滅菌的方法及注意事項課件

1、11Sterilization 滅菌A General Discussion from CGMP Perspective從CGMP角度的綜合討論11Sterilization 滅菌22Outline 討論綱要PART ITerminology 專業(yè)用詞的定義GMP Requirements in The Manufacture of Sterile Pharmaceutical Products無菌藥品生產(chǎn)過程中GMP的基本要求PART IIFacility Design 生產(chǎn)設(shè)施的設(shè)計HVAC System 空調(diào)系統(tǒng)Environmental Monitoring (EM) 環(huán)境的監(jiān)視Pha

2、rmaceutical Water 制藥用水Cleaning/Sanitation 清潔消毒Personnel 無菌區(qū)操作人員PART IIIMethods of sterilization 滅菌方法 Sterile Production and validation 無菌生產(chǎn)和驗證The Trend of Sterile Production 無菌產(chǎn)品生產(chǎn)趨勢22Outline 討論綱要PART I3Presentation Outline概要US Regulations 美國法規(guī)Moist Heat Sterilization 濕熱滅菌Dry Heat/Depyrogenation 干熱/

3、去熱原法Sterilization Process Validation 滅菌工藝驗證Other Sterilization Methods 其他滅菌方法3Presentation Outline概要US Reg4Code Federal Regulation美國聯(lián)邦法規(guī)211.84(c)(3) sterile equipment 滅菌設(shè)備Sterile equipment and aseptic sampling techniques shall be used when necessary 必要時應(yīng)使用滅菌設(shè)備和無菌取樣技術(shù)。211.94(c) and (d) sterilized(c)

4、Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use. 藥品容器和密封系統(tǒng)應(yīng)清潔并根據(jù)藥品的性質(zhì)和要求，進(jìn)行滅菌，除熱原過程以確保預(yù)期的用途。(d) Standards or specifications, methods of

5、testing, and, where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures. 應(yīng)建立并執(zhí)行對藥品容器和密封系統(tǒng)的規(guī)格或質(zhì)量標(biāo)準(zhǔn)，測試方法，清潔方法，滅菌和除熱原過程的相關(guān)書面程序。4Code Federal Regulation美國聯(lián)邦法5Code Federal Regulation美國聯(lián)邦法規(guī)211.113

6、(a) and (b) sterilization 滅菌(a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed. 應(yīng)該建立并執(zhí)行用于防止非無菌藥品被致病菌污染的相關(guān)書面程序。(b) Appropriate written procedures, designed to prevent microbiological conta

7、mination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process. 應(yīng)該建立并執(zhí)行用于阻止無菌藥品被致病菌污染的相關(guān)書面程序。這些程序應(yīng)包括任何無菌工藝的驗證。5Code Federal Regulation美國聯(lián)邦法6Code Federal Regulation美國聯(lián)邦法規(guī)211.167(a) testing （a）測試For each batc

8、h of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements. The test procedures shall be in writing and shall be followed. 對無菌和/或無熱原的每批藥品應(yīng)進(jìn)行相應(yīng)的實驗室測試以確定其與符合要求。測試程序應(yīng)有書面文件并遵照執(zhí)行。6Code Federal Regulation美國聯(lián)邦法

9、7Sterilization Methods滅菌方法Moist Heat: 濕熱For drugs and devices. The mode of action is protein denaturation. 用于藥品和設(shè)備。作用方式是使蛋白質(zhì)變性Dry Heat: 干熱For depyrogenation and equipment sterilization. The mode of action is protein denaturation 用于去熱原和設(shè)備滅菌。作用方式是使蛋白質(zhì)變性Ethylene Oxide: 氧化乙烯 Primarily for devices. The m

10、ode of action is alkylation of nucleic acids. 主要用于設(shè)備。作用方式是使核酸烷基化Radiation: 輻射Primarily for devices. The mode of action is DNA strand breakage 主要用于設(shè)備。作用方式是使DNA鏈破壞Other methods? 其他方法？7Sterilization Methods滅菌方法Moi8Bioburden生物負(fù)荷Definition: 定義Population of viable microorganisms on or in a product and/or

11、a package 產(chǎn)品和/包裝上的活性微生物的數(shù)量和類型Mixture of organisms 有機物混合 Indigenous microflora 地方微植物群 Needs to be inactivated by sterilization 需滅菌失活8Bioburden生物負(fù)荷Definition: 定義9Bioburden生物負(fù)荷Bioburden Sources 生物負(fù)荷來源Environment 環(huán)境Product contact surface, personnel, air 產(chǎn)品接觸表面，人員，空氣Materials 材料Water, raw materials. pla

12、stic, paper 水，原材料，塑料，紙張Characteristics of Bioburden 生物負(fù)荷特點Types of microorganisms 微生物類型Resistance to sterilization process 對無菌工藝的耐受Number of organisms 有機物數(shù)量9Bioburden生物負(fù)荷Bioburden Sourc10Biological Indicator (BI)生物指示劑Microbiological test system providing a defined resistance to a specific sterilizat

13、ion process 微生物測試系統(tǒng)對指定滅菌工藝有明確抵抗性。A characterized preparation of specific microorganisms resistant to a particular sterilization process某一確定的微生物(指示劑)應(yīng)具有對某一特定滅菌工藝的抵抗性10Biological Indicator (BI)生物11Typical Biological Indicators典型生物指示劑Moist heat sterilization 濕熱滅菌Geobacillus stearothermophilusBacillus s

14、tearothermophilusDry heat and EO sterilization 干熱和環(huán)氧乙烷滅菌Bacillus atrophaeusBacillus subtilis var. niger11Typical Biological Indicator12Forms of Biological Indicators生物指示劑形式Strips/discs in glassine envelopes 在透明紙信封里的條形板/光盤Strips/discs 條/光盤Self-contained 獨立包裝的Ampoules 安瓶Strips with medium 中號條形板Liquid

15、suspension 液體懸浮液Metal 金屬Fiberglass 玻璃纖維12Forms of Biological Indicato13Choice of an Appropriate BI相關(guān)生物指示劑的選擇Sterilization process 滅菌工藝Cycle design method 循環(huán)設(shè)計方法Product bioburden 產(chǎn)品生物負(fù)荷Population 數(shù)量Resistance 抵抗性13Choice of an Appropriate BI14BIs Prepared by User生物指示劑的準(zhǔn)備Performance 性能Resistance 抵抗性Po

16、pulation 數(shù)量Purity 純度D- value D 值Recovery methods 恢復(fù)方法Storage requirements 儲存要求14BIs Prepared by User生物指示劑的準(zhǔn)15Biological Indicator Use生物指示劑使用Place BI within 把BI 放進(jìn)Product 產(chǎn)品Package 包裝Sterilizer load to monitor process 滅菌器負(fù)荷以監(jiān)視滅菌工藝Expose to sterilizing conditions 暴露在滅菌狀態(tài)Remove BI and test 移除BI和測試Count

17、 survivors 生存數(shù)量的計算Growth/no growth response 生長/無生長反應(yīng)15Biological Indicator Use生物指16D-value D值The D value is the time, usually in minutes, required to achieve inactivation of 90% (or one logarithm) of a population of the test microorganism at specified conditions. D值是在特定條件下微生物數(shù)量降低的90%（或一對數(shù)）所用的時間，通常是以

18、分鐘為單位的。 Bacillus stearothermophilus has a D value: 嗜熱脂肪芽胞桿菌的D值2 min at 121oC 20 min at 110oC 0.2-0.3 min at 130oCOf all the aspects of sterilization validation, the D value is perhaps the most important. Validating a process without consideration of the D value is largely ineffective and is not acce

19、ptable from CGMP perspective 滅菌驗證中，D值可能是最重要的。不考慮D值的驗證過程多半是無效的且不被CGMP接受。16D-value D值The D value is th17Z-value Z值Z-value: number of degrees of temperature required for a 1 logarithm change in the D-value Z值：D值1對數(shù)改變需要的溫度數(shù)Z = -1/slope of the thermal resistance curve Z = -1/熱阻力曲線斜率 whereSlope = logarith

20、mic change in D-value/change in temperature 斜率 = D值上對數(shù)的改變/溫度的改變17Z-value Z值Z-value: number o18Impact of Z-value Z值的影響When z-value is small, considerably less inactivation will result below reference temperature and considerably more above the reference temperature 當(dāng)Z值較小時，較低程度的失活將導(dǎo)致溫度低于參考溫度，較大程度的失活將導(dǎo)

21、致溫度高于參考溫度。18Impact of Z-value Z值的影響When19Typical Temperature Profiles典型溫度分布19Typical Temperature Profiles20Type of Sterilization滅菌類型Moist Heat Sterilization濕熱滅菌20Type of Sterilization滅菌類型Mo21Moist Heat Sterilization濕熱滅菌Characteristics: 特征Well understood and well characterized process, first validate

22、d process in pharm industry濕熱滅菌是一已被很好地理解并描述滅菌工藝，也是在制藥工業(yè)中第一個被驗證的滅菌工藝Suitable for a wide variety of applications 適合于較大應(yīng)用范圍Equipment is readily available 設(shè)備很容易從市場購買到Cost on a per use basis is low 每次使用基準(zhǔn)花費低21Moist Heat Sterilization濕熱滅22Moist Heat Sterilization濕熱滅菌Applications: 應(yīng)用Terminal sterilization

23、of parental product 注射劑的終端滅菌Sterilization of equipment and components for use in aseptic filling 無菌灌裝線上設(shè)備和配件的滅菌Sterilization of laboratory materials 實驗室用材料的滅菌In-situ sterilization of process piping and equipment (SIP)工藝管道和設(shè)備在線滅菌 22Moist Heat Sterilization濕熱滅23Basic Types of Moist Heat Sterilization濕

24、熱滅菌基本類型Saturated steam 飽和蒸汽Autoclaves (self-closing) 高壓滅菌柜（半封閉）SIP 在線滅菌Super heated water 過熱水Spray 噴霧Submerged 浸沒的SIP 在線滅菌Steam-air-mixture (SAM) 水蒸氣空氣混合物23Basic Types of Moist Heat S24Basic Elements of Sterilization Process Validation 滅菌工藝驗證的基本元素Empty vessel heat distribution 空容器熱分布Heat distributio

25、n and penetration 熱分布和滲透3.Microbiological challenges 微生物挑戰(zhàn)24Basic Elements of Sterilizat25Steam Sterilization Validation: Prerequisites 蒸汽滅菌驗證：前提OQ for an autoclave: 高壓滅菌柜運行確認(rèn)Empty chamber temperature mapping within 1.0oC of the mean 空腔體溫度分布圖在平均值的1.0oC 內(nèi)Chamber integrity test (no leaking) 腔體完整性測試 Ce

26、rtification of HEPA filtration on the air used to break vacuum or integrity testing of the vent filter 用于隔斷真空或通氣過濾器完整性測試的空氣HEPA過濾認(rèn)證Requirements for SIP 在線滅菌要求Temperature mapping 溫度分布圖An integrity test, where appropriate 相關(guān)完整性測試Use of BI 生物指示劑的使用All critical instruments must be calibrated 所有關(guān)鍵儀器需校驗25

27、Steam Sterilization Validati26Steam Sterilization Validation: Prerequisites 蒸汽滅菌驗證：前提Acceptable test results for non-condensable gases, super-heated steam and dryness should be obtained for the clean steam used for the autoclave/SIP 應(yīng)獲得用于高壓滅菌柜/SIP的潔凈蒸汽中的不凝氣體，過熱蒸汽及干燥度的可接受測試結(jié)果5. Tools for the conduct

28、of the PQ study: 進(jìn)行PQ研究的工具BI with 106 spores and known D and Z values BI 有106個孢子，已知D值和Z值Temperature sensors 溫度傳感器Recording device capable of supporting 12 temp sensors with an accuracy of 0.5 oC, recording data every minute or less 記錄設(shè)備能支撐 12溫度傳感器，精度 0.5 oC，每分鐘或間隔更短時間記錄數(shù)據(jù)Means of introducing temp se

29、nsors into the autoclave/SIP 將溫度傳感器導(dǎo)入高壓滅菌柜/SIP的方法26Steam Sterilization Validati27Steam Sterilization Validation: Preparation of PQ protocol 蒸汽滅菌驗證：PQ方案的準(zhǔn)備A protocol shall be prepared for : 對于下列各項應(yīng)建立方案：New autoclave/SIP 新高壓滅菌柜/SIPNew loading patterns or product configurations 新裝料方式或產(chǎn)品配置Changes to exi

30、sting patterns 對現(xiàn)有裝料方式的變更Changes to operation cycle parameters 對運行周期參數(shù)的變更Major change to equipment as directed by change control 變更控制要求的設(shè)備主要變更27Steam Sterilization Validati28Steam Sterilization Validation: Preparation of PQ protocol 蒸汽滅菌驗證：PQ方案的準(zhǔn)備The protocol may include: 方案可能包括：Objectives of the va

31、lidation study 驗證研究的目的Identification and description of the sterilizer and its process controls 滅菌器的識別和說明及工藝控制Identification of SOPs for the process equipment 工藝設(shè)備SOP的識別Description of or SOP reference for instrument calibration procedures 儀器校驗程序的說明或SOP參考Identification of calibration procedures for t

32、emp-monitoring equipment, which include a two point pre-run calibration and a post-run verification for each run 溫度監(jiān)測設(shè)備校驗程序的識別，包括一個兩點預(yù)運行校驗和每次運行后的確認(rèn)Process parameter acceptance criteria 工藝參數(shù)的驗收標(biāo)準(zhǔn)28Steam Sterilization Validati29Steam Sterilization Validation: Preparation of PQ protocol 蒸汽滅菌驗證：PQ方案的準(zhǔn)備A

33、 description of the following:以下說明Biodurden determination studies 生物負(fù)荷確認(rèn)研究Empty chamber heat distribution studies ( 1 oC) 空腔體熱分布研究（ 1 oC ）Loaded chamber (including Load configuration, max lading and min loading) heat penetration studies 滿載腔體（包括裝載配置, 最大和最少）熱穿透研究Container mapping studies (may not need

34、ed if 100mL) 容器分布圖研究（如果容量100mL ，可能不需要）Microbiological challenge studies 微生物挑戰(zhàn)研究Evaluation of drug product cooling water (where applicable) 藥品冷卻水評估（若適用）Evaluation of vent filter membranes associated with the sterilizer 與滅菌器相關(guān)的通氣過濾膜的評估29Steam Sterilization Validati30Steam Sterilization Validation: Pre

35、paration of PQ protocol 蒸汽滅菌驗證：PQ方案的準(zhǔn)備4.Description of the temp sensor placement within the load 在負(fù)荷范圍內(nèi)溫度傳感器位置的說明One next to the temp controlling sensor for autoclave. 一1個接近高壓滅菌柜的溫度控制傳感器NLT 12 sensors for autoclave 不少于12 個傳感器用于高壓滅菌柜NLT 3 sensors for SIP不少于3傳感器用于在線滅菌If the temp controlling sensor is

36、not in the drain, an additional sensor shall be placed in the drain 如果溫度控制傳感器不在排水口中，應(yīng)置另一個傳感器于排水口中A minimum # of sensors meeting the calibration and verification shall be established. Any sensor that fail at the end of the study shall be investigated. Any sensor located next to the temp controlling s

37、ensor or in the drain shall meet the pre and post calibration as part of the acceptance criteria for a successful run 應(yīng)建立符合校驗和驗證的最少#傳感器。最終任何傳感器的失敗應(yīng)調(diào)查研究。任何臨近溫度控制傳感器或在排水口的傳感器應(yīng)符合預(yù)校驗和后校驗，這是成功運行的驗收標(biāo)準(zhǔn)的一部分。30Steam Sterilization Validati31Steam Sterilization Validation: Preparation of PQ protocol 蒸汽滅菌驗證：PQ方

38、案的準(zhǔn)備5.Acceptance criteria for temp. pressure, Fo where appropriate, vacuum and destructions of BIs 溫度壓力，相關(guān)Fo，真空及生物指示劑滅活的驗收標(biāo)準(zhǔn)6.A requirement for 3 consecutive, successful runs 3次連續(xù)成功運行的要求The drain is the coldest point and is outside of the sterilization zone, not included in the calculation of mean c

39、hamber temperature and not subject to chamber distribution requirement.排水口是最冷點，在滅菌區(qū)外，且不包括在平均腔體溫度計算內(nèi)，不受限于腔體分布要求Thermocouples should be placed at the same location for empty chamber and loaded chamber heat distribution studies.熱電偶應(yīng)置于相同位置，進(jìn)行空腔體和滿載腔體熱分布研究Uniformity is expected only at the steady state.僅

40、在穩(wěn)定狀態(tài)下要求均一性31Steam Sterilization Validati32Steam Sterilization Validation: Execution of PQ 蒸汽滅菌驗證：PQ執(zhí)行1.Temperature sensor shall: 溫度傳感器應(yīng)：For heat penetration data, be located such that they penetrate the equipment, or the product container and are immersed in the product 對于熱穿透數(shù)據(jù)，應(yīng)置于能穿透設(shè)備或產(chǎn)品容器處，并包含在產(chǎn)

41、品中For heat distribution data, be evenly distributed within the load or system and shall not contact metal surface 對于熱分布數(shù)據(jù)，平均分布在負(fù)荷范圍內(nèi)或系統(tǒng)中，且不能接觸金屬面2.The BI shall:生物指示劑應(yīng)：Be placed near the tip of the temperature sensor used for penetration 置于靠近用于穿透的溫度傳感器的頂端Include the identification that links to the n

42、umber of the appropriate temperature sensor of the BI 包括與相關(guān)BI溫度傳感器數(shù)量有關(guān)的識別The D value of the BI shall be determined in the product BI的D值應(yīng)在生產(chǎn)中確定32Steam Sterilization Validati33Steam Sterilization Validation: Execution of PQ 蒸汽滅菌驗證：PQ執(zhí)行The autoclave shall be loaded and operated in accordance with SOP 高

43、壓滅菌器應(yīng)按照SOP進(jìn)行裝載并運行Using 121.1 oC as the base temperature and 10 oC as the Z-value, Fo shall be calculated 121.1 oC 作為基底溫度， 10 oC 作為Z值， Fo應(yīng)為計算值A(chǔ)cceptance criteria shall be based on no growth on exposed BIs and growth on the positive control BI 驗收標(biāo)準(zhǔn)應(yīng)依據(jù)暴露的BI上未生長和陽性控制BI上的生長Failure to meet acceptance crit

44、eria shall require cycle parameter modifications, load pattern modification and/or equipment repairs/corrections 未達(dá)到驗收標(biāo)準(zhǔn)應(yīng)要求周期參數(shù)變更，負(fù)荷曲線圖變更和/或設(shè)備修理/修正33Steam Sterilization Validati34Case Study 實例分析Autoclave Sterilization Validation 高壓蒸汽滅菌驗證Table 1Acceptance Criteria of Empty Chamber Heat Distribution表1

45、 空腔體熱分布驗收標(biāo)準(zhǔn)No.Acceptance Criteria驗收標(biāo)準(zhǔn)1The 12 TCs distributed throughout the chamber must be within 1C of the mean thermocouple temperature each minute after stabilization throughout the duration of the sterilization phase. 整個滅菌階段，穩(wěn)定后，每分鐘分布在腔體內(nèi)的12個 TC必須在平均熱電偶溫度的1C 2Dwell time not less than the pre-se

46、t sterilization time of 40 minutes. 停留時間不少于預(yù)設(shè)定的滅菌時間40分鐘3The TCs monitoring the drain and chamber RTDs may not fail post check calibration. Ten of the twelve TCs must be functional at the end of the cycle. 監(jiān)測排水和腔體RTD的TC不應(yīng)在實驗后校驗失敗。循環(huán)結(jié)束時，12個TC中的10個必須在實驗后校驗時功能完好34Case Study 實例分析Autoclave St35Case Study

47、實例分析Autoclave Sterilization Validation 高壓蒸汽滅菌驗證Table 2Acceptance Criteria for Heat Distribution表2 熱分布驗收標(biāo)準(zhǔn)No.Acceptance Criteria驗收標(biāo)準(zhǔn)1Dwell time must be not less than the pre-set sterilization time of 15 minutes 停留時間不得少于預(yù)設(shè)定的滅菌時間15分鐘2The drain PT-100 and TC in the drain must be within 1.0C of each othe

48、r during the stabilized sterilization period. 在穩(wěn)定滅菌期間，排水管PT-100和排水管中TC之間溫差必須在1.0oC 之內(nèi)3The temperature deviation during holding times does not exceed -1C and +2C from the set point (during the stabilization period) 停留時間的溫度偏差不超過-1oC及設(shè)定點的 +2oC （在穩(wěn)定階段）4At least 10 TCs of 12 thermocouples must be functio

49、nal at the end of the run循環(huán)結(jié)束時，12個TC中的10個必須功能完好35Case Study 實例分析Autoclave St36Case Study 實例分析Autoclave Sterilization Validation 高壓蒸汽滅菌驗證Table 3Acceptance Criteria for Heat Penetration表3熱分布驗收標(biāo)準(zhǔn)No.Acceptance Criteria 驗收標(biāo)準(zhǔn)1F0 must be not less than preset time of 15 minutes F0不得低于預(yù)設(shè)定的15分鐘2The drain PT-1

50、00 and TC in the drain must be within 1.0C of each other during the stabilized sterilization period. 在穩(wěn)定滅菌期間，排水管PT-100和排水管中TC之間溫差必須在1.0C 之內(nèi)3The temperature sensors remained in position at the end of cycle 循環(huán)結(jié)束時溫度傳感器仍然在位4The items containing sensors are intact; bottles have not leaked, burst or broke

51、n 裝傳感器的器具完整；瓶子不漏，爆裂或破碎5No more than 1% of the bottles has burst or broken 爆裂或破碎的瓶不超過1%6The temperature measured in any fluid containers is not greater than 80 C at the end of the cycle 循環(huán)結(jié)束時，任何液體容器中測量的溫度不超過80 C 7The temperature deviation during holding time does not exceed -1C and +2C from the setpo

52、int during the stabilized sterilization period 停留時間的溫度偏差不超過-1C及穩(wěn)定滅菌階段設(shè)定點的 +2C 8No spore survival of the biological indicators 生物指示器上無孢子生存9At least 10 TCs of 12 thermocouples are functional at the end of the run for themaximum & minimum load configurations, respectively 每次最大&最小裝載配置結(jié)束時，12個熱電偶中至少10個TC起

53、作用10Autoclave and validation timers must be synchronized 高壓滅菌柜和確認(rèn)計時器必須同步36Case Study 實例分析Autoclave St37Dry Heat Sterilization 干熱滅菌 Depyrogenation去熱原37Dry Heat Sterilization 干熱滅菌 38Terminology and Definitions 術(shù)語和定義Pyrogen: Fever producing substance: endotoxin, viruses, fungi, toxin from gram(+) and g

54、ram(-) bacterials, peptiglycan 熱原：熱產(chǎn)生的物質(zhì)：內(nèi)毒素，病毒，真菌，革蘭氏陽性和陰性細(xì)菌產(chǎn)生的毒素，肽糖Endotoxin: Component from outer membrane of gram(-) bacterial, most potent pyrogens, LPS in structure 內(nèi)毒素：革蘭氏陰性細(xì)菌外膜的成分，大多數(shù)有效熱原，結(jié)構(gòu)中的LPSEnvironmental: complex of protein, carbohydrate & lipid. 環(huán)境：復(fù)合蛋白質(zhì)， 碳水化合物&脂類 Purified: lipopolysac

55、chride, used in endotoxin standards 提純后：脂多糖，用于內(nèi)毒素標(biāo)準(zhǔn)38Terminology and Definitions 39Sources of Pyrogen in Parenterals注射用藥熱原的來源Water systems and resin columns 水系統(tǒng)和樹脂交換柱APIs produced without endotoxin removal 生產(chǎn)API而未除內(nèi)毒素API & excipients from natural sources 來自自然源的API&賦形劑Manufacturing equipment 生產(chǎn)設(shè)備Anyw

56、here gram(-) microbes are growing or have been growing 革蘭氏陰性細(xì)菌生長或曾生長的任何地方39Sources of Pyrogen in Parent40Depyrogenation去熱原A process to remove or destroy Endotoxin 除去或破壞內(nèi)毒素的一種工藝 3 log reduction per USP 按照USP ， 3對數(shù)減少值Depyrogenation requires: 去熱原要求：Distillation or ultrafiltration of water 對水進(jìn)行蒸餾或超濾Dry

57、heat incineration 干熱焚燒Destruction by strong alkali or oxidation with peroxide 用強堿或過氧化物進(jìn)行氧化來破壞40Depyrogenation去熱原A process 41Types of Dry Heat Sterilizers干熱滅菌器的種類Common 常用Forced-convection batch sterilizers: utensils, glassware, stainless steel equipment, product 強制對流批滅菌器：器具，玻璃器皿，不銹鋼設(shè)備，產(chǎn)品Tunnel: glas

58、sware 烘箱：玻璃器皿Flame: ampoule sealing 火焰：安瓿封口Less common 不常用Microwave 微波Laser plasma 激光等離子體41Types of Dry Heat Sterilizer42Components for Aseptic Processing 無菌工藝元件Component部件Endotoxin內(nèi)毒素Method方法LRV*Water 水Most likely 很可能Distillation, RO 蒸餾，RO4Lg. Containers 容器Possible 可能Chemicals, CIP 化學(xué)品，CIP2Excipien

59、ts 賦形劑Possible 可能Purification 提純 NDGlass vials 玻璃瓶Never seen 未見過Dry heat 干熱4Closures 塞子Unlikely 不可能Wash/sterilize清洗/滅菌3Lubricant 潤滑油Never seen 未見過Dry heat 干熱ND42Components for Aseptic Proce43Dry Heat Depyrogenation: Glass干熱除熱原：玻璃Temp. range: 200-350 oC 溫度范圍：200-350 oC Heat tolerant materials, glassw

60、are, metal parts, scissors, oils, inorganic salts 耐熱材料，玻璃器皿，金屬部件，剪刀，油，無機鹽Process: heated, HEPA filtered air, uniformly distributed by convection & fan 工藝：加熱，HEPA 過濾空氣，通過對流&風(fēng)扇進(jìn)行均勻分布Lethal effect: oxidation of proteins and denaturation 致命效應(yīng)：蛋白質(zhì)氧化和變性USP : 3 log reduction 大于3個對數(shù)減少值43Dry Heat Depyrogenat