GELS for drug substance storage and associated methods and systems

Abstract

Gels for storing drug substances, associated systems, and associated methods are generally described. In some embodiments, the gels, systems, and methods described herein have one or more features which may advantageously allow for the storage of drug substances for extended periods of time at moderate temperatures. For example, in some embodiments, the gels, systems, and methods described herein may allow for the storage of drug substances without the need for controlled-rate freezing of drug substance-containing solutions at extremely low temperatures. Such embodiments may have several advantages, such as low cost, low energy requirements, and / or not requiring specialized equipment.

Description

[0001] GELS FOR DRUG SUBSTANCE STORAGE AND ASSOCIATED METHODS AND SYSTEMS RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 763,874, filed February 26, 2025, and entitled “Gels for Drug Substance Storage and Associated Methods and Systems,” which is incorporated herein by reference in its entirety for all purposes.

[0003] FIELD

[0004] Gels for drug substance storage, and associated systems and methods, are generally described.

[0005] BACKGROUND

[0006] Current materials, systems, and methods for storing and transporting drug substances typically require the ability to rapidly freeze drug substance-containing solutions, store these frozen solutions at extremely low temperatures, and rapidly thaw the frozen solutions. The equipment and energy costs associated with rapid freeze / thaw cycles and extremely low temperatures are large and can be prohibitive.

[0007] Accordingly, new materials, systems, and methods would be beneficial.

[0008] SUMMARY

[0009] The present disclosure generally describes gels, systems and methods. The subject matter described herein involves, in some cases, interrelated products, alternative solutions to a particular problem, and / or a plurality of different uses of one or more gels, systems, and methods.

[0010] Paragraph 1: In one aspect, a method for storing a drug substance is described. In some embodiments, the method comprises: combining the drug substance with a gelator in a mixer to form a liquid mixture; and inducing gelation of the liquid mixture to form a shearthinning gel with a volume greater than or equal to 1 L.

[0011] Paragraph 2: In another aspect, a method for producing a liquid product comprising a drug substance is described. In some embodiments, the method comprises: applying a shear stress to a shear-thinning gel with a volume greater than or equal to 1 L, the gel comprising a drug substance and a gelator, to liquefy the gel and form a recovered liquid mixture; andseparating the recovered liquid mixture to remove the gelator from the recovered liquid mixture and produce a liquid product.

[0012] Paragraph 3: In another aspect, a method for storing a drug substance is described. In some embodiments, the method comprises: combining the drug substance with a gelator to form a liquid mixture; inducing gelation of the liquid mixture to form a shear-thinning gel; and freezing the gel by holding the gel at a temperature of less than or equal to -20 °C for a period of 2 or more hours to form a frozen gel.

[0013] Paragraph 4: In another aspect, a method for producing a liquid product comprising a drug substance is described. In some embodiments, the method comprises: thawing a frozen gel, the frozen gel comprising a drug substance and a gelator, by holding the frozen gel at a temperature of greater than or equal to 5 °C for a period of 6 or more hours to form a shearthinning gel; applying a shear stress to the gel to liquefy the gel, forming a recovered liquid mixture; and separating the recovered liquid mixture to remove the gelator from the recovered liquid mixture and produce a liquid product.

[0014] Paragraph 5: In another aspect, a system for preparing a drug substance-containing gel is described. In some embodiments, the system comprises: a mixer configured to produce a mixture, the mixture comprising a gelator and a drug substance, wherein the mixer has a volume greater than or equal to 1 L; a conduit in fluidic communication with the mixer; a pump in fluidic communication with the conduit; and a process controller configured to control a flow rate of fluid through the conduit and / or a mixing rate of the mixer.

[0015] Paragraph 6: In another aspect, a system for storing a drug substance-containing gel is described. In some embodiments, the system comprises: a container containing a mixture, the mixture comprising a gelator and a drug substance, wherein the container contains a volume greater than or equal to 1 L; a filter in fluidic communication with the container and configured to remove the gelator from the mixture; a conduit in fluidic communication with the container and the filter; and a liquefier configured to apply a shear stress to a gel contained within the container.

[0016] Paragraph 7: In another aspect, a system for processing a recovered liquid mixture comprising a gelator and a drug substance is described. In some embodiments, the system comprises: a filter configured to remove the gelator from the recovered liquid mixture and form a liquid product; and a sensor configured to measure the concentration of the gelator in the liquid product.

[0017] Paragraph 8: In some embodiments, a system or method as in any preceding Paragraph further comprises one or more excipients.Paragraph 9: In some embodiments, a system or method as in any preceding Paragraph further comprises a buffer.

[0018] Paragraph 10: In some embodiments, in a system or method as in any preceding Paragraph, the gelator is a liquid solution.

[0019] Paragraph 11 : In some embodiments, in a system or method as in any preceding Paragraph, the liquid mixture comprises a biomaterial, an excipient, and a buffer.

[0020] Paragraph 12: In some embodiments, in a system or method as in any preceding Paragraph, separating the recovered liquid mixture comprises filtering the recovered liquid mixture.

[0021] Paragraph 13: In some embodiments, in a system or method as in any preceding Paragraph, separating the recovered liquid mixture comprises centrifuging the recovered liquid mixture.

[0022] Paragraph 14: In some embodiments, in a system or method as in any preceding Paragraph, centrifuging comprises continuous centrifuging.

[0023] Paragraph 15: In some embodiments, in a system or method as in any preceding Paragraph, the filter comprises a filter capsule.

[0024] Paragraph 16: In some embodiments, in a system or method as in any preceding Paragraph, the filter comprises a tangential flow filtration assembly.

[0025] Paragraph 17: In some embodiments, in a system or method as in any preceding Paragraph, the filter comprises a prefilter.

[0026] Paragraph 18: In some embodiments, a system or method as in any preceding Paragraph further comprises a filter element.

[0027] Paragraph 19: In some embodiments, in a system or method as in any preceding Paragraph, the gel is a hydrogel.

[0028] Paragraph 20: In some embodiments, a system or method as in any preceding Paragraph further comprising applying a substantially constant shear stress to the liquid mixture.

[0029] Paragraph 21: In some embodiments, in a system or method as in any preceding Paragraph, the inducing gelation of the liquid mixture comprises reducing a shear stress exerted on the liquid mixture below the critical shear stress of the liquid mixture.

[0030] Paragraph 22: In some embodiments, in a system or method as in any preceding Paragraph, the inducing gelation of the mixture comprises adjusting the pH of the mixture.

[0031] Paragraph 23: In some embodiments, in a system or method as in any preceding Paragraph, inducing gelation comprises performing drop-wise gelation.Paragraph 24: In some embodiments, in a system or method as in any preceding Paragraph, the gel forms beads and / or granules.

[0032] Paragraph 25: In some embodiments, in a system or method as in any preceding Paragraph, the gel forms a single integrated substance.

[0033] Paragraph 26: In some embodiments, in a system or method as in any preceding Paragraph, adjusting the pH of the mixture comprises adding a pH adjuster to the liquid mixture.

[0034] Paragraph 27: In some embodiments, in a system or method as in any preceding Paragraph, the pH is homogeneous in the mixture.

[0035] Paragraph 28: In some embodiments, in a system or method as in any preceding Paragraph, the pH of the mixture is a homogenous pH above the critical pH value of the mixture at which gelation of the mixture occurs.

[0036] Paragraph 29: In some embodiments, in a system or method as in any preceding Paragraph, the pH adjuster comprises an acid.

[0037] Paragraph 30: In some embodiments, in a system or method as in any preceding Paragraph, the pH adjuster comprises a base.

[0038] Paragraph 31 : In some embodiments, in a system or method as in any preceding Paragraph, the pH adjuster comprises a buffer.

[0039] Paragraph 32: In some embodiments, in a system or method as in any preceding Paragraph, adjusting the pH of the mixture comprises using a control loop comprising a pH sensor and a pH controller that controls a pump in fluidic communication with a source of a pH adjuster to maintain a consistent pH.

[0040] Paragraph 33: In some embodiments, in a system or method as in any preceding Paragraph, the gelator is a low molecular weight gelator.

[0041] Paragraph 34: In some embodiments, in a system or method as in any preceding Paragraph, the gelator comprises 3-{[(ls)-l-(dodecyl carbamoyl)-2-methylpropyl]carbamoyl [propanoic acid.

[0042] Paragraph 35: In some embodiments, in a system or method as in any preceding Paragraph, the drug substance comprises a protein.

[0043] Paragraph 36: In some embodiments, in a system or method as in any preceding Paragraph, the drug substance comprises a biomaterial.

[0044] Paragraph 37: In some embodiments, in a system or method as in any preceding Paragraph, the drug substance comprises an antibody.Paragraph 38: In some embodiments, in a system or method as in any preceding Paragraph, the drug substance comprises a vaccine.

[0045] Paragraph 39: In some embodiments, in a system or method as in any preceding Paragraph, the drug substance comprises a small molecule.

[0046] Paragraph 40: In some embodiments, in a system or method as in any preceding Paragraph, the drug substance comprises insulin.

[0047] Paragraph 41: In some embodiments, in a system or method as in any preceding Paragraph, applying a shear stress to the gel comprises changing the headspace pressure of a container comprising the gel.

[0048] Paragraph 42: In some embodiments, in a system or method as in any preceding Paragraph, changing the headspace pressure of a container comprises inflating or deflating the container.

[0049] Paragraph 43: In some embodiments, in a system or method as in any preceding Paragraph, the inflating or deflating the container comprises using a dip tube to inflate or deflate the container.

[0050] Paragraph 44: In some embodiments, in a system or method as in any preceding Paragraph, applying a shear stress to the gel comprises applying a compressive force to a container comprising the gel.

[0051] Paragraph 45: In some embodiments, in a system or method as in any preceding Paragraph, applying a shear stress to the gel comprises rotating an impeller submerged in the gel.

[0052] Paragraph 46: In some embodiments, in a system or method as in any preceding Paragraph, applying a shear stress to the gel comprises inducing vibration of the gel using an ultrasonic mixer and / or a vibromixer.

[0053] Paragraph 47: In some embodiments, in a system or method as in any preceding Paragraph, the shear stress is above a yield stress of the gel and below a critical shear stress of the drug substance.

[0054] Paragraph 48: In some embodiments, in a system or method as in any preceding Paragraph, the mixer has a volume greater than or equal to 1 liter.

[0055] Paragraph 49: In some embodiments, in a system or method as in any preceding Paragraph, the mixer has a volume greater than or equal to 100 liters.

[0056] Paragraph 50: In some embodiments, in a system or method as in any preceding Paragraph, the mixer has a volume greater than or equal to 1000 liters.Paragraph 51 : In some embodiments, in a system or method as in any preceding Paragraph, the mixer contains a mixture.

[0057] Paragraph 52: In some embodiments, in a system or method as in any preceding Paragraph, the mixer contains a mixture comprising a gelator and a drug substance, wherein the mixer has a volume greater than or equal to 1 L.

[0058] Paragraph 53: In some embodiments, in a system or method as in any preceding Paragraph, the mixer is a batch mixer.

[0059] Paragraph 54: In some embodiments, in a system or method as in any preceding Paragraph, the mixer is a single use static mixer.

[0060] Paragraph 55: In some embodiments, in a system or method as in any preceding Paragraph, the mixer is a continuous mixer.

[0061] Paragraph 56: In some embodiments, in a system or method as in any preceding Paragraph, the mixer comprises an impeller.

[0062] Paragraph 57: In some embodiments, in a system or method as in any preceding Paragraph, the mixer comprises an ultrasonic mixer.

[0063] Paragraph 58: In some embodiments, in a system or method as in any preceding Paragraph, the mixer comprises a vibromixer.

[0064] Paragraph 59: In some embodiments, in a system or method as in any preceding Paragraph, the mixer is configured to produce a homogeneous mixture of the gelator, drug substance, and buffer.

[0065] Paragraph 60: In some embodiments, in a system or method as in any preceding Paragraph, the system further comprises a turbulator.

[0066] Paragraph 61: In some embodiments, in a system or method as in any preceding Paragraph, the turbulator increases the shear stress inside the conduit to a shear stress that is greater than a yield stress of a gel comprising the gelator and the drug substance.

[0067] Paragraph 62: In some embodiments, in a system or method as in any preceding Paragraph, the system further comprises a container.

[0068] Paragraph 63: In some embodiments, in a system or method as in any preceding Paragraph, the mixture is produced in the container.

[0069] Paragraph 64: In some embodiments, in a system or method as in any preceding Paragraph, the mixer is aseptically connected to the container.

[0070] Paragraph 65: In some embodiments, in a system or method as in any preceding Paragraph, the container contains a volume greater than or equal to 1 liter.Paragraph 66: In some embodiments, in a system or method as in any preceding Paragraph, the container contains a volume greater than or equal to 100 liters.

[0071] Paragraph 67: In some embodiments, in a system or method as in any preceding Paragraph, the mixer contains a volume greater than or equal to 1000 liters.

[0072] Paragraph 68: In some embodiments, in a system or method as in any preceding Paragraph, the liquefier comprises an impeller.

[0073] Paragraph 69: In some embodiments, in a system or method as in any preceding Paragraph, the container is compressible, and compression of the container applies shear stress to the gel contained therein.

[0074] Paragraph 70: In some embodiments, in a system or method as in any preceding Paragraph, the container has a headspace pressure, the container further comprising a mechanism to adjust the headspace pressure.

[0075] Paragraph 71 : In some embodiments, in a system or method as in any preceding Paragraph, the container is a single-use container.

[0076] Paragraph 72: In some embodiments, in a system or method as in any preceding Paragraph, the system further comprises a sensor for measuring residual gelator concentration downstream of the filter.

[0077] Paragraph 73: In some embodiments, in a system or method as in any preceding Paragraph, the system for storing a drug substance-containing gel comprises a sensor configured to measure a concentration of the gelator.

[0078] Paragraph 74: In some embodiments, in a system or method as in any preceding Paragraph, the mixture is a liquid mixture, and wherein the pump and conduit are configured to convey the liquid mixture without inducing gelation of the mixture.

[0079] Paragraph 75: In some embodiments, in a system or method as in any preceding Paragraph, the conduit and the turbulator are configured to convey the liquid mixture without inducing gelation of the mixture and / or liquid mixture.

[0080] Paragraph 76: : In some embodiments, in a system or method as in any preceding Paragraph, the mixer is a single-use mixer.

[0081] Paragraph 77: : In some embodiments, in a system or method as in any preceding Paragraph, the mixer comprises one or more baffles.

[0082] Paragraph 78: In some embodiments, in a system or method as in any preceding Paragraph, the mixer comprises a radial flow impeller, a Rushton impeller, a swept Rushton impeller, a ringed Rushton impeller a helical impeller, and / or an anchor impeller.Paragraph 79: In some embodiments, in a system or method as in any preceding Paragraph, the gelator is part of a gelator solution.

[0083] Paragraph 80: In some embodiments, a system or method as in any preceding Paragraph, further comprises adjusting the pH of the gelator solution.

[0084] Paragraph 81 : In some embodiments, in a system or method as in any preceding Paragraph, adjusting the pH of the gelator solution comprises adjusting the pH of the gelator solution to a pH that is the same as or similar to the pH of the drug substance.

[0085] Paragraph 82: In some embodiments, in a system or method as in any preceding Paragraph, adjusting the pH of the gelator solution comprises adjusting the pH of the gelator solution to a pH that is the same as or similar to the pH of a gel comprising the gelator solution and the drug substance.

[0086] Paragraph 83: In some embodiments, in a system or method as in any preceding Paragraph, the mixer has a volume greater than or equal to 10 liters.

[0087] Paragraph 84: In some embodiments, in a system or method as in any preceding Paragraph, the container contains a volume greater than or equal to 10 liters.

[0088] Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting and / or inconsistent disclosure with respect to each other, then the document having the later effective date shall control.

[0089] BRIEF DESCRIPTION OF THE DRAWINGS

[0090] Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention. In the figures:FIG. 1A presents a flow chart of a method for storing a drug substance, according to some embodiments;

[0091] FIG. IB presents a flow chart of a method for storing a drug substance, according to some embodiments;

[0092] FIG. 2 presents a flow chart of a method for producing a liquid product, according to some embodiments;

[0093] FIG. 3A presents a system for preparing a drug substance-containing gel, according to some embodiments;

[0094] FIG. 3B presents a system for preparing a drug substance-containing gel, according to some embodiments;

[0095] FIGS. 3C-3D present a mixer for preparing a drug substance-containing gel, according to some embodiments;

[0096] FIG. 4A presents a system for storing a drug substance-containing gel, according to some embodiments;

[0097] FIG. 4B presents a system for storing a drug substance-containing gel, according to some embodiments;

[0098] FIG. 5 is a graph showing the pH and isoelectric point of components of a solution comprising a gelator and a drug substance, according to some embodiments;

[0099] FIGS. 6A-6B are calibration curves for a reverse-phase, high-pressure liquid chromatography apparatus, according to some embodiments; and

[0100] FIG. 7 is a graph showing pH drift during a freeze-thaw cycle for solutions with and without a gelator, according to some embodiments.

[0101] DETAILED DESCRIPTION

[0102] Gels for storing drug substances, associated systems, and associated methods are generally described. In some embodiments, the gels, systems, and methods described herein have one or more features which may advantageously allow for the storage of drug substances for extended periods of time at moderate temperatures. For example, in some embodiments, the gels, systems, and methods described herein may allow for the storage of drug substances without the need for controlled-rate freezing of drug substance-containing solutions at extremely low temperatures. Such embodiments may have several advantages, such as low cost, low energy requirements, and / or not requiring specialized equipment.

[0103] In some embodiments, the gels, systems, and methods disclosed herein may advantageously allow for the eventual recovery of the stored drug substance in relativelymoderate conditions. For example, in some embodiments, the gels, systems, and methods disclosed herein may allow for accessing stored drug substances without the need for controlled-rate thawing. Such embodiments may have several advantages, such as low cost, high flexibility, and improved accessibility.

[0104] In some embodiments, the drug substances described herein may comprise an active pharmaceutical ingredient. In some embodiments, the drug substance may comprise a bulk drug substance (e.g. the drug substance may comprise an active pharmaceutical ingredient and one or more excipients and / or a buffer). In some embodiments, it may be desirable to store a drug substance such that the drug substance is homogeneously distributed (e.g. such that the active pharmaceutical ingredient, excipients, and buffer of the drug substance have a more or less uniform condition throughout a container). This may offer several advantages. For example, if a drug substance is stored such that it has a heterogeneous concentration, it may be difficult to formulate a drug product using the drug substance, as the amount of drug product in a given volume may not be able to be predicted. In some embodiments, storing the drug substance such that the drug substance is heterogeneously distributed may result in regions of low density of drug substance and other regions of high concentration of active pharmaceutical ingredient, excipients, and a buffer of the drug substance. Some drug substances, in regions where the concentration is too high or too low, may form agglomerations which may result in the drug substance losing efficacy and / or safety due to degradation and / or nonuniformity. As such, storing the drug substance such that it is homogeneously distributed may avoid these undesirable effects.

[0105] The ability to store drug substances and / or recover stored drug substances at relatively moderate conditions may be particularly advantageous due to the sensitive nature of many drug substances. For example, many drug substances may undesirably degrade and / or become nonuniform in concentration under certain common processing conditions, including processing conditions which would not cause degradation and / or nonuniformity for many other classes of materials. Accordingly, drug substances are often handled at extreme processing conditions (e.g. temperatures as low as -80 °C) in order to avoid these undesirable effects. The ability to handle drug substances at relatively moderate temperatures may advantageously simplify drug substance storage, transportation, and other processing steps.

[0106] In some embodiments, gels, systems, and methods are described for storing drug substances using shear-thinning gels. In some embodiments, a drug substance may be contained within a shear-thinning gel. Without wishing to be bound by any particular theory, it is believed that the molecular structure of the gel may immobilize the drug substance,preventing the agglomeration and / or the development of concentration gradients within a drug substance-containing solution. It is believed that immobilizing the drug substance within the gel may allow for the drug substance to be stored at relatively moderate temperatures without losing safety or effectiveness.

[0107] In some embodiments, gels, systems, and methods are described for storing drug substances using shear-thinning gels having relatively high volumes. Drug substancecontaining gels having high volumes may have several advantages. For example, drug substance-containing gels having high volumes may allow for the bulk preparation, shipping, and / or storage of drug substances in large quantities at moderate conditions, which may reduce energy and capital costs. In some embodiments, drug substance-containing gels having high volumes may allow for small amounts of the drug substance to be dispensed discretely from a large batch for use in small-scale formulation, without requiring the thawing of large quantities of a drug substance-containing solution.

[0108] In some embodiments, the gels, systems, and methods described herein may advantageously allow for the freezing and / or thawing of relatively high volumes of drug substance-containing gels without the need for controlled-rate freezing and / or extremely low temperatures. As described above, in some embodiments, the uniform concentration of stored drug substance may be important to its safety and efficacy. However, slow freezing of drug substance-containing solutions may result in the slow growth of ice crystals, undesirably causing ‘cryo-concentration’ (i.e. non-uniform concentration) of the drug substance within the frozen solution. Without wishing to be bound by any particular theory, it is believed that the gel may immobilize the drug substance within the gel, preventing cryo-concentration when the gel is frozen, even at relatively slow rates and / or high temperatures.

[0109] In some embodiments, the gels, systems, and methods described herein may advantageously allow for the stabilization of a drug substance-containing gel during freezing and / or thawing of relatively high volumes of the drug substance-containing gel. Many drug substance-containing solutions exhibit undesirable mounding behavior during slow freezing processes that involve freezing liquid solutions instead of gels. For example, some drug substance-containing solutions may form an ice shell during slow freezing and, as the ice shell thickens and thus expands due to a decrease in density, cause the remaining liquid solution to pressurize. In some instances, this may cause fissures in the ice shell, causing drug substance-containing solution to erupt through fissures and freeze on the surface of the frozen solution, forming localized mounds of material. These mounds of material may distort the shape of a container in which the solution and frozen solid is being stored. Suchdistortion may result in rupture of the container, difficulties stacking containers of frozen drug substance-containing solutions, and / or other undesirable effects. Without wishing to be bound by any particular theory, it is believed that the presence of a gel may stabilize the drug substance-containing material as it is being frozen and suppress this mounding behavior when the gel is frozen, even at relatively slow rates and / or high temperatures.

[0110] In some embodiments, methods for storing a drug substance are disclosed. For example, in some non-limiting embodiments as shown in FIG. 1A, a method for storing a drug substance may comprise combining the drug substance with a buffer and a gelator to form a liquid mixture (step 102). In some embodiments, the liquid mixture may further comprise one or more excipients. As described in greater detail elsewhere herein, the drug substance may comprise a buffer. In some embodiments, the buffer of the drug substance may be the same buffer and / or a different buffer as the buffer with which it is combined to form the liquid mixture. In some embodiments, combining the drug substance with the buffer and the gelator to form a liquid mixture may comprise mixing the drug substance with the buffer and the gelator to form the liquid mixture. In some embodiments, combining the drug substance with the buffer and the gelator to form the liquid mixture may comprise applying a shear stress (e.g., a substantially constant shear stress) to the mixture (step 103).

[0111] In some embodiments, a method for storing a drug substance comprises inducing gelation of the liquid mixture to form a gel (step 104). In some embodiments, the liquid mixture may have a substantially constant pH. In some embodiments, inducing gelation of the liquid mixture may comprise adjusting the pH of the liquid mixture (e.g., to a value at which the liquid mixture undergoes gelation) and / or reducing the shear stress applied to the mixture to below a critical shear stress (e.g., a shear stress below which the liquid mixture undergoes gelation). In some embodiments, a constant shear stress (e.g., a substantially constant shear stress) may be applied to the liquid mixture during the step of adjusting the pH of the mixture. In some embodiments, inducing gelation of the liquid mixture may comprise sequentially adjusting the pH of the liquid mixture and reducing the shear stress applied to the mixture below a critical shear stress. In some embodiments, inducing gelation of the liquid mixture may comprise using a control loop integrating a pH sensor and one or more pH adjuster pumps to adjust the pH to a particular value or range of values (e.g., a value or range of values at which the liquid mixture undergoes gelation). In some embodiments, inducing gelation of the liquid mixture to form a gel comprises forming a shear-thinning gel having a volume of greater than or equal to 1 L.The pH of a liquid may be adjusted by titration. It is possible for a method of pH adjustment to comprise adjusting the pH in a single direction (e.g., to make it more acidic or make it more basic) or to comprise adjusting the pH in two directions (e.g., if the adjustment of the pH in one direction results in an overshoot or undershoot of a target pH). In some embodiments, adjusting the pH of a liquid may comprise using a control loop to determine whether the pH is increased or decreased and the amount of the increase or decrease.

[0112] In some embodiments, a method for storing a drug substance may optionally comprise freezing a gel to form a frozen gel (step 106). In some embodiments, freezing a gel may comprise holding the gel at or below a particular temperature for a particular period of time. For example, in some embodiments, freezing the gel may comprise holding the gel at a temperature of less than or equal to -20 °C for 2 or more hours.

[0113] Additional methods for storing a drug substance are also described herein. For example, in some non-limiting embodiments as shown in FIG. IB, a method for storing a drug substance may comprise combining a gelator with a buffer to form a gelator solution (step 152). In some embodiments, combining the drug substance with the buffer and the gelator to form the gelator solution may comprise applying a shear stress (e.g., a substantially constant shear stress) to the gelator solution. In some embodiments, applying a shear stress to the gelator solution may inhibit the formation of a gel (e.g., may inhibit gelation of the gelator solution).

[0114] In some embodiments, a method for storing a drug substance optionally comprises adjusting a pH of the gelator solution (step 154). In some embodiments, as described in greater detail below, adjusting the pH of the gelator solution may advantageously facilitate the pH of the gelator solution and the pH of a drug substance added thereto being the same and / or similar. In some embodiments, the pH of the gelator solution and the pH of the drug substance being the same and / or similar may advantageously preserve the buffering capacity of the drug substance and / or prevent the degradation of one or more pharmacological properties thereof. In some embodiments, a constant shear stress (e.g., a substantially constant shear stress) may be applied to the gelator solution during the step of adjusting the pH of the gelator solution.

[0115] The pH of a gelator solution may be adjusted by titration. It is possible for a method of pH adjustment to comprise adjusting the pH in a single direction (e.g., to make it more acidic or make it more basic) or to comprise adjusting the pH in two directions (e.g., if the adjustment of the pH in one direction results in an overshoot or undershoot of a target pH). In some embodiments, adjusting the pH of the gelator solution may comprise using a controlloop to determine whether the pH is increased or decreased and the amount of the increase or decrease.

[0116] In some embodiments, a method for storing a drug substance optionally comprises combining a drug substance with a gelator solution to form a liquid mixture (step 156). As described in greater detail elsewhere herein, the drug substance may comprise a buffer. In some embodiments, the buffer of the drug substance may be the same buffer and / or a different buffer as the buffer of the gelator solution. In some embodiments, as described in greater detail below, the gelator solution may be combined with the drug substance in a mixer. In some embodiments, a constant shear stress (e.g., a substantially constant shear stress) may be applied to the liquid mixture during the step of combining the drug substance and the gelator solution to form the liquid mixture.

[0117] In some embodiments, a method for storing a drug substance optionally comprises applying a shear stress (e.g., a substantially constant shear stress) to a liquid mixture (step 158). In some embodiments, applying a shear stress to the liquid mixture may inhibit the formation of a gel (e.g., may inhibit gelation of the liquid mixture).

[0118] In some embodiments, a method for storing a drug substance comprises forming a gel from a liquid mixture (step 160). As described in greater detail elsewhere herein, forming a gel may comprise reducing a shear stress applied to the liquid mixture to below a critical shear stress (e.g., a shear stress below which the liquid mixture undergoes gelation). In some embodiments, forming a gel may comprise inducing gelation of the liquid mixture to form a gel, for example by adjusting the pH of the liquid mixture to a value at which the liquid mixture undergoes gelation. In some embodiments, inducing gelation of the liquid mixture may comprise adjusting the pH of the liquid mixture (e.g., to a value at which the liquid mixture undergoes gelation) and reducing the shear stress applied to the mixture to below a critical shear stress (e.g., a shear stress below which the liquid mixture undergoes gelation). In some embodiments, inducing gelation of the liquid mixture may comprise sequentially adjusting the pH of the liquid mixture and reducing the shear stress applied to the mixture below a critical shear stress. In some embodiments, inducing gelation of the liquid mixture may comprise using a control loop integrating a pH sensor and one or more pH adjuster pumps to adjust the pH to a particular value or range of values (e.g., a value or range of values at which the liquid mixture undergoes gelation).

[0119] In some embodiments, a method for storing a drug substance may optionally comprise freezing a gel to form a frozen gel (step 162). In some embodiments, freezing a gel may comprise holding the gel at or below a particular temperature for a particular period of time.For example, in some embodiments, freezing the gel may comprise holding the gel at a temperature of less than or equal to -20 °C for 2 or more hours.

[0120] In some embodiments, methods for producing a liquid product comprising a drug substance are described. For example, in some non-limiting embodiments as shown in FIG.

[0121] 2, a method for producing a liquid product comprising the drug substance may optionally comprise thawing a frozen gel to form a gel (step 202). In some embodiments, thawing a frozen gel comprises holding the frozen gel at a temperature of greater than or equal to 5 °C for 6 or more hours.

[0122] In some embodiments, a method comprises applying a shear stress to a gel to liquefy the gel and form a liquid mixture (step 204). In some embodiments, applying a shear stress to a gel may comprise rotating an impeller submerged in the gel, using an ultrasonic mixer, using a vibromixer, applying a compressive force to a container comprising the gel, and / or changing the headspace pressure of a container comprising the gel. In some embodiments, a gel comprises a shear-thinning gel comprising a buffer, a gelator, and a drug substance, and applying a shear stress to the gel results in forming a liquid mixture comprising the same. In some embodiments, the shear stress may be sufficient to disrupt the gel without damaging the drug substance contained therein. For example, in some embodiments, a drug substance may be shear-sensitive (e.g. the drug substance may have a critical shear stress). In some embodiments, the physical structure of a drug substance may change if the drug substance is exposed to a shear stress greater than or equal to a critical shear stress (e.g. in some embodiments, the drug substance may comprise a shear- sensitive protein which may denature if exposed to a shear stress greater than a critical shear stress). In some embodiments, a shear stress applied to a gel may be sufficiently high to disrupt the gel (e.g., the shear stress applied to the gel may be above a yield stress of the gel) while remaining lower than the critical shear stress of a drug substance contained within the gel.

[0123] In some embodiments, a method comprises separating a recovered liquid mixture to remove a gelator from the recovered liquid mixture and form a liquid product (step 206). In some embodiments, separating the recovered liquid mixture comprises filtering the recovered liquid mixture. In some embodiments, separating the recovered liquid mixture comprises centrifuging the recovered liquid mixture. In some embodiments, the centrifuging comprises continuous centrifuging. In some embodiments, separating the recovered liquid mixture comprises the use of chromatography. In some embodiments, separating the recovered liquid mixture comprises removing a gelator from the recovered liquid mixture (e.g., via filtration, centrifugation, and / or chromatography). In some embodiments, the liquid product comprisesa buffer and a drug substance, and optionally one or more excipients. In some embodiments, filtering a recovered liquid mixture may comprise exposing the mixture to a filter. In some embodiments, a filter may comprise a filter capsule, a normal flow filtration assembly, and / or a tangential flow filtration assembly. In some embodiments, a liquid product may be of sufficient purity for use in drug product formulation.

[0124] Further details about these materials and processes are provided below.

[0125] A drug substance may comprise any of a variety of suitable compounds or combination of compounds. In some embodiments, a drug substance may comprise a bulk drug substance (i.e., a drug substance may comprise one or more compounds which may be incorporated into a final drug product). In some embodiments, a drug substance may comprise an active pharmaceutical ingredient (API). In some embodiments, a drug substance may comprise one or more excipients. In some embodiments, a drug substance may comprise any combination of an active pharmaceutical ingredient, one or more excipients, and / or a buffer. In some embodiments, a buffer of a drug substance may be chosen to provide one or more properties to and / or enhance one or more desired properties of the drug substance. For example, the buffer may be chosen to preserve and / or enhance the buffering capacity of the drug substance, thereby facilitating the drug substance maintaining a desired pH when exposed to a range of conditions (e.g., even when the drug substance comprises one or more acidic and / or basic functional groups). The buffer may have any of a variety of suitable compositions. For example, in some embodiments, the buffer may comprise citrate and / or histidine.

[0126] In some embodiments, a drug substance may comprise any of a variety of therapeutic compounds. For example, in some embodiments, a drug substance may comprise a biomaterial, a protein, an antibody, a vaccine, and / or a small molecule. In some embodiments, a drug substance may comprise insulin.

[0127] In some embodiments, a drug substance comprises an excipient. In some embodiments, an excipient may comprise any of a variety of suitable compounds. For example, in some embodiments, an excipient may comprise a surfactant. In some embodiments, the surfactant may self-assemble into a structure which suppresses adsorption at an interface. In some embodiments, the surfactant may comprise polysorbate 20 and / or polysorbate 80.

[0128] In some embodiments, an excipient may comprise a sugar. In some embodiments, the sugar may increase conformational stability of a drug product and / or drug substance. The sugar may comprise sucrose and / or trehalose.As described above, in some embodiments, a method for storing a drug substance may comprise combining the drug substance with a buffer and a gelator to form a liquid mixture. As described in greater detail below, in some embodiments, the buffer and the gelator may be combined (e.g., the buffer and the gelator may be combined along with one or more other components, such as a pH adjuster) to form a gelator solution, and the drug substance may be combined with the gelator solution to form the liquid mixture. In some embodiments, as noted above, the drug substance itself may comprise a buffer. In some embodiments, the buffer of the drug substance and the buffer of the gelator solution and / or the buffer of the liquid mixture that is not contained within the drug substance may be the same buffer or different buffers (e.g., in some embodiments, the liquid mixture may comprise two or more buffers). In some embodiments, two or more buffers contained within a liquid mixture (e.g., a buffer of the drug substance and a buffer of the gelator solution) may serve different purposes. For example, a buffer of the drug substance may provide a buffering capacity thereto, thereby preserving one or more pharmacological properties of the drug substance (e.g., the active pharmaceutical ingredient thereof), and the buffer of the gelator solution may facilitate the dissolution of the gelator in an aqueous medium and / or maintain a stable pH value of the liquid mixture.

[0129] In some embodiments, a drug substance, a buffer, and a gelator may be combined in a mixer (e.g., a mixer having any of the properties and / or characteristics described elsewhere herein) to form a liquid mixture. In some embodiments, the buffer of the liquid mixture (e.g., a buffer that is not the buffer of the drug substance) may allow for the maintenance of a stable pH value (e.g., even when the drug substance comprises one or more acidic and / or basic functional groups and / or the gelator comprises one or more acidic and / or basic functional groups). The buffer may have any of a variety of suitable compositions. For example, in some embodiments, the buffer may comprise citrate and / or histidine.

[0130] A gelator may be present in a liquid mixture in any of a variety of suitable concentrations. For example, in some embodiments, the gelator is present in the liquid mixture in an amount of greater than or equal to 2 mg / mL, greater than or equal to 5 mg / mL, greater than or equal to 10 mg / mL, greater than or equal to 15 mg / mL, or greater. In some embodiments, the gelator is present in the liquid mixture in an amount of less than or equal to 20 mg / mL, less than or equal to 15 mg / mL, less than or equal to 10 mg / mL, less than or equal to 5 mg / mL, or less. Combinations of these ranges are also possible. For example, in some embodiments, the gelator is present in the liquid mixture in an amount of greater than or equal to 2 mg / mL and less than or equal to 20 mg / mL. Other ranges are also possible. Insome embodiments, the gelator is present in the liquid mixture in an amount of greater than or equal to 20 mg / mL.

[0131] A gelator may have any of a variety of suitable compositions. In some embodiments, a gelator is a molecule which, under some conditions, can form a gel within a liquid medium through molecular self-assembly. In some embodiments, the gelator may comprise a low molecular weight gelator (e.g. the gelator may be a small molecule). For example, in some embodiments, the gelator comprises 3- {[(ls)-l -(dodecyl carbamoyl)-2-methylpropyl]carbamoyl}propanoic acid (“CD-005”).

[0132] In some embodiments, a gelator is or is part of a liquid solution (e.g., a gelator solution). In some embodiments, the gelator is part of the gelator solution prior to the addition of the drug substance (e.g., the gelator solution and the drug substance may be combined to form a liquid mixture as described herein). For example, in some embodiments, the gelator may be dissolved in a buffer to form the gelator solution. In some embodiments, any one of the gelators described above may be dissolved in any one of the buffers described above to form the gelator solution. For example, in some embodiments, the buffer is a Tris buffer or a carbonate-bicarbonate buffer. In some embodiments, the solution comprises CD-005 dissolved in a Tris buffer or a carbonate-bicarbonate buffer. It may be particularly advantageous for the gelator to be dissolved in a buffer to form a gelator solution prior to the addition of a drug substance thereto to form a liquid mixture.

[0133] As described in greater detail elsewhere herein, it is believed that the gelator being dissolved in the buffer prior to the addition of the drug substance thereto may advantageously allow for the pH of a drug substance to be more closely matched to other components of the liquid mixture (e.g., to the gelator solution) when the drug substance is first introduced to the liquid mixture. For example, in some embodiments in which the drug substance comprises a buffer (e.g., a buffer that is the same as or different from the buffer of the gelator solution), the pH of the gelator solution and the pH of the drug substance may be the same and / or similar. As described elsewhere herein, this may be achieved by adjusting the pH of the gelator solution. In some embodiments, this may advantageously prevent and / or reduce the risk of the buffering capacity of the drug substance (e.g., the buffering capacity of a buffer contained therein) being reduced upon exposure to a material having a significantly higher or lower pH than the drug substance. In some embodiments, this facilitates gelation of drug substance formulations comprising excipients that may otherwise inhibit gelation (e.g., by affecting the buffering capacity of the drug substance).In some embodiments, it is also believed that a gelator being dissolved in a buffer prior to the addition of a drug substance thereto facilitates the gelation of a liquid mixture comprising the drug substance and the gelator solution without the addition of calcium and / or calcium salts, which may otherwise be needed to achieve a stable gel structure. It may be advantageous for the gelation of the liquid mixture comprising the drug substance and the gelator solution to occur without the addition of calcium and / or calcium salts, as these may impact the pharmacological properties of the drug substance. In some embodiments, a particular buffer (e.g., a buffer of a gelator solution and / or a liquid mixture as described above) may be chosen such the gelation of the liquid mixture (e.g., the liquid comprising the drug substance and the gelator solution) occurs without the addition of calcium and / or calcium salts.

[0134] A gelator may be present in a gelator solution in any of a variety of suitable concentrations. For example, in some embodiments, the gelator is present in the gelator solution in an amount of greater than or equal to 2 mg / mL, greater than or equal to 5 mg / mL, greater than or equal to 10 mg / mL, greater than or equal to mg / mL, greater than or equal to 15 mg / mL, or greater. In some embodiments, the gelator is present in the gelator solution in an amount of less than or equal to 20 mg / mL, less than or equal to 15 mg / mL, less than or equal to 10 mg / mL, less than or equal to 5 mg / mL, or less. Combinations of these ranges are also possible. For example, in some embodiments, the gelator is present in the gelator solution in an amount of greater than or equal to 2 mg / mL and less than or equal to 20 mg / mL. In some embodiments, the gelator is present in the solution in an amount of greater than or equal to 20 mg / mL.

[0135] A gelator solution may have any of a variety of suitable pH values. For example, in some embodiments, it may be particularly advantageous for the gelator solution to have a pH that is the same as or similar to the pH of the drug substance (e.g., a pH that is within 1 pH unit of the pH of the drug substance, or preferably a pH that is within 0.1 pH unit of the pH of the drug substance) with which the gelator solution is combined and / or will be combined (e.g., the active pharmaceutical ingredient of the drug substance and / or the active pharmaceutical ingredient and the one or more excipients and / or the buffer of the drug substance). In some embodiments in which the drug substance comprises an excipient and / or a buffer, these components may alter the pH of the drug substance (e.g., relative to the active pharmaceutical ingredient alone). The gelator solution having a pH that is the same as or similar to the pH of the drug substance may advantageously increase the probability of gelation of a liquid mixture comprising the drug substance and the gelator (e.g., the gelatorcontained within the gelator solution), improve the homogeneity of a gel formed therefrom, and / or preserve the buffering capacity of the drug substance.

[0136] In some embodiments, it is advantageous for a gel formed by combining a gelator solution and a drug substance (e.g., by inducing gelation of a liquid mixture comprising the gelator solution and the drug substance and / or by reducing a shear stress applied to the liquid mixture to below a critical shear stress thereof, as described in greater detail elsewhere herein) to have a pH that is the same as or similar to the pH of the drug substance (e.g., a pH that is within 1 pH unit of the pH of the drug substance, or a pH that is within 0.1 pH unit of the pH of the drug substance). In some embodiments, it may be challenging to form a gel having a pH that is the same as or a similar to the pH of the drug substance due to the Donnan effect, which can cause the uneven distribution of mobile ions within the gel matrix of a charged gel. For example, a negatively charged gel matrix (e.g., a gel matrix formed by a gelator having a negative charge) may cause positive ions (e.g., H+ions) to be concentrated within the gel matrix, thus reducing the pH of the gel relative to a solution of the negatively charged gelator. Similarly, a positively charged gel matrix (e.g., a gel matrix formed by a gelator having a positive charge) may repel positive ions (e.g., H+ions) from the gel matrix, thus increasing the pH of the gel relative to a solution of the positively charged gelator. As such, in some embodiments, depending on the chemical structure of the gelator, the Donnan effect may result in the pH of the gel being slightly different from the pH of the gelator solution.

[0137] In some embodiments, it is advantageous to account for the Donnan effect by adjusting the pH and / or the target pH of the gelator solution relative to the desired pH of the gel (e.g., the pH of the drug substance). For example, as noted above in some embodiments, a negatively charged gelator (e.g., a gelator having an ionized carboxyl group, such as CD-005) may form a gel that has a slightly more acidic pH than the gelator solution prior to gelation. In some such embodiments, the pH of the gelator solution may be adjusted prior to the addition of the drug substance to account for this effect. For example, if the Donnan effect results in a downward shift of the pH by 0.2 after gelation for a particular gelator, and the drug substance has a pH of 6.2, it would be preferred for the gelator solution to have a pH of 6.4 prior to the addition of the drug substance and the gelation, such that the gel formed after combining the gelator solution and the drug substance has the desired pH of 6.2. In some embodiments, the Donnan effect may be measured for a particular gelator by (1) determining the pH of the gelator solution, (2) allowing the gelator solution to form a gel (e.g., by reducing a shear stress exerted on the gelator solution to below a critical shearstress), (3) determining the pH of the gel, and (4) determining the difference between the pH of the gelator solution and the pH of the gel. The difference between the pH of the gelator solution and the pH of the gel can then be used to adjust the pH of the gelator solution to the desired value prior to the addition of the drug substance.

[0138] In some embodiments, a method for storing a drug substance as described herein may comprise forming a gelator solution. In some embodiments, forming the gelator solution comprises combining a gelator and a buffer. In some embodiments, the gelator and the buffer may be combined in a mixer (e.g., a mixer having any of the properties and / or characteristics described elsewhere herein). As described in greater detail elsewhere herein, in some embodiments, one or more components of the mixer (e.g., an impeller) is configured to apply and / or capable of applying a shear stress to the liquid mixture at a sufficiently high shear stress to prevent the gelation of the gelator solution (e.g., a shear stress above a critical shear stress of the gelator solution and / or a shear stress above a yield stress of a gel comprising the buffer and the gelator).

[0139] In some embodiments, forming a gelator solution may comprise adjusting the pH of the gelator solution. The pH of the gelator solution may be adjusted by titration. It is possible for a method of pH adjustment to comprise adjusting the pH in a single direction (e.g., to make it more acidic or make it more basic) or to comprise adjusting the pH in two directions (e.g., if the adjustment of the pH in one direction results in an overshoot or undershoot of a target pH). In some embodiments, adjusting the pH of the gelator solution may comprise using a control loop to determine whether the pH is increased or decreased and the amount of the increase or decrease.

[0140] In some embodiments, adjusting a pH of a gelator solution may comprise using a control loop comprising a pH sensor and a pH controller (e.g. that controls a pump in fluidic communication with a source of a pH adjuster, as described in greater detail below) to maintain a consistent pH of the gelator solution (i.e., to maintain a pH of a particular value and / or within some tolerance of a particular value). In some embodiments, the controller is a PID controller. In some embodiments, the control loop may be used to maintain a constant pH in the gelator solution. In some embodiments, the control loop may be used to adjust the pH of the gelator solution to a particular pH and / or range of pH values in order to achieve a desired pH value (e.g., a pH value that is the same as or similar to the pH of a drug substance that will be added to the gelator solution). In some embodiments, the control loop may be configured to maintain and / or capable of maintaining the pH of the gelator solution within a range defined by a pH setpoint and a particular tolerance. For example, in someembodiments, the control loop may be used to adjust the pH of the gelator solution to a range of pH values defined which is + / - 0.1 pH unit of the pH setpoint. A PID control loop can automate setpoint tracking.

[0141] As noted above, in some embodiments, a method for storing a drug substance as described herein may comprise combining a drug substance, a buffer, and a gelator (e.g., a gelator that is part of a gelator solution) in a mixer to form a liquid mixture. As described in greater detail elsewhere herein, in some embodiments, one or more components of the mixer (e.g., an impeller) is configured to apply and / or capable of applying a shear stress to the liquid mixture at a sufficiently high shear stress to prevent the gelation of the liquid mixture (e.g., a shear stress above a critical shear stress of the liquid mixture).

[0142] As described above, in some embodiments, a method for storing a drug substance may comprise inducing gelation of a liquid mixture to form a gel. In some embodiments, a gel may be formed when the liquid mixture reaches a gel point (e.g. when the storage modulus of the mixture becomes greater than the loss modulus of the mixture).

[0143] Gelation of a liquid mixture may be induced in any of a variety of suitable ways. For example, in some embodiments, inducing gelation of a mixture may comprise adjusting the pH of the mixture. In some embodiments, adjusting the pH of the mixture may comprise adding a pH adjuster to the mixture. In some embodiments, prior to adjusting the pH of the mixture, the mixture may have a homogeneous, constant pH. In some embodiments, the mixture having a homogeneous, constant pH may be particularly advantageous, as it may allow the charge and / or conformation of the drug substance to remain stable. For example, in some embodiments in which the drug substance comprises a protein, the mixture having a homogeneous, constant pH may allow the protein to maintain its desired conformation (e.g., prevent denaturation or other changes in conformation which may result in aggregation and / or loss of activity). Without wishing to be bound by any particular theory, it is believed that certain drug substances and / or components of drug substances, such as therapeutic proteins, may only be stable (e.g., have a desired conformation, not undergo aggregation) across a small window of net charge, and, accordingly, pH value, thereby increasing the benefits associated with maintaining a homogeneous, constant pH. It is also believed that freezing and thawing processes that do not involve gels may cause the pH across the material being frozen to become inhomogeneous due to cryo-concentration of buffer components and / or percolation of heavy eutectic material through fissures and defects in an ice matrix towards the bottom of a container containing the material.In some embodiments, adjusting the pH of the mixture may comprise adding a pH adjuster to the liquid such that the liquid mixture has a constant, homogeneous pH of a different value than the pH prior to adding the pH adjuster. In some embodiments, the constant, homogeneous pH of the mixture may be achieved by stirring and / or agitating the mixture to ensure homogeneous distribution of the pH adjuster. In some embodiments, stirring and / or agitating the mixture may be performed continuously (e.g., using an inline static mixer). In some embodiments, the homogeneity of the pH of the mixture may be determined by the use of one or more pH probes (e.g., one or more pH probes at different locations). Without wishing to be bound by any particular theory, it is believed that stirring and / or agitating the mixture during the addition of a pH adjuster may desirably reduce and / or prevent premature gelation of the liquid mixture by reducing variation in the concentration of the pH adjuster across the liquid mixture.

[0144] In some embodiments, a pH adjuster may comprise an acid. In some embodiments, the acid may comprise hydrochloric acid (HC1). In some embodiments, the acid may have any of a variety of suitable concentrations. For example, in some embodiments, the acid may have a concentration of greater than or equal to 0.5 M, greater than or equal to 0.75 M, greater than or equal to 1 M, or greater than or equal to 1.25 M. In some embodiments, the acid may have a concentration of less than or equal to 1.5 M, less than or equal to 1.25 M, less than or equal to 1 M, or less than or equal to 0.75 M. Combinations of these ranges are also possible (e.g., in some embodiments, the acid may have a concentration of greater than or equal to 0.5 M and less than or equal to 1.5 M). Other ranges are also possible. In some embodiments, a pH adjuster may comprise a buffer. In some embodiments, the buffer may comprise a weak acid (e.g., citric acid) or a weak base (e.g., a Tris buffer). In some embodiments, a buffer may be chosen depending on the type of pH adjustment made by the pH adjuster. For example, in some embodiments, a weak acid buffer may be chosen if the pH adjuster is adjusting the pH down (i.e., lowering the pH value of the liquid mixture). In some embodiments, a weak base buffer may be chosen if the pH adjuster is adjusting the pH up (i.e., raising the pH value of the liquid mixture).

[0145] In some embodiments, a pH adjuster may comprise a base. In some embodiments, the base may comprise sodium hydroxide (NaOH). In some embodiments, the base may have any of a variety of suitable concentrations. For example, in some embodiments, the base may have a concentration of greater than or equal to 0.5 M, greater than or equal to 0.75 M, greater than or equal to 1 M, or greater than or equal to 1.25 M. In some embodiments, the base may have a concentration of less than or equal to 1.5 M, less than or equal to 1.25 M,less than or equal to 1 M, or less than or equal to 0.75 M. Combinations of these ranges are also possible (e.g., in some embodiments, the base may have a concentration of greater than or equal to 0.5 M and less than or equal to 1.5 M). Other ranges are also possible.

[0146] In some embodiments, a pH adjuster may be added to the liquid mixture in any of a variety of suitable amounts. In some embodiments, the amount of the pH adjuster added to the liquid mixture may be determined by the concentration of the pH adjuster and / or the volume of the liquid mixture. For example, in some embodiments, a pH adjuster may be added to the liquid in a concentration and / or amount which is determined to achieve a particular pH value and / or range of pH values in the liquid mixture.

[0147] In some embodiments, adjusting the pH of a mixture may comprise adjusting the pH to a particular value or to within a particular range of values. For example, in some embodiments, the particular pH value or range of values may be chosen such that the gelation of the liquid mixture is prevented. For example, in some embodiments, the liquid mixture may form a gel at or below a critical pH value. In some such embodiments, the pH of the liquid mixture may be adjusted to a pH or range of pH values which is above the critical pH value. In some embodiments, the pH value or range of pH values may be chosen such that the drug substance in the liquid mixture is not damaged. For example, in some embodiments in which the drug substance comprises a protein, the protein may denature and / or adopt an undesirable altered conformation at or above a certain critical pH value. In some such embodiments, the particular pH value or range of pH values may be chosen such that the pH of the liquid mixture is above the critical pH value at which the liquid mixture will form a gel but below the critical pH value at which the protein will denature and / or adopt an undesirable altered conformation. Such ranges may be chosen for other drug substances as well.

[0148] In some embodiments, adjusting the pH of a liquid mixture may cause the liquid mixture to form a gel. In some embodiments, a gelator may self-assemble into a gel structure only at certain pH values and / or within a certain range of suitable pH values. In such embodiments, adjusting the pH of the liquid mixture may comprise adjusting the pH from a value outside of the range of suitable pH values to a pH value within the range of suitable pH values. In some embodiments, the adjusting the pH of a mixture may comprise adjusting the pH to a value which results in gelation of the mixture without resulting in damage to a drug product and / or drug substance contained therein.

[0149] In some embodiments, inducing gelation of a mixture may comprise reducing a shear stress exerted on the liquid mixture below a critical value. In some embodiments, the critical value may be the gel point of the liquid mixture. In some embodiments, reducing the shearstress exerted on the mixture below the critical value may result in the liquid mixture forming a gel.

[0150] In some embodiments, inducing gelation of a liquid mixture may comprise sequentially adjusting the pH of the liquid mixture and reducing the shear stress exerted on the liquid mixture below the critical shear stress.

[0151] In some embodiments, inducing gelation of the mixture may comprise using a control loop comprising a pH sensor and a pH controller (e.g. that controls a pump in fluidic communication with a source of a pH adjuster) to maintain a consistent pH of the liquid mixture (i.e., to maintain a pH of a particular value and / or within some tolerance of a particular value). In some embodiments, the controller is a PID controller. In some embodiments, the control loop may be used prior to forming a gel to maintain a constant pH in the liquid mixture. In some embodiments, the control loop may be used to adjust the pH of the liquid mixture to a particular pH and / or range of pH values in order to induce gelation and / or form a gel. In some embodiments, the control loop may be configured to maintain and / or capable of maintaining the pH within a range defined by a pH setpoint and a particular tolerance. For example, in some embodiments, the control loop may be used to adjust the pH of the liquid mixture to a range of pH values defined which is + / - 0.1 pH unit of the pH setpoint.

[0152] In some embodiments, inducing gelation of a mixture may comprise performing dropwise gelation of the liquid mixture. For example, in some embodiments, inducing gelation of the mixture may comprise releasing the liquid mixture into air (e.g., allowing the mixture to fall freely through air from a source of liquid mixture, like a mixer containing the liquid mixture, into a container). In some embodiments, performing dropwise gelation of a liquid mixture may form beads and / or granules comprising a gel. In some embodiments, beads and / or granules comprising a gel may advantageously provide for ease of pouring and / or handling when compared to, for example, a gel comprising a single large, continuous substance.

[0153] A gel that is formed from the gelation of a liquid mixture may take any of a variety of suitable forms. For example, in some embodiments, the gel may form and / or comprise beads (e.g. in some embodiments in which dropwise gelation is performed, the resulting gel may comprise beads). In some embodiments, the gel may be a single integrated substance (e.g., it may lack components that can be separated without plastic deformation or fracture). In some embodiments, the gel that is formed from the gelation of the liquid mixture may be a hydrogel.In some embodiments, a gel may have a yield stress. The yield stress is the stress that must be applied to the gel to induce flow. At shear stresses below the yield stress, the gel may undergo elastic (solid-like) deformation. Application of shear stresses above the yield stress may, in some embodiments, cause the gel to liquefy, forming a liquid product. At shear stresses above the yield stress, the gel and / or a liquid product may undergo viscous (fluid-like) deformation. In some embodiments, at stresses above the yield stress, the gel and / or liquid product may undergo elastic deformation and viscous deformation (i.e. the gel and / or liquid product may exhibit viscoelasticity).

[0154] In some embodiments, a gel comprising a drug substance may have a relatively high storage modulus (G’). For example, in some embodiments, the gel has a storage modulus of greater than or equal to 15 Pa, greater than or equal to 25 Pa, greater than or equal to 50 Pa, greater than or equal to 100 Pa, greater than or equal to 500 Pa, greater than or equal to 1,000 Pa, greater than or equal to 5,000 Pa, greater than or equal to 10,000 Pa, greater than or equal to 15,000 Pa, greater than or equal to 20,000 Pa, greater than or equal to 25,000 Pa, or greater than or equal to 30,000 Pa. In some embodiments, the gel has a storage modulus of less than or equal to 34,000 Pa, less than or equal to 30,000 Pa, less than or equal to 25,000 Pa, less than or equal to 20,000 Pa, less than or equal to 15,000 Pa, less than or equal to 10,000 Pa, less than or equal to 5,000 Pa, less than or equal to 1,000 Pa, less than or equal to 500 Pa, less than or equal to 100 Pa, less than or equal to 50 Pa, or less than or equal to 25 Pa.

[0155] Combinations of these ranges are also possible. For example, the gel may have a storage modulus of greater than or equal to 15 Pa and less than or equal to 34,000 Pa, or greater than or equal to 25 Pa and less than or equal to 30,000 Pa. Other ranges are also possible.

[0156] Gels described herein may have storage moduli in one or more of the abovereferenced ranges at 24 hours after gel formation, 72 hours after gel formation, at a time in between 24 hours and 72 hours after formation, and / or at another time described herein (e.g., directly after formation, during one or more method steps described herein).

[0157] The storage modulus (G’) of a gel as described herein may be measured using a rheometer, such as an Anton Paar MCR 301 rheometer, using a cup-and-vane geometry at a temperature of 25 °C. In this cup-and-vane geometry, a stirrer and measuring cup may be configured to provide a 5 mm measuring gap. The gel may be transferred directly to the measuring cup, and amplitude sweep experiments may be performed with a constant angular frequency of 1 rad s-1over a strain range of 0.1% to 1000%. As used herein, the storage modulus is defined as the value within the linear viscoelastic (LVE) region, using a ±10% deviation criterion to identify the limit of LVE behavior.In some embodiments, a gel may comprise a shear-thinning gel. In some embodiments, a shear-thinning gel may be a gel whose viscosity decreases as the shear stress applied to it increases. In some embodiments, a shear-thinning gel may have a yield stress. In such embodiments, when a shear stress above the yield stress is applied, the shear-thinning gel may liquefy to form a liquid product. In some embodiments, the liquid product may be shear-thinning (i.e., the liquid product may exhibit a decrease in viscosity at higher values of applied shear stress).

[0158] In some embodiments, a shear-thinning gel may have a very high viscosity at zero shear and / or low values of applied shear. For example, in some embodiments, the shearthinning gel may have a sufficiently high viscosity that, in the absence of an externally applied shear force, the shear-thinning gel will not exhibit significant deformation and / or flow over a long period of time (e.g., the shear-thinning gel will not exhibit significant deformation and / or flow for a period of several days).

[0159] A shear-thinning liquid product may have any of a variety of suitable viscosities. For example, in some embodiments, the shear-thinning liquid product may have a viscosity of greater than or equal to 0.5 cP, greater than or equal to 1 cP, greater than or equal to 2.5 cP, greater than or equal to 5 cP, greater than or equal to 7.5 cP, greater than or equal to 10 cP, greater than or equal to 12.5 cP, greater than or equal to 15 cP, greater than or equal to 17.5 cP, greater than or equal to 20 cP, or greater than or equal to 22.5 cP. In some embodiments, the shear-thinning liquid product may have a viscosity of less than or equal to 25 cp, less than or equal to 22.5 cP, less than or equal to 20 cP, less than or equal to 17.5 cP, less than or equal to 15 cP, less than or equal to 12.5 cP, less than or equal to 10 cP, less than or equal to 7.5 cP, less than or equal to 5 cP, less than or equal to 2.5 cP, or less than or equal to 1 cP. Combinations of these ranges are also possible (e.g., in some embodiments, the shearthinning liquid product may have a viscosity of greater than or equal to 0.5 cP and less than or equal to 25 cP, greater than or equal to 1 cP and less than or equal to 22.5 cP, or greater than or equal to 1.5 cP and less than or equal to 20 cP). Other ranges are also possible.

[0160] In some embodiments, a liquid product may have any of the viscosities as described above under an applied shear stress in excess of a yield stress, a critical shear stress, and / or under a shear stress applied during one or more processes employed to cause flow of the liquid product described elsewhere herein (e.g., shear stress applied by pumping, shear stress applied by flow through one or more conduits, and / or or shear stress applied by an impeller).

[0161] In some embodiments, a liquid mixture and / or a gel may have a relatively large volume. For example, in some embodiments, the gel may have a volume of greater than orequal to 1 liter (L), greater than or equal to 2.5 L, greater than or equal to 5 L, greater than or equal to 7.5 L, greater than or equal to 10 L, greater than or equal to 25 L, greater than or equal to 50 L, greater than or equal to 75 L, greater than or equal to 100 L, greater than or equal to 250 L, greater than or equal to 500 L, greater than or equal to 750 L, greater than or equal to 1,000 L, greater than or equal to 2,500 L, greater than or equal to 5,000 L, or greater than or equal to 7,500 L. In some embodiments, the gel may have a volume of less than or equal to 10,000 L, less than or equal to 7,500 L, less than or equal to 5,000 L, less than or equal to 2,500 L, less than or equal to 1,000 L, less than or equal to 750 L, less than or equal to 500 L, less than or equal to 250 L, less than or equal to 100 L, less than or equal to 75 L, less than or equal to 50 L, less than or equal to 25 L, less than or equal to 10 L, less than or equal to 7.5 L, less than or equal to 5 L, or less than or equal to 1 L. Combinations of these ranges are also possible (e.g. the gel may have a volume of greater than or equal to 1 L and less than or equal to 10,000 L, greater than or equal to 10 L and less than or equal to 5,000 L, or greater than or equal to 50 L and less than or equal to 1,000 L). Other ranges are also possible.

[0162] In some embodiments, a method may comprise freezing a gel to form a frozen gel. In some embodiments, freezing a gel may comprise holding the gel at or below a particular temperature for a particular period of time. In some embodiments, freezing a gel may comprise holding the gel at or below a temperature of less than or equal to -20 °C, less than or equal to -25 °C, less than or equal to -30 °C, less than or equal to -35 °C, less than or equal to -40 °C, less than or equal to -45 °C, less than or equal to -50 °C, less than or equal to -55 °C, less than or equal to -60 °C, less than or equal to -65 °C, less than or equal to -70 °C, or less than or equal to -75 °C for a particular period of time. In some embodiments, freezing a gel may comprise holding the gel at a temperature of greater than or equal to -80 °C, greater than or equal to -75 °C, greater than or equal to -70 °C, greater than or equal to -65 °C, greater than or equal to -60 °C, greater than or equal to -55 °C, greater than or equal to -50 °C, greater than or equal to -45 °C, greater than or equal to -40 °C, greater than or equal to -35 °C, or greater than or equal to -30 °C for a particular period of time. Combinations of these ranges are also possible (e.g. freezing a gel may comprise holding the gel at a temperature of less than or equal to -20 °C and greater than or equal to -80 °C, less than or equal to -25 °C and greater than or equal to -75 °C, or less than or equal to -30 °C and greater than or equal to -70 °C for a particular period of time). Other ranges are also possible.In some embodiments, freezing a gel may comprise holding the gel at or below a particular temperature for a period of time of greater than or equal to 2 hours, greater than or equal to 4 hours, greater than or equal to 6 hours, greater than or equal to 8 hours, greater than or equal to 10 hours, greater than or equal to 12 hours, greater than or equal to 14 hours, greater than or equal to 16 hours, greater than or equal to 18 hours, greater than or equal to 20 hours, greater than or equal to 22 hours, greater than or equal to 24 hours, greater than or equal to 36 hours, greater than or equal to 48 hours, greater than or equal to 72 hours, greater than or equal to 96 hours, greater than or equal to 120 hours, greater than or equal to 144 hours, greater than or equal to 168 hours, greater than or equal to 192 hours, or greater than or equal to 216 hours. In some embodiments, freezing a gel may comprise holding the gel at or below a particular temperature for a period of time of less than or equal to 240 hours, less than or equal to 216 hours, less than or equal to 192 hours, less than or equal to 168 hours, less than or equal to 144 hours, less than or equal to 120 hours, less than or equal to 96 hours, less than or equal to 72 hours, less than or equal to 48 hours, less than or equal to 36 hours, less than or equal to 24 hours, less than or equal to 22 hours, less than or equal to 20 hours, less than or equal to 18 hours, less than or equal to 16 hours, less than or equal to 14 hours, less than or equal to 12 hours, less than or equal to 10 hours, less than or equal to 8 hours, less than or equal to 6 hours, or less than or equal to 4 hours. Combinations of these ranges are also possible (e.g. freezing a gel may comprise holding the gel at or below a particular temperature for a period of time of greater than or equal to 2 hours and less than or equal to 240 hours, greater than or equal to 4 hours and less than or equal to 216 hours, or greater than or equal to 6 hours and less than or equal to 192 hours). Other ranges are also possible.

[0163] In some embodiments, freezing a gel may comprise holding the gel at or below any of the above-listed temperatures for any of the above-listed periods of time. For example, in some embodiments, freezing a gel may comprise holding the gel at a temperature of less than or equal to -20 °C for a period of 2 or more hours, at a temperature of less than or equal to -40 °C for a period of 4 or more hours, a at a temperature of less than or equal to -40 °C for a period of 12 or more hours, or at a temperature of less than or equal to -40 °C for a period of 16 or more hours. Other combinations are also possible.

[0164] In some embodiments, freezing a gel may comprise rate-controlled freezing. In some embodiments, freezing a gel may comprise non-rate-controlled freezing. In some embodiments, freezing a gel may comprise using a blast freezer, a lab freezer, a walk-in freezer, or a drive-in freezer. In some embodiments, a frozen gel may be stored at or below any of the above-listed temperatures for a period of hours, days, or weeks. In someembodiments, a frozen gel may advantageously be stored at or below any of the above-listed temperatures for a period of hours, days, or weeks without degradation and / or damage to the drug product and / or drug substance in the frozen gel. In some embodiments, a frozen gel may be stored at or below any of the above-listed temperatures for a period of one year or more without degradation and / or damage to the drug product and / or drug substance in the frozen gel.

[0165] In some embodiments, a method may comprise refrigerating a gel. In some embodiments, refrigerating the gel may comprise holding the gel at or below a particular temperature. In some embodiments, refrigerating a gel may comprise holding the gel at or below a temperature of less than or equal to 8 °C, less than or equal to 6 °C, less than or equal to 4 °C, less than or equal to 2 °C, or less for a particular period of time. In some embodiments, refrigerating a gel may comprise holding the gel at a temperature of greater than or equal to 1 °C, greater than or equal to 2 °C, greater than or equal to 4 °C, greater than or equal to 6 °C, or greater for a particular period of time. Combinations of these ranges are also possible (e.g. refrigerating a gel may comprise holding the gel at a temperature of less than or equal to 8 °C and greater than or equal to 1 °C, or less than or equal to 6 °C and greater than or equal to 2 °C ). Other ranges are also possible. In some embodiments, the gel may be refrigerated for any particular period of time.

[0166] In some embodiments, a method for producing a liquid product comprising a drug substance is described. In some embodiments, a method for producing the liquid product may comprise thawing a frozen gel comprising a drug substance, a buffer, and a gelator. In some embodiments, the frozen gel may comprise any of the drug substances, buffers, and / or gelators described above. In some embodiments, the frozen gel may have any of the volumes described above for a gel.

[0167] In some embodiments, thawing a frozen gel may comprise holding the gel at or above a particular temperature for a particular period of time. For example, in some embodiments, thawing a frozen gel may comprise holding the gel at or above a temperature of greater than or equal to 5 °C, greater than or equal to 10 °C, greater than or equal to 15 °C, greater than or equal to 20 °C, greater than or equal to 25 °C, greater than or equal to 30 °C, or greater than or equal to 35 °C for a particular period of time. In some embodiments, thawing a frozen gel may comprise holding the gel at or above a temperature of less than or equal to 40 °C, less than or equal to 35 °C, less than or equal to 30 °C, less than or equal to 25 °C, less than or equal to 20 °C, less than or equal to 15 °C, or less than or equal to 10 °C for a particular period of time. Combinations of these ranges are also possible (e.g. thawing a frozen gel maycomprise holding the gel at or above a temperature of greater than or equal to 5 °C and less than or equal to 40 °C, greater than or equal to 10 °C and less than or equal to 35 °C, or greater than or equal to 15 °C and less than or equal to 30 °C for a particular period of time). Other ranges are also possible.

[0168] In some embodiments, thawing a frozen gel may comprise holding the gel at or above a particular temperature for a period of time of greater than or equal to 2 hours, greater than or equal to 4 hours, greater than or equal to 6 hours, greater than or equal to 8 hours, greater than or equal to 10 hours, greater than or equal to 12 hours, greater than or equal to 14 hours, greater than or equal to 16 hours, greater than or equal to 18 hours, greater than or equal to 20 hours, greater than or equal to 22 hours, greater than or equal to 24 hours, greater than or equal to 26 hours, greater than or equal to 28 hours, greater than or equal to 30 hours, greater than or equal to 32 hours, greater than or equal to 34 hours, greater than or equal to 36 hours, greater than or equal to 48 hours, greater than or equal to 72 hours, greater than or equal to 96 hours, greater than or equal to 120 hours, greater than or equal to 144 hours, greater than or equal to 168 hours, greater than or equal to 192 hours, or greater than or equal to 216 hours. In some embodiments, thawing a frozen gel may comprise holding the gel at or above a particular temperature for a period of time of less than or equal to 240 hours, less than or equal to 216 hours, less than or equal to 192 hours, less than or equal to 168 hours, less than or equal to 144 hours, less than or equal to 120 hours, less than or equal to 96 hours, less than or equal to 72 hours, less than or equal to 48 hours, less than or equal to 36 hours, less than or equal to 34 hours, less than or equal to 32 hours, less than or equal to 30 hours, less than or equal to 28 hours, less than or equal to 26 hours, less than or equal to 24 hours, less than or equal to 22 hours, less than or equal to 20 hours, less than or equal to 18 hours, less than or equal to 16 hours, less than or equal to 14 hours, less than or equal to 12 hours, less than or equal to 10 hours, less than or equal to 8 hours, less than or equal to 6 hours, or less than or equal to 4 hours. Combinations of these ranges are also possible (e.g. thawing a frozen gel may comprise holding the gel at or above a particular temperature for a period of greater than or equal to 2 hours and less than or equal to 240 hours, greater than or equal to 4 hours and less than or equal to 216 hours, or greater than or equal to 6 hours and less than or equal to 192 hours). Other ranges are also possible.

[0169] In some embodiments, thawing a frozen gel may comprise holding the gel at or above any of the above-listed temperatures for any of the above-listed periods of time. For example, in some embodiments, thawing a frozen gel may comprise holding the gel at a temperature of greater than or equal to 5 °C for a period of 6 or more hours. In someembodiments, thawing a frozen gel may comprise holding the gel at a temperature of greater than or equal to 5 °C for a period of 120 hours or more. Other combinations are also possible.

[0170] In some embodiments, thawing a gel may comprise rate-controlled thawing. In some embodiments, thawing a gel may comprise non-rate-controlled thawing. In some embodiments, thawing a gel may comprise holding the gel at or above a first temperature for a first period of time and at or above a second temperature for a second period of time. The first temperature and second temperature may be any of the above-listed temperatures, and the first period of time and second period of time may be any of the periods of time listed above. For example, in some embodiments, thawing a gel may comprise holding the gel at a temperature of greater than or equal to 20 °C for a period of 8 hours or more and then at a temperature of greater than or equal to 5 °C for a period of 12 hours or more. In some embodiments, thawing a frozen gel may comprise holding the gel at a temperature of greater than or equal to 20 °C for a period of 6 hours or more and then holding the gel at a temperature of greater than or equal to 5 °C for a period of 6 hours or more.

[0171] In some embodiments, a method for producing a liquid product may comprise applying a shear stress to a gel. As noted above, in some embodiments, a gel may have a yield stress and / or comprise a shear-thinning gel. In some embodiments, applying a shear stress to a gel may comprise applying a shear stress that is above the yield stress of the gel. In some embodiments, applying a shear stress to a gel that is above the yield stress of the gel may cause the gel to yield and / or begin to flow. In some embodiments, the gel yielding and / or beginning to flow may form a recovered liquid mixture.

[0172] Shear stress may be applied to a gel in any of a variety of suitable ways. For example, in some embodiments, applying a shear stress to the gel may comprise rotating an impeller submerged in the gel. In some embodiments, the impeller may comprise a radial flow impeller. For example, in some embodiments, the impeller may comprise a Rushton impeller. In some embodiments, the impeller may comprise a swept Rushton impeller and / or a ringed Rushton impeller. In some embodiments, the impeller comprises a helical impeller and / or an anchor impeller.

[0173] In some embodiments, applying a shear stress to a gel may comprise using an ultrasonic mixer and / or a vibromixer to induce vibration of the gel. In some embodiments, an ultrasonic mixer may use high-frequency sound waves (e.g. sound waves with a frequency greater than or equal to 20 Hz) to induce agitation (e.g. vibration) of the gel. In some embodiments, a vibromixer may use high-frequency vibrations of a physical component ofthe vibromixer (e.g., a disc plate with chamfered holes) to induce agitation (e.g. vibration) of the gel. In some embodiments, the physical component of the vibromixer (e.g., the disc plate with chamfered holes) is vibrated in a direction normal to the surface of the physical component. In some embodiments, the vibration of the gel may impart sufficient shear stress to overcome the yield stress of the gel and / or induce recirculation of the recovered liquid mixture.

[0174] In some embodiments, applying a shear stress to a gel may comprise applying compressive force to a container comprising the gel. For example, in some embodiments, a gel may be contained within a container which is formed from and / or comprises a flexible material such that the walls of the container may be deformed under a compressive force. In some embodiments, compression of the container, such as compression caused by applying a compressive force to the container, may cause the walls of the container to deform in such a way as to apply a shear stress to the gel within the container.

[0175] In some embodiments, applying a shear stress to a gel may comprise changing the headspace pressure of a container comprising the gel. For example, in some embodiments, changing the headspace pressure of a container comprising the gel may comprise inflating and / or deflating the container. In some embodiments, the container may comprise a collapsible conduit comprising a plurality of perforations (e.g. a dip tube). In some embodiments, the collapsible conduit may be configured to allow and / or capable of allowing all of and / or most of the recovered liquid mixture within the container to be removed from the container. In some embodiments, inflating and / or deflating the container may comprise using the collapsible conduit to inflate and / or deflate the container.

[0176] In some embodiments, a method for producing a liquid product may comprise separating the recovered liquid mixture to form a liquid product. In some embodiments, separating the recovered liquid mixture comprises filtering a recovered liquid mixture to produce a liquid product. In some embodiments, filtering the recovered liquid mixture may comprise removing a gelator (e.g., removing at least some of a gelator) from a liquid mixture. In some embodiments, filtering the recovered liquid mixture may comprise exposing the recovered liquid mixture to a filter. In some embodiments, the filter may be configured to remove and / or capable of removing the gelator from the recovered liquid mixture (e.g., by sieving). Other possible properties and configurations of filters are described below.

[0177] In some embodiments, filtering a recovered liquid mixture to produce a liquid product may comprise removing a gelator from the recovered liquid mixture. In some embodiments, the liquid product may comprise any combination of a buffer, a drug productand / or drug substance, and / or one or more excipients. As noted above, in some embodiments, the drug product comprises a buffer. The liquid product may comprise one or more other buffers that are not part of the drug product. In some embodiments, the buffer of the drug product may be the same buffer and / or a different buffer as the one or more other buffers of the liquid product (e.g., the liquid product may comprise two or more different buffers). In some embodiments, the liquid product may be of sufficient purity for use in drug product formulation. For example, in some embodiments, the liquid product may have substantially the same purity as a liquid mixture prior to gelation. In some embodiments, the quality of the liquid product may be determined by assessing the potency of the drug product and / or drug substance within the liquid product, the color and / or clarity of the liquid product, the presence of visible and / or subvisible particles within the liquid product, and the identification and quantification of any impurities present in the liquid product.

[0178] In some embodiments, a system for preparing a drug substance-containing gel is described. A non-limiting embodiment of such a system is shown in FIG. 3A. In some embodiments, a system for preparing a drug substance-containing gel may comprise a mixer 302 configured to produce and / or capable of producing a mixture comprising a buffer, a gelator, and a drug substance. As noted above, the drug substance may comprise a buffer, which may be the same buffer or a different buffer than the buffer with which the drug substance and / or the gelator are combined in the mixer. Also as noted above, in some embodiments, the gelator and the buffer may be combined in the mixer to form a gelator solution prior to the addition of the drug substance. In some embodiments, the pH of the gelator solution may be adjusted within the mixer (e.g., via the addition of a pH adjuster) prior to and / or during the addition of the drug substance to the mixer. In some embodiments, the mixer is a batch mixer, a static mixer (e.g., a single use static mixer), and / or a continuous mixer. In some embodiments, the mixer may comprise an impeller, an ultrasonic mixer, and / or a vibromixer. In some embodiments, the mixer may contain a volume of greater than or equal to 1 L.

[0179] In some embodiments, a mixer may be configured to produce a mixture and / or capable of producing a mixture. For example, in some embodiments, the mixer may be configured to produce and / or capable of producing a mixture comprising a gelator and a drug substance. In some embodiments, the mixer may be configured to produce and / or capable of producing a mixture comprising a gelator, a drug substance, and a buffer (e.g., a buffer of a gelator solution, which may be the same as or different from the buffer contained within the drug substance). In some embodiments, the mixer may be configured to produce and / orcapable of producing a homogeneous mixture of the buffer, the gelator, and the drug substance. This may be accomplished by, for example, mixing various components, such as the buffer, the gelator, and / or the drug substance, such as via an impeller, an ultrasonic mixer, and / or a vibromixer. In some embodiments, the mixer may be configured to contain and / or capable of containing a mixture. In some embodiments, the mixer contains a mixture. In some embodiments, the mixture comprises a gelator and a drug substance.

[0180] In some embodiments, a system for preparing the drug substance-containing gel may comprise one or more conduits 304 in fluidic communication with the mixer. In some embodiments, as shown in FIG. 3B, one or more conduits 304a are configured to deliver and / or capable of delivering a buffer, a gelator, and / or a drug substance to the mixer (e.g., by fluidically connecting the mixer with sources of the buffer, the gelator, and the drug substance). In some embodiments, one or more conduits are configured to deliver and / or capable of delivering a pH adjuster to the mixer (e.g., by fluidically connecting the mixer with sources of the buffer, the gelator, and the drug substance). In some embodiments, one or more conduits 304b may be configured to remove and / or capable of removing a mixture comprising the buffer, the gelator, and the drug substance from the mixer (e.g., by fluidically connecting the mixer with a location at which and / or a container in which the mixture may be received, such as container 305 as shown in FIG. 3B). In some embodiments, as shown in FIG. 3A, a system may comprise one or more pumps 306 in fluidic communication with one or more conduits. In some embodiments, the one or more pumps and one or more conduits may be configured to convey and / or capable of conveying a liquid mixture within the system (e.g., the pump may be configured to do so by applying a pressure differential and / or the conduits may be configured to do so by fluidically connecting various components of the system). In some embodiments, the one or more pumps and one or more conduits may be configured to convey and / or capable of conveying a liquid mixture without inducing gelation of the liquid mixture. In some embodiments, the one or more pumps and one or more conduits may be configured to convey and / or capable of conveying a liquid mixture without inducing gelation by applying a shear stress to the mixture which is above a critical shear stress of the mixture and / or above a yield stress of a gel comprising the mixture. In some embodiments, the one or more pumps and one or more conduits may be configured to convey and / or capable of conveying a liquid mixture without inducing gelation by conveying the liquid mixture at a relatively high flow rate, conveying the mixture through a relatively narrow conduit and / or channel, and / or conveying the mixture through a channel and / or conduit comprising one or more obstructions (e.g., a turbulator). In some embodiments, asshown in FIG. 3B, one or more pumps 306a may be configured to flow and / or capable of flowing a fluid through one or more conduits and to the mixer (e.g., by applying a pressure that would cause such flow). In some embodiments, the fluid may comprise the buffer, the gelator, the drug substance, and / or a pH adjuster. In some embodiments, one or more pumps 306b may be configured to flow and / or capable of flowing a mixture comprising the buffer, the gelator, and the drug substance out of the mixer (e.g., by applying a pressure that would cause such flow).

[0181] In some embodiments, a system for preparing the drug substance-containing gel may comprise a process controller 308. In some embodiments, the process controller may be configured to control and / or capable of controlling the flow rate of a fluid into a mixer and / or out of a mixer (e.g. via the one or more conduits). In some embodiments, the fluid may be a buffer, a gelator, a drug substance, a pH adjuster, and / or a mixture comprising the buffer, the gelator, and the drug substance. In some embodiments, the process controller may be configured to control and / or capable of controlling the flow rate of the fluid through one or more pumps.

[0182] As described above, in some embodiments, a system comprises a mixer. The mixer may have any of a variety of suitable structures. For example, in some embodiments, the mixer is a batch mixer, a continuous mixer (e.g., single use static mixer), and / or a semi-continuous mixer. Semi-continuous mixers may have some features in common with batch mixers and some features in common with continuous mixers.

[0183] A mixer may comprise any of a variety of suitable components configured to apply and / or capable of applying a shear stress to a material within the mixer. For example, in some embodiments, the mixer may comprise an impeller, such as impeller 303 as shown in FIG. 3B. In some embodiments, an impeller may be configured to be and / or capable of being submerged in a liquid mixture contained within the mixer. In some embodiments, the impeller may be configured to be and / or capable of being rotated. In some embodiments, the impeller may comprise a radial flow impeller. For example, in some embodiments, the impeller may comprise a Rushton impeller. In some embodiments, the impeller may comprise a swept Rushton impeller and / or a ringed Rushton impeller. In some embodiments, the impeller comprises a helical impeller and / or an anchor impeller. In some embodiments, a mixer may comprise an ultrasonic mixer and / or a vibromixer. In some embodiments, an ultrasonic mixer may use high-frequency sound waves (e.g. sound waves with a frequency greater than or equal to 20 Hz) to induce agitation (e.g. vibration) of a liquid mixture contained within the mixer. In some embodiments, a vibromixer may use high-frequencyvibrations of a physical component of the vibromixer to induce agitation (e.g. vibration) of a liquid mixture contained within the mixer. In some embodiments, an ultrasonic mixer and / or vibromixer may be configured to apply and / or capable of applying a shear stress to a liquid mixture contained within the mixer.

[0184] In some embodiments, a mixer may comprise one or more components configured to monitor a viscosity of a material within the mixer. In some embodiments, the component configured to monitor the viscosity the material may be part of and / or connected to one or more components of the mixer that are configured to apply and / or capable of applying a shear stress to a material within the mixer. For example, in some embodiments, an impeller may comprise a component (e.g., a sensor) configured to monitor and / or control the torque, rotational speed, and / or rotation rate of the impeller. In some embodiments, the torque, rotational speed, and / or rotation rate of the impeller may be used to infer the viscosity of the material within the mixer. For example, in some embodiments, the change in the torque, rotational speed, and / or rotation rate of the impeller over time may be used to monitor a change in the viscosity of the material over time. This may be particularly useful if the impeller is operated at different mixing rates (e.g., different rotation rates) at different times. In some embodiments, a relationship between the torque and the rotation rate of the impeller may be used to determine the viscosity of the material within the mixer.

[0185] In some embodiments, information gathered by a component configured to monitor a viscosity of a material within the mixer (e.g., a sensor as described above) may be used to control a mixing rate of the mixer. For example, as described in greater detail below, information gathered by the sensor configured to monitor the viscosity may be used to change the torque, rotational speed, and / or rotation rate of an impeller of the mixer.

[0186] In some embodiments, a mixer comprises one or more baffles. For example, the mixer 352 shown in FIG. 3C comprises the baffles 354. The one or more baffles may extend from and / or be integrated into an interior wall of the mixer. In some embodiments, the one or more baffles may advantageously improve mixing of a material contained within the mixer (e.g., a liquid mixture and / or gel comprising a drug substance) when a shear stress is applied thereto. For example, in some embodiments, the one or more baffles may reduce bubble formation within a material when a shear stress is applied to the material within the mixer.

[0187] As noted above, in some embodiments, a system comprises a single-use mixer. In some embodiments, the single-use mixer may advantageously eliminate the need to clean and / or sterilize the mixer between uses (e.g., between use for preparing different batches of a drug substance-containing gel). In some embodiments, the single-use mixer comprises acomponent configured to apply and / or capable of applying a shear stress to the material within the mixer (e.g., an impeller, an ultrasonic mixer, and / or a vibromixer having any of the properties and / or characteristics described above). An example of a single-use mixer 352 comprising an impeller 356 is shown in FIG. 3C. A top-view schematic of the single-use mixer 352 is shown in FIG. 3D.

[0188] A mixer may contain any of a variety of appropriate volumes. For example, in some embodiments, the mixer contains a volume of greater than or equal to 1 L, greater than or equal to 2.5 L, greater than or equal to 5 L, greater than or equal to 7.5 L, greater than or equal to 10 L, greater than or equal to 25 L, greater than or equal to 50 L, greater than or equal to 75 L, greater than or equal to 100 L, greater than or equal to 250 L, greater than or equal to 500 L, greater than or equal to 750 L, greater than or equal to 1,000 L, greater than or equal to 2,500 L, greater than or equal to 5,000 L, or greater than or equal to 7,500 L. In some embodiments, a mixer may contain a volume of less than or equal to 10,000 L, less than or equal to 7,500 L, less than or equal to 5,000 L, less than or equal to 2,500 L, less than or equal to 1,000 L, less than or equal to 750 L, less than or equal to 500 L, less than or equal to 250 L, less than or equal to 100 L, less than or equal to 75 L, less than or equal to 50 L, less than or equal to 25 L, less than or equal to 10 L, less than or equal to 7.5 L, or less than or equal to 5 L. Combinations of these ranges are also possible (e.g. a mixer may contain a volume of greater than or equal to 1 L and less than or equal to 10,000 L, greater than or equal to 10 L and less than or equal to 5,000 L, or greater than or equal to 50 L and less than or equal to 1,000 L). Other ranges are also possible.

[0189] In some embodiments, a mixer may comprise one or more components configured to monitor and / or control (and / or that is capable of monitoring and / or controlling) the temperature of a material contained within the mixer. For example, the mixer may comprise a sensor configured to measure and / or capable of measuring the temperature of a material contained within the mixer. In some embodiments, the mixer may comprise a heating element and / or a cooling element configured to adjust and / or capable of adjusting the temperature of a material contained within the mixer. In some embodiments, the heating element and / or the cooling element may be configured to maintain and / or be capable of maintaining the temperature of a material contained within the mixer at a desired temperature. As described in greater detail elsewhere herein, information gathered by the sensor may be used to control the heating element and / or the cooling element to maintain and / or adjust the temperature of a material contained within the mixer.As described above, in some embodiments, a system for preparing a drug substancecontaining gel may comprise one or more conduits in fluidic communication with a mixer. In some embodiments, as shown in FIG. 3B, one or more conduits 304a are configured to deliver and / or capable of delivering a buffer, a gelator, a drug substance, and / or a pH adjuster to the mixer. For example, in some embodiments, one or more conduits may be configured to deliver and / or capable of delivering a buffer to the mixer. In some embodiments, one or more conduits may be configured to deliver and / or capable of delivering a gelator to the mixer. In some embodiments, one or more conduits may be configured to deliver and / or capable of delivering a drug product and / or drug substance to the mixer. In some embodiments, one or more conduits may be configured to deliver and / or capable of delivering a pH adjuster to the mixer. A system may comprise any combination of the abovelisted conduits. Conduits may deliver such fluids by fluidically connecting the mixer to sources thereof.

[0190] In some embodiments, as shown in FIG. 3B, a system may comprise one or more conduits 304b configured to remove and / or capable of removing a mixture comprising the buffer, the gelator, and the drug substance from a mixer 302. The conduits may remove such fluids by fluidically connecting a mixer to a location to which the mixture may be delivered, such as a container 305. In some embodiments, the connection between a mixer and a location to which the mixture may be delivered (e.g., a container) may be aseptic. In some embodiments, the system comprises a single-use conduit (e.g., one or more of the conduits of the system may be single-use conduits).

[0191] In some embodiments, a system may comprise one or more conduits comprising reinforced tubing. In some embodiments, conduits comprising reinforced tubing may be advantageous in that they may be robust to the high and / or increasing viscosity of a gel, liquid mixture, and / or recovered liquid mixture within the conduit. For example, in some embodiments, reinforced tubing may allow for pressures within the tubing not to exceed the tubing specification even when the material contained therein has a high and / or increasing viscosity.

[0192] In some embodiments, a system may comprise one or more pumps in fluidic communication with any one of or any combination of one or more conduits as described above. In some embodiments, one or more pumps 306a may be configured to flow and / or capable of flowing a fluid through one or more conduits 304a and to a mixer 302 (e.g., by applying a pressure that would cause such flow). In some embodiments, a fluid may comprise a buffer, a gelator, a pH adjuster, and / or a drug substance. In some embodiments,one or more pumps 306b may be configured to flow and / or capable of flowing a mixture comprising the buffer, the gelator, and the drug substance through one or more of the conduits 304b and out of a mixer 302 (e.g., by applying a pressure that would cause such flow).

[0193] In some embodiments, a pump may be a direct drive centrifugal pump, a magnetic drive centrifugal pump, a peristaltic pump, or a diaphragm pump. In some embodiments, a system may comprise one or more pumps of the same kind and / or one or more pumps of different kinds. In some embodiments, the system may comprise a single-use pump (e.g., the system may comprise one or more single-use pumps).

[0194] In some embodiments, as shown in FIG. 3B, a system may comprise a turbulator 307. For example, in some embodiments, one or more conduits 304b may comprise a turbulator. In some embodiments, the turbulator may be configured to increase and / or capable of increasing the shear stress applied to a fluid within a conduit. For example, in some embodiments, the turbulator may be configured to increase and / or capable of increasing the shear stress applied to a liquid mixture comprising a buffer, a gelator, and a drug substance within a conduit. In some embodiments, the turbulator may increase the shear stress applied to a liquid mixture within the conduit such that the shear stress applied to the liquid remains above the yield stress of a gel comprising a buffer, a gelator, and a drug substance. The turbulator may comprise one or more obstacles which increase the shear stress applied to a liquid mixture as the liquid mixture flows past the obstacles. In some embodiments, this may prevent the liquid mixture comprising the buffer, the gelator, and the drug substance from forming a gel within the conduit. In some embodiments, the one or more pumps, one or more conduits, and the turbulator may be configured to convey and / or capable of conveying a liquid mixture within the system (e.g., the pump may apply a pressure differential that causes flow of the liquid mixture, the conduits may provide pathways along which the liquid mixture can flow, and / or the turbulator may comprise one or more topological features that cause the liquid mixture to flow). In some embodiments, the one or more pumps, one or more conduits, and turbulator may be configured to convey and / or capable of conveying a liquid mixture without inducing gelation of the liquid mixture. In some embodiments, the one or more pumps, one or more conduits, and turbulator may be configured to convey and / or capable of conveying a liquid mixture without inducing gelation by applying a shear stress to the mixture which is above a critical shear stress of the mixture and / or above a yield stress of a gel comprising the mixture. In some embodiments, one or more pumps, one or more conduits, and turbulator may be configured to convey and / or capable of conveying a liquidmixture without inducing gelation by conveying the liquid mixture at a relatively high flow rate, conveying the mixture through a relatively narrow conduit and / or channel, and / or conveying the mixture through a channel and / or conduit comprising one or more obstructions (e.g., one or more obstructions which are part of and / or within the turbulator).

[0195] In some embodiments, a system may comprise a process controller. In some embodiments, the process controller may be configured to control and / or capable of controlling a flow rate of a fluid through one or more conduits. In some embodiments, the process controller may be configured to control and / or capable of controlling a mixing rate of a mixer (e.g. the torque, rotational speed, and / or rotation rate of an impeller, the vibration frequency of a vibromixer, etc.).

[0196] In some embodiments, a process controller may comprise one or more sensors (e.g., sensor 310, as shown in FIG. 3B). In some embodiments, one or more sensors may be configured to measure and / or capable of measuring a pH of a liquid mixture contained within a mixer and / or elsewhere in a system. In some embodiments, one or more sensors may be configured to measure and / or capable of measuring the shear stress being applied to a liquid mixture within a mixer. In some embodiments, one or more sensors may be configured to measure and / or capable of measuring the temperature of the liquid mixture within the mixer. In some embodiments, one or more sensors may be configured to measure and / or capable of measuring the viscosity and / or the change in viscosity over time of a material contained within the mixer.

[0197] In some embodiments, a process controller may comprise an electronic controller 308 as shown in FIG. 3B. In some embodiments, the electronic controller may be configured to receive and / or capable of receiving a signal 322 (e.g. an electrical signal) from one or more sensors. In some embodiments, the electronic controller may be configured to control and / or capable of controlling the flow rate of a buffer, a gelator, a drug product and / or drug substance, and / or a pH adjuster through one or more conduits. In some embodiments, the electronic controller may be configured to control and / or capable of controlling a pumping rate of one or more pumps. For instance, the electronic controller may be configured to send and / or may be capable of sending one or more signals (e.g. signal 324a, signal 324b) to one or more pumps that control the pumping rate(s) of these pump(s). In some embodiments, the process controller may be configured to control and / or capable of controlling a mixing rate of the mixer. In some embodiments, the process controller may be configured to control and / or capable of controlling the temperature of a liquid mixture within the mixer (e.g., by controlling a heating element and / or cooling element contained therein).In some embodiments, a system for storing a drug substance-containing gel is described. A non-limiting embodiment of such a system is shown in FIG. 4A. In some embodiments, the system may comprise a container 402 configured to contain and / or capable of containing a gel. In some embodiments, the container may have a volume of greater than or equal to IL. In some embodiments, the container may be a mixer (e.g., a mixer having any of the properties and / or characteristics described herein). For example, the container may be a single-use mixer. In some embodiments, the container (e.g., the single-use mixer) may contain a gel that was prepared therein (e.g., by combining a drug substance with a gelator to form a liquid mixture and

[0198] inducing gelation of the liquid mixture as described elsewhere herein).

[0199] In some embodiments, the system may comprise a liquefier 403. In some embodiments, the liquefier may be configured to apply a shear stress to a gel. In some embodiments, the liquefier may be configured to apply a sufficiently high shear stress to a gel to liquefy the gel and form a recovered liquid mixture. In some embodiments, the liquefier may be configured to apply a shear stress to a gel within the container.

[0200] In some embodiments, a system for storing the drug substance-containing gel may comprise a filter 404. In some embodiments, the filter 404 may be in fluidic communication with a container 402. In some embodiments, the filter may comprise a prefilter, a normal flow filtration assembly, and / or a tangential flow filtration assembly. In some embodiments, the filter may be configured to remove and / or capable of removing the gelator from the recovered liquid mixture and form a liquid product (e.g., via sieving and / or capture of the gelator).

[0201] In some embodiments, a system for storing the drug substance-containing gel may comprise one or more conduits 406 in fluidic communication with a container and / or a filter. In some embodiments, one or more conduits may be configured to flow and / or capable of flowing a fluid from the container to the filter (e.g., they may fluidically connect the container to the filter). In some embodiments, the fluid may be a recovered liquid mixture. In some embodiments, one or more of the conduits of the system for storing the drug substance-containing gel may be a single-use a conduit.

[0202] In some embodiments, as shown in FIG. 4B, a system for storing a drug substancecontaining gel may comprise a sensor 408. In some embodiments, the sensor 408 may be downstream of a filter 404. In some embodiments, the sensor may be configured to measure and / or capable of measuring the concentration of a gelator in a liquid product. In some embodiments, the sensor 408 may be configured to measure and / or capable of measuring theresidual gelator concentration downstream of the filter (e.g., after the liquid product has passed through the filter). In some embodiments, the sensor is a single-use sensor.

[0203] As described above, in some embodiments, a system may comprise a container (e.g. container 402 as shown in FIG. 4A) configured to contain and / or capable of containing a gel. In some embodiments, the container may be configured to allow and / or capable of allowing a shear stress to be applied to a gel stored within the container. In some embodiments, the container may be configured to allow and / or capable of allowing a sufficiently high shear stress to be applied to the gel to liquefy the gel and form a recovered liquid mixture.

[0204] For example, in some embodiments, a container may comprise a compressible container. For example, in some embodiments, the container may be formed from and / or comprise a flexible material such that the walls of the container may be deformed under a compressive force. In some embodiments, compression of the container, such as compression caused by applying a compressive force to the container, may cause the walls of the container to deform in such a way as to apply a shear stress to a material (e.g., a gel, a liquid mixture) contained within the container. In some embodiments, the shear stress applied to a gel positioned within the container may be sufficient to overcome a yield stress and liquefy the gel, forming a liquid product (to which shear stress may also be applied).

[0205] In some embodiments, a container may comprise a headspace. In some embodiments, the headspace may comprise a region comprising a gas. In some embodiments, the container may have a headspace pressure, which may be the pressure of the gas within the headspace. In some embodiments, the container may be configured to allow and / or capable of allowing modification of the headspace pressure of the container, such as by a mechanism to adjust the headspace pressure. For example, in some embodiments, modifying the headspace pressure of the container comprising a gel may comprise inflating and / or deflating the container (e.g. by adjusting the volume of the container, by pumping additional gas into the headspace, and / or applying vacuum to the headspace). In some embodiments, the container may comprise a collapsible conduit comprising a plurality of perforations (e.g. a dip tube). In some embodiments, the collapsible conduit may be configured to allow and / or capable of allowing a fluid to flow into the collapsible conduit and out of the collapsible container (e.g., via the perforations).

[0206] A container may contain any of a variety of appropriate volumes. For example, in some embodiments, the container contains a volume of greater than or equal to 1 L, greater than or equal to 2.5 L, greater than or equal to 5 L, greater than or equal to 7.5 L, greater than or equal to 10 L, greater than or equal to 25 L, greater than or equal to 50 L, greater than orequal to 75 L, greater than or equal to 100 L, greater than or equal to 250 L, greater than or equal to 500 L, greater than or equal to 750 L, greater than or equal to 1,000 L, greater than or equal to 2,500 L, greater than or equal to 5,000 L, or greater than or equal to 7,500 L. In some embodiments, a container may contain a volume of less than or equal to 10,000 L, less than or equal to 7,500 L, less than or equal to 5,000 L, less than or equal to 2,500 L, less than or equal to 1,000 L, less than or equal to 750 L, less than or equal to 500 L, less than or equal to 250 L, less than or equal to 100 L, less than or equal to 75 L, less than or equal to 50 L, less than or equal to 25 L, less than or equal to 10 L, less than or equal to 7.5 L, less than or equal to 5 L, or less than or equal to 1 L. Combinations of these ranges are also possible (e.g. a container may contain a volume of greater than or equal to 1 L and less than or equal to 10,000 L, greater than or equal to 10 L and less than or equal to 5,000 L, or greater than or equal to 50 L and less than or equal to 1,000 L). Other ranges are also possible.

[0207] In some embodiments, a system may comprise a liquefier (e.g. a liquefier 403 as shown in FIG. 4A). In some embodiments, the liquefier may be configured to apply and / or capable of applying a shear stress to the gel. In some embodiments, the liquefier may be configured to be and / or capable of being used within a container. For example, in some embodiments, the liquefier may be inserted into the container. In some embodiments, the liquefier may apply shear stress to a gel in any of the variety of ways as described above (e.g. the liquefier may comprise an impeller, a vibromixer, etc.).

[0208] For example, in some embodiments, a liquefier may comprise an impeller. In some embodiments, the impeller may be configured to be and / or capable of being submerged in a gel. In some embodiments, the impeller may comprise a radial flow impeller. For example, in some embodiments, the impeller may comprise a Rushton impeller. In some embodiments, the impeller may comprise a swept Rushton impeller and / or a ringed Rushton impeller. In some embodiments, the impeller comprises a helical impeller and / or an anchor impeller.

[0209] In some embodiments, a liquefier may comprise an ultrasonic mixer and / or a vibromixer configured to induce and / or capable of inducing vibration of a gel contained within a container. The ultrasonic mixer and / or vibromixer may have any of the properties and / or configurations as described above (e.g. a vibromixer and / or ultrasonic mixer may induce vibration of the gel which imparts sufficient shear stress to overcome the yield stress of the gel, etc.).

[0210] In some embodiments, as shown in FIG. 4A, a system may comprise a filter 404. In some embodiments, the filter may be in fluidic communication with a container 402. In someembodiments, the filter is configured to remove and / or capable of removing a gelator from a recovered liquid mixture to form a liquid product. In some embodiments, the filter may comprise a filter capsule. In some embodiments, the filter may comprise a prefilter. In some embodiments, the prefilter may be configured to remove and / or capable of removing large fragments (e.g. solid gel fragments) from a recovered liquid mixture. In some embodiments, the filter may comprise a filter capsule, a normal flow filtration assembly, and / or a tangential flow filtration assembly (e.g., a tangential flow microfiltration assembly). In some embodiments, the filter comprises a depth filter. In some embodiments, the filter comprises a reverse-phase chromatography assembly. In some embodiments, an output from the filter may be a liquid product. In some embodiments, a system may comprise a filter element. In some embodiments, a filter element may comprise a filter and / or one or more additional components (e.g. a filter element may comprise a filter and / or a prefilter, a filter element may comprise a filter and / or a filter housing).

[0211] In some embodiments, a filter may comprise a membrane. For example, in some embodiments, the filter comprises a nanofiltration membrane. In some embodiments, the nanofiltration membrane has a pore size of greater than or equal to 20 nm and less than or equal to 40 nm, or greater than or equal to 20 nm and less than or equal to 80 nm. In some embodiments, the filter comprising a nanofiltration membrane may advantageously reduce the amount of a gelator contained within a liquid product that is formed when a recovered liquid mixture is passed through the nanofiltration membrane. In some embodiments, a filter assembly may comprise a prefilter (e.g., a microfiltration membrane, such as a membrane having a pore size of 0.2 micrometers) and the nanofiltration membrane.

[0212] In some embodiments, a system for storing the drug substance-containing gel may comprise one or more conduits (e.g. conduit 406 as shown in FIG. 4A) in fluidic communication with a container and / or a filter. In some embodiments, one or more conduits may be configured to flow and / or capable of flowing a fluid from the container to the filter. For example, in some embodiments, the fluid may be a recovered liquid mixture. In some embodiments, a system may comprise one or more pumps (e.g. pump 407 as shown in FIG.

[0213] 4B). In some embodiments, one or more pumps may be configured to flow and / or capable of flowing a fluid (e.g. the recovered liquid mixture) from a container 402 to a filter 404.

[0214] In some embodiments, as shown in FIG. 4B, a system for storing a drug substancecontaining gel may comprise a sensor 408. In some embodiments, the sensor may be configured to measure and / or capable of measuring the concentration of a gelator in a liquid product 409. In some embodiments, the sensor may be configured to convey and / or capableof conveying a signal 410 and / or 411 (e.g. an electrical signal) to an electronic controller 412 and / or a user interface 413. In some embodiments, the sensor 408 may convey a signal 411 to the user interface 413, which may display information about the concentration of the gelator in the output and / or a warning if the concentration of the gelator is above a certain value. In some embodiments, the sensor 408 may convey a signal 410 to an electronic controller 412. In some embodiments, the electronic controller 412 may be configured to direct a portion of the liquid product 409 (e.g., a portion of the liquid product 414) to the input to the filter (e.g., if the signal 410 indicates that the gelator concentration in the output stream is outside of an acceptable range). In some embodiments, the electronic controller 412 may be configured to direct the liquid product 409 to the next process step (e.g., if the signal 410 indicates that the gelator concentration in the output stream is within an acceptable range). In some embodiments, the electronic controller 412 may be configured to convey and / or capable of conveying a signal 415 to a pump 416, which may be configured to control and / or capable of controlling the flow rate of the portion of the liquid product 414.

[0215] In some embodiments, a liquid product may comprise some or all of the drug substance contained within a recovered liquid mixture prior to exposing the recovered liquid mixture to a filter configured to remove and / or capable of removing a gelator therefrom (e.g., the liquid product may comprise some or all of the drug substance contained within a gel from which the recovered liquid mixture is formed). In some embodiments, the liquid product may comprise greater than or equal to 10%, greater than or equal to 25%, greater than or equal to 50%, greater than or equal to 75%, greater than or equal to 90%, greater than or equal to 95%, greater than or equal to 99%, greater than or equal to 99.5%, greater than or equal to 99.9%, or more of the drug substance contained within the recovered liquid mixture. In some embodiments, the liquid product comprises less than or equal to 100%, less than or equal to 99.9%, less than or equal to 99.5%, less than or equal to 99%, less than or equal to 90%, less than or equal to 75%, less than or equal 50%, less than or equal to 25%, or less of the drug substance contained within the recovered liquid mixture. Combinations of these ranges are also possible. For example, the liquid product may comprise greater than or equal to 10% and less than or equal to 100%, or greater than or equal to 25% and less than or equal to 99.9% of the drug substance contained within the recovered liquid mixture. Other ranges are also possible. In some embodiments, the liquid product comprises an amount of the drug substance contained within the liquid mixture in one or more of the above referenced ranges on a weight basis. In some embodiments, the liquid product comprises an amount of the drug substance contained within the liquid mixture in one or more of the above -referenced rangeson a mole basis. In some embodiments, the liquid product comprises an amount of the drug substance contained within the liquid mixture in one or more of the above -referenced ranges on a volume percentage.

[0216] In some embodiments, the amount of a drug substance contained within a recovered liquid mixture relative to the amount of the drug substance contained within a liquid product formed by exposing the recovered liquid mixture to a filter may depend on one or more properties of the drug substance contained therein. For example, some drug substances such as therapeutic proteins (e.g., monoclonal antibodies), typically have an isoelectric point (pl) in the range of approximately 6.5-9.5 (e.g., as shown in FIG. 5). If the isoelectric point of the drug substance is above the pKa of a gelator solution and / or a gel (e.g., a gel comprising CD-005, which would have a pKa of less than 6.5), the drug substance will be positively charged at the gelation conditions and an electrostatic interaction may be created between the gel and the drug substance (e.g., between a therapeutic protein and a gel comprising CD-005). In some embodiments, this interaction may lead to low recovery (e.g., less than 10%) of the drug substance from a recovered liquid mixture formed from the gel. Such effects may be mitigated by adding one or more additional components to the gel and / or the recovered liquid mixture. For example, the addition of certain salts (e.g., sodium chloride) or zwitterionic compounds (e.g., glycine) may interfere with the electrostatic interaction of the drug substance and the gel, which can significantly improve the recovery of the drug substance. In some embodiments in which the isoelectric point of the drug substance is below the pKa of the gelator solution and / or the gel (e.g., if the drug substance comprises a protein such as insulin and / or beta-galactosidase, as shown in FIG. 5, and the gel comprises CD-005), it may be possible to achieve very high recoveries of the drug substance from a recovered liquid mixture formed from the gel without having to add any additional components to the gel and / or recovered liquid mixture.

[0217] EXAMPLE 1

[0218] This Example examines the recovery of a drug substance from a frozen gel.

[0219] In this Example, fluorescein isothiocyanate-dextran (FITC-Dextran) was used as a model active pharmaceutical ingredient. FITC-Dextran has a molecular weight of about 150,000 Daltons and a hydrodynamic radius of about 8.5 nm.

[0220] Gels containing 2.5 wt% and 5 wt% of FITC-Dextran and CD-005 and having a variety of storage moduli were prepared. These gels were then liquefied to form a recovered liquid mixture and exposed to a filter having 0.22 micrometer pores at a variety of flow rates.The amount of the gelator that was retained by the filter was then determined using reversephase, high-pressure liquid chromatography (for which calibration signals are shown in FIGS. 6A-6B, which were determined using standards with known concentrations (mg / mL) of CD-005), and these results are summarized in Table 1 below. It was observed that an average of 99.85% by mass of the gelator was retained from gels having a storage modulus of less than 1,300 Pa across all flow rates, and an average of 99.72% by mass of the gelator was retained from gels having a storage modulus of greater than 1,300 Pa across all flow rates. This indicates excellent capture efficiency of the gelator from the recovered liquid mixture.

[0221] Table 1. Gelator retained by the filter (on a mass basis) after exposure to a recovered liquid mixture at various flowrates.

[0222] < >

[0223]

[0224] The amount of the FITC-Dextran that passed through the filter was determined by performing fluorescence on the filter eluate. It was determined that, for the gels containing 2.5 wt% FITC-Dextran, 80% by mass of the FITC-Dextran passed through the filter into the eluate. For the gels containing 5 wt% FITC-Dextran, 74% by mass of the FITC-Dextran passed through the filter into the eluate.

[0225] The filtration apparatus used in this Example had a dead volume that prevented the entire sample from being passed through the filter in a single pass. To address this issue, the filtration apparatus was flushed with buffer after the initial filtration of the sample. It was observed that flushing the filtration apparatus with buffer after filtering the recovered liquid mixture increased the amount of the FITC-Dextran that passed through the filter into the eluate to approximately 85% by mass.

[0226] EXAMPLE 2

[0227] This Example examines the impact of freezing on the pH of gels and solutions containing a drug substance.

[0228] In this Example, the pH of a phosphate buffer without a dissolved gelator and the pH of a gel comprising the phosphate buffer and a gelator was monitored during a cycle offreezing and thawing. The gel was prepared by mixing a gelator solution comprising 20 mg / mL CD-005 in a phosphate buffer with 1 mL phosphate buffer at a CD-005 solution ratio of 0.4 mL:1.0 mL. Prior to mixing, the original CD-005 solution was pre-titrated to pH 6.75 using 1 M HC1. After addition of the phosphate buffer, the final mixture was further adjusted, if needed, to pH 6.75 using 1 M HC1.

[0229] The phosphate buffer and the gel described above were then subjected to a cycle of freezing and thawing using a freezing model system configured to replicate the freezing behavior of bags typically used for drug product storage while maintaining a lower sample volume. In this system, the cross-sectional freezing path of the bag (i.e., from the bag wall to the final freezing point at the center of the bag) was modeled using a column of liquid having a height of approximately 25 mm. The applied freezing and thawing cycle matched that used for a 6 L Celsius® FFT bag in a HOF plate freezer. The pH probe was positioned at the midpoint of approximately 12.5 mm in this liquid column.

[0230] As can be clearly seen in FIG. 7, the presence of the gelator significantly reduced the pH drift during freezing relative to the solution without the gelator. With the gelator present, the pH of the solution was reduced from approximately 6.75 at a temperature of 20 °C to approximately 5.0 at a temperature of -40 °C. In contrast, without the gelator present, the pH of the solution was reduced from approximately 6.75 at 20 °C to approximately 3.1 at a temperature of -40 °C. This indicates that the presence of the gelator helps stabilize the pH of the solution of the drug substance and the buffer during freeze-thaw cycles.

[0231] While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present invention is / are used. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may bepracticed otherwise than as specifically described and claimed. The present invention is directed to each individual feature, device, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, devices, articles, materials, kits, and / or methods, if such features, devices, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present invention.

[0232] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0233] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0234] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0235] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one elementselected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0236] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0237] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

Claims

CLAIMS1. A method for storing a drug substance, comprising:combining the drug substance with a gelator in a mixer to form a liquid mixture; and inducing gelation of the liquid mixture to form a shear-thinning gel with a volume greater than or equal to 1 L.

2. A method for producing a liquid product comprising a drug substance, comprising:applying a shear stress to a shear-thinning gel with a volume greater than or equal to 1 L, the gel comprising a drug substance and a gelator, to liquefy the gel and form a recovered liquid mixture; andseparating the recovered liquid mixture to remove the gelator from the recovered liquid mixture and produce a liquid product.

3. A method for storing a drug substance, comprising:combining the drug substance with a gelator to form a liquid mixture;inducing gelation of the liquid mixture to form a shear- thinning gel; and freezing the gel by holding the gel at a temperature of less than or equal to -20 °C for a period of 2 or more hours to form a frozen gel.

4. A method for producing a liquid product comprising a drug substance, comprising:thawing a frozen gel, the frozen gel comprising a drug substance and a gelator, by holding the frozen gel at a temperature of greater than or equal to 5 °C for a period of 6 or more hours to form a shear-thinning gel;applying a shear stress to the gel to liquefy the gel, forming a recovered liquid mixture; andseparating the recovered liquid mixture to remove the gelator from the recovered liquid mixture and produce a liquid product.

5. A system for preparing a drug substance-containing gel, comprising:a mixer configured to produce a mixture, the mixture comprising a gelator and a drug substance, wherein the mixer has a volume greater than or equal to 1 L;a conduit in fluidic communication with the mixer;a pump in fluidic communication with the conduit; anda process controller configured to control a flow rate of fluid through the conduit and / or a mixing rate of the mixer.

6. A system for storing a drug substance-containing gel, comprising:a container containing a mixture, the mixture comprising a gelator and a drug substance, wherein the container contains a volume greater than or equal to 1 L;a filter in fluidic communication with the container and configured to remove the gelator from the mixture;a conduit in fluidic communication with the container and the filter; anda liquefier configured to apply a shear stress to a gel contained within the container.

7. A system for processing a recovered liquid mixture comprising a gelator and a drug substance, comprising:a filter configured to remove the gelator from the recovered liquid mixture and form a liquid product; anda sensor configured to measure the concentration of the gelator in the liquid product.

8. A method as in any one of claims 1-4, wherein the drug substance further comprises one or more excipients.

9. A method as in claim 1 or claim 3, wherein the liquid mixture further comprises a buffer.

10. A method as in any one of claims 1-4, wherein the gelator is a liquid solution.

11. A method as in claim 1 or claim 3, wherein the liquid mixture comprises a biomaterial, an excipient, and a buffer.

12. A method as in claim 2 or claim 4, wherein separating the recovered liquid mixture comprises filtering the recovered liquid mixture.

13. A method as in claim 2 or claim 4, wherein separating the recovered liquid mixture comprises centrifuging the recovered liquid mixture.

14. A system as in claim 6 or claim 7, wherein the filter comprises a filter capsule.

15. A system as in claim 6 or claim 7, wherein the filter comprises a tangential flow filtration assembly.

16. A method as in claim 2 or claim 4, further comprising applying a substantially constant shear stress to the liquid mixture.

17. A method as in claim 1 or claim 3, wherein the inducing gelation of the liquid mixture comprises reducing a shear stress exerted on the liquid mixture below the critical shear stress of the liquid mixture.

18. A method as in claim 1 or claim 3, wherein the inducing gelation of the mixture comprises adjusting the pH of the mixture.

19. A method as in claim 1 or claim 3, wherein the gel forms beads and / or granules.

20. A method as in claim 1 or claim 3, wherein the gel forms a single integrated substance.

21. A method as in claim 18, wherein adjusting the pH of the mixture comprises adding a pH adjuster to the liquid mixture.

22. A method as in claim 1 or claim 3, wherein the pH is homogeneous in the liquid mixture.

23. A method as in claim 22, wherein the pH of the liquid mixture is a homogenous pH above the critical pH value of the mixture at which gelation of the mixture occurs.

24. A method as in claim 21, wherein the pH adjuster comprises a buffer.

25. A method as in claim 18, wherein adjusting the pH of the mixture comprises using a control loop comprising a pH sensor and a pH controller that controls a pump in fluidic communication with a source of a pH adjuster to maintain a consistent pH.

26. A method as in any one of claims 1-4, wherein the gelator is a low molecular weight gelator.

27. A method as in any one of claims 1-4, wherein the gelator comprises 3-{ [(ls)-l-(dodecyl carbamoyl)-2-methylpropyl]carbamoyl}propanoic acid.

28. A method as in claim 2 or claim 4, wherein applying a shear stress to the gel comprises changing the headspace pressure of a container comprising the gel.

29. A method as in claim 28, wherein changing the headspace pressure of a container comprises inflating or deflating the container.

30. A method as in claim 29, wherein the inflating or deflating the container comprises using a dip tube to inflate or deflate the container.

31. A method as in claim 2 or claim 4, wherein applying a shear stress to the gel comprises applying a compressive force to a container comprising the gel.

32. A method as in claim 2 or claim 4, wherein applying a shear stress to the gel comprises rotating an impeller submerged in the gel.

33. A method as in claim 2 or claim 4, wherein applying a shear stress to the gel comprises inducing vibration of the gel using an ultrasonic mixer and / or a vibromixer.

34. A method as in claim 2 or claim 4, wherein the shear stress is above a yield stress of the gel and below a critical shear stress of the drug substance.

35. A system as in claim 5, wherein the mixer has a volume greater than or equal to 1 liter.

36. A system as in any claim 5, wherein the mixer has a volume greater than or equal to 100 liters.

37. A system as in claim 5, wherein the mixer contains a mixture comprising a gelator and a drug substance, wherein the mixer has a volume greater than or equal to 1 L.

38. A system as in claim 5, wherein the mixer comprises an impeller.

39. A system as in claim 5, wherein the mixer comprises an ultrasonic mixer.

40. A system as in claim 5, wherein the mixer comprises a vibromixer.

41. A system as in claim 5, wherein the mixer is configured to produce a homogeneous mixture of the gelator, drug substance, and buffer.

42. A system as in claim 5, wherein the system further comprises a turbulator.

43. A system as in claim 42, wherein the turbulator increases the shear stress inside the conduit to a shear stress that is greater than a yield stress of a gel comprising the gelator and the drug substance.

44. A system as in claim 5, wherein the system further comprises a container.

45. A system as in claim 44, wherein the mixture is produced in the container.

46. A system as in claim 44, wherein the mixer is aseptically connected to the container.

47. A system as in claim 44, wherein the container contains a volume greater than or equal to 1 liter.

48. A system as in claim 44, wherein the container contains a volume greater than or equal to 100 liters.

49. A system as in claim 6, wherein the liquefier comprises an impeller.

50. A system as in claim 44, wherein the container has a headspace pressure, the container further comprising a mechanism to adjust the headspace pressure.

51. A system as in claim 44, wherein the container is a single-use container.

52. A system as in claim 7, wherein the system further comprises a sensor for measuring residual gelator concentration downstream of the filter.

53. A system as in claim 6, wherein the system for storing a drug substance-containing gel comprises a sensor configured to measure a concentration of the gelator.

54. A system as in claim 5, wherein the mixture is a liquid mixture, and wherein the pump and conduit are configured to convey the liquid mixture without inducing gelation of the mixture.

55. A system as in claim 42, wherein the conduit and the turbulator are configured to convey the mixture without inducing gelation of the mixture.

56. A system as in claim 5, wherein the mixer is a single-use mixer.

57. A system as in claim 5, wherein the mixer comprises one or more baffles.

58. A method as in claim 1 or claim 3, wherein the gelator is part of a gelator solution.

59. A method as in claim 58, further comprising adjusting the pH of the gelator solution.

60. A method as in claim 59, wherein adjusting the pH of the gelator solution comprises adjusting the pH of the gelator solution to a pH that is the same as or similar to the pH of the drug substance.

61. A method as in claim 59, wherein adjusting the pH of the gelator solution comprises adjusting the pH of the gelator solution to a pH that is the same as or similar to the pH of a gel comprising the gelator solution and the drug substance.

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