INSIGHT REPORT
Vol 2  #8 August 1999

INSIGHT REPORT

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How to Respond to an FDA 483 and Warning Letter

With a “friendlier FDA” one may question the need for an INSIGHT concerning how to handle a response to FDA issued FDA483s and Warning Letters. The truth is, the FDA is not friendly to all companies and they are still issuing FDA483s and Warning Letters. Knowing how to deal with these legal documents (and these are legal documents) could mean the difference between eliminating potential problems or dealing with the agency on what would appear to be a forever ongoing basis with an unending documents and problems. 

The RESPONSE is your last chance to tell your side of the story to possibly the only compassionate listeners before Washington becomes involved.  Will it help?  Maybe?  But, you can be certain, the appropriate RESPONSE will not hurt your case!

Many have viewed dealing with the FDA as a major problem.  More than likely, it may have the appearance of a nightmare with the FDA seemingly in the driver’s seat and controlling the situation.  For many companies this is, in fact, the case, especially for smaller companies. Although the agency’s policies on compliance seem to be one of capitulation, this may not appear to be the case for a company going through a tough FDA inspection.

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.

Unfortunately, how FDA investigators conduct their inspections can be as different as there are numbers of investigators.  In addition the new investigators (though relatively few in numbers), inexperienced and lacking industry-related knowledge, are not likely to rely on industry’s explanations for unknown situations. As a direct 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. I am not concerned with these situations. Companies are supposed to comply with the regulations and assure that their devices meet specifications. But, when the situation does arise that the FDA inspectional observations are not correct it is important to know how to protect yourself.

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 present experience this advice doesn't appear to hold any weight with investigators 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 or Warning Letters.)

Why try to prevent inaccuracies on the FD483?

1. The FD483 is a legal document, and inspection observations could be construed as deviations from the GMPs.  These GMP violations can be used as counts against you in legal proceedings.

2. The FD483 is part of the company's history.  If future problems arise, past FD483s could be caused to enhance legal actions against you.

3. The FD483 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 a FD483 -- 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, make them.  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 FD483 directly to the FDA office.

Even if you respond verbally to the investigator on each point, it is crucial for you to send in a written response immediately.  This assures your response is accurately given to all interested parties, which could include their supervisor and the compliance or the branch director - all of whom can have a decision as to whether a Warning Letter should be issued.

The nature of your response to the FDA has changed over the years.   Previously, your response was to defend your company's interests and interpretation of the GMPs -- that is, the investigator was interpreting the GMPs differently and your way of thinking was as valid as that of the investigator's.  This does not work any longer.

In addition, simply stating you received the FD483 and will address all issues, without outlining what the corrective actions you have planned, will not fly with the FDA any longer. This could be interpreted as a poor attitude and the agency will definitely issue an FDA 483 to assure that 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 should be aware that a WARNING LETTER is a FDA regulatory action. The FDA is now setting up a case against companies to take additional legal actions if the promised and proper correctives actions are not taken in an appropriate period of time.

The Response

Even with the FDA's present policy “voluntarism": a well-planned response to the FD483 and to any future warning letters issued as a result, 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 FD483 is issued, the only people 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 relayed 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:

• 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.

• 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.

• The FDA investigator could attempt to put his bias into their 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.  

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 FD483.

          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 this 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 examples illustrate, it is critical to show the FDA you are either in control of the situation or are attempting to comply voluntarily by doing all that is possible to assure the products or devices meet specifications.

Cooperation and Compliance

Your main objective, once you are issued a FD483, 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 my experience has been philosophical battles which are neither won nor lost but rather cost a lot of time, money and aggravation.

If you show continued contempt for the agency and its policies, chances are you will be forced into compliance through further legal procedures, which will bring on increased expenses, the possible loss of business and harsh adverse publicity.  Instead, if you show the FDA you are complying with the agency's policies without the need for further legal action, the chances are that the agency will move to a 'problem" company while continuing 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 that you know how to bend is in your RESPONSE.

Remember the  FDA is looking to work with you to achieve compliance, you have to use this chance to let the FDA off the hook and avoid additional problems.

Recently the FDA has issues a draft compliance policy to change the procedures for the issuance of Warning Letters. (See Insight Report Vol. 2 No. 2) This guideline will allow an adequate response to the investigators observations to defer the issuance of a Warning Letter. This response must be supplied to the FDA within 30 days of the issuance of the 483. The FDA will then issue a letter to the company explaining that the corrective actions supplied by the company have been accepted and a Warning Letter will not be issued. But, in the event a re-inspection finds that the Corrective Actions were not taken, the re-inspection will be conducted as if a Warning Letter was issued. This new FDA initiative makes the response to FDA 483s or other verbal observations concerning labeling or 510(k) changes more crucial than ever. The FDA is providing the industry an opportunity – it will be up to you to make the best of it.

Next Month’s Insight Report –

          ISO 9000-2000 – “Problems, Problems, Problems”

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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