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By Cindy Beehner, Independent Consultant

In recent months, it appears more companies are having difficulties meeting the requirements of FDA Form 483, List of Observations, response. The inspection situation is very stressful and if it ends with the dreaded “483”, it can be positively overwhelming. However, when the initial reaction is over, it’s time to rally the staff and prepare the corrective and preventative action strategy that will be presented in the response within the allotted time frame. It is also critical to understand what is expected of the response letter.

The 483 is a list of inspectional observations that is the result of what the inspectors viewed while in your facility. It is a legal document from federal agents performing a law enforcement function where the evidence is the collection of documents and data that the agents evaluated at the company. All of the observations should first be reviewed for accuracy. Hopefully, any discrepancies or misunderstandings were discussed during the closing meeting and resolved, but if they were not found until after the inspectors left the facility, they will need to be addressed in the response. The 483 response is also a legal document so the tenor and exact wording used are critical. It must demonstrate that the company understands the issues, has made the necessary corrective and preventative actions, and that there is documented evidence to verify the latter.

Each observation requires a response and that response must describe the associated corrective and preventative actions are taken. It should be thorough and detailed and written to present steps in the order taken. Procedures and related documents prepared and implemented during these actions must also be included. It is not enough to only describe actions, there must be documented evidence of the correction such as photographs, procedures, training records, specific forms, and other types of documentation. Many Warning Letters are issued by the FDA because a company’s response letter did not include evidence of the corrective and preventative actions taken for the FDA to evaluate to determine if the situation was appropriately addressed.

Consider three potential categories of actions to be taken for each observation; immediate, short-term and long-term. Think of this from a medical emergency perspective where initial triage occurs to keep the patient’s condition from getting worse, additional short-term actions are needed to stabilize the patient, and then long-term actions may be needed to deal with any underlying problems. A systematic issue will have to be addressed with preventative measures. It is also important to review the observations collectively, in addition to individual, to determine if other underlying systemic issues exist. These too will have to be addressed with corrective and preventative actions.

Please note that, unlike an FDA Warning Letter, a response to a 483 is not legally required. However, it is strongly recommended that a 483 response be provided to the FDA within 15 business days. Some observations can be appropriately addressed and the actions concluded within this time frame, but others, particularly systematic issues, may require more time. When that is the case, all of the planned corrective and preventative actions should be described in the initial response, immediate and short-term actions should be taken, and completion dates for long-term items provided. It is important that these proposed dates be aggressive, yet reasonable and obtainable. Monthly updates to the FDA stating the progress made on these long-term items, with supportive documented evidence included, should then follow. This strategy may prevent the FDA from escalating enforcement actions and issue a Warning Letter.

Confirmation that the FDA is satisfied with the 483 response will be provided by the issuance of an Establishment Inspection Report (EIR) which states that all of the corrective and preventative actions will be evaluated upon “the next inspection.” The EIR is also a more detailed summary of the inspectional findings and it is wise to use this as an opportunity to further review operations, controlled processes, and the overall quality system. Look at these findings from a systems approach; facilities and equipment, materials, production, packaging and labeling, laboratory controls and, of course, the most important and critical one – the quality incident system. The entirety of the inspection and the inspectional review should also be another piece to the internal audit program, make the experience work to improve compliance and not just an exercise in writing letters to the FDA.

For assistance in understanding FDA 483 findings as well as developing an appropriate response and corrective actions contact EAS.

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