This year, the available evidence continues to suggest that FDA is becoming more proactive with regard to regulatory enforcement. The evidence suggests the agency is issuing an increasing number of Form 483s and, worse, warning letters.
This column will provide an overview and explanation of FDA Form 483s and warning letters, discuss the issuance and implications associated with each, and explain how to respond to them.
FDA Form 483
FDA Form 483 is a document routinely issued to companies at the conclusion of an FDA inspection. It is used to document any conditions that—in an inspector’s judgment—may constitute violations of the Food Drug and Cosmetic Act (FDCA) or related regulations. Each of the observations noted on the Form 483 is supposed to be articulated in a clear and specific manner that allows the company to quickly act to correct the issue. Observations are made when the conditions or practices observed are indicative of possible adulteration or suggest that products are being prepared, packed, or held under potentially insanitary conditions that pose a risk to public health.
The purpose of Form 483 is to formally notify a company’s management of objectionable conditions observed during an FDA inspection. It’s usually presented during the exit interview at the conclusion of the inspection, during which FDA inspectors meet with management to present their observations, findings, and conclusions.
Engaging with inspectors, behaving diplomatically, seeking to work collaboratively, and asking good questions about what is required to fully address the agency’s concerns will show the agency that you are serious about achieving compliance.
Although recipients of Form 483 are not legally obligated to respond to the observations documented, it is vitally important to do so. Unless FDA states otherwise, the response to the 483 should be submitted within 15 business days and should provide thorough written explanations, with accompanying documentary exhibits, comprehensively detailing the corrective actions the company is implementing to remediate the observations noted on the form. If the written response adequately addresses the agency’s concerns, no further regulatory action will result. Conversely, an inadequate response will likely result in the agency issuing a “warning letter,” which amounts to the agency threatening to withdraw the company’s registration and prevent it from producing product.
Warning letters are rarer and more serious than Form 483s. A warning letter, issued when FDA alleges that a company has significantly violated FDA regulations, signals potentially significant peril for the receiving company. Warning letters will identify the alleged violations, such as insanitary manufacturing practices or labeling violations, provide detailed information relating to the specific regulatory and statutory violations alleged, and notify the recipient of their obligations with respect to a response.
After receiving a warning letter, companies can expect FDA to engage in thorough and onerous oversight intended to ensure that adequate corrective actions are implemented. The subject matter of an FDA warning letter may be based on previous interactions between the agency and the recipient, or they may be the first word on the alleged violations.
A failure to adequately address the violations described in the letter will result in withdrawal of the company’s registration, effectively shutting down the business.
An Ounce of Prevention Is Worth a Pound of Cure
Sooner or later, every company undergoes an FDA inspection. To maximize the likelihood of a successful, collaborative inspection, all companies should begin taking steps to prepare for their next FDA inspection today.
Taking the following steps can help to ensure that appropriate preparations are in place before FDA investigators arrive, to effectively navigate the inspection process once the inspection is underway, and to appropriately respond to any FDA concerns.