Practical Tips

Avoiding and responding to Form FDA 483s

“You don’t get inspection-ready, you have to be inspection-ready.”

Preventing and effectively responding to FDA 483s is crucial for drug manufacturers to ensure compliance and avoid potential consequences. Here are some best practices:

Prevention:

• Proactive Quality Management: Implement robust quality management systems (QMS) based on Good Manufacturing Practices (GMPs) and relevant regulations. Regularly conduct internal audits and risk assessments to identify and address potential non-conformities before they escalate to FDA observations.
• Continuous Training and Education: Invest in ongoing training for personnel on GMPs, regulations, and best practices. This ensures everyone understands their roles and responsibilities in maintaining compliance.
• Document Everything: Maintain accurate and complete documentation of all procedures, processes, and data. This helps demonstrate adherence to regulations and facilitates efficient investigation and corrective action in case of an issue.
• Data Integrity: Enforce strict data integrity procedures to ensure the accuracy, completeness, and reliability of all data generated during manufacturing and testing.
• Mock Inspections: Conduct regular mock inspections to simulate FDA inspections and identify areas for improvement in your QMS and operational procedures.

Pre-Inspection

1. Inspect the FDA as well. How? Find out what the latest inspection trends are. You can look up stats across not only the entire agency, but even your specific Investigator using tools like Redica Systems. 
2. Get a sense of what constitutes as big red flags for the FDA.  Although this site focuses on 483s, understanding the FDA’s trends in warning letters and their timing can help you prioritize as you prepare and clean up shop.
3. Practice inspection readiness every day.  Run “mock” audits regularly and review findings so that teams are calm and confident during actual inspections. 
4. Obtain 483s from your industry that are readily available from the FDA or other sources (such as this list we compiled of 483s based on data integrity issues).  This will give you a flavor of what they’re emphasizing (Source: B.B. @ food industry, 3/11) If you have a few days advance warning of who your inspector is, you can always do a search on previous 483s issued by your inspector & purchase them here.

During the Inspection

1. On the day of the actual inspection, only answer the question that the FDA is actually asking.  One pharma company trained their people this way:  If the FDA asks you, “do you know what time it is?”  You should say, “yes.” (Source: anonymous, 2/11)
2. Have senior people in the organization be the point person to the FDA inspectors.  You don’t need an entire team following them around all day.  Choose people who are calm and confident.  Utilize other team members in preparing, assembling requested documentation, CDs, etc.
3. A backroom is essential during FDA inspections. Ideally, this room should be projecting the chat from the inspection room. Experts from across the product lines and Quality Assurance / Regulatory Assurance should be in the back room. They should be ready to provide documentation to support the inspection at a moment’s notice. (Source: David @ big device company, 3/11)
4. Utilize the close-out meeting to clarify any items that remain unclear.   This helps you understand exactly where the inspector’s head is out, and honestly, sometimes you’ll uncover some misunderstandings and lead to less observations.  Do NOT use this meeting to defend your operation.  If you’ve already taken some corrective action during the inspection, it may be wise to ascertain whether the inspectors deem these actions sufficient. (M.R. @ international pharma company, 3/11)
5. The exit interview is VERY important in establishing the intention of Senior management to perform corrective action and CAN minimize further action. The FDA Investigator has a great deal of input as to how the Compliance Branch will classify an inspection. If senior management appears flippant and unwavering (yes this STILL happens!) – expect the District to at least attempt to upgrade a 483, to a warning letter. (Holly Scott, Biologics Consulting Group, 4/11)

Post-Inspection

1. Once the inspection is over, the best way to avoid Form FDA 483s is to respond to the current observations as specifically, comprehensively, and swiftly as possible.  The FDA is understandably not sympathetic to companies with repeat observations.
2. Just because the inspector wrote the observation doesn’t mean that you can’t dispute it.  You can disagree on the facts in which the observations were made on, or you can disagree on whether the observation actually worthy to be written up.
3. Heard: “We know within 30 seconds of scanning your response if you ‘get it’ or not.” – Tim Ulatowski, Director, Office of Compliance
4. A lot has been written on how to craft an exceptional written 483s.  Check out some of the presentations on our home page as well as the 10.5 tips from this article from Veriteq.

483 Response:

• Prompt Action: Respond to FDA 483 observations within the stipulated timeframe (usually 15 working days). Demonstrate a proactive and committed approach to addressing the issues.
• Thorough Investigation: Conduct a thorough investigation to identify the root cause of each observation. This should involve interviewing personnel, reviewing records, and analyzing data.
• Clearly Defined CAPA Plan: Develop a comprehensive Corrective and Preventive Action (CAPA) plan to address each observation. The plan should include the specific actions to be taken, the timelines for completion, and the resources required.
• Effective Communication: Maintain open and transparent communication with the FDA throughout the process. Provide regular updates on your progress and demonstrate your commitment to resolving the issues.
• Documentation and Verification: Document all investigation findings, CAPA plan details, and implemented corrective actions. Maintain records of verification and validation to demonstrate the effectiveness of your CAPA plan.
• Continuous Improvement: Learn from the experience and use it to improve your QMS and overall compliance posture. Regularly review and update your procedures to prevent similar issues from occurring in the future.
• The FDA Group has an excellent post titled “Tips for Writing an Effective FDA 483 Response“

Other Tips

1. “The main thing I learned is that quality is 100% dependent on the organizational culture.  People from all departments have to have a sense of shared ownership in quality – i.e. it’s not just the quality department’s job to ensure quality, though it’s their heads that roll if something does happen.” (Source: anonymous @ big biotech)
2. Speaking of a “culture of quality,” read this excellent guest post from Anders Vinther titled “Good Quality, Poor Quality in the Pharmaceutical Industry“.

Additional Resources:

• FDA Form 483 Frequently Asked Questions: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/fda-form-483-frequently-asked-questions
• FDA Regulatory Procedures Manual: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-manuals/regulatory-procedures-manual
• Outsourced Pharma: 5 Best Practices For Responding To FDA Form 483 Inspection Observations: https://www.outsourcedpharma.com/doc/best-practices-for-responding-to-fda-form-inspection-observations-0001

Remember, preventing FDA 483s is always preferable to responding to them. By proactively implementing these best practices, drug manufacturers can ensure a culture of quality and compliance, minimizing the risk of regulatory action and protecting the safety and efficacy of their products, and by extension, their brands.