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General Considerations
The storage conditions are chosen to preserve the purity and potency of the product so that the specifications for the product are maintained throughout storage, shipping, and handling at the clinic. Initial studies must be conducted prior to patient administration to determine acceptable storage, shipping, and handling conditions. The initial storage and shipping conditions need not be those envisioned for the commercial product. They should ensure that the product specifications are maintained beyond the initially proposed expiration dating. For products with short shelf lives, storage and shipping conditions, even within a medical center, need to be considered together because shipping constitutes the bulk of storage time after manufacturing. Special consideration should be given to the ability of gas to permeate the shipping container, especially if the cell or gene therapy product is stored or shipped on dry ice. Once stability-indicating methods are developed and the final storage and shipping conditions are chosen, these conditions are validated as discussed under Stability.
Most products with limited shelf lives will be shipped by using reliable overnight courier systems. In some cases, some critical products are hand-carried onto commercial aircraft. Special permission must be obtained by commercial carriers if scanning by airport X-ray equipment is to be avoided. Cargo shipping studies should be designed during the development of packaging systems to identify stresses to which biological products may be subjected. Bracing and insulating materials should then be chosen and validated to provide a packaging system that will alleviate the extreme conditions of shipping.
Cell Therapy Products
Cryopreservation— Cryopreservation is the main mode used for the long-term storage of cells, that is, storage of cells for periods longer than 1 year. (See also Suspensions under Formulation of Cell Therapy Products.) The rate of cooling for the cell solutions is important because of the mechanical and dehydration injuries resulting from the formation and growth of ice crystals. The ideal temperatures are dependent upon the type of cells being cryopreserved and the concentration of the cryopreservative. The optimal cooling rate for most cells is between 1 and 3 per minute. Controlled-rate freezers, which can reproducibly produce this optimal cooling rate, are critical when large numbers of vials or large volumes of cells in bags are being frozen. Once cooled to below freezing, cells need to be stored at temperatures below –130. This can be achieved with electric freezers or with liquid nitrogen. Storage of cells in the vapor phase of a liquid nitrogen freezer reduces the risk of cross-contamination with other material in the freezer. However, a map of freezer temperatures needs to be generated so that cells are not stored so far from the liquid nitrogen that they are subjected to temperatures above –130 as the liquid nitrogen evaporates or during the opening of the freezer. Some cells can be stored at –80 if the cells are to be used within a few weeks.
Thawing— Thawing is performed fairly rapidly. If a small amount of cells is to be reinfused or transplanted, DMSO does not need to be removed from the suspension, because most cell preparations can be concentrated adequately to keep the DMSO concentration within tolerable limits. DMSO use has two effects on cells after thawing: cells may clump if damaged, and DMSO reduces cell viability in minutes. If the DMSO needs to be removed or cells need to be concentrated for administration, the defrosted cell suspension is generally serially diluted to avoid osmotic shock and resuspended in a protein-containing medium. Cell viability and potency are generally determined after thawing, but the information may not influence the clinical use of the material.
Frozen Products— Frozen cell therapy products are shipped to the medical center on dry ice or in liquid nitrogen dry shippers. Dry shippers may be preferable because temperature is more readily maintained during shipping. Dry ice and liquid nitrogen are both considered hazardous materials during shipping. Storage conditions at the clinic need to be defined. Most pharmacies do not have access to liquid nitrogen freezers. At best, they have mechanical freezers capable of maintaining the temperature at –70. Clinics that have cell-processing centers or are involved with bone marrow transplantation have liquid nitrogen freezers. If further processing, for example, defrosting and administering, of the cell product is performed at the clinic, the storage conditions and expiration date for the product should be specified. Often the laboratory that is handling the cells and the clinic that will administer the product have to closely collaborate because cells in a concentrated suspension survive for only a few hours.
Unfrozen Products— Other cell therapy products are stored unfrozen. Because cells continue to metabolize during storage, their expiration period is typically between 24 and 96 hours. The expiration date can be extended to several weeks by increasing the volume of storage medium, by reducing the storage temperature, or by attaching a series of bags or compartments that allow the medium to be exchanged without breaching the sterility of the system. These products are shipped in insulating containers with refrigerant packs to maintain a defined temperature range. To stabilize the excursions from these defined and validated temperature ranges, well-designed container configurations with dense foam insulation, which protects the product from shifts in external environmental temperatures, are used. The product purity and potency should not be affected over practical shipment intervals, that is, intervals of 24 to 96 hours, either at higher or lower temperatures. However, if potency may be affected, the shipping box configuration must be re-engineered to maintain optimal potency for the longest possible shipping periods. The product itself should be placed in a lightproof, leakproof container with adequate physical support to ensure stability and prevention of leakage during typical conditions of shipment.
Gene Therapy Products
Most gene therapy products can be lyophilized or formulated by means similar to those employed for many recombinant protein products or cell therapy products. These storage formulations typically have expiration periods longer than one year and no unusual shipping requirements. Nonviral gene therapy products, which may be unstable in their final formulation, can have similar expiration periods if they are stored in a multiple-vial kit with the nucleic acid in one vial and a carrier, such as lipids, in the other. The final formulation is performed at the medical center just before administration.