“I have to upgrade my quality management system (QMS) to Class III,” is a phrase I hear often when working with companies that are undergoing a transition from marketing-only Class II medical devices in the United States to the addition of a Class III device or indication. While there are differences in some regulatory requirements — most notably labeling, the extent of reporting, and the extent of quality system review — the QMS requirements are identical between these two classes.1 In this article, we will explore the misconception of differing QMS types between classes as well as what to expect when your QMS is reviewed by the U.S. Food and Drug Administration (FDA) from a Class III perspective.
Expanding into the highest device classification in the U.S. is an exciting time for a growing company. However, questions seem to come from every direction, and it is usually up to regulatory and quality organizations to supply the answers. Queries typically include: What kind of testing do we need, what is this going to cost us, what interactions will we have with FDA, and what changes do we need to make to our QMS? While many of these questions will take months of research and time investment to answer, the last one can be rather simple; that is if you’ve successfully implemented a QMS for your Class II device. If you are currently operating under a compliant Class II QMS, the answer to what changes do we need to make to our quality system is that minimal to no updates will be required, and here’s why.
In the U.S., the Quality System Regulation requirements for medical devices are defined in FDA 21 CFR 820. The requirements documented in this subsection of the medical device regulation govern the methods, facilities and controls that are to be put in place for the design, manufacture, packaging, labeling, storage, installation and servicing of all finished medical devices intended for human use. The FDA implemented the regulation to ensure that finished medical devices will be safe and effective and in compliance with the Federal Food, Drug, and Cosmetic Act. While the general requirements are defined in the CFR, the extent of implementation and the methods of implementation is left up to each individual company. So, whether your device is Class II or Class III, a robust QMS should be adequate to successfully navigate the manufacturing section of your investigational device exemption (IDE) (if applicable); Module 4 (manufacturing module) of your premarket approval (PMA) application; your pre-market approval inspection; and all post-market regulatory/compliance activities.
However, there are a few points to consider when preparing for your transition from a Class II to a Class III device manufacturer:
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There are many definitions of a QMS and what documentation types are contained in this grouping of information. For clarity, the working definition of what encompasses a QMS for the purposes of this article includes all quality manuals, quality policies, procedures, and work instructions as well as the records generated during the design (design history files); manufacture (device master records and device history records); and market release (CAPAs, complaints, shipping records, medical device reporting, recalls, etc.) of medical devices.
Whether you submit a traditional or modular PMA application, your QMS procedures are required to be submitted with your PMA to demonstrate that you comply with 21 CFR 820. This review is different from the investigation that is completed at your facility in that each procedure is reviewed for its content as well as the interconnections between the individual procedures. This review is completed to ensure your QMS is designed to function in a complaint manner. For example, the CDRH reviewer will ensure that your complaint-handling system ties to your CAPA and MDR systems, and that your CAPA system ties to your risk management, design controls, nonconforming product/process, recall, and MDR systems.
The FDA issued the “Quality System Information for Certain Premarket Application Reviews” guidance document to help you navigate the description of your QMS as well as ensure you provide the expected procedures. Completion of your manufacturing section according to this guidance document will reduce the chances of obtaining deficiencies related to your QMS at the CDRH level, saving you time in your overall application timeframe since all deficiencies must be cleared prior to the issuance of the premarket inspection.
Along with your procedures, manufacturing process documentation applicable to your Class III device should be provided in your PMA application. For example, your validation plan is required be in place and included with the submission of your manufacturing information. Although your process validations are not required to be completed prior to submitting the manufacturing section of the PMA, any validations that have been executed should be submitted for review alongside the appropriate procedures. The validation plan and any validations submitted will be reviewed for compliance to 21 CFR 820.75. Submitting a subset of your completed validations with your PMA application will provide you valuable insight into what documentation will be expected for post-approval changes that are described below. To gain the most value, consider submitting validations for processes that are not only specific to the device under review, but are also processes that your company has not validated previously.
If you choose not to submit any validations or do not have them completed, it should be noted that all applicable process validations must be completed prior to the pre-approval inspection and prior to distribution of any finished devices. Your submission should provide an expected date of completion to ensure that the pre-approval inspection is not issued prior to your facilities being ready.
One significant difference in the review of the QMS between Class II and Class III devices is the timing of the facility inspection by the FDA’s Office of Regulatory Affairs (ORA). These are your district investigators. In general, a Class II device can be placed on the market without a facility inspection as the inspection will be completed per the ORA schedule. However, in most cases, prior to the approval of your PMA application, an inspection by ORA must be completed at all applicable design, manufacturing and contracting (such as sterilization) facilities. These inspections are referred to as pre-approval inspections, which are issued once CDRH is satisfied with the desktop review. The inspections are similar to what is conducted during a QMS inspection technique (QSIT) investigation; however, the investigator will focus on the processes and documentation that support the design and manufacture of the Class III medical device. Additionally, the CDRH reviewer may provide specific instructions to the ORA investigator based on the review of the submitted QMS documentation.
Maintaining your PMA after approval will require the submission of additional QMS information. Here is where minor changes to your QMS may be required. More specifically, your change control process should be reviewed to ensure that the correct levels of review are conducted for changes that impact not only the design, but also manufacturing processes, facility locations and the QMS. These procedural updates are necessary due to the increased level of pre-approvals (called supplements) and reporting that are required to maintain your Class III device.
There are guidance documents to help you determine what types of changes require pre-approval and which can be included in your periodic report, including: “Modifications to Devices Subject to Premarket Approval (PMA) - The PMA Supplement Decision-Making Process,” issued Dec.11, 2008, and “30-Day Notices, 135-Day Premarket Approval (PMA) Supplements and 75- Day Humanitarian Device Exemption (HDE) Supplements for Manufacturing Method or Process Changes,” issued April 13, 2011. These documents provide guidance on all types of changes to a PMA.
As a term of your PMA approval, you will be required to submit periodic reports, usually referred to as an annual report, regarding your device. These reports include changes to your manufacturing processes and device design that were implemented during the reporting period and do not impact safety or effectiveness as they are nonsignificant changes. Minimal QMS documentation will be provided in support of your periodic report.
For significant changes to the manufacturing process (see examples below) a pre-approval supplement is required. Unlike a Class II product where these changes were documented internally only, you must now gain FDA approval prior to implementation for the following:
The amount of QMS information provided is dependent on the type of change being requested and can vary from a small subset of what was submitted in your initial PMA to a full recompilation of QMS information specific to the new site or manufacturing process. Furthermore, it is highly likely a pre-approval inspection will be issued for new facilities. So, while the amount of QMS information provided to the FDA changes significantly, the QMS does not.
The quality system for your QMS is a continually changing program that must provide flexibility for your changing company. This holds true for a transition between U.S. Class II and Class III manufacturing. Slight changes to your already compliant QMS will ensure your continued compliance with the 21 CFR 820 regulation and the requirements of submitting and maintaining your PMA.
Andrea Pilon Artman founded SpectRA Compliance, LLC in 2019 to reinvent the experience medical device companies have with consulting services. She believes that each technology and company is unique and requires regulatory and quality support that is tailored to specifically meet their needs. Artman strives to partner with SpectRA’s clients by providing customized solutions designed to fit seamlessly into their organization and help them to realize their objectives.
She holds a master’s degree in bioengineering from the University of Toledo where her thesis focused on the characterization of a nanocomposite material for use in bone regeneration. Artman also holds a bachelor’s degree in bioengineering from the University of Toledo. Upon completion of her thesis work, she was a reviewer for the U.S. Food and Drug Administration (FDA) where she developed a passion for regulatory science and policy. While at the FDA, Artman reviewed cardiovascular devices in both the Office of Compliance (post-market) and the Office of Device Evaluation (pre-market).
Most recently, she was the associate director of regulatory affairs for an extracellular matrix company specializing in wound management and surgical products. Artman has also held multiple positions in regulatory affairs, quality engineering, and regulatory compliance in a wide range of device industries, including cardiovascular and orthopedics. You can reach Artman at andrea.artman@SpectRAcomplianceLLC.com. SpectRA Compliance is a referral partner of MasterControl.