Understanding FDA Advisory Action Letters: Warning Letters and Untitled Letters

Introduction to FDA Advisory Action Letters

The U.S. Food and Drug Administration (FDA) employs various communication mechanisms to ensure regulatory compliance within industries it oversees. Among the most important of these are “Advisory Action Letters,” which include both “Warning Letters” and “Untitled Letters.” These letters serve as formal notifications to companies and individuals regarding violations of federal laws and regulations, particularly the Federal Food, Drug, and Cosmetic Act (FD&C Act).

Understanding the distinctions between these letter types, their implications, and the appropriate response procedures is essential for any organization operating within FDA-regulated industries, including pharmaceuticals, medical devices, dietary supplements, food products, and cosmetics.

Warning Letters: FDA’s Principal Compliance Tool

Definition and Purpose

A Warning Letter represents a significant escalation in FDA’s regulatory enforcement process. According to Chapter 4 of FDA’s Regulatory Procedures Manual (RPM), Warning Letters are issued only for violations of regulatory significance—those violations that may lead to enforcement action if not promptly and adequately corrected.

The primary purposes of Warning Letters are:

1. Achieving Voluntary Compliance: The FDA provides companies and individuals with an opportunity to take voluntary and prompt corrective action before initiating formal enforcement proceedings. This approach reflects the agency’s preference for cooperative resolution of compliance issues.
2. Establishing Prior Notice: Warning Letters serve as official documentation that the FDA has identified violations and has notified the responsible party. This establishes a record that can be referenced in subsequent enforcement actions if violations are not corrected.
3. Protecting Public Health: By formally documenting serious violations and demanding corrective action, Warning Letters help prevent potential harm to consumers and patients.

Characteristics of Warning Letters

Warning Letters possess several distinctive characteristics that distinguish them from other FDA communications:

Regulatory Significance Threshold: Only violations deemed “significant” warrant Warning Letter issuance. Significant violations are defined as those that, if not promptly and adequately corrected, may lead to enforcement actions such as product seizure, injunction, civil money penalties, or criminal prosecution.

Public Disclosure: All Warning Letters are posted on the FDA’s website (www.fda.gov), typically within a short period after issuance. This public disclosure serves multiple purposes: it informs consumers and healthcare providers about potential safety concerns, deters other companies from similar violations, and provides transparency in FDA’s regulatory activities.

Enforcement Warning: A critical component of every Warning Letter is an explicit statement warning the recipient that failure to correct the violations promptly may result in enforcement action without further notice. This distinguishes Warning Letters from other advisory communications.

Addressee: Warning Letters are typically addressed to the highest-ranking official of an organization, such as the Chief Executive Officer or President. This ensures that senior leadership is directly aware of the violations and understands their responsibility for implementing corrective measures.

Response Requirement: Recipients are generally required to submit a comprehensive written response within fifteen (15) working days (not calendar days) from the date of receipt. The response must outline specific steps taken to address each violation, explain the root causes identified, detail corrective and preventive actions (CAPAs), and provide timelines for implementation.

Content of Warning Letters

A typical Warning Letter includes the following elements:

1. Inspection Details: Information about the facility inspected, dates of inspection, and the investigators involved.
2. Detailed Description of Violations: Each violation is described in detail, with specific references to the applicable sections of federal law or regulations that have been violated. For example, violations of Current Good Manufacturing Practice (CGMP) requirements are cited with reference to specific sections of 21 CFR Part 211.
3. Evidence: The letter may include specific observations, documentation reviewed, or test results that support the findings of violations.
4. Required Corrective Actions: While the FDA typically does not prescribe specific corrective actions, the letter clearly indicates the nature of corrections expected.
5. Legal Consequences: A statement outlining potential enforcement actions if violations are not corrected, such as seizure of products, injunctions, or other legal proceedings.
6. Response Instructions: Clear guidance on how to respond, including the deadline (typically 15 working days), the format required, and the contact information for submission.

Responding to Warning Letters

A comprehensive response to a Warning Letter should include:

Acknowledgment of Violations: While companies may disagree with FDA’s interpretation in some cases, most responses acknowledge the observations and commit to corrective action. Disputing FDA’s findings requires substantial supporting evidence and legal reasoning.

Immediate Corrective Actions: Description of actions already taken to address the violations, including any interim controls implemented to protect public health while long-term solutions are developed.

Root Cause Analysis: A thorough investigation into the underlying causes of the violations. Superficial responses that merely address symptoms without identifying systemic issues are generally deemed inadequate by FDA.

Corrective and Preventive Action Plan (CAPA): A detailed plan outlining specific actions to correct the violations and prevent their recurrence. This should include clear milestones, responsible individuals, and realistic completion dates.

System-Wide Assessment: Evidence that the company has assessed whether similar issues exist in other products, processes, or facilities. FDA expects companies to evaluate the broader implications of identified violations.

Documentation and Evidence: Supporting documentation such as revised Standard Operating Procedures (SOPs), training records, validation reports, and audit findings that demonstrate implementation of corrective actions.

Periodic Progress Updates: For long-term CAPAs, commitment to providing regular updates to FDA (typically every 90 days) on implementation progress.

The Close-Out Letter Process

For Warning Letters issued after September 1, 2009, FDA implemented the Warning Letter Close-Out Letter Program. A Close-out Letter is issued when FDA determines that a company has adequately addressed all violations cited in a Warning Letter.

Criteria for Close-out Letter Issuance:

A Close-out Letter will be issued when both of the following conditions are met:

First, the company has provided sufficient information to FDA demonstrating that the violations listed in the Warning Letter have been appropriately corrected. This verification typically occurs through one of the following mechanisms:

• Submission of comprehensive documentation demonstrating completed corrective actions
• A successful follow-up inspection by FDA investigators that confirms proper implementation of CAPAs
• Other verified, appropriate, and reliable information that enables FDA to determine a follow-up inspection is unnecessary

Second, the follow-up inspection (or other reliable information) reveals no new significant violations.

Important Considerations:

• Close-out Letters are based on actual verified corrections, not on representations or promises that actions will be taken. FDA requires objective evidence of completed implementation.
• If a Warning Letter contains violations that, by their nature, cannot be corrected (for example, past shipments of adulterated products), no Close-out Letter will be issued.
• If the recipient of a Warning Letter goes out of business or ceases operations related to the issues in the Warning Letter, FDA may decide not to issue a Close-out Letter.

Timing Considerations:

While FDA’s internal procedures specify review timelines of 30 working days (with possible extension to 60 working days) for evaluating close-out recommendations, the overall time from Warning Letter issuance to Close-out Letter receipt varies considerably based on the complexity of violations and the effectiveness of the company’s remediation efforts. Industry data suggests that the average time to achieve close-out can range from 555 days to 795 days or longer, depending on the nature of the violations and the facility type.

Post-Close-out Considerations:

Receipt of a Close-out Letter does not provide permanent immunity from future enforcement. FDA may conduct subsequent inspections and regulatory activities to assess the adequacy and sustainability of corrections. If violations are observed during later inspections, enforcement action may be taken without further notice.

Untitled Letters: Initial Compliance Notifications

Definition and Purpose

An Untitled Letter cites violations that do not meet the threshold of regulatory significance required for a Warning Letter. According to FDA’s Regulatory Procedures Manual, Untitled Letters serve as an initial notification to companies that FDA is aware of their violations of federal law.

The key purposes of Untitled Letters are:

1. Initial Notification: To inform companies that FDA has identified violations and is documenting formal notification.
2. Opportunity for Voluntary Compliance: To provide companies with an opportunity to come into compliance without the public scrutiny and enforcement warnings associated with Warning Letters.
3. Regulatory Documentation: To create a record of FDA’s awareness of violations, which may be relevant if violations persist or escalate.

Key Differences Between Warning Letters and Untitled Letters

Understanding the distinctions between Warning Letters and Untitled Letters is crucial:

Aspect	Warning Letter	Untitled Letter
Regulatory Significance	Only issued for violations of regulatory significance that may lead to enforcement action	Issued for violations that do not meet the threshold of regulatory significance
Enforcement Warning	Contains explicit warning that failure to correct may result in enforcement action without further notice	Does not include a statement warning of potential enforcement action
Public Disclosure	Automatically posted on FDA’s website	Generally not automatically posted; may be posted if FDA determines it serves public health interests (e.g., to inform public of health risks, deter violations, or in response to FOIA requests)
Severity of Violations	Significant violations requiring prompt correction	Less significant violations, though still requiring correction
Addressee	Typically sent to CEO or highest-ranking official	May be addressed to various levels of management
Response Expectation	Comprehensive written response required within 15 working days	Response expected but may be less formal; timeline may vary
Legal Implications	Establishes prior notice for potential enforcement actions	Serves as initial warning; escalation to Warning Letter possible if not addressed

Content and Format of Untitled Letters

Untitled Letters typically include:

1. Identification of Violations: Description of the specific violations observed, with citations to relevant laws and regulations.
2. Request for Corrective Action: A request that the company take prompt corrective action to address the violations.
3. Response Request: Instructions for submitting a response, though the format and timeline may be less stringent than for Warning Letters.
4. Absence of Enforcement Warning: Unlike Warning Letters, Untitled Letters do not include language warning of imminent enforcement action.

Responding to Untitled Letters

Although Untitled Letters may seem less serious than Warning Letters, they should be taken seriously and addressed promptly. A comprehensive response should include:

• Acknowledgment of the violations
• Description of corrective actions taken or planned
• Timeline for implementation
• Evidence of corrections where available

Failing to respond adequately to an Untitled Letter may result in escalation to a Warning Letter or other enforcement action. Some organizations have found that receipt of an Untitled Letter provides an opportunity to address issues before they escalate to the more serious and publicly disclosed Warning Letter stage.

FDA’s Posting Policy for Untitled Letters

FDA generally posts an Untitled Letter to its website when the agency determines posting would fulfill one or more of the following objectives:

1. Respond to three or more received or anticipated requests for the letter under the Freedom of Information Act (FOIA)
2. Inform the public about violative practices and conditions that may pose a risk to their health
3. Deter future violations and allow similarly situated regulated entities to determine what activities and practices FDA finds violative

When FDA adopts an approach to posting Untitled Letters in a particular program area, posting typically occurs within 10 workdays after the letter is issued.

Case Study: FDA and Amazon.com

Background and Initial Concerns (2019-2021)

The relationship between FDA and Amazon regarding product compliance provides an instructive case study of how Advisory Action Letters function in practice, particularly in the context of e-commerce platforms and third-party sellers.

Between December 2019 and March 2021, FDA conducted a series of investigations by purchasing products through Amazon’s website and subjecting them to laboratory analysis. The agency focused primarily on products marketed as dietary supplements for sexual enhancement and weight loss.

The July 2021 Untitled Letter

On July 26, 2021, FDA issued an Untitled Letter to Andy Jassy, CEO of Amazon.com, Inc. This communication documented serious concerns regarding products sold through Amazon’s platform:

Products and Findings:

The FDA purchased and analyzed 26 sexual enhancement products and one weight loss product. Laboratory analyses revealed that:

• Twenty-five products marketed as dietary supplements contained undeclared pharmaceutical ingredients including sildenafil, tadalafil, and/or vardenafil—the active ingredients in the FDA-approved prescription drugs Viagra, Cialis, and Levitra, respectively.
• One food product, “Kopi Jantan Tradisional Natural Herbs Coffee,” contained undeclared sildenafil.

Legal Violations:

The products were found to be in violation of the FD&C Act in multiple ways:

1. Unapproved New Drugs: Because these products contained pharmaceutical ingredients that were FDA-approved drugs, and these ingredients had not been marketed as dietary supplements or foods before drug approval, the products were classified as unapproved new drugs under Section 505(a) of the FD&C Act.
2. Misbranded Drugs: The products were misbranded under Section 502 of the FD&C Act because they failed to disclose the presence of pharmaceutical ingredients on their labeling.
3. Excluded from Dietary Supplement Definition: Under Section 201(ff)(3)(B)(i) of the FD&C Act, products containing articles approved as new drugs (unless marketed as supplements before drug approval) are excluded from the definition of “dietary supplement.”

Public Health Concerns:

FDA emphasized significant health risks associated with these products:

• PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) can interact with nitrates found in prescription medications (such as nitroglycerin), potentially lowering blood pressure to dangerous levels
• Consumers with underlying conditions such as diabetes, high blood pressure, or heart disease are at particular risk
• Undeclared pharmaceutical ingredients prevent consumers and healthcare providers from making informed decisions about drug interactions and contraindications

Pattern of Inadequate Response

The Untitled Letter documented a troubling pattern:

1. Initial FDA Notifications: As early as December 17, 2020, FDA had issued public notifications regarding undeclared drug ingredients in products available on Amazon.
2. Amazon’s Commitments: Amazon represented to FDA that it had taken actions to restrict the sale of violative products and similar products from the same third-party sellers.
3. Continued Violations: Despite these representations, FDA was able to repurchase some of the same products after Amazon claimed to have restricted them. For example, FDA repurchased “Kopi Jantan Tradisional Natural Herbs Coffee” in January 2021 after specifically advising Amazon that it contained undeclared sildenafil.
4. October 2018 Meeting: During a meeting in October 2018, FDA had advised Amazon that dozens of “Rhino” sexual enhancement products were still being offered for sale despite previous FDA warnings about these products.
5. Inadequate Filtering Systems: FDA expressed concern that Amazon’s product filtering systems were inadequate to prevent the distribution of violative products, even after Amazon implemented measures to restrict specific products.

FDA’s Concerns and Rationale for Untitled Letter

The Untitled Letter explained FDA’s decision to issue this public communication:

Despite Amazon’s efforts to restrict specific products when alerted by FDA, the continued availability of violative products posed a continuing risk of harm to the American public. FDA determined that:

1. Amazon’s reactive approach of restricting specific products after FDA notification was insufficient
2. Amazon’s filtering mechanisms failed to prevent similar violative products from being listed
3. Public warning was necessary because consumers continued to have access to potentially dangerous products through the platform

The letter emphasized Amazon’s responsibility: “Your firm is responsible for introducing, delivering, or causing the introduction or delivery into interstate commerce of products that are unapproved new drugs, misbranded drugs, and/or foods to which an approved drug has been added.”

Subsequent Developments and Warning Letters (2022-2023)

The situation with Amazon continued to evolve, ultimately resulting in escalation to Warning Letters:

October 2022 Warning Letter: FDA issued a Warning Letter to Amazon regarding products containing undeclared diclofenac (an NSAID marketed as dietary supplements). These products were marketed as “Artri Ajo King,” “Artri King Reforzado con Ortiga y Omega 3,” and “Ortiga Mas Ajo Rey.”

November 2023 Warning Letter: FDA issued a Warning Letter citing Amazon for the sale of seven different homeopathic eye drop drugs that violated FDA’s homeopathic drug guidance.

December 2023 Warning Letter: FDA issued another Warning Letter after purchasing seven products (marketed as energy-enhancing supplements) through Amazon that contained undeclared tadalafil or sildenafil. These products were introduced into interstate commerce through Amazon’s “Fulfillment by Amazon” service.

The December 2023 Warning Letter is particularly significant as it represents an escalation from the 2021 Untitled Letter, demonstrating that Amazon’s corrective actions remained insufficient despite multiple FDA communications.

Industry and Regulatory Response

Amazon’s Quality Program: In December 2020, Amazon announced the development of a dietary supplement quality program requiring third-party testing and verification. The program requires:

• Products to be manufactured in facilities compliant with FDA regulations
• Products to be free of contaminants and accurately labeled
• Third-party verification through a Testing, Inspection, and Certification (TIC) organization

However, implementation of this program has faced delays and challenges, and FDA’s continued findings of violative products suggest ongoing compliance concerns.

Legal Actions: In February 2023, a proposed class action lawsuit was filed against Amazon in California, alleging that the company sells dietary supplements that are actually misbranded “defective drugs” that are illegal and unapproved by FDA. The lawsuit claims Amazon promotes supplements with health-related claims without the FDA-mandated disclaimers required to distinguish supplements from drugs.

Broader Implications: The FDA-Amazon case illustrates several important regulatory principles:

1. Platform Responsibility: E-commerce platforms can be held responsible for products they introduce into interstate commerce, even when sold by third-party sellers, particularly when using fulfillment services.
2. Inadequacy of Reactive Measures: Simply removing specific violative products after FDA notification is insufficient; companies must implement proactive, systematic approaches to prevent violations.
3. Escalation Process: The progression from Untitled Letter to multiple Warning Letters demonstrates how FDA escalates enforcement when corrective actions prove inadequate.
4. Public Health Priority: FDA’s decision to post the Untitled Letter publicly reflects the agency’s determination that ongoing violations posed sufficient risk to warrant public notification, even though the letter type does not automatically require posting.

Lessons for Regulated Entities

The Amazon case study offers several important lessons:

Systemic Solutions Required: Addressing individual violative products is insufficient. Companies must implement robust systems to prevent violations from occurring in the first place.

Verification of Third-Party Compliance: When working with third-party sellers or suppliers, companies bear responsibility for ensuring products meet regulatory requirements.

Proactive vs. Reactive Approach: Waiting for FDA to identify violations before taking action is inadequate. Proactive compliance programs, including testing and verification, are essential.

Importance of Effective Filtering: Automated systems for detecting violative products must be regularly evaluated and updated to address evolving compliance challenges.

Supply Chain Oversight: E-commerce platforms must maintain adequate oversight of their supply chains, including sellers using fulfillment services.

Best Practices for Responding to Advisory Action Letters

Immediate Actions Upon Receipt

Whether receiving a Warning Letter or Untitled Letter, immediate action is critical:

1. Acknowledge Receipt: Confirm receipt of the letter and inform FDA of your intent to respond within the specified timeframe (typically 15 working days for Warning Letters).
2. Assemble Response Team: Create a cross-functional team including Quality Assurance, Regulatory Affairs, Operations, Legal, and relevant subject matter experts. Designate a leader with appropriate authority and expertise.
3. Implement Interim Controls: Take immediate action to protect public health, such as suspending production, quarantining affected products, or initiating recalls if appropriate.
4. Preserve Documentation: Secure all relevant records, including those that may support root cause analysis.
5. Consider External Expertise: For complex violations or serious matters, engage external consultants with regulatory expertise and experience in FDA remediation.

Conducting Thorough Investigation

A comprehensive investigation should:

1. Review All Evidence: Carefully examine all observations and evidence cited in the letter. Conduct your own investigation to understand the full scope of issues.
2. Perform Root Cause Analysis: Use systematic methods (such as Failure Mode and Effects Analysis, Fishbone diagrams, or Five Whys) to identify underlying causes, not just symptoms.
3. Assess System-Wide Impact: Evaluate whether similar issues exist in other products, processes, or facilities. FDA expects comprehensive assessment beyond the specific violations cited.
4. Identify Contributing Factors: Consider organizational, technical, and human factors that may have contributed to violations.

Developing Effective CAPAs

Corrective and Preventive Actions should be:

Specific and Measurable: Clearly define what will be done, by whom, and by when. Avoid vague commitments.

Addressing Root Causes: Focus on systemic changes that address underlying issues, not superficial fixes.

Comprehensive: Address not only the specific violations cited but also related systemic weaknesses.

Verifiable: Include objective evidence (revised SOPs, training records, validation reports) demonstrating implementation.

Sustainable: Ensure long-term effectiveness through monitoring, periodic review, and continuous improvement mechanisms.

Communicating with FDA

Effective communication with FDA includes:

1. Professional Tone: Responses should be respectful, professional, and demonstrate a serious commitment to compliance and public health.
2. Structured Format: Mirror the structure of the FDA letter, addressing each observation point-by-point.
3. Transparent and Honest: Acknowledge violations honestly. Attempting to minimize or deflect rarely succeeds and may damage credibility.
4. Regular Updates: For long-term CAPAs, commit to periodic updates (e.g., every 90 days) and follow through consistently.
5. Request Extensions if Needed: If more time is required for comprehensive response, request an extension promptly with clear justification and evidence of interim actions taken.

Preparing for Re-inspection

Following a Warning Letter, FDA will likely conduct a follow-up inspection to verify corrections:

1. Complete All Committed Actions: Ensure all CAPAs are fully implemented before requesting re-inspection.
2. Document Everything: Maintain comprehensive documentation of all corrective actions, including dates, responsible parties, and verification of effectiveness.
3. Conduct Internal Audits: Perform thorough self-assessments to identify any remaining issues before FDA’s return.
4. Train Personnel: Ensure all relevant staff understand changes implemented and their responsibilities for maintaining compliance.
5. Notify FDA of Readiness: Once all actions are complete, formally notify FDA that you are ready for re-inspection, particularly important for foreign facilities.

Current Regulatory Landscape and Future Trends

Digital Quality Management Systems (DQMS)

Modern regulatory compliance increasingly relies on Digital Quality Management Systems that provide:

• Closed-loop CAPA Management: Automated tracking, routing, and approval of CAPAs with built-in effectiveness checks
• Robust Audit Trails: Time-stamped, tamper-evident records of all quality-related activities
• Training Management: Automated deployment and tracking of training associated with revised procedures
• Real-time Monitoring: Dashboard views of compliance metrics and CAPA status
• Data Analytics: Advanced analytics to identify trends and prevent violations before they occur

FDA increasingly expects companies to leverage technology for compliance management, particularly for complex, multinational operations.

Emphasis on Quality Culture

FDA’s inspection approach increasingly focuses on organizational culture and management commitment to quality:

• Senior leadership engagement and accountability
• Adequate resources allocated to quality functions
• Open communication channels for quality concerns
• Data integrity and truthfulness in all dealings with FDA
• Continuous improvement mindset

Warning Letters increasingly cite lack of quality culture or management oversight as contributing factors to violations.

E-commerce and Platform Accountability

The cases involving Amazon and other e-commerce platforms signal FDA’s evolving approach to online marketplaces:

• Platforms cannot simply rely on third-party sellers to ensure compliance
• “Fulfillment by” models create direct responsibility for product introduction into commerce
• Proactive filtering and verification systems are expected
• Laboratory testing of products may be necessary to ensure compliance
• Terms of service provisions prohibiting violative products are insufficient without effective enforcement

International Harmonization

FDA increasingly coordinates with international regulatory authorities:

• Mutual recognition agreements with foreign regulatory agencies
• Information sharing about inspectional findings
• Coordinated enforcement actions for international companies
• Adoption of international standards (ICH, ISO) in FDA guidance

Companies operating internationally should ensure compliance with converging global standards.

Increased Transparency

FDA continues to expand public disclosure:

• More rapid posting of Warning Letters
• Increased posting of Untitled Letters for public health purposes
• Publication of inspection reports (Form 483s and Establishment Inspection Reports)
• Public dashboards showing compliance status of facilities

Companies should assume that regulatory communications and compliance issues will become public knowledge.

Conclusion

FDA Advisory Action Letters—both Warning Letters and Untitled Letters—serve as critical tools for achieving regulatory compliance and protecting public health. Understanding the distinctions between these letter types, their implications, and the appropriate response procedures is essential for any organization operating within FDA-regulated industries.

Warning Letters represent serious regulatory findings that require comprehensive, systematic responses. They signal violations of regulatory significance that, if not corrected, may lead to enforcement actions including product seizure, injunctions, or civil/criminal penalties. The public nature of Warning Letters means they can significantly impact a company’s reputation and business relationships.

Untitled Letters, while less severe, should not be disregarded. They provide an opportunity to address violations before escalation to Warning Letters and associated public disclosure. An adequate response to an Untitled Letter can prevent more serious consequences.

The Amazon case study illustrates how inadequate responses to regulatory concerns can lead to escalation from Untitled Letters to Warning Letters, public scrutiny, and legal action. It underscores the importance of proactive, systematic approaches to compliance rather than reactive measures addressing only specific cited products or violations.

As regulatory expectations continue to evolve—with increasing emphasis on quality culture, digital systems, supply chain oversight, and platform accountability—companies must adopt sophisticated, forward-looking compliance strategies. Success requires not just technical knowledge of regulations but also organizational commitment to quality, transparency in dealing with FDA, and willingness to invest in robust compliance infrastructure.

Organizations that treat Advisory Action Letters as opportunities for meaningful improvement rather than merely as problems to be managed will be better positioned for long-term regulatory success and protection of public health—the fundamental mission that unites regulated industry and FDA.

For companies that receive Advisory Action Letters, the message is clear: take them seriously, respond comprehensively and honestly, implement systemic solutions, maintain open communication with FDA, and demonstrate sustained commitment to compliance. The alternative—inadequate response and continued violations—leads to escalating enforcement, reputational damage, and ultimately may threaten the organization’s ability to continue operations.