CN1248171A

CN1248171A - Method for purifying blood plasma and apparatus suitable therefor

Info

Publication number: CN1248171A
Application number: CN97181290A
Authority: CN
Inventors: M·A·苏特; N·T·波尔顿; D·F·比肖夫; J·查普曼; R·E·赫尔曼; C·S·孙
Original assignee: Baxter International Inc; Pall Corp
Current assignee: Baxter International Inc; Pall Corp
Priority date: 1996-11-08
Filing date: 1997-11-05
Publication date: 2000-03-22
Anticipated expiration: 2017-11-05
Also published as: AU5005997A; EP0938351A1; JP2001503656A; WO1998019722A1; NO992162L; CA2270413A1; AU722640B2; NO992162D0; CN1122536C

Abstract

A method and device for purifying conventionally treated blood plasma, to remove substantially all residual leukocytes while maintaining useful flow rates for medically useful amounts of plasma, utlize a one-off, heat-sterilizable filter (1) employing one or more depth-type prefilters (29) and at least one intermediate hydrophilic microporous membrane (25a) followed by at least one final hydrophilic microporous membrane (25b) having a smaller pore size than the intermediate membrane within a common housing.

Description

The method of purifying blood plasma and the device that is fit to this method

Technical field

The present invention relates to remove leukocyte (leukocyte) and undesirable impurity in the blood plasma, the method for especially viral impurity, and the device that is fit to realize this method.

Background of invention

Blood plasma is the continuous liquid phase of blood, carries the necessary active substance that earns a bare living.Comprise electrolyte, soluble sugar and protein in the blood plasma, and various enzyme, antigen or the like.Though whole blood also contains erythrocyte and leukocyte (erythrocyte and leukocyte), these compositions are removed basically when preparation blood plasma.Blood plasma is supplied with severe case, for example fire victim usually.Also can be the blood plasma fractionated so that provide and be rich in for example fraction of antiaemophilic globulin,antihemophilic factor,platelet cofactor I of some composition, thereby the treatment numerous disease comprises hemophilia.

Regrettably, if the blood donor has infectd these diseases then blood plasma may carry many Causative viruss, for example hepatitis virus and HIV (immunodeficiency virus).Blood plasma is even without infection, gather and later processing procedure in also possible contaminated.Though centrifugal separation can be removed erythrocyte and most of leukocyte effectively, do not take the ultracentrifugation partition method can not remove infective virus usually.The common cost height of such processing, and may since separation wherein change the chemical constituent of blood plasma than macromole.

Even it all may be catastrophic that the blood plasma that contains the minimum vehicle of infection is provided, therefore proposed to utilize chemosterilization reagent to carry out the method for blood plasma sterilization.If not only contain in the blood plasma comprise the vehicle of infection or with the bonded hemocyte of the vehicle of infection, so such processing may not destroy the vehicle of infection, the danger of so still exist infecting.Therefore in fact must remove all leukocyte.

Before chemosterilization, filter blood plasma simply and exist problem, because blood plasma is very unique on following meaning, if promptly the pore size of filter membrane is too little, then except low molecular weight substance and electrolysis mass-energy easily the film by very " densification ", bigger protein material will form the polarity gel coat rapidly on film.For example, the albumin fraction of human plasma contains prealbumin and albumin, and molecular weight is in 60,000 to 70,000 scopes, and the molecular weight of fibrinogen and various immunoglobulins is 300,000 to 1 * 10 simultaneously ⁶In the scope.The molecular weight of very important beta lipoprotein is 3 * 10 concerning carrying fat and lipoid ⁸To 20 * 10 ⁶In the scope.

When blood plasma contains vehicle of infection when virus for example, remove fully these vehicles especially the necessary pore size of retrovirus make filter very fast blocked, therefore need big filter area or change filter repeatedly.For little in the blood plasma that is present in traditional method preparation but be limited amount leukocyte, blockage problem is especially serious.Leukocyte can be out of shape, even and leukocyte physically than micropore is big also may be blocking microporous.And as previously mentioned, little pore size also may cause filtering to be included in the macromolecular result of the hope in the blood plasma.

The film that the leukocyte of positively charged has been had charged point separates from blood plasma.Have the film that separates leukocytic ability by this way bigger pore size can be arranged because filtering be produce by electric attraction rather than physical separation.Bigger pore size has improved effective liquidate speed.But charged film has the charged point of limited quantity, has limited their filter capacity.And, there is such possibility, promptly a certain amount of leukocyte may pass through filter, and does not meet so that it is adhered on the filter medium with charged point.From by the vehicle angle of the danger infected of hepatitis virus and HIV (immunodeficiency virus) for example, at random " by " be unallowable.

Suitable filter not only one is removed leukocyte surely, allows bigger macromole to see through film simultaneously, and must realize having effective blood plasma volume in the above-mentioned functions under effective liquidate speed and acceptable pressure.

Summary of the invention

The present invention relates to be used for purify and passed through centrifugalize or filtering blood plasma, so that remove erythrocyte and a large amount of leukocytic method, wherein by using sterilizable multicompartment filter lamination to remove all or all residue leukocyte basically.The filter lamination comprises prefilter, removes leukocytic midparent water film filtering device (" intermediate coat ") and safety removal leukocytic final stage hydrophilic film filter (" final stage film ").

But the invention still further relates to the multicompartment filter for installation of steam disinfection, this device comprises a sterilized polymer container that preferably has intake section and exit portion, wherein intake section comprises inlet, exit portion comprises outlet, and intake section and exit portion form the flow channel between the entrance and exit; Be positioned at one or more prefilters of container, the complete cross-section flow channel of this prefilter stretches, and prefilter is near from outlet from the inlet ratio; Be positioned at two or more microporous hydrophilic membranes of container, preferably hermetic closed on container, and cross-section flow channel stretches, the contiguous prefilter of middle microporous hydrophilic membrane and near from inlet from the outlet ratio, and the final stage microporous hydrophilic membrane is close to intermediate coat at least, so that make the blood plasma that to purify order pass through prefilter, middle microporous hydrophilic membrane, then by the final stage microporous hydrophilic membrane.

Purifying blood plasma prepared in accordance with the present invention is generally through handling (for example chemical treatment), makes infectiousness vehicle for example hepatitis virus and HIV inactivation and/or destroyed.

The accompanying drawing summary

Fig. 1 is the side view of an embodiment of combination filter of the present invention;

Fig. 2 a is the assembling side view of the intake section of an embodiment of filter for installation before;

Fig. 2 b is the plane graph of seeing from the sealing surface direction according to the intake section of an embodiment of filter for installation of the present invention;

Fig. 3 a is the assembling side view of the exit portion of an embodiment of filter for installation before;

Fig. 3 b is a plane graph that embodiment sees from sealing surface according to filter for installation of the present invention;

Fig. 4 is the sectional view that the exit portion of filter for installation is cut open along the 4-4 among Fig. 3 b;

Fig. 5 is the details drawing of region D in Fig. 2 and 3.

Detailed Description Of The Invention

In the method according to purifying blood plasma of the present invention, fresh or frozen plasma at first passes through common processing, removes all erythrocyte and most of leukocyte in this processing.Though preferably remove all leukocyte, normally unpractical, and should be appreciated that and will contain a small amount of in the blood plasma that will purify but limited amount leukocyte.

In operating process, blood plasma for example preferably about 15 inches to about 48 inches pressure drops, more preferably flow through leucocyte filtration device under gravity in about 28 inches pressure drop, from then on enter collection container then, this container can be collecting bag or analog.Can use conventional apparatus source plasma (be fresh, freeze or the like) be connected on the filter.Concrete connection, supply, bypass and post-processing approach or the like are for understanding removing leukocytic method or be fit to realize the device of this method dispensable from blood plasma as claimed in claim.

Fig. 1 has described an embodiment of above-mentioned multicompartment filter.Those of ordinary skill in the art can expect other distortion.In Fig. 1, filter 1 comprises two casting parts: intake section 2 and exit portion 4.In design, device is linear basically, preferably has rounding.Yet the shape of device is not strict, and device shape and filtration device structure can improve by the needs of given application.Flow channel is formed by the inwall 5 of device outmost surface, described outmost surface from intake section from inlet 9 end 7 farthest and the suitable angle that raises from outlet 17 end 8 farthest of exit portion, for example approximately 5-15 °, preferably about 9-10 °.The flow channel of device is made of the enclosed volume that comprises inlet flow channel 10 and outlet flow channel 6 respectively.The inclined-plane that is formed by the outmost surface that raises terminates in

vertical wall

31 and 32 places substantially, and inlet 9 and outlet 17 are formed on

vertical wall

31 and 32.

Fig. 2 a has described the side view that the intake section 2 of an embodiment of above-mentioned filter for installation is cut open along the cross section 2a among Fig. 2 b.The blood plasma that 9 expressions will be handled flows into the inlet that inlet flow channel 10 is flowed through.The annular section that 11 expressions are protruded, when apparatus for assembling, this annular section forms sealing, for example wiper seal on filter.The protrusion annular rib in the common cross section triangular in shape of 13 expressions, the intake section 2 that this shape ring rib is used for handle assembly is sealed in exit portion 4 (seeing Fig. 1,3a, 3b, 4).The optional steam vent of 15 expressions, this steam vent is clogged or is covered by microporous hydrophobic membrane, so that allow air effusion device, and does not allow liquid effusion device.

With reference to figure 2b, look up from the side of sealing surface, the periphery of device portal part and is surrounded by the annular section 11 that protrudes substantially in same plane.The annular section 11 that protrudes plays the periphery of compression and/or sealing prefilter.The annular rib 13 that protrudes is spaced apart with the annular section 11 that protrudes, and when the annular matching surface 23 of the corresponding protrusion of the exit portion of pressing to device (seeing Fig. 3 a, 3b, 4) when exerting pressure, the annular rib 13 of protrusion is the pressure concentrating structure.Those skilled in the art can easily expect other hermetically-sealed constructions.The optional steam vent of 15 expressions, this steam vent is hermetic closed with politef or other micropore vent material.The micropore vent material is preferably hydrophobic, and for example the nominal pore size is 0.02 micron.

Fig. 3 a is the side view of the cross section 3a of Fig. 3 b.Exit list is shown 17.The annular matching surface 23 that protrudes cooperates (Fig. 2 a and 2b) with the annular rib 13 of corresponding protrusion, and preferably is sealed on the rib 13 by the supersonic welding connection technology subsequently.Exit passageway is represented with 6.Exit passageway is formed by the space of the surface sealing of the inwall 5 of outmost surface and microporous

hydrophilic membrane

25a and 25b (Fig. 5).Microporous

hydrophilic membrane

25a and 25b will be sealed on the sealing surfaces 27.

Fig. 3 b is the plane graph of the exit portion of device.Exit passageway 6 preferably comprises a plurality of ribs 21 that protrude from the inwall of outmost surface, thereby forms the support component of filter, shown in the cross section among Fig. 4.Rib protrudes into the minimum surface plane of filter membrane usually and provides support in filter process, do not deform, break so that guarantee filter, or with the device between sealing separate.The support component that also can use other is screen cloth, perforated plate or the like for example.During if the low pressure that only is applied in filter instils and uses, during for example gravity is supplied with, can save support component.

Protrude annular matching surface 23 and be centered around around the exit passageway, provide the parts of hermetic closed device with protruding annular rib 13 (Fig. 2 a, 2b), for example by the ultrasonic bonding locking device.Before apparatus for assembling, microporous

hydrophilic membrane

25a and 25b (Fig. 5), for example, hermetic closed on circular membrane sealing surfaces 27 by heat sealing method.After having sealed microporous hydrophilic membrane, prefilter 29 (Fig. 5) is placed on the position of film top, and intake section 1 is placed on the top of exit portion 2, handle assembly welds together (preferably by ultrasonic bonding) then.

Fig. 4 illustrates the cross section of the exit portion of device along 4-4 among Fig. 3 b.From figure, can be clear that exit passageway 6 and rib 21.The hydrophilic film of 26 expression ribs and prefilter, for clarity sake the two is expressed as a unit.Also show film phonograph seal surface 27, inwall 5 among the figure and protrude annular matching surface 23.

Fig. 5 shows when device and assembles later final stage micropore hydrophilic film 25b, middle micropore hydrophilic film 25a, the layout of prefilter 29 and the relative geometry of different annular surfaces.Microporous

hydrophilic membrane

25a and 25b preferably are sealed on airtight surperficial 27 by heat sealing method, and by rib 21 cross-brace exit passageways 6.Middle microporous hydrophilic membrane part and the annular protrusion of prefilter 29 above airtight surperficial 27 divides between 11.Protrude annular rib 13 and in heat seal process, be out of shape, so that form overall structures with the annular matching surface 23 of protrusion.Plasma flow 9 enters access road 10 by entering the mouth, and enters exit passageway 6 by prefilter 29, intermediate coat 25a and final stage film 25b, and from then on arrives outlet 17 (Fig. 1).

In use, inlet 9 is connected with source plasma.Described source plasma can provide blood plasma by gravity flow or under pressure, for example by using crawling type or piston-type pump.Gas is discharged by optional steam vent 15, and blood plasma is by prefilter 29, then by microporous hydrophilic membrane 25a and 25b.Prefilter is a degree of depth type prefilter, and so most of megalocyte can be separated by prefilter with particulate matter and any other macroparticle, and does not significantly reduce the flow velocity of blood plasma.The midparent aqueous is separated leukocytic microporous membrane and is prevented that major part (being whole in fact sometimes) from entering the processing bag by the leukocyte or the particle of prefilter.Any leukocyte, for example the leukocyte of the very small dimensions by intermediate coat is virtually completely removed by the final stage membrane filtration, as long as it is not very big passing the pressure of filter like this, to such an extent as to make filter and container separate or break, perhaps make the leukocyte distortion, to such an extent as to make them be forced through the micropore of final stage film, the blood plasma by filter will not have leukocyte substantially so.In order to ensure back one situation not occurring, the maximum pore size of final stage film should be chosen to more much smaller than the leukocytic diameter of minimum.Preferably remove leucocyte-removing, make their concentration in blood plasma reduce about at least 10 ³The individual order of magnitude preferably is approximately 10 ⁴Preferably, final leukocyte concentration is 0.

Prefilter plays the effect of removing macroparticle and gum material, stops up so that prevent intermediate filter.Prefilter also can be removed most of big leukocyte, i.e. megalocyte and particulate matter.Intermediate coat is removed the less leukocyte of the overwhelming majority, so that the blood plasma of going out from intermediate coat has been removed preferably about leukocyte more than 90%.The micropore of final stage film is littler than the intermediate coat, guarantees in fact not contain leukocyte in final filtered blood plasma.

About pore size, must be according to the function selecting pore size and the type of specific filter cell.For example,, select big relatively pore size,, filter nearly all macroparticle simultaneously so that filter fast for prefilter.For example when prefilter was membranous type degree of depth prefilter, best pore size was from about 3 microns to about 10 microns.This big relatively pore size is necessary, because the pore size scope of film filter is controlled very appropriately usually.Yet preferably prefilter is a nonwoven degree of depth type filter.Such filter has many constituted modes, for example can comprise glass fibre, spunbonded type or fusion-jetting polypropylene, polyester fiber or the like, and nominal or " on average " pore size are approximately 0.5 micron to about 5 microns.Less mean pore size has reflected the wide relatively pore size scope of this material and the selection liquid flow path that degree of depth type filter is had.Best prefilter is the non-woven glass fibre prefilter, can select Hollingsworth ﹠amp; The HB-5341 fiberglass media of Vose.

The intermediate coat filter is the hydrophilic film filter, and the pore size scope is small enough to prefilter, makes about leukocyte more than 80%, is preferably about leukocyte more than 90%, and the leukocyte that is preferably more than 95% is removed by prefilter and intermediate coat.In other words, intermediate coat will preferably approximately be no more than 10% leukocyte by being no more than about 20% leukocyte, preferably be no more than about 5% leukocyte.Yet preferably be no more than about 1% leukocyte and pass through intermediate coat.The pore size of film can change a little, but preferably in about 0.9 micron to about 2.0 microns of scope, preferably in about 0.9 micron to about 1.5 microns of scope.As long as film is hydrophilic, the composition of intermediate coat is not very strict.Therefore, the treated intrinsic hydrophobic membrane of their surface hydrophilic that makes is suitable for, and inherent hydrophilic film also is suitable for.Film can be made by for example polyacrylate, nylon, huge vinylidene fluoride, polypropylene, polysulfones, polyether sulfone, cellulose acetate or nitrocellulose.Charged membrane also is suitable for.Nylon membrane here also is suitable for.Particularly preferred film is SUPOR ^1200, a kind of nominal pore size is 1.2 microns a microporous membrane of polyethersulfone, can be from Pall Gelman Sciences, and inc., Ann Arbor, Michigan has bought.

Select the final stage film, so that make filtered blood plasma be substantially free of leukocyte.Though also can select intermediate filter, utilize less pore size to provide and do not contain leukocytic blood plasma, use the intermediate coat of less micropore and do not use the final stage film to have two significant disadvantage.The first, less pore size will reduce flow velocity soon beginning to filter, because micropore is stopped up by leukocyte.The second, for example because known leukocyte deformation, or, will make that leukocyte passes through micropore owing to influence the accidental damage of film globality, though like this blood plasma to contain leukocytic danger very little, but very serious.

Therefore, need to select final filter, enough little pore size is provided, to guarantee to remove fully basically leucocyte-removing.Because most of leukocyte and than macroparticle and more being removed with fixed attention, so the little pore size of final stage film will can transition not reduce filtering rate by prefilter and intermediate coat filter.As the situation of intermediate coat, the final stage film is hydrophilic, also can be charged membrane.The pore size scope of final stage film is preferably less than or equals the pore size of intermediate coat from about 0.3 micron to about 1.5 microns.It is suitable that the pore size scope is approximately 0.4 micron to about 1.0 microns, and scope is approximately 0.7 micron to 1.0 microns better.What especially be suitable for is that the nominal pore size is 0.8 micron SUPOR ^Microporous membrane of polyethersulfone.

Can adjust the surface area or the effective filtration area (EFA) of filter according to the flow velocity of volume that will filtering blood plasma and hope.For example, the filter container that is rectangle substantially on the reference plane has here been described described device.Yet as long as use described filter lamination, described device also can adopt other shape, comprises that pleating cylindrical filter, spiral twine cylindrical filter, or the like.The internal capacity of filter should be minimum, so that the blood plasma that filter itself is kept is the least possible.Usually, wish that in the time of 1 pound/square inch minimum flow velocity is about 1 to about 10 ml/min/square centimeters, preferably minimum flow velocity is approximately 2-3 ml/min/square centimeter.Certainly wish to have higher flow velocity.Flow velocity drop to think filter may by " obstruction " before, filter preferably should be able to filter minimum about 300 milliliters human plasma.Filter efficiency should be can be the leucocytes reduction in the blood plasma of common leukocyte concentration of containing of traditional preparation process 10 ⁴The individual order of magnitude.Under the best circumstances, in filtrate, do not contain leukocyte.For optimum device of the present invention, comprise at least one prefilter and middle and final stage microporous hydrophilic membrane, the appropriate filters area does not specifically limit.For example, the cartridge filter with pleating or screw element can be designed for big volumetrical filtration, and small-sized defecator can be used for filtering small amount.Under one situation of back, for example the EFA of the filter size of Shi Heing is about 15 to 20 square centimeters.Yet EFA is 0.1 square metre to several square metres or bigger size also to be fine.

Pre-filter material should satisfy requirement of USP particulate filter and the requirement of VI level toxicity.Best, material also further satisfies European Economic Community's toxicity requirement.

Also can use different prefilter combination with identical or different pore size.Usually, for example polypropylene should be with hydrophilic preparation processing so that make material hydrophilic for hydrophobic material.Such preparation it is well known to those having skill in the art that.Middle and final stage microporous hydrophilic membrane preferably can seal the film of being on the filter container such as the ultrasonic bonding technology by traditional.Also can use and to glue together or the film of solvent bonding.

As previously mentioned, microporous hydrophilic membrane can be intrinsic hydrophilic, maybe can handle the hydrophobic membrane surface and make it hydrophilic.Film also can comprise electronegative point, so that help the filtering leukocyte, the most important thing is that pore size is such, promptly makes and only utilizes pore size just can prevent basically that leukocyte from passing through.The microporous hydrophilic membrane that pore size is suitable can have been bought from the market, also can pass through for example method manufacturing of following patent disclosure: United States Patent (USP) 3,876,738; 4,340,479; 4,473,474; 4,673,504; 4,708,803; 4,711,793; 5,076,935; 4,900,449,4,964,990; And 5,108,607, these patents are incorporated in among the application by quoting as proof at this.Best microporous hydrophilic membrane is the Supor that can buy from Pall Gelman Sciences ^Microporous membrane.

The container of multi-component filter assembly of the present invention is preferably made by annotating compression polymer.Polymer can be thermoplasticity or thermosetting polymer, and should be can disinfectant.In addition, polymer not eluting toxic metal, oligomer, monomer or catalyst in aqueous solution.At last, though can use the thermoplastic of heat sealable or solvent bonding, polymer preferably can be by ultrasound wave or the sealing of RF solder technology.The polymer that is fit to has amorphous polyamide, high temperature polyacrylate and polyester fiber, preferably Merlon.Preferable Merlon is MAKROLON2658-1112 Natural, can be from Miles, and Inc. has bought.

Use the Ox blood serum of traditional preparation process, carried out a series of blood plasma purification screening tests under 28 inches high pressure drops.For the purpose of testing, use 47 millimeters stainless steel filter stent support master's films and prefilter.Unfiltered Ox blood serum is taken from American Biologic Tech., Inc..

By the result of these screening tests, can find that it is not obvious selecting suitable prefilter and film filter.Single 1.2 microns poly (ether sulfone) film is almost blocked immediately.When using, use and to obtain suitable flow velocity, yet use the very fast appearance of other plasma samples to stop up by some prefilter filtering " pure " blood plasma with prefilter.There are some to surpass acceptable particle sizing level in many combinations of test, leached heavy metal or pH value is higher.These tests show that double-filtration (prefilter adds single film) is inappropriate, and need minimum tertiary filter stack, comprise degree of depth type prefilter.

The test of blood plasma (removing leucocyte-removing) defecator is to adopt strict aseptic technique, in aseptic microporosity separator laminar flow hood, minimum plasma treatment unit is carried out.Remove leukocytic defecator by glass fibre/Supor ^1200/Supor ^800 films constitute, and effective filtration area (EFA) is 17 square centimeters.Obtain the human plasma freeze from the Red Cross, and remain on the same day morning of frozen state up to test.Using steady temperature is 8 ℃ the circulating water chennel blood plasma that thaws.Blood plasma from four unit (the volume scope is from 255 milliliters to 410 milliliters) focuses on 3 liters of aseptic folding mixed bags, tests (being no more than 30 minutes) then as early as possible.Blood plasma from Collapsible bag, carrying under 28 inches high pressure drops by Medical Specialties103 inch discharging doser.

Four are removed leukocytic filter for installation label is M1, M2, M3 and M4, is installed on the road E Shi lock extension apparatus (total length=6 inch), is installed in then on the above-mentioned doser.(because vent plug locking device M1, only record is from the data of other three devices).When being 10 seconds, 1,2,5,10,15,20,25 and 30 minute, measures interval and writes down the plasma volume of carrying by filter for installation.Plasma flow is a continuous uninterrupted.After test is finished, plasma sample as the biohazard mass treatment, sterilization then (121 ℃ of following high temperature sterilizes 30 minutes), and suitably disposing.If desired, employed all material is all sterilized like this and is disposed in the test.The liquid stream data are illustrated in the table 1.

Described the present invention in detail by chart and example above, the technical staff who is familiar with the technical field of the invention will expect implementing of the present invention various replacement designs and the embodiment that claim limits.

Table 1

Volume of human plasma (in accumulative total and each interval) and flow velocity

" head height passes through 17-cm to @28 ²Filteringly remove leukocytic filter for installation

Time (branch)	Device M2			Device M3			Device M4			On average			Volume/time/unit are (rise/minute/square centimeter)
	Device M2			Device M3			Device M4			On average				Volume	The accumulative total volume	Speed	Volume	The accumulative total volume	Speed	Volume	The accumulative total volume	Speed	Volume	The accumulative total volume	Speed
	??0.17	?13.4	?13.4	?80.4	?13.5	?13.5	?81.0	?11.0	?11.0	?66.0	?12.6	?12.6		Volume	The accumulative total volume	Speed	Volume	The accumulative total volume	Speed	Volume	The accumulative total volume	Speed	Volume	The accumulative total volume	Speed	?75.8	?????4.46
??1	??0.17	?13.4	?13.4	?80.4	?13.5	?13.5	?81.0	?11.0	?11.0	?66.0	?12.6	?12.6	?51.0	?64.4	?61.2	?54.0	?67.5	?64.8	?43.1	?54.1	?51.7	?49.4	?62.0	?59.2	?????3.84	?75.8	?????4.46
??1	??2	?36.0	?100.4	?36.0	?53.2	?120.7	?53.2	?28.5	?82.6	?28.5	?39.2	?101.2	?51.0	?64.4	?61.2	?54.0	?67.5	?64.8	?43.1	?54.1	?51.7	?49.4	?62.0	?59.2	?????3.84	?39.2	?????2.31
??5	??2	?36.0	?100.4	?36.0	?53.2	?120.7	?53.2	?28.5	?82.6	?28.5	?39.2	?101.2	?42.0	?142.4	?14.0	?85.8	?206.5	?28.6	?34.5	?117.1	?11.5	?54.1	?155.3	?18.0	?????1.06	?39.2	?????2.31
??5	??10	?36.9	?179.3	?7.4	?59.0	?265.5	?11.8	?39.0	?156.1	?7.8	?45.0	?200.3	?42.0	?142.4	?14.0	?85.8	?206.5	?28.6	?34.5	?117.1	?11.5	?54.1	?155.3	?18.0	?????1.06	?9.0	?????0.53
??15	??10	?36.9	?179.3	?7.4	?59.0	?265.5	?11.8	?39.0	?156.1	?7.8	?45.0	?200.3	?31.8	?211.1	?6.4	?39.0	?304.5	?7.8	?19.5	?175.6	?3.9	?30.1	?230.4	?6.0	?????0.35	?9.0	?????0.53
??15	??20	?26.0	?237.1	?5.2	?34.0	?338.5	?6.8	?24.0	?199.6	?4.8	?28.0	?258.4	?31.8	?211.1	?6.4	?39.0	?304.5	?7.8	?19.5	?175.6	?3.9	?30.1	?230.4	?6.0	?????0.35	?5.6	?????0.33
??25	??20	?26.0	?237.1	?5.2	?34.0	?338.5	?6.8	?24.0	?199.6	?4.8	?28.0	?258.4	?24.0	?261.1	?4.8											?5.6	?????0.33
??25	??30	?24.5	?285.6	?4.9									?24.0	?261.1	?4.8

Attention: the unit of volume and accumulative total volume represents with milliliter.Speed unit is a ml/min.

By removing the human plasma average cumulative volume that leukocytic defecator carries is 258.4 milliliters.The average human blood plasma volume (ml/min/square centimeter) that the EFA of unit interval unit carries is 2.31 ml/min/square centimeters according to result of the test.This numeric representation is carried after 100 liters of blood plasma flowing 2 minutes, and the mean flow rate pad value is 48.3%.

Claims

1. method that is used for purifying blood plasma, described blood plasma have been removed erythrocyte and most of leukocyte through handling, and have initial residue leukocyte concentration, and this method comprises:

By disposable multicompartment filter, described multicompartment filter comprises the filter lamination described blood plasma, and described filter lamination comprises one or more degree of depth type prefilters, and the nominal pore size is from about 0.5 micron to about 5 microns; Hydrophilic microporous membrane filters in the middle of at least one, maximum nominal pore size is less than about 3 microns; With the hydrophilic nanoporous film filter of at least one final stage, the nominal pore size is from about 0.3 micron to about 1.2 microns, the nominal pore size of described final stage microporous hydrophilic membrane is less than the nominal pore size of microporous hydrophilic membrane in the middle of described, described filter lamination is included in the container, described final stage microporous hydrophilic membrane is sealed on the described container, and the leukocytic concentration that wherein is present in the described blood plasma has descended than initial concentration after by described filter basically.

2. according to the process of claim 1 wherein that leukocytic concentration is extremely little by about 10 than described initial white cell concentration at 0 leukocyte/milliliter ³Numerical value between.

3. according to the method for claim 1 or 2, wherein after the blood plasma pressure drop was approximately 70 centimetres or equivalent pressure and filters 2 minute time period, the flow velocity of described disposable multicompartment filter surpassed 1 ml/min/square centimeter filter area.

4. according to the method for claim 1 or 2, wherein under the blood plasma pressure drop is approximately 70 centimetres or equivalent pressure, filter 2 minute time period after, the flow velocity of described disposable multicompartment filter surpasses 2 ml/min/square centimeter filter area.

5. according to the process of claim 1 wherein that described degree of depth type prefilter is the non-woven glass fibre filter, the nominal pore size is from about 0.5 micron to about 5 microns.

6. according to the process of claim 1 wherein that the nominal pore size of at least one is about 1.0 microns to about 2.0 microns in described one or more midparent water film filtering device.

7. according to the method for claim 1 or 6, the nominal pore size of at least one is about 0.5 micron to about 0.9 micron in wherein said one or more final stage hydrophilic film filters.

8. according to the process of claim 1 wherein that described filter further comprises hydrophobic membrane, one side of described hydrophobic membrane communicates with the inside of described container, the another side of described hydrophobic membrane and the exterior of described container.

9. one kind is used for removing substantially from blood plasma all remains leukocytic disposable sterilized filter, comprising:

Have the container of entrance and exit part, described intake section comprises inlet, and described exit portion comprises outlet, and described intake section and exit portion form the flow channel between the two;

Be positioned at one or more prefilters of described container, cross-section fully described flow channel stretches, and described prefilter is provided with closely from described outlet from described inlet ratio; Described prefilter is a degree of depth type prefilter, and the nominal pore size is about 0.5 micron to about 5 microns;

Hydrophilic microporous membrane filters in the middle of at least one, maximum nominal pore size are positioned at the position of contiguous described prefilter less than 3 microns, and cross-section described flow channel stretches; Microporous hydrophilic membrane is near from described access road from described exit passageway ratio in the middle of described;

At least one final stage microporous hydrophilic membrane, maximum nominal pore size be close to described middle microporous hydrophilic membrane, and cross-section described flow channel stretch from about 0.3 micron to about 1.2 microns; Described final stage microporous hydrophilic membrane is near from described access road from described exit passageway ratio; The described nominal pore size of the hydrophilic nanoporous film filter of at least one described final stage is less than the nominal pore size of at least one hydrophilic microporous membrane filters in described centre;

Described final stage microporous hydrophilic membrane is sealed in the described container, passes through around described final stage microporous hydrophilic membrane so that prevent leukocyte; And

The described intake section of wherein said container is sealed to the described exit portion of described container.

10. one kind is used for removing substantially from blood plasma all remains leukocytic disposable sterilized filter, comprising:

(a) have the container of intake section and exit portion, described intake section comprises inlet, and described exit portion comprises outlet, and described intake section and exit portion form the flow channel between the two;

(b) be positioned at one or more prefilters of described container, cross-section fully described flow channel stretches, described prefilter from described inlet than near from described outlet; Described prefilter is a degree of depth type prefilter, and the nominal pore size is from about 0.5 micron to about 5 microns;

(c) microporous hydrophilic membrane in the middle of at least one, maximum nominal pore size are positioned at the position of contiguous described prefilter less than 3 microns, and cross-section described flow channel stretches; Microporous hydrophilic membrane is near from described access road from described exit passageway ratio in the middle of described;

(d) at least one final stage microporous hydrophilic membrane, maximum nominal pore size be close to described middle microporous hydrophilic membrane, and cross-section described flow channel stretch from about 0.3 micron to about 1.2 microns; Described final stage microporous hydrophilic membrane is near from described access road from described exit passageway ratio; The described nominal pore size of at least one described final stage hydrophilic film filter is less than the nominal pore size of at least one described midparent water film filtering device;

(e) be used for described final stage microporous hydrophilic membrane is sealed to the interior device of described container, around described final stage microporous hydrophilic membrane, pass through so that prevent leukocyte; And

(f) be used for the described intake section of described container is sealed to the device of the described exit portion of described container.

11. according to the disposable filter of claim 9 or 10, wherein at least one described one or more degree of depth type prefilter comprises the non-woven glass fibre filter, the nominal pore size is from about 1 micron to about 3 microns.

12. according to the disposable filter of claim 9 or 10, wherein after the blood plasma pressure drop was approximately 70 centimetres or equivalent pressure and filters 2 minute time period, the flow velocity of described filter surpassed about 1 ml/min/square centimeter filter area.

13. according to the disposable filter of claim 9 or 10, wherein the nominal pore size of at least one described one or more midparent water film filtering device is from about 1.0 microns to about 2.0 microns.

14. according to each disposable filter in the claim 9,10 or 13, wherein the nominal pore size of at least one described one or more final stage hydrophilic film filter is from about 0.5 micron to about 0.9 micron.

15. according to the disposable filter of claim 11, wherein said prefilter comprises glass fibre, wherein provides the eluent of pH value between 5.5 to 8.0 when the described glass fibre of water eluting, and does not have heavy metal ion in eluent basically.