1、1,1,Sterilization 滅菌,A General Discussion from CGMP Perspective 從CGMP角度的綜合討論,2,2,Outline 討論綱要,PART I Terminology 專業(yè)用詞的定義 GMP Requirements in The Manufacture of Sterile Pharmaceutical Products無(wú)菌藥品生產(chǎn)過(guò)程中GMP的基本要求 PART II Facility Design 生產(chǎn)設(shè)施的設(shè)計(jì) HVAC System 空調(diào)系統(tǒng) Environmental Monitoring (EM) 環(huán)境的監(jiān)視 Pharma

2、ceutical Water 制藥用水 Cleaning/Sanitation 清潔消毒 Personnel 無(wú)菌區(qū)操作人員 PART III Methods of sterilization 滅菌方法 Sterile Production and validation 無(wú)菌生產(chǎn)和驗(yàn)證 The Trend of Sterile Production 無(wú)菌產(chǎn)品生產(chǎn)趨勢(shì),3,Presentation Outline概要,US Regulations 美國(guó)法規(guī) Moist Heat Sterilization 濕熱滅菌 Dry Heat/Depyrogenation 干熱/去熱原法 Steriliz

3、ation Process Validation 滅菌工藝驗(yàn)證 Other Sterilization Methods 其他滅菌方法,4,Code Federal Regulation美國(guó)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(shí)應(yīng)使用滅菌設(shè)備和無(wú)菌取樣技術(shù)。 211.94(c) and (d) sterilized (c) Drug product containers and closur

4、es 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(guò)程以確保預(yù)期的用途。 (d) Standards or specifications, methods of testing, and, where indicated, me

5、thods 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(duì)藥品容器和密封系統(tǒng)的規(guī)格或質(zhì)量標(biāo)準(zhǔn)，測(cè)試方法，清潔方法，滅菌和除熱原過(guò)程的相關(guān)書面程序。,5,Code Federal Regulation美國(guó)聯(lián)邦法規(guī),211.113(a) and (b) sterilization 滅菌 (a) Appropriate written proced

6、ures, 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(wú)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 contamination of drug products purporting to be sterile, shall

7、 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(wú)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(wú)菌工藝的驗(yàn)證。,6,Code Federal Regulation美國(guó)聯(lián)邦法規(guī),211.167(a) testing （a）測(cè)試 For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be app

8、ropriate laboratory testing to determine conformance to such requirements. The test procedures shall be in writing and shall be followed. 對(duì)無(wú)菌和/或無(wú)熱原的每批藥品應(yīng)進(jìn)行相應(yīng)的實(shí)驗(yàn)室測(cè)試以確定其與符合要求。測(cè)試程序應(yīng)有書面文件并遵照?qǐng)?zhí)行。,7,Sterilization Methods滅菌方法,Moist Heat: 濕熱 For drugs and devices. The mode of action is protein denaturation.

9、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 mode 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. Th

10、e 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？,8,Bioburden生物負(fù)荷,Definition: 定義 Population of viable microorganisms on or in a product and/or 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(jī)物混合 Indigenous microflora 地方微植物群 Needs to be inactivated by sterilization

11、 需滅菌失活,9,Bioburden生物負(fù)荷,Bioburden Sources 生物負(fù)荷來(lái)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. plastic, paper 水，原材料，塑料，紙張 Characteristics of Bioburden 生物負(fù)荷特點(diǎn) Types of microorganisms 微生物類型 Resistance to sterilization process 對(duì)無(wú)菌工藝的耐受 Number of o

12、rganisms 有機(jī)物數(shù)量,10,Biological Indicator (BI)生物指示劑,Microbiological test system providing a defined resistance to a specific sterilization process 微生物測(cè)試系統(tǒng)對(duì)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(duì)某一特定滅菌工藝的抵抗性,1

13、1,Typical Biological Indicators典型生物指示劑,Moist heat sterilization 濕熱滅菌 Geobacillus stearothermophilus Bacillus stearothermophilus Dry heat and EO sterilization 干熱和環(huán)氧乙烷滅菌 Bacillus atrophaeus Bacillus subtilis var. niger,12,Forms of Biological Indicators生物指示劑形式,Strips/discs in glassine envelopes 在透明紙信封里

14、的條形板/光盤 Strips/discs 條/光盤 Self-contained 獨(dú)立包裝的 Ampoules 安瓶 Strips with medium 中號(hào)條形板 Liquid suspension 液體懸浮液 Metal 金屬 Fiberglass 玻璃纖維,13,Choice 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(jì)方法 Product bioburden 產(chǎn)品生物負(fù)荷 Population 數(shù)量 Resistance 抵抗性,14,BIs Prepared by

15、 User生物指示劑的準(zhǔn)備,Performance 性能 Resistance 抵抗性 Population 數(shù)量 Purity 純度 D- value D 值 Recovery methods 恢復(fù)方法 Storage requirements 儲(chǔ)存要求,15,Biological 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) Re

16、move BI and test 移除BI和測(cè)試 Count survivors 生存數(shù)量的計(jì)算 Growth/no growth response 生長(zhǎng)/無(wú)生長(zhǎng)反應(yīng),16,D-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(duì)數(shù)）所用的時(shí)間

17、，通常是以分鐘為單位的。 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 130oC Of 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 n

18、ot acceptable from CGMP perspective 滅菌驗(yàn)證中，D值可能是最重要的。不考慮D值的驗(yàn)證過(guò)程多半是無(wú)效的且不被CGMP接受。,17,Z-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(duì)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 where Slope = logarithmic change in D-v

19、alue/change in temperature 斜率 = D值上對(duì)數(shù)的改變/溫度的改變,18,Impact 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(shí)，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)致溫度高于參考溫度。,19,Typical Temperature Profiles典

20、型溫度分布,20,Type of Sterilization滅菌類型,Moist Heat Sterilization 濕熱滅菌,21,Moist Heat Sterilization濕熱滅菌,Characteristics: 特征 Well understood and well characterized process, first validated 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(gè)被驗(yàn)證的滅菌工藝 Suitable for a wide variety of applications 適合于較大應(yīng)用范

21、圍 Equipment is readily available 設(shè)備很容易從市場(chǎng)購(gòu)買到 Cost on a per use basis is low 每次使用基準(zhǔn)花費(fèi)低,22,Moist Heat Sterilization濕熱滅菌,Applications: 應(yīng)用 Terminal sterilization of parental product 注射劑的終端滅菌 Sterilization of equipment and components for use in aseptic filling 無(wú)菌灌裝線上設(shè)備和配件的滅菌 Sterilization of laboratory m

22、aterials 實(shí)驗(yàn)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,23,Basic Types of Moist Heat Sterilization濕熱滅菌基本類型,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(guò)熱水 Spray 噴霧 Submerged 浸沒(méi)的 SIP 在線滅菌 Steam-air-mixture (SAM) 水蒸氣空氣混合物,24,B

23、asic Elements of Sterilization Process Validation 滅菌工藝驗(yàn)證的基本元素,Empty vessel heat distribution 空容器熱分布 Heat distribution and penetration 熱分布和滲透 3.Microbiological challenges 微生物挑戰(zhàn),25,Steam Sterilization Validation: Prerequisites 蒸汽滅菌驗(yàn)證：前提,OQ for an autoclave: 高壓滅菌柜運(yùn)行確認(rèn) Empty chamber temperature mapping

24、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(cè)試 Certification 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(guò)濾器完整性測(cè)試的空氣HEPA過(guò)濾認(rèn)證 Requirements for SIP 在線滅菌要求 Temperature mapping 溫度分布圖 An integrity test, whe

25、re appropriate 相關(guān)完整性測(cè)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(yàn),26,Steam Sterilization Validation: Prerequisites 蒸汽滅菌驗(yàn)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/S

26、IP 應(yīng)獲得用于高壓滅菌柜/SIP的潔凈蒸汽中的不凝氣體，過(guò)熱蒸汽及干燥度的可接受測(cè)試結(jié)果 5. Tools for the conduct 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(gè)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

27、 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(shí)間記錄數(shù)據(jù) Means of introducing temp sensors into the autoclave/SIP 將溫度傳感器導(dǎo)入高壓滅菌柜/SIP的方法,27,Steam Sterilization Validation: Preparation of PQ protocol 蒸汽滅菌驗(yàn)證：PQ方案的準(zhǔn)備,A protocol shall be prepared for : 對(duì)于下列各項(xiàng)應(yīng)建立方案： New autoclave/SIP 新高壓滅菌柜/SIP New loading patterns

28、or product configurations 新裝料方式或產(chǎn)品配置 Changes to existing patterns 對(duì)現(xiàn)有裝料方式的變更 Changes to operation cycle parameters 對(duì)運(yùn)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,28,Steam Sterilization Validation: Preparation of PQ protocol 蒸汽滅菌驗(yàn)證：PQ方案的準(zhǔn)備,The protocol may include: 方

29、案可能包括： Objectives of the validation study 驗(yàn)證研究的目的 Identification and description of the sterilizer and its process controls 滅菌器的識(shí)別和說(shuō)明及工藝控制 Identification of SOPs for the process equipment 工藝設(shè)備SOP的識(shí)別 Description of or SOP reference for instrument calibration procedures 儀器校驗(yàn)程序的說(shuō)明或SOP參考 Identification

30、of calibration procedures for temp-monitoring equipment, which include a two point pre-run calibration and a post-run verification for each run 溫度監(jiān)測(cè)設(shè)備校驗(yàn)程序的識(shí)別，包括一個(gè)兩點(diǎn)預(yù)運(yùn)行校驗(yàn)和每次運(yùn)行后的確認(rèn) Process parameter acceptance criteria 工藝參數(shù)的驗(yàn)收標(biāo)準(zhǔn),29,Steam Sterilization Validation: Preparation of PQ protocol 蒸汽滅菌驗(yàn)證：PQ方案

31、的準(zhǔn)備,A description of the following:以下說(shuō)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

32、 not needed 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(píng)估（若適用） Evaluation of vent filter membranes associated with the sterilizer 與滅菌器相關(guān)的通氣過(guò)濾膜的評(píng)估,30,Steam Sterilization Validation: Preparation of PQ p

33、rotocol 蒸汽滅菌驗(yàn)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(shuō)明 One next to the temp controlling sensor for autoclave. 一1個(gè)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(gè)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 not in the

34、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(gè)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 sensor or i

35、n 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(yàn)和驗(yàn)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(yàn)和后校驗(yàn)，這是成功運(yùn)行的驗(yàn)收標(biāo)準(zhǔn)的一部分。,31,Steam Sterilization Validation: Preparation of PQ protocol 蒸汽滅菌驗(yàn)證：PQ方案的準(zhǔn)備,5.Acceptance criteria for temp. p

36、ressure, 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(yàn)收標(biāo)準(zhǔn) 6.A requirement for 3 consecutive, successful runs 3次連續(xù)成功運(yùn)行的要求 The drain is the coldest point and is outside of the sterilization zone, not included in the calculation of mean chamber temperature and not subject

37、to chamber distribution requirement. 排水口是最冷點(diǎn)，在滅菌區(qū)外，且不包括在平均腔體溫度計(jì)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. 僅在穩(wěn)定狀態(tài)下要求均一性,32,Steam Steriliza

38、tion Validation: Execution of PQ 蒸汽滅菌驗(yàn)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(duì)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)品中 For heat distribution data, be evenly distributed wit

39、hin the load or system and shall not contact metal surface 對(duì)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 number of the appropriate temperature sensor of the B

40、I 包括與相關(guān)BI溫度傳感器數(shù)量有關(guān)的識(shí)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,33,Steam Sterilization Validation: Execution of PQ 蒸汽滅菌驗(yàn)證：PQ執(zhí)行,The autoclave shall be loaded and operated in accordance with SOP 高壓滅菌器應(yīng)按照SOP進(jìn)行裝載并運(yùn)行 Using 121.1 oC as the base temperature and 10 oC as the Z-va

41、lue, Fo shall be calculated 121.1 oC 作為基底溫度， 10 oC 作為Z值， Fo應(yīng)為計(jì)算值 Acceptance criteria shall be based on no growth on exposed BIs and growth on the positive control BI 驗(yàn)收標(biāo)準(zhǔn)應(yīng)依據(jù)暴露的BI上未生長(zhǎng)和陽(yáng)性控制BI上的生長(zhǎng) Failure to meet acceptance criteria shall require cycle parameter modifications, load pattern modification

42、 and/or equipment repairs/corrections 未達(dá)到驗(yàn)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,34,Case Study 實(shí)例分析Autoclave Sterilization Validation 高壓蒸汽滅菌驗(yàn)證,Table 1Acceptance Criteria of Empty Chamber Heat Distribution 表1 空腔體熱分布驗(yàn)收標(biāo)準(zhǔn),35,Case Study 實(shí)例分析Autoclave Sterilization Validation 高壓蒸汽滅菌驗(yàn)證,Table 2Acceptance Criteria

43、for Heat Distribution 表2 熱分布驗(yàn)收標(biāo)準(zhǔn),36,Case Study 實(shí)例分析Autoclave Sterilization Validation 高壓蒸汽滅菌驗(yàn)證,Table 3Acceptance Criteria for Heat Penetration 表3熱分布驗(yàn)收標(biāo)準(zhǔn),37,Dry Heat Sterilization 干熱滅菌,Depyrogenation 去熱原,38,Terminology and Definitions 術(shù)語(yǔ)和定義,Pyrogen: Fever producing substance: endotoxin, viruses, fung

44、i, toxin from gram(+) and gram(-) bacterials, peptiglycan 熱原：熱產(chǎn)生的物質(zhì)：內(nèi)毒素，病毒，真菌，革蘭氏陽(yáng)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LPS Environmental: complex of protein, carbohydrate mechanical circulati

45、on needed 空氣密度，溫度不同可能導(dǎo)致分層，需要機(jī)械循環(huán) Heat degradation limits materials 熱降解限制材料 Contraction during cooling may draw contaminants 冷卻過(guò)程中接觸可能引起污染,46,Depyrogenation by Tunnels 通過(guò)烘箱去熱原,HEPA-filtered, vertical laminar air flow in heating and cooling zones, or radiant heaters in heating zone and vertical lamina

46、r air flow in cooling zone 在加熱和冷卻區(qū)經(jīng)HEPA過(guò)濾的垂直層流氣流，或加熱區(qū)的輻射加熱器和冷卻區(qū)的垂直層流氣流 Conveyor belt to provide in-line continuous flow of sterile glassware to aseptic area 傳送帶提供連續(xù)在線的無(wú)菌玻璃器皿到無(wú)菌區(qū)的流動(dòng) Limited to one type of load at a time 一次限用一種裝載方式 Problem to control speed match other line equipment (filler) 控制速度以匹配其他

47、線設(shè)備（灌裝機(jī)）的問(wèn)題 Difficult to achieve uniform heating, and heat source may generate particles 很難達(dá)到均勻加熱，熱原可能產(chǎn)生顆粒 Large product volume needed to justify tunnel 調(diào)整烘箱要求大的產(chǎn)品容量,47,Validation of Depyrogenation Cycles去熱原循環(huán)驗(yàn)證,Run engineering trials to find cold spots 進(jìn)行試運(yùn)行以找到冷點(diǎn) Run trials to determine worse case

48、vial, e.g., thickest glass, packing effects 試車以確定最差狀況的玻璃瓶，如最厚的玻璃，緊束效應(yīng) Procure or prepare endotoxin indicators 獲得或制備內(nèi)毒素指示劑 Run 3 full loads with endotoxin indicators in place at cold spots and random sites 進(jìn)行3次滿載運(yùn)行，內(nèi)毒素指示劑置于冷點(diǎn)和隨機(jī)位置 Acceptance criteria 驗(yàn)收標(biāo)準(zhǔn) min. 3 log reduction in EU for spiked vials 帶

49、孔玻璃瓶3個(gè)對(duì)數(shù)減少值，單位為EU 3 successful runs with controls and documentation 受控并記錄的3次成功運(yùn)行,48,Case Study 實(shí)例分析Dry Heat Depyrogenation Tunnel 干熱去熱原隧道烘箱,Validation Acceptance Criteria 驗(yàn)證驗(yàn)收標(biāo)準(zhǔn) A minimum of three successful validation runs must be performed. 必須至少進(jìn)行三次成功的驗(yàn)證 Distribution thermocouple temperatures must

50、 be within 15oC of the set point temperature, after stabilization. 穩(wěn)定后，分配熱電偶溫度必須在設(shè)定溫度的 15oC 內(nèi) A minimum cumulative FH value of twelve minutes must be demonstrated for each penetration thermocouple at the end of each cycle. 每次循環(huán)結(jié)束時(shí)，必須證明每個(gè)滲透熱電偶12分鐘內(nèi)的最少累計(jì)FH值 A minimum 3-log reduction of endotoxin must

51、be demonstrated for each endotoxin spiked vial exposed to the depyrogenation cycle. 必須證明暴露于去熱原循環(huán)的每個(gè)內(nèi)毒素長(zhǎng)頸瓶至少有3個(gè)內(nèi)毒素對(duì)數(shù)減少值,49,Case Study 實(shí)例分析Dry Heat Depyrogenation Tunnel 干熱去熱原隧道烘箱,Validation Acceptance Criteria 驗(yàn)證驗(yàn)收標(biāo)準(zhǔn) The controlling RTD (hot zone Entrance RTD) and the thermocouple adjacent to the controlling RTD must be within 10oC of each other during the exposure/dwell phase after stabilization. 穩(wěn)定