1、VALIDATION OF COMPENDIAL PROCEDURES藥典方法的驗證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.用于評估藥品質量的檢驗方法需要滿足不同的要求。依據聯邦食品，藥品，和扮裝品法案501章，美國藥典和國家處方專題論文里的試驗和標準構成了法律標準。CGMP法規21 CFR 211.194(a)要求：用于評估藥品滿足已建立的標準的

5、檢驗方法必須滿足精確、牢靠、適當的標準。此外，依據法規21 CFR 211.194(a)(2)，USP-NF中表達的分析方法的使用者不需要驗證這些方法的精確度和可信度，僅僅需要確認在實際使用條件下的適用性。考慮到USP和NF的法律地位，接受新的或修改后的藥典分析方法的建議，并且這個建議是由充分的實驗室數據支持以證明其有效，這是十分必要的。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.這一章節的內容盡可能地和ICH文獻“分析方法的驗證和方法學文獻與包含在EC，日本和美國遞交的注冊申請中的分析方法相關協調全都。SUBMISSIONS

7、 TO THE COMPENDIA遞交至藥典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.將新的或修改后的分析方法遞交至藥典，應包含足夠的資料從而使得USP委員會專家和其專家委員會能夠評估擬定方法的價值。絕大多數情況下，評估包括透明度的評估和分析方法表達完整性的評估，確定方法需求，以及專家已經充分驗證的文件。涉及方法的類別轉變，資料可能也會轉變。然而，大局部情況下，遞交應包含如下的章節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.根本原理此章節應確定方法的需求和表達擬定的簡略的方法的能力以及它優于其它類別測定方法的緣由。對于已修改的方法，需比擬當前方法的局限性和擬定方法的

11、優點。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.擬定的分析方法此章節應包含簡略完整的分析方法的表達，使得技術人員能夠重現。應包括全部的重要的操作參數和簡略的操作，如試劑的制備，系統適應性性能的測試，空白溶液使用的表達，考前須知，和用于計算檢測結果的明確的公式。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.資料組成此章節應對分析方法的驗證供

14、應周密的和完整的文件。需要包括對于證明每一個有用功能特性的實驗數據和計算的概況、總結。這些特征在下面章節中表達。VALIDATION驗證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.分析方法的驗證是一個過程：通過實驗室的商量確立了方法的性能參數可以滿足預期的分析應用的要求。本文件表達的幾種方法的驗證需要考慮的典型的分析性能參數列在表1中。由于對術語和使用的觀點可能會有所不同，所以每共性能參數在此章節的下局部給出定義，以及典型方法或能夠測量的方法的描述。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.這些定義指的是“測試結果。“分析過程的描述應該定義這個過程的測試結果。 正如在ISO 5725-1和3534-4中所指出的，測試結果是“通過執行指定的測試方法獲得的特征值。 測試方法應該指定一個或多個單獨的度量，以及它們的平均值，或者其他適當的函數(如中值或標準差)，作為測試結果。它還可能需要進行標準的校正，例如將氣體體積調整到標準的溫度和壓力。因此，一個測試結果可以是由幾個測定值計算出來的結果。在簡潔的情況下，測試結果是測定值本身。測試結果也可以是，但不需要是，最終的，可報告的值，此值可用

21、于比擬一個標準的接受標準。物理屬性方法的驗證可能涉及到化學計量模型的評估。然而,用于方法驗證中的典型的分析可以應用于使用來源于化學計量模型的那些方法。Table 1. Typical Analytical Characteristics Used in Method Validation表1 方法驗證中使用的典型的分析特征Accuracy精確度Precision精密度Specificity專屬性Detection Limit檢測限Quantitation Limit定量限Linearity線性Range范圍Robustness耐用性Theeffectsofprocessingcondition

22、sandpotentialforsegregationofmaterialsshouldbeconsideredwhenobtaining a representative sampleto be used for validationof procedures. 當獲得代表性樣品用于驗證程序時，應考慮處理條件和材料隔離的影響。 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).如果是藥典方法，下面的一些情況下有必要進行再驗證：將修改的分析方法遞交給USP；或者將擬定的關于新產品或原輔料總的分析方法的使用見如下驗證需要的資料組成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文件給出下面的情況需要再驗證：藥品合成的變更；藥品成分的變更；分析方法的變更。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章的目的是供應適當的信息，以驗證大范圍的藥典分析方法。藥典里的方法驗證可能會用一些或者全部的在表1和表2中列出的典型分析特性。對于一些藥典方法，驗證的根本原那么可能超出了1225章所示的特性。對于這些方法，使用者可以參考單獨藥典章節，

27、這些章節表達的是特定的分析驗證特性和特定的驗證。Analytical Performance Characteristics分析性能特征accuracy精確度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.定義-分析方法的精

29、確度是接受分析方法獲得的檢測結果和真實值之間的接近程度。分析方法的精確度應在其范圍中建立。關于術語的注釋:1225的精確性的定義和ICHQ2符合于不偏性。在國際計量學(VIM)和國際標準化組織(ISO)的文獻中，“精確性有區分。在ISO中，精確性的概念融合了不偏性術語來講“真實性和精確性。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.測定-如果是藥品的含量測定，精確度可以通用接受分析方法對純度如對比品的測定來確定，也可以通過和使用其它的其次個完好的方法其精確度已說明或確定的結果比擬來確定。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.如果對某一劑型的產品的含量測定，精確度可以通過接受分析方法對參加量的分析物在方法的范圍內的制劑組分的合成混合物進行測定。假設不行以獲

33、得全部制劑組分的樣品，要么通過在制劑中參加量的分析物如，加樣是可以接受的，要么和其次個完好的方法精確度已說明或確定的結果來比擬。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.如果是定量分析雜質，精確度可以對樣品藥用物質或成品藥參加量的雜質或降解產物來評估。在不行以獲得某些雜質或降解產物的樣品情況下，結果可以和獨立的方法獲得的結果比擬。缺少其它資料的時候，有必要依據比擬雜質的反響應和藥用物質的反響，來計算雜質的量，假設知道，等量的雜質和原料藥的反響相對反響因子的比率應使用。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).精確度通過對樣品中參加量的分析物的含量測定的回收率來計算，或以平均值和可接受值的差值，以及置信區間來計算。ICH文件建議精確度通過在至少簡略范圍內，至少9次測定來評估如，三個濃度和每個濃度的三次重復測定。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.精確度的評估可以通過多種不同的方式來完成，包括評估在含量范圍內的分析物的回收率，或被估測的和實際濃度見的線性關系來評估。統計最好標準是斜率的置信區間在1.0的區間中，或替代的，斜率接近于1.0。 在每一情況下置信區間或緊密度的定義應在驗證方案中指明。認可標準取決于含量和其變化和產品。基于缺少統計學意義的檢測，假定斜率等于1。0，來設定可接受標準是不被接受的。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.定義分析方法的精密度是單個檢測結果間的全都程度，當方法重復使用于同一樣品的多個樣品時。分析方法的精密度通常以一系列測量值的標準偏差或相對標準偏差變異系數來表示。精密度可以是在正常操作條件下，分析方法重現性和重復性程度的測量。在本文中，重現性指在不同的實驗室使用分析方法，以共同商量的方式。中間精密度通常也稱為粗放性表述的是在同一實驗室范圍內的變化，不同的天數，不同的分析人員或相同實驗室內的不同儀器。重復性指的是在同一

45、實驗室內，一小段時間內，由同一實驗人員在相同的設備上進行分析。DeterminationThe precision of an analytical procedure is determined by assaying a sufficient number ofChromatography621.系統適應性檢測是基于設備，電子，分析操作，和待分析樣品組成了完整的系統。其可以評估。特別方法需要建立系統適應性檢測取決于需要評估的方法的類別。對于色譜方法，至關重要的。USP的遞交應注意系統適應性的要求，色譜法Data Elements Required for Validation驗證需求數據組

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:法定的檢測要求從高度萃取的分析測定到特征的主觀評價變化。考慮到這一廣泛的變化，不同的檢測方法要求不同的驗證工程是合理的。本章節包括了最常用的檢測分類，驗證資料中需求。這些分類如下：Category IAnalytical procedures for quantitation of major components of bulk drug substances or active ingredients (including pre

48、servatives) in finished pharmaceutical products.分類 I成品中原料藥的主要組分或活性組分的定量測定的分析方法。Category IIAnalytical procedures for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceutical products.分類 II原料藥中雜質或成品中降解物的測定These procedures include quantitative assays and l

49、imit tests.這些方法包括定量地含量測定和限度測定。Category IIIAnalytical procedures for determination of performance characteristics (e.g., dissolution, drug release).分類 III用于測量性能特征的分析方法如，溶出度，藥品釋放Category IVIdentification tests.分類IV鑒別試驗For each category, different analytical information is needed. Listed inTable 2are d

50、ata elements that are normally required for each of these categories.對于每一分類，需要不同的分析資料資料。表2中列出是每一分類需求的數據組成。Table 2. Data Elements Required for Validation表2 驗證需求的資料組成AnalyticalPerformanceCharacteristics分析性能參數Category I分類ICategory II分類IICategory III分類IIICategory IV分類IVQuantitative定量LimitTests限度Accuracy精確度Yes是Yes是*No否Precision精密度Yes是Yes是No否Yes是No否Specificity專屬性Yes是Yes是Y