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T99-32                     Print Media:         301-827-6242
July 16, 1999              
                           Consumer Inquiries:  888-INFO-FDA

SERIOUS MANUFACTURING DEFICIENCIES WITH ABBOKINASE PROMPT FDA LETTER TO ABBOTT LABS

FDA has informed Abbott Laboratories of additional concerns related to manufacturing deficiencies for urokinase (Abbokinase). Until these problems are corrected, further distribution of Abbokinase would violate federal laws designed to assure the safety of drugs for patient use. FDA's concerns about the product relate to serious deficiencies in the manufacturing processes, the testing of the product, and the screening and testing of the donors of the kidney cells used to make Abbokinase.

Abbokinase is derived from cultures of human kidney cells from newborns who have died of natural causes, and is approved in the United States to dissolve blood clots in the lungs and heart arteries. It is also approved to help clear intravenous catheters.

During inspections of Abbott Laboratories and of BioWittaker, Inc., Abbott's supplier of human kidney cells, FDA identified numerous significant deviations from current good manufacturing practice (CGMP) regulations designed to assure product safety.

Compliance with CGMP is important because products manufactured from human sources have the potential to transmit infectious agents. CGMP for products such as Abbokinase requires important, overlapping safeguards in the production process, including adequate

screening of donors and testing of the cells,
controls for proper harvesting, storage, and handling of materials used in all stages of manufacturing, and
processes to remove or inactivate infectious agents from the product.

Over the past several months, the firm has reported to FDA that a number of in-process lots of Abbokinase were contaminated with microorganisms. Six such lots were found to contain various strains of reovirus, a virus that usually results in no symptoms or causes minor respiratory or gastrointestinal symptoms. Association of reovirus infection with other human diseases has been reported, although a causal link has not been established. Another in-process lot was contaminated with mycoplasma, a microorganism that can cause respiratory infections, and, on rare occasions, other infections that may be serious. Abbott has assured FDA that none of these in-process lots were manufactured into final product or distributed.

These recent findings of contamination and Abbott's inability to locate the source of the problem have raised further concerns at FDA about Abbott's entire manufacturing process for Abbokinase. Abbott's deviations from CGMP could significantly impact the safety of the product. One FDA concern is that deficiencies in manufacturing practices could also lead to the product being contaminated with microorganisms that have not yet been detected.

In January 1999, FDA issued a letter to health care providers in order to alert them to important safety information regarding the use of Abbokinase. The letter included information about the potential risks of the product for transmitting infectious agents. It also recommended that Abbokinase be reserved for only those situations where a physician has considered the other available treatment alternatives and has determined that the use of Abbokinase is critical to the care of a specific patient in a specific situation. In addition, at FDA's request, Abbott changed the labeling of the product to include additional information to reflect these safety concerns so that physicians would have a clear understanding of the risks of using Abbokinase.

However, since the January letter to health care providers, FDA obtained additional information regarding the inadequacy of the screening and testing of the mothers and donors of the human kidney cells used to produce Abbokinase. Information was also obtained regarding the seven instances of in-process lots of product being contaminated with reovirus and mycoplasma.

In the letter to Abbott, the agency has detailed the steps Abbott needs to take to correct the serious and significant manufacturing deviations. These include:

completing a thorough and adequate investigation of the reovirus and mycoplasma contamination, including the source of the contamination,
manufacturing Abbokinase using human kidney cells that have been obtained, processed, and tested through adequate methods, and
assuring that fully validated methods are used in the manufacturing process to test for infectious agents and remove them.

The limited number of lots of Abbokinase shipped early this year were distributed only after they were tested for certain infectious agents and found negative by Abbott Laboratories and FDA. Abbott Laboratories has not distributed any new lots of the product since then.

The actual risk to patients of developing an infectious disease as a result of using Abbokinase is unknown.

Patients should discuss any concerns they may have about prior use of Abbokinase with their physicians.

Physicians should continue to report any adverse events, including infections that may be attributable to Abbokinase. These reports can be made to Abbott Laboratories, Pharmaceutical Products Division, North Chicago, Il. at 1-800-633-9110 or the FDA via the Medwatch program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178 or via the Medwatch website at www.fda.gov/medwatch/.

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SERIOUS MANUFACTURING DEFICIENCIES WITH ABBOKINASE PROMPT FDA LETTER TO ABBOTT LABS

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