【分享】FDA通用程序指导原则：无菌类器械上市前通告(510(k))申报中关于无菌证明资料的提交及审查
【分享】FDA通用程序指导原则：无菌类器械上市前通告(510(k))申报中关于无菌证明资料的提交及审查
行业和FDA人员指南
关于本指南，如果有关于受CDRH监管的器械的问题，请通过301-796-5580联系感染控制器械分部（INCB）。关于本指南，如果有关于受CBER监管的器械的问题，请通过1-800-835-4709或者240-402-8010联系CBER的沟通、推广和发展办公室（OCOD）。
美国卫生和人类服务部
美国食品药品监督管理局
医疗器械和放射卫生中心
生物学评价和研究中心
前言
如有任何意见和建议，可随时提交至http://www.regulations.gov，供FDA参考。将书面意见提交至食品药品监督管理局文档管理部，地址5630 Fishers Lane,Room 1061, (HFA-305), Rockville, MD 20852。采用文件编号FDA–2008–D–0611确定所有文件。FDA可能需等到下次修订或者更新本文件时才会对这些意见作出答复。其他副本CDRH可从网站上获得更多拷贝。您也可以发送电子邮件至CDRH-Guidance@fda.hhs.gov，申请一份指南副本。请采用文件编号1615指明您申请的指南。CBER您也可以采用书面申请的方式通过以下途径从生物制品评价和研究中心（CBER）获取更多的本指南副本：写信至沟通、推广和发展办公室（OCOD），地址是10903 New Hampshire Ave., WO71, Room 3128, Silver Spring, MD20993-0002；或者拨打电话1-800-835-4709或者240-402-8010；发送电子邮件至ocod@fda.hhs.gov；或者通过网站http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm。
无菌类器械上市前通告(510(k))申报中关于无菌证明资料的提交及审查
行业和FDA人员指南
本指南代表了食品药品监督管理局（FDA或者机构）目前在该问题上的看法。该文件并未赋予任何人任何权利，也不可用来约束FDA或者公众。如果替代方法可以满足适用的法令和法规的要求，则可以采用该替代方法。如果需要讨论某种替代方法，请联系标题页上列出的负责本指南的FDA人员或者办公室。I.引言本指南更新并澄清了我们建议申办方在无菌类器械510(k)中应该包括的关于灭菌过程的信息。本指南还详细描述了我们建议申办方在510(k)申报资料中包括的致热原性信息。关于本文件中引用的、已被FDA认可的标准的现行版，请访问FDA认可的共识标准数据库网站http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm。FDA的指南文件，包括本指南，并不具备法规强制性。相反地，指南描述的是机构目前在某个问题上的看法，仅应该被视为推荐意见，除非引用了具体的法规或者法令要求。机构指南中词语“应该”的使用意味着我们建议或者推荐进行某项活动，但并不是强制要求进行某项活动。II.背景近年来，FDA收到的无菌类器械510(k)中，有越来越多的器械采用的灭菌方法不同于传统灭菌方法，即蒸汽灭菌、干热灭菌、环氧乙烷（EO）灭菌和辐射灭菌。FDA对其他方法，例如过氧化氢、臭氧和柔性袋系统，也有一定的经验，目前将这些方法视为成熟方法。然而，我们认识到新近开发出来的方法可能会发生变化，目前也正在开发全新的灭菌技术并且计划将其用于I类和II类器械的生产。FDA将这些方法视为新方法。（术语“成熟”和“新”的定义见下文第IV节。）根据联邦食品药品和化妆品法案（下文称法案）章节513(f)(5)所述，如果不满足法案中与实质等同性决议无关的任何条款，包括不满足生产质量管理规范（GMP） ，FDA可能不会拒绝授予510(k)许可，除非FDA发现产品不满足该条款极有可能“对人体健康带来严重风险”。我们相信，如果执行不到位，新灭菌技术有重大的灭菌不充分风险。因此，应该认真评估采用这些技术灭菌的器械是否遵循GMP的要求进行生产。如果无法确保产品的无菌性，则会对人体健康造成严重的风险，因为存在感染风险。因此，对于采用新灭菌技术灭菌的器械，我们计划先审查其生产设施再授予510(k)许可。对于采用这些灭菌技术灭菌的器械，审查其生产设施将有助于确保这些器械的安全性和有效性，降低其对人体健康带来的风险。III.适用范围本指南的适用范围仅限于采用基于微生物灭活的行业最终灭菌工艺灭菌的无菌类器械的510(k)审查。此处所述灭菌流程的实例包括辐射灭菌、蒸汽灭菌、EO灭菌和新灭菌工艺。例外本指南不包括下述情况：1本身属于受510(k)管制的医疗器械的灭菌器 , 。2基于微生物排除而非微生物灭活的工艺不属于本指南的讨论范围。微生物排除工艺的实例包括药品生产中常用的无菌过滤法和无菌操作。3计划对含动物来源材料（即：人体或动物组织）的医疗器械进行灭菌的工艺不属于本指南的讨论范围。对于含人体或动物来源材料的器械，我们建议联系负责审查该器械的分部来讨论相应的问题。为了协助申办方解决与病毒污染有关的顾虑或者问题，我们建议参阅美国药典（USP）<1050>和相关文件。4涉及液体化学灭菌器的工艺 。5一次性器械再生处理的工艺。见“2002年医疗器械用户收费和现代化法案，再生处理后的一次性医疗器械的上市前通告(510(k)申报资料中的验证数据”（见 http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071434.htm）。6关于医疗机构再生处理后的可重复使用器械（以及需要在医疗机构进一步灭菌的非无菌一次性器械）的清洁、消毒和灭菌的信息。见 “医疗机构中医疗器械的再生：验证方法和贴标”（见 http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM253010.pdf ）。最后，FDA指出，生产过程中采用的灭菌方法应满足FDA的质量系统（QS）法规要求，21 CFR 820部分。IV.灭菌方法FDA认为，目前生产过程中用来灭菌医疗器械的灭菌方法有两类：成熟方法和新方法 。下文将定义这些工艺，并给出了每个类别的实例。A.成熟的灭菌方法：1.成熟A类：这些方法有较长的应用历史，有多种渠道来源的信息可证明其安全有效，例如大量的文献、510(k)许可或者上市前批准（PMA）申请获批以及令人满意的QS检查结果。对于成熟方法，例如干热灭菌、EO、蒸汽灭菌和辐射灭菌，其开发、验证和常规控制已有自发制定的共识标准，且已获得FDA认可 。 成熟A类灭菌方法实例：干热灭菌将器械置于固定的刚性容器中进行EO灭菌湿热或蒸汽灭菌辐射灭菌（例如：射线、电子束）2.成熟B类：还有一些其他的成熟方法不存在已获FDA认可的专门的共识标准，但可获得已发表的关于其开发、验证和常规控制的信息。对于采用离散周期参数的具体灭菌器，如果FDA之前已评价了其灭菌开发和验证数据，且认为其验证方法是充分的 ，则我们将这些方法视为成熟B类。成熟B类灭菌方法实例：过氧化氢（H2O2）臭氧（O3）柔性袋系统（例如：EO置于柔性袋系统中、扩散法、注射法）然而，对于FDA尚未评估过的具体工艺，如果已获FDA许可的灭菌器的参数发生了改变，或者之前已获许可或批准的申报资料中工艺验证数据并未被评估且认为是充分的，则我们将这些方法视为新方法。B. 新灭菌方法：该类别指的是新开发的方法，相关的已发表信息极少或不存在，FDA尚未全面评估灭菌开发和验证数据（即尚未授予采用此类方法灭菌的器械510(k)许可或者批准PMA），而且关于其开发、验证和常规控制，并不存在已获FDA认可的专门的共识标准。新灭菌方法指的是尚未被FDA审查并认为其足以有效灭菌相应器械使其适用于预期用途的方法。如果某种灭菌方法采用的化学试剂尚未作为化学灭菌剂获得FDA许可或批准，或者在科学文献中查找不到其作为化学灭菌剂使用的证据，则该灭菌方法被视为新方法。另外，如果某种灭菌方法同时使用多种化学试剂，而这种组合方式尚未作为灭菌剂获得FDA许可或批准，那么该灭菌方法被视为新方法，即使该组合方式中的每种化学试剂单独使用时均作为化学灭菌剂获得FDA许可或批准。对于FDA尚未评估过的具体工艺，如果已获FDA许可的灭菌器的参数发生了改变，或者之前已获许可或批准的申报资料中工艺验证数据并未被评估且认为是充分的，FDA将这些方法也视为新方法。 新灭菌方法实例：过氧乙酸蒸气高强度光或者脉冲光微波辐射声波紫外线V.无菌类器械的灭菌信息A.成熟灭菌方法申办方应该确保510(k)申报资料中包括所有下述信息。1.关于灭菌方法，申办方应该提供以下信息：a.关于灭菌方法的描述；b.关于灭菌腔的描述，如果不是刚性、固定腔体的话（例如：柔性袋）；c.关于章节IV.A.2.中描述的那些方法（成熟B类）：如果灭菌器已获510(k)许可 ，则提供510(k)编号以及灭菌器的品牌（即生产商）和型号。另外，申报资料中应该指明已获许可的灭菌器的周期参数是否发生了变化；如果灭菌器尚未获得510(k)许可，则应该指明这一点；如果该灭菌方法已经进行过评估，即采用该方法灭菌的器械已获得510(k)许可或者PMA批准或者HDE，则指明之前评估该方法的申报资料编号或者含有该信息的器械主文件 。另外，申报资料中应该指明之前已获许可或批准的申报资料中描述的周期参数是否发生了变化；d. 灭菌位置 ；e.关于辐射灭菌，应指明辐射剂量；f. 关于化学灭菌剂（例如：EO、H2O2），应指明器械上该灭菌剂的最大残留量，并解释对于相应的器械类型和预期患者接触时间而言，为什么这种残留水平是可以接受的。关于EO灭菌，CDRH已经接受了基于已获认可的现行版标准“AAMI/ANSI/ISO 10993-7医疗器械的生物学评价—第7部分：环氧乙烷灭菌残留量”测定的EO残留量信息。 2. 关于该灭菌方法，申办方应该描述用来验证灭菌周期的方法（例如：半周期法），而不是验证数据本身。申报资料中还应该指明采用的所有相关的共识标准，并阐明产品未能满足这些标准中哪些方面的要求。如果没有已获认可的标准，则应该提交关于该灭菌工艺的全面描述和完整的验证方案，以供审查。3. 对于无菌类器械，申办方应该指明其无菌保证水平（SAL）为10-6，除非预期该器械仅接触完整皮肤。关于预期仅接触完整皮肤的器械，FDA推荐的SAL为10-3。关于替代SAL的问题，我们建议直接咨询FDA，申报前与FDA召开会议进行讨论 。4.致热原性检测有助于保护患者免遭革兰氏阴性菌内毒素或者其他来源致热原（例如：材料相关的致热原）引起的发热反应。为了解决细菌内毒素的问题，下述类别下的器械应该满足致热原限值标准：植入物；与心血管系统、淋巴系统或者脑脊液直接或间接接触的器械，包括涉及类似全身暴露的器械；或者被标记为不具有致热原性的器械。注意：机构建议采用“不具有致热原性”或者“满足致热原限值标准”的说法来代替“无致热原”，除非可以证明致热原已被彻底清除。另外，对于应该满足致热原限值标准的器械，我们建议在标签中指明该器械不具有致热原性。 申办方应该提供下述信息：a.描述用来确定器械满足致热原限值标准的方法（例如：细菌内毒素检测（BET），又被称为鲎试剂（LAL）检测）；b.声明将针对每批产品进行内毒素检测，或者如果不如此做的话，按照下述FDA指南的建议，提供关于中间检测和/或成品放行中采用的采样计划的信息：致热原和内毒素检测：问答 ”（http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf）；c.指明选定的检测限值；和d.解释为什么选择这样的内毒素限值。关于一般的医疗器械，我们推荐的内毒素限值为BET：20内毒素单位（EU）/器械；对于接触脑脊液的器械，我们推荐的内毒素限值为BET：2.15 EU/器械。请参考：USP <161>：输血和输注组件和相似的医疗器械ANSI/AAMI ST72:2011细菌内毒素 – 试验方法、常规监测以及批检测的替代方法FDA的指南“致热原和内毒素检测：问答” （见 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf）申办方还应该清楚，除革兰氏阴性菌之外，还有其他的致热原来源。材料相关的致热原指的是从医疗器械中滤出的化学物质，传统做法是在生物相容性评估中来解决这一问题。由于人体接触的性质，有些器械无需满足致热原限值标准，但打算将其标记为“不具有致热原性”，对于这类器械，我们建议进行细菌内毒素以及材料相关的致热源性检测 。关于器械的具体问题，请联系相关的审查分部，因为不同类型器械的限值要求是不同的。 5. 申办方应该描述产品包装（无菌屏障系统）以及该包装如何维持器械的无菌性，并描述包装检测方法，但无需描述包装检测数据 。B. 新灭菌方法除上文第V.A节指明的信息外，对于所有的新灭菌方法，申办方还应该在510(k)中提供下述信息：1关于灭菌工艺的全面描述；2用来验证该灭菌周期的方法（例如：半周期法）；3验证方案；和4灭菌验证数据。申报资料中还应该指明所有适用的已发表的科学文献。关于新灭菌方法，根据申报的具体器械，FDA可能还会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 ResearchPreface Public Comment You may submit electronic comments and suggestions at any time for Agency consideration to http://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 http://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 http://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 http://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 http://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 lightV. 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” (http://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 http://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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