Product design freeze-dried formulations

The impact of formulation on virus reduction and product recovery (e.g., potency) was evaluated during terminal freeze dry/dry heat treatment studies with an unlicensed Fraction I derived product, that will be designated Protein G. As shown in Fig. 10, the optimum formulation, that achieved >4 logio PPV inactivation and 80% product recovery, was one that contained 2% albumin, no NaCl, and <0.3%o moisture by the Karl Fischer coulometric method. In contrast, freeze dry/dry heat treatment of product formulated with no albumin, 150mM NaCl and low moisture resulted in approximately 3 logio PPV reduction and 35% product recovery. Thus, minor changes in formulations such as the addition of 2% albumin may impact virus reduction and product recovery during a freeze dry/dry heat treatment. 

It is important to appreciate that products intended for freeze-drying will have been formulated with additives designed to stabilise the active component to prevent dehydration damage (see section 10.5). Consequently such formulations are likely to be more resistant to decay when disseminated as an aerosol during filling, freeze-drying or oversealing. 

The functional relationship between product temperature, on the one hand, and shelf temperature and chamber pressure, on the other hand, is affected by many factors including the size and design of the lyophilizer, the characteristics of the product, and the time evolved since the start of primary drying. With a sucrose formulation in vials, we have observed a maximum primary drying product temperature rise of -i-5°C when the shelf temperature was varied from -15 to -i-30°C, whereas a pressure variation from 30 to 250 microbars generated an increase of around -i-2.5°C. With a lactose formulation in ampoules lyophilized in a larger freeze-dryer equipped with a plate-type condenser, the effect of pressure was found to be predominant -i-6.5°C for a pressure move from 50 to 300 microbars, versus -t-l°C for a shelf temperature move from 0° to 25°C. 

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