Dr. Christopher Joseph Devine, President, Devine Guidance International
Devine Guidance

One and Done

By Dr. Christopher Joseph Devine
Dr. Christopher Joseph Devine, President, Devine Guidance International

Adulteration, misbranding and design validation cause a problem for one company.

Dr. D is unaware of any crystal ball that allows device establishments to peek into the future and see the outcome of an agency inspection. Generally speaking (in this case writing), when an establishment receives one Form 483 observation during an inspection, the issue is quickly mitigated and the FDA usually placated with the results. However, it is always possible to receive that one Form 483 observation in which the investigator and the agency feels strongly. Maybe it is the wording of the response, lack of objective evidence of correction, or other influencers such as adulterated/misbranded product being entered into interstate commerce. Sometimes, it can be all of the above. For the sake of the Chief Jailable Officer (CJO) on the receiving end of the warning letter referenced in this week’s guidance, the FDA’s nefarious (look-it-up) approach to the issuance of this warning letter can be viewed as a positive and the warning letter quickly mitigated. Enjoy!

Warning Letter –  September 20, 2016

It is the doctor’s extremely humble opinion that the FDA clearly tied the issue associated with the adulterated/misbranded product and the design validation issue together when they concluded a warning letter was necessary. Now granted, the line between product-line extensions and what the agency perceives as a critical design change seems to be blurrier than ever (another one of Dr. D’s humble opinions). That being said, it is imperative that regulatory professionals be involved in the decision loop when design changes are made. If the decision made by the agency is that a PMA or 510(k) was warranted, the FDA is going to win this argument 99.9% of the time. It is just not worth the regulatory pain to get these decisions wrong.

Warning Letter Excerpt

Observation One (1). “Failure to adequately conduct design validation to ensure that the device conforms to defined user need and intended uses, as required by 21 CFR 820.30(g). For example:

A.  The Instruction for Use for ZCORE Porcine Xenograft Particulate in Syringe indicates that the porcine material in the syringe is hydrated with osseous coagulum, patient blood or sterile normal saline by pulling and pushing the syringe plunger to draw and expel the blood or saline mixture. The firm conducted a functional assessment of the product by assessing the hydration using a saline solution and ease of deployment of the hydrated porcine material through the syringe tube using a (b)(4). However, the design verification or validation study was not conducted to ensure that the product conforms to defined user needs and intended uses. Complaint No. CC-347, received on 9/4/15, indicates that Porcine Mineral in Syringe, Lot No. PMCSU15A1 and Lot No. PMCSUA2, were not ejecting smoothly from the syringes.  MRB No. 0915-454, dated 9/16/15, and ICAR No. 1156, dated 11/14/15, indicate that Porcine Mineral in Syringe, Lot No. PMCSU15A1, was rejected because it was difficult to eject the porcine material from the syringe. The firm’s memo to Correction and Removals File, dated 11/17/15, indicates that Porcine Mineral in Syringe, Lot No. PMCSU15A1 and PMCSU15A2, were removed from your firm’s distributor before or on 11/17/15 due to the afore-mentioned syringe issue.”

21 CFR, Part 820.30(g)

(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

Unless a medical device is clearly defined as being exempt from the FDA’s review process, a 510(k) or pre-market approval (PMA) is required to place the product into commerce in the United States. People, this is not an option or a topic open to discussion with the FDA. Simply stated, “compliance is mandatory!” Device establishments that fail to comply with the 510(k) or PMA process will soon find themselves in the FDA’s doghouse. Can you say warning letter? Can you say product seizures? Can you say consent decree? All of the previously mentioned regulatory steps are possible, as the FDA has the ability to quickly escalate the regulatory pain as a way of enforcing their will to drive home compliance with offending establishments. On the bright side, most establishments will work diligently to achieve and remain in compliance with quality, regulatory, and statutory requirements.

As for the design validation piece, the FDA has been focusing on design controls for several years. The key to manufacturing a finished medical device that is safe and effective in its intended use is rooted in the device’s design. Design verification and design validation are salient tools needed to ensure medical devices remain safe and effective. Additionally, design validations are often entry points used by FDA to see if design changes are occurring over time. For example, if a device establishment decides to change the color of a catheter handle from blue to purple or decides to tighten the design specification through tighter tolerances, a new 510(k) is probably not warranted. However, if the design change includes additional marker bands needed for an expanded indication for use, you just might want to start working on that 510(k). You see dear readers, simple things like a change in indications for use is going to require a new 510(k). If you do not believe Dr. D, try reading §807.87(g).

Finally, just like every other event or activity associated with the highly regulated device industry, if an event or activity is not documented, it never happened in the eyes of the FDA. That being said, it is imperative that well-written protocols and test reports are used to document design validation activities. The doctor believes it was W. Edwards Deming who emphatically stated, “In God we trust, all others bring data.”


For this week’s guidance, the doctor will leave the readers with two takeaways. One: It is imperative that all design changes, regardless of how benign they appear, are adequately reviewed for the potential need for requiring a submission to our dear friends at FDA. It is always better to err on the side of caution versus being on the receiving end of a warning letter for adulterated/misbranded products driven by design control issues. In fact, the FDA is very approachable and an email or quick call may help guide establishments toward the right decision. Two: Make sure your regulatory person remains in the loop for all design changes, enhancements, line extensions, etc. They will be in a position to steer you in the right direction. In closing, thank you again for joining Dr. D, and I hope you found value in the guidance provided. Until the next installment of DG , cheers from Dr. D., and best wishes for continued professional success.


  1. Code of Federal Regulation. (April 2015). Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
  2. Code of Federal Regulation. (April 2015). Title 21 Part 803: Medical device reporting. 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. (September 2016). Inspections, Compliance, Enforcement, and Criminal Investigations. Collagen Matrix, Inc. Accessed October 4, 2016. Retrieved from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm522402.htm

About The Author

Dr. Christopher Joseph Devine, President, Devine Guidance International