You are in the middle of an FDA inspection and a significant issue just surfaced. How you handle the situation may determine whether the agency issues an FDA Form 483. Even if you do receive an FDA Form 483 at the end of your inspection, all is not lost; you just have a lot more work to do, quickly. This paper provides guidance to help you optimize the possible outcomes. Let’s start with some basic information about FDA Inspectional Observations.
The observation process is required per the Federal Food, Drug, and Cosmetic Act (FDCA) [21 USC 374(b)]. In 1953, section 704(b) was added to the FDCA to provide a process to prevent FDA enforcement action without prior notice being provided to firms. This resulted in the creation of the FDA Form 482 “Notice of Inspection” and FDA Form 483 “Inspectional Observations”. The FDA Form 482 provides firms assurance that the inspection is authentic. The FDA Form 483 documents the Investigators’ finding of significant objectionable conditions or practices. The cited Inspectional Observations may or may not constitute FDCA violations. The concern is based upon risk that the product is adulterated, may become adulterated, or there are suspected specification non-conformances that may indicate the product is unfit or unsafe for use. The FDA Inspectors are instructed to list the observations in the perceived order of significance.
The FDA and industry have related but differing views on Inspectional Observations. From the FDA’s perspective, the observations provide the agency with the opportunity to give firms feedback for voluntary compliance. The observations also comply with FDCA § 704(b) and provide warning prior to enforcement actions. From industry’s perspective, the observations are a public scorecard and many firms request confidentiality of the information since the data is available via the Freedom of Information Act (FOIA) [21 CFR 20.101(a)]. The investigators’ concerns help industry maintain and advance current Good Manufacturing Practices (cGMPs) in the absence of “best practice” sharing.
Our goal is to ensure the FDA Form 483 does not escalate into a more serious Warning Letter or enforcement action. At the conclusion of the inspection, the inspector can only issue a Form 483; a warning letter could be issued later. The FDA views a warning letter as an “advisory” action rather than an enforcement action. Warning letters are available on the FDA’s public website and explain areas of non-compliance that could lead to legal liability and might result in shareholder or consumer litigation actions; not to mention your damaged reputation and competitive disadvantage the public disclosure may bring. If you fail to address the warning letter appropriately, you may be subject to enforcement actions such as an untitled letter, product recall, product seizure, injunction, fine, debarment, disqualification, license suspension or revocation, prosecution, consent decree, withheld approval of New Drug Applications (NDA), denied Certificate to Foreign Government (CFG) for Export, or Import alert.
In view of these implications, it is important to meet the FDA Form 483 response deadline and to provide enough information to the FDA to ensure no further escalation is warranted. The FDA requires a focused response within 15 working days. Best practice for response preparation is to involve all stakeholders in the investigation, solution development, and any required mitigation of root causes that resulted in the observation. It is imperative to have commitment from all stakeholders regarding the root causes and actions to take since the outcome is so critical. In complex cases, the development of the full corrective action plan or complete implementation of the actions may take longer than the 15 working days allowed for the response. In this case you must share your detailed plans and completed actions with the FDA during the regular updates.
Co-authors Susan Shockey and Randy Jacobs.