HK1194749A - Device for filtration, drying and storage - Google Patents

Description

Apparatus for filtration, drying and storage

The invention relates to a device for filtering, drying and storing solids of suspensions (FDS unit), and to a method for post-processing and drying solid suspensions, in particular crystallizable therapeutic proteins or active ingredients, carried out in such a system. An FDS unit designed to be used as a disposable system is a device that: by this apparatus, the active component crystals can be gently and safely filtered, dried, stored and reconstituted during the course of a closed process (i.e., without intermediate opening or transfer).

The production of pharmaceutically active peptides and proteins and therapeutic antibodies is carried out by fermentation in a so-called "upstream process" (USP). The protein is then purified in a so-called "downstream processing" (DSP) and converted into a dosage form suitable for medical applications depending on the dosage form.

For DSP, separation methods based on chromatography are currently commonly used. In accordance with experience in recent years, there has been an increasing demand for purity and protection from contamination of purification processes consisting of a plurality of separation steps. This relates in particular to the production of pharmaceutically active components (e.g. therapeutic peptides and proteins), thereby excluding undesired biological side effects caused by many by-products formed during fermentation. To avoid contamination most rigorously, highly complex and expensive DSP steps are sometimes required. This severely impacted the economic efficiency of the overall process, especially since in recent years, a considerable cost shift at the expense of DSP occurred due to the increase in USP efficiency. Experts have predicted a continuing trend of this kind, and a further increasing capacity deficiency, which may have been considered today as a key bottleneck for many biological processes (http:// biopharmaceutical.

In order to be able to counteract the strong pressure on costs, new highly efficient, inexpensive and resource-saving purification and storage methods are required for therapeutic proteins and peptides in the biopharmaceutical industry. Whether these methods have a critical role in the long-term survival of biotechnological processes in competition (pressure-Information; ACHEMA 2009; 29.International Ausstellungskongressfur Chemisce technology, Umwelttschutz und Biotechnology; Frankfurt am Main, 11-15. Mai 2009; Trendericht Nr.20: Selektive Trenttechniken).

The highly selective crystallization of proteins may represent an economical alternative to the chromatographic separation techniques that are currently used primarily for the production of therapeutic proteins. The methods initially used for elucidating three-dimensional molecular structures by X-ray crystallography, as protein crystallization techniques, gradually approach modern purification methods. In this purification method, the solubility of the protein is gradually reduced by carefully adding a precipitant until the first crystals appear after a few minutes to a few hours. The advantages of this technique compared to alternative methods basically include the combination of the following features:

a high degree of purity achieved in a single process step;

high specificity, due to which even protein isoforms and/or glycosylation variants etc. can be isolated;

low cost;

high storage stability of the crystals;

reduced product loss during storage;

high crystal concentration in the case of relatively small apparatus volumes for storage;

cost-effective use of classical solid-liquid separation methods after crystallization;

the choice of sustained release dosage forms is used to balance the bioavailability of the active ingredients.

Navarro et al (Separation and Purification Technology2009,68:129-137) summarize the advantages of protein crystallization as follows:

the processes to be used in industrial production are particularly limited in downstream processing due to the chemical and thermal instability of proteins. During storage of proteins in solution, small physicochemical changes in the protein's microenvironment (changes in pH, ionic strength or temperature) can lead to reversible or mostly irreversible changes in tertiary structure, with concomitant loss of activity. Furthermore, there is the fact that proteins can be deactivated by aggregation, hydrolysis, deamidation, isomerization, deglycosylation, and oxidation or reduction, etc.

Stability problems can be minimized by storing the protein solution at the lowest possible temperature. In this way, the rate of possible chemical modification reactions is reduced. Furthermore, the environment surrounding the protein can be optimized in such a way that the denaturing effects are minimized. The protein can also be stabilized by drying, since by removing the water the reaction is slowed down in such a way that no further reaction takes place during storage, or the reaction takes place considerably more slowly. These treatments play a minor role in the dry state if deamidation and hydrolysis of the proteins in solution are major problems (McNally, e.j.; pharm. sci., 2000; 99). Furthermore, it has been observed that the oxidation reaction decreases with decreasing residual moisture content (Franks, F., Bio/technology.1994,12, 253-; Christensen, H.; Pain, R.H. Molten globule intermediates and protein folding. Eur.Biophys.J.1991,19, 221-. A substantial advantage of drying the protein is that the thermal stability of the protein is increased, which in turn leads to improved storage stability.

Currently, the standard method in the pharmaceutical industry is freeze drying (lyophilization) (Cleland, J.L et al, Critical reviews in therapeutic drug carrier systems.1993,10, 307-377; Wang, W., int.J.pharm.2000,203, 1-60). This process, which can be run continuously or discontinuously, dries uniformly at low temperatures. Reconstitution of the protein is usually performed rapidly and without problems. However, the increased time (up to one week) and energy requirements lead to a very costly process, which additionally may also have a denaturing effect on the protein. Lyophilization can only be used as the last processing step for short-term and long-term storage. No purification as in protein crystallization techniques occurs.

Thus, protein crystallization with a combined possibility of highly specific product purification and simultaneously improved storage stability is a particularly cost-effective process.

In the context of DSP of dry crystals, the transfer of active product poses a considerable risk of contamination of the environment (personnel exposure) and of the product (cross-contamination). In particular, the handling of dry powdery substances involves a very high hazard potential. In order to exclude cross-contamination between product batches and in particular between different products, the equipment for solid-liquid processing must be subjected to an intensive cleaning process with subsequent cleaning verification before being reused, which entails high expenditure of personnel and time. Furthermore, open disposal requires an expensive clean room environment and complex safety measures (protection against exposure, protection against dust explosions, etc.).

Thus, the handling of the pharmaceutically active protein crystals (or crystals of other pharmaceutically active substances), including isolation, drying, transport, storage and reconstitution, should be carried out in such a way that neither personnel are put at risk by escape of the substance nor there is a risk of contamination of the product. The error-free application of the cited process steps, but also the reduction of the expenditure of personnel and time, is of decisive importance for the safe and economical use of the crystals in DSPs. To date, no adequate technical solution has been described with respect to the special requirements for disposing of biotechnologically active components with respect to this problem.

In the current literature, only a few methods of technical post-treatment are described with respect to protein crystals and their storage.

For example, patent WO00/44767A2 describes the use of a centrifugal dryer for separating (filtering), washing and drying and further processing of insulin crystals. Here, particular attention is given to the introduction of a drying medium comprising a mixture of water and a non-aqueous solvent which is miscible with water in any ratio and has a lower vapor pressure than water. Furthermore, for drying, a nitrogen stream humidified with water was used. The amount of water is given by the optimum residual moisture determined for the protein (insulin and insulin derivatives). Disadvantages in this process are the great complexity of the apparatus of the centrifugal dryer and the common effort for cleaning and cleaning verification.

It is therefore an object of the present invention to provide an apparatus for filtration, washing, drying, transport, storage and optionally for resuspending/resolubilizing a crystalline active ingredient product, which can be handled simply, safely and in a product-saving manner, wherein the risk of contamination is minimized or excluded.

The above objects have been achieved by providing a device that can be used as a disposable system, which allows for the successive steps of filtration, washing, drying, sample removal, transport, storage and resuspension/resolubilization in a single container (i.e. without intermediate opening), hereinafter referred to as "FDS unit". For the subsequent formulation steps, using the FDS unit, the crystallized protein or peptide can be provided in a product-saving manner without risk of product contamination. Product loss or harm to personnel from unintended product release (e.g., hazardous dust emissions) can be minimized by closed processing procedures.

The invention therefore relates firstly to a filtration unit (FDS unit) for filtering solid particles of a suspension, comprising:

-a filter housing (10) comprising: a filtration chamber (13); a liquid distributor located at the end of at least one inlet (15) of the filtering chamber (13); and, a substrate (12) and a filter medium (11); wherein the filter chamber (13) and the substrate (12) are connected by a connection in the region of the filter medium (11) so as to be sealed with respect to the surroundings and the filter medium (11) thereof;

-at least one outlet (14) on the base (12) of the filter housing (10).

The material of the FDS unit is selected in such a way that cleaning and sterilization methods that are conventional in the pharmaceutical industry, such as autoclaving or gamma irradiation, can be used.

As filter medium (11) use is made of a fibre board or fibre cloth, typically made of fibre or sintered material and suitable for pharmaceutical purposes, which consists of a suitable material (e.g. plastic, glass, metal or ceramic material) known to the person skilled in the art, with pore sizes optimized for the filtration process or with product properties optimized with respect to product loss, throughput and/or pressure drop. The use of inexpensive materials, such as sintered plates or sintered fibers made of stainless steel or plastic materials (such as polyethylene, polyester, polyphenylene sulfide, polytetrafluoroethylene) is particularly preferred as FDS units as disposable systems. Pore sizes of from 0.2 to 50 μm are used, depending on the particle size or particle size distribution of the crystalline active component achievable in the crystallization process. In order to optimize the filtration process, the maximum possible pore size is selected individually for each product, by means of which a high throughput or filtration surface loading can be achieved without the infiltration of the product blocking the filter plate or leading to rinsing of the suspension.

Preferably, the filter medium (11) is clamped into the filter housing (10) horizontally as a filter plate (17). To increase the specific filtering surface area, it may be convenient to construct the filter element as a continuous (preferably cylindrical) tube that can be surrounded by a concentric outer filter tube (19) (fig. 6), or as filter candles (18) (fig. 2 and 6). In this case, the filtration takes place in an annular space formed by the filter tube (19) and the filter candle (18) with a gap width (58).

The filter housing (10) is conventionally made of plastic which is permitted in medical production. For producing the filter housing, standard methods for shaping plastics are used (injection molding, extrusion, etc.). Preferably, the filter housing is produced from a thermoplastic known to the person skilled in the art, for example polyethylene, polypropylene, PMMA, POM, polycarbonate (in particular Makrolon).

In a preferred embodiment, the product-contacting wall of the filter chamber (13) and in some cases also the substrate (12) is also made of a plastic film, so that the filter housing is constructed wholly or partially as a plastic bag. In this case, the overpressure required for the filtration is transmitted, at least within the filtration chamber (13), via the wall of the bag to a pressure-stable holding device. This solution is preferred for relatively large scales, from approximately 5 liters (l) to 50 liters (l), as the cost of the FDS unit may otherwise make single use applications difficult. As an easily detachable connection between the filtration chamber (13) and the base (12), in order to be able to use a typical clamp connection with closable clamps (e.g. triple clamps), it may be convenient to provide the filtration chamber (13) and the base (12) with respective connecting flanges. Alternatively, the filter housings may be bolted to each other (e.g., using a threaded connection or a bayonet connection). In another preferred embodiment, the filter chamber (13) and the substrate (12) are non-detachably connected to each other by welding, gluing or compression bonding.

For closed processing of the product in a sealable FDS unit, resuspension/resolubilization of the protein crystals within the FDS unit is desirable, but in case of a non-detachable connection between the filtration chamber (13) and the substrate (12) is absolutely necessary for the withdrawal of the product. In this case, the energy input required for accelerating the resuspension/resolubilization is preferably introduced non-invasively (i.e., without interfering with the closed system) into the filtration chamber (13), e.g., via orbital or rotary oscillatory vibration. In order to be able to use the mixing method of rotational oscillation, it may be expedient to provide the filter housing (10) with flow-disrupting elements (e.g. flow blockers or polygonal cross-sections) at least in the region of the filter chamber (13).

To perform the filtration, a suspension (30) of protein crystals is fed into the filtration chamber (13). In this case, the filter chamber (13) is ventilated via a sealable ventilation tube (22). For small proportions, the customary sizes for FDS units are 5 milliliters (ml) and 500 milliliters (ml). However, at large scale, FDS units with total volumes of up to 50 liters or more may also be produced. The degree of elongation (height to diameter ratio H/D) of the filter chamber (13) depends on the type and efficiency of liquid distribution at the top of the filter housing (10) and also on the achievable optimum height of the filter cake (20). The degree of elongation is usually selected in such a way that a filter cake height of 1 to 20cm, preferably between 2 and 8cm, particularly preferably between 3 and 5cm, can be achieved in the device, wherein the specific properties of the protein crystals to be filtered (in particular the size, stability and compressibility of the crystals) are taken into account.

An approximately constant cake height is advantageous when scaling up due to possible pressure drop problems (in addition to the size distribution, stability and compressibility of the crystals and the viscosity of the solution, the pressure drop is rather dependent on the cake height). Due to the use of the horizontal filter plate (17), this means that the H/D ratio of the filter chamber decreases continuously with scaling up. However, in order to achieve a uniform cake height, alternative means for efficient liquid distribution are necessary at relatively large proportions.

Typically, a suspension (30) of protein crystals is fed into the filter chamber (13) via a liquid distributor (50) having at least one inlet (15) (fig. 1, 2, 4, 5, 6 and 7). Preferably, the suspension (20) is introduced into the FDS unit in such a way that the filter cake (20) is built up uniformly. The uniform building up of the filter cake (20) is extremely important for the operation of the FDS unit, as it determines the duration and intensity of drying and thus the extent of unwanted product contamination and side reactions leading to loss of activity.

In the case of FDS units having small dimensions of 5ml and 500 ml and/or having a high degree of elongation H/D ≧ 1, the suspension (30) is fed via a liquid distributor (50), which liquid distributor (50) preferably comprises a single inlet (15) having a tangential or central axial feeding orientation (FIGS. 1 and 2).

However, in the case of large filter chambers (13) of small slenderness of up to 50 liters and/or H/D < <1, a considerably better distribution of the suspension over the cross section of the filter chamber (13) is advantageous. For this purpose, the liquid distributor (50) is preferably equipped with a distributor plate (54).

Liquid distributors with distributor plates are often used in chromatography, but are least suitable for distributing suspensions due to the low channel height (due to sharp bends, dead spaces and lack of descending orientation of the lines (settling of solids)). WO2010/138061a1 describes a tree-shaped liquid distributor having a distributor plate with exit openings arranged in a grid shape. The complex tree-like line structure is produced by "free-form fabrication" and is particularly easy to clean. The dispenser described will be well suited for dispensing suspensions, but is relatively complex to produce and expensive for the single use applications sought herein.

It is therefore an object to provide a liquid distributor which is adapted to distribute a suspension evenly (i.e. without dead spaces) and which allows a continuous regular descent of the suspension through a distributor plate, wherein the distributor should be simple and convenient to construct.

A liquid distributor (50) suitable for single use applications according to the invention has a pre-distributor (56), which pre-distributor (56) is connected to a distributor plate (54) by flexible tubular lines (52) of equal length and equal diameter, thus approximately the same pressure drop (fig. 4). A flexible tubular line (52) with an aspect ratio and gradient as continuous as possible is deployed (avoiding settling of solids) into the vertical exit opening (53) of the distributor plate (54). Depending on the diameter of the FDS unit, the outer tube fibers advantageously have an angle of attack between 5 ° and 75 °, particularly preferably an angle of attack of 20 ° to 60 °. The distribution of the exit openings (53) on the distributor plate (54) is generally such (fig. 5) that firstly the openings divided by a similar 60 ° have an approximately constant spacing from one another, whereas secondly the openings are positioned on a circular line (57), so that a uniform distribution is achieved, even close to the wall. In this case, the distance from the wall of the exit opening (53) preferably corresponds to half the distance of the loops (57) from each other. In this design of the filter plate (17) adapted to be arranged vertically, the number of drilled holes per unit circumference remains constant and in each case of a jump to the next larger loop (57) 6 exit openings (53) are added. The number of exit openings in each surface required for adequate solids distribution depends on several factors, such as particle density and particle size distribution, as well as on the rate of descent of the particles, the filtration speed, the height of the filter cake (20), and the degree of elongation of the filtration chamber (13). In a model test using 10g/l PANX particles, a filter chamber (13) filled via a dispenser according to the invention and having a diameter of 190mm delivers a median absolute height difference of approximately 2% -3% based on a cake height of approximately 40mm to deliver a H/D ratio of 0.5H/D, which is already a sufficiently good particle distribution. The required distributor thus had 7 exit openings and the drill spacing was approximately 63 mm.

In a particular embodiment of the distributor according to the invention, each exit opening is connected to a pre-distributor (56) by means of an unbranched flexible line (52). Generally, a silicone flexible tube is used as a flexible tube line. Typically, the flexible tubing lines are pushed, cast, welded or adhesively bundled into a pre-dispenser (fig. 4).

The pre-distributor is usually supplied with suspension (30) via an axially or tangentially arranged feed (15).

When the process scale is further expanded, or in the case of products which are difficult to filter, it may be advantageous not to build up a filter cake on the surface, but in the annular space between the filter candle (18) and the filter tube (19) (fig. 6). This gives the great advantage that the pressure drop can be set independently at the height of the filter cake. As a result, independently of the proportions, an elongated geometry can be achieved, which also yields considerable advantages in the space requirements or pressure load capacity of the device. In this arrangement, the height of the filter means (18,19) should preferably correspond as precisely as possible to the height of the filter cake (20). However, the filtration is started simultaneously via the two filter elements (18 and 19) and/or the outlets (14 and 16), the drying being carried out by adding drying gas via the outlet (14), in the case of starting via the outlet (16), that is to say from the inside to the outside, or by exchanging the connections in the opposite direction. This gives the advantage of a uniform pressure drop distribution in the cake and a very uniform drying of the product for the same cake and filter height. It can be advantageous to additionally introduce a small gas introduction portion of the drying gas via the inlet (15), so that, in particular in the case of too high a filling degree, the topmost layer can be dried better and the dead space region which would otherwise form above the filter cake (20) is removed. The arrangement of the exit drillings of the fractal liquid distributors in the distributor plate (54) is preferably done with the ratio L/B of the hole spacing L (59) to the width B (58) of the annular channel on the central loop (57) of the annular channel being 1.

Filtrate (40) flowing through the filter medium (11) can be removed via a preferably central outlet (14) at the base (12) of the lower filter housing.

After filtration, the filter cake (20) may be washed in an FDS unit.

The FDS unit of the present invention is preferably used in the system shown in fig. 3, but is not limited thereto. Before the protein crystals are dried, typically, the remaining filtrate (40), including the mother liquor or purge, is discharged from the filter cake (20) by a gas (140), preferably sterile filtered air or nitrogen. Gas is typically introduced via inlet (15) and gas and/or liquid is withdrawn via outlet (14). Preferably, at the end, in order to dry the gas (140), the temperature is raised to a level defined by the gas heater (160) and adjusted to a minimum residual moisture content via the gas humidifier (165). The latter is intended to prevent the product from being irreversibly damaged in the event of inadequate moisture content, for example by aggregation, discoloration or caramelization. In particular, incorrect residual moisture can lead to denaturation or difficulty in re-solubilization (including loss of activity).

After drying is performed, the inlet or outlet of the FDS unit may be clamped. For example, a flexible tube clamp (67) is suitable for this purpose, and a flexible tubular line (66) is pulled over the inlet (15) and outlet (14), preferably made of pharmaceutically compliant silicone or C-Flex. Thus, the filtered, washed and dried protein crystals can be left in the FDS unit without intermediate opening, even during transport and subsequent storage. In this way, a completely closed disposal is allowed.

If the protein crystals are to be redissolved, it may be advisable to remove the product after opening the filter unit. Preferably, however, the resolubilization or resuspension is performed within the FDS unit while maintaining a closed mode of operation. This can be done non-invasively with moderate energy input, for example by back flushing with a suitable liquid, first via the outlet (14) and then via the inlet (15). To improve hydrodynamic mixing performance, suspension of crystals, or ultimately increase solubilization speed, the FDS unit can be agitated on a special orbital shaker (60) (fig. 8). The shaker (60) has a receptacle (62) for receiving an FDS unit including a flexible line (66) and a flexible pipe clamp (67), and enters an orbital oscillatory motion via a cam (63). In the case of integrating flow disruption elements (e.g., polygonal cross-sections or flow blockers) into the filter chamber (13) of the FDS unit, the vertical rotary oscillatory reactor motion can also ensure intensive mixing, suspension and accelerated solubilization.

Thus, the invention also relates to a system for operating an FDS unit according to the invention, comprising:

-a crystallization tank (100) connected via a line to one or more reservoirs for crystallization and/or precipitation and correction medium (101) and on the other side to one or more FDS units connected in parallel, operating continuously or intermittently according to the invention;

-a mother liquor reservoir (110) connected to the outlet (14) of the FDS unit via a connection.

Technical crystallization of proteins (pharmaceutically active peptides or proteins and therapeutic antibodies) or other crystallizable or precipitable active components occurs in a crystallization tank (110), which crystallization tank (110) has a sufficient number of connections to reservoirs for all necessary crystallization and correction media.

After crystallization, the suspension (30) is conveyed as far as possible into the filter chamber (13) of the FDS unit with a moderate conveying speed by means of a slight overpressure without damaging the particles, avoiding pumping. To this end, the gas pressure is connected to the top of the crystallization tank via, for example, a three-way valve (120), and is adjusted via a pressure gauge (230). The crystal suspension is generally filtered at a filtration inlet pressure of 0.2 to 1.5bar, preferably 0.5 to 1.0 bar. The suspension (30) is retained by the filter medium (11, 17, 18 or 19, depending on the structure of the FDS unit). In a preferred embodiment, the filtrate (40) discharged from the outlet (14) of the FDS unit is fed to the filtrate reservoir (110) via another three-way valve (130).

When all the liquid from the crystallization tank (100) and the FDS unit has been forced out, the filtration is ended, so only the pre-dried over-filter cake (20) remains in the FDS unit.

After filtration, the filter cake (20) is still surrounded by the crystalline liquid. Preferably, the crystallization liquid is now replaced by a dry gas.

For this purpose, the drying gas can be conveyed through a filter unit. For drying, generally, compressed gas with a defined residual moisture is used at an inlet pressure of 1 to 3bar, preferably 2 to 3 bar. Thereby avoiding rebuilding of the apparatus for drying.

In a preferred embodiment, the system for drying comprises a drying unit comprising a separate drying gas line and a three-way valve (120, 130). These are arranged in such a way that the drying gas (with a suitable moisture loading) is guided around the crystallization reactor via a bypass. For transporting and heating the drying gas, for example, a tubular line with a heating jacket can be used as the gas heater (160). Further, it is preferable that the moisture content of the drying gas is set to a minimum value. For this purpose, the moisture of the drying gas is preferably adjusted before being introduced into the drying unit and is controlled by means of a moisture sensor (210). In the case of a relatively large moisture demand, the minimum moisture may be adjusted via a humidifying appliance (165) in the gas stream.

Preferably, the drying of the press cake is also monitored by means of a moisture sensor (220) at the outlet of the unisex FDS unit.

The filtrate (40) collected by the reservoir (110) during filtration is used as a wash liquid for the off-gas (150) when dry, thereby minimizing dust emissions that potentially occur during drying.

In another embodiment of the invention, the FDS unit according to the invention has means for minimally invasive sampling of the filter cake. For example, the FDS unit has a sealable opening for introducing a sampling scoop into the filter cake. Preferably, the sampling shovel can be introduced horizontally and vertically into the filter cake.

The invention described below allows the combination of as many process steps as there are downstream processes on a solid suspension.

Thus, the invention also relates to a method for the post-treatment of a solid suspension, comprising the steps of:

1) in a system according to any one of claims 10 to 12, filtering the solid suspension in a single filtration unit according to any one of claims 1 to 6 or in filtration units connected in parallel;

2) washing or replacing the retained solids, optionally by convection drying of the retained solids with a drying gas;

3) removing the solids-filled filtration unit from the system;

4) transporting and storing the solid-filled filtration unit, and optionally reconstituting the protein by dissolving and/or resuspending in the filtration unit.

Preferably, the convective drying is performed with controllable parameters such as temperature, volume flow rate or moisture content or a combination thereof.

By using filter plates with different pore sizes, all steps described can be adapted to the respective application or to the respective protein crystal suspension. The single-use construction of the FDS unit according to the present invention greatly reduces the expense of cleaning and cleaning validation compared to stainless steel or glass designs.

The single-use FDS unit according to the invention is particularly suitable for isolating protein crystals (pharmaceutically active peptides and proteins and therapeutic antibodies), but is not limited thereto. It is also advantageous for the isolation of other crystalline compounds, especially when the pharmaceutical manufacturing specifications have to be taken into account.

An FDS unit according to the present invention and a system for applying the FDS unit are schematically illustrated by way of example in fig. 1 to 6, but are not limited to the illustrated embodiments.

FIG. 1: FDS unit with filter plate

FIG. 2: FDS unit with filter candles

FIG. 3: incorporation of an FDS Unit into a System for performing filtration, drying and providing transportation and storage according to the invention

FIG. 4: fractal liquid distributor (side view: predistributor, distributor plate)

FIG. 5: fractal distributor (plan view: distributor plate with examples for dividing the exit opening)

FIG. 6: FDS unit with filter candles, filter tubes and fractal distributor for the annular space formed by two filter tubes, for large scale

FIG. 7: plan view on FDS Unit for Large Process Scale

FIG. 8: orbital shaker apparatus for non-invasive energy input to FDS units for the purposes of suspension and resolubilization in the case of closed processing procedures

Drawing legends

10 Filter housing

11 Filter media

12 base

13 Filter Chamber

14 outlet

15 inlet

16 outlet

17 filter plate

18 filter candle

20 Filter cake

22 ventilating pipe

30 suspension

40 filtrate

50 liquid distributor

5160 degree division

52 flexible tubular line

53 exit opening

54 distributor plate

56 Pre-distributor

57 ring line

58 annular space width

Distance of 59 holes

60 vibrator

62 Container

63 cam

66 flexible tubular line

67 flexible pipe clamp

100 crystallizer/settling tank

101 correction medium

110 reservoir

120 three-way tap/three-way valve

130 three-way tap/three-way valve

140 gas

150 waste gas

160 gas heater

165 gas humidifier

200 flow meter

210 moisture/temperature sensor

220 moisture sensor

230 pressure measurement

Example (b):

for filtering model proteins, the FDS unit according to fig. 1 is made of a filter housing (10) with a filter chamber (13) of 100ml volume, a diameter of 26mm, an elongation of 5.8 and a screw-mountable base part (12) made of Polyoxymethylene (POM). The wall thicknesses of the filter housing (10) and the substrate (12) are dimensioned for selected conditions of temperatures up to 3bar and-10 ≦ T ≦ 60 °. Sintered metal plates with a pore size of 5 μm (diameter 34 mm; thickness 5mm) were used as the filter medium (11). The filter chamber (13), the filter medium (11) and the base (12) are fastened together by means of a clamp connection using a closed clamp (tri-clamp).

Crystallization of

The model protein was introduced dissolved in 40mM sodium citrate (initial pH 2.7) at a concentration of 10 g/l. A precipitant (0.75M sodium hydroxide solution; 15ml over 15 minutes) is then added up to a nucleation pH of 3.2. At this pH, the solution was stirred for a further 3 hours (agitator speed 200 rpm). After the nucleation time, the precipitant was added to the solution to a final pH of 4.5. The solution was stirred at room temperature for 17 hours.

The optimal processing parameters for subsequent filtration and drying of the protein crystals are determined by statistical design of the experiment. A response surface model is prepared from which the principle and two-factor responses and the optimal processing parameters are generated.

Filtration

For the model protein used, an optimal filtration inlet pressure of 0.5bar was determined. For the model protein used, an optimal cake height of 4.5cm (. + -. 0.5) was determined.

Drying

For the model protein used, the optimum inlet pressure of compressed air of 2.5bar (. + -. 0.5) was determined. The drying temperature (temperature of the compressed gas) depends on the temperature stability of the target protein and is set between 30 ℃ and 50 ℃. For the model protein used, compressed air with an optimum temperature of 45 ℃ (± 0.5) was used. Compressed air at a relative humidity of 0.5-1.0% can be provided without an additional air humidifier. It is sufficiently sized to prevent product damage caused by excessive drying of the filter cake. For the model protein used, an optimal drying time of 17.5h (. + -. 1) was determined. Use byGas heater (160) with heating jacket pipeline configuration, up to 4m³The volume flow rate/h can be heated to a temperature of 55 ℃.

Under the above test conditions, the following test values were determined:

crystallization yield: 98 [% ]

Product loss in mother liquor: 1 [% ]

Filtering flux: 1556[ l/h × m²×bar]

solid/FDS unit (loading capacity): 13[ g crystalline solids/FDS Unit](volume: 22 cm)³)

Residual moisture content (Karl-Fisher method): 4 [% ]

Product purity (RP-HPLC): 95 [% ]

Claims (14)

1. A filter unit for filtering solid particles of a suspension, comprising:

-a filter housing (10) comprising: a filtration chamber (13); a liquid distributor (50) located at the end of at least one inlet (15) of the filtering chamber (13); and, a substrate (12) and a filter medium (11); wherein the filter chamber (13) and the substrate (12) are connected by a connection in the region of the filter medium (11) so as to be sealed with respect to the surroundings and the filter medium (11);

-at least one outlet (14) on the base (12) of the filter housing (10).

2. The filter unit according to claim 1, wherein the filter housing is made of plastic.

3. The filter unit according to any one of claims 1 or 2, wherein the filter housing is constructed wholly or partly as a plastic bag.

4. A filter unit according to any one of claims 1 to 3, wherein the filter media is selected from the group comprising one or more of a filter plate, a cylindrical filter, a candle or a combination thereof.

5. The filter unit according to any one of claims 1 to 4, wherein the filter chamber (13) and the base (12) are non-detachably connected.

6. A filter unit according to any one of claims 1 to 5, wherein a liquid distributor with a filter plate is used for liquid distribution.

7. Liquid distributor comprising a pre-distributor (56) connected to a distributor plate (54) by flexible tubular lines (52) of equal length and equal diameter, wherein the flexible tubular lines (52) with aspect ratio and gradient as continuous as possible open out into vertical exit openings (53) of the distributor plate (54), characterized in that the exit openings (53) are arranged on concentric tracks.

8. Liquid distributor according to claim 7, wherein the exit openings are arranged at 60 ° to each other and at the same distance from each other and at a constant distance from the outer wall of the filtering chamber, or in the best possible combination thereof.

9. Liquid distributor according to any one of claims 7 or 8, wherein each exit opening is connected to the pre-distributor (56) by means of an unbranched flexible tubular line (52).

10. A system for filtering solid particles of a suspension, comprising:

-a crystallization tank (100) temporarily connected at one end to one or more reservoirs for crystallization and correction medium (101) and at the other end to a filtration unit according to any one of claims 1 to 6, or to a plurality of said filtration units in parallel, via a line; and

-a mother liquor reservoir (110) temporarily connected to the outlet (14) of the filtration unit via a connection.

11. The system of claim 10, comprising a drying unit, a humidifying unit, or both.

12. The system of claim 11, comprising means for non-invasively agitating the contents of the FDS unit, said means selected from the group consisting of an orbital shaker or a vertical rotary oscillatory shaker.

13. Method for downstream processing of a solid suspension comprising the steps of:

-in a system according to any one of claims 10 to 12, filtering the solid suspension in a single filtration unit according to any one of claims 1 to 6 or in filtration units connected in parallel;

-washing or draining the retained solids, optionally by convective drying of the retained crystals by a drying gas;

-removing the solid-filled filtration unit from the system;

-transporting and storing the solid-filled filtration unit and optionally reconstituting the protein by dissolution in the filtration unit.

14. The method according to claim 13, wherein the convective drying is performed with controlled temperature, volume flow rate or moisture content or a combination thereof.