FDA Inspection-A Client’s Guide to FDA Inspections

The FDA just completed an inspection of your firm, and one or more FDA Form 483 inspectional observations were noted by the inspection team. How and when your firm reacts to these observations is a significant decision.  This series will provide guidance on what actions to take to minimize or avoid additional enforcement actions.

In this first part of this 3 part series, we will address how the FDA can respond to inspections.

How the FDA Can Respond to Inspections

When the FDA begins an inspection, they may for a variety of reasons, such as Pre-approval Inspections, Post-Approval Inspections, Surveillance inspections and For-cause inspections. Form 482 “Notice of Inspection” will be presented upon arriving at your plant. The 482 explains the Agency’s inspectional authority and provides expectations for the Inspector and the firm.  It will also outline contact information in the event a 483 response is issued.

Inspections vary by type of product and the size and complexity of the facility.  For example, in a drug manufacturing facility inspection, the FDA will often examine six systems – Quality, production, facilities and equipment, laboratory controls, materials and packaging and labeling.  In a food inspection, FDA will determine whether a firm has compiled with the appropriate preventative controls described in the regulations.  In device inspections, FDA focuses largely on compliance with Quality Systems Regulation.  As with all of the above inspections, the investigators will examine relevant records and processes, such as Standard Operating Procedures, laboratory test results, training records and whether employees follow procedures, and whether a firm is appropriately sterile and clean.

At the conclusion of the inspection, the investigator will issue a form entitled “Inspectional Observations”, or Form 483.  It will list observations made by the FDA representative(s) during the inspection. These observations do not represent a final agency determination regarding compliance. The 483 formally notifies the organization’s top management of objectionable conditions or practices relating to violations of the Federal Food, Drug, and Cosmetic (FD&C) Act that were observed during the inspection.

If the inspection does not yield any objectionable conditions or practices, a 483 will not be issued. However, if the FDA representative(s) does observe objectionable conditions, one or more 483’s will be issued during the closing meeting. If the agency does issue one or more 483’s at the conclusion of the inspection, it is always better to select “promise to correct” in response to each 483 observation.

Depending on the nature of the violation(s), the FDA may give the firm an opportunity to take voluntary and prompt action to correct the violation(s) before the agency initiates an enforcement action. However, the FDA generally is under no legal obligation to warn individuals or firms about violations before taking additional enforcement actions, as further described below.

The FDA uses untitled letters for violations that are not as significant as those that prompt warning letters. Unlike a warning letter, an untitled letter does not include a statement warning that failure to promptly correct a violation may result in an enforcement action.

Warning letters, on the other hand, are issued to manufacturers or other organizations that have violated some rule in a federally regulated activity, i.e., violations of regulatory significance. A warning letter is one of the agency’s primary means of achieving prompt voluntary compliance with the FD&C Act.

Injunctions may also be ordered to halt the flow of violative products and to correct the conditions that caused a violation to occur. An injunction is a type of judicial action that is considered for any significant out-of-compliance circumstance, but particularly when a health hazard has been identified. When an injunction is granted by a court, the FDA has a duty to monitor the injunction and to advise the court if the firm fails to follow through on its obligations. The three most common types of injunctions are the temporary restraining order, the preliminary injunction, and the permanent injunction.

The FDA may recommend a temporary restraining order when it believes that a serious violation has occurred, and the situation must be controlled, or the flow of product stopped immediately. A motion for preliminary injunction is subject to a full hearing before a court. Once the motion is granted, the preliminary injunction is in effect and may stand indefinitely until the case is settled or a permanent injunction has been entered, after trial.

A decree of permanent injunction may be entered at any time after the complaint is filed, either after a hearing or as a result of a negotiated settlement between the government and the defendant. A consent decree is a court-ordered agreement between the FDA and a firm that outlines the steps the firm needs to take to resume normal operations. Although each situation is unique, consent decrees often indicate necessary changes within the organization — and may even require the firm to involve outside consultants to oversee the changes and ensure ongoing compliance.

A product seizure is a judicial (court-approved) action for removing violative products from the marketplace. Product seizures typically are initiated when the firm has not voluntarily recalled product that the regulatory agency believes is in violation of the law and where there is a perceived or known health risk to the public.

After the inspection, and dependent upon the firm’s response to any 483 findings that are issued, the agency classifies the inspection with one of three statuses in the establishment inspection report (EIR):

• No action indicated (NAI) means no objectionable conditions or practices were found during the inspection (or the objectionable conditions found do not justify further regulatory action).
• Voluntary action indicated (VAI) means objectionable conditions or practices were found, and the firm’s response was satisfactory, so the agency is not prepared to take or recommend any administrative or regulatory action.
• Official action indicated (OAI) means objectionable conditions or practices were found, and/or the firm’s response was not satisfactory, so regulatory and/or administrative actions will be recommended.

In the second part of this 3 part series, we will continue the discussion on How to Respond to the FDA.

Understand that a warning letter or FDA 483 does not signal the end of your product, your job, or your company.  There are clear procedures to follow to overcome this hurdle.  We’ve helped pharmaceutical, diagnostic and medical device companies of all sizes resolve serious regulatory compliance problems. If you’re in need of help, contact our team of experts today.

References:

Sihorwala, Zoher. “What an EIR Entails and What It Means for Drug Makers.” The Hindu.Co.in.Com, 9 Jan. 2018, www.thehindubusinessline.com/specials/pulse/what-an-eir-entails-and-what-it-means-for-drug-makers/article9802971.ece.

“Issuance of Untitled Letters.” Www.Fda.Gov, FDA, www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/issuance-untitled-letters. Accessed 27 July 2021.

“What Should I Expect During an Inspection?” FDA.GOV, FDA, www.fda.gov/industry/fda-basics-industry/what-should-i-expect-during-inspection. Accessed 27 July 2021.