Recent warning letters have shed light on common mistakes companies make when responding to 483 findings. Here are a few best practices for addressing FDA’s concerns and mitigating the risk of further regulatory action.
By Kristen Grumet
In 2014, FDA conducted 527 medical device compliance inspections in the United States, almost half of which resulted in the issuance of an FDA Form 483.
The window for ensuring that FDA will consider a response before taking further regulatory action is a mere 15 business days after the close of an inspection. As such, companies are expected to correct all deficiencies within that timeframe—a difficult and highly unlikely demand—or ensure their response fully addresses the FDA 483 findings, evaluates the root cause(s), and identifies short- and long-term corrective actions with realistic milestones and timelines.
But addressing these points in a manner that satisfies FDA's expectations is perhaps more challenging than it appears. Case in point: A total of 64 U.S. medical device warning letters were issued in 2014 for violations related to quality systems, corrections/removals, medical device reporting, premarket notification, and registration/listing. The majority of these warning letters included language about how the 483 response was found deficient in some way.
So, how do companies ensure that their response adequately addresses FDA's concerns and, in turn, avoid triggering further regulatory action?
Among the most commonly cited inadequacies seen in recent letters are:
- Failure to provide evidence of training to new or revised procedures
- Failure to provide evidence that the specific example cited in the 483 observation was corrected
- Failure to conduct a retrospective review
One unfortunate firm managed to receive citations for all three inadequacies in its response to the following observation: "Failure to establish and maintain adequate requirements, including quality requirements, that must be met by suppliers, contractors, and consultants, as required by 21 CFR 820.50(a)... For example, your firm contracts [redacted]; however, there is no documentation recording the evaluation and approval of these contractors."
In its response, the company submitted its Supplier Evaluation and Monitoring SOP. But the warning letter deemed the response inadequate because it did not provide evidence of training to the procedure, did not provide evidence that the specific contractor cited in the observation was evaluated, and, finally, did not provide evidence that a retrospective review was performed to ensure other contractors and suppliers were evaluated as required.
This single example provides the following valuable lessons for developing a 483 response:
- Understand FDA's definition of "establish" when revising or creating procedures. Per 21 CFR 820.3(k), "establish means define, document (in writing or electronically), and implement." Training is an integral part of implementation and is therefore expected to be included as part of the response package when submitting new or revised procedures.
- Address the actual example cited in the 483 observation. In the effort to provide a systemic corrective action to a finding, companies sometimes end up overlooking the specific example cited in the form. It is imperative, though, to correct the cited examples (generally considered as corrections) as well as the system glitch that allowed the noncompliance to occur in order to prevent recurrence (the corrective action), and, in many cases, to also look beyond the immediate issue to see where else a similar noncompliance could occur (the preventive action). The evaluation of each 483 finding should take all three of these elements into consideration, and objective evidence supporting this evaluation should be submitted as part of the response.
- Evaluate the impact of a long-standing deficiency on past practices, decisions, and records. The procedural revisions that are often submitted as a corrective action to a 483 citation generally affect the state of compliance moving forward, but do nothing to remedy past deficiencies. Therefore, it is also important to evaluate each 483 observation for the need for a retrospective review, especially when the new or revised procedures implement significant changes to the process or decision-making criteria. FDA will generally accept two years as an adequate timeframe for a retrospective review; however, there are times when two years is not sufficient to provide the required information or to identify long-standing or high-risk issues. So, companies should be prepared to defend the duration of the retrospective review as well as any sampling plans that are used to analyze the data as part of its response.
There are other mistakes commonly cited in recent warning letter inadequacy statements. However, the three outlined above help to underscore the importance of thoroughly evaluating each finding—both specifically and systemically—developing a corrective action plan that looks both backwards and forward, and providing all of the objective evidence necessary to demonstrate and support that thorough review in the 483 response. Because completing such a thorough review is not always possible within the 15 business day deadline, the 483 response also needs to include reasonable and realistic milestones and completion timeframes for any corrective actions that have not yet been completed.
Get additional tips and advice for effectively responding to 438s during Kristen Grumet's presentation, "Effectively responding to 483s and warning letters," on Thursday, February 12, at the MD&M West conference in Anaheim, CA.
Kristen Grumet is the executive director, medical devices, at NSF Health Sciences, a division of NSF International.
[Image courtesy of Stuart Miles/FREEDIGITALPHOTOS.NET]