Best Practices for Responding to Form-483s and Warning Letters

Perhaps no enforcement actions are dreaded more by life science companies than FDA Form-483s and Warning Letters. This is not only because these actions put the company on the FDA’s radar for future audits and enforcement, but also because they open up the company’s corporate information to public scrutiny.

In order to help Medmarc policyholders deal effectively with Form-483s and Warning Letters, Medmarc produced a webinar on FDA enforcement actions titled, “Responding to Form-483s and Warning Letters: 15 Days Until Enforcement.” Distinguished expert, Steve Niedelman, presented on this topic. The slides and the recording of the webinar are both available on Medmarc’s website. This article details the contents of that webinar.

What are Form-483s and Warning Letters?

The FDA is authorized to perform inspections under the Federal Food, Drug, and Cosmetic Act (the “FDCA”), SEC. 704, "Factory Inspection." FDA Form-483, “Inspectional Observations,” is a form used by the FDA to document and communicate concerns discovered during inspections. The Form-483 states thereon that it “lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance.”

In contrast, an FDA-issued Warning Letter is of greater concern to a firm that receives it. The FDA defines a Warning Letter as "...a correspondence that notifies regulated industry about violations that FDA has documented during its inspections or investigations.” Typically, a Warning Letter notifies a responsible individual or firm that the FDA considers one or more products, practices, processes, or other activities to be in violation of the FDCA, its related regulations and other federal statutes. Warning Letters are generally only issued for violations of regulatory significance, i.e., those that may actually lead to an enforcement action if the documented violations are not promptly and adequately corrected. A Warning Letter is one of the Agency’s principal means of achieving prompt, voluntary compliance with the FDCA.

Mr. Niedelman began his presentation by describing some important aspects of the Form-483 itself, in both format and content. Among these insights, he explained that items on the Form-483 are listed in descending order of importance and that the inspection is only a “snapshot in time” and is not intended to be an exhaustive list of problems at a site.

Getting the Most Out of the Close-Out Meeting

Next, Mr. Niedelman provided advice on how to approach the close-out meeting, which takes place between senior management of the company and the FDA’s inspection agent at the end of the inspection. Mr. Niedelman pointed out that the company and the FDA approach the close-out meeting with divergent purposes. While the FDA uses the meeting to ensure that senior management has notice of the kind and degree of its findings, and to confirm that the facts underlying the observations are correct, the company should use the close-out meeting as an opportunity to (a) send the appropriate message to the investigator, namely that the company is ready and willing to cooperate and correct negative findings; (b) seek annotations and/or corrections where necessary; and (c) understand fully the observations of the inspection. To this end, Mr. Niedelman encouraged companies to have a meaningful discussion with the FDA inspection agent about each observation.

Responding to Form-483s

Mr. Niedelman next addressed what the audited company should do after the inspection and close-out meeting. He suggested that the company’s first task is to assemble a team to handle the Form-483 response. This team should work on fact-finding with respect to the individual observations listed in the Form-483, and finally, drafting the response. Here he emphasized the importance of the timeliness of the response. FDA only need consider the company’s response to the Form-483 if it is received within fifteen days. If the company fails to respond within fifteen days, the FDA need not address the adequacy of the proposed corrections listed in the response or consider the response in its decision on subsequent action.

With respect to the content of the response, Mr. Niedelman provided several pieces of advice. Generally, the response should aim to demonstrate the company’s awareness of the applicable regulations and its commitment to comply with those regulations. The response should also list the aspects of the company’s operations that were deficient and address each along with the company’s plan to correct that deficiency.

Responding to Warning Letters

Mr. Niedelman turned next to Warning Letters and how companies can best respond to them. Being that Warning Letters are of greater seriousness than Form-483s, and that responses following the receipt of a Warning Letter are mandatory, knowing how best to respond is of utmost importance to companies. After receiving a Warning Letter, a company must provide a Corrective Action Plan detailing how the company is going to immediately correct the problem cited as the subject of the Warning Letter. In structuring the response to a Warning Letter, Mr. Niedelman advised that the response should tell the whole story and stand on its own, and it should acknowledge the company’s commitment to compliance and the seriousness with which it takes the agency’s findings. Mr. Niedelman also provided some criteria by which the FDA is likely to evaluate the company’s response, including whether: (1) it is timely and understandable; (2) the company adequately addressed the seriousness of the inspection observations; (3) the company has provided objective evidence of correction; (4) the response addresses only the observations or if it also addresses the broader issues implicated by the observations; and (5) the remediation plan appears to be adequate.

Recent Data on Form-483 and Warning Letter Trends

Finally, Mr. Niedelman provided some very useful statistical analysis that gives insight into what the FDA is focusing on now and what deficiencies FDA most frequently cites in Form-483s and Warning Letters. Mr. Niedelman first provided a look at the number of Warning Letters issued by each division of the FDA, and he compared this year (through August) with 2010. This data demonstrated that the FDA’s trend of increasing enforcement actions is likely to continue. The only FDA division that is on track to issue fewer Warning Letters than it did in FY 2010 appears to be the Center for Drug Evaluation and Research. Mr. Niedelman then broke down the Warning Letters by the deficiencies they address, which showed that complaint systems were cited most frequently in Warning Letters in 2010. As for Form-483s, a similar analysis revealed that CAPA violations were those most frequently noted in Form-483s in 2010.

Steven Niedelman is the lead quality systems and compliance consultant for the FDA & Life Sciences practice team at King & Spalding, specializing in regulatory, enforcement and policy matters involving FDA-regulated industries.