环氧乙烷灭菌再验证.pdf

环氧乙烷灭菌再验证Periodical Verification of Ethylene Oxide Sterilization 目录Catalogue1.再验证计划Periodical Verification Plan2.再验证方案Periodical Verification Program3.再验证报告Periodical Verification Report4.再验证报告批准书Approval of Periodical Verification Report 1.概述General1.1 产品情况P roduct overview本灭菌过程是北京裕恒佳有限公司为其所生产的血管腔内支架人工血管系统而建立。血 管腔内支架人工血管系统包括支架人工血管和与之相配合使用的送放器材。血管腔内支架人 工血管安装在送放器内，经介入方法将支架人工血管放置在人体血管病变部位，达到治疗的 目的。本产品按照我国医疗器械分类属HI类产品，本产品以无菌状态提供医疗机构进行治疗 应用。This sterilization process is specially instituted for the endovascular stent system manufactured by B eijing YuHengJia SciTech C o.Ltd.The endovascular stent system is comprised of the stent and the matched delivery system,the former of which is installed into the delivery system.Through intervention,the stent is deployed into the vascular lesions for treatment.As C ategory III product in accordance with the national classification of medical devices,this system has provided sterile to the medical institutions for treatment and application.1.2 灭菌工艺Sterilization Technology本公司采用环氧乙烷灭菌器对产品进行灭菌，以保障产品的无菌状态。灭菌柜经过一年 的使用，需要进行再次验证，以检验灭菌柜的性能是否依然满足设计要求，从而保障正常的 生产。同时，由于本公司的产品进行了重大改进，产品性能和外观变化较大，需要重新设计 装载方式及灭菌工艺。产品的部分部件对温度敏感，在高温下易出现形变并影响产品质量。因此本次灭菌工艺的设计主要以降低灭菌温度为目的，其余变量为调节手段。O ur company performs sterilization on our products with ethylene oxide sterilizer to ensure that the products are sterile.After a year of service,the sterilizer has to undergo periodical verification to test whether the performance of the sterilizer satisfies the design requirements so as to guarantee normal manufacture.O n the same time,as significant improvement has happened to our products,the performance and appearance of the products have undergone great changes,which require new design of loading manners and sterilization technologies.C ertain components of our products are sensitive to high temperature,under which deformation happens so as to influence the qualities of the products.Therefore,this sterilization technology is designed to reduce sterilization temperature,with other variants as regulative means.2验证目的P urpose of Verification确认系统的各种仪器仪表经过校正合格；To ensure that all devices and apparatus are qualified after calibration;确认在规定的范围内操作，该系统能稳定地运行且各项指标能达到设计标准。To ensure that all operations all performed within nominal scope,that this system can operate steadily and all the indexes reach the design standards.3验证的有关人员及其职责Verification-Related Staff and Relevant Responsibilities姓名Name部门D epartment职责Responsibilities李潮Li C hao总I：C hief Engineer确认负责Validation ofresponsibilities王默然Wang Moran研发部 D evelopment D epartment确认设计 Validation ofdesign王思思Wang Sisi生产部 Manufacturing D epartment确认实施Validation ofimplementation崔娇娇C ui Jiaojiao质检部Quality Inspection D epartment确认实施Validation ofimplementation4验证相关文件Verification-Related DocumentationsG B 1827 9医疗器械环氧乙烷灭菌确认和常规控制Medical devices-Ethylene O xide Sterilization-Validation and Routine C ontrolG B 1997 3.1医疗器械灭菌微生物学方法第1部分：产品上微生物总数的估计 Sterilization of Medical D evices-Microbiological Methods-P art 1:Estimation of the P opulation of Microorganisms on P roductG B 1997 3.2医疗器械灭菌微生物学方法第2部分：确认灭菌过程的无菌试验 Sterilization of medical devices-Microbiological methods一 P art 2:Tests of sterility performed in the validation of a sterilization processG B/T 14233.2-2005医用输液、输血、注射器具检验方法 第2部分：生物试验方法 Test methods for infusion,transfusion,injection equipments for medical use-P art 2:B iological test methods5验证内容Verification D etails5.1物理性能确认Validation of physical properties检测灭菌室温度均匀性、泄漏率、真空速率、加湿效果是否符合要求。To test whether the temperature uniformity,leakage rate,vacuum velocity and moist effect meet the requirements.5.2产品生物负载验证Verification of bioburden on product 对产品初始生物负载确认，包括杂菌和真菌。The initial bioburden on product is verified,including bacteria and fungus.5.3性能验证P erformance verification5.3.1灭菌作用时间的确认Validation of sterilization exposure time5.3.1.1灭菌样品Sterilization samples灭菌样品为本公司生产的送放器内导管。样品的处理过程与产品生产过程一致。The sterilization samples are the catheters inside the delivery system produced by our company.The handling process of the samples is identical to the manufacturing process of the product.5.3.1.2生物指示物B iological indicators按照G B 18281.2医疗保健产品灭菌 生物指示物 第2部分：环氧乙烷灭菌生物指示物 的规定，采用枯草杆菌指示剂。In accordance with the provisions of Sterilization of heal th care products-Biological indicators-Part 2:Biological indicators for ethylene oxide sterilization processes,GB18281.2,the B acillus subtilis is chosen as the indicator.5.3.1.3微生物学性能确认Validation of microbial properties采用半周期法：在除时间外所有其他过程参数不变的情况下，确定无存活菌的环氧乙烷 最短作用时间。规定的灭菌作用时间应至少为最短灭菌时间的2倍。为确定灭菌最短时间，应连续三次重复同一工艺参数，以证明工艺的可再现性。Half cycle method is employed.U nder the condition of constant parameters other than time,minimum exposure time of ethylene oxide with no live bacteria is determined.The sterilization exposure time shall be at least twice of the minimum sterilization exposure time.To determine the minimum exposure time,the same technological parameter shall be repeated for 3 consecutive times to ensure the reproducibility of the technology.5.3.2产品二次灭菌的确认Validation of periodical sterilization on the product本公司产品的有效期是根据包装有效作用时间进行确认的。在库房中常常有到期的产品 需要进行二次灭菌。因此，需要确定二次灭菌对产品的影响。The validity period of our products is determined in accordance with the effective acting time of the packages.In the storehouse,the expired products often require periodical sterilization.Therefore,the effects of periodical sterilization on the products have to be determined.5.3.2.1灭菌产品Sterile products灭菌产品为本公司生产的合格产品，在洁净间重新包装后，作为二次灭菌的产品。选用 的产品距上次灭菌时间不得超过1年。The sterile products are qualified products manufactured by our company,which will be taken as the re-sterilized products after repackaging in the clean area.The products chosen for this process shal1 be within one year from the previous sterilization process.5.3.2.2二次灭菌确认Validation of periodical sterilization以产品环氧乙烷残留量解析时间、送放器断裂力、支架薄膜透水性和薄膜溶出物分析作 为指标，确定二次灭菌对产品的影响。应连续三次重复二次灭菌过程，以证明结果的有效性。The effects of periodical sterilization on the product are determined through the analyzing time of ethylene oxide sterilization residuals,the breaking force of the delivery system,the water permeability of the graft and the analysis of the extracts from the graft.The periodical sterilization process shall be repeated for 3 consecutive times to ensure the effectiveness of the results.北京裕恒佳科技有限公司 再验证方案Beijing Y uH eng|ia SciTech Co.Ltd Periodical Verification Program项目名称环氧乙烷灭菌P roject NameEthylene O xide Sterilization项目编号P roject No.EO-P R编制人王默然C ompilerWang Moran编制日期2007年11月2日C ompiling D ateNov 2,2007批准人李湘ApproverLi X iang批准日期2007年11月2日Approval D ateNov 2,20071灭菌器的描述D escriptions of the Sterilizer详细说明灭菌器的基本资料。包括：设备名称，设备型号，制造商，安装地点，铭牌 数据。The fundamental materials of the sterilizer shall be so elaborated that the equipment name,equipment model,manufacturer,installation site,nameplate data should all be listed within.2仪器仪表检定Verification of Equipment and Apparatus在进行性能确认前，检查各控制仪表是否在校验的有效期内。检查仪表精度符合实际 要求。需检仪器要求如表2T所示。B efore the validation of the performances,it should be checked whether all the apparatus are within the validity period of calibration so as to make sure that the precisions of the apparatus meet the requirements in practice.The apparatus to bp i nsppct.pd shal 1 meet the fol I owi ng requirements,whi ch can be referred to Table 2-1.表2-1仪器仪表检定内容Table 2-1 D etails of Verification of the Equipment and Apparatus仪器仪表名称Names of Equipment and Apparatus检定项目和要求Verification Items and Relevant Requirements3物理性能确认温度传感器（珀电阻）Temperature Sensor（P latinum resistor）温度测量范围应为0100,精度至少1%。The measurement range for temperature shall be within 0100 with the minimum precision of 1%.湿度传感器Humidity Sensor测量范围（相对湿度）0%100%,并至少具有20%的精度。The measurement range for relative humidity shall be within 0%100%with the minimum precision of 20%.Validation of P hysical P roperties3.1灭菌室壁温湿度均匀性确认Validation of uniformity of the temperature and humidity on the walls of the sterilizer在灭菌室空载的条件下，将10个经过校验的温度传感器按照布点图放置于灭菌室的内 壁上。位置图如附录1所示。U nder the condition of no load within the sterilizer,10 calibrated temperature sensors are placed on the inner wall of the sterilizer in accordance with the distribution diagram,which can find expression in the Annex 1.启动加热循环系统，在控制温度为50C时，用温度记录仪表记录灭菌室内各测温点的 温度。各测点与控制温度差应在3范围内。Start the heating system with a control led temperature of 50.The temperature on each temperature measurement point shall be recorded with the temperature recording apparatus.The temperature at each point shall differ from the controlled temperature within 3.3.2 灭菌室空间温度均匀性确认Validation of temperature uniformity within the sterilizer在灭菌室空载的条件下，将10个经过校验的温度传感器插入到被灭菌物品中。位置图 如附录3所示。U nder the condition of no load within the sterilizer,10 calibrated temperature sensors are placed into the sterilized products,the placement diagram for which is within the Annex 3.3.3 负载温度均匀性确认Verification of temperature uniformity on the load在灭菌室满载的条件下，将3个经过校正的温度传感器插入到被灭菌物品中。位置图如 附录3所示。U nder the condition of full load within the sterilizer,3 calibrated temperature sensors are placed into the sterilized products,the placement diagram for which is within the Annex 3.启动加热循环系统，在控制温度为50c时，用温度记录仪表记录灭菌室各测温点的温 度。各测点与控制温度差应在5范围内。Start the heating system with a controlled temperature of 50.The temperature on each temperature measurement point shall be recorded with the temperature recording apparatus.The temperature at each point shall differ from the controlled temperature within 3.3.4 灭菌室泄漏率确认Validation of leakage rate within the sterilizer灭菌器空载正常运行时，在灭菌室温度不变的条件下，分别测试正压250kP a和负压W-50kP a的压力，保压时间大于等于lh;观察记录监测泄漏率的压力指示表的压力变化，并 计算结果。在测定时间内平均泄漏率应WO.IkP a/min。【不通顺】U nder normal operation with no load and a constant temperature within the sterilizer,the pressures are measured respectively with the positive pressure no less than 50kP a and negative pressure no more than-50kP a for an hour.The pressure changes on the pressure gauge are observed for leakage rate and relative results are calculated.Within the measurement,the mean leakage rate shall be within 0.IkP a/min.3.5 灭菌器真空速率确认Validation of vacuum velocity within the sterilizer在灭菌室空载、密封、温度恒定的条件下，启动真空装置，记录真空度从常压达到-50kP a 的时间（至少重复三次），测定时间应W30min。U nder the condition of no load,sealing and constant temperature,the vacuum equipment shall be started.Record the time it takes from the atmospheric pressure to-50kP a,which shal 1 be repeated for three times with measurement time controlled within 30min.3.6灭菌室加湿效果Humidification effect in the sterilizer在灭菌室空载、密封、温度恒定的条件下，将灭菌室的相对湿度降至W40%后，通过加 湿系统向灭菌室加湿。灭菌器通过加湿系统应使相对湿度达到至少60%oU nder the condition of no load,sealing and constant temperature,bring the relative moist within the sterilizer down to less than 40%and then increase the humidity within the sterilizer through humidifier,after which,the relative humidity within the sterilizer shall at least reach 60%.4微生物性能确认Validation of microbiological properties4.1 灭菌产品的装载模式Loading mode of the products for sterilization确定产品的装载模式，并形成规范。装载模式包括：在外包装盒中放置的方式，位置，最大装载量，以及灭菌柜内容纳的外包装盒的数量。在进行性能确认时，采用与正常生产相 同过程的样品替代。The loading mode of the products shall be confirmed and documented into some standard.Loading mode includes the way,position and maximum load of the product placed in the outer container as well as the capacity of the sterilizer for outer containers.When performance qualification is performed,the products shal1 be substituted with samples undergone the same manufacturing process.4.2 产品初始生物负载的确认Validation of initial bioburdens on the products通过对本公司生产的送放器内导管的真菌和细菌培养，确定了产品的微生物负载。Through the culture of fungus and bacteria in the catheter of the delivery system produced by our company,the microbiological burden on the product shall be determined.4.3生物指示物的数量和分布P opulation and distribution of the biological indicators根据IS011135-1的要求，在灭菌柜中放置10个生物指示物。放置点应包括灭菌条件下 最难灭菌部位。主要为冷点和外包装盒的中心等蒸汽难以进入的位置，分布图如附录4所示。10 biological indicators are placed into the sterilizer in accordance with IS011135-1.The placement points should include the hardest sterilized points in a sterilization process,which mainly refer to the places as the cold points and the center of the outer container.For the distribution diagram,refer to the Annex 4.4.4确定灭菌工艺D etermination of sterilization technologies4.4.1预热P reheating设定灭菌温度为50。The sterilization temperature shall be set to 50.4.4.2抽真空Vacuumization加热至灭菌温度后，应抽真空排除灭菌室内的空气。When the equipment is heated to the temperature for sterilization,vacuumization shall be performed to remove the air within the sterilizer.达到设定的真空度23min后，保持lO min进行泄露检测，在此期间，压力的升高不应 超过 0.3kpa/min。When the vacuum degree has reached the set point for 2 or 3 minutes,continue such condition for lO min for leakage inspection.D uring this period,the increase of the pressure shall be within 0.3kP a/min.设定真空度参数为-60kP a,记录泄漏测试结果。Set the vacuum parameter to-60kP a,the leakage test result shall be recorded.4.4.3加湿Humidification通过加湿装置的加湿作用，使灭菌湿度满足灭菌要求。加湿使用纯化水。Through the humidification of the humidifier,the sterilization humidity shall meet up the sterilization requirements.For this process,purified water is used.设定灭菌湿度参数为7 0%10%,均衡时间lO min。以上过程形成记录，并记录加入蒸汽 时压力升高的程度。The sterilization parameters shall be set to 7 0%10%,which shall last for lO min.This process shall be maintained as record.The increase degree of the pressure the moment steam is added shall be recorded.4.4.4加药C hemical feeding保证环氧乙烷充分气化，以气体状态进入灭菌室。The ethylene oxide shall be fully gasified,which shall enter the sterilizer in the form of gas.对环氧乙烷的加入量和加入速度进行调节和控制，加入环氧乙烷气体后，灭菌室的压力 不应超过灭菌器的最高工作压力。记录加入环氧乙烷时压力升高的程度和达到的速度。The feeding dose and velocity of ethylene oxide shall be regulated and controlled.When ethylene oxide has been added,the pressure within the sterilizer shall not exceed the maximum operating pressure.The increase degree of the pressure and the velocity of the gas flow should be recorded.设定投药量为600g,开始加药，记录加药完成时间、加药前压力、完成时的压力、进 药过程的温度。With the chemical dosage set to 600g,chemical feeding process is started.The completion time,the pressure prior to chemical feeding,the pressure at the completion of the feeding process and the temperature within the feeding process should al1 be recorded.4.4.5清洗C leaning灭菌结束后，抽真空至-60kP a,将灭菌器中残留气体排出。When sterilization is completed,the sterilizer shall be vacuumized to-60kP a,to expel the residual air from the sterilizer.将空气过滤球阀打开，使过滤空气进入灭菌器，此时灭菌器回复正常气压，如此重复置 换7次。O pen the ball valve of the air filter to let the filtered air into the sterilizer.At this moment,the sterilizer returns to the atmospheric pressure.This process shall be repeated for 7 times.清洗完成后，灭菌物品在密闭的灭菌室内的滞留时间应W15min,否则，在门打开之前 需重新执行清洗阶段。以上操作形成记录。并记录排除环氧乙烷所需达到的真空程度和速度，以及通入空气时压力升高的程度和达到压力的速度。并记录清洗时的温度，不得低于47。When the cleaning process is completed,the sterilizing products shall stay in the sterilizer for at least 15min.O therwise,the cleaning process shall be performed before the door is opened.The whole process shall be maintained as record,which includes the vacuum degree and velocity required to expel the ethylene oxide as well as the increase of the pressure at the influx of air and the airflow velocity to reach the pressure.The cleaning temperature shall be recorded,which sh