欧盟新版GMP附录1无菌产品生产解读.pdf

Ralf Gengenbach, gempex China Ltd.Suzhou Dialogue, 27thof October 2021New Version EU GMP Annex 1 Manufacture of Sterile Products欧盟新版 GMP 附录1 无菌产品生产About gempex- 20 years international experience德 恩 拥 有 2 0 年 的 国 际 G M P 经 验gempex GmbH Set upFocused on API GMPExpand the business for Pharma and BiotechJoint VentureUS & EU in HKSubsidiary in Switzerlandgempex ChinaSet up in Guangzhou德恩是一家独立的、全球化的服务供应商，专注于生命健康领域的GMP咨询和执行。自2002年成立以来，德恩的专家由15人发展至今约100人，在全球范围提供质量管理体系的实施、优化和维护工作。gempexis an independent, international service provider specialized in consultancy and theimplementation of GMP requirements in the life science industry. The company was founded in2002 with a team of 15 experts. Today around 100 employees provide support for theimplementation, optimization and maintenance of quality management systems around theworld.Our company locates internationally我 们 公 司 的 国 际 化 分 布Wearelocatedintheseareasforservices我 们 的 各 地 办 公 地 点US GMPCooperation ConsultantsU.S.New Jersey合作顾问美国新泽西AssociateChinese GMPEU GMPGermany德国总公司Switzerland瑞士分公司Guangzhou, China中国广州分公司Suzhou, China中国苏州办事处New/Plant Improvement新建/厂房改造Planning & Design计划&设计Construction & Commissioning建设&调试Product Launch 新品上市Routine Production日常生产Our Services covers from new set up to routine production新 建 工 厂 到 日 常 维 护 的 全 过 程 的 服 务GMP ComplianceG M P 符 合 性Qualification & Validation确 认 与 验 证GMP RoutineSupportG M P 实 施 支 持GxP 咨询基础概念差距分析人员培训设计审核URS准备布局概念技术转移验证主计划风险管理风险分析FAT/SAT支持C&Q管理确认 (DQ,、IQ,、OQ、PQ）MAH服务GMP文件工艺验证方法验证模拟检查检查准备检查支持第三方审计IT System Validation计 算 机 系 统 验 证IT验证概念IT验证主计划软件验证Excel 表格验证IT-验证培训专家外派ExpertLeasing驻 场 支 持New EU GMP Annex 1 First version 1971; valid version: 2008第一版1971年; 生效版: 2008年 Reasons for revision 变更原因:- Change of technologies 技术变化- More logical structure and more details 更加有逻辑化的结构和细节- Implementation of ICH Q 9 (QRM) and ICH Q10 (PQS)ICH Q 9 (QRM) 和ICH Q10 (PQS) 的实施 Draft 2017 with more than 6200 lines of comments2017年草案，有6200多行评论 Draft 2020 (Vers. 12), comments until 20 July 2020. 2020年草案，评论收集截止2020年7月20日Background背景背景Source 来源:https:/ec.europa.eu/health/medicinal_products/consultations/2020_sterile_medicinal_products_en2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1Parties involved in commenting参与评论机构参与评论机构16 Stakeholders Associations16个协会/机构2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachA3P (Association for Products Propres and Parentals)AESGP (Association of the European Self-Medication Industry)AnimalhealthEuropeAPIC (Active Pharmaceutical Ingredient Committee)EAEPC (European Association of Euro-Pharmaceutical Companies)ECA (European Compliance Academy)EFPIA (European Federation of Pharmaceutical Industries and Associations)EGGVP (European Group for Generic Veterinary Products)EIPG (European Industrial Pharmacists Group)GIRP (European Healthcare Distribution Association)ISPE (International Society for Pharmaceutical Engineering)Medicines for EuropePDA (Parenteral Drug Association)PHSS (Pharmaceutical & Healthcare Sciences Society)EQPA (European Qualified Person Association)Vaccines EuropeNew EU GMP Annex 1Expected to become valid for all PIC/S member states新版内容将对所有新版内容将对所有PIC/S成员有效成员有效WHO and PIC/S involved in the consultation.WHO和PIC/S也参与了本次讨论。2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachPrinciple 原则General 总则Clean room and clean air device monitoring洁净室和洁净通风设备的监控Isolator technology 隔离操作技术Blow/fill/seal technology 吹/灌/封技术Terminally sterilized products 最终灭菌产品Aseptic preparation 无菌配制Personnel 人员Premises 厂房Equipment 设备Sanitation 卫生Processing 生产工艺Sterilization 灭菌Sterilization by heat 热力灭菌Moist heat 湿热灭菌Dry heat 干热灭菌Sterilization by radiation 辐射灭菌Sterilization with ethylene oxide 环氧乙烷灭菌Filtration of medicinal products 非最终灭菌药品的过滤Finishing of sterile products 无菌产品的最终处理Quality control 质量控制Scope 范围Principle 原则Pharmaceutical Quality System (PQS) 制药质量体系Premises 厂房-Barrier Technologies 屏障技术-Room Equipment Qualification 洁净室设备确认-Disinfection 消毒Equipment 设备Utilities 公用系统-Water Systems 水系统-Steam used 蒸汽作用直接灭菌介质-Gases and vacuum systems 气体和真空系统-Heating and cooling and hydraulic systems加热、冷却和液压系统Personnel 人员Production and specific technologies 生产和特殊技术-Terminally sterilized products 最终灭菌产品-Aseptic preparation and processing 无菌准备和加工-Finishing of sterile products 无菌产品最终处理-Sterilization 灭菌-heat / moist heat / dry heat / radiation / EtO / filter热力/湿热/干热/辐射/EtO/过滤灭菌-Blow/fill/seal technology 吹/灌/封技术-Lyophilization / closed systems / SUS 冻干/隔离系统/SUSViable and non-viable environmental and process monitoring 活性和非活性微粒环境和工艺监测- / Aseptic Process Simulation (Media Fill) /无菌工艺模拟Quality control (QC) 质量控制Glossary 术语Old: 16 pages旧版: 16页New: 50 pages新版：大于50页New EU GMP Annex 12021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachTable of Content (old new)内容列表内容列表 ( (旧版旧版- -新版）新版）New EU GMP Annex 1 Sterile APIs, excipients, primary packaging material, finished dosage forms无菌活性物质（无菌原料药）、辅料、内包材和制剂- For different packed sizes (single, multiple) 包装量（单个单位、多个单位）- For different processes (automated, manual) 不同工艺（高度自动化系统、人工操作）- For different technologies (biotech, small molecules, closed systems)不同的技术（生物技术，常规小分子生产以及密闭系统） Non-sterile /contamination-controlled products, consider strategies as:非无菌/污染控制产品，考虑如下策略：- Contamination Control Strategy 污染控制策略- Room qualification and classification 洁净室确认和级别- Monitoring 监控- Clothing 更衣Expanded Scope范围扩大范围扩大 （1/2）Scope of products heavily expanded, not only sterile medicinal products.扩大了适用范围，不限于无菌药品。2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1 QRM applies to this document in its entirety新版文件将质量风险管理理念贯穿整个文件- Considering the lifecycle of product, processes, and equipment考虑了产品、工艺生产和设备的生命周期- Regularly be reviewed定期回顾Expanded Scope范围扩大范围扩大 （2/2）Scope of products heavily expanded, not only sterile medicinal products.扩大了适用范围，不限于无菌药品。2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1 A planned set of controls for microorganisms, pyrogens and particulates,对微生物、热原以及颗粒污染风险的控制 derived from current product and process understanding that assures process performance and product quality (Critical Control Points CCPs).源自于对当前产品和工艺的理解以确保工艺性能和产品质量 （关键控制点-CCPs） The controls can include 控制包含- Parameters and attributes related to active substance, excipient and drug product materials and components, 与原料药、辅料和制剂原料及成分有关的参数和属性- Facility and equipment operating conditions, 设施设备的运行条件- In process controls, 工艺控制- Finished product specifications, and 成品质量标准，以及- The associated methods and frequency of monitoring and control.监测和控制相关方法和频次Newly added “Contamination Control Strategy” (CCS)新增新增“污染控制策略污染控制策略”(CCS)Def. in Glossary:Lifecyle DocumentPeriodic Review & Update生命周期文件定期回顾&更新2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1Design (plant, process) 设计（厂房和工艺）Premises & Equipment 厂房设施和设备Personnel 人员Utilities 公用系统Raw Materials Control including IPC 起始物料的控制-包含中间控制Product containers and closures 产品包装系统Vendor qualification 供应商的批准Outsourced services monitoring strategy 委托外部的服务-监测策略Process risk assessment 工艺风险评估Process validation 工艺验证Preventative maintenance 预防性维护保养Cleaning and disinfection 清洁和消毒Monitoring systems 监测系统CAPA System 纠正和预防措施系统Contamination Control Strategy Elements污染控制策略要点污染控制策略要点Referenced at numerous points in the new annex 1, must be considered and discussed in the CCS document.参考新版本的附录1文件，如下这些要素应该在污染控制策略中考虑和讨论：2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1 Risk Management (lifecycle, periodic review, justification for accepted risks)风险管理（产品生命周期，定期审查，可接受风险的论证） Knowledge Management (product, processes, CPPs, CQAs for validation)知识体系管理（产品，工艺，验证所需的CPPs, CQAs ） CAPA Management & Root Cause Analysis纠正和预防措施管理 & 根本原因分析 Transport Verification (internally, GDP)运输确认（内部，GDP） Impact Assessment in case of happenings发生事故时的影响评估 Newly added “Pharmaceutical Quality System” (PQS)新增新增“制药质量体系制药质量体系”( (PQS) )Key Elements关键要点2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1 Detailed requirements for RABS and IsolatorsRABS及隔离器的详细要求 Cleanroom qualification/classification 洁净室确认/分级:- Requirements regarding 5m particles reduced for A/B area (not for monitoring)对于A/B区减少5m 尘埃粒子数- Classification must consider “at rest” and “in operation” status洁净室分级必须考虑“静态”和“运行”状态- Also microbiology limits now included 微生物限制也是洁净室确认的一部分- For all areas recovery time must be measured 对于所有区域，恢复时间都必须测量- Smoke studies is a must for transfer openings to B areas 转移到B级需要进行烟雾测试- Re-qualification for A/B every 6 months, for C/D every 12 months对于A/B级地区，再确认的最长时间间隔为6个月，对于C/D级地区，再确认的最长时间间隔为12个月Premises厂房厂房 （1/2）Some key aspects主要方面2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1 Approved List“ for materials to transport to A/B areas对于进入到A/B级洁净区的物料需要为“批准清单” Pressure difference 10 Pa (now 10-15 Pa), continuously monitored & alarmed压差10 Pa （现在10-15 Pa），连续监测和报警 Provision of windows or remote camera access with a complete view of the area and processes to allow observation and supervision without entry.”“通过提供参观窗或远程摄像头以全面观察和监控该区域和过程以避免进入”Premises厂房厂房 （2/2）Some key aspects主要方面2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1 Defined test catalogue 测试目录- Installed filter leakage and integrity testing 已安装过滤器检漏和完整性测试- Airflow measurement - Volume and velocity 气流测试-风量和流速- Air pressure difference measurement 压差测试- Airflow direction and visualization 气流流型- Microbial airborne and surface contamination 空气微生物和表面微生物- Temperature measurement 温度测试- Relative humidity measurement 相对湿度测试- Recovery testing 恢复测试- Containment leak testing 泄漏率测试Cleanroom Qualification (test item catalogue)洁净室确认洁净室确认 ( (测试目录测试目录) )Explicitly mentioned明确提及2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1Cleanroom Qualification (non-viable particles)洁净室确认洁净室确认 ( (非活性微粒非活性微粒) )2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf Gengenbach20082020New EU GMP Annex 1Cleanroom Qualification (viable particles)洁净室确认洁净室确认 ( (活性微粒活性微粒) )2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf Gengenbach2020New EU GMP Annex 1 Re-Qualification 再确认- Appropriate requalification be carried out following 适当的再确认.的执行当： completion of remedial action implemented to rectify an out-of-compliance equipment or facility condition or为纠正不符合要求的设备或设施状况而实施的补救行动 after changes to equipment, facility or processes 设备，设施或工艺的变化Cleanroom Re-Qualification洁净室洁净室再确认再确认Clear requirement明确要求2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1 More detailed descriptions/ requirements, e.g.:更加详细的描述/需求，例如：- P&IDs assessments during CCS 在污染控制策略中对工艺管线图的评估- Trending and assessment of alarms 报警事件评估并评估其趋势- Maintenance from outside of the cleanrooms 在洁净室外对设备设施的维护- Leak detection procedures for heating / cooling devices 加热/冷却设备的检漏程序- Utilities 公用系统- CQAs and CPPs of Utilities must undergo a trend analysisCQAs和CPPs趋势分析- Compressed air with product contact - filter integrity testing for batch release与产品接触的压缩空气-批次放行过滤器完整性试验- Water sampling at the loop back-flow to the tank each day during production生产过程中每天从分配回路末端位置取样- Equipment & Utilities设备设备&公用系统公用系统Some key aspects主要方面2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1 Gowning procedures 更衣程序- Gowning procedure annual requalification 更衣程序的每年再确认- Monitoring hand, arm, breast, face when entering/ leaving critical areas进入/离开关键区域时需要监测人员的手部，手臂，胸部和面部 Access to areas A/B 进入A/B级别区域- Only after qualification and successful APS (Media Fill)只有确认后并成功通过APS才准许进入（模拟灌装）- Disqualification of persons is possible可能取消人员进入的资格Personnel/ Gowning for Areas A/B人员人员/ A/B级区工作人员的更衣级区工作人员的更衣Some key aspects主要方面2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1 Define remaining risks for aseptic processing by CCS通过污染控制策略定义无菌工艺存在的风险 Validation of the method to test the correct seating of stoppers测试塞子的阀座位置是否正确的验证方法 Built up of a defect library for filled containers 为已填充容器建立缺陷库 Dry heat sterilization validation based on CPPs 基于CPPs的干热灭菌验证 EtO sterilization validation based on CPPs 基于CPPs的EtO灭菌验证 Product sterilization by filtration 产品过滤灭菌- Consider adsorption, leachables, extractables 考虑吸附物，可浸出物，可提取物- In-place integrity testing 就地完整性测试- PUPSIT integrity test strategy (pre-use, post-sterilization)PUPSIT完整性测试策略(灭菌前、后)- Consider filtration CPPs 考虑CPPs过滤- Production and Specific Technologies生产和特定技术生产和特定技术Some key aspects主要方面2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1 Risks to be assessed in CCS 在污染控制策略评估风险- 8.124 “Assessment of suppliers of disposable systems including sterilization is critical to the selection and use of these systems. For sterile SUS, verification of sterility should be performed as part of the supplier qualification and on receipt and use of each unit.“8.124 一次性使用系统（包括灭菌）的供应商评估对于这类系统的选择和使用至关重要。对于无菌SUS，无菌状态的确认应作为供应商确认的一部分，并在每件接收和使用时确认无菌状态。- 8.125 “The adsorption and reactivity of the product with product contact surfaces should be evaluated under process conditions.”8.125 产品与产品接触表面的吸附和反应，应在工艺条件下进行评估。- 8.126 For components considered to be at high risk from leachable, including those that may absorb processed materials or those with extended material contact times, an assessment of leachable profile studies, including safety concerns, should be taken into consideration.”8.126 , 对于被认为有吸附物高风险的组件，包括那些可能吸附加工的物料或多次物料接触，应对吸附物进行研究评估，包括安全性考虑。- Single Use Systems (SUS)一次性使用系统一次性使用系统( (SUS) )For all kind of SUS适用于各种类型的一次性使用系统(SUS)2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1 9.1 The sites environmental and process monitoring program forms part of the overall CCS”9.1 工厂的环境和工艺监测程序组成了整体污染控制策略的一部分 9.8 Appropriate alert levels and action limits should be set for the results of viable and non-viable particle monitoring. Alert levels should be established based on results of cleanroom qualification tests or trend data and should be subject to periodic review.”9.8 应对颗粒和微生物监测结果设立适当的警戒限和行动限。应根据洁净区性能确认的结果或趋势数据建立警戒限，并应进行定期审核。 Limit changes 最大限度改变:- 5m particles at rest/in operation A/B area, from 20 to 29/m3 5m 悬浮粒子静态/运行状态 A/B级区，从20 到29/m3- Viable particles A area, from 1CFU to no growth“一个区域，从 1CFU到, 无生长”Viable and non-viable environmental & process monitoring活性和非活性微粒环境和工艺监测活性和非活性微粒环境和工艺监测Some key aspects主要方面2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf GengenbachNew EU GMP Annex 1- Critical Manufacturing steps listed 列出关键的生产步骤- Inherent/ corrective interventions 固有/纠正干预- APS after the last batch prior to shut down, before long periods of inactivity or before decommissioning or relocation of a line.”APS在最后一批后但在停工前、长时间不工作前、或在拆除或搬迁前一条生产线- Detailed instructions in case of APS failure APS失败的详细说明Aseptic Process Simulation (APS)无菌工艺模拟无菌工艺模拟 ( (APS) )2021-10-27 | New Annex 1 - 2021 Suzhou Dialogue | Ralf Gengenbach20092020New EU GMP Annex 1 Bioburden 生物负载- 10.3 “The bioburden assay should be performed on each batch for both aseptically filled product and terminally sterilized products a