USP化学药物质量控制分析方法验证技术指导原则.docx

1、USP化学药物质量控制分析方法验证技术指导原则1225 VALIDATION OF COMPENDIAL PROCEDURES 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 Un

2、ited 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 standa

3、rds of accuracy and reliability. Also, according to these regulations 21 CFR 211.194(a)(2), users of analytical methods described in USPNF are not required to validate the accuracy and reliability of these methods, but merely verify their suitability under actual conditions of use. Recognizing the l

4、egal 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.The text of this information chapter harmonizes, to the extent possible, with the Trip

5、artite 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. SUBMISSIONS TO THE COMPEN

6、DIA 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 clarit

7、y 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 fo

8、llowing sections.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 compendi

9、al procedure and advantages offered by the proposed procedure.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 operation

10、al 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.Data Elements This section should provide thorough and complete documentation of the valida

11、tion 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.VALIDATION Validation of an analytical procedure is the proce

12、ss 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

13、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. The definitions refer

14、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

15、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

16、. 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 compared to the acceptance criteria of a specification. Validation o

17、f physical property methods may involve the assessment of 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.The effects of processing conditions and potential for segregation of m

18、aterials should be considered when obtaining a representative sample to be used for validation of procedures.Table 1. Typical Analytical Characteristics Used in Method Validation AccuracyPrecisionSpecificityDetection LimitQuantitation LimitLinearityRangeRobustnessIn the case of compendial procedures

19、, 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).The ICH documents give guidance on the necessity f

20、or 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.Chapter 1225 is intended to provide information that is appropriate to validate a wide range of compendial analytica

21、l procedures. The validation of compendial procedures may use some or all of the suggested typical analytical characteristics used in method validation as outlined in Table 1 and categorized by type of analytical method in Table 2. For some compendial procedures the fundamental principles of validat

22、ion may extend beyond characteristics suggested in Chapter 1225. For these procedures the user is referred to the individual compendial chapter for those specific analytical validation characteristics and any specific validation requirements.Analytical Performance Characteristics accuracy Definition

23、 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 corresponds to unbiasedness onl

24、y. In the International Vocabulary of Metrology (VIM) 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.Determination In the case of the assay of a dr

25、ug 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. In t

26、he 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 samp

27、les 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.In the case of quantitative analy

28、sis 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.

29、 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.Ac

30、curacy 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 ni

31、ne determinations over a minimum of three concentration levels, covering the specified range (i.e., three concentrations and three replicates of each concentration).Assessment of accuracy can be accomplished in a variety of ways, including evaluating the recovery of the analyte (percent recovery) ac

32、ross 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 e

33、ither 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 hypothes