Part 1: Responding to FDA483 Observations and Fulfilling Commitments

Part 1: The FDA483 Response

In this two-part series will discuss responding to the FDA483 and getting the work done to fulfill the commitments in a sustainable way.

Unlike a Warning Letter, a response is not required--but highly advisable. It is standard industry practice to respond to FDA483 observations. Responsible companies that want to have a good relationship with the FDA respond to each observation by saying exactly how problems will be addressed.

There is plenty advice available, even from the FDA, on what constitutes a good response. For certain, the difference between a good and a poor response may differentiate how you are viewed by the FDA.

From my experience, the following are points to consider that have worked well when forming a response:

• Do you agree with the response? Stating up front that you either agree or disagree, in part or on the whole, stages the rest of the response. Think twice before you say you completely disagree especially with everything-- because the FDA will always have the regulations, industry good practice, and the facts on their side. But it is quite possible that the FDA investigator got the facts wrong or drew the wrong conclusion. This is why a close-out meeting with investigators at the conclusion of the inspection is important. It is better to straighten out the record at the close-out meeting than in the FDA483 response.

• Defend what you are doing right. The examples of violations cited in observation are just a snapshot in time. Although you may not be proud of what was found, the finding may not be representative of the current state of control. The example may pre-date significant improvements that you have made on your own initiative, although they may be in progress and not fully implemented. Be sure to give yourself credit for such improvements. The last thing you want to do is give the impression that the FDA was the first to call a problem to your attention.

• Take product lot numbers seriously. When the FDA mentions specific lot numbers associated with a problem, it immediately puts you in the position of having to defend why those lots are still on the market, and why you have not shut down manufacturing associated with that product, process, or facility. Put your best minds and writers to work to lay out the defense of your release decision and the state of control. Be objective and use data. If you come to the conclusion, albeit late in the game, that the product should be recalled, seriously consider the right thing to do. Also take into account causing a critical drug shortage, because the FDA will work with you to avoid a shortage while you resolve inspection-related problems.

• Defend State of Control. Some types of observations paint a picture of being out of control, particularly when it is associated with validation, sterility assurance, potency, content uniformity--you know--the SISPQ issues. Also, taken collectively, observations that run the gamut of the quality system can indicate a precarious state of control. Take your best, realistic, honest shot at how you know you are manufacturing and distributing a safe, quality product. And, for goodness sake, do not--I repeat--do not anchor your defense that there have been no complaints or dead bodies in the street. Meeting all end product specifications may be the best defense you have if statistically treated, but be aware that a "final product spec" defense will always peg you as a 1970s time traveler.

• Commit to Action. Address the specific issues that were called to your attention, but do not stop there. Carefully determine the root causes of the issues cited in the observations. There will not always be a one-to-one relationship of root cause to observation. Nonetheless, run the problem to ground and understand what is behind the problem. Determine the action required to prevent the reoccurrence of the problem cited. Undoubtedly, the solution will require changes in multiple areas at the system level. Be sure to convey that you are taking system-level action, not just addressing the superficial, specific examples. Remember, observations are just examples. Indicate the action you promise to take and target completion date. Be clear in advance what "done" looks like and the specific deliverables that will provide the evidence of successful completion.

• Commit to Developing Appropriate Action. If you do not know exactly what all is necessary to fix the problem, it is completely acceptable to indicate that the scope of activities and target dates will be established in a plan to be provided later. But state in the response when the plan will be completed and provided. Major milestones and target month are usually acceptable in a follow-up communication.

• Recognize the Minimalism. Very likely you have taken a minimum essential approach to the commitment. By the time all the internal reviewers have edited the response, you have pared down the work to something manageable for normal business. However, the work associated with FDA inspection observations is not normal business. The scope of the actual work required to prevent recurrence of the observation may be more than expected when you actually delve into the root cause and prevent recurrence through systemic changes. 

• Provide Realistic Target Dates. There is always a balance between showing responsiveness with aggressive target dates and over committing to unrealistic dates. When dealing with operational and quality system problems, there may be more work involved than meets the eye. Some problems may require engineering studies or process development in order to understand the right approach to take when solving a problem. Take time to really think through all that is involved in order to provide realistic target dates. You don't want to go back to the FDA--at least not too often--to revise target dates. Do inform the FDA of changes in completion dates. Don't let a broken promise be a surprise when they return to reinspect. It's far better to inform them in advance.

• Engage Your Internal Associates. I cannot tell you how often I discover the situation where commitments and target dates were given to the FDA in very well written responses, but those who carry out the work were not involved--even totally clueless. It's best to involve those who have to fulfill the commitments in the actual writing of the response. Time is of the essence when preparing a response, but cutting out those who actually do the work will always uncover significant execution issues at the worse possible time.

• Take FDA Suggestions. When the FDA makes a suggestion about retaining a GMP consultant to assess your overall quality system and help you to improve--take the suggestion. This recommendation usually comes in Warning Letters where the FDA has come to the conclusion from the breadth of problems and recurring problems that there is no confidence in your Quality Unit or Management Oversight. Consider such a recommendation as a direct hit and taking on water, not just a shot across the bow. So be responsive and act accordingly.

What is your experience with preparing regulatory observation responses? What has worked well? What has not worked well?

In Part 2 I will talk about organizing to get the work done to fulfill commitments.

The QA Pharm