One of the outcomes from a poorly handled 483 response is that the severity of the enforcement action taken by the FDA could be escalated to the status of a Warning Letter. This sometimes happens when companies are dealing with multiple responses, where the response time by the company is inadequate, or where the responses themselves to the 483 citations are inadequate from a technical and quality standpoint.
The FDA reserves the right to issue a Warning Letter any time during the processing of 483 responses, particularly if it feels that the company is not
approaching the response to remediation in the correct way.
Often the rapidity with which a Warning Letter may be issued can be dependent upon several factors; namely:
1. The nature of the violation
2. The severity of the violation
3. The risk impact of the violation
4. The compliance history of the company
5. The adequacy or not of the firm’s corrections
6. The documentation presented to support the remediation of the original observations.
In situations like this, it’s incumbent upon the company to move quickly as the FDA puts a 15-day response time frame on the company, after the issuance of a Warning Letter.
In reviewing the response to the observations, the FDA will look at the appropriateness of the timeframe for each individual remediation event, in
addition to whether the remediation proposed ensures sustainable compliance. As a rule, Warning Letters will not be issued if corrections are adequate and all violations have been corrected without exception.
In preparing a response to an FDA 483 or Warning Letter it is important to have a well-organized plan that will involve the whole team at the site.
The plan should lay out who will be involved, responsibilities for each portion of the response should be divided up and clearly communicated. QA will decide together with appropriate technical SMEs, who were respond to each observation listed in the 483. The timing for the response will be set by the Quality Assurance head for the site, and any additional expert help the may be needed to appropriately address all the questions and issues raised in the 483 or Warning Letter ,will be the responsibility of the site Quality Assurance head.
In summary, the FDA’s looking for an acknowledgment of the seriousness the significance of each observation. Is looking for a commitment by the site leadership management to guarantee an appropriate level of remediation to correct all the issues listed. Appropriate resources will be made available and utilized to deliver a permanent fix to each issue that will generate a status sustainable compliance. Finally, the FDA wants to understand that the site leadership has a full appreciation of why the agency is finding fault with the site’s operation and that there is a proper commitment to make things right.
Simple keys to an appropriate response include the following:
1. Address each observation in detail.
2. Explain how each observation is to be fixed and how a CAPA will be used to carry this out.
3. Set out achievable time frames for the appropriate remediation to complete what’s needed.
4. Provide complete documentation to support each remediation action.
5. Generate a final review which verifies that each observation has been appropriately addressed and corrected.
6. Once the response has been generated, let the FDA know that it is coming and make plans for a follow-up meeting if required.
In responding to 483 or Warning Letter, avoid making the most common mistake for remediation failures by not living up to your commitments.
Remember, promising remediation actions and then not delivering on those promises will impact compliance history and the credibility of the firm.