Contamination threat prompts FDA to add warning to urokinase shipments

Contamination threat prompts FDA to add warning to urokinase shipments

Judy Keller

WALKERSVILLE, MD — A CELL culture company claims that out-dated test methods, rather than an alleged contamination problem, led to a temporary halt of shipping a widely used clot-busting drug. BioWhittaker, a company supplying human tissue samples, checked its samples for various strains of hepatitis, including B and C, but the tests considered legal in Columbia, South America, are not approved in the United States by the Food and Drug Administration (FDA).

Chicago-based Abbott Laboratories, which uses the tissue samples in the manufacture of urokinase, was ordered to halt shipping its Abbokinase after the FDA raised contamination concerns in late November 1998. Following inspection of Abbott`s facility, FDA inspectors reported that some human kidney cells used in manufacturing Abbokinase were contaminated with hepatitis C or mycoplasma, which can cause walking pneumonia or strep throat. The company was allowed to resume shipping January 26, but the FDA notified healthcare professionals that there is a small danger of infection from using the drug, and to use caution in prescribing it. Abbott was ordered to put this warning in the labeling for the drug.

Additionally, the FDA on February 10 approved a more specific test to check blood for the hepatitis C virus. The test, made by Chiron Corp., is more sensitive to antibodies to the virus and can help pick out infected blood that has passed other tests. The FDA`s current screening tests were put into effect in July 1992. BioWhittaker was using tests that dated back to 1978 standards, rather than the 1992 recommendations. The newest tests are even more sensitive than the ones instituted seven years ago.

“It`s not a contamination problem,” contends Noel Buterbaugh, president of BioWhittaker. “We do screen material at the source, and Abbott screens it again when they receive it. We simply used an out-moded test. It`s the first time in 25 years we`ve ever had a problem like this. We are now going to use two tests to check for infections — the one we were using and the ones the FDA has told us to use. I`m confident we won`t have any more problems.” Buterbaugh says he could not give more detailed explanation because the FDA is still investigating the matter.

In a December 9, 1998, letter, Abbott informed customers of a temporary inability to ship the drug. The company sent the letter on its own initiative and not at the request of the FDA. In turn, the FDA was swamped with inquiries about the shutdown, and put up a web page to respond, listing alternatives to Abbokinase, or urokinase, as the drug is generically known.

The FDA`s Center for Biologics Evaluations and Research (CBER) evaluates lot release protocols for each lot of Abbokinase prior to its release to the public. During inspections at Abbott, FDA officials saw “significant deviations from current good manufacturing practices (cGMP),” according to the agency statement published on the Internet.

In addition to potential hepatitis B and C contamination, an eight-page FDA report commonly known as a “Form 483” lists other alleged problems. These include improper storage of samples, compromise of sample sterility, lack of testing for contaminant at certain stages in the manufacturing process, and failure to inform its supplier that some samples were contaminated with hepatitis B. The form also lists several documentation concerns.

Among the report`s claims are the following alleged problems:

Only one study was done to evaluate HIV inactivation by heat treatment.

Some human neonatal kidney (HNK) cells used during 1997 and 1998 were not tested for hepatitis C.

Some lots of HNK were contaminated with mycoplasma.

Some samples of HNK were taken from donors with fatal abnormal chromosome defects.

HNK cell culture supernatant (substance floating) is harvested daily and placed into a chilled tank where it is stored for a week before processing. No tests are performed to check bacteria, endotoxin, mycoplasma, or viruses at the end of this hold period.

HNK cells received by Abbot prior to implementation in 1991 of HIV and HILV-1 testing of neonates` blood are stored in the same liquid nitrogen tanks as cells tested under current procedures.

Storage tanks exceeded temperature specifications.

Sterile Abbokinase Open Cath (Abbott`s brand of urokinase used to clear catheter tubes) remains unstoppered for up to four days while being purged with filtered, compressed air. Open product vials are stored in covered trays, in aseptic transfer carts in Class 10,000 areas. No routine environmental monitoring is done to ensure open vials are maintained under Class 100 conditions during the hold period.

Some lots of the drug were rendered unsterile after a power failure and these lots were re-processed without process validation.

Problems with printed expiration dates occurred due to a 1995 human error in creating the label format. The situation went uncorrected for three years.

“I can`t answer each and every point in the report because the matter is still under investigation by the FDA,” says Melissa Brotz, spokeswoman for Abbott. “Cells that tested positive for viruses were not used and were destroyed. They were never used in manufacturing the drug.” She adds that the company worked closely with the FDA to secure release of Abbokinase and provided a written response to inspection findings in late November 1998.

She also notes that Abbott detected the contaminated samples in routine tests — tests of samples that had been certified clean by BioWhittaker. The FDA report indicates there is an issue with the documentation on how Abbott notified BioWhittaker of the contaminated samples.

In its January 25 warning letter to healthcare providers, the FDA warns that currently available lots of Abbokinase carry an unknown risk of infection of hepatitis C and a variety of infectious diseases, including tropical diseases. The letter claims that Abbott`s testing of samples from its supplier indicates that the supplier did not consistently or reliably perform screening.

But Buterbaugh claims the FDA simply doesn`t approve the kind of testing BioWhittaker conducted.

The FDA`s letter further states that neither the mothers nor the neonate donors were tested for hepatitis C virus (HCV): “Abbott has recently instituted a test of HCV in the kidney cells used in the manufacture of Abbokinase and negative test results have been obtained for currently available lots. However Abbott has not validated this test.”

The letter also warns, ” Prior to use in the manufacture of Abbokinase the kidney cells were harvested, stored and handled in a manner that may have permitted contamination with infectious agents.” According to the letter, Abbott used a viral inactivation process that substantially inactivates HIV and HCV in other biological products, but which “has not been fully validated for viral inactivation of Abbokinase.”

Continued production

Although the FDA refused to release any lots of the products during the investigation, company officials confirmed that Abbott continued to manufacture the drug, hopeful that they could begin to ship again and in anticipation of replenishing depleted hospital supplies. According to an FDA statement, Abbott agreed to beef up its safety measures and to update its labeling of the drug to include the information regarding the potential risk for infectious diseases. Major U.S. hospitals reported shortages of Abbokinase by the middle of December, about two weeks after the shutdown. By mid-January, many clinics and hospitals were out of the drug, and some physicians were angered that the FDA had halted shipments.

One of them was Dr. Kenneth Ouriel, chairman of vascular surgery at the Cleveland Foundation Clinic in Cleveland. “There is a small risk of viral contamination of this drug. The process of making it involves heat that would kill any contaminants, ” says Ouriel. “And, if the FDA was so concerned, why didn`t they recall the lots that were out there?” he asks.

Lenore Gelb, FDA spokeswoman, had this ready answer: “There was no need for a recall. There were no reports of anyone becoming infected from taking Abbokinase,” she says. However, she adds that doctors might not have recognized a connection between infections and drug usage.

Urokinase has been commonly used for about a decade to treat patients with life-threatening blood clots in the heart or lungs, as well as patients suffering strokes. It is also used to clear tubes used in kidney dialysis and chemotherapy. The manufacturing process used to make Abbokinase involves taking kidney cells from miscarried fetuses and putting them in a growth medium in a controlled environment. The resulting substance given off as the cells grow is urokinase. Many European drug manufacturers make urokinase from vast amounts of human urine, but the proprietary Abbott Laboratories method is faster and cheaper, claim industry sources. Ouriel says that the FDA does not certify the drug for use in clearing clots in the legs, although he says about a decade of use nationwide shows that it is extremely effective for this.

More than 250,000 people receive the drug Abbokinase or urokinase each year in the United States, Ouriel says. Each year more than 60,000 people die of pulmonary embolisms, or blood clots on the lung. About 600,000 pulmonary embolisms occur yearly. The Cleveland Foundation Clinic is the third-largest user of the drug worldwide.

“[Urokinase is] so effective that it is the drug of choice, the standard of care when there`s a blockage in a vein or artery in the leg. It`s not just for pulmonary embolisms,” Ouriel explains. Other clot-busting drugs such as Streptokinase or t-PA [tissue plasminogen activator] cause severe bleeding and allergic reactions. Those are drugs we used 10 years ago. Urokinase is better.”

Ouriel says that in discussions with Abbott and with the FDA, he learned that thousands of doctors nationwide were upset about the temporary shortage. He says the FDA told him it had as many as a thousand calls within days of the shipping shutdown. Ouriel is one of the principal investigators of a study that concluded using urokinase could save the leg as effectively as surgery when a patient has a blocked artery. The study, the largest to date that compares a clot-busting agent to surgery in patients with arterial blockages, was reported in the April 1998 issue of The New England Journal of Medicine. Abbott Laboratories funded the study.

However, the FDA`s January letter warns healthcare providers that urokinase is not certified for this use and urges reporting adverse reactions or infections resulting from the drug to its MedWatch program at 1-800-FDA-1088.


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