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30 Plasma KCE Reports 120 2.2.1.1 Developmental nature of production Although the plasma derivatives industry continues to use the Cohn procedure, developed in the early 1940s by Professor E. Cohn, the products now obtained by this method bear little resemblance to those obtained during the early stages of the plasma derivatives industry. The Cohn procedure consists, fundamentally, of the precipitation of the various proteins by means of changes to pH and salt concentration levels, with the proteins being separated out by centrifugation. In order to prevent the proteins from being denatured, the work is conducted at low temperatures and ethanol is added at various concentrations. While this initial protein fractionation stage has been maintained, what has changed is the process of purifying the proteins in order to obtain a safer, purer end product. Figure 5: Schema of fractionation methods (Source: unpublished document of PPTA – Plasma Protein Therapeutics Association) 2.2.1.2 Progress in purification The Cohn procedure does not produce therapeutic proteins in a pure state, and it has therefore been necessary to add purification stages which, in addition to purifying the proteins, eliminate the contaminants added during fractionation (ethanol and salts). These purification stages vary depending on the characteristics of the Cohn fraction to be purified and the nature of the product being obtained. In the case of FVIII or antihaemophiliac factor, the development of affinity chromatography techniques (whether using monoclonal antibodies or heparin) has allowed the development of FVIII with far higher purity levels than the first FVIII used in the treatment of haemophilia. Another significant advantage is that the infusion volume of FVIII which now needs to be administered is considerably lower, with resulting improvements in patient comfort and quality of life.
KCE Reports 120 Plasma 31 Figure 6: Fractionation Techniques and Available Products (Source: unpublished document of PPTA – Plasma Protein Therapeutics Association) Each of the affinity chromatography systems described above also requires 2 highly purified, but different, FVIII products. Purification using monoclonal antibodies (anti-FVIII antibodies produced in mouse cells and bound to the chromatography matrix) allows a very pure FVIII to be obtained. In contrast, if affinity chromatography with heparin is used, both FVIII and von Willebrand Factor are obtained. VWF protects the FVIII molecule and is used in the treatment of immuno-intolerance in haemophiliacs who have developed anti-Factor VIII antibodies, and can also be used to treat patients with von Willebrand Factor deficit. Immunoglobulins are another group of products where the new purification techniques have led to unforeseen therapeutic progress. Originally, immunoglobulins could only be administered intramuscularly, but this method hindered the administration of sufficient quantities of immunoglobulins, thereby bringing into question their therapeutic utility. The use of different purification stages – precipitation with polyethylene glycol, glycine etc. – and different affinity chromatography systems has made it possible to obtain intravenous immunoglobulins (IVIG). This has meant that sufficient therapeutic doses can be administered to patients, allowing not just patients with primary immunodeficiency’s to benefit from such treatments (patients suffering from immunoglobulin production deficit), but also other patients with auto-immune illnesses, together with some who have neurological diseases. 2.2.1.3 Progress in safety Because the plasma fractionation industry uses plasma as its raw material, many viral illnesses carried in the plasma can be transmitted through transfusions of the end product. In order to prevent the risk of further viral transmission, the industry developed a series of safety procedures which covered the donor, the plasma and the product. An interesting example in the development in viral safety can be found in the technical and scientific advances in the field of viral DNA detection (NAT techniques) which complement and improve upon the old viral marker techniques which used ELISA technology. The old techniques were based on detecting antibodies to different viruses. However, as there is a variable time period (known as the ‘window period’) between initial infection and the production of antibodies depending on the virus type, there is a danger that plasma with a low viral load which has tested negative using ELISA techniques can still be used in plasma fractionation.
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73. Financiering van het zorgprogra
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