Bioprocessing installation

Abstract

Embodiments relate to a bioprocessing system having a main line for conduction of a main flow of a liquid medium, having a main flow pump and having a system part connected to the main line. The bioprocessing system comprises a powder transfer system and a feed line which is connected to the powder transfer system and which opens into the main line and which comprises a return flow preventer for prevention of a return flow of liquid medium, the powder transfer system feeds the additive into the feed line in powder form and drives it toward the feed point by means of a pressurized transport gas and at least some of the fed additive is input into the liquid medium within the main line downstream of the feed point before the liquid medium enriched with the additive passes through or reaches the system part connected to the main line.

Claims

1. A bioprocessing system comprising: a main line for conduction of a main flow of a liquid medium, a main flow pump for generation of the main flow, and a system part connected to the main line, wherein the bioprocessing system further comprises: a powder transfer system for metered delivery, in particular dust-free metered delivery, of an additive, and a feed line which is connected to the powder transfer system and which opens into the main line at a feed point and which comprises a return flow preventer for prevention of a return flow of liquid medium, wherein the powder transfer system feeds the additive into the feed line in powder form and drives it toward the feed point by a pressurized transport gas and wherein at least some of the additive is input into the liquid medium within the main line downstream of the feed point before the liquid medium enriched with the additive passes through or reaches the system part connected to the main line; wherein the powder transfer system comprises a transport gas source for the pressurized transport gas and wherein the powder transfer system feeds the additive into the feed line by the pressurized transport gas.

2. The bioprocessing system as claimed in claim 1, wherein the liquid medium is fermentation broth, and/or, wherein the system part connected to the main line is a bioprocessing functional element for filtration of the fermentation broth or an accommodation container for accommodation of the liquid medium, and/or, wherein the additive is a filter aid and/or salt and/or nutrient.

3. The bioprocessing system as claimed in claim 2, wherein the bioprocessing system comprises the powder transfer system for dust-free metered delivery, of a filter aid and the feed line which is connected to the powder transfer system and which opens into the main line at the feed point and which comprises the return flow preventer for prevention of a return flow of fermentation broth, wherein the powder transfer system feeds the filter aid into the feed line in powder form and drives it toward the feed point by the pressurized transport gas and wherein at least some of the filter aid is suspended in the fermentation broth within the main line downstream of the feed point before the fermentation broth enriched with the filter aid passes through a filter arrangement.

4. The bioprocessing system as claimed in claim 1, wherein the bioprocessing system comprises a liquid storage container, and wherein the liquid medium is fed from the liquid storage container into the feed point via the main line.

5. The bioprocessing system as claimed in claim 1, wherein the feed line and/or the main line and/or the return flow preventer and/or the main flow pump, as single-use component, is/are formed at least in part from a plastics material, and/or from a polymer material.

6. The bioprocessing system as claimed in claim 1, wherein the return flow preventer blocks fluid flow in the direction of the powder transfer system and, upon exceeding of a switching pressure gradient in the flow direction of the return flow preventer, lets through a flow of the additive in the direction of the main line and/or wherein the return flow preventer is constructed in the manner of a check valve and comprises a valve body which is spring-elastic or is spring-preloaded by a spring arrangement.

7. The bioprocessing system as claimed in claim 1, wherein the feed line is always free of liquid medium between the powder transfer system and the return flow preventer.

8. The bioprocessing system as claimed in claim 1, wherein the additive is suspended or dissolved in the liquid medium.

9. The bioprocessing system as claimed in claim 1, wherein the main line comprises, on an entry side of the system part connected to the main line, an actuatable valve arrangement via which the liquid medium is recirculatable.

10. The bioprocessing system as claimed in claim 9, wherein the bioprocessing system comprises a control arrangement and wherein the powder transfer system and/or the valve arrangement relating to recirculation and/or the main flow pump is/are actuatable by the control arrangement.

11. The bioprocessing system as claimed in claim 10, wherein a sensor arrangement which ascertains a characteristic of the liquid medium enriched by the additive is provided and wherein the control arrangement actuates the powder transfer system and/or the valve arrangement relating to recirculation and/or the main flow pump depending on one or more sensor values of the sensor arrangement, wherein the characteristic ascertained is the concentration of the additive in the liquid medium and/or a temporal course of the concentration of the additive in the liquid medium and/or an input pressure or pressure profile in the main line.

12. A method for operation of a bioprocessing system as claimed in claim 1, wherein the additive is fed into the feed line in powder form by the powder transfer system and it is driven toward the feed point by a pressurized transport gas and wherein at least some of the additive is delivered into the liquid medium within the main line downstream of the feed point before the liquid medium enriched with the additive passes through or reaches the system part connected to the main line.

13. The method as claimed in claim 12, wherein the main flow pump is operated such that a switching pressure gradient in the flow direction of the return flow preventer is always fallen short of.

14. A use of a sterile-packed transfer set composed of prefabricated system components for construction of a bioprocessing system as claimed in claim 1, wherein the transfer set in the sterile packaging comprises at least the feed line including the return flow preventer.

15. The use as claimed in claim 14, wherein the transfer set in the sterile packaging additionally comprises the main line which is connected to the feed line in a prefabricated manner at the feed point, wherein the transfer set in the sterile packaging comprises at least part of the liquid storage container, which is connected to the main line in a prefabricated manner at the feed point.

16. The use as claimed in claim 14, wherein the feed line and/or the main line and/or the return flow preventer and/or the main flow pump is/are formed at least in part from a plastics material and/or from a polymer material.

17. The bioprocessing system as claimed in claim 1, wherein the powder transfer system comprises a transport gas source for the pressurized transport gas and wherein the powder transfer system feeds the additive into the feed line by the pressurized transport gas, wherein the powder transfer system feeds the additive discontinuously into the feed line or wherein the powder transfer system feeds the additive continuously into the feed line.

18. The bioprocessing system as claimed in claim 1, wherein the feed line is always free of liquid medium between the powder transfer system and the return flow preventer, wherein the feed line is free of liquid medium between the return flow preventer and the feed point at least in the case of a steady main flow.

19. The bioprocessing system as claimed in claim 1, wherein the additive is suspended or dissolved in the liquid medium, wherein the suspension or dissolution of the additive in the liquid medium stems from the liquid flow in the main line and/or in the main flow pump, wherein the main line comprises at least one mixing section downstream of the feed point, and wherein the main line comprises mixing shapes in the form of flow guiding profiles, baffles or the like in the mixing section.

20. The bioprocessing system as claimed in claim 1, wherein the powder transfer system feeds the additive discontinuously into the feed line or in that the powder transfer system feeds the additive continuously into the feed line.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Aspects of the disclosure will be more particularly elucidated below on the basis of a drawing depicting merely an exemplary embodiment. In the drawing,

(2) FIG. 1 shows a schematic depiction of a bioprocessing system according to the proposal,

(3) FIG. 2 shows a) a first embodiment and b) a second embodiment of a sterile-packed transfer set for the use according to the proposal for construction of a bioprocessing system according to the proposal.

DETAILED DESCRIPTION

(4) To begin with, it must be pointed out that the drawing only shows the components of the bioprocessing system 1 according to the proposal that are necessary for the elucidation of the teachings. Accordingly, the depiction of a plurality of additionally provided valves, sensors or the like has been dispensed with for good clarity.

(5) In this exemplary embodiment, the focus is the suspension of filter aids. However, this should not be understood as limiting. In principle, the addition of other additives 47, in particular a salt and/or nutrient in the case of buffer or media production, is instead also a conceivable application.

(6) The bioprocessing system 1 shown in FIG. 1 is equipped with a main line 2 for conduction of a main flow 3 of fermentation broth 4, with a main flow pump 5 for generation of the main flow 3 and with a filter arrangement 6 connected to the main line 2 for filtration of the fermentation broth 4.

(7) Instead of fermentation broth 4, a different liquid medium 45 can also be provided in a different application.

(8) Furthermore, instead of a filter arrangement 6, a different system part 46 connected to the main line 2 can also be provided in a different application, to which it is possible to admit the liquid medium, for example such that it is possible for the liquid medium to flow therethrough or such that the liquid medium can flow thereinto.

(9) The filter arrangement 6 functions according to the principle of precoat filtration. This means that a filter aid 7 is to be suspended in the fermentation broth 4 as additive before the fermentation broth 4 enriched with the filter aid 7 passes through the filter arrangement 6.

(10) What is essential then is that the bioprocessing system 1 comprises for this purpose a powder transfer system 8 for metered delivery, in particular dust-free metered delivery, of the filter aid 7 and a feed line 9 which is connected to the powder transfer system 8 and which opens into the main line 2 at a feed point 10. FIG. 1 shows that the feed line 9 comprises a return flow preventer 11 for prevention of a return flow of fermentation broth 4. This ensures that the feed line 9 is free of fermentation broth 4 between the powder transfer system 8 and the return flow preventer 11. This is an important aspect for the realization of the above single-use concept, as will be explained.

(11) What is furthermore essential is that the powder transfer system 8 feeds the filter aid 7 into the feed line 9 in powder form and drives it toward the feed point 10 and in particular beyond the feed point 10 into the main line 2 by means of a pressurized transport gas 12. What thus takes place is a flow of transport gas 12 and filter aid 7 from the powder transfer system 8 toward the feed point 10 that ensures that the filter aid 7 enters the main line 2 through which the fermentation broth 4 flows. As a consequence, at least some of the fed filter aid 7 is suspended in the fermentation broth 4 within the main line 2 downstream of the feed point 10 before the fermentation broth 4 enriched with the filter aid 7 passes through the filter arrangement 6.

(12) After passage through the filter arrangement 6, the filtered fermentation broth 4 is processed further, disposed of or recycled, depending on the application area. For the purpose of a simple depiction, FIG. 1 merely shows a collection container 13 for the filtered fermentation broth, which is not to be understood as limiting.

(13) A look at the depiction according to FIG. 1 shows that the addition of the filter aid 7 is only effected via the feed line 9 and thus without any mixing chambers, meaning that a change in the metering of the filter aid 7 by the powder transfer system 8 has a virtually immediate effect on the concentration of the filter aid 7 in the fermentation broth 4. The response time of the bioprocessing system 1 to a change in the metering of the filter aid 7 is thus advantageously short.

(14) In an embodiment, the bioprocessing system 1 is equipped with a bioreactor 14 which generates the fermentation broth 4 and which, in a further embodiment, comprises an assigned bioprocess bag 15 for accommodation of the fermentation broth 4. The drain port 16 of the bioreactor 14 is connected to the main line 2. From the bioreactor (14), the fermentation broth 4 is fed into the feed point 10 via the main line 2.

(15) Instead of a bioreactor 14, a different liquid storage container 48 can also be provided in a different application.

(16) For the purpose of realizing the above single-use concept, it can be the case that the feed line 9 and/or the main line 2 and/or the return flow preventer 11 and/or the main flow pump 5 is/are designed as a single-use component or as single-use components. In an embodiment, at least one of these components is formed at least in part, such as predominantly, from a plastics material, such as from a silicone material and/or from a polymer material, in particular PE (polyethylene), PP (polypropylene), PTFE (polytetrafluoroethylene), PBT (polybutylene terephthalate), PSU (polysulfone), PESU (polyether sulfone), PC (polycarbonate).

(17) The use of transfer sets composed of such single-use components for construction of the bioprocessing system 1 according to the proposal is the subject matter of a further teaching, which will be discussed below.

(18) For the design of the powder transfer system 8, various advantageous variants are conceivable. In various embodiments, the powder transfer system 8 comprises a transport gas source 17 for the pressurized transport gas 12, wherein the powder transfer system 8 feeds the filter aid 7 into the feed line 9 by means of the pressurized transport gas 12. Specifically, the transport gas source 17 comprises, here, a transport gas reservoir 18 and a compressor 19. The compressor 19 pumps the transport gas 12 for addition of the filter aid 7 through a powder chamber 20 filled with filter aid 7 such that the filter aid 7 is, as discussed above, fed into the feed line 9 by means of the pressurized transport gas 12. The transport gas 12 can be an inert gas, for example nitrogen. In principle, the transport gas 12 can, however, also simply be air.

(19) The powder chamber 20 comprises a powder inlet 21, which is connected to a powder reservoir 23 via an actuatable valve 22 assigned to the powder inlet 21. The powder chamber 20 furthermore comprises a powder outlet 24, which has assigned thereto an actuatable valve 25, which in turn is connected to the feed line 9. Lastly, the powder chamber 20 comprises a gas connection 26, to which the compressor 19 can be switched via an actuatable valve 27 assigned to the compressor 19. In addition, a vacuum pump 28 is switched to the connection 26 via an actuatable valve 29 assigned to the vacuum pump 28.

(20) For the filling of the powder chamber 20, the valve 25 assigned to the powder outlet 24 and the valve 27 assigned to the compressor 19 are closed, whereas the valve 29 assigned to the vacuum pump 28 and the valve 22 assigned to the powder inlet 21 are open. In this state, the operation of the vacuum pump 28 leads to suction of filter aid 7 from the powder reservoir 23 via the valve 22 assigned to the powder inlet 21. It is assumed here for the sake of simplicity that, in view of the large volume of the powder reservoir 23, there is initially no need for subsequent flow of gas into the powder reservoir 23.

(21) After the filling of the powder chamber 20, the valve 29 assigned to the vacuum pump 28 is closed, whereas the valve 25 assigned to the powder outlet 24 and the valve 27 assigned to the compressor 19 are open. Subsequent actuation of the compressor 19 leads to flow of transport gas 12 through the powder chamber 20 from the transport gas reservoir 18, the result being that the filter aid 7 now present in the powder chamber 20 is, as discussed above, fed into the feed line 9 and, driven by the pressurized transport gas 12, reaches the feed point 10.

(22) The above-described operation can be repeated until the respectively provided amount of filter aid 7 has been fed into the main line 2.

(23) Very generally, it is the case, here, that the filter aid 7 is fed discontinuously into the feed line 9 and thus into the main line 2 by means of the powder transfer system 8. This can be easily realized with the simple structure depicted in the drawing. Alternatively, the powder transfer system 8 can feed the filter aid 7 virtually continuously into the feed line 9.

(24) It has already been pointed out that the return flow preventer 11 of the feed line 9 is of particular significance in the solution according to the proposal. The return flow preventer 11 blocks a fluid flow in the direction of the powder transfer system 8. Upon exceeding of a switching pressure gradient in the flow direction of the return flow preventer 11, the return flow preventer 11 lets through a flow of filter aid in the direction of the main line 2. The pressure gradient arises from the difference between the pressure P.sub.1 prevailing in the feed line 9 above the return flow preventer 11 in FIG. 1 and the pressure P.sub.2 prevailing in the feed line 9 below the return flow preventer 11. In this case, the return flow preventer 11 only falls into the flow state when the pressure gradient in the flow direction reaches the predetermined switching pressure gradient. Depending on the design of the return flow preventer 11, a switching pressure gradient of differing magnitude can be present.

(25) A particularly simple embodiment of the return flow preventer 11 arises by the return flow preventer 11 being constructed in the manner of a check valve and comprising a valve body 31 which is spring-elastic or is spring-preloaded by means of a spring arrangement.

(26) In the first-mentioned variant, the return flow preventer 11 can, for example, be designed as a lip valve in which lips formed in the valve body 31 open or close depending on the direction of flow. In the case of the embodiment of the return flow preventer 11 having a spring-preloaded valve body, the valve body can, for example, be designed as a flap valve, as a ball or the like.

(27) In an embodiment, the return flow preventer 11 is designed such that the feed line 9 is always free of fermentation broth 4 between the powder transfer system 8 and the return flow preventer 11. In addition, it can be the case that the feed line 9 is free of fermentation broth 4 between the return flow preventer 11 and the feed point 10 at least in the case of a steady main flow 3. It becomes apparent here that the lower section 32 in FIG. 1 of the feed line 9, i.e., the section between the return flow preventer 11 and the feed point 10, can have a certain minimum length in order to reliably prevent fermentation broth 4 from getting into the upper section 33 in FIG. 1 of the feed line, i.e., into the section 33 between the return flow preventer 11 and the powder transfer system 8, via the return flow preventer 11 in the event of an incomplete closure of the return flow preventer 11.

(28) Nevertheless, it must be pointed out that in principle the feed line 9 manages even without the lower section 32 and/or without the upper section 33. In extreme cases, the feed line 9 can even be provided solely by the return flow preventer 11.

(29) Here, the suspension of the filter aid 7 in the fermentation broth 4 stems from the liquid flow in the main line 2 and/or in the main flow pump 5. Especially the flow turbulences arising in the main flow pump 5 lead to particularly good mixing of the filter aid 7 with the fermentation broth 4, and so the path between the feed point 10 and the filter arrangement 6 can ensure sufficient mixing. In various embodiments, the mixing in the main line 2 is further supported by the main line 2 comprising at least one mixing section, in particular downstream of the feed point 10, wherein the main line 2 comprises mixing shapes 34 in the form of flow guiding profiles, baffles or the like in the mixing section. In the exemplary embodiment depicted in FIG. 1, this has been realized by helical mixing shapes 34, in particular in the manner of a static mixer as is known in the case of two-component mixers for example. Said mixing shapes 34 can, for example, be realized as a plastics helix inserted into the main line 2, which can be realized in a simple manner with respect to production. In addition, the mixing shape can be arranged both upstream and downstream of the main flow pump 5.

(30) Alternatively or additionally, the main line 2 can comprise, on the entry side of the filter arrangement 6, an actuatable valve arrangement 35, 36 via which the fermentation broth 4, here, is recirculatable back into the bioreactor 14. An appropriate recirculation line 37 which is guided back into the bioreactor 14 is shown by the dashed line in FIG. 1. Recirculation is triggered by opening of the valve 35 and closing of the valve 36.

(31) Here, the bioprocessing system 1 depicted comprises a control arrangement 38, wherein the powder transfer system 8 and/or the valve arrangement 35, 36 relating to recirculation and/or the main flow pump 5 is/are actuatable by the control arrangement 38. The control arrangement 38 can be an electronic control arrangement, which further has control software running thereon.

(32) With the control arrangement 38, the operation of the bioprocessing system 1 according to the proposal can be automated within wide limits. This concerns in particular the automation of the addition of the filter aid 7. Provided for this purpose can be a sensor arrangement 39, which can ascertain a characteristic of the fermentation broth 4 enriched by the filter aid 7. This could be, for example, a measurement of concentration, turbidity or viscosity. Such a sensor arrangement 39 is immediately upstream of the filter arrangement 6 in FIG. 1. The sensor arrangement 39 can in principle comprise a plurality of sensors distributed in the bioprocessing system 1.

(33) It can be the case that the control arrangement 38 actuates the powder transfer system 8 and/or the valve arrangement 35, 36 relating to recirculation and/or the main flow pump 5 depending on the sensor values of the sensor arrangement 39. In an embodiment, the characteristic ascertained is the concentration of the filter aid 7 in the fermentation broth 4 and/or the temporal course of the concentration of the filter aid 7 in the fermentation broth 4. If, for example, the concentration of the filter aid 7 in the fermentation broth 4 drops below a predetermined threshold, the control arrangement 38 actuates the powder transfer system 8 to add additional filter aid 7. Alternatively, the input pressure or pressure profile, in particular in the main line 2, can be used as a control variable within the meaning of the above characteristic. This means that the amount of filter aid can be dynamically adjusted to the pressure profile in accordance with a dynamic precoat filtration. This is achieved by an appropriate actuation of the valves 25, 27 and 29, as has been elucidated above. A further control variable for filter aid metering is the weighing of the filter aid in the storage container.

(34) Alternatively or additionally, the sensor arrangement 39 can capture the volume flow rate of the fermentation broth 4 through the main line 2 and control the addition of the filter aid 7 depending on the volume flow rate ascertained.

(35) It has been elucidated above that the addition of the filter aid 7 according to the proposal is effected by means of a pressurized transport gas 12. Depending on the design of the conduction system of the bioprocessing system 1, it may be necessary to provide a counterbalance system 40 in order to absorb the energy of the transport gas 12 introduced into the conduction system without excessive mechanical loading of the conduction system.

(36) The counterbalance system 40 can be, for example, a simple counterbalance container, as indicated in FIG. 1. Specifically, the counterbalance system 40 shown in FIG. 1 comprises not only the counterbalance container, but also a venting filter, via which the transport gas 12 is discharged from the system. What is avoided as a result is that the transport gas 12 adversely affects the precoat filtration and the formation of a suitable filter cake. The counterbalance container acts in a way as a gas trap.

(37) The counterbalance container of the counterbalance system 40 can be a stirring bag in order to keep the suspended particles of the filter aid 7 floating.

(38) Alternatively, in the case of the addition of filter aid 7 according to the proposal by means of the powder transfer system 8, the recirculation line 37 can also be always activated by means of the valve arrangement 35, 36, so that the transport gas 12 gets into the bioreactor 14, where it is discharged via the exhaust port.

(39) It must be additionally pointed out that a further actuatable valve 44 is provided at the lower outlet of the bioreactor 14, which valve ensures in the steady state that the hydrostatic pressure of the fermentation broth 4 in the bioreactor 14 is not applied to the main line 2.

(40) According to a further teaching a method for operation of a bioprocessing system 1 according to the proposal is disclosed.

(41) According to the method according to the proposal, it is the case that the filter aid 7 is fed into the feed line 9 in powder form by means of the powder transfer system 8 and is driven toward the feed point 10 by means of a pressurized transport gas 12. In this connection, at least some of the fed filter aid 7 is suspended in the fermentation broth 4 within the main line 2 downstream of the feed point 10 before the fermentation broth 4 enriched with the filter aid 7 passes through the filter arrangement 6. Reference may be made to all above remarks in relation to the mode of operation of the bioprocessing system 1 according to the proposal.

(42) The method according to the proposal concerns in particular the actuation of components such as the powder transfer system 8, the main flow pump 5 or the like. Specifically, the above-discussed variants of actuation of the powder transfer system 8 by means of the control arrangement 38 are part of the method according to the proposal.

(43) Before the specific realization of the single-use concept is addressed, a measure concerning the multiple use of the powder transfer system 8 must be additionally pointed out. In the case of the exemplary embodiment depicted in FIG. 1, it is namely the case that the feed line 9 comprises a steam-to-valve 41 (STV) in the upper section 33, i.e., between the return flow preventer 11 and the powder transfer system 8. Very generally, a steam-to-valve joins a disposable component, such as the feed line 9, to a reusable component, such as the powder transfer system 8, it being possible for the reusable component to be sterilized with steam before the start of the process via the steam-to-valve, in order to subsequently establish joining with the disposable component, which can be further provided in a gamma-sterilized state.

(44) It is presently thus the case that the steam-to-valve 41 allows steam sterilization of the connection of the powder transfer system 8 before and/or after the addition of filter aid 7. This further reduces the risk of contamination even after the feed line 9 has been exchanged.

(45) According to a further teaching the use of a sterile-packed transfer set 42 composed of prefabricated system components for construction of a bioprocessing system 1 according to the proposal disclosed.

(46) After the transfer set 42 has been unpacked from the packaging 43, the transfer set is connected to the bioprocessing system 1 in addition.

(47) Alternatively, the transfer set 42 can consist of multiple individual-component sets, which are joined to one another with the aid of sterile connectors upon construction. What is then assigned to the individual-component sets in each case is a separate piece of sterile subpackaging.

(48) Two variants for a transfer set 42 to be used can be gathered from the depiction according to FIG. 2. According to the use according to the proposal, the transfer set 42 in the sterile packaging 43 comprises at least the feed line 9 including the return flow preventer 11. In the case of the exemplary embodiment shown in FIG. 2a, the above-discussed steam-to-valve 41 is additionally assigned to the feed line 9.

(49) In addition, the transfer set 42 in the sterile packaging 43 can additionally comprise the main line 2, here including the main flow pump 5, which is connected to the feed line 9 in a prefabricated manner at the feed point 10. Further, the transfer set 42 in the sterile packaging 43 can comprise at least part of the bioreactor 14, here a bioprocess bag 15 assigned to the bioreactor 14, which is connected to the main line 2 in a prefabricated manner at the feed point 10.

(50) In an embodiment, the system components assigned to the transfer set 42 are single-use components. This concerns the feed line 9 and/or the main line 2 and/or the return flow preventer 11 and/or the main flow pump 5. In an embodiment, the components assigned to the transfer set 42 are formed at least in part, such as predominantly, from a plastics material, such as flexible plastics material, such as from a silicone material and/or from a polymer material, in particular PE (polyethylene), PP (polypropylene), PTFE (polytetrafluoroethylene), PBT (polybutylene terephthalate), PSU (polysulfone), PESU (polyether sulfone), PC (polycarbonate). In this respect too, reference may be made to the remarks in relation to the bioprocessing system 1 according to the proposal.