WO2000040910A1

WO2000040910A1 - Vacuum control system for foam drying apparatus

Info

Publication number: WO2000040910A1
Application number: PCT/US2000/000157
Authority: WO
Inventors: Victor Bronshtein
Original assignee: Universal Preservation Technologies, Inc.
Priority date: 1999-01-05
Filing date: 2000-01-05
Publication date: 2000-07-13
Also published as: AU2490000A; JP2002534654A; CA2360112A1; EP1144930A1

Abstract

The present invention is related to a system for controlling the pressure in a drying apparatus. A control valve (7) located between the vacuum pump (5) and the condenser (2) is employed to regulate the pressure in the vacuum chamber (1).

Description

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 34 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 reference). 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 and/or 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 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 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 reduced/viscous 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 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 N₂ 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 (6) 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 (8), which is piped around the isolation valve. The bypass valve (7) 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 (11) 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 (6) 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 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 (8) 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 (7), 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.

Claims

WHAT IS CLAIMED IS:

1. A system for regulating pressure within a vacuum chamber, comprising:

(a) 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; (b) 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

(c) at least one pressure sensor within the vacuum chamber, said 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.

2. The system of claim 1, wherein the valve is an isolation valve located between the condenser and the vacuum pump.

3. The system of claim 2, further comprising a bypass line, said bypass line comprising a length of vacuum tubing having a diameter smaller than a diameter of said first length of vacuum tubing, wherein the bypass line is adapted to circumvent the isolation valve.

4. The system of claim 3, further comprising a bypass control valve located in the bypass line, wherein the bypass control valve has a diameter of one inch or less.

5. The system of claim 1, wherein the pressure is in a range of about 10 Torr to about 0.3 Torr.

6. A system for automated foam drying of solutions or suspensions of biological materials, comprising: (a) 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, wherein the vacuum chamber is adapted to hold the solutions or suspensions of biological materials;

(b) a valve located along the first length of vacuum tubing between the vacuum pump and the condenser, wherein said valve is adapted to control the pressure within the vacuum chamber, said valve being operably coupled to a programmable control device;

(c) at least one pressure sensor within the vacuum chamber, said pressure sensor being coupled to the programmable control device;

(d) a heating means and a cooling means, wherein said heating and cooling means are adapted to control a temperature within the vacuum chamber, said heating and cooling means being operably coupled to the programmable control device;

(e) at least one temperature sensor within the vacuum chamber, said temperature sensor being coupled to the programmable control device, wherein the programmable control device is adapted to operate said valve and said heating and cooling means in accordance with a predetermined two-dimensional program for controlling both the pressure and temperature within the vacuum chamber.

7. The system of claim 6, wherein the valve is an isolation valve located between the condenser and the vacuum pump.

8. The system of claim 7, further comprising a bypass line, said bypass line comprising a length of vacuum tubing having a diameter smaller than a diameter of said first length of vacuum tubing, wherein the bypass line is adapted to circumvent the isolation valve.