Flow measurement system for single-use containers

A venturi flowmeter for connection to single-use containers is provided. The venturi flowmeter includes a meter body formed of a polymer and configured to allow fluid flow therethrough. A first annular diaphragm is mounted proximate an inner surface of the meter body has a first internal diameter. A second annular diaphragm is mounted proximate an inner surface of the meter body has a second internal diameter different from the first internal diameter.

BACKGROUND

Single-use containers, such as bioreactors are useful for generating and supporting biological reactions for any number of purposes. The life sciences industry is moving from large, capital-intensive facilities made of stainless steel with large clean-in-place (CIP) infrastructure to smaller facilities that use polymeric bags or containers functioning as bioreactors. The bioreactor bag is used once and then discarded. The single-use bioreactor technique significantly reduces the capital cost of the plant. For example, in existing facilities that use stainless steel CIP infrastructure, up to 90% of the cost of operating the facility may be due to the clean-in place infrastructure, including very high end instrumentation designed to withstand a steam cleaning cycle. By moving to disposable, single-use bioreactor bags, the CIP portion of the capital can be eliminated and the facility can be more flexible and much smaller, which, in turn, allows the production of smaller batches that are needed for more targeted drug therapies and other smaller-scale applications.

As pharmaceutical manufacturers change over from large stainless steel process vessels to smaller-volume, pre-sterilized, disposable plastic bag systems, there is a need to measure process variables in these systems in order to control the growth environment and subsequent processes. Typically, pharmaceutical manufacturers and the life science industry, in general, have used relatively inexpensive sensors and relatively crude methods from fluid isolation, such as silicone gel. These methods can lead to inaccurate measurements, which are generally unacceptable to the life sciences industry for supporting the various biological reactions.

SUMMARY

A venturi flowmeter for connection to single-use containers is provided. The venturi flowmeter includes a meter body formed of a polymer and configured to allow fluid flow therethrough. A first annular diaphragm is mounted proximate an inner surface of the meter body has a first internal diameter. A second annular diaphragm is mounted proximate an inner surface of the meter body has a second internal diameter different from the first internal diameter.

DETAILED DESCRIPTION

Users of single-use containers, such as bioreactors, desire a relatively inexpensive and relatively accurate set of instrumentation for use with such containers. Important drivers for such single-use plastic containers are dramatically lower capital costs, as described above, no clean-in-place infrastructure, faster batch turnaround times, and smaller and more flexible process capabilities. While some developments have been undertaken in order to provide high quality pressure and level measurement with respect single-use containers, no solutions are currently provided for measuring the flow of a fluid to or from such a single-use container.

Embodiments of the present invention generally provide an effective solution for measuring the flow relative to a single-use container, such as a bioreactor. In accordance with an embodiment of the present invention a polymeric venturi-based flowmeter is used in conjunction with a relatively high quality differential pressure measurement device. Portions of the venturi flowmeter that contact the flowing fluid are constructed with relatively low-cost polymers, such as plastic, that can be pre-sterilized. The venturi flowmeter is then fluidically coupled, in one embodiment, to the relatively high quality differential pressure measurement device. Note, while embodiments of the present invention are described with respect to a single differential pressure measurement device measuring pressures relative to a venturi flowmeter, embodiments of the present invention can be practiced with such measurements being performed by separate devices.

Fluid flow measurement presents a particular difficulty for single-use containers, such as bioreactors. In particular, these vessels often contain living cells or organisms. Such cells or organisms are often particularly susceptible to sheering stresses or other acute forces as they flow through the system. Thus, in order to effectively measure a flow parameter relative to a liquid that may contain living cells or organisms, it is important to do so with as little disturbance to the flow profile as possible. For example, live cells that are transported in the tubes to and/or from a bioreactor must be treated with care so that they do not rupture or suffer other undesirable effects. Accordingly, some embodiments of the present invention generally provide a polymeric venturi with an appropriately large choke in order to be minimally disruptive to the flow of the fluid.

FIG. 1is a diagrammatic view of a bioreactor with which embodiments of the present are particularly applicable. Bioreactor100includes rigid support102containing polymeric bag104and a number of tubes106,108. Various sensors and/or tubes of the bioreactor are coupled to analyzer110that is able to measure or otherwise determine various aspects of the biological reaction and/or biological fluid therein, and provide information relative to the biological reaction and/or biological fluid. The polymeric flow measurement system in accordance with embodiments of the present invention will generally attach to one or more of tubes106,108coupled to polymeric bag104.

FIG. 2is a diagrammatic view of polymeric bioreactor bag104disposed within rigid container102. A biological fluid, such as a cell culture or fermentation mash liquid112is disposed within bioreactor bag104and undergoes a biological reaction of interest. A tube or hose114is coupled to the interior of polymeric bag104via port116. Accordingly, any suitable fluid can flow to or from biological bag104via tubing114, as indicated at bidirectional arrow115.

As shown inFIG. 2, a pressure measurement device, such as differential pressure measurement transmitter130is fluidically coupled to venturi flowmeter132via liquid-filled impulse lines134,136. In one embodiment, the liquid in liquid-filled impulse lines134,136is substantially incompressible, such as water or silicone oil that is isolated from the bioreacting fluid flowing through tubing114via a pair of annular isolation diaphragms (shown inFIG. 3). Moreover, any fluid that is substantially incompressible at the pressures of the fluid flowing through venturi flowmeter132can be used. Thus, if the venturi flowmeter is suitable for relatively low-pressure applications, then the fluids within lines134,136can be slightly compressible as long as they are virtually incompressible relative to the pressures flowing through venturi flowmeter132.

Venturi flowmeter132is coupled to cooperative fittings138,140through any suitable couplings, such as known tri-clamp couplings142,144. As will be described in greater detail with respect toFIGS. 3 and 4, as fluid flows through venturi flowmeter132, the fluid flow generates different pressures through liquid-filled impulse lines134,136. The pressure in lines134,136is sensed, in one embodiment, by differential pressure measurement transmitter130and a value indicative of the measured differential pressure is converted, via hardware, software, or a combination thereof, to a flow-related value, such as flow velocity, or mass flow. Further, the pressure of the fluid itself may also be measured and indicated via any suitable techniques. Once differential pressure measurement transmitter130has measured or otherwise determined a flow-related value, the flow-related value can be displayed locally at the bioreactor, and/or communicated to a remote device. Further, in some embodiments, instrument130may also perform diagnostics relative to the device itself and/or the biological reaction in order to provide additional information instead of simply reporting the pressure within single-use bioreactor bag104. Further still, instrument130may also be configured to convey the flow-related information to one or more additional devices via a process communication loop or segment, such as those in accordance with the Highway Addressable Remote Transducer (HART®) protocol or the FOUNDATION® Fieldbus protocol. However, other suitable process communication protocols, wired and/or wireless can be used in accordance with embodiments of the present invention. Moreover, embodiments described herein may also include wirelessly transmitting such flow-related information to any suitable device via antenna120in accordance with a wireless process communication protocol, such as IEC62591. In one embodiment, instrument130is a commercially-available hygienic pressure transmitter sold under the trade designation Model 3051 available from Emerson Process Management of Shakopee, Minn.

FIG. 3is a diagrammatic cross-sectional view of a venturi flowmeter in accordance with an embodiment of the present invention. Venturi flowmeter132is, in one embodiment, formed of a plastic that is amenable to radiation sterilization, such as by using gamma radiation. Venturi flowmeter132includes a pair of annular diaphragms146,148that are fluidically coupled to respective liquid-filled impulse lines134,136. Each annular diaphragm is generally formed of a rectangular portion of flexible polymer that has its longer sides aligned transverse to the axis of meter body152thereby forming a ring, or at least partial ring, about the internal diameter of meter body152.

While embodiments of the present invention can be practiced where annular diaphragms146and148do not extend fully around the internal diameter of meter body152, at least one embodiment includes annular diaphragms extending entirely about the internal diameter of meter body152. Additionally, as shown inFIG. 3, annular diaphragms146,148are disposed about the internal diameter of meter body152at locations that have different diameters. As shown, annular diaphragm146is provided at a relatively large-diameter portion of the inside diameter of meter body152, while annular diaphragm148is disposed at necked-down region150having a relatively smaller diameter than the portion to which annular diaphragm146is coupled. In one embodiment, annular diaphragms146,148are formed from plastic and formed to the inner surface of meter body152and plastic-welded in place. Accordingly, each annular diaphragm146,148moves in response to pressure changes in meter body152. This movement is, in turn, communicated to another diaphragm, such as a sensing diaphragm in differential pressure measurement transmitter130via liquid-filled impulse lines134,136. Venturi flowmeter132provides an effective differential pressure producer with satisfactory range ability, high pressure recovery, and strong signal production. By using one annular seal upstream of the venturi and another downstream, the differential pressure signal communicated to the differential pressure transmitter130is easily converted by differential pressure transmitter130into a flow-related value such as flow velocity or mass flow rate and communicated to any suitable device and/or indicated locally by differential pressure transmitter130.

In accordance with the embodiments of the present invention, meter body152and the seal system may be formed of materials of sufficiently low cost that the entire system, with the exception of differential pressure transmitter130, can be considered to be disposable. In one embodiment, the venturi/seal system is delivered to an end-user in a pre-sterilized condition and ready to be connected to a single-use container. In contrast, the differential pressure transmitter, such as transmitter130, is a permanent part of the infrastructure that supports the biological reaction process. This approach uses the high performance differential pressure transmitter130and allows the user to retain all of the support infrastructure including potential FDA traceability.

FIG. 4is a flow diagram of a method of measuring a flow quantity relative to a fluid flowing to or from a single-use container in accordance with an embodiment of the present invention. Method200begins at block202where a flow is generated relative to the single-use container. This flow may be into the container or from the container. Next, at block204a first venturi pressure is conveyed to a pressure measurement device via a fluid-filled isolation system. An example of block204is a pressure being conveyed from meter body152to differential pressure measurement transmitter130via fluid-filled impulse line134. At block206, a second venturi pressure is conveyed to a pressure measurement device via a second fluid fill system. An example of this is pressure from annular diaphragm148being conveyed to differential pressure measurement transmitter130via fluid-filled impulse line136. However, those skilled in the art will recognize that blocks204and206can be performed using two different pressure measurement devices. Moreover, the description of first and second pressures is not intended to indicate that one happens after the other. Instead, “first” and “second” are merely provided as labels in order to enhance clarity. Next, at block208, differential pressure between the pressures provided by the first and second fluid fill systems is measured. In one embodiment, this is accomplished by directly measuring a differential pressure between the pressures conveyed by fluid-filled impulse lines134and136. However, embodiments of the present invention can be practiced where each pressure is measured individually and the difference is calculated. Moreover, each individual pressure measurement could be done by a separate device, and the difference could be calculated by still another device.

Next, at block210a flow value is determined based on the measured differential pressure. In one embodiment, the flow value may be flow velocity212, while in another embodiment, the flow value may be a mass flow rate214. Finally, at block216, the flow value is provided as an output. This output can be provided locally by a device, such as differential pressure measurement transmitter130, or remotely, to a process controller or monitoring device via process communication, such as that set forth above.

Embodiments of the present invention provide a low-cost solution for flow measurement related to single-use containers, such as bioreactors. Devices constructed in accordance with embodiments of the present invention may be easily sterilized on site, and/or during manufacture. When such devices are sterilized during manufacture, they may be provided in sterile packaging so that an end user need not perform any sterilization prior to use. Moreover, the system may be provided having the liquid-filled impulse lines pre-filled, such that an end user need only remove a shipping cap from each line and place a membrane or flexible diaphragm of each impulse line against a respective isolation diaphragm of the differential pressure transmitter. Of course, embodiments may also be practiced where the liquid-filled impulse lines are filled on the user's site during setup.