One of the million-dollar questions that quality, regulatory and engineering professionals find themselves asking is at what point should FDA be notified when a proposed change to a cleared or approved medical device is blowing in the wind? Through the years, Dr. D has seen some pretty creative written rationales for product line extensions in lieu of what should probably have been a special or abbreviated 510(k) or a PMA supplement. During this past week’s stroll through the agency’s warning letter database, the doctor came across a warning letter citing the lack of notification being made to the FDA, when the design changes made may have potentially impacted device safety and efficacy. Unfortunately, as technology continues to change rapidly, designs predicated on older and outdated technology platforms are challenged as components have moved to obsolescence. Now in a perfect world, device establishments should be protecting themselves through supplier agreements that require some level of advance notice before critical components go “bye-bye.” However, depending on the technology or the supplier, components can disappear practically overnight. The astute supply chain professional will exude dazzling effulgence (look-it-up) if he or she is able to prevent a permanent line-down scenario, requiring an immediate design change, through the effective management of their supplier base. However, the unfortunate Chief Jailable Officer (CJO) on the receiving end of a warning letter that cites adulterated product due to unapproved design changes will want to just scream in frustration at the poor decisions that resulted in the issuance of that prized agency warning letter. Enjoy!
Warning Letter –March 7, 2017
The warning letter referenced in this week’s guidance is eloquent in its simplicity. Simply stated, the offending establishment’s device, in the opinion of the FDA, was deemed to be adulterated. This opinion was premised on changes being made to the device that the FDA believed warranted a new application (submission) documenting the changes. In the eyes of the agency, the changes made impacted the safety and efficacy of the finished device. Ouch!
Warning Letter Excerpt
“The currently marketed [DEVICE] differs from the originally cleared device, WestLabs Model 601 Blood Plasma Warming Device (BK 870009). For example, your replacement of the device’s obsolete 8-bit chip with a new (b)(4) requires, at minimum, a change to a Printed Circuit Board to handle additional pins, re-implementation of code (most likely in C language), and voltage and power management for the new chip. Additionally, the currently marketed [DEVICE] has new features that the original device lacked, including features that enable the device to handle larger bag holders and that provide alarms (i.e., lights that flash when the plasma reaches a certain temperature). Because these and other changes or modifications to the device could significantly affect its safety or effectiveness, FDA regulations require you to submit a new premarket notification to FDA for the [DEVICE] pursuant to section 510(k) of the Act, 21 U.S.C. § 360(k). See 21 C.F.R. § 807.81(a).”
21 CFR, Part 807.81(a)(3)(i)(ii)
§807.81 – When a premarket notification submission is required.
(3) The device is one that the person currently has in commercial distribution or is reintroducing into commercial distribution, but that is about to be significantly changed or modified in design, components, method of manufacture, or intended use. The following constitute significant changes or modifications that require a premarket notification:
(i) A change or modification in the device that could significantly affect the safety or effectiveness of the device, e.g., a significant change or modification in design, material, chemical composition, energy source, or manufacturing process.
(ii) A major change or modification in the intended use of the device.
Compliance for Dummies
The doctor wishes he could provide the readers with a crystal ball that device establishments could use to determine when FDA should be notified of a design change or what constitutes a significant design change. In theory, any change made to the design, material, chemical composition, energy source or manufacturing process, for a Class II device, could warrant a new, special, or abbreviated 510(k), or PMA supplement for a Class III device. However, device establishments really do need to determine the impact of design changes to a finished device’s safety and efficacy. Now granted, something as benign as changing the colorant in a resin that does not come into contact with a fluid (blood) path may not warrant notification. However, performing cytotoxicity is probably something an establishment is going to want to have in their design history file (DHF), just in case the agency has questions during a pleasant visit for a cup of coffee and an inspection. Conversely, if the number of marker bands or the composition of marker bands for a catheter changes, you just might want to consider reaching out to FDA for their input. If design changes are going to influence intended use, you might as well start working on that new 510(k) now as there is no time like the present.
As mentioned in the beginning of this week’s Devine Guidance (DG), it is not uncommon for device establishments being driven to make changes due to components moving to obsolescence. Depending on the design change, verifying and/or validating the design change through inspection and testing may suffice. However, if the change requires a complete redesign of a circuit board, additional components, and/or potentially a software or firmware change, you just might want to pick up the phone and reach out to FDA. However, Dr. D is going to climb out on a limb and guess a submission will be in your establishment’s future.
Changes to processes also warrant careful consideration. For example, if the tip-bonding process for a catheter changes from glue (Loctite) to a thermal bond process, or an ultrasonic weld is changed to a laser weld for bonding plastics or other materials, the FDA is going to probably want to know about the process changes. The FDA is also going to want the device establishment to ensure these types of process changes are appropriately validated. Can you say process validation (IQ, OQ, PQ and PPQ)?
One final concept to keep in mind is the use of concessions for the acceptance of nonconforming product. Use-As-Is (UAI) could be viewed as a design change. If an investigator from the FDA decides to spend some time reviewing device history records (DHRs) during one of their friendly visits and the DHR is loaded with nonconforming material reports with a plethora of UAIs, your CJO is going to have some serious explaining to do.
For this week’s DG, the doctor will leave the readers with just one takeaway. Please do not treat design or process changes lightly and attempt to bury them in the DHF. All changes made to a cleared or approved device need to be assessed with an appropriate level of rigor and when warranted, verification and/or validation activities pursued. It is always going to be better to pursue a conservative regulatory path and reach out to FDA versus throwing caution to the wind and hoping an FDA investigator just does not notice design or process changes made to a device during a routine examination of DHFs, change requests or nonconforming material reports. If you do not believe Dr. D, give the CJO that was the recipient of the warning letter referenced in this week’s DG a call. In closing, thank you again for joining Dr. D, and I hope you found value (and some humor) in the guidance provided. Until the next installment of DG, cheers from Dr. D. and best wishes for continued professional success.
Code of Federal Regulation. (April 2016). Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
Code of Federal Regulation. (April 2016). Title 21 Part 807: Establishment registration and device listing for manufacturers and initial importers of devices. Washington, D.C.: U.S. Government Printing Office.
Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
Devine, C. (2013). Devine guidance for managing key attributes of a FDA-compliant quality management system – 21 CFR, Part 820 Compliance. Charleston, SC: Amazon.
FDA. (March 2017). Inspections, Compliance, Enforcement, and Criminal Investigations. Arc Bio Medical Canada Corp. Accessed April 7, 2017 Retrieved from