Patent ID: 12239127

DETAILED DESCRIPTION

The present disclosure will now be described more fully hereinafter with reference to example embodiments thereof with reference to the drawings in which like reference numerals designate identical or corresponding elements in each of the several views. These example embodiments are described so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. Features from one embodiment or aspect can be combined with features from any other embodiment or aspect in any appropriate combination. For example, any individual or collective features of method aspects or embodiments can be applied to apparatus, product, or component aspects or embodiments and vice versa. The disclosure may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification and the appended claims, the singular forms “a,” “an,” “the,” and the like include plural referents unless the context clearly dictates otherwise. In addition, while reference may be made herein to quantitative measures, values, geometric relationships or the like, unless otherwise stated, any one or more if not all of these may be absolute or approximate to account for acceptable variations that may occur, such as those due to manufacturing or engineering tolerances or the like.

As used herein, the terms “biological material”, “material”, and “media” may be used synonymously and may refer to any biological material, media, or product including, but not limited to, monoclonal antibodies, vaccines, cell banks, high density cell cultures, virus banks, and cell therapy products in the form of macromolecules, cells, or virus particles. While high density cell cultures may be described as media herein, when specified, high density cell cultures are cell cultures having more than 50 million cells per milliliter (mL). In some embodiments, high density cell cultures may have more than 100 million, 120 million, or 150 million cells per mL. Exemplary cell cultures are disclosed in International Patent Publication WO2021052857, the entire contents of which are hereby incorporated by reference. In addition, as used herein, “cooling power” or “refrigeration power” refers to the ability to remove heat energy from material such that a temperature of the material is reduced. Further, as used herein, the term “container” refers to any object that is configured to hold media disposed therein and may describe a vessel that holds media therein or may describe a box or other object that holds a vessel with media disposed therein.

Typical ultra-low temperature laboratory freezers or −80° C. freezers are generally cooled by 2-stage refrigeration plants and may have set points between −86° C. and −50° C. that can be referred to generally as “ULT Freezers.” These ULT Freezers are ubiquitous in the laboratory environment and are commercially available from a variety of manufacturers including Thermo Scientific, Panasonic, and Sanyo. While ULT Freezers are intended to keep frozen material frozen but are not designed with adequate refrigeration power to freeze large amounts of liquid placed therein. In fact, Thermo Scientific rates an open door recovery time of a STP series of ULT Freezers in a range of 11-24 minutes without freezing liquids added. As such, while it may be possible to place 1 L of material to freeze in a ULT Freezer, e.g., 500×2 mL vials, as an amount of material and/or the size of the containers increase, e.g., 50×100 mL bags equating to a total of 5 L of material, an ULT Freezers is likely to show large excursions away from the set temperature as the material is frozen. These large deviations can jeopardize other material in the ULT Freezer and may not allow the material placed in the ULT Freezer to freeze at a desired rate, e.g., 1° C. per minute.

This disclosure generally relates to systems, methods, and apparatus to rapidly and reliably freeze large volumes of material, e.g., 50×100 mL bags equating to a total of 5 L of material, in a ULT Freezer without causing undesirable temperature excursions from a set point temperature. Such systems, methods, and apparatus may allow both large and small facilities to process material, e.g., rapidly freeze, without making large capital investments in specialty freezing equipment. Such systems, methods, and apparatus may allow for rapid freezing without the costs and safety concerns of handling cryogens, e.g., liquid nitrogen or dry ice.

In a typical lab or production environment, a freezing operation is not a continuous process. For example, a lab or production facility may have a limited number of batches each week that require freezing. As detailed below, it may be possible to include a thermal energy storage device (“thermal battery” or “thermal capacitor”) in a ULT Freezer that is slowly charged (“trickle charged”) between freezing operations and rapidly discharged during a freezing operation. Such a thermal capacitor may include a phase-change material (PCM) with a melting point in a range near a minimum operating temperature of the ULT Freezer but much colder than a freezing point of the material to be frozen which is typically near 0° C. The maximum operating temperature of a ULT Freezer may be in a range of −50° C. to −75° C. A thermal capacitor with a PCM may be capable of providing a pulse of refrigeration power to be frozen to prevent deviations in a temperature within the ULT Freezer. The thermal capacitor may be left in the ULT Freezer to charge when the ULT Freezer is not being used in a freezing process, sit idle once charged, and then discharge when material to be frozen is placed in the ULT Freezer. It may be beneficial to include PCMs in various locations along walls defining an interior of the ULT Freezer or even in a refrigeration plant of the ULT Freezer, however, placing the PCM or thermal capacitor closer to the material to be frozen may provide increased refrigeration power.

Referring now toFIG.1, a thermal capacitor is disclosed in accordance with an embodiment of the present disclosure and is referred to generally as capacitor100. The capacitor100includes a shell110that retains a PCM150therein to prevent the PCM150from leaking or evaporating from a cavity140defined within the shell110. The cavity140may be an enclosed compartment such that the PCM150is encapsulated or sealed within the cavity140. In some embodiments, the cavity140is an open cavity and the shell110retains the PCM150within the cavity. The shell110is formed of a thermally conductive material to conduct heat into and out of the PCM150. The material forming the shell110must also be capable of withstanding compressive forces involved in contacting containers to be frozen, as detailed below, and to withstand internal pressures within the cavity140generated by density changes within the PCM150as the PCM150changes temperature. In embodiments, the shell110is formed of a thermally conductive metal that is resistant to corrosion. In particular embodiments, the shell110is formed of aluminum. Aluminum may be advantageous for its high thermal conductivity and its relatively low cost. In addition, aluminum may be advantageous as a result of its low density such that the shell110may have a low weight compared to shells formed of other thermally conductive materials. Aluminum may also be resistant to corrosive materials and may be anodized or nickel plated to increase resistance to corrosion.

The shell110may be formed of a first half shell112and a second half shell116that are each formed from a solid block with the cavity140being machined out of the solid block. The first half shell112and the second half shell116may be joined together with fasteners, be brazed together, or be welded together, e.g., laser welded, with a gasket or sealant disposed along opposed faces thereof to seal the cavity140. The surfaces of the first half shell112and the second half shell116defining the cavity140may be treated to provide or enhance resistance to corrosion. For example, the surfaces defining the cavity140may be anodized or nickel plated to provide or enhance resistance to corrosion.

In some embodiments, the shell110may include features to enhance the structure of the shell110to reinforce or strengthen the shell100as the PCM150changes phase. For example, the shell110may include ribs and/or fillets to strengthen the shell110. The ribs or fillets may be positioned at a variety of locations within the shell110and may extend vertically, horizontally, or diagonally through the shell or the cavity140.

The shell110includes a contact surface which is a major surface of one of the half shells that is designed to contact a product container to be frozen. For example, the shell110may include a first contact surface113which is a major surface of the first half shell112and a second contact surface117which is a major surface of the second half shell116. The first contact surface113and the second contact surface117are opposite one another such that the first contact surface113is capable of contacting a first container and a second contact surface117is capable of contacting a second container.

The PCM150may be disposed within the cavity140such that the PCM150is in direct contact with the surfaces defining the cavity140. In some embodiments, the PCM150is sealed within a package152that is disposed within the cavity140. The package152may be a sealed bag that is dimensioned to be disposed within the cavity140without wrinkles and voids. In some embodiments, the package152is formed of fluoropolymers or a silicone rubber that is capable of withstanding the temperatures within the cavity140, e.g., −80° C. When the package152is formed of fluoropolymers, the fluoropolymers may include, but not be limited to, PTFE, polyimide, FEP, PFA, ETFE.

The PCM150has a phase change point in a range of −50° C. to −75° C. For example, the PCM150may have a melting point in a range of −50° C. to −75° C. The PCM150may be a eutectic solution in water such as calcium chloride with a melting point of −50° C., potassium acetate with a melting point of −62° C., lithium chloride with a melting point of −70° C., or a mixture of lithium chloride and lithium bromide. The melting points of these eutectic solutions may be tuned by creating ternary aqueous solutions of deep eutectic solvents such as ethaline which is a mixture of ethylene glycol and choline chloride. In some embodiments, a freezing point or transition temperature of a eutectic solution of lithium chloride and lithium bromide can be tuned by adjusting the ratio of lithium chloride to lithium bromide in the eutectic solution. The PCM150may be selected for other properties such as being non-flammable, non-hazardous, readily available, and having adequate energy storage density. In certain embodiments, the PCM150may have a freeze temperature in a range of −80° C. to −65° C. (e.g., −72° C.), a melt temperature in a range of −70° C. to −64° C. (e.g., −67° C.), a latent heat in a range of 200 kJ/kg to 230 kJ/kg (e.g., 200 kJ/kg), and a density in a range of 1.18 g/cm3to 1.38 g/cm3(e.g., 1.38 g/cm3). The PCM150may include additives such as nucleating agents to prevent supercoiling, anti-corrosion agents, or gelling agents to prevent separation or formation of density gradients. The additives may enhance the properties of the PCM150to ensure repeatable behavior after many freeze cycles.

In some embodiments, the PCM150may be manufactured from plant feedstocks. Such a PCM150may be non-hazardous, non-corrosive, and/or cross-linked and may have a transition temperature of −60° C. Cross-linking of a PCM150may increase a viscosity of the material such that the PCM150may be a high-viscosity gel or solid material. A high-viscosity gel or solid material may reduce or prevent leaks from the cavity140even if the cavity140is compromised with the PCM150disposed therein. In some embodiments, the cavity140is an open cavity with the cross-linking of the PCM150retaining the PCM150within the cavity140. As such, the cavity140may not be required to be sealed or the PCM150may not be required to be disposed within a package152which may reduce a cost of manufacturing the thermal capacitor100. Additionally or alternatively, if such a PCM150is non-corrosive, walls defining the cavity140may remain uncoated which may reduce a cost of manufacturing the thermal capacitor100. A PCM that is at least one of non-hazardous, non-corrosive, and/or cross-linked may reduce manufacturing costs and reduce safety concerns associated with other PCMs hazardous, corrosive, or non-cross-linked materials.

The amount of PCM150and thus, the size of the cavity140is selected to balance the refrigeration power to freeze the material and to reduce the charging time. As most biological materials can be modeled using the properties of water. For example, to freeze a 100 mL bag of material from 5° C. to −40° C. at a freeze rate of 1° C./minute using a eutectic solution of calcium chloride initially at 70° C. as the PCM150requires a transfer of 42 kilojoules (kJ) over 45 minutes or 16 Watts (W). Thus, the volume of calcium chloride required to deliver 42 kJ is 130 mL. The cavity140may be dimensioned to have the same foot print as the material to be frozen, e.g., the 100 mL, with a thickness determined by the amount of PCM150required. Continuing the current example, the cavity140having a foot print similar to a 100 mL bag would be 1.3 times as thick to hold 130 mL of calcium chloride. In some embodiments, the cavity140and/or a package152containing the PCM150may include void space to accommodate expansion of the PCM150as a phase of the PCM changes.

The thermal capacitor100may include a charge indicator120to indicate a “charge state” of the PCM150which can be considered a charge state of the thermal capacitor100. The charge indicator120may be in signal communication with a sensor122configured to determine a temperature of the PCM150. The sensor122may be a resistance temperature detector (RTD), a thermocouple, thermistor, or other sensor suitable for determining the temperature of the PCM150. The sensor122may be located at key locations of the thermal capacitor100. For example, the sensor122may be located within the cavity140. For example, the sensor122may be positioned at the center of the cavity140. The charge indicator120may include multiple sensors disposed about the thermal capacitor100. The charge indicator120may include a sensor122on a contact surface, e.g., contact surface113, to indicate a temperature of the contact surface113and thus, substantially the temperature of a media within the container in contact with the contact surface.

In some embodiments, the sensor122may include an ultrasonic sensor that operates in a transmit/receive mode or may be a pair of ultrasonic sensors with one in transmit mode and the other in receive mode. The ultrasonic sensor122may send an ultrasonic pulse through the PCM150to estimate the charge state, e.g., the extent of phase change, of the PCM150during charging or discharging of the PCM150. When a single ultrasonic sensor122is used, the ultrasonic pulse may reflect off a far wall of the cavity140. An ultrasonic sensor may be advantageous by allowing a measurement of the PCM150at the center of the cavity140by placing a sensor or sensors at the walls defining the cavity140, e.g., without requiring a physical sensor to be disposed within the PCM150.

In some embodiments, the sensor122may include an optical sensor. The optical sensor122may include a light source positioned on one side of the cavity140and a detector on the opposite side of the cavity140. The light source directing light towards the detector with the detector detecting an amount of light received. The decrease in the number of photons arriving at the detector may be indicative of the charge state as a result of deformities generated during the freezing process, e.g., crystal boundaries and frozen bubbles, which can scatter light.

The charge indicator120may include a processor that receives electrical signals from the sensor or sensors122detailed above and provide an indication of a charge state of the PCM150at least in part by the electrical signals received from the sensors122. The charge indicator122may also use other metrics to indicate a charge state of the PCM150. The other metrics may include elapsed time. Communication between the charge indicator120and the sensors122may be wired or wireless. The charge indicator120may provide visual indicia of the charge state of the PCM150. The visual indicia may be a light, e.g., green when charged or red when not charged. The visual indicia may be a gauge to show an amount of charge of the PCM150.

With additional reference toFIGS.2and3, the thermal capacitor100may be part of a rapid freezing system200provided in accordance with an embodiment of the present disclosure. The rapid freezing system200includes several thermal capacitors100slidably mounted to a top rail210and a bottom rail220. Each of the thermal capacitors100may include a top bearing or mount132and a bottom bearing or mount134that receives a respective one of the top rail210and bottom rail220therethrough to slidably mount the thermal capacitor100within the rapid freezing system200. The mounts132,134may be dimensioned to allow slide on the rails210,220and be formed of a material that resists free movement along the rails210,220such that the thermal capacitors100may maintain a position within the rapid freezing system200absent an external force.

In use, the container or box10including material to be frozen may be positioned between two thermal capacitors100in an open position relative to one another as shown inFIG.2. In the open position, two thermal capacitors100are spaced apart from one another such that a box10can be positioned between the contact surfaces113,117of the thermal capacitors100. With the box10positioned between the contact surfaces113,117of the thermal capacitors100, one or both of the thermal capacitors100are slid towards the other thermal capacitor100to capture the box10between the thermal capacitors100such that the thermal capacitors100are in a closed position relative to one another as shown inFIG.3. In the closed position, the box10is in intimate contact with a contact surface113,117of each of the thermal capacitors100. In the closed position, the mounts132,134of the thermal capacitors100may be in contact with one another to define a space between the contact surfaces113,117of the respective thermal capacitors100. Each of the mounts132,134may have a thickness substantially equal to half of a thickness of the box10such that the space is substantially equal to a thickness of the box10. The thermal capacitors100may include carriers136positioned along the contact surfaces113,117that have a thickness substantially equal to half of a thickness of the box10and positioned to contact a carrier136extending from an opposing contact surface113,117. The thermal capacitors100may include a carrier136positioned below the box10when the thermal capacitors100are in a closed position. The carriers136below the box10may support the box10thereon.

Bringing the box10into intimate contact with the contact surfaces113,117of the thermal capacitors100facilitates the rapid freezing of material within the box10. Bringing the material to be frozen into the immediate vicinity of the thermal capacitors100may improve heat transfer out of the material to be frozen.

While rapid freezing is desirable, freezing at too high or quick of a rate may be detrimental to some materials. Bringing a box, e.g., box10, into intimate contact with thermal capacitors100having sufficient PCM150to freeze material within the box10to a desired temperature may result in the cooling rate of the material being excessive or too high. To control the cooling rate, the thermal capacitors100may include an insulation layer118between the PCM150and the contact surfaces113,117to limit or tune the cooling rate. To tune the cooling rate, the thickness of the insulation layer118is increased to decrease the cooling rate and a thickness of the insulation layer118is decreased to increase the cooling rate.

An internal resistance of the PCM150may also affect a cooling rate. Specifically, an internal resistance of the PCM150may create a bottle neck in a flow of thermal energy into and out of the PCM150. Some PCMs may have low thermal conductivity such that thermal energy may not flow efficiently into or out of a center or core of the PCM150. To decrease internal resistance of the PCM150, the thermal capacitor100may include thermal energy transfer features disposed within the cavity140. In some embodiments, the cavity140may include a thermally conductive matrix disposed within the cavity140with the PCM150disposed within and about the thermally conductive matrix. The thermally conductive matrix may be in the form of an aluminum foam. In certain embodiments, the thermal energy transfer features may include thermal energy transfer fins that extend through the cavity140to transfer thermal energy into and out of the core of the PCM150. The thermal energy transfer features may be formed of material selected to be compatible with the PCM150to prevent corrosion of the thermal energy transfer features. In certain embodiments, the thermal energy transfer features may be plated, e.g., electroless nickel plated, to provide corrosion resistance thereof.

With reference now toFIGS.4-9, a box310is disclosed in accordance with an embodiment of the present disclosure. The box310is configured to securely hold a vessel20filed with biological material or media to be frozen. In some embodiments, the box310is configured to position the vessel20within the box310such that the vessel20is held in intimate contact with a thermal energy transfer wall322of the box310. The thermal energy transfer wall322of the box310may be configured to be positioned in intimate contact with the contact surface of a thermal capacitor, e.g., thermal capacitor100(FIG.1), to enhance thermal energy transfer into and out of the biological material within the vessel20. In certain embodiments, the box310may be configured to substantially immobilize the vessel20therewithin. In some embodiments, the vessel20may become brittle when frozen such that immobilizing the vessel20within the box310may protect the vessel20from damage. Immobilizing the vessel20may reduce or prevent damage to the vessel20during transport, freezing, and thawing of the biological material.

The box310includes a stationary or fixed wall assembly320including the thermal energy transfer wall322, a top wall324, a bottom wall326, and side walls328. The fixed wall assembly320defines a chamber330that is configured to receive a carrier340. The carrier340has a body that is sized and dimensioned to fit snugly within the chamber330such that the carrier340is fixed within the chamber330. The carrier340defines a well342that is sized and dimensioned to receive the vessel20filled with media. The well342may be sized to complement the shape of the vessel20and may include void or empty space about the vessel20. The void or empty space about the vessel20may be sized to allow for a change in volume of media within the vessel20as the media is frozen. For example, a volume of the media within the vessel20may increase as the media is frozen. In some embodiments, the carrier340may be formed of a compressible material such that as the media expands, the media may compress portions of the carrier340defining the well342. The carrier340may also define channels344that are sized and dimensioned to receive accessories attached to the vessel20. For example, the channels344may be sized to receive accessories such as tubing, clamps, seals, and aseptic connectors. The reception of the accessories may position the vessel20within the carrier340. The channels344may extend through an entire thickness of the carrier340or may only partially extend into a thickness of the carrier340. For example, where a channel344is configured to receive a tube, the channel344may extend partially into a thickness of the carrier340and where a channel344is configured to receive a clamp, the channel344may extend through the entire thickness of the carrier340.

The carrier340may include a thermal energy transfer element346that is positioned on one side of the well342. The transfer element346may be formed of aluminum to enhance thermal energy transfer into and out of the vessel20. The transfer element346may be coated to prevent or reduce sticking of the material of the vessel20to the transfer element346. Such a coating may promote sliding of the material of the vessel20along the transfer element346. For example, the transfer element346may be coated with polytetrafluoroethylene (PTFE) to prevent the vessel20from binding or sticking to the transfer element346. Preventing the vessel20from binding or sticking to the transfer element346may prevent or reduce breakage of the vessel20as a temperature of the media within the vessel20changes and the volume of the media changes. The transfer element346may be attached to the carrier340and may be in contact with the transfer wall322of the box310. The box310may include a thermal grease or gel disposed between the transfer wall322and the transfer element346to enhance thermal energy transfer therebetween.

The box310also includes a closure350to close the chamber330with the vessel20therein. The closure350includes a closure wall352and may include side walls354and a top wall356that fit within the chamber330or on the outside of the chamber330adjacent complementary walls of the fixed wall assembly320.

The closure350has an open position (FIG.5) in which chamber330is accessible and a closed position (FIG.6) in which the closure350prevents access to the chamber330. In some embodiments, the closure350may be hinged relative to the fixed wall assembly320. In such embodiments, the closure wall352includes a top edge351and a bottom edge353. The bottom edge353may be hinged to the bottom wall326such that the closure350pivots about a hinge355formed between the bottom wall326and the bottom edge353between the open and closed positions thereof. The top edge351may include a closure feature360to secure the top edge351relative to the top wall324when the closure350is in the closed position. The closure feature360is configured to maintain the closure350in a closed position. The closure feature360may be a hinged to the top wall324such that the closure feature360pivots between an unsecured state and a secured state. The closure feature360may include ribs362that that are received in a crease364to hold the closure feature360in the secured state. The crease364may be defined in opposite sides of the transfer wall322and the closure wall352. In some embodiments, the closure350is formed separate from the fixed wall assembly320and slides from the bottom wall326towards the top wall324to close the chamber330.

When the closure350is in the closed position, the closure wall352closes the chamber330such that the vessel20is held in place within the carrier340. In some embodiments, the carrier340may have a thickness such that as the box310is closed, the carrier340is compressed between the transfer wall322and the closure wall352. The closure350may include a pad358attached to an inside surface357of the closure wall352. The pad358may extend over the entire inside surface357or may be positioned to align with the well342such that the pad358engages the vessel20. The pad358may be formed of a material similar to the carrier340or may be formed of a different material. In some embodiments, the pad358is an insulative material to insulate the closure wall352from the vessel20. Internal surfaces of the box310including, but not limited to, the transfer wall322and the inside surface357, may have a hydrophobic or a super hydrophobic coating to prevent sticking of the vessel20. The coating may prevent damage to the vessel20when the box310is opened.

Referring now toFIGS.10-13, a carrier holder410is provided in accordance with an embodiment of the present disclosure. The carrier holder410includes a rack420having a first side422and a second side424. Each side of the rack420includes a number of box holders430that are each configured to receive a box310. As shown, the rack420includes three box holders430on each side such that the rack420supports six boxes310. In embodiments, the rack420may be sized to hold a range of one to ten or more boxes on each side. The number of box holders430of the rack420may depend on the size of the vessels within the respective boxes and the size of the freezer to which the rack is inserted as detailed below. The box holders430may be configured to orient the boxes310such that the closure walls352of the boxes310face the interior of the rack420to oppose a closure wall352of another box310and the transfer walls322face the exterior of the rack420. For example, box holders430may include a key432and the boxes310may include a keyway312that is configured to receive the key432to orient the box310is orientated within the box holder430. The key432may be a protrusion, a shaped corner, or other feature that must be received in a keyway to orient the box310. In some embodiments, the box310includes a key and the box holder430defines a keyway to receive the key to orient the box310within the box holder430. In certain embodiments, the box holder430or the box310may include more than one key and the other of the box holder430and the box310may include complementary keyways to receive the respective keys. In particular embodiments, the box holder430and the box310may each include a key and a keyway with the other including a complementary keyway and key.

The rack420includes a compression system440that allows the first side422to move towards and away from the second side424to allow for insertion and removal of the carrier holder410into a frame510without the boxes310contacting the thermal capacitors and to contact the thermal capacitors when fully inserted, as detailed below. The compression system440includes a post442and a biasing member444. The post442extends between the first side422and the second side424and includes a cap443that limits an extent that the second side424can be spaced from the first side422. The biasing member444is positioned between the first side422and the second side424to urge the first side422and the second side424apart from one another. In some embodiments, the biasing member444is a compression spring that is disposed about the post442. The compression system440also includes bosses446that are positioned on the first side422and the second side424. The bosses446extend beyond the extremity of the box holders430and are positioned at the corners of the first side422and the second side424. In some embodiments, the first side422or the second side424may include another bosses446at a midpoint of the top and bottom of the first side422and the second side424. The bosses446may be formed of a material to promote sliding or may include a slide promoting coating. For example, the bosses446may be at room temperature when inserted in a frame that is at a cryotemperature, e.g., −80° C., such that a slide promoting coating may prevent binding of the bosses446or the carrier holder410during insertion or removal. The bosses446may include bevels or chamfers448on leading and trailing surfaces thereof to aid in insertion and removal.

The rack420may include a handle428that is attached to the first side422of the rack420for a user to grip during insertion and removal of the carrier holder410into a frame. As shown, the handle428has a substantially trapezoidal profile but may have a variety of shapes including, but not limited to, a C-shaped profile or a T-shaped profile.

With reference toFIG.14, a frame510is disclosed in accordance with embodiments of the present disclosure. The frame510includes a plurality of thermal capacitors600in fixed relation relative to one another with a channel520disposed between the thermal capacitors600. The channels520are sized to receive a carrier holder410such that the transfer wall322of the boxes310within the carrier holder410are each in contact with a thermal capacitor600when the carrier holders410(FIG.11) are received within frame510.

Referring toFIGS.15and16, each of the thermal capacitors600of the frame510(FIG.14) are shaped to work in concert with the carrier holders410(FIG.11) such that as a carrier holder410is slidably inserted between adjacent thermal capacitors600, the boxes310are spaced apart from the thermal capacitors600and when the carrier holder410is fully inserted, the boxes310are in contact with the thermal capacitors600. The thermal capacitors600include a shell610that has a first contact surface613and a second contact surface617that are opposite one another and form a central portion of the thermal capacitors600.

The shell610includes a top portion660and a bottom portion670that extend above and below the first contact surface613and the second contact surface617, respectively. The top portion660and the bottom portion670are similar to one another; as such, only the bottom portion670will be detailed herein with like elements of the top portion660being labeled with a preceding “66” replacing the “67” of the similar element of the bottom portion670. The bottom portion670includes grooves672, cutouts674, and a rail676. The grooves672extend the length of the shell610and are configured to slidably receive the bosses446of the carrier holder410(FIG.11).

With additional reference toFIGS.17and18, when the bosses446are received within the grooves672, the first side422and the second side424of the rack420are in a compressed state relative to one another such that the boxes310are spaced apart from the thermal capacitors600. The cutouts674are positioned at the end of the grooves672and sized to receive the bosses446when the carrier holder410is fully received within the frame510. When the bosses446are received within the cutouts674, the first side422and the second side424of the rack420are in an uncompressed state relative to one another such that the boxes310are in contact with the thermal capacitors600. The rail676is sized to support the carrier holder410as it is inserted and removed from the frame510. The rail676may include a ramp677at a leading end thereof that guides the bosses446into the groove672.

With reference toFIGS.19-22, the insertion of a carrier holder410into a channel520of a frame510is described in accordance with the present disclosure. Initially referring toFIG.19, the carrier holder410is aligned with the channel520such that the bosses446of the carrier holder410are aligned with the grooves662,672of adjacent thermal capacitors600defining the channel520. When the carrier holder410is aligned with the channel520outside the channel520, the carrier holder410is in the uncompressed state such that transfer walls322of the boxes310within the carrier holder410may define a thickness of the carrier holder410that is greater than a width of the channel520.

As the bosses446enter the grooves662,672(FIG.15) of the thermal capacitors600, the bosses446urge the first side422and the second side424of the rack420towards one another such that the carrier holder410moves towards a compressed state as shown inFIG.20. In the compressed state, the transfer walls322of the boxes310within the carrier holder410define a thickness that is less than a width of the channel520such that as the carrier holder410is inserted into frame510the transfer walls322are spaced apart from contact surfaces613,617of the thermal capacitors600. The engagement of the bosses446with the grooves662,672maintains the carrier holder410in a compressed state during insertion as shown inFIG.21. Maintaining the carrier holder410in a compressed state may prevent contact between boxes310and other elements of the carrier holder410and the contact surfaces613,617of the thermal capacitors600during insertion to prevent or reduce possible damage to the thermal capacitors600during insertion. Preventing or reducing possible damage to the thermal capacitors600may extend the life of the thermal capacitors600.

When the carrier holder410is fully inserted as shown inFIG.22, the bosses446exit the grooves662,672and are received within the cutouts664such that the biasing members444urge the first side422and the second side424of the rack420towards the uncompressed state such that transfer walls322of the boxes310are in intimate contact with a respective one of the contact surfaces613,617of the thermal capacitors600. The intimate contact between the transfer walls322and the contact surfaces613,617may encourage or promote thermal energy transfer into or out of media within the boxes310to rapidly freeze the media.

The removal of the carrier holder410is the reverse of insertion with a user grasping the handle428(FIG.17) of the carrier holder410to remove the carrier holder410from the frame510. As the carrier holder410begins to move from the fully inserted position shown inFIG.22, the chamfers448of the bosses446engage the grooves662,672to move the carrier holder410towards a compressed position such that the boxes310disengage the contact surfaces613,617of the thermal capacitors600until the carrier holder410is fully removed from the frame510or returned to the fully inserted position.

As described above, the thermal capacitors600may be placed in a ULT Freezer to enhance capabilities of the ULT Freezer to rapidly freeze media. As noted above, the media may be disposed in boxes310which may be placed in carrier holders410to protect the media during handling and freezing. As described below, the carriers340detailed above, may also simplify handling of media during distribution of media and packing of vessels including the media into the boxes310.

Referring now toFIGS.23-25, a carrier assembly1340is disclosed in accordance with an exemplary embodiment of the present disclosure. The carrier assembly1340includes a carrier, a vessel, a latch or hook1350, and a frame1360. For the purposes of this disclosure, the carrier340and the vessel20will be used to describe the carrier assembly1340with additional features defined in the carrier340to allow the carrier to hang from a frame with the vessel20supported therein. The carrier340includes a notch1370at a bottom edge of the carrier340that is configured to be positioned towards the inside of the frame1360. The carrier340also includes a nook1380at a top edge of the carrier340on an opposite side of the carrier340that is configured to be positioned towards an outside of the frame1360also shown inFIG.7. The hook1350is received in the nook1380such that the hook1350includes a finger1352that extends from the carrier340.

The frame1360includes a lower support1362and an upper support1366. The frame1360may also include a fluid distribution system that is configured to simultaneously distribute fluid to a plurality of vessels20supported about a central distribution hub1361. The lower support1362may be a plate or a dish including a rim1364that is sized to receive the notch1370. The upper support1366is in the form of a circular rail or a ring about the central distribution hub1361. The finger1352of the hook1350engages the upper support1366to support the carrier340and thus, the vessel20within the carrier, about the central distribution hub1361. Engagement between the hook1350and the upper support1366of the frame1360and/or the notch1370with the lower support1362may limit the degrees of freedom of the carrier assembly1340with respect to the frame1360such that the carrier assembly is fixed in place until the hook1350is released from the frame1360.

When the carrier assembly1340is hung in the frame1360, an inlet tube1363of the vessel20extends from the central distribution hub1361into the vessel20such that fluid from the distribution hub flows into the vessel20. The inlet tube1363may include an aseptic seal element1365that can be aseptically severed when the vessel20is filled. The frame1360may be configured to simultaneously distribute fluid to between 1 and 40 carrier assemblies1340, e.g., 5, 10, or 20 carrier assemblies1340. An exemplary aseptic seal element is available as QUICKSEAL® from Sartorius. Various elements of distribution hubs, fluid distribution systems, and racks are described in U.S. patent application Ser. No. 17/132,958, filed Mar. 15, 2021.

Referring now toFIGS.26-29, a method is disclosed in accordance with the present disclosure and is referred to generally as method2000. The method2000may include sub-methods or processes that when combined result in the method2000. The method2000may include method2100of simultaneously distributing media to a plurality of vessels, method2200of aseptically disconnecting and removing the vessels from a fluid distribution system, and method2300of freezing the media within the vessels.

The method2100of simultaneously distributing media to a plurality of vessels is detailed with reference to the fluid distribution system1300ofFIG.24. The fluid distribution system1300is provided with a plurality of carrier assemblies1340disposed about a central distribution hub1361of the fluid distribution system1300(Step2110). The fluid distribution system1300may include any number of carrier assemblies1340. For example, the fluid distribution system1300may include between 1 and 40 carrier assemblies1340and in some embodiments may include 5, 10, or 20 carrier assemblies1340. When provided, each carrier assembly1340is hung from an upper support1366of the frame1360by a hook1350that is received in a nook1380defined in the carrier340and is supported by a lower support1362of the frame1360with a rim1364of the lower support received in a notch1370defined in the carrier340. The hook1350and the notch1370of the carrier340cooperate with the upper support1366and the lower support1362to hold the carrier assembly1340in position relative to the central distribution hub1361. The carrier assembly1340includes a vessel20supported within the carrier340. The vessel20includes inlet tube1363that fluidly connects the central distribution hub1361and the vessel20. The inlet tube1363extends through a channel344of the carrier340.

The fluid distribution system1300is connected to a vessel containing media to be distributed to the vessels20to form a closed system (Step2120). The fluid distribution system1300may include an inlet or supply tube (not explicitly shown) that fluidly connects the central distribution hub1361to the vessel. With the fluid distribution system1300connected to the vessel, a pump (not explicitly shown) is activated to provide media to the central distribution hub1361which distributes the media to the vessels20(Step2130). As media is provided to the vessels20, an amount of media in the vessels is measured to determine when a target amount of media is distributed to each vessel20(Step2140). The target amount of media may be measured by a scale weighing the fluid distribution system1300or a flow meter measuring an amount of media passing into or through the supply tube. When the target amount of media is reached, the pump is deactivated (Step2150). After the pump is deactivated, supply tube of the fluid distribution system1300may be aseptically disconnected from the vessel (Step2160). In some embodiments, media is provided to the central distribution hub1361via gravity without the use of a pump. In such embodiments, a valve may be operated to activate and deactivate flow of media to the fluid distribution system1300. In certain embodiments, after the pump is deactivated and before the supply tube is aseptically disconnected, a purge fluid may be introduced into the supply tube to push media into the vessels20. The purge fluid may be a buffer or air.

With particular reference toFIG.28, once the pump is deactivated, the carrier assemblies1340are aseptically disconnected and loaded into boxes310in accordance with exemplary embodiments of the present disclosure as detailed with respect to method2200. Initially with reference to the fluid distribution system ofFIGS.24and25, when provided the inlet tube1363includes an aseptic seal element1365disposed thereabout. To aseptically disconnect a carrier assembly1340from the fluid distribution system1300, a tool1650is used to sever the aseptic seal element1365such that the inlet tube1363is severed and aseptically sealed on both of the severed ends (Step2210). With the inlet tube1363severed, the vessel20is a closed system within the carrier assembly1340. After the inlet tube1363is severed, the carrier assembly1340can be removed from the fluid distribution system1300(Process2220). To remove the carrier assembly1340, the carrier assembly1340is lifted such that the hook1350is released from the upper support1366of the frame1360(Step2222). With the hook1350released from the upper support1366, the carrier assembly1340is tilted or pivoted about the notch1370and the lower support1362(Step2224). With the carrier assembly1340tilted or pivoted about the notch1370, the carrier assembly1340can be lifted such that the notch1370is free from the lower support1362(Step2226). In some embodiments, the carrier assembly1340is lifted and removed from the upper support1366and the lower support1362simultaneously with one another. With the inlet tube1363severed and the hook1350and the notch1370free, the carrier assembly1340is free and can be removed from the fluid distribution system1300.

When the carrier assembly1340is removed from the fluid distribution system1300, the hook1350can be separated from the carrier assembly1340(Step2230). The hook1350may be removed by pulling on the hook1350such that a portion of the hook1350engaged with the nook1380of the carrier340is separated from the carrier340. With the hook1350separated from the carrier340, the inlet tube1363is tucked into a channel344of the carrier340(Step2240) such that the inlet tube1363is disposed within the channel344as shown inFIG.7. Specifically, the inlet tube1363extends through a channel344ato exit the carrier340when connected to the fluid distribution system1300is tucked into the channel344bsuch that the inlet tube1363is disposed within the carrier340.

With the inlet tube1363disposed within the carrier340, the carrier assembly1340including the carrier340, the vessel20filled with media, and the inlet tube1363are positioned in a box310as shown inFIG.4(Step2250). The carrier assembly1340is positioned in the box310with the box310in an open configuration such that the closure350is pivoted away from the fixed wall assembly320to provide access to the chamber330. When the carrier assembly1340is positioned in the box310, a transfer element346of the carrier340is in intimate contact with the transfer wall322of the box310. The transfer wall322may include a thermal gel or material positioned where the transfer element346is positioned to enhance contact and thermal energy transfer between the transfer wall322and the transfer element346.

With the carrier assembly1340disposed in the chamber330, the closure350is pivoted to the closed configuration to enclose the carrier assembly1340within the chamber330as shown inFIG.6(Step2260). The closure350may include a pad358that engages the carrier340and/or the vessel20to urge the vessel20into contact with the transfer element346. With the closure350in the closed configuration, the closure feature360is moved to the engage the closure350and the fixed wall assembly320to lock or maintain the box310in the closed configuration (Step2270). The closure feature360may be a C-shaped element that is hinged to the fixed wall assembly320. The closure feature360may include ribs362that engage a crease364to prevent the closure350from moving towards the open configuration.

The method2200may be repeated until all the carrier assemblies1340are removed from the fluid distribution system1300and loaded into a respective box310. The method2200may reduce an amount of time to remove and pack vessels20into boxes for freezing when compared to previous methods. As such, a single lab technician or user may be able remove and pack an increased number of vessels20in a given amount of time. This increase in production may increase production efficiency of a facility. In addition, by preloading the vessels20in a carrier340that can be hung directly on the fluid distribution system1300, the precision and accuracy of the packing of the vessels20into boxes310may be improved. Further, the handling of the vessels20may be simplified from disconnecting the vessels20and packing into the boxes310.

Referring toFIG.29, method2300is described in accordance with the present disclosure to freeze the media within the vessels20. To prepare for freezing the media within the vessels20, the thermal capacitors600of a frame510are charged (Step2310). To charge the thermal capacitors600, the thermal capacitors600are placed in an appropriate freezer, e.g., a ULT Freezer, with enough time to charge PCM within the thermal capacitors600. As the PCM within the thermal capacitors600may take significant time to charge, e.g., to freeze the PCM, the thermal capacitors600may be placed or left in the freezer at least 12 or 24 hours before loading the boxes310into the frame510as detailed below. The thermal capacitors600may be charged in a freezer that will be used to freeze the boxes310or may be charged in a separate freezer specifically for charging the thermal capacitors600. In some embodiments, the frame510is installed in a freezer with the thermal capacitors600fixed within the frame510and left in the freezer when not in use such that the thermal capacitors600are slowly or trickle charged between freezing operations. When the thermal capacitors600are charged in a separate freezer, the frame510or the thermal capacitors600are moved into the freezer for freezing prior to freezing media in the vessels20. In certain embodiments, the thermal capacitors600are formed into the frame510in the freezer prior to freezing the media.

As noted above, each of the thermal capacitors600may include a charge indicator620that is in signal communication with a sensor622that provides a visual indicia of a charge state of the thermal capacitor600. The method2300may include verifying a charge state of the thermal capacitors600(Step2315).

With the thermal capacitors600charged, the boxes310are loaded into a carrier holder410as shown inFIG.11(Process2320). As noted above, the boxes310and/or the carrier holder410may include keys and keyways to orient the boxes310such that the transfer walls322of the boxes are oriented to an outside of the carrier holder410. As shown inFIG.11, the carrier holder410has six box holders430with three on each side of the rack420. As noted above, the carrier holder410may have a differing number of boxes310depending on the size of the boxes310and/or the size of the freezer holding the frame510. In some embodiments, the carriers340may be loaded into the carrier holder410without the use of boxes310such that the carriers340are insertable directly into the carrier holder410. In such embodiments, the carriers340may be in direct contact with the thermal capacitors600.

With the boxes310loaded in the carrier holder410, carrier holder410is inserted into a frame510. As shown inFIG.19, the carrier holder410is aligned with the channel520in an uncompressed state (Step2330). With the carrier holder410aligned with the channel520, the carrier holder410is urged into the frame510with the bosses446entering the grooves662,672of the thermal capacitors600such that the bosses446transitions the carrier holder410towards a compressed state as shown inFIG.20(Step2340). As detailed above, in the compressed state, the boxes310are spaced apart from the thermal capacitors600. When the carrier holder410reaches the fully inserted position, the bosses446are received in the cutouts664such that the carrier holder410expands towards the uncompressed state such that thermal walls322of the boxes310are in intimate contact with a respective contact surface613,617of a respective one of the thermal capacitors600(Step2350). Loading the carrier holders410into the frame510can be repeated until every frame510within a particular freezer is filled with carrier holders410or all of the boxes310filled with vessels20are loaded into the freezer.

When a freezer is filled or all the boxes310are loaded into a frame510, the freezer is closed such that the freezer cooperates with the thermal capacitors600to rapidly freeze media within the boxes310(Step2360). As detailed above, the thermal capacitors600may be configured to rapidly freeze media within the boxes310at a rate of 1° C. to 4° C. per minute until the media reaches a desired temperature, e.g., −80° C. to −50° C. The thermal capacitors600may allow for a large amount of media to be rapidly frozen in a traditional ULT Freezer without requiring specialty freezing equipment, e.g., 5 L or more of media.

When media reaches a desired temperature, the carrier holders410can be removed from the frame510(Step2370) and the boxes310can be removed from the carrier holders410and loaded into a transportation container for shipping, a storage container for storage, or be returned to a ULT Freezer outside of carrier holder410and frame510for storage until use (Step2380). In some embodiments, the boxes310may be placed in ultralow temperature storage and frozen to a temperature below −80° C., e.g., −150° C. or below. In certain embodiments, the boxes310may be stored for some period of time in the ULT Freezer before being placed in ultralow temperature storage or transported. The removal of the carrier holder410is the reverse of insertion with a user grasping the handle428of the carrier holder410to remove the carrier holder410from the frame510. As the carrier holder410begins to move from the fully inserted position shown inFIG.23, the chamfers448of the bosses446engage the grooves662,672to move the carrier holder410towards a compressed position such that the boxes310disengage the contact surfaces613,617of the thermal capacitors600until the carrier holder410is fully removed from the frame510or returned to the fully inserted position.

The carrier assemblies1340may increase the efficiency of distributing media to vessels, aseptically disconnecting vessels, and freezing media within the vessels. The efficiency may be gained by providing the vessels preloaded into the carrier assemblies such that a reduced number of laboratory technicians can manage the process of distributing media and freezing media from a primary vessel to a plurality of secondary vessels. The methods detailed herein reduce the steps necessary to distribute media to a plurality of secondary vessels and to load the secondary vessels into a freezer to freeze the distributed media. Such processes must be done in a timely manner so a reduction in steps and a simplification of processes may decrease an amount of time required to distribute and freeze the media. The apparatuses and methods detailed herein may allow a single laboratory technician to distribute media, disconnect vessels, load carrier assemblies into boxes, and place the boxes into a freezer within a time period necessary to preserve the media. For example, a single technician may be able to utilize the apparatus and methods detailed herein to distribute media from a single vessel to 100 secondary vessels and freeze media within the secondary vessel in an acceptable time period to preserve the media. In addition, the apparatus and methods detailed herein may allow for a reduced footprint to distribute and freeze media. This reduced footprint may allow for additional processes to be completed.

As detailed above, the boxes and secondary vessels may be perceived to be manually handled vessels up to 100 mL or even 500 mL. It is within the scope of this disclosure that the secondary vessels may be up to 16 L for manually handled vessels and 100 L for mechanically assisted vessels. The use of thermal capacitors in contact with containers may allow for the rapid freezing of these larger containers.

The thermal capacitors, boxes, systems, and methods detailed above have been described with respect to rapidly freezing media. It is contemplated that similar thermal capacitors, boxes, systems, and methods can also be used for thawing or heating media. Specifically, thermal capacitors could be filled with a PCM having a transition temperature in a range of 20° C. to 100° C. and be placed in a water bath to charge the PCM within the thermal capacitors. Once charged the thermal capacitors may be removed from the water bath and placed in contact with the boxes to rapidly heat or thaw media disposed in a container in contact with the thermal capacitor. In such applications, the thermal capacitors may provide heat to media within the container to rapidly heat or thaw the media within the container. The thermal capacitors may be charged in non-agitated liquid or water baths, agitated liquid or water baths, or recirculated liquid or water baths. The liquid or water baths may be used to heat or to cool the thermal capacitors.

While several embodiments of the disclosure have been shown in the drawings, it is not intended that the disclosure be limited thereto, as it is intended that the disclosure be as broad in scope as the art will allow and that the specification be read likewise. Any combination of the above embodiments is also envisioned and is within the scope of the appended claims. Therefore, the above description should not be construed as limiting, but merely as exemplifications of particular embodiments. Those skilled in the art will envision other modifications within the scope of the claims appended hereto.