ichm7(step4)基因毒性雜質評估和控制◆中英.doc

此文檔收集于網(wǎng)絡，僅供學習與交流，如有侵權請聯(lián)系網(wǎng)站刪除ASSESSMENT ANDCONTROL OFDNA REACTIVE(MUTAGENIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENTIALCARCINOGENICRISK為限制潛在致癌風險而對藥物中DNA活性（誘變性）雜質進行的評估和控制M7CurrentStep 4versiondated 23 June 2014This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended 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 Committee under Step 2 and release for public consultation.第2階段由籌委會批準，公開征求意見6 February 2013M7Approval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies.第4階段由籌委會批準，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 fix typographical errors and replace word “degradants” with “degradation products” throughout the document.修正輸入錯誤，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 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 the 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 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 reproduction must be obtained from this copyright holder.ASSESSMENT ANDCONTROL OFDNA REACTIVE(MUTAGENIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENTIALCARCINOGENICRISK為限制潛在致癌風險而對藥物中DNA活性（誘變性）雜質進行的評估和控制ICH Harmonised Tripartite GuidelineICH三方協(xié)調指南Having reachedStep 4of the ICH Process at the ICH Steering Committee meeting on 5 June 2014, this Guideline is recommended for adoption to the three regulatory parties to ICHTABLE 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 PRODUCTS上市產(chǎn)品應考慮的問題4.1 Post-Approval Changes to the Drug Substance Chemistry, Manufacturing, and Controls批準后原料藥化學、生產(chǎn)和質量變更4.2 Post-Approval Changes to the Drug Product Chemistry, Manufacturing, and Controls批準后制劑的化學、生產(chǎn)和質量變更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)品其它應考慮問題5. DRUG SUBSTANCE AND DRUG PRODUCT IMPURITY ASSESSMENT原料藥和制劑雜質評估5.1 Synthetic Impurities合成雜質5.2 Degradation Products降解產(chǎn)物5.3 Considerations 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風險特征7.1 TTC-based Acceptable Intakes根據(jù)TTC制訂可接受攝入量7.2 Acceptable Intakes Based on Compound-Specific Risk Assessments根據(jù)化合物特定風險評估制訂的可接受攝入量7.2.1 Mutagenic Impurities with Positive Carcinogenicity Data (Class 1 in Table 1)致癌數(shù)據(jù)有利的誘變性雜質（表1中的第1類）7.2.2 Mutagenic Impurities with Evidence for a Practical Threshold具有實用閾值證據(jù)的誘變性雜質7.3 Acceptable Intakes in Relation to LTL Exposure與LTL暴露相關的可接受攝入量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多個誘變性雜質的可接受攝入量7.5 Exceptions and Flexibility in Approaches方法例外情況和彈性8. CONTROL控制8.1 Control of Process Related Impurities工藝相關雜質的控制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 Considerations 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臨床試驗應用9.2 Common Technical Document (Marketing Application)通用技術文件（上市申報）NOTES注解GLOSSARY術語REFERENCES參考文獻APPENDICES附錄ASSESSMENT ANDCONTROL OFDNA REACTIVE(MUTAGENIC) IMPURITIES INPHARMACEUTICALS TOLIMITPOTENTIALCARCINOGENICRISK為限制潛在致癌風險而對藥物中DNA活性（誘變性）雜質進行的評估和控制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 substances 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. 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 complement ICH Q3A(R2), Q3B(R2) (Note 1), and ICH M3(R2): 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物質、試劑、溶劑、催化劑和其它工藝助劑，導致在所有原料藥及其制劑中會殘留有化學合成或其降解產(chǎn)物、雜質。在ICH Q3A(R2)新原料藥中的雜質和Q3B(R2)新制劑中的雜質（參考文獻1、2）中提供了關于主要雜質定性和控制的指南，對DNA活性雜質給出了有限的指南。本指南的目的是提供實用框架，以應用于這些誘變雜質的鑒別、分類、定性和控制，對潛在致癌風險進行控制。本指南意在補充ICH Q3A(R2)、Q3B(R2)（注解1）和ICH M3(R2)藥物人用臨床試驗和上市許可中的非臨床安全性研究（參考文獻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 mutagenic impurities that reside or are reasonably expected to reside in final drug substance or product, taking into consideration the intended conditions of human use.本指南強調在建立誘變性雜質水平時考慮安全性和質量風險管理兩方面，該水平應該僅表現(xiàn)出可忽略不計的致癌風險。指南在考慮藥物在人用時的條件下，給出了對原料藥或制劑中殘留或可能殘留的誘變性雜質評估和控制的建議。2. SCOPE OFGUIDELINE指南適用范圍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 applications 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后申報，以及之前已批準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。當上述申報符合以下情形時：Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities;原料藥合成變更，導致產(chǎn)生新雜質或已有雜質可接受標準增加Changes in the formulation, composition or manufacturing process result in new degradation products or increased acceptance criteria for existing degradation products;配方變更、組分變更或生產(chǎn)工藝變更，導致產(chǎn)生新的降解產(chǎn)物或已有降解產(chǎn)物可接受標準增加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，導致可接受癌癥風險水平受到重大影響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, oligonucleotide, radiopharmaceutical, fermentation products, herbal products, and crude products of animal or plant origin.本指南中描述的雜質潛在誘變性評估不適用于以下類型的原料藥和制劑：生物/生物技術制品、肽類、寡核苷酸、放射藥物、發(fā)酵產(chǎn)品、草藥制品和動物或植物來源的粗品。This guideline does not apply to drug substances and drug products intended for advanced cancer indications 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 genotoxic at therapeutic concentrations and may be expected to be associated with an increased cancer risk. Exposure to a mutagenic impurity in these 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4）中所定義的晚期癌癥指征用原料藥和制劑。另外，可能會有些情況下，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，已知其會使癌癥風險增加。這些情況下，暴露在具有誘變性的雜質下，不會顯著增加原料藥的癌癥風險。因此，雜質可以被控制在非誘變性雜質的可接受水平。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. Application 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 if warranted for impurities in excipients that are used for the first time in a drug product and are chemically synthesized.在本指南中所描述的對雜質潛在誘變性的評估不適用于已上市藥物中使用的輔料、調味劑、著色劑和香料。本指南不適用于藥物包材中的可浸出雜質，但指南中限制潛在致癌風險的安全風險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，且是化學合成的，則本指南的安全風險評估原則可以適用于輔料中的雜質。3. GENERALPRINCIPLES通用原則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, potentially causing cancer. This type of mutagenic carcinogen is usually detected in a bacterial reverse mutation (mutagenicity) assay. Other types of genotoxicants that are non-mutagenic typically have threshold mechanisms 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 exposure to potentially mutagenic impurities, the bacterial mutagenicity assay is used to assess the mutagenic potential and the need for controls. Structure-based assessments are useful for predicting bacterial mutagenicity outcomes based upon the established knowledge. There are a variety of approaches to conduct this evaluation including a review of the available literature, and/or computational toxicology assessment.本指南關注的焦點為可與DNA反應的物質，這些物質在較低水平時也可能會直接引起DNA損傷，導致DNA誘變，從而引發(fā)癌癥。這類誘變性致癌作用常被細菌逆式突變（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則有閾值進行控制，一般以常規(guī)水平雜質出現(xiàn)時對人類不具有致癌風險。因此，為了限制暴露于潛在誘變性雜質可能帶來的人類癌癥風險，我們使用細菌誘變含量來評估誘變可能性及控制的必要性?；诮Y構進行的評估有助于根據(jù)已有的知識來預測細菌誘變性測試結果。有很多方法可以用于實施該評估，包括對可獲得的文獻資料進行審核，和/或采用計算方式進行毒性評估。A Threshold of Toxicological Concern (TTC) concept was developed to define an acceptable intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects. The methods upon which the TTC is based are generally considered to be very conservative since they involve a simple linear extrapolation from the 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/day corresponding to a theoretical 10-5excess 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 mutagenic carcinogens referred to as the “cohort of concern”, comprises aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds.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險或其它毒性效果的化學品的可接受攝入量?；赥TC的方法一般被認為是非常保守的，因為它們牽涉到從給定的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的可接愛標準時，可以采用1.5g/天對應于十萬分之一生命時長患癌風險。有些結構基團被識別為具有較高的效價，因此即使攝入量低于TTC水平，從理論上來說仍會導致可能的顯著癌癥風險。這類具有較高效價的基團被稱為“關注隊列”，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 expected that control strategies and approaches will be less developed in earlier phases where overall development experience is limited. This 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 approximately one additional cancer per million. For later stages in development and for marketed products, acceptable increased cancer risk is set at a theoretically calculated level of approximately one in one hundred thousand. These risk levels represent a small theoretical increase in risk when compared to human overall lifetime incidence of developing any type of cancer, which is greater than 1 in 3.在臨床研發(fā)期間，如果整體研發(fā)經(jīng)驗有限，在早期臨床階段對控制策略和控制方法的要求會較低。本指南是在已建立的風險評估策略的基礎上，制訂誘變性雜質的可接受攝入量。在早期研發(fā)階段，可接受風險是建立在患癌率約為百萬分之一的理論計算水平上的。在研發(fā)后期及上市后，可接受癌癥增加風險是建立在患癌率約為十萬分之一的理論計算水平上的。相較于人類整個生命周期罹患各類癌癥的發(fā)生率（大于三分之一），這兩個不同的風險水平在理論上風險稍有增加。It is noted that established cancer risk assessments are based on lifetime exposures. Less-Than-Lifetime (LTL) exposures both during development and marketing can have higher acceptable intakes of impurities and still maintain comparable risk levels.已注意到所建立的患癌風險評估是根據(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，仍保留一定的風險水平。The use of a numerical cancer risk value (1 in 100,000) and its translation into risk-based doses (TTC) is a highly hypothetical concept that should not be regarded as a realistic indication of the actual risk.使用量化患癌風險值（十萬分之一），并將其轉化為根據(jù)風險計算的劑量（TTC值）是一種高度假想的概念，不應作為真實風險的一種實際指標。Nevertheless, the TTC concept provides an estimate of safe exposures for any mutagenic compound.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方法。However, exceeding 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值計算時采用了保守假設，超出TTC值并不一定會伴隨患癌風險增加。The most likely increase in cancer incidence is actually much less than 1 in 100,000. In addition, in cases where a mutagenic compound is a non-carcinogen in a rodent bioassay, there would be no predicted increase in cancer risk. Based on all the above considerations, any exposure to an impurity that is later identified as a mutagen is not necessarily associated with an increased cancer risk for patients already exposed to the impurity. A risk assessment would determine whether any further actions would be taken.大多數(shù)患癌可能性實際遠低于十萬分之一，另外，如果有一個誘變性化合物在嚙齒動物生物含量中顯示為非誘變性，則預測其致癌風險不會增加?；谏鲜鲞@些原因，所有暴露在之后鑒定為誘變性雜質并不一定伴隨已暴露于該雜質的患者癌癥風險增加。應進行風險評估來決定是否需要采取進一步行動。Where a 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.如果一個雜質被鑒定為具有潛在風險，則需要采用一個適當?shù)目刂撇呗詠砥胶夤に囍R和/或分析控制，以保證誘變性雜質等于或低于可接受的癌癥風險水平。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.有時一種雜質可能也是藥品的一種代謝產(chǎn)物，這時，對代謝產(chǎn)物的誘變性風險評估可以用于支持該雜質的質量水平。4. CONSIDERATIONSFORMARKETEDPRODUCTS已上市藥品要考慮的問題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 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.本指南無意回顧性地應用于在指南采納前已上市的藥物。但是，有些類型的批準后變更需要對有關的誘變性雜質安全性重新進行評估。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 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 existing mutagenic impurities. Reevaluation 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 result from the change, whether any mutagenic impurities formed during 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 starting materials or changing raw materials supplier will not require a reassessment of mutagenic impurity risk.批準后申報涉及原料藥的研發(fā)、生產(chǎn)和控制應包括起始物料后的合成路線、試劑、溶劑或工藝條件變更時，誘變性雜質對潛在風險影響的評估。特別是，變更評估要確定其是否會導致任何新的誘變性雜質或已知誘變性雜質會有更高的可接受標準。不建議對不受變更影響的雜質重新進行評估。例如，如果只有一部分生產(chǎn)工藝發(fā)生變更，則誘變性雜質的風險評估應局限于該變更是否會產(chǎn)生新的誘變性雜質、在受影響的步驟中是否有誘變性雜質含升高，以及上游步驟中的已知誘變性雜質是否升高。該變更發(fā)生時提交的法規(guī)申報資料應描述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，或變更原料供應商則不需要對誘變性雜質風險重新進行評估。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 existing drug product marketed in the assessors 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 expected.如果擬提交一個新的原料藥供應商，如有證據(jù)證明該供應商生產(chǎn)的原料藥采用了與審評區(qū)域內(nèi)已上市制劑中所用的原料藥具有相同的合成路線，則足以說明關于誘變性雜質其風險/利益是可以接受的，不需要根據(jù)本指南進行評估。如果不同這樣，則需要根據(jù)本指南進行評估。4.2 Post-Approval Changes to the Drug Product Ch