<1225>VALIDATION OF COMPENDIAL PROCEDURES

藥典規(guī)程的驗證

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 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.

評估藥品質(zhì)量水平的實驗方法受到多種要求的影響。要依據(jù)美國食品、藥品、化妝品法案501款以及美國藥典和國家處方集的各論中的含量測定和質(zhì)量標(biāo)準(zhǔn)來構(gòu)建法定標(biāo)準(zhǔn)?，F(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范【21 CFR 211.194(a)】要求，用于評價藥物與既有質(zhì)量標(biāo)準(zhǔn)之間的符合性的分析規(guī)程必須在準(zhǔn)確度和可靠性方面達(dá)到適當(dāng)?shù)臉?biāo)準(zhǔn)。并且根據(jù)【21 CFR 211.194(a)(2)】的這些規(guī)定，不要求USP-NF（《美國藥典/國家處方集》）中描述的分析方法/規(guī)程的使用者去驗證這些規(guī)程的準(zhǔn)確度和可靠性，而僅需確認(rèn)其在正確實際使用條件下的適用性。認(rèn)識到USP和NF標(biāo)準(zhǔn)的法定地位，因此，提議采納新的或更改過的藥典分析規(guī)程時，必須有充分的實驗室數(shù)據(jù)作為支持，以記錄其有效性。

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.

本信息章節(jié)的內(nèi)容盡可能地與三方國際協(xié)調(diào)會議（ICH）文件分析規(guī)程的驗證和方法學(xué)的延伸內(nèi)容保持一致，那是與包含歐盟、日本和美國注冊申請內(nèi)的分析方法相關(guān)的。

SUBMISSIONS TO THE COMPENDIA

向藥典提交的文件

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.

向藥典提交關(guān)于新的或更改過的分析規(guī)程的文件應(yīng)該包括充足的信息，以使USP專家理事會和專家委員會能夠評估擬議規(guī)程的相對優(yōu)越性。在大多數(shù)情況下，這些評估涉及對分析規(guī)程描述的清晰度和完整度的評估，對規(guī)程的需求的確定，以及它們已經(jīng)進行了適當(dāng)驗證的記錄文件。這些信息可以根據(jù)所涉及規(guī)程的種類而變化。但是，在大多數(shù)情況下，提交的文件將有下面的章節(jié)組成。

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.

理論依據(jù)---- 此部分應(yīng)該辨明對于該規(guī)程的需求，并描述具體擬議中規(guī)程的能力，以及為什么優(yōu)于其他種類檢測。對于更改的方法/規(guī)程，應(yīng)該提供對當(dāng)前藥典規(guī)程之缺陷與擬議中規(guī)程之優(yōu)勢的比較。

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.

推薦的分析方法/規(guī)程---- 此部分包含對該分析規(guī)程的完整描述，應(yīng)足夠具體以便能讓業(yè)內(nèi)技術(shù)熟練的人重復(fù)它。文章應(yīng)該包括所有重要的操作參數(shù)和具體的指令，例如：試劑制備、系統(tǒng)適用性測試表現(xiàn)、所使用空白對照的描述、預(yù)防措施、用于計算測試結(jié)果的明確公式。

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.

數(shù)據(jù)要素---- 此部分應(yīng)該提供完全徹底的分析規(guī)程驗證記錄文件。其應(yīng)該包括對于證明每一個實用功能特性的實驗數(shù)據(jù)和計算的概況、總結(jié)。這些特性在下面的部分描述。

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 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.

分析規(guī)程的驗證是，通過實驗室研究，確定該規(guī)程的工作特性達(dá)到了預(yù)定分析用途要求的過程。在此文件中所描述的規(guī)程種類的驗證中，應(yīng)當(dāng)考慮的常見分析工作特性在表1中列出。因為對于術(shù)語和使用的意見可能不同，在此通則的下個部分定義了每個工作性能，以及可以對其進行測量的常用的一個或幾個方法的描繪。

Table 1. Typical Analytical Characteristics Used in Method Validation

表1. 在方法驗證中使用的常用分析特性

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).

在藥典方法的情況下，在下面的情況有必要進行再驗證：向USP提交修改的分析規(guī)程；或?qū)⒁汛_立的通用規(guī)程用于新產(chǎn)品或原料（見下面驗證必需的數(shù)據(jù)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文件對于下列情況下再驗證的必要性做出了指導(dǎo)：藥物合成過程有變更；藥品組成的有變更；以及分析規(guī)程中有變更。

Analytical Performance Characteristics

分析性能特征 

ACCURACY

準(zhǔn)確度

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.

定義---- 分析規(guī)程的準(zhǔn)確度是由該規(guī)程得到的測試結(jié)果與真實值的接近程度。分析規(guī)程的準(zhǔn)確度應(yīng)通過它的適用范圍來建立。

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.

測定---- 當(dāng)對一種藥物進行分析時，準(zhǔn)確度可以通過該分析規(guī)程來分析一個已知純度的物質(zhì)（例如，某個標(biāo)準(zhǔn)物質(zhì)）來進行測定，或者通過比較運用這個分析方法所得的結(jié)果與另一個已經(jīng)鑒定的、其準(zhǔn)確度已被說明或被解釋過的方法所得的結(jié)果來進行測定。

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.

當(dāng)分析一種成品藥時，準(zhǔn)確度可以通過分析規(guī)程來分析成藥各組分的合成物質(zhì)來測定，而添加進去的分析物質(zhì)是在方法的范圍之內(nèi)的、是已知數(shù)量的。如果不能得到成藥的所有組分，也可以將已知數(shù)量的待分析物加入到該成藥中（例如，“增敏”），或者將結(jié)果與用第二種、成熟的、已知準(zhǔn)確度的規(guī)程得到的結(jié)果進行比較，

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.

對于雜質(zhì)的定量分析，應(yīng)使用以已知數(shù)量雜質(zhì)增敏的樣品來評估準(zhǔn)確度。當(dāng)不能獲得特定雜質(zhì)或降解產(chǎn)物的樣品時，應(yīng)將結(jié)果與另一獨立方法獲得的結(jié)果進行比較。在沒有其他信息的情況下，可能必需通過將某種雜質(zhì)的響應(yīng)值與藥物的響應(yīng)值進行比較來計算雜質(zhì)的數(shù)量；同等數(shù)量的雜質(zhì)與藥物的響應(yīng)值的比值（相對響應(yīng)因子），如果已知，則應(yīng)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.

通過測定被加入到樣品中的已知數(shù)量的被分析物來計算準(zhǔn)確度，得到回收百分比，或得到平均值與可接受的真實值之間的差異，同置信區(qū)間一起。

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文件建議精密度的評估應(yīng)當(dāng)使用覆蓋規(guī)定范圍的至少三個濃度水平進行至少九次測試（例如，三個濃度并且每個濃度三次重復(fù)進樣）。

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.

準(zhǔn)確度的評估可以通過多種不同的方式完成，包括評價在含量測定的整個范圍內(nèi)被分析物的回收率，或評價估計濃度與實際濃度之間關(guān)系的線性。具統(tǒng)計學(xué)意義的標(biāo)準(zhǔn)有二，一是斜率的置信區(qū)間被限定在約1.0的區(qū)間，二是此斜率接近1.0。在任意一種情況下，此區(qū)間或接近程度的定義應(yīng)該在驗證方案中明確規(guī)定。接受標(biāo)準(zhǔn)將取決于含量和其差異性，以及取決于該產(chǎn)品。通過測試證明該斜率為1.0的零假設(shè)沒有統(tǒng)計學(xué)意義，這樣的方法不能用于設(shè)定接受標(biāo)準(zhǔn)。

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.

定義---- 分析規(guī)程的精密度是當(dāng)該分析規(guī)程單獨分析均質(zhì)樣品的多個樣本時，若干檢驗結(jié)果的一致程度。分析規(guī)程的精密度通常以一系列測量數(shù)值的標(biāo)準(zhǔn)差或相對標(biāo)準(zhǔn)差（變異系數(shù)）來表示。精密度可以是分析規(guī)程在普通操作條件下可重現(xiàn)性或可重復(fù)性程度的度量單位。在這樣的背景下，重現(xiàn)性指的是該分析規(guī)程在不同實驗室的應(yīng)用，例如在一個協(xié)作實驗室里進行研究。中間精密度（也稱為“耐用性”）體現(xiàn)了在實驗室內(nèi)的差異，如在相同的實驗室，但在不同的日期，或使用不同的分析員或設(shè)備?？芍貜?fù)性指的是在同一個實驗室內(nèi)，一段較短的時間內(nèi)，相同的分析員使用相同的設(shè)備、同一個分析方法的應(yīng)用情況。

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.

測定----一個分析方法的精密度是通過對足夠的同一樣品的分析來計算有統(tǒng)計學(xué)意義的標(biāo)準(zhǔn)偏差或相對標(biāo)準(zhǔn)偏差來測定的。在這個背景下的分析是從樣品準(zhǔn)備到最終實驗結(jié)果的完整分析程序的對樣品的獨立分析。

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文件建議可重復(fù)性的評估應(yīng)該使用最少九次檢測，覆蓋該分析規(guī)程所規(guī)定的范圍（例如，三個濃度和每個濃度三次重復(fù)進樣，或在100%測試濃度上進行最少六次測定）。

SPECIFITY

專屬性

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.

定義---- ICH文件將專屬性定義是當(dāng)待分析物含有預(yù)期會有的其他組分（例如，雜質(zhì)、降解產(chǎn)物、矩陣組分）時，準(zhǔn)確可靠地評估待分析物的能力。某個分析規(guī)程缺乏專屬性可以通過其他輔助性分析規(guī)程進行補償?！咀⒁猓浩渌曌u卓著的國際權(quán)威機構(gòu)（IUPAC、AOAC-I）已經(jīng)提出術(shù)語“選擇性”，而將“專屬性”留給已經(jīng)具有完全選擇性的規(guī)程?！繉τ谙旅嬗懻摰臏y試，上述定義具有以下的含義。

Identification Tests: ensure the identity of the analyte.

鑒別檢測：確保待分析物的鑒別。

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).

純度檢測：確保執(zhí)行的所有分析規(guī)程能夠令對于待分析物各雜質(zhì)含量的準(zhǔn)確陳述得以做出。

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

含量檢測：提供準(zhǔn)確的結(jié)果，令對樣品中待分析物的含量或效力的準(zhǔn)確陳述得以做出。

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.

測定---- 對于定性分析（鑒別檢驗），應(yīng)當(dāng)論證其在可能存在的、結(jié)構(gòu)密切相關(guān)的物質(zhì)中進行選擇的能力。從含有待分析物的樣品中得到陽性結(jié)果（可能通過與已知標(biāo)準(zhǔn)物質(zhì)的比較），而從不含待分析物的樣品得到陰性結(jié)果，以對其選擇能力加以確認(rèn)，并還要確認(rèn)陽性響應(yīng)不是來自與待分析物結(jié)構(gòu)相似或密切相關(guān)的物質(zhì)。

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.

對于檢測雜質(zhì)的分析規(guī)程，專屬性可以通過以適當(dāng)水平的雜質(zhì)將原料藥或成藥增敏，并論證這些雜質(zhì)的測定達(dá)到了適當(dāng)?shù)臏?zhǔn)確度和精密度。

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.

對于含量檢測，對專屬性的論證要求能夠顯示出該分析規(guī)程不受各雜質(zhì)或輔料的影響。在實際操作中，通過以適當(dāng)水平的雜質(zhì)或輔料將原料藥或成藥增敏，并證明含量檢驗結(jié)果不受這些外來物質(zhì)的影響，來完成論證。

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.

如果沒有雜質(zhì)或降解產(chǎn)物的標(biāo)準(zhǔn)品，可以通過將含有雜質(zhì)或降解產(chǎn)物的樣品的測試結(jié)果與第二種、成熟規(guī)程（例如，藥典或其他驗證過的規(guī)程）的結(jié)果進行比較，來論證專屬性。這些比較應(yīng)該包括在相關(guān)破壞性條件下（例如，光、熱、濕度、酸/堿水解、氧化作用）存儲的樣品。對于含量測定，應(yīng)比較其結(jié)果；對于色譜法雜質(zhì)檢測，應(yīng)比較雜質(zhì)概況。

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文件聲明，當(dāng)使用色譜分析規(guī)程時，應(yīng)提交具代表性的色譜圖，以論證選擇性的程度，而且應(yīng)對色譜峰作適當(dāng)?shù)臉?biāo)識。也可以使用色譜峰純度測試（例如，使用二極管陣列或質(zhì)譜儀），來顯示待分析物的色譜峰僅產(chǎn)生于一個組分。

DETECTION LIMIT檢測限度

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.

定義---- 檢測限度是限度檢測的特性。它是指在規(guī)定的試驗條件下，樣品中可被檢測到的待分析物的最小數(shù)量，但是無需定量。因此，限度檢測僅僅說明了待分析物的數(shù)量高于或低于某個特定水平。檢測限度通常以在樣品中的待分析物濃度（例如，百分比、十億分率）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.

測定---- 對于非儀器分析規(guī)程，檢測限度的測定方法通常為，對含有已知濃度待分析物的樣品進行分析，并確立能夠可靠地被檢測出來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.

對于儀器分析規(guī)程，可以使用與非儀器分析規(guī)程相同的方法。對于提交用于官方藥典規(guī)程的備選方法，其幾乎從來不需要確定實際的檢測限度。而是，通過分析含有高于和低于必需的檢測水平的、已知待分析物濃度的樣品，以顯示檢測限度足夠低。例如，如果必需檢測濃度在0.1%的雜質(zhì)，則應(yīng)當(dāng)證明該分析規(guī)程將可靠地檢測在這個水平的雜質(zhì)。

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.

對于展示出背景噪音的儀器分析規(guī)程，ICH文件描述了一個通用方法，用來比較從以下樣品測得的信號，這些樣品分別為含已知低濃度被分析物的樣品和空白樣品。這樣就確立了能夠可靠檢測的待分析物的最低濃度。可接受的典型信噪比是2:1或3:1。其他方法取決于校正曲線斜率的測定和響應(yīng)值的標(biāo)準(zhǔn)差。無論用什么方法，均應(yīng)該在隨后通過分析適當(dāng)數(shù)量的、已知接近或制備于檢測限度的樣品，來驗證檢測限度。

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.

定義---- 定量限度是樣品矩陣中低含量物質(zhì)的定量分析的特性，例如在原料藥中的雜質(zhì)和成品藥物中的降解產(chǎn)物。它是在規(guī)定試驗條件下，能夠以可接受的精密度和精確度進行測定的樣品中待分析物的最小量。定量限度以樣品中待分析物的濃度（例如，百分比、十億分率）來表示。

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.

測定---- 對于非儀器分析規(guī)程，定量限度的測定方法通常為對含有已知濃度待分析物的樣品進行分析，并確立能夠以可接受的準(zhǔn)確度和精密度被檢測出來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.

對于儀器分析規(guī)程，可以使用與非儀器分析規(guī)程相同的方法。對于提交用于官方藥典規(guī)程的備選方法，其幾乎從來不需要確定實際的檢測限度。而是，通過分析含有高于和低于必需的定量水平的、已知待分析物濃度的樣品，以顯示定量限度足夠低。例如，如果必需在0.1mg每片的水平評估待分析物，則應(yīng)當(dāng)證明該分析規(guī)程將可靠地這個水平定量待分析物。

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.

對于展示出背景噪音的儀器分析規(guī)程，ICH文件描述了一個通用方法，用來比較從以下樣品測得的信號，這些樣品分別為含已知低濃度被分析物的樣品和空白樣品。這樣就確立了能夠可靠地定量待分析物的最低濃度?？山邮艿牡湫托旁氡仁?0:1。其他方法取決于校正曲線斜率的測定和響應(yīng)值的標(biāo)準(zhǔn)差。無論用什么方法，均應(yīng)該在隨后通過分析適當(dāng)數(shù)量的、已知接近或制備于定量限度的樣品，來驗證定量限度。

LINEARITY AND RANGE

線性和范圍

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, “l(fā)inearity” 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.

線性的定義---- 分析規(guī)程的線性是該規(guī)程直接地、或通過明確給出的數(shù)學(xué)轉(zhuǎn)換而間接地，得出與特定范圍內(nèi)的樣品中待分析物濃度呈比例關(guān)系的測試結(jié)果的能力。因此，在此部分，“線性”是指濃度與檢驗結(jié)果之間的線性關(guān)系。在某些情況下，為了實現(xiàn)線性，濃度和/或測量數(shù)據(jù)可以進行轉(zhuǎn)換。（注意：當(dāng)進行轉(zhuǎn)換時，在回歸分析中用到的權(quán)重因子可以變化。）雖然其他轉(zhuǎn)換方式也是可以接受的，但是可能的轉(zhuǎn)換包括對數(shù)、平方根、倒數(shù)。如果無法實現(xiàn)線性，可以使用非線性模型。其目的是得到一個精確描述濃度-響應(yīng)值關(guān)系的模型，不論是線性還是非線性。

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.

范圍的定義---- 分析規(guī)程的范圍是分析物的較高濃度和較低濃度（含）之間的區(qū)間，已經(jīng)證實在此區(qū)間內(nèi)，使用該規(guī)程進行測定具有適當(dāng)水平的精密度、準(zhǔn)確度、和線性。該范圍通常以與該分析規(guī)程得到的測試結(jié)果相同的單位表示，例如百分比，百萬分率等。

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.

線性和范圍的確定---- 應(yīng)在分析規(guī)程整個范圍內(nèi)確立線性。線性的確立最開始應(yīng)該通過目測代表內(nèi)容物中待分析物濃度的多個信號構(gòu)成的圖表來進行。如果其呈現(xiàn)線性關(guān)系，測試結(jié)果應(yīng)該通過適當(dāng)?shù)慕y(tǒng)計學(xué)方法（例如，以最小二乘方來計算回歸線）來確立。來自回歸線自身的數(shù)據(jù)可以用于提供線性程度的數(shù)學(xué)評估。應(yīng)該提交其相關(guān)系數(shù)、Y軸截距、回歸線斜率、殘差平方和。

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.

通過用規(guī)程分析含有待分析物的、濃度在范圍的極限值上和在范圍中的樣品，確認(rèn)該分析規(guī)程提供了可接受的精密度、準(zhǔn)確度、線性，以進行該規(guī)程范圍的驗證。

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建議，為了確立線性，通常使用最少五個濃度。其還建議，應(yīng)考慮下列的最小范圍的規(guī)定。

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

原料藥（或成藥）的含量測定：供試濃度的80%到120%。

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

雜質(zhì)的測定：接受標(biāo)準(zhǔn)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.

對于內(nèi)容物的均一性：最少供試濃度的70%到130%，除非由于劑型的特性（例如，定量吸入氣霧劑）而支持應(yīng)用更寬或更適合的范圍。

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)

對于溶出度檢測：在規(guī)定范圍上±20%（例如，如果一個控釋產(chǎn)品的接受標(biāo)準(zhǔn)覆蓋了從1小時后20%到24小時后最多90%的區(qū)域，則驗證區(qū)域應(yīng)該為標(biāo)簽聲稱值的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.

定義---- 分析規(guī)程的耐用性是規(guī)程文件中列出的操作參數(shù)在微小、故意的變更中不受影響的能力的衡量單位，并在日常使用中提供了其適用性的指標(biāo)。耐用性可以在分析規(guī)程的研發(fā)中確定。

SYSTEM SUITABILITY

系統(tǒng)適用性

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.

如果檢測結(jié)果易受分析條件中的差異影響，則這些差異應(yīng)當(dāng)被適當(dāng)?shù)乜刂?，或?yīng)當(dāng)在規(guī)程中加入預(yù)防性的陳述。評估耐用性的一個結(jié)果就是確立一系列系統(tǒng)適用性參數(shù)，以確保不論何時使用，均可維持分析規(guī)程的有效性。典型的差異是分析溶液、不同設(shè)備、不同分析員的穩(wěn)定性。對于液相色譜法而言，典型的差異是流動相pH值、流動相構(gòu)成、不同批號或供應(yīng)商的色譜柱、溫度、流速。對于氣相色譜法而言，典型差異是不同批號或供應(yīng)商的色譜柱、溫度、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>.

系統(tǒng)適用性測試基于這個概念，即這些設(shè)備、電子儀器、分析操作、供試樣品構(gòu)成了一個完整系統(tǒng)，此系統(tǒng)可以作為整體進行評估。為某個特定規(guī)程設(shè)定的系統(tǒng)適用性測試參數(shù)取決于被評估的規(guī)程的種類。對于色譜規(guī)程，它們尤其重要。向USP提交的文件應(yīng)該應(yīng)該注明在通則色譜法<621>中系統(tǒng)適用性章節(jié)下的要求。

Data Elements Required for Validation

驗證所需的數(shù)據(jù)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:

藥典測試的要求差別較大，從高度精確的分析測定到特性的主觀評估?？紤]到此寬幅差異，則可以理解不同測試規(guī)程需要不同的驗證計劃。此章節(jié)僅覆蓋了這些需要驗證數(shù)據(jù)的測試中最常見的種類。這些種類如下：

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

第一類：對成藥中原料藥或活性成分（包括防腐劑）的主要組分進行定量測定的分析規(guī)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.

第二類：對成藥中原料藥或降解物質(zhì)中雜質(zhì)進行測定的分析規(guī)程。這些規(guī)程包括定量測定和限度測定。

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

第三類：對工作特性（例如，溶出度、藥物釋放）進行測定的分析規(guī)程。

Category IV---- Identification tests.

第四類：鑒別測試。

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

每一個類別均需要不同的分析信息。每個種類通常所需要的數(shù)據(jù)要素在表2中列出。

Table 2. Data Elements Required for Validation

表2. 驗證必需的數(shù)據(jù)要素

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.

已經(jīng)確立的通用規(guī)程（例如，水分滴定測定、細(xì)菌內(nèi)毒素）應(yīng)當(dāng)▲進行確認(rèn)，以確立在用于新的產(chǎn)品或原料時的適用性，例如▲USP31其準(zhǔn)確度（和無可能的干擾因素）。

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.

分析規(guī)程的有效性可以通過實驗室研究來確認(rèn)。因此，此類研究成功完成的記錄文件是確定某個規(guī)程是否適用于其預(yù)定用途的基本要求。當(dāng)前的藥典規(guī)程也要符合相關(guān)管理規(guī)定，要證實在實際使用條件下的適用性?！ㄒ娝幍湟?guī)程的確認(rèn)<1226>，以了解與藥典規(guī)程確認(rèn)相關(guān)的基本原則）▲USP31適當(dāng)?shù)挠涗浳募?yīng)伴隨著任何有關(guān)新的或修改過的藥典分析規(guī)程的方案。