行業和FDA人員指南
關于本指南，如果有關于受CDRH監管的器械的問題，請通過301-796-5580聯系感染控制器械分部（INCB）。關于本指南，如果有關于受CBER監管的器械的問題，請通過1-800-835-4709或者240-402-8010聯系CBER的溝通、推廣和發展辦公室（OCOD）。
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美國衛生和人類服務部
美國食品藥品監督管理局
醫療器械和放射衛生中心
生物學評價和研究中心
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前言
如有任何意見和建議，可隨時提交至//www.regulations.gov，供FDA參考。將書面意見提交至食品藥品監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才會對這些意見作出答復。其他副本CDRH可從網站上獲得更多拷貝。您也可以發送電子郵件至CDRH-Guidance@fda.hhs.gov，申請一份指南副本。請采用文件編號1615指明您申請的指南。CBER您也可以采用書面申請的方式通過以下途徑從生物制品評價和研究中心（CBER）獲取更多的本指南副本：寫信至溝通、推廣和發展辦公室（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；發送電子郵件至ocod@fda.hhs.gov；或者通過網站//www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm。
無菌類器械上市前通告(510(k))申報中關于無菌證明資料的提交及審查
行業和FDA人員指南
本指南代表了食品藥品監督管理局（FDA或者機構）目前在該問題上的看法。該文件并未賦予任何人任何權利，也不可用來約束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，請聯系標題頁上列出的負責本指南的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菌類器械510(k)中應該包括的關于滅菌過程的信息。本指南還詳細描述了我們建議申辦方在510(k)申報資料中包括的致熱原性信息。關于本文件中引用的、已被FDA認可的標準的現行版，請訪問FDA認可的共識標準數據庫網站//www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm。FDA的指南文件，包括本指南，并不具備法規強制性。相反地，指南描述的是機構目前在某個問題上的看法，僅應該被視為推薦意見，除非引用了具體的法規或者法令要求。機構指南中詞語“應該”的使用意味著我們建議或者推薦進行某項活動，但并不是強制要求進行某項活動。II.背景近年來，FDA收到的無菌類器械510(k)中，有越來越多的器械采用的滅菌方法不同于傳統滅菌方法，即蒸汽滅菌、干熱滅菌、環氧乙烷（EO）滅菌和輻射滅菌。FDA對其他方法，例如過氧化氫、臭氧和柔性袋系統，也有一定的經驗，目前將這些方法視為成熟方法。然而，我們認識到新近開發出來的方法可能會發生變化，目前也正在開發全新的滅菌技術并且計劃將其用于I類和II類器械的生產。FDA將這些方法視為新方法。（術語“成熟”和“新”的定義見下文第IV節。）根據聯邦食品藥品和化妝品法案（下文稱法案）章節513(f)(5)所述，如果不滿足法案中與實質等同性決議無關的任何條款，包括不滿足生產質量管理規范（GMP） ，FDA可能不會拒絕授予510(k)許可，除非FDA發現產品不滿足該條款極有可能“對人體健康帶來嚴重風險”。我們相信，如果執行不到位，新滅菌技術有重大的滅菌不充分風險。因此，應該認真評估采用這些技術滅菌的器械是否遵循GMP的要求進行生產。如果無法確保產品的無菌性，則會對人體健康造成嚴重的風險，因為存在感染風險。因此，對于采用新滅菌技術滅菌的器械，我們計劃先審查其生產設施再授予510(k)許可。對于采用這些滅菌技術滅菌的器械，審查其生產設施將有助于確保這些器械的安全性和有效性，降低其對人體健康帶來的風險。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最終滅菌工藝滅菌的無菌類器械的510(k)審查。此處所述滅菌流程的實例包括輻射滅菌、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例包括藥品生產中常用的無菌過濾法和無菌操作。3計劃對含動物來源材料（即：人體或動物組織）的醫療器械進行滅菌的工藝不屬于本指南的討論范圍。對于含人體或動物來源材料的器械，我們建議聯系負責審查該器械的分部來討論相應的問題。為了協助申辦方解決與病毒污染有關的顧慮或者問題，我們建議參閱美國藥典（USP）<1050>和相關文件。4涉及液體化學滅菌器的工藝 。5一次性器械再生處理的工藝。見“2002年醫療器械用戶收費和現代化法案，再生處理后的一次性醫療器械的上市前通告(510(k)申報資料中的驗證數據”（見 //www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071434.htm）。6關于醫療機構再生處理后的可重復使用器械（以及需要在醫療機構進一步滅菌的非無菌一次性器械）的清潔、消毒和滅菌的信息。見 “醫療機構中醫療器械的再生：驗證方法和貼標”（見 //www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM253010.pdf ）。最后，FDA指出，生產過程中采用的滅菌方法應滿足FDA的質量系統（QS）法規要求，21 CFR 820部分。IV.滅菌方法FDA認為，目前生產過程中用來滅菌醫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，并給出了每個類別的實例。A.成熟的滅菌方法：1.成熟A類：這些方法有較長的應用歷史，有多種渠道來源的信息可證明其安全有效，例如大量的文獻、510(k)許可或者上市前批準（PMA）申請獲批以及令人滿意的QS檢查結果。對于成熟方法，例如干熱滅菌、EO、蒸汽滅菌和輻射滅菌，其開發、驗證和常規控制已有自發制定的共識標準，且已獲得FDA認可 。?成熟A類滅菌方法實例：?干熱滅菌?將器械置于固定的剛性容器中進行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認可的專門的共識標準，但可獲得已發表的關于其開發、驗證和常規控制的信息。對于采用離散周期參數的具體滅菌器，如果FDA之前已評價了其滅菌開發和驗證數據，且認為其驗證方法是充分的 ，則我們將這些方法視為成熟B類。成熟B類滅菌方法實例：?過氧化氫（H2O2）?臭氧（O3）?柔性袋系統（例如：EO置于柔性袋系統中、擴散法、注射法）然而，對于FDA尚未評估過的具體工藝，如果已獲FDA許可的滅菌器的參數發生了改變，或者之前已獲許可或批準的申報資料中工藝驗證數據并未被評估且認為是充分的，則我們將這些方法視為新方法。B. 新滅菌方法：該類別指的是新開發的方法，相關的已發表信息極少或不存在，FDA尚未全面評估滅菌開發和驗證數據（即尚未授予采用此類方法滅菌的器械510(k)許可或者批準PMA），而且關于其開發、驗證和常規控制，并不存在已獲FDA認可的專門的共識標準。新滅菌方法指的是尚未被FDA審查并認為其足以有效滅菌相應器械使其適用于預期用途的方法。如果某種滅菌方法采用的化學試劑尚未作為化學滅菌劑獲得FDA許可或批準，或者在科學文獻中查找不到其作為化學滅菌劑使用的證據，則該滅菌方法被視為新方法。另外，如果某種滅菌方法同時使用多種化學試劑，而這種組合方式尚未作為滅菌劑獲得FDA許可或批準，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試劑單獨使用時均作為化學滅菌劑獲得FDA許可或批準。對于FDA尚未評估過的具體工藝，如果已獲FDA許可的滅菌器的參數發生了改變，或者之前已獲許可或批準的申報資料中工藝驗證數據并未被評估且認為是充分的，FDA將這些方法也視為新方法。?新滅菌方法實例：?過氧乙酸蒸氣?高強度光或者脈沖光?微波輻射?聲波?紫外線V.無菌類器械的滅菌信息A.成熟滅菌方法申辦方應該確保510(k)申報資料中包括所有下述信息。1.關于滅菌方法，申辦方應該提供以下信息：a.關于滅菌方法的描述；b.關于滅菌腔的描述，如果不是剛性、固定腔體的話（例如：柔性袋）；c.關于章節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)編號以及滅菌器的品牌（即生產商）和型號。另外，申報資料中應該指明已獲許可的滅菌器的周期參數是否發生了變化；?如果滅菌器尚未獲得510(k)許可，則應該指明這一點；?如果該滅菌方法已經進行過評估，即采用該方法滅菌的器械已獲得510(k)許可或者PMA批準或者HDE，則指明之前評估該方法的申報資料編號或者含有該信息的器械主文件 。另外，申報資料中應該指明之前已獲許可或批準的申報資料中描述的周期參數是否發生了變化；d. 滅菌位置 ；e.關于輻射滅菌，應指明輻射劑量；f. 關于化學滅菌劑（例如：EO、H2O2），應指明器械上該滅菌劑的最大殘留量，并解釋對于相應的器械類型和預期患者接觸時間而言，為什么這種殘留水平是可以接受的。關于EO滅菌，CDRH已經接受了基于已獲認可的現行版標準“AAMI/ANSI/ISO 10993-7醫療器械的生物學評價—第7部分：環氧乙烷滅菌殘留量”測定的EO殘留量信息。?2. 關于該滅菌方法，申辦方應該描述用來驗證滅菌周期的方法（例如：半周期法），而不是驗證數據本身。申報資料中還應該指明采用的所有相關的共識標準，并闡明產品未能滿足這些標準中哪些方面的要求。如果沒有已獲認可的標準，則應該提交關于該滅菌工藝的全面描述和完整的驗證方案，以供審查。3. 對于無菌類器械，申辦方應該指明其無菌保證水平（SAL）為10-6，除非預期該器械僅接觸完整皮膚。關于預期僅接觸完整皮膚的器械，FDA推薦的SAL為10-3。關于替代SAL的問題，我們建議直接咨詢FDA，申報前與FDA召開會議進行討論 。4.致熱原性檢測有助于保護患者免遭革蘭氏陰性菌內毒素或者其他來源致熱原（例如：材料相關的致熱原）引起的發熱反應。為了解決細菌內毒素的問題，下述類別下的器械應該滿足致熱原限值標準：?植入物；?與心血管系統、淋巴系統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?被標記為不具有致熱原性的器械。注意：機構建議采用“不具有致熱原性”或者“滿足致熱原限值標準”的說法來代替“無致熱原”，除非可以證明致熱原已被徹底清除。另外，對于應該滿足致熱原限值標準的器械，我們建議在標簽中指明該器械不具有致熱原性。??申辦方應該提供下述信息：a.描述用來確定器械滿足致熱原限值標準的方法（例如：細菌內毒素檢測（BET），又被稱為鱟試劑（LAL）檢測）；b.聲明將針對每批產品進行內毒素檢測，或者如果不如此做的話，按照下述FDA指南的建議，提供關于中間檢測和/或成品放行中采用的采樣計劃的信息：致熱原和內毒素檢測：問答 ”（//www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf）；c.指明選定的檢測限值；和d.解釋為什么選擇這樣的內毒素限值。關于一般的醫療器械，我們推薦的內毒素限值為BET：20內毒素單位（EU）/器械；對于接觸腦脊液的器械，我們推薦的內毒素限值為BET：2.15 EU/器械。請參考：?USP <161>：輸血和輸注組件和相似的醫療器械?ANSI/AAMI ST72:2011細菌內毒素 – 試驗方法、常規監測以及批檢測的替代方法?FDA的指南“致熱原和內毒素檢測：問答” （見 //www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf）申辦方還應該清楚，除革蘭氏陰性菌之外，還有其他的致熱原來源。材料相關的致熱原指的是從醫療器械中濾出的化學物質，傳統做法是在生物相容性評估中來解決這一問題。由于人體接觸的性質，有些器械無需滿足致熱原限值標準，但打算將其標記為“不具有致熱原性”，對于這類器械，我們建議進行細菌內毒素以及材料相關的致熱源性檢測 。關于器械的具體問題，請聯系相關的審查分部，因為不同類型器械的限值要求是不同的。?5. 申辦方應該描述產品包裝（無菌屏障系統）以及該包裝如何維持器械的無菌性，并描述包裝檢測方法，但無需描述包裝檢測數據 。B. 新滅菌方法除上文第V.A節指明的信息外，對于所有的新滅菌方法，申辦方還應該在510(k)中提供下述信息：1關于滅菌工藝的全面描述；2用來驗證該滅菌周期的方法（例如：半周期法）；3驗證方案；和4滅菌驗證數據。申報資料中還應該指明所有適用的已發表的科學文獻。關于新滅菌方法，根據申報的具體器械，FDA可能還會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.
