Drying secondary

In many products, the residual moisture in the product after completing primary drying is still too high for optimum storage. 

Secondary drying is meant to remove the water adsorbed in the product at the inner surfaces. The freeze-dryer must be designed in such a way that, during secondary drying, the capillary force of the water can be overcome by a greater pressure gradient (e.g. through a very low pressure in the chamber), because in many cases, the product (e.g. proteins) will not accept a considerable increase in temperature. 

In addition, the secondary drying process must be controlled in such a way that overdrying of the product is not possible. 

The water content at the end of primary drying is invariably too high for optimal product stability and the drying cycle is extended by secondary drying during which additional moisture is removed by desorption, resulting in a product with a final moisture content normally below 3%. 

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M. J. Pikal, S. Shah, M. L. Roy, and R. Putman, The secondary drying stage of freeze drying drying kinetics as a function of shelf temperature and chamber pressure, Int. J. Pharm., 60, 203-217 (1990). 

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. 

Even after all ice has been removed by sublimation, the product phase, or freeze concentrate, contains a large amount of dissolved water that must be removed to produce a stable product. This water is removed by desorption during secondary drying. Secondary drying is usually carried out at elevated product temperature to achieve efficient water removal. 

During the secondary drying, the water will be removed which interacts with the solids such that the water cannot crystallize. The water can be bound to the surface of crystals in a crystallized product, or can be included in amorphous product. Pikal et al. [1.59] have listed four statements concerning secondary drying ... 

At the beginning of the secondary drying, the decrease in water content is rapid, but thereafter remains on a plateau-level. 

A change of the chamber during secondary drying to less than 0.26 mbar, e. g. to 0.065 mbar, does not change the drying speed. ... 

Point 4 above may be correct, but only if the partial water vapor pressure of the product at the product temperature is larger than the existing partial water vapor pressure in the chamber, otherwise the chamber pressure has to be lowered. Since the energy input during secondary drying is not decisive, it would be safer to use a chamber pressure as small as the condenser temperature allows. 

Pikal [1.60] described two possibilities to define the change from main to secondary drying ... 

Test run the curves 2 in Fig. 1.71 are taken from the test run, as shown in Fig. 1.63, but with pressure control 0.36 mbar (total pressure measured with Capacitron). The ice temperature has been -22 °C (constant) for 3 h and DR reached 0.05 %/h after 10 h. Secondary drying could have been started much more early, thus shortening the drying process. 

The temperature measurement during secondary drying with Th or RTD is possible, as shown in Fig. 1.63, with an accuracy of approx. 2 °C. 

The increase (I) starts at approx. 16 h and reaches Tsh at approx. 22 h. Secondary drying (SD) has been started (II) at approx. 30 h. Between 16 h and 22 h is no measurable indicator of when to start SD. Also, the safety margin between 22 h and 30 h cannot be connected with the measured product temperature (Fig. 2 from [1.64]). 

Figure 1.84 [1.69] summarizes the measurements of three runs of the product temperatures with RTD, Tice with BTM and of the pressures by CA. The plots show that the difference in pressures during main and secondary drying is largest with no pressure control and still clearly recognized with pc at 0.2 mbar in relation to an ice temperature of approx. -30 °C. 

For a product a reproducible desorption isotherm exists, and the product does not change at the end temperature during secondary drying. 

The storage of a freeze dried product starts with the end of the secondary drying and its transfer into a suitable packing. In the drying plant a certain residual moisture content (RM) is achieved as a function of the product temperature and the drying time (Section 1.2.2). 

Figure 2.8.1 shows a typical installation for flasks and other containers in which the product is to be dried. The condenser temperature for this plant is offered either as -55 °C or as -85 °C. For this type of plant, a condenser temperature of -55 °C is sufficient as this temperature corresponds with a water vapor pressure of approx. 2.1 10 2 mbar, allowing a secondary drying down to approx. 3 10-2 mbar. This is acceptable for a laboratory plant, in which the limitations are not the condenser temperature but the variation of heat transfer to the various containers, the rubber tube connections and the end pressure of the vacuum pump (2 stage pump, approx. 2 10 2 mbar). Figure 2.8.2 shows that these units are designed for very different needs. The ice condenser in this plant can take up 7.5 kg of ice at a temperature down to -53 °C. 

The condenser design and surface can handle the vapor flow during main drying of this test. The possible low temperatures could be needed during secondary drying. 

Fig. 2.40.2. Chamber pressure and nitrogen flow rate as a function of drying time. 1 main drying, 2 chamber pressure, 3 nitrogen flow, 4 secondary drying (Fig. 4 from [2.32]).

During secondary drying, a small RM should be reached, since Tg of the dry product increases with decreasing water content. Tg- of amorphous, freeze dried sucrose increases from 16 °C with 8.5 % RM to 63 °C or 64 °C between 1.0 and 0.7 % RM. It should be taken into account, that RM cannot be taken only at the end of drying, but a possible increase during storage by water desorbed from the stopper has to be considered (see Section 1.3.2 and Pikal et al. [3.7]). 

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. 

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