December 6, 2023

Responding to a Form FDA 483

One of my favorite types of work is responding to a Form FDA 483.

The specific nature and extent of an FDA 483 Observation(s) will influence FDA’s ultimate expectations for the response.  Thus, I will always need to see the exact Observation(s) to provide definitive advice.  But in general, the response needs to include, or promise to provide in scheduled course, the root cause assessment(s), a verification of effectiveness, and a plan to provide routine updates on your progress for the Corrective Action plans (among a number of other crucial elements) in order to neutralize FDA’s internal operating triggers for escalated compliance gestures like Warning Letters, your I explain further below.

FDA investigators often emphasize that the 483 response would be our planned corrective actions.  Yet my experience is that such emphasis is not to obviate us from providing implementation evidence, but rather to assure the firm knows that it doesn’t necessarily need to have all corrections and corrective actions fully closed within the 15-business-day timeline.

On that note, I’m not recalling any actual FDA regulation prescribing that we need to respond to FDA-483s within 15 business days.  But make no mistake, the 15-business-day mark is an FDA internal operating timeline built into FDA’s inspection management practices and regulatory procedures.  Specifically, FDA investigators are trained/instructed to advise the firm’s management that, if FDA receives an “adequate” response to the Form FDA 483, or other objectionable conditions, within 15 business days of the end date of the inspection, then it may impact FDA’s determination of the need for subsequent action.  This is driven by, and/or linked to, other downstream FDA internal operating procedures such as its Warning Letter trigger procedures directing FDA to make its Warning Letter decision/recommendation within fifteen working days after completion of the inspection.  Accordingly, steer clear of the notion that we don’t need to respond to an FDA-483, as such an assertion can be profoundly costly for your organization.

On the note of Warning Letters, I’ve first-hand seen repeated examples of Warning Letters and Untitled Letters that were issued wherein a cited key trigger was that the firm responded to the 483 but didn’t provide the actual evidence of completed corrections and/or corrective actions.  Here is an example of FDA’s usual language from a current active project I was hired to help resolve:

“…We reviewed your firm’s response where it’s stated that your firm will revise the firm’s CAPA procedures to include verifying or validating the corrective and preventive actions, and implementing and recording changes in the methods and procedures, in addition to perform a systemic (i.e., system wide) review of the firm’s CAPA procedures in order to identify other CAPA procedural nonconformities that may exist. However, the adequacy of your firm’s response and/or proposed actions cannot be determined at this time. Your response does not include supporting documentation to demonstrate that the corrections have been completed. These planned actions cannot be evaluated without supporting documentation...”

This type of FDA escalation is commonplace and pervasive when FDA-483 responses don’t ultimately provide actual evidence of implemented corrections/corrective actions.  Accordingly, be sure your response provides, or schedules to provide in due course, the actual implementation evidence (e.g., copies of revised procedures, copies of retrospective analyses, copies of revised/corrected documents like DHFs, complaints, CAPAs, etc., copies of training records, etc., etc.).

And don’t fall prey to the tempting notion that all of your promised corrections and corrective actions must be fully completed within the 15-business-day timeline.  That can actually increase the chances of FDA escalation when a firm makes unrealistic promises thereby showing FDA that the firm doesn’t truly understand the gravity of the issues.  The timeline for completion of your promised corrections and corrective actions needs to be done commensurate with risk and magnitude of the problems.  Urgency is certainly important; but sensibility about the true scope of the issues is also paramount for avoiding escalated FDA compliance gestures.

To further emphasize the importance of committing to give FDA (and following through) progress reports to FDA showing evidence of your completed corrections and corrective actions, remember FDA’s Warning Letter trigger consideration process for ongoing or promised corrective actions.  Specifically, FDA considers whether the firm’s 483 response contains, “…provisions for monitoring and review to ensure effectiveness…”, and, “…Whether documentation of the corrective action was provided to enable the agency to undertake an informed evaluation…”, and, “…Whether the timeframe for the corrective action is appropriate and whether actual progress has been made in accordance with the timeframe…”.  Put simply, this requires us to provide to FDA progress reports with evidence of our progress in order to help allay FDA’s Warning Letter trigger thresholds.

Regarding questions about showing FDA your root cause investigation: By regulation, FDA requires nonconformities (like those cited in your 483) to be properly processed as appropriate in accordance with the corrective action provisions of 21 CFR 820.100.  While FDA has said that not all nonconformities require corrective action, it is generally accepted best practice to automatically issue an official corrective action(s) covering each FDA-483 Observation.  And because of FDA’s aforesaid requirement for seeing the actual evidence of correction and corrective action in order to conclude that the objectionable conditions are resolved, then this consequently means providing copies of those CAPAs, which shall include the root cause investigation.

I won’t sidetrack this thread with the worn path about the pitfalls of the acronym “CAPA” other than to say that the “CAPA” acronym topic has been addressed ad nauseam in prior posts, and moreover to say that FDA is still pervasively using the “CAPA” acronym as my preceding FDA case quotation shows.  And similarly, regarding the trendy fad of declaring that there is no such thing as “root cause”, I would strongly advise against trying FDA’s patience and process with that questionable notion. I have posted extensively on this in the past where the criticality of finding the root cause(s) of a problem was previously discussed.

Also, be sure you don’t confuse or equate the standardized terms “correction” with “corrective action”.  They have distinctly different meanings and purposes for your FDA-483 response.  Convoluting or being careless about those terms in your quality system or 483 response is a perilous approach.

Don’t forget that an ultimate FDA compliance goal when receiving a Form FDA 483 is to thereafter receive from FDA what FDA has called a “VAI Letter”. The “VAI” acronym comes from FDA’s internal categorization ‘Voluntary Action Indicated’ that is generally given by FDA to inspections/investigations where no further regulatory [such as OAI (e.g., a Warning Letter)] action is expected.

A VAI Letter is issued where FDA has received and reviewed your response(s) to the 483 and does not have objections to your plan nor to the actions implemented to date. The FDA in the VAI letter will generally signal that it appears to FDA that your actions are on the right track, but will stop short of officially endorsing the adequacy/effectiveness of your actions, and that FDA will officially follow-up at the next regularly scheduled inspection.  My experiences have been that once a VAI Letter and the EIR are issued, then we are no longer expected to continue submitting the promised progress reports, though I generally confirm that to be true for each particular case before ceasing the progress reports.