医学专题一USP40-1225--药典的验证中英文对照.doc

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1、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 Pharmacope

2、ia 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 re

3、liability. Also, according to these regulations 21 CFR 211.194(a)(2), users of analytical methods described inUSPNFare 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 ofUSP andNFs

4、tandards, 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，和化装品法案501章，美国药典和国家处方专题论文里的试验和标准构成了法律标准。CGMP法规21 CFR 211.194(a)要求：用于评估药品满足已建立的标准的

5、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中表达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 Harmoniza

6、tion (ICH) documentsValidation of Analytical Proceduresand theMethodologyextension 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

7、 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 assess

8、ment 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

9、 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表达完整性的评估，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，大局部情况下，递交应包含如下的章节RationaleThis section should identify the need for the procedure and describe the capability of the specific procedu

10、re 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.根本原理此章节应确定方法的需求和表达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，需比拟当前方法的局限性和拟定方法的

11、优点。Proposed Analytical ProcedureThis 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 o

12、f 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表达，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，空白溶液使用的表达，考前须知，和用于计算检测结果的明确的公式。Data ElementsThis section should provide thoro

13、ugh 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

14、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表达。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 an

15、alytical performance characteristics that should be considered in the validation of the types of procedures described in this document are listed inTable 1. Because opinions may differ with respect to terminology and use, each of the performance characteristics is defined in the next section of this

16、 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。本文件表达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局部给出定义，以及典型方法或能够测量的方法的描述。Thedefinitionsrefer to “testresults.Thedescriptionoftheanalytical pro

17、cedure shoulddefinewhatthetestresultsfortheprocedureare. As notedinISO5725-1and3534-1,atestresultis“thevalue of acharacteristicobtainedbycarryingoutaspecifiedtest method. The test methodshouldspecifythatoneor anumberofindividual measurementsbemade, and their average,oranotherappropriatefunction(such

18、asthemedianorthe standarddeviation), bereportedasthetestresult.It may alsorequirestandardcorrectionstobeapplied, suchascorrection of gas volumestostandardtemperatureandpressure. Thus,atestresultcan be a resultcalculatedfromseveralobservedvalues. Inthesimplecase, the test result isthe observedvalueit

19、self.Atestresultalsocanbe,butneed not be, the final, reportablevaluethatwouldbecompare totheacceptance criteria of a specification. Validationof physicalpropertymethodsmayinvolve the assessment of the chemometricmodels.However,thetypicalanalytical characteristicsusedinmethodvalidationcanbeappliedtot

20、he methods derived fromtheuseofthechemometricmodels.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

21、于比拟一个标准的接受标准。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Accuracy准确度Precision精密度Specificity专属性Detection Limit检测限Quantitation Limit定量限Linearity线性Range范围Robustness耐用性Theeffectsofprocessingcondition

22、sandpotentialforsegregationofmaterialsshouldbeconsideredwhenobtaining a representative sampleto be used for validationof procedures. 当获得代表性样品用于验证程序时，应考虑处理条件和材料隔离的影响。 In the case of compendial procedures, revalidation may be necessary in the following cases: a submission to the USP of a revised analy

23、tical procedure; or the use of an established general procedure with a new product or raw material (see below inData Elements Required for Validation).如果是药典方法，下面的一些情况下有必要进行再验证：将修改的分析方法递交给USP；或者将拟定的关于新产品或原辅料总的分析方法的使用见如下验证需要的资料组成The ICH documents give guidance on the necessity for revalidation in the

24、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文件给出下面的情况需要再验证：药品合成的变更；药品成分的变更；分析方法的变更。Chapter1225isintendedtoprovideinformationthatis appropriatetovalidateawiderangeofcompendialanalyt

25、icalprocedures.Thevalidationofcompendialprocedures may use someorallof the suggested typicalanalyticalcharacteristicsusedinmethodvalidationasoutlinedinTable1andcategorizedbytypeofanalyticalmethodinTable2. For some compendialproceduresthefundamentalprinciples of validation may extend beyondcharacteri

26、sticssuggested in Chapter1225.Fortheseprocedures theuserisreferred to the individualcompendialchapterforthosespecific analyticalvalidationcharacteristicsandanyspecificvalidation.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，验证的根本原那么可能超出了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，

27、这些章节表达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DefinitionThe 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. Anoteontermi

28、nology:Thedefinitionofaccuracyin1225andICHQ2correspondstounbiasednessonly.IntheInternationalVocabularyofMetrology(VIM)anddocumentsoftheInternationalOrganizationforStandardization(ISO),“accuracyhasadifferentmeaning.InISO,accuracycombinestheconceptsofunbiasedness(termed“trueness)andprecision.定义-分析方法的准

29、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。DeterminationIn the case of the assay of a drug substance, accuracy may be determined by application of the analytical procedure to an analyte of known pur

30、ity (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拟来确定。In the case of the assay of a drug i

31、n 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 componen

32、ts, 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参加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。假设不可以获

33、得所有制剂组分的样品，要么通过在制剂中参加量的分析物如，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拟。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

34、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 amo

35、unts 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参加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拟。缺少其它资料的时候，有必要根据比拟杂质的反响应和药用物质的反响，来计算杂质的量，假设知道，等量的杂质和原料药的反响相对反响因子的比率应使用。Accuracy is calculated as the percentage of recovery b

36、y 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 concentrat

37、ion levels, covering the specified range (i.e., three concentrations and three replicates of each concentration).准确度通过对样品中参加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

38、 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 a

39、lternatively, 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 sta

40、tistical 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

41、度DefinitionThe 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 sta

42、ndard 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

43、 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 with

44、in 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

45、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。DeterminationThe precision of an analytical procedure is determined by assaying a sufficient number ofChromatography621.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Data Elements Required for Validation验证需求数据组

46、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 tes

47、ts 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工程是合理的。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 IAnalytical 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 IIAnalytical procedures for determination of impurities in bulk drug substances or degradation compou