Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02360112 2001-07-04
WO 00/40910 PCT/US00/00157
VACUUM CONTROL SYSTEM FOR FOAM DRYING APPARATUS
Background of the Invention
This invention relates to a system for controlling vacuum pressure, and more
particularly to the use of a
computer-actuated valve between the vacuum pump and the condenser in a foam
drying apparatus for preserving
solutions and suspensions containing biologically active molecules, viruses
(vaccines) and cells.
Storage of biological materials in the dry state is both commercially and
practically desirable. Successfully
dried biological materials exhibit increased storage stability, reduced weight
and volume, and require less space for
storage. Suggestions in the prior art for providing enhanced-stability
preparations of labile biological materials in
dehydrated form include freeze-drying and vacuum or air-drying. In freeze-
drying, solvent is removed from frozen samples
by sublimation under high vacuum. Unfortunately, while freeze-drying may be
scalable to yield industrial quantities, the
freezing step of freeze-drying is very damaging to many sensitive biological
materials. In addition, cycle times are typically
long, taking 3-4 days. The temperatures utilized are very low, usually less
than -60° C at the condenser and the vacuums
are high, at 0-0.1 Torr. All of this results in an energy intensive process.
Standard vacuum and air-drying methods do not
yield preparations of biological materials that are scalable to industrial
quantities. Scale-up variations on these
technologies include spray-drying and fluidized bed drying. Unfortunately,
these methods suffer from a number of
disadvantages. Fluid bed drying requires that the feed materials are in a
solid form, hence some other type of drying
prior to the fluid bed operation may be necessary. Agglomeration can be a
problem with sticky materials. Particle size
in fluid beds is somewhat constrained in order to achieve strength to
withstand the dynamics of fluidization. Even
though residence times are short, spray drying typically cannot be used for
extremely sensitive materials because of
the temperatures involved. At very large scale, the costs of cleaning a spray
dryer become prohibitive for other than
continuous operation.
An alternative method is the preservation of solutions and suspensions of
biological materials by "foam
formation" (see U.S. Patent No. 5,766,520 to Bronshtein; incorporated herein
by referencel. In this method, foams are
generated by boiling viscous solutions containing the biological materials and
sugar protectants under a low vacuum
(between 0.5 to 10 Torr) at temperatures substantially below 100° C.
During the foaming process, solvent removal is
facilitated by the increased surface area, resulting ultimately in the
formation of mechanically stable foam consisting
of thin amorphous films of concentrated solutes. The application of a low
vacuum within the pressure range of 0.3 to
10 Torr is critical to effective foaming without causing excessive boil-over
andlor freezing of the sample, as would
occur by use of standard freeze-drying control systems.
Conventional freeze-drying systems employ a vacuum pump connected by a first
length of vacuum tubing to a
condenser which is in turn connected by a second length of tubing to a sample
port or chamber. The second length of
tubing generally has a valve to isolate the samples from the vacuum in the
system. Once the condenser has been pre-
cooled and the condenser internal pressure has been sufficiently reduced, the
valve between the condenser and the
samples is opened, thereby rapidly reducing the pressure in the sample
containers. Under high vacuum, typically
pressures between 0 and 0.1 Torr, the solvent in the frozen samples sublimates
and is condensed and frozen in the
CA 02360112 2001-07-04
WO 00/40910 PCT/US00/00157
condenser, which is pre-cooled to below -50° C; the samples are
dehydrated in such a manner. After freeze-drying,
the dehydrated samples are restored to atmospheric pressure by closing the
valve from the condenser, wherein gas is
bled into the sample containers. Despite the disadvantages of conventional
freeze-drying discussed above, such
systems are nonetheless in wide spread use because of the lack of alternative
preservation methods that are scaleable
to industrial quantities.
Some freeze-drying equipment include vacuum chambers fitted with bleed valves,
to allow modest control of
the vacuum pressure within the chamber. However, while vacuum control through
a bleed device may be suitable in
systems designed to operate at high vacuum pressures of 0 to 0.3 Torr, where
the volume of gas bled into the system
would be minimal, such control means would not be suitable in a system
designed to operate at higher pressures of 0.5
to 10 Torr, where much higher volumes of gas would need to be bled into the
chamber to maintain the desired
pressures. The large volumes of gas and potential humidity entering the sample
chamber, condenser and vacuum pump
may compromise sample stability and damage the vacuum hardware. Thus, an
effective, safe and economical means
of maintaining the vacuum pressures required for implementation of the
scalable foam drying protocol is needed.
Moreover, a vacuum control system that can be adapted to existing commercial
freeze-drying systems would be highly
advantageous.
Summary of the Invention
The present invention relates to a system for regulating pressure within a
vacuum chamber. The system
includes: a vacuum pump, which is coupled by a first length of vacuum tubing
to a condenser which is coupled by a
second length of vacuum tubing to the vacuum chamber; a valve having an
actuating means, the valve being located
along the first length of vacuum tubing between the vacuum pump and the
condenser; and at least one pressure sensor
within the vacuum chamber, the pressure sensor being coupled to a control
device, wherein the control device is
adapted to actuate the valve in accordance with a predetermined vacuum
pressure.
In one variation, the valve between the condenser and the vacuum pump is an
isolation valve. The system
may also include a bypass line. This bypass line comprises a length of vacuum
tubing having a diameter smaller than
the diameter of the first length of vacuum tubing, wherein the bypass line is
adapted to circumvent the isolation valve.
Preferably, a bypass control valve is located in the bypass line, wherein the
bypass control valve has a diameter of one
inch or less. The system of the present invention is adapted to regulate
chamber pressures within a range of about 10
Torr to about 0.3 Torr.
In a preferred variation of the present invention, an automated system is
described for foam drying solutions
or suspensions of biological materials. The automated system comprises a
vacuum pump which is coupled by a first
length of vacuum tubing to a condenser which is coupled by a second length of
vacuum tubing to a vacuum chamber.
The vacuum chamber is adapted to hold the solutions or suspensions of
biological materials. The system also includes
a valve located along the first length of vacuum tubing between the vacuum
pump and the condenser, wherein the
valve is adapted to control the pressure within the vacuum chamber. The valve
is operably coupled to a programmable
control device. At least one pressure sensor is included within the vacuum
chamber, the pressure sensor being coupled
-2-
CA 02360112 2001-07-04
WO 00/40910 PCT/US00/00157
to the programmable control device. A heating means and a cooling means are
also included, wherein the heating and
cooling means are adapted to control a temperature within the vacuum chamber.
Both the heating and cooling means
are operably coupled to the programmable control device. The system
incorporates at least one temperature sensor
within the vacuum chamber. The temperature sensor is coupled to the
programmable control device, wherein the
programmable control device is adapted to operate both the valve and the
heating and cooling means in accordance
with a predetermined two-dimensional program for controlling both the pressure
and temperature within the vacuum
chamber. The simultaneous two-dimensional control of pressure and temperature
allow optimalization of foam drying
protocols for various biological samples.
Brief Description of the Drawings
Fig. 1 is a schematic view of the control system of the present invention.
Detailed Description of the Preferred Embodiment
Biologically active materials that can be preserved using the present
apparatus and methods include, without
limitation, biological solutions and suspensions containing peptides,
proteins, antibodies, enzymes, co-enzymes, vitamins,
serums, vaccines, viruses, liposomes, cells and certain small multicellular
specimens. Dehydration of biological specimens
at elevated temperatures may be very damaging, particularly for example, when
the temperatures employed for drying are
higher than the applicable protein denaturation temperature. To protect the
samples from the damage associated with
elevated temperatures, the dehydration process may preferably be performed in
steps or by simultaneous increase in
temperature and vacuum. Primary dehydration should be performed at pressures
and temperatures that permit
dehydration without loss of biological activity.
To facilitate scaling up of the drying methods, the drying step preferably
involves the formation of a
mechanically-stable porous structure by boiling under a vacuum. This
mechanically-stable porous structure, or "foam,"
consists of thin amorphous films of the concentrated fillers, e.g., sugars.
Foam formation is particularly well suited for
efficient drying of large sample volumes as an aid in preparing an easily
divisible dried product suitable for commercial use.
Preferably, before boiling under vacuum, the dilute material is concentrated
by partially removing the water to form a
viscous liquid. This concentration can be accomplished by evaporation from
liquid or partially frozen state, reverse
osmosis, other membrane technologies, or any other concentration methods known
in the art. Alternatively, some samples
may be sufficiently viscous after addition of the sugar protectants, wherein
evaporation prior to boiling under vacuum is
not employed. Subsequently, the reducedlviscous liquid is further subjected to
vacuum sufficient to cause it to boil during
further drying at temperatures substantially lower than 100° C. In
other words, reduced pressure is applied to viscous
solutions or suspensions of biologically active materials to cause the
solutions or suspensions to foam during boiling, and
during the foaming process further solvent removal causes the ultimate
production of a mechanically-stable open-cell or
closed-cell porous foam. Thus, foam drying allows for preservation of
industrial quantities, ranging from 0.1 ml up to
about 100 liters of biological solutions or suspensions.
The vacuum for the boiling step is preferably 0.3-10 Torr, and most preferably
between about 1 to 4 Torr.
Boiling in this context means nucleation and growth of bubbles containing
water vapor, not air or other gases. In fact, in
-3-
CA 02360112 2001-07-04
WO 00/40910 PCT/US00/00157
some solutions, it may be advantageous to purge dissolved gases by application
of low vacuum at room temperature.
Such "degassing" may help to prevent the solution from erupting out of the
drying vessel. Once the solution is sufficiently
concentrated and viscous, high vacuum can be applied to cause controlled
boiling and foaming. Foams prepared according
to the present invention may be stored under vacuum, dry gas, like Nz or dry
atmosphere.
Referring to Fig. 1, a typical freeze-drying is illustrated showing the
incorporation of certain specific
attributes associated with the subject invention. This equipment can be
utilized with the subject invention
modifications to facilitate the scaleable foam drying process. Solutions or
suspensions of sensitive biological samples to
be preserved would be placed in the drying chamber (1) and the chamber door
closed. The condenser would be pre-
cooled to below -20°C and preferably below -40°C via the
condenser refrigeration system (not shown). Meanwhile
the solutions or suspensions of sensitive biological samples would be cooled
to the starting temperature for drying,
typically in the range of -15° to about15°C, utilizing
conventional heating and cooling systems (4). The temperatures
could be set higher or lower depending upon the thermal sensitivity and
freezing point of the solutions or suspensions of
sensitive biological samples. Preferably, the sample is not allowed to freeze.
In another embodiment, the sample would
be pre-cooled in another device, such as a refrigerator, prior to inserting
into the drying chamber. As the sample and
condenser are cooling, the main vacuum valve (3) remains closed between the
chamber and condenser and the vacuum
isolation valve 16) also remains closed. Some versions of freeze drying
equipment incorporate internal condensers
located within the drying chamber. Although this is not the preferred format,
the invention will still perform
satisfactorily as long as a vacuum pump isolation valve (6) is located between
the condenser and vacuum pump;
however, in rare cases existing freeze drying equipment may not have such an
isolation valve. If this is the situation,
the invention requires that such a valve be installed.
Because of the closed valves, the vacuum pump (5) can be started to bring the
vacuum pump to operating
temperature, which prevents condensation inside the pump casing during
subsequent chamber evacuation. The
invention also preferably includes a bypass valve (7) connected to the
condenser vacuum line via the bypass piping (81,
which is piped around the isolation valve. The bypass valve (71 also remains
closed during the startup period. System
temperatures and pressures are monitored by sensors of appropriate ranges (9)
and (10), respectively, installed in the
chamber. Such sensors are well known to those of skill in the art of freeze
drying and preservation systems. Signals
from these instruments are directed to the programmable control device 111)
which typically would incorporate one or
more proportional, integral, derivative (PID) style control functions to
provide necessary control action based on
previously programmed setpoints and control responses. The programmable
control device could be a programmable
logic controller (PLC), personal computer (PC) or other similar control system
capable of executing previously
programmed algorithms for controlling the process.
Once product temperature setpoint and condenser setpoint have been reached,
the main vacuum valve (3) is
opened to commence the drying process. Shortly thereafter, the isolation valve
161 for the vacuum pump (5) is opened
to reduce the system pressure. When a pre-programmed vacuum setpoint is
reached, typically 0.3-10 Torr, more
preferably 1.0-5.0 Torr, and boiling begins according to the Applicant's
scaleable foam drying process, the isolation
-4-
CA 02360112 2001-07-04
WO 00/40910 PCT/US00/00157
valve (6) is closed. This is done to prevent boiling from becoming too
vigorous resulting in either severe product cooling
leading to product freezing or product carryover into the condenser. Because
the vacuum pump is typically connected
to the condenser via a large diameter line and the vacuum pump is typically
sized for fast pump-down of the system,
the vacuum pumping capability of the typical freeze drying equipment set far
exceeds that which is necessary for the
scaleable foam drying process. However, once the isolation valve is closed,
the system pressure will rise as water
vapor evolves from the ongoing boiling process. Pressure will also rise as a
result of system leaks. This will continue
until the equilibrium vapor pressure is exceeded and boiling ceases. In order
for the drying process to continue the
vacuum must be controlled to a degree not possible with the usual large
isolation valve and connecting piping. Opening
and closing the large diameter isolation valve, typically 3-6 inches in
diameter in industrial systems, will cause severe
drops in pressure leading to excessive boiling in an uncontrolled manner. The
invention resolves this problem by
installing a bypass line (81 around the large diameter isolation valve,
equipped with a smaller diameter "quick-opening"
valve (7).
The following types of valves may be used as the "quick-opening" valve in
accordance with the present
invention: diaphragm, ball, plug, butterfly and poppet. All of these are fast
opening types that are normally used as
traditional "on-off" valves in many industrial processes. Any valve that can
be made to be quick opening will suffice
for the purposes of the invention. Certain of these valves, e.g., diaphragm,
plug are also used routinely in the food and
pharmaceutical industry as variable control valves. However, butterfly valves
are most commonly used in freeze drying
systems, especially for pipelines of diameter exceeding 2 inches. Bypass
piping and valve size should be sized at 1.0
inches diameter or less, preferably 0.25 inches. Actuators for the quick
acting valve can be either pneumatic or
electric with the electric type being primarily solenoid operated. Both types
of actuators usually employ spring return
for simpler control. Solenoids are supplanted by electric motors as the size
of the valve and the force to open and
close the valve increase. Pneumatic actuators are used in virtually any size
valve. Any of the above types of valves
can be operated manually, however, because of the number of times the valve
must be opened and closed during a
typical foam-drying run, manual operation is not practical.
Signals from the temperature and pressure sensors located on the drying
chamber are fed to the
programmable control device wherein previously programmed instructions are
used to effect a control response to
either the bypass valve (71, the drying chamber heating and cooling system (4)
or both in order to precisely control the
scaleable foam drying process. At the conclusion of the drying process and the
formation of mechanically stable foam,
the bypass valve is closed and the isolation valve may be reopened to proceed
to optional secondary drying at
increased vacuum and increased temperature. In another embodiment the drying
cycle can be ended and the material
transferred to another means of drying e.g., a desiccant drying chamber to
complete secondary drying.
While a number of variations of the invention have been described in detail,
other modifications and methods of
use will be readily apparent to those of skill in the art. Accordingly, it
should be understood that various applications,
modifications and substitutions may be made of equivalents without departing
from the spirit of the invention or the scope
of the claims.
-5-
