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INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
ICH HARMONISED GUIDELINE
GUIDELINE FOR ELEMENTAL IMPURITIES
元素杂质指南
Q3D
Current Step 4 version
dated 16 December 2014
This 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.
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Q3D Document History
Code | | |
| Approval by the Steering Committee under Step 2a. | |
| Approval by the Steering Committee under Step 2b and release for public consultation. | |
| Post sign-off corrigendum in: l Table 4.1 W and A1 were removed from the list of included elemental impurities in Class 2B and 3 respectively. l Table A2.1 the Class for Ni was changed to read 3 instead of 2 | |
| Post 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). | |
| Addition of line numbers to facilitate the provision of comments by stakeholders. | |
| Approval by the Steering Committee under Step 4 and recommendation for adoption to the ICH regulatory bodies. | |
Current Step 4 Version
Code | | |
| Corrigendum 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). | |
Legal 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 ICH's 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.
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GUIDELINE FOR ELEMENTAL IMPURITIES
ICH Harmonised Guideline
Having reached Step 4 of 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 | |
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3. SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES | |
3.1 Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and Inhalation Routes of Administration | |
3.2 Other Routes of Administration | |
3.3 Justification for Elemental Impurity Levels Higher than an Established PDE | |
3.4 Parenteral Products . | |
4. ELEMENT CLASSIFICATION | |
5. RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES | |
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5.2 Potential Sources of Elemental Impurities | |
5.3 Identification of Potential Elemental Impurities | |
5.4 Recommendations for Elements to be Considered in the Risk Assessment | |
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5.6 Summary of Risk Assessment Process | |
5.7 Special Considerations for Biotechnologically-Derived Products | |
6. CONTROL OF ELEMENTAL IMPURITIES | |
7. CONVERTING BETWEEN PDES AND CONCENTRATION LIMITS | |
8. SPECIATION AND OTHER CONSIDERATIONS | |
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Appendix 1: Method for Establishing Exposure Limits | |
Appendix 2: Established PDEs for Elemental Impurities | |
Appendix 3: Individual Safety Assessments | |
Appendix 4: Illustrative Examples | |
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GUIDELINE FOR ELEMENTAL IMPURITIES
元素杂质指南
Q3D
1. 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
l If 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
l Consider 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
l If 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
n If available, evaluate the bioavailability of the element via the 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
l When 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
n If 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 μg/day
Modifying 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 μg/day
For practical purposes, this value is rounded to 400 μg/day.
为了实用，该值修约为400μg/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 derive the oral PDE. From literature sources, the plasma half-life was reported to be 4 days. This element is an impurity in an oral drug product administered once every 3 weeks (~ 5 half-lives). Using first-order kinetics, the established PDE of 1000 μg/day is modified as follows:
例2：TK调整因子方法可能也适用于未采用修正因子方法建立的元素杂质。对于元素Z，最低风险水平（MRL）为0.02mg/kg/天用以计算口服PDE值。从文献来看，血浆半衰期报道为4天。该元素是口服给药中的一个杂质，药品每三周给药一次（-5个半衰期）。使用一级动力学，已建立的PDE为1000μg/天修正如下：
Proposed level 提议的水平 = 0.02 mg/kg/d x 50 kg / 1/3.16 = 3.16 mg/day
For practical purposes, this value is rounded to 3000 μg/day.
为实用起见，该值修约为3000μg/天。
3.4 Parenteral Products 注射用药
Parenteral drug products with maximum daily volumes up to 2 liters may use the maximum daily volume to calculate permissible concentrations from PDEs. For products whose daily volumes, as specified by labeling and/or established by clinical practice, may exceed 2 liters (e.g., saline, dextrose, total parenteral nutrition, solutions for irrigation), a 2-liter volume may be used to calculate permissible concentrations from PDEs. (Ref. 4)
注射用药如果最大日给药体积达到2L，则可以使用最大日给药体积来计算PDE的允许浓度。对于日剂量在标签上注明和/或临床确定的药品，可以超过2L（例如，生理盐水、葡萄糖、总注射用营养、冲注洗剂），2L的体积可以用于计算PDE的允许浓度（参考文献4）。
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4. ELEMENT CLASSIFICATION 元素分类
The elements included in this guideline have been placed into three classes based on their toxicity (PDE) and likelihood of occurrence in the drug product. The likelihood of occurrence is derived from several factors including: probability of use in pharmaceutical processes, probability of being a co-isolated impurity with other elemental impurities in materials used in pharmaceutical processes, and the observed natural abundance and environmental distribution of the element. For the purposes of this guideline, an element with low natural abundance refers to an element with a reported natural abundance of < 1 atom/106 atoms of silicon (Ref. 5). The classification scheme is intended to focus the risk assessment on those elements that are the most toxic but also have a reasonable probability of inclusion in the drug product (see Table 5.1). The elemental impurity classes are:
本指南中包括的元素已根据其毒性（PDE）及在药品中出现的可能性分入三类。出现可能性是从几个因素中推导出的，包括：在制药工艺中使用的可能性、制药工艺中使用的原料里含有的杂质会产生共析的杂质可能性，以及观察到自然中富含的元素和在环境中广泛分布的元素。根据本指南的目的，一种在自然中存量较低的元素指其自然含量<1个原子/106个硅原子（参考文献5）。分类表目的是将风险评估的焦点集中在那些最毒，且最可能出现在药品中的元素上（参见表5.1）。元素杂质分类为：
Class 1: The elements, As, Cd, Hg, and Pb, are human toxicants that have limited or no use in the manufacture of pharmaceuticals. Their presence in drug products typically comes from commonly used materials (e.g., mined excipients). Because of their unique nature, these four elements require evaluation during the risk assessment, across all potential sources of elemental impurities and routes of administration. The outcome of the risk assessment will determine those components that may require additional controls which may in some cases include testing for Class 1 elements. It is not expected that all components will require testing for Class 1 elemental impurities; testing should only be applied when the risk assessment identifies it as the appropriate control to ensure that the PDE will be met.
第1类：元素砷、镉、汞和铅是对人有毒性的物质，已限制或不再用于药品生产中。其在药品中出现一般是来自于通常使用的物料（例如，矿物质辅料）。由于其独特的属性，这四种元素需要在风险评估中进行评价，要针对元素杂质的所有潜在来源以及所有的摄入途径。风险评估的结果将决定这些组成是否需要增加控制，在有些情况下要包括对一类元素的检测。不需要对所有成分进行一类元素杂质的检测，只有在风险评估认为需要对其进行适当控制以保证符合PDE要求时才要进行检测。
Class 2: Elements in this class are generally considered as route-dependent human toxicants. Class 2 elements are further divided in sub-classes 2A and 2B based on their relative likelihood of occurrence in the drug product.
第2类：本类别中的元素一般被认为是与摄入途径相关的人类有毒物质。根据其出现在药品的相对可能性，2类元素又被分为2A和2B两个子类。
? Class 2A elements have relatively high probability of occurrence in the drug product and thus require risk assessment across all potential sources of elemental impurities and routes of administration (as indicated). The class 2A elements are: Co, Ni and V.
2A类：在药品中出现可能性相对较高的元素，因而需要对所有元素杂质的潜在来源及所有摄入途径（如所指）进行风险评估。2A类元素为钴、镍和钒。
? Class 2B elements have a reduced probability of occurrence in the drug product related to their low abundance and low potential to be co-isolated with other materials. As a result, they may be excluded from the risk assessment unless they are intentionally added during the manufacture of drug substances, excipients or other components of the drug product. The elemental impurities in class 2B include: Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl.
2B类：由于自然含量较低、与其它物料共存可能性较低，在药品中出现的可能性较低的元素。因此，除非其在原料药、辅料或药品的其它成分生产中被有意加入，否则可能被排除在风险评估以外。2B类的元素杂质包括：银、金、铱、锇、钯、铂、铑、铷、硒和铊。
Class 3: The elements in this class have relatively low toxicities by the oral route of administration (high PDEs, generally > 500 μg/day) but may require consideration in the risk assessment for inhalation and parenteral routes. For oral routes of administration, unless these elements are intentionally added, they do not need to be considered during the risk assessment. For parenteral and inhalation products, the potential for inclusion of these elemental impurities should be evaluated during the risk assessment, unless the route specific PDE is above 500 μg/day. The elements in this class include: Ba, Cr, Cu, Li, Mo, Sb, and Sn.
第3类：本类的中元素在口服摄入时具有相对较低的毒性（高PDE，通常>500 μg/day），但可能在吸入和注射给药的风险评估中需要进行考虑。对于口服摄入，除非这些元素被有意加入，否则不需要在风险评估中进行考虑。对于注射和吸入给药药品，除非给药途径的PDE超过500μg/day，否则在风险评估中要评价这些元素杂质出现的可能性。本类中的元素包括钡、铬、铜、锂、钼、锑和锡。
Other elements: Some elemental impurities for which PDEs have not been established due to their low inherent toxicity and/or differences in regional regulations are not addressed in this guideline. If these elemental impurities are present or included in the drug product they are addressed by other guidelines and/or regional regulations and practices that may be applicable for particular elements (e.g., Al for compromised renal function; Mn and Zn for patients with compromised hepatic function), or quality considerations (e.g., presence of W impurities in therapeutic proteins) for the final drug product. Some of the elements considered include: Al, B, Ca, Fe, K, Mg, Mn, Na, W and Zn.
其它元素：有些元素杂质因为其较低的毒性和/或在地方法规中的要求不同，其PDE还没有建立，在本指南中并未说明。如果这些元素杂质出现或包括在药品中，其它指南和/或地方性法规和规范可能适用于特殊的元素（例如，铝，损害肾功能，锰和锌对于肝功能不全的病人），或对药品成品的质量考虑（例如，钨杂质在治疗性蛋白质中出现）。这些特殊考虑的元素包括：铝、硼、钙、铁、钾、镁、锰、钠、钨和锌。
5. RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES 元素杂质的风险评估和控制
In developing controls for elemental impurities in drug products, the principles of quality risk management, described in ICH Q9, should be considered. The risk assessment should be based on scientific knowledge and principles. It should link to safety considerations for patients with an understanding of the product and its manufacturing process (ICH Q8 and Q11). In the case of elemental impurities, the product risk assessment would therefore be focused on assessing the levels of elemental impurities in a drug product in relation to the PDEs presented in this guidance. Information for this risk assessment includes but is not limited to: data generated by the applicant, information supplied by drug substance and/or excipient manufacturers and/or data available in published literature.
在建立药品中元素杂质的控制方式时，要考虑ICH Q9中所述的质量风险管理的原则。风险评估应基于科学知识和原则，应将对产品和其生产工艺的了解（ICH Q8和Q11）与对患者的安全考虑相关联。对于元素杂质来说，药品风险分析就应聚焦于结合本指南中所给出的PDE来评估一种药品中的元素杂质水平。风险评估的资料包括，但不仅限于：申请人产生的数据、原料药和/或辅料生产商提供的资料，和/或在公开的文献中可以获得的数据。
The applicant should document the risk assessment and control approaches in an appropriate manner. The level of effort and formality of the risk assessment should be proportional to the level of risk. It is neither always appropriate nor always necessary to use a formal risk management process (using recognized tools and/or formal procedures, e.g., standard operating procedures.) The use of informal risk management processes (using empirical tools and/or internal procedures) may also be considered acceptable. Tools to assist in the risk assessment are described in ICH Q8 and Q9 and will not be presented in this guideline.
申报者应以适当的方式记录风险评估和控制方法。风险评估和努力水平和正式程度应与风险水平相称。没有必要每次都使用正式的风险管理过程（使用已知的工具和/或正式程序，例如，标准操作程序）。也可以使用非正式的风险评估过程（使用经验工具和/或内部程序）。风险评估中辅助工具在ICH Q8和Q9中已有描述，本指南中不再赘述。
5.1 General Principles 通则
For the purposes of this guideline, the risk assessment process can be described in three steps:
出于本指南的目的，风险评估过程可以描述为以下三步：
- Identify known and potential sources of elemental impurities that may find their way into the drug product.
- 识别已知和潜在可能进入药品的元素杂质来源，
- Evaluate the presence of a particular elemental impurity in the drug product by determining the observed or predicted level of the impurity and comparing with the established PDE.
- 通过测试已知或预期杂质，将其水平与已有PDE值比较，评估药品中特殊的元素杂质出现的可能性
- Summarize and document the risk assessment. Identify if controls built into the process are sufficient or identify additional controls to be considered to limit elemental impurities in the drug product.
- 总结和记录风险评估。识别出工艺中嵌入控制是否充分，或识别出要考虑增加控制来限制药品中的元素杂质
In many cases, the steps are considered simultaneously. The outcome of the risk assessment may be the result of iterations to develop a final approach to ensure the potential elemental impurities do not exceed the PDE.
在很多情况下，这些步骤其实是同步的。风险评估的结果，可以是一个迭代的结果，用以建立一种方法来保证潜在元素杂质不超过PDE值。
5.2 Potential Sources of Elemental Impurities 元素杂质的潜在来源
In considering the production of a drug product, there are broad categories of potential sources of elemental impurities.
在考虑一种药品的生产时，元素杂质的潜在来源有很多。
- Residual impurities resulting from elements intentionally added (e.g., catalysts) in the formation of the drug substance, excipients or other drug product components. The risk assessment of the drug substance should address the potential for inclusion of elemental impurities in the drug product.
- 在生产原料药、辅料或其它药品成分时有意加入的元素的残留杂质（例如催化剂）。原料药的风险评估要说明元素杂质出现在药品中的可能性
- Elemental impurities that are not intentionally added and are potentially present in the drug substance, water or excipients used in the preparation of the drug product.
- 非有意加入，可能会在药品制备过程中出现在原料药、水或辅料中的元素杂质
- Elemental impurities that are potentially introduced into the drug substance and/or drug product from manufacturing equipment.
- 可能从生产设备引入原料药和/或制剂的元素杂质
- Elemental impurities that have the potential to be leached into the drug substance and drug product from container closure systems.
- 可能从容器密闭系统中溶出至原料药和制剂的元素杂质
The following diagram shows an example of typical materials, equipment and components used in the production of a drug product. Each of these sources may contribute elemental impurities to the drug product, through any individual or any combination of the potential sources listed above. During the risk assessment, the potential contributions from each of these sources should be considered to determine the overall contribution of elemental impurities to the drug product.
下图表示了一种药品生产中所用的典型物料、设备和成分的一个例子。通过单独或上列潜在来源的联合，每种来源均可能引起药品中的元素杂质污染。在风险评估中，任何一种来源的潜在作用均应进行考虑，以确定对药品造成的总体元素杂质污染。
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* The risk of inclusion of elemental impurities can be reduced through process understanding, equipment selection, equipment qualification and Good Manufacturing Practice (GMP) processes.
通过对工艺的了解、设备的选择、设备确认和GMP，可以降低元素杂质引入风险。
** The risk of inclusion of elemental impurities from water can be reduced by complying with compendial (e.g., European Pharmacopoeia, Japanese Pharmacopoeia, US Pharmacopeial Convention) water quality requirements, if purified water or water for injection is used in the manufacturing process(es).
如果在生产工艺中使用了纯化水或注射用水，从水中引入元素杂质的风险可能通过符合药典水质量来降低（例如，欧洲药典、日本药典、美国药典）。
5.3 Identification of Potential Elemental Impurities 潜在元素杂质的识别
Potential elemental impurities derived from intentionally added catalysts and inorganic reagents: If any element listed in Table 5.1 is intentionally added, it should be considered in the risk assessment. For this category, the identity of the potential impurities is known and techniques for controlling the elemental impurities are easily characterized and defined.
来自有意加入的催化剂和无机试剂的潜在元素杂质：如果有意地加入了表5.1中的任何元素，则应在风险评估中考虑。对此类情况，潜在杂质是已知的，控制元素杂质的技术易于制订。
Potential elemental impurities that may be present in drug substances and/or excipients: While not intentionally added, some elemental impurities may be present in some drug substances and/or excipients. The possibility for inclusion of these elements in the drug product should be reflected in the risk assessment.
可能会出现在原料药和/或辅料中的潜在元素杂质：在非有意加入情况下，有些元素杂质可能会出在有些原料药和/或辅料中。在风险评估中要反映药品中含有这些元素的可能性。
For the oral route of administration, the risk assessment should evaluate the possibility for inclusion of Class 1 and Class 2A elemental impurities in the drug product. For parenteral and inhalation routes of administration, the risk assessment should evaluate the possibility for inclusion of the Class 1, Class 2A and Class 3 elemental impurities as shown in Table 5.1.
对于口服给药途径，风险评估应评价药品中含有1类和2A类元素杂质的可能性。对于注射和吸入给药途径，风险评估应评价含有1类、2A类和3类元素杂质的可能性，如表5.1所示。
Potential elemental impurities derived from manufacturing equipment: The contribution of elemental impurities from this source may be limited and the subset of elemental impurities that should be considered in the risk assessment will depend on the manufacturing equipment used in the production of the drug product. Application of process knowledge, selection of equipment, equipment qualification and GMP controls ensure a low contribution from manufacturing equipment. The specific elemental impurities of concern should be assessed based on knowledge of the composition of the components of the manufacturing equipment that come in contact with components of the drug product. The risk assessment of this source of elemental impurities is one that can potentially be utilized for many drug products using similar process trains and processes.
生产设备中生成的潜在元素杂质：从该途径来源的元素杂质可能会比较有限，在风险评估中需要包括的元素杂质种类将取决于药品生产所用的生产设备。工艺知识申报、设备选择、设备确认和GMP控制能保证生产设备来源的元素杂质在一个较低的水平。应根据与药品成分接触的生产设备的部件成分知识，对特别关注的元素杂质进行评估。该类来源的元素杂质风险评估可以用于使用类似设备链和工艺的多个药品。
In general, the processes used to prepare a given drug substance are considerably more aggressive than processes used in preparing the drug product when assessed relative to the potential to leach or remove elemental impurities from manufacturing equipment. Contributions of elemental impurities from drug product processing equipment would be expected to be lower than contributions observed for the drug substance. However, when this is not the case based on process knowledge or understanding, the applicant should consider the potential for incorporation of elemental impurities from the drug product manufacturing equipment in the risk assessment (e.g., hot melt extrusion).
一般来说，在评估从生产设备清除或析出元素杂质可能性时，用于制备指定原料药的工艺条件要比药品制备工艺条件严苛的多。来自制剂工艺设备中的元素杂质一般预期会低于来自原料药工艺设备的杂质。但是，如果根据工艺知识或理解并不是这样的话，则申报人应在风险评估中考虑来自制剂生产设备的元素杂质结合的可能性（例如，热融挤压）
Elemental impurities leached from container closure systems: The identification of potential elemental impurities that may be introduced from container closure systems should be based on a scientific understanding of likely interactions between a particular drug product type and its packaging. When a review of the materials of construction demonstrates that the container closure system does not contain elemental impurities, no additional risk assessment needs to be performed. It is recognized that the probability of elemental leaching into solid dosage forms is minimal and does not require further consideration in the risk assessment. For liquid and semi-solid dosage forms there is a higher probability that elemental impurities could leach from the container closure system during the shelf-life of the product. Studies to understand potential leachables from the container closure system (after washing, sterilization, irradiation, etc.) should be performed. This source of elemental impurities will typically be addressed during evaluation of the container closure system for the drug product.
从容器密闭系统中溶出的元素杂质：对可能从容器密闭系统引入的潜在元素杂质的识别应基于特殊药品类型和其它包装间的可能的相互反应的科学理解。如果对结构材料的审核证明容器密闭系统不含有任何元素杂质，则不需要进行额外的风险评估。我们认识到元素会溶出至固体剂型的可能性是非常小的，不需要进在风险评估中进行深入考虑。对于液体和半固体剂型，则在药品的货架期内，元素杂质会从容器密闭系统中溶出到药品中的可能性会比较大，此时应对容器密闭系统的潜在溶出物质进行研究（在清洁、灭菌、辐射后等）。该类元素杂质一般在药品的容器密闭系统的评估中要重点论述。
Factors that should be considered (for liquid and semi-solid dosage forms) include but are not limited to:
要考虑的因素（对于液体或半固体剂型）包括但不仅限于：
- Hydrophilicity/hydrophobicity;
- 亲水性/吸湿性
- Ionic content;
- 离子含量
- pH;
- Temperature (cold chain vs room temperature and processing conditions);
- 温度（冷链VS室温和处理条件）
- Contact surface area;
- 接触面积
- Container/component composition;
- 容器/组件成分
- Terminal sterilization;
- 最终灭菌
- Packaging process;
- 包装过程
- Component sterilization;
- 部件灭菌
- Duration of storage.
- 存贮时长
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