EDQM-OMCL-检验结果的评价和报告.docx

PA/PH/OMCL(07)28 DEF CORR检验结果的评价和报告欧洲理事会OMCL网络QUALITY ASSURANCE DOCUMENT质量保证文件PA/PH/OMCL (07) 28 DEF CORREVALUATION AND REPORTING OF RESULTS检验结果的评价和报告Full document title and reference文件全名和索引号Evaluation and reporting of results PA/PH/OMCL (07) 28 DEF CORRDocument type 文件类型GuidelineLegislative basis 立法基础-Date of first adoption首次采用时间October 1999Date of original entry into force首次生效时间February 2000Date of entry into force of revised document修订版本生效时间December 2007Previous titles/other references曾用文件名/其它索引号This document replaces document PA/PH/OMCL (07) 28 DEFCustodian Organisation管理机构The present document was elaborated by the OMCL Network/EDQM of the Council of EuropeConcerned Network 相关网络GEONREPORTING OF RESULTS 结果的报告GUIDELINE FOR OMCLs OMCL指南1. SCOPE范围This guideline defines basic principles for evaluation and reporting of results of OMCL testing of industrially manufactured medicinal products1. The purpose of this OMCL testing is to determine compliance of the product with the specifications laid down in the Marketing Authorisation and other relevant regulations. The OMCL testing can be considered as a verification of the testing by the manufacturer who has declared the same product in compliance with the specifications.本指南说明了OMCL对工业化生产的药品进行检测的结果的评价和报告原则。OMCL检测的目的是确认产品是否符合上市许可中设定的质量标准和其它相关法规要求。OMCL检测可以认为是对申明其产品符合质量标准的生产商检测的一种验证，2. INTRODUCTION概述An Official Medicines Control Laboratory (OMCL) performs testing of medicines for human and veterinary use on behalf of the Competent Authority.官方药品化验室（OMCL）代表药监机构对人用和兽用药品进行检测。The testing by an OMCL is performed within the context of activities such as market surveillance studies (MSS), testing of centrally authorised products (CAP), testing of products with mutual recognised authorisation (MRP), official control authority batch release (OCABR) and pre-licensing evaluation. The OMCL should operate the testing in a quality system based on ISO 17025 to guarantee a sufficient level of confidence in the results. The results of the OMCL testing may have significant consequences for the products involved, especially if a sample is found to be out of specification. Measures taken by the Competent Authority may include recalls, batch rejection, thorough production investigations, refusing of marketing authorisation (in pre-licensing evaluation) and it should be noted that results obtained from the testing by OMCLs are communicated within the network and to all competent authorities.OMCL检测活动是在一定情况下进行的，如上市监管研究（MSS）、集中批准产品检测（CAP）、互认组织产品检测（MRP）、官方控制批准批次放行（OCABR）和批准前评估。OMCL应在基于ISO 17025的质量体系内开展检测活动，以保证结果的充分可信度。OMCL检测结果对受检产品可能产生重大后果，尤其是当产品被发现不符合质量标准时。药监当局采取的措施可以包括召回、批拒收、彻底的生产调查、拒绝上市许可申请（在批准前评估中），要注意的是OMCL检测所得的结果会在网络内及与所有药监当局进行交流。Therefore the OMCLs have to give careful consideration to the establishment of a test result and conclusions of conformity or non-conformity of a product.因此，OMCL必须要非常谨慎地对待其得到合格与不合格检测结果和结论的过程。This document is not necessarily applicable to testing of certain products at national level (such as herbals, extemporaneous preparations, illegal products, old registrations, etc), for which validation data are not available.本文件可能不适用于国家级别的特定产品的检测（例如草药、即用即配制剂、非法药品、老的注册药品等等），因为无法获得这些产品的验证数据。3. TEST RESULTS 检验结果Test results are to be obtained using validated methods. Guidance on validation of methods by OMCLs is provided in a separate document 1. All tests are to be performed by competent staff and all results are to be verified and authorised.检验结果应该是使用验证过的方法得到的。由OMCL发布的方法验证指南在一个单独的文件里【1】。所有检验均应由具备资质的员工进行，所有结果均应经过复核和授权。Uncertainty of measurement. Information on the precision and accuracy of the results are to be included in the validation report. Where relevant, appropriate controls for precision and accuracy are to be taken into consideration in the design of the assay.测试的不确定性 结果的精确度和准确度信息应包括在验证报告里。有些时候，含量检测设计时还需要考虑到对精确度和准确度的适当控制。For all quantitative measurements the uncertainty of the measurement should be considered in the result. This uncertainty can be expressed as one of the following:对于所有的定量测试，结果中应考虑测试的不确定度。不确定可以用下列方式来表示a. confidence limits with a defined probability (e.g. P=0.95), for a predefined number of tests.对指定的检测次数的可置信区间（例如P=0.95）b. standard deviation, which should not significantly exceed the standard deviation established in the method validation. 标准偏差，应该不明显大于方法验证所建立的标准偏差Concerning Ph Eur monographs, it should be noted that the Ph Eur states that no further tolerances are to be applied to the limits prescribed since they are based on data obtained in normal analytical practice and they take account of normal analytical error, of acceptable variations in manufacture and compounding and deterioration during storage to an extent considered acceptable. This also applies to preparations described in the Ph. Eur. 关于EP各论，要注意的是EP申明其所描述的限度没有更多的允差，因为它是基于正常分析情况下所获得的数据，已考虑到了常规分析误差，生产商的接受度差异，存贮期间会产生的可接受程度的化合和分解。这也适用于EP中的制剂各论。4. EVALUATION OF RESULTS结果的评估In MSS, CAP, MRP testing and OCABR, the OMCL test results should be assessed against specifications approved in the marketing authorisation and/or the Ph Eur monograph of the product concerned.在MSS, CAP, MRP检测和OCABR测试中，OMCL检测结果需要根据上市批准中的质量标准和/或欧洲药典各论中相关产品的质量标准进行评估。The OMCL should clearly define how, if applicable, averaging of results is performed and how these results are evaluated2. The analytical acceptance criteria, should comply with predefined criteria as described in the documents “OMCL Policy on the Estimation and Application of Uncertainty in Analytical Measurements”. For quantitative (physico-) chemical methods, the exact design with repeats of the testing and the evaluation of the results is often not described in the Marketing Authorisation.OMCL应该非常清楚地规定，如果可行的话，结果如何被平均，如何对这些结果进行评估。检验的可接受标准应符合文件中所描述的标准“OMCL准则：分析测试的不确定度的估计和应用”。对于定量化学方法，InAppendixIA, two examples of approaches are given which are elaborated for pharmacopoeial testing of active substances. An approach when testing the content of active substance in finished products is given in Appendix IB. Other approaches are possible if their scientific rationale is given.在附件IA中，给出了原料药药典方法检测的例子。在附件IB中，给出了检测方法用于检验制剂产品的原料药成分。如果具备科学合理性，那么也可以采用其它的方法。Out of specification result(OOS result). When a result does not comply with the specifications, the OMCL has to operate a standard procedure to establish whether this result is due to analytical error, the influence of variables unrelated to the product, or whether this result reflects the actual condition of the product tested. This procedure should be based on the following principle:不合格结果（OOS结果）如果一个结果不符合质量标准，OMCL需要启动标准程序，判定这个结果产生原因是否是检验错误，是否波动影响是否与产品有关，检验结果是否反映了真实的产品品质。该程序应基于以下原则：a. An appropriately competent supervisor has to conduct a documented investigation of any OOS result based on information provided by the staff who performed the test3. If this investigation reveals a technical reason for the suspect result, such as an analysts mistake, malfunctioning laboratory equipment, or inappropriate sample storage, the suspect assay is not valid and the result is rejected. The OMCL repeats the assay and only the result of the repeated assay is considered for evaluation.应由一个有资质的适当的主管基于进行检测的化验员提供的信息，对所有OOS结果进行调查并记录调查结果，如果调查显示该结果由于技术原因引起，例如化验员错误，实验室仪器功能失效，或样品存贮不当，则该可疑的含量结果应宣布无效并被舍弃。OMCL对含量进行重新检测，评估时仅考虑复测时的含量结果。b. The exact cause of an OOS result by the OMCL is often difficult to identify. After the initial investigation, the OMCL may decide to involve information from the manufacturer on the production and control of the suspect batch in the investigation.通常，OMCL的OOS结果确切原因很难找到。在进行了初步调查后，OMCL可以决定调查生产商的生产信息，并对调查中的可疑批次进行控制。If the OOS result cannot be explained, the OMCL has to perform a retest programme to confirm the OOS result. In such cases the numbers of replicates, operators, sampling procedure and method for evaluating results have to be predefined and documented.如果OOS结果可以被解释，OMCL需要进行复验程序以确认OOS结果。这种情况下，重复的次数、操作人员、取样程序和对结果进行评价的方法需要进行规定并记录。Depending on the type of activity, specific documents may be available defining the different steps of the investigation and actions to be undertaken in case that OOS results are obtained (e.g. in the CAP programme, see document “Testing of Centrally Authorised Products (CAPs). Handling of out of specifications (OOS) results”).根据活动的类型，当出现OOS结果时，可能需要不同文件来界定调查的不同阶段，和需要采取的措施（例如在CAP程序中，参见文件“集中批准产品（CAPs）的OOS结果处理”）。The retest programme and evaluation should be based on sound scientific judgement and may depend on the characteristics of the assay4. Unless invalidated, the initial OOS result is not rejected and it is included in the evaluation of the product. As a general principle re-testing should be limited and not used to “test a product into compliance”.复测和评估应基于科学合理的判断，可能取决于含量的不同特性。除非另有验证，否则初始OOS结果是不可以判定无效的，应包括在产品的评价中。作为一个通则，复测应受到限制，不可以“检测产品直到合格”。5. REPORTING OF RESULTS结果报告The OMCL should transfer the result and its assessment in a written report to the competent authority and, if applicable, to other OMCLs and the EDQM. The information given in the test report is to be based on the requirements given in ISO 17025 (Chapter 5.10) and shall include all the information requested by the competent authority and necessary for the interpretation of the test result. The report shall make reference to the method used (in-house / compendial / reference material where relevant). The results and the relevant specification shall be reported as the mean of a predetermined number of replicates, given with appropriate number of figures and, if applicable, the standard deviation.OMCL应将结果及其评价誊写为书面报告，交给药监机构，适用性，抄送给其它OMCL和EDQM。检测报告中的信息应基于ISO 17025（第5.10章）的要求，应包括药监当局所要求的信息，以及检测结果的必要说明。报告应指明所采用的检测方法（自建、药典、参考文献）。结果和相应的质量标准应报告为重复检测的结果平均值（根据检测数据的个数），适当时，还应报告标准偏差值。If a product does not comply with the specification, a critical evaluation based on the OMCL failure investigation procedure has to be given and, if applicable, information from the manufacturer. A recommendation to the competent authority for follow up activities may be included in the report.如果一批产品不符合质量标准，则应根据OMCL失败调查程序进行关键评价，适当时，还应该对生产商提供的信息进行评价。在报告中可以包括提供给药监机构的跟踪措施。However, in the case where specific procedures already exist for reporting of results (e.g. OCABR EC Administrative procedure for OCABR) these should be followed and any circulation of information to other agencies should respect the limits of confidentiality characteristic of that activity (e.g. EU specific networks versus general OMCL activities). The involved OMCLs and Competent Authorities should define in addition their internal procedures for storage and internal exchange of data and any follow up measures taking into account the recommendations noted above.但是，如果对于结果报告已有相关程序规定（例如OCABR-EC管理程序），则应服从相关规定，与其它机构之间的信息交流应遵守相关的保密要求（例如EU针对通用OMCL活动的指定网络）。相关的OMCL和药监当局应规定其内部数据存贮和内部数据交换程序，考虑上述建议，规定后续措施。APPENDIX IA 附件IAEVALUATION OF RESULTS ACTIVE SUBSTANCE TWO POSSIBLE APPROACHES结果评估原料药两种可能的方法This document is based on publications in Pharmeuropa Vol. 9, No. 1, 148-156 (1997) and Pharmeuropa Vol 11, No. 4, 571-577(1999)本文件基于欧洲药物卷9第1部分页148-156（1997），和欧洲药物卷11第4部分，571-577（1999）Two approaches based on two and three determinations are presented which may be applied by OMCLs when testing active substances. However, these examples are not intended to be all-inclusive and other valid approaches may be adopted for evaluation of the acceptability of test results. These proposals were tested against data sets obtained from proficiency tests and were shown to be satisfactory to take a decision.在检测原料药时，OMCL可以采用两种方法：2次检测和3次检测。两种方法描述如下。但是，这些例子并不是排他性的，其它有效的方法也可以用来评价检测结果的可接受性。这里的两种方法均由专业检测所获得的数据包进行了测试，证明其可以用于作出产品是否合格的决定。Approach 1 方法1Perform 2 determinations. If the RSD2 1 is smaller than the RSDmax permitted for 2 determinations (see Table 1), and the mean falls within the content limits, the sample passes. If either of the two conditions is not met, one further determination is performed. If the RSD3 of the 3 values meets the criterion and the mean of the 3 results falls within the content limits, the sample passes. This can be repeated up to a maximum of 6 determinations. The sample can only be rejected if the mean is outside the content limits and the criterion for the RSDn is met. If at any stage the RSDn is greater than the value listed in Table 2, further determinations are useless because it can be predicted that the RSD will not meet the criterion. Instead, the reason for the poor repeatability should be investigated. As a consequence the sample can neither be accepted nor rejected. Only if an error in the assay procedure has been shown to have occurred, the results are rejected and the assay is repeated. This approach is illustrated in Figure 1.进行2次检测，如果2次检测RSD小于2次检测的允许最大RSD值（见表1），且平均值在含量限度内，则样品合格。如果两个条件其中任意一个不满足，则应再加测一次。如果3次结果RSD值符合标准，且3次结果平均值在含量限度内，样品合格。这种方法可以一直重复直到得到6次检测结果。只有当平均值不在含量限度内，但RSD符合要求时，样品可以判定不合格。如果在任何一步RSD值大于表2中的值，则加测没有用，因为可以预见RSD是不会符合标准的。这时，应调查找出重复性差的原因。这时，对样品不能判断合格或不合格。只有在含量检测过程中发现错误，则应判定原检测结果无效，重新开始含量检测。本方法在图1中以流程图表示。Approach 2 方法2 Perform 3 determinations. If the RSD3 is smaller than the RSDmax permitted for 3 determinations (see Table 1), and the mean falls within the content limits, the sample is accepted. If either of the two conditions is not met, 3 further determinations are performed unless the RSD exceeds the value in Table 2 in which case further assays are useless. If the RSD6 of the 6 values is smaller than the RSDmax permitted for 6 determinations, and the mean of the 6 values falls within the content limits, the sample is accepted. The sample can only be rejected if the mean is outside the content limits and the criterion for the RSD is met. If the RSD is too large, the reason for the poor repeatability should be investigated and, in such circumstances, the sample can neither be accepted nor can it be rejected. Only if an error in the assay procedure has been shown to occur, the results are rejected and the assay is repeated. This approach is illustrated in Figure 2.进行3次检测，如果3次结果RSD值小于3次检测允许的最大RSD（参见表1），且平均值在含量限度内，则样品合格。如果两个条件中有一个不能满足，则再进行3次检测（如果RSD大于表2中的值，则进行更多次检测是没有用的）。如果6次结果的RSD值小于6次检测允许的最大RSD值，且6次检测平均值在含量限度范围内，则样品合格。仅当平均值在含量限度范围之外，且RSD符合要求的水平时判定样品不合格。如果RSD值太大，则应进行调查找出重复性差的原因，这时，样品不能判定是否合格。只有当含量检测被发现有错误时，结果判定无效，重新测定含量。该方法在图2中进行图示。APPENDIX IBEVALUATION OF RESULTS FINISHED PRODUCTS A POSSIBLE APPROACH结果评估制剂成品可能的方法An approach based on three determinations is presented which may be applied by OMCLs in testing the content of active substances in finished products. However, this example is not intended to be all-inclusive and other valid approaches may be used for evaluation of the acceptability of the test results 在检测制剂时，OMCL可以采用基于3次检测的方法。该方法描述如下。但是，本例并不是排他性的，其它有效的方法也可以用来评价检测结果的可接受性。For recently registered products with fully validated analytical methods information regarding repeatability and intermediate precision of the test method is supplied in the application file. The repeatability might be reported with different degrees of freedom depending on the experimental design. The minimum degrees of freedom is 5, as given in the ICH guideline.对于最近注册的产品，其检测方法关于重复性和中间精密度的验证信息在申请文件中提供。重复性可能根据实验设计的不同自由度进行报告。在ICH指南中给出的最小自由度为5。During the assessment process the performance characteristics of the quality control processes are evaluated versus the specification limits proposed by the manufacturer. When approved the results of the tests performed shall fall within the specification limits.在评估过程中，检测方法特性会与生产商提议的质量标准限度进行对照。批准时，检测结果应符合质量标准限度。When a product is to be tested at an OMCL the MAH file is consulted in order to find the suitable conditions for the test method and also to get information on its performance characteristics. The repeatability of the results obtained during testing can therefore be used as a quality indicator and checked versus the value in the dossier.如果由OMCL进行检测的产品，其MAH文件在进行审阅，则检测应证明其检测方法适用条件，同时获得检验方法表现情况的信息。检测过程中所得的结果的重复性可以用作质量指示，与申报文件中的数值进行对比检查。The observed standard deviation varies from occasion to occasion following a skewed distribution. To test whether standard deviations, or rather variances, are not significantly different, the quotient of two variances is calculated and compared with the critical F-value at a specified probability for the relevant degrees of freedom. In Table 3 to Table 6 the critical F-values at the 5% level have been used to calculate the maximum allowable standard deviations under the assumption that the observed repeatability is not significantly worse than that reported in the dossier.所得的标准偏差可能会受到不同影响。如果标准偏差和变动性都没有显著不同，则计算两个变异值的商，与对应的自由度下的指定可能性的关键F值比较。在表3至表6中，5%水平的关键F值用于计算允许最大标准偏差，前提是假设观察到的重复性未显著差于文件报告值。Approach 3 方法31. Find the RSD and the degrees of freedom for the repeatability in the dossier.计算RSD，文件中重复性的自由度2. Perform 3 determinations and obtain the results in % of label claim. Calculate the mean and the relative standard deviation.进行3次检测，得到标签所声称的百分比结果。计算平均值和RSD。3. Check in the relevant Table 3 to Table 6 in the present Appendix I if the obtained RSD for the repeatability is larger than the critical value given in the table corresponding to the reported value in the dossier or not.在附件I的表3至表6中查得文件中报告值和重复性对应的RSD值，比较实际RSD与表中值的大小。4. If the RSD is not larger than the table-value and the mean is within the acceptance range; sample passes.如果实际RSD小于或等于表中值，平均值在可接受范围内，样品合格。5. If the RSD is not larger than the table-value, but the mean is outside the acceptance range, perform 3 more determinations and calculate the mean and the standard deviation of the 6 determinations.如果实际RSD小