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嘉峪檢測網(wǎng) 2025-12-15 20:10
近日，歐盟委員會發(fā)布了新的《變更指南》，該文件規(guī)定了制藥企業(yè)變更和更新其上市許可的詳細規(guī)則。包含變更（比如成分、工藝、包裝、說明書等）必須如何分類、如何申報、如何審批等內(nèi)容。新指南簡化了藥品的生命周期管理，以適應(yīng)科學(xué)和技術(shù)進步。
新的變更指南通過簡化和基于風(fēng)險的方法提供了更大的靈活性，促進了更快、更高效的變更處理，使上市許可持有人和監(jiān)管機構(gòu)都能夠受益。
文件將于2026年1月15日生效。
同時，EMA也發(fā)布了新版《變更分類指南 問答文件》，翻譯如下：
Classification of changes
變更分類
1.1. Administrative changes
1.1. 行政變更
1.1.1. How to apply for a change in name and/or address of a marketing authorisation holder manufacturing site? NEW Nov 2025
1.1.1. 如何申請上市許可持有人生產(chǎn)場所的名稱和/或地址變更？新增 2025年11月
Classification category E.4 should be used as long as there is no change in the physical location of the facility, and all manufacturing operations remain the same. This scope is only for changes in name and/or address that are purely administrative in nature (e.g. the municipality decides to change the name of the street or there is a change in the postal code). If the facility moves to a different physical location, classification under the appropriate Q section should be used (e.g. Q.I.a.1 for a manufacturer or a batch control/testing site of an active substance, Q.II.b.1 for a manufacturer of a finished product, Q.II.b.2 for a release site or batch control/testing site for the finished product).
只要設(shè)施的實際位置未發(fā)生變化，且所有生產(chǎn)操作保持不變，應(yīng)使用E.4類分類。此范圍僅適用于純行政性質(zhì)的名稱和/或地址變更（例如，市政當(dāng)局決定更改街道名稱或郵政編碼發(fā)生變更）。如果設(shè)施遷移至不同的實際位置，則應(yīng)使用相應(yīng)Q章節(jié)下的分類（例如，活性物質(zhì)的生產(chǎn)商或批次控制/檢測場所使用Q.I.a.1類，成品生產(chǎn)商使用Q.II.b.1類，成品的放行場所或批次控制/檢測場所使用Q.II.b.2類）。
Classification category E.4 should also be used for administrative changes to the name and/or address of manufacturing sites for active substance or finished product intermediates or any other materials mentioned in the dossier.
對于活性物質(zhì)或成品中間體的生產(chǎn)場所，或 dossier（申報資料）中提及的任何其他物料的生產(chǎn)場所的名稱和/或地址的行政變更，也應(yīng)使用E.4類分類。
In case the site impacted by the change in name and/or address is performing multiple activities, they can be included in the same Type IA submission as long as they are all part of the same classification category. For example:
如果受名稱和/或地址變更影響的場所涉及多項活動，只要這些活動均屬于同一分類類別，即可納入同一份IA類申報中。例如：
a) The same change concerns the MAH and the batch release site: a grouping of a Type IA, E.4.a and a Type IA, E.4.b should be submitted, since the conditions to be fulfilled are different and need to be declared for each activity.
a) 同一變更涉及上市許可持有人（MAH）和批次放行場所：應(yīng)提交IA類E.4.a和IA類E.4.b的組合申報，因為各項活動需滿足的條件不同，且需針對每項活動進行申報。
b) The same change concerns a site where manufacturing of final product, primary and secondary packaging and quality control are performed: a single Type IA, E.4.c can include all activities, since the conditions and documentation are the same. The company needs to confirm explicitly in the application form that conditions and documentation are met for all activities.
b) 同一變更涉及同時進行成品生產(chǎn)、內(nèi)包裝和外包裝以及質(zhì)量控制的場所：由于各項活動的條件和文件要求相同，可通過單一IA類E.4.c申報涵蓋所有活動。公司需在申請表中明確確認所有活動均滿足相關(guān)條件并提交了所需文件。
In case a CEP is used, changes in the name and/or address of the sites listed in the CEP are covered under scope Q.III.1 when the new version of the CEP is submitted. A parallel variation under classification category E.4 is not required.
如果使用歐洲藥典適用性證書（CEP），在提交新版CEP時，CEP中所列場所的名稱和/或地址變更將納入Q.III.1范圍，無需同時提交E.4類變更申請。
An official document from a relevant official body including the new name and address needs to be provided (e.g. Chamber of Commerce registry, manufacturing authorization or importation (MIA), GMP certificate…). A self-declaration issued by the MAH is not considered sufficient.
需提供相關(guān)官方機構(gòu)出具的包含新名稱和地址的正式文件（例如，商會注冊證明、生產(chǎn)或進口授權(quán)（MIA）、GMP證書等）。上市許可持有人（MAH）出具的自我聲明不被視為充分材料。
1.1.2. How to apply for the deletion of more than one manufacturing site? Rev. Nov 2025
1.1.2. 如何申請刪除多個生產(chǎn)場所？修訂 2025年11月
In case more than one manufacturer in one MA has to be deleted a single variation of type IA under classification category E.5 to delete all manufacturing sites may be submitted. However, it has to be assured that there is still one approved manufacturing site left in the documentation performing the same function as the one(s) concerned by the deletion.
如果同一上市許可（MA）下需刪除多個生產(chǎn)商，可提交一份E.5類IA類變更申請以刪除所有相關(guān)生產(chǎn)場所。但需確保申報資料中仍保留至少一個經(jīng)批準(zhǔn)的生產(chǎn)場所，且該場所承擔(dān)與擬刪除場所相同的功能。
1.2. Quality changes
1.2. 質(zhì)量變更
1.2.1. Introduction of a new manufacturing site for the finished product. What changes can I submit under a single Type II scope? (Classification category Q.II.b.1) Rev. Nov 2025
1.2.1. 新增成品生產(chǎn)場所：哪些變更可納入單一II類范圍申報？（分類類別Q.II.b.1）修訂 2025年11月
Multiple related extensive changes could be considered for submission under a single Type II scope Q.II.b.1 – Change in the manufacturing site for part or all of the manufacturing process of the finished product.
多項相關(guān)的重大變更可考慮納入單一II類Q.II.b.1范圍申報——即成品部分或全部生產(chǎn)工藝的生產(chǎn)場所變更。
Multiple related changes submitted under a single type II should always be clearly identified in the application form as following: a clear description of all the related changes should be provided in the precise scope. All the related changes should be listed in the present/proposed table.
納入單一II類申報的多項相關(guān)變更，應(yīng)在申請表中明確說明如下：在具體范圍部分詳細描述所有相關(guān)變更，并在“現(xiàn)有/擬議”表格中列出所有相關(guān)變更。
Changes affecting the FP not directly related to the introduction of the new manufacturing site such as changes in excipients, specification parameters /limits for the FP, container closure system including suppliers should be submitted as additional grouped variation scopes.
與新增生產(chǎn)場所無直接關(guān)聯(lián)的成品（FP）相關(guān)變更（例如，輔料變更、成品的質(zhì)量標(biāo)準(zhǔn)參數(shù)/限度變更、包含供應(yīng)商在內(nèi)的包裝密封系統(tǒng)變更等），應(yīng)作為額外的組合變更范圍提交。
It should be highlighted, that for variations introducing additional manufacturing or batch control/testing sites (including sub-contractors), each additional site should be declared as a separate variation on the variation application form. Such variations can be submitted as a grouping application. The precise scope should include the full name and full address of the site, and clearly list all activities performed at each site.
需重點說明的是，對于新增生產(chǎn)或批次控制/檢測場所（包括分包商）的變更，每個新增場所均應(yīng)在變更申請表中作為單獨變更申報，此類變更可作為組合申請?zhí)峤?。具體范圍應(yīng)包含場所的完整名稱和地址，并明確列出每個場所開展的所有活動。
Any pre-submission queries related to the intended submission of multiple related changes under one single Type II variation should be addressed to the Quality Specialist assigned to your product. See also question ‘Who is my contact at the European Medicines Agency during type II variation including extension of indications?’.
關(guān)于擬將多項相關(guān)變更納入單一II類變更申報的任何預(yù)審咨詢，應(yīng)聯(lián)系分配給該產(chǎn)品的質(zhì)量專員。另請參閱“在包括適應(yīng)癥擴展在內(nèi)的II類變更過程中，歐洲藥品管理局（EMA）的聯(lián)系人是誰？”這一問題。
1.2.2. Introduction of a new manufacturing site for an active substance. What changes are covered by a single Type II scope? (Classification category Q.I.a.1) Rev. Nov 2025
1.2.2. 新增活性物質(zhì)生產(chǎn)場所：單一II類范圍涵蓋哪些變更？（分類類別Q.I.a.1）修訂 2025年11月
The introduction of a new manufacturing site for an active substance supported by an ASMF should be submitted under a single Type II, Q.I.a.1.f.
新增由活性物質(zhì)主文件（ASMF）支持的活性物質(zhì)生產(chǎn)場所，應(yīng)通過單一II類Q.I.a.1.f變更申報。
The introduction of a new manufacturer of the active substance not supported by an ASMF or intermediate that requires extensive updates to 3.2.S section should be submitted under a single Type II, Q.I.a.1.b).
新增無ASMF支持的活性物質(zhì)生產(chǎn)商，或需對3.2.S章節(jié)進行重大更新的中間體生產(chǎn)商，應(yīng)通過單一II類Q.I.a.1.b)變更申報。
It should be noted that, in cases where the introduction of the new active substance manufacturer has an impact at the level of the finished product manufacturer (e.g. changes to the active substance specifications or related analytical methods) separate variations have to be submitted under the corresponding Q.I.b categories and may be grouped together, if related to the introduction of the new active substance manufacturer.
需注意的是，如果新增活性物質(zhì)生產(chǎn)商對成品生產(chǎn)商產(chǎn)生影響（例如，活性物質(zhì)質(zhì)量標(biāo)準(zhǔn)變更或相關(guān)分析方法變更），則需根據(jù)相應(yīng)的Q.I.b類別提交單獨變更；若這些變更與新增活性物質(zhì)生產(chǎn)商相關(guān)，可納入組合申報。
It should be highlighted that, for variations introducing additional manufacturing or batch control/testing sites (including sub-contractors), each additional site should be declared as a separate variation on the variation application form as a grouped application, and the precise scope should include the full name, full address of the site and list all activities performed at each site.
需重點說明的是，對于新增生產(chǎn)或批次控制/檢測場所（包括分包商）的變更，每個新增場所均應(yīng)在變更申請表中作為組合申請的單獨變更申報，具體范圍應(yīng)包含場所的完整名稱和地址，并列出每個場所開展的所有活動。
Any pre-submission queries related to upcoming submissions pertaining to such Type II changes should be addressed to the Quality Specialist assigned to your product. See also question ’Who is my contact at the European Medicines Agency during type II variation, including extension of indications?’.
關(guān)于此類II類變更擬申報的任何預(yù)審咨詢，應(yīng)聯(lián)系分配給該產(chǎn)品的質(zhì)量專員。另請參閱“在包括適應(yīng)癥擴展在內(nèi)的II類變更過程中，歐洲藥品管理局（EMA）的聯(lián)系人是誰？”這一問題。
1.2.3. How should multiple changes to Module 3.2.S or the update of an ASMF, which is part of Module 3 of a marketing authorisation be submitted? (Q.I.z) Rev. Nov 2025
1.2.3. 如何申報對3.2.S模塊的多項變更或作為上市許可3模塊組成部分的ASMF更新？（Q.I.z）修訂 2025年11月
An update of Module 3.2.S can be submitted as a grouped variation application, if conditions 5 or 6 of Annex III of the Variation Regulation (EC) No 1234/2008 are met.
若符合《歐盟第1234/2008號變更條例》（EC）附件III第5條或第6條的條件，3.2.S模塊的更新可作為組合變更申請?zhí)峤弧?/span>
An update or change of a stand-alone ASMF is not foreseen and can only be addressed in connection with a marketing authorisation. The type of variation(s) is dependent on the type of changes introduced in the updated version. The update – including changes to the open and /or restricted part - can be submitted as a grouped application, if condition 5 of Annex III of the Variation Regulation (EC) No 1234/2008 is met.
獨立ASMF的更新或變更不單獨受理，僅可結(jié)合上市許可進行申報。變更類型取決于更新版本中引入的變更性質(zhì)。若符合《歐盟第1234/2008號變更條例》（EC）附件III第5條的條件，ASMF的更新（包括公開部分和/或限制部分的變更）可作為組合申請?zhí)峤弧?/span>
In case of substantial changes or multiple minor changes to Module 3.2.S or the ASMF, it is recommended to submit a single Type II variation under category Q.I.z. It is a prerequisite for the validation of these single variations that the “present/proposed” section of the application form is filled in correctly and completely.
若3.2.S模塊或ASMF發(fā)生重大變更或多項微小變更，建議通過Q.I.z類單一II類變更申報。申請表中“現(xiàn)有/擬議”部分的正確完整填寫是此類單一變更通過驗證的前提條件。
In all cases, updates of the ASMF must be submitted by the ASMF holder (open and closed part to EMA, open part to marketing authorisation holder (MAH)) whilst the variation to the Marketing Authorisation has to be submitted by the MAH. We encourage a close dialogue between MAH and ASMF holder to ensure that the ASMF update has been submitted before or at the same time as the variation application to avoid validation issues. A clear present and proposed table listing all changes should be included in both submissions (a table of changes should be included in the ASMF submission and the same table of changes and a present and proposed section for the applicant’s part should be included in the MAH variation application). The application form needs to include the specific ASMF version number the submission relates to.
在所有情況下，ASMF的更新必須由ASMF持有人提交（向EMA提交公開部分和保密部分，向上市許可持有人（MAH）提交公開部分），而上市許可的變更則需由MAH提交。我們鼓勵MAH與ASMF持有人保持密切溝通，確保ASMF更新在變更申請之前或同時提交，以避免驗證問題。兩份申報材料中均應(yīng)包含明確列出所有變更的“現(xiàn)有/擬議”表格（ASMF申報中需包含變更表，MAH的變更申請中需包含相同的變更表以及申請人部分的“現(xiàn)有/擬議”章節(jié)）。申請表中需注明申報所涉及的具體ASMF版本號。
Minor changes to the restricted part of an ASMF are not acceptable as Type IA variations and should be submitted using classification category Q.I.a.2.d.
ASMF限制部分的微小變更不可作為IA類變更申報，應(yīng)使用Q.I.a.2.d類分類提交。
Any pre-submission queries related to upcoming submissions pertaining to extensive changes to Module 3.2.S or extensive ASMF updates should be addressed to the Quality Specialist assigned to your product. See also question ’Who is my contact at the European Medicines Agency during a type II variation, including extension of indications?’.
關(guān)于3.2.S模塊重大變更或ASMF重大更新擬申報的任何預(yù)審咨詢，應(yīng)聯(lián)系分配給該產(chǎn)品的質(zhì)量專員。另請參閱“在包括適應(yīng)癥擴展在內(nèi)的II類變更過程中，歐洲藥品管理局（EMA）的聯(lián)系人是誰？”這一問題。
1.2.4. How should I submit a revised Certificate of Suitability (CEP)? (Q.III.1a.2) Rev. Nov 2025
1.2.4. 如何提交修訂后的歐洲藥典適用性證書（CEP）？（Q.III.1a.2）修訂 2025年11月
In line with the Marketing Authorisation Holder’s (MAH) obligation to keep the dossier up to date, a new or revised Certificate of Suitability (CEP) for an active substance (AS), excipient or starting material/reagent/intermediate used in the manufacturing process of the AS should be submitted as a variation. It is however understood that only the versions of the CEP (i.e. revised certificates) which were used in the manufacturing process of a batch of finished product (FP)/ AS need to be included in the dossier, provided that there are no quality and/or safety concerns that have led to the revision of the CEP.
根據(jù)上市許可持有人（MAH）保持申報資料最新的義務(wù)，用于活性物質(zhì)（AS）生產(chǎn)過程的活性物質(zhì)、輔料或起始物料/試劑/中間體的新版或修訂版CEP，應(yīng)作為變更提交。但需明確的是，僅需將用于某一批次成品（FP）/活性物質(zhì)生產(chǎn)的CEP版本（即修訂版證書）納入申報資料，前提是CEP的修訂不涉及質(zhì)量和/或安全性問題。
In case of CEP revision related to quality and/or safety issues, the revised CEP should be implemented immediately and the appropriate variation should be submitted, even if the revised CEP is not linked to a specific production batch for the finished product.
若CEP的修訂涉及質(zhì)量和/或安全性問題，則無論該修訂版CEP是否與特定成品生產(chǎn)批次相關(guān)，均應(yīng)立即執(zhí)行修訂后的CEP，并提交相應(yīng)的變更申請。
CEP revisions should be submitted under the appropriate variation classification scope within subsection Q.III.1. Each CEP revision should be submitted as a variation scope, i.e. an update covering more than one CEP version should be submitted as a grouped variation.
CEP修訂應(yīng)在Q.III.1小節(jié)下的相應(yīng)變更分類范圍內(nèi)提交。每個CEP修訂均應(yīng)作為一個變更范圍申報，即涵蓋多個CEP版本的更新應(yīng)作為組合變更提交。
When submitting a revision of an approved CEP, the MAH should refer to the previously agreed version of the CEP within the ‘Present/Proposed’ section of the application form.
提交經(jīng)批準(zhǔn)CEP的修訂版時，MAH應(yīng)在申請表的“現(xiàn)有/擬議”部分注明此前認可的CEP版本。
If with the submission one or more revisions of the CEP are omitted, the MAH should confirm in the variation application form (section ‘Precise scope and background for change’) that substance/material from the omitted CEP version(s) was not used in the manufacture of the FP and/or AS during the validity of this certificate(s). Additionally it should be confirmed that any changes introduced by the omitted CEP revision(s), do not affect the quality of the AS and/or FP. In case such confirmation is missing, a negative Type IA notification may be issued.
若申報中遺漏了一個或多個CEP修訂版，MAH應(yīng)在變更申請表（“具體范圍及變更背景”部分）確認：在遺漏的CEP版本有效期內(nèi)，未將該版本對應(yīng)的物質(zhì)/物料用于成品和/或活性物質(zhì)的生產(chǎn)；同時需確認遺漏的CEP修訂版所引入的任何變更均不影響活性物質(zhì)和/或成品的質(zhì)量。若未提供該確認，可能會收到IA類否定通知。
The MAH should also clearly indicate in the ‘Present/Proposed’ section all changes introduced in the CEP between the latest approved version and the new revision, including all revisions that were not notified. Any changes e.g. to manufacturing sites, additional residual solvents introduced in the CEP by subsequent revisions should be declared.
MAH還應(yīng)在“現(xiàn)有/擬議”部分明確說明CEP從最新認可版本到新版修訂之間引入的所有變更，包括所有未申報的修訂版。對于后續(xù)修訂版在CEP中引入的任何變更（例如，生產(chǎn)場所變更、新增殘留溶劑等），均應(yīng)予以申報。
Example
示例
Submission of a revised CEP version for an already approved manufacturer: R0-CEP-xxxx-xx-rev02 when the current certificate in the dossier is: R0-CEP-xxxx-xx-rev00.
為已批準(zhǔn)的生產(chǎn)商提交修訂版CEP：申報資料中當(dāng)前的證書為R0-CEP-xxxx-xx-rev00，擬提交R0-CEP-xxxx-xx-rev02。
If during the validity of R0-CEP-xxxx-xx-rev01, material of the CEP was used in the manufacture of the FP and/or the AS, then the MAH should submit a grouping of two IA variations to include both certificates (rev. 01 and rev 02) in the Module 3. The foreseen conditions for each of the respective variations should be met.
若在R0-CEP-xxxx-xx-rev01的有效期內(nèi)，該CEP對應(yīng)的物料已用于成品和/或活性物質(zhì)的生產(chǎn)，則MAH應(yīng)提交兩項IA類變更的組合申請，將兩個證書（rev.01和rev.02）均納入3模塊。各項變更均需滿足預(yù)設(shè)條件。
If during the validity of R0-CEP-xxxx-xx-rev01, material of the CEP was not used in the manufacture of the FP and/or AS, the MAH should only submit a single Type IA variation to include the revised certificate R0-CEP-xxxx-xx-rev02 in Module 3. The foreseen conditions for the variation should be met.
若在R0-CEP-xxxx-xx-rev01的有效期內(nèi)，該CEP對應(yīng)的物料未用于成品和/或活性物質(zhì)的生產(chǎn)，則MAH僅需提交一項IA類變更，將修訂版證書R0-CEP-xxxx-xx-rev02納入3模塊。該變更需滿足預(yù)設(shè)條件。
The MAH should also confirm in the variation application form that material/substance from R0-CEPxxxx-xx-rev01 was not used in the manufacture of the FP and/or AS during the validity of this certificate and that changes introduced by the revision R0-CEP-xxxx-xx-rev01 do not affect the quality of the AS and/or the FP. MAH should also clearly list within the ‘Present/Proposed’ section of the application form all changes introduced to the CEP with revisions 01 and 02.
MAH還應(yīng)在變更申請表中確認：在R0-CEP-xxxx-xx-rev01的有效期內(nèi)，未將該版本對應(yīng)的物料/物質(zhì)用于成品和/或活性物質(zhì)的生產(chǎn)，且該修訂版引入的變更不影響活性物質(zhì)和/或成品的質(zhì)量。MAH還應(yīng)在申請表的“現(xiàn)有/擬議”部分明確列出rev.01和rev.02為CEP引入的所有變更。
1.2.5. What is considered to be a non-significant or an obsolete in-process control, specification attribute or acceptance criteria? (Classification category Q.I.a.4.c, Q.I.b.1.d, Q.I.c.2.c, Q.II.b.5.c, Q.II.c.1.c, Q.II.d.1.d and Q.II.e.4.c) Rev. Nov 2025
1.2.5. 什么是非重大或過時的過程控制、質(zhì)量標(biāo)準(zhǔn)屬性或驗收標(biāo)準(zhǔn)？（分類類別Q.I.a.4.c、Q.I.b.1.d、Q.I.c.2.c、Q.II.b.5.c、Q.II.c.1.c、Q.II.d.1.d及Q.II.e.4.c）修訂 2025年11月
Variation scopes Q.I.a.4.c, Q.I.b.1.d, Q.I.c.2.c, Q.II.b.5.c, Q.II.c.1.c, Q.II.d.1.d and Q.II.e.4.c of the EC 'Variations Guidelines (2025)’, deal with the deletion of a non-significant or an obsolete in-process control (IPC) test, specification attribute or acceptance criteria. Provided all relevant conditions and documentation requirements are met, all these variations fall under the Type IA category (do-and-tell).
《歐盟2025年變更指南》中的變更范圍Q.I.a.4.c、Q.I.b.1.d、Q.I.c.2.c、Q.II.b.5.c、Q.II.c.1.c、Q.II.d.1.d及Q.II.e.4.c，涉及刪除非重大或過時的過程控制（IPC）測試、質(zhì)量標(biāo)準(zhǔn)屬性或驗收標(biāo)準(zhǔn)。若滿足所有相關(guān)條件和文件要求，此類變更均屬于IA類（先實施后報告）。
The variation categories listed above are intended to be used for non-significant or obsolete IPC test, specification attribute or acceptance criteria that are no longer in line with the technical and scientific progress and part of normal specifications for newer products but have remained for historical reasons in older products (e.g. description of odour and taste). It is not intended to include changes in relation to revisions of the control strategy with an intention to minimise redundant testing of parameters and attributes (critical or non-critical) that are tested at different stages during production, or cases where process/ product characterisation performed after authorisation has shown that the attribute/ parameter is non-critical. Such changes require regulatory assessment and are to be handled as Type IB or II variations as appropriate.
上述變更類別適用于以下情況：非重大或過時的IPC測試、質(zhì)量標(biāo)準(zhǔn)屬性或驗收標(biāo)準(zhǔn)已不再符合技術(shù)和科學(xué)進展，且屬于新產(chǎn)品的常規(guī)質(zhì)量標(biāo)準(zhǔn)內(nèi)容，但因歷史原因仍保留在老產(chǎn)品中（例如，氣味和味道描述）。不適用于以下變更：為減少生產(chǎn)不同階段對參數(shù)和屬性（關(guān)鍵或非關(guān)鍵）的重復(fù)測試而修訂控制策略，或上市后通過工藝/產(chǎn)品表征證明某屬性/參數(shù)為非關(guān)鍵屬性的情況。此類變更需經(jīng)過監(jiān)管評估，應(yīng)根據(jù)具體情況按IB類或II類變更處理。
1.2.6. Which variation category should be used to remove/replace the Rabbit Pyrogen test from marketing authorisation dossiers? NEW Nov 2025
1.2.6. 從上市許可申報資料中刪除/替換家兔熱原試驗應(yīng)使用哪一變更類別？新增 2025年11月
Please refer to the EMA’s webpage of ‘Quality of medicines questions and answers: Part 1 - European Pharmacopeia (Ph. Eur.) - Phasing out Rabbit Pyrogen Test’.
請參閱EMA網(wǎng)頁“藥品質(zhì)量問答：第1部分——歐洲藥典（Ph. Eur.）——逐步淘汰家兔熱原試驗”。
1.2.7. When applying for a new pack size, what is considered to be within /outside range? (Classification category Q.II.e.6) Rev. Nov 2025
1.2.7. 申請新增包裝規(guī)格時，什么情況下屬于范圍內(nèi)/范圍外？（分類類別Q.II.e.6）修訂 2025年11月
The introduction of a new pack size (i.e. in addition to currently approved pack sizes) should be submitted as a variation under scope Q.II.e.6.a).
新增包裝規(guī)格（即現(xiàn)有批準(zhǔn)包裝規(guī)格之外的規(guī)格）應(yīng)通過Q.II.e.6.a)范圍的變更申報。
A range is defined from the smallest to the largest approved pack size (i.e. not from ‘0’) for the same pharmaceutical form and strength. The pack size equals to the number of units of the pharmaceutical form (e.g. tablets, sachets, ampoules, etc.) contained in the outer packaging. Pack sizes not included within this range are considered to be outside of the range.
對于相同劑型和規(guī)格，范圍定義為從最小批準(zhǔn)包裝規(guī)格到最大批準(zhǔn)包裝規(guī)格（即不從“0”開始）。包裝規(guī)格指外包裝中包含的劑型單位數(shù)量（例如，片劑、小袋、安瓿等）。未包含在該范圍內(nèi)的包裝規(guī)格視為范圍外規(guī)格。
For the addition of a new pack size where the number of units of the pack is within the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a Type IA_IN variation Q.II.e.6.a.1.
若新增包裝規(guī)格的單位數(shù)量處于同一劑型和規(guī)格的現(xiàn)有批準(zhǔn)包裝規(guī)格范圍內(nèi)，申請人應(yīng)提交IA_IN類Q.II.e.6.a.1變更。
For the addition of a new pack size where the number of units of the pack is outside the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a Type IB variation Q.II.e.6.a.2.
若新增包裝規(guī)格的單位數(shù)量處于同一劑型和規(guī)格的現(xiàn)有批準(zhǔn)包裝規(guī)格范圍外，申請人應(yīng)提交IB類Q.II.e.6.a.2變更。
In support of a timely introduction of new pack sizes to the market, EMA accepts the following approach for the introduction of various pack sizes falling outside the range within a single grouped submission. The biggest or the smallest pack size per strength outside the range should be classified as Type IB variation Q.II.e.6.a.2. This presentation defines the new limits of the range so that any intermediate pack size for the strength and pharmaceutical form can be classified as Type IA_IN variation Q.II.e.6.a.1.
為支持新包裝規(guī)格及時上市，EMA允許在單一組合申報中納入多個范圍外包裝規(guī)格，具體方式如下：每個規(guī)格下范圍外的最大或最小包裝規(guī)格應(yīng)歸類為IB類Q.II.e.6.a.2變更，該規(guī)格將定義新的范圍界限，因此同一劑型和規(guī)格下的任何中間包裝規(guī)格均可歸類為IA_IN類Q.II.e.6.a.1變更。
Example 1
示例1
The “Medicinal Product A” has currently two approved pack sizes of 30 and 60 tablets for the pharmaceutical form “film coated tablets” and the strength “20mg” and the MAH intends to apply for two new pack size(s) of 90 and 120 tablets at the same time.
“藥品A”的劑型為“薄膜衣片”，規(guī)格為“20mg”，目前已批準(zhǔn)的包裝規(guī)格為30片和60片，MAH擬同時申請新增90片和120片兩種包裝規(guī)格。
The introduction of a new pack size of 120 tablets for the “20mg” strength is considered outside the range of packs and should be classified as variation Q.II.e.6.a.2 (IB). This pack size defines a new limit for the range (30-120), so that the introduction of a pack size of 90 tablets as a grouped (or a latter) submission can be classified as a variation Q.II.e.6.a.1 (IA_IN).
“20mg”規(guī)格新增120片包裝規(guī)格屬于范圍外，應(yīng)歸類為Q.II.e.6.a.2（IB類）變更。該包裝規(guī)格將定義新的范圍界限（30-120片），因此新增90片包裝規(guī)格（作為組合申報或后續(xù)申報的一部分）可歸類為Q.II.e.6.a.1（IA_IN類）變更。
The MAH should therefore apply for a grouped variation of 1 x Type IB - Q.II.e.6.a.2 variation and 1x type IA_IN Q.II.e.6.a.1 variation.
因此，MAH應(yīng)提交組合變更申請，包含1項IB類Q.II.e.6.a.2變更和1項IA_IN類Q.II.e.6.a.1變更。
Example 2
示例2
The “Medicinal Product B” has currently two approved pack sizes of 2 and 10 pre-filled syringes for the pharmaceutical form “solution for injection” for both strengths of “20mg” and “40mg”. The MAH is applying for four new pack sizes: 5 prefilled syringes for the “20 mg” strength; 30 pre-filled syringes for the “20 mg” strength; 5 prefilled syringes for the “40 mg” strength; 30 pre-filled syringes for the “40 mg” strength.
“藥品B”的劑型為“注射用溶液”，規(guī)格為“20mg”和“40mg”，兩種規(guī)格目前已批準(zhǔn)的包裝規(guī)格均為2支和10支預(yù)充式注射器。MAH擬申請新增四種包裝規(guī)格：20mg規(guī)格5支裝、20mg規(guī)格30支裝、40mg規(guī)格5支裝、40mg規(guī)格30支裝。
For the “20mg” strength, the introduction of a new pack size of 5 pre-filled syringes strength is considered within the range of approved packs (2-10) and should be classified as variation Q.II.e.6.a.1 (IA_IN) and the introduction of a new pack size of 30 pre-filled syringes is considered outside the range of approved packs (2-10) and should be classified as variation Q.II.e.6.a.2 (IB).
對于20mg規(guī)格：新增5支裝預(yù)充式注射器屬于現(xiàn)有批準(zhǔn)范圍（2-10支），應(yīng)歸類為Q.II.e.6.a.1（IA_IN類）變更；新增30支裝屬于范圍外（2-10支），應(yīng)歸類為Q.II.e.6.a.2（IB類）變更。
For the “40mg” strength, the introduction of a new pack size of 5 pre-filled syringes strength is considered within the range of approved packs (2-10) and should be classified as variation Q.II.e.6.a.1 (IA_IN) and the introduction of a new pack size of 30 pre-filled syringes is considered outside the range of approved packs (2-10) and should be classified as variation Q.II.e.6.a.2 (IB).
對于40mg規(guī)格：新增5支裝預(yù)充式注射器屬于現(xiàn)有批準(zhǔn)范圍（2-10支），應(yīng)歸類為Q.II.e.6.a.1（IA_IN類）變更；新增30支裝屬于范圍外（2-10支），應(yīng)歸類為Q.II.e.6.a.2（IB類）變更。
The MAH should therefore apply for a grouped variation application under the scopes referred above.
因此，MAH應(yīng)按上述范圍提交組合變更申請。
It should be highlighted, that for variations introducing additional presentations or pack sizes for centrally approved products, each additional presentation or pack size should be declared as a separate variation on the variation application form under the section ‘variations included in this application’.
需重點說明的是，對于集中審批產(chǎn)品新增劑型或包裝規(guī)格的變更，每個新增劑型或包裝規(guī)格均應(yīng)在變更申請表的“本申請包含的變更”部分作為單獨變更申報。
Changes to strength, pharmaceutical form and route of administration are to be submitted as an Extension of a marketing authorisation.
規(guī)格、劑型和給藥途徑的變更應(yīng)作為上市許可擴展申請?zhí)峤弧?/span>
For additional guidance on changes to an existing presentation that can trigger new EU number(s) please see the EMA post-authorisation guidance for Type IA, Type IB and Type II variations.
關(guān)于現(xiàn)有劑型變更可能觸發(fā)新歐盟藥品編號的更多指導(dǎo)，請參閱EMA關(guān)于IA類、IB類和II類變更的上市后指導(dǎo)文件。
1.2.8. How should I submit a new working cell bank (WCB)? (Classification category Q.I.a.2 a) Rev. Nov 2025
1.2.8. 如何提交新的工作細胞庫（WCB）？（分類類別Q.I.a.2.a）修訂 2025年11月
If a new WCB is introduced using the limits/conditions as detailed in an approved qualification protocol, the new WCB is covered by the existing quality assurance system and there is no need to submit a variation.
若根據(jù)經(jīng)批準(zhǔn)的確認方案中詳細規(guī)定的限度/條件引入新的WCB，則該新WCB已包含在現(xiàn)有質(zhì)量保證體系內(nèi)，無需提交變更申請。
If the documentation of the WCB in the dossier does not include an approved qualification protocol for introducing new WCBs, the MAH should file a Type IB variation under Q.I.a.z.
若申報資料中關(guān)于WCB的文件未包含引入新WCB的經(jīng)批準(zhǔn)確認方案，則MAH應(yīng)提交Q.I.a.z類IB類變更申請。
To introduce a qualification protocol for preparation of a new WCB, the MAH should file a variation Type II Q.I.a.2.b. The addition of the new WCB can be covered as part of this single variation Type II.
如需引入新WCB制備的確認方案，MAH應(yīng)提交II類Q.I.a.2.b變更申請，新增WCB可納入該單一II類變更中。
Changes to an approved qualification protocol should be filed using Q.I.a.2.a, or Q.I.a.2.b, as relevant depending on the complexity of the change. The addition of a new WCB can be covered as part of this single variation.
對經(jīng)批準(zhǔn)確認方案的變更，應(yīng)根據(jù)變更的復(fù)雜程度，相應(yīng)使用Q.I.a.2.a或Q.I.a.2.b類申報，新增WCB可納入該單一變更中。
1.2.9. How should I submit a new in-house reference standard/preparation for a biological medicinal product or excipient? Rev. Nov 2025
1.2.9. 如何提交生物藥品或輔料的新內(nèi)部參考標(biāo)準(zhǔn)/制劑？修訂 2025年11月
If a new in-house reference standard/preparation for a biological active substance, excipient and/or finished product is introduced using the limits/conditions as detailed in an approved qualification protocol, the new in-house reference standard/preparation is covered by the existing quality assurance system and there is no need to file a variation.
若根據(jù)經(jīng)批準(zhǔn)的確認方案中詳細規(guī)定的限度/條件，引入生物活性物質(zhì)、輔料和/或成品的新內(nèi)部參考標(biāo)準(zhǔn)/制劑，則該新內(nèi)部參考標(biāo)準(zhǔn)/制劑已包含在現(xiàn)有質(zhì)量保證體系內(nèi)，無需提交變更申請。
For other changes to an in-house reference standard/preparation for a biological active substance, excipient and/or finished product, classification scopes under Q.I.b.3 should be used.
對于生物活性物質(zhì)、輔料和/或成品的內(nèi)部參考標(biāo)準(zhǔn)/制劑的其他變更，應(yīng)使用Q.I.b.3類分類范圍。
1.2.10. What changes in manufacturing sites, buildings and rooms are covered by the company Quality Assurance System (GMP)? Rev. Nov 2025
1.2.10. 公司質(zhì)量保證體系（GMP）涵蓋哪些生產(chǎn)場所、建筑和房間的變更？修訂 2025年11月
Provided that module 3 is not impacted, with the exception of section 3.2.A.1 (for biological medicinal products), the changes listed below (not an exhaustive list) are covered under the company’s quality management system and do not require a variation to the Marketing Authorisation:
在不影響3模塊（生物藥品的3.2.A.1章節(jié)除外）的前提下，以下變更（非詳盡列表）由公司質(zhì)量管理體系涵蓋，無需提交上市許可變更：
• Transfer of a manufacturing activity from one building to another in the same authorised site
在同一授權(quán)場所內(nèi)，將生產(chǎn)活動從一棟建筑轉(zhuǎn)移至另一棟建筑
• Transfer of a manufacturing activity from one room to another in the same authorised building
在同一授權(quán)建筑內(nèi)，將生產(chǎn)活動從一個房間轉(zhuǎn)移至另一個房間
• Transfer of QC activity from one building to another in the same authorised site
•在同一授權(quán)場所內(nèi)，將質(zhì)量控制（QC）活動從一棟建筑轉(zhuǎn)移至另一棟建筑
• New filing line identical to an already approved one in an authorised room, building, manufacturing site (in case of a duplication of line to increase the batch size of the final product, a variation under Q.II.b.4 should be submitted).
在授權(quán)房間、建筑或生產(chǎn)場所內(nèi)新增與已批準(zhǔn)生產(chǎn)線相同的灌裝線（若為擴大成品批量而復(fù)制生產(chǎn)線，則應(yīng)提交Q.II.b.4類變更）
• New isolator in an authorised building
在授權(quán)建筑內(nèi)新增隔離器
• New media or buffer preparation room in an authorised building
在授權(quán)建筑內(nèi)新增培養(yǎng)基或緩沖液制備室
• Changes in the layout of an authorised manufacturing site
授權(quán)生產(chǎn)場所的布局變更
If as a result of any of the changes listed above, any amendments are introduced to module 3 (with the exception of section 3.2.A.1 for biological medicinal products), such as changes to the manufacturing site address detail, changes to the manufacturing process, changes to the batch size, etc., the MAH should file the appropriate variation(s).
若上述任何變更導(dǎo)致對3模塊（生物藥品的3.2.A.1章節(jié)除外）進行修訂（例如，生產(chǎn)場所地址細節(jié)變更、生產(chǎn)工藝變更、批量變更等），MAH應(yīng)提交相應(yīng)的變更申請。
1.2.11. Changes in equipment used in the manufacturing process. What changes are covered by the company Quality Assurance System (GMP)? Rev. May 2018
1.2.11. 生產(chǎn)過程中使用的設(shè)備變更：公司質(zhì)量保證體系（GMP）涵蓋哪些變更？修訂 2018年5月
Provided that the new equipment is equivalent to the one currently used, and operates in the approved range of process parameters, the change is covered by company’s quality assurance system.
若新設(shè)備與當(dāng)前使用的設(shè)備具有等效性，且在批準(zhǔn)的工藝參數(shù)范圍內(nèi)運行，則該變更由公司質(zhì)量保證體系涵蓋。
If the introduction of new equipment has any impact on the processes and details registered in module 3 (with the exception of section 3.2.A.1 for biological medicinal products), the MAH should submit the appropriate variation(s).
若新增設(shè)備對3模塊（生物藥品的3.2.A.1章節(jié)除外）中注冊的工藝和細節(jié)產(chǎn)生任何影響，MAH應(yīng)提交相應(yīng)的變更申請。
1.2.12. How should I update section 3.2.A.1 for Biotech medicinal products? Rev. Nov 2025
1.2.12. 如何更新生物技術(shù)藥品的3.2.A.1章節(jié)？修訂 2025年11月
Notice to applicants for Medicinal products for human use (Eudralex – Volume 2B) establishes that information on facilities and equipment should be included in Appendix 3.2.A.1 for biotech medicinal products.
《人用藥品申請人須知》（Eudralex第2B卷）規(guī)定，生物技術(shù)藥品的設(shè)施和設(shè)備信息應(yīng)納入附錄3.2.A.1。
Any update of this section can be included as part of any upcoming variation affecting Module 3. In case the MAH wants to update this section and does not foresee any upcoming variation affecting Module 3 in the short/medium term, the MAH may consider submitting a Type IB variation (Q.II.z).
該章節(jié)的任何更新均可納入任何即將提交的涉及3模塊的變更中。若MAH希望更新該章節(jié)，但短期內(nèi)無涉及3模塊的變更計劃，可考慮提交IB類變更（Q.II.z）。
1.2.13. What do I need to consider if there are any changes to my medical device post-authorisation? Rev. Nov & Dec 2025
1.2.13. 上市后醫(yī)療器械發(fā)生變更需考慮哪些事項？修訂 2025年11月及12月
Information on the lifecycle management of a medical device when used in combination with a medicinal product can be found in ‘Questions & Answers for applicants, marketing authorisation holders of medicinal products and notified bodies regarding medicines used in combination with medical devices and consultation procedures for certain medical devices’.
關(guān)于與藥品聯(lián)合使用的醫(yī)療器械的生命周期管理信息，可參閱《針對申請人、藥品上市許可持有人和公告機構(gòu)的問答：關(guān)于與醫(yī)療器械聯(lián)合使用的藥品及特定醫(yī)療器械的咨詢程序》。
1.2.14. How should I submit the transfer of test methods for testing of medicinal products to a new or already authorized testing site? Which variation classification category is applicable and what type of supporting documentation is expected? Rev. Nov 2025
1.2.14. 如何提交藥品檢測方法向新的或已授權(quán)檢測場所的轉(zhuǎn)移？適用哪一變更分類類別，需提交何種支持性文件？修訂 2025年11月
Although, the need to submit a variation to approve an existing QC testing site for additional testing activities after analytical test transfer has been completed is not specifically foreseen by the EC Variation Classification Guideline submission of a variation following by analogy the existing foreseen variation category Q.I.a.1.i, Q.I.a.1.j, Q.II.b.2.a, Q.II.b.2.b, Q.II.b.2.c.2 or Q.II.b.2.c.3 may be necessary as outlined below under ii.
盡管《歐盟變更分類指南》未明確規(guī)定分析方法轉(zhuǎn)移完成后，需提交變更以批準(zhǔn)現(xiàn)有質(zhì)量控制（QC）檢測場所開展額外檢測活動，但可能需要參照現(xiàn)有預(yù)設(shè)變更類別Q.I.a.1.i、Q.I.a.1.j、Q.II.b.2.a、Q.II.b.2.b、Q.II.b.2.c.2或Q.II.b.2.c.3提交變更，具體如下文ii所述。
i. In case of physical, chemical and microbiological test methods to be transferred to a new testing site (i. e. not yet listed in the dossier) submission of a variation is required (category Q.I.a.1.j, Q.II.b.2 or Q.II.b.2.c.2). The documentation to be submitted is defined in the EC Variation Classification Guideline.
i. 若理化和微生物檢測方法需轉(zhuǎn)移至新檢測場所（即未列入申報資料的場所），需提交變更申請（類別Q.I.a.1.j、Q.II.b.2或Q.II.b.2.c.2）。需提交的文件按《歐盟變更分類指南》規(guī)定執(zhí)行。
ii. In case of biological, immunological, or immunochemical test methods (e.g. in vivo bioassays, in vitro bioassays, enzymatic assays, binding assays, neutralisation assays, immunochemical assays) to be transferred to a new testing site or to an already approved testing site, a variation of type Q.I.a.1.i or Q.II.b.2.b or Q.II.b.2.c.3 is to be submitted.
ii. 若生物、免疫或免疫化學(xué)檢測方法（例如，體內(nèi)生物測定、體外生物測定、酶促測定、結(jié)合測定、中和測定、免疫化學(xué)測定）需轉(zhuǎn)移至新檢測場所或已批準(zhǔn)檢測場所，需提交Q.I.a.1.i、Q.II.b.2.b或Q.II.b.2.c.3類變更。
The documentation should include at a minimum, the method transfer protocols in accordance with Eudralex Volume 4 Chapter 6 article 6.39 (which pre-define the acceptance criteria), from the old site to the new site (or new test laboratory). Depending on the variability of the specific method and the potential risk, to the quality, safety or efficacy of the product, posed by the proposed change, additional data such as a summary of the analytical method transfer test results may be required.
文件應(yīng)至少包含根據(jù)《Eudralex第4卷第6章第6.39條》制定的方法轉(zhuǎn)移方案（其中預(yù)先規(guī)定驗收標(biāo)準(zhǔn)），涵蓋從原場所到新場所（或新檢測實驗室）的轉(zhuǎn)移過程。根據(jù)具體方法的變異性以及擬變更對產(chǎn)品質(zhì)量、安全性或有效性的潛在風(fēng)險，可能需要額外數(shù)據(jù)（例如，分析方法轉(zhuǎn)移試驗結(jié)果摘要）。
1.2.15. Do I need to record in the dossier a new manufacturing site for physical importation? NEW Mar 2021
1.2.15. 是否需要在申報資料中登記新的實物進口生產(chǎn)場所？新增 2021年3月
The Member States shall ensure that the import of medicinal products into their territory is subject to an authorisation in accordance with Article 40(3) of Directive 2001/83/EC.
成員國應(yīng)根據(jù)《2001/83/EC號指令》第40(3)條的規(guī)定，確保藥品進口至其領(lǐng)土需獲得授權(quán)。
Please note that physical importation and batch certification of imported products are different operations that can take place at the same or different authorised manufacturing sites located in the Union (EEA).
需注意，實物進口和進口產(chǎn)品的批次認證是不同的操作，可在歐盟（EEA）內(nèi)同一或不同的授權(quán)生產(chǎn)場所進行。
It is not a requirement to register in the dossier of your marketing authorisation the manufacturer(s) responsible for the physical importation of the finished product, hence no variations applications are required for changes in physical importation sites. The Manufacturing and Importation Authorisation (MIA) holder responsible for batch certification of imported medicinal products should ensure that the site(s) of physical importation is appropriately authorised for this operation. The physical importer needs to hold a MIA with an entry in section 2.3.1 according to the Union Format for MIAs. A technical agreement between the physical importer and the batch release site shall be in place. For more information on the certification by a QP and on batch release in the EU, also with regards to importation, see GMP annex 16.
無需在上市許可申報資料中登記負責(zé)成品實物進口的生產(chǎn)商，因此實物進口場所的變更無需提交變更申請。負責(zé)進口藥品批次認證的生產(chǎn)和進口授權(quán)（MIA）持有人應(yīng)確保實物進口場所已獲得該操作的適當(dāng)授權(quán)。實物進口商需持有符合歐盟MIA格式、且在2.3.1章節(jié)有相關(guān)記載的MIA。實物進口商與批次放行場所之間應(yīng)簽訂技術(shù)協(xié)議。關(guān)于質(zhì)量受權(quán)人（QP）認證及歐盟內(nèi)批次放行（包括進口相關(guān)）的更多信息，參見GMP附件16。
1.3. (Non-) Clinical changes
1.3. （非）臨床變更
1.3.1. What should I consider in relation to the quality documentation in case of a change in the clinical use of marketed products meaning change in therapeutic indication, posology or maximum daily dose (MDD)? NEW Nov 2025
1.3.1. 上市產(chǎn)品的臨床用途發(fā)生變更（即治療適應(yīng)癥、給藥劑量或最大日劑量（MDD）變更）時，質(zhì)量文件需考慮哪些事項？新增 2025年11月
In case of a change in the clinical use of marketed products, meaning change in therapeutic indication (including a change in the target population), posology or maximum daily dose, a review of the quality documentation should always be performed. In this review the MAH should perform an assessment of the impact on the quality documentation of the proposed clinical change. Confirmation that the assessment has been performed should be included as part of the clinical variation. This also applies to generic products and hybrids.
若上市產(chǎn)品的臨床用途發(fā)生變更（即治療適應(yīng)癥（包括目標(biāo)人群變更）、給藥劑量或最大日劑量變更），應(yīng)始終對質(zhì)量文件進行審查。MAH應(yīng)在審查中評估擬議臨床變更對質(zhì)量文件的影響，并將已完成評估的確認納入臨床變更申請中。仿制藥和混合制劑也適用本規(guī)定。
The review performed by the MAH on the quality documentation could lead to the following scenarios:
MAH對質(zhì)量文件的審查可能導(dǎo)致以下兩種情況：
The submission of a quality variation is not required (e.g. the change in MDD does not affect the authorised acceptance criteria and control strategy for impurities). A declaration confirming the conclusions of the assessment needs to be included in the Application Form or as a separate Annex in Module 1.
無需提交質(zhì)量變更（例如，最大日劑量（MDD）變更不影響已批準(zhǔn)的雜質(zhì)驗收標(biāo)準(zhǔn)和控制策略）。需在申請表中或作為1模塊的單獨附件，納入確認評估結(jié)論的聲明。
The submission of the appropriate quality variation under the Quality Changes chapter is needed (e.g. acceptance criteria for an impurity should be changed). A quality variation should be submitted under the appropriate classification according to the Variation classification guideline and grouped with the clinical variation.
需根據(jù)“質(zhì)量變更”章節(jié)提交相應(yīng)的質(zhì)量變更（例如，需變更雜質(zhì)的驗收標(biāo)準(zhǔn)）。質(zhì)量變更應(yīng)按《變更分類指南》的相應(yīng)分類提交，并與臨床變更納入組合申報。
For both scenarios non-exhaustive examples are given below:
以下為兩種情況的非詳盡示例：
Changes to the clinical use of marketed products can warrant a re-evaluation of the mutagenic impurity limits:
上市產(chǎn)品的臨床用途變更可能需要重新評估致突變雜質(zhì)限度：
a. An increase in clinical dose, e.g. changes in the MDD could impact the authorised control strategy for mutagenic impurities, including N-nitrosamines, in active substances and medicinal products.
a. 臨床劑量增加（例如，最大日劑量（MDD）變更）可能影響活性物質(zhì)和藥品中致突變雜質(zhì)（包括N-亞硝胺）的已批準(zhǔn)控制策略。
b. An increase in duration of use, e.g. when a mutagenic impurity was controlled above the lifetime acceptable intake for a previous indication that may no longer be appropriate for the longer treatment duration associated with the new indication.
b. 用藥持續(xù)時間延長（例如，某一致突變雜質(zhì)在原有適應(yīng)癥中的控制水平高于終身可接受攝入量，而該水平對于新適應(yīng)癥的較長治療周期可能不再適用）。
c. A change in indication from a serious or life-threatening condition where higher acceptable intakes were justified to an indication for a less serious condition where the existing mutagenic impurity acceptable intakes may no longer be appropriate, e.g. for products initially intended for advanced cancer only as defined in the scope of the ICH S9 guideline, where N-nitrosamine impurities controlled according to ICH Q3A(R2) and ICH Q3B(R2) guidelines is no longer applicable.
c. 適應(yīng)癥從嚴重或危及生命的疾病變更為較輕疾病（原有適應(yīng)癥中較高的可接受攝入量具有合理性，但對于較輕疾病可能不再適用），例如，最初僅適用于ICH S9指南范圍內(nèi)的晚期癌癥的產(chǎn)品，其按ICH Q3A(R2)和ICH Q3B(R2)指南控制的N-亞硝胺雜質(zhì)限度可能不再適用。
Changes to the clinical use of marketed products can warrant a re-evaluation of organic impurities limits according to ICH Q3A and Q3B guidelines since reporting, identification and qualification threshold are established based on the MDD.
上市產(chǎn)品的臨床用途變更可能需要根據(jù)ICH Q3A和Q3B指南重新評估有機雜質(zhì)限度，因為報告閾值、鑒定閾值和界定閾值均基于最大日劑量（MDD）制定。
Changes to the clinical use of marketed products can warrant a re-evaluation of elemental impurities, as individual permitted daily exposures (PDEs) are set based on the MDD and the route of administration, according to ICH Q3D.
上市產(chǎn)品的臨床用途變更可能需要根據(jù)ICH Q3D指南重新評估元素雜質(zhì)，因為單個允許日暴露量（PDE）基于最大日劑量（MDD）和給藥途徑制定。
Changes to the clinical use of marketed products can warrant a re-evaluation of endotoxins limits for parenteral products considering the calculation formula included in European pharmacopoeia General chapter 5.1.10.
上市產(chǎn)品的臨床用途變更可能需要重新評估注射劑的內(nèi)毒素限度，參考歐洲藥典通則5.1.10中的計算公式。
Changes to the clinical use of marketed products can warrant a re-evaluation of the appropriateness of the pharmaceutical form, container closure system or dosing devices where a new target population is applied for (e.g. paediatric population, home versus hospital setting); refer to question on ‘Will I need to provide a (new or updated) EU declaration of conformity/certificate of conformity issued by a notified body/notified body opinion if there are changes to the device (or device part) after the initial marketing authorisation of the integral DDC?’ in ‘Questions & Answers for applicants, marketing authorisation holders of medicinal products and notified bodies with respect to the implementation of the Regulations on medical devices and in vitro diagnostic medical devices (Regulations (EU) 2017/745 and (EU) 2017/746)’.
若目標(biāo)人群發(fā)生變更（例如，兒科人群、家庭使用與醫(yī)院使用場景變更），上市產(chǎn)品的臨床用途變更可能需要重新評估劑型、包裝密封系統(tǒng)或給藥裝置的適用性；具體可參閱《針對申請人、藥品上市許可持有人和公告機構(gòu)的問答：關(guān)于醫(yī)療器械和體外診斷醫(yī)療器械法規(guī)（歐盟2017/745號和2017/746號法規(guī)）的實施》中“若整體組合醫(yī)療器械（DDC）初始上市許可后，醫(yī)療器械（或其部件）發(fā)生變更，是否需要提供公告機構(gòu)出具的（新的或更新的）歐盟符合性聲明/證書或公告機構(gòu)意見？”這一問題。
Changes to the clinical use of marketed products can warrant a re-evaluation of the compatibility studies with reconstitution diluents in the extremes of concentration of the product to be administered due to a change in the posology/target population.
由于給藥劑量/目標(biāo)人群變更，上市產(chǎn)品的臨床用途變更可能需要重新評估產(chǎn)品在給藥濃度極值下與復(fù)溶稀釋劑的相容性研究。
Changes to the clinical use of marketed products can warrant a re-evaluation of instructions for administration and the feasibility of dosing (e.g. with regards to volumes to be measured, measuring device to be included or recommended, and dilutions to be used).
上市產(chǎn)品的臨床用途變更可能需要重新評估給藥說明和給藥可行性（例如，需測量的體積、應(yīng)包含或推薦的測量裝置以及擬使用的稀釋液）。
Changes to the clinical use of marketed products can warrant a re-evaluation of the excipient safety and the need for excipient warnings, as excipient safety should be based on daily exposures (mg/kg), which are set based on the MDD and the route of administration. Excipient safety should also consider target population, changes in age range, in particular where younger subsets are included.
上市產(chǎn)品的臨床用途變更可能需要重新評估輔料安全性及是否需要添加輔料警示語，因為輔料安全性基于日暴露量（mg/kg），而日暴露量根據(jù)最大日劑量（MDD）和給藥途徑制定。輔料安全性還應(yīng)考慮目標(biāo)人群、年齡范圍變更（尤其是納入較年輕人群時）。
1.3.2. How should I submit a study protocol? Rev. Nov 2025
1.3.2. 如何提交研究方案？修訂 2025年11月
For imposed, non-interventional safety studies, the initial protocol submission should follow the provisions under Article 107n of Directive 2001/83/EC. Substantial amendments of such study protocol should be submitted under the provision of Article 107o of Directive 2001/83/EC (please also refer to guidance on PASS).
對于強制性非干預(yù)性安全性研究，初始方案提交應(yīng)遵循《2001/83/EC號指令》第107n條的規(guī)定。此類研究方案的重大修訂應(yīng)遵循《2001/83/EC號指令》第107o條的規(guī)定提交（另請參閱上市后安全性研究（PASS）相關(guān)指導(dǎo)文件）。
For other studies (i.e. non-imposed studies and/or interventional studies), if the initial assessment or the amendment of a study protocol does not result in a consequential change of the condition as reflected in Annex II and/ or the description of the study in the RMP it can be provided as a postauthorisation measure (PAM) (please also refer to the EMA guidance on post-authorisation measures: ‘Under which procedure should I submit my PAM?’).
對于其他研究（即非強制性研究和/或干預(yù)性研究），若研究方案的初始評估或修訂未導(dǎo)致附件II中所述條件和/或風(fēng)險管理計劃（RMP）中研究描述發(fā)生相應(yīng)變更，則可作為上市后措施（PAM）提交（另請參閱EMA關(guān)于上市后措施的指導(dǎo)文件：“我的上市后措施（PAM）應(yīng)通過何種程序提交？”）。
Once agreed, the MAH can take the opportunity of a regulatory procedure affecting the RMP to include the final updated protocol in the appropriate RMP annex(es).
方案獲得認可后，MAH可在涉及RMP的監(jiān)管程序中，將最終更新的方案納入相應(yīng)的RMP附件。
If the study description in the Annex II condition and/ or in the RMP is affected, the study protocol/ or the protocol amendment, together with the proposed updated Annex II and/or RMP should be provided as part of a type II variation application under category C.9.c.
若附件II條件和/或RMP中的研究描述受到影響，則研究方案/方案修訂應(yīng)連同擬更新的附件II和/或RMP，作為C.9.c類II類變更申請的一部分提交。
A change that affects the due date of the milestones for non-imposed studies and/or interventional studies listed in the Annex II and/or RMP can be submitted as Type IB variation under category C.9.b.
若變更影響附件II和/或RMP中所列非強制性研究和/或干預(yù)性研究的里程碑截止日期，可通過C.9.b類IB類變更提交。
1.3.3. How should non-clinical and/or clinical study reports be provided? Rev. Nov/Dec 2025 (typo correction)
1.3.3. 如何提交非臨床和/或臨床研究報告？修訂 2025年11月/12月（文字糾錯）
In line with the 'Variations Guidelines’ all ‘final’ non-clinical or clinical study reports concerning a marketing authorisation granted under the centralised procedure will have to be submitted to the Agency as part of a type II variation application, unless otherwise specifically covered in the annex to the classification guideline on variations or listed below:
根據(jù)《變更指南》，所有與集中審批程序授予的上市許可相關(guān)的“最終”非臨床或臨床研究報告，均需作為II類變更申請的一部分提交至EMA，除非變更分類指南附件中另有明確規(guī)定或?qū)儆谝韵虑闆r：
Results of imposed non-interventional safety studies covered by the Art. 107q of the Directive 2001/83/EC;
《2001/83/EC號指令》第107q條涵蓋的強制性非干預(yù)性安全性研究結(jié)果；
Submissions of final study results in support of extension of marketing authorisation applications, annual renewals or annual re-assessments;
為支持上市許可擴展申請、年度續(xù)期或年度重新評估而提交的最終研究結(jié)果；
Submission of study results related to paediatric population in line with Article 46 of Regulation 1901/2006. Submissions pursuant to Article 46 should continue to follow the procedure for postauthorisation measures, unless the MAH concludes that changes to the product information (PI) are warranted based on the data submitted. In such cases, the relevant variation should be submitted;
根據(jù)《1901/2006號法規(guī)》第46條提交的兒科人群相關(guān)研究結(jié)果。根據(jù)第46條提交的材料應(yīng)繼續(xù)遵循上市后措施程序，除非MAH根據(jù)提交的數(shù)據(jù)得出需變更產(chǎn)品信息（PI）的結(jié)論，在此情況下應(yīng)提交相應(yīng)變更；
Studies in the context of an environmental risk assessment (ERA). These are expected to be assessed during the initial marketing authorisation or relevant post-marketing procedures (e.g. extension of indication, extension applications). In the exceptional case that ERA study results are provided stand-alone, they should be submitted as a type IB C.z variation;
環(huán)境風(fēng)險評估（ERA）相關(guān)研究。此類研究應(yīng)在初始上市許可或相關(guān)上市后程序（例如，適應(yīng)癥擴展、擴展申請）中進行評估。在特殊情況下，若單獨提交ERA研究結(jié)果，應(yīng)作為IB類C.z變更提交；
Results including reports from bioequivalence studies to support quality changes to the marketing authorisation should be submitted under the applicable variation category for quality changes.
支持上市許可質(zhì)量變更的生物等效性研究結(jié)果（包括報告），應(yīng)按適用的質(zhì)量變更分類類別提交。
As a general rule, the ‘final’ study report is considered the one including the primary analysis of the study. In case the final study report has previously been submitted, further updates of data from the study without formal statistical significance after the primary analysis do not trigger additional variations, unless they lead to changes to the product information and/or to the Risk Management Plan (RMP). On the other hand, a formal extension study, generally with a different study design and objectives as compared to the initial study, is considered a separate study and it generally carries a separate study number. The submission of the final report for such an extension study triggers a variation.
一般而言，“最終”研究報告指包含研究主要分析結(jié)果的報告。若最終研究報告已提交，主要分析后無正式統(tǒng)計學(xué)意義的數(shù)據(jù)更新無需觸發(fā)額外變更，除非這些更新導(dǎo)致產(chǎn)品信息（PI）和/或風(fēng)險管理計劃（RMP）發(fā)生變更。反之，正式的擴展研究（通常與初始研究的研究設(shè)計和目標(biāo)不同）視為獨立研究，通常具有單獨的研究編號，提交該擴展研究的最終報告需觸發(fā)變更。
When a change to the product information is proposed as a consequence of the final study report, the type II variation should be submitted under variation classification categories C.a (extension of indication), C (other changes involving the SmPC, Annex II, labelling and/or Package Leaflet) or C.9.c (changes limited to the Annex II conditions). When no changes to the product information are proposed, the variation should be submitted under category C.12.
若根據(jù)最終研究報告擬變更產(chǎn)品信息（PI），II類變更應(yīng)按以下分類類別提交：C.a（適應(yīng)癥擴展）、C（涉及產(chǎn)品特性摘要（SmPC）、附件II、標(biāo)簽和/或說明書的其他變更）或C.9.c（僅限于附件II條件的變更）。若不擬變更產(chǎn)品信息（PI），則應(yīng)按C.12類提交變更。
When a final non-clinical or clinical study report is provided as part of a variation submitted under category C.12, it should be noted that one separate type II variation per study report is required. This requirement applies also in situations where the CHMP has requested several non-clinical or clinical studies to be undertaken as part of a specific post-authorisation measure (PAM) in order to address a specific issue; one type II variation under category C.12 per final study report will still be requested (provided that the product information remains unaffected) .
需注意，若最終非臨床或臨床研究報告作為C.12類變更的一部分提交，則每份研究報告需對應(yīng)一項單獨的II類變更。即使人用藥品委員會（CHMP）要求開展多項非臨床或臨床研究作為特定上市后措施（PAM）的一部分以解決某一問題，該要求仍然適用——每份最終研究報告需提交一項C.12類II類變更（前提是產(chǎn)品信息未受影響）。
It should be noted that these requirements also apply to all non-clinical studies, including the provision of final study reports for in vitro studies.
需注意，這些要求同樣適用于所有非臨床研究，包括體外研究的最終研究報告提交。
In case the final non-clinical or clinical study report leads to consequential changes to the RMP, the MAH can include an updated RMP version as part of the type II variation regardless of whether it is submitted under category C.6, C.4, C.9 or C.12.
若最終非臨床或臨床研究報告導(dǎo)致RMP發(fā)生相應(yīng)變更，則無論變更按C.6、C.4、C.9還是C.12類提交，MAH均可將更新后的RMP版本納入II類變更申請。
With regard to ‘interim’ non-clinical or clinical study results, the timelines of the progress reports for a given study should be pre-specified and indicated in the protocol. These progress reports may include available interim results, but there is in general no obligation or recommendation to include interim results in RMPs unless required as part of an agreed pharmacovigilance plan. In this case, for CAPs, the specified progress report(s)/interim results should be submitted as PAM unless the MAH considers that the interim data would require consequential changes to the product information and/or the RMP in which case a type II variation should be submitted instead. On the other hand, interim results should be reported in relevant PSURs.
關(guān)于“中期”非臨床或臨床研究結(jié)果，某一研究的進展報告時間線應(yīng)在方案中預(yù)先規(guī)定并注明。這些進展報告可包含已有的中期結(jié)果，但一般無義務(wù)或建議將中期結(jié)果納入RMP，除非作為已商定藥物警戒計劃的一部分有此要求。對于糾正和預(yù)防措施（CAPs），若有相關(guān)要求，指定的進展報告/中期結(jié)果應(yīng)作為上市后措施（PAM）提交，除非MAH認為中期數(shù)據(jù)需導(dǎo)致產(chǎn)品信息（PI）和/或RMP發(fā)生相應(yīng)變更，在此情況下應(yīng)提交II類變更。此外，中期結(jié)果應(yīng)在相關(guān)的定期安全性更新報告（PSUR）中報告。
When interim results have been requested by the CHMP and are provided in order to address a specific post-authorisation measure (PAM), the data should be submitted in line with the requirements of the PAM procedure, unless the MAH considers that the interim data result in consequential changes to the product information and/or the RMP in which case a type II variation should be submitted instead.
若CHMP要求提供中期結(jié)果以解決特定上市后措施（PAM）相關(guān)問題，則應(yīng)按PAM程序要求提交數(shù)據(jù)，除非MAH認為中期數(shù)據(jù)需導(dǎo)致產(chǎn)品信息（PI）和/或RMP發(fā)生相應(yīng)變更，在此情況下應(yīng)提交II類變更。
With reference to analyses across studies on specific topics (e.g. a biomarker report from more than one study) for which the individual final study reports have previously been submitted, the analysis should be submitted under category C.4 (in case of changes to the product information), under category C.9 (changes limited to the Annex II conditions) or as a PAM (no changes to the product information and/or the RMP are warranted). When the analyses should be submitted as variations, one variation scope per analysis (and not per study included in the analysis) should be submitted.
對于基于多項研究的特定主題分析（例如，來自多項研究的生物標(biāo)志物報告），若相關(guān)單項最終研究報告已提交，則該分析應(yīng)按以下方式提交：C.4類（若涉及產(chǎn)品信息變更）、C.9類（僅限于附件II條件變更）或作為上市后措施（PAM）（無需變更產(chǎn)品信息和/或RMP）。若分析需作為變更提交，則每項分析需對應(yīng)一個變更范圍（而非分析中涉及的每項研究）。
Final results from an imposed non-interventional post-authorisation safety study (PASS category 1 and 2 in the RMP and reflected in Annex II) should be submitted within 12 months of the end of data collection unless a written waiver has been granted by PRAC, as appropriate (please refer to guidance on imposed post-authorisation safety studies). It should be noted that the submission of final results of imposed non-interventional studies should follow the relevant Art 107q of Directive 2001/83/EC procedure (please also refer to guidance on post-authorisation safety studies), regardless of whether or not the MAH considers that changes to the product information are warranted.
強制性非干預(yù)性上市后安全性研究（PASS）（RMP中列為1類和2類且反映在附件II中）的最終結(jié)果，應(yīng)在數(shù)據(jù)收集結(jié)束后12個月內(nèi)提交，除非藥品風(fēng)險評估委員會（PRAC）酌情授予
When a change to the product information is proposed for a medicinal product containing more than one active substance to implement changes that were already assessed by a EU competent authority for a medicinal product containing one of the active substances and the same wording is proposed, the change and supportive data should be submitted as a Type II variation under category C.4.
若含多種活性物質(zhì)的藥品擬變更產(chǎn)品信息，且該變更所采用的表述與某一含單一活性物質(zhì)藥品的歐盟主管部門已評估通過的表述一致，則該變更及支持性數(shù)據(jù)應(yīng)作為C.4類II類變更提交。
Any pre-submission queries in this regard should be addressed to the appointed Product Lead.
相關(guān)預(yù)審咨詢應(yīng)聯(lián)系指定的產(chǎn)品負責(zé)人。
1.3.4. What changes to the product information (PI) can be included as part of one type II variation? Rev. Nov 2025
1.3.4. 哪些產(chǎn)品信息（PI）變更可納入單一II類變更申報？修訂 2025年11月
In principle, one change to the PI supported by one set of data constitutes one assessment and subsequently one scope i.e. one type II variation.
原則上，一項由一套數(shù)據(jù)支持的產(chǎn)品信息（PI）變更構(gòu)成一項評估，對應(yīng)一個申報范圍，即一項II類變更。
All data/study reports provided as part of a variation must support the same changes to the SmPC. If this is not the case, i.e. some data support one change (update A), and other data support another change (update B), it will be necessary to submit separate stand-alone variations or a group of variations, as appropriate; one variation for SmPC update A including the data supporting A, and one variation for SmPC update B including the data supporting B.
變更申報中提供的所有數(shù)據(jù)/研究報告必須支持同一產(chǎn)品特性摘要（SmPC）變更。若情況并非如此（即部分數(shù)據(jù)支持一項變更（更新A），其他數(shù)據(jù)支持另一項變更（更新B）），則需酌情提交單獨的獨立變更或組合變更：一項針對SmPC更新A的變更（含支持A的數(shù)據(jù)），以及一項針對SmPC更新B的變更（含支持B的數(shù)據(jù)）。
In the event that some of the data/study reports proposed to be part of an application do not support any of the proposed changes to the SmPC, the reports give rise to separate variation scopes (category C.12 – one variation per final study report as explained under ‘How should non-clinical and/or clinical study reports be provided?’), which could potentially be grouped in the same submission or may need to be removed from the proposed variation application and submitted as a separate appropriate application.
若申報中部分擬納入的數(shù)據(jù)/研究報告不支持任何擬議的SmPC變更，則這些報告應(yīng)作為單獨的變更范圍申報（C.12類——如“如何提交非臨床和/或臨床研究報告？”所述，每份最終研究報告對應(yīng)一項變更），可納入同一組合申報，或需從擬議變更申請中移除并作為單獨的適當(dāng)申請?zhí)峤弧?/span>
Thus, only when changes are consequential to the same supporting data, can one type II variation application propose changes to several different sections of the SmPC as well as corresponding changes to the Package Leaflet. Any additional changes to the PI that are consequential to the assessment of another set of data will have to be submitted as part of a separate variation (standalone or part of a grouped application to be decided on a case-by-case basis).
因此，僅當(dāng)變更源于同一支持性數(shù)據(jù)時，一項II類變更申請才可同時提議對SmPC多個不同章節(jié)的變更以及說明書的相應(yīng)變更。任何源于另一套數(shù)據(jù)評估的額外產(chǎn)品信息（PI）變更，均需作為單獨變更的一部分提交（獨立申報或納入組合申報，視具體情況而定）。
Some theoretical examples are being provided below to illustrate the principles explained above.
以下通過理論示例說明上述原則：
Example 1
示例1
Proposed application: Provision of final clinical study reports (CSR) for 3 PK studies (studies X, Y, Z).
擬申報內(nèi)容：提交3項藥代動力學(xué)（PK）研究的最終臨床研究報告（CSR）（研究X、Y、Z）。
If the data from the 3 CSRs support the same SmPC updates, the reports should be submitted as part of one single type II variation under category C.4 (scope = ‘update of the SmPC based on the results from studies X, Y and Z’).
若3份CSR的數(shù)據(jù)支持同一SmPC更新，則這些報告應(yīng)作為C.4類單一II類變更的一部分提交（范圍=“基于研究X、Y、Z的結(jié)果更新SmPC”）。
If two study reports (X, Y) support one SmPC change (update A), and the 3rd study report (Z) supports a different SmPC change, the applicant should submit one type II variation under category C.4 for SmPC update A and one type II variation under category C.4 for SmPC update B. The two variations can in this case be submitted as part of a grouped application, as it makes sense to assess the 3 PK studies together (scope = ‘update A of the SmPC based on the results of studies X and Y, and update B of the SmPC based on the results of study Z’).
若兩份研究報告（X、Y）支持一項SmPC變更（更新A），第三份研究報告（Z）支持另一項SmPC變更（更新B），則申請人應(yīng)提交一項針對SmPC更新A的C.4類II類變更，以及一項針對SmPC更新B的C.4類II類變更。由于將3項PK研究一并評估具有合理性，這兩項變更可納入同一組合申報（范圍=“基于研究X、Y的結(jié)果進行SmPC更新A，基于研究Z的結(jié)果進行SmPC更新B”）。
If two study reports (X, Y) support all proposed SmPC changes and the 3rd study report (Z) does not result in any consequential changes to the SmPC at all, the applicant should submit a grouped application including one type II variation under category C.4 (studies X, Y) and one type II variation under category C.12 (study Z). The two variations can in this case be submitted as part of a grouped application, as it makes sense to assess the 3 PK studies together (scope = ‘update of the SmPC based on the results of studies X and Y. The applicant also provides study Z as a grouped variation as a common assessment of these changes is considered meaningful’).
若兩份研究報告（X、Y）支持所有擬議的SmPC變更，第三份研究報告（Z）未導(dǎo)致任何SmPC相應(yīng)變更，則申請人應(yīng)提交組合申報，包含一項C.4類II類變更（研究X、Y）和一項C.12類II類變更（研究Z）。由于將3項PK研究一并評估具有合理性，這兩項變更可納入同一組合申報（范圍=“基于研究X、Y的結(jié)果更新SmPC。申請人同時將研究Z作為組合變更提交，因其共同評估具有實際意義”）。
Example 2
示例2
Proposed application: Provision of one CSR for study A supporting SmPC changes regarding efficacy in patient population A and overall clinical safety, and one CSR for study B supporting SmPC changes regarding efficacy in patient population B and overall clinical safety.
擬申報內(nèi)容：提交研究A的CSR（支持針對患者群體A的療效及整體臨床安全性相關(guān)SmPC變更），以及研究B的CSR（支持針對患者群體B的療效及整體臨床安全性相關(guān)SmPC變更）。
In view of the fact that the efficacy data are unrelated and concern two separate patient populations, two separate assessments will need to be undertaken and two separate Type II variations will be required. However, as the scopes of the two variations are both partly related to overall clinical safety, it is meaningful to assess them together and the applicant should therefore provide the two variations as part of one grouped application.
由于療效數(shù)據(jù)互不相關(guān)且涉及兩個獨立患者群體，需進行兩項單獨評估并提交兩項獨立II類變更。但鑒于兩項變更的范圍均部分涉及整體臨床安全性，一并評估具有合理性，因此申請人應(yīng)將兩項變更納入同一組合申報。
However, in the event that the data sets would be completely unrelated - e.g. because of different safety profiles in the two patient populations due to different posology - the reports should be provided as part of two separate stand-alone Type II variations; one for patient population A (efficacy and safety) and one for patient population B (efficacy and safety).
但若數(shù)據(jù)集完全無關(guān)（例如，由于給藥劑量不同，兩個患者群體的安全性特征存在差異），則應(yīng)將報告作為兩項獨立的II類變更提交：一項針對患者群體A（療效及安全性），另一項針對患者群體B（療效及安全性）。
Example 3
示例3
Proposed application: Update of the SmPC section 4.8 in order to add three new ADRs; ‘dyspnoea’ and ‘chromaturia’ following a review of the MAH’s safety database undertaken upon request by PRAC following a PSUSA procedure, and ‘Kounis syndrome’ following the MAH’s own signal detection.
擬申報內(nèi)容：更新SmPC第4.8節(jié)，新增三項不良反應(yīng)（ADR）：應(yīng)PRAC要求，在上市后安全性更新評估（PSUSA）程序后審查MAH的安全性數(shù)據(jù)庫得出的“呼吸困難（dyspnoea）”和“血尿（chromaturia）”，以及MAH自行信號檢測發(fā)現(xiàn)的“庫尼斯綜合征（Kounis syndrome）”。
As the three ADRs are supported by two separate data sets the MAH should submit two variations as part of a grouped application; one type II variation under category C.3.c to add ‘dyspnoea’ and ‘chromaturia’, and one Type II variation under category C.4 to add ‘Kounis syndrome’. Both variations are related to clinical safety and it makes sense to assess them together hence the acceptability of the grouping.
由于三項不良反應(yīng)由兩套獨立數(shù)據(jù)集支持，MAH應(yīng)提交兩項變更作為組合申報的一部分：一項C.3.c類II類變更（新增“呼吸困難”和“血尿”），以及一項C.4類II類變更（新增“庫尼斯綜合征”）。兩項變更均與臨床安全性相關(guān)，一并評估具有合理性，因此該組合申報可被接受。
Example 4
示例4
Proposed application: Type II variation under category C.6.a in order to propose an extension of indication, which will include both non-clinical and clinical studies.
擬申報內(nèi)容：提交C.6.a類II類變更，提議擴展適應(yīng)癥，申報材料包含非臨床和臨床研究。
Provided that all non-clinical and clinical data that will be submitted as part of the application are supportive of the new claimed indication, the studies should be provided as part of the application without the need for any additional variation.
若申報中所有非臨床和臨床數(shù)據(jù)均支持所聲稱的新適應(yīng)癥，則這些研究可直接作為該變更申請的一部分提交，無需額外申報其他變更。
However, in the event that e.g. one of the non-clinical studies is not supportive of the proposed extension of indication, it will need to be submitted as part of a separate variation application (stand-alone or part of a grouped application to be decided on a case-by-case basis).
但若例如其中一項非臨床研究不支持擬議的適應(yīng)癥擴展，則該研究需作為單獨變更申請的一部分提交（獨立申報或納入組合申報，視具體情況而定）。
Any pre-submission queries in this regard should be addressed to the Product Lead.
相關(guān)預(yù)審咨詢應(yīng)聯(lián)系產(chǎn)品負責(zé)人。
1.3.5. How do I submit changes to the Summary of Pharmacovigilance System for medicinal products for human use? Rev. Nov 2025
1.3.5. 如何提交人用藥品藥物警戒系統(tǒng)摘要的變更？修訂 2025年11月
As of 1 February 2016, changes to the summary of the pharmacovigilance system – changes in QPPV (including contact details) and/or changes in the Pharmacovigilance Master File (PSMF) location are to be notified to the authorities through the Art 57 database only without the need for any further variation.
自2016年2月1日起，藥物警戒系統(tǒng)摘要的變更——包括質(zhì)量授權(quán)人（QPPV）變更（含聯(lián)系方式）和/或藥物警戒主文件（PSMF）地點變更——僅需通過第57條數(shù)據(jù)庫通知主管部門，無需提交額外變更申請。
Upon a change in the QPPV or location of the PMSF, the Art 57 database should be updated by the MAH immediately to allow continuous supervision by the Competent Authorities.
若QPPV或PSMF地點發(fā)生變更，MAH應(yīng)立即更新第57條數(shù)據(jù)庫，以便主管部門進行持續(xù)監(jiān)管。
Please also refer to Question How to inform the authorities of a change in the summary of the pharmacovigilance system? in the Pharmacovigilance system section of the Post-Authorisation Guidance.
另請參閱《上市后指導(dǎo)文件》中“藥物警戒系統(tǒng)”章節(jié)的“如何通知主管部門藥物警戒系統(tǒng)摘要的變更？”這一問題。
References
參考文獻
News Item: Regulatory information – Green light for reliance on Article 57 database for key pharmacovigilance information on medicines for human use in Europe
新聞稿：監(jiān)管信息——歐洲人用藥品關(guān)鍵藥物警戒信息可依賴第57條數(shù)據(jù)庫
Art 57 Reporting requirements for Marketing Authorisation Holders
第57條 上市許可持有人的報告要求
Detailed Guidance on electronic submission of information on medicines
藥品信息電子提交詳細指導(dǎo)文件
1.3.6. How should I submit data requested as a follow-up to a prior regulatory procedure? Rev. Nov 2025
1.3.6. 如何提交先前監(jiān)管程序要求的后續(xù)數(shù)據(jù)？修訂 2025年11月
Occasionally, the outcome of a regulatory procedure may require the MAH to follow-up on certain aspects in a subsequent regulatory submission. The type of submission required depends on the nature of the data requested and whether the implementation impacts the Product Information (PI) and/or the Risk Management Plan (RMP).
監(jiān)管程序的結(jié)果有時可能要求MAH在后續(xù)監(jiān)管申報中跟進某些事項。申報類型取決于所要求數(shù)據(jù)的性質(zhì)，以及實施該數(shù)據(jù)是否會影響產(chǎn)品信息（PI）和/或風(fēng)險管理計劃（RMP）。
If the outcome of the prior regulatory procedure requests the submission of a (non-)clinical study report, this should always be submitted as a variation (unless this is a paediatric study submitted under Article 46 of the Paediatric Regulation (EC) 1901/2006). Any other requested information (e.g. cumulative safety review) should be submitted as a variation if it has impact for the PI or the RMP. In other cases, it can be accepted as a Post Authorisation Measure (PAM).
若先前監(jiān)管程序的結(jié)果要求提交（非）臨床研究報告，則該報告應(yīng)始終作為變更提交（除非是根據(jù)《兒科法規(guī)（EC）1901/2006》第46條提交的兒科研究）。任何其他要求提交的信息（例如，累積安全性審查），若對PI或RMP有影響，應(yīng)作為變更提交；否則可作為上市后措施（PAM）提交。
Similarly, if the prior procedure already recommends changes to the PI or the RMP, these should be submitted as variation, unless the MAH would like to provide a justification why such changes are not supported by the MAH. In the latter case, the rationale for not submitting a variation proposing the indicated PI and/or RMP changes and any requested data supporting the rationale can be submitted as a PAM. If however the data requested involves the submission of a final (non-)clinical study report, a variation should always be submitted even if no changes to the PI and/or RMP are proposed (with the exception of submissions under Article 46 of the Paediatric Regulation (EC) No 1901/2006).
同樣，若先前程序已建議變更PI或RMP，則應(yīng)作為變更提交，除非MAH希望提供理由說明不支持該等變更。在后一種情況下，不提交提議PI和/或RMP變更的變更申請的理由，以及支持該理由的所有要求數(shù)據(jù)，可作為PAM提交。但若要求提交的數(shù)據(jù)涉及最終（非）臨床研究報告，則無論是否提議變更PI和/或RMP，均應(yīng)提交變更（根據(jù)《兒科法規(guī)（EC）1901/2006》第46條提交的除外）。
The classification of the variation depends on the nature of the prior procedure the outcome of which is being implemented:
變更的分類取決于所實施的先前程序結(jié)果的性質(zhì)：
for implementation of the outcome of a Union referral procedure, the applicable variation category is C.1.
實施歐盟轉(zhuǎn)診程序的結(jié)果：適用變更類別為C.1。
for implementation of the outcome of a PSUR, PASS protocol or PASS results procedure, or the outcome of a PRAC signal recommendation, or to adapt to a joint recommendation of EU competent authorities, the applicable variation category is C.3. It should be noted that PI changes resulting from PSUR data should ideally be implemented within the PSUR procedure itself; only if additional data are required to support the PI changes which cannot be submitted and assessed during the PSUR procedure, should a follow-up variation of the C.3 category be submitted.
實施定期安全性更新報告（PSUR）、上市后安全性研究（PASS）方案或結(jié)果程序的結(jié)果，或PRAC信號建議的結(jié)果，或適應(yīng)歐盟主管部門的聯(lián)合建議：適用變更類別為C.3。需注意，由PSUR數(shù)據(jù)得出的PI變更理想情況下應(yīng)在PSUR程序內(nèi)實施；僅當(dāng)需要額外數(shù)據(jù)支持PI變更且該數(shù)據(jù)無法在PSUR程序中提交和評估時，才需提交C.3類后續(xù)變更。
in case of a procedure under article 46 of Paediatric Regulation No (EC) 1901/2006, the applicable variation scope is C.3 only in case changes to the PI are proposed. In principle, it is expected that in most cases PI changes are to be proposed. In the exceptional case that no changes to the PI are proposed, a PAM procedure should be applied for (see also question How should non-clinical and/or clinical study reports be provided?)
實施《兒科法規(guī)（EC）1901/2006》第46條規(guī)定的程序：僅當(dāng)提議變更PI時，適用變更范圍為C.3。原則上，大多數(shù)情況下應(yīng)提議PI變更；特殊情況下若不提議PI變更，則應(yīng)申請PAM程序（另請參閱“如何提交非臨床和/或臨床研究報告？”）。
for the alignment of the PI of a generic, hybrid or biosimilar medicine to that of the reference product the applicable variation category is C.2 with the exception of the implementation of wording from PSUR and PASS procedures; the applicable scope category in such cases is C.3.
仿制藥、混合制劑或生物類似藥的PI與參比制劑保持一致：適用變更類別為C.2，但實施PSUR和PASS程序相關(guān)表述的情況除外，該等情況適用變更范圍為C.3。
any other prior regulatory recommendation should be implemented via: a C.4 variation category, if changes to the PI are proposed; a C.9 variation category, if changes to the conditions in Annex II of the PI or in the RMP are proposed; a C.12 variation category, if a final (non-)clinical study report is being submitted; a PAM, if a paediatric final study report is being submitted under the requirements of Article 46 of Paediatric Regulation 1901/2006 and in all other cases where requested data and analyses are being submitted without an impact to the PI (including Annex II) and the RMP (please also refer to question Under which procedure should I submit my PAM?).
其他先前監(jiān)管建議的實施：若提議變更PI，通過C.4類變更；若提議變更PI附件II中的條件或RMP，通過C.9類變更；若提交最終（非）臨床研究報告，通過C.12類變更；若根據(jù)《兒科法規(guī)1901/2006》第46條要求提交兒科最終研究報告，或提交的要求數(shù)據(jù)和分析對PI（含附件II）及RMP無影響，通過PAM（另請參閱“我的上市后措施（PAM）應(yīng)通過何種程序提交？”）。
1.3.7. What is considered a new or modified therapeutic indication? Rev. Nov 2025
1.3.7. 什么構(gòu)成新的或經(jīng)修改的治療適應(yīng)癥？修訂 2025年11月
Applications proposing changes to the therapeutic indication aiming to extend the target population (either by modifying an existing indication(s) or by extending in a completely new indication/target disease) trigger paediatric and orphan requirements (please refer to questions ‘What aspects should I consider at time of submission of a Type II variation if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication?’, ‘Do I need to address any paediatric requirements in my type II variation application?’, ‘What aspects should I consider at time of submission of an extension application if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication?’ and ‘Do I need to address any paediatric requirements in my extension application?’ in the post-authorisation guidance for type II variations and Extension of Marketing Authorisations).
提議變更治療適應(yīng)癥以擴展目標(biāo)人群（無論是修改現(xiàn)有適應(yīng)癥還是擴展至全新適應(yīng)癥/目標(biāo)疾?。┑纳暾?，將觸發(fā)兒科和孤兒藥相關(guān)要求（另請參閱II類變更及上市許可擴展的上市后指導(dǎo)文件中的以下問題：“若存在針對與擬議治療適應(yīng)癥相關(guān)疾病的指定或授權(quán)孤兒藥，提交II類變更時應(yīng)考慮哪些事項？”“我的II類變更申請是否需要滿足兒科相關(guān)要求？”“若存在針對與擬議治療適應(yīng)癥相關(guān)疾病的指定或授權(quán)孤兒藥，提交擴展申請時應(yīng)考慮哪些事項？”“我的擴展申請是否需要滿足兒科相關(guān)要求？”）。
The EC Guideline on the elements required to support the significant clinical benefit in comparison to existing therapies of a new therapeutic indication in order to benefit from an extended (11-year) marketing protection and the EC Guideline on a new therapeutic indication for a well-established substance provide a definition of what is considered a ‘new indication’. More specifically, a new (or modified) indication is:
《歐盟關(guān)于支持新治療適應(yīng)癥相較于現(xiàn)有療法具有顯著臨床獲益以獲得延長（11年）市場保護所需要素的指南》及《歐盟關(guān)于已確立物質(zhì)新治療適應(yīng)癥的指南》對“新適應(yīng)癥”作出了定義。具體而言，新的（或經(jīng)修改的）適應(yīng)癥包括：
a new target disease;
新的目標(biāo)疾??；
different stages or severity of a disease;
疾病的不同階段或嚴重程度；
an extended target population for the same disease, e.g. based on a different age range or other intrinsic or extrinsic factors;
同一疾病的目標(biāo)人群擴展（例如，基于不同年齡范圍或其他內(nèi)在/外在因素）；
a change from first-line treatment to second-line treatment (or second-line to first-line treatment), or from combination therapy to monotherapy, or from one combination therapy (e.g. in the area of cancer) to another combination;
從一線治療改為二線治療（或二線改為一線治療），或從聯(lián)合治療改為單藥治療，或從一種聯(lián)合治療（例如癌癥領(lǐng)域）改為另一種聯(lián)合治療；
change from treatment to prevention or diagnosis of a disease;
從治療改為預(yù)防或診斷某一疾?。?/span>
change from treatment to prevention of progression of a disease or to prevention of relapses of a disease;
從治療改為預(yù)防疾病進展或預(yù)防疾病復(fù)發(fā)；
change from short-term treatment to long-term maintenance therapy in chronic disease.
慢性疾病中從短期治療改為長期維持治療。
However, in some particular situations a case-by-case assessment may be needed to determine whether the target population is extended. For example, the following may not be considered a new indication:
但在某些特殊情況下，需通過個案評估確定目標(biāo)人群是否已擴展。例如，以下情況可能不被視為新適應(yīng)癥：
information on the use of the medicinal product in the authorised target diseases in patients with renal or hepatic impairment;
該藥品在授權(quán)目標(biāo)疾病中用于腎損傷或肝損傷患者的相關(guān)信息；
information on the use of the medicinal product in the authorised target diseases in pregnant women;
該藥品在授權(quán)目標(biāo)疾病中用于孕婦的相關(guān)信息；
for vaccines, information on the concomitant administration with other vaccines.
疫苗與其他疫苗同時接種的相關(guān)信息。
In addition to applications extending the target population, orphan similarity requirements are also triggered by any extension of the Marketing Authorisation (line extension, please refer to question ‘What aspects should I consider at time of submission of an extension application if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication?’).
除擴展目標(biāo)人群的申請外，任何上市許可擴展（產(chǎn)品線擴展）均會觸發(fā)孤兒藥相似性要求（另請參閱“若存在針對與擬議治療適應(yīng)癥相關(guān)疾病的指定或授權(quán)孤兒藥，提交擴展申請時應(yīng)考慮哪些事項？”）。
Paediatric requirements are triggered by an extension of the Marketing Authorisation (line extension) for new pharmaceutical forms and/or new routes of administration (please refer to question ‘Do I need to address any paediatric requirements in my extension application?’).
針對新劑型和/或新給藥途徑的上市許可擴展（產(chǎn)品線擴展）會觸發(fā)兒科相關(guān)要求（另請參閱“我的擴展申請是否需要滿足兒科相關(guān)要求？”）。
From a procedural point of view, extensions of indication can be submitted as type II variations or extensions of the Marketing Authorisation depending on whether the change in the target population is accompanied by other changes e.g. changes to the strength, pharmaceutical form, route of administration (please refer to question ‘When will my variation application be considered a Type II variation or an Extension application?’).
從程序角度而言，適應(yīng)癥擴展可作為II類變更或上市許可擴展提交，具體取決于目標(biāo)人群變更是否伴隨其他變更（例如，規(guī)格、劑型、給藥途徑變更）（另請參閱“我的變更申請何時會被視為II類變更或擴展申請？”）。
For extensions of the Marketing Authorisation, in case the change in the indication is only intended for the new pharmaceutical form/ strength being added, the extension of indication is covered by the scope of the MA extension application. In case the change(s) in the therapeutic indication also applies to existing presentations, the application should be presented as a grouping of a line extension(s) and C.6.a scope variation.
對于上市許可擴展，若適應(yīng)癥變更僅針對新增的劑型/規(guī)格，則該適應(yīng)癥擴展已包含在上市許可（MA）擴展申請的范圍內(nèi)；若治療適應(yīng)癥變更同時適用于現(xiàn)有劑型，則該申請應(yīng)作為產(chǎn)品線擴展與C.6.a范圍變更的組合申報提交。
When the extension of indication is submitted as a type II variation application, the C.6.a scope category (i.e. addition of a new therapeutic indication or modification of an approved one) typically applies. However, not all variations under the C.6.a. scope category are actual extensions of indication (e.g. restrictions of an existing indication also fall under this scope category). The contrary is also the case: there are variations which aim to extend the target population but which do not affect the wording of the approved therapeutic indication in section 4.1 of the SmPC. So the variation category is not C.6.a but rather C.4 (changes in the Product Information due to new quality, preclinical, clinical or pharmacovigilance data). Ultimately, if the ‘target population’ is extended, the orphan and/or paediatric requirements are triggered, even though the variation may not have been submitted as a C.6.a ‘extension of indication’.
若適應(yīng)癥擴展作為II類變更申請?zhí)峤?，通常適用C.6.a范圍類別（即新增治療適應(yīng)癥或修改已批準(zhǔn)適應(yīng)癥）。但并非所有C.6.a范圍類別的變更都是實際的適應(yīng)癥擴展（例如，限制現(xiàn)有適應(yīng)癥也屬于該范圍類別）。反之亦然：部分變更旨在擴展目標(biāo)人群，但不影響SmPC第4.1節(jié)中已批準(zhǔn)治療適應(yīng)癥的表述，因此該變更類別并非C.6.a，而是C.4（基于新的質(zhì)量、非臨床、臨床或藥物警戒數(shù)據(jù)導(dǎo)致的產(chǎn)品信息變更）。歸根結(jié)底，若“目標(biāo)人群”得到擴展，無論該變更是否作為C.6.a“適應(yīng)癥擴展”提交，均會觸發(fā)孤兒藥和/或兒科相關(guān)要求。
In case of a change in therapeutic indication, a review of quality documentation should be performed. Any resulting change to the quality documentation (e.g. change to impurity limits) should be proposed with the submission of the relevant grouped quality variation. Please see also question on ‘What should I consider in relation to the quality documentation in case of a change in the clinical use of marketed products meaning change in therapeutic indication, posology or maximum daily dose (MDD)?’.
若治療適應(yīng)癥發(fā)生變更，應(yīng)審查質(zhì)量文件。由此產(chǎn)生的質(zhì)量文件變更（例如，雜質(zhì)限度變更）應(yīng)隨相關(guān)組合質(zhì)量變更一并提交。另請參閱“上市產(chǎn)品的臨床用途發(fā)生變更（即治療適應(yīng)癥、給藥劑量或最大日劑量（MDD）變更）時，質(zhì)量文件需考慮哪些事項？”。
1.3.8. When is the submission of assessments carried out on target patient groups in order to comply with Article 59(3) of Directive 2001/83/EC and any resulting change(s) to the Package Leaflet a stand-alone variation? NEW Nov 2025
1.3.8. 為遵守《2001/83/EC號指令》第59(3)條而提交的目標(biāo)患者群體評估結(jié)果，以及由此導(dǎo)致的說明書變更，何時需作為獨立變更提交？新增 2025年11月
Articles 59(3) and 61(1) of Directive 2001/83/EC, as amended, require that the package leaflet reflects the results of consultations with target patient groups (‘user consultation’) to ensure that it is legible, clear and easy to use and that the results of assessments carried out in cooperation with target patient groups are provided to the competent authority.
經(jīng)修訂的《2001/83/EC號指令》第59(3)條和第61(1)條要求，說明書應(yīng)體現(xiàn)與目標(biāo)患者群體的咨詢結(jié)果（“用戶咨詢”），以確保說明書清晰易懂、便于使用，且需向主管部門提交與目標(biāo)患者群體合作開展的評估結(jié)果。
It is expected that ‘user consultation’ results in support of post-approval changes that require a regulatory application are provided as part of the same application. However, if the ‘user consultation’ results need to be updated outside the scope of another regulatory procedure, it should be submitted as a stand-alone variation type IB, C.11.
用于支持需監(jiān)管申報的上市后變更的“用戶咨詢”結(jié)果，應(yīng)作為同一申報的一部分提交。但若“用戶咨詢”結(jié)果需在其他監(jiān)管程序范圍外更新，則應(yīng)作為IB類C.11獨立變更提交。
‘User consultation’ results should not be provided as part of a type IA/IAIN variation. The review of the results requires the involvement of the rapporteur as part of a type IB or type II variation.
“用戶咨詢”結(jié)果不得作為IA/IAIN類變更的一部分提交。該結(jié)果的審查需由報告人參與，應(yīng)作為IB類或II類變更的一部分。
A stand-alone variation type IB, C.11 can be submitted both for cases where the ‘user consultation’ results affect the product information Annex III, as for cases that do not lead to an update of Annex III.
IB類C.11獨立變更可用于兩種情況：“用戶咨詢”結(jié)果影響產(chǎn)品信息附件III，或不導(dǎo)致附件III更新。
1.4. Editorial changes
1.4. 編輯性變更
1.4.1. What can be considered an editorial change and how can it be submitted as part of a type IA/IB/II variation? Rev. Nov 2025
1.4.1. 什么構(gòu)成編輯性變更？如何將其作為IA/IB/II類變更的一部分提交？修訂 2025年11月
The European Commission 'Variations Guidelines’ 2013/C 223/01 specifies that “If amendments to the dossier only concern editorial changes, such changes should generally not be submitted as a separate variation, but they can be included in a variation concerning that part of the dossier”. Changes that can be classified as a variation as per Variations Guidelines are not considered editorial changes and should be submitted under the appropriate variation category.
歐盟委員會《2013/C 223/01號變更指南》規(guī)定：“若對申報資料的修訂僅涉及編輯性變更，則該等變更通常不應(yīng)作為單獨變更提交，但可納入涉及該申報資料相關(guān)部分的變更中”。根據(jù)《變更指南》可歸類為變更的內(nèi)容，不視為編輯性變更，應(yīng)按相應(yīng)變更類別提交。
Editorial changes in module 3
3模塊中的編輯性變更
Provided that the above condition is fulfilled, the following changes to the Module 3 may be considered editorial: adding headers for ease of use, reordering of existing information without changing the meaning, alignment of information among/within the sections provided that it can be demonstrated what is the correct reference that had been previously agreed (e.g. alignment of information in flow charts to process description), punctuation changes and grammar/orthographic corrections that do not alter the meaning of the text.
滿足上述條件的前提下，3模塊的以下變更可視為編輯性變更：為便于使用添加標(biāo)題；重新排列現(xiàn)有信息但不改變含義；調(diào)整章節(jié)間/章節(jié)內(nèi)的信息（需能證明先前商定的正確參考依據(jù)，例如，使流程圖信息與工藝描述一致）；不改變文本含義的標(biāo)點符號修改及語法/拼寫糾錯。
Examples of changes that cannot be considered editorial: removal of specification parameters or manufacturing description, update of information to bring the dossier content in line with the current manufacturing process, etc.
不可視為編輯性變更的示例：刪除質(zhì)量標(biāo)準(zhǔn)參數(shù)或生產(chǎn)描述；更新信息以使申報資料內(nèi)容與當(dāng)前生產(chǎn)工藝一致等。
Editorial changes should always be clearly identified in the application form as follows: A brief description of the editorial changes should be provided in the Precise Scope. All the editorial changes should be listed in the present/proposed table, and a justification as to why the holder considers them ‘editorial’ (i.e. why they should not trigger a specific variation) should be provided for each change.
編輯性變更應(yīng)在申請表中明確說明如下：在“具體范圍”部分簡要描述編輯性變更；在“現(xiàn)有/擬議”表格中列出所有編輯性變更；并為每項變更提供理由，說明持有人為何認為其屬于“編輯性變更”（即為何不應(yīng)觸發(fā)特定變更）。
In addition, the MAH should provide a declaration in the ‘Precise scope and background…’ section of the application form confirming that the changes proposed as editorial do not change the content of the concerned part(s) of the dossier beyond the scope of the variation within which the editorial changes are being submitted.
此外，MAH應(yīng)在申請表的“具體范圍及變更背景”部分提供聲明，確認擬議的編輯性變更未超出所提交變更的范圍，未改變申報資料相關(guān)部分的內(nèi)容。
The Agency strongly recommends the submission of editorial changes within procedures with an administrative validation phase e.g. type IB or type II variations. This allows the appropriate review of proposed editorial changes during the administrative validation phase and the consequential amendment of the submission prior to assessment if needed. The editorial changes proposed should affect the same part of the dossier concerned by the variation procedure i.e. fourth level of the eCTD dossier (e.g. “3.2.S.x” or “3.2.P.x”). For example, if a variation affects section 3.2.S.2.1 editorial changes can be submitted in sections from 3.2.S.2.1 to 3.2.S.2.7.
EMA強烈建議在具有行政驗證階段的程序（如IB類或II類變更）中提交編輯性變更。這有助于在行政驗證階段對擬議的編輯性變更進行適當(dāng)審查，并在評估前根據(jù)需要對申報資料進行相應(yīng)修正。擬議的編輯性變更應(yīng)影響變更程序所涉及的申報資料同一部分，即電子通用技術(shù)文檔（eCTD）的第四層級（例如，“3.2.S.x”或“3.2.P.x”）。例如，若某變更影響3.2.S.2.1節(jié)，則編輯性變更可在3.2.S.2.1至3.2.S.2.7節(jié)范圍內(nèi)提交。
Exceptionally, the Agency may accept minor editorial changes as part of IA variations, if affecting the same eCTD section impacted by the variation submitted (i.e. at the fifth level 3.2.S.2.1). This is due to the fact that IA notifications are of administrative nature and do not have a validation phase. In case of doubt on the acceptability of editorial changes in future type IA applications, please contact the Agency by raising a ticket via EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post-authorisation - Human”, followed by the sub option: “Variation IA queries”.
特殊情況下，若微小編輯性變更影響與所提交變更相同的eCTD章節(jié)（即第五層級，如3.2.S.2.1），EMA可接受其作為IA類變更的一部分。這是因為IA類通知屬于行政性質(zhì)，無驗證階段。若對未來IA類申請中編輯性變更的可接受性存在疑問，請通過EMA服務(wù)臺提交工單聯(lián)系EMA，選擇“業(yè)務(wù)服務(wù)”標(biāo)簽，“人類監(jiān)管”類別，子類別選擇“上市后 - 人類”，再選擇子選項“IA類變更咨詢”。
If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".
若未擁有EMA賬戶，可通過EMA賬戶管理門戶創(chuàng)建。有關(guān)創(chuàng)建EMA賬戶的更多信息或指導(dǎo)，請參閱《創(chuàng)建EMA賬戶》指南。
MAHs are reminded to follow this guidance and ensure the high quality of variation applications in support of a timely processing of submissions.
提醒MAH遵循本指導(dǎo)文件，確保變更申請的高質(zhì)量，以支持申報資料的及時處理。
The Agency expects MAHs to keep proportionality between the submissions of editorial changes versus the change which is the scope of the variation application. If the editorial changes affect sections in module 3 not impacted by any upcoming variation, the MAH may consider submitting these changes as a separate type IB variation (Q.I.z or Q.II.z respectively).
EMA期望MAH在提交編輯性變更與變更申請核心范圍之間保持比例平衡。若編輯性變更影響3模塊中未涉及任何未來變更的章節(jié)，MAH可考慮將這些變更作為單獨的IB類變更提交（分別為Q.I.z或Q.II.z）。
Editorial changes in module 4 and 5
4模塊和5模塊中的編輯性變更
Editorial changes in module 4 and 5 are in principle not foreseen.
原則上，不預(yù)見4模塊和5模塊的編輯性變更。
Only in case of alignment of information within the dossier, provided that it can be demonstrated which is the correct reference that has been previously agreed, a change to a report in module 4 and 5 can be accepted as editorial and the update submitted as part of an upcoming type II non-clinical or clinical variation submitted under the C scope categories that involves the relevant committee for the specific study. If no such variation is foreseen, a type IB variation C.z can be submitted.
僅在需調(diào)整申報資料內(nèi)部信息（且能證明先前商定的正確參考依據(jù)）的情況下，4模塊和5模塊中報告的變更可被視為編輯性變更，并可作為即將提交的、涉及該特定研究相關(guān)委員會的C范圍類別II類非臨床或臨床變更的一部分提交。若無此類變更計劃，可提交IB類C.z變更。
Other updates cannot be considered editorial and require assessment under a variation, for example correction of information in module 4 and 5, updated calculation, etc.
其他更新不可視為編輯性變更，需通過變更進行評估，例如，修正4模塊和5模塊中的信息、更新計算結(jié)果等。
Editorial changes should be clearly identified in the application form as follows: A brief description of the editorial changes should be provided in the Precise Scope. The editorial changes should be listed in the present/proposed table, and a justification as to why the change is editorial should be provided.
編輯性變更應(yīng)在申請表中明確說明如下：在“具體范圍”部分簡要描述編輯性變更；在“現(xiàn)有/擬議”表格中列出編輯性變更；并提供該變更屬于編輯性變更的理由。
In addition, the MAH should provide a declaration in the “Precise scope and background…’ section of the application form confirming that the changes proposed as editorial do not change the content of the dossier beyond the scope of the variation within which the editorial changes are submitted.
此外，MAH應(yīng)在申請表的“具體范圍及變更背景”部分提供聲明，確認擬議的編輯性變更未超出所提交變更的范圍，未改變申報資料的內(nèi)容。
Please contact the Agency in advance of an upcoming submission by raising a ticket via EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post-authorisation - Human”, followed by the relevant sub-option: “Variation IA queries” or “Variation IB queries”.
請在提交申報資料前，通過EMA服務(wù)臺提交工單聯(lián)系EMA，選擇“業(yè)務(wù)服務(wù)”標(biāo)簽，“人類監(jiān)管”類別，子類別選擇“上市后 - 人類”，再選擇相關(guān)子選項“IA類變更咨詢”或“IB類變更咨詢”。
If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".
若未擁有EMA賬戶，可通過EMA賬戶管理門戶創(chuàng)建。有關(guān)創(chuàng)建EMA賬戶的更多信息或指導(dǎo)，請參閱《創(chuàng)建EMA賬戶》指南。
Editorial changes to the product information in module 1.3
1.3模塊中產(chǎn)品信息的編輯性變更
Formatting changes, correction of typographical errors and/or mistakes to the English Product Information (PI) or translations of the Product Information are considered editorial changes provided that the meaning of the text is not altered. These changes can be included within the scope of any upcoming variation impacting the product information.
對英文產(chǎn)品信息（PI）或其翻譯文本的格式調(diào)整、拼寫錯誤/筆誤修正，若未改變文本含義，均視為編輯性變更。該等變更可納入任何即將提交的、影響產(chǎn)品信息的變更范圍中。
Changes in the scientific content cannot be accepted as an editorial change. These changes should be classified under the scope of the relevant variation as per Variations Guidelines (e.g. Type II C.4). If no relevant scope is available, a variation type IB C.z may be appropriate.
科學(xué)內(nèi)容的變更不可視為編輯性變更，應(yīng)根據(jù)《變更指南》歸類為相關(guān)變更范圍（例如，II類C.4）。若無相關(guān)變更范圍，可適用IB類C.z變更。
Proposed changes that may require confirmation by the rapporteur or linguistic review will only be accepted by the Agency when submitted within the scope of an upcoming variation type IB or type II under chapter C which impacts the product information and where linguistic review is foreseen, if applicable.
可能需要報告人確認或語言審查的擬議變更，僅當(dāng)作為即將提交的、影響產(chǎn)品信息且（如適用）包含語言審查的C章節(jié)IB類或II類變更的一部分提交時，才會被EMA接受。
Editorial changes should generally not be submitted as a separate variation and therefore no reference to a variation category is required. Should there be no upcoming variation to include the editorial changes, these could also be submitted as a stand-alone IB C.z if they affect the English SmPC. If they affect the PIL/labelling of all language versions an Art. 61(3) notification should be submitted. If other languages are affected but not the English version and in case no variation affecting the product information is upcoming, the MAHs are advised to contact the Agency to discuss how to handle these necessary changes.
編輯性變更通常不應(yīng)作為單獨變更提交，因此無需注明變更類別。若無即將提交的變更可納入該等編輯性變更：若變更影響英文SmPC，可作為IB類C.z獨立變更提交；若影響所有語言版本的說明書（PIL）/標(biāo)簽，應(yīng)提交第61(3)條通知；若影響其他語言版本但不涉及英文版本，且無即將提交的影響產(chǎn)品信息的變更，建議MAH聯(lián)系EMA協(xié)商如何處理該等必要變更。
The MAH should liaise with the Agency without delay if the mistake concerns an incorrect or missing important information (e.g. contra-indication or adverse event) in the EN or any of the other languages, that could affect the safe and effective use of the medicinal product and/or lead to a potential medication errors (e.g. wrong strength, wrong posology, wrong route of administration).
若英文或其他任何語言版本中存在可能影響藥品安全有效使用和/或?qū)е聺撛谟盟庡e誤的重要信息錯誤或缺失（例如，禁忌癥、不良反應(yīng)、錯誤規(guī)格、錯誤給藥劑量、錯誤給藥途徑），MAH應(yīng)立即聯(lián)系EMA。
The editorial changes should be clearly identified in the application form as editorial changes. A brief description of the editorial changes should be provided in the precise scope of the application form. Furthermore, editorial changes should be presented in the present/proposed table or provided as a separate Annex. A statement confirming that the proposed editorial change(s) do(es) not change the content of the previously approved Product information should be provided.
編輯性變更應(yīng)在申請表中明確標(biāo)識為編輯性變更。需在申請表的“具體范圍”部分簡要描述編輯性變更，并在“現(xiàn)有/擬議”表格中列出或作為單獨附件提交。同時需提供聲明，確認擬議的編輯性變更未改變先前批準(zhǔn)的產(chǎn)品信息內(nèi)容。
Any changes proposed by the applicants as editorial will be carefully considered by the Agency at time of submission and may be subject to further assessment at the same time as the variation. Proposed editorial changes that cannot be accepted as such will be rejected. In case of doubt, applicants can contact the Agency in advance of the planned submission by raising a ticket via EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post-authorisation - Human”, followed by the relevant sub-option: “Variation IA queries” or “Variation IB queries”.
申請人提出的所有編輯性變更提議，EMA將在提交時進行仔細審核，并可能與該變更一并進行進一步評估。不被接受的編輯性變更提議將被駁回。若存在疑問，申請人可在計劃提交前通過EMA服務(wù)臺提交工單聯(lián)系EMA，選擇“業(yè)務(wù)服務(wù)”標(biāo)簽，“人類監(jiān)管”類別，子類別選擇“上市后 - 人類”，再選擇相關(guān)子選項“IA類變更咨詢”或“IB類變更咨詢”。
If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".
若未擁有EMA賬戶，可通過EMA賬戶管理門戶創(chuàng)建。有關(guān)創(chuàng)建EMA賬戶的更多信息或指導(dǎo)，請參閱《創(chuàng)建EMA賬戶》指南。
References
參考文獻
Commission Regulation (EC) No 1234/2008
《歐盟第1234/2008號法規(guī)》
Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures (EC Variations Guidelines (2013))
《關(guān)于各類變更的詳細說明、2008年11月24日《歐盟第1234/2008號法規(guī)》（涉及人用和獸用藥品上市許可條款變更審查）第二章、第二章a、第三章和第四章規(guī)定程序的實施以及根據(jù)該等程序需提交的文件的指南》（《歐盟2013年變更指南》）
Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures (EC Variations Guidelines (2025), applicable from 15 January 2026)
《關(guān)于各類變更的詳細說明、2008年11月24日《歐盟第1234/2008號法規(guī)》（涉及人用藥品上市許可條款變更審查）第二章、第二章a、第三章和第四章規(guī)定程序的實施以及根據(jù)該等程序需提交的文件的指南》（《歐盟2025年變更指南》，2026年1月15日起適用）
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