At the conclusion of an FDA inspection, many times the Investigator issues a FDA-483 to list the observations noted during the inspection. There is no guarantee that an item listed is a true deficiency from regulations or a deviation in Current Good Manufacturing Practices (cGMPs). The observations noted are one person's opinion, which should be based on documented evidence. The item listed may simply be a wish or desire of the investigator who may want something different to be done.

Who checks the checker to determine if only significant deviations are written on the 483? A Supervisory Investigator performs the first review. FDA supervisors hesitate to criticize observations once issued to the firm, as there is a reluctance to curb the enthusiasm of the Investigator.

How does one know the difference between fact and fantasy? It is of course essential that those in regulatory and quality roles know the law as well as the intent of the regulations. When management believes an item on the 483 is in error, this should be discussed with the Investigator either during the inspection or during the close out session. Facts are important and management should request that the Investigator provide an explanation for what an item is viewed as a deficiency.

If management is confident no deficiency occurred, this should be openly discussed with the Investigator. Management should explain why the 483 item is not a deficiency. Management should review documents associated with the deficiency with the Investigator to ensure that both parties have a clear understanding of the records and the purported deficiency.

Questions and challenges are common and should not upset the Investigator. Discuss the issues without rancor and without a personal attack on the Investigator. It is important to prevent an adversarial relationship with the Investigator. Instead, use the discussion as an opportunity to educate and to learn from each other. Use this time to convey that your firm has an active Quality Assurance Program and that management supports a culture that complies with the law.

Some Investigators review the Biologic Product Deviation Reports and write up errors on the 483 that have already been identified and corrected. If the error has been corrected, and by that, one must be clear the root cause was identified, and preventive action has indeed prevented recurrence, then say so. In this case, the documentation of the identification of the error and the corrective and preventive action should be included in the response to the 483.

It is very important to ensure that issues are adequately addressed and that written proof of compliance is sent to the district office and to the Center for Biologics Evaluation and Research (CBER). Especially, if the reports have already been sent to the agency. There is no violation or departure from regulations if the error has already been reported to FDA and corrective and preventive action has been implemented.

If the corrective action was not effective, the investigator is justified in listing the error on the 483. FDA will consider the recurrence(s) as a continuing pattern of noncompliance. This is the language used by FDA in the Compliance Program and it indicates to FDA there has not been enough attention given by management to adhering to the law. The FDA will then consider if this merits issuance of a Warning Letter or other regulatory action.

There are times when a well written and prompt response to the 483 may prevent issuance of a Warning Letter. There is no guarantee but it is certainly worth the effort. Keep timelines realistic with what may be achieved. Health hazards are areas of the greatest risk so every effort must be made for swift corrective action. If you cannot meet a promised time frame advise FDA of when it will be met.

If you think that FDA may send a Warning Letter, it may be advisable to request a meeting with the local district office to give FDA reassurance that your establishment is committed to following FDA regulations. This may possibly discourage FDA from sending a Warning Letter because you have made the effort to comply. FDA Compliance Policy Guides (CPGs) address issuance of Warning Letters.

If you do schedule a meeting, use the meeting as an opportunity to clarify exactly what the issues or problems are, and what you have done to assure FDA that corrective action has been taken. If a Warning Letter is issued, respond in the time frame stated in the letter.

In November 2001 HHS directed FDA to stop issuing Warning Letters that have not been cleared for legal sufficiency and policy by the Office of Chief Counsel (OCC). This goal of this directive is to bring about a rational and risk based approach to enforcement. This takes away the ability of each district office to issue Warning Letters and will prevent issuance of letters that are not an enforcement priority for FDA. Since that time the number of Warning Letters has decreased. Only one Warning Letter is posted on the FDA website for 2002.

The question of who checks the checker is not easy to answer. Reports of inspections are reviewed by the agency but again the FDA does not communicate the failings of the investigator or the reviewing officials to their own employees or to the blood bank community. There is no list of 483 items that simply are not deviations from regulation or from cGMP.

FDA does not have enough staff to have a good method of evaluating the 483 items to determine if they are in-deed significant deviations from the regulations. A pilot program, the TURBO Establishment Inspection Report (EIR) to provide investigators with a list of observations to use for the 483 will be gradually phased in by the FDA districts if it is successful.

The FDA has a voluntary program to evaluate inspection performance but this may be compared to a driving test where the driver will make a point of adhering to the laws and will stop at all yellow lights. The evaluations are a step forward for the agency but they do little to weed out poor performance.

Blood establishments must have training and experience to distinguish be-tween the good, the bad, and the ugly incorrect 483. A well written response to FDA can make a difference in how the agency will view the direction of management to correct any problems found during an inspection. The response should be a clear statement that management understands the law and fully intends to comply with the law.

It is never a good practice to change a procedure or write a new procedure as a knee jerk reaction to the 483. Careful thought must be given before assuming you must take an action in response to a 483. Change may not be the answer, but one must be confident and not ignore what the FDA has stated. If the decision is made that the change is not in the best interest of the establishment, this decision should be documented and perhaps shared with the FDA.

The final answer to the question "Who checks the checker?" is you do! And you do this by knowing the law is its regulations and ensuring that your establishment can comply.

This article first appeared in the May 2002 issue of CITINGS®, a publication designed specifically for the blood and biological source organizations. CITINGS INFORMATION EXCHANGE® is a not-for-profit membership network facilitating the anonymous exchange of inspection experiences for over a decade. For additional information about the program, visit our website at rrix.com, or call 804/741.9229. An information packet can be requested through e-mail at rri@richmond.infi.net.

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