龍年談之一：歐盟企業(yè)如何面對(duì)藥品標(biāo)準(zhǔn)變更

       雪隨流年花開(kāi)盡，茗香自然迎春風(fēng)。雖然撰寫(xiě)此文時(shí)，中國(guó)的北方還是白雪皚皚的樣子；但是作者堅(jiān)信，目前的困難和疑惑是暫時(shí)的，終將在春天來(lái)臨時(shí)會(huì)逐漸消融。

       關(guān)于中國(guó)企業(yè)如何應(yīng)對(duì)國(guó)家藥品標(biāo)準(zhǔn)變更帶來(lái)的挑戰(zhàn)，作者在《兔年談之十五-藥品標(biāo)準(zhǔn)管理辦法的尷尬》一文中論述了目前國(guó)內(nèi)關(guān)于藥品標(biāo)準(zhǔn)變更管理政策的模糊不清。這個(gè)問(wèn)題具有全球性質(zhì)，其他國(guó)家或者地區(qū)的制藥企業(yè)，也會(huì)遇到類(lèi)似問(wèn)題。本文就介紹一下歐盟制藥企業(yè)遇到類(lèi)似問(wèn)題的應(yīng)對(duì)方案。

       第一部分：EMA關(guān)于歐洲藥典實(shí)施的問(wèn)答

       2023年10月30日，EMA發(fā)布《Q & A on implementation of Ph.Eur. Medicinal Product Monographs》。

       1.Should a finished product for which a Ph.Eur. Medicinal Product Monograph (MPM) is official comply with the requirements of that Monograph

       如果歐洲藥典（縮寫(xiě)Ph.Eur.）收載了制劑的各論（MPM），是否這個(gè)制劑藥品應(yīng)該符合該各論的要求？

       In principle, finished products for which a Ph.Eur. Medicinal Product Monograph (MPM) is official should comply with the requirements described in the Monograph, unless otherwise prescribed in General Notices of the Ph.Eur.

       原則上，如果一種制劑藥品存在歐洲藥典的制劑各論（MPM）的官方版本，那么該制劑藥品應(yīng)符合各論中描述的要求，除非在歐洲藥典的凡例中另有規(guī)定。

       Different scenarios exist:

       存在如下的各類(lèi)特殊情形：

       In case the MPM is official before the medicinal product is approved, the finished product has to comply with the requirements described in the Monograph. In this case the applicants have possibility and time to take the MPM specifications and analytical methods into account when setting specifications and developing suitable analytical methods for the specific medicinal product.

       如果藥品制劑獲批前，藥品制劑各論（MPM）已經(jīng)獲得官方認(rèn)可，成品必須符合所述各論中描述的要求。在這種情況下，申請(qǐng)人在為特定藥品設(shè)置標(biāo)準(zhǔn)和開(kāi)發(fā)適當(dāng)?shù)姆治龇椒〞r(shí)，有可能性和工作時(shí)間考慮到MPM中收載的標(biāo)準(zhǔn)和分析方法。

       In case the medicinal product is approved before the MPM is developed, the MPM should have been developed to embrace the quality of all approved medicinal products. If this has not been the case and the finished product specification is wider than the range described in the MPM, this should be communicated to the NPA (National Pharmacopoeia Authority) and EDQM (European Directorate for the Quality of Medicines & HealthCare) to be considered for inclusion in a revised monograph.

       如果藥品在藥品制劑藥典各論制定之前獲得批準(zhǔn)，藥品制劑藥典各論應(yīng)該被制定，以涵蓋所有已批準(zhǔn)藥品的質(zhì)量。如果這種情況沒(méi)有發(fā)生，并且成品的標(biāo)準(zhǔn)范圍超出了藥品藥典各論中描述的范圍，應(yīng)該向國(guó)家藥典委員會(huì)和EDQM報(bào)告，以便考慮將其納入修訂的藥典。

       See also questions below for more details.

       參見(jiàn)下面問(wèn)題以獲得更多細(xì)節(jié)。

       2. How can the compliance with the Ph.Eur. monograph for a medicinal product be demonstrated during a MA procedure, when alternative methods are proposed in the MA dossier

       如何在MA申報(bào)資料中提出了替代方法時(shí)，在MA（上市申請(qǐng)）流程中證明藥品符合歐洲藥典各論對(duì)藥品的規(guī)定？

       In order to demonstrate compliance with the Ph. Eur. MPM, the applied finished product should be tested against the Ph. Eur. MPM using same analytical methods (except for dissolution, see Question 3 below).

       為了證明符合歐洲藥典關(guān)于藥品各論的要求，應(yīng)該使用相同的分析方法對(duì)所使用的成品進(jìn)行測(cè)試（除了溶出度測(cè)試，詳見(jiàn)第3個(gè)問(wèn)題）。

       It should be demonstrated whether the Ph. Eur. analytical methods are suitable for controlling the specific product in question (composition, manufacturing method and container closure system etc.). It should be demonstrated (preferably in CTD Module 3.2.P.5), whether the MPM actually controls the entire impurity profile of the finished product (i.e. all relevant impurities, degradation products, nitrosamines) or not.

       需要證明Ph. Eur. 的分析方法是否適用于特定產(chǎn)品的質(zhì)控要求（包括組分、制造方法和容器密封系統(tǒng)等）。最好在CTD模塊3.2.P.5中進(jìn)行證明，MPM是否實(shí)際控制了成品的整個(gè)雜質(zhì)譜（例如所有相關(guān)雜質(zhì)、降解產(chǎn)物和亞硝胺）。

       According to the General Notices of the Ph. Eur., alternative methods (i.e: in-house methods) may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official methods were used. The methods of analysis confirm compliance with corresponding Ph.Eur. criteria, if tested. (see also Question 4 and 5).

       根據(jù)《歐洲藥典》的凡例規(guī)定，可以使用替代方法（即內(nèi)部方法）進(jìn)行質(zhì)控目的，前提是所使用的方法能夠明確地判斷是否符合使用官方方法所可達(dá)到的藥典標(biāo)準(zhǔn)。如果采用替代分析方法測(cè)試，需要能夠證實(shí)符合相應(yīng)的《歐洲藥典》標(biāo)準(zhǔn)。（參見(jiàn)問(wèn)題4和問(wèn)題5）

       “It is acknowledged that additional controls may be required to monitor degradation products other than those controlled by the monograph (e.g. degradation products related to different excipients or containers used, or from a different manufacturing process).” (Ph. Eur. General Notices 1.5.3.1.)

       需要認(rèn)識(shí)到除了藥典所控制的降解產(chǎn)物項(xiàng)目之外，可能需要額外的控制措施來(lái)監(jiān)測(cè)與不同輔料、容器或制造工藝相關(guān)的降解產(chǎn)物。（Ph. Eur.凡例1.5.3.1.）

       3. Is it necessary to demonstrate the compliance with the dissolution test and requirements recommended in the Ph.Eur. MPM

       是否需要證明符合歐洲藥典中收載的藥典各論中建議的溶出度測(cè)試和要求？

       Test and requirements for dissolution in MPMs are minimum requirements and not mandatory per se (see Ph. Eur. General Notices). For dissolution test, the specification should be derived from the dissolution results of the bio batch(es) in the individual marketing authorization procedure and the dissolution method should be discriminatory for the specific product (manufacturing process/product formulation).

       藥典各論（MPMs）中的溶出度測(cè)試和要求是最低要求，不是強(qiáng)制要求（詳見(jiàn)歐洲藥典的凡例）。對(duì)于溶出度測(cè)試，標(biāo)準(zhǔn)應(yīng)該基于個(gè)別上市許可程序中生物研究批次中的溶出結(jié)果，并且溶出方法應(yīng)該對(duì)特定產(chǎn)品（生產(chǎn)工藝/產(chǎn)品配方）具有區(qū)分性。

       Broadening the Q-value can only be justified by in-vivo data. It is important to note that the dissolution test described in the respective Ph. Eur. Medicinal Product Monographs can only be used if the applicant has demonstrated the suitability (including discriminatory power) of the test for the given product to the satisfaction of the competent authority. In any case, the dissolution test proposed should be approved by the competent authority in the context of the marketing authorization procedure.

       將Q值放寬范圍只能通過(guò)體內(nèi)數(shù)據(jù)證明合理性。需注意，在歐洲藥典藥品各自各論中描述的溶解度測(cè)試只有在申請(qǐng)人向主管機(jī)構(gòu)證明該測(cè)試適用于給定產(chǎn)品（包括區(qū)分能力）后才能使用。無(wú)論如何，所提議的溶解度測(cè)試都需在上市許可程序的背景下獲得主管機(jī)構(gòu)的批準(zhǔn)。

       Demonstration of compliance with the monograph dissolution test is not required as part of a MAA or MAV. However, when tested, the medicinal product has to comply with the monograph dissolution test, unless otherwise justified by the applicant.

       證明符合藥典各論的溶出度測(cè)試不是上市申請(qǐng)（MAA）或上市許可變更（MAV）的一部分要求。然而，一旦進(jìn)行了測(cè)試，除非申請(qǐng)人提出了合理的理由，否則藥品必須符合藥典各論的溶出度測(cè)試的要求。

       Further guidance on the dissolution test can be found in the Ph. Eur. General Notices (1.5.3.2).

       有關(guān)溶出度試驗(yàn)的進(jìn)一步指導(dǎo)可以在歐洲藥典凡例（1.5.3.2）中找到。

       4. Should the already approved in-house specification be changed to the one described in the MPM

       是否應(yīng)該將已經(jīng)批準(zhǔn)的內(nèi)部標(biāo)準(zhǔn)變更為MPM中描述的標(biāo)準(zhǔn)嗎？

       For medicinal products already on the market with a valid marketing authorization licence, in case the approved shelf life specification limits are in line with or stricter than the Medicinal Product monograph there is no need to change the specification(s) limits and methods.

       對(duì)于已經(jīng)在市場(chǎng)上獲得有效上市許可證的藥品，如果批準(zhǔn)的有效期標(biāo)準(zhǔn)限度與藥品專(zhuān)論要求一致或更為嚴(yán)格，就無(wú)需改變標(biāo)準(zhǔn)限度和方法。

       Alternative methods (i.e: the already approved in-house methods) may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official methods were used. The methods of analysis confirm compliance with corresponding Ph.Eur. criteria, if-tested.

       可以使用替代方法（即：已經(jīng)批準(zhǔn)的內(nèi)部方法）來(lái)進(jìn)行控制，前提是使用的方法能夠明確地判斷是否能夠達(dá)到采用官方方法實(shí)現(xiàn)的藥典各論標(biāo)準(zhǔn)的要求。如果使用替代方法，要證明符合相應(yīng)的歐洲藥典標(biāo)準(zhǔn)。

       If higher/wider limits than indicated in the Medicinal Product Monograph (limits compared using the same analytical method) have been approved for a product, and these are justified in line with current ICH/EU requirements and actual batch data, these should be communicated to the NPA and EDQM to be considered for inclusion in a revised monograph (see also Question 6 below).

       如果產(chǎn)品的批準(zhǔn)限度高于或?qū)捰谒幤匪幍涓髡撝兴镜南薅龋ㄊ褂孟嗤姆治龇椒ㄟM(jìn)行比較），并且滿足當(dāng)前ICH/EU的要求和實(shí)際批次數(shù)據(jù)的要求，應(yīng)將其通知給國(guó)家藥典委員會(huì)和EDQM，以便考慮將其納入修訂后的藥典各論（詳見(jiàn)下面的問(wèn)題6）。

       However, in case the higher/wider limits of the product are not fully justified by batch data, tightening the limits to the MPM’s requirements is needed by submission of a variation application.

       然而，如果產(chǎn)品的較高/較寬限度不能通過(guò)批次數(shù)據(jù)完全證明合理性，就需要通過(guò)提交變更申請(qǐng)將限度調(diào)整到藥品藥典各論（MPM）的要求水平。

       ‘It should be noted that the specification limit is specific for the respective analytical method and therefore, limits cannot be compared across different analytical methods’.

       應(yīng)該注意的是，標(biāo)準(zhǔn)限度是特定于各自的分析方法的，因此不能在不同的分析方法之間進(jìn)行比較。

       5. Should the in-house developed methods be changed to the methods described in the MPM

       公司內(nèi)部開(kāi)發(fā)的方法是否應(yīng)該變更為MPM中描述的方法？

       No. The product should comply with the requirements of the Medicinal Product Monograph (MPM) see Question 1, but it does not mean that it is mandatory for the manufacturer to use the monograph methods.

       不。產(chǎn)品應(yīng)符合藥品藥典各論的要求（參見(jiàn)問(wèn)題1），但這并不意味著制造商必須使用藥典各論的方法。

       According to the Ph. Eur. General Notices, alternative methods (i.e: in-house methods) may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official methods were used. The methods of analysis confirm compliance with corresponding Ph.Eur. criteria, if-tested.

       根據(jù)歐洲藥典的凡例，可以使用替代方法（即：內(nèi)部方法）進(jìn)行質(zhì)控目的，前提是所使用的方法能夠明確地判斷是否可以達(dá)到當(dāng)使用官方方法時(shí)所實(shí)現(xiàn)的各論標(biāo)準(zhǔn)的合規(guī)要求。如果采用替代方法，應(yīng)該證明分析方法在測(cè)試時(shí)確認(rèn)符合相應(yīng)的歐洲藥典標(biāo)準(zhǔn)。

       According to the Ph. Eur. General Notice, alternative methods can be used:

       根據(jù)歐洲藥典凡例，替代方法可以使用：

       “1.1.2.5. Alternative methods. The tests and assays described are the official methods upon which the standards of the Pharmacopoeia are based. With the agreement of the competent authority, alternative methods of analysis may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official methods were used. In the event of doubt or dispute, the methods of analysis of the Pharmacopoeia are alone authoritative.” (General Notices of Ph.Eur.)

       歐洲藥典凡例1.1.2.5.替代方法：

       所描述的測(cè)試和分析方法是藥典標(biāo)準(zhǔn)所依據(jù)的官方方法。在有關(guān)部門(mén)的同意下，可以使用替代的分析方法進(jìn)行質(zhì)量控制，前提是這些方法能夠明確判斷如果使用官方方法是否符合藥典標(biāo)準(zhǔn)。在存在疑問(wèn)或爭(zhēng)議的情況下，藥典的分析方法是唯一的權(quán)威。

       For dissolution testing see Question 3 above.

       對(duì)于溶出度測(cè)試，參見(jiàn)上面的問(wèn)題3.

       6. Is it possible to authorize a finished product with wider limits than those laid down in the MPM

       當(dāng)一個(gè)藥品的限度比藥典各論上的限度更寬，是否可以被批準(zhǔn)？

       A medicinal product with wider limits than those laid down in the monograph could be authorized only in very exceptional cases.

       只有非常少見(jiàn)的情況下，當(dāng)一個(gè)藥品標(biāo)準(zhǔn)限度比藥典各論限度更寬，才可以被批準(zhǔn)。

       In case the proposed wider limits than those laid down in the monograph (limits compared using the same analytical method) are appropriately justified by the applicant in line with current ICH/EU requirements (by respective preclinical/toxicological studies/references, proper development, excipients, packaging material, actual batch analysis and stability data etc.) the marketing authorisation could be granted.

       如果申請(qǐng)人能夠按照當(dāng)前ICH/EU的要求，通過(guò)相應(yīng)的臨床前/毒理學(xué)研究/參考資料、適當(dāng)?shù)拈_(kāi)發(fā)、輔料、包裝材料、實(shí)際批次分析和穩(wěn)定性數(shù)據(jù)等充分證明所建議的限度范圍比藥典規(guī)定的范圍更寬（使用相同的分析方法進(jìn)行比較），則可能獲得上市許可。

       According to the General Monograph on Pharmaceutical Preparations (2619) section “Related substances”: “In exceptional circumstances and if justified by the applicant to the satisfaction of the competent authority, the latter may approve a wider limit than that described in the monograph. In these rare cases, the competent authority shall bring this to the attention of the Ph. Eur. Commission for review of the monograph and, where appropriate, its revision”.

       根據(jù)歐洲藥典《藥用制劑通則》（2619）中“有關(guān)物質(zhì)”部分的規(guī)定：“在特殊情況下，如果申請(qǐng)人能夠向主管機(jī)關(guān)證明，并獲得其認(rèn)可，后者可以批準(zhǔn)比藥典各論中所述的更寬松的限度。在這些罕見(jiàn)情況下，主管機(jī)關(guān)應(yīng)將此事提交給歐洲藥典委員會(huì)審查各論，并在必要時(shí)進(jìn)行修訂。”

       7. Is it necessary to submit variation application in order to demonstrate compliance with the MPM

       為了證明符合歐洲藥典各論的要求，是否有必要提交變更申請(qǐng)？

       If no change is required, a variation application does not need to be submitted, but the supportive data (including suitability of the MPM methods) demonstrating compliance of the existing product with the MPM should be available at the manufacturing/control site. It should be kept in mind that the product should comply with the requirements of the MPM if tested (e.g. by an OMCL).

       如果不需要進(jìn)行任何變更，就無(wú)需提交變更申請(qǐng)，但應(yīng)該在生產(chǎn)/質(zhì)控現(xiàn)場(chǎng)準(zhǔn)備好支持性數(shù)據(jù)（包括符合MPM適用性評(píng)估的方法），以證明現(xiàn)有產(chǎn)品符合MPM的要求。需要注意的是，如果進(jìn)行測(cè)試（例如由OMCL進(jìn)行測(cè)試），產(chǎn)品應(yīng)符合MPM的要求。

       If any changes are needed, they should be submitted in line with the EC variation classification guideline.

       如果存在任何變更，應(yīng)該根據(jù)EC變更分類(lèi)指南提交變更。

       8. Which type of variation should be used for changing the specification and/or analytical methods to those described in the MPM

       應(yīng)采用哪種類(lèi)型的變更來(lái)將標(biāo)準(zhǔn)和/或分析方法變更為歐洲藥典各論（MPM）中描述的那些方法？

       The classification of the variation should correspond to the existing sub-categories of the EC Variation Classification Guideline in sections:

       藥品變更的分類(lèi)應(yīng)與歐洲委員會(huì)(EC)變更分類(lèi)指南中已有的子類(lèi)別相對(duì)應(yīng)。

       B.II.d.1 “Change in the specification parameters and/or limits of the finished product” or B.II.d.2 “Change in test procedure for the finished product”

       B.II.d.1變更制劑產(chǎn)品的標(biāo)準(zhǔn)參數(shù)和/或限度；

       B.II.d.2變更制劑產(chǎn)品的分析規(guī)程；

       According to CMDh Q&A (List for the submission of variations according to Commission Regulation (EC) 1234/2008) point 3.8.:

       根據(jù)CMDh問(wèn)答文件《List for the submission of variations according to Commission Regulation (EC) 1234/2008》的3.8點(diǎn)：

       Variation B.III.2 only relates to active substances, excipients, immediate packaging materials and active substance starting materials. Changes to comply with Ph.Eur. or with a national pharmacopoeia of a Member States affecting the finished product should be submitted according to the relevant variations listed under B.II. d.

       變更分類(lèi)B.III.2僅涉及活性物質(zhì)、輔料、內(nèi)包裝物料和活性物質(zhì)起始物料。為了符合歐洲藥典或成員國(guó)國(guó)家藥典的要求，并影響成品制劑的變更應(yīng)根據(jù)B.II. d下列出的相關(guān)變更進(jìn)行提交。

       9. Is it necessary to submit variation application if the approved shelf life limits are in line with or stricter than the MPM

       如果批準(zhǔn)的有效期限度符合或者更嚴(yán)于MPM的要求，是否有必要提交變更申請(qǐng)？

       No. In order to avoid the numerous unnecessary variation applications, it is not recommended to change the already approved specifications and/or the method in case the approved shelf-life limits are in line with or stricter than the MPM. The approved specification has already been evaluated and authorized according to EU/ICH guidelines and the obtained batch/stability data using validated analytical methods.

       不。為了避免大量不必要的變更申請(qǐng)，在已批準(zhǔn)的質(zhì)量標(biāo)準(zhǔn)和/或方法與藥典各論要求（MPM）相符或更嚴(yán)格的情況下，不建議進(jìn)行更改。已批準(zhǔn)的質(zhì)量標(biāo)準(zhǔn)已根據(jù)歐盟/ICH指南和使用經(jīng)過(guò)驗(yàn)證的分析方法獲得的批次/穩(wěn)定性數(shù)據(jù)進(jìn)行評(píng)估和授權(quán)，不需要再次評(píng)估。

       10. Is it possible to widen the specification limits to be the same as specified in the MPM

       是否有必要為了和MPM要求保持一致而放寬標(biāo)準(zhǔn)限度？

       Impurities/related substances: For already authorized products compliance with a monograph does not mean that the limits for impurities/related substances have to be widened. The specification represents process capability/product performance associated with safety and efficacy. Therefore, wider limits than previously approved need sound justification.

       雜質(zhì)/有關(guān)物質(zhì)：對(duì)于已經(jīng)獲得批準(zhǔn)的產(chǎn)品，遵守一項(xiàng)藥典并不意味著雜質(zhì)/有關(guān)物質(zhì)的限度必須擴(kuò)大。標(biāo)準(zhǔn)代表著與安全性和功效相關(guān)的工藝能力/產(chǎn)品性能。因此，放寬以前批準(zhǔn)的限度需要有充分的正當(dāng)理由。

       Dissolution: No. For dissolution test, the specification should be derived from the dissolution results of the biobatch(es) in the individual marketing authorization procedure and the dissolution method should be discriminatory for the specific product (manufacturing process/product formulation).

       溶出度：不需要。對(duì)于溶出度測(cè)試，標(biāo)準(zhǔn)應(yīng)該根據(jù)個(gè)別上市許可程序中生物批次的溶出結(jié)果來(lái)確定，并且溶出方法應(yīng)該對(duì)特定產(chǎn)品（制造工藝/產(chǎn)品配方）具有區(qū)分性。

       Broadening the Q-value can only be justified by in-vivo data.

       It is important to note that the dissolution test described in the Ph. Eur. MPM can only be used if the applicant has demonstrated the suitability of the test for the given product to the satisfaction of the competent authority. In any case, the dissolution test proposed should be approved by the competent authority in the context of the MAA assessment.

       放寬“Q值”只能通過(guò)體內(nèi)數(shù)據(jù)來(lái)證明合理性。需注意，歐洲藥典中所描述的溶出度測(cè)試方法只有在申請(qǐng)人向主管機(jī)構(gòu)證明該測(cè)試對(duì)特定產(chǎn)品的適用性并令其滿意的情況下才可使用。無(wú)論如何，在MAA申請(qǐng)?jiān)u估的背景下，所提出的溶出度測(cè)試方法都需獲得主管機(jī)構(gòu)的批準(zhǔn)。

       11. Which variation category should be used to widen the specification limits to be the same as specified in the MPM

       為了放寬標(biāo)準(zhǔn)限度和MPM要求保持一致，需要采用什么變更分類(lèi)？

       Change (widening) the impurity or assay limits of the finished product to the limits in the Ph. Eur. monograph: Type II, B.II.d.1.e (Change outside the approved specifications limits range).

       變更（放寬）制劑的雜質(zhì)或者含量限度和歐洲藥典各論保持一致，需要采用II類(lèi)變更，B.II.d.1.e（變更批準(zhǔn)的標(biāo)準(zhǔn)限度范圍）。

       Change (widening) the dissolution limits of the finished product to the limits in the Ph. Eur. monograph: Type II, B.II.d.1.e (Change outside the approved specification limits range). It is important to note that such a change should be justified by new in vivo data (see also Question 10).

       變更（放寬）制劑溶出度限度和歐洲藥典各論保持，需要采用II類(lèi)變更，B.II.d.1.e（變更批準(zhǔn)的標(biāo)準(zhǔn)限度范圍）。重要的是要注意到，這樣的變更應(yīng)該通過(guò)新的體內(nèi)數(shù)據(jù)來(lái)證明合理性（參見(jiàn)問(wèn)題10）。

       第二部分：EDQM的管理流程

       在閱讀和分析完上面EMA的問(wèn)答文件，必須看看EDQM如何說(shuō)。為什么呢？因?yàn)樗幤吩跉W盟注冊(cè)存在特殊情況。上面提到的EMA問(wèn)答只適用于制劑產(chǎn)品，對(duì)于原料藥不是很適用。EDQM不僅發(fā)布?xì)W洲藥典，還負(fù)責(zé)維護(hù)CEP認(rèn)證程序。那么，如果歐洲藥典更新了版本，原料藥企業(yè)如何應(yīng)對(duì)呢？

       2021年11月，EDQM采用新通則5.26《Implementation of pharmacopoeial procedures》，對(duì)于藥典實(shí)施細(xì)節(jié)，進(jìn)行厘清。

       每次歐洲藥典更新，EDQM官網(wǎng)會(huì)發(fā)布提醒，告知那些CEP持有人會(huì)受到影響。

       例如，2023年7月17日，EDQM發(fā)布《Implementation of the European Pharmacopoeia Supplement 11.3 – Notification for CEP holders》。

       Supplement 11.3 of the European Pharmacopoeia (Ph. Eur.) is now available. Holders of Certificates of suitability to the monographs of the Ph. Eur. (CEPs) are invited to update their applications according to the revised monographs that will be implemented on 1 January 2024, and to follow the instructions given below.

       歐洲藥典（Ph. Eur.）的增補(bǔ)版11.3現(xiàn)已發(fā)布。持有歐洲藥典各論適應(yīng)性證書(shū)（CEPs）的持有人被提醒根據(jù)將于2024年1月1日實(shí)施的修訂各論更新API注冊(cè)申請(qǐng)資料，并遵循以下給出的說(shuō)明。

       Thetable at the end of this announcement provides a list of substances covered by a CEP and for which a revised monograph will be implemented on1 January 2024 in Supplement 11.3of the Ph. Eur.

       這個(gè)公告的末尾提供了一個(gè)表格，列出了一份由CEP認(rèn)證覆蓋的物質(zhì)清單，這些物質(zhì)將在2024年1月1日實(shí)施《歐洲藥典》第11.3增補(bǔ)版中收載修訂的藥典方法。

       According to Directives 2001/83/EC and 2001/82/EC, as amended, it is the responsibility of the manufacturer to comply with the current version of a Ph. Eur. monograph, and therefore to update the specification when a revised monograph is issued. In addition, the European Directorate for the Quality of Medicines and HealthCare (EDQM) ensures that CEPs refer to the most recent version of a Ph. Eur. monograph at any time.

       根據(jù)2001/83/EC指令和2001/82/EC指令以及修訂案，制藥廠商有責(zé)任遵守歐洲藥典的最新版本，并在修訂的藥典發(fā)布后更新質(zhì)量標(biāo)準(zhǔn)。此外， EDQM確保CEP隨時(shí)參考藥典的最新版本。

       The need to submit information to the EDQM following a revised monograph depends on the changes made to the monograph. Updates to the monographs are classified by the EDQM into two categories, labelled “Case A” and “Case B”, and this influences the information required. In the list of revised monographs below, it is indicated which classification (“Case A” or “Case B”) is applicable. In addition to this web announcement, the EDQM, as a courtesy, will contact CEP holders with details of how to proceed for the dossiers impacted by the revised monograph(s). However,it remains the responsibility of the CEP holder to comply with the requirements of the monographand if necessary to update their respective applications by the implementation date of the revised monograph at the latest, regardless of whether they have been contacted by the EDQM.

       為了符合修訂后藥典各論，是否需要向EDQM提交信息取決于對(duì)藥典所做的更改情況。EDQM將對(duì)藥典的更新分為兩類(lèi)，分別標(biāo)記為“情形A”和“情形B”，并且這種分類(lèi)會(huì)影響所需提交的信息。在下面的修訂藥典各論列表中，會(huì)標(biāo)示適用的分類(lèi)（“情形A”或“情形B”）。此外，作為一種禮貌措施，EDQM將與CEP持有人聯(lián)系，并提供有關(guān)受修訂藥典影響的申報(bào)資料如何進(jìn)行修改的詳細(xì)信息。然而，CEP持有人有責(zé)任遵守藥典的要求，并在修訂藥典的實(shí)施截止日期之前更新其相應(yīng)的申請(qǐng)，無(wú)論是否受到EDQM的聯(lián)系。

       Case A-The specification of the substance should be updated according to the revised monograph. Unless the CEP holder has made reference to the “current version of the monograph” (without providing details on the Ph. Eur. tests and methods in the CEP application), the updated specification should be included in the next request for revision that is submitted to the EDQM (minor, major or renewal of the certificate) and identified as such at that time (such an update will be free of charge). Where the CEP holder has made reference to the “current version of the monograph”, the revised monograph should be implemented without the need to update the specification of the substance at the next request for revision.

       根據(jù)修訂的藥典，物質(zhì)的標(biāo)準(zhǔn)應(yīng)進(jìn)行更新。除非CEP持有人參考了“當(dāng)前版本的藥典”（在CEP申請(qǐng)中未提供Ph.Eur.測(cè)試和方法的細(xì)節(jié)），更新后的藥典標(biāo)準(zhǔn)應(yīng)包含在提交給EDQM的下一個(gè)修訂申請(qǐng)（包括小修訂、大修訂或證書(shū)的續(xù)訂）中，并在那時(shí)進(jìn)行標(biāo)識(shí)（此類(lèi)更新將免費(fèi)）。如果CEP持有人參考了“當(dāng)前版本的藥典”，則無(wú)需在下一個(gè)修訂申請(qǐng)中更新物質(zhì)的標(biāo)準(zhǔn)，而應(yīng)直接實(shí)施修訂后的藥典。

       Case B-This case concerns amendments to the monograph which require the submission of data to the EDQM.

       情形B-本情形涉及對(duì)藥典標(biāo)準(zhǔn)的修訂，要求提交數(shù)據(jù)給EDQM。

       An updated dossier demonstrating that the substance complies with the requirements of the revised monograph should be provided within three months of the EDQM contacting the CEP holder. The company is asked to provide a Module 1 briefly discussing the changes made to the application. This module should also include a clarification on whether all related substances are controlled using only the method described in the revised monograph and whether the substance contains any impurities which are not described in the revised monograph (and which are found above the reporting threshold of the Ph. Eur. general monograph 2034).

       EDQM聯(lián)系CEP持有人后的三個(gè)月內(nèi)，應(yīng)提供更新的申報(bào)資料，以證明該物質(zhì)符合修訂藥典的要求。公司被要求提供CTD模塊1，簡(jiǎn)要討論對(duì)申請(qǐng)所做的變更情況。此模塊還應(yīng)澄清是否所有有關(guān)物質(zhì)僅使用修訂藥典中描述的方法進(jìn)行控制，并且該物質(zhì)是否含有任何未在修訂藥典中描述的雜質(zhì)（且超過(guò)歐洲藥典通論2034中設(shè)定的報(bào)告閾值）。

       Module 3 should be updated to include, as necessary:

       必要時(shí)，模塊3應(yīng)該被更新以包括如下信息：

       a comparison of the impurity profile of the substance with the updated transparency list of the monograph (3.2.S.3.2 “Impurities”, 3.2.S.4.5 “Justification of Specifications”);

       將物質(zhì)的雜質(zhì)檔案與修訂后的藥典透明度列表進(jìn)行比較。（涉及3.2.S.3.2雜質(zhì), 3.2.S.4.5標(biāo)準(zhǔn)論證部分）

       a discussion on the suitability of the revised monograph to control any impurities which are not described in it;

       討論是否修訂后的藥典各論可以控制藥典各論正文未涵蓋的任何雜質(zhì)的能力。

       an updated substance specification/test methods description (3.2.S.4.1 “Specifications”, 3.2.S.4.2 “Analytical Procedures”);

       更新后的物質(zhì)標(biāo)準(zhǔn)/測(cè)試方法描述信息。（涉及3.2.S.4.1標(biāo)準(zhǔn), 3.2.S.4.2分析規(guī)程部分）。

       certificates of analysis of two batches with reference to the revised monograph (3.2.S.4.4 “Batch Analysis”);

       根據(jù)修訂后藥典各論進(jìn)行測(cè)試的2批次物質(zhì)的COA（涉及3.2.S.4.4批分析部分）。

       validation and cross-validation data when an in-house method is used as an alternative to a new test method in the monograph (3.2.S.4.3 “Validation of Analytical Procedures”).

       當(dāng)一種內(nèi)部方法被用作藥典各論的新的替代測(cè)試方法（涉及3.2.S.4.3分析方法驗(yàn)證），需要提供驗(yàn)證和交叉驗(yàn)證數(shù)據(jù)。

       In the “Case B” scenario, CEP applications require an update and therefore any holder of a CEP for a substance in the “Case B” list below is expected to provide the requested information to the EDQM, even if no specific request for information was received (this may happen namely when information regarding a change of contact person has not been submitted to the EDQM in a timely manner).

       在情形B中，CEP證書(shū)申請(qǐng)需要更新，因此，在下面的“情形B”列表中持有物質(zhì)的CEP持有人被期望向EDQM提供所請(qǐng)求的信息，即使沒(méi)有收到具體的信息請(qǐng)求（這可能發(fā)生在未及時(shí)向EDQM提交聯(lián)系人變更信息的情況下）。

       If the requested information has already been presented in the approved dossier, a simple letter stating this is deemed sufficient.

       如果所請(qǐng)求的信息已經(jīng)在批準(zhǔn)的申報(bào)資料中提供過(guò)，一封簡(jiǎn)單說(shuō)明函被認(rèn)為是足夠的。

       Failure to update the CEP application and to provide data to the EDQM may challenge the validity of the concerned granted CEP, or delay the ongoing evaluation process of the concerned application.

       未更新CEP申請(qǐng)并向EDQM提供數(shù)據(jù)可能會(huì)對(duì)已獲得的CEP證書(shū)相關(guān)有效性構(gòu)成挑戰(zhàn)，或者延遲正在進(jìn)行的申請(qǐng)的評(píng)估過(guò)程。

       Upon receipt, data will be reviewed within three months and the CEP holder will be informed of the outcome of the evaluation. The assessment may also result in arevised CEPbeing granted.

       收到數(shù)據(jù)后，數(shù)據(jù)將在三個(gè)月內(nèi)進(jìn)行審核，并將通知CEP持有者評(píng)估結(jié)果。評(píng)估可能會(huì)導(dǎo)致對(duì)CEP進(jìn)行修訂并重新授予。

       This procedure is free of charge, unless the holder submits, at the same time, a request for other changes.

       這個(gè)程序是免費(fèi)的，除非持有人同時(shí)提交其他變更的請(qǐng)求。

       作者補(bǔ)充說(shuō)明：上述表格是對(duì)EDQM文件中表格的簡(jiǎn)化，原表格內(nèi)容很多。這里只保留2個(gè)品種，以展示藥典修訂后CEP持有人應(yīng)該采取的行動(dòng)。

       Note: The Ph. Eur. monograph for Donepezil hydrochloride monohydrate (3067) is suppressed in Ph. Eur. Suppl. 11.3, as the revised monograph for Donepezil hydrochloride (2582) will cover the anhydrous and monohydrate forms of donepezil hydrochloride. EDQM will provide specific guidance to CEP holders on how this change will be managed by EDQM shortly. No action is required by CEP holders at this time.

       注釋?zhuān)?/strong>《歐洲藥典》第11.3版補(bǔ)充版中取消了Donepezil鹽酸單水合物的Ph. Eur.各論（3067），因?yàn)橐研抻喌腄onepezil鹽酸鹽的各論（2582）將涵蓋Donepezil鹽酸的無(wú)水和單水合物2種形式。EDQM將很快向CEP持有人提供關(guān)于EDQM如何管理這一變更的具體指導(dǎo)。CEP持有人目前無(wú)需采取任何行動(dòng)。