Means and methods for selective shelf temperature control

Abstract

A system including a fluid manifold and an article; the manifold having a length and a width and a plurality of inlet or outlet ports and the article comprising an element disposed within the manifold adapted for adjustable lengthwise movement within the manifold; and is suitably employed to adjust shelf temperature in for example a freeze-drying apparatus.

Description

<DP=1>²Means and Methods for Selective Shelf Temperature Control²Related Applications ²

[0001] This application claims priority to U.S. Patent Application No. ²62 / 642,767, filed on ²March 14,2018.²Field of Invention²

[0002] The disclosure relates to temperature control of shelves.²BackEround ²

[0003] Freeze-drying (i.e. lyophilization or cryodesiccation) is a process for ²removing ²volatiles such as water or solvents from products. Freeze-drying has many ²applications such ²as preserving perishable materials, allowing for transport of certain ²materials, production of ²ceramics, production of products with short reconstitution times and ²acceptable potency ²levels, and the like. Freeze-drying is employed for a wide variety of ²materials, including, but ²not limited to food, pharmaceuticals and biological specimens.²

[0004] In a typical freeze-drying process, samples, or vials or containers ²containing a sample, ²are loaded onto temperature-controlled shelves within a chamber and are cooled ²to low ²temperature until solidified. The chamber is then subjected to reduced ²pressure and the shelf ²temperature is adjusted to enable removal of a frozen solvent via sublimation ²in a step ²referred to as "primary drying". When sublimation is complete, the shelf ²temperature is ²raised during a "secondary drying" step to remove any additional solvent bound ²to the solid ²product e.g. by adsorption. When sufficient solvent is removed, the process is ²concluded. If ²samples are contained in vials or containers, the vials or containers are ²sealed, typically under ²sub-ambient pressure of inert gas.²

[0005] Freeze-dryers generally contain a plurality of shelves onto which ²samples are loaded. ²The shelves may be cooled to below ambient temperature via flow of a heat ²exchange fluid ²through the shelves. Shelves may be cooled to temperatures for instance of ²from about 5 C ²to about -55 C or colder. Cooling of a plurality of shelves during a loading ²process in which ²the shelves are exposed to ambient conditions of a loading area may result in ²undesired frost ²buildup on some or all shelves. Frost will act as an insulator and prevent ²proper heat transfer ²to a product vial or container. In addition, frost build-up can increase the ²amount of effort ²required to push product vials or trays onto a shelf. Increased force needed ²to move product²1²Date Recue / Date Received 2023-07-19²<DP=2>²CA 03093834 2020-09-11²WO 2019 / 178201 ²PCT / US2019 / 022013²onto shelves may adversely affect the performance of automatic loading ²systems. While ²there have been some designs that utilize valves for each shelf and fluid ²connection, these ²designs require a connection for each valve be extended through the pressure ²chamber in ²order to maintain process boundaries and cleanliness. Such methods increase ²the ²manufacturing cost and maintenance cost, while also add to the number of ²points of potential ²failure of the device. Desired are methods to cool shelves "just in time" ²before they are ²loaded, thereby reducing exposure time of a cold shelf to the atmosphere and ²minimizing the ²potential for frost buildup, while also doing so with fewer chamber ²penetrations.²Summary ²

[0006] Accordingly, disclosed is a system comprising a housing defining a ²chamber;²a plurality of horizontal shelves arranged vertically within the chamber, each ²shelf ²comprising an inlet, an outlet and a flow passageway disposed between the ²inlet and the ²outlet; a fluid manifold having a length and a width and in fluid ²communication with a ²respective flow passageway of each shelf; and an article comprising an element ²disposed ²within the manifold and adapted for adjustable lengthwise movement along the ²length of the ²manifold.²

[0007] Also disclosed is a method of controlling a shelf temperature in a ²system comprising a ²housing defining a chamber; a plurality of horizontal shelves arranged ²vertically within the ²chamber, each shelf containing a flow passageway, an inlet and an outlet; a ²fluid manifold ²having a length and a width and in fluid communication with each shelf; and an ²article ²comprising an element disposed within the manifold and adapted for adjustable ²lengthwise ²movement in the manifold; the method comprising adjustably moving the element ²lengthwise ²within the manifold.²

[0008] Also disclosed is a system comprising a fluid manifold having a length ²and a width ²and a plurality of inlet or outlet ports and an article comprising an element ²disposed within ²the manifold adapted for adjustable lengthwise movement within the manifold.²

[0009] Also disclosed is a method of controlling fluid flow through a fluid ²manifold, the ²manifold having a length and a width and a plurality of inlet or outlet ports, ²wherein an ²element is disposed within the manifold and adapted for adjustable lengthwise ²movement²2²<DP=3>²CA 03093834 2020-09-11²WO 2019 / 178201 ²PCT / US2019 / 022013²within the manifold; the method comprising adjustably moving the element ²lengthwise within ²the manifold.²Brief Description of the Drawings ²

[0010] The disclosure described herein is illustrated by way of example and ²not by way of ²limitation in the accompanying figures. For simplicity and clarity of ²illustration, features ²illustrated in the figures are not necessarily drawn to scale. For example, ²the dimensions of ²some features may be exaggerated relative to other features for clarity. ²Further, where ²considered appropriate, reference labels have been repeated among the figures ²to indicate ²corresponding or analogous elements.²[00111 FIG. I shows a freeze-drying system according to disclosed embodiments.²[00121 FIG. 2 shows the freeze-drying system of FIG. 1 in another stage of ²operation ²in accordance with disclosed embodiments.²100131 FIG. 3 shows the freeze-drying system of FIG. 1 in another stage of ²operation ²in accordance with disclosed embodiments.²[00141 FIG. 4 shows the freeze-drying system of FIG. 1 in another stage of ²operation ²in accordance with disclosed embodiments.²Detailed Description ²

[0015] This disclosure, in one example, relates to systems and methods for ²minimizing ²undesired frost formation on cooled shelves during loading of a freeze-drying ²process.²

[0016] A freeze-drying process includes at least a freezing stage, a primary ²drying (i.e. ²sublimation) stage and a secondary drying (i.e. desorption) stage. During the ²freezing stage, ²a product is frozen and solvent crystals are formed in the product. During the ²primary drying ²stage, solvent is removed from the product by sublimation of free solvent by ²an increase in ²temperature and reduced pressure. During the secondary drying stage, the ²temperature is ²raised higher to remove bound solvent from the product. The solvent, or ²volatiles, in general ²comprise water.²

[0017] Chambers of freeze-dryers in general contain a plurality of shelves, ²which are adapted ²with a cavity, i.e. flow passageway, to pass through a heat exchange fluid for ²temperature²3²<DP=4>²CA 03093834 2020-09-11²WO 2019 / 178201 ²PCT / US2019 / 022013²adjustment. Embodiments of the invention relate to systems and methods for ²control of shelf ²temperatures.²

[0018] FIG. 1 is a depiction of a freeze-drying system 100 according to an ²embodiment of the ²invention. The system contains a housing 101 defining a chamber 102 containing ²a plurality ²of horizontal, vertically arranged shelves 103. While only eleven shelves 103 ²are shown in ²the figure, it should be understood that more or less shelves 103 may be used. ²Each shelf ²103 contains a flow passageway 104, an inlet 105 and an outlet 106. The shelf ²inlet 105 and ²outlet 106 locations are shown for some of the shelves 103, but it should be ²understood that ²each shelf 103 will have an inlet 105 and an outlet 106 for a respective flow ²passageway 104 ²even though they are not explicitly shown here. Shelf inlets 105 and outlets ²106 may be ²aligned with each other as shown here, but need not be. The inlets 105 and ²outlets 106 may ²be at any location along the flow passageways 104 in fluid communication with ²each other ²and the flow passageways 104, respectively. For example, the 105 may be on an ²opposite ²site of the shelf 103 from inlet 106. The system contains an article 115 ²comprising an ²element having a rod 107 affixed with a stopper 108, a means 109 of moving the ²rod and ²stopper and a seal 110. The rod 107 affixed with the stopper 108 is disposed ²in a fluid ²manifold 111. The manifold 111 has ports 112, each associated and in fluid ²communication ²with a corresponding shelf 103 through tubes 113, which may also be any other ²type of ²piping of a suitable material and size to carry a heat exchange fluid. The ²stopper 108, as ²shown in FIG. 1, is in a fully retracted position. In this stopper 108 ²position, heat exchange ²fluid flow is allowed through only a top shelf 103 and an upper portion of ²manifold 111. The ²manifold 111 is in fluid communication with the shelves.²

[0019] FIG. 1 depicts the manifold 111 being connected through tubes 113 to ²outlets ²106, such that fluid flows from inlets 105 through the flow passageways 104 in ²the shelves ²103 to the outlets 106 and then to the manifold 111 exiting at 114. Not shown ²is a tube or ²fluid connection from heat transfer fluid pump 120 (discussed below) to inlets ²105. In an ²alternative embodiment, the manifold 111 may be connected through tubes 113 to ²inlets 105, ²such that fluid flows from 114 (reversing the 114 arrow), through the manifold ²111, through ²the tubes 113, through the inlets 105, through the flow passageways 104 to ²outlets 106, which ²would then flow back heat transfer fluid pump 120.²4²<DP=5>²CA 03093834 2020-09-11²WO 2019 / 178201 ²PCT / US2019 / 022013²

[0020] FIG. 2 depicts the freeze-drying system 100, for example that shown in ²FIG. 1, ²according to an embodiment of the invention. In FIG. 2, the stopper 108 is in ²a partially ²inserted position. In this stopper position, flow of a heat exchange fluid is ²permitted through ²the top two shelves 103 and the manifold 111. Flow of a heat exchange fluid ²through the ²remaining shelves and the bottom portion of the manifold is blocked by the ²stopper 108.²

[0021] FIG. 3 depicts the freeze-drying system 100, for example that shown in ²FIGS. 1 and ²2, according to an embodiment of the invention. In FIG. 3, the stopper 108 is ²in a partially ²inserted position, which is more fully inserted than as shown in FIG. 2. In ²this stopper ²position, flow of a heat exchange fluid is permitted through all shelves 103 ²and the manifold ²111 except the bottom shelf 103, shelf N. Flow of a heat exchange fluid ²through the bottom ²shelf 103 and the bottom portion of the manifold is blocked by the stopper ²108.²

[0022] FIG. 4 depicts the freeze-drying system 100, for example that shown in ²FIGS. 1 - 3, ²according to an embodiment of the invention. In FIG. 4, the stopper 108 is in ²a fully inserted ²position. In this stopper 108 position, flow of a heat exchange fluid is ²permitted through all ²shelves 103 and the entirety of the flow portion of the manifold 111.²

[0023] The freeze-drying system 100 of FIGS. 1-4 may have additional elements ²in addition ²to a plurality of shelves 103 and a chamber 102, for instance a refrigeration ²unit, a vacuum ²system, fluid lines or hoses, gas lines, etc. The chamber may be accessible ²via a door or ²doors which may seal the chamber and allow it to sustain vacuum conditions. ²The chamber ²may comprise one or more inlets and / or outlets to facilitate gas flow, liquid ²flow or to ²connect to a vacuum source.²

[0024] In some embodiments, the freeze-drying system may be adapted to perform ²steam ²sterilization cycles. The freeze-drying system may be adapted to perform clean-²in-place ²(CIP) and / or a steam sterilization (SIP) cycle after each use to ensure a ²product is not ²contaminated by a previously lyophilized material. For example, in certain ²embodiments, the ²freeze-drying system may include one or more inlets for introducing cleaning ²media and / or ²steam into a chamber. The chamber may contain a drain to remove excess water.²

[0025] The chamber may include one or more orifices for connecting to various ²valves and ²gauges. For instance, a gauge, such as a Pirani gauge, may be coupled to a ²chamber to ²measure the pressure within the chamber.²<DP=6>²CA 03093834 2020-09-11²WO 2019 / 178201 ²PCT / US2019 / 022013²

[0026] In some embodiments, the shelves may be thermally coupled to a heating ²element. A ²heating element may be an electric heating device. In some embodiments, a ²heating element ²may be one or more fluid lines thermally coupled to the shelves.²

[0027] In certain embodiments, the freeze-drying system may include a ²condenser, which ²may be contained within the housing. In other embodiments, the system may ²comprise an ²external condenser. In such embodiments, condensing plates or coils may be ²disposed ²proximate within chamber 102, a separate condensing chamber or a conduit ²connecting the ²chamber 102 to the condensing chamber. If the orifices are on the condensing ²chamber or in ²a conduit between an isolation valve and the condensing chamber, then the ²isolation valve ²separating chamber 102 and the condensing chamber will be opened to achieve ²identical ²pressures between the two. In some embodiments, more than one chamber 102 may ²be ²connected to a single condensing chamber and vice versa.²

[0028] In some embodiments, the freeze-drying system may include a control ²interface, ²which may allow a user to program a series of steps and cause the steps to be ²executed. The ²freeze-drying system may include various control hardware (e.g., one or more ²processing ²devices) and software systems adapted to command and coordinate the various ²elements of ²the system / apparatus and carry out a pre-programmed freeze-drying cycle. ²Various control ²hardware and software systems may also provide documentation, data logging, ²alarms and ²system security capabilities as well. In addition, auxiliary systems to the ²freeze-dryer system ²may include a leak check system, performance check system and various ²subsystems to clean ²and sterilize the product chamber and / or auto-load / unload the product in the ²product ²chamber, as well as associated mechanical or cryogenic refrigeration system ²accessories such ²as refrigeration skids, compressors, condensers, heat exchangers, heat ²transfer fluid systems, ²pumps, heaters, expansion tanks, cryogen tanks, piping, flow ²controllers / regulators, valves, ²sensors, etc.²

[0029] Disclosed herein are methods of controlling shelf temperatures in a ²system such as ²freeze-drying system 100. The product to be chilled is first loaded onto the ²shelves, e.g., ²shelves 103 (FIG. 1). During the loading of the product, the present system ²may minimize ²frost buildup on the product shelves. Shelves generally are loaded starting ²with the topmost ²(first) usable shelf (the very top shelf generally is for radiant heat ²transfer only). During the ²loading of the first shelf, the stopper 108 is positioned to allow heat ²transfer fluid flow ²through the radiant (very top shelf 103) and first shelves 103 only. Upon ²completion of²6²<DP=7>²CA 03093834 2020-09-11²WO 2019 / 178201 ²PCT / US2019 / 022013²loading of the first shelf (or at a point during the loading of the first ²shelf), the stopper ²element moves or is moved to allow fluid flow through the second shelf. This ²process ²repeats until all shelves have been loaded. By limiting the duration that an ²unloaded shelf is ²chilled, frost buildup can be minimized, which leads to increased heat ²transfer efficiency.²

[0030] After the product has been loaded, the shelves generally are held at ²the cold ²temperature and / or cooled further to induce nucleation of the product ²(freezing). The shelf ²temperature may be held at relatively cold values (e.g. about -50 C) for a ²period of time to ²ensure that all of the product has frozen completely. However, the temperature ²at which the ²product is held may depend on the specific product and desired cooling.²100311 After freezing of the sample is complete, drying steps are initiated ²which include a ²primary drying step and secondary drying step. Primary drying involves ²activating a vacuum ²pump and condenser refrigeration system to establish the desired sublimation ²and condensing ²conditions in the chamber 102. In some embodiments, a small bleed flow of a ²gas (e.g., an ²inert gas) may be fed into the chamber throughout the drying process to help ²control the ²vacuum level. After the vacuum pressure conditions are attained, the shelves ²are warmed ²(e.g., using an electric heater) to the desired primary drying temperature, ²which is dictated by ²the thermal, mechanical, chemical and / or biological properties of the material ²undergoing ²freeze-drying. Primary drying is completed when all the unbound water has been ²removed ²by sublimation, as determined by one or more of product temperature ²measurements, ²humidity measurements, comparison of capacitance manometer and Pirani gauge ²measurements, analysis of samples obtained with a sample thief, or other ²techniques. Once ²primary drying is complete, the freeze-dryer shelf temperatures are further ²warmed at a ²desired warming rate until the product or materials reach a temperature where ²desorption of ²bound water may be adequately achieved. This final product temperature depends ²on product ²composition and could be about 20 C or higher. After drying is complete, the ²product or ²material is removed from the chamber 102. At any time during the process, the ²freeze-drying ²system may be capable of emergency stop or shutdown, which would close ²pressurization ²and depressurization control valves while the chamber remains under vacuum.²

[0032] Shelves 103 are adapted with a cavity, i.e. flow passageway 104, to ²pass through it a ²heat exchange fluid for temperature adjustment. The flow passageway may ²advantageously ²have a serpentine shape or other shape to increase the heat transfer area ²between the fluid and²7²<DP=8>²CA 03093834 2020-09-11²WO 2019 / 178201 ²PCT / US2019 / 022013²the shelves 103. The fluid may be an aqueous or non-aqueous, for instance ²water, glycol, a ²glycol / water mixture or a silicone oil. Glycol includes ethylene glycol and ²propylene glycol.²

[0033] The manifold 111, whether it be configured as an inlet manifold or an ²outlet manifold, ²will have a length L and a width W, the width being the longest radii of the ²manifold, e.g, ²near the ports 112. In some embodiments, the manifold may have a shape that is ²cylinder-²like or rectangular box-like. The manifold 111 will have a number of ports ²112, which ²function as an inlet or outlet for the manifold depending on the configuration ²of the manifold ²111. Each port 112 is associated with a shelf outlet 106 or an inlet 105 via, ²for example a ²tube, hose, or a pipe 113. The manifold inlets or outlets are orifices or ²ports 112 for fluid ²flow. A fluid manifold 111 may have from 2 to 25 or 30 ports or more, for ²example 2, 3, 4, ²5, 6, 7, 8, 9, 10, 20, 25 or 30 ports depending on the number of shelves 103 ²in the system 100. ²The inlet or outlet manifold ports 112 may or may not be uniformly spaced ²apart.²

[0034] The article 115 includes, in one example, an element or rod 107 with ²stopper 108, ²disposed in the manifold is adapted for adjustable lengthwise movement in the ²manifold 111. ²In some embodiments, the article 115 comprises a rod 107 with a stopper 108 or ²"plunger" ²fixed to the end of the rod 107 within the manifold 111. This arrangement is ²not unlike a ²piston in a cylinder. The stopper 108 may have any shape suitable to produce ²the desired ²effect of preventing fluid flow through the manifold 111 at the location of ²the stopper. In ²some embodiments, the stopper 108 may have a disc shape, a ball shape, a ²spheroid shape, a ²piston shape, etc. In some embodiments, a diameter of the stopper 108 is ²slightly smaller ²than the interior diameter of the manifold 111, enabling the stopper 108 to be ²adjustably ²moved within the manifold 111 and also prevent fluid flow in the manifold 111. ²As the ²stopper 108 is moved up or down (or sideways if the manifold was similarly ²mounted) within ²the manifold, that is, retracted or inserted, fluid flow is enabled (allowed) ²or is prevented ²(disallowed) through one or more particular shelves 103. In one example ²embodiments, the ²system 100 comprises an article 115 disposed in an outlet manifold, in an ²inlet manifold, or in ²both manifolds.²

[0035] In one example the system 100 will include an inlet manifold and an ²outlet manifold, ²with the inlet manifold coupled to the shelf inlets and with the outlet ²manifold coupled to the ²shelf outlets. One or both of the inlet and outlet manifolds may be like ²manifold 111 having ²an article 115.²8²<DP=9>²CA 03093834 2020-09-11²WO 2019 / 178201 ²PCT / US2019 / 022013²

[0036] When fluid flow is prevented through one or more particular shelves ²103, those ²shelves 103 remain in fluid communication with the manifold 111, but the ²liquid cannot flow ²through those shelves 103. This is illustrated in the figures. As the stopper ²108 travels ²farther into the manifold 111, flow is enabled to each shelf 103 one-by-one. ²For example, for ²an system 100 containing 5 shelves 103, in a fully retracted position, flow is ²enabled to only a ²first (top) shelf 103. The stopper 108 may be partially inserted to a next ²position to enable ²flow to the first two shelves 103. The stopper 108 may be partially inserted ²to allow liquid ²flow to the first three or the first four shelves 103. The stopper 108 may be ²fully inserted to ²allow flow to all 5 shelves 103.²

[0037] The element disposed within the manifold may be associated with a ²suitable means of ²actuation 109. That is, the article 115 comprising the element also comprises ²a means of ²actuation 109, e.g. pneumatic or electric actuator, electric or hydraulic ²piston, rack and ²pinion, work gear, or other suitable device including manual means. The means ²of actuation ²109 may be any suitable means adapted to move a rod 107 in a linear motion. ²The means of ²actuation may be in communication, e.g. electrical communication, with an ²automated ²loading device. The allowance of flow may be programmed to be timed to ²coincide with ²automatic sample loading through sub-doors or through a single door (not ²shown).²

[0038] As fluid is not compressible, in one example the system 100 is designed ²to allow fluid ²to escape from below the stopper 108 as it is inserted past a bottom shelf's ²103 connection ²port 112 to a manifold. This may be accomplished, for instance, by increasing ²the diameter ²of the manifold at a connection point for the last (bottom) shelf, for example ²at 124 (FIG. 4), ²such that the width of the manifold at 124 is greater than width W. In other ²stopper 108 ²positions, fluid may escape back through a shelf or shelves whose connection ²is below the ²stopper 108 position. All of the aforementioned are means of allowing escape ²of a fluid from ²below the element when the element is in an inserted position.²

[0039] There might also be a change in flow path resistance as a stopper 108 ²is retracted or ²inserted; which change may be compensated for by any suitable means. In some ²embodiments, with reference to FIG. 1, this may be compensated by having a ²variable ²frequency drive 118 on a heat transfer liquid pump 120 and / or a bypass line ²122 with or ²without suitable valve(s) or other fluid flow control devices. These are means ²of allowing ²escape of a fluid from below the element when the element is in an inserted ²position.²9²<DP=10>²CA 03093834 2020-09-11²WO 2019 / 178201 ²PCT / US2019 / 022013²

[0040] Present systems may therefore also comprise a means to adjust the flow ²rate of fluid ²supplied to a shelf or shelves. The means may comprise a bypass line 122 ²and / or a variable ²frequency drive 118 on a heat transfer fluid pump 120, or other fluid flow ²control device(s). ²An adjustable variable flow rate will allow for maintenance of heat transfer ²equilibrium (i.e. ²constant heat transfer fluid velocity in each shelf) among the shelves as each ²shelf is ²"opened" to the liquid. Maintaining consistent heat transfer fluid velocity ²will provide ²temperature uniformity across a shelf surface.²

[0041] In some embodiments, the apparatus may contain from 2 to 25 or 2 to 30 ²shelves or ²more, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 20, 25 or 30 shelves or ²more. The shelves ²may in general be uniformly spaced apart, or not.²

[0042] Present systems and methods are not limited to freeze-dryers or freeze-²drying ²methods. For example, disclosed systems and methods are equally applicable to ²refrigerators ²and freezers without a separate vacuum or drying system. Disclosed systems may ²also be ²utilized in any other temperature control systems, including heating systems.²

[0043] The term "system" may be synonymous with "apparatus" or "device" and ²may ²include an associated collection of elements, for instance elements selected ²from hardware, ²software and electronics. The terms "element", "article" and "member" may be ²synonymous ²and may themselves consist of a single element or may comprise more than one ²element. In ²general, a system may comprise one or more articles and an article may ²comprise one or ²more elements.²

[0044] In some embodiments, vacuum conditions may be less than 1 millibar up ²to about ²1000 millibar.²

[0045] The term "configured" as used in the description and claims is intended ²to be an open-²ended term as are the terms "comprising" or "containing". The term ²"configured" is not ²meant to exclude other possible articles or elements. The term "configured" ²may be ²equivalent to "adapted".²

[0046] The term "associated" means for instance "equipped with", "coupled to", ²"connected ²to" or in "communication with", for example "electrically connected" or in ²"fluid ²communication with" or otherwise connected in a way to perfoini a function. ²The term²<DP=11>²"associated" may mean directly associated with or indirectly associated with, ²for instance ²through one or more other articles or elements.²

[0047] The articles "a" and "an" herein refer to one or to more than one (e.g. ²at least one) of ²the grammatical object. Any ranges cited herein are inclusive. The term ²"about" used ²throughout is used to describe and account for small fluctuations. For ²instance, "about" may ²mean the numeric value may be modified by 5%, 4%, 3%, 2%, 1 %, ²0.5%, ²0.4%, 0.3%, 0.2%, 0.1% or 0.05%. All numeric values are modified by ²the term ²"about" whether or not explicitly indicated. Numeric values modified by the ²term "about" ²include the specific identified value. For example, "about 5,0" includes 5.0. ²In addition, a ²feature discussed with one figure or embodiment may also be used in ²combination with or in ²the alternative of another disclosed feature or embodiment as applicable.²

[0048] Unless otherwise indicated, all parts and percentages are by weight. ²Weight percent ²(wt%), if not otherwise indicated, is based on an entire composition free of ²any volatiles, that ²is, based on dry solids content.²

[0049] What is claimed as new and desired to be protected by Letters Patent ²is:²11²Date Recue / Date Received 2023-07-19²

Claims

<DP=1>²CLAIMS²1. A system comprising²a housing defining a chamber;²a plurality of horizontal shelves arranged vertically within the chamber, each ²shelf ²comprising an inlet, an outlet and a flow passageway disposed between the ²inlet and the ²outlet;²a fluid manifold having a length and a width and in fluid communication with a ²²respective flow passageway of each shelf; and²an element disposed within the manifold and adapted for adjustable lengthwise ²movement along the length of the manifold, wherein the element comprises a rod ²connected ²to a stopper, wherein the stopper is sized to prevent a flow of a heat ²exchange fluid through ²one or more of the shelves.²2. The system according to claim 1, wherein the manifold is an outlet fluid ²manifold that ²is coupled to the outlets of each shelf²3. The system according to claim 1, wherein the manifold is an inlet fluid ²manifold that is ²coupled to the inlets of each shelf²4. The system according of claim 1, wherein the adjustable movement serves ²to allow or ²prevent flow of a heat exchange fluid through one or more of the shelves.²5. The system according to claim 1, wherein the element is connected to a ²means of ²actuation.²6. The system according to claim 1, wherein²if the element is in a fully retracted position, the flow of the heat exchange ²fluid is ²permitted through only a first of the plurality of horizontal shelves;²if the element is in a fully inserted position, the flow of the heat exchange ²fluid is ²permitted through all of the plurality of horizontal shelves; or²12²Date Recue / Date Received 2023-07-19²<DP=2>²if the element is in a partially inserted position, the flow of the heat ²exchange fluid is ²permitted through more than one of the plurality of horizontal shelves and ²fewer than all of ²the plurality of horizontal shelves.²7. The system according to claim 1, wherein the element is adapted to being ²actuated ²into a position so as to prevent the flow of heat exchange fluid through a ²desired number of ²the plurality of shelves and to permit the flow of heat exchange fluid through ²the remaining ²number of the plurality of shelves.²8. The system according to claim 7, wherein the plurality of shelved is ²from 2 to 30 ²shelves, inclusive.²9. The system according to claim 5, wherein the element is associated with ²an automated ²or a manual sample positioning device.²10. The system according to claim 1, further comprising at least one of ²bypass line, a ²variable frequency drive on a liquid pump, and a fluid flow control device.²11. The system according to claim 1, further comprising a vacuum source.²12. The system according to claim 1, wherein the system is a freeze-drying ²system.²13. A method of controlling a shelf temperature in a system comprising a ²housing ²defining a chamber;²a plurality of horizontal shelves arranged vertically within the chamber, each ²shelf ²containing a flow passageway, an inlet and an outlet;²a fluid manifold having a length and a width and in fluid communication with ²each ²shelf; and²an element disposed within the manifold and adapted for adjustable lengthwise ²movement in the manifold;²the method comprising adjustably moving the element lengthwise within the ²manifold ²wherein the element comprises a rod connected to a stopper, wherein the ²stopper is sized to ²prevent a flow of a heat exchange fluid through one or more of the shelves.²13²Date Recue / Date Received 2023-07-19²<DP=3>²14. The method ²according to claim 13, further comprising controlling fluid flow rate²through the shelves by at least one of bypassing fluid around one or more ²shelves and ²adjusting a pump rate of the fluid.²14²Date Recue / Date Received 2023-07-19²