chemicals can be based on the ide ntifi

25、catio 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(xué)意義的閾值效應(yīng)的機(jī)理正越來越為人所了 解。對于非DNA靶點(diǎn)的化合物和潛在致突變劑更是如此，因?yàn)樗鼈冊谂c關(guān)鍵靶點(diǎn)接觸前就 已經(jīng)去毒化了。對于這些化合物，研究的基礎(chǔ)可以是確定關(guān)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 i

26、n a linear manner from effects in high-dose studies to very low level (huma n) exposure may not be justified due to several protective mecha ni sms operat ing effectively at low doses. However, at prese nt it is extremely difficult to experime ntally prove the existe nee of threshold for the geno to

27、xicity 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 safe dose it is necessary to adopt a con cept of a level of exposure that carries an acceptable risk.即使對能與DNA分子發(fā)生反應(yīng)的化合物，由于低劑量

28、時有多種有效的保護(hù)機(jī)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(shí)驗(yàn)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(dāng)?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(fēng)險的暴露水平概念。5. RECOMMENDATIONS 建議As stated in the Q3A guideline, actual and potential impurities most likely to arise during synthesis, purification and storage of the new dr

29、ug substance should be identified, based on a sound scie ntific appraisal of the chemical react ions invo lved in the syn thesis, impurities associated with raw materials that could con tribute to the impurity pro the new drug substa nce, and possible degradati on products. This discussi on can be l

30、imited to those impurities that might reas on ably be expected based on kno wledge of the chemical reacti ons and con diti ons invo lved. Guided by existing genotoxicity data or the presence of structural alerts, potential genotoxic impurities should be identified. When a potential impurity contains

31、 structural alerts, additional genotoxicity testing of the impurity, typically in a bacterial reverse mutatio n assay, should be con sidered （Dobo et al. 2006, M ller et al. 2006）. While according to the Q3A guideline such studies can usually be con ducted on the drug substa nce containing the impur

32、ity to be con trolled, studies using isolated impurities are much more appropriate for this purpose and highly recomme nded.正如Q3A指導(dǎo)原則所述，根據(jù)合理的化學(xué)反應(yīng)機(jī)理分析，在新的原料藥合成、純化和貯 存過程中很有可能產(chǎn)生實(shí)際的和潛在的雜質(zhì)。依據(jù)現(xiàn)有的可能引起遺傳毒性的結(jié)構(gòu)”數(shù)據(jù)庫，潛在的遺傳毒性雜質(zhì)應(yīng)能被確認(rèn)。如果潛在的雜質(zhì)含有可引起遺傳毒性的結(jié)構(gòu)單元，該 雜質(zhì)應(yīng)考慮進(jìn)行遺傳毒性試驗(yàn)（一般是細(xì)菌回復(fù)突變試驗(yàn)）（Dobo等，2006）。雖然Q3A指導(dǎo)原則認(rèn)為這些研究采用

33、含有那些需控制雜質(zhì)的原料藥進(jìn)行是可行的，但用分離出來的雜質(zhì)進(jìn)行這些研究更恰當(dāng)，也是高度推薦的方法。For determ in ati on of acceptable levels of exposure to geno toxic carc inogens con siderati ons of possible 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 imp

34、urities may be distinguished into the following two classes:根據(jù)以上論述，遺傳毒性雜質(zhì)可以歸納成以下兩類：-Geno toxic compo unds with sufficie nt （experime ntal） evide nce for a threshold-relatedmecha nism有充分閾值相關(guān)機(jī)理證據(jù)（實(shí)驗(yàn)）的遺傳毒性化合物-Geno toxic compo unds without sufficie nt （experime ntal） evide nee for a threshold-related me

35、cha nism無充分閾值相關(guān)機(jī)理證據(jù)（實(shí)驗(yàn)）的遺傳毒性化合物5.1 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(guān)機(jī)理的基因毒性化合物Examples of 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

36、on with the spin dle apparatus of cell division leading to aneuploidy, topoisomerase inhibition, inhibition of DNA synthesis, overloading of defe nee mecha ni sms, metabolic overload and physiological perturbati ons （e.g. i nductio n of erythropoeisis, hyper- or hypothermia）.非線性或閾值明確的劑量效應(yīng)關(guān)系的遺傳毒性機(jī)理包括

37、：與細(xì)胞分化過程中紡錘體相互 作用；拓?fù)洚悩?gòu)酶抑制；DNA合成抑制；過度的防御機(jī)制；代謝過度和生理性干擾（如誘 導(dǎo)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, exposure levels which are without appreciable risk of geno toxicity can be established accord ing to the procedure as outlined for class 2 solvent

38、s in the Q3C Note for Guidance on Impurities: Residual Solvents. This approach calculates a “ Permitted Daily Exposure ” （PDE）, which ithdeNOELfrorrthe lowestobserved effect level （LOEL） in the most releva nt （ani mal） study using“ un certa（UF）.有明確遺傳毒性閾值的化合物，不產(chǎn)生遺傳毒性風(fēng)險的暴露水平可以被確定，方法可參 照Q3C“雜質(zhì)指導(dǎo)原則”中二類溶

39、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 ）。5.2 Geno toxic Compo unds Without Sufficie nt Evide nce for a Threshold-RelatedMechanism不具備充分證據(jù)支持其閾值相關(guān)機(jī)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 ident

40、ified should include both pharmaceutical and toxicological evaluations. In general,pharmaceutical measureme nts should be guided by a policy of con trolli ng levels to“ areas on ably practicable” (ALARP prin ciple), where avoid ing is not possible. Levels con sideredbeing con siste nt with the ALARP

41、 prin ciple follow ing pharmaceutical assessme nt should be assessed for acceptability from a toxicological point of view (see decisi on tree & followi ng sectio ns).對于此類遺傳毒性雜質(zhì)，研究應(yīng)包括藥學(xué)和毒理學(xué)評估?？傊?，如果雜質(zhì)無法避免，藥 學(xué)方面的控制應(yīng)遵循 合理可行的最低限量”原則(ALARP原則)。符合ALARP原則的雜質(zhì) 水平再經(jīng)毒理學(xué)方面的進(jìn)一步評估，以驗(yàn)證其合理性(見決策樹和以下章節(jié))。5.2.1 Pharm

42、aceutical Assessme nt 藥學(xué)評價A specific discussion -as part of the overall discussion on impurities (see Q3A(R)shouldbe provided in the application with regard to impurities with potential genotoxicity.申請材料應(yīng)提供關(guān)于潛在遺傳毒性雜質(zhì)的特別討論資料(見Q3A (R)。A rati on ale of the proposed formulati on/manu facturi ng strategy

43、 should be provided based onavailable formulati on opti ons and tech no logies. The applica nt should highlight, withi n the chemical process and impurity pro 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 c

44、arc inogenic (e.g. alkylat ing age nts).需要根據(jù)現(xiàn)在的配方選擇和技術(shù)， 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(yīng)在合成工藝和雜質(zhì)研究部分重點(diǎn)指出所有的化學(xué)物質(zhì)，包括用到的試劑、中間體、副產(chǎn)物，哪些是已知遺傳毒性和/或致癌性物質(zhì)(如烷化劑)。More gen erally, react ing substa nces and substa nces which show“ alerti ng structureof genotoxicity which are not shared with the active substance shoul

45、d be considered (see e.g. Dobo et al. 2006). Pote ntial alter natives which do no t lead to geno toxic residues in the final product, should be used if available.值得關(guān)注的是，雖然有些含有可能引起遺傳毒性的結(jié)構(gòu)” (alerting structure)的反應(yīng)試 劑與最終活性物質(zhì)并沒有共同結(jié)構(gòu)，但也要考慮它們的遺傳毒性 (see e.g. Dobo et al. 2006。. 如果有可能，應(yīng)該對它們進(jìn)行一些替代研究，以使最終產(chǎn)品中不會

46、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 synthesis 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 p

47、ote ntial isequivale nt to that n eeded in chemical syn thesis (e.g. 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，包括可替代的合成路線或配方， 不同的起始物料等。比如，應(yīng)證明具有遺傳毒性和/或致癌性的結(jié)構(gòu)在化學(xué)合成中(如烷化反 應(yīng))是必需的。If a geno toxic impurity is con sidered to be un avoidable in a drug substa nee, tech ni cal efforts (e.g. purificatio

48、n steps) should be undertaken to reduce the content of the genotoxic residues in the final product in complia nce with safety 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 sho

49、uld be in cluded in this assessme nt.如果遺傳毒性雜質(zhì)在原料中不可避免，則應(yīng)該采取適當(dāng)?shù)募夹g(shù)(如純化步驟)降低該雜 質(zhì)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(xué)評估還應(yīng)包括反應(yīng)中間體、反應(yīng)物和其它組件等的化學(xué)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(yīng)該使用比較先進(jìn)的分析檢測技術(shù)來檢測和量化這些殘留的雜質(zhì)。5.2.2 Toxico

50、logical Assessme nt 毒理學(xué)評價The impossibility of defi ning a safe exposure level (zero risk con cept) for geno toxic carci nogens without a threshold and the realizatio n that complete elim in ati on of geno toxic impurities from drug substances is often unachievable, requires implementation of a conce

51、pt of an acceptable risk level, i.e. an estimate of daily huma n exposure at and below which there is a n egligible risk to 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(fēng)險)是不可能的，且從原料藥中 完全除去遺傳毒性雜質(zhì)經(jīng)常是很難做到的，所以有必要提出一個可接受風(fēng)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(fēng)險。Procedures for the de

52、rivatio n of acceptable risk levels are con sidered in the Appe ndix 3 of the Q3C Note for Guidance on Impurities: Residual 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(fēng)險水平的推導(dǎo)過程請參見Q3C (雜質(zhì)指南注釋：一類溶液殘留)中的附

53、件然而，應(yīng)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 from invitro studies with the impurity (e.g. Ames test, chromosomal aberration test) are available and thus established approaches to determ ine acceptable in take levels cannot be appli

54、ed. Calculati on of“ safety multiples ” from in vitro data (e.g. Ames test) are con sidered in appropriate for justificati onof acceptable limits. Moreover, n egative carc inogeni city and geno toxicity data with the drug substa nee containing the impurity at low ppm levels do not provide sufficie n

55、t assura nee for sett ing acceptable limits for the impurity due to the lack of sensitivity of this testing approach. Even 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, i.e. at very low exposure levels. A pragmatic approach is

56、therefore n eeded which recog ni ses that the prese nee of very low levels of geno toxic impurities is not associated with an un acceptable risk.大多數(shù)情況下，遺傳毒性雜質(zhì)的毒理學(xué)評估只是局限于雜質(zhì)的體外研究(如Ames試驗(yàn)，染色體畸變試驗(yàn))，但這些方法并不適用于確定雜質(zhì)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(yàn))計算雜質(zhì)的 安全倍數(shù)(safety multiples)”、進(jìn)而確定可接受的限度， 是不合適的。此外，用含有較低(ppm級)

57、雜質(zhì)水平的原料藥研究其致癌性和遺傳毒性，即 使得出陰性結(jié)果也不足以確保該雜質(zhì)限度的合理性，因?yàn)檫@種試驗(yàn)方法缺少必要的靈敏度。 有些具有很強(qiáng)致突變性和致癌性物質(zhì)與原料藥一起進(jìn)行試驗(yàn)時，因?yàn)樵诜浅５偷谋┞端角闆r下，很有可能因?yàn)榈陀跈z測限而無法檢出。所以，如果認(rèn)識到含量非常低的遺傳毒性雜質(zhì) 不存在不可接受的風(fēng)險”(unacceptable risl)，那么可以采取實(shí)用的方法來控制該雜質(zhì)。5.2.3 Applicati on of a Threshold of Toxicological Co ncern毒理學(xué)相關(guān)的閾值應(yīng)用A threshold of toxicological concern (

58、TTC) has bee n developed to defi ne a com mon exposurelevel for any unstudied chemical that will not pose a risk of significant carcinogenicity or other toxic effects (Mu nro et al. 1999, Kroes and Kozia nowski 2002). This TTC value was estimated to be 1.5卩 g/pers on /day. The TTC, origi nally developed as a“ threshold of regulati onfor food con tact materials (Rulis 1989, FDA 1995) was established based on the an alysis of 343 carci nogens from a carc inogenic pote ncy database (Gold et al. 1984) and was