483 Observations & Warning Letters
Whether you’re vaccine or drug manufacturers, facilities that conduct clinical trials, or a medical device company manufacturing Class II or Class III devices, you can expect random and routine inspections by the FDA.
Preparing for an FDA inspection is a critical step, and ProPharma Group experts can guide you through the entire process. It’s what happens after the inspection that we are addressing here.
One unfortunate thing that can happen after an FDA inspection is receiving 483 Observations, and the potential of receiving a Warning Letter. It is important to understand the differences between the two and what you can expect as a result.
An FDA 483 Observation, also referred to as “inspectional observation,” is sent by the FDA to highlight any potential regulatory violations found during a routine inspection. A 483 Observation can relate to the company’s facility, equipment, processes, controls, products, employee practices, or records.
The financial impact of an FDA 483 Observation can be catastrophic, sometimes costing companies several million dollars. If the issues are systemic, the 483 Observation can trigger training, redesign, process implementation, and other measures.
It is better to anticipate any potential issues that might result in a 483 Observation by creating and implementing processes to avoid this scenario. Trying to repair the issues brought forward as the result of a 483 Observation is not only expensive, but very disruptive to the company, often negatively impacting employee morale.
Once the inspection has been completed, the company will receive a draft of the Establishment Inspection Report (EIR), as well as drafts of any 483 Observations. The inspector will submit these documents to the company before leaving the facility. Upon receipt of 483 Observations, the company has 15 days to respond.
If you receive a 483 Observation, the situation needs to be handled with care. First and foremost, you should review the documents with the inspector before he/she leaves the facility. You do not have much time to address these challenges, so having a full understanding of the documents and what needs to be done to correct the issues is critical.
Before the inspector leaves, be sure to:
- Gain an understanding of observations noted and assure their accuracy
- Understand the broader message the FDA is sending
- Identify and discuss any errors in the observations
- Ask questions
- Demonstrate awareness of applicable regulations
- Consult with legal counsel as necessary
A 483 Observation does not need to be addressed in writing; however, it is considered good practice to do so. It is also good practice to address your response to the district director with a courtesy copy to the lead investigator.
FDA Warning Letter
A Warning Letter is an official deficiency letter from the FDA, which is sent as a consequence of an unsuccessful inspection by the investigators of the agency. Before a Warning Letter is issued, the FDA requests the company to comment on the deficiencies listed in the 483 Observations found during the inspection. If the FDA judges this response to be unacceptable, a Warning Letter will be issued.
Typically, Warning Letters are sent to ensure overnight delivery and receipt of delivery (e.g., return receipt requested, FedEx). As with an FDA 483 Observation, the company has 15 days maximum to respond in writing. However, if the cause of the Warning Letter is severe, the FDA may shorten the deadline.
Like 483 Observations, Warning Letters can be very costly and can significantly delay time to market and consume capital in the process.
Once the FDA has determined that a company has significant violations to their regulatory policies and issued a Warning Letter, in order to remedy the issues raised, the following steps should be taken:
- Determine the root cause of the items listed in the letter
- Develop an action plan to remedy issues if one has not been developed. If a plan has been developed, modify it accordingly
- Have a high-level person in the quality group prepare a written response to the Warning Letter
- Have other people not involved with the inspection review the letter
- Ensure that personnel in high-level management are carbon copied when the letter is sent
The response letter should contain an opening statement that discusses how the company is serious about resolving the issue, what the date of the inspection was, and what the address of the site was.
The letter should also include a context for the situation, a restatement of the observation and the reference number, and a discussion of any related operations that were compliant.
Other content in the response letter depends on whether corrective actions have been taken yet and how long the corrections would take. For instance, if the corrections would take several months, the letter should include what measures personnel are going to take to be compliant in the interim.
Have You Received a 483 Observation or Warning Letter?
Whether it’s a 483 Observation or an FDA Warning Letter, addressing the issue will require a lot of work, and can be very stressful. You may want to consider engaging the assistance of outside experts like ProPharma Group to help your team through the process.
Our experts can help you monitor your sites, provide independent auditing to prepare for an FDA inspection, and train your team to ensure everyone has a strong understanding of the regulations.
We have extensive experience and can serve as an extension of your team, supporting you throughout the entire product lifecycle, or offering assistance with one particular area.
If you have received a 483 Observation or Warning Letter, or you just want to take proactive steps to avoid one, contact us today to discuss how we can help.