ICHM7step4基因毒性雜質(zhì)評估和控制◆中英

1、-. z.ASSESSMENT ANDCONTROL OFDNA REACTIVE(MUTAGENIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENTIALCARCINOGENICRISK為限制潛在致癌風(fēng)險(xiǎn)而對藥物中DNA活性（誘變性）雜質(zhì)進(jìn)行的評估和控制M7CurrentStep 4versiondated 23 June 2014This Guideline has been developed by the appropriate ICH E*pert Working Group and has been subject to consultati

2、on by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is remended for adoption to the regulatory bodies of the European Union, Japan and USA.M7Document History文件歷史Code文件代碼History歷史Date日期M7Approval by the Steering mittee under Step 2 and release fo

3、r public consultation.第2階段由籌委會(huì)批準(zhǔn)，公開征求意見6 February 2013M7Approval by the Steering mittee under Step 4 and remendation 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 2014Current Step 4 version現(xiàn)行版本第4階段M7Corrigendum to fi* typographical errors and replace word degradants”

4、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 2014Legal Notice:This document is protected by copyright and may be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided

5、that ICHs copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that th

6、e adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided.The document is provided as is without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability aris

7、ing 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 reproduction must be obtained from this copyright holder.ASSESSMENT ANDCONTROL OFDNA REACTIVE(MUTAGE

8、NIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENTIALCARCINOGENICRISK為限制潛在致癌風(fēng)險(xiǎn)而對藥物中DNA活性（誘變性）雜質(zhì)進(jìn)行的評估和控制ICH Harmonised Tripartite GuidelineICH三方協(xié)調(diào)指南Having reachedStep 4of the ICH Process at the ICH Steering mittee meeting on 5 June 2014, this Guideline is remended for adoption to the three regulatory pa

9、rties to ICHTABLE OF CONTENTS目錄1. INTRODUCTION概述2. SCOPE OF GUIDELINE指南圍3. GENERAL PRINCIPLES通用原則4. CONSIDERATIONS FOR MARKETED PRODUCTS上市產(chǎn)品應(yīng)考慮的問題4.1 Post-Approval Changes to the Drug Substance Chemistry, Manufacturing, and Controls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 Chemis

10、try, Manufacturing, and Controls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 Considerations for Marketed Products上市產(chǎn)品其它應(yīng)考慮問題5. DRUG SUBSTANCE AND DRUG PRODUCT IMPURITY ASSESSMENT原料藥和制劑雜質(zhì)評估5.1 Synthetic Impurities合成雜質(zhì)5.2 Degradation Products降解產(chǎn)物5.3 Considera

11、tions for Clinical Development臨床研發(fā)要考慮的問題6. HAZARD ASSESSMENT ELEMENTS危害性評估要素7. RISK CHARACTERIZATION風(fēng)險(xiǎn)特征7.1 TTC-based Acceptable Intakes根據(jù)TTC制訂可接受攝入量7.2 Acceptable Intakes Based on pound-Specific Risk Assessments根據(jù)化合物特定風(fēng)險(xiǎn)評估制訂的可接受攝入量7.2.1 Mutagenic Impurities with Positive Carcinogenicity Data (Class

12、 1 in Table 1)致癌數(shù)據(jù)有利的誘變性雜質(zhì)（表1中的第1類）7.2.2 Mutagenic Impurities with Evidence for a Practical Threshold具有實(shí)用閾值證據(jù)的誘變性雜質(zhì)7.3 Acceptable Intakes in Relation to LTL E*posure與LTL暴露相關(guān)的可接受攝入量7.3.1 Clinical Development臨床研發(fā)7.3.2 Marketed Products已上市產(chǎn)品7.4 Acceptable Intakes for Multiple Mutagenic Impurities多個(gè)誘變性雜

13、質(zhì)的可接受攝入量7.5 E*ceptions and Fle*ibility in Approaches方法例外情況和彈性8. CONTROL控制8.1 Control of Process Related Impurities工藝相關(guān)雜質(zhì)的控制8.2 Considerations for Control Approaches控制方法要考慮的問題8.3 Considerations for Periodic Testing定期檢查要考慮的問題8.4 Control of Degradation Products降解產(chǎn)物的控制8.5 Lifecycle Management生命周期管理8.6 C

14、onsiderations for Clinical Development臨床研發(fā)要考慮的問題9. DOCUMENTATION文件記錄9.1 Clinical Trial Applications臨床試驗(yàn)應(yīng)用9.2 mon Technical Document (Marketing Application)通用技術(shù)文件（上市申報(bào)）NOTES注解GLOSSARY術(shù)語REFERENCES參考文獻(xiàn)APPENDICES附錄ASSESSMENT ANDCONTROL OFDNA REACTIVE(MUTAGENIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENT

15、IALCARCINOGENICRISK為限制潛在致癌風(fēng)險(xiǎn)而對藥物中DNA活性（誘變性）雜質(zhì)進(jìn)行的評估和控制1. INTRODUCTION概述The synthesis of drug substances involves the use of reactive chemicals, reagents, solvents, catalysts, and other processing aids. As a result of chemical synthesis or subsequent degradation, impurities reside in all drug substanc

16、es and associated drug products. While ICH Q3A(R2): Impurities in New Drug Substances and Q3B(R2): Impurities in New Drug Products (Ref. 1, 2) provides guidance for qualification and control for the majority of the impurities, limited guidance is provided for those impurities that are DNA reactive.

17、The purpose of this guideline is to provide a practical framework that is applicable to the identification, categorization, qualification, and control of these mutagenic impurities to limit potential carcinogenic risk. This guideline is intended to plement ICH Q3A(R2), Q3B(R2) (Note 1), and ICH M3(R

18、2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorizations 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

19、鑒別、分類、定性和控制，對潛在致癌風(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 e*pected to pose negligible carcinogenic risk. It outlines reme

20、ndations for assessment and control of mutagenic impurities that reside or are reasonably e*pected to reside in final drug substance or product, taking into consideration the intended conditions of human use.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，給出了對原料藥或制劑中殘留或可能殘留的誘變性雜質(zhì)

21、評估和控制的建議。2. SCOPE OFGUIDELINE指南適用圍This document is intended to provide guidance for new drug substances and new drug products during their clinical development and subsequent applications for marketing. It also applies to post-approval submissions of marketed products, and to new marketing applicati

22、ons for products with a drug substance that is present 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)：Changes to the drug substance synthesis result in new impurities or increased acceptance crit

23、eria for e*isting 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Changes in the formulation, position or manufacturing process result in new degradation products or increased acceptance criteria for e*isting degradation 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Changes in indication or dosing regimen

24、 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 intended for the following types of drug substances and drug products: biological/biotechnological, peptide, ol

25、igonucleotide, radiopharmaceutical, fermentation products, herbal products, and crude products of animal or plant origin.本指南中描述的雜質(zhì)潛在誘變性評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)物或植物來源的粗品。This guideline does not apply to drug substances and drug products intended for advanced cancer indicat

26、ions as defined in the scope of ICH S9 (Ref. 4). Additionally, there may be some cases where a drug substance intended for other indications is itself genoto*ic at therapeutic concentrations and may be e*pected to be associated with an increased cancer risk. E*posure to a mutagenic impurity in these

27、 cases would notsignificantly add to the cancer risk of the drug substance. Therefore, impurities could be controlled at acceptable levels for non-mutagenic 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

28、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 e*cipients used in e*isting marketed products,flavoring agents, colorants, and perfumes. Application of this guideline to leachables associated with drug product packaging is not

29、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 if warranted for impurities in e*cipients that are used for the first time in a drug p

30、roduct and are chemically synthesized.在本指南中所描述的對雜質(zhì)潛在誘變性的評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)評估原則可以適用于輔料中的雜質(zhì)。3. GENERALPRINCIPLES通用原則The focus of this guideline is on DNA reactive substances that have a potential to directly

31、cause DNA damage when present at low levels leading to mutations and therefore, potentially causing cancer. This type of mutagenic carcinogen is usually detected in a bacterial reverse mutation (mutagenicity) assay. Other types of genoto*icants that are non-mutagenic typically have threshold mechani

32、sms and usually do not pose carcinogenic risk in humans at the level ordinarily present as impurities. Therefore to limit a possible human cancer risk associated with the e*posure to potentially mutagenic impurities, the bacterial mutagenicity assay is used to assess the mutagenic potential and the

33、need for controls. Structure-based assessments are useful for predicting bacterial mutagenicity outes based upon the established knowledge. There are a variety of approaches to conduct this evaluation including a review of the available literature, and/or putational to*icology assessment.本指南關(guān)注的焦點(diǎn)為可與

34、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)可能帶來的人類癌癥風(fēng)險(xiǎn)，我們使用細(xì)菌誘變含量來評估誘變可能性及控制的必要性?；诮Y(jié)構(gòu)進(jìn)行的評估有助于根據(jù)已有的知識(shí)來預(yù)測細(xì)菌誘變性測試結(jié)果。有很多方法可以用于實(shí)施該評估，包括對可獲得的文獻(xiàn)資料進(jìn)行審核，和/或采用計(jì)算方式進(jìn)行毒性評估。A Threshold of To*icological Concern (TTC

35、) concept was developed to define an acceptable intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other to*ic effects. The methods upon which the TTC is based are generally considered to be very conservative since they involve a simple linear e*trapolation from the

36、 dose giving a 50% tumor incidence (TD50) to a 1 in 106incidence, using TD50data for the most sensitive species and most sensitive site of tumor induction. For application of a TTC in the assessment of acceptable limits of mutagenic impurities in drug substances and drug products, a value of 1.5 g/d

37、ay corresponding to a theoretical 10-5e*cess lifetime risk of cancer, can be justified. Some structural groups were identified to be of such high potency that intakes even below the TTC would theoretically be associated with a potential for a significant carcinogenic risk. This group of high potency

38、 mutagenic carcinogens referred to as the cohort of concern”, prises aflato*in-like-, N-nitroso-, and alkyl-azo*y pounds.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。基于TTC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%腫瘤發(fā)生率（TD50）簡單線性外推到十萬分之一發(fā)生率，且采用的數(shù)據(jù)是來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評估原料藥和制劑中誘變性雜質(zhì)的可接愛標(biāo)準(zhǔn)時(shí)，可以采用1.5

39、g/天對應(yīng)于十萬分之一生命時(shí)長患癌風(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，從理論上來說仍會(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 e*pected that control strategies and approaches will be less developed in earlier phases where overall development e*perience is limited. Thi

40、s guideline bases acceptable intakes for mutagenic impurities on established risk assessment strategies. Acceptable risk during the early development phase is set at a theoretically calculated level of appro*imately one additional cancer per million. For later stages in development and for marketed

41、products, acceptable increased cancer risk is set at a theoretically calculated level of appro*imately one in one hundred thousand. These risk levels represent a small theoretical increase in risk when pared to human overall lifetime incidence of developing any type of cancer, which is greater than

42、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)評估策略的基礎(chǔ)上，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分之一的理論計(jì)算水平上的。相較于人類整個(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 noted that established cancer risk assessments are based on lifetime e*posures

43、. Less-Than-Lifetime (LTL) e*posures both during development and marketing can have higher acceptable intakes of impurities and still maintain parable risk levels.已注意到所建立的患癌風(fēng)險(xiǎn)評估是根據(jù)生命周期暴露情形的。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

44、translation into risk-based doses (TTC) is a highly 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 e*posures for any mutagenic po

45、und.不管怎樣，TTC概念提供了對誘變性化合物下安全暴露的一種估計(jì)方法。However, e*ceeding the TTC is not necessarily associated with an increased 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 increase in cancer incidence is actually

46、 much less than 1 in 100,000. In addition, in cases where a mutagenic pound is a non-carcinogen in a rodent bioassay, there would be no predicted increase in cancer risk. Based on all the above considerations, any e*posure to an impurity that is later identified as a mutagen is not necessarily assoc

47、iated with an increased cancer risk for patients already e*posed to the impurity. A risk assessment would determine whether any further actions would be taken.大多數(shù)患癌可能性實(shí)際遠(yuǎn)低于十萬分之一，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)測其致癌風(fēng)險(xiǎn)不會(huì)增加?；谏鲜鲞@些原因，所有暴露在之后鑒定為誘變性雜質(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)評估來決定是否需要采取進(jìn)一步行動(dòng)。Where a

48、potential risk has been identified for an impurity, an appropriate control strategy leveraging process understanding and/or analytical controls 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)目刂撇呗詠砥胶夤に囍R(shí)和/或分析控制，以保證誘

49、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 when an impurity is also a metabolite of the drug substance. In such cases the risk assessment that addresses mutagenicity 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產(chǎn)物，這時(shí)，對代產(chǎn)物的誘變性風(fēng)險(xiǎn)評估可以用于支持該雜質(zhì)的質(zhì)量水平。4. CONSIDERATIONSFORMARKETEDPRODUCTS已上市藥品要考慮的問

50、題This guideline is not intended to be applied retrospectively (i.e., to products marketed prior to adoption of this guideline). However, some types of post-approval changes warrant a reassessment of safety relative to mutagenic impurities. This section applies to these post-approval changes for prod

51、ucts marketed prior to, or after, the adoption of this guideline. Section 8.5 (Lifecycle Management) contains additional remendations for products marketed after adoption of this guideline.本指南無意回顧性地應(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)后變更需要對有關(guān)的誘變性雜質(zhì)安全性重新進(jìn)行評估。本部分適用于在指南被采納前后上市藥品的該類批準(zhǔn)后的變更。第8.5（生命周期管理）包括了對采納本指南后已上

52、市藥品的其它建議。4.1 Post-Approval Changes to the Drug Substance Chemistry, Manufacturing, and Controls上市后變更-原料藥研發(fā)、生產(chǎn)和控制Post-approval submissions involving the drug substance chemistry, manufacturing, and controls should include an evaluation of the potential risk impact associated with mutagenic impurities

53、 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 acceptance criteria for e*isting mutagenic impurities. Reevaluation o

54、f impurities not impacted by changes is not remended. For e*ample, 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 result from the change, whether any mutagenic impurities formed d

55、uring the affected step are increased, and whether any known mutagenic impurities from up-stream steps are increased. Regulatory submissions associated with such changes should describe the assessment as outlined in Section 9.2. Changing the site of manufacture of drug substance, intermediates, or s

56、tarting materials or changing 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)對潛在風(fēng)險(xiǎn)影響的評估。特別是，變更評估要確定其是否會(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)。不建議對不受變更影響的雜質(zhì)重新進(jìn)行評估。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

57、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中所列的評估。對原料藥、中間體或起始物料的生產(chǎn)場所的變更，或變更原料供應(yīng)商則不需要對誘變性雜質(zhì)風(fēng)險(xiǎn)重新進(jìn)行評估。When a new drug substance supplier is proposed, evidence that the drug substance produced by this supplier using the same route of synthesis as an e*isting drug product marketed in the assessor

58、s region is considered to be sufficient evidence of acceptable risk/benefit regarding mutagenic impurities and an assessment per this guideline is not required. If this is not the case, then an assessment per this guideline is e*pected.如果擬提交一個(gè)新的原料藥供應(yīng)商，如有證據(jù)證明該供應(yīng)商生產(chǎn)的原料藥采用了與審評區(qū)域已上市制劑中所用的原料藥具有相同的合成路線，則足

59、以說明關(guān)于誘變性雜質(zhì)其風(fēng)險(xiǎn)/利益是可以接受的，不需要根據(jù)本指南進(jìn)行評估。如果不同這樣，則需要根據(jù)本指南進(jìn)行評估。4.2 Post-Approval Changes to the Drug Product Chemistry, Manufacturing, and Controls上市后變更-制劑研發(fā)、生產(chǎn)和控制Post-approval submissions involving the drug product (e.g., change in position, manufacturing process, dosage form) should include an evaluation

60、 of the potential risk associated with any new mutagenic degradation products or higher acceptance criteria for e*isting mutagenic degradation products. If appropriate, the regulatory submission would include an updated control strategy. Reevaluation of the drug substance associated with drug produc