USP40 1225 药典的验证中英文对照

VALIDATION OF COMPENDIAL PROCEDURES

药典方法的验证

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 proposals for adoption of new or revised compendial analytical procedures be supported by sufficient laboratory data to document their validity.

用于评估药品质量的检验方法需要满足不同的要求。根据联邦食品，药品，和化妆品法案501章，美国药典和国家处方专题论文里的试验和规范构成了法律标准。CGMP法规[21 CFR 211.194(a)]要求：用于评估药品满足已建立的规范的检验方法必须满足准确、可靠、适当的标准。此外，根据法规21 CFR 211.194(a)(2)，USP-NF中叙述的分析方法的使用者不需要验证这些方法的准确度和可信度，仅仅需要确认在实际使用条件下的适用性。考虑到USP和NF的法律地位，采用新的或修改后的药典分析方法的建议，并且这个建议是由充分的实验室数据支持以证明其有效，这是十分必要的。

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.

这一章节的内容尽可能地和ICH文献“分析方法的验证和方法学”（文献与包含在EC，日本和美国递交的注册申请中的分析方法相关）协调一致。

SUBMISSIONS TO THE COMPENDIA

递交至药典

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.

将新的或修改后的分析方法递交至药典，应包含足够的资料从而使得USP 委员会专家和其专家委员会能够评估拟定方法的价值。绝大多数情况下，评估包括透明度的评估和分析方法叙述完整性的评估，确定方法需求，以及专家已经充分验证的文件。涉及方法的类别改变，资料可能也会改变。然而，大部分情况下，递交应包含如下的章节

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—此章节应确定方法的需求和叙述拟定的具体的方法的能力以及它优于其它类别测定方法的原因。对于已修改的方法，需比较当前方法的局限性和拟定方法的优点。

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.

拟定的分析方法—此章节应包含详细完整的分析方法的叙述，使得技术人员能够重现。应包括所有的重要的操作参数和具体的操作，如试剂的制备，系统适应性性能的测试，空白溶液使用的叙述，注意事项，和用于计算检测结果的明确的公式。

Data Elements—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.

资料组成—此章节应对分析方法的验证提供周密的和完整的文件。需要包括对于证明每一个实用功能特性的实验数据和计算的概况、总结。这些特征在下面章节中叙述。

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.

分析方法的验证是一个过程：通过实验室的研究确立了方法的性能参数可以满足预期的分析应用的要求。本文件叙述的几种方法的验证需要考虑的典型的分析性能参数列在表1中。因为对术语和使用的观点可能会有所不同，所以每个性能参数在此章节的下部分给出定义，以及典型方法或能够测量的方法的描述。

The definitions refer to “test results.” The description of the analytical procedure should define what the test results for the procedure are. As

noted in ISO 5725-1 and 3534-1, a test result is “the value of

a characteristic obtained by carrying out a specified test method. The test method should specify that one or a number of individual

measurements be made, and their average,or another appropriate function

(such as the median or the standard deviation), be reported as the test result.

It may also require standard corrections to be applied, such as correction of gas volumes to standard temperature and pressure. Thus, a test result can be a result calculated from several observed values. In the simple case, the test result is the observed value itself.” A test result also can be, but need not be, the final, reportable value that would be compare to the acceptance criteria of a specification. Validation of physical property methods may involve the assessment of the chemometric models. However, the typical analytical

characteristics used in method validation can be applied to the methods derived from the use of the chemometric models.

这些定义指的是“测试结果”。“分析过程的描述应该定义这个过程的测试结果。” 正如在ISO 5725-1和3534-4中所指出的，测试结果是“通过执行指定的测试方法获得的特征值”。测试方法应该指定一个或多个单独的度量，以及它们的平均值，或者其他适当的函数(如中值或标准差)，作为测试结果。它还可能需要进行标准的校正，例如将气体体积调整到标准的温度和压力。因此，一个测试结果可以是由几个测定值计算出来的结果。在简单的情况下，测试结果是测定值本身。测试结果也可以是，但不需要是，最终的，可报告的值，此值可用于比较一个规范的接受标准。物理属性方法的验证可能涉及到化学计量模型的评估。然而,用于方法验证中的典型的分析可以应用于使用来源于化学计量模型的那些方法。

Table 1. Typical Analytical Characteristics Used in Method Validation 表1 方法验证中使用的典型的分析特征

第1225章的目的是提供适当的信息，以验证大范围的药典分析方法。药典里的方法验证可能会用一些或者全部的在表1和表2中列出的典型分析特性。对于一些药典方法，验证的基本原则可能超出了1225章所示的特性。对于这些方法，使用者可以参考单独药典章节，这些章节叙述的是特定的分析验证特性和特定的验证。

Analytical Performance Characteristics

分析性能特征

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.

[A note on terminology: The definition of accuracy in ?1225? and ICH Q2 corre sponds to unbiasedness only. In the International Vocabulary of Metrology (VI M) and documents of the International Organization for Standardization (ISO),“accuracy” has a different meaning. In ISO, accuracy combines the concepts of unbiasedness (termed “trueness”) and precision.]

定义---分析方法的准确度是采用分析方法获得的检测结果和真实值之间的接近程度。分析方法的准确度应在其范围中建立。关于术语的注释:1225的准确性的定义和ICHQ2符合于不偏性。在国际计量学(VIM)和国际标准化组织(ISO)的文献中，“准确性”有区别。在ISO中，准确性的概念融合了不偏性（术语来讲“真实性”和精确性）。

Determination—In the case of the assay of a drug substance, accuracy may be determined by application of the analytical procedure to an analyte of 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---如果是药品的含量测定，准确度可以通用采用分析方法对已知纯度（如对照品）的测定来确定，也可以通过和使用其它的第二个完好的方法（其准确度已说明或确定）的结果比较来确定。

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.

如果对某一剂型的产品的含量测定，准确度可以通过采用分析方法对加入已知量的分析物（在方法的范围内）的制剂组分的合成混合物进行测定。若不可以获得所有制剂组分的样品，要么通过在制剂中加入已知量的分析物（如，加样）是可以接受的，要么和第二个完好的方法（准确度已说明或确定）的结果来比较。

In the case of quantitative analysis of impurities, accuracy should be assessed on samples (of drug substance or drug product) spiked with known amounts 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 be necessary to calculate the amount of an impurity based on comparison of its response to that of the drug substance; the ratio of the responses of equal amounts of the impurity and the drug substance (relative response factor) should be used if known.

如果是定量分析杂质，准确度可以对样品（药用物质或成品药）加入已知量的杂质或降解产物来评估。在不可以获得某些杂质或降解产物的样品情况下，结果可以和独立的方法获得的结果比较。缺少其它资料的时候，有必要根据比较杂质的反应应和药用物质的反应，来计算杂质的量，若知道，等量的杂质和原料药的反应（相对反应因子）的比率应使用。

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 intervals.

The ICH documents recommend 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).

准确度通过对样品中已知加入量的分析物的含量测定的回收率来计算，或以平均值和可接受值的差值，以及置信区间来计算。ICH文件建议准确度通过在至少具体范围内，至少9次测定来评估（如，三个浓度和每个浓度的三次重复测定）。

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 slope 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来完成，包括评估在含量范围内的分析物的回收率，或被估测的和实际浓度见的线性关系来评估。统计最好标准是斜率的置信区间在1.0的区间中，或替代的，斜率接近于1.0。在每一情况下置信区间或紧密度的定义应在验证方案中指明。认可标准取决于含量和其变化和产品。基于缺少统计学意义的检测，假定斜率等于1。0，来设定可接受标准是不被接

受的。

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 repeatedly 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 (also known as ruggedness) expresses

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—分析方法的精密度是单个检测结果间的一致程度，当方法重复使用于同一样品的多个样品时。分析方法的精密度通常以一系列测量值的标准偏差或相对标准偏差（变异系数）来表示。精密度可以是在正常操作条件下，分析方法重现性和重复性程度的测量。在本文中，重现性指在不同的实验室使用分析方法，以共同研究的方式。中间精密度（通常也称为粗放性）表述的是在同一实验室范围内的变化，不同的天数，不同的分析人员或相同实验室内的不同仪器。重复性指的是在同一实验室内，一小段时间内，由同一实验人员在相同的设备上进行分析。

Determination—The precision of an analytical procedure is determined by assaying a sufficient number of Chromatography 621.

系统适应性检测是基于设备，电子，分析操作，和待分析样品组成了完整的系统。其可以评估。特别方法需要建立系统适应性检测取决于需要评估的方法的类别。对于色谱方法，至关重要的。USP的递交应注意系统适应性的要求，色谱法<621>

Data Elements Required for Validation

验证需求数据组成

Compendial test requirements vary from 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:

法定的检测要求从高度萃取的分析测定到特征的主观评价变化。考虑到这一广泛的变化，不同的检测方法要求不同的验证项目是合理的。本章节包括了最常用的检测分类，验证资料中需求。这些分类如下：

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

分类I——成品中原料药的主要组分或活性组分的定量测定的分析方法。

Category II—Analytical procedures for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceutical products.

分类II——原料药中杂质或成品中降解物的测定

These procedures include quantitative assays and limit tests.

这些方法包括定量地含量测定和限度测定。

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

分类III——用于测量性能特征的分析方法（如，溶出度，药品释放）

Category IV—Identification tests.

分类IV——鉴别试验

For each category, different analytical information is needed. Listed

in Table 2 are data elements that are normally required for each of these categories.

对于每一分类，需要不同的分析资料资料。表2中列出是每一分类需求的数据组成。

Table 2. Data Elements Required for Validation

表2 验证需求的资料组成

分析方法的有效性可以通过实验室研究来证明。因此，成功完成这些研究的文件是确定方法是否适用的基本要求。当前法定方法也是法规的主题，需要在实际条件下证明。见1226。适当的文件应和新的或修改后的法定的方法一致。

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