U.S. patent application number 16/326958 was filed with the patent office on 2019-06-27 for container system and method for freezing and thawing a liquid product.
This patent application is currently assigned to Merck Sharp & Dohme Corp.. The applicant listed for this patent is Merck Sharp & Dohme Corp.. Invention is credited to Robert Ian ALPERN, Matthew H. FLAMM, Anthony FLAMMINO, Jeffrey Charles JOHNSON, Joseph W. LOCURCIO, Scott MCFEATERS, Mark Anton PETRICH, John H. ROOSA, JR..
Application Number | 20190191693 16/326958 |
Document ID | / |
Family ID | 61245257 |
Filed Date | 2019-06-27 |
![](/patent/app/20190191693/US20190191693A1-20190627-D00000.png)
![](/patent/app/20190191693/US20190191693A1-20190627-D00001.png)
![](/patent/app/20190191693/US20190191693A1-20190627-D00002.png)
![](/patent/app/20190191693/US20190191693A1-20190627-D00003.png)
![](/patent/app/20190191693/US20190191693A1-20190627-D00004.png)
![](/patent/app/20190191693/US20190191693A1-20190627-D00005.png)
![](/patent/app/20190191693/US20190191693A1-20190627-D00006.png)
![](/patent/app/20190191693/US20190191693A1-20190627-D00007.png)
![](/patent/app/20190191693/US20190191693A1-20190627-D00008.png)
![](/patent/app/20190191693/US20190191693A1-20190627-D00009.png)
![](/patent/app/20190191693/US20190191693A1-20190627-D00010.png)
View All Diagrams
United States Patent
Application |
20190191693 |
Kind Code |
A1 |
JOHNSON; Jeffrey Charles ;
et al. |
June 27, 2019 |
Container System and Method for Freezing and Thawing a Liquid
Product
Abstract
Container system and method for freezing (and subsequently
thawing) a liquid such as a drug substance, such that all
containers in a set have a uniform width, hence uniform freeze-path
length, in the widthwise direction and perpendicular to major walls
of the containers, irrespective of the particular length, height,
and volumetric capacity of the various containers in the set. This
leads to uniform freezing performance and thereby reduces
cryoconcentration. The system also eliminates or reduces
ice-bridging, and the potential for containers rupturing during
freezing and thawing operations.
Inventors: |
JOHNSON; Jeffrey Charles;
(West Point, PA) ; FLAMMINO; Anthony; (Whitehouse
Station, NJ) ; PETRICH; Mark Anton; (West Point,
PA) ; MCFEATERS; Scott; (West Point, PA) ;
ROOSA, JR.; John H.; (Rahway, NJ) ; ALPERN; Robert
Ian; (Lansdale, PA) ; LOCURCIO; Joseph W.;
(Whitehouse Station, NJ) ; FLAMM; Matthew H.;
(West Point, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Merck Sharp & Dohme Corp. |
Rahway |
NJ |
US |
|
|
Assignee: |
Merck Sharp & Dohme
Corp.
Rahway
NJ
|
Family ID: |
61245257 |
Appl. No.: |
16/326958 |
Filed: |
August 21, 2017 |
PCT Filed: |
August 21, 2017 |
PCT NO: |
PCT/US2017/047714 |
371 Date: |
February 21, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62378800 |
Aug 24, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B65D 81/24 20130101;
A01N 1/0273 20130101; B65D 81/00 20130101; A01N 1/0268 20130101;
A01N 1/0263 20130101; A61J 1/00 20130101; B65D 81/027 20130101;
B65D 81/18 20130101 |
International
Class: |
A01N 1/02 20060101
A01N001/02 |
Claims
1. 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 therein by the walls of the
container; wherein 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 respective container, the major walls of each
of the containers being spaced apart by a distance that defines a
width of the respective container; wherein the substance-receiving
cavity of at least one of the containers in the set has a first
volume and the substance-receiving cavity of at least another one
of the containers in the set has a second volume, which is
different from the first volume; wherein 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; and wherein the dimensions and/or geometry of each of the
containers in the set are selected so that liquid tends to freeze
within the containers along the walls of the containers at a
significantly faster rate than the liquid tends to freeze at an
upper, air/liquid interface surface thereof, whereby the occurrence
of ice-bridging is suppressed.
2. (canceled)
3. The set of containers according to claim 1, wherein the
dimensions of each of the containers in the set are selected so
that, for a given predetermined cooling medium and a given
predetermined liquid to be frozen, an ice bridging number (IBN) is
less than about 0.6.
4. The set of containers according to claim 3, wherein the
dimensions of each of the containers in the set are selected so
that, for the given predetermined cooling medium and the given
predetermined liquid to be frozen, the ice bridging number is
greater than about 0.1 and less than about 0.6.
5. A system for storing, freezing, transporting, and thawing a
liquid substance, comprising: a set of containers each having an
essentially parallelepiped configuration with a substance-receiving
cavity defined by the walls of the container, the walls of each
container in the set including a pair of major walls on opposite
sides of the container that define a length and a height of the
respective container and the major walls of each of the containers
in the set being spaced apart by a distance that defines a width of
the container; with the substance-receiving cavity of at least one
of the containers in the set having a first volume and the
substance-receiving cavity of at least another one of the
containers in the set having a second volume, which is different
from the first volume; and with all of the containers in the set
having the same width such that a freeze-path length associated
with each of the containers in the set is essentially the same; and
a container-support platform including 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 said containers on the
container-support platform, received within respective
container-receiving spaces, equally spaced from each other.
6. The system according to claim 5, wherein the dimensions and/or
geometry of each of the containers in the set are selected so that
liquid tends to freeze within the containers along the walls of the
containers at a significantly faster rate than the liquid tends to
freeze at an upper, air/liquid interface surface thereof, whereby
the occurrence of ice-bridging is suppressed.
7. The system according to claim 5, wherein the dimensions of each
of the containers in the set are selected so that, for a given
predetermined cooling medium and a given predetermined liquid to be
frozen, an ice bridging number (IBN) is less than about 0.6.
8. The system according to claim 7, wherein the dimensions of each
of the containers in the set are selected so that, for the given
predetermined cooling medium and the given predetermined liquid to
be frozen, the ice bridging number is greater than about 0.1 and
less than about 0.6.
9. A method for storing and freezing a liquid substance,
comprising: introducing said liquid substance into a plurality of
containers selected from a set of containers, wherein each of the
containers in the set has an essentially parallelepiped
configuration with a substance-receiving cavity defined therein 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 respective container, the major walls
of each of the containers being spaced apart by a distance that
defines a width of the respective container; the
substance-receiving cavity of at least one of the containers in the
set has a first volume and the substance-receiving cavity of at
least another one of the containers in the set has a second volume;
and 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; disposing the containers into which
the liquid substance has been introduced 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 the
liquid-containing containers, by flowing a cooling medium through
spaces between adjacent containers.
10. The method of claim 9, further comprising insulating headspace
disposed above the upper surface of the liquid in each of the
containers while causing the liquid to freeze.
11. The method of claim 9, wherein liquid-containing containers
with the same volumetric capacities are disposed on the same
container-support platform and subjected to freezing
simultaneously.
12. The method of claim 9, wherein liquid-containing containers
with different volumetric capacities are disposed on the same
container-support platform and subjected to freezing
simultaneously.
13. The method of claim 12, wherein multiple containers each having
a given volumetric storage capacity are assembled together to form
a cassette of containers that is disposed on the container-support
platform, which cassette of containers has an overall length and
height that is essentially the same as the length and height of a
single container having a greater volumetric storage capacity than
the volumetric storage capacity of each of said multiple
containers.
14.-16. (canceled)
17. A system for storing, freezing, transporting, and thawing a
liquid substance, comprising: a set of containers each having an
essentially parallelepiped configuration with a substance-receiving
cavity defined by the walls of the container, the walls of each
container in the set including a pair of major walls on opposite
sides of the container that define a length and a height of the
respective container and the major walls of each of the containers
in the set being spaced apart by a distance that defines a width of
the container, with all of the containers in the set having the
same width such that a freeze-path length associated with each of
the containers in the set is essentially the same; and a
container-support platform including 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 said containers on the
container-support platform, received within respective
container-receiving spaces, equally spaced from each other.
18. The system according to claim 17, wherein the dimensions and/or
geometry of each of the containers in the set are selected so that
liquid tends to freeze within the containers along the walls of the
containers at a significantly faster rate than the liquid tends to
freeze at an upper, air/liquid interface surface thereof, whereby
the occurrence of ice-bridging is suppressed.
19. The system according to claim 17, wherein the dimensions of
each of the containers in the set are selected so that, for a given
predetermined cooling medium and a given predetermined liquid to be
frozen, an ice bridging number (IBN) is less than about 0.6.
20. The system according to claim 19, wherein the dimensions of
each of the containers in the set are selected so that, for the
given predetermined cooling medium and the given predetermined
liquid to be frozen, the ice bridging number is greater than about
0.1 and less than about 0.6.
21. A method for storing and freezing a liquid substance,
comprising: introducing said liquid substance into a plurality of
containers selected from a set of containers, wherein each of the
containers in the set has an essentially parallelepiped
configuration with a substance-receiving cavity defined therein 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 respective container, the major walls
of each of the containers being spaced apart by a distance that
defines a width of the respective container; and 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; disposing the containers into which the
liquid substance has been introduced 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 the
liquid-containing containers, by flowing a cooling medium through
spaces between adjacent containers.
22. The method of claim 21, further comprising insulating headspace
disposed above the upper surface of the liquid in each of the
containers while causing the liquid to freeze.
23. The method of claim 21, wherein liquid-containing containers
with the same volumetric capacities are disposed on the same
container-support platform and subjected to freezing
simultaneously.
24. The method of claim 21, wherein liquid-containing containers
with different volumetric capacities are disposed on the same
container-support platform and subjected to freezing
simultaneously.
25. The method of claim 24, wherein multiple containers each having
a given volumetric storage capacity are assembled together to form
a cassette of containers that is disposed on the container-support
platform, which cassette of containers has an overall length and
height that is essentially the same as the length and height of a
single container having a greater volumetric storage capacity than
the volumetric storage capacity of each of said multiple
containers.
26.-28. (canceled)
29. A method for thawing a frozen liquid substance, comprising:
disposing on a container-support platform a plurality of containers
containing therein an amount of said frozen liquid substance, with
the containers equally spaced from each other; and causing the
frozen liquid substance contained within the containers 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; wherein 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 has a pair of
major walls on opposite sides of the container that define a length
and a height of the respective container, the major walls of each
of the containers being spaced apart by a distance that defines a
width of the respective container; 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; and all of the containers have
the same width to promote uniformity of thawing.
30. The method of claim 29, further comprising mechanically
agitating the substance while it is thawing.
31. The method of claim 30, wherein the substance is mechanically
agitated by rocking the liquid-containing containers in a
longitudinal direction so that liquid container therein moves back
and forth, from one end of each container to the opposite end of
each container.
32.-34. (canceled)
Description
FIELD OF THE INVENTION
[0001] 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.
BACKGROUND OF THE INVENTION
[0002] 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.
[0003] 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.
[0004] 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.
[0005] 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.
SUMMARY OF THE INVENTION
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] 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.
[0011] 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.
[0012] 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.
[0013] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] These and other features of the invention will become
clearer from the detailed description below as well as the
drawings, in which:
[0015] FIGS. 1 and 2 are diagrammatic representations of a set of
containers in accordance with the invention;
[0016] FIGS. 3A and 3B are perspective views showing a container
according to the invention from two slightly different angles;
[0017] FIG. 4 is schematic diagram illustrating the energy balance
associated with the freezing process within containers according to
the invention;
[0018] FIG. 5 is a schematic diagram illustrating the progression
over time of liquid freezing within a container in accordance with
the invention;
[0019] FIG. 6 is a perspective view of a headspace-insulating
shroud for use in accordance with a container according to the
invention;
[0020] FIG. 7 is a diagrammatic view illustrating containers
according to the invention being transported on a wheeled
pallet;
[0021] FIGS. 8, 9A, 9B, and 10 are perspective views illustrating
containers of various sizes supported on a freezing pallet in
accordance with the invention;
[0022] FIG. 11 is a schematic diagram illustrating a pallet of
containers being loaded into a blast-freezer in accordance with the
invention;
[0023] FIGS. 12A-12C illustrate liquid product being frozen in a
blast-freezer using containers in accordance with the invention;
and
[0024] FIG. 13A is a perspective view illustrating a thaw-enhancing
rocker assembly, with FIGS. 13B and 13C being side views thereof
illustrating the rocker assembly in operation.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0025] 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.
[0026] A set of containers 100 constructed in accordance with an
embodiment of the invention is illustrated in FIGS. 1 and 2. As
illustrated in FIG. 1, the set of containers 100 may include
containers 102a, 102b, 102c, and 102d, each of which is formed by a
set of walls and each of which has a different internal volume (for
receiving a liquid product that is to be frozen and subsequently
thawed), e.g., 100 liters, 50 liters, 25 liters, and 12.5 liters,
respectively. Although the set of containers 100 illustrated in
FIG. 1 has four different volumetric sizes, it will be understood
and appreciated by those skilled in the art that a set of
containers constructed in accordance with the invention may consist
of containers with as few as two different volumetric sizes, or the
set may consist of containers with five or even more different
volumetric sizes. Furthermore, although just one container of each
volumetric size is shown in FIG. 1, it will be appreciated that, in
practice, a large plurality (e.g., on the order of tens or even
hundreds) of containers of a given volumetric size may be employed
in a given processing facility.
[0027] 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.
[0028] Each of the containers in the set of containers 100 has a
length l in the x-direction, as illustrated, and a height h in the
y-direction, as illustrated. The length l 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 FIG. 1, but spaced from the walls 104 in the -z
direction--constitute the major walls of each of the containers in
the set of containers 100. In other words, the major walls are
those that have the greatest individual surface areas.
[0029] 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.
[0030] As further illustrated in FIG. 1, the volume of the
containers in the set of containers 100 may exhibit a series of
halving or other fractioning as one progresses from the largest
volumetric size to the smallest volumetric size of the individual
containers 102a, 102b, 102c, and 102d in the set of containers 100.
For example, as illustrated in FIG. 1, the containers 102a, 102b,
102c, and 102d have volume capacities of 100 liters, 50 liters, 25
liters, and 12.5 liters, respectively. This may be achieved by
halving the height of the first container 102a in the set to
"obtain" the height of the second container 102b in the set;
halving the length of the second container 102b in the set to
"obtain" the third container 102c in the set; and halving the
height of the third container 102c in the set to "obtain" the
fourth container in the set. Other integer-fractions (i.e.,
fractions 1/n, where n is an integer) such as 1/3 or 1/4 could also
be used to sequentially reduce the volume of successive sizes of
the containers in a set of containers. In all cases, however, the
width of the containers 102a, 102b, 102c, and 102d remains the
same, as noted above.
[0031] 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 FIG. 2 (e.g., via a supporting
"cassette" framework, not illustrated), where all of the groups
G.sub.1, G.sub.2, and G.sub.3 have the same overall or composite
length and height as the volumetrically largest container 202a in
the set. Additionally, although all of the containers in each of
the groups G.sub.1, G.sub.2, and G.sub.3 are the same size, it is
possible for a given group G to include different sizes of
containers while still maintaining the same overall or composite
length and height of the group G. For example, the top two
containers 202d in the left-hand column of containers in group
G.sub.3 could be replaced with a single container 202c, which has
twice the height but the same length as the containers 202d. Or,
for example, the top two rows of containers 202d (i.e., four
containers) in group G.sub.3 could be replaced by a single
container 202b. (The specific number of containers that could be
replaced by a larger container will, of course, depend on the
various integers n in the various fractional relationships between
consecutively sized containers.) By maintaining a uniform length
and height of the various groups of containers that are to be
processed (i.e., frozen or thawed), different sizes of containers
can be mixed together and processed at the same time while
maintaining the same degree of freezing and thawing control over
all of the containers being processed.
[0032] As illustrated schematically in FIGS. 1 and 2, the various
containers are shown as perfectly rectangular prisms. In practice,
however, this will likely not be the case. Rather, as illustrated
in FIGS. 3A and 3B, the containers 302 may have various features to
facilitate filling, emptying, and handling the containers at
various steps in a manufacturing process.
[0033] 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.
[0034] 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).
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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
IBN = m . hs m . liq = rate of headspace freezing rate of liquid
displacement , or IBN = Q . hs Q . liq .beta. ##EQU00001##
[0039] where [0040] {dot over (Q)}.sub.hs=rate of heat transfer in
headspace; [0041] {dot over (Q)}.sub.liq=rate of heat transfer at
liquid/container interface; and
[0041] .beta. = Expansion coefficient of phase transition = .DELTA.
.rho. .rho. ##EQU00002##
[0042] (Various parameters used in these equations are illustrated
in FIG. 4, which shows the energy balance associated with the
freezing process within containers according to the invention).
[0043] 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 FIG. 5, with the last point to freeze
being located generally centrally at the top of the solution. This
is the preferred dynamic or modality for freezing of the liquid
drug solution, as it reduces the likelihood that ice bridging, and
hence rupture, will occur.
[0044] 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.
[0045] 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.
[0046] 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 FIG. 6, once the
containers have been filled and prior to freezing of the liquid
product. The shroud or cap 614 may be fabricated from insulating
material such as high-density polyethylene or other plastic or foam
material, which has low thermal conductivity. The height h.sub.c of
the cap may be essentially the same as the height of the unfilled
headspace that exists in the container when the container is filled
to its particular, specified amount, while the length and width of
the shroud 614 may suitably be slightly larger than the length and
width of a corresponding container with which the shroud 614 is
designed to be used (e.g., about 0.25 inch longer in each
dimension). Furthermore, a flexible sealing lip 617 can be provided
around the periphery of the open, lower side of the shroud 614 to
engage the walls of the container, thereby at least partially
sealing the airspace between the container and the walls of the
shroud 614 so as to form an insulating pocket of air around the top
of the container that limits heat transfer via the headspace. Use
of such a shroud or cap 614 may be particularly important as in
practice we have found that IBN is strongly a function of the
container headspace (i.e., the amount of heat transfer that occurs
through the headspace), and use of a shroud significantly enhances
control over freezing behavior.
[0047] 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.)
[0048] Use of containers as per the invention is illustrated in
FIGS. 7-8, 9A, 9B, 10-12, and 13A-13C. As illustrated in FIG. 7, a
wheeled dolly 716 may be provided to facilitate handling (e.g.,
filling) of containers 702 per the invention--particularly those
having larger volumes. Suitably, the dolly 716 has an inclined
support platform 718, which supports the containers 702 at an angle
on the order of 10.degree. relative to horizontal. This inclination
allows each of the containers 702 to be filled via the fitting 720
at the upper left-hand corner of the container 702, while air
inside the container that is displaced by rising liquid can exit
through a vent valve (not illustrated) located in the upper
right-hand corner 722 of the container 702, which will remain above
the surface of the liquid as it rises.
[0049] Once the containers have been filled, they may be
transferred to a specially configured freezing pallet, as
illustrated in FIGS. 8, 9A, 9B, and 10. (As mentioned above,
transfer may be effected using a lifting manipulator that has pins,
which engage with or extend through the apertures 806 in the
containers.) The freezing pallet 826 has a support platform 828,
with a number of end-block formations 830 extending from it. Each
of the end-block formations has an upright end wall 832 and a pair
of sidewalls 834 that are parallel to each other and perpendicular
to the end wall 832. Together, the end wall 832 and sidewalls 834
of each end-block formation define a generally U-shaped channel
into which a container 802 fits in an upright, standing position.
To expedite freezing of the liquid in the containers 802, the
support platform 828 and the end-block formations 830 suitably are
made from metal with high heat-conductivity, e.g., aluminum, to
facilitate heat transfer and freezing at the bottoms of the
containers.
[0050] 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.
[0051] As further illustrated in FIG. 8, and as better illustrated
in FIGS. 9A and 9B, the end-block formations 930 are positioned so
as to hold adjacent containers 902 equally spaced from each other,
i.e., so that the space 936 between adjacent containers is uniform.
This is to help ensure uniformity of freezing of the liquid within
all containers on a given freezing pallet 926. Furthermore, the
inter-container spacing 936 is suitably selected so as not to
impede the flow of cooling medium between the containers 902, given
flow rates, density, and heat-absorption capabilities of the
cooling medium that is to be used.
[0052] 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 FIGS. 8, 9A, and 9B. As illustrated in FIG. 2 and
addressed above, however, multiple smaller containers can be
secured together in an arrangement with an overall size and shape
that is essentially the same as one of the larger containers. Thus,
as illustrated in FIG. 10 by way of example, four smaller
containers 1002', each having a length and a height that is
one-half the length and height of a larger container 1002 (but the
same width w), can be secured together by means of a frame 1038
that surrounds and secures together the four smaller containers
1002'. In particular, the frame 1038 extends around the periphery
of the "cassette" formed by all four of the smaller containers
1002', and side enclosure members 1040--only one of which is
illustrated in FIG. 10--can be attached to the frame on both sides
of the containers to hold them securely in place within the
cassette. In this manner, smaller containers of liquid can be
frozen using the same freezing pallet 1026 that larger containers
use, and different sizes of containers can be frozen at the same
time using the same pallet 1026.
[0053] 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 FIGS. 11 and 12A-12C. For
example, the container-bearing pallet may be lifted via a mobile
pallet-lifting device 1148. The pallet-lifting device is then
guided straight toward the freezing chamber 1144 (i.e., in a
direction perpendicular to the direction of flow of the cooling
medium through the freezing chamber 1144) by means of guide rails
1150 extending from the blast freezer assembly, which guide rails
1150 are engaged by roller-bearing arms 1152 that extend forward
from the pallet-lifting device 1148. The freezing pallet 1126, with
the containers 1102 supported on it, is then lowered onto
supporting platform 1154 within the freezing chamber 1144 and the
pallet-lifting device 1148 is backed away from the blast freezer,
thereby leaving the containers 1102 in the freezing chamber 1144
with equal space between them.
[0054] The freezing chamber is then closed and a cooling
medium--e.g., air that typically is cooled to between -20.degree.
C. and -80.degree. C. or liquid nitrogen below -80.degree. C.
(-20.degree. C. to -196.degree. C.) is circulated within the
freezing chamber 1244, as illustrated in FIG. 12. The cooling
medium flows between and along the containers 1102, causing the
liquid contained therein to freeze in a uniform, well controlled
manner. Once the containers have been frozen--the time for complete
freezing may be determined empirically and may vary depending on
the particular liquid being frozen, the particular cooling medium
being used, the temperature of the cooling medium being used, the
flow rate of the cooling medium past the containers, and various
other factors--they can be removed from the freezing chamber and
transferred to cold storage for use later on. 1246 represents a
mechanical skid; 1248 represents gaskets; 1250 represents a
compression latch with inside release; 1252 represents fan motors;
1254 represents a removable base plate; 1256 represents a steel
frame; 1258 represents a sheet metal removable from interior to
allow for the removal of the coil and fans; and 1260 represents a
fan.
[0055] 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.
[0056] 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 FIGS. 13A-13C, a motorized
lifting device 1356 may be provided adjacent the container support
platform 1354, with a lifting arm 1358 extending beneath the
support platform 1354. The lifting device 1356 is positioned such
that one end 1354a of the support platform 1354 is raised, e.g., by
about 2 inches, while the other end 1354b of the support platform
1354 stays put, with the support platform 1354 pivoting about the
end 1354b in a cyclical manner. In this manner, fluid in the
containers (not illustrated), which have their lengths oriented
left-to-right as the assembly is illustrated in FIGS. 13B and 13C,
is caused to slosh back and forth along the lengths of the
container as the frozen product thaws. So rocking the containers
significantly reduces the time it takes for the containers of
product to thaw and helps ensure uniformity of the product within
the containers, as well as from container to container, once it has
been thawed.
[0057] 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.
* * * * *