This article was originally published on September 9, 2020. It has been updated with new information.
The FDA inspection is now complete. It is time for closeout. What happens next?
In this conclusion to the four-part series summarizing Steven Niedelman’s May 28, 2020 Govzilla webinar presentation on FDA inspections, Niedelman outlines the steps following the conclusion of an FDA inspection. Part I provided background on FDA inspection authority while Part II looked at the different types of inspections FDA conducts. Part III offered advice on interacting with FDA investigators once they are onsite.
Niedelman explained that the FDA investigators will hold a closeout meeting following the inspection. Prior to this, firms the opportunity to ask for daily updates. These daily updates provide the investigators an opportunity to “discuss unfinished and open issues… including those that will be 483 observations.”
FDA 483s can be a great source of information when preparing for inspections. Click here to get a free personalized 483 Observation Report.
The 4-1-1 on 483s
If a 483 is presented, it will be at the closeout meeting.
“Hopefully no 483 is presented,” he said. “But if one is, it goes to the most responsible people at the firm, who should be at that meeting and provide a certain cultural response. There should also be a cross-functional team from the firm in the meeting to address questions that may arise.”
Niedelman recommends that those attending the closeout meeting convene before the investigators leave as the company has 15 days to respond. This provides an opportunity to ask questions about any observations.
“If you do not really understand an observation now and you want to find out about it five days from now, and you find out the investigators are in a foreign inspection, you are out of luck,” he said, adding “device firms can annotate their corrections. They can promise to correct, or note corrected and verified by the investigator, or corrected but not verified by the investigator, or under consideration.”
So, what goes on a 483? Keep in mind, there are limitations by law as to what can be included in a 483.
“There are many topics that do not go on a 483,” Niedelman explained. “For example, verification of registration and listing and labeling violations. They may collect labels, but they then are reviewed by the Center. Similarly, product approval issues, NDA issues, 510K issues for devices, PMA issues, etc.”
If a 483 is presented, it will be at the closeout meeting
Additionally, significant adverse event reporting or appropriate adverse event reporting, “will not go on a 483 unless the investigators had previously provided information to the Center and had gotten a review from the Center that the Center will support the observation that an event should have been reportable.”
How to Respond to a 483?
As stated above, companies have 15 working days to respond to FDA.
According to Niedelman, a company’s response should address any systemic issues cited by the FDA along with the individual violations listed in the 483. The response should then provide full details of actions taken or planned with timeframes plus evidence that the company is making the corrections.
“Most firms open CAPAs to demonstrate to the investigator that corrective actions will be taken to prevent a recurrence of the issue,” he said. “Most firms have monthly or bi-monthly updates that are provided to the agency demonstrating their commitment and their progress towards compliance.”
But it is critical that the response demonstrates that a company is following through on promised corrections. This will require additional documentation within a response.
Companies have 15 working days to respond to FDA
Now Back to FDA
“FDA will assess the findings and review for repeat observations. They do not look favorably upon repeat observations. Those can generate enforcement actions,” Niedelman explained. “They will assess the adequacy of your response and your progress during monthly or bi-monthly progress reports.”
Further, he explained that he has seen clients receive emails from FDA asking for status updates if a progress report is overdue. In fact, FDA may even choose to reinspect a site to verify corrections are being made.
After an inspection, FDA will classify it in one of three categories:
- Official Action Indicated (OAI): Some type of official action is forthcoming, e.g., a warning letter, an injunction, or prosecution
- Voluntary Action Indicated (VAI): While the firm deviates from regulatory requirements, they are not that significant and the agency believes the firm can manage them
- No Action Indicated (NAI): Investigators did not find any observations; more than half of FDA inspections receive this classification
If FDA finds a company’s 483 response inadequate, it could result in a warning letter. If issues continue to occur there could even be additional actions such as prosecution or civil penalties. The most drastic action the Agency could take is a consent decree.
“For firms outside the United States, FDA can impose an import alert or detention without physical examination, which stops product from coming into the United States,” Niedelman said.
[Author’s Note: For more about how FDA can respond to a 483 response, watch the clip below.]
Inspections “Not a Compliance Tool”
In his conclusion, Niedelman stated strongly that inspections are not meant to be a compliance method.
“They are not intended to be used as the tool by industry to measure compliance,” he said. “You are expected to be fully compliant with all the requirements. The inspection report is just a snapshot of what FDA looked at during the inspection.”
A negative inspection can result in consequences for a firm, including financial impact.
“Failure to come out with a good clean inspection can impact your ability to get products approved, certificates from foreign governments, and government contracts,” Niedelman concluded. “Non-compliance with regulations does have serious implications with enforcement actions that the agency has as options.”
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