GUIDELINE FOR ELEMENTAL

IMPURITIES
元素杂质指南

TABLE OF
CONTENTS 目录

1. INTRODUCTION 简介
2. SCOPE 范围
3. SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES 潜在元素杂质的安全性评估
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性评估规则
3.2 Other Routes of Administration 其他给药途径
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 阈值的合理性说明
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 通用准则
5.2 Potential Sources of Elemental Impurities 元素杂质潜在的来源
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
建议在风险评估中考虑的元素
5.5 Evaluation 评估
5.6 Summary of Risk Assessment Process 风险评估总结
5.7 Special Considerations for Biotechnologically-Derived Products 生物技术衍生产品的特殊考虑
6. CONTROL OF ELEMENTAL IMPURITIES 元素杂质控制
7. CONVERTING BETWEEN PDES AND CONCENTRATION LIMITS PDE 值和浓度限的相互转换
8. SPECIATION AND OTHER CONSIDERATIONS 元素形态和其他考虑
9. ANALYTICAL PROCEDURES 分析方法
10. LIFECYCLE MANAGEMENT 生命周期管理

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 GUIDELINE FOR ELEMENTAL IMPURITIES
元素杂质指南 Q3D
Q3D

1. INTRODUCTION 简介
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有多种来源，可能是合成过程中有意加入的金属催化剂残留或以杂
质形式出现（例如，通过与工艺设备或容器/密闭系统的相互反应，或出现在药品成分中）。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、为每个有毒性风险的元素建立 PDE（日最
大暴露量）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元素杂质的限度。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
平表现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），来考虑其它的控制限度。
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。
该方法为发展基于风险的控制策略来限制药品中的元素杂质的过程提供了一个平台。

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 中定义的产品）和含有已有原料药的新
药品。含有纯化后的蛋白质和多肽（包括重组或非重组来源的蛋白质和多肽）的药品及其衍生
物，以及其复方药品（例如，偶合物）都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

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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。在一些领域，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性评估

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性评估准则
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.
用于对每一种元素杂质分别建立 PDE 值的方法，详见附录 1。在本指南中评估的元素，是
通过对公众可获得的可用数据进行评估得到的，这些数据包括科学杂志、政府研究报告、国际
法规标准（适用于药品）和指南、以及法规机构的研究和评估报告。该评估过程符合 ICH Q3C：
残留溶剂中所述的原则。对可以获得的资料进行审核以建立口服、注射和吸入的 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 包括了一份用于设定各元素 PDE 值的关键研究的安全评估总结。对于铱、锇、铑
和钌元素，还没有足够的数据设定其任何给药途径的 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近似顺序列出如下：
 The likely oxidation state of the element in the drug product; 药品中元素的氧化状态
 Human exposure and safety data when it provided applicable information;
提供可用信息时，人类的暴露量和安全数据
 The most relevant animal study; 最相近的动物实验
 Route of administration; 给药途径
 The relevant endpoint(s).

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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.
本指南中所讨论的一些元素杂质的日摄入量标准因食物、水、空气和职业暴露量而不同。
如果适用，在安全性评估和建立 PDE 值时候会考虑这些标准。
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
相近的，则在单个安全评估中给出其理由。
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.
相对于使用微粒，进行吸入研究时可优先使用可溶性盐（可获得时）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（呼吸系统）或系统性毒性
的建立的。对于为了吸入给药建立的 PDE 值（适用时，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.
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。

3.2 Other Routes of Administration 其他给药途径

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 作为建立特定给药途径 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产生预期的局部影响
O If local effects are expected, assess whether a modification to an established PDE is necessary.
如果有预期的局部影响，需要评估是否要对已建立的 PDE 进行修正

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 o Consider the doses/exposures at which these effects can be expected relative to the adverse
effect that was used to set an established PDE.
o If local effects are not expected, no adjustment to an established PDE is necessary.
如果有预期的局部影响，需要评估是否要对已建立的 PDE 进行修正
 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:
o 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.
 If a PDE proposed for the new route is increased relative to an established PDE, quality
attributes may need to be considered.

3.3 Justification for Elemental Impurity Levels Higher than an Established PDE
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:
 Intermittent dosing;
 Short term dosing (i.e., 30 days or less);
 Specific indications (e.g., life-threatening, unmet medical needs, rare diseases).
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.
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:
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:
Proposed level = 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.
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:
Proposed level = 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.

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3.4 Parenteral Products
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)

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为三类。出现的可
能性包括：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，以及元素的可见天然丰度和在环境中分布。根据本指南的目的，一种在自然中丰度
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.
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。其在药品
中出现一般是来自于使用的物料（例如，矿物质赋形剂）。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，包含评估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.
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
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 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.
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 μ g/天），但
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 500μ
g/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遗传毒性和/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
评估应基于特定的科学知识和原则，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。风险评估的深度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 通用准则

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 For the purposes of this guideline, the risk assessment process can be described in three steps:
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的杂质水平，并将其水平与已有 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。推断出工艺中的控制是否充分，或提出要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进行的。风险评估的结果，可以是一个重复寻找建立
一种方法来保证潜在元素杂质不超过 PDE 值的结果。

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.
元素杂质的来源有很多，
 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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 Manufacturing Drug substance
equipment* 原料药
生产设备*
Elemental
impurities in
drug products
药品中元素杂质

Container Excipients
Water**
system
水** 辅料
包装系统

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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.
通过对工艺的调整、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.
源自生产设备的元素杂质：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，相对于从生产设备析出或移除元素杂质，用于制备指定原料药的工艺条件要比制
剂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的可能性（例如，热融挤压）
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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
于对特定药品类型和其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: 对于液体或半固体剂型，要考虑的因素，包括但不仅限于：
 Hydrophilicity/hydrophobicity; 亲水性/疏水性
 Ionic content; 离子含量
 pH; pH
 Temperature (cold chain vs room temperature and processing conditions); 温度
 Contact surface area; 接触面
 Container/component composition; 容器组分
 Terminal sterilization; 最终灭菌
 Packaging process; 包装工艺
 Component sterilization; 组分灭菌
 Duration of storage. 贮存时间

5.4 Recommendations for Elements to be Considered in the Risk Assessment

建议在风险评估中考虑的元素
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给出了建议。该表可以用于药品
中所有来源的元素杂质。

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 Table 5.1: Elements to be Considered in the Risk Assessment
表 5.1 风险评估中考虑的元素
Element Class If intentionally If not intentionally added
元素 分类 added (all routes) 非有意加入
有意加入（所有给
药途径）
Oral 口服 Parenteral 注射 Inhalation 吸入
Cd 镉 1 yes yes yes yes
Pb 铅 1 yes yes yes yes
As 砷 1 yes yes yes yes
Hg 汞 1 yes yes yes yes
Co 钴 2A yes yes yes yes
V 钒 2A yes yes yes yes
Ni 镍 2A yes yes yes yes
Tl 铊 2B yes no no no
Au 金 2B yes no no no
Pd 钯 2B yes no no no
Ir 铱 2B yes no no no
Os 锇 2B yes no no no
Rh 铑 2B yes no no no
Ru 铷 2B yes no no no
Se 硒 2B yes no no no
Ag 银 2B yes no no no
Pt 铂 2B yes no no no
Li 锂 3 yes no yes yes
Sb 锑 3 yes no yes yes
Ba 钡 3 yes no no yes
Mo 钼 3 yes no no yes
Cu 铜 3 yes no yes yes
Sn 锡 3 yes no no yes
Cr 铬 3 yes no no yes

5.5 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.
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.
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，要考虑进行风险
评估该元素杂质是有否多个来源。并记录评估的结论和支持性资料。
The applicant’s 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：
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 Prior knowledge; 知识积累
 Published literature; 出版的文献
 Data generated from similar processes; 相似工艺的数据
 Supplier information or data; 供应商提供的数据
 Testing of the components of the drug product; 药品成分的检测
 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);
元素的自然丰度（尤其针对非有意添加的元素）
 Prior knowledge of elemental impurity concentration ranges from specific sources;
特定来源元素杂质浓度的知识积累
 The composition of the drug product. 药品组成

5.6 Summary of Risk Assessment Process 风险评估过程总结

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的审核，并结合在产品或工艺中获得的信息和知识，进行风险评
估总结，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，已观察到的或预测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显著性的衡量方
法。控制阈值可用于确定是否需要额外的控制措施。
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.
若申请者对数据进行了恰当的评估并且阐述了足够的控制措施，当药品中所有来源的元素杂
质水平低于 PDE 的 30%时，不必进行额外的控制。
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
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 Variability of the elemental impurity level in the specific sources; 特定来源元素杂质水平的可变性
 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组分或药品
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

生物技术衍生物产品的特殊考虑
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.
对于生物技术类的产品，原料药阶段的元素杂质引起安全问题的风险较低。这很大程度上是
因为：a）通常在制作生物技术产品过程中这些元素不会用作催化剂或试剂；b)在细胞培育过程中，
元素以痕迹量级加入培养基。没有积累效应，稀释率较高；c）生物技术制造中常用的纯化步骤，
比如萃取，色谱分析法，渗析或 UF/DF 可以把细胞培养/发酵步骤中加入，或与制作设备接触得到
的杂质清除到忽略不计的程度。因此，通常不需要对生物技术类原料药进行元素杂质控制。如果
生物技术类原料药包括合成结构（比如抗体药物共轭物），应对小分子成分的元素杂质进行适当
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，应当考虑制剂生产中的潜在元素杂质来源（比如赋形剂）和其他环境类来源。需要对
这些元素杂质来源进行评估，因为他们通常被引入成品中之后没有其他的后续工艺来去除。评估
中需要考虑的风险因素应包括赋形剂的类型、处理条件和它们对环境污染的敏感度（比如，无菌
生产的控制区和使用的纯化水）和服药频率。

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6. CONTROL OF ELEMENTAL IMPURITIES 元素杂质控制
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:
元素杂质控制是药品整个控制策略的一部分，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;
通过改进特定或非特定的纯化步骤，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 PDE 值和浓度的互相转换

The PDEs, reported in micrograms per day (µg/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（μg/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
个元素允许的最大量。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;
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 在与供应商的讨论中，帮助建立上游控制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方法时，要
考虑来自容器密闭系统和生产设备的元素杂质，用于计算组分（辅料和原料药）的最大允许浓度
时。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。

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Option 1: Common permitted concentration limits of elements across drug product components
for drug products with daily intakes of not more than 10 grams:
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.
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。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，并且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
分中目标元素的允许浓度。本方法，允许对于每一成分中每一目标元素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。

PDE(μg/day)
Concentration 浓度 (μg/g)=
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.
如果在风险评估中已识别的所有药品中所有成分的目标元素均不超过方法 1 中的浓度，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，允许根据所提供的实际日摄入量，确定每种成分中的每一目标元素的固定通用的
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.
如果在风险评估中已识别的所有药品中所有成分的目标元素均不超过方法 2a 中的浓度，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：具有特定日摄入量的药品单一成分中元素的允许浓度限度

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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
concentrations in the other components of the drug product. Equation 2 may be used to demonstrate
that component-specific limits for each element in each component of a drug product assure that the
PDE will be met.
对于特定药品组分中存在的特定潜在元素杂质，本方法需要其他的资料以便申报人对数据
进行整合。申报人可以根据组分中元素的分布来设定允许浓度（例如，所讨论的元素在组分中
出现较高浓度）。对于每种被识别为药品组分中可能出现的元素，药品成品中元素杂质的最高
预期量可以通过将每种组分物料的质量乘以申请人建立的该物料中的允许浓度，然后将药品中
所有成分中的元素杂质质量相加来计算，如公式 2 所述。除非根据本指南其它相关部分进行了
论证，否则药品里元素杂质的总质量应符合附录 2 表 A.2.1 中给定的 PDE 值。如果风险评估已
认定某特定组成中特定的元素不是潜在杂质，则不需要为该元素在该组分中的含量建立定量结
果。本方法允许药品中特定组分中某元素的最高允许浓度高于方法 1 或方法 2a 中的限度，但这
就表示药品中其它组成中的允许浓度要更低。公式 2 可以用来证明通过控制各组分里特定组分
中每种元素的限度，最终保证药品符合 PDE 要求。

K=药品中 N 组成的序号
Ck=组分 K 中元素杂质的允许浓度（μ g/g）
Mk=药品最大日摄入量中组分 K 的质量（g）
An example using this option is provided in Appendix 4 Tables A.4.4 – A.4.5.
本方法的例子参见附录 4 表 A.4.4-A.4.5。
Option 3: Finished Product Analysis:成品分析
The concentration of each element may be measured in the final drug product. Equation 1 may be
used with the maximum total daily dose of the drug product to calculate a maximum permitted
concentration of the elemental impurity. An example using this option is provided in Appendix 4,
Table A.4.6.
可以检测成品中每种元素的浓度。公式 1 和最大日剂量一起用于计算最高允许元素杂质浓度。
本方法例子参见附录 4，表 A.4.6.
8. SPECIATION AND OTHER CONSIDERATIONS 元素形态和其它考虑
Speciation is defined as the distribution of elements among chemical species including isotopic
composition, electronic or oxidation state, and/or complex or molecular structure. When the toxicities
of different species of the same element are known, the PDE has been established using the toxicity
information on the species expected to be in the drug product.
元素形态是指化学形态中元素的分布情况，包括同位素组成、电子或氧化状态、和/或复合
或分子结构。如果同一元素的不同形态的毒性已知，则 PDE 可使用在药品中元素预期的化学形
态的毒性资料来计算。
When elemental impurity measurements are used in the risk assessment, total elemental impurity
levels in drug products may be used to assess compliance with the PDEs. The applicant is not
expected to provide speciation information; however, such information could be used to justify lower
or higher levels when the identified species is more or less toxic, respectively, than the species used in

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the monographs in Appendix 3.
如果元素杂质的测定被用于风险评估，药品中总元素杂质水平可以用于评估 PDE 的符合性。
申报人不需要提交元素形态资料，但是，当所识别的种类比附录 3 所用种类获得的毒性更高或
更低时，这些资料可以用于论述较低的或较高的杂质水平。
When total elemental impurity levels in components are used in the risk assessment, the applicant is
not expected to provide information on release of an elemental impurity from the component in which
it is found. However, such information could be used to justify levels higher than those based on the
total elemental impurity content of the drug product.
如果在风险评估中使用了所有组分中总元素杂质水平，则申报者不需要提交单个组分中所
发现的元素杂质资料。但是，该资料可以用于论述单个组分中元素杂质水平高于药品中总元素
杂质水平的情况。

9. ANALYTICAL PROCEDURES 分析方法

The determination of elemental impurities should be conducted using appropriate procedures suitable
for their intended purposes. Unless otherwise justified, the test should be specific for each elemental
impurity identified for control during the risk assessment. Pharmacopoeial procedures or suitable
alternative procedures for determining levels of elemental impurities should be used.
元素杂质的检测应使用适当的分析方法，适用于其既定目的。除另有论证外，在风险评估
中识别出需要控制的每种元素杂质均需有特定的检测方法。可以使用药典方法或适当的替代性
方法来测定元素杂质的水平。

10. LIFECYCLE MANAGEMENT 生命周期管理

The quality systems and management responsibilities described in ICH Q10 are intended to encourage
the use of science-based and risk-based approaches at each lifecycle stage, thereby promoting
continual improvement across the entire product lifecycle. Product and process knowledge should be
managed from development through the commercial life of the product up to and including product
discontinuation.
在 ICH Q10 中描述了质量体系和管理责任，其目的是鼓励在生命周期各阶段使用基于科学
和基于风险的方法，从而促进整个产品的生命周期内的持续改进。产品和工艺知识管理应从研
发阶段开始，贯穿整个商业历程，直至产品退市。
Knowledge gained from development combined with commercial manufacturing experience and data
can be used to further improve process understanding and process performance. Such improvements
can enhance controls on elemental impurities. It is recognized that the elemental impurity data
available for some components is somewhat limited at the date of publication of this guideline, which
may direct the applicant to a specific set of controls. Additional data, if developed, may lead to
modifications of the controls.
从研发阶段获得的知识，与商业生产经验和数据相结合，可以用于进一步改进工艺知识和
工艺性能。这种改进可以增强对元素杂质的控制。我们认识到有些组分中元素杂质数据在本指
南公布时仍是很有限的，这可能要求申报者建立特定的控制。如果在后期研究获得更多数据，
可能会导致对控制方式的修改。
If changes to the drug product or components have the potential to change the elemental impurity
content of the drug product, the risk assessment, including established controls for elemental impurities,
should be re-evaluated. Such changes could include, but are not limited to: changes in synthetic
routes, excipient suppliers, raw materials, processes, equipment, container closure systems or facilities.
All changes are subject to internal change management process (ICH Q10) and if needed appropriate
regional regulatory requirements.
如果对药品或组成的变更可能对药品中元素杂质的含量产生影响，则应重新进行风险评估，
包括对已建立的元素杂质控制方式的评估。这类变更可能包括但不仅限于：合成路线变更、辅
料供应商变更、原料变更、工艺变更、设备变更、容器密闭系统或设施变更。所有变更均应通
过内部变更管理流程进行管理，必要时应满足地区法规要求。

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