ICH Q3D 元素杂质指南 (2).doc

5.4 Recommendations for Elements to be Considered in the Risk Assessment风险评估中要考虑的要素建议The following table provides recommendations for inclusion of elemental impurities in the risk assessment. This table can be applied to all sources of elemental impurities in the drug product.以下表格对于风险评估中需要包括的元素杂质做出了建议。该表可以用于药品中所有来源的元素杂质。Table 5.1: Elements to be Considered in the Risk Assessment表5.1：在风险评估中要考虑的元素Element元素Class分类If intentionally added (al l routes)如果有意加入（所有给药途径）If not intentionally added如果无意加入Oral口服Parenteral注射Inhalation吸入Cd镉1YesYesYesYesPb铅1YesYesYesYesAs砷1YesYesYesYesHg汞1YesYesYesYesCo钴2AYesYesYesYesV钒2AYesYesYesYesNi镍2AYesYesYesYesTl铊2BYesNoNoNoAu金2BYesNoNoNoPd钯2BYesNoNoNoIr铱2BYesNoNoNoOs锇2BYesNoNoNoRh铑2BYesNoNoNoRu铷2BYesNoNoNoSe硒2BYesNoNoNoAg银2BYesNoNoNoPt铂2BYesNoNoNoLi锂3YesNoYesYesSb锑3YesNoYesYesBa钡3YesNoNoYesMo钼3YesNoNoYesCu铜3YesNoYesYesSn锡3YesNoNoYesCr铬3YesNoNoYes5.5 Evaluation评估As the potential elemental impurity identification process is concluded, there are two possible outcomes:在对潜在元素杂质进行识别后，可能会有两种结论：1)The risk assessment process does not identify any potential elemental impurities. The conclusion of the risk assessment and supporting information and data should be documented.1)风险评估未能识别出任何潜在元素杂质。风险评估的结论和支持性资料和数据要进行记录。2)The risk assessment process identifies one or more potential elemental impurities. For any elemental impurities identified in the process, the risk assessment should consider if there are multiple sources of the identified elemental impurity or impurities and document the conclusion of the assessment and supporting information.2)风险评估识别出了一个或多个潜在元素杂质。对所有识别出的元素杂质，如果该元素杂质有多个来源，要考虑进行风险评估。并记录评估的结论和支持性资料。The applicants risk assessment can be facilitated with information about the potential elemental impurities provided by suppliers of drug substances, excipients, container closure systems, and manufacturing equipment. The data that support this risk assessment can come from a number of sources that include, but are not limited to:申报人的风险评估可以利用原料药、辅料、容器密闭系统和生产设备供应商提供的关于潜在元素杂质的信息。支持风险评估的数据可以来自于许多来源，包括但不仅限于：-Prior knowledge;-之前的知识-Published literature;-出版的文献-Data generated from similar processes;-从类似工艺中产生的数据-Supplier information or data;-供应商的信息或数据-Testing of the components of the drug product;-药品组分检测-Testing of the drug product.-药品检测During the risk assessment, a number of factors that can influence the level of the potential impurity in the drug product and should also have been considered in the risk assessment. These include but are not limited to:在风险评估中，很多因素会对药品中潜在杂质的水平造成影响，因此也需要在风险评估中进行考虑。这包括但不仅限于：-Efficiency of removal of elemental impurities during further processing;-进一步加工中除去元素杂质的有效性-Natural abundance of elements (especially important for the categories of elements which are not intentionally added);-自然富含的元素（特别重要的是没有添加单身的杂质类别）-Prior knowledge of elemental impurity concentration ranges from specific sources;-特定来源的元素杂质浓度已有知识-The composition of the drug product.-药品组分5.6 Summary of Risk Assessment Process风险评估过程的总结The risk assessment is summarized by reviewing relevant product or component specific data combined with information and knowledge gained across products or processes to identify the significant probable elemental impurities that may be observed in the drug product.通过对相关产品或组成相关数据，结合在产品或工艺中获得的信息和知识进行审核，进行风险评估，以识别明显可能在药品中观察到的元素杂质。The summary should consider the significance of the observed or predicted level of the elemental impurity relative to the PDE of the elemental impurity. As a measure of the significance of the observed elemental impurity level, a control threshold is defined as a level that is 30% of the established PDE in the drug product. The control threshold may be used to determine if additional controls may be required.总结要考虑相对于元素杂质PDE值，已观察到的或预期的元素杂质水平的显著性。这里，将药品中已建立的PDE值的30%定义为控制阈值，作为对已观察到的元素杂质水平的显著性的衡量方法，If the total elemental impurity level from all sources in the drug product is expected to be consistently less than 30% of the PDE, then additional controls are not required, provided the applicant has appropriately assessed the data and demonstrated adequate controls on elemental impurities.如果药品中所有来源的总元素杂质水平预期会保持一致，且低于PDE值的30%水平，而申报人已对数据进行了适当的评估，证明对元素杂质的控制已经足够充分，则不需要采用更多的控制措施。If the risk assessment fails to demonstrate that an elemental impurity level is consistently less than the control threshold, controls should be established to ensure that the elemental impurity level does not exceed the PDE in the drug product. (See Section 6)如果风险评估未能证明一种元素杂质的水平具有一致性且低于控制阈值，则要建立控制措施来保证元素杂质水平不会超过药品的PDE值（参见第6部分）。The variability of the level of an elemental impurity should be factored into the application of the control threshold to drug products. Sources of variability may include:元素杂质水平的可变性应分解到药品阈值控制的应用中去。可变性的来源可能包括：-Variability of the analytical method;-分析方法的可变性-Variability of the elemental impurity level in the specific sources;-特定来源中的元素杂质的可变性-Variability of the elemental impurity level in the drug product.-药品中元素杂质水平的可变性At the time of submission, in the absence of other justification, the level and variability of an elemental impurity can be established by providing the data from three (3) representative production scale lots or six (6) representative pilot scale lots of the component or components or drug product. For some components that have inherent variability (e.g., mined excipients), additional data may be needed to apply the control threshold.在提交申报时，如果没有其它论证，一种元素杂质的水平和可变性可以通过提供成分或药品生产的3批生产规模或6批中试规模具代表性的批次数据来建立。对于有些具有内在可变性的成分（例如，矿物质辅料），在应用控制阈值时可能需要额外的数据。There are many acceptable approaches to summarizing and documenting the risk assessment that may include: tables, written summaries of considerations and conclusions of the assessment. The summary should identify the elemental impurities, their sources, and the controls and acceptance criteria as needed.许多总结和记录风险评估的方法都是可以接受的，包括：表格、所有考虑因素的书面总结、评估的结论。总结应识别出元素杂质、其来源、以及控制方式，需要时要制订可接受标准。5.7 Special Considerations for Biotechnologically-Derived Products生物技术衍生药品的特殊考虑For biotechnology-derived products, the risks of elemental impurities being present at levels that raise safety concerns at the drug substance stage are considered low. This is largely because: a) elements are not typically used as catalysts or reagents in the manufacturing of biotech products; b) elements are added at trace levels in media feeds during cell culture processes, without accumulation and with significant dilution/removal during further processing; c) typical purification schemes used in biotech manufacturing such as extraction, chromatography steps and dialysis or Ultrafiltration-Diafiltration (UF/DF) have the capacity to clear elements introduced in cell culture/fermentation steps or from contact with manufacturing equipment to negligible levels. As such, specific controls on elemental impurities up to the biotech drug substance are generally not needed. In cases where the biotechnology-derived drug substance contains synthetic structures (such as antibody-drug conjugates), appropriate controls on the small molecule component for elemental impurities should be evaluated.对于生物技术衍生药品，在原料药阶段引起安全关注的元素杂质的风险被认为是很低的。这很大程度是因为1）元素不是在生物技术药品生产中典型用作催化剂或试剂，2）在细胞发酵过程中培养基补料时加入的元素为痕量水平，不会累积，在进一步加工时会被显著稀释/清除，3）在生物技术生产中使用的典型的纯化过程，如萃取、色谱分离和透析或超滤-渗滤（UF/DF），具备能力将细胞生长/发酵步骤或与生产设备接触过程中引入的元素清除至可忽略的水平。在这种情况下，对生物技术原料药中元素杂质的特别控制通常并不需要。如果生物技术衍生原料药含有合成结构（例如抗体药偶合物），需要评估是否需要对小分子成分中的元素杂质进行适当的控制。However, potential elemental impurity sources included in drug product manufacturing (e.g., excipients) and other environmental sources should be considered for biotechnologically-derived drug products. The contribution of these sources to the finished product should be assessed because they are typically introduced in the drug product manufacture at a step in the process where subsequent elemental impurity removal is not generally performed. Risk factors that should be considered in this assessment should include the type of excipients used, the processing conditions and their susceptibility to contamination by environmental factors (e.g., controlled areas for sterile manufacturing and use of purified water) and overall dosing frequency.但是，生物技术衍生药品要考虑药品生产中所包括的（例如辅料），及其它环境来源的潜在元素杂质来源。这些制剂中来源的影响应进行评估，因为它们会在制剂生产工艺某步骤中被引入，之后一般没有对元素杂质的清除。在该评估中要考虑的风险因素应包括所用辅料的类型，加工条件及其被环境因素污染的难易程度（例如，无菌生产控制区域，纯化水的使用）以及总体给药频率。6. CONTROL OF ELEMENTAL IMPURITIES元素杂质的控制Control of elemental impurities is one part of the overall control strategy for a drug product that assures that elemental impurities do not exceed the PDEs. When the level of an elemental impurity may exceed the control threshold, additional measures should be implemented to assure that the level does not exceed the PDE. Approaches that an applicant can pursue include but are not limited to:控制元素杂质是药品全面控制策略的一部分，它能保证元素杂质不超过PDE值。当元素杂质有可能超过控制阈值时，需采取更多措施来保证其水平不会超过PDE值。申报人可以采用的措施包括但不仅限于：-Modification of the steps in the manufacturing process that result in the reduction of elemental impurities below the control threshold through specific or non-specific purification steps;-改进生产工艺步骤，通过特定或非特定的精制步骤将元素杂质降低至控制阈值以下-Implementation of in-process or upstream controls, designed to limit the concentration of the elemental impurity below the control threshold in the drug product;-实施中控或上游控制，用以将元素杂质的浓度限定在制剂的控制阈值以下-Establishment of specification limits for excipients or materials (e.g., synthetic intermediates);-建立辅料或原料的质标准限度（例如，合成中间体）-Establishment of specification limits for the drug substance;-建立原料药质量标准限度-Establishment of specification limits for the drug product;-建立制剂质量标准限度-Selection of appropriate container closure systems.-选择适当的容器包装系统Periodic testing may be applied to elemental impurities according to the principles described in ICH Q6A.The information on the control of elemental impurities that is provided in a regulatory submission includes, but is not limited to, a summary of the risk assessment, appropriate data as necessary, and a description of the controls established to limit elemental impurities.根据ICH Q6A中所述的原则，元素杂质可能需要定期进行测试。需要包括在法规申报中的元素杂质控制资料包括，但不仅限于，风险评估总结，必要时提交适当的数据，以及已建立的用于限制元素杂质的控制方法描述。7. CONVERTING BETWEEN PDES AND CONCENTRATION LIMITS将PDE值和浓度限度互相转换The PDEs, reported in micrograms per day (g/day) provided in this document give the maximum permitted quantity of each element that may be contained in the maximum daily intake of a drug product. Because the PDE reflects only total exposure from the drug product, it is useful to convert the PDE, into concentrations as a tool in evaluating elemental impurities in drug products or their components. The options listed in this section describe some acceptable approaches to establishing concentrations of elemental impurities in drug products or components that would assure that the drug product does not exceed the PDEs. The applicant may select any of these options as long as the resulting permitted concentrations assure that the drug product does not exceed the PDEs. In the choice of a specific option the applicant must have knowledge of, or make assumptions about, the daily intake of the drug product. The permitted concentration limits may be used:PDE值以微克每天表示（g/天），在本文中给出的是可能包括在药品最大日服用量里的每个元素允许的最大数量。由于PDE反映的只是来自药品的总暴露量，因此需要将PDE值转换为浓度，作为工具用于评估药品或其成分中的元素杂质。本部分列出的方法描述了一些可接受的方法，用于建立药品或其成分中的元素杂质浓度，从而保证药品不会超过PDE值。只要所导出的允许浓度能保证药品不会超出PDE值，申报人可以选择这些方法中的任何一种。在选择特定的方法时，申报人必须知晓，或假定，药品的日摄入量。允许浓度限度可以用于：-As a tool in the risk assessment to compare the observed or predicted levels to the PDE;-作为风险评估的工具，与观察到或预期的PDE水平进行比较-In discussions with suppliers to help establish upstream controls that would assure that the product does not exceed the PDE;-在与供应商的讨论中帮助建立上游控制可以保证产品不会超过PDE值-To establish concentration targets when developing in-process controls on elemental impurities;-在研究元素杂质中控时建立目标浓度-To convey information regarding the controls on elemental impurities in regulatory submissions.-在法规申报中传递元素杂质控制的信息As discussed in Section 5.2, there are multiple sources of elemental impurities in drug products. When applying any of the options described below, elemental impurities from container closure systems and manufacturing equipment should be taken into account before calculating the maximum permitted concentration in the remaining components (excipients and drug substance). If it is determined during the risk assessment that the container closure systems and manufacturing equipment do not contribute to the elemental impurity level in the drug product, they do not need to be considered. Where contributions from container closure systems and manufacturing equipment exist, these contributions may be accounted for by subtracting the estimated daily intake from these sources from the PDE before calculation of the allowed concentration in the excipients and drug substance.正如第5.2部分所讨论的，药品中的元素杂质有多种来源。在使用下述任何一种谅埋，在计算含有杂质的组分中（辅料和原料药）的最大允许浓度时，要考虑来自容器密闭系统和生产设备的元素杂质。如果在风险评估中已确定容器密闭系统和生产设备不会增加药品中的元素杂质，则不需要考虑。如果容器密闭系统和生产设备存在可能引入元素杂质，则在计算辅料和原料药中允许浓度前，可以从PDE中减去这些来源的估计的日摄入量。Option 1: Common permitted concentration limits of elements across drug product components for drug products with daily intakes of not more than 10 grams:方法1：日摄入量不超过10g的药品的药品组分中元素通用允许浓度限度This option is not intended to imply that all elements are present at the same concentration, but rather provides a simplified approach to the calculations.本方法无意暗示所有元素均以相同浓度出现，只是提供了一种简化的方法来进行计算。The option assumes the daily intake (amount) of the drug product is 10 grams or less, and that elemental impurities identified in the risk assessment (the target elements) are present in all components of the drug product. Using Equation 1 below, and a daily intake of 10 grams of drug product, this option calculates a common permissible target elemental concentration for each component in the drug. This approach, for each target element, allows determination of a fixed common maximum concentration in micrograms per gram in each component. The permitted concentrations are provided in Appendix 2, Table A.2.2.本方法假定药品的日摄入（量）为10g或更低，风险评估中识别的元素杂质（目标元素）出现在药品的所有成分中。使用以下公式1，药品的日摄入量为10g，本方法计算出药品中每种成分的允许目标元素浓度。本方法，对于每一目标元素，允许对于每一成分制订固定的通用最大浓度，单位为mg/g。附录2表A.2.2中给出了允许浓度。Concentration浓度(g/g)=PDE(g/day)Daily amount of drug product药品日摄入量(g/day)If all the components in a drug product do not exceed the Option 1 concentrations for all target elements identified in the risk assessment, then all these components may be used in any proportion in the drug product. An example using this option is shown in Appendix 4, Table A.4.2. If the permitted concentrations in Appendix 2, Table A.2.2 are not applied, Options 2a, 2b, or 3 should be followed.如果药品中的所有成分均不超过方法2a中在风险评估中已识别的所有目标元素的浓度，则所有这些成分均可以以任何比例用于药品生产。本方法例子在附录4表A.4.2中。如果附录2表A.2.2中的允许浓度不适用，则应使用方法2a、2b或3的数据。Option 2a: Common permitted concentration limits across drug product components for a drug product with a specified daily intake:方法2a：具有特定日摄入量的药品中药品组分的通用允许浓度限度This option is similar to Option 1, except that the drug daily intake is not assumed to be 10 grams. The common permitted concentration of each element is determined using Equation 1 and the actual maximum daily intake.本方法与方法1类似，除了药品日摄入量不会假定为10克。每种元素的通用允许浓度采用公式1和实际最大日摄入量来计算。This approach, for each target element, allows determination of a fixed common maximum concentration in micrograms per gram in each component based on the actual daily intake provided. An example using this option is provided in Appendix 4, Table A.4.3.本方法，对于每一目标元素，允许根据所提供的实际日摄入量，确定每种成分的固定通用的最大浓度（单位为mg/g）。本方法例子在附录4表A.4.3中。If all components in a drug product do not exceed the Option 2a concentrations for all target elements identified in the risk assessment, then all these components may be used in any proportion in the drug product.如果药品中的所有成分均不超过方法2a中在风险评估中已识别的所有目标元素的浓度，则所有这些成分均可以以任何比例用于药品生产。Option 2b: Permitted concentration limits of elements in individual components of a product with a specified daily intake:方法2b：具有特定的日摄入量的药品的单个成分中元素的允许浓度限度This option requires additional information that the applicant may assemble regarding the potential for specific elemental impurities to be present in specific drug product components. The applicant may set permitted concentrations based on the distribution of elements in the components (e.g., higher concentrations in components with the presence of an element in question). For each element identified as potentially present in the components of the drug product, the maximum expected mass of the elemental impurity in the final drug product can be calculated by multiplying the mass of each component material times the permitted concentration established by the applicant in each material and summing over all components in the drug product, as described in Equation 2. The total mass of the elemental impurity in the drug product should comply with the PDEs given in Appendix 2, Table A.2.1. unless justified according to other relevant sections of this guideline. If the risk assessment has determined that a specific element is not a potential impurity in a specific component, there is no need to establish a quantitative result for that element in that component. This approach allows that the maximum permitted concentration of an element in certain components of the drug product may be higher than the Option 1 or Option 2a limit, but this should then be compensated by lower allowable c