EMEA基因毒性雜質(zhì)限度指南

1、.20060628 EMEA/CH MP/QWP/251344/2006基因毒性雜質(zhì)限度指南（中英文對照）Lon do n, 28 June 2006CPMP/SWP /5199/02EMEA/CH MP/QWP /251344/2006The Euro pean Age ncy for the Evaluatio n of Medici nal P roducts歐洲共同體藥物評審委員會(EMEA)COMMITTEE FOR MEDICINAL P RODUCTS FOR HUMAN USE人用藥品委員會(CHMP)GUIDLINE ON THE LIMITS OF GENOTOXIC IM

2、P URITIES基因毒性雜質(zhì)限度指南DESCUSSION IN THE SAFETY WORKINGJune 2002-October 2002P ARTY安全工作組之內(nèi)的討論TRANSMISSION TO CPMPDecember 2002CPMP傳遞RELEASE FOR CONSULTATIONDecember 2002專家討論DEADLINE FOR COMMENTSMarch 2003建議收集最后期限D(zhuǎn)ISCUSSION IN THE SAFETY WORKINGJune 2003-February 2004P ARTY AND QUALITY WORKING P ARTY安全工作

3、組和質(zhì)量工作組之間的討論TRANSMISSION TO CPMPMarch 2004轉(zhuǎn)移給CPMP1RE-RELEASE FOR CONSULTATIONJune 2004再次放行給顧問團(tuán)DEADLINE FOR COMMENTS收集意見的最后期限D(zhuǎn)ISCUSSION IN THE SAFETY WORKINGP ARTY AND QUALITY WORKING P ARTY安全工作組和質(zhì)量工作組之間的討論December 2004February 2005-May 2006ADOP TION BY CHMP被CHMP采用28 June 2006DATE FOR COMING INTO EFF

4、ECT生效日期01Ja nuary 2007KEYWORDS關(guān)鍵詞Impurities; Genotoxicity; Threshold of toxicological concern (TTC); Structure activity relatio nship (SAR)GUIDLINE ON THE LIMITS OF GENOTOXIC IMP URITIES基因毒性雜質(zhì)限度指南TABLE OF CONTENTS 目錄EXECUTIVE SUMMARY 內(nèi)容摘要.INTRODUCTION 介紹2. SCOPE 范圍3. LEGAL BASIS法律依據(jù)4. TOXICOLOGICAL

5、BACKGROUND 毒理學(xué)背景5. RECOMMENDATIONS 建議5.1 Geno toxic Compounds 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5.2 Geno toxic Compounds 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5.2.1 P harmaceutical Assessment 學(xué)評價5.2.2

6、 Toxicological Assessme n毒理學(xué)評價5.2.3 App lication of a Threshold of Toxicological C oncern 毒理學(xué)擔(dān)憂閾值應(yīng)用5.3 Decisi on Tree for Assessme nt of Acce ptability of Geno toxic Imp urities基因毒性雜質(zhì)可接受性評價決策樹REFERENCES.參考文獻(xiàn)EXECUTIVE SUMMARY 內(nèi)容摘要The toxicological assessme nt of geno toxic imp urities and the determ

7、in ati on of acce ptable limits for such imp urities in active substa nces is a difficult issue and not addressed in sufficie nt detail in the exist ing ICH Q3X guida nces. The data set usually available for geno toxic imp urities is quite variable and is the main factor that dictates the p rocess u

8、sed for the assessme nt of acce ptable limits. In the abse nee of data usually n eeded for the app licati on of one of the established risk assessme nt methods, i.e. data from carci nogeni city Ion g-term studies or data pro vid ing evide nee for a threshold mecha nism of geno toxicity, i mp leme nt

9、ati on of a gen erally app licable app roach as defi ned by the Threshold of Toxicological Concern (TTC) is propo sed. A TTC value of 1.5 in take of a geno toxic imp urity is con sidered to be associated with an acce ptable risk (excess cancer risk of <1 in 100,000 over a lifetime) for most p har

10、maceuticals. From this threshold value, ap ermitted level in the active substa nee can be calculated based on the exp ected daily dose. Higher limits may be justified un der certa in con diti ons such as short-term exp osure p eriods.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

11、。現(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(xué)關(guān)注的閾值（TTC）的方法。一個“ 1$g/day” 的TTC值，即相當(dāng)于每天攝入1.5卩g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)險小于十萬分之 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

12、A gen eral concept of qualificati on of imp urities is described in the guideli nes for active substa nces (Q3A, I mp urities in New Active Substa nces) or medic inal p roducts (Q3B, I mp urities in New Medic inal P roducts), whereby qualificati on is defi ned as the p rocess of acquiri ng and evalu

13、at ing data that establishes the biological safety of an in dividual imp urity or a give n imp urity p rofile at the level(s) sp ecified. In the case of imp urities with a geno toxic poten tial, determ in ati on of acce ptable dose levels is gen erally con sidered as a p articularly critical issue,

14、which is not sp ecifically covered by the exist ing guideli nes.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 p ractical app roaches on how to deal with geno toxic imp uriti

15、es in new active substa nces. It also relates to new app licati ons for existi ng active substa nces, where assessme nt of the route of syn thesis, p rocess con trol and impu rity p rofile does not pro vide reas on able assura nee that no new or higher levels of geno toxic imp urities are in troduce

16、d as comp ared to p roducts curre ntly authorised in the EU containing the same active substa nee. The same also app lies to variatio ns to exist ing Market ing Authorisati ons p erta ining to the syn thesis. The guideli ne does, however, not n eed to be app lied retros pectively to authorisedp rodu

17、cts uni ess there is a sp ecific 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 compound (impu rity) as geno to

18、xic in gen eral means that there are p ositive findings in established in vitro or in vivo geno toxicity tests with the main focus on DNA reactive substa nces that have a poten tial for direct DNA damage. Isolated in vitro findings may be assessed for in vivo releva nee in adequate follow- up test i

19、ng. In the abse nee of such in formatio n in vitro geno toxica nts are usually con sidered as p resu mp tive 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 DNA反應(yīng)物質(zhì)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(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. LEGA

20、L 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 nee docume nts with sp ecial emp hasis on: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：Imp urities Testi ng Guideli ne: Imp urities in New Drug Substa nces (

21、CPMP/ICH/2737/99,ICHQ3A(R)Note for Guida nee on Imp urities in New Drug P roducts (CPMP/ICH/2738/99, ICHQ3B (R)Note for Guida nee on Imp urities: Residual Solve nts (CPMP/ICH/283/95)Note for Guida nee on Geno toxicity: Guida nee on Sp ecific Asp ects of Regulatory Geno toxicityTests for P harmaceuti

22、cals (CPMP/ICH/141/95, ICHS2A)Note for Guida nee on Geno toxicity: A Sta ndard Battery for Geno toxicity Testi ng ofP harmaceuticals (CPMP/ICH/174/95, ICHS2B)4. TOXICOLOGICAL BACKGROUND毒理學(xué)背景Accordi ng to curre nt regulatory p ractice it is assumed that (in vivo) geno toxic compounds have the poten t

23、ial to damage DNA at any level of exp osure and that such damage maylead/c on tribute to tumour devel opment. Thus for geno toxic carc inogens it is p rude nt to assume that there is no discer nible threshold and that any level of exp osure 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

24、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 wledged also for geno toxic eve nts. This holds true in p articular for compounds in teract ing with non-DNA targets and a

25、lso for poten tial mutage ns, which are rap idly detoxified before coming into con tact with critical targets. The regulatory app roach 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(xué)意義的閾值效應(yīng)的機(jī)理

26、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(guān)鍵靶點接觸前就 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。Eve n for compounds which are able to react with the DNA molecule, extra po lati on in a lin ear manner from effects in high-dose studies to very low level (huma n) expo sure may not be justified

27、due to several p rotective mecha ni sms op erat ing effectively at low doses. However, at p rese nt it is extremely difficult to exp erime ntally prove the existe nee of threshold for the geno toxicity of a give n mutage n. Thus, in the abse nee of approp riate evide nee supporting the existe nee of

28、 a threshold for a geno toxic compound making it difficult to defi ne a safe dose it is n ecessary to adopt a concept of a level of exp osure that carries an acce ptable risk.即使對能與DNA分子發(fā)生反應(yīng)的化合物，由于低劑量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(dāng)?shù)淖C據(jù)支持遺傳毒性閾值 存在的情

29、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 guideli ne, actual and poten tial imp urities most likely to arise duri ng syn thesis, p urificati on and storage of the new drug substa nee should be ide ntified, based on a sound scie ntific app raisal of the chemical r

30、eact ions invo Ived in the syn thesis, i mp urities associated with raw materials that could con tribute to the impu rity p rofile of the new drug substa nee, and p ossible degradati on p roducts. This discussi on can be limited to those imp urities that might reas on ably be exp ected based on kno

31、wledge of the chemical reacti ons and con diti ons invo Ived. Guided by existi ng geno toxicity data or the p rese nee of structural alerts, poten tial geno toxic imp urities should be ide ntified. Whe n a poten tial imp urity contains structural alerts, additi onal geno toxicity test ing of the imp

32、 urity, typ ically in a bacterial reverse mutatio n assay, should be considered (Dobo et al. 2006, M ller et ali2006). While according to the Q3A guideline such studies can usually be con ducted on the drug substa nee containing the impu rity to be con trolled, studies using isolated imp urities are

33、 much more approp riate 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（一般是細(xì)菌回復(fù)突變試驗）（Dobo等，2006）。雖然Q3A指導(dǎo)原則認(rèn)為這些研究采用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

34、 in ati on of acce ptable levels of expo sure to geno toxic care inogens con siderati ons of p ossible mecha ni sms of acti on and of the dose-res ponse relati onship are imp orta nt componen ts.Based on the above con siderati ons geno toxic imp urities may be dist in guished into the follow ing two

35、 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 compounds with sufficie nt (ex perime ntal) evide nee for a threshold-related mecha nism有充分閾值相關(guān)機(jī)理證據(jù)（實驗）的遺傳毒性化合物-Geno toxic compounds without sufficie nt (ex perime ntal) evide nee for a threshold-related mecha nism無充分閾值相關(guān)機(jī)理證據(jù)（實驗）的遺傳毒性化合物5.1 Geno toxic Comp

36、ounds 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Exa mples of mecha ni sms of geno toxicity that may be dem on strated to lead to non-I in ear or thresholded dose-res ponse relati onships in clude in teracti on with the spin dle app aratus of cell divisi on l

37、ead ing to aneupi oidy, topo isomerase in hibiti on, in hibiti on of DNA syn thesis, overloadi ng of defe nee mecha ni sms, metabolic overload and p hysiological p erturbati ons (e.g. i nductio n of erythro po eisis, hyper- or hyp othermia).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：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

38、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) compounds with clear evide nee for a thresholded geno toxicity, exp osure levels which are without app reciable risk of geno toxicity can be established accord ing to the p rocedure as outli ned for class 2 solve nts in the Q3C Note for Guida nee

39、 on Imp urities: Residual Solve nts. This approach calculates a“ Permitted Daily Exposure ” (PDE), which is derived from the NOEL, or tlowestobserved effect level (LOEL) in the most releva nt (ani mal) study using (UF).“un certa inty factors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”中二類溶劑的限度

40、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 Compounds Without Sufficie nt Evide nee 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aasThe assessme nt of acce ptability of geno toxic imp urities for which no threshold mecha ni sms are ide

41、 ntified should in clude both p harmaceutical and toxicological evaluati ons. In gen eral, p harmaceuical measureme nts should be guided by a p olicy of con trolli ng levels to reas on ably p racticable” (ALAR P principl e), where avoid ing is not p ossible. Levels con sidered being con siste nt wit

42、h the ALARP principle follow ing p harmaceutical assessme nt should be assessed for acce ptability 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，以驗證其合理性（見決策樹和以下章節(jié)）。

43、521 P harmaceutical Assessme nt 藥學(xué)評價Q3A( R)。A sp ecific discussi on -as part of the overall discussi on on imp urities (see Q3A(R)-should be pro vided in the app licati on with regard to imp urities with poten tial geno toxicity.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A rati on ale of the prop osed formulati on/m

44、anu facturi ng strategy should be pro vided based on available formulati on op ti ons and tech no logies. The app lica nt should highlight, withi n the chemical p rocess and imp urity p rofile of active substa nee, all chemical substa nces, used as reage nts or p rese nt as in termediates, or side-p

45、 roducts, known as geno toxic an d/or carc inogenic (e.g. alkylat ing age nts).” in terms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 ahsubsta nces which show“ alerti ng structure of geno toxicity w

46、hich are not shared with the active substa nee should be con sidered (see e.g. Dobo et al. 2006). Poten tial alter natives which do no t lead to geno toxic residues in the final p roduct, 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

47、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)品中不會引入基因毒性殘留。A justificati on n eeds to be p rovided that no viable alter native exists, i ncludi ng alter native routes of syn thesis or formulati ons, differe nt start ing materials. This might for in sta nee in clude cases where the structure, which

48、 is res pon sible for the geno toxic an d/or carci nogenic poten tial is equivale 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 imp urity is con sidered to be un avoidab

49、le in a drug substa nee, tech ni cal efforts (e.g. p urificati on ste ps) should be un dertake n to reduce the content of the geno toxic residues in the final p roduct in comp lia nee with safety n eeds or to a level as low as reas on ably p racticable (see safety assessme nt). Data on chemical stab

50、ility of reactive in termediates, reacta nts, and other components should 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-th

51、e-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)。522 Toxicological Assessme nt 毒理學(xué)評價The imp ossibility of defi ning a safe exp osure level (zero risk concept) for geno toxiccarci nogens without a threshold and the realizatio n that comp lete elim in ati on of geno toxic imp urities from d

52、rug substa nces is ofte n un achievable, requires imp leme ntati on of a concept of an acce ptable risk level, i.e. an estimate of daily huma n exp osure 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”（accept

53、able 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。P rocedures for the derivatio n of acce ptable risk levels are con sidered in the Appen dix 3 of theQ3C Note for Guida nee on Imp urities: Residual Solve nts for Class 1 solve nts. However, these app roaches require availability of adequate

54、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）中的附件 三。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 imp urities on ly limited data from in vitro studies with the imp urity (e.g. Ames test, chromosomal aberratio n test) are ava

55、ilable and thus established app roaches to determ ine acce ptable in take levels cannot be app lied. Calculati on of“ safety mult ip les” vitimi data (e.g. Ames test) are con sidered inapprop riate for justificati on of acce ptable limits. Moreover, n egative carc inogeni city and geno toxicity data

56、 with the drug substa nee containing the impu rity at low ppm levels do not pro vide sufficie nt assura nee for sett ing acce ptable limits for the imp urity due to the lack of sen sitivity of this test ing app roach. Eve n potent mutage ns and carc inogens are most likely to remai n un detected whe

57、 n tested as part of the drug substa nee, i.e. at very low exp osure levels. A p ragmatic app roach is therefore n eeded which recog ni ses that the p rese nee of very low levels of geno toxic imp urities is not associated with an un acce ptable 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,染色體畸變試驗)，

58、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)計算雜質(zhì)的 安全倍數(shù)(safety mult ip les)”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)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，因為這種試驗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 risi)，那么可以采取實用的方法來控制該雜質(zhì)。523 AppI icatio n 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 (TTC) has bee n devel oped to defi ne a com mon exp osure level for any un studied chemical that will not p ose a risk of sig nific