Single-use manifolds for automated, aseptic handling of solutions in bioprocessing applications

Abstract

Presteralized manifolds are provided which are designed for sterile packaging and single-use approaches. disposable tubing and flexible-wall containers are assembled via aseptic connectors. These manifolds are adapted to interact with other equipment which can be operated by a controller which provides automated and accurate delivery of biotechnology fluid. The manifold also can be used in conjunction with one or more sensors such as pressure and conductivity sensors that interact with the controller or are connected to a separate user interface. An aseptic environment obtains avoiding or reducing cleaning and quality assurance procedures.

Description

CROSS REFERENCE TO RELATED APPLICATION

This electrical electrical conductivity
The sensor-specific Cell Constant (K) is then stored in the non-volatile memory of the conductivity sensor 200.

For example, the solution conductivity for a 0.100 molar KCl solution is known to be 12,850 μS (or 0.01285 S) at 25.0° C. The typical measured conductance for a 0.100 molar KCl solution using a sensor with a ⅛ inch Luer conductivity cell with a 0.10 inch electrode separation is 0.0379 Siemens. Using the equation above, the corresponding Cell Constant (K) for the particular disposable sensor of this illustration is calculated to be 0.339 cm⁻¹.

Once the Cell Constant (K) is calculated it is stored on the sensor. The user interface will recall the Cell Constant (K) from the sensor. When undergoing normal operations, the user interface 210 measures the conductance in Siemens of the solution flowing through the fluid conduit 202 by passing a current through the electrodes 203 and measuring the current across the two inner electrodes 203. The user interface 210 will then use the Cell Constant (K) for this particular disposable sensor to determine the electrical conductivity of the solution flowing through the fluid conduit. The user interface calculates the solution's electrical conductivity by multiplying the measured conductance by the Cell Constant (K), as demonstrated in the following equation:
[Cell Constant, K, (cm⁻¹)]×[Conductance (S)]=[Solution Conductivity, (S/cm)]
The sensor, once calibrated, provides a linear response for NIST traceable standard solutions ranging from 1 to 200,000 μS.

The temperature of a solution will also affect its electrical conductivity. As a result, the sensor must also measure and account for the temperature of the solution to achieve an accurate electrical conductivity measurement. Ordinarily, un-calibrated thermistors will have a variance of ±5% between their measured reading and the actual temperature. A calibrated thermistor may achieve a variance of ±1% or less.

In this regard, a sensor-specific Temperature Offset is calibrated at the factory. To determine the Temperature Offset, temperature readings are made while a 25.0° C. KCl solution is pumped through the fluid conduit and over the electrodes. A comparison is then made between the temperature reading of the un-calibrated thermistor on the sensor (Tsen) with that of a NIST-traceable thermometer or thermistor (Tref). The difference between the two readings is the Temperature Offset (Tref-Tsen=TempOffset). The Temperature Offset may have either a positive or a negative value. The sensor-specific Temperature Offset is then stored in the non-volatile memory on the sensor.

Each sensor has an “out-of-box” performance variance value which is also stored on the sensor, typically in the non-volatile memory chip. This “out-of-box” value is a statistically derived performance variance (measured in 0.100 molar KCl at 25.0° C.) that represents the maximum measurement error for that specific sensor within a 98% confidence limit. The statistically derived variance value is based on the performance analysis of all calibrated sensors within a production run, typically of between about 100 and about 500 sensor assemblies. The factory determined performance variance represents a predictive, “out-of-box” sensor performance level. This statistical treatment is analogous to and representative of a sensor validation procedure. Factory pre-validated conductivity sensors are thereby provided. The meaning of “pre-validated” is further illustrated herein, including as follows.

In the preferred embodiment, each conductivity sensor undergoes two factory measurements. The first measurement involves sensor calibration and determination of the specific Cell Constant (i.e. response factor) using a 0.100 molar KCl solution at 25.0° C. as described herein. In another separate and distinct measurement with 0.100 molar KCl solution at 25.0° C., the solution conductivity is experimentally determined using the pre-calibrated sensor. When taking into account the experimentally derived solution conductivities for all pre-calibrated sensors, the mean conductivity value closely centers around the theoretical value of 12,850 μS with a 3-sigma standard deviation of +/−190 μS or +/−1.5% An operator may access this information via the user interface 210 or Conductivity Monitor.

In addition to the calibration information, such as the Cell Constant (K) and the Temperature Offset, the sensor-specific Device ID, Calibration Date, and statistical information are stored in the non-volatile memory. The Device ID is stored as a string of numbers, for example: nn-ss-xxxx-mmyy. In this example, the variables represent the sensor lot number (nn), fluid conduit size (ss), the device serial number (xxxx) and the manufacturing date by month and year (mmyy). For example, sensor containing the Device ID of 02-02-0122-1105 means that this sensor was the 122^nd sensor made in lot 02 of conduit size 02 (a fluid conduit with a diameter of ⅜″ or 9.5 mm having a barb connector), manufactured in November of 2005. In this illustration, the sensor-specific Calibration Date or the date on which the sensor was calibrated using 0.100 molar KCl solution at 25.0° C. is also stored in the sensor's non-volatile memory as a separate data entry.

Additionally, statistical information or statistical data about the entire lot may also be stored in the non-volatile memory. For example, the average cell constant for lot 122 may be stored in the non-volatile memory of each sensor in lot 122. The standard deviation for cell constants for each lot may also be stored (i.e. “out-of-box” variance value) in the non-volatile memory of each sensor produced in that lot. This allows the user to determine whether a particular sensor is within the statistical range to achieve the proper margin of error for a specific experiment or bio-processing operation. As those skilled in the art will appreciate, other known statistical methods may be utilized, the results of which may be stored in the non-volatile memory on the sensing device.

In addition to storing the Cell Constant (K), Temperature Offset, Device ID, the Calibration Date, and other information in the non-volatile memory on the sensor, a summary of this information may be printed on the outside of the sensor. This information may be consulted by the user, used to later re-calibrate the sensor, and allows the user to input the printed information directly into the user interface.

It will be understood that the embodiments of the present invention which have been described are illustrative of some of the applications of the principles of the present invention. Numerous modifications may be made by those skilled in the art without departing from the true spirit and scope of the invention.

Claims

1. A manifold system for biotechnology uses, comprising:

a manifold unit which is pre-sterilized and disposable so as to be adapted for single-time usage, including:

(a) at least one length of tubing having at least one inlet end portion, at least one outlet end portion, an outside surface, and an inside surface which is sterilized for passage of a biotechnology fluid therethrough,

(b) a plurality of single-use containers, each container having an access port, and

(c) at least one aseptic connector that operatively connects said length of tubing with each said single-use container;

a plurality of valves operable to engage said length of tubing, the valves being remotely operable valves;

a disposable filter positioned along said length of tubing such that the biotechnology fluid can flow therethrough at a location upstream of said outlet and end portion;

at least one pre-sterilized, calibrated and disposable electrical conductivity sensor adapted for single-time usage;

the electrical conductivity sensor senses the electrical conductivity of the biotechnology fluid within the tubing and has a memory component capable of storing data, the memory component including a sensor-specific temperature offset assigned to that specific sensor during calibration of the sensor, wherein said temperature offset was determined during manufacture employing a calibration solution, including determining the actual temperature (Tref) value of the calibration solution, using the specified pre-calibrated sensor to measure the temperature (Tsen) value of the calibration solution, and mathematically combining said Tref and said Tsen into said sensor specific temperature offset;

at least one disposable pressure sensor positioned along said length of tubing such that the biotechnology fluid can flow therethrough at a location selected from the group consisting of upstream, downstream, both upstream and downstream of said disposable filter, and upstream of said outlet end portion; and

a controller which controls operation of said remotely operable valves, said controller having control logic which dictates the timing of opening and closing of said remotely operable valves.

2. The system in accordance with claim 1, wherein said control logic of the controller dictates is operable to dictate the rate of flow of the biotechnology fluid.

3. The system in accordance with claim 2, wherein said control logic of the controller determines is operable to determine the extent of filling of at least one of the single-use containers by processing data monitored by the system to achieve filling of the single-use container by volume, by weight, or by flow rate and filling time.

4. The system in accordance with claim 1, wherein said control logic of the controller determines is operable to determine the extent of filling of at least one of the single-use containers by processing data monitored by the system to achieve filling of the single-use container by volume, by weight, or by flow rate and filling time.

5. The system in accordance with claim 1, wherein said control logic is operable to activate flow of the biotechnology fluid and opens one of the remotely operable valves for a length of time needed to flow a selected volume or weight of biotechnology fluid into a single-use container associated with that remotely operable valve, and wherein said control logic is operable to activate flow of the biotechnology fluid and opens another of the remotely operable valves for a length of time needed to flow a selected volume or weight of biotechnology fluid into another valve single-use container until a user-selected number of single-use containers are filled.

6. The system in accordance with claim 1, wherein said outlet end portion of the tubing has a plurality of serially arranged outlet passageways each having one of said aseptic connectors for operable connection with one of said single-use containers, and wherein one of said remotely operable valves controls passage of the biotechnology fluid from the tubing to the single-use container bag.

7. The system in accordance with claim 1, wherein the disposable pressure sensor is positioned along said length of tubing such that the biotechnology fluid can flow therethrough at a location upstream of said outlet end portion.

8. The system in accordance with claim 1, wherein said system is for tangential flow filtration, wherein one said single-use container is a process solution container and another said single-use container is a permeate collection container, wherein said tubing includes at least two sections including a filtration flow-through section and a filtered fluid section, said filtration flow-through section includes said process solution container, said filtered fluid section includes said permeate collection container, and said disposable filter is between said filtration flow-through section and said filtered fluid section, whereby fluid from said process solution container can be filtered through said disposable filter and collected in said permeate collection container.

9. The system in accordance with claim 8, wherein said inlet end portion is within said filtration flow-through section and in operative communication with said process solution single-use container, said filtration flow-through section further includes a recirculation length of tubing having one of said remotely operable valves between an exit port of said disposable filter and said process solution single-use container.

10. The system in accordance with claim 9, wherein the disposable pressure sensor is positioned along said filtration flow-through section tubing such that the biotechnology fluid can flow therethrough at a location downstream of said disposable filter.

11. The system in accordance with claim 8, wherein the disposable pressure sensor is positioned along said filtration flow-through section tubing such that the biotechnology fluid can flow therethrough at a location upstream of said disposable filter.

12. The system in accordance with claim 8, wherein the disposable pressure sensor is positioned along said filtered fluid length of tubing such that the biotechnology fluid can flow therethrough at a location between said disposable filter and said permeate collection single-use container.

13. The system in accordance with claim 1, wherein at least one of the single-use containers includes a shut-off clamp for its access port, and wherein said single-use container further includes a port that releases gas or pressure build-up from said container, an auxiliary access port, and a shut-off clamp for said its access port and for said auxiliary access port.

14. The manifold system in accordance with claim 1, wherein the container is a bag, and the remotely operable valve is a pinch valve that engages the outside surface of the length of tubing.

15. A manifold system for biotechnology uses, comprising:

a manifold unit which is pre-sterilized and disposable so as to be adapted for single-time usage, including:

(d a) at least one length of tubing having at least one inlet end portion, at least one outlet end portion, an outside surface, and an inside surface which is sterilized for passage of a biotechnology fluid therethrough,

(e b) at least one single-use container having an access port, and

(f c) at least one aseptic connector that operatively connects said length of tubing with said at least one single-use container;

a plurality of valves operable to engage said length of tubing, the valves being remotely operable valves;

a disposable filter positioned along said length of tubing such that the biotechnology fluid can flow therethrough at a location upstream of said outlet and end portion;

at least one pre-sterilized, calibrated and disposable electrical conductivity sensor adapted for single-time usage;

the electrical conductivity sensor senses the electrical conductivity of the biotechnology fluid within the tubing and has a memory component capable of storing data, the memory component including a sensor-specific temperature offset assigned to that specific sensor during calibration of the sensor, wherein said temperature offset was determined during manufacture employing a calibration solution, including determining the actual temperature (Tref) value of the calibration solution, using the specified pre-calibrated sensor to measure the temperature (Tsen) value of the calibration solution, and mathematically combining said Tref and said Tsen into said sensor specific temperature offset;

at least one disposable pressure sensor positioned along said length of tubing such that the biotechnology fluid can flow therethrough at a location selected from the group consisting of upstream, downstream, both upstream and downstream of said disposable filter, and upstream of said outlet end portion; and

a controller which controls operation of a plurality of said remotely operable valves, said controller having control logic which dictates is operable to dictate the timing and the extent of opening and closing of a plurality of said remotely operable valves.

16. The system in accordance with claim 15, wherein said control logic of the controller dictates is operable to dictate the rate of flow of the biotechnology fluid.

17. The system in accordance with claim 16, wherein said control logic of the controller determines is operable to determine the extent of filling of the single-use container by processing data monitored by the system to achieve filling of the single-use container by volume, by weight, or by flow rate and filling time.

18. The system in accordance with claim 15, wherein said control logic of the controller determines is operable to determine the extent of filling of the single-use container by processing data monitored by the system to achieve filling of the single-use container by volume, by weight, or by flow rate and filling time.

19. The system in accordance with claim 15, wherein the disposable pressure sensor is positioned along said length of tubing such that the biotechnology fluid can flow therethrough at a location upstream of said outlet end portion.

20. The system in accordance with claim 15, wherein the disposable pressure sensor is positioned along said length of tubing such that the biotechnology fluid can flow therethrough at a location downstream of said disposable filter and upstream of said outlet end portion.

21. The system in accordance with claim 15, wherein the single-use container includes a shut-off clamp, and wherein said single-use container further includes an access port that releases gas or pressure build-up from said container, and said container and further includes an auxiliary port, further including a shut-off clamp for said auxiliary access port.

22. The manifold system in accordance with claim 15, wherein the container is a bag, the remotely operable valve is a remotely operable pinch valve that engages the outside surface of the length of tubing, the flow imparting unit is a pump, and the control logic controls or dictates is operable to control or dictate the timing of opening and closing of the remotely operable pinch valve.

23. A system for biotechnology uses, wherein said system is for tangential flow filtration, comprising: a manifold unit which is pre-sterilized and disposable so as to be adapted for single-time usage, including: (a) at least one length of tubing having at least one inlet end portion, at least one outlet end portion, an outside surface, and an inside surface which is sterilized for passage of a biotechnology fluid therethrough, (b) a plurality of single-use containers, each having an access port, one said single-use container is a process solution container and another said single-use container is a permeate collection container, (c) said tubing includes at least two sections including a filtration flow-through section and a filtered fluid section, said filtration flow-through section includes said process solution container, said filtered fluid section includes said permeate collection container, (d) an aseptic connector of said single-use container, (e) a disposable filter between said filtration flow-through section and said filtered fluid section, whereby fluid from said process solution container is filtered through said disposable filter and is collected in said permeate collection container (f) at least one pre-sterilized, calibrated and disposable electrical conductivity sensor adapted for single-time usage, the electrical conductivity sensor senses the electrical conductivity of the biotechnology fluid within the tubing and has a memory component capable of storing data, the memory component including a sensor-specific temperature offset assigned to that specific sensor during calibration of the sensor, wherein said temperature offset was determined during manufacture employing a calibration solution, including determining the actual temperature (Tref) value of the calibration solution, using the specified pre-calibrated sensor to measure the temperature (Tsen) value of the calibration solution, and mathematically combining said Tref and said Tsen into said sensor specific temperature offset, and (g) at least one disposable pressure sensor positioned along said length of tubing such that the biotechnology fluid can flow therethrough at a location selected from the group consisting of upstream, downstreamah, both upstream and downstream of said disposable filter, and upstream of said outlet end portion; and at least one remotely operable valve, said remotely operable valve engaging said length of tubing and independently selectively allowing or stopping flow of the biotechnology fluid through said inside surface of the length of tubing.

24. The system in accordance with claim 23, wherein said inlet end is within said filtration flow-through section and in operative communication with said process solution single-use container, and said filtration flow-through section further includes a recirculation length of tubing having said valve between an exit port of said disposable filter and said process solution single-use container.

25. The system in accordance with claim 24, wherein the disposable pressure sensor is positioned along said recirculation length of tubing such that the biotechnology fluid can flow therethrough at a location between said disposable filter and said valve along said recirculation length.

26. The system in accordance with claim 23, wherein the disposable pressure sensor is positioned along said tubing such that the biotechnology fluid can flow therethrough at a location upstream of said disposable filter.

27. The system in accordance with claim 23, wherein the disposable pressure sensor is positioned along said filtered fluid length of tubing such that the biotechnology fluid can flow therethrough at a location between said disposable filter and said permeate collection single-use container.

28. The system in accordance with claim 23, wherein said outlet end portion of the tubing has a plurality of serially arranged outlet passageways for respective operable connection with said single-use containers, wherein the disposable filter is positioned such that the biotechnology fluid can flow therethrough at a location upstream of said outlet passageways.

29. The manifold system in accordance with claim 23, wherein the container is a bag, and the remotely operable valve is a pinch valve that engages the outside surface of the length of tubing.

30. A manifold and flow imparting system for biotechnology uses, wherein said system is for tangential flow filtration, comprising:

a manifold unit which is pre-sterilized and disposable so as to be adapted for single-time usage, including:

(a) at least one length of tubing having at least one inlet end portion, at least one outlet end portion, an outside surface, and an inside surface which is sterilized for passage of a biotechnology fluid therethrough,

(b) a plurality of single-use containers, each having an access port, one said single-use container is a process solution container and another said single-use container is a permeate collection container,

(c) said tubing includes at least two sections including a filtration flow-through section and a filtered fluid section, said filtration flow-through section includes said process solution container, said filtered fluid section includes said permeate collection container,

(d) an aseptic connector of said single-use container, and

(e) a disposable filter between said filtration flow-through section and said filtered fluid section, whereby fluid from said process solution container can be filtered through said disposable filter and can be collected in said permeate collection container,

(f) at least one pre-sterilized, calibrated and disposable electrical conductivity sensor adapted for single-time usage, the electrical conductivity sensor senses the electrical conductivity of the biotechnology fluid within the tubing and has a memory component capable of storing data, the memory component including a sensor-specific temperature offset assigned to that specific sensor during calibration of the sensor, wherein said temperature offset was determined during manufacture employing a calibration solution, including determining the actual temperature (Tref) value of the calibration solution, using the specified pre-calibrated sensor to measure the temperature (Tsen) value of the calibration solution, and mathematically combining said Tref and said Tsen into said sensor specific temperature offset,

(g) at least one disposable pressure sensor positioned along said length of tubing such that the biotechnology fluid can flow therethrough at a location selected from the group consisting of upstream, downstream, both upstream and downstream of said disposable filter, and upstream of said outlet end portion, and

(h) at least one remotely operable valve, the remotely operable valve located so as to engage said length of tubing and independently selectively allowing or stopping flow of the biotechnology fluid through said inside surface of the length of tubing; and

a flow imparting unit at a selected location upstream of said disposable filter.

31. The manifold system in accordance with claim 30, wherein the container is a bag, and the remotely operable valve is a pinch valve that engages the outside surface of the length of tubing.

32. An automated manifold and flow imparting system for biotechnology uses, wherein said system is for tangential flow filtration, comprising: a manifold unit which is pre-sterilized and disposable so as to be adapted for single-time usage, including: (a) at least one length of tubing having at least one inlet end portion, at least one outlet end portion, an outside surface, and an inside surface which is sterilized for passage of a biotechnology fluid therethrough, (b) a plurality of single-use containers, each having an access port, one said single-use container is a process solution container and another said single-use container is a permeate collection container, (c) said tubing includes at least two sections including a filtration flow-through section and a filtered fluid section, said filtration flow-through section includes said process solution container, said filtered fluid section includes said permeate collection container, (d) a plurality of aseptic connectors of at least one of said single-use containers, (e) a disposable filter between said filtration flow-through section and said filtered fluid section, whereby fluid from said process solution container is filtered through said disposable filter and is collected in said permeate collection container, (f) at least one pre-sterilized, calibrated and disposable electrical conductivity sensor adapted for single-time usage, the electrical conductivity sensor senses the electrical conductivity of the biotechnology fluid within the tubing and has a memory component capable of storing data, the memory component including a sensor-specific temperature offset assigned to that specific sensor during calibration of the sensor, wherein said temperature offset was determined during manufacture employing a calibration solution, including determining the actual temperature (Tref) value of the calibration solution, using the specified pre-calibrated sensor to measure the temperature (Tsen) value of the calibration solution, and mathematically combining said Tref and said Tsen into said sensor specific temperature offset, (g) at least one disposable pressure sensor positioned along said length of tubing such that the biotechnology fluid can flow therethrough at a location selected from the group consisting of upstream, downstream, both upstream and downstream of said disposable filter, and upstream of said outlet end portion, and (h) at least one remotely operable valve, the remotely operable valve engageable with said length of tubing; a flow imparting unit at a selected location upstream of said disposable filter; and a controller operatively controlling said flow imparting unit and said valve, said controller having control logic which dictates is operable to dictate timing and extent of opening and closing of said remotely operable valve and dictates is operable to dictate the rate of flow imparted by said flow imparting unit.

33. The automated system in accordance with claim 32, wherein said control logic of the controller determines is operable to determine the extent of filling of the permeate collection container by processing data monitored by the system to achieve filling of the permeate container by volume, by weight, or by flow rate and filling time.

34. The automated system in accordance with claim 32, wherein the disposable pressure sensor is positioned along a location downstream of said disposable filter for monitoring pressure of the fluid within said tubing and for transmitting data on the pressure to the controller, wherein said control logic receives said data from said disposable pressure sensor and monitors is operable to monitor the flow of fluid through the filtration flow through section of the tubing until said control logic signals that said filtration flow through section of the tubing is to be blocked by closing one of said remotely operable valves and signals that said filtered fluid section of the tubing is to be unblocked by opening another of said remotely operable valves, whereby filtered fluid begins to flow into said permeate collection container.

35. The automated system in accordance with claim 34, wherein said flow imparting unit has a flow imparting rate and said control logic directs is operable to direct the flow imparting unit to modify the flow imparting rate in response to changes in pressure at the disposable pressure sensor so as to maintain a selected rate imparted to the fluid by the flow imparting unit.

36. The automated system in accordance with claim 34, further including a fluid flow rate sensor for monitoring fluid velocity, and wherein said control logic receives is operable to receive fluid velocity data from said fluid flow rate sensor and processes is operable to process the data for controlling the automated system.

37. The automated system in accordance with claim 36, wherein said flow imparting unit has a flow imparting rate and said control logic directs is operable to direct the flow imparting unit to modify its the flow imparting rate in response to changes in flow rate at said fluid flow rate sensor so as to maintain a selected flow rate imparted to the fluid by the flow imparting unit.

38. The manifold automated system in accordance with claim 32, wherein the container is a bag, the remotely operable valve is a remotely operable pinch valve that engages the outside surface of the length of tubing, the flow imparting unit is a pump, and the control logic controls or dictates is operable to control or dictate the timing of opening and closing of the remotely operable pinch valve.