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近日，ICH發(fā)布了ICH Q3E《可提取物和可浸出物指南》草案及其配套文件。該文件當(dāng)前已完成ICH進(jìn)程的第2b步，并進(jìn)入第3步。該指南草案提出了可浸出雜質(zhì)評(píng)估和控制的框架和流程，適用于適用于藥品、生物制品、細(xì)胞和基因治療產(chǎn)品，包括藥械組合產(chǎn)品。
文件現(xiàn)已完成翻譯，現(xiàn)將中英文對(duì)照分享給大家：
GUIDELINE FOR EXTRACTABLES AND LEACHABLES
ICH Q3E《可提取物和可浸出物指南》
1.INTRODUCTION
介紹
2.SCOPE
范圍
3.RISK ASSESSMENT AND CONTROL OF EXTRACTABLES AND LEACHABLES
可提取物和可浸出物的風(fēng)險(xiǎn)評(píng)估和控制
3.1General Principles
一般原則
3.2Risk Matrix as a Multifactorial Concept
風(fēng)險(xiǎn)矩陣作為多因素概念
3.3Risk Assessment
風(fēng)險(xiǎn)評(píng)估
3.4Risk Control
風(fēng)險(xiǎn)控制
3.4.1Special Considerations
特殊考慮
3.5Documentation and Compliance
文件記錄和合規(guī)性
3.6Risk Review / Lifecyle Management
風(fēng)險(xiǎn)審核/生命周期管理
4.CHEMICAL TESTING AND ASSESSMENT
化學(xué)測(cè)試和評(píng)估
4.1Prior Knowledge
先驗(yàn)知識(shí)
4.2Component Selection
組件選擇
4.3Extractable Study
可提取物研究
4.3.1Semi-Quantitative Extractables Study
半定量可提取物研究
4.3.2Quantitative Extractables Study
定量可提取物研究
4.4Leachables Study
可浸出物研究
4.5Simulated Leachable Study
模擬可浸出物研究
4.6Extractable and Leachable Correlation
可提取和可浸出相關(guān)性
5.ANALYTICAL EVALUATION THRESHOLD
分析評(píng)估閾值
5.1Analytical Uncertainty Factor
分析不確定度因子
6.SAFETY ASSESSMENT
安全評(píng)估
6.1General Principles
一般原則
6.2Leachables Classification
可浸出物分類
6.3Safety Assessment Process
安全評(píng)估流程
6.4Route Specific Considerations and Special Cases (Local Toxicity Concerns)
給藥途徑考慮和特殊情況（局部毒性問(wèn)題）
6.4.1Ophthalmic Drug Products
眼用藥品
6.4.2Intracerebral, Intrathecal, Epidural Drug Products
腦內(nèi)、鞘內(nèi)、硬膜外藥品
6.4.3Dermal Drug Products
皮膚藥品
6.4.4Sensitization Potential
致敏潛力
6.5Considerations for ICH S9 Products
ICH S9產(chǎn)品的考慮
6.6Content of Safety Assessment
安全評(píng)估內(nèi)容
7.GLOSSARY
術(shù)語(yǔ)
8.REFERENCES
參考文獻(xiàn)
APPENDIX 1: TYPICAL WORKFLOWS FOR E&L RISK ASSESSMENT AND RISK CONTROL
附錄1：可提取物和可浸出物風(fēng)險(xiǎn)評(píng)估和風(fēng)險(xiǎn)控制的典型工作流程
APPENDIX 2: TYPES OF STUDIES
附錄2：研究類型
APPENDIX 3 AET CALCULATIONS
附錄3 AET 計(jì)算
APPENDIX 4: POTENCY CLASSES FOR LEACHABLES
附錄4：可浸出物的效力等級(jí)
APPENDIX 5: METHODS FOR ESTABLISHING EXPOSURE LIMITS
附錄5：設(shè)定暴露限值的方法
APPENDIX 6: MONOGRAPHS FOR CLASS 1 LEACHABLES
附錄6：第1類可浸出物專論
1.INTRODUCTION
介紹
Leachables are chemical entities that migrate from manufacturing components/systems, packaging or delivery device components into a drug product under the established manufacturing and labelled storage conditions. Extractables are chemical entities that are intentionally extracted from manufacturing components/systems, packaging or delivery device components under specified laboratory test conditions and thus are potential leachables.
浸出物是在既定的生產(chǎn)和標(biāo)簽標(biāo)注的儲(chǔ)存條件下，從生產(chǎn)組件 / 系統(tǒng)、包裝或給藥裝置組件遷移到藥品中的化學(xué)物質(zhì)?？商崛∥锸窃谔囟ǖ膶?shí)驗(yàn)室測(cè)試條件下，從生產(chǎn)組件/系統(tǒng)、包裝或給藥裝置組件中有意提取出的化學(xué)物質(zhì)，因此可能成為浸出物。
This guideline presents a holistic framework and process for the assessment and control of leachable impurities to further expand the existing ICH guidelines on impurities, including impurities in new drug substances (ICH Q3A) and new drug products (ICH Q3B), residual solvents (ICH Q3C), and elemental impurities (ICH Q3D), as well as DNA reactive (mutagenic) impurities (ICH M7). The framework of this guideline follows the principles of risk management as described in ICH Q9. While the guideline includes materials characterization and process understanding, its primary purpose is to protect patient safety and product quality through assessment and control of leachables in the drug product. Due to rapid advances in materials engineering, device innovations, new manufacturing paradigms and novel therapeutic modalities, the aim is to provide principles and concepts that are forward looking within the scientific and regulatory landscape.
本指南提出了一個(gè)全面的框架和流程，用于評(píng)估和控制浸出性雜質(zhì)，以進(jìn)一步擴(kuò)展現(xiàn)有的國(guó)際人用藥品注冊(cè)技術(shù)協(xié)調(diào)會(huì)（ICH）雜質(zhì)指南，包括新原料藥中的雜質(zhì)（ICH Q3A）、新制劑中的雜質(zhì)（ICH Q3B）、殘留溶劑（ICH Q3C）、元素雜質(zhì)（ICH Q3D）以及 DNA 反應(yīng)性（致突變）雜質(zhì)（ICH M7）。本指南的框架遵循 ICH Q9 中描述的風(fēng)險(xiǎn)管理原則。盡管本指南包含材料表征和工藝?yán)斫獾膬?nèi)容，但其主要目的是通過(guò)評(píng)估和控制藥品中的浸出物，保障患者安全和產(chǎn)品質(zhì)量。由于材料工程、裝置創(chuàng)新、新生產(chǎn)模式和新型治療方式的快速發(fā)展，本指南旨在提供具有前瞻性的原則和概念，以適應(yīng)科學(xué)和監(jiān)管領(lǐng)域的發(fā)展。
2.SCOPE
適用范圍
The guideline applies to the risk assessment and control of leachables in new drug products, including cell and gene therapy products. Drug-device combination products that require marketing authorizations and meet the definition of pharmaceutical or biological products are also in scope.
本指南適用于新制劑（包括細(xì)胞和基因治療產(chǎn)品）中浸出物的風(fēng)險(xiǎn)評(píng)估和控制。需要上市許可且符合藥品或生物制品定義的藥械組合產(chǎn)品也在本指南的適用范圍內(nèi)。
Organic leachables are the primary focus of this guideline. Though recommended methodologies for elemental analysis are within the scope of this guideline, the safety assessment of elemental leachables are addressed by ICH Q3D and thus out of scope for this guideline.
有機(jī)浸出物是本指南的主要關(guān)注對(duì)象。盡管元素分析的推薦方法屬于本指南的范圍，但元素浸出物的安全性評(píng)估由 ICH Q3D 規(guī)范，因此不在本指南的范圍內(nèi)。
The guideline also applies to approved products for any changes that are likely to impact the leachable profile or patient exposure such as those relating to formulation, manufacturing, dosing, and/or container closure system (i.e., life cycle management). This guideline is not intended to apply to extrinsic, extraneous or foreign substances resulting from product contamination or adulteration.
對(duì)于已獲批產(chǎn)品，任何可能影響浸出物特征或患者暴露量的變更（如與配方、生產(chǎn)、給藥和 / 或容器密封系統(tǒng)相關(guān)的變更），本指南同樣適用（即生命周期管理）。本指南不適用于由產(chǎn)品污染或摻假導(dǎo)致的外來(lái)、無(wú)關(guān)或異物。
This guideline is not intended for herbal medicinal products and crude non-processed products of animal or plant origin. For these products in liquid dosage forms, regional expectations may apply.
本指南不適用于草藥制劑以及未經(jīng)加工的動(dòng)植物來(lái)源粗制品。對(duì)于這些液體劑型產(chǎn)品，可能需遵循地區(qū)性要求。
This guideline is not intended for products used during clinical research stages of development. However, in cases of high risk to the patient, principles of this guideline may be applicable to support clinical studies.
本指南不適用于臨床研究階段使用的產(chǎn)品。但在患者面臨高風(fēng)險(xiǎn)的情況下，本指南的原則可適用于支持臨床研究。
Generally, radiopharmaceuticals are not considered in scope, unless there is a specific cause for concern.
一般而言，放射性藥品不在本指南的適用范圍內(nèi)，除非存在特定的擔(dān)憂因素。
The guideline does not apply to systems used in the manufacture or storage of excipients. Refer to Section 3.4.1 for special considerations regarding packaging components for liquid or semiliquid active pharmaceutical ingredients (APIs).
本指南不適用于輔料生產(chǎn)或儲(chǔ)存中使用的系統(tǒng)。有關(guān)液體或半液體原料藥包裝組件的特殊考慮，請(qǐng)參見第3.4.1節(jié)。
3.RISK ASSESSMENT AND CONTROL OF EXTRACTABLES AND LEACHABLES
可提取物和浸出物的風(fēng)險(xiǎn)評(píng)估與控制
3.1 General Principles
3.1 一般原則
The purpose of the guideline is to provide a holistic framework whereby leachables-associated risk can be identified, assessed, and controlled to protect the safety, efficacy, and quality attributes of the finished drug product. Figure 1 is intended to inform product development considerations leading up to product registration as well as continuous quality management process throughout lifecycle management.
本指南的目的是提供一個(gè)全面的框架，通過(guò)該框架可以識(shí)別、評(píng)估和控制與浸出物相關(guān)的風(fēng)險(xiǎn)，以保障成品藥的安全性、有效性和質(zhì)量屬性。圖 1 旨在為產(chǎn)品注冊(cè)前的開發(fā)考量以及整個(gè)生命周期管理中的持續(xù)質(zhì)量管理流程提供指導(dǎo)。
Figure 1: Overview of the Risk Management Process
(E&L = Extractables and Leachables)
圖 1：風(fēng)險(xiǎn)管理流程概述
（E&L = 可提取物與可浸出物）
The quality risk management process for E&L warrants a holistic strategy, leveraging prior knowledge and a thorough understanding of the desirable and critical attributes for the manufacturing/packaging components and drug product, as well as the manufacturing and storage conditions. Close collaboration between the analytical chemist(s) and safety expert(s) is essential for knowledge sharing and development of the E&L quality risk management process. A Quality Risk Management Process should be initiated with every product, each with its own Risk Assessment, Risk Control and Lifecycle Management process.
可提取物和浸出物（E&L）的質(zhì)量風(fēng)險(xiǎn)管理過(guò)程需要一種全面的策略，該策略應(yīng)利用已有知識(shí)，并充分理解生產(chǎn) / 包裝組件和藥品的理想屬性及關(guān)鍵屬性，以及生產(chǎn)和儲(chǔ)存條件。分析化學(xué)家與安全專家之間的密切合作對(duì)于知識(shí)共享和 E&L 質(zhì)量風(fēng)險(xiǎn)管理流程的制定至關(guān)重要。每個(gè)產(chǎn)品都應(yīng)啟動(dòng)質(zhì)量風(fēng)險(xiǎn)管理流程，且每個(gè)產(chǎn)品都有其自身的風(fēng)險(xiǎn)評(píng)估、風(fēng)險(xiǎn)控制和生命周期管理過(guò)程。
3.2 Risk Matrix as a Multifactorial Concept
3.2 作為多因素概念的風(fēng)險(xiǎn)矩陣
For the overall risk assessment and control of leachables, it is important to consider the multidimensional nature of risk, entailing both pharmaceutical quality and safety aspects. With respect to pharmaceutical quality, important dimensions include:
對(duì)于浸出物的整體風(fēng)險(xiǎn)評(píng)估和控制，必須考慮風(fēng)險(xiǎn)的多維度性質(zhì)，這既涉及藥品質(zhì)量方面，也涉及安全方面。就藥品質(zhì)量而言，重要的維度包括
The potential for interaction between manufacturing equipment or packaging component and the formulation,
生產(chǎn)設(shè)備或包裝組件與制劑之間發(fā)生相互作用的可能性；
The chemical and physical properties of the equipment or component that likely contribute to leachables, and pre-treatment of components prior to use,
可能導(dǎo)致浸出物產(chǎn)生的設(shè)備或組件的化學(xué)和物理性質(zhì)，以及組件使用前的預(yù)處理情況；
The manufacturing and storage conditions, including but not limited to, surface area to solution volume ratio, temperature, duration of contact, proximity of the downstream removal steps and their capacity to deplete potential leachables.
生產(chǎn)和儲(chǔ)存條件，包括但不限于表面積與溶液體積比、溫度、接觸時(shí)間、下游去除步驟的接近程度及其清除潛在浸出物的能力；
The leaching propensity of the formulation, including but not limited to API, pH, organic co-solvents and surfactant/chelating agents.
制劑的浸出傾向，包括但不限于原料藥（API）、pH 值、有機(jī)助溶劑以及表面活性劑 / 螯合劑。
Safety assessment dimensions relate to the potential harms posed by leachables, inclusive of exposure-related factors such as the risk impact of the route(s) of administration, pertinent patient population(s), maximal dosing, dosing frequency and/or intervals, and maximum potential treatment duration in a lifetime.
安全評(píng)估維度涉及浸出物可能造成的潛在危害，包括與暴露相關(guān)的因素，如給藥途徑的風(fēng)險(xiǎn)影響、相關(guān)患者人群、最大劑量、給藥頻率和 / 或間隔，以及一生中潛在的最長(zhǎng)治療持續(xù)時(shí)間。
The relative risks associated with various dimensions (not all inclusive) are shown in Figure 2. The overall risk of a drug product is determined by taking all those dimensions into consideration.
圖 2 展示了與各個(gè)維度（并非全部）相關(guān)的相對(duì)風(fēng)險(xiǎn)。藥品的整體風(fēng)險(xiǎn)需綜合考慮所有這些維度后確定。
Figure 2: Overview on Aspects to Consider for Risk Matrix
CSF = Cerebrospinal fluid; DP = Drug product; IM = Intramuscular; IV = Intravenous; SC = Subcutaneous
圖 2：風(fēng)險(xiǎn)矩陣需考量方面概述
（CSF = 腦脊液；DP = 藥品；IM = 肌內(nèi)（注射）；IV = 靜脈（注射）；SC = 皮下（注射） ）
Depending on the anticipated risk and leveraging prior knowledge, various approaches can be adopted ranging from compliance with relevant food-contact safety or pharmacopeial standards/regulations to more extensive E&L characterization and safety risk assessment (See Appendix 1). For oral drug products, compliance with relevant regional food-contact safety regulations may be sufficient to support the safety and quality of polymeric manufacturing equipment/systems and container closure systems if adequately justified (e.g., proposed use is consistent with regional regulations for food contact use, the leaching propensity of the drug product is similar or less than those listed in a referenced regional regulation, and all specified testing results meet acceptance criteria). For all other drug products, or for oral products that do not comply with the regulations for food contact in terms of composition, specification, and in-use limitations, extractable/leachable assessments are typically warranted.
根據(jù)預(yù)期風(fēng)險(xiǎn)并利用已有知識(shí)，可采用多種方法，從遵守相關(guān)食品接觸安全標(biāo)準(zhǔn)或藥典標(biāo)準(zhǔn) / 法規(guī)，到更廣泛的可提取物和浸出物（E&L）表征及安全風(fēng)險(xiǎn)評(píng)估（見附錄 1）。對(duì)于口服藥品，若有充分的正當(dāng)理由（例如，擬用用途符合地區(qū)食品接觸用途法規(guī)，藥品的浸出傾向與參考地區(qū)法規(guī)中所列的相似或更低，且所有規(guī)定的測(cè)試結(jié)果均滿足驗(yàn)收標(biāo)準(zhǔn)），遵守相關(guān)地區(qū)的食品接觸安全法規(guī)可能足以支持 polymeric 生產(chǎn)設(shè)備 / 系統(tǒng)和容器密封系統(tǒng)的安全性與質(zhì)量。對(duì)于所有其他藥品，或在成分、規(guī)格和使用限制方面不符合食品接觸法規(guī)的口服藥品，通常需要進(jìn)行可提取物 / 浸出物評(píng)估。
The risk matrix and factors described above highlight the complexity of the risks associated with a leachables assessment. Understanding the respective risk level of the corresponding factors is part of the risk assessment process and may inform manufacturing and packaging components selection as well as the development of an overall risk assessment/control strategy.
上述風(fēng)險(xiǎn)矩陣和因素凸顯了與浸出物評(píng)估相關(guān)的風(fēng)險(xiǎn)的復(fù)雜性。了解相應(yīng)因素各自的風(fēng)險(xiǎn)水平是風(fēng)險(xiǎn)評(píng)估過(guò)程的一部分，可能會(huì)為生產(chǎn)和包裝組件的選擇以及整體風(fēng)險(xiǎn)評(píng)估 / 控制策略的制定提供依據(jù)。
3.3 Risk Assessment
3.3 風(fēng)險(xiǎn)評(píng)估
Based on the descriptions of the Risk Management Process (Figure 1, Section 3.1), the Multidimensional Risk Matrix (Figure 2, Section 3.2) and the Typical Workflows for E&L risk assessment and risk control (Figures 4 and 5, Appendix 1) risk assessment can be summarized in three basic steps:
根據(jù)風(fēng)險(xiǎn)管理流程（圖 1，第 3.1 節(jié)）、多維度風(fēng)險(xiǎn)矩陣（圖 2，第 3.2 節(jié)）以及 E&L 風(fēng)險(xiǎn)評(píng)估和風(fēng)險(xiǎn)控制的典型工作流程（圖 4 和圖 5，附錄 1）的描述，風(fēng)險(xiǎn)評(píng)估可概括為三個(gè)基本步驟
Step 1 - Hazard Identification: Identify potential leachables that may migrate into the drug product from direct (e.g., manufacturing components/systems, container/closure systems and delivery devices components) or indirect (e.g., secondary packaging, ink or adhesives on labels particularly for semi-permeable components) contact surfaces based upon prior knowledge (experience with component, prior testing, etc.) and/or extractables and leachables testing.
步驟 1 - 危害識(shí)別基于已有知識(shí)（組件使用經(jīng)驗(yàn)、先前測(cè)試等）和 / 或可提取物與浸出物測(cè)試，識(shí)別可能從直接接觸表面（例如，生產(chǎn)組件 / 系統(tǒng)、容器 / 密封系統(tǒng)和給藥裝置組件）或間接接觸表面（例如，次級(jí)包裝、標(biāo)簽上的油墨或粘合劑，特別是對(duì)于半滲透性組件）遷移到藥品中的潛在浸出物。
Step 2 - Risk Analysis: Quantitate the potential occurrence of leachables in the drug product and assess the patient exposure to leachables.
步驟 2 - 風(fēng)險(xiǎn)分析量化藥品中浸出物的潛在出現(xiàn)情況，并評(píng)估患者對(duì)浸出物的暴露量。
Step 3 – Integrated Risk Evaluation: Evaluate the potential risk to impact product quality, safety and efficacy to determine if the selected manufacturing components/systems and container/closure systems are considered qualified for the intended use.·
步驟 3 - 綜合風(fēng)險(xiǎn)評(píng)價(jià)評(píng)估可能影響產(chǎn)品質(zhì)量、安全性和有效性的潛在風(fēng)險(xiǎn)，以確定所選生產(chǎn)組件 / 系統(tǒng)和容器 / 密封系統(tǒng)是否被認(rèn)為適合預(yù)期用途。
3.4 Risk Control
3.4 風(fēng)險(xiǎn)控制
If the comprehensive risk assessment indicates risk mitigation is needed, measures may include, but are not limited to, change of components/suppliers, pre-wash of components, pre-flushing of manufacturing equipment, and adding additional purification/isolation step(s). The adequacy of the mitigation measures ultimately implemented should be confirmed/verified via extractable and/or leachable studies.
如果綜合風(fēng)險(xiǎn)評(píng)估表明需要降低風(fēng)險(xiǎn)，所采取的措施可能包括但不限于更換組件 / 供應(yīng)商、組件預(yù)清洗、生產(chǎn)設(shè)備預(yù)沖洗以及增加額外的純化 / 分離步驟。最終實(shí)施的緩解措施的充分性應(yīng)通過(guò)可提取物和 / 或浸出物研究進(jìn)行確認(rèn) / 驗(yàn)證。
Once the components are qualified for the intended use, a control strategy should be implemented. This comprises, but is not limited, to routine GMP practices which are imperative for component quality controls. A control strategy should be in place to:
一旦組件被確認(rèn)適合預(yù)期用途，就應(yīng)實(shí)施控制策略。這包括但不限于常規(guī)的 GMP 實(shí)踐，這對(duì)組件質(zhì)量控制至關(guān)重要。應(yīng)制定控制策略以
Establish adequate acceptance quality control including acceptance criteria, analytical procedures, and sampling plan for components as appropriate.
建立充分的驗(yàn)收質(zhì)量控制，包括適當(dāng)?shù)慕M件驗(yàn)收標(biāo)準(zhǔn)、分析程序和取樣計(jì)劃。
Establish appropriate quality agreement with component venders including component lifecycle quality controls regarding any composition and/or fabrication process changes that might have impact on the extractable profiles.
與組件供應(yīng)商建立適當(dāng)?shù)馁|(zhì)量協(xié)議，包括關(guān)于可能影響可提取物特征的任何成分和 / 或制造工藝變更的組件生命周期質(zhì)量控制。
See Appendix 1 for typical workflows for E&L risk assessment and risk control, including component qualifications for manufacturing components/systems (Figure 4, Appendix 1) and for packaging and delivery device components (Figure 5, Appendix 1). Typically, extractable and leachable studies should be conducted for packaging and delivery device components. Under certain circumstances alternative approaches may be proposed with proper justifications.·
有關(guān) E&L 風(fēng)險(xiǎn)評(píng)估和風(fēng)險(xiǎn)控制的典型工作流程，包括生產(chǎn)組件 / 系統(tǒng)的組件確認(rèn)（附錄 1，圖 4）以及包裝和給藥裝置組件的確認(rèn)（附錄 1，圖 5），請(qǐng)參見附錄 1。通常，應(yīng)對(duì)包裝和給藥裝置組件進(jìn)行可提取物和浸出物研究。在某些情況下，可在有充分正當(dāng)理由的前提下提出替代方法。
The principles and practices used for identifying risk and developing mitigation strategies to address safety concerns associated with packaging and delivery device components are also applicable to formulation contacting manufacturing equipment components made of polymeric materials. Extractables studies should therefore be designed to represent the worst-case scenario of the manufacturing conditions (e.g., smallest scale with longest contact durations, highest temperature and pressure). It is recognized that the potential for leachables in a drug product originating from the manufacturing components/systems is lower than that from the packaging and delivery components, due to relatively shorter contacting time with the formulation and larger solution volume to surface area ratio. Leachables introduced in upstream manufacturing process steps might be able to be purged through downstream steps, e.g. purification/polish, lowering the risk for leachables ending up in the final drug product. These factors should be taken into consideration for manufacturing equipment selection and qualification, as well as quality investigations.
用于識(shí)別風(fēng)險(xiǎn)和制定緩解策略以解決與包裝和給藥裝置組件相關(guān)的安全問(wèn)題的原則和實(shí)踐，也適用于與制劑接觸的 polymeric 材料生產(chǎn)設(shè)備組件。因此，可提取物研究的設(shè)計(jì)應(yīng)能代表生產(chǎn)條件的最壞情況（例如，最小規(guī)模、最長(zhǎng)接觸時(shí)間、最高溫度和壓力）。眾所周知，由于與制劑的接觸時(shí)間相對(duì)較短且溶液體積與表面積比較大，藥品中源自生產(chǎn)組件 / 系統(tǒng)的浸出物潛力低于源自包裝和給藥組件的浸出物潛力。在 upstream 生產(chǎn)工藝步驟中引入的浸出物可能會(huì)通過(guò)下游步驟（例如純化 / 精制）被清除，從而降低浸出物最終進(jìn)入成品藥的風(fēng)險(xiǎn)。在選擇和確認(rèn)生產(chǎn)設(shè)備以及進(jìn)行質(zhì)量調(diào)查時(shí)，應(yīng)考慮這些因素。
For manufacturing components/systems, the leachables risk may be considered minimal and acceptable when all extractables peaks are at or below the Analytical Evaluation Threshold (AET) applicable to the drug product and no Class 1 leachables are observed (see Section 5). The analytical procedures used in extraction studies should comply with the criteria provided in Section 4.3.
對(duì)于生產(chǎn)組件 / 系統(tǒng)，當(dāng)所有可提取物峰均等于或低于適用于該藥品的分析評(píng)估閾值（AET）且未觀察到 1 類浸出物時(shí)（見第 5 節(jié)），浸出物風(fēng)險(xiǎn)可被認(rèn)為是最小且可接受的。提取研究中使用的分析程序應(yīng)符合第 4.3 節(jié)規(guī)定的標(biāo)準(zhǔn)。
In cases where manufacturing components/systems extractables are observed in concentrations above the AET, an identification of those extractables and quantification of the concentrations may be conducted to mitigate the leachables risk as long as the quantification of extractables is performed against appropriate reference standards of the same identity as the identified extractables. However, if authentic reference standards do not exist, compounds with a similar analytical response can be employed. If extractables concentrations quantified in this manner are below the relevant acceptable safety level (see Section 6), then the safety concern associated with leachables risk is considered negligible. As an alternative to qualification of extractables from manufacturing equipment at concentrations above the AET, a safety assessment of leachables may be performed.
如果觀察到生產(chǎn)組件 / 系統(tǒng)的可提取物濃度高于 AET，只要根據(jù)與已識(shí)別可提取物具有相同特性的適當(dāng)參考標(biāo)準(zhǔn)對(duì)可提取物進(jìn)行定量，就可以對(duì)這些可提取物進(jìn)行識(shí)別和濃度定量，以降低浸出物風(fēng)險(xiǎn)。然而，如果沒有真實(shí)的參考標(biāo)準(zhǔn)，可以使用具有相似分析響應(yīng)的化合物。如果以這種方式定量的可提取物濃度低于相關(guān)的可接受安全水平（見第 6 節(jié)），則與浸出物風(fēng)險(xiǎn)相關(guān)的安全擔(dān)憂被認(rèn)為是可忽略的。作為對(duì)生產(chǎn)設(shè)備中濃度高于 AET 的可提取物進(jìn)行確認(rèn)的替代方法，可以對(duì)浸出物進(jìn)行安全評(píng)估。
For a packaging component/system an abbreviated data package may be considered when patient safety risk can be adequately mitigated by prior knowledge, (e.g. established extractable/leachable correlation, similar drug product with similar leaching propensity to approved drug product formulation), or no/few extractables detected above the AET and below their applicable safety threshold (such as Class 3 leachables; See Section 6). Table A.1.2 (Appendix 1) provides examples where the overall risk is considered low, in relation to Figure 2 (Section 3.2), and an abbreviated data package may be warranted with adequate justification. When an abbreviated data package is proposed, communications with relevant regional Regulatory Agency/Health Authority is recommended to align on approach.
對(duì)于包裝組件 / 系統(tǒng)，當(dāng)通過(guò)已有知識(shí)（例如，已建立的可提取物 / 浸出物相關(guān)性、與已獲批藥品配方具有相似浸出傾向的類似藥品）可充分降低患者安全風(fēng)險(xiǎn)，或者未檢測(cè)到或僅檢測(cè)到少量高于 AET 但低于其適用安全閾值的可提取物（如 3 類浸出物；見第 6 節(jié)）時(shí)，可以考慮采用簡(jiǎn)化數(shù)據(jù)包。表 A.1.2（附錄 1）提供了與圖 2（第 3.2 節(jié)）相關(guān)的、總體風(fēng)險(xiǎn)被認(rèn)為較低且有充分理由可采用簡(jiǎn)化數(shù)據(jù)包的示例。當(dāng)提出采用簡(jiǎn)化數(shù)據(jù)包時(shí)，建議與相關(guān)地區(qū)的監(jiān)管機(jī)構(gòu) / 衛(wèi)生當(dāng)局溝通，以統(tǒng)一方法。
If identified extractables are likely to chemically transform into compounds with a higher safety risk (i.e. through chemical degradation and/or interaction with formulation components to generate compounds with a higher safety risk), or if not all extractable peaks above the applicable AET can be adequately identified and/or quantified, a leachable study should be conducted to address these concerns and demonstrate acceptability of the components.
如果已識(shí)別的可提取物可能通過(guò)化學(xué)降解和 / 或與制劑成分相互作用轉(zhuǎn)化為具有更高安全風(fēng)險(xiǎn)的化合物，或者并非所有高于適用 AET 的可提取物峰都能被充分識(shí)別和 / 或定量，則應(yīng)進(jìn)行浸出物研究，以解決這些問(wèn)題并證明組件的可接受性。
3.4.1 Special Considerations
3.4.1 特殊考慮因素
When multiple manufacturing components, especially those constructed with the same or similar material are used, the cumulative leachables risk should be assessed.
Quality risk assessment and derived control strategies, when appropriate, should also encompass potential leachables from a container used to store a liquid or semi-solid drug substance.
當(dāng)使用多個(gè)生產(chǎn)組件，特別是由相同或相似材料制成的組件時(shí)，應(yīng)評(píng)估累積的浸出物風(fēng)險(xiǎn)。
質(zhì)量風(fēng)險(xiǎn)評(píng)估及由此制定的控制策略在適當(dāng)時(shí)還應(yīng)包括用于儲(chǔ)存液體或半固體原料藥的容器中可能存在的浸出物。
Although minimal leaching occurs in the frozen state, the potential for leaching from storage component/system should be evaluated before freezing and after thawing.
In addition, for biological and biotechnology-derived products risk identification and mitigation may also include:
盡管在冷凍狀態(tài)下浸出量極少，但應(yīng)在冷凍前和解凍后評(píng)估儲(chǔ)存組件 / 系統(tǒng)的浸出潛力。
此外，對(duì)于生物制品和生物技術(shù)衍生產(chǎn)品，風(fēng)險(xiǎn)識(shí)別和緩解可能還包括
Evaluation of the potential interactions between reactive leachables and formulation components that may lead to potentially adverse impact on product quality, safety, and/or efficacy. If impacts to critical quality attributes of the product by known reactive leachables are identified, potential mechanisms of chemical modification should be considered (such as denaturation, aggregation or degradation).
評(píng)估反應(yīng)性浸出物與制劑成分之間的潛在相互作用，此類相互作用可能對(duì)產(chǎn)品質(zhì)量、安全性和 / 或有效性產(chǎn)生潛在不利影響。如果發(fā)現(xiàn)已知的反應(yīng)性浸出物對(duì)產(chǎn)品的關(guān)鍵質(zhì)量屬性有影響，則應(yīng)考慮化學(xué)修飾的潛在機(jī)制（如變性、聚集或降解）。
For manufacturing of drug substance, leachables may be removed during the last purification step. Therefore, the quality risk assessment will typically focus on subsequent manufacturing processes.·
在原料藥生產(chǎn)過(guò)程中，浸出物可能在最后的純化步驟中被去除。因此，質(zhì)量風(fēng)險(xiǎn)評(píng)估通常會(huì)側(cè)重于后續(xù)的生產(chǎn)工藝。
3.5 Documentation and Compliance
3.5 文件記錄與合規(guī)性
Registration applications should include the justification for the extractable/leachable studies conducted, the associated study reports, the safety assessment of substances above the AET and any requisite risk control strategy. Extractables and leachables studies conducted to support the acceptability of manufacturing and packaging components/systems should be included in filing submissions (as described in ICH M4Q) as applicable. Adequate leachable data should be provided to address safety and quality concerns throughout the drug product’s shelf life. It is generally acceptable to submit leachable study results aligned with available stability data, with the provision to submit additional data post-authorization, subject to prior concurrence with the relevant regional regulatory authority. The quality risk assessment as defined in Section 3.3 of this guidance should be conducted on single-use and multi-use manufacturing components/systems, primary packaging components and delivery device components. For semi-permeable packaging materials, secondary packaging should also be evaluated as applicable.
注冊(cè)申請(qǐng)應(yīng)包括所進(jìn)行的可提取物 / 浸出物研究的理由、相關(guān)的研究報(bào)告、高于分析評(píng)估閾值（AET）的物質(zhì)的安全性評(píng)估以及任何必要的風(fēng)險(xiǎn)控制策略。為支持生產(chǎn)和包裝組件 / 系統(tǒng)的可接受性而開展的可提取物和浸出物研究，應(yīng)根據(jù)適用情況納入申報(bào)材料中（如 ICH M4Q 所述）。應(yīng)提供充分的浸出物數(shù)據(jù)，以解決藥品在整個(gè)保質(zhì)期內(nèi)的安全性和質(zhì)量問(wèn)題。提交與現(xiàn)有穩(wěn)定性數(shù)據(jù)一致的浸出物研究結(jié)果通常是可接受的，前提是在獲得批準(zhǔn)后可提交補(bǔ)充數(shù)據(jù)，但需事先獲得相關(guān)地區(qū)監(jiān)管機(jī)構(gòu)的同意。本指南第 3.3 節(jié)中定義的質(zhì)量風(fēng)險(xiǎn)評(píng)估應(yīng)針對(duì)一次性和多次使用的生產(chǎn)組件 / 系統(tǒng)、 primary 包裝組件和給藥裝置組件進(jìn)行。對(duì)于半滲透性包裝材料，還應(yīng)根據(jù)適用情況對(duì)次級(jí)包裝進(jìn)行評(píng)估。
A list of extractables and leachables studies conducted should be included along with an assessment report which will typically include analytical method and extraction condition selections along with justifications (solvents, temperature, duration, surface/volume ratio, etc.) for extractables studies and a description of the sample preparation and analytical procedures for leachables studies. In addition, the quantification procedure(s) should be described including the suitability of the procedures used for quantification (e.g., limit of detection (LOD), limit of quantification (LOQ), specificity, linearity, accuracy, and repeatability). All extractables and leachables peaks above the AET (see Section 5) should be included in the filing submission with chemical name, structure, CAS Registry Number (if available) and observed level. For leachables (or extractables when such testing is used for qualification), safety risk assessment as described in Section 6 should be included.
申報(bào)材料中應(yīng)包含所進(jìn)行的可提取物和浸出物研究的清單以及評(píng)估報(bào)告，評(píng)估報(bào)告通常應(yīng)包括分析方法和提取條件的選擇，以及可提取物研究的理由（溶劑、溫度、時(shí)間、表面積 / 體積比等），并描述浸出物研究的樣品制備和分析程序。此外，還應(yīng)描述定量程序，包括用于定量的程序的適用性（如檢測(cè)限（LOD）、定量限（LOQ）、特異性、線性、準(zhǔn)確度和精密度）。所有高于 AET（見第 5 節(jié)）的可提取物和浸出物峰都應(yīng)納入申報(bào)材料，并注明化學(xué)名稱、結(jié)構(gòu)、CAS 登記號(hào)（如可用）和觀測(cè)水平。對(duì)于浸出物（或用于確認(rèn)的可提取物測(cè)試），應(yīng)包含第 6 節(jié)所述的安全風(fēng)險(xiǎn)評(píng)估。
In addition to the quality risk assessment, a leachables to extractables correlation should be included in the registration application, as appropriate (refer to Section 4.6). Finally, the adequacy of any proposed mitigation measures (for example prewashing of the packaging and delivery components/system or pre-flushing of the manufacturing components/systems) should be demonstrated by data collected before and after implementation.
除質(zhì)量風(fēng)險(xiǎn)評(píng)估外，注冊(cè)申請(qǐng)中還應(yīng)酌情包含浸出物與可提取物的相關(guān)性分析（參見第 4.6 節(jié)）。最后，任何擬議的緩解措施（例如包裝和給藥組件 / 系統(tǒng)的預(yù)清洗或生產(chǎn)組件 / 系統(tǒng)的預(yù)沖洗）的充分性應(yīng)通過(guò)實(shí)施前后收集的數(shù)據(jù)來(lái)證明。
3.6 Risk Review / Lifecycle Management
3.6 風(fēng)險(xiǎn)審查 / 生命周期管理
This section describes the types of changes that might necessitate re-evaluation of the leachable profile during the lifecycle of the drug. The following is a non-exhaustive list of potential changes and an explanation of how these represent a potential to impact the patient leachable exposure. As such, these changes should be considered and justified scientifically using new studies and/or existing information sources.
本節(jié)描述了在藥品生命周期中可能需要重新評(píng)估浸出物特征的變更類型。以下是一份非詳盡的潛在變更清單，并解釋了這些變更如何可能影響患者對(duì)浸出物的暴露量。因此，應(yīng)通過(guò)新的研究和 / 或現(xiàn)有信息來(lái)源，對(duì)這些變更進(jìn)行科學(xué)考量和論證。
New Information: If new data and/or information on a material pertinent to its suitability for use indicates a cause for concern and/or if new patient safety information for a leachable becomes available, an updated assessment may be warranted.
新信息如果關(guān)于某一材料適用性的新數(shù)據(jù)和 / 或信息表明存在擔(dān)憂因素，和 / 或出現(xiàn)了關(guān)于某一浸出物的新的患者安全信息，則可能需要進(jìn)行更新的評(píng)估。
Changes to a drug product formulation: Changes to the drug product may cause different leachables from the existing formulation contacting manufacturing components/systems and/or primary packaging and/or delivery device components. For example, changes to excipients/surfactants composition or concentrations can affect both the composition and amount of leachables.
藥品配方的變更藥品的變更可能導(dǎo)致與現(xiàn)有配方接觸的生產(chǎn)組件 / 系統(tǒng)和 / 或 primary 包裝和 / 或給藥裝置組件產(chǎn)生不同的浸出物。例如，輔料 / 表面活性劑的成分或濃度變化可能會(huì)影響浸出物的成分和量。
Changes to container closure system, delivery device, or manufacturing components/systems that contact drug substance and/or drug product: When there are known changes such as the composition, supplier, manufacturing process, geometry or pretreatment of materials contacting the drug substance (mainly for liquids and/or biologics) or drug product during the shelf-life of the drug, there is a potential for an altered leachable profile. In addition, for some products there may be a potential for non-direct packaging components to contribute potential leachables to the drug product.
容器密封系統(tǒng)、給藥裝置或與原料藥和 / 或藥品接觸的生產(chǎn)組件 / 系統(tǒng)的變更當(dāng)在藥品保質(zhì)期內(nèi)，與原料藥（主要是液體和 / 或生物制品）或藥品接觸的材料在成分、供應(yīng)商、生產(chǎn)工藝、幾何形狀或預(yù)處理等方面發(fā)生已知變更時(shí)，浸出物特征可能會(huì)發(fā)生改變。此外，對(duì)于某些產(chǎn)品，非直接接觸的包裝組件也可能向藥品中引入潛在浸出物。
Changes to a manufacturing process: Changes to process conditions may cause different leachables or different amounts of leachables from the existing formulation contact material. For example, change in solvent system, duration, temperature, pressure, pH, cleaning/sterilization process, surface area/volume ratio, pre-operation preparation (e.g., flushing), amongst others can affect both the composition and amount of leachables.
生產(chǎn)工藝的變更工藝條件的變更可能導(dǎo)致與現(xiàn)有配方接觸材料產(chǎn)生不同的浸出物或不同量的浸出物。例如，溶劑系統(tǒng)、時(shí)間、溫度、壓力、pH 值、清潔 / 滅菌工藝、表面積 / 體積比、操作前準(zhǔn)備（如沖洗）等方面的變化，都可能影響浸出物的成分和量。
Changes that might affect patient exposure: Changes such as the posology of the drug, duration of treatment, route of administration and patient population (i.e., geriatric/pediatric) have the potential to change estimates of patient exposure to previously identified leachables, which may all affect the fundamental assumptions made in the exposure assessment and toxicological risk assessment of leachables.
可能影響患者暴露量的變更藥品的劑量學(xué)、治療持續(xù)時(shí)間、給藥途徑和患者人群（如老年 / 兒科患者）等方面的變更，可能會(huì)改變對(duì)患者接觸先前已識(shí)別浸出物的估計(jì)，這些都可能影響在浸出物的暴露評(píng)估和毒理學(xué)風(fēng)險(xiǎn)評(píng)估中所做的基本假設(shè)。
Changes in indication that might affect patient benefit:risk: e.g. oncology to rheumatological disorders.
可能影響患者獲益風(fēng)險(xiǎn)比的適應(yīng)癥變更例如，從腫瘤學(xué)到風(fēng)濕病。
4.CHEMICAL TESTING AND ASSESSMENT
化學(xué)測(cè)試與評(píng)估
4.1 Prior Knowledge
4.1 已有知識(shí)
Prior knowledge may comprise information useful to obtain before performing chemical testing, including information available from a supplier and any relevant information with regard to other drug products and processes. This information may include:
已有知識(shí)可能包括在進(jìn)行化學(xué)測(cè)試前需獲取的有用信息，包括可從供應(yīng)商處獲得的信息以及與其他藥品和工藝相關(guān)的任何信息。這些信息可能包括
composition (e.g., base polymer and copolymer, any known additives such as plasticizers, processing aids, catalysts, antioxidants)
成分（如基礎(chǔ)聚合物和共聚物、任何已知的添加劑，如增塑劑、加工助劑、催化劑、抗氧化劑）
food contact compliance
食品接觸合規(guī)性
statements indicating particular (e.g., non-authorized) compounds have not been intentionally added
表明未有意添加特定（如未經(jīng)授權(quán)的）化合物的聲明
compendial testing
藥典測(cè)試
any available extractables studies
任何可用的可提取物研究
biological reactivity testing
生物反應(yīng)性測(cè)試
processing or pretreatment steps (e.g., sterilization, cleaning, flushing, siliconization, surface treatments)
加工或預(yù)處理步驟（如滅菌、清潔、沖洗、硅化、表面處理）
prior use history, including any historical use with other similar drug products, process and/or contact conditions
既往使用歷史，包括與其他類似藥品、工藝和 / 或接觸條件的任何歷史使用情況
4.2 Component Selection
4.2 組件選擇
A pharmaceutical product manufacturer is responsible for establishing requirements in alignment with regulatory expectations for the manufacturing, packaging, storage, and delivery of a unique drug product safely and effectively to an intended patient population. The level of risk for a particular material or component is relevant to the potential for interaction with the dosage form. For example, components that interact with dosage forms exhibiting a greater propensity for leaching (e.g., liquids) may be considered of higher risk than components that interact with dosage forms which exhibit a minimal propensity for leaching (e.g., non-lyophilized solids). The information obtained from the supplier (e.g., extractables report, compliance with compendial requirements) may be supplemented with additional testing appropriate for conducting a risk assessment and developing extractables/leachables procedures to demonstrate acceptable component selection. See Table A.2.1 (in Appendix 2) for a summary of extractable, leachable and simulated leachable studies.
藥品制造商有責(zé)任根據(jù)監(jiān)管要求，制定用于安全有效地向目標(biāo)患者群體生產(chǎn)、包裝、儲(chǔ)存和配送特定藥品的要求。特定材料或組件的風(fēng)險(xiǎn)水平與其與劑型的潛在相互作用有關(guān)。例如，與具有較高浸出傾向的劑型（如液體）接觸的組件，可能被認(rèn)為比與具有最小浸出傾向的劑型（如非凍干固體）接觸的組件風(fēng)險(xiǎn)更高。從供應(yīng)商處獲得的信息（如可提取物報(bào)告、符合藥典要求的證明）可輔以適當(dāng)?shù)念~外測(cè)試，這些測(cè)試適用于進(jìn)行風(fēng)險(xiǎn)評(píng)估和制定可提取物 / 浸出物程序，以證明組件選擇的可接受性?？商崛∥铩⒔鑫锖湍M浸出物研究的摘要參見附錄 2 中的表 A.2.1。
4.3 Extractable Study
4.3 可提取物研究
An extractable study is a process by which chemical entities are extracted from a test article. An adequate extractables study incorporates solvents and extraction conditions relevant to the anticipated leaching propensity of the drug product formulation under the worst-case scenario of manufacturing or storage conditions and employs multiple complementary analytical techniques to establish a comprehensive extractables profile. Key characteristics of an adequate extraction study include:
可提取物研究是從測(cè)試樣品中提取化學(xué)物質(zhì)的過(guò)程。充分的可提取物研究應(yīng)采用與藥品配方在生產(chǎn)或儲(chǔ)存條件最壞情況下的預(yù)期浸出傾向相關(guān)的溶劑和提取條件，并采用多種互補(bǔ)的分析技術(shù)來(lái)建立全面的可提取物特征。充分的提取研究的關(guān)鍵特征包括
Establishment and application of a drug product-specific AET to indicate extractable chemical entities to be identified and treated as potential leachables. Testing is performed on components or an assembled system including any processing and treatment (e.g., sterilization, molding and fabrication conditions, cleaning, siliconization) that would be representative of the final, finished component or system as intended for use
建立并應(yīng)用特定于藥品的 AET，以指示需要識(shí)別并視為潛在浸出物的可提取化學(xué)物質(zhì)。測(cè)試在組件或組裝系統(tǒng)上進(jìn)行，包括任何能代表最終成品組件或系統(tǒng)預(yù)期用途的加工和處理（如滅菌、成型和制造條件、清潔、硅化）
Proper extraction media selection, including appropriate solvents of varying pH and polarity relevant to and representative of the drug product formulation (e.g. excipients, surfactants)
適當(dāng)選擇提取介質(zhì)，包括與藥品配方相關(guān)且具有代表性的不同 pH 值和極性的適當(dāng)溶劑（如輔料、表面活性劑）
Represents the drug product specific worst-case scenario for leachables occurring during manufacturing or arising from packaging components/systems during shelf life (e.g., contact area, temperature, duration)
代表藥品在生產(chǎn)過(guò)程中產(chǎn)生的或在保質(zhì)期內(nèi)源自包裝組件 / 系統(tǒng)的浸出物的特定最壞情況（如接觸面積、溫度、時(shí)間）
The analytical procedures used are adequately qualified at a level commensurate with the purpose of the extraction study
所使用的分析程序在與提取研究目的相稱的水平上得到充分驗(yàn)證
Includes appropriate analytical procedures for volatile, semi-volatile, and non-volatile organic extractables and elemental extractables
包括針對(duì)揮發(fā)性、半揮發(fā)性和非揮發(fā)性有機(jī)可提取物以及元素可提取物的適當(dāng)分析程序
The extractables report describes details on analytical procedures
可提取物報(bào)告描述分析程序的詳細(xì)信息
Specific targeted tests for potential Class 1 leachables (see Section 6.2 Leachables Classification) should be performed based on the understanding of the material of construction and quality; risk analysis should be performed as appropriate. Analysis of potential Class 1 leachables should follow the description of a quantitative extractables study (Section 4.3.2) or leachables study (Section 4.4).
基于對(duì)構(gòu)造材料和質(zhì)量的了解，應(yīng)對(duì)潛在的 1 類浸出物（見第 6.2 節(jié)浸出物分類）進(jìn)行特定的靶向測(cè)試；并應(yīng)酌情進(jìn)行風(fēng)險(xiǎn)分析。對(duì)潛在 1 類浸出物的分析應(yīng)遵循定量可提取物研究（第 4.3.2 節(jié)）或浸出物研究（第 4.4 節(jié)）的描述。
4.3.1 Semi-Quantitative Extractables Study
4.3.1 半定量可提取物研究
A semi-quantitative extractables study may be appropriate in scenarios where a leachables study will subsequently be conducted to establish the acceptability of materials for intended use. The purpose of a semi-quantitative extractables study is to understand which extractables can be present as leachables in the drug product. Key characteristics of the semi-quantitative extractables study include:
在后續(xù)將通過(guò)浸出物研究確定材料是否適合預(yù)期用途的情況下，半定量可提取物研究可能是合適的。半定量可提取物研究的目的是了解哪些可提取物可能作為浸出物存在于藥品中。半定量可提取物研究的關(guān)鍵特征包括
Analytical procedures that are qualified using several relevant standard compounds typically observed as extractables or leachables.
使用幾種通常被視為可提取物或浸出物的相關(guān)標(biāo)準(zhǔn)化合物對(duì)分析程序進(jìn)行驗(yàn)證。
Use of analytical uncertainty factor (UF; Section 5.1) in the calculation of the drug product-specific AET.
在計(jì)算特定于藥品的分析評(píng)估閾值（AET）時(shí)使用分析不確定度因子（UF；第 5.1 節(jié)）。
Quantification of observed extractables against relevant standard compounds.
根據(jù)相關(guān)標(biāo)準(zhǔn)化合物對(duì)觀察到的可提取物進(jìn)行定量。
Semi-quantitative extractables observed above the AET can subsequently be used as targets for a quantitative extractables study or a leachables study.·
觀察到的高于 AET 的半定量可提取物可隨后作為定量可提取物研究或浸出物研究的目標(biāo)。
4.3.2 Quantitative Extractables Study
4.3.2 定量可提取物研究
To support qualification of manufacturing components/systems and certain low-risk packaging components/systems scenarios (Refer to Appendix 1 Table A.1.1 and A.1.2, respectively) for which extractables were observed at a level above the AET during the semi-quantitative extractables study, a quantitative extractables study to quantify these specific extractables would be warranted. Key characteristics of quantitative extractables study include:
為支持生產(chǎn)組件 / 系統(tǒng)和某些低風(fēng)險(xiǎn)包裝組件 / 系統(tǒng)的確認(rèn)（分別參見附錄 1 表 A.1.1 和 A.1.2），若在半定量可提取物研究中觀察到可提取物水平高于 AET，則需要進(jìn)行定量可提取物研究以量化這些特定可提取物。定量可提取物研究的關(guān)鍵特征包括
Confirmed identification of extractables above the AET.
確認(rèn)識(shí)別出高于 AET 的可提取物。
Quantification of the identified extractables above the AET using standards with identical or similar analytical response.
使用具有相同或相似分析響應(yīng)的標(biāo)準(zhǔn)品對(duì)已識(shí)別的高于 AET 的可提取物進(jìn)行定量。
The analytical procedure used for quantifying the identified extractables above the AET should be qualified for the specific standard compound.
用于量化已識(shí)別的高于 AET 的可提取物的分析程序應(yīng)針對(duì)特定標(biāo)準(zhǔn)化合物進(jìn)行驗(yàn)證。
If the amount of an adequately identified and quantified extractable exceeds its qualification limit (e.g., applicable safety threshold or permitted daily exposure (PDE)), a leachables study is warranted to demonstrate the compound as a leachable remains below its qualification limit. In addition, a leachables study can also be used to assess the quality risk for extractables above the AET when those extractables cannot be identified with confirmed identities.·
如果充分識(shí)別和定量的可提取物量超過(guò)其確認(rèn)限度（如適用的安全閾值或允許日暴露量（PDE）），則需要進(jìn)行浸出物研究，以證明該化合物作為浸出物的水平仍低于其確認(rèn)限度。此外，當(dāng)無(wú)法確認(rèn)高于 AET 的可提取物的身份時(shí)，浸出物研究也可用于評(píng)估其質(zhì)量風(fēng)險(xiǎn)。
4.4 Leachables Study
4.4 浸出物研究
Leachables studies intended to support drug product registration are designed to represent the actual manufacturing conditions and intended storage conditions throughout the proposed shelf-life and in-use period. During the shelf life and in-use period, multiple time points should be evaluated to characterize trending of leachables to estimate maximal occurrence. The leachables assessment for the container closure system is performed on the actual drug product during stability storage and may include accelerated storage conditions. For a container closure system, the study should involve multiple primary drug product stability and/or development batches manufactured with the actual packaging and delivery system intended for use with the commercial product. If multiple batches are not available, alternative approaches may be proposed with justification. Use of the same lots of components used in extractables assessments potentially enables a more meaningful correlation between extractables and leachables. Analytical procedures for specific, targeted leachables should be appropriately validated to establish that they are sensitive, selective, accurate, and precise. Non-targeted screening procedures should also be used and employ appropriate analytical techniques to facilitate detection of any unanticipated degradation of leachables, leachables from secondary packaging, and/or interaction products. The non-targeted screening study should include the application of an AET (See Section 5) to indicate a level above which leachable chemical entities should be identified, quantified, and reported for toxicological assessment.
旨在支持藥品注冊(cè)的浸出物研究旨在模擬實(shí)際生產(chǎn)條件以及擬議保質(zhì)期和使用期間的預(yù)期儲(chǔ)存條件。在保質(zhì)期和使用期間，應(yīng)評(píng)估多個(gè)時(shí)間點(diǎn)以表征浸出物的趨勢(shì)，從而估計(jì)其最大出現(xiàn)量。容器密封系統(tǒng)的浸出物評(píng)估在藥品穩(wěn)定性儲(chǔ)存期間進(jìn)行，可能包括加速儲(chǔ)存條件。對(duì)于容器密封系統(tǒng)，研究應(yīng)涉及多個(gè)主要藥品穩(wěn)定性批次和 / 或開發(fā)批次，這些批次使用與商業(yè)產(chǎn)品預(yù)期一致的實(shí)際包裝和給藥系統(tǒng)生產(chǎn)。如果無(wú)法獲得多個(gè)批次，可在提供正當(dāng)理由的情況下提出替代方法。使用與可提取物評(píng)估相同批次的組件可能有助于在可提取物和浸出物之間建立更有意義的相關(guān)性。針對(duì)特定目標(biāo)浸出物的分析程序應(yīng)進(jìn)行適當(dāng)驗(yàn)證，以確保其靈敏、特異、準(zhǔn)確和精密。還應(yīng)使用非靶向篩選程序，并采用適當(dāng)?shù)姆治黾夹g(shù)，以促進(jìn)檢測(cè)任何未預(yù)期的浸出物降解、來(lái)自次級(jí)包裝的浸出物和 / 或相互作用產(chǎn)物。非靶向篩選研究應(yīng)應(yīng)用 AET（見第 5 節(jié)），以指示高于該水平的浸出化學(xué)物質(zhì)應(yīng)被識(shí)別、定量并報(bào)告以進(jìn)行毒理學(xué)評(píng)估。
Reference standards, if available, are preferred as they facilitate more accurate and precise quantitation of target leachables that may be present as actual drug product leachables when they are used to produce either proper response factors or calibration curves; in which case the analytical accuracy and precision is high.
如果有參考標(biāo)準(zhǔn)品，應(yīng)優(yōu)先使用，因?yàn)楫?dāng)它們用于生成適當(dāng)?shù)捻憫?yīng)因子或校準(zhǔn)曲線時(shí)，有助于更準(zhǔn)確和精密地定量可能作為藥品實(shí)際浸出物存在的目標(biāo)浸出物；在這種情況下，分析的準(zhǔn)確度和精密度較高。
4.5 Simulated Leachable Study
4.5 模擬浸出物研究
Circumstances may exist when performing a drug product leachables study is not technically feasible despite thorough due diligence which may include systematic investigation of multiple diverse sample preparation techniques coupled with highly sensitive and selective analytical methods, techniques and instrumentation. Such circumstances may include challenging detection or quantification thresholds associated with large volume parenterals (LVPs), significant analytical matrix interference inherent with complex drug product formulations, or a combination of such factors. In such situations, use of a simulation study to support actual drug product leachables evaluation may be justifiable. For example, a simulation study could be performed to augment a leachables study to accomplish the objectives that cannot be obtained by leachables testing. In the case of a challenging AET (i.e., procedure LOQ > AET), the leachables study would be performed with relevant test procedure LOQ and a simulation study would be performed to fill in the gap between the LOQ and the AET. Alternatively, a simulation study could be used to replace a leachables study when, through thorough due diligence, it is established that performing the leachables study is impractical.
盡管已盡到應(yīng)有的努力（可能包括系統(tǒng)研究多種不同的樣品制備技術(shù)，結(jié)合高靈敏度和高選擇性的分析方法、技術(shù)和儀器），但在某些情況下，進(jìn)行藥品浸出物研究在技術(shù)上仍不可行。此類情況可能包括與大容量注射劑（LVPs）相關(guān)的檢測(cè)或定量閾值挑戰(zhàn)、復(fù)雜藥品配方固有的顯著分析基質(zhì)干擾，或此類因素的組合。在這種情況下，使用模擬研究來(lái)支持實(shí)際藥品浸出物評(píng)估可能是合理的。例如，可進(jìn)行模擬研究以補(bǔ)充浸出物研究，以實(shí)現(xiàn)浸出物測(cè)試無(wú)法實(shí)現(xiàn)的目標(biāo)。在 AET 難以達(dá)到的情況下（即程序定量限（LOQ）> AET），浸出物研究將使用相關(guān)測(cè)試程序的 LOQ 進(jìn)行，而模擬研究將用于填補(bǔ) LOQ 與 AET 之間的差距?；蛘?，當(dāng)通過(guò)徹底的盡職調(diào)查確定進(jìn)行浸出物研究不切實(shí)際時(shí)，模擬研究可用于替代浸出物研究。
It is important to recognize that, regardless of how well the simulation study is designed and executed, its outcome will likely only approximate the results of a drug product leachable study and cannot fully replicate a true leachable profile of the drug product. For example, a simulation study cannot and will not address any potential interaction between leachables and the components of the drug product formulation components.
重要的是要認(rèn)識(shí)到，無(wú)論模擬研究設(shè)計(jì)和執(zhí)行得多么完善，其結(jié)果可能只能近似于藥品浸出物研究的結(jié)果，無(wú)法完全復(fù)制藥品的真實(shí)浸出物特征。例如，模擬研究無(wú)法也不會(huì)解決浸出物與藥品配方成分之間的任何潛在相互作用。
The simulation study is a surrogate study that reveals likely true leachables that would be detected if a leachables study could have been conducted. Thus, the simulated leachables detected above the simulation study’s drug product specific AET should be identified, quantified, and assessed for safety. As the goal of a simulation study is to obtain a simulated leachables profile that closely mimics the actual leachables profile generated by the drug product over its shelf-life, the simulation conditions and process used in the simulation study should closely match the drug product manufacturing/storage conditions used in a leachables study, with the intent of simulating the conditions experienced by the drug product during its manufacturing, shelf-life storage, and in-use (clinical) preparation. Furthermore, the simulation solvent should be chosen so that is has a similar propensity to leach as the drug product, and the simulated manufacturing process should be performed using worst-case conditions. Moreover, a simulation study can be accelerated versus drug product shelf storage conditions to mimic the outcome of a leachable study over the entire drug product shelf life with shorter duration.
模擬研究是一種替代研究，它揭示了如果能夠進(jìn)行浸出物研究可能檢測(cè)到的潛在真實(shí)浸出物。因此，在模擬研究中檢測(cè)到的高于特定藥品 AET 的模擬浸出物應(yīng)被識(shí)別、定量并進(jìn)行安全性評(píng)估。由于模擬研究的目標(biāo)是獲得一個(gè)接近模擬藥品在其保質(zhì)期內(nèi)產(chǎn)生的實(shí)際浸出物特征的模擬浸出物特征，因此模擬研究中使用的模擬條件和過(guò)程應(yīng)與浸出物研究中使用的藥品生產(chǎn) / 儲(chǔ)存條件密切匹配，以模擬藥品在生產(chǎn)、保質(zhì)期儲(chǔ)存和使用（臨床）制備過(guò)程中所經(jīng)歷的條件。此外，選擇的模擬溶劑應(yīng)具有與藥品相似的浸出傾向，并且模擬生產(chǎn)過(guò)程應(yīng)在最壞情況下進(jìn)行。此外，與藥品保質(zhì)期儲(chǔ)存條件相比，模擬研究可以加速進(jìn)行，以在更短的時(shí)間內(nèi)模擬整個(gè)藥品保質(zhì)期內(nèi)的浸出物研究結(jié)果。
As the intent of the simulation study is to augment or replace a leachables study, the simulation study must meet all the quality requirements for a leachables study, including test procedure qualification. When properly justified, use of a simulation study is an alternative to the recommended practice of performing leachables studies. Thus, the intended application, justification, and qualification of a simulated leaching study for a particular drug product should be based on a scientifically sound rationale with demonstration of due diligence supported by appropriate testing and experimentation. When considering the use of a simulation study, consultation with the relevant regional Regulatory Agency prior to implementation may be warranted.
由于模擬研究的目的是補(bǔ)充或替代浸出物研究，因此模擬研究必須滿足浸出物研究的所有質(zhì)量要求，包括測(cè)試程序驗(yàn)證。在有充分正當(dāng)理由的情況下，使用模擬研究可作為進(jìn)行浸出物研究這一推薦做法的替代方案。因此，針對(duì)特定藥品的模擬浸出研究的預(yù)期應(yīng)用、理由和確認(rèn)應(yīng)基于科學(xué)合理的依據(jù)，并通過(guò)適當(dāng)?shù)臏y(cè)試和實(shí)驗(yàn)證明已盡到應(yīng)有的努力。在考慮使用模擬研究時(shí)，可能需要在實(shí)施前與相關(guān)地區(qū)的監(jiān)管機(jī)構(gòu)進(jìn)行咨詢。
4.6 Extractable and Leachable Correlation
4.6 可提取物與浸出物的相關(guān)性
The main purpose for generating extractables profiles is to characterize and assist selection of components, identify potential leachables, develop methods for targeted leachables, and correlate leachables and extractables. Leachables generally represent a subset of the extractables and the concentration of each leachable is typically below that of the corresponding extractable from a well conducted extractables study.
生成可提取物特征的主要目的是表征和輔助組件選擇、識(shí)別潛在浸出物、開發(fā)目標(biāo)浸出物的檢測(cè)方法，以及建立浸出物與可提取物之間的相關(guān)性。浸出物通常是可提取物的一個(gè)子集，且在設(shè)計(jì)良好的可提取物研究中，每種浸出物的濃度通常低于相應(yīng)可提取物的濃度。
Once the E&L profiles above AET are available, it is recommended that a qualitative and quantitative correlation between the two be evaluated. A correlation between leachables and extractables may be established when actual drug product leachables can be comparatively linked qualitatively and quantitatively with extractables from corresponding extractables studies of components or systems. Correlating leachables with extractables may support a justification for the use of routine extractables testing of components as an alternative to routine leachables testing during stability studies when appropriate for high-risk drug products, change control, and ongoing quality control. Potential explanations for leachables that were not detected or detected at higher levels than suggested by the extraction study conditions could include inadequate design and/or execution of the extractables study, degradation of leachables to form new compounds, interaction products of leachables with API and/or excipients, chemicals migrated from packaging, and/or new leachables resulting from materials change due to aging (e.g., exposure to UV light, heat, oxygen) during shelf-life storage. Though the E&L correlation is valuable and informative for the quality risk assessment and may be leveraged for component selection and life-cycle management decisions, it is the leachables profile that ultimately drives patient safety risk evaluations and component acceptability.
一旦獲得高于 AET 的可提取物和浸出物（E&L）特征，建議評(píng)估兩者之間的定性和定量相關(guān)性。當(dāng)藥品實(shí)際浸出物可與組件或系統(tǒng)的相應(yīng)可提取物研究中的可提取物進(jìn)行定性和定量對(duì)比關(guān)聯(lián)時(shí)，可建立浸出物與可提取物之間的相關(guān)性。在高風(fēng)險(xiǎn)藥品的穩(wěn)定性研究、變更控制和持續(xù)質(zhì)量控制中，將浸出物與可提取物相關(guān)聯(lián)可能為使用組件的常規(guī)可提取物測(cè)試替代常規(guī)浸出物測(cè)試提供依據(jù)。對(duì)于未檢測(cè)到浸出物或檢測(cè)到的浸出物水平高于提取研究條件所顯示的水平，可能的解釋包括可提取物研究設(shè)計(jì)和 / 或執(zhí)行不足、浸出物降解形成新化合物、浸出物與原料藥和 / 或輔料的相互作用產(chǎn)物、從包裝遷移的化學(xué)物質(zhì)，以及 / 或在保質(zhì)期儲(chǔ)存期間因材料老化（如暴露于紫外線、熱、氧氣）而產(chǎn)生的新浸出物。盡管 E&L 相關(guān)性對(duì)于質(zhì)量風(fēng)險(xiǎn)評(píng)估具有價(jià)值和參考意義，并可用于組件選擇和生命周期管理決策，但最終決定患者安全風(fēng)險(xiǎn)評(píng)估和組件可接受性的是浸出物特征。
Any changes occurring during the product life-cycle significantly altering the extractable/leachable profiles should prompt re-evaluation of the extractable/leachable profiles and their correlation. If a specific leachable is observed in the drug product during stability studies at a level significantly greater than anticipated from the calculated potential maximum level of the leachable as established with the extraction study conducted on the same component/system lots as were used for the drug product stability batches, it can indicate that the extraction study was incomplete and it may not be possible to establish a meaningful leachables to extractables correlation for that particular leachable.
在產(chǎn)品生命周期中發(fā)生的任何顯著改變可提取物 / 浸出物特征的變更，都應(yīng)促使對(duì)可提取物 / 浸出物特征及其相關(guān)性進(jìn)行重新評(píng)估。如果在穩(wěn)定性研究中，藥品中觀察到的特定浸出物水平顯著高于根據(jù)對(duì)與藥品穩(wěn)定性批次所用相同組件 / 系統(tǒng)批次進(jìn)行的提取研究確定的浸出物潛在最大計(jì)算水平，則可能表明提取研究不完整，且可能無(wú)法為該特定浸出物建立有意義的浸出物與可提取物相關(guān)性。
5.ANALYTICAL EVALUATION THRESHOLD
分析評(píng)估閾值
The AET is not a control threshold, but rather a threshold corresponding to a concentration above which extractables or leachables should be identified, quantitated, and reported for safety assessment, forming the foundation of the overall E&L risk assessment and control strategy. The ICH guidelines on impurities in new drug substances (ICH Q3A) and impurities in new drug products (ICH Q3B), describe a series of predetermined thresholds based upon maximum daily dosing that are intended to provide adequate control over critical quality attributes that may impact the safety and efficacy of the drug product over the course of the product shelf-life. In contrast, this guideline recommends incorporation of a Safety Concern Threshold (SCT; see Section 6 Safety Assessment) to first establish a study-specific AET.
分析評(píng)估閾值（AET）不是控制閾值，而是一個(gè)濃度閾值，高于該閾值的可提取物或浸出物應(yīng)被識(shí)別、定量并報(bào)告以進(jìn)行安全評(píng)估，它構(gòu)成了整體可提取物和浸出物（E&L）風(fēng)險(xiǎn)評(píng)估和控制策略的基礎(chǔ)。國(guó)際人用藥品注冊(cè)技術(shù)協(xié)調(diào)會(huì)（ICH）關(guān)于新原料藥中的雜質(zhì)（ICH Q3A）和新制劑中的雜質(zhì)（ICH Q3B）的指南，描述了一系列基于最大日劑量的預(yù)定閾值，旨在充分控制可能影響藥品在保質(zhì)期內(nèi)安全性和有效性的關(guān)鍵質(zhì)量屬性。相比之下，本指南建議納入安全關(guān)注閾值（SCT；見第 6 節(jié)安全評(píng)估），以首先建立特定于研究的 AET。
An extraction study should include the establishment and application of an AET to indicate extractable chemical entities to be detected, identified and reported as potential leachables for the drug product. For a leachable study, the AET is established at a concentration above which compounds should be identified and quantitated to enable appropriate safety assessment. For Class 1 leachables (See Appendix 4, Table A.4.1), the compound-specific safety limit, instead of a product-specific SCT, should be used for quantification.
提取研究應(yīng)包括分析評(píng)估閾值（AET）的建立和應(yīng)用，以指示需要檢測(cè)、識(shí)別并報(bào)告為藥品潛在浸出物的可提取化學(xué)物質(zhì)。對(duì)于浸出物研究，AET 設(shè)定為一個(gè)濃度閾值，高于該濃度的化合物應(yīng)被識(shí)別和定量，以便進(jìn)行適當(dāng)?shù)陌踩u(píng)估。對(duì)于 1 類浸出物（參見附錄 4 表 A.4.1），應(yīng)使用化合物特異性安全限值而非產(chǎn)品特異性安全關(guān)注閾值（SCT）進(jìn)行定量。
Derivation of the study-specific AET depends on dosing considerations (e.g., maximum dose level, frequency of dosing, and duration of treatment). The AET may be expressed using various units of measure depending on the type of study (extractable vs leachable) and what is being evaluated. For example, weight of extractable per weight of component material (e.g., µg/g) or weight of extractable per extraction solution volume (e.g., µg/mL) are commonly used units for extractables in solutions. For leachables studies, weight of leachables per packaging or delivery component/system (e.g., µg/component, µg/mL, µg/g, ppm) may be used to represent the leachables AET based on the entire container closure system or set of manufacturing components. Regardless of the units used to express the AET, they will all equate to an equivalent potential patient dose for a given study. Example AET calculations are presented in Appendix 3.
特定于研究的 AET 的推導(dǎo)取決于給藥因素（如最大劑量水平、給藥頻率和治療持續(xù)時(shí)間）。根據(jù)研究類型（可提取物研究 vs 浸出物研究）和評(píng)估對(duì)象的不同，AET 可采用多種計(jì)量單位。例如，溶液中可提取物常用的單位有每重量組件材料中的可提取物重量（如 µg/g）或每體積提取溶液中的可提取物重量（如 µg/mL）。對(duì)于浸出物研究，可基于整個(gè)容器密封系統(tǒng)或整套生產(chǎn)組件，采用每包裝或給藥組件 / 系統(tǒng)中的浸出物重量（如 µg / 組件、µg/mL、µg/g、ppm）來(lái)表示浸出物 AET。無(wú)論用于表示 AET 的單位如何，對(duì)于特定研究，它們都等同于潛在的患者等效劑量。附錄 3 提供了 AET 計(jì)算示例。
5.1 Analytical Uncertainty Factor
5.1 分析不確定度因子
When an AET is used in semi-quantitative analytical methods, an appropriate uncertainty factor should be applied to account for potential underestimation of analyte concentrations due to differences in response factors between analytes and the reference standard.
當(dāng)在半定量分析方法中使用 AET 時(shí)，應(yīng)應(yīng)用適當(dāng)?shù)牟淮_定度因子，以考慮由于分析物與參考標(biāo)準(zhǔn)品之間的響應(yīng)因子差異而可能導(dǎo)致的分析物濃度低估。
The determination of the appropriate magnitude for the analytical uncertainty factor(s) in a given extractable/leachable study depends on the prior knowledge and understanding of the materials of construction, the possible chemical structure of the potential extractables/leachables, the availability of the reference standards covering the range of response factors, and the limitations of the analytical methods.
在特定的可提取物 / 浸出物研究中，分析不確定度因子的適當(dāng)大小取決于對(duì)構(gòu)造材料的已有知識(shí)和理解、潛在可提取物 / 浸出物的可能化學(xué)結(jié)構(gòu)、涵蓋響應(yīng)因子范圍的參考標(biāo)準(zhǔn)品的可獲得性，以及分析方法的局限性。
Under certain circumstances an acceptable approach is to multiply an uncertainty factor (UF) of no greater than 0.5. Alternatively, an uncertainty factor can be derived from statistical analysis of appropriately constituted response factor database of relevant reference compounds. Justification of UF applied should be included in the extractable/leachable study report.
在某些情況下，可接受的做法是采用不大于 0.5 的不確定度因子（UF）進(jìn)行乘法運(yùn)算?；蛘?，可通過(guò)對(duì)相關(guān)參考化合物的適當(dāng)構(gòu)成響應(yīng)因子數(shù)據(jù)庫(kù)進(jìn)行統(tǒng)計(jì)分析來(lái)推導(dǎo)不確定度因子?？商崛∥?nbsp;/ 浸出物研究報(bào)告中應(yīng)包含所應(yīng)用的 UF 的論證依據(jù)。
6.SAFETY ASSESSMENT
安全評(píng)估
6.1 General Principles
6.1 一般原則
A risk-based scientific evaluation is needed to provide confidence that any potential leachables in the drug product are at levels where they pose negligible risk to the patient. Within this overall risk-based evaluation, the focus of the safety assessment is the toxicological evaluation of leachables in the drug product exceeding a predefined SCT for that drug product. Within this context, the SCT is considered the threshold below which a leachable would have an exposure so low as to present negligible mutagenic and non-mutagenic toxicity concerns. The outcome of the safety assessment can be used to determine if levels of Class 1 leachables from a material are considered acceptable and may be used to set specifications for leachables in the drug product if needed.
需要進(jìn)行基于風(fēng)險(xiǎn)的科學(xué)評(píng)估，以確保藥品中任何潛在浸出物的水平對(duì)患者構(gòu)成的風(fēng)險(xiǎn)可忽略不計(jì)。在這種基于風(fēng)險(xiǎn)的整體評(píng)估中，安全評(píng)估的重點(diǎn)是對(duì)藥品中超過(guò)該藥品預(yù)定義 SCT 的浸出物進(jìn)行毒理學(xué)評(píng)估。在此背景下，SCT 被視為一個(gè)閾值，低于該閾值時(shí)，浸出物的暴露量極低，以至于其致突變性和非致突變性毒性擔(dān)憂可忽略不計(jì)。安全評(píng)估的結(jié)果可用于確定某一材料中 1 類浸出物的水平是否可接受，并可在需要時(shí)用于設(shè)定藥品中浸出物的規(guī)格。
Since the SCT is defined to be protective of both mutagenic and non-mutagenic effects, it must consider both mutagenicity concerns and concerns related to alternative toxicity endpoints and is based on whichever is more limiting with respect to exposure. As such, in addition to amount of exposure, the SCT dependent on both route and duration of exposure. For mutagenicity concerns, the Threshold of Toxicological Concern (TTC) as described in ICH M7 is considered applicable. For non-mutagenic toxicity endpoints, a Qualification Threshold (QT) is used in this guideline and may be considered as a dose at which potential non-mutagenic toxic effects are negligible. Subsequently, the SCT is the lowest value of either the TTC or QT for a specific drug product, considering route and potential duration of exposure. Oral and parenteral QT values have been derived by review of approximately 330 potential leachable permitted daily exposures (PDEs). An overview of these systemic safety thresholds (expressed in µg/day) for oral, parenteral, dermal/transdermal and inhalation routes of exposure, are provided in Table 1. In addition, local toxicity thresholds for leachable concentrations in drug products for topical ophthalmic, subcutaneous/intradermal, dermal/transdermal and inhalation routes of exposure are presented. For other routes of administration, the concepts described in this guideline may be used to determine acceptable exposure levels.
由于 SCT 被定義為可同時(shí)防范致突變和非致突變效應(yīng)，因此它必須同時(shí)考慮致突變性擔(dān)憂和與其他毒性終點(diǎn)相關(guān)的擔(dān)憂，并基于在暴露方面更具限制性的因素。因此，除暴露量外，SCT 還取決于暴露途徑和持續(xù)時(shí)間。對(duì)于致突變性擔(dān)憂，ICH M7 中描述的毒理學(xué)關(guān)注閾值（TTC）被認(rèn)為是適用的。對(duì)于非致突變性毒性終點(diǎn)，本指南使用確認(rèn)閾值（QT），該閾值可被視為潛在非致突變性毒性效應(yīng)可忽略不計(jì)的劑量。因此，對(duì)于特定藥品，SCT 是考慮暴露途徑和潛在暴露持續(xù)時(shí)間后，TTC 或 QT 中的較低值。通過(guò)對(duì)約 330 種潛在浸出物的允許日暴露量（PDE）進(jìn)行審查，得出了口服和胃腸外給藥途徑的 QT 值。表 1 提供了口服、胃腸外、皮膚 / 經(jīng)皮和吸入給藥途徑的全身安全閾值（以 µg / 天表示）概述。此外，還列出了局部眼科、皮下 / 皮內(nèi)、皮膚 / 經(jīng)皮和吸入給藥途徑的藥品中浸出物濃度的局部毒性閾值。對(duì)于其他給藥途徑，可使用本指南中描述的概念來(lái)確定可接受的暴露水平。
Table 1: Systemic and Local Toxicity Thresholds
表 1：全身毒性與局部毒性閾值
QT values for inhalation and dermal/transdermal routes have been established based upon parenteral QT in lieu of available PDE values.
吸入和皮膚/經(jīng)皮給藥途徑的確認(rèn)閾值（QT）是基于胃腸外給藥的QT確立的，以替代現(xiàn)有的允許日暴露量（PDE）數(shù)值。
6.2 Leachables Classification
6.2 浸出物分類
Potential leachables from various materials encompass a large variety of chemicals, and thus toxicological characteristics. To provide a pragmatic, risk-based approach to leachables safety assessment, certain compounds need to be controlled at levels that are lower than the established qualification threshold due to their potential for highly potent toxicity. Such chemicals are categorized as Class 1 leachables in the current guideline. For mutagenic carcinogens, the Cohort of Concern as defined in ICH M7 and ICH M7 Class 1 impurities with an AI below 1.5 µg/day are considered Class 1 leachables. Similarly, there are some compounds, such as bisphenol A (BPA) or benzo(a)pyrene, that may have potent non-mutagenic toxicity concerns that may theoretically be associated with a greater than negligible patient safety risk at or below the drug product QT value. For such Class 1 leachables, it is considered most practical to avoid the use of materials which may leach such compounds (see Section 5). However, if the use of such materials or components is considered unavoidable, a compound-specific safety limit for these substances should be used.
來(lái)自各種材料的潛在浸出物包含多種化學(xué)物質(zhì)，因此具有不同的毒理學(xué)特征。為了對(duì)浸出物安全評(píng)估采用務(wù)實(shí)的、基于風(fēng)險(xiǎn)的方法，某些化合物由于具有強(qiáng)效毒性潛力，需要控制在低于既定確認(rèn)閾值的水平。此類化學(xué)物質(zhì)在本指南中被歸類為1類浸出物。對(duì)于致突變性致癌物，ICH M7中定義的“關(guān)注隊(duì)列”（Cohort of Concern）以及AI低于1.5 µg/天的ICH M7 1類雜質(zhì)均被視為1類浸出物。類似地，某些化合物（如雙酚A（BPA）或苯并（a）芘）可能具有強(qiáng)效非致突變性毒性，理論上在藥品QT值或以下水平時(shí)，可能對(duì)患者安全構(gòu)成不可忽略的風(fēng)險(xiǎn)。對(duì)于此類1類浸出物，最切實(shí)的做法是避免使用可能浸出這些化合物的材料（見第5節(jié)）。然而，如果認(rèn)為無(wú)法避免使用此類材料或組件，則應(yīng)采用這些物質(zhì)的化合物特異性安全限值。
Class 3 leachables are compounds established to have relatively low potency for systemic toxicity with derived chronic parenteral PDEs in excess of the levels at which leachables are typically observed (i.e., PDE ≥ 1 mg/day using the methodology described in Appendix 5). Class 3 leachables would not require further safety qualification if observed at daily exposure levels < 1 mg/day. In between these two classes are compounds with a toxicity potential that may be relevant at levels commonly encountered for leachables (Class 2 leachables). Appendix 4 provides an overview of these three leachable classes.
3類浸出物是被證實(shí)具有相對(duì)較低全身毒性潛力的化合物，其推導(dǎo)的慢性胃腸外給藥允許日暴露量（PDE）超過(guò)浸出物通常被觀察到的水平（即使用附錄5中描述的方法得出的PDE ≥ 1 mg/天）。如果3類浸出物的日暴露水平< 1 mg/天，則無(wú)需進(jìn)一步的安全確認(rèn)。介于這兩類之間的是在浸出物常見水平下可能具有相關(guān)毒性潛力的化合物（2類浸出物）。附錄4概述了這三類浸出物。
6.3 Safety Assessment Process
6.3 安全評(píng)估流程
Organic leachables exceeding the AET should be identified, quantified, and reported for safety risk assessment. Acceptability of partial or incomplete elucidation of the compound structure should be justified from an analytical perspective. If toxicologically justified, partial elucidation providing tentative structures may inform a safety assessment in certain cases. The general process for safety assessment of leachables is presented in a flowchart (Figure 3) and includes an assessment of both mutagenicity and general toxicity concerns.
超過(guò)分析評(píng)估閾值（AET）的有機(jī)浸出物應(yīng)被識(shí)別、定量并報(bào)告，以進(jìn)行安全風(fēng)險(xiǎn)評(píng)估?；衔锝Y(jié)構(gòu)的部分或不完全解析的可接受性應(yīng)從分析角度進(jìn)行論證。在某些情況下，如果有毒理學(xué)依據(jù)，提供暫定結(jié)構(gòu)的部分解析可能有助于安全評(píng)估。浸出物安全評(píng)估的一般流程如圖3所示，包括對(duì)致突變性和一般毒性的評(píng)估。
Figure 3: Safety Assessment Process for Leachables Using Safety Evaluation Thresholds
圖 3：利用安全性評(píng)估閾值開展可浸出物安全性評(píng)估流程
As described in ICH M7.
** If daily exposure to leachable is >1 mg/day, genotoxicity studies should be considered, as recommended in ICH Q3A and ICH Q3B (e.g., bacterial mutagenicity study and in vitro chromosomal aberration assay).
如 ICH M7 中所述。
** 若浸出物的日暴露量 > 1 mg / 天，應(yīng)考慮進(jìn)行遺傳毒性研究，如 ICH Q3A 和 ICH Q3B 中建議的（例如，細(xì)菌致突變性研究和體外染色體畸變?cè)囼?yàn)）。
Potential Class 1 leachables should ideally be identified and avoided during materials and component selection. However, if such compounds cannot be avoided, lower compound-specific thresholds and specifications to adequately control their presence as leachables should be implemented as an initial step in the process. Subsequently, all leachables above the TTC applicable to the drug product should be evaluated for mutagenic potential according to ICH M7. Leachables considered potentially mutagenic should be appropriately controlled within TTC limits unless de-risked by appropriate mutagenicity studies.
在材料和組件選擇過(guò)程中，理想情況下應(yīng)識(shí)別并避免潛在的 1 類浸出物。然而，若無(wú)法避免此類化合物，作為流程的初始步驟，應(yīng)實(shí)施更低的化合物特異性閾值和規(guī)格，以充分控制其作為浸出物的存在。隨后，所有高于藥品適用毒理學(xué)關(guān)注閾值（TTC）的浸出物應(yīng)根據(jù) ICH M7 評(píng)估其致突變潛力。被認(rèn)為具有潛在致突變性的浸出物應(yīng)在 TTC 限值內(nèi)進(jìn)行適當(dāng)控制，除非通過(guò)適當(dāng)?shù)闹峦蛔冃匝芯拷档土孙L(fēng)險(xiǎn)。
In addition to the mutagenicity assessment, all leachables above the applicable QT for the drug product should also be evaluated for general toxicity concerns. If adequate data are available to support the safety of the leachable at the maximal potential patient exposure, then no further toxicological assessment is needed (See Appendix 5 for further information). Conversely, if data do not sufficiently support the safety of the leachable, further action is needed to reduce the potential exposure to a known acceptable level (material replacement, etc.), generation of additional toxicological data to qualify the observed level, or a risk/benefit assessment providing justification of exposure at the observed level.
除致突變性評(píng)估外，所有高于藥品適用確認(rèn)閾值（QT）的浸出物還應(yīng)評(píng)估其一般毒性風(fēng)險(xiǎn)。若有充分?jǐn)?shù)據(jù)支持浸出物在患者潛在最大暴露量下的安全性，則無(wú)需進(jìn)一步的毒理學(xué)評(píng)估（詳見附錄 5）。相反，若數(shù)據(jù)不足以支持浸出物的安全性，則需要采取進(jìn)一步措施將潛在暴露量降低至已知可接受水平（如更換材料等）、生成額外的毒理學(xué)數(shù)據(jù)以確認(rèn)觀察到的水平，或進(jìn)行風(fēng)險(xiǎn) / 獲益評(píng)估以證明觀察到的暴露水平的合理性。
It should be noted that for leachables where adequate data to inform on the safety of the compound are not available, a read across approach using a highly similar compound(s) with toxicological data is encouraged. If suitable surrogate(s) can be identified that have sufficient data to support the safety of the observed leachable at the level observed, further safety risk assessment and/or studies can be avoided.
應(yīng)注意，對(duì)于缺乏充分?jǐn)?shù)據(jù)說(shuō)明其安全性的浸出物，鼓勵(lì)采用“交叉參照” 法，即使用具有毒理學(xué)數(shù)據(jù)的高度相似化合物進(jìn)行評(píng)估。若能確定合適的替代物，且其數(shù)據(jù)足以支持觀察到的浸出物在該水平下的安全性，則可避免進(jìn)一步的安全風(fēng)險(xiǎn)評(píng)估和 / 或研究。
If the generation of novel toxicological data is considered necessary to support the safety of exposure to a leachable, New Approach Methodologies (NAMs) including in silico and in vitro models may be considered if appropriately justified. Otherwise, a toxicological qualification study(ies) as described in ICH Q3A and Q3B should be considered in order support safety assessment of the compound(s).
若認(rèn)為需要生成新的毒理學(xué)數(shù)據(jù)以支持浸出物暴露的安全性，在有充分理由的情況下，可考慮采用新方法學(xué)（NAMs），包括計(jì)算機(jī)模擬和體外模型。否則，應(yīng)考慮按照 ICH Q3A 和 Q3B 中描述的毒理學(xué)確認(rèn)研究，以支持對(duì)化合物的安全評(píng)估。
6.4 Route Specific Considerations and Special Cases (Local Toxicity Concerns)
6.4 特定給藥途徑的考慮因素和特殊情況（局部毒性關(guān)注）
Safety risk assessments for potential systemic toxicity are typically sufficient to support the safety of exposure to leachables. However, there are certain scenarios where potential local toxicity effects may be pertinent due to the potential for damage to vulnerable tissues related to the local concentration of a compound (e.g., pulmonary drug products, ophthalmic drug products, and intracerebral/intrathecal/epidural drug products). When relevant, the toxicological risk assessment should address the potential impact of a leachable on local tissue toxicity as well as factors that may potentially reduce such concerns (e.g., formulation and excipients, contact duration, recovery of tissue damage). Additionally, when potential local toxicity needs to be considered, the SCT used should be the lowest (on a daily exposure basis) of the mutagenic (i.e., TTC), non-mutagenic (i.e., QT), and local toxicity thresholds (pertinent concentration converted to a maximum daily exposure level).
對(duì)潛在全身毒性的安全風(fēng)險(xiǎn)評(píng)估通常足以支持浸出物暴露的安全性。然而，在某些情況下，由于化合物的局部濃度可能對(duì)脆弱組織造成損害，潛在的局部毒性效應(yīng)可能更為相關(guān)（例如，肺部用藥品、眼科用藥品以及腦內(nèi) / 鞘內(nèi) / 硬膜外用藥品）。在相關(guān)情況下，毒理學(xué)風(fēng)險(xiǎn)評(píng)估應(yīng)說(shuō)明浸出物對(duì)局部組織毒性的潛在影響，以及可能降低此類擔(dān)憂的因素（如配方和輔料、接觸時(shí)間、組織損傷的恢復(fù)）。此外，當(dāng)需要考慮潛在局部毒性時(shí)，所使用的安全關(guān)注閾值（SCT）應(yīng)為（基于日暴露量）致突變性閾值（即 TTC）、非致突變性閾值（即 QT）和局部毒性閾值（相關(guān)濃度轉(zhuǎn)換為最大日暴露水平）中的最低值。
6.4.1 Ophthalmic Drug Products
6.4.1 眼科用藥品
Ophthalmic products are often administered topically, while some products are injected directly into ocular tissues. There is a paucity of data to characterize the potential local toxicity of leachables when in contact with ocular tissues. Based on historical precedence, in the absence of a relevant database, a compound-specific risk assessment should be completed for topically administered products to justify the safety of a leachable when it exceeds a concentration of 20 ppm in the final to-be-marketed topical ophthalmic products. This concentration limit is not considered applicable to irrigation fluids that are in transient contact with ocular tissues. For products injected into ocular tissues no threshold is given. A qualitative safety assessment of any leachables present should be provided, since such leachables may be of relevance even when present at a concentration below 20 ppm.
眼科用藥品通常為局部給藥，部分產(chǎn)品則直接注射到眼部組織中。關(guān)于浸出物與眼部組織接觸時(shí)的潛在局部毒性，相關(guān)數(shù)據(jù)較為匱乏。根據(jù)歷史先例，在缺乏相關(guān)數(shù)據(jù)庫(kù)的情況下，對(duì)于局部給藥產(chǎn)品，當(dāng)浸出物在最終上市的局部眼科用藥品中的濃度超過(guò) 20 ppm 時(shí)，應(yīng)完成化合物特異性風(fēng)險(xiǎn)評(píng)估，以證明其安全性。該濃度限值不適用于與眼部組織短暫接觸的沖洗液。對(duì)于注射到眼部組織的產(chǎn)品，未設(shè)定閾值。應(yīng)對(duì)存在的任何浸出物進(jìn)行定性安全評(píng)估，因?yàn)榧词節(jié)舛鹊陀?nbsp;20 ppm，此類浸出物也可能具有相關(guān)性。
6.4.2 Intracerebral, Intrathecal, Epidural Drug Products
6.4.2 腦內(nèi)、鞘內(nèi)、硬膜外用藥品
Intracerebral, intrathecal, and epidural drug products may directly interact with vital central nervous system (CNS) tissues that have a limited capacity for repair following insult, yet there is a paucity of data to characterize the potential toxicity of compounds directly administered into or in close proximity to neuronal tissue. In vitro data suggest chemically induced biological effects can occur in the very low parts per billion (ppb) range for some compounds with known neurotoxicity. Therefore, a compound-specific risk assessment should consider local concentration of observed leachables and the potential local toxicity concerns on neuronal tissue (e.g., neurons, astrocytes, glia, myelin) including an assessment of the potential for a local inflammatory response.
腦內(nèi)、鞘內(nèi)和硬膜外用藥品可能直接與重要的中樞神經(jīng)系統(tǒng)（CNS）組織相互作用，這些組織在受損后的修復(fù)能力有限，但關(guān)于直接給藥至神經(jīng)組織或其附近的化合物的潛在毒性，相關(guān)數(shù)據(jù)較為匱乏。體外數(shù)據(jù)表明，對(duì)于某些已知具有神經(jīng)毒性的化合物，在極低的十億分率（ppb）范圍內(nèi)即可產(chǎn)生化學(xué)誘導(dǎo)的生物學(xué)效應(yīng)。因此，化合物特異性風(fēng)險(xiǎn)評(píng)估應(yīng)考慮觀察到的浸出物的局部濃度，以及對(duì)神經(jīng)組織（如神經(jīng)元、星形膠質(zhì)細(xì)胞、神經(jīng)膠質(zhì)細(xì)胞、髓鞘）的潛在局部毒性擔(dān)憂，包括對(duì)局部炎癥反應(yīng)潛力的評(píng)估。
6.4.3 Dermal Drug Products
6.4.3 皮膚用藥品
With regard to any local toxicity effects, sensitization potential (see Section 6.4.4) is likely the most sensitive non-genotoxic endpoint when the leachable concerns a strong or extreme potency skin sensitizer. For High Potency Chemicals (HPC), a Dermal Sensitization Threshold (DST) of 1 µg/cm²/day has been derived. This threshold corresponds to 500 ppm in a dermal drug product, using the Cutaneous and Transcutaneous Concentration Limit (CTCL) calculation for conversion as described in ICH Q3D. Consequently, a local toxicity threshold corresponding to 500 ppm concentration in the product can be used for dermal products below which there is no need for local non-mutagenic toxicity evaluation including sensitization potential (See Table 1.).
關(guān)于局部毒性效應(yīng)，當(dāng)浸出物為強(qiáng)效或極強(qiáng)效皮膚致敏劑時(shí)，致敏潛力（見第 6.4.4 節(jié)）可能是最敏感的非遺傳毒性終點(diǎn)。對(duì)于高 potency 化學(xué)品（HPC），皮膚致敏閾值（DST）為 1 µg/cm²/ 天。使用 ICH Q3D 中描述的皮膚和經(jīng)皮濃度限值（CTCL）計(jì)算進(jìn)行轉(zhuǎn)換后，該閾值相當(dāng)于皮膚用藥品中的 500 ppm。因此，皮膚用藥品可采用相當(dāng)于產(chǎn)品中 500 ppm 濃度的局部毒性閾值，低于該閾值時(shí)，無(wú)需進(jìn)行包括致敏潛力在內(nèi)的局部非致突變性毒性評(píng)估（見表 1）。
6.4.4 Sensitization Potential
6.4.4 致敏潛力
Sensitizers are compounds that may trigger hypersensitivity reactions after repeated exposure. The concern for these compounds is dependent on the sensitization potential of the compound, the route of exposure and the susceptibility of the individual exposed. Different types of hypersensitivity with multiple modes of action have been described for various routes of exposure; however, validated prediction models exist for the dermal route only. This guidance addresses the risk for induction of sensitization potential and provides local toxicity thresholds for this risk where appropriate. If patients are sensitized to a compound, elicitation of sensitization reactions may occur at lower thresholds.
致敏劑是反復(fù)暴露后可能引發(fā)超敏反應(yīng)的化合物。對(duì)這些化合物的擔(dān)憂取決于化合物的致敏潛力、暴露途徑以及暴露個(gè)體的易感性。針對(duì)不同暴露途徑，已描述了多種作用模式的超敏反應(yīng)類型；但目前僅針對(duì)皮膚途徑存在經(jīng)過(guò)驗(yàn)證的預(yù)測(cè)模型。本指南闡述了致敏潛力誘導(dǎo)的風(fēng)險(xiǎn)，并在適當(dāng)情況下為此類風(fēng)險(xiǎn)提供局部毒性閾值。若患者對(duì)某一化合物致敏，在更低閾值下即可引發(fā)致敏反應(yīng)。
Dermal exposure
皮膚暴露
Most data on sensitization potential have been obtained using the dermal route. Besides human data, in silico, in chemico, in vitro, and in vivo models have been developed and used to characterize the dermal sensitization potential of compounds. DSTs have been derived based on sensitization potency.1,2
大多數(shù)關(guān)于致敏潛力的數(shù)據(jù)來(lái)自皮膚途徑。除人體數(shù)據(jù)外，已開發(fā)并使用計(jì)算機(jī)模擬、化學(xué)體外、體外和體內(nèi)模型來(lái)表征化合物的皮膚致敏潛力。皮膚致敏閾值（DST）是基于致敏 potency 推導(dǎo)得出的 1,2。
Where an identified leachable is administered dermally below the DST for the relevant potency category, it can be concluded that no concern for dermal sensitization is expected, and no further action is required. If the DST is exceeded, available compound-specific data on sensitization potential should be evaluated. If no such data are available, or when these data raise concerns, risk mitigation measures need to be considered. These may include replacement of the component leaching the compound or reduction of the level of the leachable.
若已識(shí)別的浸出物通過(guò)皮膚給藥時(shí)的劑量低于相應(yīng) potency 類別的 DST，則可得出結(jié)論預(yù)計(jì)不存在皮膚致敏擔(dān)憂，無(wú)需采取進(jìn)一步措施。若超過(guò) DST，應(yīng)評(píng)估現(xiàn)有的化合物特異性致敏潛力數(shù)據(jù)。若缺乏此類數(shù)據(jù)，或數(shù)據(jù)引發(fā)擔(dān)憂，則需考慮風(fēng)險(xiǎn)緩解措施，可能包括更換浸出該化合物的組件或降低浸出物水平。
As transdermal drugs are applied to the skin as well, the same approach can be used to evaluate the risk for sensitization potential. For multi-day patches it is assumed that all leachables migrate within a day. A slower migration rate should be justified with data.
由于經(jīng)皮給藥藥品也施用于皮膚，因此可采用相同方法評(píng)估其致敏潛力風(fēng)險(xiǎn)。對(duì)于多日貼劑，假設(shè)所有浸出物在一天內(nèi)遷移完畢。遷移速率較慢的情況需有數(shù)據(jù)支持。
Inhalation exposure
吸入暴露
Knowledge of the respiratory sensitization potential of a compound is primarily from human data. Currently, suitable non-clinical models for respiratory sensitization are not established for safety risk assessment. The modes of action for dermal and respiratory sensitizers show commonalities, but also deviate, especially after T-cell activation. Consequently, dermal sensitization data should not be used to estimate the risk for respiratory sensitization and no threshold for respiratory sensitization can be provided.
關(guān)于化合物的呼吸道致敏潛力，相關(guān)知識(shí)主要來(lái)自人體數(shù)據(jù)。目前，尚未建立適用于安全風(fēng)險(xiǎn)評(píng)估的呼吸道致敏非臨床模型。皮膚致敏劑和呼吸道致敏劑的作用模式雖有共性，但也存在差異，尤其是在 T 細(xì)胞激活后。因此，皮膚致敏數(shù)據(jù)不應(yīng)用于評(píng)估呼吸道致敏風(fēng)險(xiǎn)，且無(wú)法提供呼吸道致敏的閾值。
The respiratory tract is very sensitive to compounds with sensitizing (and irritating) properties3. Therefore, any compound with structural elements that may suggest sensitizing potential or irritation should be evaluated (e.g. isocyanates, nitriles, styrenes, short-chain aldehydes). If a compound is considered to be an irritant or have sensitizing potential, patient risk should be assessed on a case-by-case basis after evaluating the available information for the specific compound. Additionally, available clinical data should be evaluated for evidence of any adverse effects. If no concern is identified for irritancy or sensitization, a systemic toxicity QT aligned with parenteral, as presented in Table 1, is considered appropriate.
呼吸道對(duì)具有致敏（和刺激）特性的化合物非常敏感 3。因此，任何具有可能提示致敏潛力或刺激性的結(jié)構(gòu)元素的化合物都應(yīng)進(jìn)行評(píng)估（例如，異氰酸酯、腈類、苯乙烯、短鏈醛類）。若某一化合物被認(rèn)為具有刺激性或致敏潛力，在評(píng)估該特定化合物的現(xiàn)有信息后，應(yīng)逐案評(píng)估患者風(fēng)險(xiǎn)。此外，還應(yīng)評(píng)估現(xiàn)有臨床數(shù)據(jù)，以尋找任何不良效應(yīng)的證據(jù)。若未發(fā)現(xiàn)刺激性或致敏性擔(dān)憂，則采用與表 1 中胃腸外給藥一致的全身毒性 QT 是適當(dāng)?shù)摹?/span>
Parenteral Exposure
胃腸外暴露
Regarding potential risk for sensitization, a distinction should be made between the subcutaneous/intradermal route and the intravenous/intramuscular/intraperitoneal routes of exposure. For the subcutaneous route, the drug is administered in the vicinity of the same tissues and cells (i.e., Langerhans cells) that are pivotal in triggering dermal sensitization. Especially, when the leachable is not readily distributed and remains for more extended periods in the subcutis, the same modes of action may be activated. Consequently, available data on dermal sensitization potential can be informative when evaluating the sensitization potential for leachables that are administered subcutaneously. Likewise for products administered intradermally, dermal sensitization data may be of relevance. In contrast, dermally applied compounds need to penetrate the skin barrier first. To account for this difference a ten-fold lower threshold for subcutaneous and intradermal products as compared to dermal products is considered justified, i.e., 50 ppm instead of 500 ppm.
關(guān)于致敏的潛在風(fēng)險(xiǎn)，應(yīng)區(qū)分皮下 / 皮內(nèi)給藥途徑與靜脈 / 肌內(nèi) / 腹腔內(nèi)給藥途徑。對(duì)于皮下途徑，藥物施用于與觸發(fā)皮膚致敏至關(guān)重要的相同組織和細(xì)胞（即朗格漢斯細(xì)胞）附近。特別是當(dāng)浸出物不易分布且在皮下組織中長(zhǎng)時(shí)間停留時(shí)，可能激活相同的作用模式。因此，在評(píng)估皮下給藥浸出物的致敏潛力時(shí)，現(xiàn)有的皮膚致敏潛力數(shù)據(jù)可能具有參考價(jià)值。對(duì)于皮內(nèi)給藥產(chǎn)品，皮膚致敏數(shù)據(jù)也可能具有相關(guān)性。相比之下，經(jīng)皮應(yīng)用的化合物首先需要穿透皮膚屏障。為考慮這一差異，皮下和皮內(nèi)產(chǎn)品的閾值被認(rèn)為應(yīng)比皮膚用產(chǎn)品低 10 倍是合理的，即 50 ppm 而非 500 ppm。
Several types of systemic hypersensitivity (Type I-IV) are known, each having different modes of action. Type IV is dependent on hapten formation and thus shares some mechanistic aspects with dermal sensitization. However, contrary to dermal application, intramuscular and intravenous administered substances are rapidly distributed systemically, and large amounts are required to activate the immune system and induce sensitization. Since leachables are present at low concentrations in drug products, it is considered unlikely that sensitization potential will be of concern for drugs administered via intravenous or intramuscular injection.
已知存在多種類型的全身性超敏反應(yīng)（I-IV 型），每種類型都有不同的作用模式。IV 型依賴于半抗原的形成，因此與皮膚致敏存在一些機(jī)制上的共性。然而，與經(jīng)皮給藥不同，肌內(nèi)和靜脈給藥的物質(zhì)會(huì)迅速全身分布，且需要大量物質(zhì)才能激活免疫系統(tǒng)并誘導(dǎo)致敏。由于浸出物在藥品中的濃度較低，因此靜脈或肌內(nèi)注射給藥的藥品其浸出物的致敏潛力被認(rèn)為不太可能引起擔(dān)憂。
6.5 Considerations for ICH S9 Products
6.5 ICH S9 藥品的考慮因素
For drug products within the scope of ICH S9, leachables should generally be identified according to the scientific principles outlined in Section 3 above. The safety risk assessment may be conducted according to the ‘Evaluation of Impurities’ Section in ICH S9. In this case, the TTC would not be applicable and the SCT would be defined by the QT. Risk assessment may be conducted with a focus on general safety for the intended patient population and is relevant for genotoxic APIs covered by ICH S9 Q&A, 2018.
對(duì)于 ICH S9 范圍內(nèi)的藥品，浸出物的識(shí)別通常應(yīng)遵循上文第 3 節(jié)所述的科學(xué)原則。安全風(fēng)險(xiǎn)評(píng)估可按照 ICH S9 中的 “雜質(zhì)評(píng)估” 部分進(jìn)行。在這種情況下，毒理學(xué)關(guān)注閾值（TTC）不適用，安全關(guān)注閾值（SCT）由確認(rèn)閾值（QT）定義。風(fēng)險(xiǎn)評(píng)估可側(cè)重于目標(biāo)患者群體的總體安全性，且適用于 ICH S9 問(wèn)答（2018 年）所涵蓋的具有遺傳毒性的原料藥。
6.6 Content of Safety Assessment
6.6 安全評(píng)估的內(nèi)容
A safety assessment should be conducted for observed Class 1 leachables, Class 2 leachables detected at levels above the relevant SCT, and Class 3 leachables when present at levels above 1.0 mg/day. The safety assessment should provide sufficient information to conclude on the acceptability of the anticipated patient exposure levels. Further details on the information to be considered and the methodology for deriving an acceptable exposure level is provided in Appendix 5.
應(yīng)對(duì)觀察到的 1 類浸出物、檢測(cè)水平高于相關(guān)安全關(guān)注閾值（SCT）的 2 類浸出物，以及水平超過(guò) 1.0 mg / 天的 3 類浸出物進(jìn)行安全評(píng)估。安全評(píng)估應(yīng)提供充分信息，以得出關(guān)于預(yù)期患者暴露水平可接受性的結(jié)論。附錄 5 提供了關(guān)于需考慮的信息以及推導(dǎo)可接受暴露水平的方法的更多細(xì)節(jié)。
7.GLOSSARY
術(shù)語(yǔ)表
Analytical Evaluation Threshold (AET):
The threshold above which an extractable or leachable should be identified, quantified, and reported for safety assessment.
分析評(píng)估閾值（AET）
高于該閾值的可提取物或浸出物應(yīng)被識(shí)別、定量并報(bào)告，以進(jìn)行安全評(píng)估。
Chemical characterization:
The process of obtaining chemical information about the composition of an item such as pharmaceutical packaging and a pharmaceutical manufacturing component.
化學(xué)表征
獲取某一物品（如藥品包裝和藥品生產(chǎn)組件）成分的化學(xué)信息的過(guò)程。
Component:
A single item, composed of one or more materials of construction, that serves a single purpose or performs a single and specific task.
組件
由一種或多種構(gòu)造材料組成的單個(gè)物品，用于實(shí)現(xiàn)單一目的或執(zhí)行單一特定任務(wù)。
Extraction:
The chemical or physical process of transferring constituents of a test article into an extraction medium.
提取
將測(cè)試樣品中的成分轉(zhuǎn)移到提取介質(zhì)中的化學(xué)或物理過(guò)程。
Critical quality attribute:
A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
關(guān)鍵質(zhì)量屬性
為確保達(dá)到預(yù)期的產(chǎn)品質(zhì)量，應(yīng)處于適當(dāng)限度、范圍或分布內(nèi)的物理、化學(xué)、生物學(xué)或微生物學(xué)性質(zhì)或特征。
Drug product:
The dosage form in the final immediate packaging intended for marketing.
藥品
處于最終直接包裝中、擬用于銷售的劑型。
Drug substance:
The unformulated active pharmaceutical ingredient that may subsequently be formulated with excipients to produce the dosage form (or drug product).
原料藥
未配制的活性藥物成分，后續(xù)可與輔料一起配制成劑型（或藥品）。
Extractables Profile:
Qualitative or semi-quantitative/quantitative accounting of the extractables present in an extract.
可提取物特征
對(duì)可提取物中存在的可提取物的定性或半定量 / 定量描述。
Leachables Profile:
Qualitative and/or quantitative accounting of the leachables present in a drug product.
浸出物特征
對(duì)藥品中存在的浸出物的定性和 / 或定量描述。
Lifecycle:
All phases in the life of a product from the initial development through marketing until the product’s discontinuation
生命周期
產(chǎn)品從初始開發(fā)到上市直至停產(chǎn)的所有階段。
Lowest-Observed (Adverse) Effect Level (LO(A)EL):
The lowest dose of substance in a study or group of studies that produces biologically significant increases in frequency or severity of any (adverse) effects in the exposed humans or animals.
最低觀察到（不良）效應(yīng)水平（LO (A) EL）
在一項(xiàng)或一組研究中，使暴露的人或動(dòng)物出現(xiàn)任何（不良）效應(yīng)的頻率或嚴(yán)重程度產(chǎn)生生物學(xué)意義上顯著增加的物質(zhì)最低劑量。
Read-across:
A technique for predicting endpoint information for one substance by using data from the same endpoint from (an)other structurally-related substance(s).
交叉參照
通過(guò)使用來(lái)自一種或多種結(jié)構(gòu)相關(guān)物質(zhì)的相同終點(diǎn)數(shù)據(jù)，來(lái)預(yù)測(cè)某一物質(zhì)的終點(diǎn)信息的技術(shù)。
Margin of Safety:
A correlation between the PDE of the specific leachable and actual patient intake based on the daily dose.
安全邊際
特定浸出物的允許日暴露量（PDE）與基于日劑量的患者實(shí)際攝入量之間的關(guān)聯(lián)。
Materials of construction:
Individual materials used to construct a packaging or manufacturing component or system.
構(gòu)造材料
用于制造包裝或生產(chǎn)組件或系統(tǒng)的各種單獨(dú)材料。
New drug product:
A pharmaceutical product type, for example, tablet, capsule, solution, cream, which has not previously been registered in a region or Member State, and which contains a drug ingredient generally, but not necessarily, in association with excipients.
新藥品
一種藥品類型（例如片劑、膠囊劑、溶液劑、乳膏劑），此前未在某一地區(qū)或成員國(guó)注冊(cè)，通常含有藥物成分（但不一定與輔料結(jié)合）。
No Observed (Adverse) Effect Level (NO(A)EL):
The highest concentration or amount of a leachable or extractable that does not cause any statistically or biologically significant (adverse) effects in the exposed population compared to a control group.
未觀察到（不良）效應(yīng)水平（NO (A) EL）
與對(duì)照組相比，在暴露群體中不會(huì)引起任何統(tǒng)計(jì)學(xué)或生物學(xué)意義上顯著（不良）效應(yīng)的浸出物或可提取物的最高濃度或量。
Permitted Daily Exposure (PDE):
The maximum acceptable intake per day of a leachable in pharmaceutical products per day (for a lifetime).
允許日暴露量（PDE）
藥品中某一浸出物的每日最大可接受攝入量（終生）。
Point of Departure (PoD):
Starting point in the calculation of PDE of leachables; it can be derived from the human dose or appropriate animal study.
起始點(diǎn)（PoD）
計(jì)算浸出物允許日暴露量（PDE）的起始點(diǎn)；可從人體劑量或適當(dāng)?shù)膭?dòng)物研究中得出。
Qualification Threshold (QT):
Threshold above which a leachable should be qualified for potential non-mutagenic toxicity unless the leachable is identified as being Class 1.
確認(rèn)閾值（QT）
高于該閾值的浸出物應(yīng)進(jìn)行潛在非致突變性毒性確認(rèn)，除非該浸出物被確定為 1 類浸出物。
Safety Concern Threshold (SCT):
Threshold at or below which a leachable would have a dose so low as to present negligible safety concerns from mutagenic and non-mutagenic toxic effects unless the leachable is identified as being a leachable of high concern.
安全關(guān)注閾值（SCT）
在該閾值或以下時(shí)，浸出物的劑量極低，以至于其致突變性和非致突變性毒性效應(yīng)帶來(lái)的安全擔(dān)憂可忽略不計(jì)，除非該浸出物被確定為高關(guān)注浸出物。
Simulated Drug Product:
Matrix or solvent that mimics closely the leaching characteristics of the drug product formulation with respect to leaching propensity and solubility of leachables.
模擬藥品
在浸出傾向和浸出物溶解度方面，密切模擬藥品配方浸出特性的基質(zhì)或溶劑。
Substance (Compound, Chemical, Chemical Entity):
An association of different elements or chemical entities which have a definite chemical composition and distinct chemical properties.
物質(zhì)（化合物、化學(xué)品、化學(xué)實(shí)體）
由不同元素或化學(xué)實(shí)體結(jié)合而成，具有確定的化學(xué)組成和獨(dú)特的化學(xué)性質(zhì)。
System:
The sum of individual components (or assemblies) which together perform a specific function, such as manufacturing, delivery or storage/packaging.
系統(tǒng)
共同執(zhí)行特定功能（如生產(chǎn)、給藥或儲(chǔ)存 / 包裝）的各個(gè)組件（或組件集合）的總和。
Threshold of Toxicological Concern (TTC):
Threshold at or below which a leachable is not considered for safety assessment for mutagenic effects as described in ICH M7.
毒理學(xué)關(guān)注閾值（TTC）
如 ICH M7 所述，在該閾值或以下時(shí)，浸出物無(wú)需進(jìn)行致突變性效應(yīng)的安全評(píng)估。
8.REFERENCES
參考文獻(xiàn)
International Conference on Harmonisation (2006). Q3A(R2): Impurities in New Drug Substances.
International Conference on Harmonisation (2006). Q3B(R2): Impurities in New Drug Products.
International Council for Harmonisation (2024). Q3C(R9): Guideline for Residual Solvents.
International Council for Harmonisation (2022). Q3D(R2): Guideline for Elemental Impurities.
International Council for Harmonisation (2023). M7(R2): Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.
International Council for Harmonisation (2023). Q9(R1): Quality Risk Management.
International Conference on Harmonisation (2009). S9: Nonclinical Evaluation for Anticancer Pharmaceuticals.
International Council for Harmonisation (2018). S9: Nonclinical Evaluation for Anticancer Pharmaceuticals Questions and Answers.
Chilton ML, Api AM, Foster RS, Gerberick GF, Lavelle M, Macmillan DS, et al. Updating the Dermal Sensitisation Thresholds using an expanded dataset and an in silico expert system. Regul Toxicol Pharmacol. 2022; Aug;133:105200,
Parris P, Whelan G, Burild A, Whritenour J, Bruen U, Bercu J, et al. Sensitization Assessment of Extractables and Leachables in Pharmaceuticals: ELSIE Database Analysis. PDA J Pharm Sci Technol. 2024 Aug 23;78(4):399-444.
Ball D, Blanchard J, Jacobson-Kram D, McClellan RO, McGovern T, Norwood DL, et al. Development of Safety Qualification Thresholds and Their Use in Orally Inhaled and Nasal Drug Product Evaluation. Toxicol Sci. 2007 Jun;97(2):226-36.
Appendix 1: Typical workflows for E&L risk assessment and risk control
附錄 1: 可提取物和浸出物（E&L）風(fēng)險(xiǎn)評(píng)估及風(fēng)險(xiǎn)控制的典型工作流程
The following diagrams illustrate typical workflows for E&L overall risk assessment and risk control, for component qualifications for manufacturing components/systems packaging (Figure 4) and packaging and delivery device components/systems (Figure 5). Typically for manufacturing components/systems and under most circumstances for packing systems, a safety assessment of leachable studies considering worst case conditions is expected. However, under certain low risk circumstances, alternative approaches can be proposed. In all instances, similar to the examples given in Table A.1.1 and Table A.1.2 and where other low-risk scenarios could occur, the approach taken should be justified (see Table A.1.1 and Table A.1.2). Overall, it is expected that the extent of data requirements and subsequent quality and safety assessment is commensurate with the overall level of risk.
以下圖表展示了 E&L 整體風(fēng)險(xiǎn)評(píng)估及風(fēng)險(xiǎn)控制的典型工作流程，涉及生產(chǎn)組件 / 系統(tǒng)包裝的組件確認(rèn)（圖 4）以及包裝和給藥裝置組件 / 系統(tǒng)的組件確認(rèn)（圖 5）。通常對(duì)于生產(chǎn)組件 / 系統(tǒng)，以及在大多數(shù)情況下對(duì)于包裝系統(tǒng)，需要結(jié)合最壞情況對(duì)浸出物研究進(jìn)行安全性評(píng)估。然而，在某些低風(fēng)險(xiǎn)情況下，可以提出替代方法。在所有情況下，與表 A.1.1 和表 A.1.2 中給出的示例類似，以及在可能出現(xiàn)其他低風(fēng)險(xiǎn)場(chǎng)景時(shí)，所采用的方法都應(yīng)提供正當(dāng)理由（參見表 A.1.1 和表 A.1.2）。總體而言，數(shù)據(jù)要求的范圍以及后續(xù)的質(zhì)量和安全性評(píng)估應(yīng)與整體風(fēng)險(xiǎn)水平相匹配。
Figure 4: Typical workflow for E&L assessment related risk identification and mitigation for manufacturing components/systems
圖 4：與生產(chǎn)組件 / 系統(tǒng)相關(guān)的可提取物與可浸出物（E&L）評(píng)估的典型工作流程 — 風(fēng)險(xiǎn)識(shí)別與緩解
Refer to Section 4.3 for method qualification and chemical identification expectations as well as scenarios where a leachable study is recommended.
有關(guān)方法確認(rèn)、化學(xué)物質(zhì)識(shí)別的要求以及建議進(jìn)行浸出物研究的場(chǎng)景，請(qǐng)參見第 4.3 節(jié)。
Amount of extractable(s) or leachable(s) are below the applicable safety threshold for each compound.
每種化合物的可提取物或浸出物量低于適用的安全閾值。
** For manufacturing process employing multiple components constructed with the same or similar material, cumulative leachables risk should be assessed for the final drug product (see Section 3.4.1).
** 對(duì)于使用多個(gè)由相同或相似材料制成的組件的生產(chǎn)工藝，應(yīng)評(píng)估最終藥品中浸出物的累積風(fēng)險(xiǎn)（參見第 3.4.1 節(jié)）。
Figure 5: Typical workflow for E&L assessment related risk identification and mitigation for packaging and delivery device components
圖 5：與包裝及給藥裝置組件相關(guān)的可提取物與可浸出物（E&L）評(píng)估的典型工作流程 — 風(fēng)險(xiǎn)識(shí)別與緩解
Table A.1.1: Manufacturing Equipment Components/Systems Scenarios
表 A.1.1：生產(chǎn)設(shè)備組件 / 系統(tǒng)場(chǎng)景
In general, comprehensive extractable and leachable data should be provided for all primary packaging components/systems and delivery device components.
一般而言，應(yīng)為所有初級(jí)包裝組件 / 系統(tǒng)和給藥裝置組件提供全面的可提取物和浸出物數(shù)據(jù)。
However, for overall low - risk scenarios (see Figure 2, Section 3.2) an abbreviated data package that includes a quantitative extractables study may be adequate with justification.
然而，對(duì)于整體低風(fēng)險(xiǎn)場(chǎng)景（見第 3.2 節(jié)圖 2），經(jīng)合理說(shuō)明后，包含定量可提取物研究的簡(jiǎn)化數(shù)據(jù)包可能就足夠。
See Section 3.4 for situations where a leachable study should be conducted to address the specific concerns and demonstrate acceptability of the components.
若需開展浸出物研究以解決特定問(wèn)題并證明組件的可接受性，相關(guān)情形請(qǐng)見第 3.4 節(jié) 。
Table A.1.2: Examples For Abbreviated Data Package for Packaging and Delivery Device Components
表 A.1.2：包裝及給藥裝置組件簡(jiǎn)化數(shù)據(jù)包示例
Note 1 for Table A.1.1 and Table A.1.2:
表 A.1.1 和表 A.1.2 的注釋 1
Refer to section 4.3 for recommendations for extractable and leachable study, as appropriate.
如需可提取物和浸出物研究相關(guān)建議，酌情參考第 4.3 節(jié) 。
Refer to section 3.5 for recommendation for appropriate documentation and compliance, as appropriate.
如需恰當(dāng)文件記錄和合規(guī)性相關(guān)建議，酌情參考第 3.5 節(jié) 。
*If no or few extractables are detected above the AET, and below their applicable safety threshold (such as Class 3 leachables; See Section 6), in conjunction with prior knowledge an abbreviated data package may be warranted with adequate justification. When an abbreviated data package is proposed, communications with relevant regional Regulatory Agency/Health Authority is recommended to align on approach.
* 若檢測(cè)到高于分析評(píng)估閾值（AET）但低于其適用安全閾值（如 3 類浸出物；見第 6 節(jié) ）的可提取物數(shù)量為零或很少，結(jié)合先前知識(shí)，經(jīng)充分論證后，采用簡(jiǎn)化數(shù)據(jù)包可能是合理的。若提議采用簡(jiǎn)化數(shù)據(jù)包，建議與相關(guān)地區(qū)的監(jiān)管機(jī)構(gòu) / 衛(wèi)生當(dāng)局溝通，以在方法上達(dá)成一致 。
Appendix 2: Types of Studies
附錄 2：研究類型
Table A.2.1: Summary of Extractable, Leachable and Simulated Leachable Studies
表 A.2.1：可提取物、可浸出物及模擬可浸出物研究概述
Refer to Section 4.3 for detailed recommendations for extractable and leachable study, as appropriate.
酌情參考第 4.3 節(jié)，獲取有關(guān)可提取物和可浸出物研究的詳細(xì)建議。
Appendix 3: AET Calculations
附錄 3: 分析評(píng)估閾值（AET）計(jì)算
Each of the examples provided are based upon using the applicable SCT (µg/day) for the drug product. In some instances, an alternative starting point may be pertinent (such as for a potential Class 1 leachable). In all calculations, worst-case assumptions such as maximum approved dosing of the drug product should be assumed. Common examples for both extractables and leachables studies are provided. Calculation of the AET should clearly indicate what the units are and how the calculation was performed. Regardless of the units used to express the AET, the final value for a given study should always equate to the same patient exposure level (i.e., the SCT multiplied by the analytical uncertainty factor [UF]).
所提供的每個(gè)示例均基于藥品適用的安全關(guān)注閾值（SCT，單位：微克/天 ）。在某些情況下，替代起始點(diǎn)可能適用（比如針對(duì)潛在的1類可浸出物 ）。在所有計(jì)算中，均應(yīng)采用最壞情況假設(shè)，如假設(shè)藥品的最大獲批給藥劑量 。提供了可提取物和可浸出物研究的常見示例。分析評(píng)估閾值（AET）的計(jì)算應(yīng)明確說(shuō)明單位是什么以及計(jì)算是如何進(jìn)行的 。無(wú)論用于表示AET的單位如何，特定研究的最終值應(yīng)始終等同于相同的患者暴露水平（即SCT乘以分析不確定因子（UF） ）。
Maximum Daily Dose (MDD) and Safety Concern Threshold (SCT)
最大日劑量（MDD）與安全關(guān)注閾值（SCT）
For each product the calculation of the AET should be based on the MDD.The MDD is the maximum approved dose of a drug administered in a single day.
對(duì)于每種產(chǎn)品，AET 的計(jì)算均應(yīng)基于 MDD 。MDD 是指藥品在一日內(nèi)給藥的最大獲批劑量 。
To determine the SCT, both the TTC and QT should be considered, as indicated in Table 1.The lowest of these values determines the SCT.
如表格 1 所示，確定 SCT 時(shí)，應(yīng)同時(shí)考量毒理學(xué)關(guān)注閾值（TTC）和定量閾值（QT） 。這些數(shù)值中的最小值決定 SCT 。
Intermittent Dosing
間歇性給藥
If a drug is not administered every day, for derivation of the applicable TTC ICH M7 is followed (e.g., when total number of dosing days is ≤30, the TTC = 120 µg).
若藥品并非每日給藥，推導(dǎo)適用的 TTC 時(shí)應(yīng)遵循 ICH M7（例如，當(dāng)給藥總天數(shù)≤30 天，TTC = 120 微克 ）。
For derivation of the QT, when total number of dosing days is ≤30 days or the dosing frequency is once per month or less, the ≤ 1 month QT can be used.
推導(dǎo) QT 時(shí)，若給藥總天數(shù)≤30 天，或給藥頻率為每月一次或更低，可采用≤1 個(gè)月對(duì)應(yīng)的 QT 。
Multi - day Products
多日使用產(chǎn)品
For products that are applied and may remain in place for multiple days (e.g. multi - day patches, depot injections, implants), the applicable TTC is defined by the total duration of treatment.For mutagenic impurities, per ICH M7 an average daily exposure should be used.For non - mutagenic leachable, the default assumption is that all leachables migrate within a day.In this case, the applicable QT is defined by the total number of applications.A slower migration rate would decrease the daily dose to a non - mutagenic leachable but increase the number of dosing days.A slower migration rate should be justified with data.
對(duì)于施用后可能留存多日的產(chǎn)品（如多日貼劑、緩釋注射劑、植入物），適用的 TTC 由治療總時(shí)長(zhǎng)界定 。對(duì)于致突變性雜質(zhì)，依據(jù) ICH M7，應(yīng)采用平均每日暴露量 。對(duì)于非致突變性可浸出物，默認(rèn)假設(shè)是所有可浸出物在一日內(nèi)遷移 。在此情形下，適用的 QT 由施用總次數(shù)界定 。遷移速率較慢會(huì)降低非致突變性可浸出物的日劑量，但會(huì)增加給藥天數(shù) 。遷移速率較慢的情況需以數(shù)據(jù)為依據(jù)進(jìn)行說(shuō)明 。
Example AET Calculations
示例分析評(píng)估閾值（AET）計(jì)算
Extractable Scenario 1: Filter used as part of a manufacturing process for a liquid drug product
可提取物場(chǎng)景 1：用于液體制藥生產(chǎn)工藝的過(guò)濾器
(1)AET (µg/filter) = SCT (µg/day) × UF × Doses per drug product batch* ÷ Filters/batch
（1）AET（微克 / 過(guò)濾器）= 安全關(guān)注閾值（SCT，微克 / 天）× 不確定因子（UF）× 每批藥品的劑量數(shù) * ÷ 每批所用過(guò)濾器數(shù)量
(2)AET (µg/g filter) = AET (µg/filter) ÷ Weight (g)/filter
（2）AET（微克 / 克過(guò)濾器）= AET（微克 / 過(guò)濾器）÷ 過(guò)濾器重量（克 / 個(gè)）
(3)AET (µg/mL extraction solvent) = AET (µg/filter) ÷ Extraction solvent (mL)/filter
（3）AET（微克 / 毫升提取溶劑）= AET（微克 / 過(guò)濾器）÷ 每個(gè)過(guò)濾器所用提取溶劑體積（毫升）
(4)AET (µg/cm²) = AET (µg/filter) ÷ Contact surface area (cm²)/filter
（4）AET（微克 / 平方厘米）= AET（微克 / 過(guò)濾器）÷ 每個(gè)過(guò)濾器的接觸表面積（平方厘米）
*The MDD administered in a single day and the minimum potential batch size should be used to determine the number of doses per drug product batch (i.e., the worst-case scenario). Thus, if the maximum approved dose given in a single day is 100 mg (= 0.1 g) and the minimum potential batch size in 1 kg (= 1000 g), the doses per drug product batch is 1000 g/batch ÷ 0.1 g/dose = 10,000 doses per drug product batch.
* 應(yīng)使用單日最大日劑量（MDD）和最小潛在批量來(lái)確定每批藥品的劑量數(shù)（即最壞情況）。因此，若單日最大獲批劑量為 100 毫克（=0.1 克），最小潛在批量為 1 千克（=1000 克），則每批藥品的劑量數(shù)為 1000 克 / 批 ÷ 0.1 克 / 劑量 = 10,000 劑量 / 批。
Extractable Scenario 2: Rubber vial stopper as part of CCS for a liquid drug product
可提取物場(chǎng)景 2：作為液體制品容器密閉系統(tǒng)（CCS）組成部分的橡膠瓶塞
(1)AET (µg/stopper) = SCT (µg/day) × UF × Volume/vial (mL/stopper) ÷ Maximum dose in a day (mL)*
（1）AET（微克 / 瓶塞）= 安全關(guān)注閾值（SCT，微克 / 天）× 不確定因子（UF）× 每瓶體積（毫升 / 瓶塞）÷ 單日最大劑量（毫升）*
(2)AET (µg/g stopper) = AET (µg/stopper) ÷ Stopper weight (g)
（2）AET（微克 / 克瓶塞）= AET（微克 / 瓶塞）÷ 瓶塞重量（克）
(3)AET (µg/mL extraction solvent) = AET (µg/stopper) ÷ Extraction solvent (mL)/Stopper
（3）AET（微克 / 毫升提取溶劑）= AET（微克 / 瓶塞）÷ 每個(gè)瓶塞所用提取溶劑體積（毫升）
(4)AET (µg/mL extraction solvent) = AET (µg/g stopper) ÷ Extraction solvent (mL)/gram of Stopper
（4）AET（微克 / 毫升提取溶劑）= AET（微克 / 克瓶塞）÷ 每克瓶塞所用提取溶劑體積（毫升）
*The maximum approved volumetric dose administered in a single day should be used (i.e., the worst-case scenario). If dosing is described on a mass basis (e.g., mg/day), it should be converted to a volume (mL) based upon the concentration of the active ingredient. Thus, if the maximum approved dose given in a single day is 100 mg (= 0.1 g) and the concentration of the drug product is 10 mg/mL, the maximum dose in a day for the calculation is 100 mg ÷ 10 mg/mL = 10 mL.
* 應(yīng)使用單日最大獲批體積劑量（即最壞情況）。若劑量以質(zhì)量單位描述（如毫克 / 天），應(yīng)根據(jù)活性成分濃度轉(zhuǎn)換為體積（毫升）。因此，若單日最大獲批劑量為 100 毫克（=0.1 克），藥品濃度為 10 毫克 / 毫升，則計(jì)算所用的單日最大劑量為 100 毫克 ÷ 10 毫克 / 毫升 = 10 毫升。
Leachable Scenario 1: Leachables for manufacturing equipment for liquid drug product
可浸出物場(chǎng)景 1：液體制藥生產(chǎn)設(shè)備的可浸出物
(1)AET (µg/batch) = SCT (µg/day) × UF × Doses per drug product batch*
（1）AET（微克 / 批）= 安全關(guān)注閾值（SCT，微克 / 天）× 不確定因子（UF）× 每批藥品的劑量數(shù) *
(2)AET (µg/mL drug product) = SCT (µg/day) × UF ÷ Maximum dose in a day (mL)
（2）AET（微克 / 毫升藥品）= 安全關(guān)注閾值（SCT，微克 / 天）× 不確定因子（UF）÷ 單日最大劑量（毫升）
*The MDD administered in a single day and the minimum potential batch size should be used to determine the number of doses per drug product batch (i.e., the worst-case scenario). Thus, if the maximum approved dose given in a single day is 5 mL and the minimum potential batch size in 10 L (= 10,000 mL), the doses per drug product batch is 10,000 mL/batch ÷ 5 mL/dose = 2,000 doses per drug product batch.
* 應(yīng)使用單日最大日劑量（MDD）和最小潛在批量來(lái)確定每批藥品的劑量數(shù)（即最壞情況）。因此，若單日最大獲批劑量為 5 毫升，最小潛在批量為 10 升（=10,000 毫升），則每批藥品的劑量數(shù)為 10,000 毫升 / 批 ÷ 5 毫升 / 劑量 = 2,000 劑量 / 批。
Leachable Scenario 2: Leachables for a prefilled syringe (PFS)
可浸出物場(chǎng)景 2：預(yù)填充注射器（PFS）的可浸出物
(1)AET (µg/mL drug product) = SCT (µg/day) × UF ÷ Maximum dose in a day (mL)*
（1）AET（微克 / 毫升藥品）= 安全關(guān)注閾值（SCT，微克 / 天）× 不確定因子（UF）÷ 單日最大劑量（毫升）*
(2)AET (µg/PFS) = AET (µg/mL drug product) × Volume per PFS (mL)
（2）AET（微克 / 預(yù)填充注射器）= AET（微克 / 毫升藥品）× 每個(gè)預(yù)填充注射器的體積（毫升）
*The maximum approved volumetric dose administered in a single day should be used (i.e., the worst-case scenario). If dosing is described on a mass basis (e.g., mg/day), it should be converted to a volume (mL) based upon the concentration of the active ingredient. Thus, if the maximum approved dose given in a single day is 10 mg and the concentration of the drug product is 10 mg/mL, the maximum dose in a day for the calculation is 10 mg ÷ 10 mg/mL = 1 mL.
* 應(yīng)使用單日最大獲批體積劑量（即最壞情況）。若劑量以質(zhì)量單位描述（如毫克 / 天），應(yīng)根據(jù)活性成分濃度轉(zhuǎn)換為體積（毫升）。因此，若單日最大獲批劑量為 10 毫克，藥品濃度為 10 毫克 / 毫升，則計(jì)算所用的單日最大劑量為 10 毫克 ÷ 10 毫克 / 毫升 = 1 毫升。
Appendix 4: Potency Classes for Leachables
附錄 4：可浸出物的效力等級(jí)
The chemical nature of potential leachable compounds is varied as are their safety databases. In order to remain patient protective while maintaining a practical approach to setting safety thresholds, a leachables classification scheme has been developed, in addition to the thresholds applied in the guideline.
潛在可浸出物的化學(xué)性質(zhì)各異，其安全性數(shù)據(jù)庫(kù)也各不相同。為在保護(hù)患者的同時(shí)，以切實(shí)可行的方式設(shè)定安全閾值，除本指南中應(yīng)用的閾值外，還制定了可浸出物分類體系。
The classification scheme is based on systemic effects and is broadly applicable to all routes of administration. However, the concentration thresholds applicable to drug products with specific routes of administration as indicated in Section 6.1 Table 1 are not impacted by this classification scheme. As such, the default concentration thresholds for potential local effects of a leachable are the same regardless of leachable class.
該分類體系基于全身效應(yīng)，廣泛適用于所有給藥途徑。但第 6.1 節(jié)表 1 中所列特定給藥途徑藥品的濃度閾值不受此分類體系影響。因此，無(wú)論可浸出物屬于哪一等級(jí)，其潛在局部效應(yīng)的默認(rèn)濃度閾值均相同。
Class 1 leachables are generally those compounds for which the thresholds for mutagenic and systemic effects as described in this guideline have not been demonstrated to be sufficiently patient protective. Thus, for Class 1 leachables an acceptable exposure level should be established on a compound-specific basis.
1 類可浸出物通常指本指南中所述的致突變效應(yīng)和全身效應(yīng)閾值未被證明能充分保護(hù)患者的化合物。因此，1 類可浸出物的可接受暴露水平應(yīng)根據(jù)具體化合物確定。
Class 1 includes: ICH M7 cohort of concern compounds, ICH M7 Class 1 compounds with an AI < 1.5 µg/day, and non-mutagenic leachables with a derived Permitted Daily Exposure (PDE) following the methodology described in Appendix 5 for which the established QT values may not be protective of patient safety (see Appendix 6).
1 類可浸出物包括：ICH M7 關(guān)注組化合物、每日可接受攝入量（AI）<1.5 微克的 ICH M7 1 類化合物，以及采用附錄 5 所述方法得出允許日暴露量（PDE）、且既定定量閾值（QT）可能無(wú)法保護(hù)患者安全的非致突變性可浸出物（見附錄 6）。
Class 2 is the default leachable classification and includes compounds for which the chronic parenteral administration thresholds for mutagenicity (TTC) and systemic toxicity (QT), as described in this guideline, are considered to be sufficiently patient protective.
2 類是可浸出物的默認(rèn)分類，包括本指南所述的慢性腸外給藥致突變性閾值（TTC）和全身毒性閾值（QT）被認(rèn)為能充分保護(hù)患者的化合物。
This includes all compounds for which a PDE was not specifically listed in this guideline.
這包括本指南中未具體列出允許日暴露量（PDE）的所有化合物。
Class 3 leachables are compounds established to have relatively low potency for systemic toxicity with derived chronic parenteral PDE in excess of the levels at which leachables are typically observed. Class 3 leachables would not require further safety qualification if observed at daily exposure levels < 1.0 mg/day.
3 類可浸出物是經(jīng)確認(rèn)具有相對(duì)較低全身毒性效力的化合物，其得出的慢性腸外給藥允許日暴露量（PDE）超過(guò)可浸出物通常觀察到的水平。若 3 類可浸出物的每日暴露水平 < 1.0 毫克 / 天，則無(wú)需進(jìn)一步的安全性確認(rèn)。
A summary of these leachables classes is provided in Table A.4.1, below.
這些可浸出物等級(jí)的概述詳見下文表 A.4.1。
Leachable levels greater than identified in Table A.4.1 should be scientifically justified as described in Appendix 5.
超過(guò)表 A.4.1 中規(guī)定水平的可浸出物，應(yīng)按照附錄 5 所述進(jìn)行科學(xué)論證。
Table A.4.1: Potency Classes for Leachables
表 A.4.1：可浸出物的效力等級(jí)
Class 1 Leachables to be avoided
1 類應(yīng)避免的可浸出物
Class 3 Leachables With Relatively Low Toxic Potential (Chronic Parenteral PDE ≥ 1 mg/day). Monographs In Supporting Documents.
3 類毒性潛力相對(duì)較低的可浸出物（慢性腸外給藥允許日暴露量≥1 毫克 / 天 ）。支持性文件中的各論 。
Appendix 5: Methods for Establishing Exposure Limits
附錄 5：暴露限值的確定方法
Background
背景
For Class 1 leachables and Class 2/3 leachables exceeding their applicable safety threshold as defined in this guideline, further safety assessment is performed to establish the potential risk associated with exposure to these leachables when a patient is administered a specific drug product.
對(duì)于 1 類可浸出物以及超出本指南所定義適用安全閾值的 2 類 / 3 類可浸出物，當(dāng)患者使用特定藥品時(shí)，需開展進(jìn)一步安全評(píng)估，以確定接觸這些可浸出物帶來(lái)的潛在風(fēng)險(xiǎn)。
Permitted Daily Exposure (PDE) values intended to support safe exposure to a compound in any drug product are not currently established for the vast majority of potential leachables.
目前，對(duì)于絕大多數(shù)潛在可浸出物，尚未確立能支持其在任意藥品中安全暴露的允許日暴露量（PDE）數(shù)值。
Furthermore, due to the varied nature of currently available drug products and the complexity of extractables and leachables safety risk assessment, a one size fits all approach, such as an established PDE, is not always most pertinent.
此外，鑒于現(xiàn)有藥品的多樣性以及可提取物和可浸出物安全風(fēng)險(xiǎn)評(píng)估的復(fù)雜性，“一刀切” 的方法（如既定的 PDE ）并非總是最恰當(dāng)?shù)摹?/span>
Although the focus of this guideline is not on the generation of acceptable exposure levels for individual compounds, the need for compound-specific limits on a product-by-product basis may commonly arise.
盡管本指南重點(diǎn)并非針對(duì)單個(gè)化合物生成可接受暴露水平，但按產(chǎn)品逐個(gè)確定化合物特定限值的需求經(jīng)常出現(xiàn)。
Therefore, this appendix provides guidance to appropriately establishing the safety of leachables for a variety of drug product types and administration scenarios using a risk-based approach.
因此，本附錄提供指導(dǎo)，以基于風(fēng)險(xiǎn)的方法，針對(duì)各類藥品類型和給藥場(chǎng)景，合理確立可浸出物的安全性。
The extent of the information considered sufficient to conclude on the acceptability of potential patient exposure levels for a leachable may vary extensively and there are multiple methodologies which may be employed to establish this acceptability.
判定可浸出物潛在患者暴露水平是否可接受所需的信息詳盡程度差異極大，且有多種方法可用于確立這種可接受性。
The most straight-forward methodology is to employ already established safe exposure levels which have conservatively assumed worst scenarios.
最直接的方法是采用已確立的、保守假設(shè)最壞情形的安全暴露水平。
Thus, when there is an established PDE in an available ICH guidance (e.g., Q3C or M7) it is sufficient to refer to this value assuming all requisite considerations are met.
因此，若現(xiàn)有 ICH 指導(dǎo)原則（如 Q3C 或 M7 ）中已確立 PDE，且滿足所有必要考量，直接引用該數(shù)值即可。
Alternatively, an acceptable exposure derived using similar methodologies and scientific principles as previously established in such guidelines may be deemed more applicable or necessary.
或者，采用與這些指導(dǎo)原則中先前確立的類似方法和科學(xué)原理推導(dǎo)得出的可接受暴露水平，可能被認(rèn)為更適用或更有必要。
In still other scenarios, the dose ratio between a well-defined, supported and justified NOAEL and the anticipated patient exposure may be so large (e.g., >10,000) that a detailed derivation may not be necessary.
在其他情形下，清晰界定、有依據(jù)且合理的未觀察到不良反應(yīng)水平（NOAEL ）與預(yù)期患者暴露量的劑量比可能極大（如 > 10,000 ），此時(shí)可能無(wú)需詳細(xì)推導(dǎo)。
Though in certain circumstances, in vitro and/or in vivo studies (as a last resort) may be deemed necessary to establish an acceptable exposure level, scientific justification (if applicable) via available in silico analyses and through read across to similar compounds (i.e., surrogate compound[s]) is encouraged to establish acceptable exposure levels.
盡管在某些情況下，體外和 / 或體內(nèi)研究（作為最后手段 ）可能被認(rèn)為是確立可接受暴露水平所必需的，但仍鼓勵(lì)通過(guò)現(xiàn)有計(jì)算機(jī)模擬分析以及關(guān)聯(lián)到類似化合物（即替代化合物 ）的科學(xué)論證（如適用 ）來(lái)確立可接受暴露水平。
Although a variety of in silico toxicological tools are available, mutagenicity is the only toxicological endpoint for which such an appropriately conducted evaluation is currently well-established for stand-alone use in lieu of biological data within the context of this guideline (see ICH M7).
盡管有多種計(jì)算機(jī)毒理學(xué)工具可用，但在本指南范圍內(nèi)，致突變性是目前唯一一種經(jīng)恰當(dāng)開展的評(píng)估、已確立可單獨(dú)用于替代生物學(xué)數(shù)據(jù)的毒理學(xué)終點(diǎn)（見 ICH M7 ）。
However, with appropriate scientific justification, predictions of other toxicological endpoints using in silico, in vitro, or in vivo models should be incorporated into the safety risk assessment to supplement any existing data in a weight-of-evidence risk-based approach.
不過(guò)，在有合理科學(xué)論證的情況下，使用計(jì)算機(jī)模擬、體外或體內(nèi)模型對(duì)其他毒理學(xué)終點(diǎn)的預(yù)測(cè)，應(yīng)納入安全風(fēng)險(xiǎn)評(píng)估，以基于證據(jù)權(quán)重的風(fēng)險(xiǎn)評(píng)估方法補(bǔ)充現(xiàn)有數(shù)據(jù)。
Within each of these categories, greater priority should be given to data from validated models that account for the relevant exposure route(s).
在上述每類方法中，應(yīng)優(yōu)先考慮經(jīng)驗(yàn)證模型得出的數(shù)據(jù)，且這些模型需涵蓋相關(guān)暴露途徑。
Due to the limited nature or even lack of toxicological datasets for a large number of potential leachables, a read-across approach may also be incorporated.
由于大量潛在可浸出物的毒理學(xué)數(shù)據(jù)集有限甚至缺失，也可采用關(guān)聯(lián)（read-across）方法。
In a read-across approach, toxicological data for a surrogate compound (or multiple surrogates) with pertinent toxicological data are used to support the safety assessment of a leachable of interest either as part of a weight-of-evidence approach or in lieu of data for the leachable of interest when none is available.
在關(guān)聯(lián)方法中，具有相關(guān)毒理學(xué)數(shù)據(jù)的替代化合物（或多個(gè)替代物）的毒理學(xué)數(shù)據(jù)，可用于支持目標(biāo)可浸出物的安全評(píng)估—— 作為證據(jù)權(quán)重方法的一部分，或在目標(biāo)可浸出物無(wú)數(shù)據(jù)時(shí)替代其數(shù)據(jù)。
Safety assessments incorporating a surrogate compound should provide clear justification for the selection of the surrogate(s).
納入替代化合物的安全評(píng)估，應(yīng)對(duì)替代物的選擇提供清晰論證。
There are various attributes that should be considered (if known) during the selection of a suitable surrogate, including mode of action, the principal toxicophore and surrounding chemical environment (e.g., presence of functional groups that may impact biological activity), overall structural similarity, toxicokinetic properties, physicochemical properties (e.g., polarity, solubility, ionizability, and molecular weight).
選擇合適替代物時(shí)（如有已知信息），應(yīng)考慮多種屬性，包括作用模式、主要毒效基團(tuán)及周邊化學(xué)環(huán)境（如可能影響生物活性的官能團(tuán)存在情況）、整體結(jié)構(gòu)相似性、毒代動(dòng)力學(xué)性質(zhì)、理化性質(zhì)（如極性、溶解度、離子化程度和分子量）。
When properly justified, in silico tools and data from NAMs may be used to support the selection of surrogates and inform the read-across approach, but the above-mentioned criteria need to be considered.
在恰當(dāng)論證后，計(jì)算機(jī)模擬工具和非動(dòng)物實(shí)驗(yàn)方法（NAMs ）的數(shù)據(jù)可用于支持替代物選擇并為關(guān)聯(lián)方法提供信息，但仍需考慮上述標(biāo)準(zhǔn)。
How a surrogate is incorporated into the safety assessment for the leachable of interest should be scientifically justified.
替代物如何納入目標(biāo)可浸出物的安全評(píng)估，應(yīng)進(jìn)行科學(xué)論證。
Potential uncertainties related to the read-across approach should also be indicated and appropriately accounted for, such as when using for an acceptable exposure level determination (see F7 discussion below).
與關(guān)聯(lián)方法相關(guān)的潛在不確定性也應(yīng)指明并合理考量，比如用于確定可接受暴露水平時(shí)（見下文 F7 討論 ）。
Data to be Evaluated and Incorporated into the Safety Assessment
需評(píng)估并納入安全評(píng)估的數(shù)據(jù)
In order to establish the safety of a leachable in a specific drug product, a thorough safety assessment of the compound should be provided.
為確定特定藥品中某可浸出物的安全性，應(yīng)對(duì)該化合物開展全面的安全評(píng)估。
Data elements to be included (where data are available) are listed below. The relevance and quality of these datasets should also be assessed.
以下列出需納入的各類數(shù)據(jù)（如有相關(guān)數(shù)據(jù)）。還應(yīng)評(píng)估這些數(shù)據(jù)集的相關(guān)性與質(zhì)量。
As noted above, any use of surrogate compound data with in silico analyses should also be incorporated into the safety assessment and justified.
如前文所述，使用替代化合物數(shù)據(jù)結(jié)合計(jì)算機(jī)模擬分析的情況，也應(yīng)納入安全評(píng)估并進(jìn)行論證。
Additionally, if several observed leachables are grouped together for evaluation, the details and justification of this grouping should be included.
此外，若將多種已觀測(cè)到的可浸出物分組進(jìn)行評(píng)估，需說(shuō)明分組細(xì)節(jié)及理由。
Pharmacological/Biological Data
藥理 / 生物學(xué)數(shù)據(jù)
Consider available in vivo or in vitro data that suggest the potential for biological effects that could impact the overall safety assessment (e.g., endocrine disruption, anticholinergic activity).
考量現(xiàn)有體內(nèi)或體外數(shù)據(jù)，這些數(shù)據(jù)若提示可能存在影響整體安全評(píng)估的生物學(xué)效應(yīng)（如內(nèi)分泌干擾、抗膽堿能活性），需加以關(guān)注。
Toxicokinetics (TK)
毒代動(dòng)力學(xué)（TK）
Assess and summarize data relevant to the drug product’s route of administration
評(píng)估并總結(jié)與藥品給藥途徑相關(guān)的數(shù)據(jù)
Consider potential differences between absorption and bioavailability, especially when route-to-route extrapolations are required.
考量吸收與生物利用度間的潛在差異，尤其在需要進(jìn)行給藥途徑間外推時(shí)
Bioaccumulation potential should be considered.
應(yīng)考量生物蓄積潛力
Systemic Toxicity
全身毒性
Summarize relevant acute, subacute/subchronic and chronic toxicity studies.
總結(jié)相關(guān)的急性、亞急性 / 亞慢性和慢性毒性研究
Indicate relevance of data to humans.
說(shuō)明數(shù)據(jù)對(duì)人類的相關(guān)性
Identify critical study (or studies) for evaluating human systemic toxicity potential.
確定用于評(píng)估人體全身毒性潛力的關(guān)鍵研究（一項(xiàng)或多項(xiàng)）
Sensitization Potential/Local Irritation
致敏潛力 / 局部刺激性
Relevant available clinical and non-clinical data (supplemented with in silico evaluation, if justified) should be summarized.
應(yīng)總結(jié)現(xiàn)有相關(guān)臨床和非臨床數(shù)據(jù)（若合理，可輔以計(jì)算機(jī)模擬評(píng)估）
Regulatory classifications (or lack thereof) may be leveraged as pertinent.
可合理利用監(jiān)管分類（或無(wú)相關(guān)分類的情況）
Developmental and Reproductive Toxicity (DART)
發(fā)育與生殖毒性（DART）
In addition to summarizing available DART studies, data and/or classifications with respect to endocrine disrupting properties should evaluated and included.
除總結(jié)現(xiàn)有 DART 研究外，還應(yīng)評(píng)估并納入與內(nèi)分泌干擾特性相關(guān)的數(shù)據(jù)和 / 或分類
Genotoxicity and Carcinogenicity
遺傳毒性與致癌性
Summarize available data and indicate potential relevance to humans.
總結(jié)現(xiàn)有數(shù)據(jù)并說(shuō)明對(duì)人類的潛在相關(guān)性
If data are not available, in silico methods consistent with ICH M7 should be used for evaluation (Note: ICH M7 Class 4 is not applicable to leachables).
若無(wú)數(shù)據(jù)，應(yīng)使用符合 ICH M7 的計(jì)算機(jī)模擬方法進(jìn)行評(píng)估（注：ICH M7 的 4 類不適用于可浸出物 ）
Mechanism(s) for genotoxicity and/or carcinogenicity should be provided if applicable as this is particularly pertinent for acceptable exposure determinations.
若適用，應(yīng)提供遺傳毒性和 / 或致癌性的作用機(jī)制，因這對(duì)確定可接受暴露量尤為關(guān)鍵
Additional Information
補(bǔ)充信息
Additional pertinent information to the safety assessment should also be included as available.
應(yīng)納入現(xiàn)有與安全評(píng)估相關(guān)的補(bǔ)充信息（如有）
Examples: Existing heath-based risk limit/assessments, clinical and epidemiological data, toxicological data from similar/related compounds
示例：現(xiàn)有基于健康的風(fēng)險(xiǎn)限值 / 評(píng)估、臨床和流行病學(xué)數(shù)據(jù)、來(lái)自類似 / 相關(guān)化合物的毒理學(xué)數(shù)據(jù)
Acceptable Exposure Calculations
可接受暴露量計(jì)算
The PDE concept has been implemented as a health-based exposure limit in ICH guidelines in addition to other health-based limits such as the Acceptable Intake (AI).
在 ICH 指南中，除可接受攝入量（AI）等其他基于健康的限值外，允許日暴露量（PDE）概念也被用作基于健康的暴露限值。
The process for calculation of a PDE is generally aligned across these guidelines.
這些指南中 PDE 的計(jì)算流程基本一致。
This same basic approach has been used to generate PDE values in support of the identified qualification thresholds of the current guideline (with the inclusion of additional modifying factors for bioavailability and for when a read-across approach is used).
本指南中，為支持已確定的資質(zhì)認(rèn)定閾值，也采用了相同的基本方法來(lái)生成 PDE 值（包括針對(duì)生物利用度和使用關(guān)聯(lián)方法時(shí)的額外修正因子）。
This approach is briefly described and summarized below and may be used as the basis for an acceptable exposure level for a leachable in a specific drug product.
下文簡(jiǎn)要描述和總結(jié)了該方法，其可作為特定藥品中可浸出物可接受暴露量的基礎(chǔ)。
Although the method for deriving an acceptable exposure level described here is based on the PDE methodology described in other ICH guidelines, it should be noted that the acceptable exposure may not necessarily be the same as the PDE.
盡管此處描述的可接受暴露量推導(dǎo)方法基于其他 ICH 指南中所述的 PDE 方法，但需注意，可接受暴露量未必與 PDE 完全一致。
Whereas the PDE is by definition an exposure level for lifetime and is applicable across many products, the product-specific acceptable exposure takes into account the duration of exposure and maximum daily dose.
PDE 按定義是終身暴露水平，適用于多種產(chǎn)品，而特定產(chǎn)品的可接受暴露量則需考慮暴露持續(xù)時(shí)間和最大日劑量。
Subsequent to review and evaluation of the available data and information for the leachable as described above, the derivation process begins with the selection of an appropriate point of departure (PoD) and then applying modifying factors (F1–F7).
在按上述內(nèi)容審查和評(píng)估可浸出物的現(xiàn)有數(shù)據(jù)和信息后，推導(dǎo)過(guò)程首先是選擇合適的起始點(diǎn)（PoD），然后應(yīng)用修正因子（F1–F7）。
The most relevant study should be used to select the PoD, taking into consideration the species used, the route and duration of exposure, the toxicological endpoints monitored, and the quality of the study data, if justified, it may not always be necessary to select the lowest NO(A)EL as a PoD.
應(yīng)使用最相關(guān)的研究來(lái)選擇 PoD，需考慮所用物種、暴露途徑和持續(xù)時(shí)間、監(jiān)測(cè)的毒理學(xué)終點(diǎn)以及研究數(shù)據(jù)的質(zhì)量；若有合理依據(jù)，未必一定要選擇最低的未觀察到（有害）效應(yīng)水平（NO (A) EL）作為 PoD。
Previous guidelines have used specific modifying factors for inter- and intraspecies variability (F1 and F2, respectively), duration of the study from which the PoD is taken (F3), severity of the toxicity (F4), and a factor to account for the absence of a NOAEL (F5).
先前的指南已使用特定修正因子來(lái)分別考慮種間和種內(nèi)變異（分別為 F1 和 F2）、PoD 所來(lái)源研究的持續(xù)時(shí)間（F3）、毒性嚴(yán)重程度（F4）以及無(wú)未觀察到不良反應(yīng)水平（NOAEL）時(shí)的修正因子（F5）。
As leachables cover a wide chemical space, bioavailability via various administration routes may vary.
由于可浸出物涉及廣泛的化學(xué)物質(zhì)，其通過(guò)不同給藥途徑的生物利用度可能存在差異。
Since toxicity data are often only available for a single route, the incorporation of an additional modifying factor (F6) is recommended in the current guideline to account for differences in bioavailability when route-to-route extrapolation is required.
由于毒性數(shù)據(jù)通常僅針對(duì)單一途徑，本指南建議加入額外修正因子（F6），以在需要進(jìn)行給藥途徑間外推時(shí)考慮生物利用度的差異。
Additionally, as noted previously, a PoD from a surrogate compound (read across approach) may also sometimes be necessary.
此外，如前文所述，有時(shí)可能需要使用來(lái)自替代化合物（關(guān)聯(lián)方法）的 PoD。
Thus, another modifying factor (F7) to account for uncertainty related to using this surrogate compound is recommended.
因此，建議使用另一個(gè)修正因子（F7）來(lái)考慮與使用該替代化合物相關(guān)的不確定性。
As the criteria for selecting values for F1–F5 have been detailed in existing guidelines, they are not repeated here.
由于 F1–F5 的取值標(biāo)準(zhǔn)已在現(xiàn)有指南中詳細(xì)說(shuō)明，此處不再贅述。
However, the newly introduced modifying factors (F6 and F7) pertinent to leachables are summarized below.
但下文總結(jié)了新引入的與可浸出物相關(guān)的修正因子（F6 和 F7）。
F6 = A variable factor to account for route of exposure extrapolation (e.g., oral to parenteral).
F6 = 用于考慮暴露途徑外推的可變因子（例如，從口服到腸外）。
In the absence of sufficient toxicity data on the leachable via the intended route of exposure of the drug product, F6 should be used to adjust for any pertinent difference in bioavailability between the PoD study route of administration and the drug product route of exposure.
若缺乏可浸出物通過(guò)藥品預(yù)期暴露途徑的充分毒性數(shù)據(jù)，應(yīng)使用 F6 來(lái)調(diào)整 PoD 所來(lái)源研究的給藥途徑與藥品暴露途徑之間在生物利用度上的任何相關(guān)差異。
Ideally, F6 should be based on bioavailability of the parent compound.
理想情況下，F(xiàn)6 應(yīng)基于母體化合物的生物利用度。
If a radiolabel study is used, it should be referred to as absorption because it is not clear if the radiolabel is the parent, a metabolite, or a combination of parent and metabolites.
若使用放射性標(biāo)記研究，應(yīng)稱為吸收度，因?yàn)闊o(wú)法明確放射性標(biāo)記是母體化合物、代謝物，還是母體與代謝物的混合物。
If the quality of data is good, the relative bioavailability estimate can be used to directly inform F6.
若數(shù)據(jù)質(zhì)量良好，相對(duì)生物利用度估算值可直接用于確定 F6。
When there is significant uncertainty for the bioavailability estimate, default factors may alternatively be applied.
當(dāng)生物利用度估算存在顯著不確定性時(shí)，可改用默認(rèn)因子。
For example, when using oral toxicity data to derive a parenteral acceptable exposure level:
例如，當(dāng)使用口服毒性數(shù)據(jù)推導(dǎo)腸外可接受暴露量時(shí)：
F6= 100 when oral bioavailability is <1% (divide by a modifying factor of 100)
當(dāng)口服生物利用度 < 1% 時(shí)，F(xiàn)6=100（除以修正因子 100）
F6= 10 when oral bioavailability is ≥ 1% and <50% (divide by a modifying factor of 10)
當(dāng)口服生物利用度≥1% 且 < 50% 時(shí)，F(xiàn)6=10（除以修正因子 10）
F6= 2 when oral bioavailability is ≥50% and <90% (divide by a modifying factor of 2), and
當(dāng)口服生物利用度≥50% 且 < 90% 時(shí)，F(xiàn)6=2（除以修正因子 2），以及
F6=1 when oral bioavailability is ≥ 90% (divide by a modifying factor of 1)
當(dāng)口服生物利用度≥90% 時(shí)，F(xiàn)6=1（除以修正因子 1）
In the absence of sufficient in vivo data, additional approaches should be employed as part of a weight-of-evidence strategy or in lieu of in vivo data.
在缺乏充足體內(nèi)數(shù)據(jù)時(shí)，應(yīng)采用額外方法，作為證據(jù)權(quán)重策略的一部分，或替代體內(nèi)數(shù)據(jù)。
For example, a NAM approach (combining in vitro data estimating absorption and internal clearance, with an in silico PBPK model) can be used to generate data to assess bioavailability if properly supported and scientifically justified.
例如，若有充分支持且科學(xué)合理，非動(dòng)物實(shí)驗(yàn)方法（NAM，結(jié)合估算吸收和內(nèi)在清除率的體外數(shù)據(jù)與計(jì)算機(jī)模擬的生理藥代動(dòng)力學(xué)（PBPK）模型 ）可用于生成數(shù)據(jù)以評(píng)估生物利用度。
Alternatively, a default modifying factor of 100 is suggested for F6, with smaller values requiring justification (e.g., reasoning based on the physicochemical characteristics of the compound).
或者，建議為 F6 設(shè)定默認(rèn)修正因子 100，使用更小數(shù)值需進(jìn)行論證（如基于化合物理化特性的推理 ）。
When suitable bioavailability data are available for a surrogate molecule allowing a read-across approach these data may be leveraged to inform the bioavailability estimate, if sufficiently justified.
若有適用于替代分子的生物利用度數(shù)據(jù)且可采用關(guān)聯(lián)方法，在充分論證后，這些數(shù)據(jù)可用于輔助生物利用度估算。
For some routes, such as inhalation, additional considerations are warranted when determining an appropriate F6 value.
對(duì)于某些給藥途徑（如吸入），確定合適的 F6 值時(shí)需額外考量。
For example, for an inhalation toxicology study, data on respiratory tract deposition, respiratory absorption rate and pulmonary metabolism may inform on F6.
例如，對(duì)于吸入毒理學(xué)研究，呼吸道沉積、呼吸吸收率和肺部代謝的數(shù)據(jù)可能會(huì)為 F6 提供參考。
For dermal routes, if toxicokinetic data are available these can be used to estimate the systemic dose.
對(duì)于經(jīng)皮給藥途徑，若有毒代動(dòng)力學(xué)數(shù)據(jù)，可用于估算全身劑量。
The parenteral QT can be referred to when evaluating the estimated total daily systemic dose of the leachable.
評(píng)估可浸出物的每日估算全身總劑量時(shí)，可參考腸外定量閾值（QT）。
In the absence of toxicokinetic data, when extrapolating from dermal dose to systemic dose, a default absorption of 70% or 50% is assumed to be sufficiently conservative for most organic solvent-based dilutes and water-based or dispersed dilutes, respectively.
缺乏毒代動(dòng)力學(xué)數(shù)據(jù)時(shí)，從經(jīng)皮劑量外推至全身劑量，對(duì)于大多數(shù)基于有機(jī)溶劑的稀釋液和水基或分散稀釋液，默認(rèn)分別采用 70% 或 50% 的吸收率，被認(rèn)為具有足夠保守性。
If both the molecular weight is greater than 500 and the logPow is either below –1 or above 4, a default absorption factor of 10% is assumed.
若分子量大于 500 且辛醇 - 水分配系數(shù)對(duì)數(shù)值（logPow ）小于 - 1 或大于 4，默認(rèn)采用 10% 的吸收因子。
Leachables may penetrate the skin to a greater extent when present in dermal drug products that are formulated for enhanced percutaneous absorption or where skin integrity may be compromised.
當(dāng)可浸出物存在于為增強(qiáng)經(jīng)皮吸收而配制的皮膚用藥品中，或皮膚完整性可能受損時(shí)，其滲透皮膚的程度可能更高。
A higher rate of absorption should be assumed in such cases.
此類情況下，應(yīng)假設(shè)更高的吸收率。
F7= A variable factor that may be applied if a Read Across Approach is used.
F7 = 采用關(guān)聯(lián)方法（Read Across Approach ）時(shí)可能應(yīng)用的可變因子。
When read across strategy is utilized, a factor of up to 5 may be used depending on the level of (dis)similarity to the leachable compound of interest.
采用關(guān)聯(lián)策略時(shí)，根據(jù)與目標(biāo)可浸出化合物的（不）相似程度，最多可使用 5 倍的因子。
In general, when a surrogate is considered similar based on the criteria described in this guideline, an F7 of 1 may be applicable.
一般而言，若根據(jù)本指南所述標(biāo)準(zhǔn)，替代物被認(rèn)為具有相似性，F(xiàn)7 可取 1。
References
參考文獻(xiàn)
Copies of articles (or other documents) referenced to support a proposed PDE should be provided.
應(yīng)提供用于支持?jǐn)M議允許日暴露量（PDE）的參考文獻(xiàn)（或其他文件 ）副本。
Margin of Safety (MOS) and justification for leachable levels higher than a calculated acceptable exposure level or established PDE
安全邊際（MOS）及可浸出物水平高于計(jì)算得出的可接受暴露水平或既定 PDE 的論證
For each substance for which an acceptable exposure level (e.g., PDE or AI) has been determined, a margin of safety can be calculated using the following formula:
對(duì)于每個(gè)已確定可接受暴露水平（如 PDE 或 AI ）的物質(zhì)，可使用以下公式計(jì)算安全邊際：
For any substances with an MOS <1, risk mitigation measures (such as the selection of alternate materials) that might reduce or eliminate the leachable of concern should be considered.
對(duì)于任何安全邊際（MOS）<1 的物質(zhì)，應(yīng)考慮采取風(fēng)險(xiǎn)緩解措施（如選擇替代材料 ），以減少或消除相關(guān)可浸出物。
Alternatively, it should be demonstrated that a limit greater than the acceptable exposure level (e.g., PDE) does not pose a safety concern for a specific drug product.
或者，應(yīng)證明高于可接受暴露水平（如 PDE ）的限值，對(duì)特定藥品而言不會(huì)引發(fā)安全性問(wèn)題。
An acceptable exposure level to a leachable higher than the calculated or established PDE may be acceptable in certain cases, taking into account relevant product-specific considerations. These cases could include, but are not limited to, the following situations:
在某些情況下，考慮到特定產(chǎn)品的相關(guān)因素，可浸出物高于計(jì)算得出或既定 PDE 的可接受暴露水平可能是可接受的。這些情況包括但不限于以下情形：
Intermittent administration of the drug to patients;
向患者間歇性給藥；
Short term administration (i.e., 30 days or less);
短期給藥（即 30 天或更短 ）；
Limited patient population (e.g., adult males only);
患者人群有限（如僅成年男性）；
Specific indications (e.g., life-threatening, unmet medical needs, rare diseases).
特定適應(yīng)癥（如危及生命、未滿足的醫(yī)療需求、罕見?。?。
Additionally, it should be noted, that for drugs administered for less than lifetime to the patient, it may be appropriate to use a lower value for F3 than would usually be applied where a toxicity study of short-term exposure is selected as PoD.
此外，應(yīng)注意，對(duì)于給藥持續(xù)時(shí)間短于患者 lifetime（一生 ）的藥品，若選擇短期暴露毒性研究作為PoD，使用比通常更低的 F3 值可能是合適的。
In this case an acceptable exposure level is derived, as opposed to PDE. If additional animal studies are available with longer duration, these may have NOAEL values based on findings that may not be relevant to shorter term exposures and therefore may not be the most appropriate PoD for a given drug product.
此時(shí)推導(dǎo)得出的是可接受暴露水平，而非 PDE。若有持續(xù)時(shí)間更長(zhǎng)的其他動(dòng)物研究，其未觀察到不良反應(yīng)水平（NOAEL ）可能基于與短期暴露不相關(guān)的發(fā)現(xiàn)，因此對(duì)特定藥品而言可能并非最恰當(dāng)?shù)?nbsp;PoD。
However, while toxicity studies of short-term exposure may be acceptable as a PoD in this circumstance, this does not include LD50 studies.
不過(guò)，雖然短期暴露毒性研究在此情況下可作為 PoD，但不包括半數(shù)致死量（LD50 ）研究。
In cases where a product is administered intermittently, a subfactor approach for F2 as described in ICH Q3D can be applied if supported by data. Alternatively, the value for F3 can be modified.
若產(chǎn)品為間歇性給藥，如有數(shù)據(jù)支持，可采用 ICH Q3D 中所述的 F2 子因子方法?；蛘撸烧{(diào)整 F3 的值。
Table A.5.1: Example considerations for a weight of evidence justification when qualification of leachables is necessary. Non-animal methods should be prioritized where possible.
表 A.5.1：當(dāng)需要對(duì)可浸出物進(jìn)行資質(zhì)認(rèn)定時(shí)，證據(jù)權(quán)重論證的示例考量因素。應(yīng)盡可能優(yōu)先采用非動(dòng)物實(shí)驗(yàn)方法。
Appendix 6: Monographs for Class 1 Leachables
附錄 6：1 類可浸出物各論
Benzo[a]pyrene
苯并 [a] 芘
Summary of Acute Acceptable Exposure Level and Chronic PDE Values for Benzo[a]pyrene (CAS# 50-32-8)
苯并 [a] 芘（CAS 編號(hào) 50 - 32 - 8）的急性可接受暴露水平及慢性允許日暴露量（PDE）值總結(jié)
*Acute acceptable exposure level is applicable to ≤1 - month daily administration
* 急性可接受暴露水平適用于每日給藥≤1 個(gè)月的情況
Introduction
介紹
Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) consisting of five fused benzene rings.
苯并 [a] 芘（BaP）是由五個(gè)稠合苯環(huán)組成的多環(huán)芳烴（PAH）。
It is not produced or used commercially but is formed as a result of incomplete combustion of organic matter.
它并非通過(guò)商業(yè)途徑生產(chǎn)或使用，而是由有機(jī)物不完全燃燒產(chǎn)生。
BaP may leach from materials in which carbon black is present.
苯并 [a] 芘可能從含有炭黑的材料中浸出。
BaP is a mutagenic carcinogen and as such, control according to the current version of ICH M7 is appropriate, in addition to the relevant Acceptable Exposure or PDE values derived below.
苯并 [a] 芘是致突變致癌物，因此，除下文推導(dǎo)的相關(guān)可接受暴露或允許日暴露量（PDE）值外，按照現(xiàn)行版 ICH M7 進(jìn)行控制是恰當(dāng)?shù)摹?/span>
Based on a non - mutagenic endpoint, two oral and two parenteral values for BaP were developed for ICH Q3E.
基于非致突變終點(diǎn)，為 ICH Q3E 推導(dǎo)了苯并 [a] 芘的兩個(gè)口服和兩個(gè)腸外給藥的數(shù)值。
Safety Summary and Limiting Non - Mutagenic Toxicity
安全性總結(jié)及限制性非致突變毒性
Oral exposure to BaP has been shown to result in developmental toxicity (including developmental neurotoxicity), reproductive toxicity, and immunotoxicity in repeat dose toxicity studies, including adult and juvenile animals.
在重復(fù)給藥毒性研究（包括成年和幼年動(dòng)物研究）中，口服暴露于苯并 [a] 芘已被證明會(huì)導(dǎo)致發(fā)育毒性（包括發(fā)育神經(jīng)毒性）、生殖毒性和免疫毒性。
Overall, human studies report toxicological effects that are generally analogous to those observed in animals, and provide qualitative, supportive evidence for hazards associated with BaP exposure.
總體而言，人體研究報(bào)告的毒理學(xué)效應(yīng)與在動(dòng)物中觀察到的效應(yīng)大致相似，為苯并 [a] 芘暴露相關(guān)危害提供了定性的支持性證據(jù)。
Based on critical non - mutagenic effects of BaP, the non - GLP oral developmental toxicity study in neonatal rat (Chen et al., 2012) was selected as the PoD study for oral and parenteral PDE derivation.
基于苯并 [a] 芘的關(guān)鍵非致突變效應(yīng)，選擇新生大鼠的非良好實(shí)驗(yàn)室規(guī)范（GLP）口服發(fā)育毒性研究（Chen 等人，2012 年）作為推導(dǎo)口服和腸外給藥 PDE 的起始點(diǎn)（PoD）研究。
Oral Acceptable Exposure and PDE
口服可接受暴露量和 PDE
The rat neurodevelopmental study by Chen et al., 2012 administered doses of BaP at 0, 0.02 mg/kg, 0.2 mg/kg, and 2 mg/kg on postnatal day 5 to 11 by oral gavage.
Chen 等人 2012 年開展的大鼠神經(jīng)發(fā)育研究中，在新生大鼠出生后第 5 天至第 11 天，通過(guò)灌胃給予苯并 [a] 芘，劑量分別為 0、0.02 mg/kg、0.2 mg/kg 和 2 mg/kg。
Altered responses in three behavioral tests (Morris water maze, elevated plus maze, and open field tests) were selected to represent the critical effect of abnormal behavior, due to the consistency of the observations across groups/studies (i.e., each of these responses were affected in two separate cohorts of rats, including testing as juveniles and as adults; similar effects in these behavioral tests were observed across studies) and sensitivity of these responses, and the observed dose - response relationship of effects across dose groups.
由于在不同組 / 研究中觀察結(jié)果具有一致性（即這些反應(yīng)在兩組不同的大鼠中均受到影響，包括幼鼠和成年鼠測(cè)試；在不同研究中觀察到這些行為測(cè)試有類似效應(yīng)）、這些反應(yīng)的敏感性以及在不同劑量組中觀察到的效應(yīng)劑量 - 反應(yīng)關(guān)系，選擇三項(xiàng)行為測(cè)試（Morris 水迷宮、高架十字迷宮和曠場(chǎng)試驗(yàn)）中的反應(yīng)改變來(lái)代表異常行為的關(guān)鍵效應(yīng)。
Benchmark dose (BMD) modeling for each of the three endpoints resulted in BMD lower bound for 1 standard deviation (BMDL1SD) values in the range 0.092−0.16 mg/kg - day.
對(duì)這三個(gè)終點(diǎn)分別進(jìn)行基準(zhǔn)劑量（BMD）建模，得出 1 倍標(biāo)準(zhǔn)偏差的基準(zhǔn)劑量下限（BMDL1SD）值在 0.092 - 0.16 mg/kg?天范圍內(nèi)。
Taking the lower end of the range, 0.092 mg/kg - day, was selected to represent the PoD from the neurodevelopmental study.
選取該范圍的下限 0.092 mg/kg?天，作為神經(jīng)發(fā)育研究的PoD。
Parenteral Acceptable Exposure and PDE
腸外可接受暴露量和PDE
In the absence of parenteral administration repeat dose toxicity studies, the same POD study was used to derive the parenteral PDE with the inclusion of a bioavailability modifying factor (F6), based on physiochemical characteristics of BaP (MW = 252.3 g/mol and predicted LogP 3.0 (PubChem, 2024)).
在沒有進(jìn)行腸外給藥重復(fù)劑量毒性研究的情況下，使用相同的 POD 研究，根據(jù)BaP的物理化學(xué)特性（MW = 252.3 g/mol和預(yù)測(cè)LogP 3.0（PubChem，2024）），得出腸外 PDE，其中包括生物利用度修正因子（F6）。
REFERENCES
參考文獻(xiàn)
International Conference on Harmonisation (2023). M7(R2): Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.
PubChem (2024) Compound Summary for CID 2336, Benzo[a]pyrene, National Center for Biotechnology Information. Retrieved May 2, 2024, from https://pubchem.ncbi.nlm.nih.gov/compound/Benzo_a_pyrene.
Chen, C; Tang, Y; Jiang, X; Qi, Y; Cheng, S; Qiu, C; et al. (2012). Early postnatal benzo(a)pyrene exposure in Sprague-Dawley rats causes persistent neurobehavioral impairments that emerge postnatally and continue into adolescence and adulthood. Toxicol Sci 125: 248-261. https://academic.oup.com/toxsci/article/125/1/248/1668305.
Bisphenol A
雙酚A
Summary of Acute Acceptable Exposures and Chronic PDE Values for Bisphenol A?(CAS# 80-05-7)
雙酚 A (CAS# 80-05-7 )急性可接受暴露量和慢性 PDE 值總結(jié)
*Acute Acceptable Exposure value is applicable to ≤1-month daily administration
* 急性可接受暴露值適用于每日給藥≤1 個(gè)月的情況
Introduction
介紹
Bisphenol A (BPA) is 4,4'-methanediyldiphenol where the methylene hydrogens are replaced by two methyl groups.
雙酚 A（BPA）是 4,4'- 亞甲基二苯酚，其亞甲基上的氫被兩個(gè)甲基取代。
It is a key building block of polycarbonate plastic and a precursor for the manufacturing of monomers of epoxy resins.
它是聚碳酸酯塑料的關(guān)鍵組成部分，也是環(huán)氧樹脂單體生產(chǎn)的前體。
BPA may be present in primary packaging material and manufacturing equipment used in the manufacturing process of medicines, in medicine containers, medicine/device combinations, and in parenteral nutrition bags (Parris et al, 2020).
雙酚 A 可能存在于藥品生產(chǎn)過(guò)程中使用的初級(jí)包裝材料和生產(chǎn)設(shè)備、藥品容器、藥械組合產(chǎn)品以及腸外營(yíng)養(yǎng)袋中（Parris 等人，2020 年）。
Safety Summary and Limiting Toxicity
安全性總結(jié)及限制性毒性
BPA is not mutagenic and non-genotoxic.
雙酚 A 無(wú)致突變性，也無(wú)遺傳毒性。
ECHA listed BPA capable of producing skin sensitization responses in humans and may damage fertility or the unborn child.
歐洲化學(xué)品管理局（ECHA）將雙酚 A 列為可能在人體中引起皮膚致敏反應(yīng)，并可能損害生育能力或未出生胎兒的物質(zhì)。
BPA is not a skin irritant; however, it is irritating to the eye (ECHA, 2024).
雙酚 A 對(duì)皮膚無(wú)刺激性，但對(duì)眼睛有刺激性（ECHA，2024 年）。
The European Medicines Agency (EMA) obligates the use of an apical endpoint to minimize uncertainty in relation to human health risk assessment; ICH Q3E is aligned with EMA, and therefore non-mutagenic PDEs were derived for evaluation of BPA as a potential leachable in pharmaceutical products (EFSA EMA, 2023).
歐洲藥品管理局（EMA）要求使用 apical 終點(diǎn)（ apical endpoint，指整體生物學(xué)效應(yīng)終點(diǎn) ）以最大限度減少人體健康風(fēng)險(xiǎn)評(píng)估中的不確定性；ICH Q3E 與 EMA 保持一致，因此推導(dǎo)了非致突變性允許日暴露量（PDE），用于評(píng)估雙酚 A 作為藥品中潛在可浸出物的情況（歐洲食品安全局與歐洲藥品管理局，2023 年）。
Oral Acceptable Exposure and PDE
口服可接受暴露量和 PDE
BPA was tested in a two-generation study in mice (Tyl et al 2008).
在小鼠中開展了雙酚 A 的兩代研究（Tyl 等人，2008 年）。
The GLP and OECD 416-compliant study in mice, evaluated dietary BPA concentrations of 0, 0.018, 0.18, 1.8, 30, 300, or 3500 ppm (approximately 0.003, 0.03, 0.3, 5, 50, or 600 mg/kg/day) ad libitum.
這項(xiàng)符合良好實(shí)驗(yàn)室規(guī)范（GLP）和經(jīng)合組織（OECD）416 號(hào)準(zhǔn)則的小鼠研究，評(píng)估了飲食中雙酚 A 濃度為 0、0.018、0.18、1.8、30、300 或 3500 ppm（約 0.003、0.03、0.3、5、50 或 600 mg/kg/ 天）時(shí)的自由攝食情況。
Concurrent positive control group of dietary 17β-estradiol (0.5 ppm; 28 per sex) was included to evaluate potential for endocrine disruption.
同時(shí)納入飲食中含 17β- 雌二醇（0.5 ppm；雌雄各 28 只）的陽(yáng)性對(duì)照組，以評(píng)估內(nèi)分泌干擾潛力。
F0 generation animals received respective formulations in the diet for 8 weeks prior to mating (i.e., until ~14 weeks of age).
F0 代動(dòng)物在交配前 8 周（即直至約 14 周齡）的飲食中接受相應(yīng)制劑。
The animals were then mated for a period of 14 days.
隨后動(dòng)物交配 14 天。
Animals continued dosing through gestation (~20 days) and lactation (3 weeks).
動(dòng)物在妊娠期（約 20 天）和哺乳期（3 周）持續(xù)給藥。
No BPA-related effects at any dose were observed for adult mating, fertility or gestational indices, ovarian primordial follicle counts, estrous cyclicity, pre-coital interval, offspring sex ratios or post-natal survival, sperm parameters or reproductive organ weights or histopathology (including the testes and prostate).
在任何劑量下，均未觀察到與雙酚 A 相關(guān)的對(duì)成年動(dòng)物交配、生育力或妊娠指數(shù)、卵巢原始卵泡計(jì)數(shù)、發(fā)情周期、交配前間隔、后代性別比例或出生后存活率、精子參數(shù)或生殖器官重量及組織病理學(xué)（包括睪丸和前列腺）的影響。
Systemic effects observed in adults were centrilobular hepatocyte hypertrophy at ≥300 ppm, reduced body weight, increased kidney and liver weights, centrilobular hepatocyte hypertrophy, and renal nephropathy in males.
在成年動(dòng)物中觀察到的全身效應(yīng)為：≥300 ppm 劑量組出現(xiàn)小葉中心肝細(xì)胞肥大；雄性動(dòng)物出現(xiàn)體重下降、腎和肝重量增加、小葉中心肝細(xì)胞肥大以及腎腎病。
In conclusion, the NOAEL for reproductive toxicity was 300 ppm (~50 mg/kg/day) and NOEL for adult (F0) systemic toxicity was 30 ppm (~5 mg/kg/day).
結(jié)論：生殖毒性的未觀察到不良反應(yīng)水平（NOAEL）為 300 ppm（約 50 mg/kg/ 天），成年（F0 代）全身毒性的未觀察到效應(yīng)水平（NOEL）為 30 ppm（約 5 mg/kg/ 天）。
Parenteral Acceptable Exposure and PDE
腸外可接受暴露量和允許日暴露量（PDE）
In the absence of parenteral administration repeat dose toxicity studies, the same POD study was used to derive the parenteral PDE with the inclusion of a bioavailability modifying factor (F6).
在缺乏腸外給藥重復(fù)劑量毒性研究的情況下，采用相同的起始點(diǎn)（POD）研究，并納入生物利用度修正因子（F6），來(lái)推導(dǎo)腸外給藥的 PDE。
Oral systemic bioavailability of unconjugated BPA of 2.8% in rats and less than 1% in mice, monkey and dogs was reported (ANSES, 2013).
有報(bào)道稱，非結(jié)合型雙酚 A（BPA）在大鼠中的口服全身生物利用度為 2.8%，在小鼠、猴和犬中小于 1%（法國(guó)國(guó)家食品、環(huán)境及勞動(dòng)衛(wèi)生署（ANSES），2013 年）。
來(lái)源：GMP辦公室
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