So your organization has received a warning letter from the FDA – now what? From FDA’s perspective, you either failed to respond promptly and completely to the Form 483 observations; or the agency just decided that your organization’s QMS is irrevocably broken.

For starters, the agency has quickly upped the ante in regards to taking the next steps in ensuring your organization clearly understands that a continued state of non-compliance is not acceptable. In short, FDA issues warning letters when:

1. Form 483 responses are seriously deficient; 
2. An organization has failed to respond to a Form 483; 
3. The violations of the Act are so egregious, the FDA has decided to move rapidly to warning letter; or 
4. All of the above. 

In fact, the warning letter signifies the beginning of some serious regulatory whoop-ass being unleashed by the agency. Dr. D likes to call this FDA Purgatory. Once an organization migrates to under the umbrella of an FDA warning letter, business as usual comes to an abrupt end. The agency is no longer obliged to review and approve new product submissions. Can you say no PMA approvals? Additionally, letters needed by foreign governments for product exportation, a.k.a., FDA Export Certificates are no longer reviewed, approved, and signed. For medical device manufacturers these certificates are formally known as: (a) Certificate to Foreign Government; and (b) Certificate of Exportability. The impact to an organization’s bottom line can be severe, as these certificates begin to expire.

The amount of time spent in warning-letter land is entirely up to the organization and the number of objectionable conditions noted in the warning letter. If the responses formulated and sent to the agency lack depth and detail, and FDA believes the responses are inadequate or ineffective, the time spent in the proverbial “land of lost opportunities” can be years. Dr. D strongly recommends the pulling out of all stops so organizations can quickly extricate themselves from FDA Purgatory. One thing your chief financial officer (CFO) will find out quickly. is the healthy “remuneration” (look-it-up) paid to specialists capable of assisting in the cleanup of the warning letter mess. Folks, correcting a warning letter is never going to be cheap; and Dr. D says you can take that to the bank.

What is a Warning Letter?

Just because an organization is a Form 483 recipient, at the close of an inspection, does not necessarily translate into a warning letter. Upon conclusion of an inspection, the FDA investigator is tasked with writing the Establishment Inspection Report (EIR). The completed EIR will be reviewed at the local district office; and if the reviewer believes the content and evidence depicted in the EIR points to serious deficiencies in an establishment’s quality system, then a warning letter will be issued. Additionally, as of April 2009, the agency has adopted a policy of automatically issuing warning letters to establishments failing to respond to a Form 483 within the allotted 15-days. Ouch! There will be no susurrous (look-it-up) opening phrases in the initial paragraph of the FDA’s warning letter. In fact, the warning letter’s opening paragraph typically commences with, “During an inspection of your firm” and ends with “Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include documentation of the corrective action you have taken.”

According to FDA, the issuance of a warning letter is one of the tools in their enforcement bag. The purpose of the warning letter is to attempt to extract a voluntary correction of objectionable conditions by the agency. Remember, the issuance of a warning letter is not the final regulatory action available to the agency. In fact, Dr. D’s position is the warning letter is the proverbial warning shot. As the doctor stated in the opening paragraph, the warning letter results in a significant interruptions in the day-to-day activities of the recipients.  

What happens next?

The good news is that the U.S. Marshalls have not shown up at your establishment’s doorstep to chain and padlock the doors. More good news – a warning letter, although painful, is a recoverable event and can make an organization stronger. Similar to the saying: “What doesn’t kill you makes you stronger!” Dr. D strongly recommends that if the organization does not have the expertise to respond to the warning letter or does not retain legal counsel that understands the entire process, this expertise be acquired immediately. One thing an organization must remember is that the warning letter is not a simple overnight fix. Warning letters typically result in a protracted period where corrections to the objectionable conditions are achieved. This is not rocket science folks, the more observations depicted in the warning letter, the longer the stay in FDA Purgatory. 

Responding to a Warning Letter

Responding to a warning letter is similar to that of a Form 483. Upon receipt of the warning letter, an organization has 15 working days to respond. Additionally, the doctor strongly recommends that legal council review all correspondence with the agency. Once again, the recipient of the warning letter should draft a cover letter with all correspondences back to the agency. There will be several during the life of the warning letter so meticulous records of each submission should be kept. For example, in responding to the warning letter, the doctor recommends the following information should be considered in the response:

1. A restatement of the Form 483 Observation;
2. The proposed corrective action or plan (ensure past, current, and future states influenced by the observation are assessed);
3. Reference to the specific CAPA number;
4. Ensure root cause is determined and addressed;
5. Don’t forget about the verification of effectiveness for all CAPAs pursued;
6. Potential impact to product;
7. Potential impact to the quality system; and
8. The targeted date for completion.

Warning Letter watch-outs – what not to do

Dr. D has a few watch outs he will share with the readers. 

1. Never, never, never, never, complain that FDA has singled out your company and is intentionally picking on you. 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 organization as part of the correction activities.
3. Remember, the agency will verify objectionable conditions have been closed prior to lifting the warning letter, so ensure all correction activities are closed prior to scheduling a follow-up visit by the agency.
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 FDA a 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, FDA would not have issued the warning letter if they did not believe the enforcement action was warranted,

Takeaways

Yes, warning letters are life-changing events for device manufacturers; however, they are recoverable. Dr. D always recommends getting legal counsel and industry experts involved when responding to a warning letter, reviewing subsequent correspondences to the agency, and the actual steps pursued in correction the objectionable conditions. Always remember, the FDA is not picking on you but they have a responsibility to protect public health. It is the agency’s position that the objectionable conditions delineated within each waning letter could have an adverse effect on public health.

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. (2012, April). Title 21 Part 820: Quality system regulation. Washington, D.C.: U. S. Government Printing Office.
2. Cooper, R. & Fleder, J. (2005). Responding to a form 483 or warning letter: A practical guide. Food and Drug Law Journal, 60(4).
3. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
4. Lookabaugh, M. (2006, May). Responding to FDA 483s and warning letters – presentation to Parenteral Drug Association. Parexel Consulting. Lowell, MA.