ICHM7(step4)基因毒性雜質(zhì)評(píng)估和控制◆中英解析

1、ASSESSMENT AND CONTROL OF DNA REACTIVE(MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TOLIMITPOTENTIAL CARCINOGENIC RISK 為限制潛在致癌風(fēng)險(xiǎn)而對(duì)藥物中 DNA活性(誘變性)雜質(zhì)進(jìn)行的評(píng)估和控制 M7 Curre nt Step 4 version dated 23 June 2014 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to c

2、onsultation by the regulatory parties, in accordanee with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the Europea n Union, Japa n and USA. M7 Docume nt History 文件歷史 Code文件代碼 History 歷史 Date 日期 M7 Approval by the Steeri ng Committe

3、e un der Step 2 and release for public con sultati on. 第2階段由籌委會(huì)批準(zhǔn)，公開(kāi)征求意見(jiàn) 6 February 2013 M7 Approval by the Steeri ng Committee un der Step 4 and recommendation for adoption to the three ICH regulatory bodies. 第4階段由籌委會(huì)批準(zhǔn)，推薦 ICH三方藥監(jiān)局采用 5 June 2014 Current Step 4 version 現(xiàn)行版本第 4階段 M7 Corrige ndum to f

4、ix typographical errors and replace word “degradants ” with “degradation products ” throughout the document. 修正輸入錯(cuò)誤，將全文中“ degradants ”替換成 “ degradation products ” . 23 June 2014 Legal Notice: This document is protected by copyright and maybe used, reproduced, in corporated into other works, adapted,

5、 modified, tran slated or distributed un der a public lice nse provided that ICHs copyright in the docume nt is ack no wledged at all times. In case of any adaption, modification or translation of the document, reas on able steps must be take n to clearly label, demarcate or otherwise ide ntify that

6、 cha nges were made to or based on the origi nal docume nt. Any impressi on that the adapti on, modificati on or tran slati on of the origi nal docume nt is en dorsed or spon sored by the ICH must be avoided.The docume nt is provided as is without warra nty of any kind. In no eve nt shall the ICH or

7、 the authors of the origi nal docume nt be liable for any claim, damages or other liability arising from the use of the document. The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for rep

8、roduct ion must be obta ined from this copyright holder.ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TOLIMIT POTENTIALCARCINOGENICRISK 為限制潛在致癌風(fēng)險(xiǎn)而對(duì)藥物中 DNA活性(誘變性)雜質(zhì)進(jìn)行的評(píng)估和控制 ICH Harmoni sed Tripartite Guideli ne ICH三方協(xié)調(diào)指南 Havi ng reached Step 4 of the ICH Process at

9、the ICH Steeri ng Committee meeti ng on 5 June 2014, this Guideli ne is recomme nded for adoptio n to the three regulatory parties to ICH TABLE OF CONTENTS 目錄 1. INTRODUCTION 概述 2. SCOPE OF GUIDELINE 指南范圍 3. GENERAL PRINCIPLES 通用原則 4. CONSIDERATIONS FOR MARKETED PRODUCT上 市產(chǎn)品應(yīng)考慮的問(wèn)題 4.1 Post-Approval

10、Changes to the Drug Substa nee Chemistry, Manu facturi ng, and Con trols 批準(zhǔn)后原料藥化學(xué)、生產(chǎn)和質(zhì)量變更 4.2 Post-Approval Changes to the Drug Product Chemistry, Manu facturi ng, and Con trols 批準(zhǔn)后制劑的化學(xué)、生產(chǎn)和質(zhì)量變更 4.3 Changes to the Clinical Use of Marketed Products 上市產(chǎn)品臨床使用變更 4.4 Other Con siderati ons for Marketed P

11、roducts 上市產(chǎn)品其它應(yīng)考慮問(wèn)題 5. DRUG SUBSTANCE AND DRUG PRODUCT原料藥和制齊U雜質(zhì)評(píng)估 IMPURITY ASSESSMENT 5.1 Synthetic Impurities 合成雜質(zhì) 5.2 Degradati on Products 降解產(chǎn)物 5.3 Con sideratio ns for Cli nical 臨床研發(fā)要考慮的冋題 Developme nt 6. HAZARD ASSESSMENT ELEMENTS 危害性評(píng)估要素 7. RISK CHARACTERIZATION 風(fēng)險(xiǎn)特征 7.1 TTC-based Acceptable I

12、n takes 根據(jù)TTC制訂可接受攝入量 7.2 Acceptable In takes Based on 根據(jù)化合物特定風(fēng)險(xiǎn)評(píng)估制訂的可接受攝 Compo un d-Specific Risk Assessme nts 入量 7.2.1 Mutagenic Impurities with Positive 致癌數(shù)據(jù)有利的誘變性雜質(zhì)（表 1中的第1 Carcinogenicity Data (Class 1 in Table 1) 類） 7.2.2 Mutagenic Impurities with Evidence 具有實(shí)用閾值證據(jù)的誘變性雜質(zhì) for a Practical Thresh

13、old 7.3 Acceptable In takes in Relati on to LTL 與LTL暴露相關(guān)的可接受攝入量 Exposure 7.3.1 Clinical Development 臨床研發(fā) 7.3.2 Marketed Products 已上市產(chǎn)品 7.4 Acceptable In takes for Multiple 多個(gè)誘變性雜質(zhì)的可接受攝入量 Mutagenic Impurities 7.5 Excepti ons and Flexibility in 方法例外情況和彈性 Approaches 8. CONTROL 控制 8.1 Control of Process

14、 Related Impurities 工藝相關(guān)雜質(zhì)的控制 8.2 Considerations for Control Approaches 控制方法要考慮的冋題 8.3 Con siderati ons for Periodic Test ing 定期檢查要考慮的冋題 8.4 Con trol of Degradati on Products 降解產(chǎn)物的控制 8.5 Lifecycle Man ageme nt 生命周期管理 8.6 Con sideratio ns for Cli nical 臨床研發(fā)要考慮的冋題 Developme nt 9. DOCUMENTATION 文件記錄 9.

15、1 Cli nical Trial Applicati ons 臨床試驗(yàn)應(yīng)用 9.2 Common Tech ni cal Docume nt (Market ing 通用技術(shù)文件（上市申報(bào)） Applicati on) NOTES 注解 GLOSSARY 術(shù)語(yǔ) REFERENCES 參考文獻(xiàn) APPENDICES 附錄 IN PHARMACEUTICALS TOLIMIT POTENTIALCARCINOGENICRISK 為限制潛在致癌風(fēng)險(xiǎn)而對(duì)藥物中 DNA活性（誘變性）雜質(zhì)進(jìn)行的評(píng)估和控制 1. INTRODUCTION 概述 The synthesis of drug substanc

16、es involves the use of reactive chemicals, reagents, solve nts, catalysts, and other process ing aids. As a result of chemical syn thesis or subsequent degradation, impurities reside in all drug substances and associated drug products. While ICH Q3A(R2): Impurities in New Drug Substances and Q3B(R2)

17、: Impurities in NewDrug Products (Ref. 1, 2) provides guidanee for qualification and control for the majority of the impurities, limited guidanee is provided for those impurities that are DNA reactive. The purpose of this guideline is to provide a practical framework that is applicable to the identi

18、fication, categorization, qualification, and control of these mutagenic impurities to limit potential carcinogenic risk. This guideline is intended to complement ICH Q3A(R2), Q3B(R2) (Note 1), and ICH M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authoriza

19、tions for Pharmaceuticals (Ref. 3). 原料藥合成牽涉到使用活性化學(xué)物質(zhì)、試劑、 溶劑、催化劑和其它工藝助劑，導(dǎo)致在所有原 料藥及其制劑中會(huì)殘留有化學(xué)合成或其降解產(chǎn)物、雜質(zhì)。在 ICH Q3A(R2)新原料藥中的雜質(zhì) 和Q3B(R2)新制劑中的雜質(zhì)(參考文獻(xiàn) 1、2)中提供了關(guān)于主要雜質(zhì)定性和控制的指南，對(duì) DNA活性雜質(zhì)給出了有限的指南。本指南的目的是提供實(shí)用框架，以應(yīng)用于這些誘變雜質(zhì)的 鑒別、分類、定性和控制，對(duì)潛在致癌風(fēng)險(xiǎn)進(jìn)行控制。本指南意在補(bǔ)充ICH Q3A(R2)、Q3B(R2) (注解1 )和ICH M3(R2)藥物人用臨床試驗(yàn)和上市許可中的非臨床安

20、全性研究 (參考文獻(xiàn)3 )。 This guideline emphasizes considerations of both safety and quality risk management in establishing levels of mutagenic impurities that are expected to pose negligible carcinogenic risk. It outlines recommendations for assessment and control of mutage nic impurities that reside or are

21、 reas on ably expected to reside in final drug substa nee or product, tak ing into con siderati on the inten ded con diti ons of huma n use. ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES 本指南強(qiáng)調(diào)在建立誘變性雜質(zhì)水平時(shí)考慮安全性和質(zhì)量風(fēng)險(xiǎn)管理兩方面， 該水平應(yīng)該僅表現(xiàn) 出可忽略不計(jì)的致癌風(fēng)險(xiǎn)。指南在考慮藥物在人用時(shí)的條件下， 給出了對(duì)原料藥或制劑中殘 留或可能殘留的誘變性雜質(zhì)評(píng)

22、估和控制的建議。 2. SCOPE OF GUIDELINE 指南適用范圍 This document is intended to provide guidanee for new drug substances and new drug products during their clinical development and subsequent applications for marketi ng. It also applies to post-approval submissi ons of marketed products, and to new marketi ng ap

23、plicati ons for products with a drug substa nee that is prese nt in a previously approved product, in both cases only where: 本指南意在給研發(fā)期間和上市申報(bào)期間的新原料藥和新制劑提供指南。 它也適用于已上市藥 物的批準(zhǔn)后申報(bào)，以及之前已批準(zhǔn)上市的制劑中的同樣原料藥生產(chǎn)的另一制劑新上市申報(bào)。 當(dāng)上述申報(bào)符合以下情形時(shí)： Chan ges to the drug substa nee syn thesis result in new impurities or in crea

24、sed accepta nce criteria for existi ng impurities; 原料藥合成變更，導(dǎo)致產(chǎn)生新雜質(zhì)或已有雜質(zhì)可接受標(biāo)準(zhǔn)增加 Chan ges in the formulati on, compositi on or manu facturi ng process result in new degradati on products or in creased accepta nce criteria for existi ng degradati on products; 配方變更、組分變更或生產(chǎn)工藝變更，導(dǎo)致產(chǎn)生新的降解產(chǎn)物或已有降解 產(chǎn)物可接受標(biāo)準(zhǔn)增加

25、Changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level. 指征變更或給藥方案變更，導(dǎo)致可接受癌癥風(fēng)險(xiǎn)水平受到重大影響 Assessment of the mutagenic potential of impurities as described in this guideline is not inten ded for the follow ing types of drug substa nces and drug produc

26、ts: biological/biotech no logical, peptide, oligo nu cleotide, radiopharmaceutical, ferme ntati on products, herbal products, and crude products of ani mal or pla nt origi n. 本指南中描述的雜質(zhì)潛在誘變性評(píng)估不適用于以下類型的原料藥和制劑：生物 /生物技術(shù)制 品、肽類、寡核苷酸、放射藥物、發(fā)酵產(chǎn)品、草藥制品和動(dòng)物或植物來(lái)源的粗品。 This guideli ne does not apply to drug substa

27、nces and drug products inten ded for adva need cancer in dicati ons as defi ned in the scope of ICH S9 (Ref. 4). Additi on ally, there may be some cases where a drug substa nee inten ded for other in dicati ons is itself genotoxic at therapeutic concentrations and may be expected to be associated wi

28、th an in creased cancer risk. Exposure to a mutage nic impurity in these cases would not significantly add to the cancer risk of the drug substanee. Therefore, impurities could be con trolled at acceptable levels for non-m utage nic impurities. 本指南不適用于ICH S9 (參考文獻(xiàn)4)中所定義的晚期癌癥指征用原料藥和制劑。另外，可 能會(huì)有些情況下，制劑

29、用于其它治療， 而其自己本身在治療濃度下就具有基因毒性， 已知其 會(huì)使癌癥風(fēng)險(xiǎn)增加。這些情況下，暴露在具有誘變性的雜質(zhì)下， 不會(huì)顯著增加原料藥的癌癥 風(fēng)險(xiǎn)。因此，雜質(zhì)可以被控制在非誘變性雜質(zhì)的可接受水平。 Assessment of the mutagenic potential of impurities as described in this guideline is not intended for excipients used in existing marketed products, flavoring agents , colorants, and perfumes. App

30、lication of this guideline to leachables associated with drug product packaging is not intended, but the safety risk assessment principles outlined in this guideline for limiting potential carcinogenic risk can be used if warranted. The safety risk assessment principles of this guideline can be used

31、 if warranted for impurities in excipients that are used for the first time in a drug product and are chemically syn thesized. 在本指南中所描述的對(duì)雜質(zhì)潛在誘變性的評(píng)估不適用于已上市藥物中使用的輔料、調(diào)味劑、 著色劑和香料。本指南不適用于藥物包材中的可浸出雜質(zhì)， 但指南中限制潛在致癌風(fēng)險(xiǎn)的安 全風(fēng)險(xiǎn)評(píng)估原則在一定情況下是可以使用的。 如果輔料是首次用于藥物中， 且是化學(xué)合成的， 則本指南的安全風(fēng)險(xiǎn)評(píng)估原則可以適用于輔料中的雜質(zhì)。 3. GENERAL PRINCIPLE

32、S 通用原貝U The focus of this guideline is on DNA reactive substances that have a potential to directly cause DNA damage when present at low levels leading to mutations and therefore, pote ntially caus ing cancer. This type of mutage nic carci nogen is usually detected in a bacterial reverse mutatio n (

33、mutage ni city) assay. Other types of genotoxicants that are non-mutagenic typically have threshold mechanisms and usually do not pose carci nogenic risk in huma ns at the level ordin arily prese nt as impurities. Therefore to limit a possible human cancer risk associated with the exposure to potent

34、ially mutagenic impurities, the bacterial mutagenicity assay is used to assess the mutage nic pote ntial and the n eed for con trols. Structure-based assessme nts are useful for predict ing bacterial mutage ni city outcomes based upon the established kno wledge. There are a variety of approaches to

35、con duct this evaluati on in clud ing a review of the available literature, an d/or computati onal toxicology assessme nt. 本指南關(guān)注的焦點(diǎn)為可與 DNA反應(yīng)的物質(zhì)，這些物質(zhì)在較低水平時(shí)也可能會(huì)直接引起 DNA 損傷，導(dǎo)致DNA誘變，從而引發(fā)癌癥。這類誘變性致癌作用常被細(xì)菌逆式突變(誘變)含量 檢出。其它類型不具有典型誘變性的基因毒性物質(zhì)則有閾值進(jìn)行控制， 一般以常規(guī)水平雜質(zhì) 出現(xiàn)時(shí)對(duì)人類不具有致癌風(fēng)險(xiǎn)。 因此，為了限制暴露于潛在誘變性雜質(zhì)可能帶來(lái)的人類癌癥 風(fēng)險(xiǎn)，我們使用

36、細(xì)菌誘變含量來(lái)評(píng)估誘變可能性及控制的必要性。 基于結(jié)構(gòu)進(jìn)行的評(píng)估有助 于根據(jù)已有的知識(shí)來(lái)預(yù)測(cè)細(xì)菌誘變性測(cè)試結(jié)果。 有很多方法可以用于實(shí)施該評(píng)估， 包括對(duì)可 獲得的文獻(xiàn)資料進(jìn)行審核，和 /或采用計(jì)算方式進(jìn)行毒性評(píng)估。 A Threshold of Toxicological Concern (TTC) con cept was developed to defi ne an acceptable in take for any un studied chemical that poses a n egligible risk of carcinogenicity or other toxic e

37、ffects. The methods upon which the TTC is based are gen erally con sidered to be very con servative since they in volve a simple lin ear extrapolation from the dose giving a 50%tumor incidenee (TD50) to a 1 in 106incidenee, using TD50 data for the most sen sitive species and most sen sitive site of

38、tumor in duct ion. For applicati on of a TTC in the assessme nt of acceptable limits of mutagenic impurities in drug substances and drug products, a value of 1.5 卩 g/day corresponding to a theoretical 10-5 excess lifetime risk of cancer, can be justified. Some structural groups were identified to be

39、 of such high potency that in takes even below the TTC would theoretically be associated with a pote ntial for a sig ni fica nt carci nogenic risk. This group of high pote ncy mutage nic carci nogens referred to as the “ cohort of concern ”，co mprises aflatoxin-like-, N-nitroso-, and alkyl-azoxy com

40、po un ds. 已經(jīng)建立了 TTC概念，用于界定所有未經(jīng)研究，但具有可忽略的致癌風(fēng)險(xiǎn)或其它毒性效果的 化學(xué)品的可接受攝入量?；赥TC的方法一般被認(rèn)為是非常保守的， 因?yàn)樗鼈儬可娴綇慕o定 的50%中瘤發(fā)生率（TD50）簡(jiǎn)單線性外推到十萬(wàn)分之一發(fā)生率，且采用的數(shù)據(jù)是來(lái)自于最敏 感物種和最敏感腫瘤部位的 TD50數(shù)據(jù)。在使用TTC評(píng)估原料藥和制劑中誘變性雜質(zhì)的可接 愛(ài)標(biāo)準(zhǔn)時(shí)，可以采用1.5卩g/天對(duì)應(yīng)于十萬(wàn)分之一生命時(shí)長(zhǎng)患癌風(fēng)險(xiǎn)。有些結(jié)構(gòu)基團(tuán)被識(shí)別 為具有較高的效價(jià)，因此即使攝入量低于 TTC水平，從理論上來(lái)說(shuō)仍會(huì)導(dǎo)致可能的顯著癌癥 風(fēng)險(xiǎn)。這類具有較高效價(jià)的基團(tuán)被稱為“關(guān)注隊(duì)列”，包括黃曲霉素

41、類、 N-亞硝基化合物， 以及烷基-氧化偶氮基化合物。 During clinical development, it is expected that control strategies and approaches will be less developed in earlier phases where overall development experience is limited. This guideli ne bases acceptable in takes for mutage nic impurities on established risk assessme nt

42、 strategies. Acceptable risk duri ng the early developme nt phase is set at a theoretically calculated level of approximately one additi onal cancer per milli on. For later stages in developme nt and for marketed products, acceptable in creased cancer risk is set at a theoretically calculated level

43、of approximately one in one hun dred thousa nd. These risk levels represe nt a small theoretical in crease in risk whe n compared to huma no verall lifetime in cide nce of develop ing any type of cancer, which is greater tha n 1 in 3. 在臨床研發(fā)期間，如果整體研發(fā)經(jīng)驗(yàn)有限，在早期臨床階段對(duì)控制策略和控制方法的要求會(huì) 較低。本指南是在已建立的風(fēng)險(xiǎn)評(píng)估策略的基礎(chǔ)上，

44、制訂誘變性雜質(zhì)的可接受攝入量。 在早 期研發(fā)階段，可接受風(fēng)險(xiǎn)是建立在患癌率約為百萬(wàn)分之一的理論計(jì)算水平上的。 在研發(fā)后期 及上市后，可接受癌癥增加風(fēng)險(xiǎn)是建立在患癌率約為十萬(wàn)分之一的理論計(jì)算水平上的。 于人類整個(gè)生命周期罹患各類癌癥的發(fā)生率 （大于三分之一），這兩個(gè)不同的風(fēng)險(xiǎn)水平在理 論上風(fēng)險(xiǎn)稍有增加。 It is no ted that established cancer risk assessme nts are based on lifetime exposures. 相較 Less-Tha n-Lifetime (LTL) exposures both duri ng developm

45、e nt and marketi ng can have higher acceptable in takes of impurities and still maintain comparable risk levels. 已注意到所建立的患癌風(fēng)險(xiǎn)評(píng)估是根據(jù)生命周期內(nèi)暴露情形的。 在研發(fā)期間和上市期間低于 生命周期(LTL)暴露都可能允許攝入更多雜質(zhì)，仍保留一定的風(fēng)險(xiǎn)水平。 The use of a numerical cancer risk value (1 in 100,000) and its translation into risk-based doses (TTC) is a h

46、ighly hypothetical concept that should not be regarded as a realistic indication of the actual risk. 使用量化患癌風(fēng)險(xiǎn)值(十萬(wàn)分之一)，并將其轉(zhuǎn)化為根據(jù)風(fēng)險(xiǎn)計(jì)算的劑量( TTC值)是一種 高度假想的概念，不應(yīng)作為真實(shí)風(fēng)險(xiǎn)的一種實(shí)際指標(biāo)。 Nevertheless, the TTC concept provides an estimate of safe exposures for any mutage nic compo und. 不管怎樣，TTC概念提供了對(duì)誘變性化合物下安全暴露的一種估計(jì)方法

47、。 However, exceedi ng the TTC is not n ecessarily associated with an in creased cancer risk given the conservative assumptions employed in the derivation of the TTC value. 但是，假出在TTC值計(jì)算時(shí)采用了保守假設(shè)，超出 TTC值并不一定會(huì)伴隨患癌風(fēng)險(xiǎn)增加。 The most likely in crease in cancer in cide nee is actually muchless tha n 1 in 100,0

48、00. In additi on, in cases where a mutage nic compo und is a non-carci nogen in a rode nt bioassay, there would be no predicted in crease in can cer risk. Based on all the above considerations, any exposure to an impurity that is later identified as a mutagen is not n ecessarily associated with an i

49、n creased cancer risk for patie nts already exposed to the impurity. A risk assessme nt would determ ine whether any further actions would be take n. 大多數(shù)患癌可能性實(shí)際遠(yuǎn)低于十萬(wàn)分之一， 另外，如果有一個(gè)誘變性化合物在嚙齒動(dòng)物生物 含量中顯示為非誘變性， 則預(yù)測(cè)其致癌風(fēng)險(xiǎn)不會(huì)增加。 基于上述這些原因， 所有暴露在之后 定是否需要采取進(jìn)一步行動(dòng)。 Where a potential risk has been identified for an

50、impurity, an appropriate control 鑒定為誘變性雜質(zhì)并不一定伴隨已暴露于該雜質(zhì)的患者癌癥風(fēng)險(xiǎn)增加。 應(yīng)進(jìn)行風(fēng)險(xiǎn)評(píng)估來(lái)決 strategy leveragi ng process un dersta nding an d/or an alytical con trols should be developed to ensure that the mutagenic impurity is at or below the acceptable cancer risk level. 如果一個(gè)雜質(zhì)被鑒定為具有潛在風(fēng)險(xiǎn)，則需要采用一個(gè)適當(dāng)?shù)目刂撇呗詠?lái)平衡工藝知識(shí)和 / 或

51、分析控制，以保證誘變性雜質(zhì)等于或低于可接受的癌癥風(fēng)險(xiǎn)水平。 There may be cases whe n an impurity is also a metabolite of the drug substa nee. In such cases the risk assessme nt that addresses mutage nicity of the metabolite can qualify the impurity. 有時(shí)一種雜質(zhì)可能也是藥品的一種代謝產(chǎn)物， 這時(shí)，對(duì)代謝產(chǎn)物的誘變性風(fēng)險(xiǎn)評(píng)估可以用于 支持該雜質(zhì)的質(zhì)量水平。 4. CONSIDERATIONS FOR MARK

52、ETED PRODUCTS 已上市藥品要考慮的問(wèn)題 This guideli ne is not inten ded to be applied retrospectively (i.e., to products marketed prior to adoption of this guideline). However, sometypes of post-approval cha nges warra nt a reassessme nt of safety relative to mutage nic impurities. This sect ion applies to these

53、 post-approval cha nges for products marketed prior to, or after, the adoption of this guideline. Section 8.5 (Lifecycle Management) contains additional recommendations for products marketed after adoption of this guideline. 本指南無(wú)意回顧性地應(yīng)用于在指南采納前已上市的藥物。 但是，有些類型的批準(zhǔn)后變更需要 對(duì)有關(guān)的誘變性雜質(zhì)安全性重新進(jìn)行評(píng)估。 本部分適用于在指南被采納前

54、后上市藥品的該類 批準(zhǔn)后的變更。第 8.5 (生命周期管理)包括了對(duì)采納本指南后已上市藥品的其它建議。 4.1 Post-Approval Chan ges to the Drug Substa nee Chemistry, Manu facturi ng, and Controls 上市后變更-原料藥研發(fā)、生產(chǎn)和控制 Post-approval submissi ons in volvi ng the drug substa nee chemistry, manu facturi ng, and controls should include an evaluation of the pot

55、ential risk impact associated with mutagenic impurities from changes to the route of synthesis, reagents, solvents, or process conditions after the starting material. Specifically, changes should be evaluated to determine if the changes result in any new mutagenic impurities or higher accepta nee cr

56、iteria for exist ing mutage nic impurities. Reevaluati on of impurities not impacted by changes is not recommended. For example, when only a portion of the manufacturing process is changed, the assessment of risk from mutagenic impurities should be limited to whether any new mutagenic impurities res

57、ult from the change, whether any mutagenic impurities formed during the affected step are in creased, and whether any known mutage nic impurities from up-stream steps are in creased. Regulatory submissi ons associated with such cha nges should describe the assessment as outlined in Section 9.2. Chan

58、ging the site of manufacture of drug substa nee, in termediates, or start ing materials or cha nging raw materials supplier will not require a reassessment of mutagenic impurity risk. 批準(zhǔn)后申報(bào)涉及原料藥的研發(fā)、 生產(chǎn)和控制應(yīng)包括起始物料后的合成路線、 試劑、溶劑或工 藝條件變更時(shí)，誘變性雜質(zhì)對(duì)潛在風(fēng)險(xiǎn)影響的評(píng)估。 特別是，變更評(píng)估要確定其是否會(huì)導(dǎo)致 任何新的誘變性雜質(zhì)或已知誘變性雜質(zhì)會(huì)有更高的可接受標(biāo)準(zhǔn)。 不建

59、議對(duì)不受變更影響的雜 質(zhì)重新進(jìn)行評(píng)估。例如，如果只有一部分生產(chǎn)工藝發(fā)生變更， 則誘變性雜質(zhì)的風(fēng)險(xiǎn)評(píng)估應(yīng)局 限于該變更是否會(huì)產(chǎn)生新的誘變性雜質(zhì)、 在受影響的步驟中是否有誘變性雜質(zhì)含升高， 以及 上游步驟中的已知誘變性雜質(zhì)是否升高。 該變更發(fā)生時(shí)提交的法規(guī)申報(bào)資料應(yīng)描述 9.2中所 列的評(píng)估。對(duì)原料藥、中間體或起始物料的生產(chǎn)場(chǎng)所的變更， 或變更原料供應(yīng)商則不需要對(duì) 誘變性雜質(zhì)風(fēng)險(xiǎn)重新進(jìn)行評(píng)估。 When a new drug substa nee supplier is proposed, evide nee that the drug substa nee produced by this su

60、pplier using the same route of syn thesis as an existi ng drug product marketed in the assessor s region is considered to be sufficient evidenee of acceptable risk/benefit regarding mutagenic impurities and an assessment per this guideli ne is not required. If this is not the case, the n an assessme