Liquid purification or separation – Processes – Liquid/liquid solvent or colloidal extraction or diffusing...
Utility Patent
2000-02-10
2001-01-02
Kim, John (Department: 1723)
Liquid purification or separation
Processes
Liquid/liquid solvent or colloidal extraction or diffusing...
C210S436000, C210S472000, C210S483000, C210S488000, C210S489000, C210S490000, C210S650000, C210S767000, C435S002000
Utility Patent
active
06168718
ABSTRACT:
TECHNICAL FIELD
The present invention pertains to a method for purifying blood plasma of white blood cells (leukocytes) and undesirable contaminants, particularly viral contaminants, and to an apparatus suitable for this use.
BACKGROUND ART
Plasma is the continuous liquid phase of blood which transports the necessary active substance which feed and maintain the body. Included within plasma are electrolytes, soluble sugars and proteins, and numerous enzymes, antigens, etc. While whole blood also contains red and white blood cells (erythrocytes and leukocytes), these components are substantially removed in the preparation of plasma. Plasma is frequently administered to patients who are seriously ill, for example burn victims. Plasma may also be fractionated to provide fractions enriched in certain components such as Factor VIII to treat many diseases, including Haemophilia.
Unfortunately, many disease-causing viruses, such as Hepatitis and HIV, may be transported by plasma if the blood donor has been infected by these diseases. Even without such infection, plasma may be contaminated during collection and subsequent processing. While centrifugation is effective to remove erythrocytes and the majority of leukocytes, infective viruses cannot generally be removed without resorting to ultracentrifugation. Such treatment is not generally cost effective and moreover may change the chemical make-up of the plasma by separation of larger molecules contained therein.
Administration of plasma containing even the most minor amounts of infectious agents can be catastrophic, and thus methods have been proposed to sterilize plasma utilizing chemical sterilizing agents. Unfortunately, if the plasma contains leukocytes which contain or are bound to infectious agents, these latter may not be destroyed by such processes, and thus a risk of infection is present. Virtually all leukocytes must therefore be removed.
Simple filtration of the plasma prior to chemical sterilization is problematic, as plasma is unique in the sense that in addition to low molecular weight species and electrolytes which may easily pass through even “tight” membranes, the larger protein species will rapidly form a polarized gel coating on the membrane should the pore size be too small. For example, the albumin fraction of human plasma contains prealbumin and albumin, with molecular weights in the 60,000 to 70,000 range, while fibrinogen, and various immunoglobulins have molecular weights in the range of 300,000 to 1×10
6
. The &bgr;-lipoproteins, important in the transport of fats and lipids, have molecular weights in the range of 3×10
6
to 20×10
6
.
When the plasma contains infectious agents such as viruses, the pore size necessary to completely remove these agents, particularly retroviruses, is such that the filter becomes rapidly clogged, thus requiring large filter area or repeated filter replacement. Clogging is particularly important with respect to the small but finite amount of leukocytes present in conventionally prepared plasma. Leukocytes are deformable, and may clog fine pores even though the leukocytes are physically larger than the pore. Further, and as indicated previously, a small pore size may also filter out desirable macromolecules contained in the plasma.
Leukocytes, which are positively charged, have been separated from plasma by membranes having charged sites. The ability to separate leukocytes in this fashion allows membranes with larger pore sizes to be used, as the removal is due to electrostatic attraction rather than physical separation. The larger pore size enhances the useful flow rate. Unfortunately, the charged membranes have a finite number of charged sites which limit their capacity. Moreover, the possibility exists that a given leucocyte may pass through the filter without encountering a charged site to bind it to the filtration medium. Random “pass through” cannot be tolerated in view of the danger of infection by agents such as hepatitis and HIV.
A suitable filter must not only be capable of removing leukocytes while allowing larger macromolecules to permeate the membrane, but must do so while processing a useful volume of plasma at a useful flow rate and acceptable pressure.
DISCLOSURE OF THE INVENTION
The subject invention pertains to a process for purifying blood plasma which has been subjected to centrifugation or filtration to remove erythrocytes and a substantial quantity of leukocytes, wherein all or substantially all the remainder of the residual leukocytes are removed through the use of a sterilizable multicomponent filter stack. The filter stack consists of a prefilter, a leukocyte retaining, intermediate hydrophilic membrane filter (“intermediate membrane”) and a final, leukocyte retaining safety hydrophilic membrane filter (“final membrane”).
The subject invention further pertains to a steam sterilizable multi-element filter assembly comprising a housing, preferably of sterilizable polymer having inlet and outlet portions, the inlet portion including an inlet port and the outlet portion including an outlet port, the inlet and outlet portions defining a flow channel between the inlet and outlet ports; one or more prefilter(s) retained within the housing fully extending across the flow channel, the prefilter(s) disposed closer to the inlet port than the outlet port; two or more hydrophilic microporous membrane(s) retained within and preferably hermetically sealed to the housing and extending across the flow channel, an intermediate hydrophilic microporous membrane adjacent to the prefilter and disposed closer to the outlet port than the inlet port and at least a final hydrophilic microporous membrane adjacent the intermediate membrane; such that plasma to be purified must pass in order through the prefilter(s), the intermediate hydrophilic microporous membrane, and then the final hydrophilic microporous membrane.
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Bischof Daniel F.
Borton Noel Tod
Chapman John
Herman Robert E.
Sun Chong-Son
Kim John
Leydig , Voit & Mayer, Ltd.
Pall Corporation
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