Parallel Separation System

Abstract

A separation system may include a number of parallel fluid paths. Each parallel fluid path may include a separation module, and an adjustable flow restrictor. Each adjustable flow restrictor is operable sequentially and operable such that the hydraulic resistance of all the parallel fluid paths is substantially the same and is equal to or higher than the hydraulic resistance of a fluid path identified to have the highest hydraulic resistance. The system includes a pressure sensor that measures pressure loss over the whole separation system. The system is operable such that the hydraulic resistances of the respective separation modules are synchronised, and such that when operated in parallel and at substantially the same time, the respective modules have substantially the same time residence times. The system may include a control system for automated operation.

Claims

1. A separation system comprising: a number of parallel fluid paths, wherein each parallel fluid path comprises a separation module, and an adjustable flow restrictor, each adjustable flow restrictor being operable sequentially and operable such that the hydraulic resistance of all the parallel fluid paths is substantially the same and is equal to or higher than the hydraulic resistance of a fluid path identified to have the highest hydraulic resistance; and a pressure sensor that measures pressure loss over the whole separation system, wherein the system is operable such that the hydraulic resistances of the respective separation modules are synchronised, and such that when operated in parallel and at substantially the same time, the respective modules have substantially the same time residence times.

2. The separation system of claim 1, wherein the separation modules are disposable.

3. The separation system of claim 1, further comprising one sensor of the same type provided in all the parallel fluid paths.

4. The separation system of claim 3, wherein the sensors are disposable probes measuring conductivity or UV absorbance.

5. The separation system of claim 1, further comprising one sensor of the same type provided in all the parallel fluid paths except one.

6. The separation system of claim 5, wherein the sensors are disposable probes measuring conductivity or UV absorbance.

7. The separation system of claim 1, further comprising one system sensor configured to measure at least one characteristic for the whole separation system.

8. The separation system of claim 1, further comprising control system configured to measure, store and compare sensor signals and information, control the synchronization of the hydraulic resistance, and control the position of the restrictors.

9. A method in a separation system comprising parallel fluid paths each comprising a separation module, the method comprising: providing an adjustable flow restrictor in each fluid path; identifying the fluid path with highest hydraulic resistance by measuring the hydraulic resistance of each fluid path sequentially and separately while stopping the fluid flow through all other fluid paths or alternatively by measuring sequentially the hydraulic resistance of all fluid paths except one fluid path and additionally measuring the hydraulic resistance of the whole system and using the hydraulic resistance measurements for obtaining also the hydraulic resistance of the one fluid path; adjusting the hydraulic resistance of each of the parallel fluid paths to be substantially the same, by adjusting the adjustable flow restrictors in the fluid paths sequentially and separately while stopping the fluid flow through all other fluid paths, such that the hydraulic resistance of each fluid path is equal or higher than the hydraulic resistance of the fluid path identified to have the highest hydraulic resistance; and after adjusting the hydraulic resistance, operating the separation modules in parallel and at substantially the same time with synchronised hydraulic resistance to provide substantially the same residence times for each module.

10. The method of claim 9, wherein the method of identifying and adjusting is automated.

11. The method of claim 10, wherein the separation system comprises a control system that performs the identifying, the adjusting, and the operating.

12. The method of claim 9, wherein each separation module is a chromatography column.

13. The method of claim 9, wherein each the separation module is disposable.

14. The method of claim 9, further comprising: providing a sensor of the same type in either each of the parallel fluid paths or in each of the parallel fluid paths except one; and measuring a characteristic fluid property with at least one of the sensors in the parallel fluid paths.

15. The method of claim 14, further comprising: measuring the same characteristic fluid property with a system sensor positioned in the outlet of the separation system; and comparing the measured characteristic fluid properties to evaluate and/or qualify the performance of the separation system.

16. The method of claim 14, wherein the measuring comprises measuring residence time and/or chromatographic efficiency.

17. The method of claim 14, further comprising a comparing sensor response from at least one sensor in one of the fluid paths with the sensor response from the system sensor.

18. The method of claim 14, wherein the characteristic fluid property is fluid flow rate, concentration, conductivity, pH, force, pressure, temperature or changes in the absorption, reflection, or extinction of light or energy.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 shows schematically a separation system comprising a parallel assembly of separation modules according to one embodiment of the invention.

[0012] FIG. 2 is a flow chart of the method of the invention according to one embodiment of the invention.

[0013] FIG. 3 shows a pulse response diagram for one example of a parallel assembly comprising three separation modules.

[0014] FIG. 4 shows schematically a separation system comprising sensors according to one embodiment of the invention.

[0015] FIG. 5 shows a pulse response diagram for one example according to the embodiment shown in FIG. 4.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0016] FIG. 1 shows schematically a separation system 1 comprising a parallel assembly 3 of separation modules M1, M2, . . . Mn according to one embodiment of the invention. The parallel assembly 3 comprises a number of parallel fluid paths F1, F2, . . . Fn. Three fluid paths are shown here but it could be any number of parallel fluid paths. Each fluid path F1, F2, . . . Fn comprises a separation module M1, M2, . . . Mn. According to the invention each fluid path F1, F2, . . . Fn also comprises an adjustable flow restrictor R1, R2, . . . Rn. The adjustable flow restrictors R1, R2, . . . Rn should be possible to open completely, i.e. adjust to a position where no flow restriction is provided. Suitably the flow restrictors should also be possible to close completely, i.e. adjust such that no flow at all can pass. Alternatively or complementary a valve can be provided in each fluid path F1, F2, . . . Fn such that the fluid paths can be opened or closed. The separation system 1 further comprises an inlet fluid path 5 entering the parallel assembly 3 and an outlet fluid path 7 leaving the parallel assembly 3. The inlet fluid path 5 comprises in this embodiment a pump 9, a flow meter 11 and a pressure sensor 13. Alternatively the flow meter could be positioned downstream the parallel assembly 3, which is shown as flow meter 11′. In another alternative embodiment, the pump 9 in the separation system is a pump of metering type, hereby allowing for a prior determination of delivered flow rate by calculation from a number of pump revolutions, a displaced volume or similar. In this alternative, flow meters 11 and 11′ described above may be omitted as the flow rate is pre-determined. Yet another alternative embodiment of the system may employ a calibration curve for the system pump to avoid the need for a flow meter in the system.

[0017] The separation modules M1, M2, . . . Mn can be chromatography columns packed with a porous matrix, which fall in the category of fixed beds. Alternatively, the separation modules M1, M2, . . . Mn could be expanded or fluidized bed columns. It is obvious that the invention can also be applied to reaction modules and columns, here including fixed bed systems as well as expanded and fluidized bed systems aimed for changing, coupling or modifying a substance by contact with the particulate matter in the reactor.

[0018] In some embodiments, the separation modules M1, M2, . . . Mn are preferably disposable modules, hereby allowing the use of inexpensive standardized disposable modules in a parallel fashion to adapt to the capacity required in the specific application.

[0019] Single use systems, also called disposable systems are more and more used in the bioprocess industry. For example separation or reaction systems such as chromatography systems, filter systems or bioreactor systems have today at least partly been provided as disposable systems. This eliminates the need for cleaning and cleaning validation before processing, in between processes and cycles or after processing before re-use as required for conventional re-usable equipment. With disposable systems cross-contamination is avoided.

[0020] The wetted part of the adjustable flow restrictors R1, R2, . . . Rn may be part of the corresponding separation modules itself and can therefore be disposable and of low cost. The controlling unit of the adjustable restrictors may be re-usable, like a pinch valve principle, for example.

[0021] FIG. 2 is a flow chart of the method of the invention according to one embodiment of the invention. The method steps are described in order below.

[0022] S1: Opening one of the flow restrictors R1, R2, . . . Rn completely and at the same time closing all other flow restrictors completely, i.e. there will only be flow through one of the separation modules M1, M2, . . . Mn.

[0023] S2: Adjusting flow rate for hydraulic resistance measurement. Hydraulic resistance is measured by relating the measured pressure drop over the fluid line to the actual flow rate in this line, the latter may be measured by a flow meter or may be known in case of a metering pump or when using a calibration curve. In this example, the flow rate is adjusted to a defined constant flow rate. In practice, the flow rate will often be adjusted in proportion to the number of modules in the parallel assembly. For example, for a system set up with 5 modules that shall be operated in parallel with a system flow rate of 100 l/h over all modules, a flow rate of 100/5=20 l/h is suitably applied to the individual module when running the sequential identification of hydraulic resistance at each individual module and also when adjusting the hydraulic resistance subsequently. However, any constant flow rate could be applied as long as it allows for a predictable and scalable measurement and adjustment of the hydraulic resistance that ensures the synchronization of the parallel assembly described by this invention. Given that this condition is followed, even different flow rates may be applied for measuring and adjusting the hydraulic resistance(s). Preferably, the flow rate selected in practice would be constant and within the range of typical operating flow rates suitable for the separation module and parallel assembly.

[0024] S3: Measuring the hydraulic resistance of the system, i.e. of the only fluid path that is open.

[0025] The hydraulic resistance is suitably measured by measuring a pressure loss over the open fluid path by a pressure sensor positioned upstream the parallel fluid path to be characterised. (pressure sensor 13 in FIG. 1)

[0026] The hydraulic resistance of the system measured in S3 is substantially equal to the hydraulic resistance of the separation module in the fluid path where the flow restrictor has been completely opened.

[0027] S5: Opening another one of the flow restrictors R1, R2, . . . Rn completely and closing the others completely.

[0028] S6: Keeping the flow rate at the same constant level as in S2. If the pressure loss over the fluid path and separation module is in linear proportion to the flow rate over a wider range, the hydraulic resistance may be measured at different flow rates within said linear range. However, in practice the flow rate will be selected to the same constant level for measuring the resistance in all parallel lines.

[0029] S7: Measuring the hydraulic resistance of the system, i.e. the pressure loss over the fluid path comprising the flow restrictor that now is completely open. That is now the measure of the hydraulic resistance of the separation module comprised in that fluid path.

[0030] S9: Repeating the steps S5-S7 until all flow restrictors R1, R2, . . . Rn has been completely opened and the hydraulic resistance of each one of the separation modules has been measured alone.

[0031] S11: Determining which one of the separation modules M1, M2, . . . Mn having the highest hydraulic resistance. This is determined by comparing the measurement results from S3 and S7 above.

[0032] S13: Adjusting the adjustable flow restrictors R1, R2, . . . Rn such that the hydraulic resistance of all the parallel fluid paths F1, F2, . . . Fn is substantially the same as the hydraulic resistance of the separation module with highest hydraulic resistance. The goal is to achieve the same hydraulic resistance in all parallel fluid paths. Substantially the same is used here just to make it clear that it is hard to achieve exactly the same hydraulic resistance and also small differences should be covered by this invention. The differences should not be more than 10%, preferably less than 5%, and most preferable less than 2.5%. Hereby, the flow restrictor provided in the fluid path comprising the separation module having the highest hydraulic resistance need not be adjusted but kept open and all the other flow restrictors need to be adjusted such that the total hydraulic resistance in each fluid path, i.e. hydraulic resistance of separation module and flow restrictor, equals the hydraulic resistance of the separation module with highest hydraulic resistance. When performing the adjusting the flow rate is kept at the same constant level as in S2 and S6. Only the flow path comprising the flow restrictor to be adjusted is open and all other flow paths are closed and the pressure loss over the open flow path is watched by the pressure sensor. The adjustable restrictor of the open fluid path is adjusted until the measured pressure loss is equal to the pressure loss measured for the fluid path having the highest pressure loss (in other words hydraulic resistance) as measured in S3 and S5. By adjusting the hydraulic resistance in each flow path to match the characteristics of the flow path with the highest resistance as described above, the final pressure drop over the complete parallel assembly will be kept as low as possible, and required, respectively. Alternatively, it is of course possible to adjust the hydraulic resistance in each fluid path in the parallel assembly to match a hydraulic resistance that is higher than the measured highest hydraulic resistance in the fluid path of highest resistance. Hereby, the overall objective of synchronising the hydraulic resistance between all fluid paths will still be achieved, however, this will be on expense of higher overall pressure drop over the system at the operating flow rate.

[0033] An alternative to the procedure of measuring hydraulic resistance described above would be to measuring the hydraulic resistance of all fluid paths except one sequentially and additionally measuring the hydraulic resistance of the whole system and using these measurements (i.e. subtracting the hydraulic resistance of each separately measured fluid path from the hydraulic resistance for the whole system) for achieving the hydraulic resistance of also the last fluid path.

[0034] An alternative to the preferred embodiment described in FIG. 1 where a single pressure sensor 13 is used to determine the pressure drop over each and every fluid line during the adjustment of hydraulic resistance, pressure sensors could be provided in each fluid path of the parallel assembly 3 upstream the respective separation modules M1 . . . Mn to measure the pressure drop in the fluid paths F1 . . . Fn. However, it is the objective of this invention to simplify the instrumentation and equipment needed for adjusting the parallel assembly and therefore the use of a single pressures sensor in the system 1 upstream the parallel assembly 3 is preferable.

[0035] These method steps described above can suitable be automated. In that case a control system is provided that a) measures, stores and compares sensor signals and information on pressure low and flow rate for each fluid line, b) controls the sequential procedure for synchronizing the hydraulic resistance, and c) controls the position of the restrictors.

[0036] The method steps described above can also suitably be repeated between process cycles or process steps. This can be suitable if the hydraulic resistance of the fluid paths will vary somewhat after time due to aging, alteration or similar of the chromatography matrix inside the separation module, for example.

[0037] FIG. 3 shows a pulse response diagram for one example of a parallel assembly comprising three separation modules, here chromatography columns. This is just a fictive example showing how different hydraulic resistance in the fluid paths of the parallel assembly can affect the response. An assumption here is that all columns have the same target capacity (in terms of mass/column volume) and the same chromatographic efficiency in terms of plate height. They shall differ only by their individual hydraulic resistance. A first curve 21 is shown in the diagram and this is the nominal response, i.e. ideal output pulse in a system where the hydraulic resistances of all fluid paths are equal as response to a pulse sent into the system. A second curve 23 is the actual response in this specific fictive example that results from a parallel assembly of three separation modules that are not synchronized in regard to their hydraulic resistance and where all three modules are of different hydraulic resistance. The actual response of the separation system shown by curve 23 indicates that the hydraulic resistance of the different fluid paths not are equal as it deviates from the ideal response, curve 21. A third, a fourth and a fifth curve 25a, 25b, 25c are theoretic curves of responses from each one of the fluid paths. Here it is clear that the fourth and fifth curves 25b, 25c correspond to two fluid paths having a greater hydraulic resistance than the fluid path corresponding to the third curve 25a, which is obvious by the fact that the average residence time for curve 25a is smaller than for curves 25b and 25c. The smaller residence time is due to the smaller hydraulic resistance over this fluid line in comparison to the other two lines.

[0038] An adjustment of hydraulic resistance in a parallel assembly according to the invention will ideally result in a pulse response diagram where all curves will superimpose to the nominal pulse response, curve 21.

[0039] FIG. 4 shows schematically a separation system 31 comprising a parallel assembly 33 of separation modules M1′, M2′, . . . Mn′ according to one embodiment of the invention. The parallel assembly 33 comprises a number of parallel fluid paths F1′, F2′, . . . . Fn′. Three fluid paths are shown here but it could be any number of parallel fluid paths. Each fluid path F1′, F2′, Fn′ comprises a separation module M1′, M2′, . . . Mn′. According to the invention each fluid path F1′, F2′, . . . Fn′ also comprises an adjustable flow restrictor R1′, R2′, . . . Rn′ as described above. The separation system 31 further comprises an inlet fluid path 35 entering the parallel assembly 33 and an outlet fluid path 37 leaving the parallel assembly 33. The inlet fluid path 35 comprises in this embodiment a pump 39, a flow meter 41 and a pressure sensor 43. According to this embodiment of the invention each fluid path F1′, F2′, . . . Fn′ also comprises a sensor S1, S2, . . . Sn and the outlet fluid path 37 in the system 31 comprises at least one system sensor 45. Sensors S1 . . . Sn and system sensor 45 are adapted to measure the residence time and/or chromatographic efficiency over each individual separation module M1′, M2′, . . . Mn′ when running the separation modules in parallel and at the same time these features can also be measured on a system level by means of the system sensor 45. Hereby the overall response on system level as measure by the system sensor 45 can be compared to the individual response of each separation module as measured by the sensors S1 . . . Sn. In an alternative embodiment of the invention sensors S1, . . . Sn are only provided in all the fluid paths except from one. The sensor response from the last fluid path can still be calculated by using the response from the system sensor and subtracting the other sensor responses. Suitably, these sensors are disposable probes measuring different fluid properties such as for example flow rate, concentration, force, pressure, temperature, conductivity, pH or the absorbance, reflectance or emission of light as for example the measurement of UV absorbance.

[0040] FIG. 5 shows a pulse response diagram for one example according to the embodiment shown in FIG. 4. In this example there are three fluid paths. F1′, F2′, F3′ and thus three separation modules M1′, M2′, M3′. The curve denoted 51 shows the actual response on system level, i.e. measured by the system sensor 45. Here residence time is measured as the average residence time calculated by integration over the curve. In a simplified procedure, residence time may be deducted from the residence time at the maximum pulse response (maximum height of the peak). The leading in the curve suggests that either one (or more) module(s) in the parallel system may deviate from the nominal response in terms of residence time or that at least one module may have a packed bed efficiency showing excessive leading. However, the overall response signal alone gives no detailed information about the status of the individual modules and the root cause for the leading in the curve. This information can only be provided by the signals form the individual modules. The curve denoted 53 shows the actual response as measured in the first sensor 51 in the first fluid path F1′. This is hereby the actual response from the first separation module M1′ when run in parallel with the other separation modules M2′, M3′ of the system. The curve denoted 55 shows the actual response as measured in the second sensor S2 in the second fluid path F2′. This is hereby the actual response from the second separation module M2′ when run in parallel with the other separation modules M1′, M3′ of the system. The curve denoted 57 shows the actual response as measured in the third sensor S3 in the third fluid path F3′. This is hereby the actual response from the third separation module M3′ when run in parallel with the other separation modules M1′, M2′ of the system. For the example discussed here, all of the separation modules have residence time curves of symmetric shape, but one separation module, the first separation module M1′, has a decreased average residence time. This reveals that the hydraulic resistance for this module is lower and the actual flow rate higher than for the other modules, respectively. As a result, the assessment of signals on the subsystem level gives full insight in the efficiency of the parallel assembly as required for GMP manufacturing processes. Acceptance criteria for the performance of the individual separation modules as well as for the overall performance of the parallel assembly (as measured using sensor 45) can be set and monitored at installation of the parallel assembly as well as before and throughout a process. Three main parameters would typically be measured and evaluated for a parallel assembly of chromatography modules: [0041] a) average residence time for each module in the parallel assembly compared to the average residence time in the response curve on system level [0042] b) chromatographic efficiency in terms of peak width (band broadening) for each module in the parallel assembly compared to the peak width for the response curve on system level, and [0043] c) peak symmetry for the response curve for each module in the parallel assembly compared to the symmetry in the response curve on system level.

[0044] In order to reduce complexity and cost of systems for purposes of control and measurement described in this invention, multiplexing techniques can be used. Multiplexing techniques allow the combined use of a common signal processing channel from or to the control system in order to sequentially access and modify the position of the control valves for example. Further, multiplexing techniques allow for the sequential or simultaneous reading of sensor information to a transmitter or control system, respectively. During the sequential adjustment of the hydraulic resistance of the fluid lines as described in this invention, the multiplexing principle is especially suitable for building a control system. With regard to the reading of sensor information as described for the performance monitoring of the separation modules, multiplexing enabled as the sequential and cyclic reading of discrete sensor signals is also applicable due to the rather slow changes in the pulse response signals that are to be monitored at column modules and system.