By Adrienne R. Lenz, Principal Medical Device Regulation Expert & Lisa M. Baumhardt, Senior Medical Device Regulation Expert & Anne K. Walsh —
While we hope readers of the Blog, as our clients and friends, come out of any FDA inspection with a clean bill of health, we know that based on FDA FY2024 data to date, approximately 40% of inspections of medical device companies end up classified as voluntary or official action indicated (VAI or OAI). These classifications usually result from observations listed on the FDA investigator’s report (a Form 483).
When an establishment receives a Form 483, FDA’s Compliance Program Manual for Inspection of Medical Device Manufacturers indicates that “Corrections and corrective action proposals and plans, including evidence of corrections implemented, should be submitted by the firm in writing within 15 business days of the inspection close, detailing the action(s) taken or to correct the deviations within a specified time frame.” Fifteen business days go by quickly! Although the timeline is short, developing and submitting a strong response is critical to reduce the chance that FDA takes further action from the inspection, like the issuance of a warning letter or other enforcement action.
So, what makes for a strong response? Ideally, you will be able to investigate each observation, identify a root cause, take corrective action, make corrections, and explain with written evidence that you completed these actions. While this may be possible for some observations, most of the time the issues that rise to the level of ending up on a Form 483 are challenging problems that take more than 15 business days to address.
Regardless of whether the company can complete activities by the time the initial 483 response is due, or simply sets forth its plan for how it intends to get there, a well-organized response is important. The readers of your response at FDA typically include individuals who were not at the inspection, and even if the original investigator is reviewing your response, they may not remember all of the details given the number of other inspections on their plate.
Given this, most companies will start the response for each observation by reiterating the actual language in the Form 483. Device companies often have a procedure that requires that a corrective or preventive action (CAPA) record is opened for each audit finding, including FDA observations. If you are able to get through the process and have a solid CAPA record before your initial 483 response is due, you should include it as an attachment to the response document. If the actions within the CAPA are still a work-in-progress, the response should include a reference to the CAPA number, and the complete record can be submitted to FDA as part of a later update to the company’s 483 response or made available for review during a future inspection.
An effective 483 response usually looks similar in structure to a CAPA record. First, the company should describe how you have or how you plan to investigate the issue. Will you interview employees, review procedures, review records, and/or use investigative tools such as 5-whys or fishbone diagrams? Be specific. If you have had time to at least start the investigation, describe what you have learned. If continued investigation is planned, describe the next steps and timeline. If you have identified the root cause, or causes, identify them in the 483 response and note that you have completed the root cause investigation.
The next paragraph, or section, of the 483 response should describe any corrective actions you have identified to address the root cause, or if you have not yet completed your root cause investigation by the time your 483 response is due, you should set forth a plan to identify corrective actions based on the results of the investigation. It is important to include targeted completion dates for these activities (more on this below), and if you already have implemented any corrective actions, describe them and provide evidence of completion.
Another important piece to include in your initial 483 response is your corrections to any specific records that FDA identified in the observation. Most companies reflexively do this and assume that is adequate to address the FDA’s concern. FDA expects that the company not only correct the specific finding, but that it conducts a broader retrospective review of other similar records (usually going back two years) to find and correct any other records with the same problem. There is a natural tendency to want to do this first, and sometimes that is the right approach, but often it is best to wait until you have fixed any procedural gaps so that you can apply the improved procedures when correcting regulatory records. For implemented procedural changes, consider providing evidence of training records for those functions impacted by the change. For manufacturing and product-related observations especially, don’t forget to do a “right-left look” to identify if a similar issue has occurred with another product line offered by the company.
Going back to timing, we cannot stress enough the importance of providing reasonable deadlines in your response to give FDA the assurance that you are prioritizing remediation of the observations. We have seen some companies be too aggressive or aspirational with their timelines, and then must explain to FDA in a later update why they missed a deadline. And we have seen some companies include deadlines that are too long and drawn out, which then leads to follow-up questions from FDA. If the 483 response identifies a longer-term plan to address an issue, the company should develop a timeline for completion of each step of the process and share that with FDA.
This means that the frenetic 15 business days to develop a robust response is not the end of the matter. We typically recommend that if a company’s initial 483 response contains outstanding action items, the company should commit to providing FDA with regular updates about progress, usually on a bimonthly basis, until all actions have been completed. We recommend, as part of your initial response or in the first update, providing FDA with a table identifying each observation, listing the corrections and corrective actions, and showing which have been completed or the targeted due dates for completion. This table can then be updated easily for the periodic updates and makes it easier for FDA to see the company’s progress towards completion of committed activities.
FDA can take several actions on a 483. If satisfied with your written response, and subsequent updates, FDA may notify you that it will review the corrective actions at the next inspection, which may be scheduled based, in some part, on the timelines provided in responses to the 483. A repeat finding in another 483 not only reopens the 15-business day cycle to prepare a response, but it is more likely to result in the issuance of a warning letter or enforcement action (like an injunction). All of this headache can be avoided through a robust, strategic plan being developed and submitted in the initial 483 response.
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