WO1996014890A1 - Hollow-filament plasma-filtering membrane and plasma-filtering module - Google Patents

Abstract

A hollow-filament plasma-filtering membrane and a plasma-filtering module, for use in separating the blood into the cells and the plasma, cooling the separated plasma to a temperature ranging from the solidifying point thereof to 35 °C, and removing therefrom a gel containing medium- to high-molecular-weight pathogenic substances. By using as the filtering membrane a membrane constituted of a polyolefin and having a hollow filament inner diameter of 50-300 νm and an inhibitory rate of 90-99 % against the passage of 0.1-νm polystyrene latex particles, the membrane and the module have an excellent biocompatibility and can be reduced in the albumin removal rate.

Description

 Specification

 Hollow fiber type plasma filtration membrane and plasma filtration module

 Technical field

 The present invention relates to a hollow fiber type plasma filtration membrane for plasma filtration and a plasma filtration module. More specifically, a filtration membrane and a plasma filtration module suitable for separating a gel containing multiple pathological substances formed by cooling plasma obtained by separating blood from blood. About.

 Background technology

 It has been 80 years since Abe 1 et al. Used plasmapheresis for animals for the first time in 1914, and various plasmapheresis methods have been invented to date.

 Plasmapheresis is a treatment method in which blood is separated into blood cell components and plasma components by extracorporeal circulation, harmful substances in the plasma components are removed, and then mixed with the blood cell components again and returned to the body. .

 There are two methods for separating blood cell components and plasma components: centrifugal separation and membrane filtration. A membrane that is free from platelet contamination, has a small and inexpensive device, and is easy to separate. The filtration method is common.

Plasmapheresis first discards all plasma containing separated pathogens and replaces it with normal plasma. Substitution method (PE) is the basis.

 However, PE requires a large amount of fresh frozen plasma of 2-3 liters per treatment, making it difficult to secure the volume of normal human plasma, and in addition to viral infection due to transfusion. It is dangerous and has fundamental problems as a versatile treatment. Due to the high cost of treatment, the indication is now limited to some cases such as drug addiction and fulminant hepatitis.

 Examples of the material of the film used for PE include polyethylene, polypropylene, polystyrene, cellulose acetate, cellulose acetate, and the like.

 Aki et al. Developed the double filtration plasma exchange method (DFPP) in 1979 to solve this problem. Once separated, plasma is separated from plasma immunoglobulin, a macromolecule in plasma, by the molecular sieve effect of a hollow fiber filter called a plasma component separator with a pore size of 0.01 to 0.1 lm. To reduce the loss of useful proteins.

As a result, it was not necessary to use fresh frozen plasma for the replacement solution, and only 5% albumin had to be replenished. However, the sieving capacity of the plasma component separator is also limited.For example, immunoglobulin IgM having a molecular weight of 950,000 and albumin having a molecular weight of 67,000 have good separation efficiency. Molecular weight Separation efficiency of 190,000 immunoglobulin IgG and 67,000 molecular weight of albumin may be inadequate and tens of grams of albumin may be required in one treatment .

 In other words, if we try to suppress the loss of albumin, IgG will not be sufficiently removed, and conversely, a considerable amount of albumin will be lost to remove enough IgG. Problems remained.

 In other words, how to efficiently remove only pathogenic substances and avoid losing useful proteins such as albumin became a very important technological focus.

 Examples of the material of the film used for DFPP include ethylene vinyl alcohol, cellulose acetate, and the like.

 In order to solve the above problems, Nose et al. Devised a plasma cold filtration method (CF) as disclosed in Japanese Patent Publication No. 1-346266 in 1981.

 CF is cooled by cooling plasma separated online to a temperature above its freezing point and below 35 ° C, thereby reducing the amount of plasma, fibrinogen, and fibronectin. This is a treatment method in which a gel-like macromolecule (cryogel, CG) with the nucleus as the core is formed, and the CG is removed using a PE or DFPP membrane instead.

The power of CG has not yet been elucidated The advantage of this method is that the composition of the cryogel can be changed by changing the plasma cooling conditions and the filter washing conditions.

 CG itself also functions as a kind of adsorbent, and small and medium molecular weight substances such as amyloid protein, which cannot be removed only by the molecular sieve effect, can be adsorbed by affinity for cryogel. Has been reported. (Yonekawa, et al., Journal of Japanese Society of Transfusion 34 (1): 71-75, 1988) o

 CF can reduce the loss of albumin more than DFPP because the effect of separating CG and albumin can be improved by changing the method such as cooling conditions and washing conditions. It has the feature of being able to

 At the time of its development, its excellence in focus was the result of vigorous clinical research conducted by researchers around the world, and active presentations at academic conferences. Today, only a few enthusiastic clinicians are conducting research treatment.

One of the causes is that, even though the loss of albumin is smaller than that of DFPP, if plasma is actually treated with 4 liters and sufficient CG is removed, about 20 g of albumin is replenished. Is often needed, and separation of CG and albumin The effect is insufficient.

 In the past, clinical applications preceded and CF was simply a modified version of DFPP, so it was hard to imagine developing a new membrane material exclusively for CF.

 In fact, the plasma separators and plasma component separators used in PE have been diverted as they are and have been used for more than 10 years until the current research treatment.

 As described above, the filtration module that has been conventionally diverted to CF has a problem in that the separation efficiency of CG containing multiple pathogens and albumin of useful proteins is insufficient.

 In order to solve the above-mentioned problems, the present inventors have started to develop a film material most suitable for CF, and have focused on a biorefinable polyolefin film. Conventionally, cellulosic (for example, “Plasma Flow AP — 06 MJ made by Asahi Medical Co., Ltd.)” was often used for CF, and the force (literature: 0 m 0 kawa S, eta 1, Trans ASAI 0, As described in 33, 112, 198 7), polyethylene membranes have better biocompatibility in plasma polishes than cellulose acetate membranes. For example, it is shown as specific data such as little change in complement titer (CH50), leukocytes, and platelets.

Although it is a polyrefin film with the above characteristics, There were no examples used for F, and it was not possible to know what specifications were suitable, as well as whether they could be used.

 As the plasma component separation membrane made of polyethylene, for example, those disclosed in JP-A-58-75555 and JP-A-63-68176 are known. Have been. The latter is for AIDS virus removal. Nevertheless, none of them are considered to be used for CF at all, so that, of course, the study of suitable specifications for improving the separation effect of CG and albumin has been completely done. Absent.

 Disclosure of the invention

 One object of the present invention is to provide a membrane material suitable for CF, which is excellent in biocompatibility and has a high separation efficiency between CG and albumin.

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 Yet another object of the present invention is to provide a filtration module suitable for CF.

 The present inventors have focused on the capture rate (rejection rate) of a latex standard particle having a membrane separation coefficient of 0.1 zm, and have studied a plurality of polyrefin hollow fibers having different rejection rates. When a film was prepared and the removal rate of albumin and the removal rate of CG were determined, it was found that good results could be obtained especially when the rejection was in a specific range. Was completed.

That is, the present invention provides a method of separating blood into blood cells and plasma. A hollow fiber type filtration membrane for cooling the separated separated plasma to a temperature not lower than its freezing point and not higher than 35 ° C, and removing a gel containing a medium-molecular-weight pathogenic substance from the cooled separated plasma; The filtration membrane is composed of a polyolefin, the hollow fiber has an inner diameter of 50 / m or more and 300 ^ m or less, and is composed of 0.1 l ^ m of polystyrene latex particles. Another object of the present invention is to provide a hollow fiber type plasma filtration membrane having a rejection of 90% or more and 99% or less.

 Further, the present invention comprises a cylindrical case and a plurality of the above-mentioned hollow fiber type plasma filtration membranes arranged in the case, wherein the case has at least a plasma inlet, a waste liquid outlet and a filtrate. A plasma filtration module provided with an outlet, wherein the hollow fiber type plasma filtration membrane is fixed in the case by at least one partition and the inside of the case is The filtration membrane and the partition partition the space occupying the inner surface of the filtration membrane and the space occupying the outer surface of the filtration membrane.The plasma inlet and the drainage outlet are connected to one of the spaces, Also, the filtrate outlet is connected to the other of the above-mentioned spaces, thereby providing a plasma filtration module.

In the present invention, the plasma filtration module may include a washing liquid inlet in addition to the plasma inlet, the waste liquid outlet, and the filtrate outlet. According to the present invention, since the hollow fiber membrane is composed of polyolefin, it is excellent in biocompatibility and has a rejection of 0.1 m of polystyrene latex particles of 90%. Since it is not more than 99% or less, the removal rate of albumin can be significantly reduced as compared with the hollow fiber membrane conventionally used as a substitute.

 BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 is an enlarged cross-sectional view showing one embodiment of the hollow fiber type plasma filtration membrane of the present invention.

 FIG. 2 is a schematic explanatory view showing one embodiment of the plasma filtration module of the present invention.

 FIG. 3 is a schematic explanatory view showing another embodiment of the plasma filtration module of the present invention.

 FIG. 4 is a schematic explanatory view showing still another embodiment of the plasma filtration module of the present invention.

 FIG. 5 is a schematic explanatory view showing still another embodiment of the plasma filtration module of the present invention.

 Figure 6 is the circuit diagram used in the performance experiment.

 BEST MODE FOR CARRYING OUT THE INVENTION Preferred embodiments of the present invention are described below with reference to the accompanying drawings.

Fig. 1 is an enlarged cross-sectional view of a hollow fiber type plasma filtration membrane according to the present invention. The filtration membrane 1 is composed of a polyolefin. Polyolefins include ethylene, propylene, 1-butene, 1-pentene, 1-hexene, and 4—methylol 1-pentene Etc. or a copolymer of two or more of these homopolymers.Polyethylene homopolymer or polyethylene from the viewpoint of moldability. rather good to adopt a copolymer of other O-les-off fin, main Norre door Lee down de click Waals forces, '1 to 1 5 at a density Kaka' 0. 9 5 5 g / cm 3 or more Polyethylene having few branches (linear polyethylene) is preferred. Even cry, main Norre door Lee down de click Waals forces, '1 density at ~ 8 _0. 9 6 0 β; ιη ³ or more of the port re-ethylene-les-down is especially good or arbitrariness. Further, the inner diameter d of the filtration membrane 1 is appropriately selected and determined from a range of 50 m or more and 300 m or less.

 By the way, if the internal diameter d exceeds 300 m, it will be too thick, so the number of installations per unit cross-sectional area will decrease and the filtration efficiency will decrease, and if it does not reach 50 m Not only is it too thin to make it difficult to manufacture, but also there is a risk of clogging at an early stage, neither of which is preferred. A particularly preferable range of the inner diameter d is from 150 to 300111.

The thickness t is not particularly limited. Usually, the thickness t is appropriately selected and determined from a range of 20 to 100 m. The method for producing the filtration membrane 1 includes, for example, the melt spinning and drawing aperture method described in JP-B-63-35726, JP-B-63-2004, and the like. Is available. That 1-1 5 of main Le Bokui Nde' click scan values and 0. 9 5 5 (: πι less inherently branched having ³ or more density po Re ethylene les down (linear Po Re ethylene les down) In a temperature range of about 20 ° C or more from the melting point of the polymer and not exceeding 80 ° C, a spinning draft 100 to 1 using a hollow fiber manufacturing nozzle. After the melt-spinning is performed in the range of 0.000 and the obtained highly oriented crystalline undrawn hollow fiber is subjected to an annealing treatment at a polymer melting point or lower as required, a temperature of 40 ° C or lower is obtained. Cold stretching is then performed in a temperature range of 80 to 125 ° C in one stage or multiple stages, and the total stretching amount of the cold stretching and the hot stretching is 100 to By performing heat setting in the temperature range of 100 to 125 ° C as needed, a hollow fiber type filtration membrane can be manufactured. You.

In the present invention, out of the hollow fiber type filtration membrane produced by the above production method, the rejection of 0.11 m polystyrene latex particles is 90% or more and 99% or less. Preferably, 90% or more and 95% or less are selected and used, which can significantly reduce the albumin removal rate. Prior to use, the hollow fiber filtration membrane of the present invention is preferably subjected to a treatment for increasing the affinity with water so as to favor the filtration of plasma. As a method of the treatment, for example, a method of successively treating with alcohol and polyethylene glycol described in Japanese Patent Publication No. 3-64544 is common.

 The measurement of rejection of latex standard particles can be performed by the following method.

For measurement, a large number of hollow fiber membranes are used by filling them in a container so that the total membrane area is 50 cm ² .

 Before the measurement, the hollow fiber membrane was mixed with ethanol and 0.1% (wZV) of a surfactant (polyethylene glycol (P)). (Water) to increase the affinity with water.

A suspension containing 0.1% (WZV) monodisperse polystyrene latex particles (particle diameter: 0.1 m) is subjected to a pressure of 0.1 T kg Z cm by the hollow fiber membrane. ^After filtration, the concentration of the latex particle suspension before and after filtration was measured using a Hitachi spectrophotometer (U-340) to measure the absorbance at a wavelength of 320 nm. And calculate the rejection rate.

 FIGS. 2 to 5 schematically show various types of plasma filtration modules according to the present invention.

The plasma filtration module shown in Figure 2 is preferably cylindrical Is provided with a cylindrical case 2 and a plurality of hollow fiber type plasma filtration membranes 1 according to the present invention installed in the case 2 ₍ FIG. The book is shown. Normally, about 200 to 100 books are installed per case.

 The above case 2 is provided with a washing liquid inlet 6 as required in addition to the plasma inlet 3, the drainage outlet 4 and the filtrate outlet 5.

 In the type shown in FIG. 2, the filtration membranes 1 are fixed to the inside of the case 2 via partition walls 7, 7 at two locations at both ends.

 The inside of the case 2 is composed of a filter membrane 1… and partition walls 7, 7, a space occupying the inner surface side of the filter membrane 1, ie, an inner chamber 8, and a space occupying the outer surface side of the filter membrane 1, ie, an outer chamber 9. It is divided into

 The plasma inlet 3 and the drain outlet 4 are respectively connected to the inner chamber 8, and the filtrate outlet 5 and the washing liquid inlet 6 are connected to the outer chamber 9, respectively.

 In the plasma filtration module shown in FIG. 3, there is no substantial difference from the type shown in FIG. 2 except that the washing liquid inlet 6 is omitted.

In the plasma filtration module shown in FIG. 4, the above-mentioned filtration membranes 1 ... are folded back in a U-turn, and accordingly, only one partition wall 7 is provided. The plasma inlet 3 and the drainage outlet 4 are respectively connected to the outer chamber 9 side, and the filtrate outlet 5 is connected to the inner chamber 8 side.

 FIG. 5 shows the reverse type of FIG. 4. In this case, the plasma inlet 3 and the drainage outlet 4 are individually connected to the inner chamber 8 via both ends 1a and 1b of the filtration membrane 1. The filtrate outlet 5 is connected to the outer chamber 9.

 In the various types of modules shown in FIGS. 2 to 5, during the normal operation of plasma filtration, the drainage outlet 4 and the washing liquid inlet 6 (type in FIG. 2) are closed.

 Hereinafter, the present invention will be described in more detail with reference to Examples 1 and 2.

Example 1

Main Norre DOO Lee Nde' click scan 5.5, using a hollow fiber shaping Roh nozzle having a double pipe structure of dense potentiation Re ethylene les down Density 9 6 8 g Z cm ^3, temperature 1 6 2 ° (: The spinning draft was melt spun at 354. The obtained undrawn yarn was annealed on a roller heated to 113 ° C, and then dried at 25 ° C for 80 ° C. % Cold stretching, followed by hot stretching in a heating box at a temperature of 112 ° C until the total stretching amount reaches 5 25%, and then 25% in a heating box at 115 ° C. The resulting porous polyethylene hollow fiber membrane had an inner diameter of 22.5 μm, a thickness of 35; «m, a porosity of 72%, and 0.1 l. "m The rejection of styrene latex particles was 92%, which satisfied the constituent requirements of the hollow fiber type plasma filtration membrane of the present invention.

Example 2

 Using the same polyethylene as in Example 1, according to the production method described in Example 1, inner diameter 270 / zm, film thickness 55 m, porosity 70% 0.1 A porous polyethylene hollow fiber membrane with a rejection of 90% for ^ m polystyrene latex particles was manufactured.

 The performance experiments and results of the hollow fiber plasma filtration membrane of the present invention obtained from Example 12 are shown below.

 (Performance experiment)

 An experiment was performed using the filtration module shown in Fig. 2 and the circuit shown in Fig. 6. In Figure 6,

1 1 is a blood pump, 1 2 is a blood line, 13 is a plasma separator, 14 is a plasma pump, 15 is a cooling section, 16 is a plasma line, 16 a is an on-off valve, 17 Is the filtration module, 18 is the return line, 19 is the woma, 20 is the inlet pressure gauge, 21 is the outlet pressure gauge, 22 is the waste line, and 2a is the waste line. On-off valve, 23 is physiological saline, 24 is collecting pipe, 25 is branch pipe, 25a is on-off valve, 26 is branch pipe, 26a is on-off valve, 27 is cleaning liquid pump, 2 Reference numeral 8 denotes an on-off valve, and reference numeral 29 denotes a plasma pool. The circuit shown in Fig. 6 with 2 liters of plasma pool 29 was prepared, and the plasma separator 13 had a nominal pore diameter of 0.3 m, an inner diameter of 350 / m, a film thickness of 50 zm, and a membrane. A 0.5 m ² polystyrene hollow fiber membrane (“Plasma Flow OP — 05” manufactured by Asahi Medical Co., Ltd.) is used, and the CF filter module 17 is filled with hollow. Yarns having the specifications shown in Table 1 were used.

 The plasma flow rate was 30 ml / min and the plasma throughput was 4 liters.

The cooling temperature of the plasma was adjusted to 10.5 ° C, and the washing and regenerating method of the filtration module 17 was, for example, the method described in W092-17202. That is, the filter module 17 clogged, and when the difference between the pressure gauges 20 and 21 reached 30 OmmHg, the on-off valve 28 was closed first, and then 22a is opened to lower the internal pressure of the filtration module 17 to atmospheric pressure, and then the on-off valves 16a and 22a are closed to collect useful proteins trapped in the filtration module. The opening and closing valves 25a and 28 are opened, and physiological saline is supplied to the filtration module in a volume of 30 ml Z until the specified volume is reached, and useful proteins are collected. To clean the CG remaining in the container 17, close the on-off valves 25 a and 28, open the 22 a and 26 a, and allow the saline to flow at a flow rate of 10 Om1. Place Backwash the filtration module with a constant volume. After backwashing, close valves 22a and 26a and open valves 16a and 18 to return to normal filtration. Before starting the above-mentioned performance experiment, it is necessary to perform a process to increase the affinity with water in advance as described above, because the polyrefin hollow fiber membrane does not pass water because it is hydrophobic until then. For this treatment, for example, the method described in Japanese Patent Publication No. 3-64454-4 can be used. That is, ethyl alcohol is passed through the inside of the hollow fiber membrane at a flow rate of 100 m1Z so as to pass through the membrane and exit to the outside, and the air in the micropores of the hollow fiber membrane is removed by alcohol. After the replacement, the treatment was carried out by flowing a polyethylenated alcohol at 100 ml for 1 minute for 5 minutes instead of alcohol. Table 1 shows the results of the removal rate of albumin and G obtained using the hollow fiber membrane of each specification. Here, the removal rate is defined by the following equation. r After filtration, the plasma protein content _Ί

Removal rate (%) = 1 — \ X 1 0 0

¹ Plasma protein content before filtration J Table 1 Specifications and performance of the hollow fiber membrane used in the study of CF filters

In Table 1, as Comparative Example 1, a commercially available polypropylene plasma component separation membrane “Diacrystal II” (manufactured by Mitsubishi Rayon Co., Ltd.) was used as Comparative Example 2. A hollow fiber membrane having the specifications and performance shown in Table 1 manufactured according to the manufacturing method described in Example 1 was used as a comparative example 3 as a conventional alternative filtration module, a hollow fiber membrane. “Plasma Flow AP-0.6 M” (manufactured by Asahi Medical Co., Ltd., nominal pore size 0.2 μm) made by mouth diacetate was used.

The volume of physiological saline used for the recovery of useful proteins was 100 ml for polypropylene and polyethylene, and 200 ml for Senoroku-Sui-Acetate. The amount of physiological saline used to backwash CG was 300 m 1 for both. And

 Here, the CG removal rate was measured according to the method described in the literature (Abe, eta1 Trans ASAI 0, 30, 2989 to 2994, 1984) Calculated from the concentration of cryo-presipitab 1 eprotein.

 Two clinical reports (Abe, etal, Trans ASAI 0,30, p291, 1984; Yonekawa, et al., Human organs 22 (1), p22, 1993 ) Indicate that 64% of the cryo-iminoglobulin force and 69% of the cryo-aip-linogen have been removed, respectively. It is considered that a therapeutic effect can be achieved if 60% or more of CG can be obtained in clinical practice because it is considered to be the main component of CG. The experimental system in this case is for invitro, and it is impossible to say that this number will be applied as it is, but we can refer to this number.

The rejection rate of latex particles from the CG removal rate of 0.Polyethylene hollow fibers with a force of 90% or more and 99% or less The hollow fiber inner diameter of the hollow fiber membrane is 50 zm or more and 300 m or less. The finalizers of Examples 1 and 2 exhibited a CG removal rate of 60% or more, although the removal rate of albumin was suppressed to a low level. Thus, the filters using the conventional substitute membrane were used. Very high separation efficiency compared to filter The results showed good performance.

 On the other hand, the final letter of Comparative Example 1, in which the rejection of the latex particles is 100%, is too high at an albumin removal rate of 79%, and the final letter of 80% in Comparative Example 2 is 80%. On the other hand, the noteter cannot be used because the CG removal rate is too low at 30%.

 The finoleta of Comparative Example 3 was made of cellulose diacetate and had poor biocompatibility compared to polyolefin and had a latex rejection of 95%. Even at this point, the albumin removal rate was 52%, much higher than the 28% and 33% in Examples 1 and 2, and the performance was not good.

 Here, the separation efficiency of substance A from substance B refers to the ratio of the removal rate of substance B to the removal rate of substance A. For example, the separation efficiency of CG from albumin can be obtained by dividing the CG removal rate by the albumin removal rate.

 The invention's effect

 According to the filtration module using the hollow fiber type plasma filtration membrane of the present invention, the removal rate of albumin can be significantly reduced as compared with a filtration module which has been used in the past as a substitute. On the other hand, CG can be removed in a sufficient amount, and the separation efficiency can be greatly improved, and the replenishment of albumin can be reduced. Furthermore, since the filtration membrane is composed of polyolefin, it has excellent biocompatibility.

Claims

The scope of the claims 1. Separates blood into blood cells and plasma, cools the separated plasma to a temperature above its freezing point and below 35 ° C, and removes gel containing medium-high molecular weight pathogenic substances from the cooled separated plasma A hollow fiber type filtration membrane for filtering, wherein the filtration membrane is composed of a pol- yrofinker, the hollow fiber having an inner diameter of 50 m or more and 300 mm or less. A hollow fiber type plasma filtration membrane, characterized in that the rejection rate of the styrene latex particles is 90% or more and 99% or less. 2. A polyolefin having a refractive index of 1 to 15 and a density of 0.955 g Z cm ³ or more. The hollow fiber type plasma filtration membrane according to the above. 3. Po the Rio les off Lee Lanka, main Honoré preparative Lee emissions de Tsu claim density click Waals forces 1-8 is 0. 9 6 O g Z cm ³ or more linear Po Li E Ji les down 2. The hollow fiber type plasma filtration membrane according to item 2.  4. The hollow fiber plasma filtration membrane according to claim 2 or 3, wherein the rejection of the polystyrene latex particles of 4.0 is 90% or more and 95% or less.  5. The hollow fiber type plasma filtration membrane according to claim 4, wherein the inner diameter of the hollow fiber is 150 m or more and 300 m or less, and the film thickness is 20 to 1 OO ^ m. 6. A cylindrical case and claims 1 to disposed in the case. 5 A plasma filtration module provided with a plurality of the hollow fiber type plasma filtration membranes described in any one of the above, wherein the case is provided with at least a plasma inlet, a waste liquid outlet, and a filtrate outlet. The hollow fiber type plasma filtration membrane is fixed in the case by at least one partition, and the inside of the case occupies the inner surface side of the filtration membrane by the filtration membrane and the partition. The plasma inlet and the drain outlet are connected to one of the spaces, and the filtrate outlet is connected to the other of the spaces. A plasma filtration module characterized by the following.  7. The cylindrical case is provided with a washing liquid inlet in addition to the plasma inlet, the draining liquid outlet and the filtrate outlet, and the washing liquid inlet is connected to a space on the same side as the filtrate outlet. Plasma filtration module.