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【分享】FDA通用程序指導(dǎo)原則：無(wú)菌類器械上市前通告(510(k))申報(bào)中關(guān)于無(wú)菌證明資料的提交及審查

日期:2021-01-22

【分享】FDA通用程序指導(dǎo)原則：無(wú)菌類器械上市前通告(510(k))申報(bào)中關(guān)于無(wú)菌證明資料的提交及審查

致眾醫(yī)療器械無(wú)菌類器械上市前通告(510(k))申報(bào)中關(guān)于無(wú)菌證明資料的提交及審查

行業(yè)和FDA人員指南

關(guān)于本指南，如果有關(guān)于受CDRH監(jiān)管的器械的問(wèn)題，請(qǐng)通過(guò)301-796-5580聯(lián)系感染控制器械分部（INCB）。關(guān)于本指南，如果有關(guān)于受CBER監(jiān)管的器械的問(wèn)題，請(qǐng)通過(guò)1-800-835-4709或者240-402-8010聯(lián)系CBER的溝通、推廣和發(fā)展辦公室（OCOD）。

美國(guó)衛(wèi)生和人類服務(wù)部

美國(guó)食品藥品監(jiān)督管理局

醫(yī)療器械和放射衛(wèi)生中心

生物學(xué)評(píng)價(jià)和研究中心

前言

如有任何意見(jiàn)和建議，可隨時(shí)提交至//www.regulations.gov，供FDA參考。將書(shū)面意見(jiàn)提交至食品藥品監(jiān)督管理局文檔管理部，地址5630 Fishers Lane,Room 1061, (HFA-305), Rockville, MD 20852。采用文件編號(hào)FDA–2008–D–0611確定所有文件。FDA可能需等到下次修訂或者更新本文件時(shí)才會(huì)對(duì)這些意見(jiàn)作出答復(fù)。其他副本CDRH可從網(wǎng)站上獲得更多拷貝。您也可以發(fā)送電子郵件至CDRH-Guidance@fda.hhs.gov，申請(qǐng)一份指南副本。請(qǐng)采用文件編號(hào)1615指明您申請(qǐng)的指南。CBER您也可以采用書(shū)面申請(qǐng)的方式通過(guò)以下途徑從生物制品評(píng)價(jià)和研究中心（CBER）獲取更多的本指南副本：寫(xiě)信至溝通、推廣和發(fā)展辦公室（OCOD），地址是10903 New Hampshire Ave., WO71, Room 3128, Silver Spring, MD20993-0002；或者撥打電話1-800-835-4709或者240-402-8010；發(fā)送電子郵件至ocod@fda.hhs.gov；或者通過(guò)網(wǎng)站//www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm。

無(wú)菌類器械上市前通告(510(k))申報(bào)中關(guān)于無(wú)菌證明資料的提交及審查

行業(yè)和FDA人員指南

本指南代表了食品藥品監(jiān)督管理局（FDA或者機(jī)構(gòu)）目前在該問(wèn)題上的看法。該文件并未賦予任何人任何權(quán)利，也不可用來(lái)約束FDA或者公眾。如果替代方法可以滿足適用的法令和法規(guī)的要求，則可以采用該替代方法。如果需要討論某種替代方法，請(qǐng)聯(lián)系標(biāo)題頁(yè)上列出的負(fù)責(zé)本指南的FDA人員或者辦公室。I.引言本指南更新并澄清了我們建議申辦方在無(wú)菌類器械510(k)中應(yīng)該包括的關(guān)于滅菌過(guò)程的信息。本指南還詳細(xì)描述了我們建議申辦方在510(k)申報(bào)資料中包括的致熱原性信息。關(guān)于本文件中引用的、已被FDA認(rèn)可的標(biāo)準(zhǔn)的現(xiàn)行版，請(qǐng)?jiān)L問(wèn)FDA認(rèn)可的共識(shí)標(biāo)準(zhǔn)數(shù)據(jù)庫(kù)網(wǎng)站//www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm。FDA的指南文件，包括本指南，并不具備法規(guī)強(qiáng)制性。相反地，指南描述的是機(jī)構(gòu)目前在某個(gè)問(wèn)題上的看法，僅應(yīng)該被視為推薦意見(jiàn)，除非引用了具體的法規(guī)或者法令要求。機(jī)構(gòu)指南中詞語(yǔ)“應(yīng)該”的使用意味著我們建議或者推薦進(jìn)行某項(xiàng)活動(dòng)，但并不是強(qiáng)制要求進(jìn)行某項(xiàng)活動(dòng)。II.背景近年來(lái)，F(xiàn)DA收到的無(wú)菌類器械510(k)中，有越來(lái)越多的器械采用的滅菌方法不同于傳統(tǒng)滅菌方法，即蒸汽滅菌、干熱滅菌、環(huán)氧乙烷（EO）滅菌和輻射滅菌。FDA對(duì)其他方法，例如過(guò)氧化氫、臭氧和柔性袋系統(tǒng)，也有一定的經(jīng)驗(yàn)，目前將這些方法視為成熟方法。然而，我們認(rèn)識(shí)到新近開(kāi)發(fā)出來(lái)的方法可能會(huì)發(fā)生變化，目前也正在開(kāi)發(fā)全新的滅菌技術(shù)并且計(jì)劃將其用于I類和II類器械的生產(chǎn)。FDA將這些方法視為新方法。（術(shù)語(yǔ)“成熟”和“新”的定義見(jiàn)下文第IV節(jié)。）根據(jù)聯(lián)邦食品藥品和化妝品法案（下文稱法案）章節(jié)513(f)(5)所述，如果不滿足法案中與實(shí)質(zhì)等同性決議無(wú)關(guān)的任何條款，包括不滿足生產(chǎn)質(zhì)量管理規(guī)范（GMP），F(xiàn)DA可能不會(huì)拒絕授予510(k)許可，除非FDA發(fā)現(xiàn)產(chǎn)品不滿足該條款極有可能“對(duì)人體健康帶來(lái)嚴(yán)重風(fēng)險(xiǎn)”。我們相信，如果執(zhí)行不到位，新滅菌技術(shù)有重大的滅菌不充分風(fēng)險(xiǎn)。因此，應(yīng)該認(rèn)真評(píng)估采用這些技術(shù)滅菌的器械是否遵循GMP的要求進(jìn)行生產(chǎn)。如果無(wú)法確保產(chǎn)品的無(wú)菌性，則會(huì)對(duì)人體健康造成嚴(yán)重的風(fēng)險(xiǎn)，因?yàn)榇嬖诟腥撅L(fēng)險(xiǎn)。因此，對(duì)于采用新滅菌技術(shù)滅菌的器械，我們計(jì)劃先審查其生產(chǎn)設(shè)施再授予510(k)許可。對(duì)于采用這些滅菌技術(shù)滅菌的器械，審查其生產(chǎn)設(shè)施將有助于確保這些器械的安全性和有效性，降低其對(duì)人體健康帶來(lái)的風(fēng)險(xiǎn)。III.適用范圍本指南的適用范圍僅限于采用基于微生物滅活的行業(yè)最終滅菌工藝滅菌的無(wú)菌類器械的510(k)審查。此處所述滅菌流程的實(shí)例包括輻射滅菌、蒸汽滅菌、EO滅菌和新滅菌工藝。例外本指南不包括下述情況：1本身屬于受510(k)管制的醫(yī)療器械的滅菌器 , ?。2基于微生物排除而非微生物滅活的工藝不屬于本指南的討論范圍。微生物排除工藝的實(shí)例包括藥品生產(chǎn)中常用的無(wú)菌過(guò)濾法和無(wú)菌操作。3計(jì)劃對(duì)含動(dòng)物來(lái)源材料（即：人體或動(dòng)物組織）的醫(yī)療器械進(jìn)行滅菌的工藝不屬于本指南的討論范圍。對(duì)于含人體或動(dòng)物來(lái)源材料的器械，我們建議聯(lián)系負(fù)責(zé)審查該器械的分部來(lái)討論相應(yīng)的問(wèn)題。為了協(xié)助申辦方解決與病毒污染有關(guān)的顧慮或者問(wèn)題，我們建議參閱美國(guó)藥典（USP）<1050>和相關(guān)文件。4涉及液體化學(xué)滅菌器的工藝。5一次性器械再生處理的工藝。見(jiàn)“2002年醫(yī)療器械用戶收費(fèi)和現(xiàn)代化法案，再生處理后的一次性醫(yī)療器械的上市前通告(510(k)申報(bào)資料中的驗(yàn)證數(shù)據(jù)”（見(jiàn) //www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071434.htm）。6關(guān)于醫(yī)療機(jī)構(gòu)再生處理后的可重復(fù)使用器械（以及需要在醫(yī)療機(jī)構(gòu)進(jìn)一步滅菌的非無(wú)菌一次性器械）的清潔、消毒和滅菌的信息。見(jiàn) “醫(yī)療機(jī)構(gòu)中醫(yī)療器械的再生：驗(yàn)證方法和貼標(biāo)”（見(jiàn) //www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM253010.pdf ）。最后，F(xiàn)DA指出，生產(chǎn)過(guò)程中采用的滅菌方法應(yīng)滿足FDA的質(zhì)量系統(tǒng)（QS）法規(guī)要求，21 CFR 820部分。IV.滅菌方法FDA認(rèn)為，目前生產(chǎn)過(guò)程中用來(lái)滅菌醫(yī)療器械的滅菌方法有兩類：成熟方法和新方法。下文將定義這些工藝，并給出了每個(gè)類別的實(shí)例。A.成熟的滅菌方法：1.成熟A類：這些方法有較長(zhǎng)的應(yīng)用歷史，有多種渠道來(lái)源的信息可證明其安全有效，例如大量的文獻(xiàn)、510(k)許可或者上市前批準(zhǔn)（PMA）申請(qǐng)獲批以及令人滿意的QS檢查結(jié)果。對(duì)于成熟方法，例如干熱滅菌、EO、蒸汽滅菌和輻射滅菌，其開(kāi)發(fā)、驗(yàn)證和常規(guī)控制已有自發(fā)制定的共識(shí)標(biāo)準(zhǔn)，且已獲得FDA認(rèn)可。?成熟A類滅菌方法實(shí)例：?干熱滅菌?將器械置于固定的剛性容器中進(jìn)行EO滅菌?濕熱或蒸汽滅菌?輻射滅菌（例如：?射線、電子束）2.成熟B類：還有一些其他的成熟方法不存在已獲FDA認(rèn)可的專門(mén)的共識(shí)標(biāo)準(zhǔn)，但可獲得已發(fā)表的關(guān)于其開(kāi)發(fā)、驗(yàn)證和常規(guī)控制的信息。對(duì)于采用離散周期參數(shù)的具體滅菌器，如果FDA之前已評(píng)價(jià)了其滅菌開(kāi)發(fā)和驗(yàn)證數(shù)據(jù)，且認(rèn)為其驗(yàn)證方法是充分的，則我們將這些方法視為成熟B類。成熟B類滅菌方法實(shí)例：?過(guò)氧化氫（H2O2）?臭氧（O3）?柔性袋系統(tǒng)（例如：EO置于柔性袋系統(tǒng)中、擴(kuò)散法、注射法）然而，對(duì)于FDA尚未評(píng)估過(guò)的具體工藝，如果已獲FDA許可的滅菌器的參數(shù)發(fā)生了改變，或者之前已獲許可或批準(zhǔn)的申報(bào)資料中工藝驗(yàn)證數(shù)據(jù)并未被評(píng)估且認(rèn)為是充分的，則我們將這些方法視為新方法。B. 新滅菌方法：該類別指的是新開(kāi)發(fā)的方法，相關(guān)的已發(fā)表信息極少或不存在，F(xiàn)DA尚未全面評(píng)估滅菌開(kāi)發(fā)和驗(yàn)證數(shù)據(jù)（即尚未授予采用此類方法滅菌的器械510(k)許可或者批準(zhǔn)PMA），而且關(guān)于其開(kāi)發(fā)、驗(yàn)證和常規(guī)控制，并不存在已獲FDA認(rèn)可的專門(mén)的共識(shí)標(biāo)準(zhǔn)。新滅菌方法指的是尚未被FDA審查并認(rèn)為其足以有效滅菌相應(yīng)器械使其適用于預(yù)期用途的方法。如果某種滅菌方法采用的化學(xué)試劑尚未作為化學(xué)滅菌劑獲得FDA許可或批準(zhǔn)，或者在科學(xué)文獻(xiàn)中查找不到其作為化學(xué)滅菌劑使用的證據(jù)，則該滅菌方法被視為新方法。另外，如果某種滅菌方法同時(shí)使用多種化學(xué)試劑，而這種組合方式尚未作為滅菌劑獲得FDA許可或批準(zhǔn)，那么該滅菌方法被視為新方法，即使該組合方式中的每種化學(xué)試劑單獨(dú)使用時(shí)均作為化學(xué)滅菌劑獲得FDA許可或批準(zhǔn)。對(duì)于FDA尚未評(píng)估過(guò)的具體工藝，如果已獲FDA許可的滅菌器的參數(shù)發(fā)生了改變，或者之前已獲許可或批準(zhǔn)的申報(bào)資料中工藝驗(yàn)證數(shù)據(jù)并未被評(píng)估且認(rèn)為是充分的，F(xiàn)DA將這些方法也視為新方法。?新滅菌方法實(shí)例：?過(guò)氧乙酸蒸氣?高強(qiáng)度光或者脈沖光?微波輻射?聲波?紫外線V.無(wú)菌類器械的滅菌信息A.成熟滅菌方法申辦方應(yīng)該確保510(k)申報(bào)資料中包括所有下述信息。1.關(guān)于滅菌方法，申辦方應(yīng)該提供以下信息：a.關(guān)于滅菌方法的描述；b.關(guān)于滅菌腔的描述，如果不是剛性、固定腔體的話（例如：柔性袋）；c.關(guān)于章節(jié)IV.A.2.中描述的那些方法（成熟B類）：?如果滅菌器已獲510(k)許可，則提供510(k)編號(hào)以及滅菌器的品牌（即生產(chǎn)商）和型號(hào)。另外，申報(bào)資料中應(yīng)該指明已獲許可的滅菌器的周期參數(shù)是否發(fā)生了變化；?如果滅菌器尚未獲得510(k)許可，則應(yīng)該指明這一點(diǎn)；?如果該滅菌方法已經(jīng)進(jìn)行過(guò)評(píng)估，即采用該方法滅菌的器械已獲得510(k)許可或者PMA批準(zhǔn)或者HDE，則指明之前評(píng)估該方法的申報(bào)資料編號(hào)或者含有該信息的器械主文件。另外，申報(bào)資料中應(yīng)該指明之前已獲許可或批準(zhǔn)的申報(bào)資料中描述的周期參數(shù)是否發(fā)生了變化；d. 滅菌位置；e.關(guān)于輻射滅菌，應(yīng)指明輻射劑量；f. 關(guān)于化學(xué)滅菌劑（例如：EO、H2O2），應(yīng)指明器械上該滅菌劑的最大殘留量，并解釋對(duì)于相應(yīng)的器械類型和預(yù)期患者接觸時(shí)間而言，為什么這種殘留水平是可以接受的。關(guān)于EO滅菌，CDRH已經(jīng)接受了基于已獲認(rèn)可的現(xiàn)行版標(biāo)準(zhǔn)“AAMI/ANSI/ISO 10993-7醫(yī)療器械的生物學(xué)評(píng)價(jià)—第7部分：環(huán)氧乙烷滅菌殘留量”測(cè)定的EO殘留量信息。?2. 關(guān)于該滅菌方法，申辦方應(yīng)該描述用來(lái)驗(yàn)證滅菌周期的方法（例如：半周期法），而不是驗(yàn)證數(shù)據(jù)本身。申報(bào)資料中還應(yīng)該指明采用的所有相關(guān)的共識(shí)標(biāo)準(zhǔn)，并闡明產(chǎn)品未能滿足這些標(biāo)準(zhǔn)中哪些方面的要求。如果沒(méi)有已獲認(rèn)可的標(biāo)準(zhǔn)，則應(yīng)該提交關(guān)于該滅菌工藝的全面描述和完整的驗(yàn)證方案，以供審查。3. 對(duì)于無(wú)菌類器械，申辦方應(yīng)該指明其無(wú)菌保證水平（SAL）為10-6，除非預(yù)期該器械僅接觸完整皮膚。關(guān)于預(yù)期僅接觸完整皮膚的器械，F(xiàn)DA推薦的SAL為10-3。關(guān)于替代SAL的問(wèn)題，我們建議直接咨詢FDA，申報(bào)前與FDA召開(kāi)會(huì)議進(jìn)行討論。4.致熱原性檢測(cè)有助于保護(hù)患者免遭革蘭氏陰性菌內(nèi)毒素或者其他來(lái)源致熱原（例如：材料相關(guān)的致熱原）引起的發(fā)熱反應(yīng)。為了解決細(xì)菌內(nèi)毒素的問(wèn)題，下述類別下的器械應(yīng)該滿足致熱原限值標(biāo)準(zhǔn)：?植入物；?與心血管系統(tǒng)、淋巴系統(tǒng)或者腦脊液直接或間接接觸的器械，包括涉及類似全身暴露的器械；或者?被標(biāo)記為不具有致熱原性的器械。注意：機(jī)構(gòu)建議采用“不具有致熱原性”或者“滿足致熱原限值標(biāo)準(zhǔn)”的說(shuō)法來(lái)代替“無(wú)致熱原”，除非可以證明致熱原已被徹底清除。另外，對(duì)于應(yīng)該滿足致熱原限值標(biāo)準(zhǔn)的器械，我們建議在標(biāo)簽中指明該器械不具有致熱原性。??申辦方應(yīng)該提供下述信息：a.描述用來(lái)確定器械滿足致熱原限值標(biāo)準(zhǔn)的方法（例如：細(xì)菌內(nèi)毒素檢測(cè)（BET），又被稱為鱟試劑（LAL）檢測(cè)）；b.聲明將針對(duì)每批產(chǎn)品進(jìn)行內(nèi)毒素檢測(cè)，或者如果不如此做的話，按照下述FDA指南的建議，提供關(guān)于中間檢測(cè)和/或成品放行中采用的采樣計(jì)劃的信息：致熱原和內(nèi)毒素檢測(cè)：?jiǎn)柎?”（//www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf）；c.指明選定的檢測(cè)限值；和d.解釋為什么選擇這樣的內(nèi)毒素限值。關(guān)于一般的醫(yī)療器械，我們推薦的內(nèi)毒素限值為BET：20內(nèi)毒素單位（EU）/器械；對(duì)于接觸腦脊液的器械，我們推薦的內(nèi)毒素限值為BET：2.15 EU/器械。請(qǐng)參考：?USP <161>：輸血和輸注組件和相似的醫(yī)療器械?ANSI/AAMI ST72:2011細(xì)菌內(nèi)毒素 – 試驗(yàn)方法、常規(guī)監(jiān)測(cè)以及批檢測(cè)的替代方法?FDA的指南“致熱原和內(nèi)毒素檢測(cè)：?jiǎn)柎稹?（見(jiàn) //www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf）申辦方還應(yīng)該清楚，除革蘭氏陰性菌之外，還有其他的致熱原來(lái)源。材料相關(guān)的致熱原指的是從醫(yī)療器械中濾出的化學(xué)物質(zhì)，傳統(tǒng)做法是在生物相容性評(píng)估中來(lái)解決這一問(wèn)題。由于人體接觸的性質(zhì)，有些器械無(wú)需滿足致熱原限值標(biāo)準(zhǔn)，但打算將其標(biāo)記為“不具有致熱原性”，對(duì)于這類器械，我們建議進(jìn)行細(xì)菌內(nèi)毒素以及材料相關(guān)的致熱源性檢測(cè) 。關(guān)于器械的具體問(wèn)題，請(qǐng)聯(lián)系相關(guān)的審查分部，因?yàn)椴煌愋推餍档南拗狄笫遣煌摹?/span>?5. 申辦方應(yīng)該描述產(chǎn)品包裝（無(wú)菌屏障系統(tǒng)）以及該包裝如何維持器械的無(wú)菌性，并描述包裝檢測(cè)方法，但無(wú)需描述包裝檢測(cè)數(shù)據(jù) 。B. 新滅菌方法除上文第V.A節(jié)指明的信息外，對(duì)于所有的新滅菌方法，申辦方還應(yīng)該在510(k)中提供下述信息：1關(guān)于滅菌工藝的全面描述；2用來(lái)驗(yàn)證該滅菌周期的方法（例如：半周期法）；3驗(yàn)證方案；和4滅菌驗(yàn)證數(shù)據(jù)。申報(bào)資料中還應(yīng)該指明所有適用的已發(fā)表的科學(xué)文獻(xiàn)。關(guān)于新滅菌方法，根據(jù)申報(bào)的具體器械，F(xiàn)DA可能還會(huì)要求提供更多的信息。

Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile Guidance for Industry and Food and Drug Administration Staff

Document issued on January 21, 2016.?The draft of this document was issued on December 12, 2008.As of March 21, 2016, this document supersedes “Updated 510(k) Sterility Review Guidance K90-1” issued August 30, 2002.This guidance has been updated March 16, 2016 to correct an inadvertent editorial change regarding reporting of endotoxin limits.

For questions about this document regarding CDRH-regulated devices, contact the Infection Control Devices Branch (INCB) at 301-796-5580.?

For questions about this document regarding CBER-regulated devices, contact CBER’s Office of Communication, Outreach, and Development (OCOD) at 1-800-835-4709 or 240-402-8010.

U.S. Department of Health and Human Services?Food and Drug Administration?Center for Devices and Radiological Health?Center for Biologics Evaluation and Research
Preface?Public Comment?You may submit electronic comments and suggestions at any time for Agency consideration to //www.regulations.gov. Submit written comments to the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852. Identify all comments with the docket number FDA–2008–D–0611. Comments may not be acted upon by the Agency until the document is next revised or updated.
Additional CopiesCDRHAdditional copies are available from the Internet. You may also send an e-mail request to CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document number 1615 to identify the guidance you are requesting.?CBERAdditional copies of this guidance document are also available from the Center for Biologics Evaluation and Research (CBER) by written request, Office of Communication, Outreach, and Development (OCOD), 10903 New Hampshire Ave., WO71, Room 3128, Silver Spring, MD 20993-0002, or by calling, 1-800-835-4709 or 240-402-8010, by email, ocod@fda.hhs.gov, or from the Internet at //www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm.
Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile Guidance for Industry and Food and Drug Administration Staff
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff or Office responsible for this guidance as listed on the title page.
I. Introduction?This guidance document updates and clarifies the information regarding sterilization processes that we recommend sponsors include in 510(k)s for devices labeled as sterile. This guidance document also provides details about the pyrogenicity information that we recommend sponsors include in a 510(k) submission. For the current edition of the FDA-recognized standards referenced in this document, see the FDA Recognized Consensus Standards Database Web site at //www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm.FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
II. BackgroundIn recent years, FDA has received an increasing number of 510(k)s for devices labeled as sterile that use sterilization methods other than the traditionally used methods of steam, dry heat, ethylene oxide (EO), and radiation. FDA has experience with other methods, such as hydrogen peroxide, ozone and flexible bag systems, and now considers them to be established methods. However, we recognize that there may be alterations to the more recently developed methods, as well as original, innovative sterilization technologies, which are being developed and proposed for use in the manufacture of class I and class II devices. FDA considers these to be novel?methods. (The terms established and novel are defined in Section IV below.)?Under section 513(f)(5) of the Federal Food, Drug, and Cosmetic Act (the act), FDA may not withhold 510(k) clearance for failure to comply with any provision of the act unrelated to a substantial equivalence decision, including failure to comply with Good Manufacturing Practice (GMP),1 unless FDA finds that there is a substantial likelihood that failure to comply with the provision “will potentially present a serious risk to human health.” We believe that novel sterilization technologies carry a substantial risk of inadequate sterility assurance if not conducted properly. Consequently, compliance with GMP for devices sterilized using these technologies should be closely evaluated. Failure to assure sterility presents a serious risk to human health because of the risk of infection. Therefore, we intend to inspect the manufacturing facility before clearing a 510(k) for a device that is sterilized by a novel sterilization process. Inspecting the manufacturing facility for devices sterilized using these sterilization technologies will help ensure the safety and effectiveness of these devices and mitigate the risks to human health.

III. Scope?The scope of this guidance is limited to the review of 510(k)s for devices labeled as sterile that are subject to industrial terminal sterilization processes based on microbial inactivation. Examples of these processes include radiation, steam, EO, and new technology sterilization processes.
Exclusions?The following are excluded from this guidance:?1. Sterilizers that are themselves medical devices subject to 510(k).?2. Processes that rely on microbial exclusion, rather than microbial inactivation, are outside the scope of this guidance. Examples of microbial exclusion processes include sterilizing filtration methods and aseptic processing, commonly used in pharmaceutical manufacturing.?3. Processes intended to sterilize medical devices that incorporate materials of animal origin (i.e., human or animal tissues) are outside the scope of this guidance. We recommend contacting the branch responsible for the review of your device to discuss questions about devices that contain materials of human or animal origin. To assist sponsors in addressing the concerns or issues related to viral contamination, we recommend review of UnitedStates Pharmacopeia (USP) <1050> and related documents.4. Processes that incorporate the use of liquid chemical sterilants.5. Processes intended to be used by reprocessors of single-use devices. See “Medical Device User Fee and Modernization Act of 2002, Validation Data in Premarket Notification Submissions (510(k)s) for Reprocessed Single-Use Medical Devices” (available at //www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocument s/ucm071434.htm).?6. Information on the cleaning, disinfecting, and sterilizing of reusable devices that are reprocessed at healthcare facilities (and for single-use devices that are provided nonsterile for further sterilization at healthcare facilities). See “Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling” (available at //www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc eDocuments/UCM253010.pdf).
Finally, FDA notes that the sterilization methods used in manufacturing settings are subject to FDA’s Quality System (QS) regulation requirements, 21 CFR Part 820.
IV. Methods of Sterilization?FDA considers there to be two categories of sterilization methods currently used to sterilize medical devices in manufacturing settings: established and novel. 5 These processes are defined below, and examples are provided for each category.
A. Established Sterilization Methods:1. Established Category A: These are methods that have a long history of safe and effective use as demonstrated through multiple sources of information such as ample literature, clearances of 510(k)s or approvals of premarket approval (PMA) applications, and satisfactory QS inspections. For established methods such as dry heat, EO, steam, and radiation, there are voluntary consensus standards for development, validation, and routine control that are recognized by FDA.6Examples of these Established Category A Sterilization Methods:?· Dry heat· EO with devices in a fixed, rigid chamber· Moist heat or steam?· Radiation (e.g., gamma, electron beam)

2. Established Category B: There are other established methods for which there are no FDA-recognized dedicated consensus standards, but for which published information on development, validation, and routine control is available. In cases where FDA has previously evaluated sterilization development and validation data for specific sterilizers using discrete cycle parameters and determined the validation methods to be adequate, 7 we consider these to be Established Category B.Examples of these Established Category B Sterilization Methods:?· Hydrogen peroxide (H2O2)?· Ozone (O3)?· Flexible bag systems (e.g., EO in a flexible bag system, diffusion method, injection method)However, for those cases where the specific process does not appear to have been evaluated by FDA, either because the parameters of an FDA-cleared sterilizer have been altered, or because process validation data have not been evaluated and found to be adequate in previous cleared or approved submissions, we consider these methods to be novel.
B. Novel Sterilization Methods:These are newly developed methods for which there exists little or no published information, no history of comprehensive FDA evaluation of sterilization development and validation data through an FDA-cleared 510(k) or approved PMA for devices sterilized with such methods, and no FDA-recognized dedicated consensus standards on development, validation, and routine control. A Novel Sterilization Method is a method that FDA has not reviewed and determined to be adequate to effectively sterilize the device for its intended use.
A sterilization method that uses chemical(s) that have not been previously cleared or approved by FDA as a chemical sterilant or has not been identified in the scientific literature as a chemical sterilant would be considered novel. In addition, a sterilization method that uses a combination of chemicals, and the combination has not been previously cleared or approved by FDA as a sterilant, would be considered novel even if the individual chemicals in the combination have been previously cleared or approved independently as chemical sterilants. FDA also considers methods where the specific?process does not appear to have been evaluated by FDA, either because the parameters of an FDA-cleared sterilizer have been altered, or because process validation data have not been evaluated and found to be adequate in previous cleared or approved submissions, to be novel.
Examples of Novel Sterilization Methods:?· Vaporized peracetic acid?· High intensity light or pulse light?· Microwave radiation · Sound waves?· Ultraviolet light
V. Sterilization Information for Devices Labeled as Sterile?A. Established Sterilization MethodsSponsors should ensure that a 510(k) submission includes all of the information outlined below.1. For the sterilization method, the sponsor should provide the following:a. a description of the sterilization method;?b. a description of the sterilization chamber if not rigid, fixed (e.g., flexible bag);?c. for those methods described in Section IV.A.2. (Established Category B):?· if the sterilizer has received 510(k) clearance, 8 the 510(k) number, and the make (i.e., manufacturer) and model of the sterilizer. Additionally, the submission should state whether or not the cycles for which the sterilizer was granted clearance have been altered;?· if the sterilizer has not received 510(k) clearance, this should be stated;?· if the sterilization method has been evaluated through clearance of a 510(k) or approval of a PMA or HDE for a device using that method, the submission number where the method was previously evaluated or the identification of a Device Master File9 containing this information. Additionally, the submission should state whether or not the cycles that were previously evaluated in the cleared or approved submission have been altered;?d. the sterilization site;e. in the case of radiation sterilization, the radiation dose;?f. for chemical sterilants (e.g., EO, H2O2), the maximum levels of sterilant residuals that remain on the device, and an explanation of why those levels are acceptable for the device type and the expected duration of patient contact.
In the case of EO sterilization, CDRH has accepted EO residuals information based on the currently recognized version of the standard, “AAMI/ANSI/ISO 10993-7, Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide Sterilization Residuals.”
2. For the sterilization method, the sponsor should provide a description of the method used to validate the sterilization cycle (e.g., the half-cycle method) but not the validation data itself. The submission should also identify all relevant consensus standards used and identify any aspects of the standards that were not met. In the absence of a recognized standard, a comprehensive description of the process and the complete validation protocol should be submitted and reviewed.?3. The sponsor should state the sterility assurance level (SAL) of 10-6 for devices labeled as sterile unless the device is intended only for contact with intact skin. FDA recommends a SAL of 10-3 for devices intended only for contact with intact skin. For questions related to alternative SALs, we recommend direct consultation and pre-submission meetings with FDA. 11?4. Pyrogenicity testing is used to help protect patients from the risk of febrile reaction due to either gram-negative bacterial endotoxins or other sources of pyrogens (e.g., material-mediated pyrogens). To address the presence of bacterial endotoxins, devices that fall under the following categories should meet pyrogen limit specifications:· implants;?· devices in contact directly or indirectly with the cardiovascular system, the lymphatic system, or cerebrospinal fluid, including devices that are present for similar systemic exposure; or?· devices labeled non-pyrogenic.
Note: The Agency recommends use of the expressions “non-pyrogenic” or “meets pyrogen limit specifications” instead of “pyrogen free,” unless the complete removal of pyrogens can be established. In addition, for devices that should meet pyrogen limit specifications, we recommend the labeling state that the device is non-pyrogenic.
The sponsor should provide the information outlined below:a. a description of the method used to make the determination that the device meets pyrogen limit specifications (e.g., bacterial endotoxins test (BET), also known as the Limulus amebocyte lysate (LAL) test);?b. a statement confirming that endotoxin testing will be conducted on every batch or if not, information regarding the sampling plan used for inprocess testing and/or finished product release, as recommended in the FDA guidance, Pyrogen and Endotoxins Testing: Questions and Answers” (//www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryIn formation/Guidances/UCM310098.pdf);?c. identification of the chosen testing limit; and?d. an explanation supporting the selected endotoxin limit.
We recommend the following endotoxin limits for the BET: 20 endotoxin units (EU)/Device for general medical devices (e.g., blood contacting and/or implanted) and 2.15 EU/Device for devices that contact cerebrospinal fluid. See:· USP <161>, Transfusion and Infusion Assemblies and Similar Medical Devices?· ANSI/AAMI ST72:2011, Bacterial endotoxins – Test methods, routine monitoring, and alternatives to batch testing?· FDA’s guidance “Pyrogen and Endotoxins Testing: Questions and Answers” (available at //www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInf ormation/Guidances/UCM310098.pdf)
Sponsors should also be aware that there are additional sources of pyrogens beyond gram-negative bacteria. Material-mediated pyrogens are chemicals that can leach from a medical device and are traditionally addressed as part of the biocompatibility assessment.?
For devices that do not need to meet pyrogen limit specifications because of the nature of body contact, but are intended to be labeled as “non-pyrogenic,” we recommend that both bacterial endotoxin and material mediated pyrogenicity testing be conducted.12 For device-specific questions, please contact the relevant review branch as limits vary for specific device types.
5. The sponsor should provide a description of the packaging (sterile barrier system) and how it will maintain the device’s sterility, and a description of the package test methods, but not package test data.
B. Novel Sterilization Methods?In addition to the information identified in Section V.A above, the sponsor should provide the following information in a 510(k) for all novel sterilization methods:1. a comprehensive description of the sterilization process;?2. the method used to validate the sterilization cycle (e.g., the half-cycle method);?3. the validation protocol; and?4. the sterilization validation data. The submission should also identify any applicable published scientific literature. For novel sterilization methods, FDA may also request additional information based on the specific device submitted for review.

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