Insight Report Vol. 12 No.1
How to Respond to an FDA 483 and
Warning Letter
This Insight was originally posted in 1999 when the FDA was a
“friendlier FDA” and the importance of knowing how to respond to an FDA
483 or Warning Letter may not have been that important in protecting a
company from the FDA regulatory wrath.
That was then, this is now. With the present FDA regulatory policies as
defined by the new FDA Commissioner, Dr. Margaret Hamburg (confirmed in
2009) who basically declared regulatory war on the industry and that the
FDA will expect companies bring their operations into immediate
compliance. (see FDA UPDATE – August 2009 ,
“New FDA Commissioner – New Edits on dealing with the Industry – But, is
New always good for the Industry?”)
Understanding how to deal with the FDA investigator during and
inspection, the issuance of the
483 and signing (or not signing) FDA affidavits could mean the
difference between minimizing FDA regulatory problems or getting caught
in an FDA quagmire.
This Insight will key into the “How to Respond” to the 483 and Warning
Letter. The other areas of concern ? Dealing with the FDA Investigator
and FDA Affidavits ? will be covered in future Insights.
It
used to be that The RESPONSE is your last chance to tell your side of
the story to possibly the only compassionate listeners before Washington
becomes involved. That was the old FDA. At that time, after an FDA
inspection which resulted in the issuance of a 483, the FDA expected
companies to respond within 30 days. In the response, companies stated
to the FDA a time frame when they plan to address the concerns outlined
in the 483. Based on the response, the FDA would determine if a warning
letter was to be issued. That decision in some cases took up to 6
months. After the original 483 response by the company, the FDA usually
did not expect any further follow from the company as to how they were
progressing with bringing the firm into compliance.
Things are much
different now. How you respond, what your corrective actions will be,
what documentation you supply and your follow up with the agency is not
only important but could mean the difference between being issued a
Warning Letter or the FDA taking other significant regulatory actions.
The FDA is expecting much more comprehensive responses to the 483
observations, including the effect of the observation on the device(s),
how the observation will be corrected, timeframe for the correction,
employee training (if necessary), verification and documentation.
Will the proper “Response” guarantee that the FDA would not pursue
further actions? This will be determined on a case by case basis.
However, you can be assured that without a strong, proactive response to
the FDA concerning your 483 observations, you can certainly expect to
receive a certified letter from the Agency.
The FDA Inspection
Many have viewed dealing with the FDA as a major problem. Well, with
today’s FDA, it is. It may appear more like a nightmare as the FDA takes
control of the inspection and you don’t seem to know which way to turn.
For many companies this in fact is the case, especially for the smaller
company.
Knowing what you can do to protect your company is imperative. What you
must make available to the FDA and what you are allowed to withhold from
the Agency could make the difference between a major problem and no
problem.
FDA
investigators and how they conduct their inspections, unfortunately,
could be as different as there are numbers of investigators. In
addition, you need to take into account the newly hired investigators
(the FDA was given the ok to hire over 7000 staffer over the last
several years as the FDA personnel were starting to age out). These
inexperienced and lacking industry-related knowledge investigators are
not likely to rely on industry’s explanations for situations that are
unknown to them and thus will go back to their superiors for advise on
how to proceed (basically you will find many FDA inspections are being
run by the district office and not the investigators). As a result of
this inexperience, the FDA's 483s are increasing in complexity,
regardless of whether the inspector's observations are relevant to the
company's product or operations. Please understand that there are times
when the FDA’s observations are relevant and a company does deserve a
Warning Letter.
Companies are
supposed to comply with the regulations and assure that their devices
meet specifications. On the other hand, there are situation when the FDA
inspectional observations are not correct and in this case, it is
important to know how to protect your company.
Precautionary Measures
The FDA themselves state it is industry's responsibility to work with
investigators before they leave the company to remove all incorrect
points on the 483. The FDA is also supposed to annotate the 483
concerning your corrective actions that were accomplished during the
inspection.
From latest experience with the new FDA investigators, this advice
doesn't appear to hold any weight when they are trying to prove
themselves while still on the learning curve. Some seem to think the
longer the list on the FD483, the better their chances for advancement
-- though, that is not always the case (in fact, FDA promotions are
based on the candidate’s actions not just the number of issued 483’s or
Warning Letters).
Why try to prevent inaccuracies on the FD483?
1. The FDA483 is a legal document, and inspectional observations could
be construed as deviations from the GMPs. These GMP violations can be
used as counts against you in legal proceedings.
2. The FDA483 is part of the company's regulatory history. If future
problems arise, past FDA483’s could be caused to enhance legal actions
against you.
3. The FDA483 is available via the Freedom of Information Act so the
competition could get a copy and use it against you in the market.
The issuance of the FDA 483
You have just been issued an FDA483 -- now what? The investigator will
try to elicit your response to each point, one by one. In cases where
your responses can be made without any uncertainty as to the outcome and
conclusion, definitely provide them to the investigator at the close out
meeting. But, if you are not sure of your response, it would be better
to explain to the investigator that you will supply a written response
to the FDA483 directly to the FDA district office.
Even if you respond verbally to the investigator on each point, it is
crucial, let me repeat, it is crucial, that you also send in a written
response as soon as possible. This assures your response is accurately
given to all interested parties which could include the investigator’s
supervisor, the compliance officer assigned to your case (yes, you will
now be considered a “case”) and the branch director ? all those who
could be a part of the decision as to whether a Warning Letter should be
issued.
The nature of your response to the FDA has changed over the years.
Simply stating you received the FDA483 and will address all issues,
without outlining the specific corrective actions you have planned and
their implementation time frames will not fly with the FDA any longer.
Such response could be interpreted as a poor attitude on the part of the
company and the agency will definitely issue a Warning Letter to assure
that the corrective actions are taken.
Remember the observations on the FDA 483 are just the investigator’s
opinions. These observations are not always supported for additional
legal action by the district office or the Division of Compliance in
Washington. But, the investigator is the main advocate for additional
action, though they may have the least amount of input on whether
additional regulatory action would be taken.
You must understand that the issuance of the 483 is the FDA’s regulatory
action and the issuance of a WARNING LETTER is the next level of FDA
regulatory action.
The FDA is now setting up a case against companies to take additional
legal actions if proper correctives actions are not taken and in the
appropriate period of time.
The Response
Under the FDA's present regulatory policy a well-planned response to the
FDA483 and to any future warning letters is imperative. It should
contain a full explanation of the investigator's observations, the
possible reason for the observation, what was done to assure that the
observed situation did not affect device specifications and how and when
you will address the observation.
Once the FDA483 is issued, the only people at the FDA to read it before
additional legal actions against the company are recommended are the
investigator's supervisor, possibly the director of investigations and
the compliance officer. If you and the investigator have some
disagreement during the inspection, there is no way you can be sure the
investigator would relay these problems to anyone else. It is your
responsibility to do so, and you must make the most of this opportunity
in a rapid manner.
Here are examples of how to appropriately respond and explain the events
that may lead up to how the observations were put on the FD483:
1 - Opening remarks. Give the next line reviewer
an overview of the company, its products and operations. The compliance
officer gets his information secondhand from the investigator, which
could be tainted.
Include a paragraph concerning the business' history, length of
operation; the type of products produced; and its past FDA history. If,
in the past year, the number of complaints has been relatively small
compared to the number of units distributed, include that and any other
information to indicate to the compliance officer things may not be
exactly as reported by the investigator.
2 - Specific observations. Depending on the
observation, the response should give back-ground information on the
point, why it was made and why it was inappropriate.
If the observation was appropriate, state what is being done to
determine its effect on the device and what will be done to correct the
problem.
The main objective once you are issued a 483 is to limit the
financial and legal damage to the company.
3. The FDA investigator could attempt to put his or her
bias into the observations which may not be correct or appropriate for
you operations. Your response should address your experience with the
process or item and why you feel that the investigator’s observation is
inappropriate and not valid. If you are sure about this, you have to
make it very clear in your response.
Dos and Don'ts
Samples of actual FD483s:
Observation A: The results recorded for the electrical
testing were only qualitative, not quantitative.
Response 1 (inadequate):
Quantitative data for these tests was not required in the standard
operating procedures (SOPs) and should not have been a point on the
FDA483.
Response 2 (appropriate):
The test the investigator thought required quantitative data was for
determining conductivity only. The process has been evaluated, and
recording quantitative data would not supply any information that could
be used to determine if a trend was developing. (Additional option: This
information was conveyed to the investigator who could not understand
why quantitative data was not necessary to assure the device would meet
specifications.)
Observation B: There were no recording charts on the
storage refrigerator, and the products stored required conditions of 4
to 8 degrees C.
Response 1 (inadequate):
We will put recording charts on the refrigerators.
Response 2 (appropriate):
A check of all products stored in the refrigerators will be made by
rerunning all finished testing to assure the storage conditions did not
affect the product. The sample will be made using statistical sampling
plan using AQL 2.5. If any of the products fail, the entire lot will be
destroyed or reworked if possible. A copy of the tests will be supplied
upon test completion, which should be within two weeks. Recording charts
will be installed on all storage refrigerators within 30 days.
Observation C: The freeze drier’s manual states you
should have 6 month maintenance to maintain the unit. You presently do
not have any routine maintenance on the freeze drier.
Response 1(inappropriate)
We will contact the freeze drier manufacturer and ask for a maintenance
contract immediately.
Response 2(appropriate)
The freeze drier
is on breakdown maintenance. In the twenty years of use we never had a
problem with any of the products freeze dried that was caused by the
unit. Preventative maintenance is not necessary to assure the correct
operations of the unit. (FDA accepted is response on the company’s
history and experience of the company not the investigator ‘s
observation based on his minimum experience and just reading a manual
and not listening to the company. It also saved the company $6000/yr in
a maintenance contract.)
As you can see
with these examples, you want to show the FDA you are either in control
of the situation or are attempting to comply voluntarily, doing all that
is possible to assure the products or devices meet specifications.
Cooperation and Compliance
Your main objective once you are issued a FDA483 is to limit the
financial and legal damage to the company and to get into compliance as
soon as possible. If you think a philosophical battle with the FDA will
meet these goals, then take that route. But our experience has been
philosophical battles are not won or lost and cost a lot of time, money
plus aggravation.
If
you show continued contempt for the agency and its policies, chances are
you will be forced into compliance through further legal proceedings
which will cost much more money, possible loss of business and adverse
publicity. Instead, if you show the FDA you are complying with the
agency's policies without the need for further legal action, there is a
chance the agency will move to another “problem" company and continue to
work with you to achieve compliance. These results could be obtained by
knowing your rights, operations, products and when to bend. The FDA's
first indication you know how to bend is in your RESPONSE.
Remember the FDA’s function it to assure that you are in compliance and
to do what they feel is necessary to assure that. You have to use your
483 response as a chance to give the FDA the ability to agree with your
corrective actions and feel that the need for additional regulatory
actions would not be warranted. At the present time, the FDA is more apt
to act than to stay idle. Your pro-action is imperative to show the FDA
your ability to understand and assure full compliance.
Next Insight Report - to be announced.
If you
have any comments on these INSIGHTS we hope that you let us hear them. If you have any of
your own INSIGHTS that you feel would be of value to other companies, we would be pleased
to hear from you and to discuss them with you and if you allow, we would even put them up
on this site for others to learn from.
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