（一）背景 Background
In 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 vaporized 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),3 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.
无菌类器械510(k)中，成熟的灭菌方法包括蒸汽灭菌、干热灭菌、环氧乙烷（EO）灭菌、辐射灭菌、汽化过氧化氢、臭氧等。正在开发的全新灭菌技术并将用于I类和II类器械生产的，被视为新方法。对于采用新灭菌技术灭菌的器械，如果操作不当，会带来灭菌不到位的重大风险。因此，应密切评估使用这些技术灭菌的器械是否符合GMP。FDA计划先审查其制造机构再授予510(k)许可，这将有助于确保器械的安全性和有效性，并降低对人类健康的风险。
（二）范围 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 United States Pharmacopeia (USP) <1050>, Viral Safety Evaluation of Biotechnology products derived from cell lines of human or animal origin, 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 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/medical-device-user-fee-and-modernization-act-2002-validation-data-premarket-notification)
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 non-sterile for further sterilization at healthcare facilities). See “Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling” (available at https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/reprocessing-medical-devices-health-care-settings-validation-methods-andlabeling)
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.
由医疗质量检测技术及测试仪器展知悉，该指南仅限于采用基于微生物灭活、生产最终灭菌过程无菌类器械的510(k)审查。上述灭菌过程的示例包括辐射灭菌、蒸汽灭菌、EO灭菌和新技术灭菌。
指南不包括下述情况：
1.灭菌器本身是受510(k)管制的医疗器械。
2.依赖于微生物排除而非微生物灭活的工艺过程，如药品生产中常用的灭菌过滤法和灭菌处理。
3.对包含动物源性材料（即人类或动物组织）的医疗器械进行灭菌的过程。
4.使用液体化学灭菌剂的工艺过程。
5.供一次性使用器械再处理人员使用的过程。
6.关于在医疗保健机构进行再处理的可重复使用器械（以及需要在医疗保健机构进一步灭菌的非无菌一次性使用器械）。
最后，FDA指出，制造环境中使用的灭菌方法应符合FDA QSR 820要求。
（三）灭菌方法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.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, radiation, and vaporized hydrogen peroxide, there are voluntary
consensus standards for development, validation, and routine control that are
recognized by FDA.
Examples 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)
• Vaporized Hydrogen Peroxide (H2O2)
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, we consider these to be Established Category B.
Examples of these Established Category B Sterilization Methods:
• 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.
FDA 认为，目前在生产环境中用于医疗器械灭菌的灭菌方法分为两类：成熟方法Established Methods和新型方法Novel Methods.
A.成熟的灭菌方法（Established Methods）：
1.成熟A类（Established Category A）：这些方法有较长的使用史，有多种渠道来源的信息可证明其安全有效，例如大量文献、510(k)许可或者上市前批准（PMA）申请获批以及令人满意的QSR 820检查结果。对于成熟方法，例如干热灭菌、EO灭菌、蒸汽灭菌、辐射灭菌和汽化过氧化氢灭菌，其开发、确认和常规控制已有自发制定的共识标准，且已获得FDA认可。示例：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，伽马辐照、电子束）、汽化过氧化氢（H2O2）。
2.成熟B类（Established Category B）：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、确认和常规控制的信息。示例：臭氧（O3）、柔性袋系统（如柔性袋系统中扩散法或注入法的环氧乙烷灭菌）。
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
B.新型灭菌方法（Novel Sterilization Methods）：
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。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确认数据（即尚未授予采用此类方法灭菌的器械FDA许可510(k)或者批准PMA），而且也没有FDA认可的关于开发、确认和常规控制的专门的共识标准。 如果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，则该灭菌方法被视为新方法，即使该组合方式中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尚未评估过的特定过程，如果已获FDA许可灭菌器的参数发生改变，或者之前已获许可或批准的申报资料中过程确认数据并未被评估且认为是充分的，这些方法也被视为新方法。示例：汽化过氧乙酸、高强度光或脉冲光、微波辐射、声波、紫外线。
（四）申办方应向FDA提供的信息Sterilization Information for Devices Labeled as Sterile
A. Established Sterilization Methods
Sponsors 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 III.A.2. (Established Category B):
• if the sterilizer has received 510(k) clearance,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 File12 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, “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.
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” (https://www.fda.gov/regulatory-information/search-fdaguidance-documents/pyrogen-and-endotoxins-testing-questions-andanswers);
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>, Medical Devices-Bacterial Endotoxin and Pyrogen Tests
• ANSI/AAMI ST72, Bacterial endotoxins – Test methods, routine
monitoring, and alternatives to batch testing
• FDA’s guidance “Pyrogen and Endotoxins Testing: Questions and
Answers” (available at https://www.fda.gov/regulatoryinformation/search-fda-guidance-documents/pyrogen-and-endotoxins-testing-questions-and-answers)
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.15 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.
A. 成熟灭菌方法
510(k)申报资料应包括所有下述信息：
1. 对于灭菌方法，申请方应提供以下信息：
a. 关于灭菌方法的描述；
b. 关于灭菌室的描述，如果灭菌室不是刚性的、固定的（例如，柔性袋）；
c. 对于成熟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（即制造商）和型号。如果灭菌器尚未获得510(k)许可，则应予以说明；如果采用该方法灭菌的器械已获得510(k)许可或PMA批准或者HDE，则指明之前评估该方法的申报资料编号或含有该信息的器械主文档。
d. 灭菌场所和位置；
e. 辐射灭菌剂量；
f. 化学灭菌剂（例如：EO、H2O2），应指明器械上该灭菌剂的最大灭菌剂水平，并解释其可以接受。
2. 关于灭菌方法，描述用于确认灭菌周期的方法（例如：半周期法）。还应阐明器械满足所有相关标准的情况。如果没有已获认可的标准，则应提交关于该灭菌过程的全面描述和完整的确认方案，以供审查。
3. 对于无菌类器械，应指明其无菌保证水平（SAL）为10-6，除非器械预期仅与完好皮肤接触。FDA建议预期仅与完好皮肤接触的器械的SAL为10-3。
4. 以下类别的器械应符合热原限值规范：植入物；与心血管系统、淋巴系统或脑脊液直接或间接接触的器械，包括具有类似全身暴露的器械；或被标记为无热原的器械。注：监管机构建议使用“不具有致热原性”或“符合热原限值规范”来代替“无热原”，除非可以证明热原已被彻底清除。另外，对于应满足热原限值规范的器械，建议在标签中指明该器械不具有致热原性。
申请方应提供下述信息：a. 描述确定器械满足热原限值规范的方法（例如：细菌内毒素试验（BET）；b. 对每个批次进行内毒素试验，或者不进行内毒素试验，则提供用于过程中试验和/或成品放行的抽样计划信息的声明；c. 指明所选试验限值；d. 解释为什么选择这样的内毒素限值。建议BET的内毒素限值如下：一般医疗器械（例如，血液接触和/或植入式器械）为20个内毒素单位（EU）/器械，接触脑脊液的器械为2.15 EU/器械。参见USP <161>、ANSI/AAMI ST72、FDA’s guidance “Pyrogen and Endotoxins Testing: Questions and Answers” 。
5. 申请方应描述器械包装（无菌屏障系统）以及该包装如何维持器械的无菌性，并描述包装试验方法，但无需描述包装试验数据。
B. Novel Sterilization Methods
In addition to the information identified in Section IV.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.
B.新型灭菌方法
除上文指明的信息外，对于所有的新灭菌方法，申请方还应该在510(k)中提供下述信息：
1. 关于灭菌过程的全面描述；
2. 用于确认灭菌周期的方法（如，半周期法）；
3. 验证方案；
4. 灭菌验证数据。申报资料中还应指明所有适用的已发表科学文献。关于新灭菌方法，根据申报的特定器械，FDA可能还会要求提供更多的信息。
想要了解更多请前往医疗质量检测技术及测试仪器展
文章来源：质量从业者
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