Freeze-dried products process

Therefore, freeze-drying should be carried out at the highest allowable product temperature that maintains the appropriate attributes of a freeze-dried product. This temperature depends on the nature of the formulation. Process development and validation requires characterizing the physical state of the solute, or solutes, that result from the freezing process and identifying a maximum allowable product temperature for the primary drying process [20,21]. 

Nail, St. L., Johnson, W. Methodology for in-process determination of residual water in freeze-dried products. Developments in Biological Standardization, Vol. 74, p. 137-152. Acting Editors Joan C. May, F. Brown, S. Karger AG, CH-4009 Basel (Switzerland), 1992... 

Neorecormon is one such product. Produced in an engineered CHO cell line constitutively expressing the EPO gene, the product displays an amino acid sequence identical to the native human molecule. An overview of its manufacturing process is presented in Figure 6.7. The final freeze-dried product contains urea, sodium chloride, polysorbate, phosphate buffer and several amino acids as excipients. It displays a shelf-life of 3 years when stored at 2-8 °C. A pre-filled syrine form of the product (in solution) is also available, which is assigned a 2 year shelf-life at 2-8 °C. 

In addition to characterizing frozen systems intended to be freeze dried, it is important to characterize the freeze-dried product. This includes determination of the physical state of the dried product that is, crystalline, partially crystalline, or amorphous. It may also include identification of the polymorph of a crystallizing component which exhibits polymorphism and determination of whether the crystal form observed is affected by changes in formulation and processing conditions. For amorphous systems, the glass transition temperature of the amorphous solid, as well as the extent to which Ts changes with residual moisture, may be a critical attribute of the product with regard to both physical and chemical stability. 

A subtle aspect of stability analysis of freeze-dried products in vials with rubber stoppers is the tendency for water vapor to be transferred from the stopper to the solid during storage. Representative data for residual moisture as a function of time at different temperatures are shown in Figure 11. As expected, the residual moisture level increases more rapidly at higher temperature, but the plateau level is independent of temperature as equilibrium is established between the freeze-dried solid and the stopper. The extent to which this is observed depends on several factors. First, the nature of the rubber stopper formulation affects the diffusivity of water in the rubber. Second, the processing of the stopper can affect the level of residual moisture present. It is not uncommon for extended drying of the stopper to be necessary to minimize residual moisture. Finally, the mass of the freeze-dried solid determines the extent to which the percent residual moisture is affected by water vapor transfer from the stopper, where large cakes may be relatively unaffected by the small amount of water vapor that is... 

Nail, St.L., Johnson, W. Methodology for in-process determination of residual water in freeze-dried products. In Developments in Biological Standardization,... 

Residual moisture is the low level of water, usually in the range of less than 1-3% (wt/wt), remaining in a freeze-dried product after the freeze-drying (vacuum sublimation) process [1-5] is complete. Nail [6] has described in-process methods to monitor the endpoint of freeze-drying using residual gas analysis, pressure rise, comparative pressure measurement, and product temperature measurement. Roy and Pikal [7] used an electronic moisture sensor inside the lyophilization chamber. Residual moisture [8] content is important in the final freeze-dried product because it affects the potency of the product, its long-term stability, and the official shelf life of the product. 

The freeze-dried product contains the freeze-dried biological material, residuals of the manufacture of the product such as buffer, and any excipient such as lactose, sucrose, mannitol, sodium chloride, or sorbitol that has been added to the product to optimize the freeze-drying process and protect product potency. The types of water present in the freeze-dried product cake may be different for each product depending on the residuals of manufacture and the excipients present the water could be surface water, bound water, or trapped water. 

Studies on Development of Manufacturing Processes for Pharmaceutical Freeze-Dried Products... 

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