Forgot to mention 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.
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Original Message:
Sent: 06-Dec-2023 12:38
From: Kevin Randall
Subject: Response to a FDA Form 483
Great topic; probably my favorite type of work!
The specific nature and extent of the three FDA-483 Observations will influence FDA's ultimate expectations for your response. I would need to see those Observations to provide definitive advice. But in general, YES, to neutralize FDA's internal operating triggers for escalated compliance gestures like Warning Letters, your response needs to include, or promise to provide in scheduled course, the particulars about which you're asking [the root cause assessment, 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)]. I explain further below.
FDA investigators often emphasize that the 483 response would be our planned corrective actions. But 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. I discuss that further later in this thread.
On that note, I'm not recalling any 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 your question 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 threads, 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. Check out this prior Forum thread 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.
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Kevin Randall, ASQ CQA, RAC (U.S., Europe, Canada)
Principal Consultant
Ridgway, CO
United States
© Copyright 2023 by ComplianceAcuity, Inc. All rights reserved.
Original Message:
Sent: 06-Dec-2023 06:01
From: Dan O'Leary
Subject: Response to a FDA Form 483
First, you don't need to respond to a 483. However, if you don't you run the risk of a Warning Letter. Your goal is to prevent a Warning Letter. You need to keep FDA informed of what you are doing to ensure they know you take the observations seriously and doing the right things.
Frame your actions using corrections to fix the problem and corrections to identify the cause and prevent recurrence. (There is no such thing as root cause!) For corrective action make sure your procedure follows 820.100.
I recommend monthly updates on each observation. They should include a plan, the actions you have taken based on the plan, and the objective evidence. Use the structure of 820.100 to build the plan. One thing that will trigger a Warning Letter is an inadequate response.
For the objective evidence be specific. For example, if an observation dealt with lack of training then identify the people trained, by name and position, and include the training records.
You should have received information about how to submit the response. The last one I did for a client requested PDF files with contents, so you need software that will do that.
Include a "map" of each response showing how it relates to the observation and what you have included. Make it easy for the FDA person to follow and, therefore, generate a warm fuzzy feeling about your company.
Include a letter of transmittal signed my Management with Executive Responsibility. This shows management commitment to resolving the observations.<o:p></o:p>
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Dan O'Leary CQA, CQE
Swanzey NH
United States
Original Message:
Sent: 05-Dec-2023 09:42
From: Anonymous Member
Subject: Response to a FDA Form 483
This message was posted by a user wishing to remain anonymous
Hello,
The company I work for had our first FDA inspection. This is also the first FDA inspection I have experienced. I am working on the response to the three observations on our 483. There is not much guidance from the FDA on the format for a response, but I am finding some variance with the guidance I am finding online. The items in particular that I am not sure about including are the root cause assessment, a verification of effectiveness, and including a plan to provide routine updates on our progress for the Corrective Action plans. Our inspector made it seem like a response to the 483 would be just our planned corrective actions, so I was surprised to see so much 483 guidance suggest providing periodic updates on the progress. I am also used to our Notified Body who is very clear about what they want to see as a response.
I was curious if anyone had any guidance on when to provide more than just restating the observations and providing the planned corrective actions.
Thank you,