U.S. patent application number 16/610485 was filed with the patent office on 2021-06-17 for freeze-drying methods and related products.
This patent application is currently assigned to Massachusetts Institute of Technology. The applicant listed for this patent is Massachusetts Institute of Technology, Politecnico di Torino. Invention is credited to Luigi Carlo Capozzi, Roberto Pisano, Bernhardt Levy Trout.
Application Number | 20210180865 16/610485 |
Document ID | / |
Family ID | 1000005623298 |
Filed Date | 2021-06-17 |
United States Patent
Application |
20210180865 |
Kind Code |
A9 |
Trout; Bernhardt Levy ; et
al. |
June 17, 2021 |
FREEZE-DRYING METHODS AND RELATED PRODUCTS
Abstract
The disclosure in some aspects relates to systems and related
methods for the continuous freeze-drying of materials (e.g.,
pharmaceuticals) with high speed and control.
Inventors: |
Trout; Bernhardt Levy;
(Lexington, MA) ; Pisano; Roberto; (Rivalta Di
Torino, IT) ; Capozzi; Luigi Carlo; (Canosa Di
Puglia, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Massachusetts Institute of Technology
Politecnico di Torino |
Cambridge
Torino |
MA |
US
IT |
|
|
Assignee: |
Massachusetts Institute of
Technology
Cambridge
MA
Politecnico di Torino
Torino
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20200158431 A1 |
May 21, 2020 |
|
|
Family ID: |
1000005623298 |
Appl. No.: |
16/610485 |
Filed: |
May 2, 2018 |
PCT Filed: |
May 2, 2018 |
PCT NO: |
PCT/US18/30629 PCKC 00 |
371 Date: |
November 1, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62500466 |
May 2, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
F26B 5/048 20130101;
A23L 2/14 20130101; F26B 5/042 20130101; F26B 15/04 20130101; A23V
2002/00 20130101; A61K 9/19 20130101; F26B 5/06 20130101 |
International
Class: |
F26B 5/04 20060101
F26B005/04; F26B 5/06 20060101 F26B005/06; F26B 15/04 20060101
F26B015/04; A23L 2/14 20060101 A23L002/14; A61K 9/19 20060101
A61K009/19 |
Claims
1. A method for processing a composition, the method comprising:
continuously moving a vessel configured to contain a composition
through a plurality of modules arranged to promote step-wise
freezing and/or drying of the composition, wherein the vessel
comprises a housing defining a boundary between an exterior
surrounding of the vessel and an interior space configured to
contain the composition, and wherein, during movement of the vessel
through the plurality of modules, the vessel is arranged to promote
heat transfer between the exterior surrounding and the interior
space across a portion of the housing contactable with the
composition in the interior space when the composition is present
in the interior space.
2. The method of claim 1, comprising operating one or more control
systems to control the temperature of the vessel as it moves
through the plurality of modules.
3. The method of claim 2, wherein while the vessel contains the
composition, the method comprises inputting one or more
measurements from a wireless thermocouple into a model-based
control system so as to adjust the temperature of a heat transfer
fluid in order to maintain the temperature of the composition at a
controlled value during freezing and/or drying.
4. The method of claim 1, wherein the vessel is suspended from a
conveyor configured to continuously move the vessel through the
plurality of modules.
5. The method of claim 1, wherein a product, comprising one or more
components of the composition, resulting from the processing method
has an average pore size of between or equal to 20 microns and 1000
microns.
6. The method of claim 1, wherein a product, comprising one or more
components of the composition, resulting from the processing method
has an average pore size of between or equal to 40 microns and 70
microns.
7. The method of claim 1, comprising moving the vessel through a
filling module and filling the vessel with the composition to
between or equal to 1% and 90% volume capacity of the vessel.
8. The method of claim 7, comprising moving the vessel through the
filling module and filling the vessel with the composition to
between or equal to 10% and 50% volume capacity of the vessel.
9. The method of claim 1, comprising moving a plurality of vessels,
each configured to contain a respective composition, through the
plurality of modules at a rate of between or equal to 10 vessels
per hour per module and 100 vessels per hour per module.
10. The method of claim 1, comprising moving a plurality of
vessels, each configured to contain a respective composition,
through the plurality of modules at a rate of between or equal to
40 vessels per hour per module and 60 vessels per hour per
module.
11. The method of claim 1, comprising moving the plurality of
vessels, each configured to contain a respective composition,
through the plurality of modules at a rate of between or equal to
10 vessels per hour and 1000 vessels per hour.
12. The method of claim 1, comprising moving the plurality of
vessels, each configured to contain a respective composition,
through the plurality of modules at a rate of between or equal to
200 vessels per hour and 400 vessels per hour.
13. A method for freeze-drying a substance, the method comprising:
a) continuously moving a vessel that contains a composition
comprising a substance through a conditioning module, wherein the
vessel resides in the conditioning module for a time sufficient to
bring the composition to a conditioning temperature; b)
continuously moving the vessel from the conditioning module to, and
then through, a freezing module, wherein the vessel resides in the
freezing module for a time sufficient to freeze the composition;
and c) continuously moving the vessel from the freezing module to,
and then through, a primary drying module, wherein the vessel
resides in the primary drying module for a time sufficient to
sublimate a frozen solvent from the composition.
14. The method of claim 13 further comprising: d) continuously
moving the vessel from the primary drying module to, and then
through, a secondary drying module, wherein the vessel resides in
the secondary drying module for a time sufficient to desorb
residual solvent from the substance.
15. The method of claim 13 or 14 further comprising, prior to step
a), filling the vessel with the composition.
16. The method of any one of claims 13-15 further comprising, after
step d), continuously moving the vessel from the secondary drying
module to a pre-storage module, wherein the vessel resides in the
pre-storage module for a time sufficient to bring the substance to
a storage temperature.
17. The method of any one of claims 13-16 further comprising
filling the vessel with an inert gas and closing an opening of the
vessel to seal in the inert gas.
18. The method of claim 13 or 14, wherein the vessel comprises a
housing defining a boundary between an exterior surrounding and an
interior space configured to contain the composition, and wherein,
during one or more of steps a) to d), the vessel is arranged to
promote heat transfer between the exterior surrounding and the
interior space across a portion of the housing contactable with the
composition in the interior space.
19. The method of any one of claims 13 to 18, wherein the vessel is
suspended from a conveyor configured to continuously move the
vessel through the modules.
20. The method of claim 19, wherein the vessel comprises a housing
defining a boundary between an interior space configured to contain
the composition and an exterior, and wherein the vessel is
suspended from the conveyor such that the portion of the housing
contactable with the composition in the interior space is fully
exposable on the exterior to convective air flow in one or more
modules.
21. The method of any one of claims 1 to 20, wherein the
composition comprises a pharmaceutical substance.
22. The method of any one of claims 1 to 21, wherein the
composition comprises an excipient.
23. The method of any one of claims 1 to 20, wherein the
composition comprises fruit pulp, juices or another liquid
mixture.
24. The method of claim 13, wherein the time required to freeze-dry
a substance is between 2 and 10 times less than that required by
using a reference batch process.
25. The method of claim 13, wherein a product comprising the
substance resulting from the method for freeze-drying has an
average pore size of between or equal to 20 microns and 1000
microns.
26. The method of claim 13, wherein a product comprising the
substance resulting from the method for freeze-drying has an
average pore size of between or equal to 40 microns and 70
microns.
27. A system for processing a composition, the system comprising: a
plurality of modules arranged to promote step-wise freezing and
drying of a composition; and a conveyer system configured to
continuously move a vessel configured to contain the composition
through the plurality of modules, wherein the vessel comprises a
housing defining a boundary between an exterior surrounding of the
vessel and an interior space configured to contain the composition,
and wherein, when present in a module of the plurality of modules,
the vessel is arranged to promote heat transfer between the
exterior surrounding and the interior space across the entire
portion of the housing contactable with the composition in the
interior space when the composition is present in the interior
space.
28. The system of claim 27, further comprising one or more control
systems configured to control one or more processing
conditions.
29. The system of claim 28, wherein the one or more control systems
comprises a model-based control system.
30. The system of claim 28, wherein the one or more control systems
comprises one or more wireless temperature sensors.
31. The system of claim 28, wherein the one or more control systems
comprises one or more platinum resistance thermometers.
32. The system of claim 28, wherein the one or more control systems
comprises one or more pneumatic valves.
33. The system of claim 28, wherein the one or more control systems
comprises one or more pressure sensors.
34. The system of claim 28, wherein the one or more control systems
comprises one or more cameras or laser sensors configured for
in-line control of vacuum induced surface freezing.
35. The system of claim 28, wherein the system is configured for
fully automated control of processing the composition.
36. The system of claim 27, further comprising one or more
cleaning/sterilization modules, configured to sterilize one or more
modules while a respective module does not contain a vessel
containing the composition.
37. The system of claim 27, wherein the plurality of modules
occupies a total volume of between or equal to 0.1 m.sup.3 and 4
m.sup.3.
38. The system of claim 27, wherein the plurality of modules
occupies a total volume of between or equal to 2 m.sup.3 and 3
m.sup.3.
39. The system of claim 27, comprising a freezing module.
40. The system of claim 39, wherein the freezing module comprises a
serpentine pattern along which the vessel is configured to move
through the freezing module.
41. The system of claim 27, comprising a drying module.
42. The system of claim 41, wherein the drying module comprises a
serpentine pattern along which the vessel is configured to move
through the drying module.
43. The system of claim 27, wherein the plurality of modules
comprises one freezing module and one drying module, wherein the
drying module is connected to the freezing module by an interface
apparatus.
44. The system of claim 27, wherein the plurality of modules
comprises one freezing module and 6 drying modules, wherein the 6
drying modules are configured to operate in parallel and each of
the 6 drying modules is connected to the freezing module by a
respective interface apparatus.
45. The system of claim 27, wherein the plurality of modules
comprises a filling module.
46. The system of claim 27, wherein the plurality of modules
comprises a conditioning module.
47. The system of claim 27, wherein the plurality of modules
comprises a nucleation chamber.
48. The system of claim 27, further comprising a refrigeration
system.
49. The system of claim 27, further comprising a vacuum system.
50. The system of claim 49, wherein the vacuum system comprises one
or more vacuum pumps and one or more condensers.
51. The system of claim 50, wherein the vacuum system comprises 3
vacuum pumps and 2 condensers.
52. The system of claim 27, further comprising a load-lock system
located at a vessel outlet of a first module and a vessel inlet of
a second module configured to accommodate a change in pressure
between the first module and the second module.
53. A system for the continuous freeze-drying of a composition, the
system comprising: a first module and a second module, wherein the
first module comprises a freezing chamber and the second module
comprises a drying chamber, and wherein vessels comprising a
composition are suspended in a line along a conveyor; and an
interface apparatus connecting the first module to the second
module.
54. A method for processing a composition, the method comprising
using the system of 27 or 53 to continuously freeze-dry a
composition.
55. The system of claim 27 or 53 or the method of claim 54, wherein
the composition comprises a pharmaceutical.
56. The system of claim 25 or 53 or the method of claim 54, wherein
the composition comprises an excipient.
57. The system or method of claim 56, wherein the excipient
comprises sucrose.
58. The system or method of claim 56, wherein the excipient
comprises mannitol.
59. The system of claim 25 or 53 or the method of claim 54, wherein
the composition comprises fruit pulp, juices or another liquid
mixture.
60. The system of claim 53, wherein the first module is configured
to operate at atmospheric pressure.
61. The system of claim 53, wherein each vessel comprises a unit
dose of a pharmaceutical.
62. The system of claim 53, further comprising a third module.
63. The system of claim 62, wherein the third module is a secondary
drying chamber.
64. The system of claim 62, wherein the third module is a
conditioning chamber.
65. The system of claim 62, wherein the third module is a
nucleation chamber.
66. The system of claim 53, further comprising a refrigeration
system.
67. The system of claim 66, wherein the first module is connected
to the refrigeration system.
68. The system of claim 66, wherein the second module is connected
to the refrigeration system.
69. The system of claim 66, wherein the refrigeration system
comprises liquid nitrogen.
70. The system of claim 53, further comprising a vacuum system.
71. The system of claim 70, wherein the second module is connected
to the vacuum system.
72. The system of claim 53, wherein the interface apparatus
comprises a sluice-gate system.
73. The system of any one of claims 43-44 or 53, wherein the
interface apparatus comprises a load-lock system.
74. The system of any one of claims 43-44 or 53, wherein the
interface apparatus comprises a valve.
75. The system of claim 53, wherein the interface apparatus allows
for the passage of the vessels from the first module to the second
module.
76. The system of claim 53, wherein the system is configured to
continuously move the vessels through the modules.
77. The system of claim 53, wherein the pressure in the first
module is at least two times that of the pressure in the second
module.
78. The system of claim 53, wherein the chamber walls comprise
stainless steel.
79. The system of claim 53, wherein the drying chamber comprises an
external heat exchanger.
80. The system of claim 79, wherein the walls of the drying chamber
comprise silicone oil.
81. The system of claim 53, wherein the second module comprises an
infrared source of heat.
82. The system of claim 55, wherein the maximum allowable
temperature of the pharmaceutical is negative 19.5 degrees
Celsius.
83. The system of claim 53, wherein the exterior surface of the
vessels are coated in a polymer film.
84. The system of claim 53, wherein the drying rate in the second
module determines the flow rate of the vessels required to result
in the appropriate residence time of the vessels in each
module.
85. The system of claim 53, wherein system is configured to
continuously move the vessels along the conveyor at a rate between
0.01 m/hr and 2 m/hr.
86. The system of claim 27, wherein the volume of a given module is
fifteen times less than that of a freezing and/or drying chamber
used in a reference batch process.
87. A method for processing a composition, the method comprising:
continuously moving a plurality of vessels along a common path and
at a common rate through a plurality of modules arranged to promote
step-wise freezing and/or drying of the composition, wherein each
vessel is configured to contain the composition, wherein each
vessel comprises a housing defining a boundary between an exterior
surrounding of the vessel and an interior space configured to
contain the composition.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35
U.S.C. .sctn. 119(e) to U.S. Provisional Patent Application Ser.
No. 62/500,466, filed May 2, 2017, and entitled "CONTINUOUS
FREEZE-DRYING METHODS AND RELATED PRODUCTS," which is incorporated
herein by reference in its entirety for all purposes.
FIELD
[0002] The present disclosure relates to methods for the
freeze-drying of substances, e.g., pharmaceuticals and
biopharmaceuticals in unit doses, and related products and
apparatus. This technology is also suitable for processing other
kinds of products, e.g., fruit pulps and juices. The disclosure
also includes lyophilized products produced using this process.
BACKGROUND
[0003] It is desirable to freeze-dry substances, for example, to
preserve biological activity in the case of pharmaceuticals.
Freeze-drying, or lyophilization, is a technique that is often used
for drying high-value products without damaging their physical
structure and/or preserving the stability of the product during
long storage. For example, many pharmaceuticals and
biopharmaceuticals are delicate and unstable in liquid solution,
and are also heat-sensitive. Therefore, certain methods cannot be
used to dry these materials and freeze-drying is a potential
solution. Improved methods for freeze-drying are needed.
SUMMARY
[0004] The present disclosure relates to methods for the
freeze-drying of substances, e.g., pharmaceuticals and
biopharmaceuticals in unit doses, and related products and
apparatus. This technology is also suitable for processing other
kinds of products, e.g., fruit pulps and juices. The disclosure
also includes lyophilized products produced using this process.
[0005] In some aspects, the present disclosure provides methods for
processing a composition.
[0006] In some embodiments, a method comprises continuously moving
a vessel, configured to contain a composition, through a plurality
of modules arranged to promote step-wise freezing and/or drying of
the composition, wherein the vessel comprises a housing defining a
boundary between an exterior surrounding of the vessel and an
interior space configured to contain the composition, and wherein,
during movement of the vessel through the plurality of modules, the
vessel is arranged to promote heat transfer (e.g., substantially
uniform heat transfer) between the exterior surrounding and the
interior space across a portion of the housing contactable with the
composition in the interior space when the composition is present
in the interior space.
[0007] In other aspects, the present disclosure provides methods
for freeze-drying a substance. In some embodiments, a method
comprises: a) continuously moving a vessel that contains a
composition comprising a substance through a conditioning module,
wherein the vessel resides in the conditioning module for a time
sufficient to bring the composition to a conditioning temperature;
b) continuously moving the vessel from the conditioning module to,
and then through, a freezing module, wherein the vessel resides in
the freezing module for a time sufficient to freeze the
composition; c) continuously moving the vessel from the freezing
module to, and then through, a primary drying module, wherein the
vessel resides in the primary drying module for a time sufficient
to sublimate a frozen solvent from the composition; and in some
embodiments d) continuously moving the vessel from the primary
drying module to, and then through, a secondary drying module,
wherein the vessel resides in the secondary drying module for a
time sufficient to desorb residual solvent from the substance.
[0008] In some embodiments, a method comprises continuously moving
a plurality of vessels along a common path and at a common rate
through a plurality of modules arranged to promote step-wise
freezing and/or drying of the composition, wherein each vessel is
configured to contain the composition, wherein each vessel
comprises a housing defining a boundary between an exterior
surrounding of the vessel and an interior space configured to
contain the composition.
[0009] According to some aspects, the present disclosure also
provides systems for processing a composition. In some embodiments,
a system comprises a plurality of modules arranged to promote
step-wise freezing and drying of a composition; and a conveyer
system configured to continuously move a vessel, configured to
contain the composition, through the plurality of modules, wherein
the vessel comprises a housing defining a boundary between an
exterior surrounding of the vessel and an interior space configured
to contain the composition, and wherein, when present in a module
of the plurality of modules, the vessel is arranged to promote heat
transfer (e.g., substantially uniform heat transfer) between the
exterior surrounding and the interior space across the entire
portion of the housing contactable with the composition in the
interior space when the composition is present in the interior
space.
[0010] In other aspects, the present disclosure also provides
systems for the continuous freeze-drying of a composition. In some
embodiments, a system comprises a first module and a second module,
wherein the first module comprises a freezing chamber and the
second module comprises a drying chamber, and wherein vessels
comprising a composition are suspended in a line along a conveyor;
and an interface apparatus connecting the first module to the
second module.
[0011] Other advantages and novel features of the present
disclosure will become apparent from the following detailed
description of various non-limiting embodiments of the disclosure
when considered in conjunction with the accompanying figures. In
cases where the present specification and a document Incorporated
by reference include conflicting and/or inconsistent disclosure,
the present specification shall control.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] Non-limiting embodiments of the present disclosure will be
described by way of example with reference to the accompanying
figures, which are schematic and are not intended to be drawn to
scale. In the figures, each identical or nearly identical component
illustrated is typically represented by a single numeral. For
purposes of clarity, not every component is labeled in every
figure, nor is every component of each embodiment of the disclosure
shown where illustration is not necessary to allow those of
ordinary skill in the art to understand the disclosure. In the
figures:
[0013] FIG. 1 provides a non-limiting schematic diagram of a
continuous freeze-drying process for liquid solutions comprising:
(1) moving tracks, (2) sluice-gate/load-lock system, (3) condenser
and vacuum pumps, and (4) temperature controlled surfaces;
[0014] FIG. 2 provides a non-limiting schematic diagram of a
continuous freeze-drying process for liquid solutions, which
performs controlled nucleation through vacuum-induced surface
freezing;
[0015] FIG. 3 provides a non-limiting schematic diagram of a
continuous freeze-drying process for particle-based material and
for spin-frozen products;
[0016] FIG. 4 shows a non-limiting side perspective view of an
illustrative transport system based on the use of a gripper;
[0017] FIG. 5 shows a non-limiting side perspective view of an
illustrative transport system based on the use of a conveyor;
[0018] FIG. 6 shows a non-limiting side perspective view of an
illustrative transport system where vials are moved along the
equipment through a side-piston;
[0019] FIG. 7 is a non-limiting schematic of a load-lock system,
based on the use of an elevator, that moves the vessels between two
modules operating at different pressure and temperature from one
another;
[0020] FIG. 8 is a non-limiting schematic of a load-lock system,
based on the use of an elevator, that moves the vessels between two
modules operating at different pressure and temperature from one
another, wherein the pressure inside the conditioning chamber is
not controlled;
[0021] FIG. 9 shows non-limiting top and side perspectives of a
load-lock system that involves the use of an elevator and a
rotating device;
[0022] FIG. 10 shows non-limiting top and side perspectives of a
load-lock system that involves the use of an elevator and a
rotating device and pressure control;
[0023] FIG. 11 shows a non-limiting top perspective of a rotating
load-lock system;
[0024] FIG. 12 depicts a non-limiting process flow diagram of a
continuous freeze-dryer comprising: (A) conditioning module, (B)
load-lock system, (C) freezing chamber, (D) primary drying chamber,
and (D) secondary drying chamber;
[0025] FIG. 13 is a non-limiting schematic of a freezing/drying
module wherein the vessels are moved along the equipment following
an illustrative non-linear path;
[0026] FIG. 14 is a non-limiting schematic of a freezing/drying
module wherein the vessels are moved along the equipment following
a spiral path;
[0027] FIG. 15A and FIG. 15B depict non-limiting temperature
profiles during freezing in the case of conventional batch freezing
(FIG. 15A) and continuous freezing (FIG. 15B), wherein temperature
of the (.largecircle.) shelf/equipment surface and of the
(.circle-solid.) gas within the drying chamber are also shown;
[0028] FIG. 16 shows a non-limiting comparison of a lyophilized
product as produced using both conventional freeze-drying (left)
and continuous freeze-drying (right);
[0029] FIG. 17A-FIG. 17F show a non-limiting comparison of heat
flux between batch freeze-drying and continuous freeze-drying; FIG.
17A shows a schematic of vial positions in a non-limiting case of a
batch lyophilizer; FIG. 17B shows a spatial distribution of heat
flux in a non-limiting case of a batch lyophilizer; FIG. 17C shows
a maximum product temperature for vessels placed at the edge and in
center of a shelf in a non-limiting case of a batch lyophilizer;
FIG. 17D shows a schematic of vessels arrangement in a non-limiting
case of a continuous lyophilizer (i.e., freeze-dryer); FIG. 17E
shows a spatial distribution of heat flux in a non-limiting case of
a continuous lyophilizer; and FIG. 17F shows the maximum product
temperature of products as a function of clearance in a
non-limiting case of a continuous lyophilizer;
[0030] FIG. 18 shows non-limiting illustrative plots comparing heat
flux in batch freeze-drying (left) and in continuous freeze-drying
(right);
[0031] FIG. 19 shows non-limiting illustrative plots comparing
total cycle time for batch freeze-drying and continuous
freeze-drying in the case of a precautionary cycle (left) and of a
more aggressive cycle (right);
[0032] FIG. 20 shows non-limiting illustrative plots comparing the
temperature of a heat transfer fluid for a batch freezer-dryer and
a continuous freeze-dryer in the case of a precautionary
(conservative) batch cycle and a more aggressive batch cycle;
[0033] FIG. 21 shows a non-limiting illustrative plot comparing
average pore size for three samples produced by a batch lyophilizer
(non-suspended vials) and a continuous lyophilizer (suspended
vials), wherein error bars refer to size variations along the axial
position;
[0034] FIG. 22 shows non-limiting scanning electron microscopy
(SEM) images of lyophilized samples as produced by a batch
apparatus (left images) and a continuous lyophilizer (right
images);
[0035] FIG. 23 shows non-limiting statistical distributions of
average pore size of lyophilized samples as produced by a batch
lyophilizer (left, Non-suspended vials) and a continuous
lyophilizer (right, Suspended vials);
[0036] FIG. 24 shows non-limiting statistical distributions of
residual moisture as observed at the end of secondary drying in the
case of batch freeze-drying and continuous freeze-drying;
[0037] FIG. 25 depicts a non-limiting example of potential
configurations for a continuous lyophilizer;
[0038] FIG. 26 shows non-limiting illustrative plots comparing
equipment size for a batch lyophilizer and a continuous lyophilizer
in the case of two different yields (left plot and right plot);
[0039] FIG. 27 shows a non-limiting illustrative plot comparing
process time for a batch lyophilizer and a continuous
lyophilizer;
[0040] FIG. 28 shows a non-limiting schematic diagram of an
illustrative network pipe system to connect modules, wherein Module
type A and Module type B are modules that have different
functionality;
[0041] FIG. 29 provides a non-limiting schematic diagram of an
illustrative stack module system wherein Module type A, Module type
B, and Module type C are modules that have different
functionality;
[0042] FIG. 30 provides a non-limiting schematic diagram of
operations that a continuous lyophilizer may carry out for
different states of a product to be freeze dried;
[0043] FIG. 31 shows non-limiting photographs and scanning electron
micrographs of a product of batch freeze-drying (FD) and a product
of continuous freeze-drying;
[0044] FIG. 32 is a non-limiting schematic of an apparatus for
freeze-drying a composition;
[0045] FIG. 33 shows non-limiting schematics of a freezing module
or a drying module;
[0046] FIG. 34 is a non-limiting schematic of an apparatus for
freeze-drying a composition;
[0047] FIG. 35 shows non-limiting schematics of drying modules;
and
[0048] FIG. 36 shows a non-limiting apparatus for freeze-drying
compositions contained in vessels.
DETAILED DESCRIPTION
[0049] The disclosure in some aspects relates to systems and
related methods for the continuous freeze-drying of materials
(e.g., pharmaceuticals) with high speed and control. Aspects of the
disclosure relate to recognizing deficiencies in conventional batch
freeze-drying, a downstream process in the pharmaceutical industry
used to gently dry high-value products which are sensitive to heat.
In some cases, batch freeze-drying is a relatively long and
expensive process that presents serious limitations.
[0050] A batch lyophilizer may comprise a chamber equipped with
shelves and connected to a condenser and vacuum pumps. Shelves may
be designed to freeze and to heat the product through internal
channels, allowing circulation of silicone oil or an equivalent
fluid. The silicone oil may be cooled down or heated by a
cooling/heating system.
[0051] Batch freeze-drying may comprise three stages: (a) freezing
the liquid solution in a container (e.g. a vessel; e.g. a vial),
(b) drying the material by removing water via sublimation under
vacuum, and (c) removing residual moisture via desorption under
vacuum. As a first step, vessels may be loaded over the shelves
into the chamber. In the freezing step, the shelf temperature may
be reduced until product in vessels is completely frozen. After
freezing, the pressure in the chamber may be reduced, causing
sublimation of ice. Finally, the shelf temperature may be
increased, causing desorption of residual moisture in the
products.
[0052] More specifically, the batch freeze-drying process may
comprise various stages: (1) filling and loading of the material,
(2) freezing, (3) primary drying, (4) secondary drying, (5)
backfill and stoppering, (6) unloading of the material, (7)
defrosting of condenser, (8) cleaning in place, (9) sterilization
in place, (10) further sterilization with H.sub.2O.sub.2, (11) leak
test.
[0053] The whole batch freeze-drying process can take from 40 to
300 hours, and more than 50% of this time is dead time (e.g.,
stages 1, 5, 6, 7, 8, 9, 10, and 11).
[0054] Issues related to batch freeze-drying may include: lack of
flexibility of processing; large apparatus volume required to
process the product; long dead time for loading/unloading and
cleaning/sterilizing; safety issues related to manual handling,
product contamination, and operator contamination; technical issues
related to breakdown of components and failure to obtain the
desired pressure reduction, due to pump breakdown or leaks in the
apparatus; non-uniformity of the products; non-uniform heat/mass
transfer during the process; lack of control during the process;
and/or difficulties in the scale-up of the process.
[0055] Certain embodiments of the present disclosure may overcome
issues associated with batch freeze-drying related to ancillary
operation by shortening the cycle time. In some embodiments, the
present disclosure eliminates or minimizes the dead time of batch
freeze-drying. Dead time may arise from for example filling and/or
loading (about 5 hours), backfill and/or stoppering (about 1 hour),
unloading (about 5 hours), cleaning in place, sterilization in
place and further sterilization with H.sub.2O.sub.2 (5 to 10 hours)
and leak test (3 to 6 hours).
[0056] Freezing often plays role in the lyophilization of
pharmaceuticals because it may influence the final structure of the
dried product, affect the composition of polymorphs and the
stability of many drugs, and influence the duration of the drying
stage and the final moisture content in the dried product.
Moreover, freezing may influence the intra-vessel and the
vessel-to-vessel heterogeneity. For example, in batch freeze-drying
of pharmaceuticals, vessels may be filled with the liquid solution
and then placed directly on the shelf of the freeze-drier. Once the
vessels are loaded in the chamber, the shelf temperature may be
reduced to below freezing temperature following a freezing
protocol.
[0057] In batch freezing, some mechanisms involved in the heat
transfer between the refrigerant fluid and the product in the
vessel may be the conduction through air in the gap between the
vessel and the shelf, radiation from the shelf and the
surroundings, the contact between shelf and vessel, and the natural
convection of air over the vessel side. During batch freezing, the
product temperature may be an intermediate value between the
temperature of the shelf and the air in the chamber. During batch
freezing, the shelf may cool down the product temperature from the
bottom, whereas the air in the chamber may supply heat to the side
of the vessel. This may lead to temperature gradients within the
product of between or equal to 4 degrees Celsius (.degree. C.) and
5.degree. C. and resultant heterogeneity in the structure of the
dried product.
[0058] During a primary drying stage of conventional batch
freeze-drying, variables to be controlled may include product
temperature and drying time. Product temperature may be maintained
below a limit value to satisfy the product quality requirements,
while drying time may be long enough to ensure that ice sublimation
is completed in all the vessels of the batch. The process
parameters that can be directly controlled during primary drying
may be shelf temperature and chamber pressure.
[0059] In conventional batch freeze-drying, vessels may be in
direct contact with the shelves and occupy different positions over
the shelf. The heat flux between the heating shelf and the vessels
may be the result of various mechanisms that depend on dryer and
vessel geometry, as well as on pressure and temperature of the
shelves and the surroundings. In conventional batch freeze-drying,
heat may be supplied by, for example, (i) direct conduction from
the shelf to the glass at the points of contact, (ii) conduction
through the gas in the small gap between the shelves and the bottom
of the vessel, (iii) radiation from the bottom and upper shelf, and
from the surroundings (i.e., chamber walls and door), and (iv) the
natural convection of air over the vessel side. The heat supplied
by direct contact and the heat supplied by radiation may be
independent of chamber pressure, whereas convection and conduction
may depend also on pressure.
[0060] Aspects of the disclosure relate to a recognition that
heterogeneity in heat transfer may arise due to vessel-to-vessel
variability of the contact surface between a shelf and a vessel;
and vessel-to-vessel variability of gap distance between a shelf
and a vessel bottom. Furthermore, the radiative contribution may
depend on the position of the vessel in relation to a shelf or
other support structure, e.g. vessels located in the center of the
shelf receive radiative heat from bottom and upper shelves, vessels
located in the periphery of the shelf receive also radiative heat
from chamber walls or door, etc. This may present challenges for
scaling-up of the process and in the process control itself. Other
issues giving rise to heat transfer heterogeneity in the context of
batch processes may include for example variability in shelf
temperature (e.g., shelf temperature varies by between or equal to
1.degree. C. and 3.degree. C. along the shelf) and non-uniformity
of pressure in the lyophilizer chamber, which may result in
variation in drying rate and temperature within the lot during
drying. Non-uniformity of pressure in a lyophilizer chamber may
occur for manufacturing units working under full-load conditions.
Under full-load conditions, pressure may vary from 1 Pa to 2 Pa or
higher, from the center of a shelf to an edge of the shelf (see,
e.g., Barresi et al. 2010, Drying Technology 28: 577-590).
[0061] Accordingly, in some embodiments, it is an object of the
present disclosure to obviate or reduce the disadvantages of batch
freeze-drying. In some embodiments, it is an object of the present
disclosure to provide a lyophilization apparatus having one or more
of the following features: a smaller apparatus that needs less
space than conventional freeze-drier; no manual intervention during
the whole process so as to avoid contamination of the product and
operators; reduced cycle time and no dead time; increased
homogeneity within the production and the standardization of the
products; increased energy efficiency of the process; no need to
scale up the process; and increased flexibility, resulting in
complete integration with a given upstream process and modularity
of the apparatus. In some embodiments, the present disclosure
decreases drying time (e.g., by a factor of from 2 to 10, e.g., by
a factor of from 2 to 5) over a conventional batch process.
[0062] In some embodiments, the present disclosure provides systems
and related methods for continuous freeze-drying of pharmaceuticals
and biopharmaceuticals in unit dose. In some embodiments, the
present disclosure provides a unit dose continuous lyophilizer. In
some embodiments, this system and related methods can be used with
slurries, pulps, juice, or any fluid comprising any suitable target
product to be freeze-dried in small vessels.
[0063] In some embodiments, advantages to the system and associated
methods described herein include increased control and/or
uniformity of heat supplied to products during primary and
secondary drying. In some embodiments, systems and associated
methods described herein minimize or eliminate edge-vessel effects
because every vessel containing a composition to be freeze-dried
follows approximately the same path and experiences approximately
identical conditions. By contrast, an alternative method of
freeze-drying developed for shortening cycle time, e.g.,
spin-freezing, may have less control over product structure.
[0064] Vessels containing compositions to be freeze-dried by
methods described herein may have any suitable dimensions or
filling volume, without limitation. By contrast, an alternative
method of freeze-drying developed for shortening cycle time, e.g.,
spin-freezing, may be limited in filling volume and vessel
dimensions.
[0065] In some embodiments, systems and methods described herein
were designed to produce end-use products, and to avoid the
drawbacks of batch lyophilization in vessels (e.g., vials). By
contrast, alternative continuous lyophilization systems and methods
may not produce end-use products, but rather may produce bulk
materials in the form of fine particles which must be subsequently
handled, which handling may reduce product quality. In addition,
alternative continuous lyophilization systems and methods may have
less control over product temperature and final moisture within the
product.
[0066] In some embodiments, a system for processing a composition
is provided. In some embodiments, a system provided herein
comprises a plurality of modules (e.g., 104, 106, 108, 110 of FIG.
1) arranged to promote step-wise freezing and drying of a
composition (e.g., 112 of FIG. 1), and a conveyer system (e.g., 114
of FIG. 1) configured to continuously move a vessel (e.g., 102 of
FIG. 1), configured to contain the composition, through the
plurality of modules. In some embodiments, a vessel (e.g., 102 of
FIG. 1) comprises a housing (e.g., 103 of FIG. 1) defining a
boundary between an exterior surrounding (e.g., 109 of FIG. 1) of
the vessel and an interior space (e.g., 101 of FIG. 1) configured
to contain the composition, and wherein, when present in a module
(e.g., 106, 108, 110 of FIG. 1) of a plurality of modules, the
vessel is arranged (e.g., using conveyor system 114 of FIG. 1) to
promote heat transfer (e.g., substantially uniform heat transfer)
between the exterior surrounding and the interior space across the
entire portion (e.g., 105 of FIG. 1) of the housing contactable
with the composition in the interior space when the composition is
present in the interior space.
[0067] In some embodiments, a method for processing a composition
is provided (e.g., as in FIG. 1). In some embodiments, a method
provided herein comprises continuously moving a vessel (e.g., 102
of FIG. 1), configured to contain a composition (e.g., 112 of FIG.
1), through a plurality of modules (e.g., 104, 106, 108, 110 of
FIG. 1) arranged to promote step-wise freezing and/or drying of the
composition, wherein the vessel comprises a housing (e.g., 103 of
FIG. 1) defining a boundary between an exterior surrounding (e.g.,
109 of FIG. 1) of the vessel and an interior space (e.g., 101 of
FIG. 1) configured to contain the composition, and wherein, during
movement of the vessel (e.g., vial movement direction of FIG. 1)
through the plurality of modules, the vessel is arranged (e.g.,
using conveyor system 114 of FIG. 1) to promote heat transfer
(e.g., substantially uniform heat transfer) between the exterior
surrounding and the interior space across a portion (e.g., 105 of
FIG. 1) of the housing contactable with the composition in the
interior space when the composition is present in the interior
space.
[0068] In some embodiments, a system for the continuous
freeze-drying of a composition is provided (e.g., FIG. 12). In some
embodiments, a system provided herein comprises a first module
(e.g., freezing module 1206 of FIG. 12) and a second module (e.g.,
primary drying module 1208 of FIG. 12) and an interface apparatus
(e.g., load-lock system 1230 of FIG. 12) connecting the first
module to the second module. In some embodiments, the first module
comprises a freezing chamber and the second module comprises a
drying chamber. In some embodiments, vessels (e.g., 1202 of FIG.
12) comprising a composition (e.g., 1212 of FIG. 12) are suspended
in a line along a conveyor (e.g., 1214 of FIG. 12).
[0069] In some embodiments, a method for freeze-drying a substance
is provided. In some embodiments, a method provided herein
comprises a) continuously moving a vessel (e.g., 202 of FIG. 2)
that contains a composition (e.g., 212 of FIG. 2) comprising a
substance through a conditioning module (e.g., 216 of FIG. 2),
wherein the vessel resides in the conditioning module for a time
sufficient to bring the composition to a conditioning temperature;
b) continuously moving the vessel from the conditioning module to,
and then through, a freezing module (e.g., secondary freezing
module 206 of FIG. 2), wherein the vessel resides in the freezing
module for a time sufficient to freeze the composition; and c)
continuously moving the vessel from the freezing module to, and
then through, a primary drying module (e.g., 208 of FIG. 2),
wherein the vessel resides in the primary drying module for a time
sufficient to sublimate a frozen solvent from the composition.
[0070] In some embodiments, a system comprises a single module. In
some embodiments, a system comprises a plurality of modules (e.g.,
one or more freezing modules and one or more drying modules). In
some embodiments, two or more modules (e.g., some or all modules)
are configured to work in parallel. In some embodiments, a system
supports partial automation or full automation of a freeze-drying
method. Systems provided herein may function under good
manufacturing practices (GMP) conditions.
[0071] In some embodiments, a system comprises a filling module in
which vessels (e.g., vials) are at least partially filled with a
composition (e.g., comprising a target product) to be freeze-dried.
In some embodiments, a filling module is configured for continuous
filling of vessels. In some embodiments, filling involves at least
partially filling one or more vessels with a composition to be
freeze-dried. In some embodiments, filling comprises filling a
vessel with a composition to between or equal to 1% and 90% volume
capacity of the vessel (e.g., between or equal to 5% and 80% volume
capacity, between or equal to 10% and 70% volume capacity, between
or equal to 15% and 60% volume capacity, between or equal to 20%
and 50% volume capacity, between or equal to 25% and 40% volume
capacity, between or equal to 30% and 40% volume capacity). In some
embodiments, a vessel is filled with a composition to between or
equal to 10% and 50% volume capacity of the vessel. In some
embodiments, a composition fills the vessel by less than half of
the volume capacity of the vessel so as to prevent or diminish
heterogeneous heat transfer resulting from contact between the
vessel and conveying instrumentation (e.g., tracks) for the vessel.
In some embodiments, a filling module is configured and operated to
at least partially fill between or equal to 100 files per hour and
1000 vessels per hour (e.g., vials per hour) (e.g., between or
equal to 200 vessels per hour and 900 vessels per hour, between or
equal to 300 vessels per hour and 800 vessels per hour, between or
equal to 300 vessels per hour and 100 vessels per hour, between or
equal to 300 vessels per hour and 600 vessels per hour, 300 vessels
per hour). In some embodiments, a system comprises a plurality of
filling modules configured to function in parallel.
[0072] In some embodiments, a system provided herein comprises a
conditioning module. In a conditioning module, flow of a cryogenic
gas may cool down a vessel (e.g., vial), bringing a composition to
a desired temperature. In some embodiments, a conditioning module
is connected to a filling module. Methods described herein may
involve moving a vessel from a filling module to a conditioning
module. In some embodiments, a system comprises a plurality of
conditioning modules configured to function in parallel.
[0073] In some embodiments, a system provided herein comprises a
nucleation chamber, also referred to as a vacuum induced surface
freezing (VISF) chamber. In a nucleation chamber, the pressure may
be low enough to induce nucleation of solid crystals of a
composition in the nucleation chamber. In some embodiments, a
nucleation chamber is connected with a conditioning module. Methods
described herein may involve moving a vessel from a conditioning
module to a nucleation chamber. In some embodiments, a system
comprises a plurality of nucleation chambers configured to function
in parallel.
[0074] In some embodiments, a system provided herein comprises a
freezing module. A system may comprise a plurality of freezing
modules. In some embodiments, at least some freezing modules (e.g.,
all freezing modules) are connected to a refrigeration module (also
herein referred to as a refrigeration system). In some embodiments,
a system comprises 2 freezing modules, 3 freezing modules, 4
freezing modules, 5 freezing modules, 6 freezing modules, 7
freezing modules, 8 freezing modules, 9 freezing modules, 10
freezing modules, or another suitable number of freezing modules.
In some embodiments, each freezing module is connected with a
nucleation chamber (e.g., a respective nucleation chamber, a common
nucleation chamber). In some embodiments, each freezing module is
connected with a respective nucleation chamber. In some
embodiments, each freezing module is connected with a common
nucleation chamber. Methods described herein may involve moving a
vessel from a nucleation chamber to a freezing module. In some
embodiments, a system comprises a plurality of freezing modules
configured to function in parallel.
[0075] In some embodiments, a system provided herein comprises a
drying module. In some embodiments, a system comprises a plurality
of drying modules. In some embodiments, a system comprises 2 drying
modules, 3 drying modules, 4 drying modules, 5 drying modules, 6
drying modules, 7 drying modules, 8 drying modules, 9 drying
modules, 10 drying modules, or another suitable number of drying
modules. In certain embodiments, a system comprises 6 drying
modules. In some embodiments, a system comprises a plurality of
drying modules configured to function in parallel. In some
embodiments, a system comprises a primary drying module and a
secondary drying module configured in series. In some embodiments,
a system comprises a plurality of drying module sets, each set
comprising a primary drying module and a secondary drying module
configured in series, wherein the drying module sets are configured
to function in parallel.
[0076] In some embodiments, a freezing module in a system is
connected to a plurality of drying modules. In some such
embodiments, a freezing module directs one or more vessels (each
containing a composition to be freeze-dried) to each drying module
in a parallel configuration. In some embodiments, each vessel
passes through a single freezing module and a single drying module
during the freeze-drying process.
[0077] In some embodiments, a drying module or at least some drying
modules (e.g., all drying modules) are connected to one or more
refrigeration modules (also referred to herein as refrigeration
systems). In some embodiments, at least some freezing modules and
at least some drying modules are connected to a common
refrigeration module or to respective refrigeration modules. In
some embodiments, all drying modules are connected to a
refrigeration system (e.g., a respective refrigeration system, a
common refrigeration system). In some embodiments, all drying
modules are connected to a comment refrigeration system. In some
embodiments, all drying modules are connected to a respective
refrigeration system.
[0078] In some embodiments, each drying module is connected to a
vacuum system. In some embodiments, each drying module is connected
to one or more condensers, each of which condensers is connected to
one or more vacuum pumps. In some embodiments, a vacuum system
comprises two vacuum pumps connected to two condensers; the two
condensers in turn may be connected to each drying module. In some
embodiments, a vacuum system comprises 3 vacuum pumps connected to
2 condensers; the two condenses in turn may be connected to each
drying module. In some embodiments, a vacuum system comprises 3
vacuum pumps, with one vacuum pump for maintenance purposes. In
certain illustrative embodiments, each condenser consumes between
or equal to 1 kg of ice and 10 kg of ice per 72 hours, e.g., 4 kg
of ice per 72 hours, 3.6 kg of ice per 72 hours. In certain
illustrative embodiments, each condenser consumes between or equal
to 1 kg of ice and 10 kg of ice per 12 hours, e.g., 4 kg of ice per
12 hours. In some embodiments, a system comprises a centralized
vacuum system and a cooling system that distributes to each
conditioning module, each freezing module, each primary drying
module, and/or each secondary drying module. In some embodiments, a
final drying module for a given series of modules (e.g., a
secondary drying module) is connected to a backfill or stoppering
module in which a product is sealed in a vessel. A backfill module
or stoppering module may be connected to a source of nitrogen or
other inert gas (e.g., Argon).
[0079] In some embodiments, throughput of a system (e.g., number of
vessels per hour from composition to freeze-dried product) depends
on a rate of advancement (movement) of vessels through the system.
In some embodiments, each module has a fixed length. In some
embodiments, throughput depends on length of some modules in a
system. In some embodiments, throughput depends on the length of a
path traveled by a vessel through some modules in a system. In some
embodiments, throughput of a system depends on the rate of
advancement of vessels and on the length of some modules. In some
embodiments, where the rate of advancement of vessels is constant,
the throughput of a system is determined by the number of modules
working in parallel. In some embodiments, a system is configured
and operated so as to freeze-dry compositions at a rate of between
or equal to 10 vessels per hour per freezing module or drying
module and 100 vessels per hour per freezing module or drying
module (e.g., between or equal to 40 vessels per hour per module
and 60 vessels per hour per module, 50 vessels per hour per
module). In certain illustrative embodiments, a system is
configured and operated so as to freeze-dry compositions at a rate
of 300 vessels per hour. The throughput of freeze-dried vessels
from a system may be 200,000 vessels per week. The throughput of
freeze-dried vessels from a system may be two vessels per
second.
[0080] In some embodiments, a system is arranged and operated such
that one or more vessels containing a composition move through the
system. In some embodiments, a system may be arranged and operated
so as to continuously move a vessel containing a composition
through a plurality of modules arranged to promote step-wise
freezing and drying of the composition. In some embodiments, a
system may be configured to continuously move a vessel containing a
composition across a first module within the first module
(intra-module movement), from the first module to the second module
(module-to-module movement), and continuing along the remaining
modules in continuous movement.
[0081] In some embodiments, a system comprises a load-lock system.
In some embodiments, a system comprises one or more load-lock
systems so that each vessel can move from a first module to a
second module, e.g., in cases wherein the pressure condition of the
first module is significantly different from the pressure condition
of the second module. In some embodiments, a system comprises two
load-lock systems for each module through which a vessel travels,
one at an inlet to the module and one at an outlet to the module. A
load-lock system may be located at an inlet for vessels (e.g.,
vials) to enter a module and/or an outlet for vessels (e.g., vials)
to exit a module, e.g., to accommodate pressure changes between
modules.
[0082] A vacuum duct may be configured to connect a freezing module
or drying module to a condenser and/or vacuum pump. A freezing
module or drying module may comprise a fluid inlet and a fluid
outlet, e.g., through which a heat transfer fluid is flowed into
and out of the freezing module or drying module, respectively. In
some embodiments, a freezing module or drying module is configured
for movement of a vessel (e.g., vial, e.g., 10R vial) through the
freezing module or drying module and comprises a serpentine
pattern, e.g., to compact the area occupied by the freezing module
or drying module and to increase the length of the path traveled by
a vessel moving through the freezing module or drying module (e.g.,
FIG. 33).
[0083] In some embodiments, a system provided herein includes one
or more control systems for controlling one or more processing
conditions, e.g., heat transfer fluid temperature, source
temperature, and/or pressure. Non-limiting examples of control
systems include one or more platinum resistance thermometers
(PRTs), one or more pneumatic valves, or one or more pressure
sensors, one or more wireless temperature sensors (one or more
thermocouples), one or more cameras or laser sensors for in-line
control of vacuum induced surface freezing (VISF), and/or one or
more advanced control systems. In some embodiments, a system is
configured for fully automated control of freeze-drying
compositions in vessels. A system may be configured so as to employ
process analytical technology (PAT), advanced control, scheduling,
and/or other automated control systems and methods to control a
temperature of a vessel (e.g., a temperature of a composition
within the vessel) as it moves through a plurality of modules. A
system may be configured so as to employ process analytical
technology (PAT), advanced control, scheduling, and/or other
automated control systems and methods to control a temperature of a
composition within a vessel as the vessel moves through a plurality
of modules.
[0084] In some embodiments, control of product quality is
accomplished by precise control of the temperature of a composition
being freeze-dried. In some embodiments, precise control involves
maintaining the temperature of a composition being freeze-dried
below a critical temperature above which the composition undergoes
structural damage or denaturation of the active pharmaceutical
ingredient. In some embodiments, maintaining the temperature of a
composition below a critical temperature is accomplished by
monitoring the temperature of the composition by wireless
thermocouples and inputting measurements from the wireless
thermocouples to a feedback control system that adjusts the
temperature of a heat transfer fluid accordingly.
[0085] In some embodiments, a system comprises a model-based
control system (also referred to herein as a feedback control
system) for temperature regulation of a composition being
freeze-dried. In some embodiments, a system includes wireless
thermocouples for monitoring the temperature of a composition being
freeze-dried. In some embodiments, measurements from wireless
thermocouples, of the temperature of a composition being
freeze-dried, are input into a model predictive controller (also
referred to herein as a model-based control system) so as to adjust
the temperature of a heat transfer fluid (or equivalently the
temperature of a radiative surface within a freezing module or
drying module in which the composition is located) and therefore so
as to maintain the temperature of the composition at its desired
value during freezing and/or drying, which may result in improved
product quality.
[0086] A feedback control system for temperature of a composition
being freeze-dried may be beneficial during a drying step, while a
vessel containing the composition is in a drying module. By
contrast, if a feedback control system is not employed, drying
parameters including temperature, pressure, and time would likely
be developed empirically by lyophilization professionals in a
costly process, as is currently the case in some batch
freeze-drying methods.
[0087] In some embodiments, a system includes one or more cleaning
modules, one or more sterilization modules, and/or one or more
cleaning/sterilization modules. In some embodiments, a common
cleaning/sterilization module is connected to each freezing module
and each drying module. In some embodiments, a respective
cleaning/sterilization module is connected to each freezing module
and each drying module. In some embodiments, a
cleaning/sterilization module is operated to sterilize a freezing
module or drying module, or to sterilize another module in a system
provided herein, while the module is empty. In embodiments where a
system provided herein comprises a plurality of freezing modules
and a plurality of drying modules, a freeze-drying process may
continue during sterilization of an empty freezing module or drying
module. In some embodiments, sterilization of a freezing module or
drying module is between or equal to 10 minutes and 2 hours in
duration (e.g., between or equal to 30 minutes and one hour
induration).
[0088] In some embodiments, the volume occupied by the one or more
freezing modules and one or more drying modules of a system
provided herein may be significantly less than the volume occupied
by equipment used in batch freeze-drying for a similar number and
volume of vessels containing compositions to be freeze-dried. In
some embodiments, the volume occupied by the one or more freezing
modules and one or more drying modules in a system provided herein
is between or equal to 0.1 m.sup.3 and 4 m.sup.3 (e.g., between or
equal to 0.1 m.sup.3 and 0.3 m.sup.3, between or equal to 0.15
m.sup.3 and 0.25 m.sup.3, 0.2 m.sup.3, between or equal to 1
m.sup.3 and 2 m.sup.3, between or equal to 1.2 m.sup.3 and 1.8
m.sup.3, between or equal to 1.4 m.sup.3 and 1.8 m.sup.3, between
or equal to 1.5 m.sup.3 and 1.7 m.sup.3, 1.6 m.sup.3, 3 m.sup.3, 2
m.sup.3). In some embodiments, the volume occupied by an entire
system provided herein is between or equal to 0.1 m.sup.3 and 4
m.sup.3 (e.g., between or equal to 1 m.sup.3 and 3 m.sup.3). In
some embodiments, the volume occupied by an entire system provided
herein is 2 m.sup.3 or 3 m.sup.3, whereas the volume of a
comparable batch freeze-drying system may be 16 m.sup.3. In some
embodiments, the surface area occupied by each of the one or more
freezing modules and one or more drying modules in a system
provided herein is between or equal to 1 m.sup.2 and 2 m.sup.2
(e.g., between or equal to 1.2 m.sup.2 and 1.7 m.sup.2, 1.5
m.sup.2). In some embodiments, one or more modules are stacked
together. In certain illustrative embodiments, one or more freezing
modules and one or more drying modules are stacked together. In
certain illustrative embodiments, each of the one or more freezing
modules and one or more drying modules in a system provided herein
has a size of 1.2 m in length, 1.2 m in width, and 0.1 m in height.
In certain illustrative embodiments, a stack of one or more
freezing modules and one or more drying modules may be 1.2 m in
length, 1.2 m in width, and 1.1 min height.
[0089] In some embodiments, module volume in a system disclosed
herein is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times smaller than
that of a module in a batch system (e.g., FIG. 26, precautionary
cycles). In some embodiments, module volume in a system disclosed
herein is 13, 14, or 15 times smaller than that of a module in a
batch system (e.g., FIG. 26, conventional cycles).
[0090] In some embodiments, a system is operated to freeze-dry a
pharmaceutical formulation. In some embodiments, freeze-drying
occurs at least in part by vacuum induced surface freezing (VISF).
In some embodiments, a pharmaceutical formulation comprises an
excipient (e.g., sucrose, mannitol). An excipient may comprise a
salt (e.g., sodium chloride). In some embodiments, a pharmaceutical
formulation comprises an excipient at between or equal to 1 weight
percent (wt %) and 10 weight percent versus the total weight of the
pharmaceutical formulation (e.g., between or equal to 2 wt % and 8
wt %. between or equal to 3 wt % and 7 wt %. between or equal to 4
wt % and 6 wt %, 5 wt % versus the total weight of the
pharmaceutical formulation). A composition to be freeze-dried may
be a pharmaceutical formulation comprising 5 weight percent
mannitol versus the total weight of the pharmaceutical formulation.
In some embodiments, a pharmaceutical formulation comprises an
active pharmaceutical ingredient (also referred to herein as a
pharmaceutical; e.g., antidiuretic hormone (ADH)). An active
pharmaceutical ingredient in a pharmaceutical formulation may be
present in an amount such that a product of freeze-drying the
pharmaceutical formulation comprises between or equal to 1 mg per
gram and 10 mg per gram of the active pharmaceutical ingredient
versus the total weight of the product. In a non-limiting certain
illustrative embodiment, a pharmaceutical formulation comprises 5
weight percent sucrose versus the total weight of the
pharmaceutical formulation and 0.05 weight percent ADH versus the
total weight of the pharmaceutical formulation.
[0091] In some embodiments, a system is configured and operated so
as to freeze-dry compositions at a rate of between or equal to 10
vessels per hour and 1000 vessels per hour. In some embodiments, a
system is configured and operated to yield between or equal to 30
and 60 vessels per hour of freeze-dried product. In some
embodiments, a system is configured and operated under conditions
so as to produce between or equal to 10 vessels per hour and 1000
vessels per hour (e.g., between or equal to 40 vessels per hour and
60 vessels per hour, 50 vessels per hour, between or equal to 100
vessels per hour and 1000 vessels per hour, between or equal to 200
vessels per hour and 1000 vessels per hour, between or equal to 200
vessels per hour and 900 vessels per hour, between or equal to 200
vessels per hour and 800 vessels per hour, between or equal to 200
vessels per hour and 700 vessels per hour, between or equal to 200
vessels per hour and 600 vessels per hour, between or equal to 200
vessels per hour and 500 vessels per hour, between or equal to 200
vessels per hour and 400 vessels per hour, 300 vessels per
hour).
[0092] The morphology (e.g., porosity, micro-porosity) of a product
of freeze-drying may be defined by an excipient (e.g., sucrose,
mannitol, lactose) rather than by an active pharmaceutical
ingredient, e.g., in embodiments where the active pharmaceutical
ingredient is present with the excipient in an amount between or
equal to 1 mg of active pharmaceutical ingredient per gram of
product and 10 mg of active pharmaceutical ingredient per gram of
product.
[0093] In certain illustrative embodiments, a system comprises a
filling module connected to a freezing module which is in turn
connected to a drying module. In some such illustrative
embodiments, both the freezing module and the drying module are
connected to a refrigeration module, and the drying module is
connected to two condensers which are in turn connected to vacuum
pumps (e.g., FIG. 32).
[0094] In certain illustrative embodiments, a system comprises a
continuous filling module connected to a freezing module, which is
in turn connected to a plurality of drying modules. In some such
illustrative embodiments, a refrigeration module is connected to
both the freezing module and each of the plurality of drying
modules. In some such embodiments, a cleaning/sterilization module
is connected to both the freezing module and each of the plurality
of drying modules. In some such embodiments, 3 vacuum pumps are
connected to 2 condensers, which in turn are connected to each of
the drying modules (e.g., FIG. 34).
[0095] In certain illustrative embodiments, a system includes one
freezing module, 6 drying modules, 2 condensers, 3 vacuum pumps, 2
load-lock systems for each module, an automatic filling system, a
cleaning/sterilization module, instrumentation for heat transfer
fluid temperature control and pressure control (e.g., pneumatic
valve, one or more pressure sensors, one or more platinum
resistance thermometers), and automated control instrumentation
(e.g., wireless temperature sensors, model-based controllers for
selection of processing conditions for a composition of interest).
In some such illustrative embodiments, the automatic filling system
is connected to the freezing module, which is connected to each of
the 6 drying modules so that the 6 drying modules are configured in
parallel to one another, the load-lock systems connect the
automatic filling system to the freezing module and/or connect the
freezing module to each of the drying modules, the 3 vacuum pumps
are connected to the 2 condensers which are connected to each of
the 6 drying modules, a cleaning/sterilization module is connected
to the freezing module and the 6 drying modules.
[0096] In some embodiments, non-limiting systems and associated
methods for continuous lyophilization of pharmaceuticals in the
form of unit-doses are provided. In some embodiments, a constant
flow of vials may enter and leave a system provided herein, passing
through different, specialized, chambers (e.g., FIG. 36).
[0097] In some embodiments, an apparatus (also referred to herein
as a system) comprises a plurality of modules (e.g., a first module
and a second module; e.g. a first chamber and a second chamber) in
which vessels comprising target product flow along, experiencing
different temperature and pressure conditions. In some embodiments,
continuous flow is achieved by suspending vessels (e.g., vials)
between two moving tracks (e.g., on a conveyor). In some
embodiments, vessels are first continuously filled with a solution
comprising target product and then move along modules having
different conditions. A system, in some embodiments, comprises
modules, each of which is dedicated to a single process step, that
are connected each other to result in continuity of vessel flow and
integration with downstream processes. In some embodiments, a first
module is connected to a second module by an interface apparatus
(e.g., a sluice-gate system, a load-lock system, a valve), so that
each vessel can move from the first module to a second module in
cases wherein the pressure condition of the first module is
significantly different from the pressure condition of the second
module.
[0098] In some embodiments, a module (e.g., comprising a chamber)
may have a shape that is a cylinder, a rectangular prism, or any
other suitable shape. In some embodiments, the walls of modules
comprise stainless steel. In some embodiments, the walls of a given
module have a relatively high emissivity coefficient (e.g., 0.85).
In some embodiments, the temperature of the walls of a given module
will be adjusted so as to regulate heat transfer from the equipment
(e.g., walls) of the module to the product being freeze-dried,
using known quantities such as the emissivity coefficient of the
module walls.
[0099] In some embodiments, a system comprises three modules
connected to one another in series: one freezing module and two
drying modules. In such embodiments, it may be that in all three
modules, vials are suspended and move continuously over a track. A
freezing module may also be connected to a refrigeration system,
that for example allows the introduction of flow of liquid nitrogen
and regulation of flow rate of liquid nitrogen to cool vials as
fast as possible. In some cases, a freezing module is configured to
operate at atmospheric pressure, so it is not required to be
connected to a vacuum system. Each drying module may be connected
to a vacuum system.
[0100] By utilizing a configuration wherein vials are suspended,
this may allow equipment-to-vial heat transfer to be very uniform.
By contrast, a configuration used in conventional batch
freeze-drying might require that vials are in direct contact with a
temperature-controlled surface, promoting vial-to-vial variations
in heat transfer due to variations in the geometry at the bottom of
the vial. The gap at the bottom of vials may not be identical
across vials, and even small variations can produce dramatic
changes in heat transfer during freezing and/or during drying in
batch processes. Vials that are commonly used in batch
freeze-drying can also be used for continuous freeze-drying
equipment. In some cases, if a maximum allowable product
temperature is very low (e.g., below negative 30 degrees Celsius),
external walls of vials may be coated with a polymeric film to
reduce the emissivity of the vial material. A polymer film coating
may allow for the use of a higher temperature of the equipment wall
during drying, which would save energy for the refrigeration
system.
[0101] In some embodiments, the condensing temperature of a solvent
in a starting composition is greater than the minimum temperature
reached by the surface of the condenser (e.g., negative 80 degrees
Celsius). A condenser in some embodiments is a part of a vacuum
system and is placed just before a vacuum pump to promote
separation of condensable gases evacuated from the drying
chambers.
[0102] In some embodiments, the length of a primary drying chamber
is designed so as to provide a given productivity rate (e.g.,
number of vials per week) and facilitate appropriate residence
time. As residence time may be product-specific, if a primary
drying chamber is used for different types of product, it can be
designed for a product that requires a long residence time, e.g.,
48 h for primary drying. In some embodiments, primary drying is the
bottle neck of a system provided herein, so primary drying
determines the speed of travel of the vials. In some embodiments,
for various productivity rates and cycle times, the speed of travel
of vials is in the range of from 0.01 m/h to 2 m/h.
[0103] In some embodiments, modules may be configured in single
file, e.g., linearly, and/or may be configured in parallel lines in
order to increase productivity rate and flexibility (e.g., to
respond to production variations).
[0104] In some embodiments, presently disclosed methods and systems
exhibit one or more of the following advantages: [0105] a) Reduced
risk of contamination of products and operators; [0106] b) No
manual handling during a whole method; [0107] c) Increased safety
of the method; [0108] d) Modular equipment and facilities increase
flexibility and the productivity rate of the method; [0109] e)
Reduced inventory; [0110] f) Reduced capital costs and reduced
amount of partially processed materials; [0111] g) Smaller
ecological footprint; [0112] h) Ready scale-up from laboratory to
production units; [0113] i) Continuous freeze-drying of different
forms of products possible: bulk materials, spin-frozen materials,
particle-based materials; [0114] j) Continuous freeze-drying using
different vessels possible: vials of desired dimension and
material, syringes, double chamber cartridges, ampoule, phials
(vials); [0115] k) Improved product quality and standardization;
and [0116] l) In-line control of product quality.
[0117] In some embodiments, average pore size, in a composition
being processed by system and method described herein, has an
impact on both drying behavior and on preservation efficiency of
biological activity of an active pharmaceutical ingredient in a
product of freeze-drying. In some embodiments, the larger the pores
are, the lower the resistance of the porous structure to vapor flow
and hence the faster the drying. In some embodiments, the average
pore size of product obtained from continuous freeze-drying systems
and methods herein was greater than the average pore size of
product obtained from batch freeze-drying systems and methods
(e.g., FIG. 22, FIG. 31). It follows that in some embodiments,
continuous freezing speeds up drying relative to batch freezing.
Furthermore, in some embodiments, many active ingredients (e.g.,
active pharmaceutical ingredients) degrade because of adsorption
over the solvent crystals surface (e.g., ice crystals surface). It
follows that in some embodiments, the larger the pores are, the
smaller the specific surface area of the product and the smaller
the degradation of the active ingredients. Again, in some
embodiments, systems and methods described herein for continuous
freezing are beneficial to the efficiency of preservation of the
active ingredients. In some embodiments, the average pore size of
product obtained from continuous freeze-drying systems and methods
herein is between or equal to 20 microns and 1000 microns, between
or equal to 50 microns and 1000 microns, between or equal to 100
microns and 600 microns, between or equal to 100 microns and 400
microns, between or equal to 50 microns and 300 microns, between or
equal to 50 microns and 200 microns, between or equal to 20 microns
and 80 microns, between or equal to 40 microns and 70 microns, or
between or equal to 100 microns and 200 microns. In certain
embodiments, the average pore size of product obtained from
continuous freeze-drying systems and methods herein was between or
equal to 100 microns and 200 microns (e.g., FIG. 22, FIG. 31).
Average pore size may be measured, e.g., by scanning electron
microscopy. Turning to the figures, FIG. 1 shows a non-limiting
illustrative schematic diagram of a continuous freeze-drying
process and associated system for liquid solutions, slurries,
pulps, juices, broth, foam, and any other suitable starting
composition in vials.
[0118] A system provided in FIG. 1 comprises a plurality of modules
comprising filling module 104, freezing module 106, primary drying
module 108, and secondary drying module 110 arranged to promote
step-wise freezing and drying of a composition 112, and a conveyer
system 114 configured to continuously move a vessel 102, configured
to contain the composition, through the plurality of modules. A
vessel 102 in FIG. 1 comprises a housing 103 defining a boundary
between an exterior surrounding 109 of the vessel and an interior
space 101 configured to contain the composition, and wherein, when
present in a module (e.g., 106, 108, 110) of a plurality of
modules, the vessel is arranged (e.g., using conveyor system 114)
to promote heat transfer (e.g., substantially uniform heat
transfer) between the exterior surrounding and the interior space
across the entire portion 105 of the housing contactable with the
composition in the interior space when the composition is present
in the interior space.
[0119] FIG. 1 also provides a schematic diagram for a non-limiting
method for processing a composition. A non-limiting method as
illustrated in FIG. 1 comprises continuously moving a vessel 102,
configured to contain a composition 112, through a plurality of
modules (e.g., 104, 106, 108, 110) arranged to promote step-wise
freezing and/or drying of the composition, wherein the vessel
comprises a housing 103 defining a boundary between an exterior
surrounding 109 of the vessel and an interior space 101 configured
to contain the composition, and wherein, during movement of the
vessel (vial movement direction) through the plurality of modules,
the vessel is arranged (e.g., using conveyor system 114) to promote
heat transfer (e.g., substantially uniform heat transfer) between
the exterior surrounding and the interior space across a portion
105 of the housing contactable with the composition in the interior
space when the composition is present in the interior space.
[0120] The same concept can be applied for different vessels. In
some embodiments, a process comprises the following steps: [0121]
a) a vessel 102 is continuously filled with a composition 112 in a
sterile environment ("continuous filling") at filling module 104;
[0122] b) the vessel 102 is loaded into a conditioning module
("loading") and reaches the desired temperature (not shown); [0123]
c) the vessel 102 is moved into a freezing module 106 where it is
cooled down by air convection until complete solidification occurs;
[0124] d) the vessel 102 is moved through an interface apparatus
120 into a primary drying module 108, where external pressure
(using vacuum system 122) and temperature (using refrigeration
system 124) are set to the values required to promote sublimation
of ice from the frozen product; [0125] e) the vessel 102 is moved
into a secondary drying module 110, where external pressure and
temperature are set to values in order to promote desorption of
residual moisture from the dried product; [0126] f) the vessel is
moved into a pre-storage module 118, where the vessel is
conditioned to storage temperature, backfilled with a proper inert
gas and then closed.
[0127] A non-limiting system and associated method for
freeze-drying a substance is provided in FIG. 2. A non-limiting
method as illustrated in FIG. 2 comprises a) continuously moving a
vessel 202 that contains a composition 212 comprising a substance
through a conditioning module 216, wherein the vessel resides in
the conditioning module for a time sufficient to bring the
composition to a conditioning temperature; b) continuously moving
the vessel from the conditioning module to, and then through, a
freezing module (e.g., secondary freezing module 206), wherein the
vessel resides in the freezing module for a time sufficient to
freeze the composition; and c) continuously moving the vessel from
the freezing module to, and then through, a primary drying module
208, wherein the vessel resides in the primary drying module for a
time sufficient to sublimate a frozen solvent from the
composition.
[0128] FIG. 2 shows a non-limiting illustrative schematic diagram
of a continuous freeze-drying process for liquid solutions,
slurries, pulps, juices, broth, foam, and any other suitable
starting composition in vials in which nucleation is induced
through vacuum-induced surface freezing. The same concept can be
applied for different vessels. The process comprises the following
steps: [0129] a) a vessel 202 is continuously filled in a sterile
environment ("continuous vials filling and loading") at filling
module 204; [0130] b) the vessel is loaded into a conditioning
module 216 ("conditioning and cooling below T.sub.m" where T.sub.m
is melting temperature of the composition) and reaches the
temperature at which nucleation is desired; [0131] c) the vessel is
moved into a nucleation module 226, where the pressure is set to
the desired pressure at the desired temperature and nucleation is
induced in the product; [0132] d) the vessel is moved into a
secondary freezing module 206 where it is cooled down by air
convection until complete solidification occurs; [0133] e) the
vessel is moved into a primary drying module 208, where the
pressure and temperature are set to the values required to promote
sublimation of ice from the frozen product; [0134] f) the vessel is
moved into a secondary drying module 210, where the pressure and
temperature are set to the values required to promote desorption of
residual moisture from the dried product; [0135] g) the vessel is
moved into the pre-storage module 218, where the vessel is
conditioned to storage temperature, backfilled with a proper inert
gas and then closed.
[0136] FIG. 3 shows a non-limiting illustrative schematic diagram
of a continuous freeze-drying process in the case of particle-based
material and spin-frozen products. The same concept can be applied
for different vessels. The "production of frozen microparticle"
(e.g., granules, spin-frozen materials) is outside of the scope of
this disclosure. The process comprises the following steps: [0137]
a) a vessel (vial 302), already filled with a frozen composition
312 comprising a target product, is loaded into a conditioning
module 316 until desired temperature is reached; [0138] b) the
vessel is moved into a primary drying module 308, where pressure
and temperature are set to values in order to promote sublimation
of ice from the frozen product; [0139] c) the vessel is moved into
a secondary drying module 310, where pressure and temperature are
set to values in order to promote desorption of residual moisture
from the dried product; [0140] d) the vessel is moved into a
pre-storage module 318, where a vial 302 is conditioned to storage
temperature, backfilled with a proper inert gas and then
closed.
Continuous Filling and Loading
[0141] The systems provided herein, in some embodiments, can
process different types of products and can be used with different
types of vessels. Certain embodiments provide a process for
carrying out freeze-drying of (a) liquid solutions, (b)
particle-based materials, (c) slurries, (d) pulps, (e) juices, (f)
broths, (g) foams, and any other suitable starting composition. In
some cases, the liquid material is an aqueous solution or
suspension typical of the pharmaceutical industry. This disclosure
can also be applied to solutions having solvents other than water.
The starting composition may comprise antibiotics, vaccines,
enzymes, drugs, serum and/or other chemical or biochemical
components. The starting composition may comprise slurries, pulps,
soups and/or juices typical of the food industry.
[0142] The starting composition can be processed using different
vessels (e.g., vials of the desired dimension and material,
syringes, double chamber cartridges, ampoule, phials, etc.).
[0143] In the case of liquid solutions, slurries, pulps and juices,
in some embodiments the starting composition is continuously filled
into vessels. In the case of particle-based material, in some
embodiments the frozen particles are continuously filled into
vessels. Once the vessel is filled, the vessel may be partially
stoppered and then continuously loaded into the apparatus. In some
embodiments, a fully automated system provides a sufficient number
of vessels per minute to feed the freezing modules. Filling may be
carried out in a sterilized and temperature-controlled
environment.
Moving Vessels Through the Continuous Freeze-Drier
[0144] A number of non-limiting examples are provided for moving
vials though the various modules, and facilitating the transfer of
vials to/from environments working at different temperature and
pressure.
[0145] FIG. 4 shows a non-limiting first configuration for moving
vials through a continuous freeze-dryer. As a vial 402 enters a new
module, a piston 440 may lift vial 402 up in direction 447 so that
the vial 402 is sufficiently close to a gripper 442. Then, the
gripper 442 may grab the vial 402 (with gripper direction of motion
443) and hold onto the vial 402 (at which point the piston 440
retreats in direction 453) until the end of a module where the vial
302 is released (with gripper direction of motion 441) and travels
in direction 449. The gripper 442 can effectively transport the
vial 302 along the module through a trolley 444 that moves over a
track in direction 451 (with wheels 443 turning in direction
445).
[0146] FIG. 5 shows a non-limiting second configuration for the
transport of vials along a continuous freeze-dryer. As a vial 502
enters a new module, a piston (not shown) may lift vial 502 up so
that the vial 502 is sufficiently close to two metallic
semicircular parts 550. When the vial 502 reaches the correct
position, the two metallic parts join one another along parallel
directions 549, forming a skate 552, and may maintain that position
until the end of the module where the vial is released, e.g., in a
reverse manner as the metallic parts are separated from one
another. The skate 552 can effectively transport the vial along the
module sliding over a track 554.
[0147] FIG. 6 shows another non-limiting system for moving vials
along a continuous freeze-dryer. First, a vertical piston 640 lifts
the vial 602 up in direction 647; then, a second piston 642 pushes
the vial along a track 654 in direction 661 and, in this way, the
entire row of vials is moved ahead in direction 661. The piston 642
is withdrawn in direction 663 between vials fed from piston
640.
Moving Vessels Between Modules
[0148] At least four different non-limiting configurations for
load-lock systems to be used to transfer vessels between modules
operating at different pressure and temperature are described
herein.
[0149] FIG. 7 shows a non-limiting example of a load-lock system
700 to be used to transfer the vessels from one module (e.g.,
module A) to a subsequent module (e.g., module B). At the end of
each module, vessel 702 is picked up through a piston 740 and is
transferred into an intermediate chamber 716, named a conditioning
chamber 716. As vessel 702 is transferred into the conditioning
chamber 716, a metallic sheet 770 at the base of the piston 740
isolates this chamber 716 from the module A (FIG. 7, second from
left). After that, the pressure in chamber 716 is reduced through a
vacuum pump, or increased by introducing a controlled flow rate of
sterile gas at atmospheric pressure, by in-line pump 772. Once a
desired pressure in chamber 716 has been reached, the conditioning
chamber 716 is opened (FIG. 7, second from right) and a second
piston 742 pushes the vessel 702 along direction 761 through the
track 754 of module B (FIG. 7, right). Once the vessel 702 has been
transferred, the conditioning chamber 716 is closed, the pressure
is adjusted according to that of module A (using in-line pump 772),
and finally conditioning chamber 716 is re-opened using piston 740.
This apparatus can also be used to induce nucleation by
vacuum-induced surface freezing; see FIG. 2.
[0150] FIG. 8 is a non-limiting alternative apparatus 800 (and
associated methods) to the load-lock system 700 shown in FIG. 7. In
this version, once the vessel 802 has been transferred into the
conditioning chamber 816 and isolated from module A, the
conditioning chamber 816 is re-opened without any preventive
pressure regulation. As the volume of the conditioning chamber is
much smaller than that of module B, the pressure disturbance
introduced by this operation is negligible.
[0151] FIG. 9 shows a non-limiting schematic diagram in perspective
view 9100 and bird's eye view 9200 of an alternative load-lock
system 900 (also referred to herein as a load-lock apparatus) to
transfer vessel 902 between two modules (e.g., module A and module
B). The apparatus comprises two coaxial cylinders: an internal
cylinder 990 that can rotate, and an external cylinder 992 that
remains fixed. As can be seen in FIG. 9, the vessel 902 enters the
load-lock system from a first module (9200, second-from-top to
third-from-top), through upper opening 991; then, the internal
cylinder 990 of the apparatus rotates 90 degrees as illustrated by
rotation direction 993 and piston 940 moves vial 902 in direction
947. During rotation, upper opening 991 is closed and then a new
opening 995 appears in the lower part. At this point, a piston 942
pushes vessel 902 in direction 961 out of the load-lock system over
a track (not shown) of a second module.
[0152] FIG. 10 shows a non-limiting alternative load-lock system
1000 (and associated methods) to the load-lock system 900 described
in FIG. 9, in perspective view 1100 and bird's eye view 1200. The
apparatus comprises two coaxial cylinders: an internal cylinder
1090 that can rotate, and an external cylinder 1092 that remains
fixed. Vessel 1002 enters the load-lock system from a first module
(1200, second-from-top to third-from-top), through upper opening
1091; then, internal cylinder 1090 of the load-lock system 1000
rotates 90 degrees in direction 1093, closing upper opening 1091
and isolating load-lock chamber 1094. Vessel 1002 is lowered down
through piston 1040 in direction 1047 and the pressure surrounding
vessel 1002 is regulated through a vacuum system 1072. After that,
the inner cylinder 1090 rotates 90 degrees in direction 1099
creating an opening 1095 in the lower part of the apparatus through
which the vessel exits the load-lock apparatus in direction 1061,
via a side-piston 1042, and moves over a track of a second module
(not shown).
[0153] FIG. 11 shows a non-limiting schematic diagram of a rotating
load-lock system. As vessel 1102 enters the load-lock apparatus, a
rotary valve 1140 moves the vessel ahead. During this transition,
the valve 1140 can undergo different values of pressure, decreasing
or increasing pressure, depending on the request. This rotating
load-lock system can also be used to induce solvent nucleation by
vacuum-induced surface freezing. Nucleation may here be promoted by
vacuum. As vial 1102 is picked up, vial 1102 travels through three
subsequent chambers, 1108, 1110, and 1112 and is exposed to
progressively decreasing pressure. Vacuum promotes solvent
evaporation on the top surface of a liquid composition in vial 1102
and hence its cooling. This phenomenon may stabilize solvent
clusters and allow formation of stable nuclei and, thus, induce
nucleation at a desired temperature, e.g., a temperature of the
product at the end of the conditioning chamber. In chamber 1114,
atmospheric pressure is re-established. In principle, vacuum
induced nucleation can be achieved by using only two chambers,
chamber 1108 for vacuum and chamber 1114 for re-stablishing
atmospheric pressure. More specifically, e.g., vessel 1102, coming
from conditioning chamber 1116 which is at atmospheric pressure,
moves into rotary valve 1140, where pressure is decreased to the
desired pressure. During its passage into the valve 1140, vessel
1102 may experience decreasing pressure (at 1108, 1110, 1112) which
may assure that nucleation occurs instantaneously. The valve 1140
is connected to a vacuum system and a controlled leakage line to
regulate the final pressure (at connections 1141, 1143, 1145,
1147). After chamber 1112, vessel 1102 exits rotary valve 1140 and
is pushed, over a track (not shown), into the next module 1106
(e.g., a freezing module).
The Freezing Module
[0154] As can be seen in FIG. 1, FIG. 2, and FIG. 3, a vessel may
be filled in with a given volume of liquid or frozen particles and
then transferred through a load-lock system into a freezing module.
Here, vessels may be suspended and moved over a moving track using
one the various strategies depicted in FIG. 4, FIG. 5, and FIG.
6.
[0155] As can be seen in FIG. 12, a non-limiting system for the
continuous freeze-drying of a composition is provided. A system
provided in FIG. 12 comprises a first module (e.g., freezing module
1206) and a second module (e.g., primary drying module 1208) and an
interface apparatus (e.g., load-lock system 1230) connecting the
first module to the second module. A first module 1206 in FIG. 12
comprises a freezing chamber and a second module 1208 in FIG. 12
comprises a drying chamber. In FIG. 12, vessels 1202 comprising a
composition 1212 are suspended in a line along a conveyor 1214.
[0156] A freezing module in FIG. 12 comprises three sub-modules in
some embodiments: (A) a conditioning module 1216, (B) a load-lock
system 1231 where controlled nucleation can eventually occur, and
(C) an equilibration/freezing module 1206. In a conditioning module
1216 in FIG. 12, in some embodiments, a vessel 1202 containing a
composition 1212 (vessel 1202 having been filled at filling module
1204) is cooled down and equilibrated to a desired temperature by
adjusting temperature and flow rate of a cryogenic gas using
cooling system 1224. At the end of conditioning module 1216, vessel
1202 may enter load-lock system 1231. After entering, vessel 1202
can simply be transferred to the subsequent module (freezing module
1206), or vessel 1202 is exposed to a vacuum that makes nucleation
occur and vessel 1202 then is transferred to the subsequent module.
This last operation can be effectively done if for example the
starting material is liquid. Once vessel 1202 has been transferred
to freezing module 1206, its temperature is lowered until
completion of solution solidification.
[0157] Table 1 shows an overview of operations that may be involved
in freezing modules depending on the initial state of a material to
be freeze-dried.
TABLE-US-00001 TABLE 1 Freezing operations for different types of
material Continuous freezing Conditioning Nucleation Freezing
Materials Filling module chamber module Liquid Yes Yes (not Yes
(not Yes solutions, compulsory) compulsory) slurries, broth, pulps,
juices and foam Particle-based Yes Yes (not No No materials
compulsory)
FIG. 30 depicts a summary of operations that a continuous
lyophilizer may carry out depending on the physical state of the
product to be freeze-dried: 3001, no nucleation (e.g.,
particle-based materials; 3002, spontaneous nucleation (e.g.,
liquid solutions, slurries, broth, pulps, juices, foam, etc.); and
3003, controlled nucleation (e.g., liquid solutions, slurries,
broth, pulps, juices, foam, etc.).
The Conditioning Module
[0158] In the conditioning module, in some embodiments, vessels are
conditioned to a desired temperature by flowing a cryogenic fluid
(e.g., nitrogen gas, liquid nitrogen) at a controlled temperature
and flow rate. In some embodiments, vessels are suspended over a
moving track and moved along a module using an apparatus comprising
a track described herein. In some embodiments, vessels move along a
conditioning module with a velocity that is determined by a drying
module. In such embodiments, temperature and flow rate of a
cryogenic fluid may be adjusted so that the vessels reach their
desired temperature before leaving the conditioning module.
[0159] In some embodiments, conditioning of a starting composition
to be freeze-dried improves the homogeneity of the composition
during freezing by resulting in all vessels having the same
temperature as one another as they exit from a conditioning
module.
Control of Nucleation Temperature
[0160] In accordance with some embodiments, nucleation temperature,
for a composition to be processed by a system and method described
herein, is controlled in order to make both the drying behavior and
the product morphology more uniform. Non-limiting examples of
methods to control nucleation temperature include ultrasound, ice
fog, and pressure disturbance. All of these methods can be
integrated into a nucleation module, but mainly vacuum-induced
surface freezing is discussed herein, which uses a vacuum system to
instantaneously induce a nucleation event in a composition herein,
at least because in some embodiments, a vacuum system can easily be
added to a load-lock system used to load vessels into the freezing
module. Nucleation in a composition may be induced by reducing
pressure directly inside a load-lock chamber; the pressure
reduction may promote partial evaporation of a solvent in the
composition and hence cool the solution, facilitating formation of
stable nuclei. In some embodiments, this method results in
consistent nucleation temperature across multiple vessels and
therefore results in consistent ice morphology among the
vessels.
The Freezing Module
[0161] In some embodiments, in a freezing module, vessels are
cooled down by natural convection or forced air circulation until
complete solidification of the product occurs. A vessel in some
cases is suspended over a moving track and is introduced into a
freezing module.
[0162] In a freezing module, heat may be prevalently transferred by
gas convection and radiation from the surroundings. In order to
speed up the freezing process and make heat transfer between the
freezing module equipment and a vessel more uniform, a cryogenic
fluid can be forced to move along the freezing module, similarly to
the conditioning module. In such cases, external surfaces of the
vessel may be equally flushed by the cryogenic fluid (e.g.,
cryogenic gas), resulting in significantly reduced heterogeneity of
heat flux relative to that in conventional batch freezing.
[0163] Different freezing protocols, including annealing that makes
the frozen product morphology further uniform, can be performed by
modulating the velocity of cryogenic fluid and its temperature.
Additionally, these two process parameters can be adjusted to
control the duration of the freezing and, thus, replicate the
forward velocity of the vessels selected for the drying module on
the freezing module.
The Primary and Secondary Drying Module
[0164] In some embodiments, each drying module (e.g., primary
drying module 1208 and secondary drying module 1210 in FIG. 12) is
connected to a vacuum system (e.g., centralized vacuum system 1222
in FIG. 12), condenser and vacuum pump, which allows control to the
desired pressure, while temperature of the equipment surfaces is
controlled by adjusting the temperature of the heat transfer fluid,
silicone oil, by a refrigeration (cooling) system (e.g., 1224 in
FIG. 12) as shown in FIG. 12. An external heat exchanger may be
used to control the temperature of a heat transfer fluid, silicone
oil, which is flowing within the equipment walls. In some
embodiments, a chiller may be used, and then an electrical
resistance may be used to adjust to a final temperature. As an
alternative, an infrared source of heating the product may be used
during drying.
[0165] In this configuration, in some embodiments, the vessels are
not in contact with the shelves, and heat is primarily transferred
by radiation. In fact, low pressure, below 1 mbar, may make heat
transfer by convection and conduction negligible with respect to
the radiative contribution. This configuration may allow the heat
to be uniformly transferred to the vessel, avoiding those issues
that are typical of batch freeze-drying. Besides that, temperature
and pressure gradients within the equipment may no longer represent
a cause of heterogeneity in heat transfer because vessels,
following the same path, experience the same identical
conditions.
[0166] In this module, heat may be supplied by radiation through
temperature controlled surfaces, but can potentially be transferred
by using other technologies such as infrared radiation or
microwave. In some embodiments, as heat is primarily transferred by
radiation, the control of the temperature of the product being
dried may be much easier and allows uniformity in heat transfer
and, thus, in drying behavior.
[0167] The same equipment configuration may be suitable for both
the primary drying module and the secondary drying module; the two
modules may in some embodiments be identical but operate at
different pressures and temperatures from one another.
[0168] The continuous equipment can be adapted to carry out
atmospheric freeze-drying. In such cases, the primary and secondary
drying modules may operate at atmospheric pressure; sublimation and
desorption are promoted by exposing the product to a controlled
flow of dried nitrogen, or another gas, at controlled temperature.
In this last case, in some embodiments, the gas at the outlet of
the drying chamber is treated in a system that removes its
moisture, its temperature is adjusted through an appropriate
cooling system, and finally is re-circulated in the drying
chamber.
Backfill and Stoppering/Closing
[0169] In some embodiments, the system may comprise a module for
backfilling and stoppering/closing of the vessel. In some
embodiments, at the end of the secondary drying module, a piston
pushes down and the stopper is placed over the vessel, sealing the
vessel under vacuum conditions. In some embodiments, this procedure
avoids any contamination of the product.
Design of the Modules
[0170] In order to minimize the amount of space occupied by the
equipment, in some embodiments, the vessels can flow within the
various modules, both freezing modules and drying modules, as
either a straight path, e.g. along modules 1216, 1206, 1208, 1210
in FIG. 12, or more compact paths, e.g., as depicted by directional
arrows in FIG. 13 and FIG. 14.
[0171] The following examples are intended to illustrate certain
embodiments of the present disclosure, but do not exemplify the
full scope of the disclosure.
EXAMPLES
[0172] In this section, non-limiting examples of results that can
be obtained by presently disclosed systems (e.g., continuous
lyophilizers) and methods are shown.
Example 1--Freezing
[0173] Freezing conditions may in some embodiments influence the
size and the shape of frozen crystals (e.g., ice crystals) in a
composition, determine the microstructure of the product (e.g., of
freeze-drying), and finally, affect the intra- and inter-vessel
heterogeneity within a production. Freezing may impact not only
product quality but also the rate of sublimation and desorption
during primary and secondary drying.
[0174] Relative aspects of a reference batch process, in which
vessels were loaded onto temperature-controlled shelves (and other
conventional batch techniques were employed), were compared with
those of a continuous-convective process using, as a model
composition, aqueous solutions of excipients mannitol 5% w/w,
sucrose 5% w/w, and lactose 5% w/w. In these tests, glass vials
were used as vessels which were filled with 3 ml of solution. For
continuous freezing, vials were lined up over a track.
[0175] FIG. 15A and FIG. 15B show examples of the results obtained.
In particular, temperature trends are shown for the composition
being dried, mannitol 5% w/w, for the shelves in the case of batch
freezing (e.g., FIG. 15A), and for the equipment surfaces and the
cryogenic gas for the continuous freezing (e.g., FIG. 15B).
[0176] Where batch freezing is used, (e.g., FIG. 15A), it was
observed that the mean temperature of the composition was, as
expected, between the shelf temperature and the temperature of air
within the chamber. It was also observed that temperature gradients
within the frozen composition were significant, between about 1
degrees Celsius and about 5 degrees Celsius depending on the
filling volume, with the lowest temperature corresponding to the
vial bottom and the highest temperature corresponding to the top
surface of the composition. Once nucleation occurred, it was also
observed that crystal growth was much faster close to the bottom of
the vial with respect to the top surface of the liquid being
frozen. Because of that, the ice morphology changed along the axial
position of the composition.
[0177] In the case of continuous freezing, the liquid sample was
prevalently cooled down by convection of a cryogenic gas,
consisting of nitrogen, trapped within the freezing chamber. FIG.
15B shows the temperature evolution of a sample in a vial. In this
case, all of the surfaces of the vial experienced identical
conditions, because the vessels were immersed within the cryogenic
gas, having uniform temperatures nearby the vial, and no contact
with the shelf occurred. No preferential direction of heat removal
occurred and the solution (composition) had a similar thermal
history throughout the whole volume. It can thus be hypothesized
that, after nucleation, crystal growth uniformly occurred within
the filling volume (that is, within the volume of the composition),
leading to a much more uniform product structure as discussed
herein.
[0178] In the case of continuous freezing, temperature and flow
rate of a cryogenic fluid can be adjusted so as to perform
different freezing conditions on a composition and, hence,
manipulate the porous structure of the lyophilized product
resulting from processing the composition using a system and method
described herein. In some embodiments, if air is used as cooling
medium and its forward velocity can be modulated in the range of
between 0 m s.sup.-1 and 10 m s.sup.-1, the heat transfer
coefficient can be modified in the range of between 5 W m.sup.2
K.sup.-1 and 80 W m.sup.2 K.sup.-1. Overall, it was observed that
these conditions allowed the modification of pore sizes in the
range from 20 microns to 100 microns at constant nucleation
temperature, for example approximately negative 8 degrees
Celsius.
[0179] In conclusion, the lyophilized product as obtained by a
non-limiting continuous lyophilizer met the aesthetic requirements
of the pharmaceutical industry. FIG. 16 shows two lyophilized
samples, containing mannitol, as obtained by the batch lyophilizer
(left, lyophilized sample 1604 in vial 1601) and continuous
lyophilizer (right, lyophilized sample 1606 in vial 1602).
Corresponding scanning electron micrographs are shown in FIG. 31.
FIG. 31 shows photographs and scanning electron micrographs, each
scanning electron micrograph with a scale bar of 400 microns, of a
product of batch freeze-drying (FD) (left, photograph 3101 and
scanning electron micrograph 3103) and continuous freeze-drying
respectively (right, photograph 3102 and scanning electron
micrograph 3104), each product containing mannitol, according to
some illustrative embodiments. An increased average pore size may
result from continuous freeze-drying by a method described herein
relative to batch freeze-drying a similar sample (see, e.g., pores
3110 from batch freeze-drying and pores 3112 from continuous
freeze-drying). In some embodiments, continuous freeze-drying
resulted in up to 5 times shorter of a cycle time compared with
batch freeze-drying. The non-limiting continuous freeze-drying
configuration and method may have contributed to large pores, with
constant shelf temperature during freezing. The larger pores may
have corresponded to smaller resistance to vapor flow and therefore
shorter drying time. Breaks during a typical batch production may
be between or equal to 20% and 50% of the total cycle time. By
reducing the total cycle time using continuous freeze-drying
methods as described herein, energy consumption may be reduced as
well.
Example 2--Drying
Uniformity in Drying Behavior
[0180] In batch freeze-drying, heat transfer significantly varied
with the position of the vessel within the batch. A batch of
vessels was conventionally divided into zones, as shown in FIG.
17A. The vessels at the edge of the batch received more heat
compared to those located in the center, due to the contribution of
radiation from chamber walls. This heterogeneity is well described
in FIG. 17B, which shows a spatial distribution of heat flux during
primary drying, as calculated by a standard gravimetric procedure.
FIG. 17C also shows that the maximum product temperature reached
during primary drying was related to the position of vials. For
example, the vessels at the edge of the batch had a product
temperature that was 5 degrees Celsius higher than that of the
vessels loaded in the center of the batch. This is typical behavior
in batch freeze-drying, which leads not only to tremendous
differences in terms of drying times among the vessels of the same
batch, but also to issues during the scale-up of the process from
the laboratory to production scale, or more generally the lack of
control of the drying process. Moreover, the process is usually
designed based upon the maximum temperature allowed to be reached
by the product during primary drying; since this temperature
changed with the position of the vessel within the drying chamber,
it would be a risk to design a cycle that is efficient for
edge-vessels, but too precautionary for vessels placed in the
center, making the process not efficient and longer than that would
be necessary if heat were uniformly distributed over a batch of
vessels.
[0181] By contrast, when a continuous lyophilizer disclosed herein
was used, all the vessels underwent virtually identical heat
transfer conditions; see, e.g., FIG. 17D. In FIG. 17E and FIG. 17F,
heat flux and maximum product temperature is shown for a continuous
lyophilizer in the case of different clearances, that is the
distance between a vessel surface and that of the equipment (e.g.,
chamber walls, floor, or ceiling). Both heat flux and product
temperature did not change with the position of the vessel on the
track.
[0182] FIG. 18 compares drying behavior, product temperature, and
drying time as observed for a batch lyophilizer and a continuous
lyophilizer. This comparison was done at constant temperature of a
heat transfer fluid and pressure. The continuous lyophilizer showed
the shortest drying time, 14 hours (vs. 22 hours for batch), and
the lowest product temperature, negative 20 degrees Celsius (vs.
negative 16 degrees Celsius for batch). Drying time was estimated
by comparing a pressure signal given by a thermo-conductive gauge
and a capacitive one (e.g., by a pressure ratio in FIG. 18), which
is a well-established method in the literature. The onset time and
offset time of this pressure signal was also used to estimate
drying time variance for vessels. The continuous lyophilizer had
the shortest difference between the onset and offset times relative
to the batch system, indicating that the drying behavior of the
vessels was more uniform in the continuous lyophilizer. Variations
in drying time were less in the case of continuous freeze-drying
relative to batch freeze-drying.
Total Cycle Time
[0183] A continuous lyophilizer, as presently disclosed, may allow
for a tremendous reduction in drying time. Since there may be no
difference in temperature among the vessels during production (that
is, during a method described herein), a cycle (also referred to
herein as a method) can be designed to maximize efficiency for all
vessels. By contrast, in batch freeze-drying, a cycle is often
designed using vessels at the edge of the equipment, that might be
easily damaged, as reference, making the designed cycle very
precautionary for the rest of the batch.
[0184] FIG. 19 compares the total cycle time for the batch and
continuous lyophilizer. The reduction in cycle time by using a
continuous lyophilizer can be up to 5 times, and this includes both
reduction in drying time and time saved from elimination of all
breaks that are typical of the batch system and methods. With
constant shelf temperature and pressure, continuous freeze-drying
may have between or equal to 3 and 5 times shorter cycle time
compared with batch freeze-drying. In addition, continuous
freeze-drying may have no dead time, whereas batch freeze-drying
may have, e.g., between or equal to 20% and 40% dead time.
Energy Saving
[0185] In the presently disclosed process, radiant energy may be
used to supply heat to allow sublimation of the solid solvent in a
frozen composition being processed (e.g., ice sublimation). This
allows the use of a higher temperature of a heat transfer fluid,
reducing the energy to be supplied to a refrigeration system and
thus enhancing the energy efficiency of the continuous equipment.
As an example, FIG. 20 compares the temperature of the heat
transfer fluid to be used in a continuous lyophilizer and in a
batch lyophilizer to keep the product temperature at a desired
value. The comparison is given for a very heat sensitive product
(precautionary cycle, left) and a more robust formulation
(aggressive cycle, right).
Example 3--Intra-Vessel and Vessel-to-Vessel Heterogeneity
Intra-Vessel Heterogeneity
[0186] Samples lyophilized by continuous apparatus systematically
showed larger pores than those obtained by the batch lyophilizer;
see, e.g., FIG. 21. In order to evaluate the impact of a continuous
lyophilizer on product uniformity, the internal structure of
individual samples was analyzed, by dividing them into three parts:
top, center and bottom. Overall, batch freezing led to smaller
pores than those obtained by a continuous lyophilizer,
approximately 30 microns (vs. preferable 70 microns for continuous
lyophilization). Furthermore, samples as obtained by the continuous
apparatus were much more uniform (see, e.g., the error bars in FIG.
21).
[0187] In some embodiments, intra-vial heterogeneity in average
pore size of a product was reduced by continuous freeze-drying
apparatus and methods described herein relative to batch
freeze-drying (e.g., FIG. 22). An example of SEM images for the
lyophilized samples is given in FIG. 22. FIG. 22 shows scanning
electron microscopy images with a scale bar of 400 microns for each
image. FIG. 22 demonstrates that intra-vial heterogeneity in pore
size was reduced by continuous freeze-drying relative to batch
freeze-drying. This may have been at least in part because during a
continuous freeze-drying process with suspended vials, heat was
more uniformly removed from the liquid composition being frozen,
relative to batch freeze-drying with vials directly contacting the
base of a chamber.
[0188] In certain embodiments, the average pore size of a product
resulting from a continuous freeze-drying process including
vacuuming-induced surface freezing was 70 microns, whereas a batch
process produced a product with an average pore size of 44 microns.
In certain embodiments, the average pore size of a product
resulting from a continuous freeze-drying process including
vacuuming his surface freezing was 40 microns, whereas a batch
process produced a product with an average pore size of 20
microns.
Vessel-to-Vessel Heterogeneity
[0189] As can be seen in FIG. 23, the lot of lyophilized samples
produced by a continuous apparatus with suspended vials was much
more uniform, in terms of average pore size, than that obtained by
a conventional batch lyophilizer with non-suspended vials. It
follows that a non-limiting continuous lyophilization system and
method reduced vessel-to-vessel heterogeneity and thus enhanced
uniformity of the lot. A similar result was also observed in terms
of final moisture content C.sub.w (% kg.sub.H2O
kg.sub.dried.sup.-1, percent kilograms of water (H.sub.2O) per
kilogram of lyophilized sample (dried)), within a lyophilized
sample, which is a parameter that may be controlled to enhance the
stability of the active ingredient during storage (see, e.g., FIG.
24). FIG. 24 demonstrates a residual moisture distribution at the
end of secondary drying for batch freeze-drying (left) and
continuous freeze-drying (right). Heterogeneity in residual
moisture was reduced for continuous freeze-drying relative to batch
freeze-drying. Therefore, in some embodiments, continuous
freeze-drying systems and methods herein provided increased
stability of an active ingredient during storage relative to batch
freeze-drying.
Example 4--Flexibility/Modularity
[0190] Systems and methods disclosed herein use different modules
in some embodiments, each of which are specialized to a single
operation. These modules can be combined in order to produce
products from different upstream feeds and, eventually, in
different form or with different characteristics, as depicted e.g.
in FIG. 25, making this technology very flexible. As shown in FIG.
25, in some embodiments, modularity is provided and modules can
work in parallel, depending for example on the desired productivity
of the system (e.g., number of vials per week). The modularity of
the system may also allow for synchronization of processing time
and therefore speed of travel of vessels through the various
modules.
Example 5--Equipment Size
[0191] FIG. 26 compares equipment size of a batch lyophilizer and a
continuous lyophilizer in the case of two non-limiting case
studies, which were characterized by different yields. In some case
studies with 200,000 vials per week, in the case of continuous
freeze-drying, the chamber volume was up to 12 times smaller than
that of a batch unit. In some case studies with 100,000 vials per
week, in the case of continuous freeze-drying, the chamber volume
was up to 15 times smaller than that of a batch unit. The
continuous lyophilizer allowed a reduction in equipment size by up
to 15 times for a given yield.
[0192] The size of a given module (e.g., chamber) may be
customizable depending on the desired productivity. Module size can
be designed based upon, for example, a) residence time, b) speed of
travel, and c) dimensions of the channel in the chamber. a)
Residence time may be product-specific, and depends for example on
the drying time. b) Once the dimensions of a module are fixed, a
speed of travel may be determined in order to obtain a certain
residence time for a vial in the module. c) The dimensions of a
channel (e.g., in a module) may depend for example on the type of
vessels used in the process and vessel size. An example of a
calculation for a drying chamber is included in Table 2.
TABLE-US-00002 TABLE 2 Quantity Value Method of Determination
Residence time 30 h Determined by a process Channel dimension 0.05
m by 0.03 m Determined by vial type Total length of the path 35 m
Designed Dimension of the chamber Length 1.82 m Height 0.07 m Width
3.00 m Speed of travel 1.2 m/h Determined from the total length of
a path and residence time Productivity 49 vials/h
Example 6--Connections Between Modules
[0193] Each module in a system for continuous freeze-drying may be
dedicated to one process step and may be connected with the other
modules through small pipes. The length of these pipes may depend
on the dimension of the whole lyophilizer and on the number of
modules. To achieve flexibility of use, when a vial reaches the end
of a module, it can be sent to one of a selection of other modules,
as shown in FIG. 28. FIG. 28 shows a non-limiting network pipe
system to connect modules, wherein Module type A (2806) and Module
type B (2808, 2809, or 2810) are modules that have different
functionality. At the end and at the beginning of each module,
there may be an interface apparatus (2800, e.g., a valve, a gate
system, a load-lock system) connecting the module 2806 with other
module(s) 2808, 2809, and/or 2810. In some embodiments, an
automatic selector system sends each vial along a correct path that
has been dedicated for that production method in order to reach a
respective next module. For example, once a vial exits module type
A (2806, e.g., a freezing module) it follows a specific path to
reach one of the modules type B (2808, 2809, or 2810, e.g., primary
drying modules). For example, a vial may move from Module type A
(2806) to Module type B2 (2809). The pipe network system 2812 may
be essentially confined within a box that allows control to a
desired temperature. For example, if vials move from a module type
A (2806, e.g., primary drying module) to module type B2 (2809,
e.g., a secondary drying module), pressure within connecting pipe
2813 is regulated according to the conditions of module type B2
(2809). This system imparts advantages of high modularity and
flexibility.
[0194] In some embodiments, an alternative to this configuration
involves stacking modules with different functionality. In such
cases, it is possible to work with predefined lines of production
that are dedicated to a certain process or product. FIG. 29
provides a non-limiting schematic diagram of a stack module system
wherein Module type A (2906), Module type B (2908), and Module type
C (2910) are modules that have different functionality. At the
inlet and outlet of each module, there is an interface apparatus
(2900, e.g., a valve, a gate system, a load-lock system) connecting
the module with other module(s). For example, vials may be
processed in production line 2910, as in the schematic diagram.
This system imparts advantages of ease of design and ease of
management during production.
Example 7
[0195] FIG. 32 is a schematic of an apparatus for freeze-drying a
composition, in accordance with some illustrative embodiments. The
apparatus may comprise a filling module connected to a freezing
module which is in turn connected to a drying module. Both the
freezing module and the drying module may be connected to a
refrigeration module, and the drying module may be connected to two
condensers which are in turn connected to vacuum pumps. The drying
module may be operated under conditions so as to produce 50 vials
per hour. Each condenser may consume 4 kg of ice per 72 hours.
Example 8
[0196] FIG. 33 is a schematic of a top view of a drying module
(left), and a perspective view of a freezing module or a drying
module (right), in accordance with some illustrative embodiments.
The freezing module or drying module may have a serpentine path for
vials to travel through. At the vial inlet and the vial outlet may
be located a respective load-lock system (also referred to herein
as a load-lock valve) to accommodate a difference in pressure
between the freezing module or drying module and another module in
the apparatus from which or to which a vial is traveling.
Example 9
[0197] FIG. 34 is a schematic of an apparatus for freeze-drying a
composition, in accordance with some illustrative embodiments. The
apparatus may comprise a continuous filling module connected to a
freezing module, which is in turn connected to a plurality of
drying modules. A refrigeration module may be connected to both the
freezing module and each of the plurality of drying modules. A
cleaning/sterilization module may be connected to both the freezing
module and each of the plurality of drying modules. Three vacuum
pumps may be connected to two condensers, which in turn may be
connected to each of the drying modules
Example 10
[0198] FIG. 35 is a schematic of a top view of a drying module
(left), and a front view (center) and back view (right) of a
parallel stack of drying modules, in accordance with some
illustrative embodiments. The drying modules may be accommodating
vials that move in parallel, each vial entering a drying module
from a common freezing module. Each of the drying modules may
include a dismountable door.
Example 11
[0199] FIG. 36 shows a system for freeze-drying compositions
contained in vials, in accordance with some illustrative
embodiments.
[0200] A method of operating a system, for freeze-drying
compositions contained in vials, may begin with continuously
filling vials with a fluid composition to be freeze-dried, which
vials are suspended over a moving track before or after filling.
The vials may then be moved into a conditioning module. In the
conditioning module, the flow of a cryogenic gas may cool down the
vial, bringing the composition to the desired temperature. At the
end of the conditioning module, the vial may move into a nucleation
chamber, also referred to as a vacuum induced surface freezing
(VISF) chamber, where the pressure is low enough to induce
nucleation of solid crystals of the composition.
[0201] Following the nucleation chamber, the vial may move into a
freezing module, where, again, a cryogenic gas cools down the vial,
achieving complete solidification of the composition. It may be
possible to create customizable freezing protocols by changing the
gas velocity, and so, modulating the freezing rate. The vial may
then be transferred to a drying module by means of a load-lock
system, which facilitates the passage of the vial from a module at
a higher pressure to another module at lower pressure without
breaking the vacuum. In the drying module, vials may be suspended
over a track and move in the module following a serpentine path. A
freezing module and/or a drying module may comprise
temperature-controlled walls that supply heat to the product via
radiation. By changing the temperature of the walls of a module in
which a composition resides, it may be possible to modulate heat
transferred to the composition, and, hence, to carry out both
gentle and aggressive cycles. The last step of a method provided
herein may comprise backfilling and vial stoppering. An entire
method herein may be carried out continuously, without breaks or
manual intervention between steps or modules.
[0202] This non-limiting system and associated methods may result
in increased control of product structure, which can be facilitated
by VISF, and increased control and uniformity of heat supplied to
the composition during drying. By using VISF, nucleation
temperature may be approximately the same for every sample of a
composition, minimizing or eliminating differences in freezing
history of the product, and, thus, minimizing or eliminating
differences in final product structure for different vials. This
technique may facilitate production of freeze-dried products with
desired morphological attributes by changing cooling rate after
nucleation has occurred.
[0203] In addition, contrary to batch lyophilization, small
variations in geometry of the vials used in continuous
freeze-drying methods herein with suspended vials may have no
significant effect on the heat supplied by radiation. Heat by
radiation may be independent of chamber pressure, facilitating
further reduction of pressure and therefore increased sublimation
rate from the composition.
[0204] Non-limiting methods herein produced very uniform products,
with approximately the same characteristics as one another in
different vials, because each vial underwent approximately the same
process conditions. Non-limiting methods provided herein may also
be used to process particle-based materials in vessels, and may
employ any shape of vessel for containing a composition to be
freeze-dried. In some experiments, drying duration was shortened by
between or equal to 2 and 4 times, and total freeze-drying cycle
duration was shortened by up to 10 times, at least because dead
time was eliminated.
[0205] In some embodiments of the current disclosure, processing
time and equipment footprint were dramatically reduced, no manual
operation or breaks were necessary, in-line control was
implemented, and scale-up is straightforward and involves adding
parallel modules.
[0206] Non-limiting systems and methods herein involve VISF
protocols, but can also be extended to particle-based products in
vessels. Using VISF, product structure may be well-controlled, and
methods herein can be designed to modulate the freezing rate of a
composition.
[0207] While several embodiments of the present disclosure have
been described and illustrated herein, those of ordinary skill in
the art will readily envision a variety of other means and/or
structures for performing the functions and/or obtaining the
results and/or one or more of the advantages described herein, and
each of such variations and/or modifications is deemed to be within
the scope of the present disclosure. More generally, those skilled
in the art will readily appreciate that all parameters, dimensions,
materials, and configurations described herein are meant to be
exemplary and that the actual parameters, dimensions, materials,
and/or configurations will depend upon the specific application or
applications for which the teachings of the present disclosure
is/are used. Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the disclosure described
herein. It is, therefore, to be understood that the foregoing
embodiments are presented by way of example only and that, within
the scope of the appended claims and equivalents thereto, the
disclosure may be practiced otherwise than as specifically
described and claimed. The present disclosure is directed to each
individual feature, system, article, material, and/or method
described herein. In addition, any combination of two or more such
features, systems, articles, materials, and/or methods, if such
features, systems, articles, materials, and/or methods are not
mutually inconsistent, is included within the scope of the present
disclosure.
[0208] The indefinite articles "a" and "an," as used herein in the
specification and in the claims, unless clearly indicated to the
contrary, should be understood to mean "at least one."
[0209] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified unless clearly
indicated to the contrary. Thus, as a non-limiting example, a
reference to "A and/or B," when used in conjunction with open-ended
language such as "comprising" can refer, in one embodiment, to A
without B (optionally including elements other than B); in another
embodiment, to B without A (optionally including elements other
than A); in yet another embodiment, to both A and B (optionally
including other elements); etc.
[0210] As used herein in the specification and in the claims, "or"
should be understood to have the same meaning as "and/or" as
defined above. For example, when separating items in a list, "or"
or "and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e. "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of." "Consisting essentially of," when used in the
claims, shall have its ordinary meaning as used in the field of
patent law.
[0211] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
non-limiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0212] In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," and the like are to
be understood to be open-ended, i.e., to mean including but not
limited to. Only the transitional phrases "consisting of" and
"consisting essentially of" shall be closed or semi-closed
transitional phrases, respectively, as set forth in the United
States Patent Office Manual of Patent Examining Procedures, Section
2111.03.
[0213] Use of ordinal terms such as "first," "second," "third,"
etc., in the claims to modify a claim element does not by itself
connote any priority, precedence, or order of one claim element
over another or the temporal order in which acts of a method are
performed, but are used merely as labels to distinguish one claim
element having a certain name from another element having a same
name (but for use of the ordinal term) to distinguish the claim
elements.
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