EP4735814A1 - Freeze-drying systems and methods - Google Patents

Abstract

Freeze-drying systems and methods. Such a system includes a phased array RF system configured to emit electromagnetic waves into a process chamber via an antenna array to form an electromagnetic field in the process chamber. The phased array RF system varies the electromagnetic field distribution in the chamber, for example, by randomly varying over time a phase-shift between two or more separate RF signals emitted into the process chamber from separate antennas of the antenna array.

Description

FREEZE-DRYING SYSTEMS AND METHODS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of provisional U.S. Patent Application No. 63/524,382 filed June 30, 2023, the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] The invention generally relates to systems, components, and/or processes for freeze-drying items using electromagnetic energy, and, in some nonlimiting embodiments, to freeze-drying biopharmaceutical products.

[0003] Freeze-drying (also referred to as lyophilization) is a process of removing water from a material and has been used to preserve perishable materials, extend shelf life, and/or make a material more convenient for transport. Freeze-drying works by freezing the material, then reducing the pressure and adding heat to allow the frozen water in the material to sublimate. A benefit of freeze-drying is that it can reduce drying times of the material by up to 30% over other conventional drying processes, such as passive or active air and/or thermal drying processes.

[0004] Typically, conventional freeze-drying methods include three phases. In the first phase (the freezing phase), the material is cooled below its triple point to ensure sublimation occurs. For biological materials, this initial freezing phase is accomplished rapidly to prevent cell wall damage caused by large ice crystals that form during slower freezing processes. In the second phase (the primary drying (sublimation) phase), the pressure in and around the material is reduced and the product is warmed slightly to sublimate the ice (frozen water) in the material, yielding water vapor. This phase typically removes about 95% of the frozen water. In the third phase (the secondary drying (adsorption) phase), ionically-bound water molecules are removed from the material by raising the temperature further above that in the sublimation phase while maintaining a vacuum. This adsorption phase breaks the bonds between the material and remaining water molecules and results in the material having a porous structure. Typically, the freeze-drying process ends by breaking the vacuum using an inert gas before sealing the material, and typically achieves a residual moisture of about 1-5%. [0005] Freeze-drying can be used to stabilize biomaterials, including but not limited to highly sensitive pharmaceutical drugs and biological products, prior to long-term storage. Freeze-drying of biologic materials, such as biopharmaceuticals, has gained significant interest in recent years due to the high demand for product stabilization, and has become widely used in the pharmaceutical industry because it permits the processing of thermolabile products in sterile conditions. Further, there is rising demand for lyophilized injectable medicines and molecular diagnostics. Unfortunately, freeze-drying is a very time-consuming industrial processes with a relatively low energy efficiency typically of less than 10%.

[0006] To address these limitations, some methods of freeze-drying have been investigated that also use various forms of electromagnetic energy. For example, radio frequency (RF)/microwave-based lyophilization has been investigated because it significantly accelerates such processes relative to typical conventional freeze-drying processes. However, most existing microwave-assisted lyophilization systems operate in the common industrial, science, and medical (ISM) band of about 2.45 GHz, which usually results in high batch inhomogeneity due to hot spots generated inside the dryer. It also typically results in a longer drying time since ice absorption to RF energy is significantly lower than 18 GHz. Pulsed electric field (PEF) freeze-drying methods have also been investigated because it can intensify the dehydration process when freeze-drying biologies. However, PEF-assisted methods can lead to damage or death of cells in biologic materials due to the formation of pores that also appear to result in the reduced drying times.

[0007] Some previous approaches to RF-assisted freeze-drying utilize a metallic Faraday chamber ("RF chamber" or "RF box") containing mechanical stirrers and a radiator (antenna) to be placed inside the freeze-dryer. However, such a metallic chamber inside the freeze-dryer does not allow product stoppering. Hence, the dried products are exposed to humid air, increasing the products’ residual moisture content. Moreover, using a fully metallic encapsulated RF chamber prevents the visual inspection of the products during freeze-drying. In addition, the utilized mechanical stirrers are large, limiting the number of vials containing the biopharmaceuticals that can be placed inside the RF box during drying. Since the mechanical stirrers need to be moving for effective uniformity, motors are attached to the RF box inside the freeze-dryer. This constitutes another drawback of previous approaches. Finally, integrating temperature sensor probes inside the vials is inconvenient and time- consuming due to the existence of the RF box. One conventional approach is described in U. S. Patent 11,454,443, whose contents are incorporated herein by reference.

[0008] In view of the above, it would be desirable if systems, components, and/or methods of freeze-drying biologic materials were available that were capable of reducing the time and improving the energy efficiency of a freeze-drying process, reducing damage to cells of a biomaterial during freeze-drying, improving the effectiveness of a biomaterial freeze-drying process, and/or mitigate any of the drawbacks and limitations noted above.

BRIEF SUMMARY OF THE INVENTION

[0009] The intent of this section of the specification is to briefly indicate the nature and substance of the invention, as opposed to an exhaustive statement of all subject matter and aspects of the invention. Therefore, while this section identifies subject matter recited in the claims, additional subject matter and aspects relating to the invention are set forth in other sections of the specification, particularly the detailed description, as well as any drawings.

[0010] The present invention provides, but is not limited to, freeze-drying systems and methods of freeze-drying products, including biomaterials.

[0011] According to a nonlimiting aspect, a freeze-drying system includes a process chamber configured for freeze-drying a product, and a phased array RF system configured to emit electromagnetic waves into the process chamber via an antenna array to form an electromagnetic field in the process chamber having an electromagnetic field distribution. The phased array RF system is configured to vary the electromagnetic field distribution in the chamber.

[0012] According to another nonlimiting aspect, a method of freeze-drying a product includes maintaining a product in a frozen condition inside a process chamber, lowering the pressure of the process chamber to induce sublimation of a frozen solvent of the product, heating the product during the sublimation with an electromagnetic field formed by electromagnetic waves emitted from an antenna array, and varying the electromagnetic field distribution inside the process chamber over time during the sublimation.

[0013] Technical aspects of systems and methods as described above preferably include the ability to reduce the time needed to freeze-dry products, such as biomaterials, improve energy efficiency during freeze-drying, reduce damage to cells in biomaterials that are being freeze-dried, and/or improve effectiveness of a biomaterial freeze-drying process.

[0014] These and other aspects, arrangements, features, and/or technical effects will become apparent upon detailed inspection of the figures and the following description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. l is a schematic diagram of a freeze-drying system according to a nonlimiting embodiment of the invention.

[0016] FIG. 2 is a schematic diagram of a phased array RF system capable of beam forming in the system of FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The intended purpose of the following detailed description of the invention and the phraseology and terminology employed therein is to describe what is shown in the drawings, which include the depiction of and/or relate to one or more nonlimiting embodiments of the invention, and to describe certain but not all aspects of the embodiment(s) to which the drawings relate. The following detailed description also identifies certain but not all alternatives of the embodiment(s) depicted in the drawings. As nonlimiting examples, the invention encompasses additional or alternative embodiments in which one or more features or aspects shown and/or described as part of a particular embodiment could be eliminated, and also encompasses additional or alternative embodiments that combine two or more features or aspects shown and/or described as part of different embodiments. Therefore, the appended claims, and not the detailed description, are intended to particularly point out subject matter regarded to be aspects of the invention, including certain but not necessarily all of the aspects and alternatives described in the detailed description.

[0018] The invention will be described hereinafter in reference to a freeze-drying system 10 shown in the drawings and described as used to freeze-dry biologic materials (biomaterials), and particularly biopharmaceuticals. However, it will be appreciated that the teachings of the invention are more generally applicable to a variety of types of freeze-drying systems and can be used for freeze-drying many other types of materials.

[0019] FIG. 1 schematically illustrates the freeze-drying system 10. In some nonlimiting embodiments, the system 10, its components and associated methods, addresses one or more of the above-discussed limitations by applying high-frequency (e.g., 8 GHz to 18 GHz) electromagnetic waves that volumetrically heat the products as they dry. The system and method are preferably capable of significantly reducing the drying time relative to conventional lyophilization while simultaneously improving overall heating uniformity among the product locations. For example, in some circumstances the system and method are capable of drying biologic material samples twice as fast as conventional freeze-drying systems and methods.

[0020] The nonlimiting embodiment of the freeze-drying system 10 represented in FIG. 1 includes a process chamber 12 and a condenser chamber 14. The process chamber 12 has an interior cavity in which material ("product") 60 to be freeze-dried is placed during the freeze- drying process. The condenser chamber 14 has an interior cavity in which vapors that sublime during the freeze-drying process can be trapped and a ballast gas utilized during the freeze- drying process can be removed. The product 60 is represented as being contained in multiple vials, though various other means of containing the product 60 are foreseeable and well known in the art, as nonlimiting examples, trays, medical devices, foams, tissue, food, etc. The process chamber 12 may have an RF resistant layer, such as a Faraday cage, surrounding the interior cavity to prevent electromagnetic energy from escaping from the interior cavity. A duct 16 operatively couples the process chamber 12 with the condenser chamber 14 to allow gas within the cavity of the process chamber 12 to flow into the condensing chamber 14, and an isolation valve 18 is provided within the duct 16 to regulate gas flow between the chambers 12 and 14. The isolation valve 18 may be selectively opened to allow gas flow between the chambers 12 and 14 or closed to prevent or at least inhibit gas flow between the chambers 12 and 14. As such, when closed the isolation valve 18 is able to separate and optionally seal the process chamber 12 where the product 60 is dried from the condenser 14 where sublimed vapors are trapped and a ballast gas is removed.

[0021] A phased array RF system 20 is operatively coupled to the process chamber 12 so as to be able to emit electromagnetic energy (also referred to herein as beam forming) into the process chamber 12 as described in more detail hereinafter. The RF system 20 generates high- frequency, high-power electromagnetic (RF) waves that are injected into the process chamber 12. As represented in FIG. 2, the system 20 includes an antenna array 22 of individual antennas that direct focused RF energy inside the process chamber 12 of the freeze-drying system 10. The antenna array 22 may also generate non-focused RF energy as well. The RF system 20 emits RF signals, referred to as “beams” 21 herein, that have a random (or pseudo-random) change of the phases from the antenna array 22. The generated RF beams 21 result in the formation of different and varying electromagnetic field distributions inside the process chamber 12. Such a change in the distribution of the electromagnetic field is attributed to the change of the coefficients associated with the different excited modes. In this way, the variation of the phases of the RF beams 21 emitted from different antennas of the antenna array 22 can cause both in-phase excitation as well as out-of-phase excitation of the product 60 inside the process chamber 12. When the electromagnetic field distribution inside the process chamber 12 is randomly (or pseudo-randomly) changed (e.g., by changing the phases of the RF beams emitted from the different antennas), an average uniform field can be obtained within the cavity of the process chamber 12, since any hot and cold spots generated by the RF beams 21 would be constantly redistributed and changing over time due to the varying phase shifts between at least two or more of the separate RF beams being emitted from antennas in the antenna array 22. Additional details of one possible configuration for the system 20 are provided hereinafter.

[0022] The phased array RF system 20 is represented in FIG. 1 as completely externally connected outside of the process chamber 12; however, in other configurations it can be disposed completely or partially inside the process chamber 12, depending on the utilized application. For applications that require sterility, the phased array RF system 20 may be mounted to an external side of a door 26 to the chamber 12 through which vials of the product 60 are inserted and removed. In the example shown in FIG. l, both the antenna array 22 and the remaining components of the system 20 are disposed outside of the process chamber 12. However, for other applications, the RF system 20 could be mounted inside the process chamber 12 due to its relatively small size and portability. Furthermore, some components of the phased array RF system 20 may be mounted or otherwise located outside of the process chamber 12 and other components of the phased array RF system 20 may be partially or completely located outside the process chamber 12. For example, the antenna array 22 may at least partially extended to the inside of the process chamber 12, or even be completely located therein, and other components of the phased array RF system 20, such as oscillators, amplifiers, splitters, phase shifters, couplers, and/or circulators, may be mounted to the outside of the process chamber 12 or otherwise disposed outside of the process chamber 12. Regardless of the way the phased array RF system 20 is connected to the process chamber 12, suitable RF shielding may be provided and configured to prevent RF energy from escaping the process chamber 12. RF shielding may include, for example, a metallic coating on the door 26 and/or a separate metallic mesh attached to the door 26.

[0023] One or more shelves 24 may be disposed inside the process chamber 12, for example, on which product 60 that is to be freeze-dried may be placed during the freeze-drying process. The shelves 24 are preferably temperature controlled to be able to cool (e.g., freeze) and/or heat any products 60 disposed on the shelves 24. For example, the shelves 24 may have heating and/or cooling units associated therewith so that the temperatures of the shelves 24 themselves can be decreased or increased to correspondingly cool or heat products 60 disposed thereon. Any cooling and/or heating units capable of providing the necessary cooling/heating may be used.

[0024] A viewport 28, such as a small glass-covered window, may be provided in the door 26 to allow for visual (or IR) inspection of the products 60 during freeze-drying. A shielding metallic mesh or coating may also cover the viewport 28 to prevent or minimize any RF leakage that might occur through the viewport 28. The size of the mesh may be chosen to ensure that visual inspection is possible through the viewport 28 into the process chamber 12 while also keeping the RF energy stored inside the chamber 12.

[0025] FIG. 12 represents an inlet duct 30 through a wall of the process chamber 12 to allow a ballast gas 62 to be injected into the process chamber 12. The ballast gas 62 is typically a non-condensable and/or inert gas that is introduced into the process chamber 12 to regulate pressure around a user-defined setpoint. An example of a typical ballast gas is nitrogen gas. [0026] A vacuum pump 32 is operatively coupled to the condenser chamber 14 to draw a vacuum from the condenser chamber 14. The vacuum pump 32 can also draw a vacuum from the process chamber 12 when the isolation valve 18 is open. A second vacuum pump 36 may be operatively coupled to the process chamber 12 to directly draw a vacuum from the cavity inside the process chamber 12, for example, when the isolation valve 18 is closed. One or more vacuum sensors and/or gauges 34 are represented as operatively coupled with the interior cavity of the process chamber 12 to measure vacuum pressure inside the cavity and to provide any data feedback to the freeze-drying system 10 necessary to regulate pressure inside the cavity around a user-defined setpoint.

[0027] FIG. 2 shows additional details of a nonlimiting embodiment of the RF system 20. In addition to the antenna array 22, the system 20 is represented as including a local oscillator 40, amplifiers 42, 44, and 46, an RF splitter 48, phase shifters 50, directionals couplers 52, and circulators 54. Preferably, components of the RF system 20 are assembled as a single unit, for example, within and/or on a single support such as a housing 23, that can be easily mounted to a single support surface, such as the door 26 or an interior wall of the process chamber 12. In some configurations, the antenna array 22 could be assembled as part of the single unit to mount with the housing 23 or the antenna array 22 could be separate or separable from the housing 23 so it can be mounted remote from the housing 23. The RF system 20 may also include a controller 56 configured to execute field mixing algorithms for varying the RF beams 21 as disclosed herein. The controller 56 may, for example, an on-board central processing unit (CPU) configured with appropriate software instructions and/or hardware components or other digital and/or analog system configured to execute the RF field mixing algorithms for changing the phases of the RF beams 21 emitted by the antenna array 22 to randomly or pseudo-randomly or otherwise vary the RF field within the process chamber 12 over time as described herein. In other embodiments, the controller 56 could be located remote from or have at least some components located remote from the system 20. In the example embodiment shown in FIG. 2, the antenna array 22 is a 3 X 1 antenna array, and the controller 56 is configured to change the relative phases of individual antennas of the array 22 relative to each other over time to change the structure of their respective beams 21, thereby resulting in different varying electromagnetic RF field distributions inside the process chamber 12 that change over time.

[0028] The local oscillator 40 generates a low-power, high-frequency RF signal. One possible local oscillator is a voltage-controlled oscillator (VCO), which takes electrical voltage as an input and outputs an RF signal. Because the RF signal generated by the VCO is usually low power, the low-noise amplifier 42 is provided to increase the power of the RF signal output from the local oscillator 40 before it is divided into different paths. The output of the low-noise amplifier 42 goes into the RF splitter 48 that functions as a power divider to divide the RF signals into a preselected number (e.g., “n”) separate RF signals. Preferably, the RF splitter 48 splits the incoming RF signal into a number of different RF signals that correspond with the number of antennas in the antenna array 22. For example, in the nonlimiting example of FIG. 2, the RF splitter 48 splits the amplified RF signal from the low-noise amplifier 42 into three separate RF signals, one signal to correspond to each of the three antennas in the antenna array 22. Of course, fewer or more separate signals could be generated if fewer or more antennas are provided in the antenna array 22. Because each signal output from the RF splitter 48 is again at a lower power, the separate signals from the RF splitter 48 are fed through another set of power amplifiers 44 to increase the power of the split RF signals.

[0029] Next, the separate RF signals from the power amplifiers 44 are directed to the phase shifters 50 to control the phases of the different RF signals. Preferably, at least two phase shifters are used in order to be able to separately shift the phases of at least two RF signal streams so that they can be at different phases from each other. In some configurations, a different phase shifter 50 is provided for each signal stream emitted from the RF splitter 48. The phase shifters 50 make it possible to change the radiation pattern of the antenna array 22, thereby generating a desired RF radiation pattern. However, because the phase shifters 50 are lossy (they reduce the power of the RF signals), the output phase shifted RF signals are fed into a final amplification stage at the power amplifiers 46, such as GaN power amplifiers, before being fed to the antenna array 22. To protect the whole RF system 20 from any reflected RF signals, the phase-shifted and re-amplified RF signals from the third power amplifiers 46 are directed through one or more circulators 54 operatively disposed between the antennas 22 and the power amplifiers 46. FIG. 2 represents one or more directional couplers 52 and/or signal detectors 58 may be provided for monitoring the output power from the phase shifters 50.

[0030] The phased-array RF system 20 may be a self-contained "bolt-on" unit configured to be installed on most commercial lyophilizers with minimal modification. Preferably, the self-contained "bolt-on" unit interfaces with a client computer and/or other control devices, allowing basic operating parameters such as frequency, output power, azimuth, and zenith angle to be controlled by the user.

[0031] The configuration of the system 20 shown in FIG. 2 is just one possible example of how to generate high power RF beams 21 for use with the freeze-drying system 10. However, the beams 21 may be generated in various other manners and/or by other configurations of components. The primary factor that determines a desired configuration for the RF system 20 is the choice of components and their corresponding operating conditions and electrical specifications.

[0032] Next, an example method of freeze-drying a material, such as a biopharmaceutical or any other product that is to be freeze-dried, is provided in the context of using the freeze- drying system 10 of FIGS. 1 and 2. The freeze-drying system 10 may perform freeze-drying through various operations. Some of the following operations may change depending on the particular implementation and/or material being freeze-dried, such as the product 60 represented in FIG. 1.

[0033] The product 60 to be dried is loaded into the process chamber 12, such as onto the temperature-controlled shelves 24. The product 60 and/or its container may include liquid- filled vials or trays, medical devices, foams, tissue, food, etc. In some cases, the product 60 may be frozen prior to loading and the shelves 24 are cooled to a user-defined temperature prior to loading. In the example of FIG. 1, the product 60 being dried includes a mixture of solvent and solute disposed in vials that are loaded onto the shelves 24. The solvent may be any liquid within which a solid solute is mixed. For example, the solvent may include or be water, a biological solvent, an organic solvent, an inorganic solvent, or any other liquid solvent that can be frozen from its liquid form to a solid form.

[0034] After the product 60 is loaded into the drying cavity, the process chamber 12 is then sealed, for example by closing the door 26 and/or closing the isolation valve 18, and the temperatures of the shelves 24 are lowered until the product 60 freezes and/or otherwise reaches a target temperature. This primary freezing step separates the solvent from the solute and provides a stable solid matrix in preparation for primary drying (sublimation phase).

[0035] After the product 60 has frozen and equilibrated at the target temperature, the pressure inside of the process chamber 12 is lowered, for example using the vacuum pump 36, during a primary drying/sublimation phase. During the sublimation phase, the pressure inside the process chamber 12 is reduced to be low enough to induce sublimation of the frozen solvent inside the vials containing the product 60 in the process chamber 12. The isolation valve 18 is open to allow sublimated moisture from the product 60 within the vials to flow through the duct 16 and into the condenser chamber 14, where a condenser 38 condenses the sublimated moisture. [0036] While the pressure is reduced during the primary drying phase, the RF system 20 is activated, and the antenna array 22 radiates electromagnetic energy in the form of RF beams (signals) 21 into the process chamber 12, which adds heat into the process chamber 12. The added heat from the electromagnetic energy offsets latent heat lost through sublimation. Additional heat may also be supplied by the shelves 24, for example, with a heating unit. An inert and non-condensable ballast gas 62, such as nitrogen, is also introduced into the process chamber 12 to regulate the pressure inside the chamber 12 to be at or around a user-defined setpoint. The vacuum sensors and/or gauges 34 can provide feedback to a control system (e.g., the controller 56) to perform this operation. The ballast gas 62 bypasses the condenser 38 and is removed by the vacuum pump 32. The sublimed solvent vapor flows out of the vials, through the duct 16, and into the condenser chamber 14. The condenser 38 is maintained at a very low temperature sufficient to condense the solvent vapor onto its surface. The freeze-drying system 10 may have an additional pump 37 to remove the condensate formed by vapors condensed by the condenser 38. The primary drying (sublimation) phase is typically the longest phase of the freeze-drying process and can take anywhere from days to weeks to successfully complete.

[0037] After all bulk frozen solvent has been removed from the product 60 inside the process chamber 12, the temperature of the resulting partially dry matrix is raised and maintained at a user-defined value in order to desorb remaining bound water or other liquid within the product 60. This operation is known as the secondary drying phase, and heating provided during this phase may be accomplished by either or both the shelves 24 and the RF system 20.

[0038] When the secondary drying phase is complete, the RF system 20 is deactivated and the product 60 is typically sealed inside of the sterile environment of the process chamber 12. Thereafter, the pressure inside the process chamber 12 can be restored to atmosphere, and the product 60 can be removed from the process chamber 12 for further processing as desired.

[0039] An advantage of the freeze-drying system 10 from previously known systems is that that the system 10 and freeze-drying process do not require any mechanical stirrers and/or scatterers inside the process chamber 12. Rather, the system 10 implements an “electronic” stirring of an electromagnetic field by means of the beams 21 generated by the system 20 randomly varying the electromagnetic field inside the process chamber 12. [0040] The freeze-drying system 10 and associated method are preferably capable of providing several technical advancements over conventional approaches. For example, unlike previously known RF-assisted freeze-drying systems, the freeze-drying system 10 does not need an RF box or mechanical stirrers found in conventional approaches. For example, the system 10 and methods described herein replace the mechanical stirrers of conventional RF- assisted systems with the RF system 20, which improves the electromagnetic field homogeneity in and around the drying product 60 while taking up less or no space inside the freeze-dryer process chamber 12 compared with conventional mechanical stirrers. The RF system 20 may be affixed to a metallic door, or some other portion, of a freeze-dryer due to its compact size. The absence of an RF Box allows for, among other advantages, the stoppering of the product- filled vials at the end of the cycle.

[0041] As previously noted above, though the foregoing detailed description describes certain aspects of one or more particular embodiments of the invention, alternatives could be adopted by one skilled in the art. For example, the freeze-drying system 10 and its components could differ in appearance and construction from the embodiments described herein and shown in the drawings, functions of certain components of the freeze-drying system could be performed by components of different construction but capable of a similar (though not necessarily equivalent) function, and various materials could be used in the fabrication of the freeze-drying system and/or its components. As such, and again as was previously noted, it should be understood that the invention is not necessarily limited to any particular embodiment described herein or illustrated in the drawings.

Claims

CLAIMS:

1. A freeze-drying system comprising: a process chamber configured for freeze-drying a product; and a phased array RF system configured to emit electromagnetic waves into the process chamber via an antenna array to form an electromagnetic field in the process chamber having an electromagnetic field distribution, wherein the phased array RF system is configured to vary the electromagnetic field distribution in the chamber.

2. The freeze-drying system of claim 1, wherein the phased array RF system varies the electromagnetic field distribution randomly or pseudo-randomly over time.

3. The freeze-drying system of claim 1, wherein the phased array RF system comprises a plurality of phase shifters that phase shift a plurality of RF signals to generate a corresponding plurality of phase-shifted RF signals that have different phases from each other, wherein the phase-shifted RF signals are delivered to the antenna array to form the electromagnetic waves.

4. The freeze-drying system of claim 3, wherein the varying of the electromagnetic field distribution is caused by phase shifting of the RF signals by the phase shifters.

5. The freeze-drying system of claim 4, wherein the phased array RF system comprises a controller configured to control variation of the phase shifting.

6. The freeze-drying system of claim 5, wherein the controller is configured to cause the antenna array to vary phases of the focused RF energy emitted into the process chamber.

7. The freeze-drying system of claim 5, wherein the controller is configured to cause the antenna array to emit focused RF energy inside the freeze-dryer.

8. The freeze-drying system of claim 7, wherein the controller is configured to cause the antenna array to generate non-focused RF energy in addition to the focused RF energy.

9. The freeze-drying system of claim 1, wherein the phased array RF system is mounted to an exterior of the process chamber.

10. The freeze-drying system of claim 9, further comprising a door configured to permit access into the process chamber, wherein the phased array RF system is coupled to the door.

11. A method of freeze-drying a product, the method comprising: maintaining a product in a frozen condition inside a process chamber, wherein in the frozen condition, the product includes a frozen solvent; lowering the pressure of the process chamber to induce sublimation of the frozen solvent; heating the product during the sublimation with an electromagnetic field formed by electromagnetic waves emitted from an antenna array, wherein the electromagnetic field has an electromagnetic field distribution within the process chamber; and varying the electromagnetic field distribution inside of the process chamber over time during the sublimation.

12. The method of claim 11, wherein the step of varying comprises varying the electromagnetic field distribution randomly or pseudo-randomly over time.

13. The method of claim 11, wherein the step of varying comprises: generating a plurality of separate RF signals; phase shifting at least one of the RF signals such that at least two of the separate RF signals are out of phase with each other; and varying the phase shifting over time to form different and varying electromagnetic field distributions inside the process chamber.

14. The method of claim 13, wherein the antenna array comprises at least two antennas, wherein each of the at least two separate RF signals is emitted by respective separate one of the at least two antennas.

15. The method of claim 11, further comprising at least one of: freezing the product inside the process chamber prior to the heating; regulating pressure in the process chamber with a ballast gas during the sublimation; and desorbing remaining liquid from the product after the sublimation by raising the temperature of the product and maintaining a vacuum within the process chamber.