Patent Application
20220095610
In general, the present disclosure relates to a system and method for processing liquid bulk drug substances and other pharmaceutical solutions. More particularly, the disclosure relates to a system, including a set of containers and other processing apparatuses, that is particularly well suited for freezing, transporting, and subsequently thawing such substances.
In various contexts, there is a need to freeze and thaw a liquid product in a controlled manner, and to do so while maintaining quality of the liquid product. For example, it is common to produce a drug substance such as a vaccine, biologic, or pharmaceutical product, in bulk, liquid form; transfer the drug substance in liquid form into individual containers; and then freeze the drug substance in the containers. The frozen drug substance may then be shipped to a cold-storage facility, and subsequently shipped to a final-drug production site, where it is thawed and incorporated into a drug product being produced at the drug production site.
In this context, there are at least two important reasons to exercise precise control over the process for freezing the liquid drug substance in the containers. First, non-uniform freezing can lead to cryoconcentration, where freezing (e.g., of the water molecules in a given drug-substance solution) at different rates within a given container can lead to different levels of concentration of the drug substance throughout the container. Cryoconcentration can lead to degradation of the active molecule in the drug substance prior to freezing at a given, specific location in the container.
Second, if freezing is not uniform throughout the container, it is possible for the container to be breached or ruptured as the liquid drug substance freezes. This, of course, can allow contaminants such as bacteria or bioburden to enter into the container. Considering the loss of product yield associated with a breached container—depending on its size, a given container can hold more than $100,000 worth of product—it is crucial to avoid such freezing-related container failures if at all possible.
Additionally, it is important to control the subsequent thawing process so that thawing is uniform across the entire group of solution-bearing containers being thawed at a given time. This is because uneven and/or non-uniform thawing within a given container or from container to container can lead to molecular aggregation; formation of precipitates; and/or other adverse consequences.
Embodiments of the present invention provide a system and method for freezing and subsequently thawing a liquid product, such as a liquid drug substance or other pharmaceutical solution (for example active ingredient such as chemical compound, vaccine, antibody, protein, peptide, DNA, RNA or derivatives thereof) which significantly encourages uniform freezing (and uniform thawing) of the liquid drug substance throughout the container, while substantially reducing cryoconcentration and container ruptures. In particular, this is accomplished by controlling the freezing of liquid substance so as to maintain an essentially constant freeze-path length from one container to another, irrespective of the total volume of a given container, so as to provide consistent freezing and thawing performance across a range of container sizes.
Thus, in a first aspect, the invention features a set of containers for storing therein a liquid substance which is to be frozen and thawed, with each of the containers in the set having an essentially parallelepiped configuration with a substance-receiving cavity defined by the walls of the container. Each of the containers in the set has a pair of major walls on opposite sides of the container that define a length and a height of the container, and the major walls of each of the containers are spaced apart by a distance that defines a width of the respective container. Even though the substance-receiving cavities of various containers in the set may have different volumes, all of the containers in the set have the same width, such that a freeze-path length associated with each of the containers in the set is essentially the same.
In specific embodiments, the geometric configuration of containers within the set are designed with an ice bridging number (IBN) in mind. The IBN is a dimensionless parameter that is based on comparative rates of heat transfer through the headspace above the liquid in the container and through the walls of the container in which the liquid is in contact, and that is indicative of the relative rates at which water in the solution tends to freeze 1) at the air-liquid interface, and 2) along the walls of the container. Accordingly, IBN is a function of container geometry, heat transfer areas, heat transfer coefficients, and the thermal properties of the liquid in the container before and after freezing. In some embodiments, the configuration of the containers in the set—which bears on heat-transfer rates—will be set so that the IBN is significantly less than 1 (i.e. IBN<<1) for a predetermined liquid to be frozen therein when a predetermined cooling medium is used to freeze the predetermined liquid. Typically, the geometry of the containers in a set will be configured so that the IBN is less than about 0.6, and suitably greater than about 0.1 and less than about 0.6. In other embodiments, the set of containers may all have the same internal, nominal volume, with the same width so as to keep the freeze-path length essentially uniform for all containers in the set.
In another aspect, the invention features a system for storing, freezing, transporting, and subsequently thawing a liquid substance. The system includes a set of containers as described immediately above, either with different containers in the set having different volumes or all containers in the set having the same volume, along with a container-support platform. The container-support platform includes a plurality of formations that define a plurality of container-receiving spaces, with each of the container-receiving spaces being essentially equal in width to the width of the containers, and with groups of the formations being positioned so as to support a plurality of the containers on the container-support platform, received within respective container-receiving spaces, equally spaced from each other.
In yet another aspect, the invention features a method for storing and freezing a liquid substance. The method includes introducing the liquid substance into a plurality of containers selected from a set of containers as described immediately above; disposing the liquid-containing containers on a container-support platform, with the liquid-containing containers equally spaced from each other; and causing the liquid substance contained within the liquid-containing containers to freeze, with generally uniform progression of the freeze front or freeze fronts within each of containers, by flowing a cooling medium through spaces between adjacent containers.
In specific embodiments, the headspace located above the liquid in each of the containers may be insulated with a shroud while the liquid is being frozen in order to limit heat transfer that occurs through the headspace, thereby suppressing the tendency for ice to form at the upper surface of the liquid and allowing it to form more quickly along the sidewalls of the container. In this specific embodiment, the frozen substance contained within the fluid-containing containers may subsequently be caused to thaw, with generally uniform progression of the thawing within each of containers, by flowing a heating medium through spaces between adjacent containers and, if required, while rocking the containers to mechanically agitate liquid contained therein.
In yet another aspect, the invention provides a method for thawing a frozen liquid substance. According to this aspect, a number of containers containing an amount of the frozen liquid substance are placed on a container-support platform, with the containers equally spaced from each other, and the frozen liquid substance contained within the containers is caused to thaw, with generally uniform progression of the thaw front or thaw fronts within each of the containers, by flowing a warming medium through spaces between adjacent containers.
Each of the containers has an essentially parallelepiped configuration, with frozen liquid substance contained within a substance-receiving cavity defined by the walls of the container. Each of the containers also has a pair of major walls on opposite sides of the container that define a length and a height of the container, with the major walls of each of the containers being spaced apart by a distance that defines a width of the respective container. In one embodiment, the substance-receiving cavity of at least one of the containers has a first volume and the substance-receiving cavity of at least another one of the containers set has a second volume. In other embodiments, the set of containers may all have the same internal, nominal volume, with the same width so as to promote uniformity of thawing. The substance may be mechanically agitated while it is thawing. For example, the containers may be rocked in a longitudinal direction so that liquid contained therein moves back and forth, from one end of each container to the opposite end of each container, as the frozen substance melts.
These and Other Features of the Invention Will Become Clearer from the Detailed Description Below as Well as the Drawings, in which:
In this disclosure, the last two digits of each reference numeral identify a given component, element, or algorithm step, and the preceding one or two digits of each reference numeral correspond(s) to the number of the figure in which the element or step is depicted. Thus, if a given element is shown in multiple figures, strictly speaking, the element will have different reference numerals in each of the several figures; however, the last two digits will be the same across all related figures being discussed at the same time in order to explain a particular concept or aspect of embodiments of the invention. If multiple figures are being addressed at the same time within this disclosure, just the reference numeral used in the lowest-numbered figure will be used in the text. Furthermore, different elements that are illustrated in different figures, which are discussed at different points within this disclosure, may have reference numerals in which the last two digits are the same; the fact that the elements are being discussed at different points in the disclosure should, however, prevent such commonality of the last two reference-numeral digits from causing confusion.
A set of containers 100 constructed in accordance with an embodiment of the invention is illustrated in
Suitably, the containers 102 are fabricated from rigid or semi-rigid plastic, which keeps their manufacturing cost relatively low. This, in turn, facilitates disposal of the containers after a single use, thereby eliminating the cost to clean and inspect containers if they were otherwise to be reused. Materials such as high-density polyethylene (HDPE) and blends of HDPE and low-density polyethylene (LDPE) are preferred. (Material selection may depend to some extent on freezing temperatures and storage conditions for the frozen product.) Furthermore, containers made from plastic such as HDPE can be gamma-irradiated to minimize the risk of bioburden contamination.
Each of the containers in the set of containers 100 has a length 1 in the x-direction, as illustrated, and a height h in the y-direction, as illustrated. The length 1 and height h of each container in the set of containers 100 are the two longest dimensions of each container, and the walls 104a, 104b, 104c, and 104d (collectively referred to as walls 104) and their respectively opposing walls—not visible given the orientation of the containers in
Each of the containers in the set of containers 100 also has a width w in the z-direction, by which distance w the major surfaces of a given container are spaced apart from each other. Notably, the width w is the same for all of the containers in the set of containers 100, regardless of the particular volume of the container. As addressed further below, this results in the freeze-path length associated with each of the containers 102a, 102b, 102c, and 102d in the set of containers 100 being essentially the same for all containers in the set, which permits the uniform and consistent freezing performance to be scaled up or scaled down as desired. The freeze-path length largely dictates the time for liquid solution in the containers to freeze. Having a freeze-path of essentially the same length across all of the containers 102a, 102b, 102c, and 102d affords greater control over the freezing process and results in greater uniformity of the frozen product from one container to another and tends to eliminate or significantly reduce cryoconcentration and breakage of the containers, thereby preventing contamination and reducing waste.
As further illustrated in
By providing a set of containers with different volumes that are integer-fractions of larger containers in the set, different numbers of multiple smaller containers can be secured together into a group G as illustrated in
As illustrated schematically in
For example, the containers 302 may have a series of apertures 306 extending inwardly from the major walls 304—perhaps even extending all the way through the entire width of the containers. These apertures 306 facilitate lifting and transporting of the containers using a lifting device (not illustrated) having a number of pins that fit into the apertures 306, either extending all the way through the apertures in the case of containers 302 with apertures 306 that extend all the way through the containers or grasping the containers 302 between opposing pins that function like pincers in the case of containers with apertures that extend only partially into the interiors of the containers 302.
Furthermore, the containers may include recesses 308, 310 along their upper peripheries to house or accommodate container-filling ports or fittings and container-emptying ports or fittings, respectively. These ports or fittings may be configured as disclosed, for example, in U.S. Pub. 2015/0360815, entitled “Phase-Change Accommodating Rigid Fluid Container” and published on Dec. 17, 2015, the contents of which are incorporated by reference. Alternatively, the ports or fittings may be configured in some other manner as may be desired, e.g., with male or female threads. Preferably, the ports or fittings are constructed to facilitate securing one or more samples of the fluid that is to be stored in the containers (e.g., a tailgate sample).
Further still, the corner 312 nearest the container-emptying port of each container 302 is suitably chamfered, i.e., angled relative to the planes of the nearest end-wall of the container 302 and the upper wall of the container 302. This chamfer feature facilitates emptying of the container 302 when liquid product is to be removed from it in terms of physically handling or manipulating the container as well as minimizing residual fluid that is unable to be removed completely from the container.
Thus, given these various structural features, containers constructed according to certain embodiments of the invention may not be perfectly prismatic. Rather, for purposes of the invention, it is sufficient for the containers to be essentially parallelepiped in construction, with the most salient feature being that the major walls of each of the containers in a set are spaced apart by the same distance w, such that the freeze-path length associated with each of the containers in the set is essentially the same.
As indicated above, maintaining a fairly consistent freeze-path length from container to container provides better control over the freezing process, with consequent reduction or elimination of variation in cryoconcentration within a given container and from container to container. It also helps avoid container rupture. In this regard, containers according to the invention are designed to reduce or eliminate cryoconcentration and container breakage by causing the liquid product that is adjacent to the major walls and the bottom wall of the containers to freeze first, with the liquid/solid interface progressing inwardly and upwardly (generally like a “U,” with gradually thickening lines) when a cooling medium is flowed past both major walls and the bottom wall of the container simultaneously, or by causing the liquid product that is adjacent to one of the major walls and the bottom wall of the containers to freeze first when a cooling medium is flowed past one of the major walls. (The freeze-path length in the former case will be approximately one-half the container width, since there will be two freeze fronts that progress inwardly toward each other and meet generally in the middle of the container; the freeze-path length in the latter case will be essentially the width of the container.) This designed-to freeze dynamic is intended to avoid ice-bridging, i.e., the formation of a covering sheet of ice at the upper surface of the liquid product. Such ice-bridges tend to trap a “pocket” of liquid product in the middle of the container, which can cause the containers to bulge and break as the trapped liquid expands when freezing and then presses against the walls of the containers.
Therefore, to avoid the occurrence of ice-bridging, containers constructed in accordance with the invention may suitably be designed with an Ice Bridging Number (IBN) in mind. The Ice Bridging Number is a dimensionless parameter that can be thought of as relating the rate at which water freezes at the air-liquid interface above the product (i.e., at the bottom of the headspace above the liquid) to the rate of water displacement at the container walls, which is directly proportional to the rate of freezing along the container walls. (Leaving a portion of the container unfilled, i.e., with a small amount (e.g., 10% of the total fill capacity) of air above the liquid, limits heat transfer from, and therefore helps avoid initial freezing at, the upper surface of the liquid.) More particularly, we have defined the IBN as
where
Thus, if IBN is significantly greater than 1 (e.g., by an order of magnitude), then heat-transfer via the headspace above the water will strongly predominate and cause the top layer of water to freeze at a significantly faster rate than water is being displaced along the walls of the container, thereby leading to undesirable ice-bridging and an increased likelihood of container rupture. On the other hand, if IBN is significantly less than 1, then heat-transfer will occur predominantly through the walls of the container, and ice-formation will progress generally inwardly and upwardly, as illustrated in
By modeling the rates of heat-transfer through the walls of the containers and through the headspace above the surface of the liquid as functions of surface areas that are exposed to a cooling medium; flow-rates of the cooling medium past the walls of the container; specific heat capacity of the cooling medium; any effect the thickness and/or material of the walls of the container may have; and other thermodynamic variables that will be apparent to those having skill in the art, suitable dimensions (length, width, height) of containers according to the invention—which dimensions determine surface areas over which freezing occurs—can be determined consistent with the principle that IBN should be substantially less than 1.
By way of example, we have found empirically that the critical value for thin-walled containers (0.15″ wall thickness) we have been working with is approximately 0.6. Presumably, however, the actual critical value for a given system of containers will depend on container wall-thickness, container shape (i.e., length-to-height ratios), and potentially other factors.
Furthermore, to reduce the amount of heat transfer out of the liquid product that occurs through the headspace, thereby further reducing the risk of ice-bridging, it may be useful to cover the upper portion of each of the containers with an insulating shroud or cap 614, illustrated in
For example, of the containers that we have found to perform acceptably well in terms of uniform freezing performance across various sizes (or that we believe will perform acceptably well across various sizes), a set may include containers designed to hold nominal volumes of 100, 25, and 12.5 liters of fluid. In practice, these containers will have an actual working volume in the freezing process of 75, 16, and 7 liters, respectively. In accordance with the invention, all such containers suitably may be 127 mm (5 inches) wide (inside dimension), so as to provide an essentially uniform freeze-path length across all such containers. As for length, height, and fill levels, a container designed to hold up to 100 liters of fluid may suitably be 1150 mm long and 700 mm high, with a specified fill level of 570 mm and a headspace height 130 mm. A container designed to hold up to 20 liters of fluid suitably may be 560 mm long and 290 mm high, with a specified fill level of 260 mm and a headspace height of 30 mm. Furthermore, smaller containers fabricated from high density polyethylene may have a wall thickness of 3.8 mm (0.15 inch), whereas containers designed to hold 50 liters of fluid or more, also fabricated from high density polyethylene, have a wall thickness of 6.4 mm (0.25 inch) to increase the strength and prevent bowing of the walls due to the increased static pressure of the fluid within the containers. (Such bowing would impede controlled cooling behavior both directly, by causing the freeze path length to vary over the height of the container, and indirectly, by interrupting or interfering with the flow of the cooling medium past the containers at the location of the bowing.)
Use of containers as per the invention is illustrated in
Once the containers have been filled, they may be transferred to a specially configured freezing pallet, as illustrated in
To facilitate secure holding of the containers 802, the sidewalls 834 of each end-block formation 830 are spaced apart by a distance that is essentially the same as the width w of the containers, or just a slight bit more. Additionally, pairs of end-block formations 830 are positioned across from each other at opposite ends of the support platform 828, with their end walls 832 spaced apart from each other by a distance that is essentially the same as the length of the containers 802 that are to be supported by the freezing pallet 826 or just a slight bit more. The end-block formations 830 are arranged so that their respective U-shaped channels face each other and define container-receiving “slots” or spaces on the freezing pallet 826.
As further illustrated in
As noted above, the end-block formations are spaced apart from each other so as to define a container-receiving slot that is as long as the containers 802, 902 that are to be frozen, as illustrated in
Once a freezing pallet has been loaded with containers of liquid to be frozen, the pallet and containers may be transferred into a refrigeration chamber, e.g., the freezing chamber 1144 of a blast freezer 1146 as illustrated in
The freezing chamber is then closed and a cooling medium—e.g., air that typically is cooled to between −20° C. and −80° C. or liquid nitrogen below −80° C. (−20° C. to −196° C.) is circulated within the freezing chamber 1244, as illustrated in
Finally, it should be noted that the uniform width of the containers, which leads to uniform freeze-path length and uniform freezing performance across all containers, will also contribute to uniform thawing performance when the frozen drug product is subsequently to be used. Furthermore, it may be the case that the blast freezer includes heating elements, so that the same apparatus and facilities used to freeze the pharmaceutical material can be used to thaw the frozen pharmaceutical material, by flowing warmed air past the containers.
To enhance thawing of the frozen material, it may be desirable to agitate the material inside the containers as it is thawing. For example, as illustrated in
The foregoing disclosure is only intended to be exemplary of the methods and products of the present invention. Departures from and modifications to the disclosed embodiments may occur to those having skill in the art. The scope of the invention is set forth in the following claims.
| Number | Date | Country | |
|---|---|---|---|
| 62378800 | Aug 2016 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16326958 | Feb 2019 | US |
| Child | 17545118 | US |
