上市后变更是RA人永恒的话题，接着昨天的文章全球生物制品变更相关法规，再给大家分享一下中国, EU, FDA和ICH化学药品变更相关法规和指南（下载链接在文末），希望对大家日常工作有帮助，如有遗漏，也欢迎大家补充和指正~~
20080515_NMPA_关于印发已上市化学药品变更研究的技术指导原则的通知
20170829_NMPA_关于发布已上市化学药品生产工艺变更研究技术指导原则的通告（2017年第140号）
20210113_NMPA_关于发布《药品上市后变更管理办法（试行）》的公告（2021年 第8号）
20210210_CDE_《已上市化学药品和生物制品临床变更技术指导原则》（2021年第16号）
20210210_CDE_《已上市化学药品药学变更研究技术指导原则（试行）》（2021年第15号）
20210210_NMPA_《已上市化学药品变更事项及申报资料要求》（2021年 第15号）
20221108_CDE_《已上市化学药品药学变更研究技术指导原则（试行）》溶出曲线研究的问答
20240613_CDE_关于发布《〈已上市化学药品药学变更研究技术指导原则（试行）〉原料药变更的问答》的通告（2024年第27号）
20130802 EC No. 1234_2008 Guidelines on EU VariationsGuidelines 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（关于各类变更细节、2008年11月24日第1234/2008号委员会条例（EC）第二章、第二章a、第三章和第四章规定的程序操作的指南，该条例涉及审查人用药品和兽药上市后变更，以及根据这些程序需要提交的文件）https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=OJ:C:2013:223:FULL
Questions and answers on post approval change management protocols（上市后变更管理方案的问答）https://www.ema.europa.eu/en/documents/scientific-guideline/questions-and-answers-post-approval-change-management-protocols_en.pdf
小格笔记：如果境外持有人在欧洲，大家可以把EC No. 1234_2008打印出来深入研读，这是欧洲关于变更的分类、判定规则和技术要求，我国的《已上市化学药品药学变更研究技术指导原则（试行）》（2021年第15号）很多地方借鉴了该指南。深入研读这个指南可以有助于和欧洲的Global Regulatory Lead非常顺畅地沟通。以下为EU的三种变更类别：
| Type IA | Do & Tell 先实施再报告 | Such minor
variations do not require any prior approval, but must be notified by the
holder within 12 months following implementation. 此类微小变更不需要任何事先批准，但持有人必须在实施后12个月内通知。 |
| Type IB | Tell, Wait & Do 通知，等待，再实施 | Such
minor variations must be notified before implementation. The holder must wait a period of 30 days to ensure that the notification is
deemed acceptable by the relevant authorities before implementing the change 在实施之前，必须通知此类微小变更。持有人必须等待30天，以确保通知被有关当局视为可接受，然后才能实施变更 |
| Type II |
| Such
major variations require approval of the relevant competent authority before
implementation 此类重大变更在实施前需要相关主管部门的批准 |
FDA
Changes to an Approved NDA or ANDA（NDA和ANDA上市后变更指南）
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/changes-approved-nda-or-anda
CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports（将记录在年度报告中的上市后CMC生产变更）https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cmc-postapproval-manufacturing-changes-be-documented-annual-reports
Postapproval Changes to Drug Substances（原料药的上市后变更）https://www.fda.gov/regulatory-information/search-fda-guidance-documents/postapproval-changes-drug-substances-guidance-industry
SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation（速释固体口服剂型：扩大规模和上市后CMC变更、体外溶出度测试和体内生物等效性文件）https://www.fda.gov/regulatory-information/search-fda-guidance-documents/supac-ir-immediate-release-solid-oral-dosage-forms-scale-and-post-approval-changes-chemistry
SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation（改性释放固体口服剂型的扩大和上市后CMC变更；体外溶出度试验和体内生物等效性文件）https://www.fda.gov/regulatory-information/search-fda-guidance-documents/supac-mr-modified-release-solid-oral-dosage-forms-scale-and-postapproval-changes-chemistry
SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation（非甾体半固体剂型；扩大规模和上市后CMC变更；体外释放试验和体内生物等效性文件）https://www.fda.gov/regulatory-information/search-fda-guidance-documents/supac-ss-nonsterile-semisolid-dosage-forms-scale-and-post-approval-changes-chemistry-manufacturing
SUPAC-IR Questions and Answers about SUPAC-IR Guidance（关于速释制剂扩大规模和上市后变更指南的问答）https://www.fda.gov/regulatory-information/search-fda-guidance-documents/supac-ir-questions-and-answers-about-supac-ir-guidance
小格笔记：同上，如果境外持有人在美国，大家可以把Changes to an Approved NDA or ANDA（NDA和ANDA上市后变更指南）打印出来深入研读，这样可以有助于和美国的Global Regulatory Lead非常顺畅地沟通。该指南也是我国《已上市化学药品药学变更研究技术指导原则（试行）》（2021年第15号）的主要参考文献之一，以下为其中定义的美国的三种上市后变更类别（重大、中等和微小）：
A major change is a change that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. A major change requires the submission of a supplement and approval by FDA prior to distribution of the drug product made using the change. This type of supplement is called, and should be clearly labeled, a Prior Approval Supplement (§ 314.70(b)). An applicant may ask FDA to expedite its review of a prior approval supplement for public health reasons (e.g., drug shortage) or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. This type of supplement is called, and should be clearly labeled, a Prior Approval Supplement - Expedited Review Requested (§ 314.70(b)(4)). FDA is most likely to grant requests for expedited review based on extraordinary hardship for manufacturing changes made necessary by catastrophic events (e.g., fire) or by events that could not be reasonably foreseen and for which the applicant could not plan.重大变更是指可能对药品的特性、强度、质量、纯度或效力产生不利影响的变化，因为这些因素可能与药品的安全性或有效性有关。一项重大变更要求在分销使用该变更制成的药品之前提交补充申请并获得FDA的批准。这种类型的补充称为事先批准补充，并应明确标记（§314.70（b））。出于公共卫生原因（如药品短缺），申请人可以要求FDA加快审查事先批准的补充申请，或者如果延迟进行其中所述的更改会给申请人带来极大的困难。这种类型的补充申请被称为“事先批准补充-要求快速审查”（§314.70（b）（4）），并应明确标记。FDA最有可能根据灾难性事件（如火灾）或无法合理预见且申请人无法计划的事件所必需的制造变更的特殊困难，批准快速审查请求。
A moderate change is a change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. There are two types of moderate change. 中等变更是指对药品的特性、强度、质量、纯度或效力产生中度不利影响的变化，因为这些因素可能与药品的安全性或有效性有关。有两种类型的中等变更。
One type of moderate change requires the submission of a supplement to FDA at least 30 days before the distribution of the drug product made using the change. This type of supplement is called, and should be clearly labeled, a Supplement - Changes Being Effected in 30 Days (§ 314.70(c)(3)). The drug product made using a moderate change cannot be distributed if FDA informs the applicant within 30 days of receipt of the supplement that a prior approval supplement is required (§ 314.70(c)(5)(i)). For each change, the supplement must contain information determined by FDA to be appropriate and must include the information developed by the applicant in assessing the effects of the change (§ 314.70(a)(2) and (c)(4)). If FDA informs the applicant within 30 days of receipt of the supplement that information is missing, distribution must be delayed until the supplement has been amended to provide the missing information (§ 314.70(c)(5)(ii)).第一种类型的中等变更要求在使用该变更制成的药品分销前至少30天向FDA提交补充申请。这种类型的补充申请被称为“补充申请-30天内生效的变更”（CBE30）（§314.70（c）（3）），并应明确标记。如果FDA在收到补充申请后30天内通知申请人需要事先批准的补充申请（重大变更），则使用中等变更制成的药品不能分销（§314.70（c）（5）（i））。对于每一项变更，补充申请必须包含FDA确定的适当信息，并且必须包括申请人在评估变更影响时开发的信息（§314.70（a）（2）和（c）（4））。如果FDA在收到补充材料后30天内通知申请人信息缺失，则必须推迟分销，直到补充申请被修改以提供缺失的信息为止（§314.70（c）（5）（ii））。
FDA may identify certain moderate changes for which distribution can occur when FDA receives the supplement (§ 314.70(c)(6)). This type of supplement is called, and should be clearly labeled, a Supplement - Changes Being Effected. （第二种类型）FDA可能会判定某些中等变更，在FDA收到补充申请之后，药品即可分销（§314.70（c）（6））。这种类型的补充被称为“补充-即时生效的变更”（CBE），并应明确标记。
A minor change is a change that has minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. The applicant must describe minor changes in its next Annual Report (§ 314.70(d)).微小变更是指对药品的特性、强度、质量、纯度或效力产生不利影响的可能性最小的变化，因为这些因素可能与药品的安全性或有效性有关。申请人必须在其下一份年度报告中描述微小变更（§314.70（d））。
ICH
Q12：药品生命周期管理的技术和监管考虑
Q12附件
https://pan.baidu.com/s/1upJaEukHTOGh_emmntdJTg?pwd=iReg
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