Refrigeration – Processes – Congealing flowable material – e.g. – ice making
Reexamination Certificate
2002-07-15
2003-10-14
Tapocai, William E. (Department: 3744)
Refrigeration
Processes
Congealing flowable material, e.g., ice making
C062S356000, C062S457900
Reexamination Certificate
active
06631616
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to biopharmaceutical material cryogenic preservation methods and apparatus, and more particularly to a biopharmaceutical material cryogenic preservation system and method which maintain controlled freezing of biopharmaceuticals contained within a container including a controlled dendritic freezing front velocity.
DESCRIPTION OF RELATED ART
Cryopreservation of biopharmaceutical materials is important in the manufacturing, use, storage and sale of such materials. For example, biopharmaceutical materials are often cryopreserved by freezing between processing steps and during storage. Similarly, in certain cases, biopharmaceutical materials are frozen and thawed as part of the development process to enhance their quality or to simplify the development process.
When utilizing cryopreservation, the overall quality, and in particular pharmaceutical activity, of the pharmaceutical materials is desirably preserved, without substantial degradation of the biopharmaceutical materials.
Currently, in some aspects, cryopreservation of biopharmaceutical materials involves placing a container comprising the biopharmaceutical materials in a cabinet or chest freezer and allowing the biopharmaceutical materials to freeze. In current cryopreservation techniques, a container enclosing biopharmaceutical materials is placed on a solid or wire-frame shelf in the cabinet or chest freezer. The biopharmaceutical materials are left to freeze until they are solid, in an uncontrolled fashion.
Significant losses in biopharmaceutical material activity have been noted using such current techniques. For example, observers have noted that stability and conformation of biopharmaceutical materials can be affected by low temperature alone, without any significant changes in variables such as solute concentration or pH.
Further, it has been noted that conventional cryopreservation methods can lead to cryoconcentration, or the redistribution of solutes including biopharmaceutical product from the frozen volume to the unfrozen cavity where their concentration may significantly increase. The result of cryoconcentration can include the crystallization of buffer components leading to a pH change that can affect stability, folding, cause undesirable chemical reactions, or even create cleavage of the biopharmaceutical material. Cryoconcentration in conjunction with low temperature effects may cause a decrease in solubility of the biopharmaceutical material, with resulting precipitation. Product aggregation (i.e., increase in molecular weight) has also been observed.
Additionally, damage to the containers has been noted using conventional cryopreservation techniques. Container damage may be caused by freezing stress due to volumetric expansion of aqueous biopharmaceutical materials within the container during freezing. Rupture or damage to the integrity of the container is undesirable, as it can compromise sterility or lead to biopharmaceutical material contamination or leakage or loss of the biopharmaceutical material.
Another problem faced by those of skill in the art is that currently available process methods and apparatus designs intended for cryopreservation of biopharmaceutical materials generally do not exhibit good linear scalability. In biopharmaceutical manufacturing, there is a constant need for simple, efficient and predictable scale-up. Methods developed at research and pilot stages should be directly scalable to the production scale without compromising biopharmaceutical material quality (e.g., biological activity of the biopharmaceutical material) or process productivity. The predictability of process behavior based on information developed on a small scale is often referred to as linear scalability.
In scaling up a cryopreservation process, discrete containers such as bottles, carboys, tanks, or similar single containers are available in different sizes. In virtually all cases, the rate of freezing and time to completely freeze the biopharmaceutical materials in each container is related to the largest distance from the cooling surface. Consequently, longer times are required to freeze the contents of larger containers if the same cooling surface temperature is maintained. Such longer times are undesirable because this results in lower process throughputs. Further, the slow freezing is known to cause cryoconcentration effect with its detrimental effects upon the product.
Various strategies have been adopted to mitigate this scale up problem. To freeze large quantities, one could for example use multiple smaller containers. However, adjacent placement of multiple containers in a freezer creates thermal conditions differences and temperature differences from container to container. The freezing rate and product quality depend on the actual freezer load, spacing between the containers, container shape, and air movement in the freezer. The result is different thermal history for the contents of individual containers thus creating problems with compliance with the Good Manufacturing Practices (GMP) as will be understood by those skilled in the art. For a large batch, it is also time consuming and counter-productive to divide the lot into a large number of subunits. Product loss is likely to be important as it is, to some extent, proportional to the container surface and to the number of containers.
Accordingly, there is a need for apparatus and methods for cryopreservation of biopharmaceutical materials that solve the deficiencies noted above.
SUMMARY OF THE INVENTION
The present invention provides, in a first aspect, a biopharmaceutical cyropreservation system which includes a container having an outer surface area with the container being adapted to contain a biopharmaceutical material for freezing and thawing therein. The system further includes a cryocooling enclosure having an interior cavity configured to receive the container and at least one heat transfer surface within the cryocooling enclosure. The at least one heat transfer surface is configured to contact the outer surface of the container when the cryocooling enclosure interior cavity receives the container. The system further includes a cryocooler thermally coupled to the cryocooling enclosure which is configured to flow fluid to the at least one heat transfer surface to control the temperature of the heat transfer surface and biopharmaceutical material within the container. The fluid is isolated from contacting the container, but may flow within or in thermal contact with the heat transfer surface to transfer heat to or from the container and biopharmaceuticals therein. Also, a temperature sensor is thermally coupled to the cryocooling enclosure, the at least one heat transfer surface, the fluid, and/or the cryocooler.
Further, the at least one heat transfer surface may be configured to contact at least ten percent (10%) of the total outer surface area of the container. Preferably, the at least one heat transfer surface is configured to contact at least fifty percent (50%) of the total outer surface area of the container with at least seventy-five percent (75%) being most preferable. Moreover, the at least one heat transfer surface may include two heat transfer surfaces opposite one another. The outer surface area of the container may include a first outer surface area configured to contact the first heat transfer surface and a second outer surface area configured to contact the second heat transfer surface. A combination of the surface areas of the first outer surface area and the second outer surface area may include at least ten percent (10%) of the total outer surface area of the container with fifty percent (50%) of the total outer surface area of the container being preferable. Most preferably, the first and second outer surface areas include at least seventy-five percent (75%) of the outer surface area of the container. Also, the container may be flexible and adapted to conform to the shape of the interior cavity of the cryocooling enclosure.
The present invention provides, in a second aspect,
Lee Eric K.
Wisniewski Richard
Cardona, Esq. Victor A.
Heslin Rothenberg Farley & & Mesiti P.C.
Tapocai William E.
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