How to respond to FDA warning letters

What’s the fastest way to ruin a quality manager’s day?

Receiving a warning letter from the United States Food and Drug Administration (FDA).

Unfortunately, thousands of medical device and biopharmaceutical startups fall out of compliance with FDA regulations. These kinds of issues prevent even the most growth-oriented life sciences companies from achieving terminal velocity. 

And without an electronic quality management system (eQMS) by your side, mitigating quality and compliance issues is virtually impossible.

So, what’s the best way to respond to FDA warning letters?

Keep reading for a breakdown of the mission-critical steps your life sciences company needs to follow to adequately reply to an FDA warning letter. 

And use the expert insights found in this article to identify the corrective and preventive actions (CAPA) that your company needs to take to resolve quality issues quickly and efficiently and bring your products to market faster.

What to do when you receive an FDA warning letter

Have you recently received an FDA warning letter? If so, don’t panic.

Start by taking a deep breath. Read the warning letter carefully. 

The FDA typically issues warning letters when manufacturers violate major rules and regulations. After receiving the warning letter, you must outline your response plan and provide a rough timeline for completed corrections. The FDA may then schedule an on-site inspection to ensure that all corrections are satisfactory.

If you’re unsure of how to respond to an FDA warning, we’ve outlined the three most common types of warning letters below, with a response plan for each.

FDA 483 observation notice

FDA’s Office of Regulatory Affairs (ORA) may issue an FDA 483 observation notice after the organization identifies a compliance or quality violation during a routine facility inspection.

If you receive an FDA 483 observation notice, we recommend responding within 14 business days. Your written response should include the following elements: 

• Acknowledgment of the 483 notice
• Statement outlining your company’s commitment to resolving compliance issues
• Confirmation of CAPA procedures
• Timeline for the complete resolution of all citations
• Documentation supporting all design control and quality assurance procedures

6 key considerations when responding to an FDA 483 letter

1. Always act

You aren’t legally obligated to respond to 483 observations. But if you choose not to, you’re borrowing trouble in the future.

Inspectors always review the EIR and any 483 findings from the last audit and will ensure they cover those topics specifically. Repeat findings are a sure pathway to a warning letter, as they represent systemic breakdowns and a huge lack of commitment to quality and continuous improvement on the part of your organization.

2. Question, don't argue

Ask questions of your inspector during the inspection. Ask even more questions at the close-out meeting. Ensure you clearly understand the issue they have identified.

You may not agree with them, but the responsibility to correct the identified problem is clearly with you. It is rare for an inspector to not come around if you truly are meeting the intent of the regulations, and your documented process or records are just unclear to them.

Arguing with your inspector is fruitless and just changes the tone of the inspection for the worse. But ensuring clarity before they leave your facility is critical to correcting the issues identified.

Top tip: the FDA’s Operations Investigations Manual is a helpful tool for learning what they look for and how they expect organizations to adhere to quality standards. 

3. Investigate before you act

Once you have the 483 in hand with your list of non-conformances, immediately assemble cross-functional teams to assess the issues. Sometimes, the different items can be grouped together to be addressed.

Use your CAPA system and thoroughly investigate root causes. Consider if the issue might touch other systems also.

Resist the urge to jump to an immediate conclusion before a thorough root cause investigation can take place. A solid CAPA system will ensure you don’t miss the boat with your corrections.

4. Keep the FDA in the loop with next steps

Establish and stick to solid timelines. The typical response time to a form 483 is about 30 days. If you can correct items within that timeframe with meaningful corrections that truly address the identified issue, then summarizing the corrections made in your response to the Agency is ideal.

If the issues are bigger and more systemic in nature, then you should at least respond with:

• The immediate corrective/ containment action taken
• A summary of the investigation findings (or an explanation that the investigation is ongoing)
• A timeline for completion of the investigation

If you’ve identified corrections, but the implementation timeline is going to be longer, then report that.

Keep in mind that any commitments you make in this response letter will be followed up on. You shouldn’t pad the timeline unnecessarily, but be realistic and don’t overcommit.

5. Get a second opinion if you need one

If you truly disagree with the finding, an external independent opinion should be sought.

Sometimes, a company is too entrenched in their existing systems to be able to see, from an outsider’s perspective, that things are unclear or incomplete. Your initial 483 response can buy you some time that explaining  that you’re investigating further.

But outright dismissing their finding is a dangerous move for a company to make, and puts you on the path to bigger issues in the future. Once you’ve had an independent assessment, and are in agreement that the intent of the cited regulation is met, you can clearly explain your position. There are formal processes in place should you be unable to resolve the issue with your inspector directly.

6. Treat it as a learning experience

Even the best planned and executed quality systems have opportunities to improve, and this is where having independent inspections can be very helpful. If you consider your FDA interactions as opportunities to improve your patient outcomes and business practices, you can view your 483 letter receipt as a more positive experience.

General warning letter

The FDA issues a warning letter after witnessing compliance or quality violations during an audit or inspection. Unlike the FDA 483, a warning letter does not include the recommended actions that your startup or scale-up should take to resolve the violation.

In recent years, the FDA has issued an onslaught of warning letters related to quality procedures documented under 21 CFR Part 820. 

For this reason, more and more life science companies are relying on Qualio’s quality management system (QMS), a results-driven quality tool used to document quality procedures and design next-generation medical devices and biopharmaceutical products that align with new and evolving FDA regulations.

If you receive a general warning from the FDA, we recommend responding within 15 days of receipt. 

As a best practice, consider including a detailed description of your standard operating procedures (SOPs), as well as a brief overview of your CAPA response plan.

RELATED READING: The 8 Essential Functions of CAPA Management

Close-out letter

An FDA close-out letter is only issued after corrections are deemed satisfactory.

According to the FDA, a close-out letter will not be used based on representation that some action will or has been taken. The corrective actions must actually have been made and verified by the FDA. Usually, the standard for verifying that corrections have been implemented will be a follow-up inspection.

Great news! A close-out letter does not require a written response. 

However, future inspections will measure the long-term effectiveness of corrective actions.

RELATED READING: Identifying the 4 Most Common Problems With Your CAPA Process

Strengthening your CAPA process with an eQMS

Designing a results-driven CAPA process is the only way to prevent compliance or quality issues - and resulting FDA letters - from recurring. 

Following the aforementioned procedures and implementing permanent corrective actions will dramatically reduce your chances of receiving repeat FDA 483 observation notices or warning letters.

Avoiding these kinds of roadblocks is absolutely essential, especially if you’re preparing to introduce your medical device or biopharmaceutical product to market in the near future.

If you think your CAPA process isn't fully optimized, try our free self-assessment. The entire quiz only takes a few minutes of your time, and it’ll give you all the insights you need to level up your quality and compliance programs. 

Once you’re done, you’ll even have an opportunity to connect with one of our quality professionals to discuss your results live!

Today, hundreds of quality professionals at some of the most impressive biotech, pharma, and life sciences companies in the world rely on our eQMS to power their quality programs. 

Are you ready to use quality as a competitive advantage and stop those FDA letters arriving?