Anticipating and Closing Out FDA Warning Letters - 5 Best Practices for Regulated Companies

    Stay one step ahead of the regulator by noting red flags about faulty internal processes and rectifying them before a Warning Letter is received and closing out the same quickly and efficiently.

    How can the FDA-regulated company know that a Warning Letter is definitely on its way? What are the signs that can help firms anticipate a letter from the regulator? What is the groundwork that can be done before the receipt of the Warning Letter so that when it indeed arrives, the company is ready for it and implements the close-out process quickly and effectively?

    The answers to these questions are vital in ensuring the FDA Warning Letter response and close-out program are handled in a thorough manner that leaves nothing to chance. This article details some of the best practices companies can follow so they can handle the Warning Letter, its implications and resolution without unnecessary delays and loss in revenue or reputation.

    What is a Warning Letter?

    A Warning Letter is issued by the FDA to a regulated manufacturer if it is found that any significant regulatory violations have occurred.

    Violations identified in the Warning Letter can include:

    • nonconformance with Good Manufacturing Practices (GMP) or
    • false claims about a product or
    • inadequate training for personnel or
    • wrong directions for use and so on

    Once the manufacturer receives the Warning Letter, it has to correct the violations noted by the agency.

    The manufacturer has to provide a clear timeframe to the FDA in which the corrections will be done and the regulatory will follow up to check that these have been accomplished.

    What is a Close-out Letter?

    Once the FDA has checked and verified that corrective actions have been done to rectify the violations noted in the Warning Letter, it will issue a "close-out" letter.

    It must be noted that if the Warning Letter includes violations that cannot be corrected, then no close-out letter will be issued. The FDA office which issued the Warning Letter will issue the close-out letter as well.

    Why Should Companies Respond to a Warning Letter within Deadlines?

    Choosing not to respond to a Warning Letter within the timelines/deadlines imposed by the FDA can lead to further enforcement actions. The sooner the company implements corrective actions to rectify the violations noted in the Warning Letter, the faster the follow-up inspection will be held and a close-out letter issued.

    If on the follow-up inspection it is found that violations have not been rectified, further enforcement actions will come into play. These can include:

    • Seizure of goods
    • Shutdown of facilities
    • Injunctions
    • Consent decrees

    These can take more one and money to resolve, affecting the company's revenues.

    If the company is publicly traded, news of enforcement actions can lead to a plunge in share prices, another negative impact on the organization's revenues. In order to resolve the issues, outside consultants and legal experts may have to be hired leading to further expenses. So, it is best to get the issues noted in the Warning Letter resolved from the beginning.

    5 Best Practices to Ensure a Proper Warning Letter Close-Out Process

    1. Watch Out for Warning Letter Signs
    2. It is important to remember that in the case of Warning Letters, the FDA issues these due to long standing problems that occur in a company. So, companies should not be surprised if they do get a Warning Letter - the signs would have been there all along. The following can help in foreseeing the advent of a Warning Letter and rectifying them in advance can avoid further enforcement action:

      • Long standing internal problems that have not yet caught the attention of the FDA but are known within the company
      • Form 483 notifications
      • Red flags from the quality unit
      • Adverse events
      • High volume of customer complaints
      • Prior investigations about the same issue or same type of issue
      • FDA responses to communications from the company that do not signal satisfaction with issue resolution and so on
      • Product contamination
      • Off-label promotional activities that have caught the attention of the FDA
      • Repeated FDA inspections of facilities

      If a company experiences any of the above, it is sure that a Warning Letter could be on its way if robust fixes are not implemented. Even if the Warning Letter is received, the company is at least ready to tackle the problems more efficiently and fix these, leading to a hassle-free close-out process.

    3. Don't Ignore Long Standing Problems
    4. As mentioned above, long standing problems within the company are a sure sign that a Warning Letter could be on its way. If these are known to the FDA (and they are aware enough of it to issue a Warning Letter), it should be obvious that they are known within the company as well.

      Armed with foreknowledge, a company can leverage its resources to correct the problems before the Warning Letter lands, or move quickly enough after the citation is received to close-out the letter. The following are red alerts that a Warning Letter could be on its way:

      • Adverse events (the most obvious sign)
      • Reports in the media about the company's quality issues, product reliability and so on
      • Customer complaints about the same issue or large number of complaints about varying issues (another red flag about a glaring internal process problem)
      • Internal quality issues highlighted by the quality department
      • Vendor audits that are problematic and highlight non-compliance
      • Raw materials that do not conform to quality specifications
      • Inspection results of incoming materials that are out of spec
      • Yield variances in the production process

      All of the above, like those signs highlighted in the previous section, should be noted and resolved ahead of the receipt of a Warning Letter, or used to quickly address and close-out the violations noted in the Warning Letter.

    5. Set Post-Inspection Deadlines and Adhere to Them
    6. It is important for companies that receive citations in the form of 483s or Warning Letters to ensure they respond within the set deadlines. In the case of Form 483s, companies should respond within the 15-day timeline to the significant FDA findings.

      If the Warning Letter is issued and the FDA does expect corrective actions to be taken within certain time frames, the imperative is on the company to set deadlines to achieve these and adhere to them.

      Tactics such as stalling and excessive back and forth communications will only push the date of resolution further and prevent a quick and smooth close-out process.

      As the FDA has taken the initiative to speed up the Warning Letter process and issue these only for significant legal issues, the onus is on the company to take a proactive stance and finish the close-out process before reputations or profit margins are damaged.

    7. Do a Proper Internal Audit
    8. As mentioned in previous sections of this article, long standing problems are often well known within the company - so proactive action should be taken, in the form of internal audits.

      In order to implement and execute successful internal audits, lead with the quality unit. It is best not to involve those units that might be at the root of the non-compliance and violations. Personnel from manufacturing, distribution or other operations should not be in charge of internal audits. It is the quality personnel who have to lead the audits.

      To resolve the Warning Letter quickly, the following should be done:

      • Understand the inspector's observations thoroughly
      • Understand the Warning Letter citations (which may be different from those on the 483)
      • Drill down to the root causes
      • Document the audit

      The audit will help to find the faults that led to the observations and Warning Letter citations, making it easier to devise and implement corrective actions. A methodical internal audit is a key part of a fast and trouble-free close-out program.

    9. Retain and Provide Proper Documentation
    10. Documentation must be properly done and retained for a quick and smooth Warning Letter close-out process. Companies should ensure:

      • All remediation activities are properly recorded
      • These records are retained in an easily accessible and retrievable manner
      • The documentation is available for FDA inspectors to examine on follow-up inspections to verify that corrective actions have been undertaken

      The FDA follows the mantra "If it isn't documented, it didn't happen". So, records play a very important role in the Warning Letter close-out process. The FDA shouldn't be left with an unclear view of whether remediation activities have taken place or not.


    It has to be emphasized that when it comes to the successful handling of the FDA Warning Letter and its implications, anticipation and advance preparation can never be underestimated. In closing out the Warning Letter or even addressing the 483 observations that precede it, the quality department has to take the lead in remedial actions. And these actions will have to be documented carefully and the records retained so that when the FDA does come visiting again, the inspector's questions can be answered properly.

    The proper close-out of a Warning Letter will boost not just the company, but also most importantly, consumer confidence in its products.

    How can FDA compliance training help?

    The areas highlighted above are just a small part of the wide range of practices and processes for FDA compliance. Subjects such as FDA compliance are multi-faceted and complex and can be better understood after attending a training course such as the ones offered by ComplianceOnline. Our courses are available as live webinars, training recordings and seminars. We also offer customized training courses developed in conjunction with organizations that wish to train large groups of their employees.