Residual moisture content during

Oetjen, G. W., 2001. Method of determining residual moisture content during secondary drying in a freeze-drying process. United States Patent No. 6176121 Bl. 

In addition to the additives used in a formulation to help stabilize the protein to freezing, the residual moisture content of the lyophilized powder needs to be considered. Not only is moisture capable of affecting the physicochemical stability of the protein itself, equally important is the ability of moisture to affect the Tg of the formulation. Water acts as a plasticizer and depresses the Tg of amorphous solids [124,137,138]. During primary drying, as water is gradually removed from the product, the Tg increases accordingly. The duration and temperature of the secondary drying step of the lyophilization process determines how much moisture remains bound to the powder. Usually lower residual moisture in the finished biopharmaceutical product leads to enhanced stability. Typically, moisture content in lyophilized formulations should not exceed 2% [139]. The optimal moisture level for maximum stability of a particular product must be demonstrated on a case-by-case basis. 

The water is not crystallized to its maximum and can be removed during freeze drying only with difficulty, or not at all. The residual moisture content remains undesirably high. 

This residual moisture content d W (% of the solids) is calculated as shown in Fig. 2.39. The automatic measurement of DR, which is more accurate than a hand operation of the valve and the visual reading of the pressure gauge, supplies additional information about the main drying as shown in Fig. 2.40.1. The same granulate has been dried at the different pc 0.27, 0.44 and 1.46 mbar corresponding to three Tice -27, -24.5 and -15 °C during main... 

Greiff [3.24] studied the stability of purified influenza virus of the strain PR 8 in physiological NaCl solution with calcium lactobionate and human serum albumin (each 1 % in the solution). The freezing rate was approx. 1 °C/min down to -30 °C. During the freeze drying, the product temperature was raised in 12 to 16 h from -30 °C to 0 °C and the product was dried at this temperature. After 24 h, the first 145 vials were removed, and additional vials after intervals of 24 h each. The residual moisture content was 3.0,2.0,1.5, 1.0 and 0.5 %. The stability of the freeze dried virus (expressed in days during which the titer of the infectivity decreased by a factor of 10 was most unfavorable at 0.4 % and 3.2 % RM, (4 and 7 days respectively at +10 °C) and best at 1.7 % RM 145 days or more than 1000 days at -10 °C. 

Fig. 3.22. Shelf temperature (Tsh) as a function of drying time during the freeze drying of bone corticalis and spongiosa and the related residual moisture content (RM).

Merika [3.51] emphasized from his 17 years of experience with the quality control of freeze dried transplants the importance of sterility and residual moisture control as the decisive characteristics. Furthermore, the leak tightness of the storage containers was constantly controlled. Merika did not measure the product temperature during drying, but controled the process by measuring water vapor pressure and temperatures of the shelves and the condenser. The residual moisture content after 2 years of storage must be below 5 %. All products were sterilized by gamma radiation. 

Kapsalis et al. [4.12] showed, that the residual moisture content RM of peas should neither be to small nor too high. During 84 days-storage at +43 °C and RM below 5 %, the thiamine content was barely reduced, but the carotene content fell to approx. 36 %. On the other hand, the thiamine content fell at RM 33 % to 81 %, while 50 % of the carotene content was preserved. These and other reasons not discussed here led Kapsalis to the conclusion, that an optimum RM does generally not exist, but only a desirable RM for one type of product under given storage conditions. 

The outer vials are influenced (if the shelf temperature is uniform) by a different temperature of the walls and door of the chamber. If the chamber walls and the door are not kept at shelf temperature, the outer vials must be shielded or they may be too warm during freezing (e. g. freezing differently) or too cold during secondary drying (see Fig. 1.68), and this may lead to a different residual moisture content, from that in inner vials. 

Flence the Roots pump RUVAC WA 1001 would be the suitable pump. The permissible remaining moisture in the product determines the attainable ultimate pressure. The relationship between the ultimate pressure and the remaining moisture is fixed for every product but different from product to product. LEYBOLD has many years of experience to its record regarding applications in this area. Assume that a 0.1 % residual moisture content is required, for which the necessary ultimate pressure is 6 10 mbar. During the fast 5 h the remaining 6 % of the moisture content, or 5 kg of water, is removed. At a mean pressure of about 0.65 mbar, 2000 m /h of vapor is evolved. Two possibilities are offered ... 

Test run (see Fig. 1.63 and Table 1.9) Without pressure control, in this installation -with the given shelf area, condenser temperature, the dimensions of the connection between chamber and condenser - a total pressure of 0.15 mbar exists for approx. 5 h. The gas in the chamber is always pure water vapor. The ice temperature is during this time almost constant at approx. -27 °C. The heat transfer coefficient at this pressure is small at approx. 65.7 kJ/m2 h °C. The product temperature (resistance thermometer) increases only after these 5 h above the ice temperature. Afterl2 h the desorption rate (DR) is only approx. 0.7 %/h. The total drying time, depending on the desired residual moisture content is between 13 and 15 h. 

The freezing of a product is a very important step. The structure in the frozen product decides whether the product can be freeze-dried at all and under which conditions it can be done. For this reason, the consequences of the freezing rate, layer thickness of the product and excipients are discussed in some detail. The second main point is the measurement and control of the two drying phases the main and secondary drying and the third concentrates on the residual moisture content, its measurement and the consequences during storage of the dry product. There will be critical opinions that some of the processes are unilaterally represented. aim was to show the, hmrts and the advantages ot certain procedures to enable the reader to decide whether the ideas of the quoted authors, or my own can be applied to his tasks. 

Thermal analysis data also dictate the maximum product temperature allowable during primary drying. Shelf temperatures and chamber pressures are then selected to assure that the product remains below this critical threshold temperature during primary drying. Secondary drying conditions necessary to achieve the desired residual moisture content are also identified. Determination of these processing parameters requires numerous process studies and corresponding stability studies to define optimal conditions. 

During the storage of a freeze-dried product, its qualities can change under the influence of at least three conditions residual moisture content, storage temperature and gas mix in the packing, assuming that the freeze-drying itself has been carried out under optimum conditions and the product had the intended qualities at the end... 

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