歐洲藥典CEP證書修訂更新規(guī)定指南中英對照版

1、date of implementation: 1 march 2010 introduction: the holder of a certificate of suitability shall inform the edqm of any change to the information in the certification dossier by sending an application form and all necessary documents demonstrating that the conditions laid down in the present guid

2、eline are met. classification of changes the changes have been classified in three categories (notification/minor/major) depending on the potential impact of the change on the quality of the final substance. these three categories are based on those (ia-iain/ib/ii) of the commission regulation (ec)

3、no 1234/2008 concerning the examination of variations to the terms of marketing authorisation for medicinal products for human use and veterinary medicinal products. any change not classified as a notification or a major change should be classified as a minor change except in the following cases whe

4、re a new application should be submitted: - addition of a new route of synthesis and/or a new manufacturing site where the specifications of the final substance are different from the one already approved - transfer to a new holder that is not the same legal entity as the approved one, where the tra

5、nsfer does not occur because of a merger or because the company is sold, and where the manufacturer does not take out the certificate of suitability in their own name. the changes related to ph. eur. monograph revisions or any other regulatory requirements are treated separately and generally initia

6、ted by the edqm. 執(zhí)行日期： 2010 年 3 月 1 日介紹：歐洲藥典適用性證書持有人必須向edqm 報告所有與申報文件有關(guān)的變更，申報時應(yīng)填寫申請表格和所有必要的資料，證明變更符合現(xiàn)行指南的規(guī)定。變更分類根據(jù)變更對最終產(chǎn)品可能產(chǎn)生的影響程度，變更分為三類（通知/微小 /重大） 。分類原則是根據(jù)ec 法規(guī) 1234/2008 (ia-iain/ib/ii)：ec 成員國審核人用和獸用制劑銷售許可證變更規(guī)定所有未劃為通知或者重大變更的變更都是微小變更，但以下情形必須按新證書申請辦理：- 增加新合成途徑或新生產(chǎn)場地，而且成品質(zhì)量標準發(fā)生變化。- 持有人轉(zhuǎn)讓，新持有人與現(xiàn)行法人不同

7、，這種轉(zhuǎn)讓不是公司合并、出售的結(jié)果，生產(chǎn)廠也沒有以自己名義獲取原有證書。歐洲藥典修訂或其它法規(guī)要求而產(chǎn)生的變更另論，通常由edqm 發(fā)起。documentation to be provided for any revision the documentation should consist of: - a cover letter - the application form, duly filled and listing all the changes applied for - a description of each change together with a justific

8、ation - data showing, when applicable, that the conditions have been met - update of the relevant section(s) of the dossier (presented in eu-ctd format). - the specific documents described below for each change and supporting the change - supportive information, including comparative data with the p

9、revious version of the dossier (in tabular format), showing the approved and the proposed section and highlighting the changes consequential changes should be identified and the relation between the changes should be described. each time batch data are needed: - they should be in accordance with the

10、 specifications of the current ph. eur. monograph and when relevant with the additional requirements included in the certificate of suitability - the manufacturing site, the manufacturing date and the size of the batches should be specified. - quantitative results should be presented numerically (i.

11、e. not in general terms such as “ complies” ) and with the appropriate number of decimal places. 需要申報的文件所有變更的申報文件必須包括以下內(nèi)容：- 附函- 申請表，列出申請的變更- 變更內(nèi)容并說明變更的合理性- 若適用的的話，表明符合條件的數(shù)據(jù)- 更新申報文件相關(guān)的章節(jié)（按eu-ctd 格式）- 下述各種變動所要求的具體文件- 支持性信息，包括與原版本的對比數(shù)據(jù)（以表格格式），表明原內(nèi)容及現(xiàn)內(nèi)容，強調(diào)變更應(yīng)該識別間接的變更，并描述變更之間的關(guān)系。所有變更都需要申報批分析數(shù)據(jù)：- 而且必須現(xiàn)行歐洲

12、藥典標準、以及cep 證書附加的有關(guān)要求。- 必須說明生產(chǎn)場地、生產(chǎn)日期和生產(chǎn)批量。- 應(yīng)以數(shù)字形式表示定量結(jié)果（即：不得籠統(tǒng)表達為“ 合格 ” 等） ，數(shù)位應(yīng)合理。the changes are presented in five sections: - notifications (n and t) - typical minor revisions for certificates of suitability for chemical purity and microbiological quality or for tse certificates of suitability -

13、major revisions (maj) - renewal - transfer of holdership editorial changes should not be submitted as separate variations but should be reported at the same time as changes concerning the respective part of the dossier. in any case, a declaration should be provided that the content of the concerned

14、part of the dossier has not been changed by the editorial changes (except for the change itself). 以下分五節(jié)討論各種變更情況：通知（ n 和 t）化學(xué)純度和微生物質(zhì)量的cep 證書或 tse 證書的典型微小變更重大變更（ maj ）更新證書持有人轉(zhuǎn)讓文字性變更不應(yīng)作為單獨的變更提交，但當文件相關(guān)部分變更時應(yīng)當同時報告。不管怎么樣， 應(yīng)該申明：除了變更本身之外， 文件相關(guān)部分的內(nèi)容沒有因文字性的變更而發(fā)生變更。notifications (in/an) notifications are split

15、 into immediate notifications and notifications with annual reporting. 1. immediate notifications (in): in1) change in the name and/or address of the certificate holder of the final substance (former n1) conditions: - the certificate holder shall remain the same legal entity (except where the compan

16、y is sold or in case of a merger). specific documentation: - a formal document from a relevant official body (e.g. chamber of commerce) in which the new name or the new address is mentioned - all updated declarations (annexes to the application form). 通知（ （in/an ）通知分為立即通知和年度報告的通知1. 立即通知in in1 原料藥證書持

17、有人名稱或地址變更（以前的 n1）條件：- 證書持有人法人地位不變（公司出讓或被兼并除外）。文件要求：- 官方出具（如：商會）的有關(guān)新名稱和新地址的正式文件- 所有更新的聲明（見申請表附錄）in2) change in the name and/or address of the manufacturing site for the final substance (former n2) conditions: - the location of the manufacturing site shall remain the same. specific documentation: - a

18、formal document from a relevant official body (e.g. chamber of commerce) in which the new name or the new address is mentioned - updated declarations of manufacture in accordance with the dossier and according to gmp rules and of willingness to be inspected. in2 原料藥生產(chǎn)場所名稱或地址變更（以前的n2）條件：生產(chǎn)場所具體位置應(yīng)保持不變

19、。文件要求：- 官方出具（如：商會）的有關(guān)新名稱和新地址的正式文件- 更新的聲明：按申報文件和gmp 法規(guī)組織生產(chǎn)及愿意接受檢查的聲明in3) deletion of any manufacturing site for the final substance (former n3) conditions: - the deletion should not be due to critical deficiencies concerning manufacturing. specific documentation: - the justification of the deletion.

20、in3 原料藥生產(chǎn)場地的取消（以前的n3）條件：取消不應(yīng)該是由于與生產(chǎn)有關(guān)的嚴重缺陷文件要求：證明取消的合理性。in4) change or addition of a manufacturer of a starting material or intermediate used in the manufacturing process of the final substance when the proposed manufacturer is part of the same group as the currently approved manufacturer conditions

21、: - the specifications and the route of synthesis (including in-process controls, methods of analysis of all materials used) of the concerned material are identical to those already approved - the final substance is not a biological substance or a sterile substance. specific documentation: - a decla

22、ration from the holder of the certificate of suitability that the specifications of the final substance are the same as those already approved - a declaration from the holder of the certificate of suitability that the synthetic route (or in case of herbal material, where appropriate, the method of p

23、reparation, geographical source and production), the specifications and the quality control procedures of the starting material or intermediate are the same as those already approved - a list of approved and proposed sites - batch analysis data (in a comparative tabular format) for at least two batc

24、hes (minimum pilot scale) of the final substance from the approved and proposed sites. in4 變更或增加原料藥生產(chǎn)工藝過程中所使用的起始物料或中間體生產(chǎn)廠家，新廠家與原廠家同屬一個集團條件- 相關(guān)物料的質(zhì)量標準和合成路線（包括中控、所有原料的分析方法）與已批準的相同- 原料藥不是生物制品或無菌制品文件要求：- cep 證書持有者申明原料藥的質(zhì)量標準與已批準的一致- cep 證書持有者申明起始物料或中間體的合成路線（或當原料為草藥時，其制備方法，地理來源和制造） 、質(zhì)量標準和檢測方法與已批準的一致- 新舊地址

25、的清單- 新舊地址至少兩批（至少為中試批次）原料藥的批分析數(shù)據(jù)（對比表格）。in5) change or addition of a manufacturing site/workshop for the final substance when the proposed manufacturer is part of the same group as the currently approved manufacturer conditions: - the specifications of the final substance (including in process control

26、s, methods of analysis of all materials), method of preparation (including batch size) and detailed route of synthesis are identical to those already approved - the final substance is not a biological substance or a sterile substance. specific documentation: - a declaration from the holder of the ce

27、rtificate of suitability that the synthetic route (or in case of herbal material, where appropriate the method of preparation, geographical source and production), quality control procedures and specifications of the final substance are the same as those already approved - a list of approved and pro

28、posed sites - batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot scale) of the final substance from the approved and proposed sites - updated declarations of manufacture in accordance with the dossier and according to gmp rules and of willingness to be insp

29、ected for the new site. in5 變更或增加原料藥的生產(chǎn)地址/車間，新廠家與原廠家同屬一個集團條件- 原料藥的質(zhì)量標準（包括中控、所有原料的分析方法）和制備方法（包括批量）及詳細的合成路線與已批準的相同- 原料藥不是生物制品或無菌制品文件要求：- cep 證書持有者申明原料藥的合成路線（或當原料為草藥時，其制備方法，地理來源和制造） 、質(zhì)量標準和檢測方法與已批準的一致-新舊地址的清單-新舊地址至少兩批（至少為中試批次）原料藥批分析數(shù)據(jù)（對比表格）- 更新的聲明：按申報文件和gmp 法規(guī)組織生產(chǎn)及愿意接受檢查的聲明in6) tightening of the specifi

30、cation limits for the final substance (former n8) conditions: - the change does not result from unexpected events arising during manufacture - any change should be within the range of currently approved limits - the test procedure remains the same, or changes in the test procedure are minor. specifi

31、c documentation: - comparative table of approved and proposed specifications. in6) 提高成品質(zhì)量標準（以前的n8）條件 : - 該變動不是生產(chǎn)過程的異常引起- 所有變動必須符合現(xiàn)行已經(jīng)批準的質(zhì)量標準范圍- 分析方法不變或微小變化文件要求- 變動前后質(zhì)量標準對照表in7) minor changes to a test procedure for the final substance. editorial changes to a method description annexed to a certifica

32、te of suitability (former n7) conditions: - appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure - there have been no changes of the total impurity limits; no new unq

33、ualified impurities are detected - the method of analysis should remain the same (e.g. a change in column length or temperature, but not a different type of column or method) - the test method is not a biological method, or a method using a biological reagent for a biological substance (does not inc

34、lude standard pharmacopoeial microbiological methods). specific documentation: - updated description of the method in a format to be appended to the certificate of suitability - amendment of the relevant section(s) of the dossier, including description of the analytical method, summary of validation

35、 data, - comparative validation results, or if justified comparative analysis results showing that the approved test and the proposed one are equivalent. in7) 成品檢驗方法微小變動。cep 證書規(guī)定方法的表述形式變動。（以前的n7）條件 : - 已按有關(guān)指南要求進行適當?shù)尿炞C研究，證明更新的檢驗方法至少等同于原方法- 總雜質(zhì)限度不變，未檢出新雜質(zhì)- 分析方法本身不變(如：柱長或柱溫改變，但柱子類別或方法不變); - 檢測方法不是生物方法或

36、生物產(chǎn)品使用生物試劑的方法（不包括藥典中標準的微生物方法）文件要求- 更新后的方法描述，表述應(yīng)符合cep 證書附件方法格式- 文件相關(guān)部分的修訂，包括分析方法的描述，驗證數(shù)據(jù)總結(jié)等- 驗證結(jié)果對比，或僅對比檢測結(jié)果表明新方法與原方法等同in8) addition of a specification parameter for the final substance conditions: - the change does not result from unexpected events arising during manufacture - any new test method do

37、es not concern a novel non-standard technique or a standard technique used in a novel way - the test method is not a biological method or a method using a biological reagent for a biological substance (does not include standard pharmacopoeia microbiological methods) - the change does not concern a g

38、enotoxic impurity specific documentation: - comparative table of approved and proposed specifications - details of any new analytical method and validation data, where relevant - batch analysis data on two production batches of the relevant substance for all specification parameters. in8) 增加原料藥標準的參數(shù)

39、條件- 該變動不是生產(chǎn)過程的異常引起- 任何新的檢測方法不涉及新的非標準技術(shù)或以新方式使用的標準技術(shù)- 檢測方法不是生物方法或生物產(chǎn)品使用生物試劑的方法（不包括藥典中標準的微生物方法）- 變更不涉及基因毒性雜質(zhì)文件要求- 變動前后質(zhì)量標準對照表- 若有，任何詳細的新的檢測方法和驗證數(shù)據(jù)- 包括相關(guān)原料藥所有規(guī)格參數(shù)的兩批正式生產(chǎn)的批檢驗數(shù)據(jù)in9) removal/reduction of the re-test period from the certificate of suitability / change to more restrictive storage conditions

40、(former n11) conditions: - the change should not be the result of unexpected events arising during manufacture or because of stability concerns specific documentation: - the justification of the removal/reduction of the re-test period in9 從 cep 證書上取消 /減少再檢驗日期/貯藏條件變?yōu)楦鼑栏瘢ㄒ郧暗膎11）條件：該變更不是生產(chǎn)過程的異常或穩(wěn)定性實驗出現(xiàn)

41、問題引起文件要求：說明取消/減少再檢驗日期的合理性in10) deletion of an approved change management protocol for design space submission conditions: - the deletion of the approved change management protocol is not a result of unexpected events or out of specification results during the implementation of the change (s) describ

42、ed in the protocol. specific documentation: - amendment of the relevant section(s) of the dossier in10 刪除已批準的用于設(shè)計空間提交的變更管理方案條件- 刪除已批準的變更管理方案不是由于異常結(jié)果，或在執(zhí)行該方案所描述的變更過程中引起的 oos 結(jié)果文件要求：- 修訂文件相關(guān)的部分2. notification with annual reporting (an): an1) change in the name and/or address of a manufacturer of a sta

43、rting material or intermediate used in the manufacture of the final substance conditions: - the location of the manufacturing site shall remain the same specific documentation: - updated list of manufacturers of starting material/intermediate 2. 年度報告的通知（ an）an1 原料藥生產(chǎn)工藝過程中所使用的起始物料或中間體廠家名稱和/或地址變更條件- 生

44、產(chǎn)地址的地理位置不變文件要求-更新的起始物料/中間體廠家清單an2) deletion of a manufacturer of a starting material/intermediate used in the manufacture of the final substance (former n4) conditions: - the deletion should not be due to critical deficiencies concerning manufacturing specific documentation: - the justification of t

45、he deletion - updated list of manufacturers of starting material/intermediate an2 取消原料藥生產(chǎn)工藝過程中所使用的中間體/起始物質(zhì)的生產(chǎn)廠家條件：取消不應(yīng)該是由于與生產(chǎn)有關(guān)的嚴重缺陷文件要求：-證明取消的合理性-更新的起始物料/中間體廠家清單an3) change in the code product/reference number and/or in the brand name of the final substance or any material used in its manufacture (

46、former n9)condition: - the change does not regard the quality of the final substance or the concerned material specific documentation: - approved and proposed code product / reference number / brand name an3 原料藥或生產(chǎn)過程使用的任一物料的產(chǎn)品代碼或索引號或商標名變更（以前的n9）條件 : - 變更與原料藥質(zhì)量或相關(guān)的物料質(zhì)量無關(guān)文件要求- 產(chǎn)品代碼、索引號、商標名新舊對照表an4) mi

47、nor change in the manufacturing process of the final substance (former r1) conditions: - the specifications of the final substance or intermediates are unchanged and there is no adverse change in qualitative and quantitative impurity profile - the synthetic route remains the same, i.e. intermediates

48、 remain the same and there are no new reagents, catalysts or solvents used in the process. in the case of herbal products, the geographical source and production of the herbal material remain unchanged - the final substance is not a biological substance. specific documentation: - batch analysis data

49、 (in comparative tabular format) of at least two batches (minimum pilot scale) manufactured according to the currently approved and proposed process. an4 原料藥生產(chǎn)工藝的微小變化（以前的r1）條件 : - 原料藥或中間體標準不變，并且定性、定量的雜質(zhì)概況均沒有不利的變化- 合成途徑未變，即：中間體不變，而且工藝中未用到新試劑、催化劑或溶劑。對于植物制劑產(chǎn)品，其地理來源及生產(chǎn)操作不變- 原料藥不是生物制品文件要求- 工藝變動前后至少兩個批號產(chǎn)品

50、的批分析數(shù)據(jù)(對比表格 ) (至少應(yīng)為中試批) an5) change in batch size of final substance or intermediate up to 10-fold compared to the original batch size (former n5) conditions: - any changes to the manufacturing methods are only those necessitated by scale-up, e.g. use of different-sized equipment - test results of a

51、t least two batches of the final substance complying with the approved specifications should be available for the proposed batch size - the substance is not a biological substance or a sterile substance - the change does not affect the reproducibility of the manufacturing process - the specification

52、s of the final substance/intermediates remain the same - the currently approved batch size was not approved via a notification specific documentation: - the batch numbers of the tested batches having the proposed batch size - approved and proposed batch size - updated description of the full process

53、 specifying the proposed batch size - a declaration from the certificate holder that the changes to the manufacturing methods are only those necessitated by scale-up, that the change does not adversely affect the reproducibility of the process, and that the specifications of the final substance/inte

54、rmediates remain the same. an5 成品或中間體批量變動，但不超過原批量10 倍（以前的n5）條件- 生產(chǎn)方法所有變動只與批量放大有關(guān)，如：使用不同大小的設(shè)備- 至少有符合已批準質(zhì)量標準的兩個成品批號檢驗結(jié)果（新批量）- 產(chǎn)品不是生物或無菌產(chǎn)品- 變更不影響生產(chǎn)工藝的重現(xiàn)性- 成品 /中間體質(zhì)量標準不變- 原批量不是經(jīng)過通知批準的文件要求- 新生產(chǎn)批號（新批量）- 原批準批量和新批量- 批量變動后，新的工藝描述- 證書持有者申明： -生產(chǎn)方法所有變動只與批量放大有關(guān)；變動不影響生產(chǎn)工藝的重現(xiàn)性；成品 /中間體質(zhì)量標準不變an6) change in batch siz

55、e of final substance or intermediate: downscaling (former n6) conditions: - any changes to the manufacturing methods are only those necessitated by the downscaling, e.g. use of different-sized equipment - test results of at least two batches of the final substance complying with the approved specifi

56、cations should be available for the proposed batch size - the substance is not a biological substance or a sterile substance - the change does not affect the reproducibility of the manufacturing process - the change should not be the result of unexpected events arising during manufacture or because

57、of stability concerns - the currently approved batch size was not approved via a notification. specific documentation: - the batch numbers of the tested batches having the proposed batch size - approved and proposed batch size - updated description of the full process specifying the proposed batch s

58、ize - a declaration from the certificate holder that the changes to the manufacturing methods are only those necessitated by downscaling, that the change does not adversely affect the reproducibility of the process, that it is not the result of unexpected events arising during manufacture or because

59、 of stability concerns and that the specifications of the final substance/intermediates remain the same. an6 成品或中間體批量變更：變?。ㄒ郧暗膎5）條件 : - 生產(chǎn)方法所有變動只與批量變小有關(guān)，如：使用不同大小的設(shè)備- 至少有符合已批準質(zhì)量標準的兩個成品批號檢驗結(jié)果（新批量）- 產(chǎn)品不是生物或無菌產(chǎn)品- 變更不影響生產(chǎn)工藝的重現(xiàn)性- 該變動原因不是生產(chǎn)過程的異?；蛴捎诜€(wěn)定性有關(guān)的問題引起的- 原批量不是經(jīng)過通知批準的文件要求- 新生產(chǎn)批號（新批量）- 原批準批量和新批量- 批量變動后

60、，新工藝的完整描述- 證書持有者申明： -生產(chǎn)方法所有變動只與批量變小有關(guān)；變動不影響生產(chǎn)工藝的重現(xiàn)性，不是生產(chǎn)過程的異?；蛴捎诜€(wěn)定性有關(guān)的問題引起的；成品/中間體質(zhì)量標準不變an7) addition of a new in-process test and limit applied during the manufacture of the final substance conditions: - the change does not result from unexpected events arising during manufacture - any new test met