Folks, for those of you that work for an establishment that has recently been blessed with a visit from FDA, for a cup of coffee and inspection, you have probably noticed that the investigator(s) spent more time on design controls versus previous visits. As part of the inspection, the investigator(s) probably inquired about design changes made to your establishment’s products, including how the changes were validated. Remember, even what may appear as simple design changes need to be reviewed for the need to repeat design validation (DV). Considering that Mr. Murphy is alive and well and living in the medical device industry; benign changes such as changing the color of a catheter shaft by adding a new colorant to the resin; or adding a couple of additional pages to the Instructions for Use (IFU); because of the need to add additional information, still requires a validation and/or written rationale as to why repeating DV is not required. Conversely, you can be like the establishment Dr. D selected for this week’s warning-letter bashing and just throw caution to the wind and not perform DV. Besides, what is the absolute worst-possible thing that can happen—an agency warning letter? After all, attempting the “nomothetic” (look-it-up) characterization of 21 CFR, Part 820, while deciding to pick and choose which sections of the Quality System Regulation (QSR) an establishment wishes to comply with, will always end badly for the establishment. Just ask the Chief Jailable Officer (CJO) for the establishment awarded the warning letter discussed in this week’s guidance. Enjoy! 

Warning Letter –  February 4, 2015

Simply stated, ensuring that designs are properly validated is one of the salient requirements associated with the design, development and entering into commerce a finished medical device to ensure that is safe and effective in its intended use. In fact, depending upon the design change and device class, a new 510(k) (abbreviated, special, or traditional) or a PMA supplement may be required. If the doctor was the CJO, me thinks that Dr. D would be asking questions about the DV. If DV had not been performed, the question to be asked would be: What in the heck is going on? Obviously, premised on Observation One (1) in the warning letter, the winner of this warning letter prize failed to understand the requirements delineated within Subpart C, and specifically, §820.30(g) of the QSR. Note to CJO, warning letters are great learning opportunities, but seriously, this is a major league screw-up. Additionally, providing the FDA with a less-than-adequate response—well, you might as well poke a polar bear in the eye with a sharp stick. Either way, bad things are about to happen.

Warning Letter Excerpt

“Violations include, but are not limited to, the following:
 
Observation One (1): Failure to establish and maintain procedures for validating device design. [21 CFR 820.30(g)]
 
For example:

• You failed to validate the BR2 Bilirubin Calibrator (list #9459), which included a change from (b)(4) to (b)(4) source material.
• You failed to conduct stability tests for the BR2 Bilirubin Calibrator (list #9459, which has a 15 month expiration date).
• You failed to conduct stability tests and performance validations on all products affected (and at least 14 other products) when cap design of 5 mL Amber Vial (list 4050) was changed from a threaded cap to a crimped cap. Additionally, your firm received Complaint CG010 dated 5/10/12 which revealed JAS Ammonia Ethanol Control lots manufactured with crimped caps resulted in elevated ammonia levels. Your investigation report states that the firm was aware of a leaching problem with the cap change.
• Stability testing for the Bilirubin Standard Kit (list # 9450) is inadequate, in that there is no statistical rationale for testing one vial from each of 5 activity levels.

We have reviewed your response and have concluded that it is inadequate. Please provide documentation to verify when the CAPAs have been completed. A follow up inspection will be required to assure that corrections are adequate.”

Subpart C – Design Controls

Section 820.30 – Design Controls
(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

The doctor purposely decided to just cover one segment of design control this week, as to adequately cover all of design control in one blog article is just not possible, even for Dr. D. In breaking down the QSR requirements, DV can be broken down into a 6-Step Model. In fact, let’s call it Dr. D’s 6-Step DV Model. Remember, the purpose of DV is to ensure that the devices being designed conform to the proposed intended use and specified user needs (use the product specification for guidance).

• Step 1 (Manufacturing Test Samples). Best practice is to ensure that DV is performed using samples manufactured under normal operating conditions or in conditions that can be deemed as equivalent.
• Step 2 (Risk Management). Ensure risk management is an essential ingredient (EN ISO 14971:2012) of the DV process. Note: The last time Dr. D checked, ISO 14971:2007 was identified by FDA as a consensus standard.
• Step 3 (Software Validation). Remember, our friends from the agency also care about software, so it is a fundamental requirement to validate software, if deemed applicable for the finished medical device.
• Step 4 (Testing & Inspection). All product testing and inspection should be performed under actual production conditions. However, simulated use conditions are acceptable.
• Step 5 (Protocol & Report Generation). DV testing always requires a: (a) well-written protocol; (b) trained operators; (c) sample sizes premised on written rational (attribute versus variable); (d) suitable test, calibrated measuring, and calibrated monitoring equipment; (e) an appropriate application of statistical analysis; and last but not least, (f) a validation report that captures all of the relevant DV information (note: it is retained in the Design History File (DHF).
• Step 6 (Written Procedure). Finally, and yes this is Dr. D’s broken record time; “please do not forget about scripting a robust procedure for DV.” If the decision is to incorporate all design control requirements into on robust procedure; well that is acceptable too.

Takeaways

For this week’s guidance, the doctor will leave the readers with five takeaways.

1. DV is a salient requirement when designing and developing finished medical devices that are safe and effective in their use.
2. Some design changes may require a new 510(k) or PMA supplement (premised on device class – II or III).
3. DV starts with a robust protocol.
4. All DV work must be documented in a written report.
5. All DV activities are retaining in the DHF.

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. (April 2014) Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
2. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
3. Devine, C. (2013). Devine guidance for managing key attributes of a FDA-compliant quality management system – 21 CFR, Part 820 Compliance. Charleston, SC: Amazon.
4. FDA. (February 4, 2015). Inspections, Compliance, Enforcement, and Criminal Investigations. Verichem Laboratories, Inc. Accessed April 7, 2015. Retrieved from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm433248.htm