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201410 PA/PH/OMCL(13) 113 2R : 结果的评估和报告：核心文件
OMCL Network of the Council of Europe
QUALITY ASSURANCE DOCUMENT
欧洲委员会OMCL网络质量保证文件
PA/PH/OMCL (13) 113 2R
Evaluation and Reporting of Results
结果的评估和报告：核心文件
Core document
Full document title and reference Evaluation and reporting of Results---Core Document PA/PH/OMCL (13) 113 2R
全名和索引 结果的评估和报告---核心文件 PA/PH/OMCL(13) 113 2R
Document type
文件类型
Legislative basis
法规依据
Date of first adopt
首次采纳日期
Date of original entry into force
首次实施日期
Date of entry into force of revised document
修订版生效日期
Previous titles/other references/last valid version This document replaces document PA/PH/OMCL (07) 28 DEF CORR Former titles / references: Evaluation and Reporting of Results from Assays, PA/PH/OMCL (02) 52 DEF Evaluation and Reporting of Results, PA/PH/OMCL (99) 38 DEF
之前题目/其它索引号/上一有效版本 本文件替代PA/PH/OMCL(07) 28 DEF CORR 前版本题目/索引： 含量结果的评估和报告，PA/PH/OMCL (02) 52 DEF 结果的评估和报告, PA/PH/OMCL (99) 38 DEF
Custodian Organisation The present document was elaborated by the OMCL Network/EDQM of the Council of Europe
责任机构
Concerned Network
相关网络
EVALUATION ANDREPORTING OF RESULTS
CORE DOCUMENT
GUIDELINE FOROMCLs
OMCL指南：结果的评估和报告：核心文件
1. SCOPE 范围
This guidelinedefines basic principles for evaluation and reporting of results of OfficialMedicines Control Laboratory (OMCL) testing of industrially-manufacturedmedicinal products [1], extemporaneousproducts and APIs. The purpose of this OMCL testing is to secure compliance ofa product with the specifications laid down in the Marketing Authorisation andother relevant regulations. The OMCL testing can be considered as averification of the testing by the manufacturer who has declared that the sameproduct is in compliance with the specifications.
本指南定义了官方药品控制化验室（OMCL）对制药公司生产的药品的检测结果的评估和报告基本通则，临时的药品和原料药。该OMCL检测的目的是保证药品符合上市许可和其它相关法规中制订的质量标准。OMCL检测可以认为是对生产商检测结果的一种核查，生产商已经声明其相同的药品符合上述标准。
In order tosimplify the management of the guideline, the present document contains onlythe general chapters. The annexes can be found in separate documents.
为了简化指南的管理，现行的只包括了通用章节，附录作为单独的文件发行。
The list ofannexes, included in this document, will be updated as soon as new annexes areissued.
附录的清单包括在本文件里，它们会在签发新附录时即时更新。
2. INTRODUCTION 概述
An OMCL performstesting of medicines for human and veterinary use on behalf of the CompetentAuthority.
OMCL是代表官方对人药和兽药进行检测的。
The testing byan OMCL is performed within the context of activities such as marketsurveillance studies (MSS), testing of centrally authorised products (CAP),testing of products with mutual recognised or decentralised authorisation(MRP/DCP) or national authorisation, official control authority batch release(OCABR) and pre-licensing evaluation. The OMCL should operate the testingwithin a quality system based on ISO 17025 to guarantee a sufficient level ofconfidence in the results. The results of the OMCL testing may have significantconsequences for the products involved, especially if a sample is found to beout-of-specification (OOS). Measures taken by the Competent Authority mayinclude recalls, batch rejection, thorough production investigations, refusalof marketing authorisation (in pre-licensing evaluation) and it should be notedthat results obtained from the testing by OMCLs are communicated within theOMCL Network and to all Competent Authorities.
OMCL做检测一般是在一些活动中实施的，例如上市监管研究（MSS）、集中审评药品（CAP）检测、互认审评程序或非集中审评（MRP/DCP）或国家审评中药品的检测、官方控制批放行（OCABR）和许可发放前的评估检测。OMCL的检验操作应基于ISO17025的质量体系，以保证结果的可信度在很高的水平。OMCL检测的结果可能会对牵涉的药品产生重大的后果，特别是如果样品被检出是不符合质量标准（OOS）的时候。药监机构可能采取的措施包括召回、拒绝放行批次、全面生产调查、拒绝发放上市许可（在许可发放前评估中），因此要注意OMCL检测结果应在OMCL内部及所有药监机构进行沟通。
Therefore, OMCLshave to give careful consideration to the establishment of a test result andany conclusions of conformity or non-conformity of a product.
因此，OMCL必须认真考虑检验结果的获得过程以及药品是否符合标准的结论。
This document isnot necessarily applicable to medicinal products for which a clearspecification is missing, as they are neither monographed nor required to gothrough a complete marketing authorisation procedure (e.g. some Europeancountries define reduced marketing authorisation requirements for herbals fortraditional use).
本文件不一定适用于不具有清楚质量标准的药品，因为这种药品没有药典各论，也不要求通过药监机构批准上市（例如，一些欧洲国家决定对传统用途草药免除上市许可要求）。
3. TEST RESULTS 检验结果
Test results areto be obtained using validated methods. Guidance on validation of methods byOMCLs is provided in a separate document [1]. Operating conditions have to befollowed and analytical acceptance criteria (e.g. system suitability tests)have to be met. All tests are to be performed by competent staff and allresults are to be verified and authorised.
检验结果应使用验证过的方法来获得。OMCL方法验证指南已单独公布。必须遵守操作条件，并符合分析可接受标准（例如系统适用性）。所有检测要由有资质的员工实施，所有结果要经过确认和批准。
A singlereportable test result or determination may be calculated from a number ofindividual observations (e.g. readings or injections). This number has to bepredefined in the test protocol.
单个可报告的检验结果或决定可能是从许多单个结果（例如，读数或进样）中计算出来的。用于计算的结果的个数必须在检验方法里预先说明。
Uncertainty ofmeasurement. Information on the precision or measurement uncertainty of the resultshas to be available (preferably by in-house validation according to the OMCLsinternal quality control criteria, or by access to the manufacturer’s data inthe relevant marketing authorisation dossier; see OMCL Guideline “Uncertaintyof Measurement” Part 1) and the OMCL has to be able, where appropriate, toreport on this issue. Appropriate controls for precision and accuracy must betaken into consideration, where relevant, in the design of the assay.
测量不确定性：应可以提供结果的测量不确定度或精密度资料（最好是根据OMCL内部质量控制标准进行内部验证，或获得生产商在上 市许可文档中的数据，参见OMCL指南“测量不确定度”第一部），OMCL必须能报告该问题。如果有相关性，在含量设计中必须考虑采取适当的精密度和准确度控制。
For allquantitative measurements, the uncertainty of the measurement should beconsidered in the result. This uncertainty can be expressed as one of thefollowing:
对所有定量测量来说，在检测结果中应考虑测量不确定度。该不确定度可以表达如下之一：
a) confidencelimits with a defined probability (e.g. P=0.95), for a defined number ofobservations.
a) 对指定的结果个数来说，置信限度为指定的概率（例如P=0.95）
b) relativestandard deviation, which should not significantly exceed the relative standarddeviation established in the method validation [2].
b) 相对标准偏差，不应显著超过方法验证中建立的相对标准偏差
For Ph. Eur.monographs, it should be noted that the Ph. Eur. states that no furthertolerances are to be applied to the limits prescribed since they are based ondata obtained in normal analytical practice and they take account of normalanalytical errors, acceptable variations in manufacturing and compounding anddeterioration to an extent considered acceptable. This also applies topreparations described in the Ph. Eur.
对于欧洲药典各论，要注意欧洲药典声明给定的限度没有更大的允许误差，因为它们是根据常规分析操作中所获得的数据计算的，他们还考虑了常规的分析错误、生产和配方中可接受的波动，以及可接受程度的腐败。这也适用于欧洲药典中所述的制剂。
4. EVALUATION OFRESULTS 结果的评估
In MSS, CAP,MRP/DCP testing and OCABR, the OMCL test results should be assessed againstspecifications approved in the marketing authorisation and/or the Ph. Eur.monograph of the product concerned.
在MSS、CAP、MRP/DCP检测和OCABR中，OMCL检验结果应根据上市许可中批准的质量标准和/或药品相关的欧洲药典各论进行评估。
The OMCL shouldclearly define how, if applicable, averaging of results is performed and howthese results are evaluated [3]. The analyticalacceptance criteria should comply with predefined criteria as described in thedocuments “OMCL Policy on the Estimation and Application of Uncertainty inAnalytical Measurements”.
OMCL应清楚说明如何对结果计算平均值，这些结果是如何评估的。分析可接受标准应符合预定文件“OMCL评估分析测量不确定度估计和应用的原则”中所述的标准。
4.1 FAILUREINVESTIGATION OF OUT-OF-SPECIFICATION (OOS) RESULTS
OOS结果失败调查
When a resultdoes not comply with the specifications (“suspected OOS”), the OMCL has tooperate a standard procedure to establish whether this result is due toanalytical error, the influence of variables unrelated to the product, orwhether this result reflects the actual quality of the product tested.
当一个结果不符合质量标准时（“疑似OOS”），OMCL必须运行一个标准程序来决定是否该结果是由分析错误、与药品无关的波动影响引起的，或是否该结果反映了被测药品的实际质量。
A supervisor ora nominated staff member that was not directly involved in the analysis and whohas appropriate competence for the specific analytical technique has to conducta documented investigation of any suspected OOS result, based on theinformation provided by the staff that performed the test [4][5]. If thisinvestigation reveals a technical reason for the suspected OOS result, such asan analyst’s mistake, malfunctioning laboratory equipment, unsuitablereagents/reference substances or inappropriate sample storage, the assay is notvalid and the result must be rejected. Non-conformities detected during thefailure investigation should be managed according to the quality managementsystem in place, as appropriate. The OMCL must repeat the test and only theresult of the repeated test can be considered for evaluation.
一个主管或指定的未直接牵涉入分析，并具备特定分析技术适当资质的员工必须根据实施初始检验的化验员所提供的信息，对可疑OOS结果进行调查并记录。如果该调查发现该可疑OOS结果是由于一个技术性原因，例如化验员犯错、化验室仪器故障、试剂/对照品不适用，或样品存贮不适当，则含量无效，必须否定该结果。必要时，在失败调查中发现的不符合性操作应根据已有质量管理体系进行管理。OMCL必须重复该检验，在评估中只能考虑重新检验的结果。
The exact causeof an OOS result by the OMCL can often be difficult to identify. After theinitial investigation, the OMCL or the Competent Authority that gives the orderto test the medicinal product may decide to review information from themanufacturer on the production and control of the suspect batch in theinvestigation.
OMCL检测中得到的OOS结果的确切原因可能经常是难以识别的。在初始调查后，OMCL或下达药品检测指令的药监机构可以决定对生产商提交的调查中可疑批次的生产和检测资料进行审核，
4.2 RE-TESTPROGRAMME FOR CONFIRMATION OF OOS RESULTS
确认OOS结果的复验程序
If the suspectedOOS result cannot be explained by a non-conformity detected during failureinvestigation, it is considered as “initial OOS result” and the OMCL has toperform a re-test programme to confirm the OOS result. In such cases, thenumbers of replicates and operators, sampling procedure and the method forevaluating the results have to be predefined and documented, either by astandard operating procedure or for the individual case. The OMCL may decide onalternative analytical approaches, as long as it is able to demonstrate theirvalidity as confirmatory testing.
如果在失败调查中发现的不符合性问题无法解释可疑的OOS结果，则应考虑将其作为“初始OOS结果”，OMCL必须进入复验程序以确认该OOS结果。在这种情况下，重复的次数和操作人员、取样程序和结果评估的方法必须预先确定并记录，可以是采用标准操作规程，也可以是单独制订。OMCL可以决定采用另一可替代的检验方法，只要能够证明该替代方法的有效性。
If the re-testprogramme is defined in the Ph. Eur. (e.g. repetition of the rabbit pyrogentest), that re-test programme should be followed. The exact design of there-test programme, in terms of repeat testing and evaluation of the results, isgenerally not described in the Marketing Authorisation dossier.
如果复验程序已在EP里进行了定义（例如，兔热源测试的重复），则应遵守该复验程序。复验程序的设计中关于测试的重复和结果的评估，一般不会在上市许可文档中描述。
Depending on thetype of activity, specific documents may be available that define the differentsteps of the investigation and actions to be taken in cases where OOS resultsare obtained (e.g. in the CAP programme, see document “Testing of Centrally AuthorisedProducts (CAPs): Handling of out of specification (OOS) results”).
根据所承担活动类型的不同，如果产生了OOS结果，可以获得的描述调查步骤和采取措施的特定文件可以找到（例如，在CAP程序中，参见文件“集中评审程序CAP检测：OOS结果的处理”）。
The re-testprogramme and its evaluation should be based on sound scientific judgement andmay depend on the characteristics of the test. Several examples of approachesfor a re-test programme are given in Annexes II A-D. These examples are notmandatory and other approaches are possible if their scientific rationale isdocumented and the mandatory basic principles of this core document arefollowed:
复验程序和其评估应基于科学合理的判定，可能还依赖于测试的特性。在附录IIA-D中给出了复验程序的几个例子，这些例子并不是说必须采用这样的方式，其它科学合理的方法经过记录，符合本核心文件的以下基本原则的话，则也可以采用：
? Unless proven tobe invalid, the initial OOS result must not be rejected, but has to be includedin the evaluation of the product, as for all other valid results.
? 除非被证明是无效的，否则初始OOS结果不能够拒绝，而必须与其它有效结果一样，包括在对药品的评估中。
? All re-testsshould be performed independently of each other, including sample preparation.
? 所有复验应相互独立，包括样品制备。
? The maximumnumber of re-tests should be predefined and limited and should not be definedso as to “test a product into compliance”. The results should give a basis forthe estimation of measurement uncertainty if this is not known from availablevalidation data (preferably in-house, alternatively from the marketingauthorisation dossier).
? 最多可复验的次数应预先界定并受到限制，不应该定义为“测试一个产品直到合格”。如果现有验证数据（最好是公司内的验证，或者是来自上市许可文档）没有测量不确定度的话，结果应能给出对测量不确定度的估算基础。
5. REPORTING OFRESULTS 结果报告
The OMCL shouldtransfer the result and its assessment in a test report to the CompetentAuthority and, if applicable, to other OMCLs and the EDQM. The informationgiven in the test report must be based on the requirements given in ISO 17025(Chapter 5.10) and should include all the information requested by theCompetent Authority and necessary for the interpretation of the test result,e.g. the relevant specification. The report must make reference to the methodused (in-house/compendial/reference material, where relevant). The resultsshould be reported as the mean of all valid results, given with the adequatenumber of figures and, where appropriate, information on the uncertainty ofmeasurement (e.g. the relative standard deviation or the 95% confidence interval).The OMCL may report the results differently, taking into account internal orcustomer requirements, as long as they still comply with ISO 17025 (Chapter5.10).
OMCL应将其结果和评估以检验报告的形式转移给药监机构，适当时，移交给其它OMCL和EDQM。在检验报告中给出的信息必须是根据ISO17025（第5.10章）中的要求给出的，应包括药监机构所要求的所有信息，以及检验结果诠释所需的信息，例如，相关质量标准。报告必须给出所用的方法索引号（内控/药典/对照物料，如果有关的话）。结果应报告为所有有效结果的平均值，结果应保留足够的有效数字。适当时，还要提供测量不确定度信息（例如，相对标准偏差或95%置信区间）。考虑到内部或客户要求，OMCL可以不同形式报告，只要这些结果仍符合ISO17025(第5.10章)。
If a productdoes not comply with the specification, a critical evaluation based on the OMCLfailure investigation procedure has to be given and, if applicable, informationfrom the manufacturer. A recommendation to the Competent Authority forfollow-up activities may be included in the report.
如果药品不符合标准，必须提供根据OMCL失败调查程序所进行的关键评估，适用时，还应包括来自生产商的信息。在报告中可能要包括对官方进行跟踪的建议。
However, wherespecific procedures already exist for the reporting of results (e.g. OCABR – ECAdministrative procedure for OCABR), these should be followed and anycirculation of information to other organisations should respect the limits ofconfidentiality characteristic of that activity (e.g. EU-specific networksversus general OMCL activities). In addition, the OMCLs and CompetentAuthorities involved should define their in-house procedures for storage andinternal exchange of data and any follow-up measures, taking into account therecommendations described above.
但是，如果已有结果报告程序存在（例如，OCABR-EC行政程序），则应遵守该程序，向其它组织发布的所有信息均应符合该活动的保密要求（例如，EU特定网络VS常规OMCL活动）。另外，所涉及的OMCL和药监机构应考虑上述建议，来制订其内部数据存贮和数据交换程序，以及跟踪措施。
6. GLOSSARY 术语
API Active Pharmaceutical Ingredient
CAP Centrally Authorised Product
MRP/DCP Mutual Recognition Procedure / Decentralised Procedure
MSS Market Surveillance Study
OCABR Official Control Authority Batch Release
OOS
7. REFERENCES 参考文献
(For allreferences, the latest version applies 所有参考文献均以最新版本为准)
1. OMCL Guideline“Validation of Analytical Procedures” (PA/PH/OMCL (05) 47 DEF).
1. OMCL指南“分析方法验证”(PA/PH/OMCL (05) 47 DEF)
2. OMCL Guideline“Uncertainty of Measurement Part 1 - General OMCL Policy for Implementation ofMeasurement Uncertainty in Compliance Testing” (PA/PH/OMCL (05) 49 DEF CORR).
2. OMCL指南“测量不确定度第一部分—在符合性测试中实施测量不确定度时通用的OMCL原则”(PA/PH/OMCL (05) 49 DEF CORR)
3. FDA “Guidancefor Industry - Investigating Out-of-Specification (OOS) Test Results forPharmaceutical Production”
3. FDA“行业指南---药品生产中的检验结果OOS调查”
4. EN ISO/IEC 17025General Requirements for the Competence of Testing and Calibration Laboratories
4. EN ISO/IEC 17025 检测和校正实验室资质符合性通用要求
8. ANNEXES 附录
The annexes ofthis Guideline contain several examples of approaches to failure investigationand the re-test programme. Other approaches are possible if their scientificrationale is documented and the basic principles of this core document arefollowed.
本指南的附录包括几个失败调查方法的例子和复验程序。其它科学合理的方法也可以使用，仍需要记录下其科学合理性并遵守核心文件中的基本原则。
I FAILUREINVESTIGATION OF INITIAL OOS RESULTS 初始OOS结果的失败调查
I A ModelTemplate for failure investigation of OOS results
OOS结果失败调查模板样例
I B FDA“Guidance for Industry - Investigating Out-of-Specification (OOS) Test Resultsfor Pharmaceutical Production” chapter III.B “Responsibilities of theLaboratory Supervisor” (Annex I.B, for consultation).
FDA“行业指南---药品生产中的检验结果OOS调查”第IIIB节“化验室主管的职责”（附录IB征求意见）
II EXAMPLES FORRE-TEST PROGRAMMES 复验程序举例
II A Re-testprogrammes for quantitative tests 定量测试复验程序
II B Calculatingtool for Annex II A – FOR INTERNAL USE ONLY; NOT INCLUDED IN THEPUBLISHED PACKAGE 附录IIA 的计算工具—仅供内部使用，不包括在公布的文件包中
II C Re-testprogrammes for qualitative tests 定性测试复验程序
II D Specialconsiderations for animal testing 动物试验特殊考量
[1] The term“medicinal product” follows the definition of Directive 2004/27/EC, as amended.
[2] The use of therelative standard deviation as a global estimation of uncertainty is asimplified approach and, when necessary, the OMCL should take into accountother relevant sources of uncertainty, such as calibration andrecovery.
使用RSD是全球性的简化不确定度估计方法，必要时，OMCL应考虑其它相关的不确定度来源，例如校正或回收率。
[3] An average canprovide more information about the true value of a product than an individualtest result, but it can also hide variability among individual test results.
一个平均值可以提供比单个检测结果更多的药品真值的信息，但它也可能会隐藏了单个检测结果之间的波动性。
[4] Annex I.A givesan example of a template for use in the failure investigation of OOS results.
附录IA给出一个表格样例，用于OOS结果失败调查。
[5] Annex I.B, FDA"Guidance for Industry - Investigating Out-of-Specification (OOS) TestResults for Pharmaceutical Production” chapter III.B “Responsibilities of theLaboratory Supervisor” gives information concerning the steps taken as part ofthe supervisor’s assessment.
附录IB，FDA“行业指南---药品生产中的检测结果OOS调查”第IIIB节“实验室主管职责”，提供作为主管评估职责部分。
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