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1) How do I respond to FDA Form 483?
What is the significance of FDA Form-483?
Response to the FDA 483
Who Checks the Checker?
2) How do I respond to a warning letter?
3) How do I respond to a license suspension?
4) How do I perform a 510(k) submission?
What is the significance of FDA Form-483?
by Mary Ann Tourault
At the conclusion of many inspections by the Food and Drug Administration (FDA) the investigator issues a list of observations documented on form FDA 483. So what does it mean? It is a list of items the investigator believes demonstrates deviation from "current" Good Manufacturing Practices (cGMPs). FDA communicates inspection findings to company officials by presenting the 483 at the conclusion of the inspection. Blood establishments should take full advantage of the close out session with the FDA to find out exactly why the investigator believes the issues listed are significant.

FDA written guidance to investigators concerning the 483 may be found in the Investigations Operations Manual (IOM) at www.fda.gov/ora/inspect_ref/iom/chaptertext/510part2.html#512. The guidance states that only significant deviations from the regulations should be placed on the 483 and therein lies the difficulty. What defines a significant deviation from regulations? If something happened only one time should that be on the 483? It depends on what that one time practice was. If the "one time" deviation was a viral marker testing error that resulted in release of unsafe blood components, then this "one time" incident will carry great weight with the agency.

But what if the one time item was the fact that a donor card was not properly filled out and blood components were released from the donation? If the missing information pertained to behaviors that place the donor at high risk for HIV, this is viewed differently than if a blood pressure was not filled in on the donor record.

There is always great angst when only one example of a practice is listed or if the firm believes the item was already corrected. If convincing evidence is presented that nullifies an observation the investigator should delete the item from the 483 or annotate the 483 to add explanatory information about corrected observations, but many times this does not happen.

The actions taken in response to the items listed on the 483 are varied. The actions range from doing nothing to making significant changes to processes and policies. Blood establishments should avoid the following:

  • Rushing to change procedures and practices as soon as possible.
  • Sending a response to the 483 stating that changes will be made but only taking action on some promised changes.
  • Listing impossible to meet timelines in the promised actions.
  • Making changes that do not help in safe and sound practices.
The most important part of the inspection process is for managers of the blood establishment to carefully consider the observations and to recognize that 483 items are the written opinions of one person that works for FDA. Having an item written on the 483 MAY mean that your establishment has deviated from the FDA regulations and guidance. To be accurate, most times this is the case with 483 findings. However, management should weigh each observation against whether it represents an unacceptable practice and, if so, what is the best corrective action for the blood establishment.

There are times when the investigator does not like a practice or the manner in which a procedure is done, and the investigator's personal opinion may be reflected in an observation on the 483. Must you change how you do something to gain the approval of the investigator? Again, the answer is, "it depends." There are times when the situation requires clarification as to FDA policy. In those cases you may want to contact others in FDA to determine FDA policy. If such contact is made during the inspection, it is best to include the investigator in any discussion. If you contact others in FDA, document the question asked, identity of the FDA contact person, and the response. Telephone calls are not ideal when trying to get clarification on an issue. When you speak with one person you get only one person's opinion, and this may or may not represent agency policy.

The best way to seek clarification regarding agency policy is to write to the Center for Biologics Evaluation and Research (CBER) to request a written response from the agency. Why not write to the local district office instead of CBER? It is important to understand who does what in FDA. Policy issues are determined at the headquarters level of FDA. In the case of blood and blood products, policy is determined by CBER. The address for CBER is 1401 Rockville Pike, Rockville, MD 20852-1448.

This article first appeared in the March 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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  Who Checks the Checker
by Mary Ann Tourault

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.





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