U.S. patent application number 11/252926 was filed with the patent office on 2006-02-16 for enhanced thawing of biopharmaceutical solutions using oscillatory motion.
This patent application is currently assigned to Integrated Biosystems, Inc.. Invention is credited to Richard Wisniewski.
Application Number | 20060032607 11/252926 |
Document ID | / |
Family ID | 22474018 |
Filed Date | 2006-02-16 |
United States Patent
Application |
20060032607 |
Kind Code |
A1 |
Wisniewski; Richard |
February 16, 2006 |
Enhanced thawing of biopharmaceutical solutions using oscillatory
motion
Abstract
Disclosed are methods for thawing frozen biopharmaceutical
solutions including providing a container that contains a
biopharmaceutical solution, at least a portion of the
biopharmaceutical solution being frozen, providing an oscillatory
driver coupled to the biopharmaceutical solution; providing a heat
flux into the biopharmaceutical solution; and inducing oscillatory
motion of the biopharmaceutical solution via oscillatory motion of
the oscillatory driver to accelerate thawing, compared to
motionless thawing, of the portion of the biopharmaceutical
solution that is frozen. Also disclosed are devices for thawing
frozen biopharmaceutical solutions.
Inventors: |
Wisniewski; Richard; (San
Mateo, CA) |
Correspondence
Address: |
HESLIN ROTHENBERG FARLEY & MESITI PC
5 COLUMBIA CIRCLE
ALBANY
NY
12203
US
|
Assignee: |
Integrated Biosystems, Inc.
Napa
CA
94558
|
Family ID: |
22474018 |
Appl. No.: |
11/252926 |
Filed: |
October 18, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09579846 |
May 25, 2000 |
|
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|
11252926 |
Oct 18, 2005 |
|
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60136708 |
May 28, 1999 |
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Current U.S.
Class: |
165/47 ;
165/109.1 |
Current CPC
Class: |
B01F 2015/062 20130101;
B01F 11/0082 20130101; B01F 15/065 20130101; B01F 11/0025 20130101;
A61M 5/445 20130101; B01F 11/04 20130101; B01F 15/00915 20130101;
B01F 11/0022 20130101; A61M 1/0254 20140204; B01F 11/0094 20130101;
A61M 1/025 20130101 |
Class at
Publication: |
165/047 ;
165/109.1 |
International
Class: |
F24H 3/00 20060101
F24H003/00 |
Claims
1. A method for thawing frozen biopharmaceutical solutions
comprising: providing a container that contains a biopharmaceutical
solution, at least a portion of the biopharmaceutical solution
being frozen, providing an oscillatory driver coupled to the
biopharmaceutical solution; providing a heat flux into the
biopharmaceutical solution; and inducing oscillatory motion of the
biopharmaceutical solution via oscillatory motion of the
oscillatory driver to accelerate thawing, compared to motionless
thawing, of the portion of the biopharmaceutical solution that is
frozen.
2. The method of claim 1, wherein the oscillatory motion of the
oscillatory driver is harmonic motion.
3. The method of claim 1, wherein the oscillatory motion of the
oscillatory driver is disharmonic motion.
4. The method of claim 1, wherein an amplitude of the oscillatory
motion of the oscillatory driver ranges from about from about
0.0002 mm to about 10,000 mm.
5. The method of claim 2, wherein an amplitude of the oscillatory
motion of the oscillatory driver ranges from about more preferably
from about 0.015 mm to about 350 mm.
6. The method of claim 1, wherein a frequency of the oscillatory
motion of the oscillatory driver ranges from about 0.01 Hz to about
20 GHz.
7. The method of claim 4, wherein a frequency of the oscillatory
motion of the oscillatory driver ranges from about 0.1 Hz to about
1 kHz.
8. The method of claim 5, wherein a frequency of the oscillatory
motion of the oscillatory driver ranges from about 0.4 Hz to about
40 Hz.
9. The method of claim 1, wherein the oscillatory motion of the
oscillatory driver is induced by inducing oscillatory motion of the
container.
10. The method of claim 1, wherein the oscillatory motion of the
oscillatory driver is induced by inducing oscillatory motion of the
portion of the biopharmaceutical solution that is frozen.
11. The method of claim 1, wherein the oscillatory motion of the
oscillatory driver is induced by inducing oscillatory motion of an
unfrozen portion of the biopharmaceutical solution.
12. A device for accelerated thawing of a biopharmaceutical
solution comprising a container configured to contain the
biopharmaceutical solution, wherein at least a portion of the
biopharmaceutical solution is frozen; a heating element, coupled to
the container, that provides heat flux into the container; and an
oscillatory driver capable of being coupled to the
biopharmaceutical solution, for inducing oscillatory motion of the
biopharmaceutical solution to accelerate thawing, compared to
motionless thawing, of the portion of the biopharmaceutical
solution that is frozen.
13. The device of claim 12, wherein the container comprises a
thermal jacket.
14. The device of claim 12, wherein the container comprises an
agitator.
15. The device of claim 12, wherein the oscillatory driver is
mechanically coupled to the container.
16. The device of claim 12, wherein the oscillatory driver is
magnetically coupled to the container.
17. The device of claim 12, wherein the oscillatory driver is
coupled to an internal structure, and the internal structure is
located internally to the container.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Patent Application
Ser. No. 60/136,708, filed May 28, 1999.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to thawing of biopharmaceutical
solutions, more particularly this invention relates to enhanced
thawing of biopharmaceutical solutions using oscillatory
motion.
[0004] 2. Description of Related Art
[0005] Freezing and thawing of biological materials, particularly
in the form of biopharmaceutical solutions, are useful as an
intermediary processing steps during production operations, or for
preservation. Until now only small individual quantities of
materials, or solutions, have been successfully processed. These
quantities may be contained in vials, straws, test tubes, bottles,
bags, pouches, trays, etc. However, the materials handling costs,
possibility of small container mix-ups, and dangers of
contamination during processing and handling such small quantities
meant that freezing and thawing processes were disfavored unit
operations. Processing larger individual quantities would reduce or
eliminate the handling or contamination problems, but such
processing has met with very limited success.
[0006] A significant contributor to the final product quality is
the thawing step. However, in conventional techniques, the thawing
time is undesirably long. In fact, lengthy thawing times, combined
with layering and cryoconcentration effects during freezing, leads
to significant product degradation. While in small individual
quantities the thawing step could be performed relatively rapidly
in a controlled way, the thawing of large individual quantities was
plagued by extensive thawing times and product degradation.
[0007] Accordingly, what is needed is a method for thawing
biopharmaceutical materials, particularly biopharmaceutical
solutions, in large quantities, with very good final product
quality.
SUMMARY OF THE INVENTION
[0008] In an aspect, the invention relates to methods for thawing
frozen biopharmaceutical solutions comprising providing a container
that contains a biopharmaceutical solution, at least a portion of
the biopharmaceutical solution being frozen, providing an
oscillatory driver coupled to the biopharmaceutical solution;
providing a heat flux into the biopharmaceutical solution; and
inducing oscillatory motion of the biopharmaceutical solution via
oscillatory motion of the oscillatory driver to accelerate thawing,
compared to motionless thawing, of the portion of the
biopharmaceutical solution that is frozen.
[0009] In another aspect, the invention relates to devices for
accelerated thawing of a biopharmaceutical solution comprising a
container configured to contain the biopharmaceutical solution,
wherein at least a portion of the biopharmaceutical solution is
frozen; a heating element, coupled to the container, that provides
heat flux into the container; and an oscillatory driver capable of
being coupled to the biopharmaceutical solution, for inducing
oscillatory motion of the biopharmaceutical solution to accelerate
thawing, compared to motionless thawing, of the portion of the
biopharmaceutical solution that is frozen.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 shows a side view of a container according to the
invention.
[0011] FIGS. 2A-B show a cross-sectional view of devices according
to the invention.
[0012] FIG. 3 shows a cross sectional view of a device according to
the invention.
[0013] FIG. 4 shows a cross sectional view of a device according to
the invention.
[0014] FIG. 5 shows a cross sectional view of a device according to
the invention.
[0015] FIG. 6A shows a cross sectional view of device according to
the invention.
[0016] FIGS. 6B-D show paths of motion tables according to the
invention.
[0017] FIG. 7 shows an elevation of a device according to the
invention.
[0018] FIG. 8 shows a cross-sectional view of a device according to
the invention.
[0019] FIGS. 9A-D show various devices according to the invention,
together with embodiments of tracks on which the devices move.
[0020] FIGS. 10A-B shows an elevation of a device according to the
invention, together with a representation of the oscillatory motion
of the device.
[0021] FIGS. 11A-L show cross-sections of various containers
according to the invention.
[0022] FIGS.12A-P show overhead elevations of various containers
according to the invention.
[0023] FIGS. 13A-H show overhead elevations of various containers
according to the invention.
[0024] FIGS. 14A-L show overhead elevations of various containers
according to the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The inventor has unexpectedly discovered that inducing
oscillatory motion of a biopharmaceutical solution, at least a
portion of which is frozen, accelerates thawing of the
biopharmaceutical, compared to motionless thawing.
[0026] Thawing rates may be accelerated by generation of movement
of partially-thawed solid-liquid mixture comprising a
biopharmaceutical solution against heat transfer surfaces in a
container, preferably a container configured to contain, freeze,
and/or thaw a biopharmaceutical solution. This movement may be
generated wherein a liquid is moving against the heat transfer
surfaces and a solid in the liquid is moving against the liquid and
against the heat transfer surfaces. The patterns of liquid and
solid movement may or may not be similar (the floating solid mass
dynamics inside the vessel may or may not be similar to the liquid
mass dynamics). The dynamic movements of liquid and solid versus
the container and its internal structures may turbulize the liquid
phase, affect the boundary layer at the heat transfer surfaces and
at the melting solid surface, and mix the liquid (important for
liquid phasehomogeneity). As a result, the heat transfer between
the heated surfaces and liquid and solid phases of the
biopharmaceutical solution is significantly enhanced. Increased
heat transfer rate leads to very rapid thawing. Rapid thawing
reduces or eliminates product degradation present in conventional,
slow thawing, processes.
[0027] A structure useful in the practice of this invention is that
of L. Quan et al., Effects of Vibration on Ice Contact Melting
Within Rectangular Enclosures, Transactions of the ASME 120:518-520
(May 1998). However, the inventor notes that the Quan document does
not disclose use of vibration in the thawing of frozen
biopharmaceutical solutions; but only pure ice, which crystallizes
and melts differently than complex aqueous solutions, such as
biopharmaceutical solutions. Thus the Quan document neither teaches
nor suggests the present invention.
[0028] Motion of liquid and solid phases can be generated in a
variety of ways. An intensive relative motion of melting solid and
liquid phases is of interest. Therefore, the dynamics of those two
phases is of interest. An intensive mutual motion of these two
phases may further enhance the thawing rate by additional surface
melting via ablation. For example, movement of internal heat
transfer surfaces present in a container that contains a
biopharmaceutical solution or material of interest, while the
container remains stationary, may provide this intensive mutual
motion. Alternatively, this may be accomplished by mutual movement
of the vessel and the internal heat transfer surfaces or via
movement of the vessel with the internal heat transfer surfaces
attached to the vessel. Such an attachment may be rigid (permanent
fixing), or elastic (via springs, torsion bars, cables, etc.). In a
preferable embodiment, the container is driven and moves, while
internal structures, such as internal heat transfer structures, can
vibrate or oscillate according to their natural frequency. Thus,
the forced movement of the container is combined with the inner
heat transfer surfaces dynamics and the dynamic and dampening
characteristics of the liquid and solid free phases of the
biopharmaceutical solution in the container. In a preferred
embodiment, the inner structure(s) vibrates at natural frequency
imposing micromotion on the liquid phase. This micromotion is
transferred into the solid product through the liquid. A
macromotion is imposed upon the container, resulting in mutual
movement of liquid and solid phases and their relative movement
versus the container walls and internal structures. In such a way
the container and the internal heat transfer surfaces move
differently (a relative movement is induced) and the liquid and
solid phases move in another pattern. This generates high mixing
and turbulence rates in the liquid phase and a very high heat
transfer coefficient at the heat transfer surfaces and the
solid-liquid interface of the melting solid. As a result, the
thawing rate is very high.
[0029] A system according to the invention is shown in FIG. 1,
which shows wheeled container 102 and drivers 104 and 106 inducing
oscillatory motion of a biopharmaceutical solution within the
wheeled container. FIG. 2A shows finned heat exchanger 202 which is
driven around pivot 206 by driver 204. FIG. 2B shows the finned
heat exchanger of FIG. 2A in container 208, with pivot 206 and
driver 204 as discussed above. FIG. 3 shows container 202 which
contains frozen biopharmaceutical portion 204 in contact with
liquid biopharmaceutical portion 210, and frozen biopharmaceutical
portion 204 being coupled to driver 208 via rod 206. Rod 206 is
embedded in frozen biopharmaceutical portion 204. Frozen
biopharmaceutical portion 204 may be driven in various directions
by driver 208 to induce oscillatory motion.
[0030] Another embodiment is shown in FIG. 4, where frozen
biopharmaceutical portion 402 is driven in an up-and-down direction
406 or a rotational direction 408 by rod 404. In FIG. 5, frozen
biopharmaceutical portion 502, which is in free-floating contact
with liquid biopharmaceutical portion 504, is driven by driver 506.
Driver 506 sends pressure waves through liquid biopharmaceutical
portion 504 to move frozen biopharmaceutical portion 502 with an
oscillatory motion. In FIG. 6A, container 602 is coupled to motion
table 606. Motion table 606 can be moved, in linear directions, as
suggested in FIG. 6B, or in two dimensions, as suggested in FIGS.
6C-D, or even three dimensions. FIG. 7 shows container 702,
suspended by springs 704, and driven by drivers 706 and 708.
[0031] A basic harmonic motion (for instance, a sinusoidal
amplitude/frequency pattern) may be used to force the movement of
the inventive device or to practice the inventive method. Other
types of oscillatory movements also may be applied to take full
advantage of the dynamics of the container, its internal
structures, and the solid and liquid phases contained by it. The
oscillatory motion according to the invention may be disharmonic.
For example, the oscillatory motion may be in a form of
asymmetrical amplitude/frequency curves (induced, for example, by
preprogrammed movement of a driver coupled to the container). The
movement pattern may include asymmetrical sinusoidal waves,
sinusoidal waves with cut off tops/bottoms or cut sideways. Square
or triangular waves (symmetrical or asymmetrical sawtooth wave
shape) movement patterns may also be applied. Combinations and
variations of the above are also contemplated by the invention.
These patterns may have variations in amplitude and frequency, and
various combinations of waveforms, wherein each waveform may have
differing amplitude and frequency, may be used. For example, a
small sine wave may be superimposed over a large sine wave (same
with other oscillatory shapes beyond the sine waves--for example,
involving shapes as described above). In addition to amplitude and
frequency acceleration and deceleration patterns not only the
container with the internal structures but also the resulting
dynamics (acceleration and deceleration) of the liquid and solid
phases are considered. Movement periodicities may be selected given
consideration of the container and liquid and solid phase dynamics.
Aperiodic oscillatory motions may also be used. For example, a step
movement back and forth with varying periods of no motion in
between the step movements may be used. Orbital oscillatory motions
may also be used in the practice of this invention.
[0032] An example of oscillatory motion according to the invention
may be seen in FIGS. 9A-D. In FIG. 9A, a container 902 moves along
a bumpy track, where the bumps 904 are in phase with one another.
FIG. 9B shows the bumpy track in elevation, with bumps 904 being in
phase. FIG. 9C shows container 906 moving along a bumpy track,
where bumps 908 and 910 are out of phase with one another. FIG. 9D
shows the bumpy track in elevation, with bumps 908 and 910 being
out of phase.
[0033] The phenomena in the liquid-solid mixture caused by small
amplitude, high frequency motion (termed "micromotion") and large
amplitude, low frequency motion (termed "macromotion") may be very
different. Micromotion frequencies may preferably be greater than
200 Hz, with micromotion amplitudes preferably being less than 3.0
mm. Macromotion frequencies may preferably be 200 Hz or less, with
macromotion amplitudes preferably being 3.0 mm or greater. During
micromotion, there are small amplitude, high frequency waves in
liquid phase reaching the melting surface with the frozen mass
remaining steady, while, in macromotion, there is a significant
mutual macro movement between the solid and liquid phases.
[0034] The difference in physical phenomenona causes difference in
thawing mechanisms. For example, macromotion thawing may result in
improved product yield versus micromotion thawings. Micromotion
thawing might induce vibration of ice crystals in the frozen
product mass in relation to the softening glassy states around the
ice crystals. Since the biopharmaceutical or pharmaceutical
material may be embedded in those glassy states, the product may be
exposed to effects of mechanical and hydrodynamic shear forces.
These shear forces can be minimized by selection of the
biopharmaceutical solution solutes and their concentration. Low
amplitudes and high frequencies can make the ice crystals to
vibrate stationary positions, thus minimizing the effect of ice
crystal movement on the softened glassy state with embedded
product. The waves will be then transferred through the softened
glass states with the corresponding dampening effect of such glassy
states. The ice crystals will behave as almost elastic bodies
submerged into the soft, rubbery or viscous substance. The
dampening effect reduces the penetration of waves deeply into the
solid substance, although deeper in the solid where the
temperatures are lower, the glassy states are rigid and can
transfer waves as solids. Thus after the dampening of waves near
the surface, the waves may travel through the solid rigid body.
Such microscopic motion may disturb the ice matrix at the solid
product surface and rapidly release ice crystals from the softened
glassy states containing product. This may lead to a significant
increase in the thawing rate.
[0035] This is a process significantly different than thawing ice
only, as in Quan, where there are no softened glassy states among
the ice crystals near the frozen material surface. In pure ice the
crystals melt because of the liquid phase movement at the solid ice
surface. Here, the movement of ice crystals and the softened glassy
state (with the biopharmaceutical or pharmaceutical material in it)
can be carried deeply into the material (depending on the glass
transition temperature of the glassy/amorphous state; for example,
if sucrose has the glass transition temperature of -32 C and the
center of the frozen product is at about -45 C with the temperature
gradient towards the frozen mass surface being 45 C/100 mm then the
depth of such softened material (mixture of the ice crystals and
softened glassy states based on sucrose) will be approximately 71
mm e.g. majority of the solid material. At such large proportion of
softened material between the ice crystals, the block of solid
material may rapidly disintegrate if additional motion
(macromotion) is imposed. This process is unique for this
application and completely different than in the case of the ice
thawing where the direct wave effect on the ice crystals at surface
leading to some mechanical movement of ice crystal might only reach
to about one crystal diameter in depth.
[0036] Macromotion as described does not involve significant
deformation of the softened glassy states near the solid product
surface (and not at all deeper inside the product) and therefore,
well protects the biopharmaceutical product (such as for example,
proteins) since there is an absence of mechanical or hydrodynamic
shear in the softened glassy between the ice crystals. Macromotion
can gently rearrange the ice crystals in the softened glassy states
near the thawing solid surface and cause release and melting of ice
crystals and dissolution of the glassy states. Therefore, this
method is more versatile regarding the number of products,
formulations used (types of formulation solutes) and concentration
of formulation solutes.
[0037] A combination of micromotion and macromotion may be used in
the practice of the invention. For example, an oscillatory movement
may be constructed using a mechanical drive with a cam and a
connecting arm with superimposed vibrations using a vibrator
(electromagnetic, pneumatic, hydraulic, etc.) attached to the
container, its internal structures or its frame. Such an embodiment
is illustrated in FIGS. 10A-B. FIG. 10A shows container 1002 being
driven by driver 1004 with a large amplitude motion in combination
with driver 1004 which induces a vibration. The resultant waveform
is shown in FIG. 10B. The oscillatory motion may be continuously
adjusted to take consideration of change of proportion of solid and
liquid phases inside the container (the solid phase mass decreases,
while the liquid phase mass increases).
[0038] For harmonic oscillatory motion, the range of amplitudes and
frequency may be sufficiently broad so as to accelerate thawing
compared to motionless thawing. In a preferable embodiment, the
amplitude may range from about 0.0002 mm to about 10,000 mm, more
preferably from about 0.015 mm to about 350 mm, and the frequency
preferably from about 0.01 Hz to about 20 Hz, more preferably from
about 0.01 Hz to about 155 kHz, still more preferably from about
0.1 Hz to about 1 kHz, and most preferably from about 0.4 Hz to
about 40 Hz. These ranges may also cover superimposed harmonic
movements. An example of such superimposed harmonic movements
comprises an oscillatory motion with frequency of 0.5 Hz and the
amplitude of 30 mm with superimposed motion of amplitude of 0.5 mm
and frequency of 50 Hz.
[0039] Very often biopharmaceutical materials and/or solutions
contain sensitive biological macromolecules or cell products. The
biological macromolecule active product recovery level after the
freezing-thawing cycle depends on the thawing rate. Generally, very
rapid thawing of very small samples may provide higher yields of
the product than slower thawing. The rapid thawing rate is
typically of some significance in recovery of viable biological
macromolecules or cells. In many cases, biological products have a
strict upper temperature exposure limitation, meaning that the
amount of heat applied for thawing may have an upper limit, with
some safety margin imposed. For example, the heat transfer surface
temperature may be limited to 8.degree. C., 12.degree. C.,
18.degree. C., 25.degree. C. or 37.degree. C. depending on type of
product. (these being examples only, other temperatures can be used
between 0 C and, say 70 C). Sometimes, even lower temperatures are
required as an upper limit. Such a low temperature of heat transfer
surfaces imposes a limit upon the heat flux during thawing, because
the bulk liquid phase temperature may remain close to 0.degree. C.
during most of the thawing process. The liquid phase temperature
may increase above this level (e.g. 0.degree. C.) at the end of
thawing when the solid frozen mass disappears or its volume versus
volume of liquid becomes relatively insignificant. Having the bulk
liquid temperature close to 0.degree. C. during thawing is a
significant factor in protecting product quality during the thawing
time (some products should be stored in the liquid phase within a
temperature ranging between 0.degree. C. and 4.degree. C., or up to
8.degree. C.). During thawing, the temperature may be close to
0.degree. C. in bulk liquid, but in a boundary layer close to the
heat transfer surface the temperature in the liquid phase would
approach the temperature of that surface. During the stationary
thawing there may be some natural convection in the liquid phase,
causing some limited molecular exchange in the boundary layer
(product molecules or cells residence time may still be substantial
at the elevated temperatures). Such a natural convection may,
however, not sufficiently agitate the liquid phase, therefore no
homogenization is present and product stratification/layering may
occur within the liquid volume (for example, higher product
concentration may occur at the bottom). In the case of biological
cells or cellular fragments (product is a suspension), a settling
of suspended particles can occur. Inducing an oscillatory motion of
the biopharmaceutical solution, particularly the liquid phase, not
only homogenizes and mixes the liquid, but also turbulizes the
boundary layer causing product molecules (or cells) residence time
and exposure to elevated temperature in this layer to be
significantly reduced.
[0040] Heat may be added to the biopharmaceutical solution in a
variety of ways. Heat flux may be indirectly coupled to the
biopharmaceutical solution via heating jackets applied to the
container. Alternatively, heat flux may be directly coupled to the
biopharmaceutical solution by use of submersion heaters or other
submerged heat transfer surfaces, such as those disclosed in U.S.
patent application Ser. Nos. 08/895,782; 08/895,777, and
08/895,936, all filed on Jul. 17, 1997. Virtually any source of
heat flux in which the heat flux can be controlled, and which
source is suitable for use in biopharmaceutical applications, may
be conventionally used in the practice of this invention.
[0041] The lowest permitted temperatures of heat transfer surfaces
as mentioned above also limit the heat transfer driving force, e.g.
temperature difference heat transfer wall-frozen product
surface/bulk liquid temperature during thawing. The thawing rate
may be increased only by an increase in the heat transfer surface
area. The container/vessel designs as described in U.S. patent
application Ser. Nos. 08/895,782; 08/895,777, and 08/895,936, all
filed on Jul. 17, 1997, possess such a large surface area of heat
transfer surfaces. These documents, and all other documents cited
to herein are incorporated by reference as if reproduced fully
herein. Further increase in heat transfer and resulting increase in
the thawing rate may be accomplished by turbulization of the liquid
phase. This may change the heat transfer pattern in the vicinity of
the heat transfer surfaces from a laminar character to a turbulent
one. From heat transfer principles it is known that, at the same
temperature difference (limited for thawing of biological
products), the heat transfer rate (heat flux) can be significantly
increased by changing from laminar to turbulent patterns. The heat
flux increase between the liquid phase and the heat transfer
surface permits an increase of heat flux (container is well
insulated, thus energy balance can be assumed) from the melting
solid into the liquid phase. An increase in the heat flux melting
solid-liquid means faster thawing rate, e.g. faster removal of the
layers of the frozen product at the solid-liquid interface. An
overall effect is a significant shortening of the thawing time.
Oscillatory agitation with internal structures generates high rates
of liquid phase turbulization inside the container. Liquid phase
turbulization may cause more rapid release of ice crystals from the
soft glassy state matrix at the solid mass surface.
[0042] In certain cases, biopharmaceutical materials and/or
solutions may be shear sensitive and/or extensively foam when
agitated. The oscillatory movement may be then adjusted to reduce
the shear rate, and also wave motion on the liquid surface. Any
internals of the container may also be configured to eliminate
liquid flow over the structures--indeed the structures may contain
the liquid and solid phase movements in compartments shaped to not
only to enhance the heat transfer but also to reduce shear and
foaming.
[0043] Biopharmaceutical solutions according to the invention
comprise any conventional biopharmaceutical or pharmaceutical
material. In preferable embodiments, biopharmaceutical solutions
may comprise biological macromolecules such as proteins/enzymes,
peptides, DNA, RNA, amino acids, nucleic acids, growth factors,
coagulation factors, antibodies, and the like; biological cells or
cell fragments/components, including bacteria, fungi, yeast, single
cell organisms, mammalian (particularly human) cells, animal cells,
plant cells, organelles, cell membranes, or pieces of tissue and
the like; viral materials; organic or inorganic molecules or ions
including carbohydrates, antibiotics; or cell growth media.
Specific examples include blood and blood products (red and white
blood cells, plasma, human serum albumin, etc.), and two or more
phase emulsions comprising biological or pharmaceuticals materials.
A separate domain comprises the vesicles, liposomes and similar
membrane-based entities comprising biological components.
[0044] The inventive oscillatory motion also may include
consideration for relative movement of liquid and the solid
(melting) phases. This includes hydrodynamics of the liquid phase
and dynamics/hydrodynamics of the floating piece of frozen product.
For example, a fin (or fin/baffle) configuration inclined towards a
major direction of the oscillatory motion may cause streamlined
liquid flow along the fins and an elongated shape of the
compartment exposes large side surface areas of the melting mass to
this flowing liquid. Location of active heat transfer surfaces at
the ends of the elongated compartment may cause formation of larger
initial cavities there (more liquid contained there) and the
movement of the container causes flow of liquid from cavity to
cavity along the fins. In such a way the frozen mass is surrounded
by highly turbulent flowing liquid phase, with a concomitant
potential increase in thawing rates.
[0045] The oscillatory motion according to the invention may be
induced in a number of ways, using a number of oscillatory drivers
that are coupled to the biopharmaceutical solution. For example,
the oscillatory motion may be induced mechanically, such as by an
electric motor with a gear box and a cam (that may have various
profiles/movement characteristics) with an arm. Alternatively, the
oscillatory motion may be induced in a variety of ways, including
but not limited to by an electromagnetic solenoid (push/pull), a
spring loaded driver (one way movement forced), return by a spring
(spring characteristics may vary--linear or nonlinear), a hydraulic
drive (motor or cylinder), a pneumatic drive (motor, actuator or
cylinder), or a magnetic driver (coupling/decoupling using natural
or electro-magnets). The oscillatory drivers may be indirectly
coupled to the biopharmaceutical solution through the container or
another similar structure, or may be coupled directly to the
biopharmaceutical solution, or a combination of indirect and direct
coupling may be used.
[0046] An advantage of a electromagnetic driver is that the
operations may be automated: rolling the container in--coupling it
magnetically to the drive--processing--decoupling and rolling out.
The electromagnetic driver might also be combined with safety
features (decoupling if sensors detect someone approaching from a
wrong side, etc.). Coupling arms may be rigid or flexible or
contain an internal spring/elastic element to affect the movement
characteristics and affect the system dynamics. A cable drive may
also be applied (cable(s) pulling in both directions
alternatively).
[0047] Driver characteristics may be further altered by shaping any
rollers/wheels (for example, an off-center axis) or rails on which
the container moves back and forth. The rails can be slightly
curved sideways to add a side motion vector to the main movement or
also be vertically curved parallel arches or alternatively located
arches to add a vertical or/and sideways component to the major
movement. Placing springs/elastic elements (linear or nonlinear)
between the container and the rolling frame can further alter the
movement characteristics. In a preferable embodiment, end motion
elastic bumpers to cause a jolt (shock) at each end of oscillatory
movement travel path are installed.
[0048] Agitation may be provided to further enhance thawing by
enhancing the thermal transfer characteristics of the
biopharmaceutical solution subject to oscillatory motion. For
example, agitation may be provided by a moving internal heat
transfer surface. Alternatively, it may be a rocker moving the
solid phase, or it can be an oscillating frame/grid/grate located
closely to active (heated) heat transfer surfaces. In another
embodiment, agitation may be provided by an array of rods embedded
into the frozen blocks close to their centers (last freezing, last
melting parts). The array of those rods may then be driven/moved in
oscillatory pattern, moving most, if not all, of the frozen
portions together within the liquid phase which surrounds them
(movement cannot start until sufficient portion of the liquid phase
forms). In another embodiment, agitation may be provided in the
form of a perforated plate with converging/diverging perforations
causing a directional flow of liquid phase. Alternatively, instead
of a perforated plate, a frame with "funnels" may be used;
oscillatory frame movement would cause directional liquid flow
through the funnels. Shaft agitators with paddles at the end could
also be used, but the shaft movement instead of being rotational is
preferably oscillatory. The paddles and part of the shaft may be
embedded in the solid frozen material and move it through the
liquid phase. The agitators moving the solid phase in the liquid
induce not only a mutual liquid-solid product motion, but also
turbulize the liquid around the moving solid and therefore,
increase the heat transfer between liquid and heat transfer
surfaces, thus cause accelerating thawing.
[0049] Internal structures present in the container can combine the
tasks of heat transfer enhancement and intensify agitation/mixing
during oscillatory motion. For example, internal heat exchangers
with fins acting on the principle of thermal bridges formed during
freezing, as described in U.S. patent application Ser. Nos.
08/895,782; 08/895,777, and 08/895,936, all filed on Jul. 17, 1997,
may also act as stationary mixing baffles/barriers to a wavy
movement of liquid phase inside the container. Any thermal bridge
gaps present will open at the beginning of the warming/thawing
process permitting the liquid phase to flow around the fins between
the compartments. Such a flow pattern turbulizes the liquid phase
near heated surfaces and significantly increases the heat transfer
and as a result the thawing rate. Cross sections of containers
having such internal structures according to the invention are
shown in FIGS. 11A-L. Internal structures may be actively heated
(for example through use of a heat exchange fluid or an electrical
resistance heater), be passively thermally conductive (such as a
thermally conductive fin), or combinations of the two types of
structures. FIGS. 12A-P show top views of circular cross-sections
of inventive containers comprising structures according to the
invention. FIGS. 13A-H show top views of circular cross-sections of
inventive containers comprising structures according to the
invention that include both actively heated structures and
passively thermally conductive structures.
[0050] The effect is further enhanced if there are multiple active
heat transfer surfaces within the container volume with a
multiplicity of fins hanging between those heat transfer surfaces.
The baffled structures may be baffles perpendicular to the movement
of the vessel. The baffles may be placed under the angle to the
main movement (to cause converging/diverging channels for the
dynamically moving liquid phase with the floating (in aqueous
solutions, the frozen material may float due to any density
differences) solid phase. If the solid and liquid move into a
converging channel of an internal structure, at one point the solid
mass becomes trapped between converging structures. Its movement
then stops and the relative movement of liquid phase versus that
solid phase accelerates. Such an acceleration further turbulizes
the boundary layer at the solid surface, thus increasing heat
transfer. In addition, contact heat transfer can take place between
the heat transfer structure and the thawing solid mass. Reversal of
motion (second part of oscillatory movement) may release the solid,
which now moves with the liquid through the diverging channel.
Movements of two-phase composition through the diverging-converging
channel causes additional relational movement between the solid and
liquid phases causing increase in turbulence, mixing, heat transfer
and resulting increase in the thawing rate.
[0051] The application of converging and diverging channels within
the internal structures adds another benefit for two-phase
hydrodynamics. In the converging channels the liquid may accelerate
if there is an outflow at the end of the channel, while in the
diverging channel the liquid phase may decelerate. If there is no
outflow, the converging and diverging channels can increase the
static liquid height at the channel end during converging flow, or
lower the liquid level in the diverging flow. Such surface level
differences in the liquid phase cause differences in static liquid
pressure and increase the flow of liquid phase through the gaps
around the baffles (such as any thermal bridge openings). A
combination of converging and diverging channels can cause peaks
and valleys on the surface of liquid phase to occur on both sides
of the baffle causing a large level difference and liquid flow
increase driven by this difference in static heads of liquid.
[0052] Internal structures in the container may also be configured
to utilize dynamic pressure (due to the liquid mass motion) of the
liquid phase (with the suspended solid phase) to propel the liquid
phase through openings in the baffle or through gaps around the
baffle. Multiple structures can be located "in series" for a better
control of the movement of the, liquid and solid phases. Heat
exchangers with a radial fin configuration, such as those disclosed
in U.S. patent application Ser. Nos. 08/895,782; 08/895,777, and
08/895,936, all filed on Jul. 17, 1997, are a variation of this
concept--the fins divide container volume into multiple
compartments, with most of them providing baffling effect across
the main direction of oscillatory movement.
[0053] The internal structures may have special
flow-enhancing/directing elements shaped into them like, for
example, converging-diverging nozzles. These elements may work for
all situations and/or all internal structures, e.g. when the
container only moves and the internal structure is fixed to the
container, if the internal structure only moves and container is
stationary, and when both, the container and the structure move
with a relative motion against each other.
[0054] In general, the internal structures may divide the volume of
the container, thus preventing formation of big liquid waves moving
from side to side of the whole container. Any gaps around the
internal structures, such as baffles, are beneficial since liquid
moves through such gaps with relatively high velocity. The gaps may
be located next to active (heated) heat transfer
surfaces--particularly if the gaps serve as thermal bridges. The
high velocity is turbulized and increases heat transfer rate and as
a result, increases the thawing rate.
[0055] In a preferable embodiment, the internal structures may
direct the liquid flow (due to dynamics caused by the oscillatory
motion) at high velocity through areas in a vicinity of active
(heated) heat transfer surfaces as well as agitate the bulk liquid
volume. The liquid streams may be further directed towards the
central part of the volume (compartment) where the floating frozen
mass is located. In such a way, the liquid stream passes next to
the active heat transfer surface (warms up there) and then is
directed through the bulk liquid onto the melting surface passing
its enthalpy to this melting surface to be converted into the
latent heat of melting. Division of the container volume into
compartments, and reducing large amplitude liquid phase waves may
reduce splashing and foaming, thereby enhancing final product
yields by reducing, for example, biological product denaturation at
gas-liquid interfaces.
[0056] The oscillatory motion according to the invention may also
take the form of rocking/swinging of the container or an internal
structure contained within the container. For example the internal
structure may be placed on a pivot located in a middle of the
container (centrally) or above, or below the center. In another
embodiment, the oscillatory motion may be induced by placing the
container on a dynamically oscillatorily moving table driven by
pre-programmed drive(s) to provide complex motion patterns
(adjustable). Such tables may be controlled by accelerometers, and
may be driven in multiple axis, etc.
[0057] FIGS. 14A-L show top views of non-circular cross-sections of
inventive containers according to the invention. FIGS. 14A-D show
top views of non-circular cross-sections of inventive containers
without internal structures. FIGS. 14E-L show containers according
to the invention that include both actively heated structures and
passively thermally conductive structures.
[0058] It will be apparent to those skilled in the art that various
modifications and variations can be made in the circulators,
systems and methods of the present invention without departing from
the spirit or scope of the invention. Thus, it is intended that the
present invention covers the modifications and variations of this
invention provided they come within the scope of the appended
claims and their equivalents.
* * * * *