上市后变更是RA人永恒的话题，昨天花了一些时间整理了中国, EU, FDA, ICH和WHO生物制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~~
20051014_CDE_生物制品生产工艺过程变更管理技术指导原则.pdf 290 KB
20140108_NMPA_关于印发疫苗生产场地变更质量可比性研究技术指导原则的通知.pdf 179 KB
20150415_CDE_生物制品稳定性研究技术指导原则（试行）.docx 28 KB
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）.pdf 1441 KB
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）.pdf 374 KB
20210618_NMPA_《已上市生物制品变更事项及申报资料要求》（2021年第40号）.pdf 269 KB
20210622_CDE_关于发布《生物制品变更受理审查指南（试行）》的通告（2021年第30号）.pdf 388 KB
20210625_CDE_《已上市生物制品药学变更研究技术指导原则（试行）》（2021年第31号）.pdf 697 KB
20240614_CDE_关于发布《临床试验期间生物制品药学研究和变更技术指导原则（试行）》和《已上市疫苗药学变更研究技术指导原则（试行）》的通告（2024年第29号）.pdf 2479 KB
20130802 EC No. 1234_2008 Guidelines on EU Variations .pdf 1189 KB
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，这样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 | Such minor variations do not require any prior approval, but must be notified by the holder within 12 months following implementation. |
| Type IB | Tell, Wait & Do | 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 |
| Type II | Such major variations require approval of the relevant competent authority before implementation. |
Chemistry, Manufacturing, and Controls Changes to an Approved Application_Certain Biological Products.pdf 480 KB
Guidance for industry-CMC postapproval manufacturing changes to be documented in annual reports.pdf 298 KB
小格笔记：同上，如果境外持有人在美国，大家可以把上面两个FDA Guidance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。以下为US的三种变更类别（重大、中等和微小）：
Prior Approval Supplement (PAS): Changes that have a substantial potential to have an adverse effect on product quality (i.e., major changes) require an applicant to report the change to the FDA in a supplement to the approved BLA. A PAS must be approved by the FDA prior to distribution of the product manufactured using the change (21 CFR 601.12(b)).
Changes Being Effected in 30 Days (CBE30)/Changes Being Effected (CBE): Changes Being Effected in 30 Days/Changes Being Effected Supplements10 (CBE30/CBE) - Changes that have a moderate potential to have an adverse effect on product quality (i.e., moderate changes) require an applicant to report the change to the FDA in a supplement at least 30 days prior to distribution of the product made using the change (21 CFR 601.12(c)).
Annual Report (AR): Changes that have a minimal potential to have an adverse effect on product quality (i.e., minor changes) shall be documented by the applicant in an annual report (21 CFR 601.12(d)).
Q5A（R2）：来源于人或动物细胞系生物技术产品的病毒安全性评价.pdf 1454 KB
Q5B：源自重组DNA技术的蛋白质产品的表达载体分析.pdf 380 KB
Q5C：生物技术生物制品质量：生物技术生物制品稳定性试验.pdf 488 KB
Q5D：用于生物技术产品及生物制品生产的细胞基质的来源和鉴定.pdf 187 KB
Q5E：生物技术产品生物制品在生产工艺变更前后的可比性.pdf 588 KB
Q12：药品生命周期管理的技术和监管考虑.pdf 1303 KB
Q12附件.pdf 889 KB
Guidelines on procedures and data requirements for changes to approved biotherapeutic products.pdf 382 KB
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