USP36 <232> ELEMENTAL IMPURITIES 元素杂质--限度 （中英文）

巴西木

<232>ELEMENTAL IMPURITIES—LIMITS 元素杂质—限度

-------翻译人：Julia

INTRODUCTION 介绍

This general chapter specifies limits for the amounts of elemental impurities in drug products. Elemental impurities include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment). When elemental impurities are known to be present, have been added, or have the potential for introduction, assurance of compliance to the specified levels is required. A risk-based control strategy may be appropriate when analysts determine how to assure compliance with this standard. Due to the ubiquitous nature of As, Cd, Pb, and Hg, they (at the minimum) must be considered in the risk-based control strategy. Regardless of the approach used, compliance with the limits specified is required for all drug products.

本章说明了药品中元素杂质的数量限度。元素杂质包括可能会存在于原料药、辅料或制剂中的催化剂和环境污染物。这些杂质可能会自然生成的、有意加入的或不可逆引入（例如与生产设备的相互反应）的。如果已知元素杂质存在、被加入或有引入的可能性，则必须保证其符合指定限度。分析人员在决定如何保证符合本标准时，可以适当采用基于风险的控制策略。由于砷、镉、铅和汞在自然中普遍存在，在采用基于风险的控制策略时必须包括对这四种元素的考虑。不论采用何种方式，所有药品均需符合指定的限度。

The limits presented in this chapter do not apply to excipients and drug substances, except where specified in this chapter or in the individual monographs. However, elemental impurity levels present in drug substances and excipients must be known and reported.

在本章中给出的限度不适用于辅料和原料药，除非在本章或各论中有说明。但是，原料药和辅料中的元素杂质水平必须知道并报告。

The limits indicated in this chapter are not required for articles intended only for veterinary use and conventional vaccines. Dietary supplements and their ingredients are addressed in Elemental Contaminants in Dietary Supplements2232 .1

本章中指出的限度不适用于仅供兽用品种和传统疫苗。膳食补充剂及其成分在《膳食补充剂元素污染物2232》中已有说明。

SPECIATION 杂质形态

The determination of the oxidation state, organic complex, or combination is termed speciation. Each of the elemental impurities has the potential to be present in differing oxidation or complexation states. However, arsenic and mercury are of particular concern because of the differing toxicities of their inorganic and complexed organic forms.

不同形式如氧化态、有机复合物或复合状态称为杂质形态。每一种元素杂质都可能会以不同的氧化或复合状态存在。但因为砷和汞的有机形态和复合无机形态的毒性有差异，因而其受到特别关注。

The arsenic limits are based on the inorganic (most toxic) form. Arsenic can be measured using a total arsenic procedure under the assumption that all arsenic contained in the material under test is in the inorganic form. Where the limit is exceeded using a total arsenic procedure, it may be possible to show via a procedure that quantifies the different forms that the inorganic form meets the specification.

砷限度是基于无机（大多是有毒的）形式。假定物料中含有的砷均为无机形式，则可以采用总砷测试方式进行检测，如果采用总砷量检测结果显示超出限度，也可以对不同砷的存在方式进行定量检测，来证明有机砷符合限度规定。

The mercury limits are based upon the inorganic (2+) oxidation state. The methyl mercury form (most toxic) is rarely an issue for pharmaceuticals. Thus, the limit was established assuming the most common (mercuric) inorganic form. Limits for articles that have the potential to contain methyl mercury (e.g., materials derived from fish) are to be provided in the monograph.

汞限度是基于无机二价氧化态。甲基汞形式（毒性最强）对于药物来说影响最大。因而，对汞的限度设定是假定其为最常见（汞盐）无机形式。对于可能含有甲基汞（例如鱼制品）的产品，其限度在各论中均有包括。

ROUTES OF EXPOSURE 暴露途径

The toxicity of an elemental impurity is related to its extent of exposure (bioavailability). The extent of exposure has been determined for each of the elemental impurities of interest for three routes of administration: oral, parenteral, and inhalational. These limits are based on chronic exposure. The other two routes of administration, mucosal and topical, are considered to be the same as oral for the purpose of this standard, and the PDEs described in Table 1 would apply to these products. [NOTE—The routes of administration of drug products are defined in general chapterPharmaceutical Dosage Forms 1151 . ]

每种元素杂质的毒性与其暴露程度（生物利用度）有关。各元素杂质的在三种给药途径下的暴露程度已经过测定：口服、注射和吸入。这些限度是基于长期暴露的数据制订的。其它两种给药途径：粘膜和局部给药，是作为与口服一样考虑的，因此在相同PDE下，表1中的限度同样适用于该类产品。【注---制剂给药途径在通论中有定义《药物制剂形式1151》】

DRUG PRODUCTS 制剂

The limits described in the second through fourth columns of Table 1 are the base daily dose PDEs of the elemental impurities of interest for a drug product taken by the patient according to indicated routes of administration. Parenterals with an intended maximum dose of greater than 10 mL and not more than 100 mL must use theSummation Option described below.

在表1的第2至第4列所指限度是基于日剂量计算的各元素杂质的由病人在指定摄入途径下的日最大允许暴露量。注射剂如果最大剂量超过10ml，但不超过100ml，必须使用下述的《加和方式》计算。

Large Volume Parenterals 大容量注射液

When the daily dose of an injection is greater than 100 mL (large volume parenteral (LVP)), the amount of elemental impurities present in the drug product must be controlled through the individual components used to produce the product. The amounts of elemental impurities present in each component used in an LVP are less than the values included in the fifth column of Table 1.

如果注射剂日剂量超过100ml（大容量注射剂LVP），药品中的元素杂质必须通过用于生产的单个原辅料来进行控制。LVP中每一种原辅料中存在的元素杂质的数量应不超过表1中第5列的数值。

Table 1. Elemental Impurities for Drug Products

表1： 药品元素杂质

Element 元素	Oral Daily Dose PDE 口服 (ug/day)	Parenteral Daily Dose PED 注射 (ug/day)	Inhalational Daily Dose PDE 吸入 (ug/day)	LVP Component Limit 大容量成份限度 (ug/g)
Cadmium 镉	25	2.5	1.5	0.25
Lead 铅	5	5	5	0.5
Inorganic arsenic 无机砷	1.5	1.5	1.5	0.15
Inorganic mercury无机汞	15	1.5	1.5	0.15
Iridium 铱	100	10	1.5	1.0
Osmium 锇	100	10	1.5	1.0
Palladium 钯	100	10	1.5	1.0
Platinum 铂	100	10	1.5	1.0
Rhodium 铑	100	10	1.5	1.0
Ruthenium 钌	100	10	1.5	1.0
Chromium 铬	*	*	25	*
Molybdenum 钼	100	10	250	1.0
Nickel 镍	500	50	1.5	5.0
Vanadium  钒	100	10	1.5	5.0
Copper 铜	1000	100	70	25

a  PDE = Permissible daily exposure based on a 50-kg person.

以50kg体重计算的允许日暴露量

b  See Specification section. 见质量标准部分

*  Not a safety concern. 无安全性问题

Options for Demonstrating Compliance 证明符合的方式

DRUG PRODUCT ANALYSIS OPTION 制剂分析方式

The results obtained from the analysis of a typical dosage unit, scaled to a maximum daily dose, are compared to theDaily Dose PDE.

对具有代表性的制剂单位中进行检测，采用所测得的结果，计算至最大日服用剂量，与日剂量允许日暴露量进行比较。

Daily Dose PDE ≥ measured value (μg/g) × maximum daily dose (g/day)

日剂量允许日暴露量 ≥ 实测值（微克/克）× 最大日剂量（克/天）

The measured amount of each impurity is NMT the Daily Dose PDE, unless otherwise stated in the individual monograph.

除非各论中另有规定，每一元素测得的数量应不超过日剂量允许日暴露量。

SUMMATION OPTION 加和方式

Separately add the amounts of each elemental impurity (in μg/g) present in each of the components of the drug product using the following equation:

将制剂所用原辅料中存在的所有元素杂质（ug/g）采用以下公式分别加和

Daily Dose PDE ≥ [ΣM1(CM×WM)] ×DD

Where 其中

M = each ingredient used to manufacture a dosage unit

一个制剂单位中所用的原辅料

CM = element concentration in component (drug substance or excipient) (μg/g)

原辅料中存在元素的浓度（原料药或辅料）（ug/g）

WM = weight of component in a dosage unit (g/dosage unit)

     一个制剂单位中所用原辅料的重量（g/制剂单位）

DD = number of units in the maximum daily dose (unit/day)

     最大日服用剂量的制剂单位数（单位/天）

The result of the summation of each impurity is NMT the Daily Dose PDE, unless otherwise stated in the individual monograph. Before products can be evaluated using this option, the manufacturer must validate that additional elemental impurities cannot be inadvertently added through the manufacturing process.

除非在各论中另有规定，每个元素加和的结果应不超过日剂量允许最大暴露值。在产品使用此方法进行评估前，生产商必须验证在生产过程中不会有更多的该元素杂质被不可逆地加入。

DRUG SUBSTANCE AND EXCIPIENTS 原料药和辅料

The presence of elemental impurities in drug substances and excipients must be controlled and, where present, reported. The acceptable levels for these impurities depend on the material's ultimate use. Therefore, drug product manufacturers must determine the acceptable level of elemental impurities in the drug substances and excipients used to produce their products.

原辅料中的元素杂质必须进行控制，如果存在，必须报告。这些元素杂质的可接受标准取决于该物料的使用上限，因此药品生产商必须决定用于制剂生产的原辅料中的元素杂质的可接受限度。

The values provided in Table 2 represent concentration limits for components (drug substances and excipients) of drug products dosed at a maximum daily dose of 10 g/day. These values serve as default concentration limits to aid discussions between drug product manufacturers and the suppliers of the components of their drug products. [NOTE—Individual components may need to be limited at levels different from those in the table depending on monograph-specific mitigating factors. ]

在表2中提供的数值代表用于日剂量不超过10克/天的制剂生产所用药物成份（原料药和辅料）中的浓度限。这些数值是默认的浓度限值，帮助制剂生产商和其原辅料供应商对此进行讨论。【注—单个成分可能需要根据各论特定的减轻因素来制订不同于表中数值的限度。】

Table 2. Default Concentration Limits for Drug Substances and Excipients

表2 原料药和辅料中默许浓度限度

Element 元素	Concentration limits (ug/g) for Oral Drug Products with a Maximum Daily Dose of 口服最大剂量 ≤10g/day	Concentration limits (ug/g) for Parenteral Drug Products with a Maximum Daily Dose of ≤10g/day 注射	Concentration limits (ug/g) for Inhalational Drug Products with a Maximum Daily Dose of ≤10g/day 吸入
Cadmium 镉	2.5	0.25	0.15
Lead 铅	0.5	0.5	0.5
Inorganic arsenic 无机砷	0.15	0.15	0.15
Inorganic mercury无机汞	1.5	0.15	0.15
Iridium 铱	10	1.0	0.15
Osmium 锇	10	1.0	0.15
Palladium 钯	10	1.0	0.15
Platinum 铂	10	1.0	0.15
Rhodium 铑	10	1.0	0.15
Ruthenium 钌	100	10	1.5
Chromium 铬	*	*	2.5
Molybdenum 钼	10	1.0	25
Nickel 镍	50	5.0	0.15
Vanadium  钒	100	10	30
Copper 铜	100	10	7

* Not a safety concern. 无安全性问题

ANALYTICAL TESTING 分析测试

If, by validated processes and supply-chain control, manufacturers can demonstrate the absence of impurities, then further testing is not needed. When testing is done to demonstrate compliance, proceed as directed in general chapter Elemental Impurities—Procedures 233 , and minimally include As, Cd, Pd, and Hg in the Target Element evaluation.

如果生产商能通过采用经验证的工艺和供应商链控制，证明杂质不可能出现，则不需要进行进一步的测试。在为证明杂质符合规定而进行测试时，应根据《通论》中《元素杂质—检测方法 233》要求进行，并在《目标元素评估》中必须包括砷、镉、铅和汞。

【译者注---此处原文为砷、镉、钯（Pd）和汞，但根据第一段介绍内容及“自然中普遍存在”的特性，应为“铅（Pb）”。】

This dietary supplement chapter is still under revision and appears online in PF 38(3) [May-June 2012].

膳食补充剂章节仍在修订中，其修订内容可由在线PF38(3)【5-6月2012】查得。

Auxiliary Information – Please check for your question in the FAQs before contacting USP.

Topic/Question	Contact	Expert Committee
General Chapter	Kahkashan Zidi, Ph.D Senior Scientific Liaison 1-301-816-8269	(GCCA2010) General Chapters – Chemical Analysis

USP 36-NF31 Page 151

Pharmacopeial Forum: Volume No. 37(3)

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