Answer: Few regulatory actions pose as much of a concern for life sciences companies as FDA-483s and Warning Letters. Knowing how to respond effectively, however, can allow companies to successfully avoid future enforcement actions.
An FDA-483 is the form issued at the conclusion of the FDA inspection, which lists significant observations made by the investigator(s) during the inspection. When assessing an FDA-483, there are several things a company should be mindful of. First, do not minimize the importance of issues that were identified but were not included on the 483. These items will still be included in the report. It is also important to note that items are listed in descending order of importance, and that the 483 is not intended to be an exhaustive list of problems at a site, rather it is only a “snapshot in time.” Even if not included on the 483 or in the report, it is still your responsibility to ensure your company’s compliance with all applicable laws and regulations. The first step in responding effectively to an FDA-483 is understanding the observations listed in it. This means understanding the basis for each observation as well as the underlying facts that support them. The close out meeting that takes place between company senior management and the investigator(s) after the inspection provides a valuable opportunity for the company to ensure that it has this understanding. You should aim to have a meaningful discussion about each observation. This is also your opportunity to raise any discrepancy you may have with any observation. The company’s purpose going into the close-out meeting should be to send the appropriate message to the investigator—one of cooperation, to understand the observations and assure their accuracy, and to understand the broader message that the FDA is sending.
The timeliness of your response is of the utmost importance. FDA only need consider a company’s response to the 483 if it is received within fifteen days. If the company fails to respond within the fifteen days, the FDA need not address the adequacy of the proposed corrections listed in the response, or to consider the response in its decision on subsequent action. Your response should be thorough, and based on objective evidence that demonstrates you are operating in a state of control and are compliant. Your response should identify the changes your company has already implemented, and set forth your plan for longer-term items with a schedule for completion.
Warning Letters are of greater seriousness than FDA-483s. Though they still do not represent final agency action and are merely advisory in nature, “the agency position is that Warning Letters are issued only for violations of regulatory significance. Significant violations are those violations that may lead to enforcement action if not promptly and adequately corrected.” 1
Warning Letters are usually addressed to top management, to ensure they know the seriousness by which FDA considers the observed violations. It is management’s responsibility to ensure adequate resources are available to fully correct the violations, and to prevent their recurrence. It is also management’s responsibility to ensure that all requirements of the Act are being complied with—not just those identified in the Warning Letter.
When composing your response to a Warning Letter, it is important both to set the right tone, and to be thorough in you’re the content of your Corrective Action Plan. Overall, your response should be complete, well-organized, supported with appropriate documentation, easy to understand, and grammatically correct and thoroughly proof-read. Your response should acknowledge your company’s commitment to compliance, and address the nature and seriousness of the inspection observations. In addition, your response should aim to address the broader issued implicated by the observations, and attempt to decipher and acknowledge the larger message the FDA is sending through its Warning Letter. It is not enough, however, to assert that you are committed to addressing the deficiencies and being compliant, your company must set forth in detail a comprehensive plan for corrective action. This plan should address both the specific observations and the systemic issues the observations likely indicate, include a timetable with specific and realistic milestones, and demonstrate that your company understands the general “good practices” that should govern long-term operations. If a correction has already been made prior to submission of the response, you should include objective evidence of the correction.
After the submission of your response, it is important to follow through on your plan to avoid future, more severe enforcement actions. Stay abreast of all commitments and notify the FDA of any “slippage.” As corrections are successfully implemented, follow up with the FDA and provide objective evidence of the correction.
1 FDA Regulatory Procedures Manual, Chapter 4: Advisory Actions.