Folks, obviously device establishments would like to enjoy some autonomy and freedom to process minor design changes without FDA scrutiny. In fact, many benign changes do not require regulatory oversight. However, even the most minor of design changes require some level of due diligence, including the placement of documentation, which clearly delineating the changes made, being placed into the Design History File (DHF). This includes the need to perform additional verification and validation activities, as appropriate, to ensure the changes made do not negatively impact the safety and efficacy of the finished medical device.

For this week’s guidance, the doctor has come across a warning letter citing a device establishment for their failure to notify FDA of significant product changes. Although Dr. D is not a polymer engineer, the old doctor has been in this business long enough to know that a change in resin formulation is a significant change requiring FDA’s scrutiny and subsequent approval, prior to entering the redesigned/reformulated product(s) into commerce. Simply stated, failure to do so will result in the agency’s infamous comment; “Your product is adulterated.” Device establishments that wish to employ a blatant display of “apophasis” (look-it-up) will soon find themselves in the FDA’s proverbial doghouse, which is not a nice place to be. That being said, Dr. D hopes you enjoy this week’s guidance.

FDA warning letter – 24 July 2014

A December 2013 visit by FDA to a device establishment located in sunny Boynton Beach, FL, resulted in the agency awarding a warning letter. The doctor is not quite sure why it took over seven months for the agency to issue this warning letter. Although purely conjecture on the part of the doctor, me thinks this establishment’s initial response to the Form 483 observations were inadequate resulting in an escalation on the part of FDA. Regardless, it is always better to contact FDA to discuss any potential design changes to cleared/approved devices, unless your Chief Jailable Officer (CJO) is absolutely positive no agency action (traditional, special, or abbreviated 510(k), PMA or PMA supplement) is required.

In support of this week’s guidance, Dr. D has taken the liberty to extract one of the salient issues noted in a warning letter dated 24 July 2014.

“Our inspection revealed that after the ProTech Plus Hard Reline and Repair Acrylic received 510(k) clearances (K983547 and K925062), the following significant modifications were made to the denture base resins:

• Your firm currently uses a “(b)(4)” process during the manufacturing process. The 510(k) clearance is for a product which utilizes a “(b)(4)” process. The “ (b)(4)” process uses component ingredients that are different from those listed in the 510(k) clearance.
• Your firm currently uses the coloring components Pigment Red 187, Pigment Yellow 180, and Pigment Red 149. The 510(k) clearance lists colorant components as FD&C Red 40.

Our inspection revealed that the ProTech Plus Self Cure Hard Reline and Repair Acrylic are adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. § 351(f)(1)(B), because your firm does not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. § 360e(a), or an approved application for an investigational device exemption under section 520(g) of the Act, 21 U.S.C. § 360j(g). The devices are also misbranded under section 502(o) of the Act, 21 U.S.C. 352(o), in that a notice or other information respecting the aforementioned modifications to the denture base resins were not provided to the FDA as required by section 510(k), 21 U.S.C. 360(k), and 21 CFR 807.81(a)(3)(i). For a device requiring premarket approval, the notification required by section 510(k) is deemed satisfied when a PMA is pending before the agency [21 CFR 807.81(b)]. The kind of information that your firm needs to submit in order to obtain approval or clearance for the device is described on the Internet at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/default.htm. The FDA will evaluate the information that your firm submits and decide whether the product may be legally marketed.”

21 CFR, Part 807 – Subpart E–Premarket Notification Procedures Section 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

Not wanting to state the obvious but obliged to do so, if your organization enters Class II products into the U.S. market place, then a fundamental understanding of Part 807 should be deemed a salient requirement for all quality and regulatory professionals in your organization, including the R & D engineers. Pursuing a minor change such as changing the color of a polycarbonate catheter handle from white to green (no contact with the blood path) is probably not going to require a traditional, special, or abbreviated 510(k), PMA, or PMA supplement. Just document the changes and the due diligence activities pursued in the DHF. However, if the catheter shaft material is changed from PEBAX to Pellethane, you just might want to let the agency know, as this changed is probably going to be categorized as significant.

If the product is Class III, then a PMA supplement is the order of the day. If marker bands are added or removed from a coronary ablation catheter, you are going to need a PMA supplement (Class III device). If an organization decides to modify, change, or add an indication for use for a cleared/approved device, FDA will want to review the changes before entering the device into commerce. Such changes will require that a new 510(k) or potentially a new PMA be submitted to FDA for review. Please keep in mind, each change is going to be evaluated premised on risk: (a) patient risk; and (b) user risk.

Additionally, it is important to remember that significant process changes may warrant a traditional, special, or abbreviated 510(k), PMA, or PMA supplement. For example, if the process employed to impregnate the drug component of drug eluding coronary stent into a polymer substrate changes, the agency is going to want to assess the changes. Depending on the nature of the change, a PMA supplement or new PMA may be required. Remember, when in doubt contact FDA and ask. Why? Because the agency does not like surprises and typically rewards such surprises with some form of regulatory action such as a WARNING LETTER!

Takeaways

For this week’s guidance, the doctor will leave the readers with two takeaways. One – significant changes made to the design or processing of finished medical devices, that are safe and effective in their intended use, require the review and subsequent approval of FDA. This includes changes in the indication for use. For Class II devices, the regulatory pathway will be the submission of a traditional, special, or abbreviated 510(k). For Class III devices the regulatory pathway will be through the submission of a PMA or PMA supplement. When in doubt, contact FDA and ask.

Two – ensure all design changes, whether agency approval is required or not, are adequately documented in the DHF, including the verification and validation activities pursued in support of ascertaining such changes have not impacted the performance of the finished medical device.

In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Until the next installment of DG – cheers from Dr. D. and best wishes for continued professional success.

References:

1. Code of Federal Regulation. (2013, April) Title 21 Part 807: Establishment registration and device listing for manufacturers and initial importers of devices. Washington, D.C.: U.S. Government Printing Office.
2. Code of Federal Regulation. (2013, April) Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
3. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
4. Devine, C. (2013). Devine guidance for managing key attributes of a FDA-compliant quality management system – 21 CFR, Part 820 Compliance. Charleston, SC: Amazon.
5. FDA’s enforcement page. (2014, August). FDA.gov Website. Retrieved August 17, 2014, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm407468.htm.