15 Days of Panic: You Received FDA Form 483 Warning Letter, Now What?

Remember the last time you were pulled over by the police? Maybe you had a taillight out. Perhaps you were speeding. You may have believed that you had done nothing wrong. Regardless of the specific situation, you probably panicked a little. It's human nature to panic when the law enforcement (or in this case the US FDA) tells you that you've done something wrong.

Of course, the best thing to do is to remain calm throughout the process, respond politely to the officer's questions and comments, graciously accept the ticket, then pay the ticket by the deadline or argue in court if you think you have been wronged. This is much like how we recommend responding to an FDA 483 or Warning Letter from the FDA.

As an FDA regulated medical device, biologic, or drug manufacturer, it is more a question of 'when' instead of 'if.' Continuing the analogy above: are you ready for your inspection and related "ticket" from the FDA? Do you have adequate staffing to dedicate the required time and effort to a successful FDA 483 inspection response? Don't panic yet! Let's pause for a bit more information.

What is an FDA Form 483 Observation Letter?

The FDA issues a FDA Form 483 at the conclusion of an FDA inspection when the investigators have observed conditions that, in their judgment, may constitute significant problems with your facility or equipment, the processes and controls you have in place, the products themselves, the practices of your employees, or your records.

The 483 is not a final Agency determination of whether any condition is in violation of the Food Drug and Cosmetic (FD&C) Act or any related regulations. The COVID-19 pandemic changed FDA's approach and timing for inspections. Some inspections are now done remotely, some have been deferred, however we are seeing an increase in on-site inspections by FDA. Either way, the FD&C Act did not change.

Responding to a 483: Planning for Success

The first thing to do is to take a deep breath and do not panic. Don't even get defensive. It's not the end of the world for your drug or device. Remember it’s not the intent of FDA to put you out of business. They are protecting the interests and well-being of the public's health. Also know that failure to correct deficiencies can lead to increased enforcement such as a Warning Letter, Untitled Letter or Consent Decree which are explained later. Great 483 responses and thorough corrective action can prevent increased enforcement activities.

Simply look at the FDA 483 as an opportunity to learn from your mistakes and improve your processes by responding and correcting the observed conditions. It's just someone else looking at your processes from the outside and saying, "Hey, look at this issue and make the necessary corrections."

Now that you are calm, make sure you understand the observations. You can't make corrections unless you are clear on the underlying reasons for the observations in the FDA 483.

Assessing your 483 Observations

Ask the right people within your organization what the FDA saw, heard, or read. Did you collect the same documents that FDA read? Are the right protocols in place? Are they being followed? Has the FDA observed these issues detailed in the 483 before? Has the FDA raised any of those issues before and documented "Repeat Observations"? Answers to these questions will help you prepare your written response and take the necessary corrective action. If systemic, cross system or repeat observations are noted, this may signal a need for a third-party consultant to assist with assessment and responses.

Responding to your 483

In your written FDA 483 response, make it clear that you are taking the observations and your responsibility to correct the observed conditions seriously. Acknowledge all observations and describe the corrections being made. Make corrections immediately, if possible, otherwise set realistic timeframes. You should expect the FDA to follow-up, so always do exactly what you said you would do at the time that is listed in your response. The FDA does not look favorably upon missed commitments and deadlines.

Make sure that your response contains sufficient evidence to address the observations made in the 483. For instance, you have some information that the inspectors wanted but wasn't presented correctly. Perhaps there was a miscommunication, or they were given the wrong document. Simply explain the situation, and make sure the right document is available before the next inspection. The strategic approach should always include a comprehensive review of all systems, departments and processes that could be impacted by a FDA 483 observation and the written response. Check everything imaginable. It's worth it.

Response Suggestions and FDA Priorities

Never mislead the FDA in your response. Don't make excuses related to short staffing or inadequate funds. Adequate staffing is required by the Code of Federal Regulations (CFR). Misleading is like giving the Agency the opportunity to pull that loose thread on your favorite sweater. Once they start pulling, the whole thing will unravel. Always remain compliant with SOPs even if it means slowing production.

A note about FDA priorities. The FDA currently inspects facilities using a risk-based approach. The facilities that make life saving therapeutics, produce high volumes, and have a low compliance record will likely end up at the top of the list. Those facilities with low volume, non-life saving therapeutics and high compliance levels will fall to the lower part of the FDA list. Example: if your organization makes millions of IV bags a year and has an active Warning Letter, you are at the top of the list. Be prepared!

The Consequences of Not Responding to the 483 Letter

When you receive an FDA Form 483, you must respond within 15 business days. However, to make sure that your response is timely, it's best to respond within 15 calendar days. That shows the Agency that you are being proactive and that you are taking the observations seriously.

483 Warning Letter

If you don't take the 483 seriously and either fail to respond within the 15 days, or fail to provide an adequate 483 response, you will face consequences. Essentially, there is an escalation. The next step is a Warning Letter. This letter is a formal notification that allows for voluntary and prompt corrective action relating to specific observations. The biggest reason to not let your FDA 483 escalate to a Warning Letter is that your competitors and customers will find out about your Warning Letter. Your written response to the Warning Letter must communicate a revised plan of action. This plan is your last chance to avoid further escalation of consequences and a good opportunity to work with a third-party consultant like ProPharma's MedTech team to support your efforts.

You may also receive a Warning Letter if FDA officials review the 483 and conclude that a serious violation may exist. This can happen when you respond to the FDA 483 observation(s) in a response letter, but should never prevent you from providing an adequate response.

Consent Decree

If you don't respond to the Warning Letter, or your response is inadequate, the next step in the escalation process can be a consent decree. A Consent Decree is a legal agreement reached between a company and the FDA and overseen by a federal judge. To make it even worse, the FDA can "skip steps". If your organization is significantly out of compliance, the FDA can go directly from a FDA 483 to a Consent Decree.

Essentially, the Consent Decree serves as a negotiated agreement detailing your company's pledged voluntary actions to avoid litigation. Consent Decrees commit companies to perform corrective action in a timely manner. In laymen's terms, it is a court order that something must be done. Well-planned and detail-oriented FDA 483 responses can prevent such significant negative impacts to your organization.

Further, Consent Decrees empower the FDA to impose fines for not completing the corrective actions according to the agreed upon timeline. The Agency may also halt production, which may remove your device from development, result in bankruptcy and shut your organization permanently.

ProPharma can help with FDA 483 Letters or Untitled Letters

Panic is never good. It leads to bad judgment and mistakes. When you receive an FDA 483, you have two options: panic or plan for success. We suggest you contact us immediately so that we can help you plan for success. We'll work with you to put together an appropriate response, structure it in a logical format, and submit it before the deadline. ProPharma has a Remediation Team of seasoned, regulated industry professionals who can support you through this process.

We also recommend that you have ProPharma conduct a mock inspection or an effectiveness check audit after you've remediated the observations outlined in the FDA 483. This inspection will give you clear feedback as to whether what you told the FDA you would do has been done, and that everything observed is now compliant. Having this inspection completed communicates to the FDA that you've taken the FDA 483 seriously and had a third-party assist in the remediation.

Worried that your organization has lost its "edge"? ProPharma can also provide FDA Inspection Readiness training or a pre-inspection audit to prepare for an FDA audit.

An FDA 483 is nothing to panic over. You need to have the right partner to calmly work through what needs to be done. Contact us today and, together, we can work to successfully resolve an FDA 483.

Are you reading this after you submitted your FDA 483 response to the FDA and have corrective action to take? We can help with that as well. Contact us for immediate, proven, successful support. We can manage the generation of Corrective and Preventive Action (CAPA) in your QMS for each FDA 483 observation, monitor the investigational planning, root cause determination, and implementation of the actions identified to eliminate the 483 observation. Often this involves training of staff and we can provide that documented training. Even though the response time for FDA 483 observations is 15 days, many times it is not possible to complete the CAPA in that timeframe – a structured timeframe for monthly updates to FDA can be documented in the 483 response letter. We have done this for many clients and have a proven successful formula for managing FDA 483/Warning Letters/Untitled Letters.