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The QA Pharm

FDA Compliance

Responding to FDA 483 Observations, Part 1

Analyzing the inspection results and committing to action

Published: Tuesday, November 4, 2014 - 12:47

This three-part series will discuss how to respond to the U.S. Food and Drug Administration’s Form 483 (FDA 483), which is issued at the conclusion of an inspection to document potential violations to the Federal Food, Drug, and Cosmetic Act. We’ll look at how to assess the work needed to address the possible violations in a sustainable way, and how to establish a method to guide the remediation work.

Although not legally required, it’s standard industry practice to respond to FDA 483 observations. Companies that want to be responsive and have a good relationship with the FDA respond to each observation by describing exactly how problems will be addressed.

There’s plenty of advice available, even from the FDA, on what constitutes a good response. For certain, the difference between a good and a poor response may calibrate 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 upfront that you either agree or disagree, in part or entirely, 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 practices, and the facts on its 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’s better to straighten out the record during the close-out meeting than in an FDA 483 response.

Defend what you are doing right
The examples of violations cited in an FDA 483 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 quality control. The example may predate significant improvements that you have made on your own initiative, which may be in progress. 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, this immediately puts you in the position of having to defend why those lots are still on the market, and why you haven’t 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 that your action could cause a 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 a process or product out of control, particularly when it is associated with sterility assurance, potency, or content uniformity—the SISPQ issues (i.e., safety, integrity strength, purity, quality). Also, when collective observations run the gamut across the quality system, this can indicate a precarious state of control. Take your best, realistic, and 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—justify your defense when there have been reported dead bodies. “Meeting all end-product specifications” may be the best defense you have if statistically treated, but be aware that this defense will always peg you as a quality dinosaur living in the 1970s.

Commit to action
Address the specific issues that were called to your attention, but don’t stop there. Carefully determine the root causes of the issues cited in the observations. There won’t always be a one-to-one relationship of root cause to observation. Nonetheless, run the problem to ground and understand what’s behind it. 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 the target completion date. Be clear in your own mind what “done” looks like and the specific deliverables that will provide the evidence of completion.

Commit to developing appropriate action
If you don’t know exactly what’s necessary to fix the problem, it’s completely acceptable to indicate that the scope of activities and target dates will be established in a plan to be provided later. But indicate the date that the plan will be completed and communicated. Major milestones of a plan 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, and neither is the scope of the actual work required to prevent recurrence of the observation when you delve into the root cause and prevent recurrence through systemic changes.

Provide realistic target dates
There’s 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 to solve them. Really think through all that’s involved so you can provide realistic target dates. You don’t want to go back to the FDA—at least not too often—to revise target dates.

Engage your internal associates
I can’t tell you how often I discover the situation where commitments and target dates were given to the FDA in well-written responses, but those who carry out the work were clueless. It’s best to involve those who have to carry out the promises made in the response 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 worst possible time.

Take the FDA’s 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 after the FDA has concluded, from the breadth of problems discovered, that it has no confidence in your quality unit or management oversight. Consider such a recommendation as a direct hit, not a shot across the bow, and that you’re taking on water. Be responsive and act accordingly.

In part two I’ll talk about organizing to get the work done to fulfill commitments.

First published Oct. 17, 2014, on The QA Pharm.

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The QA Pharm

The QA Pharm is a service of John Snyder & Co. Inc., provider of consulting services to FDA-regulated companies to build quality management systems and develop corrective actions that address regulatory compliance observations and communication strategies to protect against enforcement action. John E. Snyder worked at the lab bench, on the management board, and as an observer of the pharmaceutical industry for more than 30 years. His posts on The QA Pharm blog are straight talk about the challenges faced by company management and internal quality professionals. Synder is the author of Murder for Diversion (Jacob Blake Pharma Mystery Series Book 1).