Folks, I know the doctor has mentioned on a few occasions the fact that there is no magic number or equation that translates FDA Form 483 observations into warning letters. Now granted, most recipients of that prized agency warning letter usually rack up several Form 483 observations before winning that prestigious prize. However, the establishment referenced in this week’s Devine Guidance (DG) managed to receive only one. I guess the Chief Jailable Officer (CJO) thought that some blithesome (look-it-up) days must be in the future of his or her establishment premised on receiving just one Form 483 observation. Oops, the folks at the agency’s New England office thought otherwise and turned what could appear to be a relatively pain-free inspection on the surface into a source of some serious regulatory angst. Enjoy!

Warning Letter –September 30, 2015

As mentioned in the opening paragraph, this establishment received only one Form 483 observation, but was it a doozy. I guess investigators tend to frown down upon having two distinct design validation reports that share the same title but not the same results. Additionally, testing units that appear to be of a different design, without written rationale as to why testing two sets of disparate samples was an acceptable approach, oops. Furthermore, failing to perform and document a formal failure investigation into potential design validation failures, oops. And for not completing an aging study, as required by the report, clearly qualifies for another oops. For not having an approved protocol that delineates the entire proposed design validation process, that qualifies for a serious oops. For providing the FDA with an inadequate response to the Form 483 observation, that was probably the ultimate oops that resulted in the issuance of the warning letter.

Warning Letter Excerpt

Observation One: “Failure 1. Failure to establish and maintain procedures for validating device design to ensure that devices conform to defined user needs and intended uses to ensure that the results of the design validation, including identification of the design, method(s), the date, and the individual(s) performing the validation, is documented in the DHF, as required by 21 CFR 820.30(g). For example, design validation studies performed on your Banyan Cannula and Trocar Packs revealed the following deficiencies:

• For report entitled, “Physical Bench Testing Study performed on Banyan Medical Cannula/Trocar new, accelerated and real time aged product, per GeoTec protocol 170004-01”, signed 2/28/2013”:◦Your firm did not have an approved protocol that listed accepted specification criteria to demonstrate the finished products met your approved criteria.
• We observed two separate versions (B) of the same report both dated February 28, 2013.  One version included failing bend testing results. The second version did not include the failing data and did not provide any explanation for the failing results.
• For compression testing performed on the cannulas, there was no justification for various differences between the cannulas tested as part of this study; for example, the number of cannulas tested ((b)(4) vs. (b)(4)), the lengths tested ((b)(4) vs. (b)(4)), whether or not the cannulas had side-ports, whether or not the samples were sterilized prior to testing, or whether or not the cannulas went through accelerated aging.
• For the mechanical tensile testing performed on the trocars, there was no justification for various differences between the trocars tested as part of this study; for example, the number of devices tested ((b)(4) vs. (b)(4)), the length tested ((b)(4) vs. (b)(4)), the tip type ((b)(4) vs. (b)(4)), or aging ((b)(4)-year accelerated vs. date of manufacture).
• For the mechanical puncture testing performed on the trocars, there was no justification for various differences between the trocars tested as part of this study; for example, the differences in quantities tested ((b)(4) vs.(b)(4)), length ((b)(4) vs. (b)(4)), tip type ((b)(4) vs. (b)(4)), or whether or not the samples were sterilized prior to testing.
• There are no comparisons of results from one specific group to another to show if the results were within acceptable limits (i.e. test success or failure).
• For report entitled, “Report of Shelf-Life of Banyan Medical Disposable Cannula and Trocar Accelerated and Real-time Aging Analysis dated 2/4/2013”: There is no explanation for three failing sterile package peel strength tests.
• Your firm has not conducted real time aging study for the Banyan Medical Cannula/Trocars as required by this report. The report summary states that the real time aging study should be completed by June 14, 2015; however this test has not yet been initiated.

FDA Response

“Your response is not adequate to address this violation. You have justified your rationale for the failures discussed on the FDA-483, but have not provided documentation to show that the above devices have undergone appropriate deign validation testing nor have you provided any documentation of real time stability testing.   In response to the Warning Letter, you should provide us with a description of the steps you are taking to remedy this violation, including any recent validation and stability testing conducted to correct this violation.”

21 CFR, Part 820.30(g) – Design Validation

“Each manufacturer shall establish and maintain procedures for validating the device design. Design validation shall be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents. Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing of production units under actual or simulated use conditions. Design validation shall include software validation and risk analysis, where appropriate. The results of the design validation, including identification of the design, method(s), the date, and the individual(s) performing the validation, shall be documented in the DHF.”

Compliance for Dummies

If you have not made the connection by now, the FDA takes design validation extremely seriously. After all, design validation is what device establishments should be using to ensure that the correct device was designed versus design verification and answers the question of was the device designed correctly. Like any other validation exercise, design validation commences with a well-written protocol that contains clear and concise objectives for the testing to be performed. This includes:

• Scope and purpose
• List of approvers
• Sample size rationale premised on risk
• Equipment to be employed
• Manufacturing and traceability requirements for the samples
• Metrology requirements
• Training requirements
• Detailed description of the testing to be performed (e.g., aging study)
• Pass/fail criteria
• Requirements for handling deviations and failures
• Requirements for repeating design validation
• Record retention

Once the validation protocol has been scripted, reviewed and approved, it is time to execute the protocol. Make sure the protocol is 100% executed. If deviations are noted, ensure each deviation is sufficiently documented in the report. Since the design, development and subsequent verification and validation testing of medical devices is not necessarily a precise science, design validation failures are bound to occur. When such failures do occur, the expectation is that a thorough failure investigation will be performed. If it is determined that a repeat of design validation is warranted, so be it! Please do not be the CJO that is bullied into accepting data that cannot be defended when the agency knocks on your establishment’s front door for a cup of coffee and an inspection.

Finally, make sure the design validation report is complete. This includes conclusions made (pass or fail) supported by documented evidence. If the evidence fails to support an acceptable result, the report should never sugarcoat the outcome. People, the outcome is real simple in a design validation report: Pass or Fail!

Takeaways

For this week’s guidance, the doctor will leave the readers with three takeaways. One: Always script a well-written protocol that documents all of the design validation activities to be pursued. Two: Always ensure that the validation protocol is fully executed. Three: Ensure the validation report reflects all aspects of the design validation protocol requirements being completed, including a definitive Pass or Fail statement. 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

• Code of Federal Regulation. (2015, April). Title 21 Part 820: Quality system regulation. 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. (September 30, 2015). Inspections, Compliance, Enforcement, and Criminal Investigations. Banyan Medical, LLC. Accessed October 19, 2015. Retrieved from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm465681.htm