以风险管理为基础的验证模式和各国GMP要求--Robert E. Chew,PE 2011.10.27

B级 Grade
Examples of operations for aseptic preparations. Aseptic preparation,filling, stoppering, capping Preparation of solutions which chould not be filtered in a grade A zone Transfer of partially closed containers in the process of freezing drying with a grade B Assembly, storage and transfer of closed containers of packaging material and background. in contact with product directly Crush、cribration, mixing, and dividing of raw materials. Transfer of closed containers in the processs of freezing drying Transferring of packaging material and implement in contact with product B closed containers
High product recovery and robust production process 高收率与稳健的工艺
ISPE-CCPIE CHINA CONFERENCE 2011
无菌附录1对环境级别的要求：非终端灭菌产品 Requirement on back ground in Annex 1：nonterminal sterilized product
Acknoledgment: 感谢：
Olivier Cochet, PhD Director Industrial Biotechnology Centre d‘Immunologie Pierre Fabre
Pump
Class 100
Components pre-assembled by vendors 由供应商预先安装 Assemblies sterilized by vendors
Aseptic connections replaced by 无菌连接 被替代
Sterile connectors, 无菌连接器 Tube welders Process 过程 焊接的管路
ISPE-CCPIE CHINA CONFERENCE 2011
A/B 环境监控要求 Environment monitoring
第十条 应当按以下要求对洁净区的悬浮粒子进行动态监测： 在关键操作的全过程中，包括设备组装操作，应当对A级洁净区进行悬浮粒子监测。生产过程中的 污染（如活生物、放射危害）可能损坏尘埃粒子计数器时，应当在设备调试操作和模拟操作期间进行测 试。A级洁净区监测的频率及取样量，应能及时发现所有人为干预、偶发事件及任何系统的损坏。灌装 或分装时，由于产品本身产生粒子或液滴，允许灌装点≥5.0μm的悬浮粒子出现不符合标准的情况。…… 第十一条 应当对微生物进行动态监测，评估无菌生产的微生物状况。监测方法有沉降菌法、定量空 气浮游菌采样法和表面取样法（如棉签擦拭法和接触碟法）等。动态取样应当避免对洁净区造成不良影 响。成品批记录的审核应当包括环境监测的结果。 Article 10： For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a hazard, e.g. live organisms and radiological hazards. In such cases monitoring during routine equipment set up operations and simulated operations should be undertaken. The Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. It is accepted that it may not always be possible to demonstrate low levels of ≥5.0 μm particles at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself. Article 11: Where aseptic operations are performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates).Sampling methods used in operation should not interfere with zone prothould be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitization.
Reduce Aseptic area without compromising SAL 在不降低无菌保证的前提下，减少无菌 工艺区的面积 Connect together sterile entities (container, tubing) in a non “classify A/B” environment. 在非无菌环境下的无 菌连接 Disposable technology without needs for cleaning validation 采用可抛 弃技术避免交叉污染及清洁验证要求 Ready-to-deploy, prequalified units 可立即部署、预先验证合格的单元装置 Robust, scalable unit operations and applications expertise稳健、可扩展的单元式操作， 和应用专家
使用标准部件进行结合 bags, tubing, connectors, filters, mixers, transfer containers, filling system, sampling bag for QC testing 袋子、管路、连接器、过滤器、搅拌器、转移容器取 样、罐装系统，用于QC检测的样品袋 Disposable assemblies can be customized to meet defined application
ISPE-CCPIE CHINA CONFERENCE 2011
China New GMP requirement and disposable solution 从新版GMP看一次性解决方案
Merck Millipore 默克密理博 Bill dun regulatory compliance manger 顿昕 法规符合经理
由供应商提供无菌组合
gamma radiation 伽马射线辐照
Discard and incinerate disposable components
ISPE-CCPIE CHINA CONFERENCE 2011
What is a Single-use Assembly? 什么是一次性使用装置
Transfer Manual assembly
灭菌过程
Autoclave 灭菌斧
转移，手动装配
ISPE-CCPIE CHINA CONFERENCE 2011
Modern Aseptic Processing 现代无菌过程
Class 10 000
Disposable mixer Disposable Filtration system Disposable Filling
October 25-28 2011
Shanghai
1
Challenges and possible solutions 面临的挑战和可能的解决方案
High expense on facility, equipment and EM for Aseptic process 在无菌设施和环境监测方面的 高投入 Requirement on sterile assurance level 无菌保障水平 Cleaning Validation process takes too long 验证花费太长时间