Sterilization Innovations Lead to New Guidance Document

It took more than seven years, but the U.S. Food and Drug Administration (FDA) has, at long last, released a final version of its 2008 draft guidance on sterility data needed for 510(k) product submissions. Issued Jan. 21, the guidance applies to medical devices labeled as sterile through microbial inactivation.

Keeping its predecessor’s title, “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,” the guidance distinguishes between established and novel sterilization methods. Established methods are those that are recognized by the FDA and well-accepted (e.g., dry heat, ethylene oxide, steam, radiation) as well as those not recognized by the agency but backed by “published information on development, validation, and routine control” and/or those previously reviewed and accepted by the FDA as an acceptable sterilization method (e.g., hydrogen peroxide, ozone, flexible bag systems).

Novel sterilization methods, according to the guidance, are “newly developed methods for which there exists little or no published information, no history of comprehensive FDA evaluation” and no FDA-recognized consensus standard. Novel methods include new sterilization processes, changes to parameters of established methods, and combinations of established sterilants the FDA has never reviewed or cleared, an FDA law blog states. The guidance, however, does not disclose how significant the changes must be in order to be considered novel.

While many in the industry might think of sterilized medical products as routine, the FDA feels otherwise, placing significant focus on the method, validations, and labeling of devices labeled as sterile. The agency’s attitude toward sterilization is evident in the eight-page guidance, as it covers a lot of ground. For example, the document states the FDA will inspect medical device manufacturing facilities using novel sterilization before clearing any 510(k) applications for such devices. In addition, priority post-clearance inspections are slated for facilities using non-FDA recognized sterilization standards, but for which there is published data on its validation, and the agency has previously reviewed and accepted the method. 

The more than seven-year gap between the draft and final guidances reveals the FDA’s reasoning behind its latest recommendations for sterilizing medical devices. “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…” the final guidance states. Between 2008 and 2016, the FDA has learned much about different forms of sterilization, and it wants to share its current thinking on the matter. Note that the FDA puts established sterilization methods into two categories, Category A and Category B. Novel sterilization methods are also addressed in this column. 

The Is/Is Not table (Table 1) is a simple way to summarize the scope of this guidance document.  

TABLE 1
IS (in scope)	IS NOT (not in scope)
Review of 510(k)s for devices labeled as sterile that are subject to industrial terminal sterilization process.	Sterilizers that are themselves medical devices subject to 510(k).
	Process that relies on microbial exclusion, rather than microbial inactivation. Examples of microbial exclusion are filtration methods and aseptic processing.
	Sterilization processes for medical devices that incorporate materials of animal origin (i.e., human or animal tissue).
	Processes using liquid chemical steriliants that would fall under: Liquid chemical steriliants/high level disinfectants, 21 CFR 880.6885 Automated endoscope reprocessors under Endoscope and accessories, 21 CFR 875.1500
	Processes intended to be used by reprocessors of single-use devices.
	Cleaning, disinfecting, and sterilization of reusable devices reprocessed at healthcare facilities; and single-use devices that are provided non-sterile for further sterilization at healthcare facilities.

What information must be provided for each of the categories? And, what does this mean for the 510(k) in development? The answer: Each category has specific requirements for every sterilization method category. Table 2 provides details.

TABLE 2
“Established Category A”  Sterilization Methods	“Established Category B” Sterilization Methods	“Novel” Sterilization Methods
Definition: 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 Quality System inspections.	Definition: Methods for which there are no FDA-recognized dedicated consensus standards, but for which published information on development, validation, and routine control is available.  Also, cases where FDA has previously evaluated sterilization development and validation data for specific sterilizers using discrete cycle parameters and determined the validation method to be adequate.	Definition: Methods the FDA has not reviewed and determined to be adequate to effectively sterilize a device for its intended use.
INFORMATION REQUIRED	INFORMATION REQUIRED	INFORMATION REQUIRED
Description of the sterilization method.	Same	Same
Description of the sterilization chamber if not rigid, fixed (e.g., flexible bag).	Same	Same
	If the sterilizer is intended for use in a healthcare facility, and 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.	Same
	If the sterilizer has not received 510(k) clearance, this should be stated.	Same
	If the sterilization method has been evaluated through clearance of a 510(k) or approval of a premarket application (PMA) or Humanitarian Device Exemption (HDE) for a device using that method, the submission number where the method was previously evaluated or the identification of a Device Master File  ( go to http://bit.ly/MPOreg1) 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.	Same
	The sterilization site.	Same
	For radiation sterilization, the radiation dose.	Same
	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.    Note: In the case of EO sterilization, the FDA Center for Devices and Radiological Health (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.”	Same
	A description of the method used to validate the sterilization cycle (e.g., the half-cycle method) but not the validation data itself. 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.	Same
	A statement of Sterility Assurance Level (SAL) of 10-6 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.    Note: For questions related to alternative SALs, FDA recommends direct consultation and pre-submission meetings with FDA. The guidance document for this is “Request for Feedback on Medical Device Submissions:  The Pre-Submission Program and Meetings with FDA Staff” – go to http://bit.ly/MPOreg2.	Same
	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 Devices labeled non-pyrogenic Note: The FDA recommends the use of “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, FDA recommends the labeling state the device is “non-pyrogenic.”	Same
	More requirements for Bacterial Endotoxins: 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 Limulus amebocyte lysate (LAL) test A statement confirming that endotoxin testing will be conducted on every batch or if not, information regarding the sampling plan used for in-process testing and/or finished product release, as recommended in the FDA guidance “Pyrogen and Endotoxins Testing:  Questions and Answers” – go to www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310098.pdf Identification of the chosen testing limit An explanation supporting the selected endotoxin limit Note 1: The FDA recommends the following endotoxin limits for the BET: Twenty endotoxin units (EU)/Device for general medical devices (e.g. blood contact and/or implanting) and 2.15 EU/Device for devices that contact cerebrospinal fluid. Note 2: The FDA refers to these documents: USP , Transfusion and Infusion Assemblies and Similar Medical Devices ANSI/AAMI ST72:2011, Bacterial endotoxins – Test methods, routine monitoring, alternatives to batch testing FDA’s guidance “Pyrogen and Endotoxins Testing:  Questions and Answers”	Same
	Even more requirements for Bacterial Endotoxins: 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	Same
		A comprehensive description of the sterilization process
		The method used to validate the sterilization cycle (e.g., the half-cycle method)
		The validation protocol
		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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James Dunning’s consulting career began in 2001. He has provided quality and regulatory consulting services for various companies ranging from Fortune 500 medical device firms to startups. Dunning’s passion, however, lies with startups and small companies, especially those in regulatory distress. He has amassed significant experience in preparing 510(k) applications, developing complete Quality Management Systems, providing Quality System Training, and advising on quality, business, and leadership issues. Dunning is a senior member of the American Society for Quality and a member of the Regulatory Affairs Professional Society.