This invention relates to methods and apparatus for lyophilizing liquids, solids and suspensions of cells and the like. More specifically, this invention relates to processes and apparatus for lyophilization of the above materials in containers composed of plastic film.
As is well known, lyophilization is a process for dehydrating materials by sublimation from the frozen state in a vacuum. In many applications, and especially when the final product must contain a discrete mass and/or be free of bacterial contamination, the original material is frozen and then dehydrated completely within the container in which it will subsequently be shipped, rehydrated and from which it will be dispensed for use. The container is generally a glass bottle with walls thick enough to withstand a vacuum. The material to be dried is aseptically transferred to the sterile bottle and it is partially closed with a slotted stopper. The material is frozen in the bottle. The water leaves the frozen material (sublimes) as water vapor through the slots in the stopper and collects on a cold condenser in a vacuum chamber. After the water is removed, and while still under vacuum, the stopper is pressed fully into the bottle (up to a flange) occluding the slots and making a vacuum tight seal before the bottle is removed from the vacuum.
However, there are certain drawbacks to the prior art. In order to give the glass bottle sufficient strength to withstand sterilization, vacuum and shipping, its shape must be a tall, narrow cylinder. This shape results in a thick layer of frozen material with a small surface area. These conditions are just the opposite of the conditions necessary for optimum lyophilization, resulting in following deficiencies:
a. Slow heat transfer through the thick bottle walls and thick material layers causing a slow rate of freezing and thereby large crystal formation that ruptures delicate structures, especially in cells.
b. Poor heat transfer through the thick bottle walls and thick material layers, causing partial melting of the frozen material during sublimation when heat must be applied to replace the heat lost in sublimation. This melting of the partially dried solution exposes delicate molecular and cellular structures to extraordinary salt concentrations and surface forces, resulting in denaturation and destruction.
c. Narrow mean free path for water vapor molecules through the thick material layer and narrow stopper slots slows the sublimation rate and contributes to partial melting.
d. The slow rate of movement of reconstituting water through the thick material layer again exposes the material to extraordinary salt concentrations during the rehydration process.
e. The large, heavy, glass containers are bulky to store and costly in energy and money to make, ship, and dispose.
One method used to improve the physical conditions for lyophilization by increasing the surface area and reducing the thickness of the frozen layer is called shell freezing. In this method, the bottle containing the liquid to be lyophilized is tilted and rotated while partially immersed in a freezing bath.
This results in the material being frozen in a thinner layer along the vertical as well as bottom wall. This process is too labor intensive for mass production. Furthermore, it is difficult to heat the sides at the same rate as the bottom in the usual freeze dry chamber with heated shelves.
It should be understood that the rate of freeze drying is related to the rate at which water leaves the frozen material. This in turn is related to the vapor pressure of water in the material. This in turn is related to the temperature of the frozen material. As water sublimes, it absorbs the latent heat of vaporization, cooling the frozen material further and reducing sublimation. Outside heat must be added to replace this loss, but at a controlled rate to prevent uneven temperature distribution, with partial melting. There is negligible convective heat transfer in-vacuo and conductive heat transfer from a warm shelf (the usual production method) is poor through a partially dry, thick layer. Other means of heat input including infra red, microwave and dielectric heating have been employed to overcome the difficulties inherent in conductive heat transfer.