MIGUEL BOYAYANIn the next 60 days, the government of the State of São Paulo should start the tender process for the works of the blood plasma products factory, to produce proteins obtained from plasma. The project comes from the Butantan Institute. The factory, which will start operating in a year and a half, is budgeted at R$ 100 million and will be installed in an area close to the Paço das Artes, in the University City of the University of São Paulo (USP). “The product of the greatest interest will be immunoglobin, which will account for 50% of sales. We will also produce coagulation factors VIII and IX, used in the treatment of hemophilia A and B, and albumin”, reveals Isaias Raw, from Butantan’s Biotechnology Center and the president of the Butantan Foundation.
Starting operations will depend on an agreement between the state of São Paulo and the Federal Public Health System (SUS), for the supply of the raw material – plasma -, since the purchase of blood and the sale of its by-products are prohibited in Brazil by a constitutional stipulation. “The major part of the blood is collected by the SUS, in São Paulo”, Raw explains. It is transported, frozen, to be processed in Brazil’s only blood byproduct factory, in Pernambuco, which at the moment is at a halt. When in operation, it only produces albumin, and in a quantity sufficient to meet 7% of the domestic demand. Raw notes, though, that the market of albumin obtained from plasma is in decline, as the product is being replaced by virus-free synthetic polymers, for shock treatment.
Another portion of the plasma is processed by two companies – one French and the other Austrian – selected in 2002 by an international tender process, to produce part of the domestic needs for immunoglobulin and VIII and IX factors. The deficit in the supply of blood plasma products – which requires the country to spend something like US$ 150 million to meet all the demand – and the fact that a good part of the plasma collected is discarded – justify investments in national production, according to Raw.
The blood byproducts from the Butantan factory will be obtained by chromatography, a method that uses a cylindrical column containing synthetic resins that allow the proteins to be separated. “Passing through the column, the purification process is repeated thousands of time and ends up separating each protein in a very purified form”, Raw explains. This procedure uses different resins for separating the proteins by size, electrical charge, rejection of water, or even by their biological activity. Chromatography is already used by the researchers at the Butantan Institute to produce antitetanic toxins, a recombinant vaccine against type B hepatitis, and for purifying hyperimmune serums.
To guarantee the quality of the blood byproducts, the products are treated with an organic solvent and a detergent that decomposes the hepatitis B virus and all the other viruses with a lipoprotein capsule. “However, the detergent and the solvent too have to be removed, which is only possible using chromatography”, Raw observes. A second procedure is used to remove non-encapsulated viruses. The new factory should also incorporate the technique for producing factors VIII and IX using the biotechnology that is being developed by the Brazilian Network for Cloning and Expression of Coagulation Factors, made up of four Brazilian laboratories, amongst them the Ribeirão Preto Hemocenter.
Raw points out that the direct production of factor IX from plasma will meet the domestic demand totally, “since hemophilia B is much rarer”. The Ribeirão Preto Hemocenter will be responsible for controlling the plasma processed and the blood byproducts produced by the Butantan factory, since it already has a laboratory with high technology, to analyze a large number of samples.
There is also provision for the installation of a laboratory – “a factory within a factory”, Raw explains – for the production of hyperimmune serums. The idea is to vaccinate donors at the blood centers with vaccines against tetanus or hepatitis B produced at Butantan and to process this plasma separately, to produce antitetanic and anti-hepatitis B serums. “A specialized collection center is being designed to work within the Pasteur Institute”, he explains.
Chromatography, he reckons, is more efficient than the traditional technology for producing blood byproducts by plasma fractioning, used since the 1960’s, which consists of separating the protein mass precipitated with the freezing of the plasma bag. “This technology is now obsolete. The old blood byproduct factories have kept to the old technology, adding afterwards stages that have the objective of eliminating the viruses: heating and treating with solvent-detergent, amongst others.”
“For two decades we have been trying to set up a blood byproduct plant”, Raw recalls. With access to plasma blocked by law, Butantan invested in producing blood byproducts using small quantities of plasma available in the placenta, a technique developed by Merrieux, in France, but which presented a problem: it used frozen placentas, and the consequent bursting of the red blood cells would thus contaminate the plasma. “Butantan developed a technology to isolate simultaneously from the placentas the albumin, immunoglobulin, transferrin, catalase and superoxide dismutase”, he says.
The “harvesting” of placentas and the isolation of proteins, though, were procedures that were much more expensive than using the blood from donors. This challenge stimulated the researchers to seek solutions that were cheaper and, at the same time, safer. “Butantan developed and is patenting a technology where the thawed plasma passes directly through a column, separating and purifying about a hundred times the coagulation factor. Eliminating separation by freezing, the yield of factor VIII doubles. The concentrate makes it possible to separate the factors and, after the antiviral treatment, to arrive at a much cheaper product for treating hemophiliacs”, Raw explains.
The Union also has plans for building the Brazilian Corporation for Plasma Fractioning (Hemobrás), a factory budgeted at US$ 60 million, architected to produce blood byproducts using blood plasma fractioning, and which has the objective of meeting part of the demand from the Centralized Health System. The Hemobrás project, though, is at a standstill in the National Congress. “The proposal from São Paulo does not intend to monopolize plasma fractioning. Quite the contrary: it is offering all the details and training for its project to be replicated at other points of the national territory. A technological leap forward is not to be wasted, by repeating obsolete installations and processes”, Raw concludes.