1、CLEANING VALIDATIONA LEAN CASE STUDYJPT ConsultingKeith Powell-Evans 1. Cleaning Strategy p 1 9 清洁策略清洁策略 2. Cleaning Validation p 9 19 清洁验证清洁验证 A) Objective p 9 目标目标 B) Scope p 9 范围范围 C) Approach: 方法方法: Family/ Grouping p 9 14 族族/组组 CV Tests/ Limits p 15 清洁验证测试清洁验证测试/限度限度 CV Life-cycle p 16 清洁验证生命周期
2、清洁验证生命周期 Document structure p 17-18 文件结构文件结构 Clean Hold Time p 19 清洁持续时间清洁持续时间 3. Summary p 20 概要概要 Described in SOP- xxx 在在SOP-XXX中进行描述中进行描述 COP: Parts washers (incl. COP baths) COP:零件清洗机零件清洗机(包括包括COP批次批次) CIP: Cleaning by CIP skids Chromatography cleaning UF/DF cleaning CIP:由在线清洁由在线清洁(CIP) SKID进行清
3、洁进行清洁色谱清洁色谱清洁UF/DF清洁清洁4Equipment 设备设备Equipment 设备设备1) COP LOCATIONS COP位置位置 COP-001COP-002COP-003COP-0045CIP-008CIP-002CIP-001CIP-005CIP-006CIP-0072) CIP Locations: CIP位置位置CIP-0096CHR-012CHR-001CHR-004CHR-0113) CIP skids Chromatography & UF/DF: CIP 色谱与色谱与UF/DFCHR-010CHR-013FIL-005FIL-014FIL-009FIL-0
4、08ProductVessel产品罐产品罐ProductVessel产品罐产品罐BufferVessel缓冲罐缓冲罐ProductVessel产品罐产品罐ProductVessel产品罐产品罐BufferVessel缓冲罐缓冲罐CIP SUPPLYCIP供应供应CIP RETURNCIP返回返回CIP SUPPLYCIP供应供应CIP RETURNCIP返回返回CIP SUPPLYCIP供应供应12456 3Typically 6 cleaning Phases: 典型的典型的6个清洁阶段个清洁阶段:PRE-RINSE PHASE 预先冲洗阶段预先冲洗阶段WASH 1 (Caustic) 洗涤
5、洗涤1(碱碱)3) POST RINSE 后冲洗后冲洗4) WASH 2 (Acid) 洗涤洗涤2(酸酸)PRE QUALITY RINSE 高质量冲洗高质量冲洗FINAL RINSE (hot WFI) 最后冲洗最后冲洗(热注射用水热注射用水)Specific cleaning procedures 具体的清洁程序具体的清洁程序= how to prepare to be cleaned systems 如何准备清洁系统如何准备清洁系统= Cleaning Recipe to be used, which defines: 所使用的清洁方法所使用的清洁方法,其规定其规定:Flows 流量Ti
6、mes 时间Concentration cleaning agents 清洁剂浓度Temperatures 温度Dirty Hold Time/ Clean Hold Time脏东西保持时间脏东西保持时间/清洁保持时间清洁保持时间= defined in SOP- xxx 在在SOP-XXX中进行规定中进行规定 VAL-VMP- xxxObjective: Demonstrate cleaning efficiency (incl. Dirty Hold Times) and Clean Hold Times目的目的:证明清洁效率证明清洁效率(包括脏东西保持时间包括脏东西保持时间)以及清洁保持
7、时间以及清洁保持时间2. Scope: 范围范围:COP: Parts washers 零件清洗机零件清洗机CIP: Cleaning by CIP skids 用在线用在线SKID清洁清洁 Chromatography SKID cleaning 色谱色谱SKID清洁清洁 UF/DF SKID cleaning UF/DF SKID清洁清洁VAL-VMP- XXX3.Approach: 方法方法: Product (Drug Substance) dedicated产品产品(原料药原料药)专用专用 COP: Validation of max. loadCOP:最大装量验证最大装量验证 CI
8、P: Family/Groups worst case (see next pages) 族族/组组最差情况最差情况 (见后页见后页)Downstream bufferPreparation下游缓冲制备下游缓冲制备 Process Schematic:工艺图工艺图Media preparation培养基制备培养基制备Purification 提纯提纯Harvest 收获收获Cell culture 细胞培养细胞培养Final Formulation成品配置成品配置Downstream bufferPreparation下游缓冲制备下游缓冲制备Upstream bufferPreparation
9、上游缓冲制备上游缓冲制备Drug Substance Contact Systems (DSCS) 原料药接触系统原料药接触系统Non-Drug Substance Contact Systems (non-DSCS) 非原料药接触系统非原料药接触系统GROUPING APPROACH 组方法组方法 FAMILY APPROACH 族方法族方法For the DSCS the CV Families are based on:对于原料药接触系统对于原料药接触系统,清洁验证族基于清洁验证族基于: CIP system (e.g. CIP-00 x, CIP-00y,.) CIP系统系统 Equi
10、valent manufacture and operational functionality (e.g. seed bioreactors vs product vessels) 等同制造与操作功能性等同制造与操作功能性(如如,种子生物反应器与产品罐种子生物反应器与产品罐) Equivalent design (e.g. vessels vs transfer lines) 等同设计等同设计(如如,罐与连管线生产罐与连管线生产) Equivalent cleaning method 等同清洁方法等同清洁方法= cleaning sequence, chemical agents and c
11、oncentrations, temperatures and minimum durations during the wash phases (cfr. SOP- xxx) 清洁次序清洁次序,化学试剂与浓度化学试剂与浓度,温度与在清晰阶段最短时间温度与在清晰阶段最短时间(参考参考SOP-xxx)= CV Families are defined 确定清洁验证的族确定清洁验证的族The worst case selection is based on an assessment of:选择最坏情况基于评估选择最坏情况基于评估: Location = relative CIP distance
12、s 位置位置=相对相对CIP距离距离 Design = surface area, number of subcircuits 设计设计=表面面积表面面积,支路数量支路数量 Position within manufacturing train 在制造序列的位置在制造序列的位置= e.g. product vessel used during first DS operations is considered less worst case than an equivalent product vessel used within the last DS operations 如如,在最早原料
13、药操作中使用产品罐可以考虑比最晚原料药操作中在最早原料药操作中使用产品罐可以考虑比最晚原料药操作中使用产品罐的最坏情况小使用产品罐的最坏情况小 Remark: worst case product selection is not applicable since systems are product dedicated 注注:由于系统专用由于系统专用,不接受最坏情况产品选择不接受最坏情况产品选择 For the non-DSCS two groups are identified: 对于非原料药接触系统对于非原料药接触系统,识别两个组识别两个组: Media group 培养基组培养基组
14、Buffer group 缓冲组缓冲组Similar manufacture and operational functionality and design. 相似的制造与操作方式以及设计相似的制造与操作方式以及设计Similar cleaning method with regard to cleaning sequence, chemical agents and concentrations, temperatures and minimum durations during the wash phases (cfr. SOP- xxx)在清洁先后次序在清洁先后次序,化学试剂与浓度化学
15、试剂与浓度,温度与冲洗阶段最短温度与冲洗阶段最短时间相似的清洁方法时间相似的清洁方法(参见参见SOP- xxx)The worst case selection is based on sound scientific rational:最坏情况选择基于良好的科学原理最坏情况选择基于良好的科学原理: MIX systems and worst case media or buffer = most concentrated and highest risk with repect to cross-contamination MIX系统与最坏情况的培养基或缓冲系统与最坏情况的培养基或缓冲=交叉
16、污染方面最浓的与最高风险交叉污染方面最浓的与最高风险 FF Buffer vessel = because of its position within manufacturing train (and risk of a theorethical impurity to end up in the final product bulk) FF缓冲罐缓冲罐=因为其位置在制造序列中因为其位置在制造序列中(以及理论杂质直以及理论杂质直到最终原料药中风险到最终原料药中风险)Family/Group Report implemented= all CV Family/Group members are
17、 considered validated族族/组报告实施组报告实施=所有清洁验证族所有清洁验证族/组成员都认为经组成员都认为经过验证过验证212223 Data report (per CV member) Family Report (all CV members per CV Family)Sampling (rinse+ swab)Data report worst case CV member implementedCIP performance verification (Flow, Temperature, Conductivity and Time)CIP performanc
18、e verification (Flow, Temperature, Conductivity and Time)-Cleaning recipe verification against worst case CV member24数据报告(每个清洁验证成员)族报告(所有清洁验证成员,每个清洁验证族)取样(淋洗+擦拭)报告实施的清洁验证成员最坏情况数据CIP性能核实(流量,温度,电导率与时间)CIP性能核实(流量,温度,电导率与时间)-清洁方法根据清洁验证成员的最坏情况进行核实 Clean Hold Times (CHT) 清洁保持时间清洁保持时间 CHT Groups (Product/M
19、edia/Buffer Vessels and Bioreactors) 清洁保持时间组清洁保持时间组(产品产品/培养基培养基/缓冲罐与生物反应器缓冲罐与生物反应器) Focus on bioburden and endotoxins 关注生物负荷与内毒素关注生物负荷与内毒素= Worst cases systems with most microbial risk 最坏情况最坏情况最大微生物风险体统最大微生物风险体统= theorethical the largest vessels 理论上最大的罐理论上最大的罐 Sampling and Criteria: 取样与标准取样与标准 Biobu
20、rden: Purified Water limit (i.e. 100 cfu/ ml) 生物负荷生物负荷:纯水限度纯水限度(例如例如 100 cfu/ ml) Endotoxin: 0.25 EU/ ml 内毒素内毒素: 0.25 EU/ ml Cleaning strategy outlined in SOP- xxx 清洁策略在清洁策略在SOP-xxx中描述中描述 Cleaning validation outlined in VAL-VMP- xxx 清洁验证清洁验证VAL-VMP- xxx中描述中描述 Scope: CIP and COP 范围范围:CIP与与COP Approach: 方法方法 Product dedicated 产品专用产品专用 Family/Grouping - worst case 族族/组组-最坏情况最坏情况
