濕熱滅菌的介紹參數(shù)放行

1、baxter confidential1parametric release of moist heat sterilized products at baxter百特濕熱滅菌產(chǎn)品的參數(shù)放行百特濕熱滅菌產(chǎn)品的參數(shù)放行mike sadowskidirector, sterile manufacturing support無菌生產(chǎn)技術(shù)支持總監(jiān)round lake, illinois usabaxter confidential2introduction介紹介紹this presentation will be limited to parametric release as it relates

2、to baxter moist heat sterilization processes本次演講僅限于百特濕熱滅菌生產(chǎn)產(chǎn)品的參數(shù)放行baxter confidential3parametric release-general definition參數(shù)放行參數(shù)放行 -基本定義基本定義sterile release of product based on the achievement of validated process parameters 產(chǎn)品無菌放行應(yīng)基于所有經(jīng)過驗(yàn)證的工藝參數(shù)符合要求baxters position: parametric release is the “natura

3、l end” to a properly validated process 百特觀點(diǎn)：參數(shù)放行是生產(chǎn)過程經(jīng)過驗(yàn)證的“自然結(jié)果”not dependent on results of sterility test 不依靠無菌檢查的結(jié)果baxter confidential4baxters us implementation history百特在美國實(shí)施參數(shù)放行的歷史百特在美國實(shí)施參數(shù)放行的歷史first parametric release submission in the united states in 1981. delay in approval due to conflict wi

4、thin the agency. 1981年第一次在美國申請參數(shù)放行，由于管理機(jī)構(gòu)(fda)內(nèi)部意見不統(tǒng)一而被推遲審批approval granted for lvps & svps in january, 1985, prior to issuance of formal guidance to the industry. 1985.1獲得fda批準(zhǔn)對大小容量輸液實(shí)行參數(shù)放行。此時fda尚無正式工業(yè)指南the initial submission served as the model for future requirements百特的首次申請所遞交的材料被fda視為將來要求的模式

5、fda compliance policy guide 7132a.13 issued in 1987. 1987年，fda頒布了參數(shù)放行政策指南7132a.13baxter confidential5all moist heat sterilized us products produced at the north cove, nc, jayuya, pr and cleveland, ms facilities are released parametrically. 在north cove, nc, jayuya, pr and cleveland, ms facilities工廠生產(chǎn)

6、的濕熱滅菌的美國產(chǎn)品才用參數(shù)放行。all new products in the united states, for the above facilities, are submitted for parametric release.以上工廠生產(chǎn)的所有美國新產(chǎn)品將遞交申請參數(shù)放行。baxters us implementation history百特在美國實(shí)施參數(shù)放行的歷史百特在美國實(shí)施參數(shù)放行的歷史baxter confidential6current baxter parametric release locations目前百特實(shí)施參數(shù)放行的地區(qū)australia 澳大利亞brazil

7、 巴西canada* 加拿大chile 智利china* 中國columbia 哥倫比亞germany 德國*manf. locations: us and canada *生產(chǎn)地址：美國和加拿大*in combination w/sterility test*與無菌檢驗(yàn)結(jié)合實(shí)施ireland以色列mexico墨西哥spain西班牙singapore新加坡united kingdom 英國(thetford)united states美國baxter confidential7sterility test vs. parametric release無菌檢驗(yàn)無菌檢驗(yàn) vs. 參數(shù)放行參數(shù)放行b

8、axter confidential8limitations of sterility test無菌檢查的局限性無菌檢查的局限性an inadequate process monitor不充分的生產(chǎn)過程監(jiān)測10 to 20 product units per batch每批僅抽取10-20個樣品successful tests for sterility tells us little about the sterility assurance level (sal) of units in the batch樣品檢測合格不能完全代表同批其它產(chǎn)品的無菌水平(sal)baxter confide

9、ntial9statistically limited統(tǒng)計(jì)學(xué)局限統(tǒng)計(jì)學(xué)局限detection sensitivity (n = 20 samples) 檢驗(yàn)靈敏度檢驗(yàn)靈敏度microorganism concentration微生物污染probability of one sterility test positive無菌檢查陽性概率1.01.00.10.880.010.180.0010.0210-61.9 x 10-5limitations of sterility test無菌檢查的局限性無菌檢查的局限性baxter confidential10sterility testing is p

10、rone to inaccurate results無菌檢查易獲得不精確的結(jié)果false positive rate is high 假陽性率高 complexity of test sample 檢測樣品復(fù)雜 number of manipulations required需要多次處理 number/experience of “testers”檢驗(yàn)人員的經(jīng)驗(yàn)/人員差異 environmental factors環(huán)境因素 unnecessary product rejection 不必要的產(chǎn)品報(bào)廢limitations of sterility test無菌檢查的局限性無菌檢查的局限性bax

11、ter confidential11sterility test is costly to perform執(zhí)行無菌檢查耗費(fèi)成本multiple product samples from each load 每個滅菌柜次取樣test environment validation maintenance 測試環(huán)境驗(yàn)證及保養(yǎng)specially trained personnel 特殊培訓(xùn)操作人員labor cost 人工成本media and equipment preparation 準(zhǔn)備培養(yǎng)基和設(shè)備high product inventories required 產(chǎn)品庫存量大14 day st

12、erility test “hold” 14天無菌檢驗(yàn)等待期product cost 產(chǎn)品成本limitations of sterility test無菌檢查的局限性無菌檢查的局限性baxter confidential12moist heat sterilization process濕熱滅菌工藝的特點(diǎn) non-toxic無毒 less expensive經(jīng)濟(jì) universally recognized普遍認(rèn)可 broad spectrum lethality廣譜殺菌能力（molds霉菌，yeasts酵母，bacteria細(xì)菌/spores孢子，viruses病毒） oldest, sa

13、fest, most dependable process最古老，最安全，最可靠的工藝 easily controlled and validated易于控制和驗(yàn)證 preferred by most regulatory bodies被多數(shù)法規(guī)機(jī)構(gòu)推薦使用why the moist heat sterilization process?為什么采用濕熱滅菌工藝？為什么采用濕熱滅菌工藝？baxter confidential13“natural” candidate for parametric release參數(shù)放行是“自然”結(jié)果minimal key parameters 至少關(guān)鍵滅菌參數(shù)t

14、emperature: 115 125oc溫度溫度：105135ocexposure time: 12 - 120 minutes 暴露時間暴露時間：5200 minutespressure: -saturated steam pressure 121oc = 30 psia/15 psig 壓力壓力：121oc的飽和蒸汽壓=30 psia/15 psigwhy the moist heat sterilization process?為什么采用濕熱滅菌工藝？為什么采用濕熱滅菌工藝？baxter confidential14parametric release requirements us參

15、數(shù)放行要求參數(shù)放行要求 美國美國fda compliance policy guide 7132a.13, issued in 1987fda 法規(guī) 7132a.13, 1987年出版us pharmacopoeia 31 美國藥典 31版aami tir 13: principles of industrial moist heat sterilizationaami 技術(shù)指引：工業(yè)濕熱滅菌原理iso 11134: sterilization of healthcare products requirements for validation and routine control indu

16、strial moist heat sterilizationiso 11134:醫(yī)療產(chǎn)品的滅菌 驗(yàn)證及日?？刂埔?工業(yè)濕熱滅菌pda technical report no. 30 (1999) pda 技術(shù)報(bào)告no 30(1999)baxter confidential15fda compliance policy guide 7132a.13fda 政策法規(guī)指南政策法規(guī)指南 7132a.13parametric release:參數(shù)放行定義a sterility release procedure based upon effective control of a validated

17、sterilization process cycle in lieu of release based upon end-product sterility testing. all parameters within the procedure must be met before the lot is released.參數(shù)放行：為一種替代對最終產(chǎn)品作無菌檢查的無菌放行系統(tǒng)。它基于對一個經(jīng)過驗(yàn)證的滅菌生產(chǎn)過程進(jìn)行有效的控制。一批產(chǎn)品放行前，系統(tǒng)中規(guī)定的所有參數(shù)必須符合規(guī)定。 baxter confidential16fda cpg 7132a.13 requirementsfda cpg

18、 7132a. 13要求要求cycle validation滅菌循環(huán)驗(yàn)證container/closure integrity validated容器或封口完整性驗(yàn)證bio-burden testing 微生物負(fù)載檢測chemical or biological indicators in each individual sterilizer truck (carrier or pallet).每一滅菌車(貨架或托盤)放化學(xué)或生物指示劑biological indicator (bi) documentation文件化管理生物指示劑baxter confidential17us pharmac

19、opoeia 31美國藥典美國藥典 31版版usp : terminally sterilized pharmaceutical productparametric releaseusp：最終滅菌藥品：最終滅菌藥品 參數(shù)放行參數(shù)放行mode of sterilization well understood滅菌過程被充分理解critical physical processing parameters defined定義關(guān)鍵過程物理參數(shù)lethality of the cycle validated microbiologically 驗(yàn)證滅菌循環(huán)的微生物致死性10-6 sal required

20、要求10-6 sal （無菌保證）fda approval required得到fda批準(zhǔn)baxter confidential18aami tir 13where reliable process measurement and control can be documented for the entire manufacturing process, and correlated with sterility assurance, terminally sterilized items can be considered for release in accordance with de

21、livered process parameters 當(dāng)可靠的過程測量和控制可以用來記錄整個生產(chǎn)過程及與其相關(guān)的無菌保證，那么最終滅菌產(chǎn)品可以按生產(chǎn)過程參數(shù)進(jìn)行放行。compliance with ansi/aami/iso 11134 in its entirety allows for parametric release符合ansi/aami/iso 11134的要求，可以允許執(zhí)行參數(shù)放行。aami (association for the advancement of medical instrumentation)baxter confidential19iso 11134title

22、: sterilization of healthcare productsrequirements for validation and routine controlindustrial moist heat sterilization標(biāo)題：醫(yī)療產(chǎn)品的滅菌標(biāo)題：醫(yī)療產(chǎn)品的滅菌 驗(yàn)證及日?？刂埔篁?yàn)證及日常控制要求-工業(yè)濕熱滅菌工業(yè)濕熱滅菌note: iso 11134 has been replaced by iso 17665 (fully effective end of 2009)注意：iso11134將被iso17665（2009年底生效）(for medical devices)

23、 general considerations, including personnel training and packaging總要求，包括人員培訓(xùn)和包裝equipment設(shè)備process development 工藝開發(fā)process validation過程驗(yàn)證routine sterilization常規(guī)滅菌baxter confidential20iso 111348.5 release of sterilized products滅菌產(chǎn)品的放行滅菌產(chǎn)品的放行process parameters monitored during routine sterilization sh

24、all be within the validated limits日常生產(chǎn)過程中監(jiān)控的生產(chǎn)參數(shù)應(yīng)該在驗(yàn)證限度內(nèi)。a system to differentiate between processed and unprocessed items shall be used應(yīng)該建立區(qū)分加工過產(chǎn)品及未加工過產(chǎn)品的系統(tǒng)。only authorized persons shall release products after sterilization只有授權(quán)人才可以放行滅菌后產(chǎn)品。a.8.5 release of sterilized products滅菌產(chǎn)品的放行“finished product

25、 testing or biological indicator testing might be required by some regulatory authorities.”“某些國家法規(guī)可能要求最終產(chǎn)品測試或微生物指示劑測試?！眀axter confidential21pda technical report no. 30 (1999)pda 技術(shù)報(bào)告技術(shù)報(bào)告no 30(1999) applies only to products with 10-6 sal 僅適用于10-6 無菌保證的產(chǎn)品critical parameters must be met to achieve rele

26、ase關(guān)鍵參數(shù)滿足要求后，才能進(jìn)行放行demonstrate that entire load exposed to sterilization process證明整個裝載都經(jīng)過滅菌過程procedures in place to document qualification, processing, and release requirements.有程序記錄驗(yàn)證、生產(chǎn)過程和放行要求note: this document is currently under revision in final review and expected to be issued in q3, 2009.注意：該

27、文件正在做最終復(fù)核，預(yù)計(jì)2009年第三季度發(fā)布。baxter confidential22baxter compliance百特執(zhí)行要求百特執(zhí)行要求 product design control產(chǎn)品設(shè)計(jì)控制 sterilization equipment滅菌設(shè)備 sterilization process validation滅菌工藝驗(yàn)證physical lethality (combination studies) 物理性細(xì)菌致死性（聯(lián)合實(shí)驗(yàn)）microbiological lethality微生物致死性container / closure integrity容器或封口完整性 steril

28、e/non-sterile segregation滅菌/非滅菌的隔離 risk assessment / failure mode and effects analysis (fmea) 風(fēng)險(xiǎn)分析/失敗模式及效應(yīng)分析(fmea)baxter confidential23product design control產(chǎn)品設(shè)計(jì)控制產(chǎn)品設(shè)計(jì)控制formal product design and validation procedures正式產(chǎn)品設(shè)計(jì)和驗(yàn)證過程bill of materials產(chǎn)品物流清單incoming inspection and sampling of raw materials

29、and components原料和組件的進(jìn)廠取樣檢驗(yàn)evaluation of change procedures變更流程的評估baxter confidential24sterilization equipment滅菌設(shè)備滅菌設(shè)備equipment configuration control設(shè)備配置控制hardware and software硬件和軟件robust recirculating water system設(shè)計(jì)可靠的水循環(huán)系統(tǒng)以防非無菌水進(jìn)入滅菌后的系統(tǒng)redundant instrumentation 多種檢測儀器routine calibration 常規(guī)校驗(yàn)routine

30、maintenance常規(guī)維護(hù)保養(yǎng)iq/oq validation安裝/運(yùn)行驗(yàn)證baxter confidential25validated and controlled software programs軟件程序需經(jīng)驗(yàn)證并受控control system monitors and ensures delivery of critical parameters and compares results with redundant instrumentation控制系統(tǒng)監(jiān)測并確保關(guān)鍵參數(shù)的實(shí)現(xiàn)，并與多種檢測結(jié)果比較sterilization equipment滅菌設(shè)備滅菌設(shè)備baxter co

31、nfidential26sterilization process validation滅菌過程驗(yàn)證滅菌過程驗(yàn)證combination penetration/distribution studies to validate minimum and maximum product requirements are met聯(lián)合熱穿透及熱分布研究，以驗(yàn)證最小和最大產(chǎn)品符合規(guī)定fractional validation to ensure sufficient lethality in solution and closure system用分段驗(yàn)證確保對溶液和密封的包裝系統(tǒng)有足夠的殺滅能力rout

32、ine requalification of process 工藝常規(guī)再驗(yàn)證closure integrity validated 密封完整性驗(yàn)證specified loading patterns 特定裝載方式驗(yàn)證baxter confidential27sterility assurance level無菌保證水平無菌保證水平most medical devices and drug/pharmaceutical products require a 10-6 sal大多數(shù)醫(yī)療器械和藥品/醫(yī)藥產(chǎn)品需要10-6 無菌保證there cannot be more than one non-st

33、erile unit in every 1,000,000 processed每一百萬產(chǎn)品中不能存在多于一個非無菌產(chǎn)品most sterilization processes far exceed this probability濕熱滅菌過程可以遠(yuǎn)高于這個可能性。baxter confidential28bioburden testing生物負(fù)荷檢測生物負(fù)荷檢測conducted on each batch of pre-sterilized (non sterile) drug product 每批產(chǎn)品應(yīng)在滅菌前檢測微生物負(fù)載quantity and resistance of spore

34、forming organisms found must be monitored and compared to that of the organism used to validate the cycle對新發(fā)現(xiàn)的孢子進(jìn)行耐熱研究并與驗(yàn)證所用的微生物比較baxter confidential29in-process bioburden testing results生產(chǎn)過程生物負(fù)荷測試結(jié)果生產(chǎn)過程生物負(fù)荷測試結(jié)果performed for over 20 years since parametric release approved自從參數(shù)放行被批準(zhǔn)后，執(zhí)行了自從參數(shù)放行被批準(zhǔn)后，執(zhí)行了

35、20年年total counts show low levels of organisms總菌數(shù)顯示了低水平的微生物rarely detect spores幾乎沒有監(jiān)測到孢子spore resistance significantly less than bi used to validate the process孢子的熱抗性遠(yuǎn)低于用于過程驗(yàn)證的生物指示劑（bi）due to history of demonstrated control, fda has approved parametric release for baxter without holding for bio-burde

36、n results根據(jù)歷史數(shù)據(jù)證實(shí)過程受控制，fda批準(zhǔn)百特的參數(shù)放行且無需等待生物負(fù)荷結(jié)果。baxter confidential30bi documentation生物指示劑文件管理生物指示劑文件管理each moist heat bi lot (in-house)每批濕熱用的bi批號organisms name微生物名稱source來源d-valued值spore concentration孢子濃度expiration date 有效期storage conditions貯存條件baxter confidential31container / closure integrity包裝容器及

37、封口的完整性包裝容器及封口的完整性robust design產(chǎn)品設(shè)計(jì)validated to demonstrate microbial barrier effectiveness for in-process and post-process over the products shelf life驗(yàn)證產(chǎn)品在生產(chǎn)過程中及生產(chǎn)后有效期內(nèi)均可防止被污染validation should include physical or microbial ingress tests驗(yàn)證應(yīng)包括物理或微生物侵入實(shí)驗(yàn)“worst case” heat history processing歷史“最差”加熱過程mu

38、st utilize representative units from typical production必須使用正常生產(chǎn)的產(chǎn)品baxter confidential32sterile/non-sterile segregation滅菌滅菌/未滅菌產(chǎn)品隔離未滅菌產(chǎn)品隔離physical barriers物理隔斷物理隔斷l(xiāng)oad reconciliation count to ensure the quantity of product entering the sterilizer equals the quantity exiting sterilization area裝載平衡 數(shù)量計(jì)

39、算以確保進(jìn)入滅菌器的產(chǎn)品數(shù)量等于到達(dá)已滅菌區(qū)域產(chǎn)品數(shù)量sterilizer product truck design prevents loss of a unit - sidescreens or tray design產(chǎn)品滅菌車設(shè)計(jì)防止產(chǎn)品丟失 側(cè)窗或者板設(shè)計(jì)chemical indicators on every product truck demonstrate exposure to a sterilization cycle化學(xué)指示劑放置在每個滅菌車 證明產(chǎn)品曾經(jīng)暴露于滅菌循環(huán)baxter confidential33chemical or biological indicator

40、s (bis)化學(xué)或生物指示劑（化學(xué)或生物指示劑（bi）must be included in each truck, tray or pallet of each sterilizer load每個滅菌循環(huán)內(nèi)每載車必須放置化學(xué)或生物指示劑 time and/or temperature response characteristics and stability of the indicator are documented記錄指示劑對時間及溫度的反應(yīng)特性和穩(wěn)定性minimum degradation values or color change (e.g. autoclave tape) required for each sterilization cycle are established建立每個滅菌循環(huán)的最小降解值chemical indicators cannot be used to evaluate cycle microbiological lethality化學(xué)指示劑不能用于評估滅菌循環(huán)的殺滅能力bis are typically not used for routine release of moist heat sterilized pharmaceutical products生物指