空气和蒸汽混合式的灭菌方案 -洁定 Hans Larsson.ppt

air-steam mixture sterilization solution delicate bfs containers and pre-filled syringes 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 pdi jinan september 2012 pdi ， 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 your delicate containers 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 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 2012 difficulties with terminal sterilization of your delicate containers 柔性容器终端灭菌相对困难 how to choose? 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 process 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 能选择两项 3sep 2012hans larsson - getinge - pdi jinan 2012 steam sterilization 蒸汽灭菌柜 traditional steam sterilizer 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、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 2012 why risk of deformation? 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？ 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 other 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 2012 why risk of deformation?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 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 2012 why risk of deformation?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？ 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 have the time to wait 如果您有时间去等待的话 7sep 2012hans larsson - getinge - pdi jinan 2012 difficulties with terminal sterilization of your delicate containers 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？ 8sep 2012hans larsson - getinge - pdi jinan 2012 processes available 可实现的灭菌方式 9sep 2012hans larsson - getinge - pdi jinan 2012 water cascade 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。 circulating 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可实现的灭菌方式 10sep 2012hans larsson - getinge - pdi jinan 2012 steam and air mixture 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f0值 11sep 2012hans larsson - getinge - pdi jinan 2012 steam and air mixture 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 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f0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 same 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 12sep 2012hans larsson - getinge - pdi jinan 2012 performing tests 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 process 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 13sep 2012hans larsson - getinge - pdi jinan 2012 14sep 2012hans larsson - getinge - pdi jinan 2012 key findings temperature control 重要结论结论 温度控制 temperature control 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 simulator (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.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 2012 key findings temperature control 重要结论结论 温度控制 temperature control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 level, 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 during cooling phase, temperature spread at the end of cycle may be a safety issue as late cooled / hot containers 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 2012 key findings pressure control 重要结论结论 压压力控制 pressure control 压力控制 support pressure is a key parameter, in particular if the load is not densely packed 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 of the container as well as the container material. 有多种方式进行压力补偿，最 适合的压力控制取决于容器的设计与材质 17sep 2012hans larsson - getinge - pdi jinan 2012 key findings other parameters 重要结论结论 其他参数 other parameters 其他参数 to optimize cooling time on a steam and air mixture sterilizer, it is necessary 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 冷却能力 distribute the air uniformly within the load 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/water level 液面上空间/液位 weight of closure. 容器的重量 18sep 2012hans larsson - getinge - pdi jinan 2012 key findings conclusion 重要结论结论 结论结论 conclusion 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 19 nested syringes 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 目标是优化灭菌过程 lateral air flow turbo option 水平气流 提供turbo 选项 criterias: 标准 en285 f0 spread 8 min f0差值为8min visually 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 development & testing 优化及测试 20 nested syringes temperature distribution 巢状注射器 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3min optimized processing of pre-filled syringes 优化预灌装注射器的灭菌过程 development & testing 优化及测试 21 nested syringes dry load 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 increases 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 development & testing 优化及测试 22 nested syringes stopper movement 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 优化预灌装注射器的灭菌过程 development & testing 优化及测试 23 nested syringes biological sterilization efficacy 生物学灭 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 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 development & testing 优化及测试 24 nested syringes 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 conclusions 结论 what is most important for you? 什么对您最重要？ getinge gev ts turbo is flexible! 洁定gev最灵活！ 25 infusion bags 输液袋 heat up 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 at 115 c )温差较小 optimized processing 优化的灭菌过程 development & testing 优化与测试 26 infusion bags 输液袋 lateral air flow turbo o