Cleaning up the blood supply

TORONTO — Contaminated blood supplies and donor shortages may be minimized, thanks to dedicated research efforts to yield blood substitutes that some say are cleaner and safer than the real thing.

One such manufacturer in the race to bring these products to market is Hemosol Inc., a biopharmaceutical company in Toronto. It has spent the last several years developing its patented version, Hemolink, which is made using human hemoglobin extracted from outdated blood from FDA-approved collection agencies. Executives hope to license and sell the product in the United States and Canada by early 2001.

“We plan to finish our [Phase III] clinical trials and file applications during this first quarter,” Dirk Alkema, Hemosol's vice president of operations, says, noting that the product could be made available sometime in 2000 in the United Kingdom. “Of course, [delivery] is up to the regulatory agencies.”

Workers at Hemosol use proprietary clean methods to extract, purify and modify hemoglobin derived from human sourced donations.
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Alkema claims in the course of extensive testing Hemolink has exhibited no clinically limiting side effects in trials covering orthopedic and coronary artery bypass grafting (CABG) surgeries and chronic anemia in renal dialysis patients.

“It’s been shown to be safe and effective in these types of procedures,” he adds, saying potential demand for the product is significant with about 12 million red blood cell transfusions reported in the US and Canada each year.

Thomas Ming Swi Chang, M.D., Ph.D., director of the Artificial Cells and Organs Research Centre and professor of Physiology, Medicine and Biomedical Engineering at McGill University (Montreal), believes the role of blood substitutes—although promising—will be restricted to short-term applications because they can stay in the body's circulation for only an estimated 20 to 30 hours, the extent of their life span.

That kind of limited survival rate is viewed by the American Red Cross as a drawback despite the advantages blood substitutes offer. The organization estimates that they survive in circulation for an even shorter amount of time—a few hours, as opposed to an average 120 days for a pint of typical red blood cells. Therefore, officials don't foresee blood substitutes having a significant impact on operations.

“We consider these artificial oxygen carriers to be a niche product,” says Dr. Richard Davey, chief medical officer for the American Red Cross, Biomedical Services (Arlington, VA). “We see them playing a role in emergency or microsurgery situations. When the products are licensed, we'll use them appropriately when we can for our patients. They'll be part of our mix, not a replacement.”

Alkema of Hemosol maintains the substitute product has characteristics that are superior to human red blood cells. He says Hemolink has a shelf life of at least a year at both refrigerated and ambient temperatures, compared to that of allogeneic blood whichis less than 42 days; it is universally compatible, which means doctors don't have to cross-match patients before administration to avoid adverse reactions; and it is also proving to be more efficient at oxygen delivery, which widens the scope for other therapeutic applications.

In addition, Alkema says Hemolink is manufactured using “increasingly clean” proprietary methods to extract, purify and modify hemoglobin derived from its human-sourced donations.

Individual units are opened and pooled into a large tank under aseptic conditions, he explains. Extracted hemoglobin is then pasteurized and subjected to nanofiltration under negative containment in Class 10,000 areas. During these steps, Alkema says the material is screened further to remove or destroy viruses that may have escaped detection at blood collection agencies. He notes that challenges by viruses such as HIV, Hepatitis A and bovine viral diarrhea (known as BVD or the model for Hepatitis C) have been conducted and meet FDA requirements.

“These two processes effectively remove 10 to 12 logs of virus, which translates into an average 100 billion fold reduction,” Alkema says.

Another factor enhancing the product's reliability is the next step in the manufacturing process in which the material is purified and chemically modified under positive pressure containment in Class 10,000 conditions. The final step — sterile filtration and filling operations — takes place in a Class 100 cleanroom.

“It offers quite a degree of safety, and we suspect it's potential is higher,” Alkema predicts, “but we haven't done full validation yet.”

According to the FDA's new drug application (NDA) pipeline (at press time), Hemosol is one of 11 companies that have blood substitute products publicly disclosed and under development in pre-clinical and end stages of clinical trials. The group includes Northfield Laboratories Inc. (Evanston, IL) and Biopure Corp. (Cambridge, MA), which Hemosol views as its primary competitors.

“There are many variables,” Richards stresses, “but barring complications or concerns, Hemosol could be ready [for delivery] as early as 2001 if it filed its application during the first quarter of this year.”

The pending release of blood substitutes is exciting news for many, but not everyone sees them as a cure-all.

Chang of McGill University says these first-generation blood substitutes are the result of the tainted blood tragedy that occurred in the 1980s and infected more than 60,000 people in the Western world with the AIDS virus.

“The basic approach for [producing] these blood substitutes has been available since the 1960s, but at that time, there was no urgency so it was put on the shelf,” says Dr. Chang, an authority on red blood cell research, who has published more than 400 scientific papers and 21 books.

“When we discovered HIV people started to worry and do catch up work and development.”


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