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1、产品质量回顾Product Quality ReviewAugust 2013本次研讨的目的是：1. 什么是产品质量回顾？What is a Product Quality Review?2. 有哪些法规要求？What is the official requirements？3. 应该包括哪些数据和信息？What data and information are necessary?4. 如何来组织和实施回顾？What is the best way to organise the reviews?5. 可以产生哪些结果和影响？What are the possible consequenc
2、es of the reviews?产品质量回顾的定义和意义产品质量回顾的定义产品质量回顾：是指企业针对一系列的生产和质量相关数据的回顾分析，以评价产品生产工艺的一致性，及相关物料和产品质量标准的适用性，以对其趋势进行识别并对不良趋势进行控制，从而确保产品工艺稳定可靠，符合质量标准的要求，并为持续改进产品质量提供依据。 美国CFR： Annual Product Review (APR) 欧盟GMP： Product Quality Review (PQR)产品质量回顾的意义产品质量回顾是质量保证体系的基本要素之一，可以视为持续改善的一部分。它的实施有利于： 降低投诉、退货和召回的风险redu
3、cing the risk of complaints, returns and product recalls 降低检验不合格的风险reducing the risk of OOS (out of specification) results 防止差错带来的损失preventing errors and the resulting costs 提高生产力increasing productivity 扩展校准和维护周期extending calibration and maintenance intervals产品质量回顾的意义产品质量回顾是质量保证体系的基本要素之一，可以视为持续改善的一部
4、分。它的实施有利于： 促进生产、工程、QC、QA和法规部门间的沟通improving communication between Production, Engineering, Quality Control, Quality Assurance, Regulatory Affairs 检查验证状态checking the validation status 升级限度和要求（例如，产率限度）updating limits and requirements (e.g. yield limits) 及时检查法规一致性和供应链符合性checking the conformity of the ma
5、rketing authorisation and the supply chain in good time产品质量回顾的意义产品质量回顾的目的不仅在于评价产品质量、工艺和系统，还可以从以下方面检查目前状态与注册申报时的一致性： 生产和检验要求manufacturing and testing requirements 原辅料、中间体和成品的质量标准specifications of starting materials, intermediate and finished products 已注册/备案的原辅料供应商registered manufacturers of starting
6、materials 已批准的委托生产或委托检验registered contract laboratories or contract manufacturers.确保产品质量和法规一致性产品质量回顾的法规要求中国GMP的要求我国的药品生产和质量管理规范（2010年修订）的第十章“质量控制与质量保证”中第八节“产品质量回顾分析”进行了针对性的要求。第二百六十六条第二百六十六条应当按照操作规程，每年对所有生产的药品按品种进行产品质量回顾分析，以确认工艺稳定可靠，以及原辅料、成品现行质量标准的适用性，及时发现不良趋势，确定产品及工艺改进的方向。应当考虑以往回顾分析的历史数据，还应当对产品质量回顾分
7、析的有效性进行自检。当有合理的科学依据时，可按照产品的剂型分类进行质量回顾，如固体制剂、液体制剂和无菌制剂等。回顾分析应当有报告。中国GMP的要求企业至少应当对下列情形进行回顾分析：（一）产品所用原辅料的所有变更，尤其是来自新供应商的原辅料；（二）关键中间控制点及成品的检验结果；（三）所有不符合质量标准的批次及其调查；（四）所有重大偏差及相关的调查、所采取的整改措施和预防措施的有效性；（五）生产工艺或检验方法等的所有变更；（六）已批准或备案的药品注册所有变更；（七）稳定性考察的结果及任何不良趋势；（八）所有因质量原因造成的退货、投诉、召回及调查；（九）与产品工艺或设备相关的纠正措施的执行情况和
8、效果；（十）新获批准和有变更的药品，按照注册要求上市后应当完成的工作情况；（十一）相关设备和设施，如空调净化系统、水系统、压缩空气等的确认状态；（十二）委托生产或检验的技术合同履行情况。中国GMP的要求第二百六十七条第二百六十七条应当对回顾分析的结果进行评估，提出是否需要采取纠正和预防措施或进行再确认或再验证的评估意见及理由，并及时、有效地完成整改。第二百六十八条第二百六十八条药品委托生产时，委托方和受托方之间应当有书面的技术协议，规定产品质量回顾分析中各方的责任，确保产品质量回顾分析按时进行并符合要求。欧美GMP的要求在1978年发布的cGMP - 21CFR 211.280(e)中，美国F
9、DA正式引人了产品质量回顾的要求，要求药品生产企业建立自己的流程，按照GMP的要求每年对产品有关的各种记录进行回顾，进而评价药品的质量标准。该项制度1979年正式开始执行。2001年8月，FDA采纳了ICH Q7A的API GMP指南，并将其作为工业界指南正式颁布。2005年10月，欧盟GMP指南中也采用了Q7A作为PartII中的指南要求。指南中的2.5 和12.6 中规定需要对原料开展产品质量回顾。 而在Part I的第一章“制药质量体系”中也对制剂的产品质量回顾进行了专门小节的要求，该章节在2013年1月刚刚修改。现在很多国家已经在相关GMP指南中包括了产品质量回顾的内容，要求企业对产品
10、质量相关的各种信息开展回顾，以确认产品生产的整个过程的可靠性，发现不良趋势应建立相关整改行动。相关法规要求对比要求中国GMPICH Q7AEU GMPUS GMP1Time interval时间间隔12 months12 months12 months12 months2Number of batches回顾批次All batchesunstatedAll batchesrepresentative selection3Starting and packaging material原辅包材o+o4In-process control data中间控制数据+(+)5Yields产量和收率(+)+
11、(+)6Release results成品(放行)结果+7OOS resultsOOS 结果+(+)+(+)8Deviations偏差+9Changes control变更+o相关法规要求对比要求中国GMPICH Q7AEU GMPUS GMP10Status of variations (requested changes)药政状态变更+11Stability test稳定性考察+(+)12Complaints, returns, product recalls投诉、退货和召回+13Status of CAPA actions纠正预防措施的状态+(+)14Status of post-mar
12、keting commitments上市后工作完成情况o+15Qualification status of equipment and facilities 验证状态+16Technical agreements技术协议+ 要求开展 called for；(+) 期望开展 expected；o 部分要求partly included； 暂未要求 not used相关法规要求对比：批次和分组除了对回顾项目的要求有所不同，中欧GMP的PQR和美国GMP的APR之间有两处明确的区别。回顾期间评估批次的要求不同。中欧要求评价所有批次，美国允许评价有代表性的批次，但是要求必须包括那些有变更和异常的批次
13、。A major distinction between PQR and APR lies in the number of batches to be evaluated within the evaluation period. Whereas in the case of PQRs all batches must be reviewed with regard to the specified aspects, 21 CFR 211.180(e) requires only a representative number of batches. However, it must be
14、ensured here that changes or anomalies be taken into account. Some examples of this are released, rejected or recalled batches, batches with deviations or unexplained anomalies and batches that were the subject of a field alert report.回顾报告是否分组的要求不同。美国要求必须按产品回顾，中欧允许按一定原则组合开展回顾，例如类似工艺的产品或者相同剂型的产品。Comb
15、ining requirements to form groups is not allowed for the APR, regardless of how similar the processes in question may be. In contrast, this sort of grouping together is possible for the PQR, but there must be good reason for doing so. For example, products with similar processes can be grouped toget
16、her for evaluation. Combining dosage forms may also be feasible. However, this depends on the number and complexity of products and processes. As the variability of products, specifications and process steps increases, it becomes more difficult to conduct an adequate specific evaluation.产品质量回顾的内容起始物
17、料和包装材料Starting materials and packaging materials.除了简单的统计汇总，关键项目应该进行趋势分析的评估。例如原辅料的粒度分布、原料的杂质、包材的技术参数等。Aside from simple statistical observation, critical aspects should be evaluated in trend analyses. For example, such aspects can include particle size distribution of starting materials (active subst
18、ances or excipients), impurity profiles of active substances or technical parameters of packaging materials. 本项回顾的目的是为了尽早查明那些可能影响产品质量的可能趋势。The objective of this evaluation is to pinpoint possible tendencies at an early date that could have an impact on product quality. 本项回顾的结果可以指明供应商资格确认的依据。GMP要求新供应
19、商应该事先得到调查评估，而对已有的变更进行评估对此是有帮助的。这些变更应该遵循变更控制程序事先进行对产品质量的影响评估（前瞻或回顾的方法）。Depending on the particular organisation, the results of this evaluation find entry into the system for supplier qualification or they can be drawn from it. The GMP Guide requires that new supply sources in particular be investiga
20、ted. This is useful for the evaluation of those changes that were made within the scope of the change control procedure with regard to their effect on product quality (prospective or retrospective). 起始物料和包装材料Starting materials and packaging materials.通过回顾可以将供应商资格确认与变更控制程序有意义得联系在一起。In this case, the
21、supplier qualification and change control systems are meaningfully linked together by the review. The importance of transparency and of monitoring the entire supply chain of active substances is underscored by the corresponding requirement in the revised version of Chapter 1 of the EU GMP Guide Part
22、 I (effective as of 31 January 2013). 对当前物料供用体系的变更或者偏差，可以开展目标/实际的比较评价，并评估相关风险。Changes in or deviations from the existing stages of the supply chain can be set down in a target/actual comparison and assessed with regard to their risk.必须检查确认是否接收到不合格批次。In this connection, there must be a check for whet
23、her batches or goods received had to be rejected. 还应该对原辅包材的供应商来源是否与注册和备案文件相一致进行检查。Furthermore, within the framework of the PQR a check must be made to determine whether supply sources for starting materials and packaging materials continue to conform to the authorisation documents.Ps. 中国GMP条款只要求原辅料、
24、未明确指明包括包材，但应该根据剂型特点、产品特性和公司要求予以考虑。中间控制和成品的检验结果Results of In-Process Controls, Yields and Finished Products在开展关键中间控制检查之前，必须要预先定义哪些控制点是关键的。这个关键控制点的识别与研发和工艺验证时的关键点识别是一致的。Before critical in-process controls are inspected, there must be an advance definition of which tests are to be considered critical.
25、It may be helpful to accept aspects for the PQR that are assessed as being critical within the framework of development and process validation. 识别关键和非关键可以有效地减少不必要的数据收集和分析活动。A lack of differentiation here between critical and non-critical could lead to far greater effort in collecting and analysing d
26、ata, without any gain in terms of content. 与仅评估成品数据相比，系统得分析关键工艺数据可以为评价工艺是否受控提供更加重要的信息。Systematically evaluating critical process data can provide important information on controlling the process and is superior to merely considering release data. 中间控制和成品的检验结果Results of In-Process Controls, Yields an
27、d Finished Products为评价注册资料的时效性，申报时的全部中控过程都应该被回顾，来评估是否需要对申报内容进行调整。In order to check topicality of the information in the authorisation documentation, the complete in-process controls on file should be included and evaluated, to allow for adjustments to the authorisation documents, 有时收率也可以作为中控点被考虑，随着生
28、产批次的不断增加，可以制定更合适的收率限度。if applicable. Yields can also be considered to be in-process controls. Yield limits can be set appropriately as the number of batches produced increases.Ps. 中国和欧盟GMP要求对关键中间控制数据和成品数据进行回顾，美国GMP没有明确对中间控制的回顾要求，但是同样期望企业开展这方面的回顾。不符合质量标准的批次Out-of-Specification (OOS) Batches回顾涵盖了全部批次，
29、应该把关注点放在相关OOS调查的罗列和评估上。At any rate, the report in the PQR has to include all batches. A crucial and central point here lies in listing and evaluating the relevant OOS investigations.调查的程度要与OOS的类型和发生频次相适应，尤其是有来自供应商确认、变更控制或者验证的数据时。For this purpose the types and frequency of failures are matched with t
30、he investigations. This has proved to be helpful, especially since information from other systems is linked in (e.g. supplier qualification, change control, qualification). 通过产品质量回顾，可以将原本独立分析调查的OOS放在分类环境中分析，从而得出进一步的结论。这也可以对已有的调查失败做出批判性质疑。In this way, evaluations of individual OOS results that may ha
31、ve been handled separately are put into a context that makes it possible to draw further conclusions. Furthermore, this provides the opportunity to critically question failure investigations that have already been made . 因为不同国家/地区的药政要求不尽相同，但是不论回顾是不是包括周期内的所有生产批次，全部的不合格批次需要被回顾评估是毋庸置疑的。Even though 21 C
32、FR 180(e) only stipulates that a representative number of rejected batches must be evaluated for the APR, in practice the FDA expects all batches to be presented that have results outside of specifications.偏差Deviations回顾期间生产批次的偏差应该被调查，法规明确要求回顾可以只限于重大偏差。基于的前提是未回顾的正式偏差都已经评估对质量没有影响。因此偏差管理体系中应该有适当的分级评估方
33、法，以便于非相关偏差可以被筛选掉。Deviations from batches manufactured during the evaluation period must be investigated for both reviews. For PQRs this is explicitly required only for significant deviations. This type of differentiation is also common for APRs. This is only reasonable as otherwise every formal devi
34、ation with no impact on product quality would have to be evaluated. Therefore, an appropriate classification system should be established in the deviation system, through which non-relevant deviations can be filtered out .偏差应该与调查和纠正预防措施一起被评估，基于偏差的类型和影响大小，评估的重点要放在根本原因的发现和纠正预防措施的合理性上。检查预防措施的有效性和实施进展是质
35、量管理体系的重要职能，也是质量回顾的一部分，关于有效性，可以通过重复性偏差的数量来评价。In the course of the review, the deviations are evaluated together with the investigations and the defined actions pertaining to them. Aside from the type of deviations and their impact, the focal point here lies above all in the root causes found and in t
36、he appropriate actions. Examining the effectiveness of the actions and the status of their implementation is a vital function of the quality management system and is therefore expected as part of the review. The effectiveness, for example, can be evaluated on the basis of the number of recurring dev
37、iations (repeated occurrence of the same deviation).变更Changes中国GMP使用可“所有变更”的字眼，但是如果变更控制系统有适当的分级评估方法的话，也可以考虑在产品质量回顾中只评估显著变更来降低数据量。The data quantities can be reduced by making the restriction that only significant changes have to be evaluated. Therefore, an appropriate classification system should be
38、established within the framework of the change control procedure.变更评估是还可以从各类文件的升级历史中获取信息。Aside from the evaluation of changes in terms of content, the review would benefit from the addition of a revision history of relevant documents, requirements and methods. In addition to manufacturing and testin
39、g procedures this revision history also includes changes to machine-aided processing programs (e.g. process controls, such as coating programs that are unique to a specific product). 在回顾中进行变更的影响评估时，不光要考虑单个变更的影响，更要评估相关变更在整体实施后产出的总体影响。When evaluating the impact of changes is it is imperative not only
40、to take the aspects of individual changes into consideration, but also the total implemented changes as a whole.Ps. 对工艺和分析方法的变更开展回顾是中欧GMP的明确要求，美国没有直接的法规要求，但也已是普遍做法。药政变更状态Status of Variations在产品质量回顾中，期望包括对产品的药政变更状的审核态。包括企业已经提交的、得到批准的、或者被拒绝的上市许可变更申请（如许可、再注册、补充申请、备案等等），也包括向第三国递交的仅用于出口的上市许可申请。In PQRs it
41、 is expected that the status of changes (variations) in the marketing authorisation procedure be included. Aside from changes that have been reported, requested or approved, these changes also include those concluded or rejected within the time period. This is also true for dossiers for third countr
42、ies (solely for export).稳定性考察Stability Tests稳定性考察的结果和任何不良趋势是中国和欧盟GMP中明确要求的质量回顾分析内容，同时FDA也期望企业将稳定性内容纳入回顾评价之中。The evaluation of results of stability studies is required for the PQR. This requirement is not specifically given in the CFR. However, since the FDA expects it, all results of studies and tes
43、ts should also be added to the evaluation made in the APR. 作为通用规则，应该使用数据和趋势分析来显示稳定性考察结论，且应与满足注册时的要求。As a general rule data and trend analyses should be used to show the extent to which stability statements contained in the current marketing authorisation can be upheld. 稳定性考察中的偏差和趋势可以作为变更和偏差的指标。通常需要通
44、过检查来确认全部的稳定性考察和研究（如持续稳定性考察）都开展了，并且得到应有的管理。Deviations and trends in the stability studies serve as indicators for planned or unknown changes and deviations. In general, a check is made to determine whether all required stability tests and studies (such as ongoing stability) have been established and/
45、or conducted.投诉、退货和召回Complaints, Returns and Product Recalls所有质量相关的投诉、退货和产品召回都应该被评估。Not only APRs, but also PQRs require that all quality-relevant complaints, returns and product recalls be evaluated. 回顾应该包括对纠正预防行动和实施状态的评估，并且有可能产出对产品质量的新观点（例如包装缺陷）。These include the appropriate investigations togethe
46、r with the defined actions and their status. Thus, it becomes possible to gain an additional, external perspective on the product quality, e.g. defective packaging.纠正措施状态Status of Corrective Actions评价范围应该包括之前回顾的纠正预防措施、以及所有的与产品、工艺或设备相关的未关闭的CAPA。对于预防措施的评价在之前的小节中已经多次提到，此处可以作为一个整体评价产品相关CAPA行动状态。In addit
47、ion to the requirements already described for presenting the status of corrective actions, for the PQR all actions of the previous review or all open actions relevant to products, processes or equipment must be evaluated. As a whole, this corresponds to the documentation of the product-relevant stat
48、us in the CAPA system. 无论在各国的法规中是否明确提出，CAPA的评估包含在产品质量回顾中都是普遍做法。There is no corresponding requirement for the APR. However, the description corresponds to common practice.上市后工作完成情况Status of Post-marketing Commitments本部分内容通常是针对新获批准或者有补充申请的药品。按照注册要求或者是批件上的特别要求，企业如有应该在产品上市后继续完成的工作，则应在产品质量回顾中总结工作的完成情况。这些
49、工作例如有：产品质量标准的继续研究、提交工艺验证和进一步稳定性考察的结果等等。The extent to which requirements, actions and obligations have been met as part of the authorisation (post-marketing commitments) must be determined in an evaluation within the scope of the PQR. For example, this can be done by giving the results of process val
50、idations and stability studies.验证状态Qualification Status评估的内容应该包括相关工艺设备和公用设施的确认状态。公用设施中空调通风系统、水系统和压缩空气系统都是必需的。Contrary to the APR, for the PQR an evaluation of the qualification status of relevant equipment and supply systems such as ventilation, water supply, or compressed air systems is required.实际