EA041838B1 - LOWER SECTION FOR CONNECTION WITH DISC ASSEMBLY AND DISC ASSEMBLY - Google Patents

Description

The technical field to which the invention belongs

The invention relates to a lower section for connection with an assembly for separating a solid component from a fluid medium, said assembly comprising an inclined disc separator. The present invention also relates to an assembly comprising such a bottom section and an inclined disc separator. In addition, the present invention relates to the use of the lower section for connection with the assembly containing the inclined disc separator. The present invention also relates to a process for separating solid components from a fluid.

State of the art

Assembly for the implementation of the selection of the component from the fluid may contain an inclined disc separator. The sedimentation trays, on which the recovery component can be deposited, of the inclined tray separator extend in an oblique rather than a vertical direction, that is, in a direction that is inclined relative to the direction of gravity. Examples of inclined disc separators are described in US patent applications 2012/0302741 A1, 2793186 A1, 753646 A1 and 2002/0074265 A1.

Fluid is supplied to such a tray separator at its lower edge at a sufficiently high pressure such that the fluid flows upward along the separator's sediment trays. The solid component to be isolated may, for example, already be present in the supplied fluid in solid form. Alternatively, the release component may, for example, precipitate under the influence of gravity. The rest of the fluid flows on and eventually exits from the outlet at the top edge of the disc separator. The separated component (eg solid component) is collected at the bottom edge of the disc separator.

The bottom edge of the disc separator may be connected to a component, often referred to as the bottom section, containing supply channels for supplying fluid containing the component to be separated, and collecting channels for collecting the separated component.

The inclined tray separator may comprise a plurality of sediment trays. Thus, the separation process can take place simultaneously on each of the sedimentation trays. Since both the fluid containing the recovery component is supplied and the recovered component is collected at the bottom edge of the disc separator, the recovered component can be mixed into the newly supplied fluid and thus carried back up along the disc separator. This may reduce the efficiency of the separation method. Thus, it would be desirable to further improve the efficiency of the plate separator separation process.

Therefore, there is a need for an assembly comprising an inclined disc separator and/or a lower section for such an assembly adapted to overcome at least one of the disadvantages discussed above.

The essence of the invention

Aspects of the above objective are achieved by the bottom section embodiments, by the assembly embodiments of the present invention, and by the use of the bottom section of the present invention, respectively.

Aspects of the present invention relate to a lower section for connection with an assembly for separating a solid component from a fluid, said assembly comprising an inclined disc separator with at least one sedimentation channel to allow separation of the solid component by settling, the disc separator comprises a lower part and an upper part and at least one sedimentation channel extending from the bottom to the top, where the bottom section is configured to connect with the bottom of the inclined disc separator.

The term bottom section in the present context should not be understood to mean that the bottom section must necessarily rest on the bottom of the assembly in use and/or that the assembly rests on the bottom section (so that it plays the role of the bottom). The bottom section may or may not be on the bottom. In other words, the bottom section itself can, for example, rest on another component located partly or completely below the bottom section. The bottom section may or may not constitute the bottom member on which the assembly rests partially or wholly, depending on the embodiment(s) under consideration.

The present invention encompasses separately formed bottom sections that can (directly or indirectly) be connected to an inclined disc separator. However, the present invention also encompasses assemblies with bottom sections that are part of a larger, integrally formed part (eg, the bottom section can be made integral with another component of the assembly).

The lower section may include at least one inlet for introducing a fluid containing a solid component to be separated into the disc separator and at least one collecting channel for collecting the settled solid component descending from at least one sedimentation channel. The solid component may be collected as such, or it may be collected in suspended form to form part of the fluid. The solid component may already be present in solid form in the supplied fluid, or it may precipitate from the fluid into

- 1 041838 disc separator. The collection channel may also be used to collect a fluid component (eg, a heavier component) of the fluid supplied to the assembly containing the disc separator.

Said at least one inlet channel and said at least one collecting channel are separated from each other with respect to fluid communication. As separated from fluid communication, it is understood that there is no direct fluid communication between the inlet channel and the collection channel in the lower section. For example, a wall in the lower section may separate the inlet channel and the collection channel. However, an indirect fluid communication connection (eg via a sedimentation channel in the assembly connected to the bottom section) can, of course, be present. The latter is not excluded in the absence of a separation regarding the communication of fluids, in accordance with the terminology used in this context.

The inlet channel and the collecting channel may be connected to at least one sedimentation channel of the assembly, to which the lower section may be connected to form fluid communication connections between said at least one inlet channel and said at least one sedimentation channel and between said at least at least one collecting channel and said at least one sedimentation channel, respectively.

Separation with respect to fluid communication between the inlet channel and the collecting channel (ie, in the absence of direct fluid communication) can improve the control of the behavior of fluid flows in the lower section. Specifically, the turbulences resulting from the mixing of the feed fluid and the descending separated solid component (e.g., precipitate) and/or the descending separated fluid (e.g., containing the solid component to be recovered) in the lower section or ultimately in the lower section can be reduced. or even eliminate. Also, it is possible to reduce or eliminate the amount of isolated component that can be mixed into the newly supplied fluid. Thus, the efficiency of the extraction method carried out by the assembly connected to the lower section can be improved by the lower section according to these embodiments.

In some embodiments, the lower section is configured to connect to a tray separator assembly comprising a plurality of sediment channels and separator trays separating adjacent sediment channels. The lower section may comprise a plurality of inlet channels and a plurality of collecting channels, where said at least one inlet channel and said at least one collecting channel are separated in terms of fluid communication from all other inlet channels and collecting channels, respectively.

The number of input channels may be the same or different from the number of collecting channels. Likewise, the corresponding number of inlet channels and collection channels may be the same or different from the number of sedimentation channels of the assembly to which the lower section is configured to connect. For some embodiments, the number of inlet channels is identical to the number of collecting channels and also identical to the number of sedimentation channels, so that the bottom section contains one inlet channel and one collection channel per sedimentation channel. This can, in particular, increase the efficiency of the extraction method of the assembly connected to the lower section.

The flow connection between said at least one inlet channel and the corresponding sedimentation channel and said at least one collecting channel and the corresponding sedimentation channel may be separate from the fluid communication connections between all other sedimentation channels and all other inlet channels and collecting channels, respectively. Thus, turbulent flows and/or other flow disturbances in the lower section associated with a pair of channels constituting said at least one inlet channel and said at least one collecting channel, and the corresponding sedimentation channel, and with other pairs of channels, can be reduced or even completely eliminated. This can further improve the efficiency of the assembly connected to the bottom section.

The bottom section, in some embodiments, may comprise one individual inlet channel and one individual collection channel for at least 50% of the sedimentation channels of the respective assembly to which the bottom section is configured to connect. This can improve performance when the degree of pairing is high, in the sense that the number of channels not associated with the corresponding paired channel is 50% or less. This may make it possible to reduce or suppress corresponding turbulent flows or other flow disturbances associated with adjacent channels that are not separated in terms of belonging to different pairs of channels.

Optionally, one individual inlet channel and one individual collection channel may be provided for at least 75% of the sedimentation channels of the respective assembly, or at least 95% of the sedimentation channels. This can further improve efficiency accordingly.

In some embodiments, the bottom section may comprise one individual collection channel and one individual inlet channel for each of the plurality of sedimentation channels, where a separate fluid connection may be formed for each respective pair of inlet and sedimentation channels and for each respective pair of sedimentation channels. collecting channel and sedimentation channel, respectively. This can result in a particularly high efficiency of the assembly comprising the disc separator integrated with the lower section. Specifically, disturbing flows associated with adjacent channel pairs can be minimized and the loss of isolated solids can be kept low or even eliminated.

In some embodiments, the lower section may be configured to connect with the assembly oriented in the operating position such that the ends of the inlet channels and the ends of the collection channels proximal to the disc separator extend in the direction of gravity. In other words, the connecting part of the lower section for connecting with the assembly can be oriented relative to the end part of the inlet channels and collecting channels, respectively, so that when the connecting part is oriented relative to the direction of gravity in the state of connection between the assembly and the lower section ready for use, the end parts extend in the direction of gravity. In some embodiments, there may be some angle between the direction of extension when the bottom section is oriented as described and the direction of gravity. The angle may be between 0 and 15°, optionally between 0 and 10°, or even between 0 and 5°. This can further improve efficiency.

An extension direction identical to or similar to the direction of gravity (ie vertical direction) of the end portions can induce similar or the same hydrostatic pressures in the various supply channels and/or collection channels, respectively. This means that the uniform use of the apparatus with the disc separator connected to the bottom section can be facilitated.

The lower sections according to some embodiments may comprise at least one flush fluid collection passage for supplying flush fluid (or other fluid) to the sedimentation passage or collection passage, said at least one flush fluid collection passage being separated regarding the communication of fluids from other supply channels for flushing fluid and from all input channels. Again, the separation regarding fluid communication refers to the absence of direct communication with the lower section, but does not exclude the possible presence of an indirect connection (eg, via a sedimentation channel). The separation of fluid communication from other flush fluid supply channels and inlet channels can reduce or even eliminate the occurrence of efficiency degrading flow disturbances such as turbulence associated with adjacent channels.

The one or more flush fluid feed channels allow the supply of another fluid, such as a flush fluid, which can be used to accelerate collection of the separated fluid or solid component (eg, precipitate). This can increase the efficiency of the extraction method. For example, when a solid component does not tend to be removed effectively, perhaps due to a tendency to stick to the sediment tray parts or other parts of the assembly, or to a collection channel, for example, the supply of a flushing fluid can effectively contribute to the collection of the solid. component and sweeping it down through one or more collecting channels in the bottom section. The flushing fluid may also enhance the separation of the solid component and the (remainder) of the feed fluid. This may be important, for example, since the fluid phase may be of high value and/or it may contain impurities that one wishes to get rid of. The use of a flushing fluid is optional in the sense that the removal of bound or stuck solids can also be carried out without the use of a flushing fluid.

At least one collection channel for flushing fluid and at least one collection channel corresponding to the same sedimentation channel can be connected to fluid communication, for example, using an opening in a part of the wall common to said supply channel for flushing fluid and said collecting channel. The fluid communication connection may be direct in the sense that the fluid communication connection may exist in the lower section. This can slow down or even prevent the inadvertent direction of the supplied flushing fluid along the sedimentation channel and its removal from the upper edge. It may also reduce the amount of flush fluid transported up along the disc separator and removed at the top edge.

A fluid communication connection between the flush fluid supply conduit and the collection conduit in the lower section can improve the efficiency of the process of washing off the separated fluid or solid component and collecting it through the collection conduit(s). It can also further improve flow efficiency by slowing down or preventing flow disturbances since the flushing fluid can be directed directly in the direction

- 3 041838 (directions) of the collecting channel (channels).

The bottom section, according to some embodiments, may comprise at least one intrachannel distribution portion for evenly distributing fluid flow over the portion of the first channel proximal to the respective sedimentation channel in at least one direction of extension along the cross section of said particular channel. The first channel may be adjacent to the sedimentation channel for connection with it, or there may be an additional component between them. The intra-channel distribution part can improve the efficiency of the use of a disc separator device, since it can, for example, increase the uniformity of the load applied to the associated sedimentation channel in question.

Said first channel is an inlet or collection channel or collection channel for flushing fluid. The intra-channel distribution part may, more generally, be provided for one or more inlet channels and/or one or more collecting channels and/or one or more supply channels for flushing fluid. For some embodiments, there is one intrachannel distribution portion for each inlet channel, one intrachannel distribution portion for each collection channel, and one intrachannel distribution portion for each flush fluid supply channel present. This can improve the efficiency of the lower section, especially when it can contribute to a particularly uniform flow distribution across all considered channels in the lower section, both for fluids supplied to the connected assembly, and for fluids/components removed (collected) from it.

The bottom section, in some embodiments, may include at least one interchannel distribution portion for evenly distributing fluid flow toward or away from the disc separator over a plurality of flush fluid inlet and/or supply channels and/or collection channels. . There may be one or more inter-channel distribution parts. One or more inter-channel distribution parts may be provided for some or all of the inlet channels, one or more inter-channel distribution parts may be provided for some or all of the collecting channels, and one or more inter-channel distribution parts may be provided for a portion of the flushing fluid supply channels. or for all of them. However, several inter-channel distribution parts may also be referred to simply as an inter-channel distribution part in this context.

In some embodiments, all inlet channels, all collection channels, and all flush fluid supply channels may be fluidly connected to the inter-channel distribution portion. This can improve the efficiency of the lower section, in particular because it can facilitate a particularly uniform distribution of flow across all channels present, both for fluids supplied to the connected assembly and for fluids removed from it. In some embodiments, the first inter-channel distribution portion may be connected to all inlet channels, the second inter-channel distribution portion may be connected to all collection channels, and the third inter-channel distribution portion may be connected to all flush fluid supply channels. The terms first, second and third are used simply as labels to distinguish between the three inter-channel distribution parts.

The intra-channel distribution part may connect the upper part of the first channel with the lower part of the specified first channel, where the specified upper part is located near the corresponding sedimentation channel. The latter means that the upper part is closer to where the lower section should be connected to the device containing the disc separator than the lower part.

The lower part of the first channel may be divided into two (or more) connecting channels with the same first cross sections, and these connecting channels are optionally at least once again divided into (two or more) corresponding connecting subchannels with corresponding identical second cross sections. By the same first cross sections and the same second cross sections, it is meant that all the cross sections of the channels after the first separation are the same, and the same is true for the channels after the second separation. The channels after separation may or may not have the same cross sections as the channels before separation. Thus, the first cross sections may be identical to or different from the corresponding second cross sections, and the like.

The end parts of all connecting subchannels, after the respective last divisions, are connected to the top part so that they are evenly distributed in the distribution direction. This can, in particular, contribute to the even distribution of the fluid, which is affected by the in-channel distribution part. The flow rate may or may not be kept substantially constant before and after the split (the point where the channel splits into two or more channels). In some embodiments, all partitions can double the number of channels. For other embodiments, splitting into three or more channels at the split point may be performed. Also, different numbers of splits may be associated with different split points.

Successive divisions can be made at the same height when the channels are oriented with an extension in the vertical direction. For example, the first split could be into two channels, and after N splits (where each split occurs at a specific height), there could be 2N channels. The height differences for successive sets of partitions may be identical or different. The cross sections of all channels may be identical. The cross sections may be the same or different for each pair of channels corresponding to different stages in the branched channel system, relative to the number of previous sets of divisions.

Each one or more inter-channel distribution parts may include an upper part for connection with one or more inlet channels or one or more flushing fluid channels or one or more collecting channels, and with a lower part. The lower part can be divided into two connecting channels of the same first cross section.

Said connecting channels can be further divided at least once more into respective connecting subchannels with corresponding other identical cross sections, where the first cross sections are identical or different from the corresponding other cross sections, and where the end parts of all connecting subchannels after the respective last divisions are connected to upper part for even distribution in the direction of distribution. The direction of distribution may be substantially or completely perpendicular to the direction of extension of at least a portion of the inlet channels and/or collecting channels and/or supply channels for the flushing fluid.

This can especially contribute to uniform distribution of the fluid under the action of the inter-channel distribution part. The flow rate may or may not be maintained substantially constant before and after the fork (the point where the channel splits into two or more connecting channels). In some embodiments, all partitions can double the number of channels. For other embodiments, the division point may be divided into three or more channels. The number of splits at a split point may be different for different split points or be the same for all of them.

Successive divisions can be made at the same height when the connecting channels are oriented extending in the vertical direction. For example, a first division into two connecting channels may be performed, and after N divisions (where each set is at a particular height), 2N channels may be obtained. The difference in height between successive sets of partitions may be identical or different. The cross sections of all connecting channels can be identical. The cross sections may be the same or different for each pair of connecting channels corresponding to different degrees in the branched channel system, relative to the number of previous sets of divisions.

According to some embodiments, the intra-channel distribution portion and the inter-channel distribution portion may be connected. The series combination of two types of distribution parts can especially contribute to the uniformity of the distribution of the flow and thus be particularly beneficial to the efficiency of the lower section (and thus, to the device connected to the lower section). The in-channel distribution part can be configured to be located closer to the disc separator than the inter-channel distribution part.

There may be one inter-channel distribution part connected to several intra-channel distribution parts, one of the latter is connected to each inlet channel, and/or there may be one inter-channel distribution part connected to several intra-channel distribution parts, one of the latter is connected to each collecting channel. There may be one inter-channel distribution part connected to several intra-channel distribution parts, one of the latter is connected to each supply channel for flushing fluid. When there is one duct for each inlet, one for each collection duct, and one for each flush fluid supply duct, respectively, and when the respective sets of inlet-related ducts, associated collecting ducts of ducts, and associated ducts for flushing fluid, the intra-channel distribution parts are each preceded (in terms of flow direction in the direction of the connected device) by one or more inter-channel flow distribution parts, this can particularly contribute to the efficiency and productivity of the lower section. In particular, this can particularly contribute to a uniform distribution of the flow in the direction of the device and thus also of the flows in the various sedimentation channels of the inclined disc separator.

- 5 041838

All inlet channels and collection channels can be provided in pairs in the sense that there can always be a collection channel for each inlet channel (and vice versa), so that one pair is connected to one or more respective sedimentation channels of the disc separator, respectively. All inlet channels, collecting channels and supply channels for flushing fluid can be provided in triplets.

All inlet channels can be fed by one corresponding inter-channel distribution part, each, all collecting channels can be connected with one corresponding inter-channel distribution part. All supply channels for flushing fluid can be supplied by means of a corresponding inter-channel distribution part.

All input channels can be connected to one in-channel distribution part, all collecting channels can be connected to one in-channel distribution part. All supply channels for flushing fluid can be associated with one intrachannel distribution part. This relationship is to be understood to mean that one respective in-channel distribution part is provided in the fluid flow path leading in the direction of the respective inlet channel.

For some embodiments of the bottom section, which comprise one or more intra-channel distribution parts and one or more inter-channel distribution parts, the direction of distribution of the intra-channel distribution parts may be the direction of the longitudinal extent of the cross section of the connecting end part of the first channel, which should be located near the disc separator. The first channel may also extend entirely in this contemplated direction. The distribution direction of the inter-channel distribution parts may be perpendicular to the distribution direction of the intra-channel distribution parts. This can give a particularly efficient flow distribution structure. In particular, this may allow a compact construction of the lower section.

One or more intra-channel distribution parts may be fractal flow distributors. Likewise, one or more of the interchannel distribution portions may be fractal flow distributors. Fractal flow distributors split sequentially at multiple split levels and can be scaled up or down by increasing or decreasing the number of split levels.

Some embodiments of the bottom section are configured to connect to an assembly that has bottom surfaces of adjacent sediment channels extending parallel to each other, said bottom surfaces including at least a portion that is not inclined in any direction other than the direction of the inclined sediment channels. Also, the lower surfaces generally can only tilt in the direction of the slope of the sedimentation channels.

The angle of inclination of the sedimentation channels with respect to the direction of action of gravity may lie in the range from 5 to 85° (or from 15 to 75°). This may contribute (or even additionally contribute) to the efficiency of the isolation method. In some embodiments, this angle is in the range of 50 to 70°, optionally in the range of 55 to 65°, and optionally in the range of 58 to 62°. Angles within these ever narrower ranges can increasingly contribute to the efficiency of the extraction method.

Another aspect of the present invention relates to an assembly for separating a solid component from a fluid. The assembly may comprise an inclined disc separator with a bottom part, a top part and at least one sedimentation channel to allow separation of the solid component by settling. The sediment channel may extend from the bottom to the top.

The disc separator may be an inclined disc separator. It can be oriented in use such that at least one sedimentation channel extends from the bottom to the top in a direction that is inclined relative to the direction of gravity. At least one sedimentation channel of the disc separator may be connected to a fluid outlet for removing residual fluid in the upper part, connected to the lower section according to any embodiment in the lower part. Residual fluid from which some or all of the fluid (or only the solid component) is released can be removed from the top through the fluid outlet.

The assembly may comprise a plurality of sedimentation channels to enable separation of the solid component by settling, said sedimentation channels extending from the bottom to the top, and the tray separator may further comprise separating trays separating adjacent channels. The disc separator can be configured for orientation in use such that the separator discs do not overlap in the direction of gravity. The dividing trays can be oriented in the direction of gravity in the sense that they are vertically extending dividing walls between adjacent sediment channels when the assembly is positioned as it is oriented in use.

A plurality of sediment channels may be connected to at least one fluid outlet to remove residual fluid at the top. A plurality of sedimentation channels are connected to the lower section according to any of the previous claims in the lower part. Each sedimentation channel from the specified set may be connected to one or more inlet channels and one or more collecting channels, and it may optionally also be connected to one or more channels for supplying flushing fluid. In some embodiments, a one-to-one correspondence between pairs of inlet and collection channels and one sedimentation channel can be realized, and in some embodiments, there may be a trinity of one inlet, one collection channel, and one flush fluid supply channel, for one sedimentation channel.

The width of the sedimentation channels for the assembly embodiments of the present invention may typically be in the range of 5 to 200 cm, optionally in the range of 40 to 150 cm. range from 10 to 200 cm. The distance between two besieging plates can, as a rule, lie in the range from 0.3 to 10 cm.

The number of fluid outlets per centimeter of tray width (after the last separation of the flow distributor closest to the disc separator) may be in the range of 0.2 to 2 outlets/cm, optionally in the range of 0.5 to 1 outlet/cm. cm.

The longitudinal section of the fluid channels of the flow distributors in the lower section of the present invention may be (at least partially) square, or rectangular, or circular.

The present invention also relates to the use of the lower section according to any of the embodiments described herein, with the assembly according to any of the embodiments described herein (as long as they are not incompatible), so that the relative difference between the hydrostatic pressures in the various sedimentation channels does not exceed the threshold of 10%. Optionally, this difference does not exceed the 5% threshold, and optionally, it does not exceed the 3% threshold. These thresholds can (to an increasing extent at a lower threshold) provide very similar (or even substantially or completely identical) hydrostatic pressures in the various sediment channels. This contributes to a uniform and balanced use of the assembly, and thus to an increase in efficiency, since it can ensure that the capacity of the assembly is used optimally.

According to some embodiments of the assembly application, said application includes supplying a fluid containing a solid component to be separated into a disc separator through at least one inlet and a wash buffer fluid through at least one wash fluid collection channel, where the density of the wash buffer the fluid medium is equal to or greater than the density of the fluid containing the solid component to be isolated. This can increase the efficiency of the desired isolation method. It may also reduce or even eliminate wastage of flushing fluid, as the tendency of flushing fluid to inadvertently be transported up the sedimentation channel (and possibly even removed through the top end exit) can be reduced.

The present invention also relates to a process for separating solid components from a fluid. This method includes the step of introducing a fluid containing solid components into at least one inlet channel in the lower section of the present invention; the stage of allowing the precipitation of solid components; a step of removing (ie collecting) the residual fluid (ie a fluid depleted in solids); and the step of collecting the deposited components through at least one collecting channel of said lower section. These steps may be carried out sequentially (ie one after the other), but preferably these steps are carried out as part of a continuous process, where several steps are carried out simultaneously (ie at the same time). For example, fluid containing solids may be continuously introduced into the lower section and residual fluid may be continuously removed so that solids contained in the input fluid may be deposited before residual fluid is removed. The step of collecting the precipitated components may be carried out periodically, for example at regular intervals.

In some embodiments, the solid components to be isolated are precipitates. In some embodiments, the solid components to be isolated are cells. These cells may be freely suspended, or they may adhere to, for example, microcarriers.

When the solid components are cells, the cells may be capable of producing a biologically active substance, such as a coagulation factor. In such a case, the cells may be cultured in a fluid medium (eg, cell culture broth fluid) until

- 7 041838 introduction of the specified fluid medium (containing the cells contained in it) in the lower section according to the present invention. During such pre-culture, the cells can produce a biologically active substance. Therefore, in this embodiment of the present invention, the fluid that is introduced into the lower section of the present invention may contain said biologically active substance.

In another embodiment of the process for separating solids from a fluid of the present invention, the lower section is contained in (ie, a part of) the assembly of the present invention. In these embodiments, the step of allowing solid components (e.g., cells) to settle out by settling is the step of allowing solid components to settle in at least one sedimentation channel of the inclined tray separator that is part of the assembly of the present invention.

In carrying out the above method of the present invention, we have found that solid components (eg, cells) that are contained in a fluid (eg, cell culture broth fluid) can be efficiently separated from said fluid with minimal loss of any components. that are dissolved in the fluid, such as biologically active substances. Thus, in accordance with the method of the present invention, any components that are dissolved in the fluid can be effectively collected together with the phase of the fluid depleted in solids. Accordingly, the present invention provides an improved process for separating solids from fluids.

Additional advantages and features of the present invention, which can be implemented alone or in combination with one or more of the features described above, as long as these features do not conflict with each other, will become apparent from the following description of specific embodiments.

Brief description of the drawings

For a better understanding of the present invention and to show how it can be carried out, the accompanying drawings will now be referred to by way of example only.

The description is given with reference to the drawings, in which:

fig. 1 is a sectional view of a schematic representation of an embodiment of the lower section of the present invention;

fig. 2 is a sectional view of a schematic representation of an embodiment of the lower section of the present invention;

fig. 3 is a schematic 3D perspective view of an embodiment of the lower section and more generally of the plate separator assembly of the present invention;

fig. 4 is a sectional view of the inlet channel, collection channel and supply channel for flushing fluid of an embodiment of the lower section of the present invention;

fig. 5 is a schematic three-dimensional perspective view of an embodiment of the lower section of the present invention;

fig. 6 is a schematic three-dimensional perspective view of an embodiment of the lower section of the present invention;

fig. 7 is a schematic representation of a flow distributor that forms part of an embodiment of the lower section of the present invention;

fig. 8A is a schematic representation of a flow distributor which is part of an embodiment of the lower section of the present invention;

fig. 8B is a schematic representation of a flow distributor which is part of an embodiment of the lower section of the present invention;

fig. 8C is a schematic representation of a flow distributor which is part of an embodiment of the lower section of the present invention;

fig. 9A is a schematic representation of separation in a flow distributor which is part of an embodiment of the lower section of the present invention;

fig. 9B is a schematic representation of separation in a flow distributor which is part of an embodiment of the lower section of the present invention;

fig. 9C is a schematic representation of separation in a flow distributor which is part of an embodiment of the lower section of the present invention;

fig. 9D is a schematic representation of separation in a flow distributor which is part of an embodiment of the lower section of the present invention;

fig. 9E is a schematic representation of separation in a flow distributor which is part of an embodiment of the lower section of the present invention;

fig. 9F is a schematic representation of separation in a flow distributor which is part of an embodiment of the lower section of the present invention;

fig. 10 is a schematic representation of an embodiment of a lower section and, more generally, a plate separator assembly of the present invention;

- 8 041838 fig. 11 is a schematic representation of an embodiment of the lower section of the present invention;

fig. 12 is a schematic representation of an embodiment of the lower section of the present invention; and fig. 13 is a schematic representation of an embodiment of a lower section and, more generally, a plate separator assembly of the present invention.

fig. 14 is a schematic drawing of an assembly of a bioreactor [1] and an inclined tray separator assembly with a lower section [3] as used in Example 1. The assembly includes a plurality of pumps [2] by which the cell culture broth is transferred to the assembly, the wash solution [ 5] is fed into the lower section and the solid components (cells) [6] are collected from the lower section. The clarified fluid is collected at the top outlet of the assembly [4]. The dashed lines show the double jacket and cryostat that constitute an additional fluid circuit [7] that is not connected to fluid communication with cell culture broth, solids-lean fluid, or collected solids (cells);

fig. 15 is the yield and recovery of product (FVIII) in fluid streams collected from the upper and lower outlets of an inclined plate separator assembled with a lower section under temperature control using a double jacket as described in example 1. Recovery = sum of yields in both streams, leaving the assembly of the inclined disc separator and the lower section. The top and bottom panels show the results of two separate experiments;

fig. 16 is the output and recovery of glucose in the fluid streams collected from the upper and lower outlets of the inclined plate separator assembly with the lower section under temperature control using a double jacket, as described in example 1. Recovery = the sum of the outputs in both streams leaving the inclined plate assembly disc separator and lower section. The top and bottom panels show the results of two separate experiments;

fig. 17 is a schematic drawing of an assembly of a bioreactor [1] and an inclined tray separator assembly with a lower section [3] as used in Example 2. The assembly includes a plurality of pumps [2] by which the cell culture broth is transferred to the assembly, the wash solution [ 5] is fed into the bottom section and the solids [6] are collected from the bottom section. The clarified fluid is collected at the top outlet of the assembly [4]. The installation as a whole, with the exception of the bioreactor, is in a cold room at 2-8°C;

fig. 18 shows product exit and recovery (top) and glucose exit and recovery (bottom) in fluid streams collected from the top and bottom outlets of the inclined tray separator and bottom section as described in Example 2 (corresponding to FIG. 17). Retrieval=sum of outputs in both streams leaving the inclined plate and lower section assembly;

fig. 19 shows product exit and recovery (top) and glucose exit and recovery (bottom) in fluid streams collected from the top and bottom outlets of the inclined tray separator and bottom section as described in Example 3 (corresponding to FIG. 17). Retrieval=sum of outputs in both streams leaving the inclined plate and lower section assembly;

fig. 20 is a schematic drawing of the lower section assembled with an inclined tray separator [5] connected to a supply vessel [1], which may be a bioreactor or a vessel containing a process fluid such as 1M sodium hydroxide solution or buffer. The assembly contains three-way valves for switching between different fluid paths (marked *) and three-way sampling valves (marked +). In addition, it contains a container for supplying a wash solution [2], a receiving container for, for example, spent fluid [3], a receiving container for collected solids [4] and a receiving container for fluid depleted in solids [6]. All receptacles contain an additional connection that encircles the sterile filter, so pressure can be exchanged without compromising aseptic conditions in the assembly;

fig. 21 is the yield of tryptophan in a fraction containing collected solids (ie, precipitates) suspended in a wash fluid obtained at various collection flow rates. Tryptophan is initially contained in the precipitate suspension;

fig. 22 is the yield of proprietary blue V in a fraction containing collected solids suspended in a wash fluid obtained at various collection flow rates. The proprietary blue V is initially contained in the flush fluid.

Fig. 1 shows an embodiment of the lower section 1 according to the present invention. The lower section 1 is connected to an embodiment of the assembly 2 for separating the solid component from the fluid of the present invention.

Assembly 2 includes an inclined disc separator 20. This is referred to as inclined because it extends at an angle α relative to the direction of gravity (the vertical direction in FIG. 1).

This embodiment of the tray separator 20 includes one sedimentation channel 21 to allow separation of the fluid by settling (eg, separating the solid component). The inclined tray separator 20 has an angle of inclination a that is adapted to the densities of the fluid introduced into the tray separator 20 and to the density (specific gravity, etc.) of the component to be separated out (in this case, the solid component at the bottom of the sedimentation channel 20).

The inclination angle α of the disc separator 20 with respect to the direction of gravity of the various embodiments of the assemblies and lower sections of the present invention may lie between 5° and 85°.

The disc separator 20 includes a bottom 22 and a top 23. A sedimentation channel 21 extends from the bottom 22 to the top 23. The bottom section 1 is connected to the bottom 22. The top 23 is connected to the fluid outlet 24. Residual fluid from which (at least partially) the fluid (in this case the precipitated solid component) is expelled is removed from the top 23 via the fluid outlet 24 . The fluid exiting exit 24 (and its direction of movement) is indicated by arrow D in FIG. 1 (D stands for delete).

The fluid (containing the release component) is introduced into the assembly 2 through the bottom section 1 at the bottom edge. The selected component is also collected on the bottom edge. This is indicated by the double arrow P in FIG. 1.

The lower section 1 in Fig. 1 can be separated from the assembly 2. However, the present invention also covers the lower sections 1, which are integrally formed with the assembly 2 (the assembly 2 and the lower section 1 are manufactured as a single unit). The connection between the assembly 2 and the lower section 1 according to some embodiments may be detachable, and it may be one-piece for other embodiments.

Fig. 2 shows another embodiment of the lower section 1 according to the present invention. The bottom section 1 is connected to an embodiment of the assembly 2 for separating the solid component from the fluid of the present invention.

The assembly 2 includes an inclined tray separator 20. This embodiment of the tray separator 20 includes a plurality of sedimentation channels 22 to enable separation of the component by precipitation.

The disc separator 20 includes a bottom 22 and a top 23. Sediment channels 21 extend from the bottom 22 to the top 23. The bottom section 1 is connected to the bottom 22. The top 23 is connected to the fluid outlet 24. Residual fluid from which the (at least partially) fluid (in this case the precipitated solid component) has been separated is removed from the top 23 through the fluid outlet 24 . The fluid exiting outlet 24 (and its direction of movement) is indicated by arrow D in FIG. 2 (D stands for delete).

Adjacent sedimentation channels 21 are separated by dividing walls 25.

The fluid (containing the release component) is introduced into the assembly 2 through the bottom section 1 at the bottom edge. Arrow F denotes fluid being injected (F denotes administration). The selected component is also collected at the bottom edge. This is indicated by arrow C in FIG. 2 (C stands for collection).

The lower section 1 in Fig. 2 can be separated from the assembly 2. However, the present invention also covers the lower sections 1, which are formed integrally with the assembly 2 (assembly 2 and the lower section 1 are manufactured as a single unit). The connection between the assembly 2 and the lower section 1 according to some embodiments may be detachable, and it may be one-piece for other embodiments.

Fig. 3 is a schematic three-dimensional perspective view of an embodiment of the lower section 1 according to the present invention. The bottom section 1 is connected to an embodiment of the assembly 2 for separating the solid component from the fluid of the present invention.

Assembly 2 includes a disc separator 20. FIG. 3 shows only two sedimentation channels 21 in order to keep the schematic diagram simple, however, the number of sedimentation channels 21 may be greater (eg, much more).

The width w of the sedimentation channels 21 may, as a rule, for embodiments of the assembly 2 according to the present invention lie in the range from 5 to 200 cm, optionally in the range from 40 to 150 cm. as a rule, lie in the range from 10 to 200 cm. The distance d between two besieging plates can, as a rule, lie in the range from 0.3 to 10 cm.

The settling trays (bottom walls) of the sedimentation channels 21 of the present embodiment comprise stainless steel, which is optionally electropolished (to a resolution equal to or less than 0.8 µm). In some embodiments, the settling trays are made of stainless steel. Alternatively, they may contain plastics, such as acrylic glass (eg, polymethyl methacrylate (PMMA) and/or glycol-modified polyethylene terephthalate (PETG)), or consist of plastics.

The bottom section 1 according to the present embodiment is made of stainless

- 10 041838 steel and/or plastics and assembled from layers. Alternatively, it may be manufactured using additive manufacturing (eg, 3D printing). However, all of these features may be present in some embodiments and absent in others.

The lower section 1 in Fig. 3 comprises a plurality of inlets 10 for introducing a fluid containing a solid to be separated to a tray separator 20. The lower section 1 also comprises a plurality of collection channels for collecting the settled solid component descending from the sedimentation channels 21. Other embodiments comprise only one collection channel 11 and/or only one input channel 10.

The inlet channels 10 and collection channels 11 are provided in pairs in the sense that each one of these two channels is connected to a respective sedimentation channel 21 of the disc separator 20.

Each of the inlet channels 10 and collection channels 11 is connected to one respective sedimentation channel 21 to form fluid communication connections. The inlet channels 10 and the collection channels 11 are fluid-separated in the sense that there is no direct connection with fluid communication between them in the lower section 1. They are separated by a wall. However, there is an indirect connection with the communication of fluids through the sedimentation channel 21 (in this way, the separated solid component can return downwards in Fig. 3 from the tray separator 20).

The introduction angle φ between the inlet channels 10 and sedimentation channels 21 in this case is equal to 90°. In other words, the end portions of the inlet channels 10 closest to the disc separator 20 extend in the direction of gravity. In addition, also the end parts of the collecting channels 11 closest to the disc separator 20 extend in the direction of gravity.

In other embodiments, the angle φ may be between 5 and 90°, optionally between 15 and 75°, or between 30 and 60°. The angle φ may also be identical or similar to the inclination angle α for the inclination of the disc separator 20. When the angle φ is less than 90°, the main part of the feed channel may, for example, extend in the direction of gravity, and the part closest to the edge (or end part) for connection to the sedimentation channel may have a part where the inclination of the supply channel changes. For example, a bend (eg, with a sharp boundary) in the supply channel may be provided, or the collection channel may comprise a curved portion such that the angle of extension relative to the horizontal plane changes from 90° to an angle φ of less than 90°.

Separation with respect to fluid communication (i.e., no direct fluid communication) between inlet channels 10 and collection channels 11 helps to improve the control of the behavior of fluid flows in the lower section 1. Specifically, turbulences arising from mixing of the supplied fluid and the descending separated solid component (for example , precipitate) and/or the descending separated fluid (eg containing a solid component to be separated) in the lower section 1 or via the lower section 1 can be reduced or even eliminated. Thus, the efficiency of the extraction method can be improved by using the lower section 1 according to the present embodiments.

The flow connection between the inlet channels 10 and the respective sedimentation channels 21 and between the collecting channels 11 and the respective sedimentation channels 21, respectively, is separated from the fluid communication connections between all other sedimentation channels 21 and all other inlet channels 10 and the collecting channels 11, respectively. In this way, turbulent flows and/or other flow disturbances in the lower section 1 associated with a channel pair comprising a respective inlet channel 10 and a collecting channel 11 and a respective sedimentation channel 21 and other channel pairs can be reduced or even completely eliminated. This can further improve the efficiency of the assembly 2 connected to the lower section 1.

The lower section 1 in Fig. 3 contains one individual collection channel 12 and one individual inlet channel 11 for each of the plurality of sedimentation channels 21, where a separate fluid communication connection is formed for each respective pair from the inlet channel 10 and the sedimentation channel 21 and for each respective pair from the collection channel 11 and sedimentation channel 21, respectively. This can give a particularly high efficiency of the assembly 2 comprising the disc separator 20 integrated with the bottom section 1. Specifically, flow disturbances associated with adjacent pairs of channels 10, 11, 21 can be minimized.

For the sake of simplicity, the schematic representation in FIG. 3 makes no distinction between the collection channel 11 and the respective supply channels 12 for flushing fluid. The flush fluid supply conduit 12 is located between the inlet conduits 10 and the feed conduits 12. The flush fluid is introduced through the flush fluid feed conduits 12 and is used to increase the efficiency of the excreted component removal through the collecting conduits 11. FIG. 4 shows in more detail how the triplets are configured from inlet 10, collection 11, and flush fluid supply 12.

The flush fluid supply channels 12 can more generally be used to supply flush fluid to one or more sedimentation channels 21, or to one or more collection channels 12, directly. The flush fluid supply channels 12 are fluidly separated from the other flush fluid supply channels 12 and from all inlet channels 10. This is shown, for example, in FIG. 4.

Separation with respect to fluid communication from other supply channels 12 for flushing fluid and from inlet channels 10 can reduce or even eliminate the occurrence of flow disturbances that reduce efficiency, such as, for example, turbulence associated with adjacent channels 12. Separation with respect to fluid communication refers to the lower section 1 itself, but does not mean that there is no indirect fluid communication, for example, through an attached disc separator 20.

The washing fluid may contribute to the efficiency of the isolation process. For example, when the solid component does not tend to be removed effectively, perhaps because there is a tendency to permanently or temporarily adhere to parts of the sedimentation tray or collection channel 11, for example, the flushing fluid supply may provide a sufficient contribution to collect the solid component and its washing in one or more collecting channels 11 of the lower section 1.

As can be seen in FIG. 4, respective flushing fluid supply channels 12 and collection channels 11 (together corresponding to the same sedimentation channel 21) are connected to fluid communication via an opening 14 in a wall portion 15 common to said flushing fluid supply channel 12 and said collection channel 11. The fluid communication connection may be direct in the sense that a fluid communication connection may exist in the lower section 1. This may slow or even prevent inadvertent direction of the supplied flushing fluid along the sedimentation channel 21 and its removal at the upper edge. The fluid communication connection in the lower section 1 can increase the efficiency of the process of washing the separated fluid or solid component and collecting it with the collection channels 11. It can also further increase the efficiency of the flow by slowing down or preventing the occurrence of flow disturbances, since the washing fluid can directly be directed towards the collecting channels 11.

Holes 14 are also shown in FIG. 3. The angle ω of the flushing fluid outlets (holes 14) in this case is 90° with respect to the direction of gravity (vertical direction in FIG. 3). Alternatively, it may lie between 15° and 90° relative to the horizontal direction, for example it may extend in the same (or similar) direction as the main direction of extension of the sedimentation channels 21 of the tray separator 20.

Fig. 5 and 6 are schematic three-dimensional views of embodiments of the lower section 1 of the present invention.

The lower section 1 in Fig. 5 includes an intra-channel distribution portion 30 for evenly distributing fluid flow through inlet channels 10, collecting channels 11 and supply channels 12 for flushing fluid, respectively. The intra-channel distribution part 30 is a fractal flow distributor. The intra-channel distribution part 30 can improve the efficiency of the assembly 2 connected to the lower section 1, since this can, for example, increase the uniformity of the load applied to the respective sedimentation channels 21.

The intra-channel distribution part 30 distributes evenly over all inlet channels 10, collecting channels 11 and supply channels 12 for flushing fluid. In the case of collecting channels 11, uniform distribution should be understood as some form of uniform collection over the entire diameter of the collecting channel 11 as a whole.

For each inlet channel 10, for example, the intra-channel distribution part 30 contains a channel 300, which is divided into two channels 301, which are then again divided into two channels 302 in the direction of approach to the part for connecting the assembly 2 to the disc separator 20. This can be scaled according to with the desired application and may be referred to as a fractal flow distributor design.

The embodiment in FIG. 5 comprises conical distribution portions that evenly distribute the fluid exiting the channels 302 to achieve the entire cross-section in the width direction of the respective inlet channel 10 on the connection portion for connection to the disc separator 20.

For each collection channel 11, for example, the intra-channel distribution part 30 includes a channel 300, which splits into two channels 301, which then again split into two channels 302 in the direction of approach to the part for connecting the assembly 2 to the disc separator 20. This can be scaled according to with the desired application and can be described as related to the fractal design of the flow distributor.

- 12 041838

Similar fractal channel systems are also provided for each of the collection channels 11 and each of the flush fluid supply channels 12. To avoid repetition, channels 300, 301, and 302 are explained for input channels 10.

The lower section 1 in Fig. 5 also includes an inter-channel distribution portion 40 for evenly distributing fluid flow toward or away from the disc separator over a plurality of inlet passages 11 and flush fluid supply passages 12 and collection passages 11, respectively. This can further increase the efficiency of the lower section 1, since it can contribute to a particularly even distribution of flow across all of the present channels, both for fluids supplied to the connected assembly and for fluids removed from it.

In particular, the inter-channel distribution part 40 is a fractal flow distributor and contains a distribution part for all inlet channels 10, for all collecting channels 11 and for all supply channels 12 for flushing fluid.

For example, channel 400 collects fluid from (all) collection channels 11. In the direction towards the disc separator 20 connected to the lower section 1, channel 400 splits into two channels 401, which again split into two respective channels 402 each. This illustrates the fractal configuration of the flow distributor. A similar structure exists for the inter-channel distribution part serving all inlet channels 10, and similarly for the inter-channel distribution part serving all supply channels 12 for flushing fluid.

The inter-channel distribution part 40 and the intra-channel distribution part 30 are connected in series, while the intra-channel distribution part 30 must be located closer to the attached disc separator 20 than the inter-channel distribution part 40.

The example explains how two flow distributors connected in series work. For each collection channel 11, for example, the intrachannel distribution part first collects the fluid uniformly (uniformly across the cross section of the collection channel 11. This is done by sequentially combining the channels leading from the connecting part between the assembly 2 and the lower section 1 towards the connecting part between the two flow distributors 30, 40. Then, uniform collection, made uniform across the various intra-channel distribution parts associated with the various collecting channels 11, is carried out across all collecting channels 11 by means of the inter-channel distribution part. for flushing fluid.

Fig. 6 shows another embodiment of the lower section 1 comprising an intra-channel distribution portion 30 and an inter-channel distribution portion 40. This embodiment is similar to that of FIG. 5. Therefore, we will refer to the explanation offered with respect to FIG. 5 and only the differences will be discussed. Interchannel distribution part 40 in FIG. 6 specifically includes tapered distribution portions 410 on the portion of inter-channel distribution portion 40 connected to adjacent intra-channel distribution portion 30. Some embodiments include these while others do not. The cones are one of several aspects that can contribute to the equalizing effect of the flow distributor.

More generally, fractal flow distributors, which are examples of inter-channel distribution parts and/or intra-channel distribution parts of the lower section 1 according to the present invention, may contain channels that are divided into two (or more) connecting channels with the same first cross sections, and said connecting channels are preferably at least once further divided into (two or more) respective connecting sub-channels with corresponding other equal cross sections. There may be one split, two splits, or multiple splits.

Fig. 7 illustrates an example of a stream distributor 5 with three levels of splitting, where the splits always double the number of channels. Specifically, channel 50 is divided into two channels 51, which are again divided into two channels 52, each, where each of the channels 52 is again divided into two corresponding channels 53. This can be scaled as desired to scale the assembly to extract the component of interest from the fluid. environment.

A fractal fluid distributor 5 such as illustrated in FIG. 7 can be used for each individual inlet 10 and/or each individual collection passage 11 and/or each individual flush fluid supply passage 12 of the lower section 1 of the present invention. In this way, the fluid distributor 5 can serve as the in-channel distribution part 30 (or part thereof).

The fractal fluid distributor 5 in FIG. 7 may additionally or alternatively be used for some (or all) of the inlet channels 10 and/or for some (or all) of the collecting channels 11, and/or for some (or all) of the supply channels 12 for flushing. 13 041838 In this way, the fluid distributor 5 can serve as (or part of) the inter-channel distribution part 40.

The flow distributor 5 in FIG. 7 is arranged in such a way that the cross section of each channel after splitting is identical to the cross section of the channel before splitting. In other words, the cross section of channel 50 is equal to the cross section of each of channels 51, 52, and 53. Such an equal cross-section separation pattern is also illustrated in FIG. 8A.

However, the present invention covers other embodiments. Fig. 8B, for example, describes a flow distributor splitting scheme where the channel cross section is reduced after each split. In other words, in the case of FIG. 8B, the cross section of channels 52 is smaller than the cross section of channels 51, and the cross section of channels 51 is smaller than the cross section of channel 50. In contrast, in the case of FIG. 8C, the cross section is sometimes the same before and after separation, and sometimes it is different before and after separation. Specifically, the cross sections of the channels 51 and 52 are of the same size, while the cross section of the channel 50 is larger.

Fig. 9A-9F illustrate various possible separation geometries that can be used in the flow distributors, which are the inter-channel and/or intra-channel distribution part (or part thereof) of the lower section 1 according to the present invention.

The division may differ, for example, by two angles β and γ. Fig. 9A shows a separation configuration where β=γ=90°. In the case of FIG. 9B, both β and γ are less than 90°. In the case of FIG. 9C, both β and γ are greater than 90°. Fig. 9D shows the case in which the angles β and γ are replaced by the geometry associated with one angle δ. The separation may also be formed with a curve instead of using any sharp corners, as illustrated in FIG. 9E. In the case of FIG. 9F, the two angles β and γ are 90°, but the edges are flattened so that the shape at the corners is curved. All these separations can be used as binary separations (separations into two channels) in the flow distributors of the lower sections 1 according to the present invention. However, non-binary splits (eg splits into three, four or more channels) may also be used.

Fig. 10 schematically depicts two fractal flow distributors connected in series as an intra-channel distribution part 30 and an inter-channel distribution part 40 of a lower section 1 connected as an assembly 2 to an inclined disc separator 20. The intra-channel distribution part 30 and the inter-channel distribution part 40 are rotated by 90° relative to each other, so that the width directions are perpendicular to each other. As a consequence, the staging of the inter-channel distribution portion 40 can be seen in FIG. 10, while the components of the intraduct distribution portion 30 are shown as lines in FIG. 10.

The connection between two flow distributors can, as in the case of FIG. 10 be in the form of conical projections so that one joint joint zone is provided. Alternatively, the connection zone may be present but without any conical portions, as illustrated in FIG. 11. Another example is shown in FIG. 12 where there is no fluid communication connection between the various parts of the inter-channel distribution part 40 that are connected to the intra-channel distribution part 30.

Fig. 13 shows another example of a serial connection of two fractal flow distributors of both the intra-channel distribution part 30 and the inter-channel distribution part 40, where there is an angular distance of 90° between them (as described with respect to the assembly in FIG. 10). In the case of FIG. 13, another 90° angular distance exists in the intra-channel distribution portion 30, before the last separation level. In other words, bi-channeling occurs in the direction perpendicular to the previous separations in the part of the intra-channel distribution part 30 closest to the plate separator 20 of the connected assembly 2. The last bi-channeling 60 in the perpendicular direction can be especially useful, for example, when from a fluid very large solid components must be released, since the width of the collection zones can then be quite large. Dividing the width in half can make suction of solids from the collection area more efficient.

Some embodiments of the lower sections 1 and/or assemblies 2 of the present invention can be used such that the relative difference in hydrostatic pressures in the various sedimentation channels does not exceed a threshold of 10%. Optionally, this difference does not exceed a 5% threshold, and optionally, it does not exceed a 3% threshold. These thresholds can (increasingly, as the threshold is lowered) provide very similar (or even substantially or completely identical) hydrostatic pressures in the various sediment channels. This contributes to uniform and balanced use of the assembly and thus to an increase in efficiency, since it can ensure optimal utilization of the capacity of the assembly.

The maximum linear velocity in the channel of the flow distributor (intra-channel and/or inter-channel distribution part(s)) can be 1 ml/min/cm of tray width for the volume flow rate during the removal of the solid component (and flushing flow), up to 50 ml/min/ cm plate width. Fluid Reynolds number at the top outlets of the top flow distributor

- 14 041838 (closest to the disc separator) may be less than 2000. The length of the fluid passage of the flow distributor may be in the range of 0.5 to 5 cm.

The present invention also relates to a process for separating solid components from a fluid. Said method includes the step of introducing a fluid containing solids into at least one inlet of the lower section of the present invention; the stage of allowing the precipitation of solid components; a step of removing (ie collecting) residual fluid (ie a fluid depleted of solids) and a step of collecting deposited components through at least one collecting channel of said lower section. Preferably, in the residual fluid removal step, the residual fluid is not removed directly from the bottom section, but rather from other parts of the assembly that the bottom section may be part of. For example, residual fluid may be removed through at least one fluid outlet that is connected to at least one sedimentation channel of the assembly, of which the lower section may be a part.

In some embodiments, the solid components to be isolated are precipitates. These precipitates may be formed by chemical reactions in the fluid and may already be present in solid form in the fluid when it is introduced into the lower section, or may precipitate from the fluid, for example in the tray separator of the present invention.

In some embodiments of the method for separating solid components from a fluid of the present invention, the solid components to be isolated are cells. These cells may be any kind of cells, but preferably these cells are mammalian cells such as Chinese Hamster Ovary (CHO) cells, Baby Hamster Kidney (BHK) cells or Human Embryonic Kidney (HEK) cells. Mammalian cells are routinely used to produce biologically active substances, in particular recombinant proteins, which can be secreted into the cell culture broth fluid and can ultimately be recovered for formulation as a pharmaceutically active drug. Accordingly, according to some embodiments of the method of the present invention, the cells of the present invention contain genetic information encoding a biologically active substance, so that the cells can produce said biologically active substance.

In some embodiments, the biologically active substance of the present invention is a protein, such as an antibody, hormone, or coagulation factor. Preferably the protein is a recombinant protein. In a particularly preferred embodiment, the biologically active substance is a coagulation factor such as factor VII (FVII) or factor VIII (FVIII). A preferred coagulation factor of the present invention is factor VIII (FVIII), preferably human FVIII, which can be recombinantly produced, for example, in CHO cells. FVIII is a microscopic plasma glycoprotein found in mammals that is implicated as a factor IXa cofactor in factor X activation. Hereditary factor VIII deficiency results in a haemophilia A bleeding disorder that can be successfully treated with purified factor VIII. Such purified factor VIII can be extracted from blood plasma, or it can be produced using recombinant DNA technologies.

In another embodiment of the process for separating solids from fluids of the present invention, the precipitated components are collected by pumping flush fluid into at least one collection channel of the lower section and pumping the precipitated components and flush fluid from at least one collection channel of the lower section. Such collection may be carried out at regular intervals. The frequency of collection (ie intervals) should be adjusted, for example, depending on the concentration of solids in the fluid containing the solids. When the solid components are cells, the tendency of these cells to adhere to surfaces must also be taken into account when adjusting the frequency of collection. In a particularly preferred embodiment, the wash buffer should have the same, preferably higher density than the fluid containing the solids to be isolated and lower than the solids. This ensures that solid components can sediment in the flush fluid and will reduce mixing of the flush fluid with the fluid of the present invention. When the solids-containing fluid is a cell culture broth fluid and the solids are cells, the washing fluid may contain 14 g/L sodium chloride, 0.2 g/L potassium dihydrogen phosphate, 1.15 g/L sodium dihydrogen phosphate, and have a pH of 7.

In some embodiments of the process for separating solids from a fluid of the present invention, the lower section is contained in (ie, a part of) the assembly of the present invention. In this embodiment, the step of allowing the solid components (e.g., cells) to precipitate out is the step of allowing the solid components to settle in at least one sedimentation channel of the inclined tray separator which is part of the assembly of the present invention. . In this embodiment, residual fluid (i.e., fluid lean in solids) may be removed at the top of at least one sedimentation channel that is part of the tray separator of the present invention, for example, through at least one fluid outlet. environment, which is connected to at least one sedimentation channel.

By carrying out the process for separating solid components from a fluid according to the present invention, the authors found that solid components (for example, cells) that are contained in a fluid medium (for example, cell culture broth fluid) can be efficiently separated from said fluid with minimal loss of any components that are dissolved in the fluid, such as biologically active substances. Accordingly, in some embodiments, the amount of solids in the residual fluid removed is less than 20%, preferably less than 10%, most preferably less than 5% of the solids in the fluid that is introduced into at least one inlet of the lower section. In another embodiment, the amount of biologically active substance in the residual fluid to be removed is greater than 80%, preferably greater than 90%, most preferably greater than 95% of the amount of biologically active substance in the fluid that is introduced into at least one inlet of the lower section. The amount of solids in the fluid preferably refers to the concentration (eg, volume/volume) of the solids in said fluid. Those skilled in the art are aware of various methods for determining this concentration. For example, the (relative) concentrations of solids in a fluid can be determined using turbidity measurements. The amount of biologically active substance in the fluid preferably refers to the concentration (eg, as mass/volume or as units of activity per unit volume) of the biologically active substance in said fluid. The person skilled in the art knows various ways to determine such a concentration. For example, the concentration of FVIII mass/volume can be determined using antigenic ELISA. The concentration of FVIII in units of activity per unit volume (ie, FVIII activity) can be determined using chromogenic assays. Such chromogenic assays allow for the determination of active FVIII, and give the concentration, for example, in international units (IU) per ml.

In another embodiment of the process for separating solids from fluids of the present invention, a fluid containing solids is continuously introduced into at least one inlet of the lower section. In this embodiment, it is preferred that the residual fluid (ie fluid depleted in solids) is also continuously removed. The person skilled in the art knows how to control the volumetric flow rate in the lower section to ensure that the solid components have sufficient time to settle, for example, in at least one sedimentation channel of the present invention. When the method of the present invention is used to isolate cells from a fluid containing a biologically active substance, continuous introduction into the lower section can be from a bioreactor containing a continuous cell culture. Such a continuous cell culture may be a chemostat, a turbidostat, or a perfusion culture.

The temperature at which the method of the present invention is carried out is not limited in any way. The person skilled in the art knows how to select the appropriate temperature based on, for example, stability and any materials used and any substances contained in a fluid containing solids. However, temperature differences in the assembly that is used to carry out the solids recovery process of the present invention can result in temperature-induced density differences that can lead to convection and thereby reduce the separation efficiency of the wash fluid and the residual fluid, therefore, is it is preferable that the process for separating solids from fluids of the present invention be carried out at a uniform temperature, i.e. that the assembly (comprising, for example, the lower section and the disc separator) that is used to carry out the process is maintained at a predetermined temperature of ± 5 ° C, preferably at a given temperature of ±3°C.

In accordance with the above, the present inventors have found that the removal of cells from the cell culture broth fluid is particularly effective when the assembly of the present invention is in a cold room with a temperature between 2 and 8°C. Accordingly, in some embodiments, the method of the present invention is carried out at a temperature between 0 and 10°C (i.e., at a set temperature of 5°C±5°C), preferably at a temperature between 2 and 8°C (i.e., at set temperature 5°С ±3°С). Such temperatures can be achieved, for example, by placing the assembly in a cold room. If, in the method of the present invention, the assembly is connected to a bioreactor, the bioreactor can be operated at a temperature that is different from the temperature at which the process for separating solids from a fluid is carried out. In particular, if the process of the present invention is carried out at a temperature between 0 and 10°C or between 2 and 8°C by placing the assembly in a cold room, the bioreactor preferably operates at a higher temperature (for example,

37°C) and therefore not placed in a cold room.

The use of embodiments of the lower section and assembly of the present invention is illustrated by the following examples, without being limited to them.

Examples

In the examples shown, embodiments of the lower section of the present invention (and, more generally, assembly embodiments of the present invention) are used to isolate animal cells from an animal cell culture suspension and to isolate a precipitated solid component from its fluid phase.

In Examples 1-3, Chinese hamster ovary (CHO) cells expressing recombinant blood coagulation factor VIII (FVIII) were cultured continuously at a CHO cell culture operating temperature of 37°C. On average, the cell culture broth showed an initial turbidity of 46.6 FNU (formazine turbidity units). The outlet of the bioreactor is directly connected to the inlet of the lower section, assembled with an inclined plate separator, which is schematically represented in FIG. 2. In these examples, the inclined disc separator is inclined at an angle α'=30° with respect to the vertical direction, which is perpendicular to the horizontal direction (this is the direction of gravity). Thus, the angle relative to the horizontal direction is 60°. The inclined disc separator is made of stainless steel and the surfaces in contact with the process fluid are electropolished to Ra<0.6 µm. The internal retention volume of the assembly is 803 ml. The settling section is divided into four sedimentation channels, i.e. settling trays (similar to (21) in Fig. 2), which are separated by separating walls made ((25) in Fig. 2) of stainless steel in examples 1 and 2 and of PMMA in example 3. Washing solution is fed into the lower section and used in it. The wash solution consists of 14 g/l sodium chloride, 0.2 g/l potassium dihydrogen phosphate, 1.15 g/l sodium dihydrogen phosphate, pH 7.

The cell culture broth is continuously transferred from the bioreactor to the assembly. The clarified fluid, i.e. the cell-poor fluid, is continuously collected at the top outlet of the assembly. The recovered solids are collected from the collection channels of the bottom section at regular intervals of 60 minutes. Collection of separated solids from the solids collection channels of the lower section is carried out by simultaneous operation of the flush fluid pump and the collected solids pump at a flow rate of 62 and 60 ml/min, respectively. The interval for collecting cells, or collecting the solid component, is generally optimized depending on the cell counts, that is, the load of the solid component, cell culture broth. The rate of cell collection flow or solids collection is generally optimized depending on the characteristics of the solids, which may, for example, be the tendency of cells to adhere to surfaces to prevent sedimenting solids from becoming stuck in the collection channels of the lower section.

Samples for analysis are taken at regular intervals from the bioreactor and the fluid streams leaving the assembly. Fluid phase glucose concentration is determined using a commercial glucose analyzer (Stat Profile Prime Device, Nova Biomedical). Product concentration (FVIII) is determined by chromogenic analysis using the Chromogenix Coatest® SP4 Factor VIII kit. The chromogenic assay allows for the measurement of FVIII cofactor activity when it activates factor X to factor Xa together with factor IXa in the presence of phospholipids and calcium. Activated FXa hydrolyzes the chromogenic substrate (S-2765), thus releasing the pNA chromogenic group, whose absorbance can be measured at 405 nm. Under conditions of uptake of factor X assay and thus generation of a chromogenic substance, pNA depends only on the amount of FVIII (e.g., Peyvandi, F., Oldenburg, J. & Friedman, K.D.: A critical appraisal of one-stage and chromogenic assays of factor VIII activity; Journal of thrombosis and haemostasis: JTH 14, 248-261 (2016)). The concentration of analytes, glucose and FVIII, in the streams collected at the top and bottom section of the assembly are used to establish a mass balance, where the amount of analyte recovered in a given period is related to the amount produced/present in the bioreactor in that same period. Cell removal is assessed by measuring turbidity using a Hach 2100Q which is a portable turbidometer. The turbidometer measures light scattered by a sample in a circular cuvette (diameter 25 mm, height 60 mm) at an angle of 90° relative to the direction of light incidence, where the light source is an LED.

Example 1 Lower section to connect to a plate separator assembly, and a plate separator assembly (isolation of CHO cells with an additional fluid circuit).

The inclined tray separator is cooled with a double jacket connected to a cryostat which is set at 4°C. The double jacket and cryostat are shown schematically in dashed lines along with the pump in FIG. 14. Bottom section not cooling. Disposable bag containing

- 17 041838 flushing fluid, placed on wet ice to control the temperature, thus obtaining a temperature of approximately 0°C. Carry out two experiments, which last 49 and 90 hours, respectively, in this mode of temperature control.

To show that the bottom section of the inclined tray separator of the present invention allows cell separation from a product containing a liquid fraction with minimal product loss, glucose and FVIII concentrations are measured. In the lower section, the cells are sedimented in the provided washing fluid, while the entire liquid fraction of the culture broth is collected at the upper outlet. The wash buffer should have a higher density than the liquid fraction of the culture broth and a lower density than the solid components. By doing so, the cells can sediment in the wash buffer and minimal mixing of the wash fluid with the culture broth fluid is achieved. In the examples shown, this corresponds to the case of said wash buffer. Cells can be successfully removed while the product-containing fluid fraction can be collected in high yield at the top outlet. FVIII and glucose yield data are shown in the graphs in FIG. 15 and 16, their values are given in table. 1 and 2. Turbidity as a measure of cell removal can be found in Table. 1. Under the conditions of Example 1, glucose can be used as product indicator (FVIII) since it is not metabolized by the cells.

Table 1 Product yield (FVIII) is given as a percentage of the amount present in the fraction of the fluid collected at the bottom and top outlet of the assembly of Example 1, and turbidity is given in FNU measured in the fluid collected at the top outlet of Example 1. Cell turbidity contained in the culture broth averages 46.6 FNU. LOD=detection limit; 0.2

Experience 1 Experience 2 Experience time [hour] FVIII outlet at bottom outlet FVIII output at the top outlet Turbidity at the top outlet Experience time [hour] FVIII outlet at bottom outlet FVIII output at the top outlet Turbidity at the top outlet 3 3.47 85.2 0.86 19 6.97 99.5 6.85 5 3.51 97.0 0.87 20 below LOD 94.7 1.98 6 3.04 94.0 0.77 21 4.62 93.0 1.03 8 2.48 97.4 0.95 24 5.86 94.7 1.81 24 3.84 97.8 1.24 27 5.21 93.0 2.00 25 3.93 97.8 0.95 40 5.24 92.6 4.87 29 3.76 106 1.27 44 5.19 92.8 1.87 31 2.76 98.6 1.32 49 5.30 92.8 2.71 47 2.79 99.1 2.06 65 5.35 89.6 2.58 48 3.01 97.0 2.47 68 5.33 91.5 4.08 49 3.12 96.5 2.16 72 5.65 91.4 3.23 89 5.74 92.5 8.42 90 below LOD 90.7 7.83

TABLE 2 Glucose yield is given as a percentage of the amount present in the fraction of fluid collected at the bottom and top outlet of the Assembly of Example 1. n.d. = not defined

Experience 1 Experience 2 Experience time [hour] Low Output Glucose Output Glucose outlet at the top outlet Experience time [hour] Low Output Glucose Output Glucose outlet at the top outlet 3 7.05 90.5 19 8.00 92.1 5 4.71 95.4 20 6.98 97.7 6 4.89 96.4 21 7.15 91.5 8 4.81 94.9 24 6.89 93.8 24 4.40 93.9 27 6.24 90.4 25 4.94 92.5 40 6.69 87.0 29 4.71 92.5 44 6.59 93.8 31 4.49 92.0 49 15.9 89.8 47 4.25 90.5 65 6.18 97.2 48 4.51 90.0 68 n.d. 88.7 49 4.65 90.5 89 n.d. 96.0

Example 2 Lower section to connect to a plate separator assembly, and plate separator assembly (isolation of CHO cells without additional fluid circuit).

In example 2, an inclined plate separator assembly with a bottom section containing all feed and receive vessels (except for the bioreactor) is installed in a cold room where

- 18 041838 the temperature is 2-8°C. The installation is shown schematically in Fig. 17. Inclined plate separator and bottom section identical to Example 1. One test run under these conditions lasting 70 hours. loss of the product, measure the concentration of glucose and FVIII. In the lower section, the cells are sedimented in the provided washing fluid, while the entire liquid fraction of the culture broth is collected at the upper outlet. The wash buffer should have a density higher than the liquid fraction of the culture broth and lower than the solid components. This allows the cells to sediment in the wash buffer, and minimal mixing of the wash fluid with the culture broth fluid is achieved. In the examples shown, this corresponds to the case of said wash buffer. Cells can be successfully removed while the product-containing fluid fraction can be collected in high yield at the top outlet. The data obtained in Example 2 for FVIII and glucose yields are shown in the graphs in FIG. 18, while the value of the output of the product (FVIII) in the table. 3 and the glucose yield and turbidity measured on samples collected at the top outlet are given as a measure of cell removal in Table 1. 4. Turbidity data show that cell removal is more efficient and more stable over time when the inclined plate separator and bottom section are installed in a cold room compared to double jacket cooling (as described in Example 1).

Table 3

Product yield (FVIII) is given as a percentage of the amount present in the fraction of fluid collected. on the lower and upper output of the assembly of example 2

Experience time [hour] FVIII outlet at bottom outlet FVIII output at the top outlet 26 2.01 84.1 51 0.56 90.4 70 0.56 97.8

Table 4 Glucose yield is given as a percentage of the amount present in the fraction of the fluid collected at the bottom and top outlet of the assembly of Example 2, and turbidity is given in FNU measured in the fluid collected at the top outlet of Example 2. Turbidity of the culture broth, containing cells averages 46.6 FNU

Experience time [hour] Low Output Glucose Output Glucose outlet at the top outlet Turbidity at the top outlet 18 2.67 99.5 2.62 22 2.67 101 0.72 26 2.84 99.0 0.87 42 2.67 101 1.38 47 2.58 100 1.98 51 2.67 93.8 1.69 67 2.49 94.7 1.49 70 2.31 95.2 1.06

Example 3 Bottom section for connection to plate separator assembly, and plate separator assembly (isolation of CHO cells with physical barriers from PMMA).

In Example 3, an inclined plate separator assembly with a bottom section containing all feed and receive vessels (except for the bioreactor) is installed in a cold room where the temperature is 2-8°C. The installation is shown schematically in Fig. 17. The inclined disc separator is made of stainless steel, and the surfaces in contact with the cell culture broth are electropolished to Ra<0.6 µm. The settling section is divided into four sedimentation channels, i.e. the settling trays (similar to (21) in Fig. 2) are separated by dividing walls made of polymethyl methacrylate (PMMA) ((25) in Fig. 2). This setup is used for a single run lasting 94 hours. To show that the bottom section of the inclined tray separator of the present invention allows cells to be isolated from a product containing a liquid fraction with minimal product loss, glucose and FVIII concentrations are measured. In the lower section, the cells are sedimented in the provided washing fluid, while the entire liquid fraction of the culture broth is collected at the upper outlet. The wash buffer should have a density higher than the liquid fraction of the culture broth and lower than the solid components. By doing so, the cells can sediment in the wash buffer and minimal mixing of the wash fluid with the culture broth fluid is achieved. In the examples shown, this corresponds to the case of a specific wash buffer. Cells can be successfully removed while the product-containing fluid fraction can be collected in high yield at the top outlet. Data for FVIII and glucose yields are plotted in FIG. 19, while the values for the output of the product (FVIII) in the table. 5 and the values for glucose yield and turbidity measured on samples collected at the top outlet are given as a measure of cell removal in Table 1. 6. Turbidity data show that cell removal is more efficient and more stable over time when the inclined plate separator and bottom section are installed in a cold room, compared to double jacket cooling (as described in Example 1). There is no difference in separation performance (based on available data) with respect to the material of the separation walls between example 2 (stainless steel) and example 3 (PMMA).

Table 5

Product yield (FVIII) is given as a percentage of the amount present in the fraction of fluid collected at the bottom and top outlet of the assembly of example 3. LOD = detection limit; 0.2. IU/ml

Experience time [hour] FVIII outlet at bottom outlet FVIII output at the top outlet 6 2.43 95.2 29 1.18 99.9 54 1.18 93.9 78 below LOD 96.1 94 below LOD 95.8

Table 6

The yield of glucose is given as a percentage of the amount present in the fraction of the fluid collected at the bottom and top outlet of the assembly of example 3, and the turbidity is given in FNU measured in the fluid collected at the top outlet of example 3

Example 4 Lower section to be connected to a plate separator assembly, and a plate separator assembly (feeding and collecting process streams in the lower section for cleaning in place).

Example 4 relates to an embodiment of an assembly of a lower section with an inclined disc separator containing switchable connections for supply and receiving tanks. The inclined disc separator and bottom section with attached tanks are assembled as a closed system. The containers used are reusable glass laboratory glassware, which are autoclaved prior to use. Connectors are made from silicone tubing and c-flex tubing, Luer connectors and metal connectors. Silicone tubing and Luer connectors are considered disposable. However, all containers and connectors may also be (1) disposable and (2) pre-assembled. In the default state, the three-way valves located in the lower section are configured to provide a direct fluid connection between the tanks [1], [2] and [4] and the assembly. For cleaning-in-place (CIP), 1 M sodium hydroxide solution is pumped from the supply tank ([1] in FIG. 20) into the plate separator and bottom section assembly. The assembly is completely filled and the sampling valves (indicated by +) are flushed with 1 M sodium hydroxide solution. The assembly is incubated for at least 15 minutes with 1M sodium hydroxide. At the end of the incubation time, the three-way valves located in the lower section are switched so that a direct fluid communication connection is established between the assembly and the receiving vessel ([3] in Fig. 20). The 1 M sodium hydroxide solution is removed into the receiving vessel by gravity flow. During the removal of the fluid from the assembly, air flow through the receiving container is provided [6]. When the assembly is empty, the three-way valves switch back to their original position, creating a direct fluid connection between the containers [1], [2] and [4] and the assembly, and it can be filled again. The filling and removal procedure, including rinsing the sampling valves, is repeated at least twice with an aqueous buffer solution (e.g. 8 g/l sodium chloride, 0.2 g/l potassium dihydrogen phosphate, 1.15 g/l sodium dihydrogen phosphate, pH 7). Compliance with the CIP procedure is confirmed by measuring the pH of the samples taken from the sampling valves, while accepting a pH<7.2.

Example 5 Bottom section for connection to plate separator assembly and plate separator assembly (separation of precipitated solids at various collecting flow rates in the presence of an amino acid).

- 20 041838

In Example 5, the precipitate slurry is separated into its solid fraction, ie the precipitate, and its fluid fraction, ie the supernatant from the precipitation.

The precipitate suspension is prepared by supplementing an aqueous solution containing 10 mM tris-(hydroxymethyl)aminomethane, 100 mM sodium chloride and 100 mg/ml tryptophan, pH 8.5, 2.7 mM phosphate ions and 15 mM calcium ions. The formed solid phase is a non-stoichiometric calcium phosphate. The precipitate slurry is directly and continuously transferred to the inlet of the lower section in an inclined plate separator assembly. In these examples, the inclined disc separator is inclined at an angle α'=30° from the vertical direction, ie at an angle α=60° from the horizontal direction (in the direction of gravity). The inclined disc separator is made from stainless steel where the surfaces in contact with the process fluid are electropolished to Ra<0.6 µm. The internal retention volume, consisting of a lower section and an inclined disc separator with one settling channel, is 630 ml. Washing solution is fed into the lower section and used in it. The rinsing fluid is an aqueous solution containing 2 mM tris(hydroxymethyl)aminomethane, 252 mM sodium chloride and 6 mM calcium chloride. The density of the wash fluid must be higher than the density of the fluid in the precipitate slurry and lower than the density of the suspended solids to precipitate the solids from the fluid where they are initially suspended in the wash buffer provided in the lower section. For the precipitate slurry and flush fluid in this example, the densities meet this criterion.

When the assembly is in operation, solids depleted fluid is continuously collected at the top outlet of the assembly. The separated solids are collected from the collection channels of the lower section at regular time intervals of 15 minutes. Solids collection is accomplished through the simultaneous operation of a flush fluid and a solids collection pump at flow rates of 20, 40 and 60 ml/min.

To demonstrate successful recovery and washing of suspended solids (ie, precipitate), a tracer, namely tryptophan, is added to the precipitate suspension. Parts of the fluid originally contained in the precipitate slurry are transferred to the wash fluid, and thus the collected solids can be monitored by absorbance measurement based on the tryptophan absorbance maximum at 280 nm. Measurement samples are taken after each collection cycle of solids from the fluid streams leaving the assembly. The data in the graphs in Fig. 21 (see also Table 7) show a low yield of tryptophan in the collected solids suspended in the wash solution over the entire range of collection flow rates tested. A low yield of tryptophan in the wash fluid corresponds to a low carryover from the fluid carrying the solids to be isolated. As a consequence, the largest fraction of the fluid present in the fraction of collected solids is the wash buffer, which demonstrates the effective washing of the precipitate.

Table 7

Tryptophan yield values in the fraction containing the collected solids (i.e., precipitate) suspended in the wash fluid obtained at various collection flow rates

Number of release cycle at volumetric flow rate [-] Volume flow rate [ml/min] Yield of amino acid in wash solution carrying collected solids [%] 1 20 1.02 2 20 2.25 3 20 3.91 4 20 6.45 5 20 6.47 1 40 10.14 2 40 7.43 3 40 5.34 4 40 4.65 5 40 5.15 1 60 5.22 2 60 4.30 3 60 3.78 4 60 4.25 5 60 4.07

Tryptophan is initially contained in the precipitate suspension. The volume of the released fraction is 40 ml, regardless of the volumetric flow rate during release.

Example 6 Lower section for connection to a plate separator assembly, and a plate separator assembly (precipitate separation at various collecting flow rates in the presence of a dye).

In example 6, the precipitate slurry is separated into its solid fraction, i.e. the precipitate, and into

- 21 041838 its fraction of the fluid medium, that is, on the precipitation supernatant. The precipitate suspension is obtained by supplementing an aqueous solution containing 10 mM tris-(hydroxymethyl)aminomethane and 100 mM sodium chloride, pH 8.5, 2.7 mM phosphate ions and 15 mM calcium ions. The precipitate slurry is directly and continuously transferred to the inlet of the lower section in an inclined plate separator assembly. In these examples, the inclined disc separator is inclined at an angle α'=30° from the vertical. The inclined disc separator is made from stainless steel where the surfaces in contact with the process fluid are electropolished to Ra<0.6 µm. The internal retention volume, consisting of a lower section and an inclined disc separator with one settling channel, is 630 ml. Washing solution is fed into the lower section and used in it. The rinsing fluid is an aqueous solution containing 2 mM tris(hydroxymethyl)aminomethane, 252 mM sodium chloride, 6 mM calcium chloride and 25 mg/l of proprietary blue V, which has an absorbance maximum at 620 nm. The density of the wash fluid must be higher than the density of the fluid in the precipitate slurry and lower than the density of the suspended solids to precipitate the solids from the fluid where they are initially suspended in the wash buffer provided in the lower section. For the precipitate slurry and flush fluid in this example, the densities meet this criterion.

During the operation of the assembly, solids depleted fluid is continuously collected at the top outlet of the assembly. The recovered solids are collected from the collection channels of the bottom section at regular time intervals of 15 minutes. Solids collection is accomplished through the simultaneous operation of a flush fluid and a solids collection pump at flow rates of 20, 40 and 60 ml/min.

To demonstrate successful separation and washing of suspended solids (ie, precipitate), a tracer, namely Proprietary Blue V, is added to the wash fluid. Portions of the fluid originally contained in the precipitate slurry are transferred to the wash fluid, and thus the collected solids can be monitored by absorbance measurement based on the absorbance maximum at 620 nm of the proprietary blue V. Samples are taken for analysis after each solid collection cycle. components from fluid streams leaving the assembly. The plot data in Fig. 22 (see also Table 8) show a high yield of proprietary blue V in collected solids suspended in the wash fluid. Here, low yield corresponds to high carryover from the fluid carrying the solids to be isolated. Therefore, high recovery values confirm the successful separation of the precipitate from the precipitate suspension with efficient washing of the collected precipitate.

Table 8

Yields of proprietary blue V in collected solids suspended in flush fluid,

The proprietary blue V is initially contained in the flush fluid. The volume of the released fraction is 40 ml, regardless of the volume flow rate of the release.

Those skilled in the art will appreciate that various modifications and changes can be made to the described devices and systems without departing from the scope of the present invention. Other aspects of the present invention will become apparent to those skilled in the art upon consideration of the description and implementation of the features described herein. The description and examples are intended to be considered as illustrations only. Additional variations and modifications are possible and are understood to fall within the scope of the present invention.

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Claims (35)

CLAIM 1. A lower section configured to be connected to an assembly for separating a solid component from a fluid, where said assembly includes an inclined disc separator with at least one sedimentation channel for discharging a separable solid component, where said disc separator contains a lower part and an upper part, where the specified at least one sedimentation channel passes from the bottom to the top, and the lower section is made with the possibility of connection with the lower part of the inclined plate separator, where the lower section contains at least one inlet channel, made with the possibility of introducing a fluid, containing a solid component to be separated in a tray separator, at least one collecting channel configured to collect the precipitated component descending from at least one sedimentation channel, and at least one flushing fluid supply channel for supplying flushing fluid into one sedimentation channel or into one collecting channel, where said at least one flushing fluid supply channel is hydraulically separated from other flushing fluid supply channels and from all inlet channels, where said at least one inlet channel and indicated by at least one collecting channel is fluidly separated from each other, where said inlet channel and said collecting channel are configured to connect with said at least one sedimentation channel to form fluid communication connections between said at least one inlet channel and said at least one sedimentation channel and between said at least one collecting channel and said at least one sedimentation channel, respectively. 2. The lower section according to claim 1 connected to the assembly with a disc separator containing a plurality of sedimentation channels and separating plates separating adjacent sedimentation channels, where the lower section contains a plurality of inlet channels and a plurality of collecting channels, where the specified at least one inlet channel and said at least one collecting channel is fluidly separated from all other inlet channels and collecting channels, respectively, and fluid connections between all other sedimentation channels and all other inlet channels and collecting channels, respectively. 3. The lower section according to claim 2, containing one separate inlet channel and one separate collecting channel for at least 50% of the sedimentation channels of the corresponding assembly, to which the lower section is connected, made with the possibility of connection, while a separate connection with communication of fluid media is formed for each corresponding pair of inlet channel and sedimentation channel, and for each corresponding pair of collecting channel and sedimentation channel, respectively. 4. The bottom section of claim 2, comprising one separate collection channel and one separate inlet channel for each of the plurality of sedimentation channels. 5. The bottom section according to claim 1, wherein the bottom section is configured to be connected to an assembly oriented in the position of use such that the end portions of the inlet channels and the end portions of the collecting channels closest to the disc separator are oriented in the direction of gravity. 6. The lower section of claim 1, wherein at least one flushing fluid supply passage and at least one collection passage corresponding to the same sedimentation passage are fluidly connected through an opening in a portion of the wall shared by the flushing supply passage. fluid and the specified collecting channel. 7. The lower section according to claim 1 in combination with a disc separator, where the lower section contains at least one intra-channel distribution part for uniform distribution of fluid flow through the part of the first channel, made with the possibility of being near the corresponding sedimentation channel in at least one direction the length of the cross section of the specified specific channel, where the specified first channel is an input channel or a collecting channel or a channel for supplying flushing fluid; and/or at least one inter-channel distribution portion for evenly distributing fluid flow towards or away from the disc separator through the plurality of flush fluid inlet and/or supply channels and/or collection channels. 8. The lower section according to claim 6, where the intra-channel distribution part and the inter-channel distribution part are connected, and where the intra-channel distribution part is arranged to be located closer to the disc separator than the inter-channel distribution part. - 23 041838 9. The lower section according to claim 6, where all inlet channels and collecting channels are provided in pairs or in triplets together with one supply channel for flushing fluid, and all inlet channels are fed by one corresponding inter-channel distribution part, where all collecting channels are connected with one corresponding inter-channel distribution part; and/or where all input channels are connected to one intra-channel distribution part, and all collecting channels are connected to one intra-channel distribution part. 10. The bottom section of claim 9, wherein all flush fluid channels are powered from each respective inter-channel distribution portion. 11. The lower section of claim 9, wherein all flushing fluid channels are connected to one intrachannel distribution portion. 12. The lower section in combination with the separator according to claim 7, containing in-channel distribution parts and inter-channel distribution parts, where the direction of distribution of the inter-channel distribution parts is perpendicular to the distribution direction of the in-channel distribution parts. 13. The lower section in combination with the separator of claim 12, wherein the direction of distribution of the intra-channel distribution portions is a longitudinal direction along the cross section of the connecting end portion of the first channel located proximate the disc separator. 14. The lower section of claim 1 in combination with a disc separator having at least one sedimentation channel, where the bottom surfaces of adjacent sedimentation channels run parallel to each other and include at least a part that is not inclined in any direction other than the direction of inclination sedimentation channels, and/or where the angle of inclination of the sedimentation channels relative to the direction of gravity is in the range from 15 to 85°. 15. A method for separating solid components from a fluid, where the method includes the following steps (i)-(iv): (i) introducing a fluid containing solid components, at least one inlet channel of the lower section according to any one of paragraphs. 1 and 6-14; (ii) allowing solid components to precipitate; (iii) removing residual fluid; (iv) collecting the deposited components through at least one collecting channel of said lower section. 16. A method for separating solid components from a fluid according to claim 15, wherein the solid components to be isolated are precipitates. 17. The method for isolating solid components from a fluid according to claim 15, wherein the solid components to be isolated are cells. 18. A method for separating solid components from a fluid according to claim 17, wherein the cells contribute to the production of a biologically active substance and where the fluid contains said biologically active substance. 19. A method for separating solid components from a fluid according to claim 18, wherein the biologically active substance is a coagulation factor or where the biologically active substance is a factor VIII. 20. The method of separating solids from a fluid according to claim 15, wherein the bottom section is provided in said assembly, and wherein the step of allowing solids to settle is the step of allowing solids to settle in at least one sedimentation channel of the inclined disc separator. 21. A method for separating solids from a fluid according to claim 20, wherein in step (iii) residual fluid is removed at the top of at least one sedimentation channel. 22. The method for separating solids from a fluid according to claim 21, wherein the amount of solids in the residual fluid to be removed is less than 20% of the amount of solids in the fluid that is introduced into at least one inlet of the lower section. 23. The method for separating solid components from a fluid according to claim 21, where the solid components to be isolated are cells, where the cells are capable of producing a biologically active substance, where the fluid contains said biologically active substance, and where the amount of biologically active substance in the residual fluid to be removed more than 80% of the amount of biologically active substance in the fluid, which is injected into at least one inlet channel of the lower section. 24. The method for separating solids from a fluid according to claim 15, wherein the solids-containing fluid is continuously introduced into at least one inlet of the lower section. 25. A method for separating solids from a fluid according to claim 15, wherein the method is carried out at a temperature in the range of 0 to 10°C or at a temperature in the range of 2 to 8°C. 26. An assembly for separating a solid component from a fluid, where the assembly contains an inclined disc separator with a lower part, an upper part and at least one sedimentation channel, which allows separating the solid component by settling, where the specified sedimentation - 24 041838 the channel extends from the bottom to the top, the disc separator is configured for orientation in use in such a way that at least one sedimentation channel extends from the bottom to the top in a direction that is inclined relative to the direction of gravity, where at least at least one sedimentation channel is connected to a fluid outlet for removing residual fluid in the upper part and is connected to the lower section according to claim 1 in the lower part. 27. The assembly according to claim 26, containing a plurality of sedimentation channels that allow separating the solid component by settling, where these sedimentation channels pass from the lower part to the upper part, and the disc separator further comprises separating plates separating adjacent channels, where the plurality of sedimentation channels are connected at least at least one fluid outlet to remove residual fluid from the top and connected to the bottom section at the bottom. 28. Assembly according to claim 26, where the relative difference in hydrostatic pressures in the various sedimentation channels does not exceed a threshold of 10%. 29. Assembly according to claim 28, where the relative difference in hydrostatic pressures in the various sedimentation channels does not exceed a threshold of 3%. 30. The assembly of claim 26, further comprising supplying a fluid containing a solid separation component to the disc separator through at least one inlet port, and supplying a wash buffer fluid through at least one wash fluid supply port, where the density of the wash buffer fluid is equal to or greater than the density of the fluid containing the solid component to be isolated. 31. The lower section, made with the possibility of connection with the assembly for separating the solid component from the fluid, where the said assembly includes an inclined disc separator with at least one sedimentation channel for discharging the separated solid component, where the specified disc separator contains a lower part and an upper part, where the specified at least one sedimentation channel passes from the bottom to the top, and while the lower section is made with the possibility of connection with the lower part of the inclined plate separator, where the lower section contains at least one input channel configured to supply a fluid containing solid component to be separated into a tray separator, at least one collection channel configured to collect the precipitated component exiting at least one sedimentation channel, at least one intra-channel distribution section for uniform distribution of p fluid outflow through the section of the first channel closest to the corresponding sedimentation channel, in at least one direction of expansion of the cross section of the specified specific channel, while the specified at least one inlet channel and the specified at least one collecting channel are separated by fluid from each other another, and said inlet channel and said collecting channel are configured to be connected to said at least one sedimentation channel to form hydraulic connections between said at least one inlet channel and said at least one sedimentation channel and between said at least one collecting channel and said at least one sedimentation channel, respectively, wherein said first channel is an inlet channel, or a collecting channel, or a flushing fluid supply channel, while the upper part of the first channel is located near the corresponding sedimentation the lower part of the first channel is divided into two connecting channels with equal first cross sections, and said connecting channels are at least once additionally divided into corresponding connecting subchannels with corresponding other equal sections, while the first section cross sections are identical or different from the respective other cross-sections, while the end parts of all connecting subchannels after the respective last divisions are connected to the upper section for uniform distribution in the direction of distribution. 32. A lower section configured to be connected to an assembly for separating a solid component from a fluid, where said assembly includes an inclined disc separator with at least one sedimentation channel for discharging a separable solid component, where said disc separator contains a lower part and an upper part, where the specified at least one sedimentation channel extends from the bottom to the top, and while the lower section is made with the possibility of connection with the lower part of the inclined plate separator, where the lower section contains at least one inlet channel configured to supply fluid, containing - 25 041838 total solid component to be separated into a tray separator, at least one collecting channel configured to collect the precipitated component exiting at least one sedimentation channel, at least one inter-channel distribution part for uniform distribution guiding fluid flow towards or away from the disk separator into a plurality of inlet channels and/or flush fluid supply channels and/or collecting channels, wherein said at least one inlet channel and said at least one collecting channel are fluidly separated from each other, said inlet channel and said collecting channel are configured to be connected to said at least one sedimentation channel to form hydraulic connections between said at least one inlet channel and said at least one sedimentation channel and between said at least one collecting channel and said at least one sedimentation channel, respectively, wherein the inter-channel distribution part includes an upper part that is connected to one or more input channels, or one or more channels for flushing fluid, or one or several collecting channels, and the lower section, and the lower part is divided into two connecting channels of equal first cross section. 33. The bottom section of claim 32, wherein said connecting channels are at least once further divided into respective connecting subchannels having other equal cross sections, wherein the first cross sections are identical or different from the respective other cross sections, and the end portions of all connecting subchannels after the respective last splits are connected to the upper section so that they are evenly distributed in the distribution direction. 34. The lower section, made with the possibility of connection with the assembly for separating the solid component from the fluid, where the said assembly includes an inclined disc separator with at least one sedimentation channel for the discharge of the separated solid component, where the specified disc separator contains a lower part and an upper part, where the specified at least one sedimentation channel passes from the bottom to the top, and while the lower section is made with the possibility of connection with the lower part of the inclined plate separator, where the lower section contains at least one input channel configured to supply a fluid containing the solid component to be separated into a disc separator, at least one collecting channel configured to collect the deposited component exiting at least one sedimentation channel, at least one intra-channel distribution part for even distribution of sweat fluid flow through the section of the first channel closest to the corresponding sedimentation channel in at least one direction of expansion of the cross-section of said specific channel, while said at least one inlet channel and said at least one collecting channel are fluidly separated from each other , and said inlet channel and said collecting channel are configured to be connected to said at least one sedimentation channel to form hydraulic connections between said at least one inlet channel and said at least one sedimentation channel, and between said at least one collecting the channel and the specified at least one sedimentation channel, respectively, while the specified first channel is an input channel, or a collecting channel, or a channel for supplying a flushing fluid, while the intra-channel distribution part includes a fractal distributor b flow. 35. A lower section configured to be connected to an assembly for separating a solid component from a fluid, where said assembly includes an inclined disc separator with at least one sedimentation channel for discharging a separable solid component, where said disc separator contains a lower part and an upper part, where the specified at least one sedimentation channel passes from the bottom to the top, and while the lower section is made with the possibility of connection with the lower part of the inclined plate separator, where the lower section contains at least one input channel configured to supply a fluid containing solid component to be separated into a tray separator, at least one collection channel configured to collect the precipitated component exiting at least one sedimentation channel, at least one inter-channel distribution part for uniform flow distribution fluid in the direction of the disc separator or in the direction from the disc separator