20141216 ICH Q3D 元素杂质指南 (1).doc

INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USEICH HARMONISED GUIDELINEGUIDELINE FOR ELEMENTAL IMPURITIES元素杂质指南Q3DCurrentStep 4versiondated 16 December 2014This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Switzerland, Japan, USA and Canada.Q3D Document HistoryCodeHistoryDateQ3DApproval by the Steering Committee under Step 2a.6 June 2013Q3DApproval by the Steering Committee under Step 2b and release for public consultation.6 June 2013Q3DPost sign-off corrigendum in:lTable 4.1 W and A1 were removed from the list of included elemental impurities in Class 2B and 3 respectively.lTable A2.1 the Class for Ni was changed to read 3 instead of 214 June 2013Q3DPost sign-off minor editorial corrections including: removal of references to Appendix 5 (pgs i&13); deletion of redundant text (pg4); change of Option 2 to Option 2a(pg10); insertion of text under Safety Limiting Toxicity (pg35); reference to “metals” in text and “metal” in Table A4.7 title with “elementals” and “elements” (pg 73); and deletion of header Table A4.10 (pg75).26 July 2013Q3DAddition of line numbers to facilitate the provision of comments by stakeholders.30 September 2013Q3DApproval by the Steering Committee under Step 4 and recommendation for adoption to the ICH regulatory bodies.12 November 2014Current Step 4 VersionCodeHistoryDateQ3DCorrigendum to correct: the modifying factor in the text of the safety assessment for Selenium (changed to 2 instead of 10 consistent with Section 3.1); and two references for consistency in the safety assessments for Barium (deleted reference ) and Vanadium (reviewed reference).16 December 2014Legal notice:This document is protected by copyright and may be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICHs copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided.The document is provided as is without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document.The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder.GUIDELINE FOR ELEMENTAL IMPURITIESICH Harmonised GuidelineHaving reachedStep 4of the ICH Process at the ICH Steering Committee meeting on 12 November 2014, this guideline is recommended for adoption to the regulatory parties to ICH.TABLE OF CONTENTS目录1. INTRODUCTION前言2. SCOPE范围3. SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES潜在元素杂质的安全评估3.1 Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and Inhalation Routes of Administration口服、注射和吸入给药中元素杂质安全评估的原则3.2 Other Routes of Administration其它给药途径3.3 Justification for Elemental Impurity Levels Higher than an Established PDE元素杂质水平高于已建立的PDE时的论证3.4 Parenteral Products .注射用药4. ELEMENT CLASSIFICATION元素分类5. RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES元素杂质的风险评估和控制5.1 General Principles通用原则5.2 Potential Sources of Elemental Impurities元素杂质的潜在来源5.3 Identification of Potential Elemental Impurities潜在元素杂质的识别5.4 Recommendations for Elements to be Considered in the Risk Assessment建议中风险评估中考虑的元素5.5 Evaluation评估5.6 Summary of Risk Assessment Process风险评估过程总结5.7 Special Considerations for Biotechnologically-Derived Products生物技术衍生产品特殊考虑6. CONTROL OF ELEMENTAL IMPURITIES元素杂质的控制7. CONVERTING BETWEEN PDES AND CONCENTRATION LIMITSPDE和关注限度之间的转换8. SPECIATION AND OTHER CONSIDERATIONS物种形成和其它考虑9. ANALYTICAL PROCEDURES分析方法10. LIFECYCLE MANAGEMENT生命周期管理GLOSSARY术语REFERENCES参考文献Appendix 1: Method for Establishing Exposure Limits附录1：建立暴露限度的方法Appendix 2: Established PDEs for Elemental Impurities附录2：已建立的元素杂质PDEAppendix 3: Individual Safety Assessments附录3：单独安全评估Appendix 4: Illustrative Examples附录4：举例说明GUIDELINE FOR ELEMENTAL IMPURITIES元素杂质指南Q3D1. INTRODUCTION介绍Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in synthesis or may be present as impurities (e.g., through interactions with processing equipment or container/closure systems or by being present in components of the drug product). Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. There are three parts of this guideline: the evaluation of the toxicity data for potential elemental impurities; the establishment of a Permitted Daily Exposure (PDE) for each element of toxicological concern; and application of a risk-based approach to control elemental impurities in drug products. An applicant is not expected to tighten the limits based on process capability, provided that the elemental impurities in drug products do not exceed the PDEs. The PDEs established in this guideline are considered to be protective of public health for all patient populations. In some cases, lower levels of elemental impurities may be warranted when levels below toxicity thresholds have been shown to have an impact on other quality attributes of the drug product (e.g., element catalyzed degradation of drug substances). In addition, for elements with high PDEs, other limits may have to be considered from a pharmaceutical quality perspective and other guidelines should be consulted (e.g., ICH Q3A).药品中的元素杂质可能会有几个来源，它们可能是有意加入合成反应的催化剂的残留，也可能是作为杂质出现（例如，通过与工艺设备或容器/密闭系统相互反应，或出现在药品的组分中）。由于元素杂质并不给患者提供任何治疗益处，其在药品中的水平应被控制在可接受限度以内。本指南分为三个部分：潜在元素杂质毒性数据的评估、为每个毒性关注元素建立PDE值，以及应用基于风险的方法来控制药品中的元素杂质。如果药品中的元素杂质没有超过PDE阈值的话，申报人不需要根据其工艺能力加严限度。本指南中建立的PDE阈值足以保护所有患者人群的公共健康。在有些情况下，如果毒性阈值以下的元素杂质水平表示出对药品的其它质量属性有影响（例如，对药品降解有催化作用的元素），则可能需要保证一个更低的元素杂质水平。另外，对于具有较高PDE值的元素，可能需要从药品质量的角度，以及要参照的其它指南（例如ICH Q3A）来考虑其它限度。This guideline presents a process to assess and control elemental impurities in the drug product using the principles of risk management as described in ICH Q9. This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the drug product.本指南给出一个采用ICH Q9中所述风险管理原则来评估和控制药品中元素杂质的方法。该方法提供了一个基于风险控制策略的平台来限制药品中的元素杂质。2. SCOPE范围The guideline applies to new finished drug products (as defined in ICH Q6A and Q6B) and new drug products containing existing drug substances. The drug products containing purified proteins and polypeptides (including proteins and polypeptides produced from recombinant or non-recombinant origins), their derivatives, and products of which they are components (e.g., conjugates) are within the scope of this guideline, as are drug products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides.本指南适用于新的制剂产品（如ICH Q6A和Q6B定义）和含有已有原料药的新药品。含有纯化后的蛋白质和多肽（包括采用复合或非复合来源生产的蛋白质和多肽）的药品、其衍生物，以及其复方药品（例如，偶合物）在本指南适用范围内。含有合成多肽、多核苷酸和低聚糖的药品也适用本指南。This guideline does not apply to herbal products, radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood derivatives including plasma and plasma derivatives, dialysate solutions not intended for systemic circulation, and elements that are intentionally included in the drug product for therapeutic benefit. This guideline does not apply to products based on genes (gene therapy), cells (cell therapy) and tissue (tissue engineering). In some regions, these products are known as advanced therapy medicinal products.本指南不适用于草药产品、放射性药品、疫苗、细胞代谢物、DNA产品、过敏提取物、细胞、全血、细胞血成分或血液制品，包括血浆和血浆制品、非系统循环用透析液，和用于治疗用途加入的元素。本指南不适用于基于基因（基因治疗）、细胞（细胞治疗）和组织（组织工程）的药品。在有些地区，这些产品是作为先进治疗药品的。This guideline does not apply to drug products used during clinical research stages of development. As the commercial process is developed, the principles contained in this guideline can be useful in evaluating elemental impurities that may be present in a new drug product.本指南不适用于研发的临床研究阶段药品。由于商业过程是在不断发展的，评估新药中可能出现的元素杂质时也可应用本指南中的原则。Application of Q3D to existing products is not expected prior to 36 months after publication of the guideline by ICH.在本指南由ICH发布后36个月内，不需要对已有产品应用Q3D。3. SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES潜在元素杂质的安全评估3.1 Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and Inhalation Routes of Administration口服、注射和吸入给药途径的元素杂质安全评估原则The method used for establishing the PDE for each elemental impurity is discussed in detail in Appendix 1. Elements evaluated in this guideline were assessed by reviewing the publicly available data contained in scientific journals, government research reports and studies, international regulatory standards (applicable to drug products) and guidance, and regulatory authority research and assessment reports. This process follows the principles described in ICH Q3C: Residual Solvents. The available information was reviewed to establish the oral, parenteral and inhalation PDEs. For practical purposes, the PDEs to be applied to the drug product that are presented in Appendix 2 Table A.2.1 have been rounded to 1 or 2 significant figures.用于建立各元素杂质的方法在附录1中进行了讨论。在本指南中评估的元素，是通过对科学杂质、政府研发报告和研究、国际法规标准（适用于药品）和指南、以及法规当局研究和评估报告里公众可以获得的数据进行审核得到的。该方法是根据ICH Q3C：残留溶剂中所述的原则制订的。对可以获得的资料进行审核以建立口服、注射和吸入PDE值。为了实用，附录2里表A.2.1中适用于药品的PDE阈值被修约至1位或2位有效数字。A summary safety assessment identifying the critical study for setting a PDE for each element is included in Appendix 3. There are insufficient data to set PDEs by any route of administration for iridium, osmium, rhodium, and ruthenium. The PDEs for these elements were established on the basis of their similarity to palladium.附录3包括了一份各元素PDE设定的关键研究识别安全评估总结。对于铱、锇、铑和铷没有足够的数据设定口服给药途径的PDE阈值。这些元素的PDE值是基于其与钯的相似性上建立的。The factors considered in the safety assessment for establishing the PDE are listed below in approximate order of relevance:在建立PDE所进行的安全评估中考虑的因素按大致的相关性顺序列出如下：-The likely oxidation state of the element in the drug product;-药品中的元素可能的氧化状态-Human exposure and safety data when it provided applicable information;-当其提供可用信息时，人类暴露量和安全数据-The most relevant animal study;-最相关的动物研究-Route of administration;-给药途径-The relevant endpoint(s).-相关终点Standards for daily intake for some of the elemental impurities discussed in this guideline exist for food, water, air, and occupational exposure. Where appropriate, these standards were considered in the safety assessment and establishment of the PDEs.在本指南中讨论的有些元素杂质日服用量的标准The longest duration animal study was generally used to establish the PDE. When a shorter duration animal study was considered the most relevant, the rationale was provided in the individual safety assessment.一般使用最长的动物研究时长来建立PDE值。如果有一个较短的动物研究时长被认为是最为相关的，则在单个安全评估中给出了其理由。Inhalation studies using soluble salts (when available) were preferred over studies using particulates for inhalation safety assessment and derivation of inhalation PDEs. Depending on available data, inhalation PDEs were based on either local (respiratory system) or systemic toxicity. For PDEs established for inhalation (and oral or parenteral routes as applicable), doses were normalized to a 24-hour, 7-day exposure.相对使用粒子的研究，使用可溶性盐（可获得时）进行的吸入研究优先用于吸入安全性评估和计算吸入PDE值。根据可获得的数据，吸入PDE值是基于局部（喷雾系统）或系统性毒性的。对于为了吸入给药建立的PDE值（适用时，和口服或注射途径），剂量一般统一为24小时7天暴露时长。In the absence of data and/or where data are available but not considered sufficient for a safety assessment for the parenteral and or inhalation route of administration, modifying factors based on oral bioavailability were used to derive the PDE from the oral PDE:如果没有数据，和/或有数据但认为不足以用于注射和/或吸入途径的安全评估，则基于口服生物利用度的修正因子用于从口服PDE来推导PDE：? Oral bioavailability 1%: divide by a modifying factor of 100;? Oral bioavailability 1% and 50%: divide by a modifying factor of 10;? Oral bioavailability 50% and 90%: divide by a modifying factor of 2; and? Oral bioavailability 90%: divide by a modifying factor of 1.?口服生物利用度1%:除以100作为修正因子;?口服生物利用度 1% and 50%:除以10作为修正因子;?口服生物利用度50% and 90%:除以2作为修正因子；以及?口服生物利用度 90%:除以1作为修正因子。Where oral bioavailability data or occupational inhalation exposure limits were not available, a calculated PDE was used based on the oral PDE divided by a modifying factor of 100 (Ref. 1).如果没有口服生物利用度数据或职业吸入暴露限，则在根据口服PDE值计算出PDE值后除以修正因子100（参考文献1）。3.2 Other Routes of Administration其它摄入途径PDEs were established for oral, parenteral and inhalation routes of administration. When PDEs are necessary for other routes of administration, the concepts described in this guideline may be used to derive PDEs. An assessment may either increase or decrease an established PDE. The process of derivation of the PDE for another route of administration may include the following:PDE是针对口服、注射和吸入给药途径建立的。如果需要其它给药途径的PDE，则可以使用本指南的概念来推导PDE。评估结果可能会升高或降低已建立的PDE值。从一种给药途径推导出另一种给药途径的PDE值的计算过程包括以下：? Consider the oral PDE in Appendix 3 as a starting point in developing a route-specific PDE. Based on a scientific evaluation, the parenteral and inhalation PDEs may be a more appropriate starting point.将附录3中的口服PDE作为建立摄入途径特定PDE的起始点。基于科学评价，注射和吸入PDE可能是一个更适当的起始点。? Assess if the elemental impurity is expected to have local effects when administered by the intended route of administration:评估该元素杂质在通过预定给药途径摄入时是否预期产生局部影响lIf local effects are expected, assess whether a modification to an established PDE is necessary.l如果预期有局部影响，需要评估是否要对已建立的PDE进行修正lConsider the doses/exposures at which these effects can be expected relative to the adverse effect that was used to set an established PDE.l考虑预期产生这些影响时的剂量/暴露量，与用于设定已建立的PDE所用的不良反应相比较lIf local effects are not expected, no adjustment to an established PDE is necessary.l如果预期没有局部影响，则对于已建立的PDE不需要进行调整nIf available, evaluate the bioavailability of the elementviathe intended route of administration and compare this to the bioavailability of the element by the route with an established PDE:n如果可以，应评估该元素的通过预定给药途径的生物利用度，并将此与该元素通过已建立PDE的给药途径的生物利用度进行比较lWhen a difference is observed, a correction factor may be applied to an established PDE. For example, when no local effects are expected, if the oral bioavailability of an element is 50% and the bioavailability of an element by the intended route is 10%, a correction factor of 5 may be applied.l如果观察到差异，则可能需要对已建立的PDE值使用校正因子。例如，如果预期有局部影响，如果一种元素的口服生物利用度为50%，一种元素的生物利用度在预定的给药途径为10%，则可以使用5作为校正因子nIf a PDE proposed for the new route is increased relative to an established PDE, quality attributes may need to be considered.n如果提议一种新的给药途径的PDE相对于已建立的PDE有增加，则可能需要考虑对质量属性3.3 Justification for Elemental Impurity Levels Higher than an Established PDE元素杂质水平高于已建立的PDE水平时的论证Levels of elemental impurities higher than an established PDE (see Table A.2.1) may be acceptable in certain cases. These cases could include, but are not limited to, the following situations:元素杂质水平高于已建立的PDE时（参见表A.2.1），在特定情况下可能也可以接受。这些情况可能包括但不仅限于以下情形：-Intermittent dosing;-间歇给药-Short term dosing (i.e., 30 days or less);-短期给药（即，30天或更短）-Specific indications (e.g., life-threatening, unmet medical needs, rare diseases).-特定指示（例如，生命威胁、药品供给不足、罕见病）Examples of justifying an increased level of an elemental impurity using a subfactor approach of a modifying factor (Ref. 2,3) are provided below. Other approaches may also be used to justify an increased level. Any proposed level higher than an established PDE should be justified on a case-by-case basis.以下提供了使用修正因子的子因子方法（参见2.3）对升高的元素杂质水平进行论证的例子。其它方法也可以用来论证较高的杂质水平。提议任何高于已建立的PDE的杂质水平均需根据各案进行论证。Example 1: element X is present in an oral drug product. From the element X monograph in Appendix 3, a No-Observed-Adverse-Effect Level (NOAEL) of 1.1 mg/kg/day was identified. Modifying factors F1-F5 have been established as 5, 10, 5, 1 and 1, respectively. Using the standard approach for modifying factors as described in Appendix 1, the PDE is calculated as follows:例1：元素X出现在口服药品中。元素X各论见附录3，其NOAEL水平为1.1mg/kg/天。修正因子F1-F5分别设定为5、10、5、1和1。使用附录1中所述的修正因子标准方法，PDE计算如下：PDE = 1.1 mg/kg/d x 50 kg / 5 x 10 x 5 x 1 x 1 = 220 g/dayModifying factor F2 (default = 10) can be subdivided into two subfactors, one for toxicokinetics (TK) and one for toxicodynamics, each with a range from 1 to 3.16. Using the plasma half-life of 5 days, the TK adjustment factor could be decreased to 1.58 for once weekly administration (1 half-life), and to 1 for administration once a month (5 half-lives). Using the subfactor approach for F2, the proposed level for element X administered once weekly can be calculated as follows:修正因子F2（默认=10）可以分成2个子因子，一个作为毒性动力学(TK)，另一个作为毒理动力学，2个因子范围均为1-3.16。采用5天使用血浆半衰期，对于每次一周摄入（-1半衰期）TK调整因子可以降低为1.58，对于每次一个月摄入（-5个半衰期）可以降低为1。通过对F2使用子因子方法，元素X每次一周摄入建议水平可以计算如下：Proposed level建议水平= 1.1 mg/kg/d x 50 kg / 5 x (1.6 x 3.16) x 5 x 1 x 1 = 440 g/dayFor practical purposes, this value is rounded to 400 g/day.为了实用，该值修约为400g/day。Example 2: The TK adjustment factor approach may also be appropriate for elemental impurities that were not developed using the modifying factor approach. For element Z, a Minimal Risk Level (MRL) of 0.02 mg/kg/day was used to