Fluid Isolating Peristaltic Pump

This application is a continuation of U.S. application Ser. No. 18/079,719, filed Dec. 12, 2022, which is a continuation of U.S. application Ser. No. 17/004,991, filed Aug. 27, 2020, which claims the benefit of U.S. Provisional Application No. 62/893,163, filed Aug. 28, 2019, U.S. Provisional Application No. 62/894,689, filed Aug. 31, 2019, U.S. Provisional Application No. 62/989,906, filed Mar. 16, 2020, and U.S. Provisional Application No. 63/038,581, filed Jun. 12, 2020, all of which are incorporated by reference in their entirety.

The present disclosure generally relates to the manufacturing of biological and non-biological materials or fluids, and more specifically to a peristaltic pump and processes for isolating a material or fluid for a predetermined amount of time in continuous flow. This includes but is not limited to the production of chemical compounds, reagents, antibodies, living and non-living biologicals, and various other types of liquids used in the manufacturing of chemicals, compounds, pharmaceuticals and cell and gene therapies.

Many chemical and biological products (such as cell and gene therapies, pharmaceutical products, etc.) are manufactured in a “batch” method, meaning that a pre-determined volume or “batch” is manufactured at a time. To ensure quality and efficacy of the product, each batch may undergo its own quality control (QC) testing to verify purity, potency, and sterility. Batch processing, however, inherently has limitations on batch size or batch volume and uses significantly more resources when compared to a continuous manufacturing method. Some processes, however, are not ideal candidates for continuous manufacturing.

For example, many of the fluids or products used in the manufacturing of cell and gene therapies are limited to batch manufacturing because they often require complex incubations as part of their workflows. Essentially, during the production process, some ingredients need to mix and then “incubate” for a specified period of time before the next ingredient(s) may be added. In some cases, multiple incubations may be required. In a batch manufacturing environment, this is easily achieved.

An alternative to batch processing is “continuous” processing, meaning that a manufacturing system outputs a product on a consistent basis. Continuous processing removes some of the costs and time constraints found in batch processing. It is also scalable to theoretically achieve any desired throughput. In contrast to batch processing, which may require each batch to undergo strict quality control testing, continuous processing is less resource dependent because quality tests and assays may be performed on a schedule.

In the bioprocessing industry, a standard method of continuous processing involves pumping fluid through sterile tube sets, also known as consumable sets. Peristaltic pumps are often used to transfer the fluid within these sterile tube sets. The benefit of peristaltic pumps is that they apply pressure external to the tubing to transfer fluid within it, effectively maintaining the sterility of the functionally-closed system. This design may be effective at transferring fluids within tubing, such as silicone, PVC or TPE.

However, it can be difficult to achieve proper manufacturing of certain products using continuous flow processing. In particular, it may difficult to achieve proper incubation of fluids when operating in a continuous flow fashion.

Disclosed is a fluid isolating pump for isolating volumes of liquid to allow the volumes of liquid to incubate for a predetermined amount of time. The fluid isolating pump mechanically and fluidically isolates small volumes of the fluid being incubated to allow for proper incubation of the resulting product.

The fluid isolating pump includes a rotating cage, one or more roller assemblies mounted on the rotating cage, a cam plate, and a non-rotating central shaft. The cage includes a front plate and a back plate connected by multiple connecting rods. Each roller assembly is rotatably attached to a corresponding connecting rod of the cage. Each roller assembly includes one or more arms rotatably attached to the connecting rod, a connecting bar coupled to the one or more arms, one or more levers rotatably attached to the connecting rod, one or more suspensions, and a roller. Each suspension is coupled to at least one arm and to at least one lever. The roller is coupled to the one or more levers. The cam plate includes multiple openings having a first end and a second end. The connecting rod of each roller assembly is configured to slide from the first end of the opening to the second end of a corresponding opening.

In some embodiments, the fluid isolating pump additionally includes a central gear mounted on the non-rotating central shaft. In addition, the fluid isolating pump may include multiple peripheral gears. Each peripheral gear may be mounted to a corresponding connecting rod of the cage. Moreover, the peripheral gears may be engaged to the central gear.

In some embodiments, the roller assembly further includes a roller gear coupled to the roller of the roller assembly. The roller gear may be engaged with a corresponding peripheral gear.

In some embodiments, the peripheral gears are configured to rotate around the central gear as the cage rotates around the non-rotating central shaft.

In some embodiments, the roller gear of a roller assembly is configured to rotate the roller based on the rotation of the corresponding peripheral gear.

In some embodiments, a roller assembly is in a disengaged position when the connecting bar of the roller assembly is in the first end of the corresponding opening, and wherein the rollers assembly is in an engaged position when the connecting bar of the roller assembly is in the second end of the corresponding opening.

In some embodiments, the roller of the roller assembly is compressing a tubing of the consumable when the roller assembly is in the engaged position. In some embodiments, when the roller assembly is in the engaged position, the cam plate applies a pressure to the connecting bar of the roller assembly, compressing the one or more suspensions

In some embodiments, the non-rotating central shaft has a non-circular cross section

In some embodiments, the fluid isolating pump additionally includes a motor coupled to the cage. The motor axially is aligned with the non-rotating central shaft. The motor is configured to rotate the cage around the non-rotating central shaft.

Additionally, disclosed is a roller assembly to be used in a fluid isolating pump for isolating volumes of liquid to allow the volumes of liquid to incubate for a predetermined amount of time. The roller assembly is configured to be mounted on an axle. The roller assembly includes one or more arms configured to be rotatably attached to the axle, a connecting bar coupled to the one or more arms, one or more levers configured to be rotatably attached to the axle, one or more suspensions, each suspension coupled to at least one arm and to at least one lever, and a roller coupled to the one or more levers.

In some embodiments, the roller assembly further includes a roller gear coupled to the roller of the roller assembly. The roller gear is configured to control a rotation of the roller. Moreover, in some embodiments, the roller assembly further includes a peripheral gear configured to be rotatably attached to the axel. The peripheral gear is configured to be coupled to a central gear. The peripheral gear is additionally configured to control a rotation of the roller gear.

In some embodiments, the roller assembly further includes an auxiliary gear between the roller gear and the peripheral gear. The auxiliary gear is configured to reverse a direction or rotation of the roller gear.

In some embodiments, in an engaged position, the connecting bar of the roller assembly is configured to receive a force compressing the one or more suspensions. In some embodiments, the one or more suspensions are configured to apply a compressive force to the roller to press the rollers against a consumable. In some embodiments, the one or more suspensions may be a spring suspension, a hydraulic suspension, or a pneumatic suspension.

Additionally, disclosed is a consumable to be used in a fluid isolating pump for isolating volumes of liquid to allow the volumes of liquid to incubate for a predetermined amount of time. The consumable includes a rigid tube and a tubing wrapped around the rigid tube. In some embodiments, the rigid tube has a substantially cylindrical shape. Moreover, in some embodiments, the rigid tube has a hollow center.

In some embodiments, the rigid tube has an inlet hole and an outlet hole. The inlet hole and the outlet hole may match an outer diameter of the tubing.

In some embodiments, the consumable additionally includes a back endcap coupled to a first end of the rigid tube and a front endcap coupled to a second end of the rigid tube. The back endcap includes a mounting hole to mount the consumable on an axle. The front endcap includes one or more openings to allow the tubing from entering or exiting the hollow center of the rigid tube.

In some embodiments, the tubing is made of an elastic material.

In some embodiments, the consumable additionally includes electrical connections for transmitting electrical signals to the fluid isolating pump and to receive electrical signals from the fluid isolating pump.

In some embodiments, the consumable additionally includes sensors for determining a property of a liquid flowing through the tubing. For example, a sensor may be a bubble sensor.

In some embodiments, the consumable additionally includes pumps for controlling an intake of fluid into the tubing of the consumable.

In some embodiments, the consumable additionally includes a thermal element (such as a heating element, a cooling element, or a combination thereof) to control a temperature of a fluid disposed inside the tubing. In some embodiments, the consumable additionally includes a temperature sensor to track the temperature of the fluid disposed inside the tubing.

The figures (FIG.) and the following description relate to preferred embodiments by way of illustration only. It should be noted that from the following discussion, alternative embodiments of the structures and methods disclosed herein will be readily recognized as viable alternatives that may be employed without departing from the principles of the embodiments.

Reference will now be made in detail to several embodiments, examples of which are illustrated in the accompanying figures. It is noted that wherever practicable, similar or like reference numbers may be used in the figures and may indicate similar or like functionality. The figures depict embodiments for purposes of illustration only.

To facilitate understanding of the invention, a number of terms and abbreviations as used herein are defined below as follows:

Fluid. As used herein, the term “fluid” refers to a substance that flows continuously under an applied shear stress, wherein the substance is in liquid, gas, or plasma phases. As stated above, materials used for cell and gene therapies are examples of fluids that may include biological and non-biological components.

Batch production. As used herein, the term “batch production” refers to a method of manufacturing which can go through a series of steps to make the target product across a number of sets or batches, and steps which often vary across the sets or batches.

Continuous production. As used herein, the term “continuous production” refers to a method of manufacturing that occurs without interruption over a manufacturing time period.

Large molecule: As used herein, the term “large molecule” refers to a protein, synthetic polymer, antibody, lipid, carbohydrate, nucleic acid, or other entities which exceed 1000 atoms.

Small molecule. As used herein, the term “small molecule” refers to an organic and inorganic molecule which does not exceed 1000 atoms.

shows a block diagram of a system for continuous in-line incubation, according to one embodiment. As shown in, fluid from two vessels may be pumped into a common tube in an effort to incubate the two fluids for a period of time before ultimately entering an output vessel. Peristaltic pumpcan rotate clockwise to transfer fluid from vesselthrough tubeand into tube. Concurrently, peristaltic pumpcan rotate counterclockwise to transfer fluid from vesselthrough tubeinto tube. Additionally, the length of tubecan be designed to be sufficient to contain fluids from vesselsandfor the duration of the desired incubation. After the incubation time is complete, the two fluids enter output vessel.

In some embodiments, at the end of tube, a third reagent may be mixed with the incubated fluid. For example, tubemay be connected to T-fitting that connects the tubewith a third pump that dispenses the third reagent.

The system shown inis more effective when the friction of the inner surface of the tubeis low or when the effect of the friction is negligible (e.g., for short incubation times over a relatively short length of tube, or when only a small amount of reagents are being processed). As shown in, without friction between the tubing and the fluid, the velocity of fluid near the tubing wall would be the same as at the center of the tubing. The length of each arrow represents its relative velocity. However, when the effect of the friction is more pronounced, this friction results in adhesive forces between the fluid and the inner walls of tube. As shown in, the relative velocity profile within tubeis parabolic. Fluid at the fluid-tube boundary has zero velocity or near zero velocity, while fluid at the center of the tube has the highest relative velocity.

This property of fluid-dynamics may prevent adequate incubation within tubing (e.g., tube) because, even with the pump speeds of pumpandremaining constant, the fluids from vesselsandare not maintained at the correct ratios for the duration of the incubation. If collected and analyzed over a period of time, the incubated fluid entering output vesselwill contain inconsistent amounts of each ingredient and the fluid entering output vesselwill contain molecules that have experienced different incubation times, some more and some less than the desired time.

If the friction of the inner surface of the tubeis significant, a fluid isolating pump may be used in conjunction with the tubeto mechanically and fluidically isolate small volumes of the fluid being incubated, and to help each small volume of fluid to move in tandem as they travel through the tube.

In a continuous in-line incubation process using a fluid isolating pump, two or more fluids are combined and mixed prior to entering a long tube. Upon entering the long tube, the fluid is segmented into small volumes by means of mechanical rollers external to the tubing and then progressed down the length of the tube. Each small volume of fluid remains mechanically and fluidically isolated as the volume of fluid travels along a length of a tubing. Each fluid segment will move from a first end to a second end of the tubing in an amount of time equal to, or approximately equal to, the desired incubation time. As incubated fluid continuously exits at the second end, new non-incubated fluid is continuously drawn into the first end of the tubing.

Since each volume of fluid is isolated as it travels through the tubing, and therefore cannot communicate or interact with adjacent isolated segments of fluid, the system can ensure adequate incubation of the fluid while maintaining a continuous manufacturing method. As such, a continuous in-line incubation process using a fluid isolating peristaltic pump mitigates many of the limitations and problems that are associated with batch manufacturing. Example processes that may utilize continuous in-line incubation include the manufacturing of thioamide and the manufacturing of recombinant proteins. Some example processes that may benefit from a continuous in-line incubation process are explained in more detail hereinbelow.

show block diagrams of different configurations of a system for continuous in-line incubation, according to other embodiments.show perspective views of some of the components of the system shown in, according to one embodiment. In the example of, a bulk reagent (liquid A) (e.g., acetophenone in the manufacturing of thioamide) is to be mixed with other reagents (liquids B and C) (e.g., morphine and S8 in the manufacturing of thioamide). The bulk reagent is typically the reagent with the highest relative volume. The bulk reagent may be stored in a bag, while other reagents may be stored in syringes. The syringes are installed on a syringe pumpwhich is capable of accurately and independently dispensing the contents of both syringes. In some embodiments, as shown in the configuration of, the bagis connected to a pump(e.g., a peristaltic pump or a gear pump) to control the dispensing of the bulk reagent. In other embodiments, as shown in the configuration of, the fluid isolating pumpis used to control the dispensing of the bulk reagent. As such, in this embodiment, pumpmay be omitted because the fluid isolating pump will draw or pull the bulk reagent during operation.

Fluidic junctionis a junction where liquids A, B, and C intersect. The fluidic junctionis coupled to a mixerwhere liquids A, B, and C mix. For example, in the configuration shown in, the mixermay be an active mixer. Here, the pumpdraws liquid A from baginto the active mixer while syringe pumpdoses contents from syringesinto the active mixer. The active mixer may include a sterile container having blades coupled to a motor. As the blades rotate, the blades provide agitation that causes the liquids held inside the sterile container become homogenous. In some embodiments, the liquid to be mixed is provided and mixed in batches. For example, the pumpsandare configured to pump liquids A, B, and C into the active mixer when the fluid level inside the mixer reaches a lower threshold, and stops dispensing the liquids into the active mixer when the fluid level inside the mixer reaches an upper threshold. In another example, in the configuration shown in, the mixermay be a static mixer. The output of the mixeris then coupled to a fluid isolating pumpto allow the mixed fluid to incubate or react for a specified amount of time.

In some embodiments, the fluid isolating pump is then coupled to a fluidic junctionwhere the output of the fluid isolating pump is intersected with an additional reagent (liquid D) (e.g., nickel (II) chloride solution in the manufacturing of thioamide). Liquid D may be stored in a reservoir. In some embodiments, the additional reagent is pumped to the fluidic junctionby means of a peristaltic pump. The final product is then collected or distributed to a collection reservoir.

Fluid isolating pumpsupports the continuous production or manufacturing of various fluidic chemistries historically restricted to batch processing. The fluid isolating pumpallows for the continuous production of liquid products by providing the capability of performing complex incubations in a continuous flow environment within a functionally-closed (sterile) system.

Using peristalsis, the fluid isolating pumpis capable of isolating predetermined volumes of fluid (e.g., liquid) within a continuous flow environment (e.g., a tube) to facilitate incubation or biological/chemical reaction(s). The system achieves fluid isolation by compressing portions of a tubing using multiple rollers that traverse the length of the tubing. As the rollers move from one end of the tubing to an opposite end of the tubing, the fluid that is confined within the space between two rollers is isolated from the rest of the fluid. Moreover, as the rollers traverse the length of the tubing, the compression of the tubing forces the fluid to also move across the length of the tubing.

shows a cross-sectional view of a tubing in an uncompressed state. The tubingis disposed over a rigid surface. In an uncompressed state, center of the tubingis open and may enclose a fluid that can travel through/along the tubing.