System and method for testing the integrity of virus removal filters

Abstract

A single-use valve arrangement including a valve housing, a diaphragm carried by the valve housing, a pressure sensor, and a controller coupled to the pressure sensor. The valve housing defines an inlet and an outlet, the inlet adapted to be fluidly connected to the outlet of the virus removal filter. The diaphragm divides the valve housing into a first chamber and a second chamber fluidly isolated from the first chamber. The pressure sensor is configured to measure a pressure change in the second chamber due to movement of the diaphragm in response to a pressure change in the first chamber. The controller is configured to determine an actual leak rate of the filter based on the measured pressure change, and the controller is further configured to determine the integrity of the filter by comparing the actual leak rate to an estimated leak rate of the filter.

Description

Technical Field

[0001] The present disclosure generally relates to a virus removal filtration system, and more specifically, to a system and method for testing the integrity of a virus removal filter before and after use.

Background Art

[0002] Pharmaceuticals manufactured, extracted, or synthesized from biological sources need to pass through a virus reduction step to reduce the potential for viral contamination in the drug formulation. Similarly, blood products and derivatives need to pass through a virus reduction step to reduce the potential for viral contamination in the formulation. One such known method of virus reduction is by size exclusion filtration. By size exclusion filtration, a feed stream containing the formulation to be filtered passes through a virus removal filter. The virus removal filter has a virus filtration membrane that captures the viruses removed from the formulation. To capture viruses, the membrane is manufactured to have millions of voids that connect to a plurality of capillaries that interconnect to form a lattice through which fluid must pass to exit the filter. Thus, the viruses contained in the fluid flow have a meandering path to find a way out through the virus filter membrane. In this meandering path, due to size exclusion, the viruses may be trapped in the capillaries or around the capillaries. Also, it can be retained within the voids by hydrodynamic forces or affinity to the void walls. Thus, for example, to capture a virus having a cross-sectional diameter of 17 nanometers ("nm"), the capillaries must have a cross-sectional diameter less than 17 nm somewhere along their length, or the voids must retain a virus having a cross-sectional diameter of 17 nanometers by hydrodynamic forces or affinity to the void walls.

[0003] If the integrity of the filter membrane is compromised (for example, due to damage to the filter membrane), viruses contained in the fluid flow may pass through or around the membrane without being retained. Therefore, federal regulations require that filter membranes be tested for integrity before use (i.e., before filtration) and after use (i.e., after filtration) for all virus removal filters. To meet these federal regulations and verify the structural integrity and proper operation of filter membranes, various integrity tests have been developed. One such test, known as the Planova Leak Tester ("PLT"), is an independent instrument that can assess the integrity of a filter membrane by measuring the diffusion and leakage of pressurized gas (applied upstream of the wet filter membrane) through or around the filter membrane. However, the PLT has several significant drawbacks. First, the PLT must be prepared manually (including manual installation of the virus removal filter), and its operation can be cumbersome. Furthermore, and most importantly, PLT is not ideal for pre- and post-use testing, because pre-use testing with PLT inevitably destroys the sterility of the virus removal filter, and post-use testing with PLT can act to contaminate the PLT with the used filter. Also, because PLT cannot be easily cleaned, the same PLT cannot be used for both pre- and post-use testing. Another such test is known as the visual leak test ("VLT"). The VLT involves applying pressurized gas to the upstream side of the wetted membrane. The pressurized gas diffuses through the membrane, generating bubbles on the downstream side of the membrane. One or more operators visually inspect the outlet of the virus removal filter to check for bubbles diffusing and flowing out through or around the filter membrane. If bubbles diffuse and flow out at a sufficient rate, and more than three or four bubbles appear or accumulate per minute, the operator can be confident that the filter membrane is leaking or otherwise not functioning correctly. While VLT may be useful for pre- and post-use testing, it is largely met with resistance in the industry because it is a manual, subjective measurement. [Brief explanation of the drawing]

[0004] Features of this disclosure that are considered novel are specifically described in the attached claims. This disclosure can be best understood by referring to the following description in conjunction with the attached drawings, where similar reference numbers identify similar elements in some of the drawings.

[0005] [Figure 1] This is a schematic diagram of an example system constructed in accordance with the teachings of this disclosure for filtering formulations and testing the integrity of virus removal filters. [Figure 2] Figure 1 shows the valve configuration of the system configured to perform integrity testing on the virus removal filter. [Figure 3] Similar to Figure 2, this figure shows the diaphragm of the valve configuration positioned relative to the air trap inlet of the valve configuration in order to close the air trap coupled to the valve configuration. [Figure 4] This is a schematic diagram of another example of a system for filtering formulations and testing the integrity of virus removal filters, constructed in accordance with the teachings of this disclosure. [Figure 5] This is a schematic diagram of another example of a system for filtering formulations and testing the integrity of virus removal filters, constructed in accordance with the teachings of this disclosure. [Modes for carrying out the invention]

[0006] This disclosure relates, in general, to a system and method for testing the integrity of a virus removal filter to ensure that the virus removal filter adequately retains viruses from formulations that pass through it. The systems and methods disclosed herein can generally be positioned downstream of the virus removal filter and, when fluidically connected thereto, can evaluate the diffusion and flow rate of the virus removal filter to determine the integrity of the virus removal filter both before and after use, thereby utilizing a single-use valve configuration that meets federal regulations. Beneficially, the single-use valve configuration maintains the sterility of the virus removal filter and achieves the above in a manner that reduces, if not eliminates, the risk of contamination, unlike the PLT and other known tests described above. Furthermore, unlike the VLT described above, the single-use valve configuration determines the integrity of the virus removal filter automatically (i.e., without human intervention).

[0007] Figure 1 shows an example of a closed system 100 for filtering a formulation (e.g., a pharmaceutical in solution) and constructed in accordance with the teachings of this disclosure. The system 100 generally includes multiple inlets 104 (three in this example), a pump 108, a virus removal filter 112, multiple outlets 116, and multiple valves 120 (nine in this example, V1-V7, V 11 , and V 12The system includes a plurality of sensors 124 (three in this example), a plurality of vents 128 (three in this example), and a valve configuration 132 for performing integrity testing on the virus removal filter 112. In this example, the virus removal filter 112 has a hollow fiber filter membrane 136, which is generally configured to achieve virus removal from the formulation flowing through it, supplied to the virus removal filter 112 by a pump 108, by capturing any viruses in the formulation within the membrane 136. The hollow fiber filter membrane 136 is preferably manufactured using regenerated cellulose, for example, by Asahi Kasei Medical Corporation, but the membrane 136 can instead be manufactured from a variety of materials including polysulfone or polyvinylidene fluoride. In other examples, and as will be described in more detail below, the virus removal filter 112 may instead be a different type of virus removal filter (e.g., a virus removal filter with a sheet or cartridge membrane).

[0008] Figure 2 shows further details of a valve configuration 132 used in system 100. In this example, the valve configuration 132 includes a valve housing 150, a diaphragm 154 held by the valve housing 150, and a pressure sensor 158 held by the valve housing 150. In this example, the valve configuration 132 also includes an air trap 166 coupled to the valve housing 150, and three shut-off valves 170, 174, and 178 configured to selectively shut off various components of the valve configuration 132. However, in other examples, the valve configuration 132 may include more, fewer, or different components. For example, the valve configuration 132 does not include a spring within the valve housing 150, but in other examples, the valve configuration 132 may include such a spring to bias the diaphragm 154 to a particular position. In another example, the air trap 166 is located outside the valve housing 150, but in other examples, the air trap 166 may be located partially or entirely within the valve housing 150.

[0009] As shown in Figure 2, the valve housing 150 in this example is defined by two housing portions that are manufactured separately and then joined together. More specifically, the valve housing 150 in this example is defined by a first housing portion 182 and a second housing portion 186 (which may also be called a pressure sensor housing), and the first housing portion 182 and the second housing portion 186 are removably joined to each other via physiological clamps (also known as tri-clamps) (not shown). However, in other examples, the first housing portion 182 and the second housing portion 186 may be joined to each other in different ways (for example, they may be joined to each other irremovably). For example, the first housing portion 182 and the second housing portion 186 may be formed integrally with each other so that the valve housing 150 has a monolithic structure. In any case, the valve housing 150 defines an inlet 190, an outlet 194, and an air trap inlet 198. In this example, both the inlet 190 and the outlet 194 are defined by the first housing portion 182, but in other examples, the inlet 190 and / or the outlet 194 may instead be defined by the second housing portion 186. On the other hand, the air trap inlet 198 is preferably located between the inlet 190 and the outlet 194. Therefore, in this example, the air trap inlet 198 is also defined by the first housing portion 182.

[0010] The diaphragm 154 is generally configured to provide a sterile interface to the pressure sensor 158 and to block the bubble trap 166 as needed. As shown in Figure 2, in this example, the diaphragm 154 is bonded (e.g., glued or welded) to the bottom surface of the first housing portion 182. When the second housing portion 186 is bonded to the first housing portion 182, the diaphragm 154 is trapped between the first housing portion 182 and the second housing portion 186 of the valve housing 150. In some examples, one or more seals (e.g., seal gaskets 200) may also be positioned between the first housing portion 182 and the second housing portion 186 when bonded to each other. With the diaphragm 154 positioned in this manner, the diaphragm 154 divides the valve housing 150 into two chambers: the first chamber 202 and the second chamber 206. The first chamber 202 is defined adjacent to the first side 210 of the diaphragm 154 and is in fluid communication with the inlet 190, the outlet 194, and the air trap inlet 198, respectively. The second chamber 206 is defined adjacent to the second side 214 of the diaphragm 154 opposite to the first side 210. The diaphragm 154 functions to provide a barrier between the first chamber 202 and the second chamber 206 so that the second chamber 206 is fluidly isolated from the first chamber 202. As a result, at least in this example, the second chamber 206 is fluidly isolated from the inlet 190, the outlet 194, and the air trap inlet 198. The diaphragm 154 also functions to provide a barrier to the external environment when the second housing portion 186 is removed from the first housing portion 182.

[0011] The diaphragm 154 is generally movable in response to pressure changes in the first chamber 202 caused, for example, by the opening and closing of the inlet 190, the opening and closing of the outlet 194, some fluid flowing through the inlet 190, or some fluid flowing through the outlet 194. For example, as the pressure in the first chamber 202 increases, the diaphragm 154 moves in a first direction (downward in the direction shown in Figure 2), away from the inlet 190, outlet 194, and air trap inlet 198, and toward the pressure sensor 158. This movement of the diaphragm 154 reduces the volume of the second chamber 206, which acts to increase the pressure in the second chamber 206. Conversely, as the pressure in the first chamber 202 decreases, the diaphragm 154 moves in a second direction (upward in the direction shown in Figure 2), toward the inlet 190, outlet 194, and air trap inlet 198, and toward the pressure sensor 158. The movement of the diaphragm 154 in this manner increases the volume of the second chamber 206, which acts to decrease the pressure within the second chamber 206.

[0012] The pressure sensor 158 is generally configured to measure pressure changes within the first chamber 202. In this example, the pressure sensor 158 is held by a second housing portion 186 such that it interfaces with a second side 214 of the diaphragm 154 and is in fluid communication (more specifically, direct fluid communication) with the second chamber 206. Thus, the pressure sensor 158 is configured to indirectly measure pressure changes within the first chamber 202 by directly measuring the pressure changes within the second chamber 206 caused by the movement of the diaphragm 154 in response to the pressure changes within the first chamber 202. In some cases, the pressure changes within the second chamber 206 will precisely match the pressure changes within the first chamber 202, and in other cases, the pressure changes within the second chamber 206 will be linearly related (or correspond in some other form) to the pressure changes within the first chamber 202. However, in other examples, the pressure sensor 158 may be positioned to be in direct fluid communication with the first chamber 202.

[0013] The air trap 166 is generally configured to capture a certain amount of air (or other compressible fluid) to suppress the pressure increase in the first chamber 202. In this example, the air trap 166 is a single piece of plastic tube that is directly coupled to the air trap inlet 198 (for example, via a barbed connector projecting outward from the valve housing 150) and clamped by a third shut-off valve 178 at a desired length to capture a predetermined amount of air. Thus, generally speaking, the length of the tube determines the predetermined amount of air contained within it. In one example, the length of the tube forming the air trap 166 is equal to approximately 13 inches, so that the predetermined amount is approximately 29 ml. In other examples, the air trap 166 can be partially or entirely integrated within the valve housing 150 (more specifically, the first housing portion 182), in which case a shorter length of tube is required to maintain the same predetermined amount.

[0014] Referring back to Figure 1, the first shut-off valve 170 is coupled to the valve housing 150 such that the first shut-off valve 170 is positioned upstream of the inlet 190. The first shut-off valve 170 has an open position that allows the valve 170 to flow into the inlet 190 and a closed position that prevents the valve 170 from flowing into the inlet 190. In other words, when the valve 170 is in the closed position, the valve 170 closes the inlet 190. The second shut-off valve 174 is coupled to the valve housing 150 such that the second shut-off valve 174 is positioned downstream of the outlet 194. The second shut-off valve 174 has an open position that allows the valve 174 to flow out through the outlet 194 and a closed position that prevents the valve 174 from flowing out of the outlet 194. In other words, when the valve 174 is in the closed position, the valve 174 closes the outlet 194. In this example, the third shut-off valve 178, which is a pinch valve, is coupled to the air trap 166 (coupled to the valve housing 150) such that the length of the third shut-off valve 178 and the air trap tube 166 defines a predetermined amount of air trap when the third shut-off valve 178 is in the closed position. The third shut-off valve 178 has an open position in which the valve 178 allows air to flow out of the air trap inlet 198 through the air trap 166, and the closed position in which the valve 178 traps a predetermined amount of air in the air trap 166.

[0015] As also shown in Figure 2, the valve configuration 132 also includes a controller 162 that is communicably connected (via one or more wired and / or one or more wireless connections) to the components of the valve configuration 132 and other components of the system 100 as needed in order to control the operation of the valve configuration 132. In particular, the controller 162 controls the first, second, and third shut-off valves 170, 174, and 178 to open and close the inlet 190, outlet 194, and air trap 166 as needed, respectively. For example, the controller 162 controls the second shut-off valve 170 to open and close the outlet 194 as needed.

[0016] In this example, the controller 162 includes a module base 212, a processor 214 disposed within the module base 212, a memory 218 disposed within the module base 212, a communication interface 222 within the module base 212, and computing logic 226. Although not shown herein, the above components are arranged in known configurations, but can be arranged in any configuration. The processor 214 may be a general-purpose processor, a digital signal processor, an ASIC, a field-programmable gate array, a graphics processing unit, an analog circuit, a digital circuit, or any other known or later-developed processor. The processor 214 operates according to computer-readable instructions stored in the memory 218. The memory 218 may be volatile or non-volatile memory. The memory 218 may include one or more of the following types of memory: read-only memory (ROM), random-access memory (RAM), flash memory, electronically erasable program read-only memory (EEPROM), or other types of memory. The memory 218 may include optical, magnetic (hard drive), or any other form of data storage device. The communication interface 222 is provided to enable or facilitate electronic communication between the controller 162 and the components of the valve configuration 132. This electronic communication may occur via any known communication protocol. The logic 226 includes one or more routines and / or one or more subroutines embodied as computer-readable instructions stored in memory 204. The controller 162, in particular its processor 214, can execute the logic 226 to cause the processor 214 to perform actions related to the integrity test of the virus removal filter 112, as will be described in more detail below.

[0017] Referring back to Figure 1, the valve configuration 132 is located downstream of the virus removal filter 112 and is fluidly coupled to the virus removal filter 112 so as to be fluidly connected to the shell outlet 230 of the virus removal filter 112. Next, the first shut-off valve 170 is located between the shell outlet 230 and the inlet 190 of the valve housing 150, and the remaining components of the valve configuration 132 are located downstream of the shell outlet 230 of the virus removal filter 112 (some components are also located downstream of the valve housing 150). Furthermore, the valve configuration 132 is located downstream of one of the multiple sensors 124, upstream of one of the multiple vents 128, downstream of the remaining vents 128, downstream of the source 234 for the test fluid (in this example, pressurized air, but other compressible fluids can be used), and downstream of the source 238 for the cleaning fluid (in this example, pressurized air, but other compressible fluids can be used).

[0018] During the normal filtration operation of system 100, the formulation is supplied into the virus removal filter 112, passes through the virus removal filter 112, and at least the first shut-off valve 170 is closed. More specifically, the pump 108 draws the formulation from one or more of the multiple inlets 104, passes the formulation through various components (e.g., one of the multiple sensors 124, the pre-filter 239, and one of the multiple valves 120), and draws it into the virus removal filter 112. Once in the virus removal filter 112, the product passes through the filtration membrane 136 of the filter 112. As described above, the filtration membrane 136 has a grid structure consisting of various interconnected voids and capillaries with diameters smaller than the cross-section of the virus to be removed from the formulation. This grid structure forms a meandering path for the formulation to flow, trapping the virus contained in the formulation and to be removed from the formulation. After passing through the filtration membrane 136, the formulation can then exit the filter 112 through the filtrate outlet 240 and be discharged from the system 100 through one of the multiple outlets 116.

[0019] As described above, the valve configuration 132 is configured to automatically perform an integrity test of the virus removal filter 112 both before and after this normal filtration operation of the system 100 (and the virus removal filter 112) to ensure that the filter 112 is properly installed and operating and that the filtration membrane 136 has sufficient integrity (so that viruses do not pass through the membrane 136 or pass around the membrane 136). To perform the integrity test, the following steps are generally performed by the controller 162 (however, in some examples, one or more of these steps can be performed manually). (1) The controller 162 purges pressurized air from the cleaning fluid source 238 by sending it through the air trap 166, through the air trap inlet 198, through the valve housing 150, out of the valve housing 150 via the valve outlet 194, and to the vent 128 downstream of the valve configuration 132; (2) The controller 162 moves the third shut-off valve 178 to its closed position to shut off the air trap 166 (thus clamping it at a predetermined position in the tube to define the volume of the air trap 166); (3) The controller 162 wets the filter membrane 136 and immerses the outlet 116 (sending the wetting agent supplied by one of the multiple inlets 104 to the filter membrane 136 and out of the filter 112 to the outlet 116 via the filtrate outlet 240). (4) Controller 162 floods the valve 150 (by sending the flood agent supplied to the filter membrane 136 by one of the multiple inlets 104 from the filter 112 via the shell outlet 230 of the filter 112, through the valve housing 150, from the valve housing 150 via the outlet 194, to the vent 128 downstream of the valve configuration 132), (5) Controller 162 sends the test fluid (in this example, pressurized air) from the test fluid source 234 toward the filter membrane 136, and the test fluid is pressurized with the test fluid until the fibers of the filter membrane 136 are in equilibrium position, at which point (6) Controller 162 opens the first shut-off valve 170 (if not already open) and closes the second shut-off valve 174 (if not already closed). The pressurized test fluid then begins to diffuse through the filter membrane 136 of the filter 112.In some cases, the pressurized test fluid will also flow through and / or around the filtration membrane 136. Since the system 100 is a closed type, the diffusion (and outflow) of the test fluid moves the fluid downstream of the filtration membrane 136, thereby increasing the pressure at the shell outlet 230 and subsequently at the inlet 190 of the valve housing 150.

[0020] The diffusion of the pressurized test fluid through the filtration membrane 136 is generally defined according to the following formula:

Number

Number

[0021] The pressure increase at inlet 190 acts to increase the pressure within the first chamber 202, thereby moving diaphragm 154 from the first position (e.g., the position shown in FIG. 2) to the second position in the first direction. Thus, the movement of diaphragm 154 from the first position to the second position similarly acts to increase the pressure within the second chamber 206. Pressure sensor 158 is configured to measure this pressure increase within the second chamber 206 over a predetermined time interval (e.g., 5 seconds). For example, pressure sensor 158 is configured to measure the pressure within the second chamber 206 at a first point in time (e.g., when diaphragm 154 is in the first position), and the pressure within the second chamber 206 at a second point in time after the first point in time (e.g., when diaphragm 154 is in the second position), and the time interval is the time between the first point in time and the second point in time.

[0022] Controller 162 is configured to determine the actual leak rate of the virus removal filter 112, which corresponds to the amount of test fluid per second that actually diffuses and leaks through and / or around membrane 136 over a predetermined time interval. Controller 162 is generally configured to determine the actual leak rate based on the pressure increase measured downstream of membrane 136, which functions as a proxy for the amount of test fluid per second that diffuses and leaks through and / or around membrane 136 over a predetermined time interval. As an example, if pressure sensor 158 measures a pressure of 50 Pa within the second chamber 206 at a first point in time, and a pressure of 100 Pa within the second chamber 206 at a second point in time (5 seconds later), controller 162 determines that the actual leak rate of the virus removal filter 112 is 50 Pa per 5 - second time interval, or 10 Pa per second.

[0023] The controller 162 is configured to then compare the determined actual leak rate with the estimated leak rate of the virus removal filter 112. The estimated leak rate is typically determined before the integrity test and stored in the controller 162's memory 218, although in some cases the estimated leak rate may be determined during the integrity test. The estimated leak rate may be determined by the controller 162 or by the operator of the system 100. In either case, the estimated leak rate generally refers to the amount of test fluid per second that is estimated to diffuse and flow through and / or around the membrane 136 over a given time interval, given that the filter 112 is properly installed and operating and the filtration membrane 136 has sufficient integrity. The estimated leak rate can be determined by analyzing how the test fluid has diffused and flowed through and / or around the membrane 136 in the past, parameters such as the test fluid, diffusion coefficient, solubility coefficient of the test fluid in the wet fluid, differential pressure available at the membrane 136, liquid layer thickness within the membrane 136, effective filter area, and other parameters associated with the filter 112.

[0024] Next, the controller 162 is configured to determine the integrity of the virus removal filter 112 based on this comparison. In some cases, the controller 162 determines that the virus removal filter 112 has sufficient integrity for further use (i.e., the filter 112 is properly installed and functioning, and the membrane 136 has sufficient integrity) when it determines that the actual leakage rate is less than or equal to the estimated leakage rate of the virus removal filter 112. In some cases, the controller 162 determines that the virus removal filter 112 has sufficient integrity for further use when it determines that the actual leakage rate is greater than the estimated leakage rate of the virus removal filter, but is within a predetermined threshold difference of, for example, 10% of the estimated leakage rate of the virus removal filter 112. Conversely, if the controller 162 determines that the actual leakage rate is greater than the estimated leakage rate, or greater than the estimated leakage rate by a certain threshold difference, the controller 162 attributes the difference between the actual and estimated leakage rates to unexpected diffusion and leakage of the test fluid around or through the membrane 136 of the virus removal filter 112. In other words, the controller 162 attributes the difference to leakage around or through the membrane 136 caused, for example, by the filter 112 not being properly installed and / or functioning and / or being damaged. Thus, the controller 162 determines that the virus removal filter 112 is not suitable for further use because it is not sufficiently intact. In some examples, the controller 162 may then indicate (for example, via a warning to the operator of system 100) that the virus removal filter 112 (or its components) needs to be reinstalled and / or replaced.

[0025] After the integrity test is performed by the valve configuration 132, the controller 162 is configured to (7) close the first shut-off valve 170 and / or open the second shut-off valve 174, and (8) stop the delivery of the test fluid from the test fluid source 234 toward the filtration membrane 136. If the integrity test is performed before the normal operation of the system 100, the formulation may be supplied to the virus removal filter 112 by the pump 108 and passed through the virus removal filter 112 for normal filtration by the virus removal filter 112, provided that the valve configuration 132 determines that the membrane 136 has sufficient integrity and that the filter 112 is properly installed and operating. Furthermore, when desired (for example, when it is desired to measure the volume of the air trap 166), the air trap 166 may be closed by moving the diaphragm 154 to engage tightly with the air trap inlet 198. In some examples, such as those shown in Figure 3, the diaphragm 154 can be moved in that manner, and the air trap 166 can be closed by selectively supplying pressurized fluid from the pressurized fluid source 242 to the second chamber 206.

[0026] It will be understood that the valve configuration 132 described herein is a single-use valve configuration. More specifically, at least a portion of the components of the valve configuration 132 are single-use components. In this example, the first housing portion 182, the diaphragm 154, the bubble trap 166, and the tubing used to fluidly connect the components of the valve configuration 132 are single-use components. For this purpose, these components of the valve configuration 132 are made from disposable materials such as plastic materials like gamma-stabilized plastic, while the remaining components are made from more permanent materials (for example, in this example, the second housing portion 186 and the pressure sensor 158 are made from stainless steel). However, in other examples, more components of the valve configuration 132 may be single-use components made from disposable materials. For example, the controller 162 may be a single-use component. In any case, since the valve configuration 132 is a single-use valve configuration, the valve configuration 132 may be used to perform an integrity test on the virus removal filter 112 before and / or after the normal operation of the system 100, and then the single-use components of the valve configuration 132 may be discarded thereafter.

[0027] Figure 4 shows another example of a closed system 400 for filtering a formulation (e.g., a pharmaceutical in solution) and constructed in accordance with the teachings of this disclosure. The system 400 shown in Figure 4 is substantially similar to the system 100 shown in Figure 1 and has common components indicated using common reference numerals, but the system 400 differs in that it includes a different type of virus removal filter than the system 100. More specifically, the system 400 includes a virus removal filter 412 having a cartridge filter membrane 436 (instead of a hollow fiber filter membrane like the filter 112). However, like the hollow filter membrane 136, the cartridge filter membrane 436 is configured to remove viruses from the formulation flowing through it, which is supplied to the virus removal filter 412 by the pump 108. Although there are differences between the system 100 and the system 400, the valve configuration 132 can be used to perform integrity testing on the virus removal filter 412, as described above in relation to the virus removal filter 112.

[0028] Figure 5 shows another example of a closed system 500 for filtering a formulation (e.g., a pharmaceutical in solution) and constructed in accordance with the teachings of this disclosure. System 500 shown in Figure 5 is substantially similar to systems 100 and 400 shown in Figures 1 and 4, respectively, and has common components indicated by common reference numbers, but system 500 differs in that it includes a different type of virus removal filter than systems 100 and 400. More specifically, system 500 includes a virus removal filter 512 having a sheet membrane 536 (instead of a hollow fiber filter membrane like filter 112 or a cartridge filter membrane like filter 412). However, like membranes 136 and 436, the sheet membrane 536 is configured to remove viruses from the formulation flowing through it, which is supplied to the virus removal filter 512 by pump 108. Although there are differences between systems 100 and 400 and system 500, the valve configuration 132 can be used to perform integrity testing on the virus removal filter 512, as described above in relation to the virus removal filter 112.

[0029] Those skilled in the art will recognize that a wide variety of modifications, alterations, and combinations can be made with respect to the embodiments described above without departing from the scope of this disclosure, and such modifications, alterations, and combinations will be deemed to fall within the scope of the concept of the present invention.

Claims

1. A valve configuration for testing the integrity of a virus removal filter, wherein the valve configuration is A valve housing defining an inlet and an outlet, wherein the inlet is adapted to be fluidly connected to the outlet of the virus removal filter, A diaphragm held by the valve housing, wherein the diaphragm divides the valve housing into a first chamber and a second chamber fluidly isolated from the first chamber, the first chamber is in fluid communication with both the inlet and the outlet, and the diaphragm is movable in response to pressure changes within the first chamber. A pressure sensor having fluid communication with the second chamber, wherein the pressure sensor is configured to measure the pressure change in the second chamber due to the movement of the diaphragm in response to the pressure change in the first chamber, A valve configuration comprising: a controller coupled to the pressure sensor and configured to determine the actual leakage rate of the virus removal filter based on the measured pressure change, wherein the controller is further configured to determine the integrity of the virus removal filter by comparing the actual leakage rate with the estimated leakage rate of the virus removal filter.

2. The valve configuration according to claim 1, wherein the valve housing further defines the air trap inlet.

3. The valve configuration according to claim 2, wherein the air trap inlet is defined between the inlet and the outlet.

4. The valve configuration according to claim 2, wherein the diaphragm is movable to a position in which it engages with the air trap inlet and thereby closes the air trap inlet.

5. The valve configuration according to claim 2, further comprising an air trap connected to the air trap inlet.

6. The valve configuration according to claim 1, further comprising an inlet shut-off valve disposed upstream of the aforementioned inlet.

7. The valve configuration according to claim 1, further comprising an outlet shut-off valve disposed downstream of the aforementioned outlet.

8. The valve configuration according to claim 1, wherein the controller includes a processor and a memory, the memory is configured to store the estimated leakage rate of the virus removal filter, and the processor is configured to obtain the estimated leakage rate of the virus removal filter and determine the integrity of the virus removal filter by comparing the actual leakage rate with the estimated leakage rate.

9. The valve configuration according to claim 1, wherein the valve configuration is a single-use valve configuration.

10. A single-use valve configuration for testing the integrity of a virus removal filter, wherein the valve configuration is A valve housing defining an inlet, an outlet, and an air trap inlet, wherein the inlet is adapted to be fluidly connected to the outlet of the virus removal filter, A diaphragm held by the valve housing, wherein the diaphragm divides the valve housing into a first chamber and a second chamber fluidly isolated from the first chamber, the first chamber is in fluid communication with both the inlet and the outlet, and the diaphragm is movable from a first position to a second position in response to pressure changes in the first chamber. A pressure sensor that is in fluid communication with the second chamber, wherein the pressure sensor is configured to measure a first pressure in the second chamber when the diaphragm is in the first position, and to measure a second pressure in the second chamber when the diaphragm is in the second position, A single-use valve configuration comprising: a controller coupled to the pressure sensor and configured to determine the actual leakage rate of the virus removal filter based on the difference between the first pressure and the second pressure, wherein the controller is further configured to determine the integrity of the virus removal filter by comparing the actual leakage rate with the estimated leakage rate of the virus removal filter.

11. The valve configuration according to claim 10, wherein the air trap inlet is defined between the inlet and the outlet.

12. The valve configuration according to claim 10, wherein the diaphragm is movable to a third position in which it engages with an air trap inlet, thereby closing the air trap inlet.

13. The valve configuration according to claim 10, further comprising an air trap connected to the air trap inlet.

14. An inlet shut-off valve is installed upstream of the aforementioned inlet, The valve configuration according to claim 10, further comprising an outlet shut-off valve disposed downstream of the aforementioned outlet.

15. The valve configuration according to claim 10, wherein the controller is configured to determine that the virus removal filter has sufficient integrity for use when it determines that the actual leakage rate is less than the estimated leakage rate, equal to the estimated leakage rate, or the difference between the actual leakage rate and the estimated leakage rate is less than a predetermined threshold.

16. The valve configuration according to claim 10, wherein the controller includes a processor and a memory, the memory being configured to store the estimated leakage rate of the virus removal filter, and the processor being configured to obtain the estimated leakage rate of the virus removal filter and determine the integrity of the virus removal filter by comparing the actual leakage rate with the estimated leakage rate.

17. A method for testing the integrity of a virus removal filter, wherein the method is To provide a valve configuration comprising: a valve housing defining an inlet and an outlet; a diaphragm held by the valve housing and dividing the valve housing into a first chamber and a second chamber fluidly isolated from the first chamber; a pressure sensor fluidly communicating with the second chamber; and a controller coupled to the pressure sensor, wherein the first chamber fluidly communicates with both the inlet and the outlet, and the diaphragm is movable in response to pressure changes within the first chamber. The inlet of the valve housing is fluidly connected to the outlet of the virus removal filter, The test fluid is passed through the virus removal filter such that a portion of the test fluid flows from the outlet of the virus removal filter through the inlet of the valve housing, When the diaphragm moves, the pressure sensor is used to measure the pressure change in the second chamber due to the movement of the diaphragm in response to the pressure change in the first chamber, Based on the measured pressure change, the actual leakage rate of the virus removal filter is determined, A method comprising determining the integrity of the virus removal filter by comparing the actual leakage rate with the estimated leakage rate of the virus removal filter.

18. The method according to claim 17, further comprising closing an outlet shut-off valve disposed downstream of the outlet of the valve housing after the passage and before the measurement.

19. The method according to claim 17, further comprising the valve housing further defining an air trap inlet and closing the air trap inlet by moving the diaphragm to a position in which the diaphragm engages with the air trap inlet.

20. The method according to claim 17, wherein the controller includes a processor and a memory configured to store the estimated leak rate of the virus removal filter, and determining the integrity of the virus removal filter further includes obtaining the estimated leak rate of the virus removal filter via the processor.

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