無菌工藝設(shè)計及風(fēng)險控制--楊軍ppt課件

1、2019 ISPE CHINA ANNUAL CONFERENCE 無菌無菌 沒有活體微生物存在。沒有活體微生物存在。 Aseptic No Viable Microbe Exists Aseptic No Viable Microbe Exists 無菌藥品無菌藥品 - - 法定藥品規(guī)范中列有無菌檢查工程的制劑和法定藥品規(guī)范中列有無菌檢查工程的制劑和 原料藥，包括無菌制劑和無菌原料藥。原料藥，包括無菌制劑和無菌原料藥。 - - 摘自中國摘自中國GMPGMP20192019年修訂年修訂 Aseptic Drug Product The drug product Aseptic Drug Pro

2、duct The drug product which needs to be tested for their sterility by the which needs to be tested for their sterility by the legal standards, including aseptic formulation and legal standards, including aseptic formulation and APIs.APIs. - From Chinese GMP(2019) - From Chinese GMP(2019)無菌藥品的消費工藝無菌藥

3、品的消費工藝Type of Manufacturing Process按去除微生物方法的不同：Removing of microbe from product:最終滅菌工藝 Process with final sterilization非最終滅菌工藝 Process without final sterilization非最終滅菌工藝非最終滅菌工藝Process without final sterilizing 適用于產(chǎn)品不耐高溫，不能采用通常的熱力學(xué)方法最后適用于產(chǎn)品不耐高溫，不能采用通常的熱力學(xué)方法最后進展滅菌以去除產(chǎn)品中的微生物。進展滅菌以去除產(chǎn)品中的微生物。 For those p

4、roduct which are thermal-sensitive and For those product which are thermal-sensitive and the microbe in the microbe in it can not be removed by thermal sterilization. it can not be removed by thermal sterilization. 常用于凍干粉針、粉針、無菌原料藥的消費。常用于凍干粉針、粉針、無菌原料藥的消費。 Normally used in manufacturing of freeze dry

5、ing Normally used in manufacturing of freeze drying powders, aseptic powderspowders, aseptic powdersand APIs and APIs 非最終滅菌工藝又稱為無菌消費工藝。非最終滅菌工藝又稱為無菌消費工藝。 This process is also called Aseptic Processing This process is also called Aseptic Processing2019 ISPE CHINA ANNUAL CONFERENCE 在無菌消費工藝中，產(chǎn)品、容器、密封件等分

6、別經(jīng)過滅菌后再進展灌裝、封口，而液體產(chǎn)品那么經(jīng)過無菌過濾以去除微生物。由于產(chǎn)品裝入最終容器后不再作進一步的滅菌處置，因此整個消費過程必需保證不被微生物所污染。 All the product/container/closures are pre-sterilized All the product-liquid must be sterile filtered No further sterilization required after filling and closing Microbe contamination must be avoided during the whole pro

7、cessing 2019 ISPE CHINA ANNUAL CONFERENCE無菌消費工藝設(shè)計的關(guān)鍵無菌消費工藝設(shè)計的關(guān)鍵 2019 ISPE CHINA ANNUAL CONFERENCE 中心區(qū)就是無菌產(chǎn)品、容器、包裝物及其產(chǎn)品接觸的外表直接暴露在環(huán)境條件下的區(qū)域，該區(qū)域的設(shè)計必需保證產(chǎn)品的無菌度要求。(FDA/ISPE) A CRITICAL AREA is one in which the sterilized drugproduct, containers/closures or product contact surfacesare exposed to environment

8、al conditions that must bedesigned to maintain product sterility. (FDA/ISPE)l 產(chǎn)品流向 Product Flowsl 容器/包裝物流向 Container/Closure Flowl l 操作人員 Operatorsl 工藝設(shè)備 Process Equipmentl摘自ISPE 無菌消費指南lFrom ISPE Guideline of lSterile Manufacturing Facilities2019 ISPE CHINA ANNUAL CONFERENCE稱量稱量Weighing配料配料Liq. Prep

9、.無菌過濾無菌過濾Sterile Filtration灌裝、半加塞灌裝、半加塞Filling, Semi-Stopper滅菌滅菌Sterilization洗瓶、洗塞洗瓶、洗塞Washing凍干、壓塞凍干、壓塞Lyophilizing軋蓋軋蓋Capping貼簽、包裝貼簽、包裝Labeling & Packaging廢品廢品Finished Goods瓶、膠塞瓶、膠塞Vials, Stoppers原輔料原輔料R.M.例：無菌凍干粉針消費工藝例：無菌凍干粉針消費工藝 Typical LYO Process2019 ISPE CHINA ANNUAL CONFERENCE無菌凍干粉針工藝布置圖

10、無菌凍干粉針工藝布置圖 Typical Layout Typical Layout瓶塞瓶塞原輔料原輔料人員人員人員人員鋁蓋鋁蓋廢品廢品包裝物流向包裝物流向人員流向人員流向物料流向物料流向產(chǎn)品流向產(chǎn)品流向包物流向包物流向人員流向人員流向無菌凍干粉針消費人物流向分析無菌凍干粉針消費人物流向分析 Operator and Material Flow for LYO Production無菌消費區(qū)無菌消費區(qū) BAseptic Area中心區(qū)中心區(qū) ACritical area中心區(qū)中心區(qū) ACritical areaDCBA2019 ISPE CHINA ANNUAL CONFERENCE無菌消費區(qū)的

11、風(fēng)險控制無菌消費區(qū)的風(fēng)險控制Risk Control of Aseptic Manufacturing Area2019 ISPE CHINA ANNUAL CONFERENCE無菌消費風(fēng)險類型無菌消費風(fēng)險類型The type of risks in Aseptic Manufacturing Areal塵埃粒子污染塵埃粒子污染l Particles Contamination Particles Contaminationl微生物污染微生物污染l Microbe Contamination Microbe Contaminationl物料的交叉污染物料的交叉污染l Cross Contami

12、nation Cross Contamination2019 ISPE CHINA ANNUAL CONFERENCE風(fēng)險的來源風(fēng)險的來源 The Sources of Riskl空氣空氣 Airl物料物料 Materialsl設(shè)備、器具設(shè)備、器具 Equipment/Toolsl人員人員 Operators2019 ISPE CHINA ANNUAL CONFERENCE空氣的處置空氣的處置 Air Treatmentl 室外空氣中含有大量的微粒和微生物室外空氣中含有大量的微粒和微生物l Large amount of particles and microbe in atmospherel

13、 空氣必需經(jīng)高效過濾空氣必需經(jīng)高效過濾l Air must be filtered with HEPA filter l 無菌消費區(qū)的空氣干凈等級必需滿足無菌消費區(qū)的空氣干凈等級必需滿足GMP的要求的要求l Clean air class in compliance with GMP principle 無菌藥品消費環(huán)境的干凈度規(guī)范無菌藥品消費環(huán)境的干凈度規(guī)范潔凈級別潔凈級別 懸浮粒子最大允許數(shù)懸浮粒子最大允許數(shù)/ /立方米立方米 靜靜 態(tài)態(tài) 動動 態(tài)態(tài) 0.5m5m 0.5m5mA級級3,52020352020B級級3,52029352,0002,900C級級352,0002,9003,52

14、0,00029,000D級級3,520,00029,000- - The cleanliness standards of production area無菌藥品消費環(huán)境的微生物檢測規(guī)范無菌藥品消費環(huán)境的微生物檢測規(guī)范 The microbe standards of production area潔凈級別潔凈級別 浮游菌浮游菌cfu/m3沉降菌沉降菌（ 90mm）cfu /4小時小時 表面微生物表面微生物接觸碟接觸碟（ 55mm）cfu /碟碟5 5指手套指手套cfu /手套手套A級級 1 1 1 1B級級10555C級級1005025D級級200100502019 ISPE CHINA A

15、NNUAL CONFERENCEl無菌消費區(qū)的氣流組織、送風(fēng)口和回排風(fēng)口位置、相無菌消費區(qū)的氣流組織、送風(fēng)口和回排風(fēng)口位置、相對臨近區(qū)域的壓差等均需經(jīng)過合理設(shè)計對臨近區(qū)域的壓差等均需經(jīng)過合理設(shè)計l Air flow pattern, Location of air outlets, Air Air flow pattern, Location of air outlets, Air pressure differencespressure differencesl必需關(guān)注無菌消費區(qū)必需關(guān)注無菌消費區(qū)A A級單向流的回風(fēng)對級單向流的回風(fēng)對B B級環(huán)境氣流的級環(huán)境氣流的l 影響影響l Minimi

16、zing the influence of return air flow of Minimizing the influence of return air flow of class A to air supply pattern of class B areaclass A to air supply pattern of class B areal塵埃粒子和微生物進展動態(tài)監(jiān)控塵埃粒子和微生物進展動態(tài)監(jiān)控l Monitoring of particles and microbe in aseptic Monitoring of particles and microbe in asept

17、ic area area A A級單向流罩回風(fēng)位置的影響級單向流罩回風(fēng)位置的影響 - - 頂回風(fēng)頂回風(fēng) LF氣流短路氣流短路HEPA Filling Room傳統(tǒng)單向流罩頂回風(fēng)，有氣流上升和短路景象傳統(tǒng)單向流罩頂回風(fēng)，有氣流上升和短路景象LF LF 頂回風(fēng)頂回風(fēng)上升氣流ABLFReturn AirHEPA Return Air Filling Room側(cè)下回風(fēng)，側(cè)下回風(fēng)，B B級氣流全部頂送下回，無短路和上升氣流景象級氣流全部頂送下回，無短路和上升氣流景象A A級單向流罩回風(fēng)位置的影響級單向流罩回風(fēng)位置的影響 - - 下側(cè)回風(fēng)下側(cè)回風(fēng)粒子在線監(jiān)控點粒子在線監(jiān)控點Particle Monitor

18、ing粒子監(jiān)控點粒子監(jiān)控點Monitoring Point粒子監(jiān)控點粒子監(jiān)控點Monitoring Point2019 ISPE CHINA ANNUAL CONFERENCE物料的控制物料的控制 Material Control Material Control2019 ISPE CHINA ANNUAL CONFERENCE 物料所致的污染物料所致的污染Material ContaminationMaterial Contamination 物料本身未經(jīng)過徹底滅菌物料本身未經(jīng)過徹底滅菌/ /除菌處置除菌處置 Materials not thoroughly Materials not th

19、oroughly sterilized/filteredsterilized/filtered 物料進出無菌消費區(qū)的傳送過程物料進出無菌消費區(qū)的傳送過程 Pass way through aseptic area (in/out) Pass way through aseptic area (in/out) 物料間的相互交叉污染物料間的相互交叉污染 Cross contamination Cross contamination2019 ISPE CHINA ANNUAL CONFERENCE l 液體物料必需經(jīng)過除菌過濾液體物料必需經(jīng)過除菌過濾l Liquid materials must b

20、e filtered Liquid materials must be filteredl 無菌物料暴露操作必需在無菌物料暴露操作必需在A A級維護下進展級維護下進展l Class A protection for the exposed operation of Class A protection for the exposed operation of productproductl 無菌區(qū)必需采用注射用水無菌區(qū)必需采用注射用水l Only the WFI allowed into aseptic area Only the WFI allowed into aseptic areal

21、環(huán)境消毒液必需采用注射用水配制，并經(jīng)除菌過濾環(huán)境消毒液必需采用注射用水配制，并經(jīng)除菌過濾l Disinfectant must be prepared by WFI and be Disinfectant must be prepared by WFI and be filtered before usefiltered before use物料的控制物料的控制 Material Controls2019 ISPE CHINA ANNUAL CONFERENCE l 進入無菌區(qū)的物料外包裝必需徹底消毒進入無菌區(qū)的物料外包裝必需徹底消毒l A proper sterilization of th

22、e product packaging A proper sterilization of the product packaging is needed is needed l 無菌區(qū)所用的氣體必需無菌過濾無菌區(qū)所用的氣體必需無菌過濾l All process gas must be filtered All process gas must be filteredl 無菌區(qū)內(nèi)廢品和廢品必需采用可靠方法運出無菌區(qū)內(nèi)廢品和廢品必需采用可靠方法運出l A proper way out of finished goods/waste from A proper way out of finishe

23、d goods/waste from aseptic area aseptic area l 消費終了，一切與物料直接接觸的設(shè)備、器具必需經(jīng)過消費終了，一切與物料直接接觸的設(shè)備、器具必需經(jīng)過 徹底清洗、滅菌，防止物料殘留引起交叉污染徹底清洗、滅菌，防止物料殘留引起交叉污染l A proper cleaning and sterilizing of equipment/ A proper cleaning and sterilizing of equipment/ closure contacting with the materials is required closure contacti

24、ng with the materials is required after productionafter production2019 ISPE CHINA ANNUAL CONFERENCE無菌區(qū)物料的運出無菌區(qū)物料的運出 Goods out Goods out清潔洗手脫外衣退出通道控制滅菌前室穿衣待洗 B 級走道無菌 清潔滅菌后暫存C 級走道洗瓶滅菌灌封氣鎖中間 儲液配料無菌 A/C 內(nèi)衣 外衣檢測DCBACNCA級維護級維護Class A無菌區(qū)無菌區(qū)B傳送帶分段傳送帶分段正壓氣流正壓氣流A A級維護級維護滅菌前室滅菌前室P無菌區(qū)無菌區(qū)滅菌前室滅菌前室正壓氣流正壓氣流傳送柜傳送柜HE

25、PAHEPAPB緩沖緩沖正壓氣流正壓氣流帶層流傳送柜帶層流傳送柜無菌區(qū)無菌區(qū)B滅菌前室滅菌前室PHEPAHEPA正壓氣流正壓氣流無菌區(qū)無菌區(qū)B有交叉污染風(fēng)險有交叉污染風(fēng)險氣鎖氣鎖滅菌前室滅菌前室2019 ISPE CHINA ANNUAL CONFERENCE操作人員的風(fēng)險控制操作人員的風(fēng)險控制Risk Control of Operators操作人員的風(fēng)險操作人員的風(fēng)險The Risk of Operatorsl操作人員身上會分發(fā)大量的微粒操作人員身上會分發(fā)大量的微粒l Large particles from operator Large particles from operatorl操

26、作人員分發(fā)的微粒含有大量的微生物操作人員分發(fā)的微粒含有大量的微生物l The particles are viable with microbe The particles are viable with microbe 操作人員是無菌消費區(qū)內(nèi)的最大污染源，也是最難控制的污染源 The Operators are the largest sources of pollutions in aseptic areaand very difficult to control2019 ISPE CHINA ANNUAL CONFERENCE操作人員的控制操作人員的控制 Operators Contro

27、l Operators Control人員在無菌區(qū)的操作站位和行為人員在無菌區(qū)的操作站位和行為Position and action of operators in aseptic area人員的正確更衣程序人員的正確更衣程序Gowning procedures 2019 ISPE CHINA ANNUAL CONFERENCE人員位置和動作人員位置和動作 Positions and Actions Positions and Actionsl 人員位于中心區(qū)下風(fēng)向人員位于中心區(qū)下風(fēng)向l Position and action of operators in aseptic areal 運用滅

28、菌工具，防止直接干涉運用滅菌工具，防止直接干涉l No direct intervene to process, use toolsl 行為緩慢，防止猛烈動作呵斥微粒和微生物添加行為緩慢，防止猛烈動作呵斥微粒和微生物添加l Slowly moving，no strong action to increase particles and microbe 2019 ISPE CHINA ANNUAL CONFERENCE操作人員的控制操作人員的控制 Operators Control Operators Control 操作人員的正確更衣程序操作人員的正確更衣程序Gowning procedure

29、s GMP GMP 對凈化更衣的條款對凈化更衣的條款 GMP Requirement for GMP Requirement for GowningGowning 中國中國GMPGMP20192019年修訂對操作人員進出干凈區(qū)域的更年修訂對操作人員進出干凈區(qū)域的更衣控制，制定了許多詳細的要求衣控制，制定了許多詳細的要求 新版新版GMPGMP附錄附錄1 1：無菌藥品，第：無菌藥品，第1919條第條第2727條、第條、第3030條條 Chinese GMP (2019) Requirement for Gowning Chinese GMP (2019) Requirement for Gowni

30、ng (Annex 1, items 19-27, 30) (Annex 1, items 19-27, 30) 第三十條第三十條 該當按照氣鎖方式設(shè)計更衣室，使更衣的不同該當按照氣鎖方式設(shè)計更衣室，使更衣的不同階段分開，盡能夠防止任務(wù)服被微生物和微粒污染。更衣室階段分開，盡能夠防止任務(wù)服被微生物和微粒污染。更衣室該當有足夠的換氣次數(shù)。更衣室后段的靜態(tài)級別該當與其相該當有足夠的換氣次數(shù)。更衣室后段的靜態(tài)級別該當與其相應(yīng)干凈區(qū)的級別一樣。必要時，可將進入和分開干凈區(qū)的更應(yīng)干凈區(qū)的級別一樣。必要時，可將進入和分開干凈區(qū)的更衣間分開設(shè)置。普通情況下，洗手設(shè)備只能安裝在更衣的第衣間分開設(shè)置。普通情況下

31、，洗手設(shè)備只能安裝在更衣的第一階段。一階段。 Changing rooms should be designed as air lock, in order to separate its differentstages. A suitable air change rate is required. The grade of final stage in rest shouldbe same as the area into which it leads. A separate area changing area for enteringand leaving are required i

32、n some cases. In general hand washing facilities should beonly provided at its first stage of changing room.GMPGMP關(guān)于干凈更衣的要點：關(guān)于干凈更衣的要點：Key Points of Gowning by GMPKey Points of Gowning by GMP更衣分段更衣分段 Different Gowning Different Gowning AreaArea氣鎖設(shè)計氣鎖設(shè)計 Air Lock Design Air Lock Design更衣分級更衣分級 Classifi

33、cation Classification退出通道退出通道 Leaving Way Leaving Way更衣分段更衣分段 Different Gowning Area Different Gowning Areal以進入無菌區(qū)為例，更衣程序普通分為：換鞋 - 脫外衣 - 洗手 - 穿無菌內(nèi)衣 - 手消毒 - 穿無菌外衣 - 手消毒l l Gowning Procedure:l Shoes Changing - Overcoat removing - hands washing - sterile underwear - hands disinfection - sterile overcoa

34、t - hands disinfection l前段“換鞋-脫外衣-洗手-穿無菌內(nèi)衣屬于相對“污l First steps: l Shoes Changing - Overcoat removing - hands washing - l sterile underwear “Dirtyl后段“穿無菌外衣-手消毒，屬于相對“潔l Second Steps: l sterile overcoat - hands disinfection “Cleanl干凈更衣的中心是“污和“凈分別，以防止干凈的l 任務(wù)服在更衣過程中被微生物和微粒污染。l Two gowning steps must be se

35、parate 氣鎖設(shè)計氣鎖設(shè)計 Air Lock Design Air Lock Designl更衣前后段要分開設(shè)置，不在同一個區(qū)域內(nèi)，并且穿干凈衣房間按氣鎖設(shè)計，連鎖門和壓差控制。l Air lock design for gowning room with door interlock and pressure controll由于按氣鎖設(shè)計，且靜態(tài)級別與消費區(qū)一致，因此更衣最后的緩沖間可以取消某些情況下由于男女更衣室布置需求，可以保管，但不是必需)。l Buffer room after 2nd gowning not required更衣分級更衣分級 Clean Class for G

36、owning Clean Class for Gowning l更衣后段的干凈級別，與其效力的干凈消費區(qū)的靜態(tài)級別相一致無動態(tài)要求l Clean class of 2nd gowning room is equal to production area at restl更衣前段不定級，但需送入經(jīng)過 HEPA 過濾的干凈空氣，有一定的換氣次數(shù)可視所效力的消費區(qū)級別的不同，分別參照C級或D級規(guī)范設(shè)計，但不定級。前段和后段之間要堅持合理的氣流流向和壓差。l Clean air is preferred for 1st gowning area, with reliable air pattern a

37、nd pressure different controls退出通道退出通道 Leaving Way Leaving Way lGMP第30條要求：必要時，可將進入和分開干凈區(qū)的更衣間分開設(shè)置。 l Entering/Leaving changing rooms can be separately if necessary l什么是必要時？ What is necessary?l退出時衣服上所帶微粒和微生物污染干凈更衣區(qū)l Change room may be contaminated by the particles and microbel with the clothesl消費操作產(chǎn)生的

38、有害物質(zhì)經(jīng)過更衣區(qū)外溢；l To avoid polluted air blow out from process area要思索的要素 Considerations: 產(chǎn)品特點致敏、強效、毒性、活菌 Characteristics of product (susceptibility, high potent, toxic, viable) 空氣污染情況 (粉塵分發(fā)嚴重) Air pollution (dust) 無菌區(qū)操作人員數(shù)量 vs. 更衣空間大小 The number of operator vs. space of changing area 人員進出干凈區(qū)頻率 Frequency

39、 of enter/leaving clean areal無菌消費區(qū)風(fēng)險分析結(jié)果需求設(shè)置的l Aseptic area (if necessary required)l含活菌、活毒類生物制品消費區(qū)l Bio-pharmaceutical area with Viable and Toxicl特殊藥品消費區(qū)高致敏、高活性、激素、毒性類l Special drug manufacturing area (susceptibility/high potent/l hormone/toxic)l粉塵分發(fā)嚴重的消費區(qū)l Dust release productionl為防止有害物質(zhì)經(jīng)過更衣區(qū)溢出，需設(shè)置

40、正/負壓氣鎖l Where positive/negative air lock is required 傳統(tǒng)更衣設(shè)計傳統(tǒng)更衣設(shè)計 Traditional Gowning Layout Traditional Gowning Layout男脫外衣男脫外衣?lián)Q鞋換鞋氣鎖氣鎖/ /手消毒手消毒女脫外衣女脫外衣無菌內(nèi)衣無菌內(nèi)衣洗手洗手無菌外衣無菌外衣無菌外衣無菌外衣洗手洗手無菌消費區(qū)無菌消費區(qū) B B無菌內(nèi)衣無菌內(nèi)衣?lián)Q鞋換鞋 - - 脫衣脫衣 - - 洗手洗手 - - 穿無菌內(nèi)衣穿無菌內(nèi)衣 - - 手消毒手消毒 - - 穿無菌外衣穿無菌外衣 - - 手消毒手消毒一個步驟一個房間，比較煩瑣一個步驟一個房間，比較煩瑣II門連鎖門連鎖 InterlockInterlock干凈更衣設(shè)計舉例干凈更衣設(shè)計舉例1 1 - - 普通區(qū)進入普通區(qū)進入C C級區(qū)級區(qū)Gowning room to C areaGowning room to C area換 鞋 凳氣流方向氣流方向Air FlowAir Flow門連鎖門連鎖 InterlockInterlock干凈更衣舉例干凈更衣舉例- -2 2 ( (帶