无菌检查之风险评估及风险预防

Risk of FALSE POSITIVE 假阳性风险
Sterility test - Class A environment
无菌检查场所——A级环境
Sterility testing should be carried out in a work zone that offers sufficient space and material should be placed in such a way that it does not disrupt the laminar airflow. 无菌检查应该放在一个可提供足够的空间，物品放置不能扰乱层流的工作区 域 Each operator should be trained and certified in gowning procedures with training records maintained.在进行无菌测试前，操作人员必须熟练无菌操作，经过 专门的培训并通过资格认证 The sterility test operator should change into sterile clean room garments consisting of a one-piece coverall suit, head cover, beard cover (if applicable), overshoes, gloves and mask.无菌衣，头套，鞋套，护目镜，口罩，手套 Protective garments should be changed for each work session每次进入更换新的 无菌服，并登记 Surfaces and operators' gloved hands should be disinfected regularly during the test session.实验过程中操作表面和操作人员要经常用消毒剂消毒双手 PIC/S 2007
1. Sterility testing introduction无菌检查介绍 2. Risks assessment风险评估
Environmental considerations环境因素 Method considerations方法因素 Device & Hardware consideration 实验器材因素 Culture Media considerations培养基 因素
Sterility test: introducing material 物品流转
CORRUGATED BOXES: Generates a high amount of particles 瓦楞纸箱：产生大量的粒子 PARTICLES = vehicles and vector for development of bacteria and fungi (storage in humid and dirty areas)粒子=细菌和真菌的载体

Sterility Testing - Method principle
无菌检查—方法原理
Test from Pharmacopoeias (compendial method) Sterility is demonstrated by growth and reproduction (Growth Based test) 无菌性通过生长和繁殖来证明（基于生长实 验） Alternative tests (under development and implementation) 替代检查
High level of particles on blister exteriors大量粒子
High concentration of Gram + bacteria / fungi on the blister exterior 高浓度微生物
Potential risk of poor (alcohol) decontamination 潜在污染见险
o Potential inspection by regulatory
Batch scrap 整批报废 o If no root cause is proven
o High loss of money possible
False NEGATIVES: What consequences?
假阴性：什么后果？
3. Conclusions结论
Sterility Testing Introduction 无菌检查介绍
Sterility Testing What is the Test for Sterility ?
什么是无菌检查

Presence / Absence test存在/不存在检查 Reference test法规要求的实验室 Quality assurance requirement 质量保证的要求 Represents one set of data which contributes to the decision of whether or not the product lot meets the stated claims. 代表一组数据，用来判断产品是否符合既定标准化 Not intended as a sole product release test 并不是产品放行的唯一指标
Sterility Testing - Limitations
无菌检查—局限
不能检出病毒/支原体
破坏性测试 概率性测试 • 非统计学有效的，无代表性 • 不能整批测试，只是样品 • 基于出现微生物生长 培养时间长: 14 天 只有两种培养基: • 细菌，真菌和酵母
6
Presentation in footer | 00 Month 0000
Test passed and contaminated product is released检查通过，污染产品放行 o Patient injury risks 病人受伤风险 o Recalls 召回 o Branding damages 品牌受损 o Plant shutdown risks 工厂被关
False POSITIVES: What consequences?
假阳性：什么后果？
Regulation forbids to just redo the test without finding first the root cause of the contamination 如是没有找到造成污染的根本原因，法 规是禁止进行重复测试的 Heavy investigation to find out the root cause大量的调查以找到问 题根源 o Time and resource consuming
somecasesretainfluidcompletelydissolveproductbeforefiltration充分溶解稀释产品minimizecontacttimemembrane降低接触滤膜时间uselowbindingmembranepvdf选择低吸附滤膜如pvdf膜maximizepumpspeedproductfiltration提高泵速加快过滤速度optimizerinsing优化冲洗条件rinsesusingrightfluidtypesk用合适的冲洗液增加冲洗次数optimizedrainagerightfiltrationunitadditionaldrainageringbasedesign优化排水通路reducepumpspeedrinsingsteps降低冲洗速度goldenrulesantibiotics抗生素无菌检查的黄金原则riskassessmentmedia风险评估之培养基culturemediaregulatoryrequirements培养基的要求中国药典二部ep261usp71硫乙醇酸盐流体培养基接种前培养基氧化层的高度不得超过培养基深度的15
Risk Assessment & Risk Mitigation in Sterility testing
无菌检查之风险评估及风险预防
Merck Millipore
Major Account sales team of Lab Annlytical China
吕黎兵 13926063207 Libing.lv@
Sterility Testing – Guidelines
指导方针
中国药典 2.6.1 Sterility European Pharmacopoeia 5.1.9 Guidelines for using the test for Sterility US Pharmacopoeia, <71> Japanese Pharmacopoeia ICH (International Committee Harmonization) Regulatory Guidelines/Guidance TGA : Therapeutic Good Administration from Australia – September 2006 PIC/S : Pharmaceutical Impection Convention / Pharmaceutical Impection Co-operation Scheme - September 2007 FDA : Food and Drug Administration EMEA : European Agency for the Evaluation of Medicinal Products PDA : Parenteral Drug Administration AAMI : Association for the Advancement of Medical Instrumentation ISO : International Organization for Standardization WHO : World Health Organization
Sterility Testing - General implications 无菌检查要素 ——人员
Users must undergo training programs! “Because sterility testing is a very exacting procedure, where asepsis of the procedure must be ensured for a correct interpretation of results, it is important that personnel be properly trained and qualified” (USP 31)无菌检查有非常严格 的程序，在进行无菌测试前，操作人员必须熟练无菌操作，经过专门的培训并 通过资格认证
人员的资质
人员的技能 人员的意识
Sterility Testing - General implications 无菌检查要素
Considering the requirements and the limitations, each test component is critical! 每一步都至关重要 Environment 环境 Method 实验方法 Device & Hardware 实验器材 Media 培养基 Failure may bring false positive results with the risk of batch rejection and false negative results with safety hazard to the recipients! 失败可能会 带来假阳性、假阴性结果
Risk Assessment Environmental considerations 风险评估之——环境因素
Where to conduct the test?
哪里进行无菌检查操作
2010版中国药典二部附录Ⅺ H无菌检查法：无菌检查应在环境洁净度10000级下 的局部洁净度100级的单向流空气区域内或隔离系统中进行。单向流空气区、工作 台面和环境应定期按《医药工业洁净室(区)悬浮粒子、浮游菌和沉降菌的测试方法 》的现行国家标准进行洁净度验证。 Aseptic conditions for performance of the test can be achieved using for example a class A laminar-air-flow cabinet located within a class B-room, or an isolator (EP, 5.1.9) 无菌检查可以在环境洁净度B级区下的局部洁净度A级的单向流空气区域内或隔离系统 The sterility test should be conducted within a class A laminar airflow cabinet located within a class B clean room, or in an isolator that need not be located within a controlled environment. The test may also be performed within a class A clean room, if available. (PIC/S, 2007) 无菌检查应该在B级区下的局部A级单向流层流台中实施，如果有条件，也可以在A级 区中进行。