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【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
致众医疗器械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
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 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 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” (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.
