1、Air-Steam Mixture Sterilization Solution Delicate BFS containers and pre-filled syringes空氣蒸汽混合滅菌解決方案空氣蒸汽混合滅菌解決方案應用于吹灌封和預灌裝注射器產品的終端滅菌應用于吹灌封和預灌裝注射器產品的終端滅菌PDI Jinan September 2012PDI ， 2012年9月于濟南Presentation by Hans Larsson/Kevin Qian Getinge主講人：潔定公司 樂瀚森/錢鼎Difficulties with terminal sterilization of yo

2、ur delicate containers 柔性容器終端滅菌相對困難柔性容器終端滅菌相對困難Important features on sterilization process滅菌過程的重要特征滅菌過程的重要特征Fast process 過程迅速High degree of Sterility Assurance高度的無菌保證值No deformation on products 產品不變形2Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Difficulties with terminal sterilization of your deli

3、cate containers 柔性容器終端滅菌相對困難柔性容器終端滅菌相對困難How to choose? 如何選擇如何選擇Process it quickly and to a high degree of Sterility Assurance, but then it will not be in good shape. 滅菌迅速并獲得高的無菌保證值，但產品形狀受到影響Process it quickly and ensure it remains in good shape, but it may not be fully sterile.滅菌迅速并保持產品形狀，但不能完全滅菌Pro

4、cess it to a high degree of Sterility Assurance and remain in good shape, but it will take a long time. 獲得高的無菌保證值并保持產品形狀，但需要很長的滅菌時間At first glance you can only pick any two在快速處理、無菌保證和產品形狀三者之間只在快速處理、無菌保證和產品形狀三者之間只能選擇兩項能選擇兩項3Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Steam Sterilization 蒸汽滅菌柜蒸汽滅菌柜

5、Traditional Steam Sterilizer 傳統(tǒng)的蒸汽滅菌柜傳統(tǒng)的蒸汽滅菌柜 Used for sterilization of many different products within Healthcare, Biomedical Research and Pharmaceutical Production 廣泛應用于醫(yī)療、生物醫(yī)學和制藥行業(yè) Used for a variety of products such as: 可用于不同的產品，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 （比如織物、Tyvek袋子）Liquids, Parenterals 液體、注射劑 Both for sterilization of products as well as decontamination of Bio-Hazardous waste. 可對產品滅菌，也可以對有生物危害的廢物滅菌4Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Why risk of deformation? 為何產品包裝會產生變形

7、為何產品包裝會產生變形What happens during heating of product in a Steam Sterilizer?在蒸汽滅菌過程中的加熱階段發(fā)生了什么？在蒸汽滅菌過程中的加熱階段發(fā)生了什么？Steam is used to heat the product from the outside pressure in the chamber rises 蒸汽在容器外部對產品進行加熱，滅菌器腔體壓力不斷上升Pressure in a sealed container rises as it is heated due to expansion of air and ot

8、her factors 被加熱的密閉容器由于氣體膨脹及其他因素引起容器內部的壓力上升Total internal pressure will be sum of water vapor pressure and air pressure 內部壓力為水蒸汽壓力和空氣壓力之和5Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Why risk of deformation?為何產品包裝會產生變形為何產品包裝會產生變形What happens during cooling of product in a Steam Sterilizer?在蒸汽滅菌過程中的

9、冷卻階段發(fā)生了什么？在蒸汽滅菌過程中的冷卻階段發(fā)生了什么？Energy is only lost from container by transmission to environment need to remove steam from chamber 密閉容器能量的損失只能通過向腔體內傳遞的方式 所以需要去除腔體內的蒸汽Replace the steam with air so that the containers do not explode 采用空氣代替蒸汽，以防止密閉容器爆裂Radiation from external surfaces Slow cooling process

10、 容器外表面熱輻射 非常緩慢的冷卻過程Pressure in the sealed container is still very high 密閉容器內的壓力仍然很高 The container can be sterilized in a steam sterilizer only if the container can withstand a pressure difference只有能承受內外壓差的密閉容器才能在普通蒸汽滅菌器內進行滅菌6Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Why risk of deformation?為何產品

11、包裝會產生變形為何產品包裝會產生變形Which Products can withstand a pressure difference? 哪些產品可以承受壓差？哪些產品可以承受壓差？LVP:s and parenteral in delicate containers cannot withstand a pressure difference柔性容器不能承受壓差Some SVP:s like glass ampoules and crimp-capped vials can withstand a pressure difference.一些玻璃安瓿和軋蓋西林瓶能承受壓差If you ha

12、ve the time to wait如果您有時間去等待的話7Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Difficulties with terminal sterilization of your delicate containers柔性容器終端滅菌相對困難柔性容器終端滅菌相對困難How to have it fast, sterile and in good shape? 如何實現(xiàn)快速滅菌、包材形狀完好？如何實現(xiàn)快速滅菌、包材形狀完好？8Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Pr

13、ocesses available 可實現(xiàn)的滅菌方式可實現(xiàn)的滅菌方式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. 為何采用水浴？水是良好的能量載體， 特別在冷卻過程中。Water is filled in the chamber and circulated during process. 水進入滅菌腔，并在整個過程中循環(huán)。Circulat

14、ing water is heated with e.g. steam to heat up product 循環(huán)水被蒸汽加熱，進而加熱產品Possibility to add air support pressure可以加壓力補償Circulating water is cooled with e.g. cold water to cool down product循環(huán)水被冷卻，進而冷卻產品Extremely fast process, but products are wet afterwards 滅菌過程非常快，但滅菌完成后產品是濕的。Processes available可實現(xiàn)的滅菌方

15、式可實現(xiàn)的滅菌方式10Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Steam and air mixture 蒸汽和空氣混合式蒸汽和空氣混合式Steam and Air mixed in process 在滅菌過程中蒸汽和空氣混合Steam is used to heat up product蒸汽用于加熱產品Dry pre-heating is optional 預熱可作為選項Possibility to add air support pressure - Fan makes the surrounding homogenous 可以加壓力補

16、償 頂部風機使滅菌腔內環(huán)境更均一Air cooled by internal heat exchanger is used to cool down product. Air is circulated with fan 內部熱交換器冷卻腔內空氣，進而冷卻產品。 空氣在風機的作用下在腔內循環(huán)Process time can be very fast, depending on cooling system, and products are dry afterwards 滅菌過程可以非常快速，產品在滅菌后為干燥狀態(tài)Temperature Gradient and F0 溫度梯度和溫度梯度和F0

17、值值11Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Steam and air mixture 蒸汽和空氣混合蒸汽和空氣混合 Example on steam and air mixture sterilizer: 蒸汽和空氣混合滅菌器示例 During heatup, product at the bottom heats more quickly than product at the top 加熱階段，在滅菌底部的產品比頂部的產品升溫快 Conversely, during cooling, the load at the bottom

18、cools more quickly 相反，在冷卻階段，底部比頂部的冷卻快The net result is that the total heating effect (F0 value) is the same所以整個過程的所以整個過程的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 這是廣泛接受并能理解的原則，在滅菌器驗證中完全實現(xiàn)If steam/air flow is horizontal, the sa

19、me applies but with a temperature gradient horizontally如果蒸汽/空氣的流向為水平，以上結論同樣適用，但溫度梯度是水平的。Extensive testing 大量的測試大量的測試12Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Performing tests 性能測試性能測試Getting a “perfect” process requires extensive testing 取得完美的滅菌過程需要大量的測試How products are placed during the proc

20、ess 產品如何放置“Stand-alone” products “站立式”Stacked products “堆積式”Process flow 過程流向Vertical flow 垂直流向Horizontal flow 水平流向Placement of load sensor 裝載傳感器的放置Different locations to optimize cycle不同位置優(yōu)化滅菌過程Also important for safety對于安全性也很重要Extensive testing 大量測試大量測試13Sep 2012Hans Larsson - Getinge - PDI Jinan

21、201214Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Key Findings Temperature Control重要結論重要結論 溫度控制溫度控制Temperature Control 溫度控制溫度控制Placement of load sensors is critical to optimize the cycle in both preliminary study and lab testing. 裝載傳感器的放置裝載傳感器的放置對優(yōu)化滅菌過程非常關鍵，無論在初步研究階段還是在實驗室測試階段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. 精確的裝載模擬 （或稱之為”仿制容器”）對于敏感性產品非常重要。對于每一個特殊裝載都要進行裝載模擬測試It is important to place the load sensor in the slowest product to make sure all products reach sterilization temperature

23、.將裝載傳感器放置于溫度上升最慢的產品是非常關鍵的，可以確認所有的產品都能達到滅菌溫度Improving temperature spread has a significant impact on process time, in particular during cooling phase.提高熱分布對滅菌時間，特別是冷卻階段有巨大的影響 Focus on low temperature spread only at those temperature ranges where it matters: slow heating and cooling above 90 C. 關注低溫度分

24、布，只有在溫度范圍發(fā)生問題，在90 C. 以上升降溫緩慢。15Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Key Findings Temperature Control重要結論重要結論 溫度控制溫度控制Temperature Control溫度控制溫度控制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. 對于一個快速滅菌過程，必須考慮加熱和冷卻階段的F0值的積累。從無菌保障值來講是被接受的，但也不充分，因為熱分布會導致某些柔性包材變形因為熱分布會導致某些柔性包材變形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. 在冷卻過程中，在滅菌過程的最后階段，熱分布可能熱分布可能產生安全問題產生安全問題，因為開門的時候熱的容器可能會爆裂。16Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Key Findings Pressure Control重要結論重要結論 壓力控制壓力控制Pressure Control 壓力控制壓力控制Support pressure is a key parameter, in particular if the load is not densely packe

27、d or supported by loading accessories. 壓力補償是關鍵參數(shù)，特別是在裝載不是特別緊密的情況下Support pressure needs to be adjusted during the course of the cycle. 在滅菌過程中壓力補償需要調節(jié)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. 有多種方式進行壓力補償，最適合的壓力控最適合的壓力控制取決于容器的設計與材質制取決于容器的設計與材質17Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Key Findings Other Parameters重要結論重要結論 其他參數(shù)其他參數(shù)Other Parameters 其他參數(shù)其他參數(shù)To optimize cooling time on a steam and air mixture sterilizer, it is necessary

29、 to: 為了優(yōu)化冷卻時間，必須具備以下要素：Have sufficient cooling power 具有足夠的具有足夠的冷卻能力冷卻能力Distribute the air uniformly within the load將空氣均勻的分布在裝載物上將空氣均勻的分布在裝載物上Characteristics of the BFS containers have a significant impact on their processability: 吹灌封容器的特性對滅菌過程中有很大的影響：Wall thickness/flexibility 容器壁厚/柔韌性Head space/wat

30、er level 液面上空間/液位Weight of closure. 容器的重量18Sep 2012Hans Larsson - Getinge - PDI Jinan 2012Key Findings Conclusion重要結論重要結論 結論結論Conclusion 結論結論Cycles need to be optimized for each type of container. 各種容器的滅菌循環(huán)都需進行優(yōu)化Requires cooperation between BFS machine and sterilizer manufacturer. 需要吹灌封設備和滅菌設備需要吹灌封設

31、備和滅菌設備的供應商進行技術合作的供應商進行技術合作Can be developed at site or in advance.需要預先或者在現(xiàn)場進行優(yōu)化19Nested Syringes 巢狀注射器巢狀注射器Tests performed with 1,25 ml Nested syringes 用1.25ml的巢狀注射器進行測試448 nests per Rack (44800 syringes) 每個滅菌架車裝載448個注射器巢 （共44800支注射器）Objective to develop an optimized process for Nested syringes 目標是優(yōu)化

32、滅菌過程Lateral Air Flow Turbo option 水平氣流 提供Turbo選項Criterias: 標準EN285F0 spread 8 min F0差值為8minVisually dry load 滅菌后負載目測干燥No movement of stopper 注射器插桿未移動OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES優(yōu)化預灌裝注射器的滅菌過程優(yōu)化預灌裝注射器的滅菌過程Development & Testing 優(yōu)化及測試20Nested Syringes Temperature Distribution巢狀注射器巢狀注射器 熱分

33、布熱分布Temperature monitoring from inside the syringes 在注射器內部進行溫度監(jiān)控Low temperature spread above 80 C 80 C 以上溫差很小Low temperature spread when F0 calculation starts ( 5-6 C at 115 C ) 當F0開始積累時( 5-6 C at 115 C ) ，溫差很小Low F0 spread (121 C ): 3 min with a total F0 of 30 min 小的F0差值(121 C ): 滅菌30分鐘，F(xiàn)0差值小于3min

34、OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES優(yōu)化預灌裝注射器的滅菌過程優(yōu)化預灌裝注射器的滅菌過程Development & Testing 優(yōu)化及測試21Nested Syringes Dry Load 干燥負載干燥負載Visible droplets on load and shelves after regular GEV process 在常規(guī)的GEV程序滅菌后在負載和層架上可見小的水滴Adding preheat phase reduces droplets (but not completely dry) but increases temp

35、erature spread below 80 C 增加預熱程序可以減少水滴（但不會完全干燥），但提高了80 C 下的溫度差Adding Fan Drying removes droplets but increases temperature spread below 80 C 增加風扇干燥可以去除水滴，但提高了80 C 下的溫度差OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES優(yōu)化預灌裝注射器的滅菌過程優(yōu)化預灌裝注射器的滅菌過程Development & Testing 優(yōu)化及測試22Nested Syringes Stopper Movement 插

36、桿移動插桿移動Stopper movement measured before and after process is small 滅菌前后插桿移動很少Stopper movement during the process is rather large! 在滅菌過程中插桿的移動相當大！ Inwards outwards appr. 2-3 mm! But The GEV TS can control it with precision!但是GEV TS能夠更精確的進行控制OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES優(yōu)化預灌裝注射器的滅菌過程優(yōu)化預灌

37、裝注射器的滅菌過程Development & Testing 優(yōu)化及測試23Nested Syringes Biological sterilization efficacy 生物學滅生物學滅菌效果菌效果Biological indicator (cotton threads) placed inside rubber cap at the needle of the syringe 生物指示劑（棉線）放置于注射器針頭一側的橡皮帽內Tests performed both with needles pointing upwards, downwards and horizontally 分別對

38、針頭向上、向下和水平方向進行測試No growth in when needles were pointing upwards or horizontally. Growth in one specimen where needle was pointing downwards 針頭向上和水平放置時無微生物生長，針頭向下放置時有一個微生物生長OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES優(yōu)化預灌裝注射器的滅菌過程優(yōu)化預灌裝注射器的滅菌過程Development & Testing 優(yōu)化及測試24Nested Syringes 巢狀注射器巢狀注射器Temp

39、erature distribution throughout the load is very good 溫度均一性非常好Dryness of the load can be controlled with additions in the process 負載的干燥度在滅菌過程中有很好的控制Process times 100 min with Preheat and Fan Drying 滅菌時間大約為100min，包括預熱和風扇干燥時間OPTIMIZED PROCESSING OF PRE-FILLED SYRINGES優(yōu)化預灌裝注射器的滅菌過程優(yōu)化預灌裝注射器的滅菌過程Conclusions 結論What is most important for You?什么對您最重要？什么對您最重要？Getinge GEV TS Turbo is flexible!潔定潔定GEV最靈活！最靈活！25Infusion Bags 輸液袋輸液袋 Heat Up 加熱加熱 Big Temperature spread initially 加熱開始階段的溫差較大Low temperature spread when F0 calculation starts ( 4-7 C at 115 C ) 當F0開始累積時( 4-7