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1、欧盟欧盟GMPGMP对隔离操作技术的要求对隔离操作技术的要求EU GMP Regulations on isolated operationsJPT Consulting Stan ONeill CPAPE 2011 AnnualPHARMACEUTICAL INSPECTION CONVENTIONPHARMACEUTICAL INSPECTION CO-OPERATION SCHEME药品检查互认公约/药品检查合作计划25 September 2007 PI 014-32007年9月25日 PI 014-3RECOMMENDATIONISOLATORS USED FOR ASEPTICPR
2、OCESSING AND STERILITY TESTING关于无菌生产和无菌检测中隔离器的建议Regulatory reference;Regulatory reference;参考法规参考法规Flexible isolatorsFlexible isolators 软隔离器软隔离器Rigid Isolators Rigid Isolators 硬隔离操作器硬隔离操作器硬隔离操作器DefinitionDefinition 5.1.Pharmaceutical Isolator An isolator is an arrangement of physical barriers that ar
3、e integrated to the extent that the isolator can be sealed in order to carry out a routine leak test based on pressure to meet specified limits.Internally it provides a workspace,which is separated from the surrounding environment.Manipulations can be carried out within the space from the outside wi
4、thout compromising its integrity.定义定义 5.1.药品隔离操作器 隔离器作系物理屏障系统，它组装的程度达到可根据压力测试，进行常规检漏，以符合设定的密封技术要求。其内部形成一个工作区，可与周围环境隔离。可在隔离器外部进行操作而不会损坏其完整性。DefinitionDefinition 5.2.Industrial isolators used for aseptic processing.Industrial isolators used for aseptic processing are isolators in which the internal sp
5、ace and exposed surfaces are microbiologically controlled.Control is achieved by the use of microbiologically retentive filters,sterilization processes,sporicidal processes(usually by gassing)and prevention of recontamination from the external environment.、定义定义 5.2.无菌生产用工业隔离操作器 无菌生产用工业隔离器是一种内部工作区和外部
6、暴露表面受微生物控制的隔离器。通过利用微生物保持性过滤器、灭菌工艺、杀孢子工艺（通常使用气体处理）和预防受到外部环境的再污染来达到控制的目的。RABSRABS Can be open or closed Not sealed to the background Full rules of engagement for aseptic processing apply Be careful not to adopt rules of engagement for isolators.RABS-RABS-限止接触系统限止接触系统 可打开或关闭 对周围环境不密封 须完全按无菌生产法规要求生产 注意，
7、不要将隔离器的规定应用于此RABS-RABS-限止接触系统限止接触系统 One group has the main objective of providing containment for the handling of dangerous materials either aseptically or not.Another group has the main objective of providing a microbiologically controlled environment within which aseptic operations can be carried
8、out.有一组主要用于隔离，以处理无菌或有菌，或有害的物质。另一组的主要目的是提供进行无菌操作抽需的微生物受控境。RABS-RABS-限止接触系统限止接触系统 Key issue;why is the isolator being used product protection or operator protection?关键问题；为什么使用隔离操作器 保护产品还是保护操作人员?PIC/S background classificationPIC/S background classificationPIC/S PIC/S 背景级别背景级别 A smaller number of contr
9、olled environments are provided by clean rooms,of Grade D or better containing equipment called isolators providing a Grade A environment.由D 级清净间提供一个比较小的控制环境，或在优于D 级的清净间内安装一个称为隔离操作器的设备，以获得A 级的环境。PIC/S background classificationPIC/S background classificationPIC/S PIC/S 背景级别背景级别 When isolators are use
10、d for sterility testing there is no formal requirement for them to be placed in a Grade D environment.The environment should be controlled e.g.allow access only to trained staff,but not necessarily classified.当隔离器用作无菌检查时，并没有设备应置于D 级环境下的正式要求。环境应当受控，如只允许接受过培训的员工进入，但没必要划分清净级别。PIC/S background classific
11、ationPIC/S background classificationPIC/S PIC/S 背景级别背景级别 6.5 If the isolator is used for aseptic processing the surrounding room should comply with EC Grade D as a minimum.The potential for contamination from the room to enter the isolator during,for example maintenance,should be taken into account
12、when returning the isolator to its production status.若隔离操作器用于无无菌生产，则周围环境应最低达到欧盟D 级区的标准。当从房间进入隔离操作器中，如进行维修，再把隔离操作器调回生产状态时，应考虑潜在污染的风险。PIC/S background classificationPIC/S background classificationPIC/S PIC/S 背景级别背景级别 Note many aseptic processing isolators located in a Grade C environment.注 很多无菌生产用隔离操作
13、器位于C 级区。Many of these sites are now considering reclassifying these to a Grade D(cost saving in energy,environmental monitoring programme and garb)现在，很多这样的生产区又重新将其划归为D 级区（在能源、环境监控计划和服装方面可节约成本)Isolators-key inspection issuesIsolators-key inspection issues隔离操作器隔离操作器 关键检查点关键检查点 What is the background t
14、o the isolator?隔离操作器的背景状况?How frequently are the gloves tested 手套检测的频次是多久？How frequently is the isolator tested?隔离操作器检测的频次?Is the isolator aseptic or sterile?隔离操作器是无菌的还是经消毒的?Decontamination Decontamination 去除污染去除污染 Decontamination historically using formaldehyde,peracetic acid,chlorine dioxide and u
15、sually hydrogen peroxide 历史上曾用甲醛、过氧乙酸、二氧化氯和过氧化氢去除污染 Sporicidal process effective against all microbial forms 杀孢子工艺 对所有形式的微生物均有效 Can result in sterile conditions/state 可获得无菌条件/状态Decontamination Decontamination 去除污染去除污染 Should be a controlled,repeatable,quantifiable and validatable surface decontamina
16、tion 表面去污染应是一个可控的、可反复进行的、可量化的并可经验证的过程 Permanent record of critical parameters supports product release 关键参数的持续记录有助于产品放行 Sensor monitoring and alarms in place 设有传感器监测并有警报系统PIC/SPIC/S A sporicidal process,usually delivered by gassing,can be used to aid microbiological control.杀孢子工艺通常采用气体处理方式，该方法也可用于强化
17、微生物控制。PIC/SPIC/S 6.4.1 All surfaces that may be contaminated with microorganisms and that are in any way or at any time exposed to the critical zone should be sterilized or subjected to a validated sporicidal process.This includes the resident surfaces of the isolator and transient surfaces of mater
18、ials moving into and out of the isolator.所有可能受微生物污染的表面，产品无论何时以何种方式暴露的关键区，都应灭菌或用经验证的杀孢子方法处理。这包括隔离器的内表面和物料进、出隔离器的暴露表面。VHP Systems VHP Systems 汽化汽化过氧化氢系统过氧化氢系统Sporicidal Process Sporicidal Process 杀孢子工艺杀孢子工艺 7.4.1 The agent selected for gas generation should be sporicidal.选作产生气体的物质，应具有杀孢子的效力。7.4.2 The
19、correct identity and composition of the gassing agent charged into the gas generator should be assured.应确保杀孢子投入气体发生器之前，其成分准确无误。7.4.3 Gas generators should not be assumed to be equivalent to each other.不能假设，各种气体发生器的效能都相同。Sporicidal ProcessSporicidal Process 7.4.4 The way in which the gas generator wo
20、rks should be understood by company staff.All critical parameters related to its operation should be identified and recorded throughout the process.Measuring instruments should be calibrated and where critical should have independent monitors or an assured and confirmed reliability.The gas generator
21、 should be included in the preventative maintenance program.杀孢子工艺杀孢子工艺 7.4.4 企业员工应能了解气体发生器的工作原理。应明确并记录全过程中操作的关键参数。测量仪表应进行校准，关键部位应配备独立的监控器，或确保并确认关键仪表的可靠性。气体发生器应列入预防性维护计划。Sporicidal Process Sporicidal Process 杀孢子工艺杀孢子工艺 7.4.5 The release of the gassing process with regard to the gas generator should v
22、erify that all critical parameters met the specifications defined during validation.7.4.5 就释放气体的气体发生器而言，应检查所有关键参数符合在验证过程中确定的标准Sporicidal Process Sporicidal Process 杀孢子工艺杀孢子工艺 7.4.6 The delivery of gas from the generator into the isolator should assure that only the gas generated is supplied.All inle
23、t and outlet filters associated with the isolator should be exposed to gas or sterilized.Any air supplied by the generator e.g.during a purge stage,should be filtered though microbiologically retentive filters that have been sterilized or subjected to a sporicidal process.当气体从发生器进入隔离器的时，应确保只有发生器中生成的
24、气体才能进入隔离器。与隔离器相连的过滤器中的所有进出口都应经过气体处理或灭菌处理。发生器中的任何气体，如净化阶段的气体，都必须用经灭菌或杀孢子剂处理有除菌过滤器过滤。Validation of the sporicidal processValidation of the sporicidal process杀孢子工艺的验证杀孢子工艺的验证 Chemical and biological indicators 化学指示剂和生物指示剂 Potential for residual steriliant in environmental monitoring media or sterility
25、test media 环境监测和无菌检查用培养基中可能含有杀菌剂的残余 Validation of loads 要验证装载 Use of max/min loads very questionable 采用最大/最小装载存在很多问题Validation of the sporicidal processValidation of the sporicidal process杀孢子工艺的验证杀孢子工艺的验证 Current issues 当前问题 Clumping of Bis 生物指示剂密集使用 Use 3 BIs in each location,2 must not show growth
26、.每个部位使用3个生物指示剂反应试条，其中必须有2个不得长菌Cleaning Cleaning 清洁清洁 7.4.8 The isolator should be cleaned prior to the sporicidal process.The surfaces of packaged materials and all other items to be gassed within the isolator should be clean.在用杀孢子进行消毒前，应清洁隔离操作器。包装材料的表面和其他需要在隔离器内进行气体处理的物体都应进行清洁。Cleaning Cleaning 清洁清
27、洁 7.4.11 The sequence of the different aspects of cleaning,sterilization,sporicidal treatment,gassing,and degassing are of critical importance and should be carefully defined and verified before formal release of the system for production.清洁、灭菌、杀孢子处理、气体消毒和排气的顺序是至关重要的，应仔细定义，只有对这些进行检查确认后，方可将系统投入生产使用。M
28、onitoring Monitoring 监控监控 7.4.12 The range of parameters and events that should be monitored to assure the delivery of the validated process should be defined.应对参数范围和操作监控，以确保执行经验证过的工艺。Key concerns how are the parameters and events checked for batch release purposes 关键问题 如何检查参数和操作，以放行产品Design aspects
29、 Design aspects 设计方面设计方面 7.5.2 The control of leaks between the isolator and surrounding room and between different parts of the isolator system as necessary,should be assured as far as possible.As a guide a minimum of 10 Pascal positive differential air pressure should be maintained to protect agai
30、nst unforeseen circumstances.The maintenance of positive pressure should be monitored and fitted with an alarm.应尽量保证控制隔离器和周围环境以及隔离器系统的各部件之间的泄漏。为防止意外事件，建议正压差最少保持在10帕。正压应监控并安装警报装置。Design aspects Design aspects 设计方面设计方面 Note:Some agencies require 50 to 60Pa P 注意：有一些监管机构要求压差保持在 50-60Pa(P)Design aspects
31、Design aspects 设计方面设计方面 7.5.4 Transfer of material out of the isolator should not compromise the critical zone.将物料从隔离器中转运出来时，不应污染关键区域Design aspects Design aspects 设计方面设计方面 7.5.6.1 The design of the isolator system should include consideration of air change rate,the use of laminar,unidirectional or t
32、urbulent airflow,the application of aseptic technique and risk of error due to human fallibility.The rationale for the decisions taken should be documented.隔离系统的设计应考虑到换气率、层流、单向流或涡流、无菌技术的应用以及人为失误带来的风险。所作各种决定的理由应有相应记录。Specific points of inspection interestSpecific points of inspection interest检查过程主要关注
33、点检查过程主要关注点 Environmental monitoring 环境监控 Consistent with Annex 1 与附录1一致 Danger of introduction of contaminated media 引入受污染的介质的风险 Danger of false negatives due to residual sporicidal agent 残余杀孢子剂造成假阴性结果的风险 Use of aseptic processing 无菌工艺的应用Specific points of inspection interestSpecific points of inspe
34、ction interest检查过程主要关注点检查过程主要关注点 Transfer of materials for sterility testing into sterility test isolator;no ingress of sterilant 将物料转运至无菌检测隔离器进行无菌检查；不得含杀菌剂 Change out of gloves in operation 在操作过程中更换手套 Classification of area outside isolators if Grade C then no outdoor clothing worn underneath 隔离器外部
35、若为C 级，则里面不能穿户外衣物Current issues Current issues 当前的问题当前的问题 Sterile footprint 无菌足迹 Integrity testing 完整性测试Integrity testing Integrity testing 完整性测试完整性测试 7.5.3 A program to minimize the risk of loss of integrity of gloves,sleeves and suits should be present.This should include operator practices,vigilan
36、ce and the absence of sharp edges.There should also be an all encompassing preventative maintenance program that includes specification of examination and preemptive replacements.最大程度降低手套、袖子和服装方面不符合完整性的风险。这涉及操作人员的习惯、警戒性和无尖角类物品。还应有全面的预防性维护计划，包括检查和预先转换等技术要求。Glove testing Glove testing 手套检测手套检测 Glove Integrity Testing FailuresGlove Integrity Testing FailuresBenchmarking EventBenchmarking Event手套完整性测试失败与基准测试