空气和蒸汽混合式的灭菌方案 -洁定Hans Larsson

1、Air-Steam Mixture Sterilization Solution Delicate BFS containers and pre-filled syringes空气蒸汽混合灭菌解决方案空气蒸汽混合灭菌解决方案应用于吹灌封和预灌装注射器产品的终端灭菌应用于吹灌封和预灌装注射器产品的终端灭菌PDI Jinan September 2012PDI ， 2012年9月于济南Presentation by Hans Larsson/Kevin Qian Getinge主讲人：洁定公司 乐瀚森/钱鼎Difficulties with terminal sterilization of yo

2、ur delicate containers 柔性容器终端灭菌相对困难柔性容器终端灭菌相对困难Important features on sterilization process灭菌过程的重要特征灭菌过程的重要特征Fast process 过程迅速High degree of Sterility Assurance高度的无菌保证值No deformation on products 产品不变形2Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Difficulties with terminal sterilization of your deli

3、cate containers 柔性容器终端灭菌相对困难柔性容器终端灭菌相对困难How to choose? 如何选择如何选择Process it quickly and to a high degree of Sterility Assurance, but then it will not be in good shape. 灭菌迅速并获得高的无菌保证值，但产品形状受到影响Process it quickly and ensure it remains in good shape, but it may not be fully sterile.灭菌迅速并保持产品形状，但不能完全灭菌Pro

4、cess it to a high degree of Sterility Assurance and remain in good shape, but it will take a long time. 获得高的无菌保证值并保持产品形状，但需要很长的灭菌时间At first glance you can only pick any two在快速处理、无菌保证和产品形状三者之间只在快速处理、无菌保证和产品形状三者之间只能选择两项能选择两项3Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Steam Sterilization 蒸汽灭菌柜蒸汽灭菌柜

5、Traditional Steam Sterilizer 传统的蒸汽灭菌柜传统的蒸汽灭菌柜 Used for sterilization of many different products within Healthcare, Biomedical Research and Pharmaceutical Production 广泛应用于医疗、生物医学和制药行业 Used for a variety of products such as: 可用于不同的产品，比如：Hard goods (e.g. instruments, components, glassware parts)硬物（比如器械

6、、部件、玻璃器皿）Porous / Wrapped Goods (e.g. textiles, Tyvek bags)多孔/包裹物品 （比如织物、Tyvek袋子）Liquids, Parenterals 液体、注射剂 Both for sterilization of products as well as decontamination of Bio-Hazardous waste. 可对产品灭菌，也可以对有生物危害的废物灭菌4Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Why risk of deformation? 为何产品包装会产生变形

7、为何产品包装会产生变形What happens during heating of product in a Steam Sterilizer?在蒸汽灭菌过程中的加热阶段发生了什么？在蒸汽灭菌过程中的加热阶段发生了什么？Steam is used to heat the product from the outside pressure in the chamber rises 蒸汽在容器外部对产品进行加热，灭菌器腔体压力不断上升Pressure in a sealed container rises as it is heated due to expansion of air and ot

8、her factors 被加热的密闭容器由于气体膨胀及其他因素引起容器内部的压力上升Total internal pressure will be sum of water vapor pressure and air pressure 内部压力为水蒸汽压力和空气压力之和5Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Why risk of deformation?为何产品包装会产生变形为何产品包装会产生变形What happens during cooling of product in a Steam Sterilizer?在蒸汽灭菌过程中的

9、冷却阶段发生了什么？在蒸汽灭菌过程中的冷却阶段发生了什么？Energy is only lost from container by transmission to environment need to remove steam from chamber 密闭容器能量的损失只能通过向腔体内传递的方式 所以需要去除腔体内的蒸汽Replace the steam with air so that the containers do not explode 采用空气代替蒸汽，以防止密闭容器爆裂Radiation from external surfaces Slow cooling process

10、 容器外表面热辐射 非常缓慢的冷却过程Pressure in the sealed container is still very high 密闭容器内的压力仍然很高 The container can be sterilized in a steam sterilizer only if the container can withstand a pressure difference只有能承受内外压差的密闭容器才能在普通蒸汽灭菌器内进行灭菌6Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Why risk of deformation?为何产品

11、包装会产生变形为何产品包装会产生变形Which Products can withstand a pressure difference? 哪些产品可以承受压差？哪些产品可以承受压差？LVP:s and parenteral in delicate containers cannot withstand a pressure difference柔性容器不能承受压差Some SVP:s like glass ampoules and crimp-capped vials can withstand a pressure difference.一些玻璃安瓿和轧盖西林瓶能承受压差If you ha

12、ve the time to wait如果您有时间去等待的话7Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Difficulties with terminal sterilization of your delicate containers柔性容器终端灭菌相对困难柔性容器终端灭菌相对困难How to have it fast, sterile and in good shape? 如何实现快速灭菌、包材形状完好？如何实现快速灭菌、包材形状完好？8Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Pr

13、ocesses available 可实现的灭菌方式可实现的灭菌方式9Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Water Cascade 水浴式水浴式Why water? Water very good carrier of energy. Especially good during cooling phase. 为何采用水浴？水是良好的能量载体， 特别在冷却过程中。Water is filled in the chamber and circulated during process. 水进入灭菌腔，并在整个过程中循环。Circulat

14、ing water is heated with e.g. steam to heat up product 循环水被蒸汽加热，进而加热产品Possibility to add air support pressure可以加压力补偿Circulating water is cooled with e.g. cold water to cool down product循环水被冷却，进而冷却产品Extremely fast process, but products are wet afterwards 灭菌过程非常快，但灭菌完成后产品是湿的。Processes available可实现的灭菌方

15、式可实现的灭菌方式10Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Steam and air mixture 蒸汽和空气混合式蒸汽和空气混合式Steam and Air mixed in process 在灭菌过程中蒸汽和空气混合Steam is used to heat up product蒸汽用于加热产品Dry pre-heating is optional 预热可作为选项Possibility to add air support pressure - Fan makes the surrounding homogenous 可以加压力补

16、偿 顶部风机使灭菌腔内环境更均一Air cooled by internal heat exchanger is used to cool down product. Air is circulated with fan 内部热交换器冷却腔内空气，进而冷却产品。 空气在风机的作用下在腔内循环Process time can be very fast, depending on cooling system, and products are dry afterwards 灭菌过程可以非常快速，产品在灭菌后为干燥状态Temperature Gradient and F0 温度梯度和温度梯度和F0

17、值值11Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Steam and air mixture 蒸汽和空气混合蒸汽和空气混合 Example on steam and air mixture sterilizer: 蒸汽和空气混合灭菌器示例 During heatup, product at the bottom heats more quickly than product at the top 加热阶段，在灭菌底部的产品比顶部的产品升温快 Conversely, during cooling, the load at the bottom

18、cools more quickly 相反，在冷却阶段，底部比顶部的冷却快The net result is that the total heating effect (F0 value) is the same所以整个过程的所以整个过程的F0值是相同的值是相同的This is a well accepted and understood principle, and customers validate their sterilizers accordingly 这是广泛接受并能理解的原则，在灭菌器验证中完全实现If steam/air flow is horizontal, the sa

19、me applies but with a temperature gradient horizontally如果蒸汽/空气的流向为水平，以上结论同样适用，但温度梯度是水平的。Extensive testing 大量的测试大量的测试12Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Performing tests 性能测试性能测试Getting a “perfect” process requires extensive testing 取得完美的灭菌过程需要大量的测试How products are placed during the proc

20、ess 产品如何放置“Stand-alone” products “站立式”Stacked products “堆积式”Process flow 过程流向Vertical flow 垂直流向Horizontal flow 水平流向Placement of load sensor 装载传感器的放置Different locations to optimize cycle不同位置优化灭菌过程Also important for safety对于安全性也很重要Extensive testing 大量测试大量测试13Sep 2012Hans Larsson - Getinge - PDI Jinan

21、201214Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Key Findings Temperature Control重要结论重要结论 温度控制温度控制Temperature Control 温度控制温度控制Placement of load sensors is critical to optimize the cycle in both preliminary study and lab testing. 装载传感器的放置装载传感器的放置对优化灭菌过程非常关键，无论在初步研究阶段还是在实验室测试阶段An accurate load sim

22、ulator (or “dummy” container) is key for sensitive loads. For each specific load a unique load simulator needs to be developed. 精确的装载模拟 （或称之为”仿制容器”）对于敏感性产品非常重要。对于每一个特殊装载都要进行装载模拟测试It is important to place the load sensor in the slowest product to make sure all products reach sterilization temperature

23、.将装载传感器放置于温度上升最慢的产品是非常关键的，可以确认所有的产品都能达到灭菌温度Improving temperature spread has a significant impact on process time, in particular during cooling phase.提高热分布对灭菌时间，特别是冷却阶段有巨大的影响 Focus on low temperature spread only at those temperature ranges where it matters: slow heating and cooling above 90 C. 关注低温度分

24、布，只有在温度范围发生问题，在90 C. 以上升降温缓慢。15Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Key Findings Temperature Control重要结论重要结论 温度控制温度控制Temperature Control温度控制温度控制F0 accumulation during heating and cooling phase shall be considered when aiming for a fast cycle. This is accepted from a sterility assurance lev

25、el, but might not sufficient as temperature spread may lead to deformation of certain delicate containers. 对于一个快速灭菌过程，必须考虑加热和冷却阶段的F0值的积累。从无菌保障值来讲是被接受的，但也不充分，因为热分布会导致某些柔性包材变形因为热分布会导致某些柔性包材变形During cooling phase, temperature spread at the end of cycle may be a safety issue as late cooled / hot contain

26、ers may explode when opening the door. 在冷却过程中，在灭菌过程的最后阶段，热分布可能热分布可能产生安全问题产生安全问题，因为开门的时候热的容器可能会爆裂。16Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Key Findings Pressure Control重要结论重要结论 压力控制压力控制Pressure Control 压力控制压力控制Support pressure is a key parameter, in particular if the load is not densely packe

27、d or supported by loading accessories. 压力补偿是关键参数，特别是在装载不是特别紧密的情况下Support pressure needs to be adjusted during the course of the cycle. 在灭菌过程中压力补偿需要调节There are various strategies to control support pressure during the cycle and the most suitable pressure control is generally dependent on the design o

28、f the container as well as the container material. 有多种方式进行压力补偿，最适合的压力控最适合的压力控制取决于容器的设计与材质制取决于容器的设计与材质17Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Key Findings Other Parameters重要结论重要结论 其他参数其他参数Other Parameters 其他参数其他参数To optimize cooling time on a steam and air mixture sterilizer, it is necessary

29、 to: 为了优化冷却时间，必须具备以下要素：Have sufficient cooling power 具有足够的具有足够的冷却能力冷却能力Distribute the air uniformly within the load将空气均匀的分布在装载物上将空气均匀的分布在装载物上Characteristics of the BFS containers have a significant impact on their processability: 吹灌封容器的特性对灭菌过程中有很大的影响：Wall thickness/flexibility 容器壁厚/柔韧性Head space/wat

30、er level 液面上空间/液位Weight of closure. 容器的重量18Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Key Findings Conclusion重要结论重要结论 结论结论Conclusion 结论结论Cycles need to be optimized for each type of container. 各种容器的灭菌循环都需进行优化Requires cooperation between BFS machine and sterilizer manufacturer. 需要吹灌封设备和灭菌设备需要吹灌封设

31、备和灭菌设备的供应商进行技术合作的供应商进行技术合作Can be developed at site or in advance.需要预先或者在现场进行优化19Nested Syringes 巢状注射器巢状注射器Tests performed with 1,25 ml Nested syringes 用1.25ml的巢状注射器进行测试448 nests per Rack (44800 syringes) 每个灭菌架车装载448个注射器巢 （共44800支注射器）Objective to develop an optimized process for Nested syringes 目标是优化

32、灭菌过程Lateral Air Flow Turbo option 水平气流 提供Turbo选项Criterias: 标准EN285F0 spread 8 min F0差值为8minVisually dry load 灭菌后负载目测干燥No movement of stopper 注射器插杆未移动OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES优化预灌装注射器的灭菌过程优化预灌装注射器的灭菌过程Development & Testing 优化及测试20Nested Syringes Temperature Distribution巢状注射器巢状注射

33、器 热分布热分布Temperature monitoring from inside the syringes 在注射器内部进行温度监控Low temperature spread above 80 C 80 C 以上温差很小Low temperature spread when F0 calculation starts ( 5-6 C at 115 C ) 当F0开始积累时( 5-6 C at 115 C ) ，温差很小Low F0 spread (121 C ): 3 min with a total F0 of 30 min 小的F0差值(121 C ): 灭菌30分钟，F0差值小于3

34、min OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES优化预灌装注射器的灭菌过程优化预灌装注射器的灭菌过程Development & Testing 优化及测试21Nested Syringes Dry Load 干燥负载干燥负载Visible droplets on load and shelves after regular GEV process 在常规的GEV程序灭菌后在负载和层架上可见小的水滴Adding preheat phase reduces droplets (but not completely dry) but increa

35、ses temperature spread below 80 C 增加预热程序可以减少水滴（但不会完全干燥），但提高了80 C 下的温度差Adding Fan Drying removes droplets but increases temperature spread below 80 C 增加风扇干燥可以去除水滴，但提高了80 C 下的温度差OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES优化预灌装注射器的灭菌过程优化预灌装注射器的灭菌过程Development & Testing 优化及测试22Nested Syringes Stoppe

36、r Movement 插杆移动插杆移动Stopper movement measured before and after process is small 灭菌前后插杆移动很少Stopper movement during the process is rather large! 在灭菌过程中插杆的移动相当大！ Inwards outwards appr. 2-3 mm! But The GEV TS can control it with precision!但是GEV TS能够更精确的进行控制OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES优化预灌装

37、注射器的灭菌过程优化预灌装注射器的灭菌过程Development & Testing 优化及测试23Nested Syringes Biological sterilization efficacy 生物学灭生物学灭菌效果菌效果Biological indicator (cotton threads) placed inside rubber cap at the needle of the syringe 生物指示剂（棉线）放置于注射器针头一侧的橡皮帽内Tests performed both with needles pointing upwards, downwards and

38、horizontally 分别对针头向上、向下和水平方向进行测试No growth in when needles were pointing upwards or horizontally. Growth in one specimen where needle was pointing downwards 针头向上和水平放置时无微生物生长，针头向下放置时有一个微生物生长OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES优化预灌装注射器的灭菌过程优化预灌装注射器的灭菌过程Development & Testing 优化及测试24Nested Syr

39、inges 巢状注射器巢状注射器Temperature distribution throughout the load is very good 温度均一性非常好Dryness of the load can be controlled with additions in the process 负载的干燥度在灭菌过程中有很好的控制Process times 100 min with Preheat and Fan Drying 灭菌时间大约为100min，包括预热和风扇干燥时间OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES优化预灌装注射器的灭菌过程优化预灌装注射器的灭菌过程Conclusions 结论What is most important for You?什么对您最重要？什么对您最重要？Getinge GEV TS Turbo is flexible!洁定洁定GEV最灵活！最灵活！25Infusion Bags 输液袋输液袋 Heat Up 加热加热 Big Temperature spread initially 加热开始阶段的温差较大Low temperature spread when F0 calculation starts ( 4-7 C at 115 C ) 当F0开始累积时( 4-7 C