An establishment does not need to rack up a small mountain of Form 483 observations to find their way into the FDA’s doghouse. In fact, sometimes all it takes is two or three poorly written responses deemed inadequate by the agency to receive that prized warming letter. My dear readers, there is definitely an art form associated with responding to Form 483 observations. Simply stated, the FDA expects a thorough 360-degree assessment of the deficiency (a.k.a. observation) noted including the past, present and future state of the system or process that fails to comply with the quality system regulation (QSR). A simple promise to fix with no supporting evidence of compliance is not going to do the trick. Sometimes it takes a Chief Jailable Office (CJO) with the ability to generate perspicuous (look-it-up) prose to ensure the FDA clearly understands, and buys-into, an offending establishment’s plan for bringing the quality management system (QMS) back into compliance with all applicable quality, regulatory and statutory requirements. Enjoy!

Warning Letter – May 8, 2017

The warning letter mentioned in this week’s guidance is fairly innocuous with one exception: All of the responses were deemed to be inadequate by the FDA. In baseball, three strikes and you’re out. I guess when dealing with FDA, three for three, when it comes to inadequate responses, and you receive a warning letter. The doctor is just kidding of course, as there really is no set formula for what triggers the awarding of a prized agency warning letter. However, inadequate responses surely must be a factor.

Warning Letter Excerpt

Observation One (1) – “We reviewed your response, dated September 29, 2016 and find it is not adequate. The response states that the hypodermic syringes were sterilized using the validated (b)(4) however the response has not provided evidence to ensure the medical devices met specified sterilization parameters.”

Observation Two (2) – “We reviewed your response, dated September 29, 2016 and find it is not adequate. Your firm’s response has not addressed all lots of syringes affected by the omission of the requirement. The revision includes requirements that state the product shall be sterilized using a specified validation protocol. However, there still is no indication whether your supplier processed the devices using the specified conditions to ensure sterility.”

Observation Three (3) – “We reviewed your response, dated September 29, 2016 and find it is not adequate. The response explains that some of the corrective /preventive actions were not verified for their effectiveness due to a lack of process for quality personnel to identify the CARs/ SCARs that required follow up on verification of their effectiveness. Your firm has not addressed the CAPAs that were deemed effective on the same day the corrective action was implemented. The CAPAs did not contain objective evidence for their closure as required by your firm’s CAPA procedure in section 2.7.3 that states corrective actions will be identified as effective when there is supporting objective evidence. No further information was provided.”

Compliance for Dummies

As mentioned in beginning of this week’s guidance, responding to a FDA Form 483 Observation is an art form. For starters, regardless of what the investigator states verbally, establishments have 15 days to respond to the initial observations. The good news is establishments are not obliged to respond to the FDA. The bad news is that if an establishment fails to respond to the observations, the FDA can quickly open up a special can of regulatory whoop-ass. The first thing out of the can is usually the warning letter. If the warning letter doesn’t capture the CJO’s attention, a consent decree popping out of the can should do the trick. If that doesn’t work than product seizures, injunctions and U.S. Marshalls with chains and padlocks can quickly ruin a CJO’s afternoon. However, this can all be prevented with some steps rooted in common sense:

1. Respond to the Form 483 observations within 15 days.
2. When responding to the Form 483 observation, begin the response with an acknowledgement that the seriousness of the violations are understood and clearly convey a commitment to bring the establishment back into compliance (a.k.a., the CJO needs to be willing to fall on the proverbial sword).
3. In the initial response, attempt to provide initial root cause and containment activities being pursued.
4. If procedures are being revised, ensure copies of the revisions are provided to FDA. Just in case you have not noticed, the agency loves documented evidence of compliance.
5. Depending on the number of observations received, put together a robust correction plan. The FDA does not expect everything to fixed immediately; however, they do expect the compliance issues to be resolved quickly.
6. If you make commitments to the FDA in the initial observation response plan, make sure you keep your commitments. If the commitments cannot be made, provide the agency with adequate rationale. Remember, not having adequate resources is not adequate rationale. Besides, when it comes to quality, money should never be a concern, right?
7. Best practice is to provide FDA monthly updates until all corrections have been made. The FDA may choose to stop by for a cup of coffee and a re-inspection once the corrections have been implemented. Heck, extend the invitation for that next visit.
8. Remember, documentation and good communication skills are your best friends when working with FDA on closing out Form 483 observations.

Takeaways

For this week’s guidance, Dr. D will leave the readers with just one takeaway. Responding to Form 483 observations is an art form. It is imperative that the steps an establishment is going to pursue in mitigating Form 483 observations must be clear, concise and supported by documented evidence. Remember, documentation and good communication skills are always going to be your best friends when working with FDA. In closing, thank you again for joining Dr. D, and I hope you found value (and some humor) 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 2016). Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
2. Code of Federal Regulation. (April 2016). Title 21 Part 806: Medical devices: reports of corrections and removals. 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. (May 2017). Inspections, Compliance, Enforcement, and Criminal Investigations. International Medsurg Connection, Inc. Accessed June 25, 2017. Retrieved from https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm558368.htm