USP36 <233> ELEMENTAL IMPURITIES—PROCEDURES元素杂质-方法（中英文）

巴西木

<233> ELEMENTAL IMPURITIES—PROCEDURES元素杂质-方法

----翻译人：Julia

INTRODUCTION  说明

This chapter describes two analytical procedures (Procedures 1 and 2) for the evaluation of the levels of the elemental impurities. The chapter also describes criteria for acceptable alternative procedures. Alternative procedures that meet the validation requirements described herein may be considered equivalent to Procedures 1 and 2 for the purposes of this test. In addition, system standardization and suitability evaluation using applicable reference materials should be performed on the day of analysis. The requirement for an elemental impurity test is specified in General Notices and Requirements or in the individual monograph. By means of verification studies, analysts will confirm that the analytical procedures described herein, as well as alternative analytical procedures, are suitable for use on specified material.

本章共提供了两种评价元素杂质水平的方法（方法1和方法2）。也提供了替代方法的接受标准。达到本章的验证要求的替代方法在进行元素杂质测定时可以认为与方法1和方法2具有同等的效果。另外每日分析前应当使用合适的对照物质进行系统标准化和适应性评价。元素杂质测定的要求在总则或各论中进行了说明。 通过确认研究，分析员必须保证本章所述的方法和替代分析方法适用于测定特定的物质。

Speciation 形态

The determination of the oxidation state, organic complex or combination is termed speciation. Analytical procedures for speciation are not included in this chapter but examples may be found elsewhere in the USP–NF and in the literature.

氧化状态、有机配位或组合的确定叫做形态。本章不涉及形态的分析方法，但是可以在USP-NF或文献中找到这种方法的例子。

Definitions 定义

Concentrated Acid: Concentrated ultra-pure nitric, sulfuric, hydrochloric, or hydrofluoric acids orAqua Regia.

浓酸：浓的超纯硝酸、硫酸、盐酸或氢氟酸或王水。

Aqua Regia: Aqua regia is a mixture of concentrated hydrochloric and nitric acids, typically at ratios of 3:1 or 4:1, respectively.

王水：王水是浓盐酸和浓硝酸以3:1或4:1的比例混合而成的混合物。

Matched Matrix: Solutions having the same solvent composition as the Sample solution. In the case of an aqueous solution, Matched Matrix would indicate that the same acids, acid concentrations, and mercury stabilizer are used in both preparations.

匹配基质：与样品溶液具有相同溶剂成分的溶液。如果是水溶液，匹配基质是指相同的酸和酸浓度并且在两种溶液中都加入了水银稳定剂。

Target Elements: Elements with the potential of being present in the material under test. Include As, Cd, Pd, and Hg in the target element evaluation when testing is done to demonstrate compliance. Target elements should also include any elements that may be added through material processing or storage, and any elements whose presence may interfere with the operation of the analytical procedures.

目标元素：被测样品中可能含有的元素。当进行符合性测试时，目标元素评价包括砷、镉、铅、汞。目标元素可能还包括在物质生产或储存过程中加入的其他元素。目标元素的存在可能会受分析方法操作的干扰。

Target Limit or Target Concentration: The acceptance value for the elemental impurity being evaluated. Exceeding the target limit indicates that a material under test exceeds the acceptable value. The determination of compliance is addressed in other chapters. [NOTE—When applying this chapter to Elemental Impurities—Limits 232 and Elemental Contaminants in Dietary Supplements 2232 ,1 Target Limits can be approximated by dividing the Daily Dose PDEs by the maximum daily dose for the Drug Product Analysis Option in 232 or the Daily Serving PDE divided by the maximum daily serving size in 2232 ]

目标限度或目标浓度:被测元素杂质的可接受数值。超出了目标限度标明被测化合物超出了可接受值。符合性确认在其他章节中已进行了说明。【注意：当在<232>元素杂质-限度和<2232>食品添加剂的元素污染重应用这些章节时，目标限度可以通过日剂量PDE除以<232>中的药品分析方法中的最大日剂量或者日食用PDE除以<2232>中的最大日用量来进行估算。】

J: The concentration (w/w) of the element(s) of interest at the Target Limit, appropriately diluted to the working range of the instrument. For example, if the target elements are Pb and As for an analysis of an oral solid drug product with a daily dose of 10 g/day using an inductively coupled plasma–mass spectrometry (ICP-MS). The target limit for these elements would be 0.5 μg/g and 0.15 μg/g (see Table 2 in chapter 232 ). However, in this case, the linear dynamic range of the ICP-MS is known to extend from 0.01 ng/mL to 0.1 μg/mL for these elements. Therefore, a dilution factor of at least 1:10 is required to ensure that the analysis occurs in the linear dynamic range of the instrument. J would thus equal 0.05 μg/mL and 0.015 μg/mL for Pb and As, respectively, when the dilution factor is added.

J：目标元素在目标限度时的浓度（W/W），被适当地稀释至仪器的工作范围。例如：在利用ICP-MS分析剂量为10g/天的口服固体药品时，如果目标元素为铅和砷，这些元素的目标限度可以为0.5μg/g和0.15μg/g（见<232>中表2）。但是ICP对这些元素的线性范围在0.01μg/mL至0.1[url=]μg/mL[/url]之间。因此，为了保证分析在仪器的线性范围内进行，要求稀释因子至少是1:10。当引入稀释因子时，分别相当于0.015μg/mL的铅和0.015μg/mL的砷。

Appropriate Reference Materials: Where Appropriate Reference Materials are specified in the chapter, certified reference materials (CRM) from a national metrology institute (NMI), or reference materials that are traceable to the CRM of a NMI should be used. An example of a NMI in the United States is the National Institute of Standards and Technology.

合适的对照物质：当在章节中说明适当的对照物质时，应当使用[url=]国家计量院的有证对照物质[/url]或者是可溯源至国家计量院的有证对照物质的对照物质。美国的计量院指的是国家标准与技术委员会。

COMPENDIAL PROCEDURES 1 AND 2 法定方法1和2

Procedure and Detection Technique 方法和检测技术

Procedure 1 can be used for elemental impurities generally amenable to detection by inductively coupled plasma–atomic (optical) emission spectroscopy (ICP–AES or ICP–OES). Procedure 2can be used for elemental impurities generally amenable to detection by ICP–MS. Before initial use, the analyst should verify that the procedure is appropriate for the instrument and sample used (procedural verification) by meeting the Alternative Procedure Validation requirements below.

方法1适用于感应耦合等离子-原子发射光谱检测（ICP-AES）到的元素杂质。方法2适用于ICP-MS检测到的元素杂质。最终使用前，分析人员必须通过达到下述的替代方法验证的要求，确保使用的检测方法适用于仪器和样品。

Sample Preparation 样品制备

Forms of sample preparation include Neat, Direct Aqueous Solution, Direct Organic Solution, andIndirect Solution. The selection of the appropriate sample preparation depends on the material under test and is the responsibility of the analyst. When a sample preparation is not indicated in the monograph, an analyst may use any of the following appropriately verified preparation procedures. In cases where spiking of a material under test is necessary to provide an acceptable signal intensity, the blank should be spiked with the same Target Elements, and where possible, using the same spiking solution. Standard solutions may contain multiple Target Elements. [NOTE—All liquid samples should be weighed. ]

样品的形式包括纯的、直接水溶液、直接有机溶液和间接溶液。适当的样品形式的选择取决于被测样品。分析人员有责任选择合适的样品形式。当各论中没有明确样品形式时，分析人员可以使用以下合适的经过确认的样品制备方法。为了得到可接受的信号强度可能需要在待测物质中加标时，空白中也应该加入相同的目标元素或加标溶液。标准溶液中可能含有多种目标元素。【注意：所有液体样品应当被称重。】

Neat: Used for liquids or alternative procedures that allows the examination of unsolvated samples.

纯物质：用于液体或允许被测样品不经溶解的替代方法。

Direct Aqueous Solution: Used when the sample is soluble in an aqueous solvent.

直接水溶液：适用于易溶于水的样品。

Direct Organic Solution: Used where the sample is soluble in an organic solvent.

直接有机溶液：适用于易溶于有机溶剂的样品。

Indirect Solution: Used when a material is not directly soluble in aqueous or organic solvents. Digest the sample using a closed-vessel digestion procedure, similar to the procedure provided below. The sample preparation scheme should yield sufficient sample to allow quantification of each element at the limit specified in the corresponding monograph or chapter.

间接溶液：适用于不能直接溶于水或有机溶剂的样品。用与下述方法相似的密闭消化方法对样品进行消化。样品制备方案应能回收足够的样品，以便在各论或总则中规定的限度水平对每种元素进行定量测定。

Closed Vessel Digestion: This sample-preparation procedure is designed for samples that must be digested in a Concentrated Acid using a closed-vessel digestion apparatus. Closed-vessel digestion minimizes the loss of volatile impurities. The choice of a Concentrated Acid depends on the sample matrix. The use of any of the Concentrated Acids may be appropriate, but each introduces inherent safety risks. Therefore, appropriate safety precautions should be used at all times. [NOTE—Weights and volumes provided may be adjusted to meet the requirements of the digestion apparatus used. ]

密闭消化：这种样品制备方法被设计用于必须在密闭消解器内用浓酸进行消化的样品。密闭消化使挥发性杂质的损失降到最低。浓酸的选择取决于样品基质。无论使用哪种浓酸可能都是合适的，但是每种都会带来固有的安全风险。因此，整个过程中必须进行合适的安全防护。【注意：可以对重量和体积进行调整已达到消解器的要求。】

An example procedure that has been shown to have broad applicability is the following. Dehydrate and predigest 0.5 g of primary sample in 5 mL of freshly prepared Concentrated Acid. Allow to sit loosely covered for 30 minutes in a fume hood. Add an additional 10 mL of Concentrated Acid, and digest, using a closed vessel technique, until digestion or extraction is complete. Repeat if necessary by adding an additional 5 mL of Concentrated Acid.

下述的方法具有广泛的适用性：将0.5g初始样品脱水并用5mL新制备的浓酸消化。在通风处加盖放置30min。继续加入10mL浓酸用密闭技术进行消化，直到消化或萃取完全。如有需要可继续加入5mL浓酸。

[NOTE—Where closed vessel digestion is necessary, follow the manufacturer’s recommended procedures to ensure safe use. ]

【注意：需要密闭消化时，请遵循制造商推荐的方法，以确保使用安全。】

Reagents: All reagents used for the preparation of sample and standard solutions should be free of elemental impurities, in accordance with Plasma Spectrochemistry 730 .

试剂：所有用于制备样品和标准溶液的试剂应不含元素杂质，并与等离子光谱<730>一致。

Procedure 1: ICP-AES 方法1：ICP-AES

Standardization solution 1: 2J of the Target Element(s) in a Matched Matrix

[url=]标准化溶液1[/url]：[url=]一个匹配基质中含有[/url]2J目标化合物。

Standardization solution 2: 0.5J of the Target Element(s) in a Matched Matrix

[url=]标准化溶液2[/url]：一个匹配基质中含有0.5J目标化合物。

Sample stock solution: Proceed as directed in Sample Preparation above. Allow the sample to cool, if necessary.  For mercury determination, add an appropriate stabilizer.

样品储备液：见样品制备一节。如有需要，将样品放冷。测定汞时，还应加入适量的稳定剂。

Sample solution: Dilute the Sample Stock Solution with an appropriate solvent to obtain a final concentration of the Target Elements at NMT 2J.

样品溶液：用合适的溶剂将样品储备液进行稀释，使最终目标化合物的浓度不超过2J。

Blank: Matched Matrix

[url=]空白[/url]：匹配基质。

Elemental spectrometric system (See Plasma Spectrochemistry 730 .)

[url=]元素光谱系统（见[/url]等离子光谱<730>）

Mode: ICP

模式:ICP.

Detector: Optical detection system

检测器：光学检测系统。

Rinse: Diluent used

[url=]冲洗液：即稀释液。[/url]

Standardization: Standardization solution 1, Standardization solution 2, and Blank

[url=]标准化：[/url]标准化溶液1、标准[url=]化[/url]溶液2、空白。

System suitability系统适用性

Sample: Standardization solution 1

样品：标准化溶液1

Suitability requirements适用性要求：

Drift: Compare results obtained from Standardization solution 1 before and after the analyis of theSample solutions.

[url=]飘移：在样品溶液分析之前和之后比较标准溶液1[/url]的结果。

Suitability criteria: NMT 20% for each Target Element. [NOTE—If samples are high in mineral content, rinse system well (60 seconds) before introducing the Sample in order to minimize carryover. ]

[url=]适应性标准：每种目标元素不超过20%[/url]。【注意：如果样品中矿物质含量较高，应在进样前冲洗系统（60s）使残留降至最低。】

Analysis: Analyze according to the manufacturer's suggestions for program and wavelength. Calculate and report results on the basis of the original sample size. [NOTE—Appropriate measures must be taken to correct for matrix-induced interferences (e.g., Wavelength overlaps). ]

[url=]分析：按照制造商建议的程序和波长进行测定。在初始样品量的基础上计算并报告结果。【注意：必须进行适当的测定以校正基质带来的干扰。】[/url]

Procedure 2: ICP-MS 方法2：ICP-MS

Standardization solution 1: 2J of the Target Element(s) in a Matched Matrix

标准化溶液1：一个匹配基质中含有2J目标化合物。

Standardization solution 2: 0.5J of the Target Element(s) in a Matched Matrix

标准化溶液2：一个匹配基质中含有0.5J目标化合物。

Sample stock solution: Proceed as directed for Sample Preparation above. Allow the sample to cool, if necessary. For mercury determination, add an appropriate stabilizer.

样品储备液：见样品制备一节。如有需要，将样品放冷。测定汞时，还应加入适量的稳定剂。

Sample solution: Dilute the Sample stock solution with an appropriate solvent to obtain a final concentration of the Target Elements at NMT 2J.

样品溶液：用合适的溶剂将样品储备液进行稀释，使最终目标化合物的浓度不超过2J。

Blank: Matched Matrix

空白：匹配基质。

Elemental spectrometric system (See Plasma Spectrochemistry 730 .)

元素光谱系统（见等离子光谱<730>）

Mode: ICP. [NOTE—An instrument with a cooled spray chamber is recommended. (A collision cell or reaction cell may also be beneficial.) ]

模式：ICP，【注意：推荐使用带有冷却喷雾室的仪器（最好带有碰撞池或反应池）。】

Detector: Mass spectrometer

检测器：质谱检测器。

Rinse: Diluent used

冲洗液：即稀释液。

Standardization: Standardization solution 1, Standardization solution 2, and Blank

标准液：标准化溶液1、标准化溶液2、空白。

System suitability

[url=]系统适用性[/url]

Sample: Standardization solution 1

样品：标准化溶液1.

Suitability requirements 适用性要求：

Drift: Compare results obtained from Standardization solution 1 before and after the analysis of theSample solutions.

飘移：在样品溶液分析之前和之后比较标准溶液1的结果。

Suitability criteria: Drift NMT 20% for each Target Element. [NOTE—If samples are high in mineral content, rinse system well (60 seconds) before introducing the Sample in order to minimize carryover. ]

适应性标准：每种目标元素不超过20%。【注意：如果样品中矿物质含量较高，应在进样前冲洗系统（60s）使残留降至最低。】

Analysis: Analyze according to the manufacturer's suggestions for program and m/z. Calculate and report results based on the original sample size. [NOTE—Appropriate measures must be taken to correct for matrix induced interferences (e.g., argon chloride interference with arsenic determinations. ]

分析：按照制造商建议的程序和m/z进行测定。在初始样品量的基础上计算并报告结果。【注意：必须进行适当的测定以校正基质带来的干扰（例如：氯化氩对砷测定时的干扰）。】

ALTERNATE PROCEDURE VALIDATION 替代方法的验证

If a specified compendial procedure does not meet the needs of a specific application, an alternative procedure may be used (see General Notices 6.30). Alternative procedures must be validated and must be acceptable and therefore equivalent to the compendial procedures for the purposes of the test. The principles of validation are provided in general chapter Validation of Compendial Procedures 1225 . The level of validation necessary to ensure that an alternative procedure is acceptable depends on whether a limit test or a quantitative determination is necessary. The requirements for validation of an elemental impurities procedure for either type of determination are described below. Where this information differs from that presented in Validation of Compendial Procedures 1225 , the parameters and acceptance criteria presented in this chapter take precedence. Any alternative procedure that has been validated and meets the acceptance criteria that follow is considered to be equivalent to the compendial procedures for the purposes of this test.

如果特定的法定方法不能满足特殊应用的需要，可以使用替代方法（见总则6.30）。替代方法必须经过验证且验证结果是可接受的，并等同于法定方法的测定目的。在[url=]附录[/url]<1225>法定方法的验证中给出了验证的原则。验证的水平需要确保不管是限度测定还是定量测定都应当是可接受的。元素杂质方法的两种测定方法的验证要求见下文。当这些要求与附录<1225>法定方法的验证不同时，以本章提供的参数和接受标准为准。任何一种经过验证并达到下述的接受标准的此类测试目的方法都可以被认为与法定方法等效。

LIMIT PROCEDURES 限度方法

The following section defines the validation parameters for the acceptability of alternative limit procedures. Meeting these requirements must be demonstrated experimentally using an appropriate system suitability procedure and reference material. Meeting these requirements demonstrates that the procedure is equivalent to the compendial procedure as a limit procedure for the Target Element.

下面的部分阐述了限度测定替代方法验证的可接受参数。要达到这些要求必须通过使用合适的系统适用性方法和对照物质的试验来证明。达到这些要求意味着这个方法做为目标元素的限度测定的方法与法定方法是等效的。

The suitability of the method must be determined by conducting studies with material or mixture under test supplemented with known concentrations of each Target Element of interest at the appropriate acceptance limit concentration. The material or mixture under test must be spiked before any sample preparation steps are performed.

方法适用性必须通过对物料或混合物进行研究来决定，研究可以是对含有已知浓度的每一个目标元素可接受限度浓度进行测定。用于测定的物料或混合物必须在样品制备步骤前加入主成份样品。

Detectability 检测限

Standard solution: A preparation of reference materials for the Target Element(s) at the Target Concentrations.

标准溶液：目标元素的对照物质的浓度为目标限度的溶液。

Spiked sample solution 1: Prepare a solution of sample under test, spiked with appropriate reference materials for the Target Elements at the Target Concentration, solubilized or digested as described in Sample Preparation.

[url=]加标样品溶液[/url]1：[url=]在被测样品溶液中加入浓度为目标浓度的目标元素的对照物质，按照样品制备一节中的要求溶解或消化。[/url]

Spiked sample solution 2: Prepare a solution of the sample under test, spiked with appropriate reference materials at 80% of the Target Concentration for the Target Elements, solubilized or digested as described in Sample Preparation.

加标样品溶液2：在被测样品溶液中加入浓度为80%目标浓度的对照物质，按照样品制备一节中的要求溶解或消化。

Unspiked sample solution: A sample of material under test, solubilized or digested in the same manner as the Sample solutions.

不加标样品溶液：待测物质的样品，按照样品溶液的方法溶解或消化。

Acceptance criteria 接受标准：

Non-instrumental procedures: Spik ed sample solution 1 provides a signal or intensity equivalent to or greater than that of the Standard Solution. Spik ed sample solution 2 must provide a signal or intensity less than that of the Spik ed sample solution 1. [NOTE—The signal from each Spiked sample solution is NLT the Unspiked sample solution determination. ]

非仪器方法:[url=]加标溶液[/url]1的信号或强[url=]度[/url]≥标准溶液的信号或强度；加标溶液2度﹤加标溶液1的信号或强度。

Instrumental procedures: The average value of the three replicate measurements of Spik ed sample solution 1 is within (±15%) of the average value obtained for the replicate measurements of the Standard solution. The average value of the replicate measurements of Spik ed sample solution 2 must provide a signal intensity or value less than that of the Standard solution. [NOTE—Correct the values obtained for each of the spiked solutions using the Unspiked sample solution. ]

仪器方法: [url=]加标溶液[/url]1三次重复测定的平均值在标准溶液三次重复测定平均值的±15%以内；加标溶液2三次重复测定的强度或数值的平均值应小于标准溶液。

Precision for Instrumental Methods (Repeatability) 精密度（仪器方法）

[NOTE—Non-instrumental precision is demonstrated by meeting the Detectability requirement above. ]

【注意：非仪器方法的准确度用上述的检测限表述。】

Sample solutions: Six independent samples of the material under test, spiked with appropriate reference materials for the Target Elements at the Target Concentration.

样品溶液；6份待测物质样品加入浓度为目标浓度的目标元素的对照物质。

Acceptance criteria 接受标准：

Relative standard deviation: NMT 20% for each Target Element.

每种目标元素的RSD[url=]≤[/url]20%。

Specificity 专属性

The procedure must be able to unequivocally assess (see Validation of Compendial Procedures1225 ) each Target Element in the presence of components that may be expected to be present, including other Target Elements, and matrix components.

[url=]方法必须能明确地评价组分中可能出现的的每种目标元素，包括其他目标元素和基质组分（见附录[/url]<1225>法定方法的验证）。

QUANTITATIVE PROCEDURES 定量方法

The following section defines the validation parameters for the acceptability of alternative quantitative procedures. Meeting these requirements must be demonstrated experimentally, using an appropriate system suitability procedure and reference materials. Meeting these requirements demonstrates that the procedure is equivalent to the compendial procedure for the purpose of quantifying the Target Elements.

下面的部分阐述了定量测定替代方法验证的可接受参数。要达到这些要求必须通过使用合适的系统适用性方法和对照物质的试验来证明。达到这些要求意味着这个方法做为目标元素的限度测定的方法与法定方法是等效的。

Accuracy准确度

Standard solutions: Prepare solutions containing the Target Elements at concentrations ranging from 50% to 150% of J, using appropriate reference materials.

标准溶液：目标元素浓度为50%-105%J的对照物质溶液。

Test samples: Prepare samples of the material under test spiked with appropriate reference materials before any sample preparation steps (digestion or solubilization) at concentrations ranging from 50% to 150% of J for each Target Element.

测定样品：在样品配制步骤前，向被测样品中加入目标元素浓度为50%-105%J的对照物质。

Acceptance criteria 接受标准：

Spike recovery: 70%–150% for the mean of three replicate preparations at each concentration

加样回收率：每种浓度的三次测定回收率在70%-150%之间。

Precision 精密度

REPEATABILITY 重复性

Test samples: Six independent samples of material under test (taken from the same lot) spiked with appropriate reference materials for the Target Element(s) at the indicated level.

被测样品：往同一批的6份样品中加入控制水平的合适的目标元素的对照物质。

Acceptance criteria

Relative standard deviation: NMT 20% for each Target Element

接受标准：[url=]每种目标元素的[/url]RSD≤20%。

RUGGEDNESS 耐受性

Perform the Repeatability analysis over three independent events using the following events or combinations thereof: 在不同时间、使用不同仪器或不同分析员（以上三项任选或组合）进行重复性测试。

1. on different days, or

2. with different instrumentation, or

3. with different analysts.

Acceptance criteria 接受标准：

Relative standard deviation: NMT 25% for each Target Element

每种目标元素的RSD≤25%。

Specificity专属性

The procedure must be able to unequivocally assess (see Validation of Compendial Procedures1225 ) each Target Element in the presence of components that may be expected to be present, including other Target Elements, and matrix components.

方法必须能明确地评价组分中可能出现的的每种目标元素，包括其他目标元素和基质组分（见附录<1225>法定方法的验证）。

Limit of Quantitation, Range, and Linearity定量限、线性和范围

Demonstrated by meeting the Accuracy requirement.

应达到准确性的要求。

蓝色星期六

巴西木去奥星搞法规翻译去了吗?{:soso_e179:}

Whats

楼主辛苦了！

syhorchid

谢谢分享

一花一世界

现在正好用到 谢谢啦