EDQA OMCL分析方法驗(yàn)證指南

1、PA/PH/OMCL (13) 82 2R 分析方法驗(yàn)證OMCL Network of the Council of Europe歐洲理事會(huì)OMCL網(wǎng)絡(luò)GENERAL DOCUMENT通用文件PA/PH/OMCL (13) 82 2RVALIDATION OF ANALYTICAL PROCEDURES檢驗(yàn)方法驗(yàn)證Full document title and reference文件全名和參考號(hào)Validation of Analytical Procedures分析方法驗(yàn)證PA/PH/OMCL (13) 82 2RDocument type文件類型Guideline指南Legislative

2、 basis立法基礎(chǔ)The present document was also accepted by EA as recommendation document to be used in the context of Quality Management System audits of OMCLsOMCL質(zhì)量管理體系審計(jì)Date of first adoption首版采用日期October 19991999年10月Date of original entry into force原生效日期February 20002000年2月Date of entry into force of re

3、vised document修訂版生效日期February 20142014年2月Previous titles/other references原標(biāo)題/其它參考號(hào)This document replaces document PA/PH/OMCL (05) 47 DEFFormer titles/references: PA/PH/OMCL (99) 37 DEF本文件替代文件PA/PH/OMCL (05) 47 DEF原文題目/索引號(hào)：PA/PH/OMCL (99) 37 DEFCustodian Organisation責(zé)任機(jī)構(gòu)The present document was elabo

4、rated by OMCL Network/EDQM of the Council of Europe目前文件由OMCL網(wǎng)絡(luò)/歐洲議會(huì)EDQMConcerned Network相關(guān)網(wǎng)絡(luò)GEONVALIDATION OF ANALYTICAL PROCEDURESGUIDELINE FOR OMCLsOMCL分析方法驗(yàn)證指南INTRODUCTION 概述The two ICH Guidelines on “Validation of Analytical Procedures: “Definition/ Terminology and Methodology” (Q2A and Q2B) con

5、stitute a discussion of the validation characteristics that should be considered during the validation of an analytical procedure (the guideline has also been adopted for veterinary products during VICH discussion). They are primarily addressed to pharmaceutical industry indicating which validation

6、data need to be provided in an application file. These data should demonstrate that the proposed testing and acceptance criteria are sufficiently under control to guarantee reproducible quality of the products at release and adequate control during shelf-life (stability). 兩個(gè)關(guān)于分析方法驗(yàn)證的ICH指南“分析方法的驗(yàn)證”和“

7、定義/術(shù)語(yǔ)和方法學(xué)”（Q2A和Q2B）包括了一個(gè)分析方法驗(yàn)證中應(yīng)該考慮的驗(yàn)證特性的討論（該指南在VICH討論中也被應(yīng)用于獸藥產(chǎn)品），它們告訴制藥企業(yè)在提交申請(qǐng)文件時(shí)，需要提供哪些驗(yàn)證數(shù)據(jù)。這些數(shù)據(jù)應(yīng)證明所提交的檢驗(yàn)項(xiàng)目、方法、可接受標(biāo)準(zhǔn)是受控的，足以保證產(chǎn)品放行質(zhì)量重現(xiàn)性及其生命周期（穩(wěn)定性）內(nèi)質(zhì)量充分受控。As the circumstances under which an OMCL works are different from those of a pharmaceutical company in most cases no routine analysis, but often

8、responses to be made in a short period of time -, the extent of analytical validation requested before performing an analysis needs to be reconsidered. On the other hand it has in all cases to be guaranteed that the result submitted is reliable. It should also be emphasised here, that adequate refer

9、ence materials are an important factor in both the performance of the validation studies and the analysis it-self. The use of widely accepted reference preparations can in certain circumstances avoid the consideration of some validation characteristics, mainly in the field of biological products: th

10、is has then to be justified on a case by case basis.由于OMCL的工作情況與制藥公司并不一樣-在大多情況下，并沒(méi)有常規(guī)檢驗(yàn)，但經(jīng)常需要在很短時(shí)間內(nèi)做出反應(yīng)，在進(jìn)行分析前所要求的方法驗(yàn)證的程度需要再進(jìn)行考慮。另一方面，在所有情況下都需要保證所呈交的結(jié)果是可靠的。在此還需要強(qiáng)調(diào)的是，在驗(yàn)證研究和分析檢測(cè)中對(duì)照物質(zhì)均是重要的因素，采用被廣泛認(rèn)可的對(duì)照品在某些特定情況下可以避免考慮某些驗(yàn)證特征，這主要表現(xiàn)在生產(chǎn)產(chǎn)品方面，這些需要個(gè)案單獨(dú)判斷。The scope of this document specifically addressed to OM

11、CLs - is to give guidance on the extent of validation needed, depending on various circumstances i.e. objective of the analysis (e.g. screening for non compliance), amount of validation data already available (e.g. in case of a method transfer), experience or historical data already available in the

12、 individual OMCL (e.g. recovery from a complex matrix; routine use of a standard titration even if different substances are titrated), etc. This document is equally applicable to products of synthetic and of biological origin. It does not address common laboratory practice: for instance specific use

13、 of the equipment, calibration etc.本文件的范圍尤其對(duì)于OMCL來(lái)說(shuō)是提供驗(yàn)證所需進(jìn)行的深度的指南，它取決于不同的環(huán)境，也就是分析的目的（例如，剔除不符合者），已有驗(yàn)證數(shù)據(jù)的數(shù)量（例如對(duì)一個(gè)方法進(jìn)行轉(zhuǎn)移的情況），在單個(gè)OMCL實(shí)驗(yàn)室已有的歷史數(shù)據(jù)和經(jīng)驗(yàn)（例如，一個(gè)復(fù)雜矩陣的回收率，即使是對(duì)不同物質(zhì)同樣適用的常規(guī)標(biāo)準(zhǔn)滴定法）等等。本文件同等適用于合成產(chǎn)品和生化產(chǎn)品。本文件未對(duì)一般化驗(yàn)室規(guī)范提出要求，例如儀器的特定使用、校正等。This document is a note for guidance, which provides detailed recomme

14、ndations of the extent of the validation exercise dependent on the category of the analytical procedure; it should be noted that other approaches are always possible. In all cases a short description and/or justification of the approach chosen, including the methods, should be described in the inter

15、nal documentation of the analysis. Validation data of validated methods (compendial, marketing authorisation dossier) should be available. Modifications from the original validated method should be justified. The same definitions as in the ICH document apply.本文件是對(duì)指南的一個(gè)注釋，其中詳細(xì)說(shuō)明了驗(yàn)證的深度取決于分析方法的類別，需要注意的

16、是總會(huì)有一些其它方法來(lái)實(shí)現(xiàn)相同目的。不管怎樣，對(duì)所選擇方法的論述，包括方法本身，應(yīng)在內(nèi)部分析文件中做一個(gè)簡(jiǎn)短的描述。已驗(yàn)證方法（藥典、上市文件）的驗(yàn)證數(shù)據(jù)應(yīng)該保存可查，對(duì)原始的經(jīng)過(guò)驗(yàn)證的方法進(jìn)行修訂需要進(jìn)行論證。ICH文件中的定義在此適用。CATEGORIES OF ANALYSIS 分析的類別This chapter defines the different analytical situations (categories) which might occur in an OMCL and the corresponding validation characteristics whic

17、h should be considered. (As a reminder the table in the annex describes in general the validation characteristics to be considered, depending on the different types of analytical procedures). 本章定義了可能發(fā)生在一個(gè)OMCL里的不同分析情況（類別），以及需要考慮的相關(guān)的驗(yàn)證特性。（附件表中描述了根據(jù)不同分析程序類別需要考慮的驗(yàn)證特性供參考）Formal validation studies , accor

18、ding to the ICH requirements, has to be performed for a new developed method or when for an existing method the validation data have to be completed. 正式驗(yàn)證研究：根據(jù)ICH指南，對(duì)于新建方法，或已有方法需要提交完整數(shù)據(jù)時(shí)必須實(shí)施Method transfer check (verification of suitability ) has to be done to show that under actual conditions of us

19、e in the individual laboratories the method is adequate (fit for use). This might imply for instance the carrying out of the system suitability tests (e.g. resolution in a chromatographic method), the control of the reporting threshold, the control of the completeness of a reaction step (e.g. extrac

20、tion, hydrolysis reaction) before the actual determination can be performed, the verification of the precision of the method etc. So for instance the system suitability tests described in a fully validated liquid chromatography method will in all cases have to be performed, as these tests are part o

21、f the analytical procedure. This is particular true for the category Transfer of a method. 方法轉(zhuǎn)移檢查（適用性驗(yàn)證）：方法轉(zhuǎn)移檢查必須要進(jìn)行，以表明該方法在指定的實(shí)驗(yàn)室內(nèi)在實(shí)際使用情況下，方法可以滿足使用的要求。這可能表示，例如在實(shí)際檢測(cè)進(jìn)行前需要實(shí)施系統(tǒng)適用性（例如，色譜方法分辨率），報(bào)告閥值的控制，反應(yīng)步驟的結(jié)束（例如萃取、水解反應(yīng)），方法精密度確認(rèn)等。所以，由于有些測(cè)試是分析方法的一部分，例如一個(gè)完整的驗(yàn)證過(guò)的液相色譜方法里描述的系統(tǒng)適用性，在任何情況下都需要進(jìn)行確認(rèn)。對(duì)于方法轉(zhuǎn)移尤其如此。In

22、all cases, a short note, explaining the rational for the chosen approach -depending on the complexity of the analysis required-, will have to be provided in the internal documentation of the analysis. Deviation from this guideline should be justified. 所有情況下，在內(nèi)部分析文件中均需要提供一個(gè)簡(jiǎn)短的注釋，以解釋所選擇方法的合理性（取決于所需分析的

23、復(fù)雜程度）。不符合本指南的情況需要進(jìn)行判定。The following categories of analysis are considered: 考慮的情況為以下三類- Transfer of a method方法轉(zhuǎn)移- Screening 篩選- Development of a new analytical procedure 建立新方法1. Transfer of a Method 方法轉(zhuǎn)移In this category it is assumed that a certain amount or elements of validation data for this parti

24、cular analysis is already available: so no or only a few validation characteristics need to be considered. In an ideal situation, this can also be done by comparison of the results of two laboratories performed on the same sample. “No formal validation required” indicates that the respective validat

25、ion characteristics have already been considered by others. However a verification of suitability under conditions of use (=method transfer check) has to be done in all cases by the OMCL. 此類中，假定該方法已經(jīng)有了一定數(shù)量或因素的驗(yàn)證數(shù)據(jù)：所以沒(méi)有或僅有少量驗(yàn)證特性需要考慮。在理想的狀態(tài)下，可以由兩個(gè)化驗(yàn)室對(duì)同一個(gè)樣品進(jìn)行測(cè)定，對(duì)結(jié)果進(jìn)行比較?！安恍枰降尿?yàn)證”表示前驗(yàn)證項(xiàng)目已經(jīng)由其它人考慮過(guò)了。當(dāng)然，任何

26、情況下，OMCL都必須進(jìn)行在實(shí)際使用情況下（=方法轉(zhuǎn)移檢查）的方法適用性驗(yàn)證。1.1. Pharmacopoeial (compendial) method.藥典方法Active substance活性物質(zhì)The analytical procedures described in a monograph of a pharmacopoiea are considered to be validated. In this case it should be made sure that all reference materials needed are available and the r

27、equired system suitability tests are performed. Nevertheless, it should also be considered that a pharmacopoeial monograph is only considered validated (related substances test) when it is applicable to the control of the listed impurities (specific source material, see Ph Eur). 藥典的專論中所述的分析方法被認(rèn)為是經(jīng)過(guò)驗(yàn)

28、證的。這種情況下，需要確認(rèn)所有的對(duì)照品都是有效的，需要進(jìn)行系統(tǒng)適用性測(cè)試。無(wú)論如何，還需要考慮藥典專論中檢驗(yàn)方法（有關(guān)物質(zhì)）的驗(yàn)證內(nèi)容僅針對(duì)列出的雜質(zhì)（已知來(lái)源物料，見(jiàn)歐洲藥典）。Identification:鑒別no formal validation required; 不需要正式驗(yàn)證Testing for Impurities:雜質(zhì)檢測(cè)no formal validation required; 不需要正式驗(yàn)證Assay:含量no formal validation required.不需要正式驗(yàn)證Note注: To fall under this category, the proce

29、dures must be described in detail, not for instance as in some cases for biologicals where there is only a general description of the method. 此類情況下，需要詳細(xì)敘述檢測(cè)方法，而不是象有些生物制品案例中僅有方法的概述藥品The pharmacopoeial monograph for a specific dosage form is a good basis for the analysis; however as in many cases ther

30、e is no indication about the exact composition of the product (qualitative and quantitative composition of the excipients), it must at least be made sure that these do not interfere in the analysis of the active substance, unless addressed in the monograph. 藥典中對(duì)特定劑型的專論是建立分析方法的一個(gè)很好基礎(chǔ)，盡管如此，在許多情況下，并沒(méi)有制

31、劑產(chǎn)品中確切成分信息（賦形劑的定性和定量組成情況），除非專論中有說(shuō)明，否則至少必須保證賦形劑對(duì)活性物質(zhì)的分析不產(chǎn)生干擾。- Identification:鑒別no formal validation required;不需要正式驗(yàn)證- Testing for Impurities:雜質(zhì)檢測(cè)specificity: no interference from excipients;專屬性：賦形劑無(wú)干擾reporting threshold (at least the quant.limit)報(bào)告閥值（最少需要定量限）- Assay:含量specificity,專屬性accuracy: mainly

32、 recovery, minimum 1 determination.,準(zhǔn)確度：主含量回收率，最小一次測(cè)定precision (repeatability): around the target test concentration (minimum 2 independent determinations)精確度（重復(fù)性）：在目標(biāo)濃度上下（最少2次獨(dú)立測(cè)定）linearity at three measuring points in the range around the target value. 目標(biāo)值范圍內(nèi)三個(gè)檢測(cè)點(diǎn)線性1.2 Method of a manufacturer.生產(chǎn)商

33、的檢驗(yàn)方法 the analytical procedures have been fully validated by the company.檢驗(yàn)方法已由公司進(jìn)行了全面驗(yàn)證與項(xiàng)下相同：申請(qǐng)同時(shí)作為活性物質(zhì)和藥品Identification:鑒別no formal validation required;不需要正式驗(yàn)證Testing for Impurities:雜質(zhì)檢測(cè)no formal validation required不需要正式驗(yàn)證Assay:含量no formal validation required不需要正式驗(yàn)證 old application file with no or

34、 insufficient validation data published.老的申請(qǐng)文件中沒(méi)有驗(yàn)證數(shù)據(jù)或驗(yàn)證數(shù)據(jù)不充分This case should be notified to the authorities. For the validation characteristics to be considered please refer to 1.4, 1.5, 2.1 or 3. 此情況下應(yīng)通知官方。需要考慮的驗(yàn)證特性參見(jiàn) 1.4，1.5，2.1或3。1.3 Non compendial published method.非藥典方法The validation characteri

35、stics to be considered will always depend on the amount of validation data provided. If the method has been fully validated and data published in the literature, the same as under 1.1 applies (active substance and medicinal product). If not, the following has to be considered:驗(yàn)證時(shí)需要考慮的特性總是依賴于提供驗(yàn)證數(shù)據(jù)的數(shù)

36、量。如果方法已被充分驗(yàn)證，數(shù)據(jù)已文字化，與1.1項(xiàng)下應(yīng)用（活性物質(zhì)和藥品）相同；如果不是，需要考慮下列情況Identification:鑒別no formal validation required不需要正式驗(yàn)證Testing for Impurities:雜質(zhì)檢測(cè)- specificity;- 專屬性- reporting threshold (limit of quantitation);- 報(bào)告閥值（定量限）- precision/accuracy over the range.- 指定范圍的精密度/準(zhǔn)確度Assay:含量- specificity: no interference fr

37、om excipients- 專屬性：賦形劑無(wú)干擾- accuracy: around the target concentration- 準(zhǔn)確度：目標(biāo)濃度上下- repeatability: around the target concentration (minimum 2 independent determinations)- 重復(fù)性：目標(biāo)濃度上下（最少2次獨(dú)立測(cè)試）- linearity at three measuring points in the range around the target value.- 目標(biāo)值范圍內(nèi)三個(gè)檢測(cè)點(diǎn)線性1.4 Method of a first

38、 manufacturer to be used for a product of a 2nd manufacturer.第二個(gè)生產(chǎn)商采用第一個(gè)生產(chǎn)商的檢驗(yàn)方法活性物質(zhì)Identification:鑒別no formal validation required不需要正式的驗(yàn)證Testing for Impurities:雜質(zhì)檢測(cè)specificity (impurity profile) 專屬性（雜質(zhì)概況）(if the impurity profile is different, further validation data might be necessary 如果雜質(zhì)概況不同，可能需要

39、進(jìn)一步驗(yàn)證的數(shù)據(jù))Assay:含量- no formal validation required in case of a titration;- 如果是滴定方法則不需要正式驗(yàn)證- Stability indicating: see testing for impurities.- 穩(wěn)定性考察：參見(jiàn)雜質(zhì)檢測(cè)藥品A prerequisite is, that we have here comparable formulations (matrix): 一個(gè)前提條件是我們有可以比較的制劑（母體）Identification:鑒別no formal validation required 不需要正式

40、驗(yàn)證Testing for Impurities: 雜質(zhì)檢測(cè)- Specificity (interference of excipients); - 專屬性（賦形劑干擾）- reporting threshold (quantit. limit); - 報(bào)告閥值（定量限）- precision/accuracy over the range .- 涵蓋范圍的精密度/準(zhǔn)確度Assay: 含量- specificity: no interference from excipients - 專屬性：賦形劑無(wú)干擾- accuracy: around the target concentration

41、- 準(zhǔn)確度：目標(biāo)濃度上下- repeatability: around the target concentration (minimum 2 independent determinations) - 重復(fù)性：目標(biāo)濃度上下（最少2次獨(dú)立檢測(cè)）- linearity at three measuring points in the range around the target value. - 線性：目標(biāo)值上下范圍內(nèi)三個(gè)檢測(cè)點(diǎn)如果矩陣相同，參見(jiàn)1.5 Method for an active substance to be used for a medicinal product. 藥用活性

42、物質(zhì)檢測(cè)方法The main factor to be considered here is the influence of the matrix on the analysis including interference from the excipients. 此處主要需要考慮的矩陣對(duì)分析影響包括賦形劑的干擾Identification: 鑒別no formal validation required不需要正式驗(yàn)證Testing for Impurities: 雜質(zhì)檢測(cè)- specificity;- 專屬性- reporting threshold (quantit. limit);

43、- 報(bào)告閥值（定量限）- precision/accuracy over the range .- 涵蓋范圍的精密度/準(zhǔn)確度Assay:含量- specificity: no interference from impurities and excipients - 專屬性：雜質(zhì)和賦形劑不產(chǎn)生干擾- accuracy: around the target concentration - 準(zhǔn)確度：目標(biāo)濃度上下- repeatability: around the target concentration (minimum 2 independent determinations)- 重復(fù)性：目標(biāo)

44、濃度上下（最少2次獨(dú)立測(cè)試）- linearity at three measuring points in the range around the target value. - 線性：目標(biāo)值上下范圍內(nèi)三個(gè)檢測(cè)點(diǎn)1.6 Methods validated to reduce, refine or replace animal use (3Rs) 方法驗(yàn)證用來(lái)減少、精簡(jiǎn)或替代獸用（3R）In these cases the transfer will generally involve methods validated through collaborative trials, valid

45、ated by the manufacturer for a particular product, or validated and published by another laboratory. The validation characteristics to be considered will always depend on the amount of validation data provided. If the method has been fully validated and data is published in the literature or availab

46、le in the MA dossier, the same as under 1.1 applies (active substance and medicinal product). Elements highlighted under 1.2 to 1.4 may also be relevant in these situations. The OMCL should identify the key parameter(s) which should ensure the precision of the test procedure. Wherever possible the s

47、ame protocols and reference material should be used in all labs. When a laboratory participated in a collaborative study to develop a method, data generated during the study can also be used in the validation package for regular lab use.在這種情形下，轉(zhuǎn)移通常涉及到通過(guò)綜合試驗(yàn)來(lái)進(jìn)行驗(yàn)證、由特定產(chǎn)品的生產(chǎn)商進(jìn)行驗(yàn)證、或由另一個(gè)化驗(yàn)室驗(yàn)證或公布。要考慮的驗(yàn)證屬性取

48、決于所提供的驗(yàn)證數(shù)據(jù)的量。如果方法已經(jīng)過(guò)了全面驗(yàn)證，數(shù)據(jù)在文獻(xiàn)上發(fā)布，或在MA文檔中可以獲得，則適用1.1相同條款（活性物質(zhì)和制劑）。在1.2至1.4下所強(qiáng)調(diào)的要素在這些情形下也相關(guān)。OMCL應(yīng)識(shí)別關(guān)鍵參數(shù)，這些關(guān)鍵參數(shù)應(yīng)能保證檢驗(yàn)方法的精密度。應(yīng)盡可能在所有化驗(yàn)室使用相同的方案和對(duì)照物質(zhì)。如果一個(gè)化驗(yàn)室專注于綜合性研究來(lái)建立一個(gè)方法，則在研究期間所產(chǎn)生的數(shù)據(jù)也可以在常規(guī)化驗(yàn)室的驗(yàn)證包中使用。2. Screening 篩選2.1. Screening for non-compliance 不符合檢測(cè)篩選Screening for non-compliance means that the ta

49、rget of the analysis is to detect potential noncompliance of the product with the specifications. This type of screening would be performed when a rapid analysis is requested and/or when no validation data of the method are at disposal. The procedure must in all cases be documented. 不符合篩選是指分析的目的是檢測(cè)出

50、產(chǎn)品潛在的與質(zhì)量標(biāo)準(zhǔn)不符合的項(xiàng)目。當(dāng)需要一個(gè)快速分析方法和/或當(dāng)方法的驗(yàn)證數(shù)據(jù)得不到時(shí)，會(huì)采用篩選。任何情況下均需要記錄所用的程序。Minimum validation required: 最小驗(yàn)證要求Identification: 鑒別specificity 專屬性Testing for Impurities: 雜質(zhì)檢測(cè)- specificity; - 專屬性- reporting threshold (quantit. limit); - 報(bào)告閥值（定量限）- precision over the range .- 涵蓋范圍的精密度Assay: 含量- specificity: no in

51、terference from excipients and impurities; - 專屬性：賦形劑和雜質(zhì)無(wú)干擾- precision: around the target test concentration, (minimum 2 independent determinations) - 專屬性：目標(biāo)檢測(cè)濃度上下（最少2次獨(dú)立測(cè)試）If non-compliance is detected or suspected, the extent of validation has to be expanded. The follow-up of possible OOS situation

52、 has to be regulated by a standard operation procedure. 如果檢出不合格或存疑，需要補(bǔ)充驗(yàn)證，可能的OOS情況需要按標(biāo)準(zhǔn)操作規(guī)程進(jìn)行跟蹤。2.2. Analysis of an unknown product 未知產(chǎn)品的分析In this case there is a lack of information on the product which has to be tested with respect to its label claim (presence or absence of certain substances) or

53、to clarify other aspects asked by the Inspectorate. 如果沒(méi)有需要檢測(cè)的產(chǎn)品關(guān)于其標(biāo)簽申明的相關(guān)信息（特定物質(zhì)是否存在），或由審計(jì)方詢問(wèn)的其它方面申明內(nèi)容Testing to be considered: identification, assay and perhaps purity testing. The first important step is to identify the major components of the product.檢測(cè)時(shí)要考慮：鑒別、含量以及可能需要純度檢測(cè)，第一個(gè)重要步驟是鑒別產(chǎn)品中的主成份Identi

54、fication: Specificity 鑒別：專屬性Assay: 含量- specificity: no interference from the matrix- 專屬性：主峰不受干擾- accuracy: around the target test concentration, mainly recovery (performed on 2 independent determinations) - 純度：在目標(biāo)檢測(cè)濃度左右，主成份回收率（需進(jìn)行2次獨(dú)立檢測(cè)）- precision: around the target test concentration, (performed o

55、n 2 independent determinations) - 精密度：目標(biāo)檢測(cè)濃度左右（需進(jìn)行二次獨(dú)立檢測(cè)）污染物/痕量分析方法篩選Mainly the situations as under 1 (transfer of a method) can be encountered; the most important validation characteristics which need to be considered are of course specificity, detection limit and quantitation limit. 主要會(huì)在第1種情況下（方法轉(zhuǎn)移）時(shí)碰到，最重要的驗(yàn)證特點(diǎn)是當(dāng)然