Occasionally, small establishments with an inexperienced staff, or those that seek out incompetent consultants, struggle with scripting an acceptable response to Form 483 observations that are awarded as a result of inspection deficiencies. It happens, and the result is typically a warning letter. In fact, it happened far too frequently. However, Dr. D is struggling to understand how a “well-established establishment” (try saying that three-times fast) fails to provide FDA with cohesive responses to Form 483 observations. In a recently issued warning letter (hot off the presses, ladies and gentlemen), the offending establishment received a warning letter with seven observations. Unfortunately, the agency was not impressed by this establishment’s responses. For example, four of the responses received the infamous, “We reviewed your firm’s response and conclude that it is not adequate.” Three of the responses received the somewhat less innocuous, “The adequacy of your firm’s response cannot be determined at this time. Your firm has not provided evidence of the implementation of all proposed corrective actions.” Seriously, 0 for 7 is horrible in baseball and could be fatal to a Chief Jailable Officer’s (CJO) career in the medical device industry. The lesson to be learned here is that a farraginous (look-it-up) response to agency Form 483 observations will probably result in a warning letter. Enjoy!

Warning Letter – March 17, 2016

Similar to last week’s Devine Guidance, this offending establishment provided multiple responses to violations noted during an October 2015 inspection. In fact, the warning letter mentions four responses—ouch! If you are keeping score, this establishment appears to now be 0 for 7 and 0 for 4, in the eyes of the FDA. Does the medtech industry have a minor league? You can’t make this stuff up. Now granted, sometimes a wayward response (one without much thought) makes it way to FDA. Usually, the agency will provide a quick follow-up and request qualification and a subsequent revision. But missing the mark on all seven responses is never going to endear the offending establishment with FDA.  In fact, the FDA is going to turn up the flame of regulatory pain just a tad bit higher to ensure it singes the backside of the CJO. The doctor hopes the CJO is wearing Kevlar.

Warning Letter Excerpt

For those CJOs who just do not feel the burn (sorry Hillary, not to be confused with Bernie), the agency likes to provide little reminders (more like threats) in each warning letter. This not-so pretty-prose is used to remind the offending establishment’s CJO that bad things happen to device establishments that fail to comply with the agency’s wishes. Remember, the FDA really could not care less if a device establishment needs to ship product to keep the cash flow going. The FDA wants compliance, PERIOD!

“Your firm should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and civil money penalties. Also, federal agencies may be advised of the issuance of Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation violations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.”

Compliance for Dummies

The first thing to do when receiving a Form 483 observation is to acknowledge the receipt (typically at the end of the inspection), and if you agree with the observation, promise to correct the violation. If you believe the Form 483 observation is incorrect, it is acceptable to discuss it with the investigator, but never argue to the point where you are angering the FDA. It might be better to just poke a sleeping bear in the eye with a sharp stick. Upon receipt of the Form 483 observation, an establishment will have 15 working days to respond to the FDA.

Additionally, the doctor strongly recommends that quality, regulatory and legal departments review all correspondence prior to shipping it off to the agency. The recipient of the Form 483 observation(s) should always draft a cover letter and include it with all correspondences sent back to the FDA. There may be several correspondences during the life of the Form 483 mitigation activities, so meticulous records for each submission should be kept.

Furthermore, when responding to a Form 483 observation, the doctor recommends the following information should be considered in the response:

• A restatement of the Form 483 Observation
• The proposed corrective action or plan (ensure past, current, and future states influenced by the observation are assessed), including containment activities
• The opening of a CAPA and reference to the specific CAPA number opened by your establishment
• Determination of root cause as part of a robust investigation (Note: Simply stating operator error or poor training will not be acceptable to FDA)
• Verification of effectiveness for all CAPA activities pursued
• Potential impact to product must always be assessed and ascertained
• Potential impact to the quality system shall always be assessed and ascertained.
• The targeted date for completion must be provided

Warning Letter Watch-outs: What Not to Do

Finally, Dr. D has a few watch-outs to share with the readers.

1. Never, never, never, never, complain that the FDA has singled out your establishment and is intentionally picking on your firm. The argument will never fly.
2. Never fail to respond back to the agency, within the 15 days allotted or fail to meet committed dates made by your establishment as part of the Form 483 mitigation activities.
3. Remember, the agency will verify objectionable conditions have been closed during the next inspection period, so ensure all correction activities are closed prior to their next visit. A repeat violation will result in a warning letter being issued.
4. Always provide the agency with sufficient detail and supporting documentation that reflects the actions pursued in support of the corrections.
5. If the corrections are going to take a significant amount of time, give the FDA reasonable timetable for correcting all of the objectionable conditions. Ensure that status updates are routinely provided to the agency.
6. Never downplay or minimize the seriousness of the observation. Remember, the investigator would not have issued the Form 483 observation if they did not believe the action was warranted.

Takeaways

For this week’s takeaway, Dr. D will just reiterate a point that the doctor has made on multiple occasions. A well-written response to a Form 483 observation is an establishment’s best defense against a warning letter. Remember, an establishment has 15 days to formulate a response, which is ample time to script a reasonable and hopefully effective response to FDA. Please do not be that CJO that has to break the bad news to the management team when a warning letter is received for subpar responses made to FDA. 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. (2015, April). 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. (March 17, 2016). Inspections, Compliance, Enforcement, and Criminal Investigations. Terumo Medical Corp. Accessed March 23, 2016. Retrieved from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm491287.htm