USP〈1225〉药典规程的验证(中英文对照)

<1225>VALIDATION OF COMPENDIAL PROCEDURES

药典规程的验证

Test procedures for assessment of the quality levels of pharmaceutical articles are subject to various requirements. According to Section 501 of the Federal Food, Drug, and Cosmetic Act, assays and specifications in monographs of the United States Pharmacopeia and the National Formulary constitute legal standards. The Current Good Manufacturing Practice regulations [21 CFR 211.194(a)] require that test methods, which are used for assessing compliance of pharmaceutical articles with established specifications, must meet proper standards of accuracy and reliability. Also, according to these regulations [21 CFR 211.194(a)(2)], users of analytical methods described in USP-NF are not required to validate the accuracy and reliability of these methods, but merely verify their suitability under actual conditions of use. Recognizing the legal status of USP and NF standards, it is essential, therefore, that proposal for adoption of new or revised compendial analytical procedures be supported by sufficient laboratory data to document their validity.

用于评价药物质量水平的测试规程受到多种要求的影响。根据联邦食品、药物、化妆品法案501款，在美国药典和国家处方集的各论中的含量测定和质量标准构成了法定标准。现行药品优良生产规范【21 CFR 211.194(a)】要求，用于评价药物与既有质量标准之间的符合性的分析规程必须在准确度和可靠性方面达到适当的标准。并且根据这些法规【21 CFR 211.194(a)(2)】，在USP-NF中描述的分析规程的使用者无需验证这些规程的准确度和可靠性，而仅需确认其在实际使用条件下的适用性。认识到USP和NF标准的法律地位，因此，提议采纳新的或更改过的药典分析规程时，以充分的实验室数据作为支持，以记录其有效性，成为基本要求。

The text of this information chapter harmonizes, to the extent possible, with the Tripartite International Conference on Harmonization (ICH) documents Validation of Analytical Procedures and the Methodology extension text, which are concerned with analytical procedures included as part of registration applications submitted within the EC, Japan, and the USA.

本信息章节的内容尽可能地与三方国际协调会议（ICH）文件分析规程的验证和方法学的延伸内容保持一致，ICH的内容关注的是作为在欧盟、日本、美国提交注册申请的一部分的分析规程。

SUBMISSIONS TO THE COMPENDIA向药典提交的文件

Submissions to the compendia for new or revised analytical procedures should contain sufficient information to enable members of the USP Council of Experts and its Expert Committees to evaluate the relative merit of proposed procedures. In most cases, evaluations involve assessment of the clarity and completeness of the description of the analytical procedures, determination of the need for the procedures, and documentation that they have been appropriately validated. Information may vary depending upon the type of method involved. However, in most cases a submission will consist of the following sections.

向药典提交关于新的或更改过的分析规程的文件应该包括充足的信息，以使USP专家大会和其专家委员会能够评估拟议规程的相对优势。在大多数情况下，这些评估涉及对分析规程描述的清楚和完整程度的评价，对规程的需求的确定，以及它们已经进行了适当验证的记录文件。这些信息可以根据所涉及规程的种类而变化。但是，在大多数情况下，提交的文件将有下面的章节组成。

Rationale---- This section should identify the need for the procedure and describe the capability of the specific procedure proposed and why it is preferred over other types of determinations. For revised procedures, a comparison should be provided of limitations of the current compendial procedure and advantages offered by the proposed procedure.

基本原理---- 此部分应该辨明对于该规程的需求，并描述具体拟议中规程的能力，以及其为什么优于其他种类检测。对于更改的规程，应该提供对当前药典规程之缺陷与拟议中规程之优势的比较。

Proposed Analytical Procedure--- This section should contain a complete description of the analytical procedure sufficiently detailed to enable persons “skilled in the art” to replicate it. The write-up should include all important operational parameters and specific instructions such as preparation of reagents, performance of system suitability tests, description of blanks used, precautions, and explicit formulas for calculation of test results.

拟议的分析规程---- 此部分包含对该分析规程的完整描述，应足够具体以便能让业内技术熟练

的人重复它。文章应该包括所有重要的操作参数和具体的指令，例如试剂制备、系统适用性测试表现、所使用空白对照的描述、预防措施、用于计算测试结果明确公式。

Data Element---- This section should provide thorough and complete documentation of the validation of the analytical procedure. It should include summaries of experimental data and calculations substantiating each of the applicable analytical performance characteristics. These characteristics are described in the following section.

数据要素---- 此部分应该提供完全彻底的分析规程验证记录文件。其应该包括对于证明每一个实用工作特性的实验数据和计算的总结。这些特性在下面的部分描述。

VALIDATION验证

Validation of an analytical procedure is the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the requirements for the intended analytical applications. Typical analytical performance characteristics that should be considered in the validation of the types of procedures described in this document are listed in Table 1. Because opinions may differ with respect to terminology and use, each of the performance characteristics is defined in the next section of this chapter, along with a delineation of a typical method or methods by which it may be measured.

分析规程的验证是，通过实验室研究，确定该规程的工作特性达到了预定分析用途要求的过程。在此文件中所描述的规程种类的验证中，应当考虑的常见分析工作特性在表1中列出。因为对于术语和使用的意见可能不同，在此通则的下个部分定义了每个工作性能，以及可以对其进行测量的常用的一个或几个方法的描绘。

Table 1. Typical Analytical Characteristics Used in Method Validation

表1. 在方法验证中使用的常用分析特性

Accuracy准确度

Precision精密度

Specificity专属性

Detection Limit检测限度

Quantitation Limit定量限度

Linearity线性

Range范围

Robustness耐用性

In the case of compendial procedures, revalidation may be necessary in the following cases: a submission to the USP of a revised analytical procedure; or the use of an established general procedure with a new product or raw material (see below in Data Elements Required for Validation). 对于药典规程，在下面的情况下可能必需在验证：向USP提交修改的分析规程；或将已确立的通用规程用于新产品或原料（见下面验证必需的数据要素）

The ICH documents give guidance on the necessity for revalidation in the following circumstances: changes in the synthesis of the drug substance; changes in the composition of the drug product; and changes in the analytical procedure.

ICH文件对于下列情况下再验证的必要性做出了指导：原料药合成中的变更；成药组成中的变更；以及分析规程中的变更。

Analytical Performance Characteristics分析工作特性

ACCURACY准确度

Definition---- The accuracy of an analytical procedure is the closeness of test results obtained by that procedure to the true value. The accuracy of an analytical procedure should be established across its range.

定义---- 分析规程的准确度是由该规程得到的测试结果与真实值的接近程度。分析规程的准确度应该在其整个范围内得到确立。

Determination---- In the case of the assay of a drug substance, accuracy may be determined by application of the analytical procedure to an analyte to known purity (e.g., a Reference Standard) or by comparison of the results of the procedure with those of a second, well-characterized procedure,

the accuracy of which has been stated or defined.

测定---- 对于原料药的含量测定，可以用该分析规程来分析已知纯度的被分析物（例如，某个标准物质），或将以此规程所得的结果与第二种、成熟的、已知准确度的规程所得的结果进行比较，以测定其精确性。

In the case of the assay of a drug in a formulated product, accuracy may be determined by application of the analytical procedure to synthetic mixtures of the drug product components to which known amounts of analyte have been added within the range of the procedure. If it is not possible to obtain samples of all drug product components, it may be acceptable either to add known quantities of the analyte to the drug product (i.e., “to spike”) or to compare results with those of a second, well-characterized procedure, the accuracy of which has been stated or defined.

对于处方产品中某个药物的含量测定，以该分析规程来分析成药各组分的合成混合物，其中已经在这些组分的范围之内加入已知数量的待分析物。如果不可能得到成药的所有组分，也可以将已知数量的待分析物加入到该成药中（例如，“增敏”），或者将结果与用第二种、成熟的、已知准确度的规程得到的结果进行比较，

In the case of quantitative analysis of impurities, accuracy should be assessed on samples (of drug substance or drug product) spiked with known amount of impurities. Where it is not possible to obtain samples of certain impurities or degradation products, results should be compared with those obtained by an independent procedure. In the absence of other information, it may necessary to calculate the amount of an impurity based on comparison of its response to that of the drug substance; the ratio of the response of equal amounts of the impurity and the drug substance (relative response factor) should be used if known.

对于杂质的定量分析，应使用以已知数量杂质增敏的样品来评估准确度。当不可能获得特定杂质或降解产物的样品时，应将结果与得自独立规程的的结果进行比较。在没有其他信息的情况下，可能必需通过将某种杂质的响应值与药物的响应值进行比较来计算杂质的数量；同等数量的杂质与药物的响应值的比值（相对响应因子），如果已知，则应使用。

Accuracy is calculated as the percentage of recovery by the assay of the known added amount of analyte in the sample, or as the difference between the mean and the accepted true value, together

with confidence interval.

通过测定被加入到样品中的已知数量的被分析物来计算准确度，得到回收百分比，或得到平均值与接受的真实值之间的差异，并给出置信区间。

The ICH documents recommended that accuracy should be assessed using a minimum of nine determinations over a minimum of three concentration levels, covering the specified range (i.e., three concentrations and three replicates of each concentration).

ICH文件建议精密度的评估应当使用覆盖规定范围的至少三个浓度水平进行至少九次测试（例如，三个浓度并且每个浓度三次重复进样）。

Assessment of accuracy can be accomplished in a variety of ways, including evaluating the recovery of the analyte (percent recovery) across the range of the assay, or evaluating the linearity of the relationship between estimated and actual concentrations. The statistically preferred criterion is that the confidence interval for the slope be contained in an interval around 1.0, or alternatively, that the slope be close to 1.0. In either case, the interval or the definition of closeness should be specified in the validation protocol. The acceptance criterion will depend on the assay and its variability and on the product. Setting an acceptance criterion based on the lack of statistical significance of the test of the null hypothesis that the slop is 1.0 is not an acceptable approach.

准确度的评估可以通过多种不同的方式完成，包括评价在含量测定的整个范围内被分析物的回收率，或评价估计与实际浓度之间关系的线性。具统计学意义的标准有二，一是斜率的置信区间被限定在约1.0的区间，二是此斜率接近1.0。在任意一种情况下，此区间或接近程度的定义应该在验证方案中明确规定。接受标准将取决于含量和其差异性，以及取决于该产品。通过测试证明该斜率为1.0的零假设没有统计学意义，这样的方法不能用于设定接受标准。

PRECISION精密度

Definition---- The precision of an analytical procedure is the degree of agreement among individual test results when the procedure is applied separately to multiple samplings of a homogeneous sample. The precision of an analytical procedure is usually expressed as the standard deviation or relative standard deviation (coefficient of variation) of a series of measurements. Precision may be a measure

of either the degree of reproducibility or of repeatability of the analytical procedure under normal operating conditions. In this context, reproducibility refers to the use of the analytical procedure in different laboratories, as in a collaborative study. Intermediate precision (as known as ruggedness) express within-laboratory variation, as on different days, or with different analysts or equipment within the same laboratory. Repeatability refers to the use of the analytical procedure within a laboratory over a short period of time using the same analyst with the same equipment.

定义---- 分析规程的精密度是当该分析规程单独分析均质样品的多个样本时，若干检验结果的一致程度。分析规程的精密度通常以一系列测量数值的标准差或相对标准差（变异系数）来表示。精密度可以是分析规程在普通操作条件下可重现性或可重复性程度的度量单位。在此内容里，可重现性涉及在协作研究中，分析规程在不同实验室的使用。中间精密度（也称为“耐久性”）体现了在实验室内的差异，如在相同的实验室，但在不同的日期，或使用不同的分析员或设备。可重复性涉及在同一个实验室内，一段较短的时间内，使用相同的分析员和相同的设备的情况下，对分析规程的应用。

Determination---- The precision of an analytical procedure is determined by assaying a sufficient number of aliquots of a homogeneous sample to be able to calculate statistically valid estimates of standard deviation or relative standard deviation (coefficient of variation). Assays in this context are independent analyses of samples that have been carried through the complete analytical procedure from sample preparation to final test result.

测定----分析规程的精密度的测定，通过对充足数量的均质样品的等分试样做含量测定来进行，以便能够计算标准差或相对标准差（变异系数）的具有统计学意义的估计值。在此内容中的含量测定是样品的多次独立分析，其样品已经用完整分析规程（从样品制备到最终检验结果）进行过分析。

The ICH documents recommended that repeatability should be assessed using a minimum of nine determinations covering the specified range for the procedure (i.e., three concentration and three replicates of each concentration or using a minimum of six determinations at 100% of the test concentration).

ICH文件建议可重复性的评估应该使用最少九次检测，覆盖该分析规程所规定的范围（例如，

三个浓度和每个浓度三次重复进样，或在100%测试浓度上进行最少六次测定）。

SPECIFITY专属性

Definition---- The ICH documents define specificity as the ability to assess unequivocally the analyt in the presence of components that may be expected to be present, such as impurities, degradation products, and matrix components. Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedures. [NOTE--- Other reputable international authorities (IUPAC, AOAC-I) have preferred the term “selectivity”, reserving “specificity” for those procedures that are completely selective.] For the tests discussed below, the above definition has the following implications.

定义---- ICH文件将专属性定义是当待分析物含有预期会有的其他组分（例如，杂质、降解产物、矩阵组分）时，准确可靠地评估待分析物的能力。某个分析规程缺乏专属性可以通过其他辅助性分析规程进行补偿。【注意：其他声誉卓著的国际权威机构（IUPAC、AOAC-I）已经提出术语“选择性”，而将“专属性”留给已经具有完全选择性的规程。】对于下面讨论的测试，上述定义具有以下的含义。

Identification Tests: ensure the identity of the analyte.

鉴别检测：确保待分析物的鉴别。

Purity Tests: ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte (e.g., related substances test, heavy metals limit, organic volatile impurities).

纯度检测：确保执行的所有分析规程能够令对于待分析物各杂质含量的准确陈述得以做出。

Assays: provide an exact result, which allow an accurate statement on the content or potency of the analyte in a sample.

含量检测：提供准确的结果，令对样品中待分析物的含量或效力的准确陈述得以做出。

Determination---- In the case of qualitative analyses (identification tests), the ability to select

between compounds of closely related structure that are likely to be present should be demonstrated. This should be confirmed by obtaining positive results (perhaps by comparison to a known reference material) from samples containing the analyte, coupled with negative results from samples that do not contain the analyte and by confirming that a positive response is not obtained from materials structurally similar to or closely related to the analyte.

测定---- 对于定性分析（鉴别检验），应当论证其在可能存在的、结构密切相关的物质中进行选择的能力。从含有待分析物的样品中得到阳性结果（可能通过与已知标准物质的比较），而从不含待分析物的样品得到阴性结果，以对其选择能力加以确认，并还要确认阳性响应不是来自与待分析物结构相似或密切相关的物质。

In the case of analytical procedures for impurities, specificity may be established by spiking the drug substance or product with appropriate levels of impurities and demonstrating that these impurities are determined with appropriate accuracy and precision.

对于检测杂质的分析规程，专属性可以通过以适当水平的杂质将原料药或成药增敏，并论证这些杂质的测定达到了适当的准确度和精密度。

In the case of the assay, demonstration of specificity requires that it can be shown that the procedure is unaffected by the presence of impurities or excipients. In practice, this can be done by spiking the drug substance or product with appropriate levels of impurities or excipients and demonstrating that the assay result is unaffected by the presence of these extraneous materials.

对于含量检测，对专属性的论证要求能够显示出该分析规程不受各杂质或辅料的影响。在实际操作中，通过以适当水平的杂质或辅料将原料药或成药增敏，并证明含量检验结果不受这些外来物质的影响，来完成论证。

If impurity or degradation product standards are unavailable, specificity may be demonstrated by comparing the test results of samples containing impurities or degradation products to a second well-characterized procedure (e.g., Pharmacopeial or other validated procedure). These comparisons should include samples stored under relevant stress conditions (e.g., light, heat, humidity, acid/base hydrolysis, oxidation). In the case of assay, the results should be compared; in the case of chromatographic impurity test, the impurity profiles should be compared.

如果没有杂质或降解产物的标准品，可以通过将含有杂质或降解产物的样品的测试结果与第二种、成熟规程（例如，药典或其他验证过的规程）的结果进行比较，来论证专属性。这些比较应该包括在相关破坏性条件下（例如，光、热、湿度、酸/碱水解、氧化作用）存储的样品。对于含量测定，应比较其结果；对于色谱法杂质检测，应比较杂质概况。

The ICH documents state that when chromatographic procedures are used, representative chromatograms should be presented to demonstrate the degree of selectivity, and peaks should be appropriately labeled. Peak purity tests (e.g., using diode array or mass spectrometry) may be useful to show that the analyte chromatographic peak is not attributable to more than one component.

ICH文件声明，当使用色谱分析规程时，应提交具代表性的色谱图，以论证选择性的程度，而且应对色谱峰作适当的标识。也可以使用色谱峰纯度测试（例如，使用二极管阵列或质谱仪），来显示待分析物的色谱峰仅产生于一个组分。

DETECTION LIMIT检测限度

Definition---- The detection limit is a characteristic of limit tests. It is the lowest amount of analyte in a sample that can be detected, but not necessarily quantitated, under the stated experimental conditions. Thus, limit tests merely substantiate that the amount of analyte is above or below a certain level. The detection limit is usually expressed as the concentration of analyte (e.g., percentage, parts per billion) in the sample.

定义---- 检测限度是限度检测的特性。它是指在规定的试验条件下，样品中可被检测到的待分析物的最小数量，但是无需定量。因此，限度检测仅仅说明了待分析物的数量高于或低于某个特定水平。检测限度通常以在样品中的待分析物浓度（例如，百分比、十亿分率）表示。

Determination---- For non-instrumental procedures, the detection limit is generally determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be reliably detected.

测定---- 对于非仪器分析规程，检测限度的测定方法通常为，对含有已知浓度待分析物的样品进行分析，并确立能够可靠地被检测出来的待分析物的最低水平。

For instrumental procedures, the same approach may be used as for non-instrumental procedures. In the case of procedures submitted for consideration as official compendial procedures, it is almost never necessary to determine the actual detection limit. Rather, the detection limit is shown to be sufficiently low by the analysis of samples with known concentrations of analyte above and below the required detection level. For example, if it is required to detect an impurity at the level of 0.1%, it should be demonstrated that the procedure will reliably detect the impurity at that level.

对于仪器分析规程，可以使用与非仪器分析规程相同的方法。对于提交用于官方药典规程的备选方法，其几乎从来不需要确定实际的检测限度。而是，通过分析含有高于和低于必需的检测水平的、已知待分析物浓度的样品，以显示检测限度足够低。例如，如果必需检测浓度在0.1%的杂质，则应当证明该分析规程将可靠地检测在这个水平的杂质。

In the case of instrumental analytical procedures that exhibit background noise, the ICH documents describe a common approach, which is to compare measured signals from samples with known low concentrations of analyte with those of blank samples. The minimum concentration at which the analyte can reliably be detected is established. Typically acceptable signal-to-noise ratios are 2:1 or 3:1. Other approaches depend on the determination of the slope of the calibration curve and the standard deviation of responses. Whatever method is used, the detection limit should be subsequently validated by the analysis of a suitable number of samples known to be near, or prepared at, the detection limit.

对于展示出背景噪音的仪器分析规程，ICH文件描述了一个通用方法，用来比较从以下样品测得的信号，这些样品分别为含已知低浓度被分析物的样品和空白样品。这样就确立了能够可靠检测的待分析物的最低浓度。可接受的典型信噪比是2:1或3:1。其他方法取决于校正曲线斜率的测定和响应值的标准差。无论用什么方法，均应该在随后通过分析适当数量的、已知接近或制备于检测限度的样品，来验证检测限度。

QUANTITATION LIMIT定量限度

Definition---- The quantitation limit is a characteristic of quantitative assay for low levels of compounds in sample matrices, such as impurities in bulk drug substances and degradation products in finished pharmaceuticals. It is the lowest amount of analyte in a sample that can be determined

with acceptable precision and accuracy under the stated experimental conditions. The quantitation limit is expressed as the concentration of analyte (e.g., percentage, parts per billion) in the sample. 定义---- 定量限度是样品矩阵中低含量物质的定量分析的特性，例如在原料药中的杂质和成品药物中的降解产物。它是在规定试验条件下，能够以可接受的精密度和精确度进行测定的样品中待分析物的最小量。定量限度以样品中待分析物的浓度（例如，百分比、十亿分率）来表示。

Determination---- For non-instrumental procedures, the quantitation limit is generally determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be determined with acceptable accuracy and precision.

测定---- 对于非仪器分析规程，定量限度的测定方法通常为对含有已知浓度待分析物的样品进行分析，并确立能够以可接受的准确度和精密度被检测出来的待分析物的最低水平。

For instrumental procedures, the same approach may be used as for non-instrumental procedures. In the case of procedures submitted for consideration as official compendial procedures, it is almost never necessary to determine the actual quantitaion limit. Rather, the quantitation limit is shown to be sufficiently low by the analysis of samples with know concentrations of analyte above and below the quantitation level. For example, if it is required that an analyte be assayed at the level of 0.1 mg per tablet, it should be demonstrated that the procedure will reliably quantitate the analyte at that level.

对于仪器分析规程，可以使用与非仪器分析规程相同的方法。对于提交用于官方药典规程的备选方法，其几乎从来不需要确定实际的检测限度。而是，通过分析含有高于和低于必需的定量水平的、已知待分析物浓度的样品，以显示定量限度足够低。例如，如果必需在0.1mg每片的水平评估待分析物，则应当证明该分析规程将可靠地这个水平定量待分析物。

In the case of instrumental analytical procedures that exhibit background noise, the ICH documents describe a common approach, which is to compare measured signals from samples with known low concentrations of analyte with those of blank samples. The minimum concentration at which the analyte can reliably be quantified is established. A typically acceptable signal-to-noise ratio is 10:1. Other approaches depend on the determination of the slope of the calibration curve and the standard deviation of responses. Whatever method is used, the quantitation limit should be subsequently

validated by the analysis of a suitable number of samples known to be near, or prepared at, the quantitation limit.

对于展示出背景噪音的仪器分析规程，ICH文件描述了一个通用方法，用来比较从以下样品测得的信号，这些样品分别为含已知低浓度被分析物的样品和空白样品。这样就确立了能够可靠地定量待分析物的最低浓度。可接受的典型信噪比是10:1。其他方法取决于校正曲线斜率的测定和响应值的标准差。无论用什么方法，均应该在随后通过分析适当数量的、已知接近或制备于定量限度的样品，来验证定量限度。

LINEARITY AND RANGE线性和范围

Definition of Linearity---- The linearity of an analytical procedure is its ability to elicit test results that are directly, or by a well-defined mathematical transformation, proportional to the concentration of analyte in samples within a given range. Thus, in this section, “linearity” refers to the linearity of the relationship of concentration and assay measurement. In some cases, to attain linearity, the concentration and/or the measurement may be transformed. (Note that the weighing factors used in the regression analysis may change when a transformation is applied.) Possible transformations may include log, square root, or reciprocal, although other transformations are acceptable. If linearity is not attainable, a non-linear model may be used. The goal is to have a model, whether linear or non-linear, that describes closely the concentration-response relationship.

线性的定义---- 分析规程的线性是该规程直接地、或通过明确给出的数学转换而间接地，得出与特定范围内的样品中待分析物浓度呈比例关系的测试结果的能力。因此，在此部分，“线性”是指浓度与检验结果之间的线性关系。在某些情况下，为了实现线性，浓度和/或测量数据可以进行转换。（注意：当进行转换时，在回归分析中用到的权重因子可以变化。）虽然其他转换方式也是可以接受的，但是可能的转换包括对数、平方根、倒数。如果无法实现线性，可以使用非线性模型。其目的是得到一个精确描述浓度-响应值关系的模型，不论是线性还是非线性。

Definition of Range---- The range of an analytical procedure is the interval between the upper and lower levels of analyte (including these levels) that have been demonstrated to be determined with a suitable level of precision, accuracy, and linearity using the procedure as written. The range is normally expressed in the same units as test results (e.g., percent, parts per million) obtained by the

analytical procedure.

范围的定义---- 分析规程的范围是分析物的较高浓度和较低浓度（含）之间的区间，已经证实在此区间内，使用该规程进行测定具有适当水平的精密度、准确度、和线性。该范围通常以与该分析规程得到的测试结果相同的单位表示，例如百分比，百万分率等。

Determination of Linearity and Range---- Linearity should be established across the range of the analytical procedure. It should be established initially by visual examination of a plot of signals as a function of analyte concentration of content. If there appears to be a linear relationship, test results should be established by appropriate statistical methods (e.g., by calculation of a regression line by the method of least squares). Data from the regression line itself may be helpful to provide mathematical estimates of the degree of linearity. The correlation coefficient, y-intercept, slope of the regression line, and residual sum of squares should be submitted.

线性和范围的确定---- 应在分析规程整个范围内确立线性。线性的确立最开始应该通过目测代表内容物中待分析物浓度的多个信号构成的图表来进行。如果其呈现线性关系，测试结果应该通过适当的统计学方法（例如，以最小二乘方来计算回归线）来确立。来自回归线自身的数据可以用于提供线性程度的数学评估。应该提交其相关系数、Y轴截距、回归线斜率、残差平方和。

The range of the procedure is validated by verifying that the analytical procedure provides acceptable precision, accuracy, and linearity when applied to sample containing analyte at the extremes of the range as well as within the range.

通过用规程分析含有待分析物的、浓度在范围的极限值上和在范围中的样品，确认该分析规程提供了可接受的精密度、准确度、线性，以进行该规程范围的验证。

ICH recommends that, for the establishment of linearity, a minimum of five concentrations normally be used. It is also recommended that the following minimum specified ranges should be considered: ICH建议，为了确立线性，通常使用最少五个浓度。其还建议，应考虑下列的最小范围的规定。

Assay of a Drug Substance (or a finished product): from 80% to 120% of the test concentration.

原料药（或成药）的含量测定：供试浓度的80%到120%。

Determination of an Impurity: from 50% to 120% of the acceptable criterion.

杂质的测定：接受标准的50%到120%。

For Content Uniformity: a minimum of 70% to 130% of the test concentration, unless a wider or more appropriate range based on the nature of the dosage form (e.g., metered-dose inhalers) is justified.

对于内容物的均一性：最少供试浓度的70%到130%，除非由于剂型的特性（例如，定量吸入气雾剂）而支持应用更宽或更适合的范围。

For Dissolution Testing: ±20% over the specified range (e.g., if the acceptance criteria for a controlled-release product cover a region from 20%, after 1 hour, and up to 90%, after 24 hours, the validated range would be 0% to 110% of the label claim)

对于溶出度检测：在规定范围上±20%（例如，如果一个控释产品的接受标准覆盖了从1小时后20%到24小时后最多90%的区域，则验证区域应该为标签声称值的0%到110%）。

ROBUSTNESS耐用性

Definition---- The robustness of an analytical procedure is a measure of its capability to remain unaffected by small but deliberate variations in procedural parameters listed in the procedure documentation and provides an indication of its suitability during normal usage. Robustness may be determined during development of the analytical procedure.

定义---- 分析规程的耐用性是规程文件中列出的操作参数在微小、故意的变更中不受影响的能力的衡量单位，并在日常使用中提供了其适用性的指标。耐用性可以在分析规程的研发中确定。

SYSTEM SUITABILITY系统适用性

If measurements are susceptible to variations in analytical conditions, these should be suitably controlled, or a precautionary statement should be included in the procedure. One consequence of the

evaluation of robustness and ruggedness should be that a series of system suitability parameters is established to ensure that the validity of the analytical procedure is maintained whenever used. Typical variations are the stability of analytical solutions, different equipment, and different analysts. In the case of liquid chromatography, typical variations are the pH of the mobile phase, the mobile phase composition, different lots or suppliers of columns, the temperature, and the flow rate. In the case of gas chromatography, typical variations are different lots or suppliers of columns, the temperature, and the flow rate.

如果检测结果易受分析条件中的差异影响，则这些差异应当被适当地控制，或应当在规程中加入预防性的陈述。评估耐用性的一个结果就是确立一系列系统适用性参数，以确保不论何时使用，均可维持分析规程的有效性。典型的差异是分析溶液、不同设备、不同分析员的稳定性。对于液相色谱法而言，典型的差异是流动相pH值、流动相构成、不同批号或供应商的色谱柱、温度、流速。对于气相色谱法而言，典型差异是不同批号或供应商的色谱柱、温度、流速。

System suitability tests are based on the concept that the equipment, electronics, analytical operations, and samples to be analyzed constitute an integral system that can be evaluated as such. System suitability test parameters to be established for a particular procedure depend on the type of procedure being evaluated. They are especially important in the case of chromatographic procedures. Submissions to the USP should make note of the requirements under the System Suitability section in the general test chapter Chromatography <621>.

系统适用性测试基于这个概念，即这些设备、电子仪器、分析操作、供试样品构成了一个完整系统，此系统可以作为整体进行评估。为某个特定规程设定的系统适用性测试参数取决于被评估的规程的种类。对于色谱规程，它们尤其重要。向USP提交的文件应该应该注明在通则色谱法<621>中系统适用性章节下的要求。

Data Elements Required for Validation验证所需的数据要素

Compendial test requirements vary form highly exacting analytical determinations to subjective evaluation of attributes. Considering this broad variety, it is only logical that different test procedures require different validation schemes. This chapter covers only the most common categories of tests for which validation data should be required. These categories are as follows:

药典测试的要求差别较大，从高度精确的分析测定到特性的主观评估。考虑到此宽幅差异，则可以理解不同测试规程需要不同的验证计划。此章节仅覆盖了这些需要验证数据的测试中最常见的种类。这些种类如下：

Category I---- Analytical procedures for quantitation of major components of bulk drug substances or active ingredients (including preservatives) in finished pharmaceutical products.

第一类：对成药中原料药或活性成分（包括防腐剂）的主要组分进行定量测定的分析规程。

Category II---- Analytical procedures for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceutical products. These procedures include quantitative assays and limit tests.

第二类：对成药中原料药或降解物质中杂质进行测定的分析规程。这些规程包括定量测定和限度测定。

Category III---- Analytical procedures for determination of performance characteristics (e.g., dissolution, drug release).

第三类：对工作特性（例如，溶出度、药物释放）进行测定的分析规程。

Category IV---- Identification tests.

第四类：鉴别测试。

For each category, different analytical information is needed. Listed in Table 2 are data elements that are normally required for each of these categories.

每一个类别均需要不同的分析信息。每个种类通常所需要的数据要素在表2中列出。

Table 2. Data Elements Required for Validation

Analytical

Performance

Characteristics Category I Category II Quantitative Limit Tests Category III Category IV

Accuracy

Precision

Specificity

Detection Limit

Quantitation Limit

Linearity

Range Yes Yes Yes No No Yes Yes Yes Yes Yes No Yes Yes Yes * No Yes Yes No No * * Yes * * * * * No No Yes No No No No *May be required, depending on the nature of the specific test.

表2. 验证必需的数据要素

分析工作特性

第一类

准确度

精密度

专属性

检测限度

定量限度

线性

范围 是 是 是 否 否 是 是 定量测试 是 是 是 否 是 是 是 限度测试 * 否 是 是 否 否 * 第三类 * 是 * * * * * 第四类 否 否 是 否 否 否 否 第二类

可能需要，取决于具体测试的特性

Already established general procedure (e.g., titrimetric determination of water, bacterial endotoxins) should be ▲verified to establish their suitability for use, such as▲USP31 their accuracy (and absence of possible interference) when used for a new product or raw material.

已经确立的通用规程（例如，水分滴定测定、细菌内毒素）应当▲进行确认，以确立在用于新的产品或原料时的适用性，例如▲USP31其准确度（和无可能的干扰因素）。

The validity of an analytical procedure can be verified only by laboratory studies. Therefore, documentation of the successful completion of such studies is a basic requirement for determining

whether a procedure is suitable for its intended application(s). Current compendial procedures are also subject to regulations that require demonstration of suitability under actual conditions of use ▲(see Verification of Compendial Procedures <1226> for principles relative to the verification of compendial procedures). ▲USP31 Appropriate documentation should accompany any proposal for new or revised compendial analytical procedures.

分析规程的有效性可以通过实验室研究来确认。因此，此类研究成功完成的记录文件是确定某个规程是否适用于其预定用途的基本要求。当前的药典规程也要符合相关管理规定，要证实在实际使用条件下的适用性。▲（见药典规程的确认<1226>，以了解与药典规程确认相关的基本原则）▲USP31适当的记录文件应伴随着任何有关新的或修改过的药典分析规程的方案。

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