The QA Pharm

This blog is straight talk about quality assurance in the pharmaceutical industry. Not the technical
aspects as much as the challenges faced by company management and their internal quality
assurance professionals—sometimes side-by-side and often toe-to-toe.

Friday, October 17, 2014

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 indicate 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 in 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.

John Snyder
The QA Pharm

The QA Pharm is a publication of John Snyder & Company, Inc.

John Snyder & Company, Inc., provides consulting services to companies regulated by the Food and
Drug Administration. We help our clients to build an effective Quality Management System to enable
reliable supply of quality products to their patients. We also help our clients to develop corrective
action plans to address regulatory compliance observations and communication strategies to protect
against accelerated enforcement action.

Contact us at john@john-snyder.com.

John E. Snyder (The QA Pharm) at 5:10 PM

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John E. Snyder (The QA Pharm)

I'm an observer of the pharmaceutical industry from inside and out for over 30 years. I've worked at the
lab bench and on the management board. If you have a passion for Quality Assurance and understand
the relationship of current Good Manufacturing Practices to your patients and your business, you will
find a kindred spirit here.
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