Regulation and Compliance: 483 Responses

Q. How important is it to respond to an FDA–483 within 15 days?

A. It has always been in a company's interest to respond in writing to an FDA–483, List of Inspectional Observations, issued at the conclusion of their inspection. In so doing, the inspected company demonstrates to FDA that it understands the inspectional observations and that it is committed to implementation of corrective and preventive action. A thoughtful, complete, and timely response establishes credibility with FDA.

David Elder

On Aug. 9, 2009, FDA Commissioner Margaret Hamburg delivered a landmark enforcement speech at the Food and Drug Law Institute. In this speech, she outlined her vision for a strong FDA and, more specifically, her new enforcement initiatives, stating, "First, the FDA will set post-inspection deadlines. When the FDA finds that a firm is significantly out of compliance, we expect a prompt response to our findings. Once the FDA provides inspection findings identifying a serious problem, the firm will generally have no more than 15 working days in which to respond before the FDA moves ahead with a warning letter or enforcement action. This will help FDA issue warning letters on a timely basis and facilitate prompt corrective action."

Two days later, FDA formalized this aspect of its new enforcement initiatives in the Federal Register (1). Fully aligned with the Commissioner's speech, the agency outlined its intent to support public-health protection by facilitating the timely issuance of Warning Letters and the establishment of a timeframe for the submission and agency review of postinspection responses. Very clearly, FDA stated it will not ordinarily delay the issuance of a Warning Letter in order to review an FDA-483 response that is received by FDA more than 15 business days after the inspection concluded.

FDA, at its discretion, may issue Warning Letters at any time, independent of receiving a response. The Warning Letter serves two purposes within FDA: to give firms the opportunity to promptly and voluntarily correct deficiencies; and to establish prior notice, which FDA considers when pursuing subsequent enforcement actions. As a general rule, the agency should not issue a Warning Letter if the agency concludes, through review of the response and supporting evidence, that the violations that would have supported the letter have been corrected. However, ongoing or promised corrective actions generally do not preclude the issuance of a Warning Letter (see FDA's 2011 Regulatory Procedures Manual, Chapter 4) (2).

Of course it's optimal to ensure that operations remain in compliance at all times, precluding significant FDA–483 observations and subsequent enforcement actions, and assuring only high quality, safe, and effective products are produced and distributed to the market.

When faced, however, with an FDA inspection that results in an FDA–483, be sure to promptly initiate corrective actions and be sure to respond in writing within 15 days of issuance.

FDA may issue Warning Letters at any time, independent of receiving a response.

The agency will consider the firm's response to be thoughtful and complete, if it:

• addresses the specific observation

• treats the specific observation as a "signal," that may require review and implementation of systemic corrective actions in related areas and even at other related facilities under a corporate umbrella

• includes appropriate evidence that demonstrates the corrective actions were completed

• identifies the timeframe for completion of other corrective actions and in a timeframe that is both aggressive and realistic

• addresses the impact on product already distributed

• identifies actions taken to monitor the effectiveness of the corrective actions

• includes actions to prevent recurrence of the observation.

Sources: 1) Federal Register 40212, 74 (153), Aug. 11, 2009. 2) FDA, Regulatory Procedures Manual, Chapter 4 (Rockville, MD, 2011).