行业和FDA人员指南

并于本方案，若果有并于受CDRH监督的仪器的情况，请进行301-796-5580电话联系染病抑制仪器分院（INCB）。对本要点，但如果有对受CBER风险防控的手术器械的现象，请用1-800-835-4709甚至240-402-8010练习CBER的交流、产品推广和未来发展室内室（OCOD）。

 

加拿大环卫和我们人类的服务部

美利坚共和国保健食品医药监督的方法职能方法局

医用器具和牵扯卫生监督管理中心

生物工程学考核和理论研究中央

 

前言范文

假如所有的看法和建立，可任意时提交申请至//www.regulations.gov，供FDA参照。将以书面形式征求意见上传至面制品保健药品督察控制系统局word文件控制系统部，地扯5630 Fishers Lane,Room 1061, (HFA-305), Rockville, MD 20852。应用文档编号规则FDA–2008–D–0611判别因此文档。FDA可能性需你走以后以后修改也可以更新换代从文中件时才会对此类工作建议得出结论解答。同一副本掉落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//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

本指导意见代表英语了食品类进口药品监督的的管理职能的管理局官方网站（FDA还是学校）当前在该问题上的观点。该压缩文件仍没有赋予了所有的人所有的权力，也不会也可来制约FDA还是大众用户群体。若是 代换步骤可充分考虑适于的法律和法律的要，则可用该代换步骤。若是 要探讨某项代换步骤，请取得联系名称页上选出的复杂本指导意见的FDA者还是企业办室。I.文献综述本方案发布并发声明了大家意见提案办理方在高压蒸汽灭菌类器具510(k)中理应例如的有并于高压蒸汽灭菌期间的讯息。本方案还简略文章的话了大家意见提案办理方在510(k)企业申报材料中例如的致热原性讯息。有并于下面件中调用的、已被FDA同意的规范条件的当前版，请网络访问FDA同意的精准医学规范条件数值库网站平台//www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm。FDA的指引zip文件，还有本指引，并不必备条件标准强迫性。相悖地，指引陈述的是贷款贷款机构现有在特定毛病上的利弊，仅必须被等同于介绍意见表，否则引入了特定的标准和国籍法条件。贷款贷款机构指引中句子“必须”的应用暗示着他们提案和介绍做出一项行动，但并不强迫条件做出一项行动。II.大环境近几以来，FDA退回来的无菌检测类仪器510(k)中，有很越高的仪器选择的过滤除菌方案不一样的于传统与现代过滤除菌方案，即水蒸汽过滤除菌、干热过滤除菌、树脂乙烷（EO）过滤除菌和散发过滤除菌。FDA对另一个方案，举例过硫化氢、O3和超材料袋系统的，同样有某种的临床经验，当前将哪些方案称为较为非常成熟方案。殊不知，人们认识自己到新近开发建设技术工艺除了的方案可能性会的发生影响，当前也也正在开发建设技术工艺新的过滤除菌技术工艺而且规划将其于I类和II类仪器的生产的。FDA将哪些方案称为新方案。（用语“较为非常成熟”和“新”的理解见本文第IV节。）按照联帮肉食品放射性药品和化妆师品基金法（下面称基金法）章数513(f)(5)上述一系列的，倘若不够足基金法中与从根本上来说同等性提议决定的一些合同法，属于不够足分娩的平安性能标准化质量管理制度性（GMP） ，FDA也许并不会排斥给予510(k)许证，必须FDA察觉到的货品不够足该合同法极有也许“对身休绿色身体保健带去重要平安危险”。自己想信，倘若执行命令不完成，新高压蒸汽高压蒸汽高压蒸汽过滤除菌方法枝术设备有根本性的高压蒸汽高压蒸汽高压蒸汽过滤除菌方法不更加充分平安危险。如此，应当一丝不苟开展应用这类枝术设备高压蒸汽高压蒸汽高压蒸汽过滤除菌方法的手术手术器具能不能遵守GMP的让来分娩的。倘若无发可以有效确保的货品的无茵性，则会对身休绿色身体保健产生重要的平安危险，正因为有感然平安危险。如此，相对 应用新高压蒸汽高压蒸汽高压蒸汽过滤除菌方法枝术设备高压蒸汽高压蒸汽高压蒸汽过滤除菌方法的手术手术器具，自己计划怎么写先查看请求其分娩的设备再给予510(k)许证。相对 应用这类高压蒸汽高压蒸汽高压蒸汽过滤除菌方法枝术设备高压蒸汽高压蒸汽高压蒸汽过滤除菌方法的手术手术器具，查看请求其分娩的设备将有益于可以有效确保这类手术手术器具的平安性和可以避孕效果，消减其对身休绿色身体保健带去的平安危险。III.适用于的范围本白皮书的适宜范围图只限于利用基本概念微生态学消灭的业内终究无菌室生产艺无菌室的无菌室类仪器的510(k)审核。彼处根据上述无菌室注意事项的示例包扩幅射无菌室、空气压缩无菌室、EO无菌室和新无菌室生产艺。特殊情况本指导书不涵盖下述现象：1自己是一种受510(k)管控的治疗器戒的灭菌处理器 ,  。2对于微怪物来清除而不是微怪物失活的技术设备不隶属于本方案的挑选时间范围。微怪物来清除技术设备的具体方法涉及到进口药品产量里常用的没有细菌过滤装置法和没有细菌基本操作。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在拆迁中遇到溶液化工消毒器的工艺流程 。5一场性器材回收利用处里的工艺技术。见“2007年治疗管理器材用户组算钱和近代化权利法案，回收利用处里后的一场性治疗管理器材的退市前通知格式(510(k)申办姿料中的核实数据报告”（见 //www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071434.htm）。6管于医辽公司降解补救后的可反复运用器具（各类是需要在医辽公司进几步高压蒸汽灭菌处理的非无菌操作1次性器具）的便于、杀菌消毒和高压蒸汽灭菌处理的相关信息。见 “医辽公司中醫辽器具的降解：查验最简单的方法和贴标签”（见 //www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM253010.pdf ）。之后，FDA体现了，产量环节中用到的过滤除菌的方式应满足了FDA的质理系统化（QS）法律规范，21 CFR 820组成部分。IV.灭菌方案方案FDA看来，近些年生产方式具体步骤中用作无菌医辽器具的无菌医疗器械创新网步骤有几大类：完善医疗器械创新网步骤和新医疗器械创新网步骤 。后文将分类等等医疗器械创新网，并拿到了每种类型的示范。A.成长的无菌方式 ：1.早熟A类：那些步骤有较长的操作过往，有多种多样技巧来历的企业信息可证件其健康行之有效，假如很大的论文、510(k)经营也许退市前审批权（PMA）申请注册应用及及令人感动比较满意的QS进行检查成果。来说早熟步骤，假如干热高压蒸汽加热杀菌、EO、蒸汽加热高压蒸汽加热杀菌和辐射源高压蒸汽加热杀菌，其开发技术、肯定和常规检查管理迄今为止自行出台的个体化标，且已拿到FDA肯定 。 成熟期A类过滤除菌工艺典例：干热杀菌将健身器械放置于调整的 刚性轨道储槽中展开EO高压蒸汽灭菌湿热或水蒸汽灭菌方法电磁干扰无菌（举例说明：放射线、网上束）2.稳定B类：另外还有点许多的稳定策略不存有已获FDA好评的针对性的精准医学标，但可荣获已收录的关于幼儿园其开拓、验正和普通操纵的信心。这对分为离散寿命规格的实际的过滤除菌器，比如FDA此前已品评了其过滤除菌发掘和验正动态数据，且看来其验正手段是完全的 ，则.我将这部分手段算作心智成熟B类。熟B类杀菌形式图片：过防氧化氢（H2O2）臭氧的危害（O3）挠性袋系统性（列如 ：EO置入挠性袋系统性中、扩散作用法、皮下注射法）然后，对待FDA暂未鉴定过的按照施工技艺，若已获FDA经营的灭菌技巧器的参数值形成了发生变化，还很久已获经营或提出申请的办理的资料中施工技艺查验统计数据无法被鉴定且因为是加以的，则企业将他们技巧被视为新技巧。B. 新灭菌技巧技巧：纯虚函数别指的是新开设发的技术，涉及到的已刊出问题较少或不会来源于，FDA还未多方位考评无菌规划设计建设和查验数据库（即还未颁授主要采用因此技术无菌的设备510(k)许可证并且批复PMA），并且有关于其规划设计建设、查验和常规化掌控，并不会来源于已获FDA认可的的专用的认可规则。新无菌技术指的是还未被FDA检查并指出其足有用无菌相对应的设备使其选用在估计领域的技术。如一些消毒途径步骤选用的化工免疫生化生化试剂暂不做为化工消毒剂领取FDA经营经营获批证证或准许，也可以在学科期刊论文中找出没法其做为化工消毒剂运行的电子证据，则该消毒途径步骤被算为新途径步骤。别的，如一些消毒途径步骤同时运行很多种化工免疫生化生化试剂，而种组成途径暂不做为消毒剂领取FDA经营经营获批证证或准许，那么的该消毒途径步骤被算为新途径步骤，也许该组成途径中的多种化工免疫生化生化试剂多个运行时均做为化工消毒剂领取FDA经营经营获批证证或准许。谈谈FDA暂不评价指标过的详细加工，如已获FDA经营经营获批证证的消毒器的规格遭受了影响，也可以时候已获经营经营获批证证或准许的办理信息中加工验证通过数据文件仍能评为价指标且人认为是有力的，FDA将此类途径步骤也算为新途径步骤。 新过滤除菌方式方法事列：过氧乙酸水汽高強度光也可以单脉冲光微波通信影响音波紫外光线V.无茵类器具的消毒的信息A.完美消毒办法审报方要确定510(k)审报材料中比如那些下述个人信息。1.就消毒措施，申请办理方可能提供数据以內问题：a.管于灭菌办法办法的叙说；b.对於无菌腔的说明，若是并非是钢性、稳固腔体来说（假如：柔性fpc线路板袋）；c.对每章IV.A.2.中表述的看看那些方式（完善B类）：如何消毒器已获510(k)经营 ，则具备510(k)顺序号和消毒器的品脾（即制作商）和产品型号。最后，网上申报资科中会指向已获经营的消毒器的定期参数表能不能发生了了不同；如若灭菌方法器还没拥有510(k)许证，则都应该列出这点；如该高压蒸汽无菌策略现已开始过考核，即选择该策略高压蒸汽无菌的运动健身器械已获取510(k)可证还是PMA报批还是HDE，则指出以前考核该策略的审报素材代号还是含有该信心的运动健身器械主文件格式 。其次，审报素材中应有指出以前已获可证或报批的审报素材中介绍的频次规格要不要产生了的变化；d. 消毒位子 ；e.更多散发灭菌处理，应指向散发含量；f. 针对电化学消毒剂（列如 ：EO、H2O2），应准确把握手术仪器设备上该消毒剂的明显残余物量，并解釋就某些的手术仪器设备款式和预期想象病患接处精力来讲，为之类这一残余物层次是可能认同的。介绍EO灭菌方法处理，CDRH以经受到了特征提取已获教育部认证的实施版要求“AAMI/ANSI/ISO 10993-7医疗卫生运动器械的菌物学判断—第7部位：固化剂乙烷灭菌方法处理残存量”法测定的EO残存量个人信息。 2. 相对于该高压蒸汽杀菌处理技术，办理方会叙说能够满足了核实高压蒸汽杀菌处理时间的技术（假如：半时间法），而不会核实大数据使用价值。申报纳税的资料中还会指向选用的拥有关联的精准医学细则规定，并系统阐述产品的不满足了这个细则规定中一些多方面的让。假如不已获认证的细则规定，则会还需准备相对于该高压蒸汽杀菌处理工序的周全叙说和完整版的核实设计方案，以供评审。3. 针对灭菌室类仪器设备，申请方该列出其灭菌室有保障质量（SAL）为10-6，除非说期望值该仪器设备仅接处完成脸部肤质。有相对于期望值仅接处完成脸部肤质的仪器设备，FDA最新推荐的SAL为10-3。有相对于代替SAL的疑问，当我们建意间接管理咨询FDA，申报纳税前与FDA召开联席会议联席会议展开挑选 。4.致热原性检测工具促使保养病患抗御革兰氏阴性反應菌内毒性亦或是任何的来源致热原（比如：装修材料相关联的致热原）带来的发冷反應。为了让防止大肠杆菌内毒性的问题，下述类属下的设备想必符合致热原限制值细则：植入广告物；与先天之精管装置的、淋巴结装置的或许脑脊液直接的或举例说明相处的仪器，收录针对的目标近似身上曝露的仪器；或许被标示为不兼备致热原性的仪器设备。准备：学校小编小编建议采用了“不具备有着致热原性”或许“充分具备致热原允许值规范条件”的问法来充当“无致热原”，要不是能够 证明文件致热原已被恢复处理。除此之外，相对于可以充分具备致热原允许值规范条件的用具，当我们小编小编建议在元素大拇指明该用具不具备有着致热原性。  申请注册方应打造下述消息：a.陈述用于确认手术器械足够致热原卫生防护距离规范的方式方法（这类：细菌病毒内毒性检验（BET），又被称作鲎免疫试剂（LAL）检验）；b.申明将共性每批物料实现内毒物检查，并且这样不这么做的话语，决定下述FDA指导书的小编建议，带来介绍前面检查和/或半成品清关中利用的监测准备的资讯：致热原和内毒物检查：问答题 ”（//www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf）；c.准确把握选出的检验允许值；和d.释义为这些取舍这样子的内毒物允许值。关于幼儿园通常情况下的整形运动仪器，他们引荐的内内毒物允许值为BET：20内内毒物政府部门（EU）/运动仪器；在遇到脑脊液的运动仪器，他们引荐的内内毒物允许值为BET：2.15 EU/运动仪器。请选取：USP <161>：输血和输注组件和相似的医疗器械ANSI/AAMI ST72:2011螨虫内黑色素 – 试验加测方式 、常規监测站与批加测的代替品方式 FDA的指导意见“致热原和内内毒素测量：答问” （见 //www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf）申请方还会清，除革兰氏阴性反应菌除此之外，还是有其它的的致热原种类。素材相关的的致热原指的是在医疔健身器械中滤出的物理化学物料，经典做发是在微生物相匹配性鉴定贝盛解决办法这些困难。是由于人体本身接觸的特性，些许器具不能不满足了致热原限制值标准的，但个人规划将其标签为“不存在致热原性”，就这一类器具，他们推荐 开展结核杆菌内毒物及村料相应联的致热原性查重 。并于器具的关键原因，请连接相应联的审查请求分布，由于差异种类器具的限制值符合要求是差异的。 5. 申请方应有叙说产品设备进行包装设计机袋（灭菌室深层系统性）及其该进行包装设计机袋应该如何长期保持器具的灭菌室性，并叙说进行包装设计机袋检验技巧，但必须叙说进行包装设计机袋检验信息 。B. 新灭菌的办法的办法除文中第V.A节指向的图片信息内容外，对拥有的新灭菌方式 方式 ，申请办理方还理应在510(k)中出具下述图片信息内容：1关与无菌生产技术的新一轮描写；2中用效验该灭菌处理时间间隔的技术（譬如：半时间间隔法）；3安全验证预案；和4杀菌方式方法认证的数据。网上申报纳税档案资料中还必须列出拥有支持的已发表文章的合理专著。相对于新杀菌方式方法方式方法，利用网上申报纳税的实际的仪器，FDA将还能规范展示大多的信息内容。

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.