5培訓(xùn)_產(chǎn)品質(zhì)量回顧

1、產(chǎn)品質(zhì)量回顧Product Quality ReviewAugust 2013本次研討的目的是：什么是產(chǎn)品質(zhì)量回顧？What is a Product Quality Review?有哪些法規(guī)要求？What is the official requirements？應(yīng)該包括哪些數(shù)據(jù)和信息？What data and information are necessary?如何來組織和實(shí)施回顧？What is the best way to organise the reviews?可以產(chǎn)生哪些結(jié)果和影響？What are the possible consequences of the revie

2、ws?2產(chǎn)品質(zhì)量回顧的定義和意義13產(chǎn)品質(zhì)量回顧的定義產(chǎn)品質(zhì)量回顧：是指企業(yè)針對一系列的生產(chǎn)和質(zhì)量相關(guān)數(shù)據(jù)的回顧分析，以評(píng)價(jià)產(chǎn)品生產(chǎn)工藝的一致性，及相關(guān)物料和產(chǎn)品質(zhì)量標(biāo)準(zhǔn)的適用性，以對其趨勢進(jìn)行識(shí)別并對不良趨勢進(jìn)行控制，從而確保產(chǎn)品工藝穩(wěn)定可靠，符合質(zhì)量標(biāo)準(zhǔn)的要求，并為持續(xù)改進(jìn)產(chǎn)品質(zhì)量提供依據(jù)。美國CFR： Annual Product Review (APR)歐盟GMP： Product Quality Review (PQR)4產(chǎn)品質(zhì)量回顧的意義產(chǎn)品質(zhì)量回顧是質(zhì)量保證體系的基本要素之一，可以視為持續(xù)改善的一部分。它的實(shí)施有利于：降低投訴、退貨和召回的風(fēng)險(xiǎn)reducing the risk

3、of complaints, returns and product recalls降低檢驗(yàn)不合格的風(fēng)險(xiǎn)reducing the risk of OOS (out of specification) results防止差錯(cuò)帶來的損失preventing errors and the resulting costs提高生產(chǎn)力increasing productivity擴(kuò)展校準(zhǔn)和維護(hù)周期extending calibration and maintenance intervals5產(chǎn)品質(zhì)量回顧的意義產(chǎn)品質(zhì)量回顧是質(zhì)量保證體系的基本要素之一，可以視為持續(xù)改善的一部分。它的實(shí)施有利于：促進(jìn)生產(chǎn)、工程

4、、QC、QA和法規(guī)部門間的溝通improving communication between Production, Engineering, Quality Control, Quality Assurance, Regulatory Affairs檢查驗(yàn)證狀態(tài)checking the validation status升級(jí)限度和要求（例如，產(chǎn)率限度）updating limits and requirements (e.g. yield limits)及時(shí)檢查法規(guī)一致性和供應(yīng)鏈符合性checking the conformity of the marketing authorisation

5、 and the supply chain in good time6產(chǎn)品質(zhì)量回顧的意義產(chǎn)品質(zhì)量回顧的目的不僅在于評(píng)價(jià)產(chǎn)品質(zhì)量、工藝和系統(tǒng)，還可以從以下方面檢查目前狀態(tài)與注冊申報(bào)時(shí)的一致性：生產(chǎn)和檢驗(yàn)要求manufacturing and testing requirements原輔料、中間體和成品的質(zhì)量標(biāo)準(zhǔn)specifications of starting materials, intermediate and finished products已注冊/備案的原輔料供應(yīng)商registered manufacturers of starting materials已批準(zhǔn)的委托生產(chǎn)或委托檢驗(yàn)r

6、egistered contract laboratories or contract manufacturers.7確保產(chǎn)品質(zhì)量和法規(guī)一致性8產(chǎn)品質(zhì)量回顧的法規(guī)要求29中國GMP的要求我國的藥品生產(chǎn)和質(zhì)量管理規(guī)范（2010年修訂）的第十章“質(zhì)量控制與質(zhì)量保證”中第八節(jié)“產(chǎn)品質(zhì)量回顧分析”進(jìn)行了針對性的要求。第二百六十六條應(yīng)當(dāng)按照操作規(guī)程，每年對所有生產(chǎn)的藥品按品種進(jìn)行產(chǎn)品質(zhì)量回顧分析，以確認(rèn)工藝穩(wěn)定可靠，以及原輔料、成品現(xiàn)行質(zhì)量標(biāo)準(zhǔn)的適用性，及時(shí)發(fā)現(xiàn)不良趨勢，確定產(chǎn)品及工藝改進(jìn)的方向。應(yīng)當(dāng)考慮以往回顧分析的歷史數(shù)據(jù)，還應(yīng)當(dāng)對產(chǎn)品質(zhì)量回顧分析的有效性進(jìn)行自檢。當(dāng)有合理的科學(xué)依據(jù)時(shí)，可按照產(chǎn)品的

7、劑型分類進(jìn)行質(zhì)量回顧，如固體制劑、液體制劑和無菌制劑等?；仡櫡治鰬?yīng)當(dāng)有報(bào)告。10中國GMP的要求企業(yè)至少應(yīng)當(dāng)對下列情形進(jìn)行回顧分析：（一）產(chǎn)品所用原輔料的所有變更，尤其是來自新供應(yīng)商的原輔料；（二）關(guān)鍵中間控制點(diǎn)及成品的檢驗(yàn)結(jié)果；（三）所有不符合質(zhì)量標(biāo)準(zhǔn)的批次及其調(diào)查；（四）所有重大偏差及相關(guān)的調(diào)查、所采取的整改措施和預(yù)防措施的有效性；（五）生產(chǎn)工藝或檢驗(yàn)方法等的所有變更；（六）已批準(zhǔn)或備案的藥品注冊所有變更；（七）穩(wěn)定性考察的結(jié)果及任何不良趨勢；（八）所有因質(zhì)量原因造成的退貨、投訴、召回及調(diào)查；（九）與產(chǎn)品工藝或設(shè)備相關(guān)的糾正措施的執(zhí)行情況和效果；（十）新獲批準(zhǔn)和有變更的藥品，按照注冊要求上

8、市后應(yīng)當(dāng)完成的工作情況；（十一）相關(guān)設(shè)備和設(shè)施，如空調(diào)凈化系統(tǒng)、水系統(tǒng)、壓縮空氣等的確認(rèn)狀態(tài)；（十二）委托生產(chǎn)或檢驗(yàn)的技術(shù)合同履行情況。11中國GMP的要求第二百六十七條應(yīng)當(dāng)對回顧分析的結(jié)果進(jìn)行評(píng)估，提出是否需要采取糾正和預(yù)防措施或進(jìn)行再確認(rèn)或再驗(yàn)證的評(píng)估意見及理由，并及時(shí)、有效地完成整改。第二百六十八條藥品委托生產(chǎn)時(shí)，委托方和受托方之間應(yīng)當(dāng)有書面的技術(shù)協(xié)議，規(guī)定產(chǎn)品質(zhì)量回顧分析中各方的責(zé)任，確保產(chǎn)品質(zhì)量回顧分析按時(shí)進(jìn)行并符合要求。12歐美GMP的要求在1978年發(fā)布的cGMP - 21CFR 211.280(e)中，美國FDA正式引人了產(chǎn)品質(zhì)量回顧的要求，要求藥品生產(chǎn)企業(yè)建立自己的流程，按照

9、GMP的要求每年對產(chǎn)品有關(guān)的各種記錄進(jìn)行回顧，進(jìn)而評(píng)價(jià)藥品的質(zhì)量標(biāo)準(zhǔn)。該項(xiàng)制度1979年正式開始執(zhí)行。2001年8月，F(xiàn)DA采納了ICH Q7A的API GMP指南，并將其作為工業(yè)界指南正式頒布。2005年10月，歐盟GMP指南中也采用了Q7A作為PartII中的指南要求。指南中的2.5 和12.6 中規(guī)定需要對原料開展產(chǎn)品質(zhì)量回顧。 而在Part I的第一章“制藥質(zhì)量體系”中也對制劑的產(chǎn)品質(zhì)量回顧進(jìn)行了專門小節(jié)的要求，該章節(jié)在2013年1月剛剛修改?，F(xiàn)在很多國家已經(jīng)在相關(guān)GMP指南中包括了產(chǎn)品質(zhì)量回顧的內(nèi)容，要求企業(yè)對產(chǎn)品質(zhì)量相關(guān)的各種信息開展回顧，以確認(rèn)產(chǎn)品生產(chǎn)的整個(gè)過程的可靠性，發(fā)現(xiàn)不良

10、趨勢應(yīng)建立相關(guān)整改行動(dòng)。13相關(guān)法規(guī)要求對比要求中國GMPICH Q7AEU GMPUS GMP1Time interval時(shí)間間隔12 months12 months12 months12 months2Number of batches回顧批次All batchesunstatedAll batchesrepresentative selection3Starting and packaging material原輔包材o+o4In-process control data中間控制數(shù)據(jù)+(+)5Yields產(chǎn)量和收率(+)+(+)6Release results成品(放行)結(jié)果+7OOS

11、resultsOOS 結(jié)果+(+)+(+)8Deviations偏差+9Changes control變更+o14相關(guān)法規(guī)要求對比要求中國GMPICH Q7AEU GMPUS GMP10Status of variations (requested changes)藥政狀態(tài)變更+11Stability test穩(wěn)定性考察+(+)12Complaints, returns, product recalls投訴、退貨和召回+13Status of CAPA actions糾正預(yù)防措施的狀態(tài)+(+)14Status of post-marketing commitments上市后工作完成情況o+15

12、Qualification status of equipment and facilities 驗(yàn)證狀態(tài)+16Technical agreements技術(shù)協(xié)議+ 要求開展 called for；(+) 期望開展 expected；o 部分要求partly included； 暫未要求 not used15相關(guān)法規(guī)要求對比：批次和分組除了對回顧項(xiàng)目的要求有所不同，中歐GMP的PQR和美國GMP的APR之間有兩處明確的區(qū)別。回顧期間評(píng)估批次的要求不同。中歐要求評(píng)價(jià)所有批次，美國允許評(píng)價(jià)有代表性的批次，但是要求必須包括那些有變更和異常的批次。A major distinction between

13、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 ensured here that changes or

14、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.回顧報(bào)告是否分組的要求不同。美國要求必須按產(chǎn)品回顧，中歐允許按一定原則組合開展回顧，例如類似工藝的產(chǎn)品或者相同劑型的產(chǎn)品。Combining requirements to form gr

15、oups 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 together for evaluation. Combining

16、 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.16產(chǎn)品質(zhì)量回顧的內(nèi)容317起始物料和包裝材料Starting materials

17、 and packaging materials.除了簡單的統(tǒng)計(jì)匯總，關(guān)鍵項(xiàng)目應(yīng)該進(jìn)行趨勢分析的評(píng)估。例如原輔料的粒度分布、原料的雜質(zhì)、包材的技術(shù)參數(shù)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 substances or excipients), im

18、purity profiles of active substances or technical parameters of packaging materials. 本項(xiàng)回顧的目的是為了盡早查明那些可能影響產(chǎn)品質(zhì)量的可能趨勢。The objective of this evaluation is to pinpoint possible tendencies at an early date that could have an impact on product quality. 本項(xiàng)回顧的結(jié)果可以指明供應(yīng)商資格確認(rèn)的依據(jù)。GMP要求新供應(yīng)商應(yīng)該事先得到調(diào)查評(píng)估，而對已有的變更進(jìn)行評(píng)估對

19、此是有幫助的。這些變更應(yīng)該遵循變更控制程序事先進(jìn)行對產(chǎn)品質(zhì)量的影響評(píng)估（前瞻或回顧的方法）。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 investigated. This is useful for

20、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). 18起始物料和包裝材料Starting materials and packaging materials.通過回顧可以將供應(yīng)商資格確認(rèn)與變更控制程序有意義得聯(lián)系在一起。In this case, the supplier qualification

21、 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 I (effective as of 31

22、 January 2013). 對當(dāng)前物料供用體系的變更或者偏差，可以開展目標(biāo)/實(shí)際的比較評(píng)價(jià)，并評(píng)估相關(guān)風(fēng)險(xiǎn)。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.必須檢查確認(rèn)是否接收到不合格批次。In this connection, there must be a check for whether batches or goods r

23、eceived had to be rejected. 還應(yīng)該對原輔包材的供應(yīng)商來源是否與注冊和備案文件相一致進(jìn)行檢查。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. 中國GMP條款只要求原輔料、未明確指明包括包材，但應(yīng)該根據(jù)劑型特點(diǎn)、產(chǎn)品

24、特性和公司要求予以考慮。19中間控制和成品的檢驗(yàn)結(jié)果Results of In-Process Controls, Yields and Finished Products在開展關(guān)鍵中間控制檢查之前，必須要預(yù)先定義哪些控制點(diǎn)是關(guān)鍵的。這個(gè)關(guān)鍵控制點(diǎn)的識(shí)別與研發(fā)和工藝驗(yàn)證時(shí)的關(guān)鍵點(diǎn)識(shí)別是一致的。Before critical in-process controls are inspected, there must be an advance definition of which tests are to be considered critical. It may be helpful to

25、 accept aspects for the PQR that are assessed as being critical within the framework of development and process validation. 識(shí)別關(guān)鍵和非關(guān)鍵可以有效地減少不必要的數(shù)據(jù)收集和分析活動(dòng)。A lack of differentiation here between critical and non-critical could lead to far greater effort in collecting and analysing data, without any gai

26、n in terms of content. 與僅評(píng)估成品數(shù)據(jù)相比，系統(tǒng)得分析關(guān)鍵工藝數(shù)據(jù)可以為評(píng)價(jià)工藝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. 20中間控制和成品的檢驗(yàn)結(jié)果Results of In-Process Controls, Yields and Finished Product

27、s為評(píng)價(jià)注冊資料的時(shí)效性，申報(bào)時(shí)的全部中控過程都應(yīng)該被回顧，來評(píng)估是否需要對申報(bào)內(nèi)容進(jìn)行調(diào)整。In order to check topicality of the information in the authorisation documentation, the complete in-process controls on be included and evaluated, to allow for adjustments to the authorisation documents, 有時(shí)收率也可以作為中控點(diǎn)被考慮，隨著生產(chǎn)批次的不斷增加，可以制定更合適的收率限度。if appli

28、cable. Yields can also be considered to be in-process controls. Yield limits can be set appropriately as the number of batches produced increases.Ps. 中國和歐盟GMP要求對關(guān)鍵中間控制數(shù)據(jù)和成品數(shù)據(jù)進(jìn)行回顧，美國GMP沒有明確對中間控制的回顧要求，但是同樣期望企業(yè)開展這方面的回顧。21不符合質(zhì)量標(biāo)準(zhǔn)的批次Out-of-Specification (OOS) Batches回顧涵蓋了全部批次，應(yīng)該把關(guān)注點(diǎn)放在相關(guān)OOS調(diào)查的羅列和評(píng)估上。At an

29、y 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.調(diào)查的程度要與OOS的類型和發(fā)生頻次相適應(yīng)，尤其是有來自供應(yīng)商確認(rèn)、變更控制或者驗(yàn)證的數(shù)據(jù)時(shí)。For this purpose the types and frequency of failures are matched with the investigations. This has

30、proved to be helpful, especially since information from other systems is linked in (e.g. supplier qualification, change control, qualification). 通過產(chǎn)品質(zhì)量回顧，可以將原本獨(dú)立分析調(diào)查的OOS放在分類環(huán)境中分析，從而得出進(jìn)一步的結(jié)論。這也可以對已有的調(diào)查失敗做出批判性質(zhì)疑。In this way, evaluations of individual OOS results that may have been handled separately a

31、re 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?yàn)椴煌瑖?地區(qū)的藥政要求不盡相同，但是不論回顧是不是包括周期內(nèi)的所有生產(chǎn)批次，全部的不合格批次需要被回顧評(píng)估是毋庸置疑的。Even though 21 CFR 180(e) only stipulates th

32、at 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.22偏差Deviations回顧期間生產(chǎn)批次的偏差應(yīng)該被調(diào)查，法規(guī)明確要求回顧可以只限于重大偏差?；诘那疤崾俏椿仡櫟恼狡疃家呀?jīng)評(píng)估對質(zhì)量沒有影響。因此偏差管理體系中應(yīng)該有適當(dāng)?shù)姆旨?jí)評(píng)估方法，以便于非相關(guān)偏差可以被篩選掉。Deviation

33、s 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 deviation with no impact on pr

34、oduct 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 .偏差應(yīng)該與調(diào)查和糾正預(yù)防措施一起被評(píng)估，基于偏差的類型和影響大小，評(píng)估的重點(diǎn)要放在根本原因的發(fā)現(xiàn)和糾正預(yù)防措施的合理性上。檢查預(yù)防措施的有效性和實(shí)施進(jìn)展是質(zhì)量管理體系的重要職能，也是質(zhì)量回顧的一部分，關(guān)于有效

35、性，可以通過重復(fù)性偏差的數(shù)量來評(píng)價(jià)。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 the appropriate actions. Ex

36、amining 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 deviations (repeated occurren

37、ce of the same deviation).23變更Changes中國GMP使用可“所有變更”的字眼，但是如果變更控制系統(tǒng)有適當(dāng)?shù)姆旨?jí)評(píng)估方法的話，也可以考慮在產(chǎn)品質(zhì)量回顧中只評(píng)估顯著變更來降低數(shù)據(jù)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 established within the f

38、ramework of the change control procedure.變更評(píng)估是還可以從各類文件的升級(jí)歷史中獲取信息。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 testing procedures this revisi

39、on history also includes changes to machine-aided processing programs (e.g. process controls, such as coating programs that are unique to a specific product). 在回顧中進(jìn)行變更的影響評(píng)估時(shí)，不光要考慮單個(gè)變更的影響，更要評(píng)估相關(guān)變更在整體實(shí)施后產(chǎn)出的總體影響。When evaluating the impact of changes is it is imperative not only to take the aspects of i

40、ndividual changes into consideration, but also the total implemented changes as a whole.Ps. 對工藝和分析方法的變更開展回顧是中歐GMP的明確要求，美國沒有直接的法規(guī)要求，但也已是普遍做法。24藥政變更狀態(tài)Status of Variations在產(chǎn)品質(zhì)量回顧中，期望包括對產(chǎn)品的藥政變更狀的審核態(tài)。包括企業(yè)已經(jīng)提交的、得到批準(zhǔn)的、或者被拒絕的上市許可變更申請（如許可、再注冊、補(bǔ)充申請、備案等等），也包括向第三國遞交的僅用于出口的上市許可申請。In PQRs it is expected that the

41、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 countries (solely for export

42、).25穩(wěn)定性考察Stability Tests穩(wěn)定性考察的結(jié)果和任何不良趨勢是中國和歐盟GMP中明確要求的質(zhì)量回顧分析內(nèi)容，同時(shí)FDA也期望企業(yè)將穩(wěn)定性內(nèi)容納入回顧評(píng)價(jià)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 tests should also be ad

43、ded to the evaluation made in the APR. 作為通用規(guī)則，應(yīng)該使用數(shù)據(jù)和趨勢分析來顯示穩(wěn)定性考察結(jié)論，且應(yīng)與滿足注冊時(shí)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. 穩(wěn)定性考察中的偏差和趨勢可以作為變更和偏差的指標(biāo)。通常需要通過檢查來確認(rèn)全部的穩(wěn)定性考察和研究（如持

44、續(xù)穩(wěn)定性考察）都開展了，并且得到應(yīng)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/or conducted.26投訴、退貨

45、和召回Complaints, Returns and Product Recalls所有質(zhì)量相關(guān)的投訴、退貨和產(chǎn)品召回都應(yīng)該被評(píng)估。Not only APRs, but also PQRs require that all quality-relevant complaints, returns and product recalls be evaluated. 回顧應(yīng)該包括對糾正預(yù)防行動(dòng)和實(shí)施狀態(tài)的評(píng)估，并且有可能產(chǎn)出對產(chǎn)品質(zhì)量的新觀點(diǎn)（例如包裝缺陷）。These include the appropriate investigations together with the defined

46、 actions and their status. Thus, it becomes possible to gain an additional, external perspective on the product quality, e.g. defective packaging.27糾正措施狀態(tài)Status of Corrective Actions評(píng)價(jià)范圍應(yīng)該包括之前回顧的糾正預(yù)防措施、以及所有的與產(chǎn)品、工藝或設(shè)備相關(guān)的未關(guān)閉的CAPA。對于預(yù)防措施的評(píng)價(jià)在之前的小節(jié)中已經(jīng)多次提到，此處可以作為一個(gè)整體評(píng)價(jià)產(chǎn)品相關(guān)CAPA行動(dòng)狀態(tài)。In addition to the requi

47、rements 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 status in the CAPA s

48、ystem. 無論在各國的法規(guī)中是否明確提出，CAPA的評(píng)估包含在產(chǎn)品質(zhì)量回顧中都是普遍做法。There is no corresponding requirement for the APR. However, the description corresponds to common practice.28上市后工作完成情況Status of Post-marketing Commitments本部分內(nèi)容通常是針對新獲批準(zhǔn)或者有補(bǔ)充申請的藥品。按照注冊要求或者是批件上的特別要求，企業(yè)如有應(yīng)該在產(chǎn)品上市后繼續(xù)完成的工作，則應(yīng)在產(chǎn)品質(zhì)量回顧中總結(jié)工作的完成情況。這些工作例如有：產(chǎn)品質(zhì)量標(biāo)準(zhǔn)的繼

49、續(xù)研究、提交工藝驗(yàn)證和進(jìn)一步穩(wěn)定性考察的結(jié)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 validations and s

50、tability studies.29驗(yàn)證狀態(tài)Qualification Status評(píng)估的內(nèi)容應(yīng)該包括相關(guān)工藝設(shè)備和公用設(shè)施的確認(rèn)狀態(tài)。公用設(shè)施中空調(diào)通風(fēng)系統(tǒng)、水系統(tǒng)和壓縮空氣系統(tǒng)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.實(shí)際的生產(chǎn)工藝和生產(chǎn)環(huán)境都需

51、要被評(píng)估，這也符合產(chǎn)品質(zhì)量回顧的整體評(píng)價(jià)觀點(diǎn)。 In this way the process environment is included in the evaluation in addition to the actual production process. This requirement is consistent with the concept of a holistic treatment.30委托技術(shù)合同Agreements on Responsibilities應(yīng)該對技術(shù)協(xié)議/合同進(jìn)行檢查，確保合同是最新的有效版本。For PQRs, agreements on de

52、limitation of responsibilities (technical agreements) must be checked to ensure that they are up to date. 技術(shù)協(xié)議首先涉及的是委托生產(chǎn)和委托檢驗(yàn)，從更廣的范圍來看，還有一些合同可以納入檢查的范疇。例如一些與質(zhì)量相關(guān)的外包服務(wù)，而不是針對某一產(chǎn)品的。如蟲害防治或者潔凈服準(zhǔn)備等等。This requirement refers primarily to contract manufacturing and contract testing. In broader surroundings ho

53、wever, additional contracts can be made the object of the check, e.g. contracts with service providers for performing quality-relevant functions not specific to a product, such as Pest Control or preparing cleanroom clothing. An evaluation of this nature is not expected for the APR.31評(píng)價(jià)和結(jié)論Evaluation

54、 and Results評(píng)估和結(jié)論是回顧的核心內(nèi)容，報(bào)告中必須要包括。The evaluation of results represents a core part of the review and must be included in both the APR and in the PQR. 利用數(shù)據(jù)和趨勢分析來前瞻性地評(píng)估他們在未來生產(chǎn)中的批次。Data and trends are assessed prospectively with regard to their risk for future batches.應(yīng)該制定糾正和預(yù)防措施并說明理由。如果有必要，這些措施可以例如是工

55、藝或分析方法的再驗(yàn)證、標(biāo)準(zhǔn)的修改等等，如果涉及到藥政的變更注冊，則也應(yīng)考慮在內(nèi)。Corrective and preventive actions are defined and explained, if necessary. Examples of such actions are the re-validation of processes or analytical methods or the adaptation of specifications; necessary changes in the authorisation must be taken into consider

56、ation where applicable. 行動(dòng)措施必須及時(shí)有效地完成。行動(dòng)措施的進(jìn)展?fàn)顟B(tài)和有效性應(yīng)該在下一年度被調(diào)查評(píng)估。The actions must be completed in a timely and effective manner. The status of the actions and their effectiveness for product quality shall be investigated in the following year. Again, this is where a connection to the CAPA system can

57、be found.32產(chǎn)品質(zhì)量回顧的工作流程433產(chǎn)品質(zhì)量回顧SOP企業(yè)應(yīng)制定程序文件來明確實(shí)施產(chǎn)品年度回顧的基本要求，SOP至少應(yīng)該規(guī)定：產(chǎn)品質(zhì)量回顧的目的 Purpose產(chǎn)品質(zhì)量回顧的職責(zé) Responsibilities產(chǎn)品質(zhì)量回顧的相關(guān)定義 Related Definitions產(chǎn)品質(zhì)量回顧的工作流程（包括計(jì)劃）Workflow （include Planning）產(chǎn)品質(zhì)量回顧的文件要求 Requirements for documentation委托生產(chǎn)和委托檢驗(yàn)的回顧要求 Contract manufacturing and analysis34目的 Purpose (示例)定期地

58、回顧產(chǎn)品質(zhì)量和記錄、生產(chǎn)文件的符合情況能夠保證：Formally reviewing product quality and compliance related records and manufacturing documentation at regular intervals is a mechanism to: 監(jiān)控工藝流程的執(zhí)行情況和產(chǎn)品質(zhì)量。Monitor process performance and product quality. 確認(rèn)產(chǎn)品和其相關(guān)的生產(chǎn)工藝維持驗(yàn)證狀態(tài)。Confirm the maintenance of the validated status of p

59、roducts and their associated manufacturing processes. 在產(chǎn)品生命周期內(nèi)發(fā)現(xiàn)產(chǎn)品和工藝過程的改進(jìn)點(diǎn)，以反映更新的產(chǎn)品信息并規(guī)避質(zhì)量風(fēng)險(xiǎn)。Identify product and manufacturing process improvements to reflect updated product knowledge and address quality risks for the product life-cycle. 35目的 Purpose (示例)定期地回顧產(chǎn)品質(zhì)量和記錄、生產(chǎn)文件的符合情況能夠保證：Formally review

60、ing product quality and compliance related records and manufacturing documentation at regular intervals is a mechanism to: 應(yīng)用定期產(chǎn)品回顧的流程會(huì)對產(chǎn)品、工藝和系統(tǒng)有更深入的理解，對工藝變更在產(chǎn)品質(zhì)量的潛在影響有更廣泛的評(píng)估。更新的產(chǎn)品信息將支持改善工藝流程和減少質(zhì)量缺陷事故.Application of this Periodic Product Review process will lead to a deeper understanding of the prod