Development and Manufacture of Protein Pharmaceuticals

Steven L Nail, Shan Jiang, Suchart Chongprasert, Shawn A Knopp, Nail, Steven L, Jiang, Shan, Chongprasert, Suchart, Knopp, Shawn A, Nail, Steven L., Knopp, Shawn A.

Given the increasing importance of reducing development time for new pharmaceutical products, formulation and process development scientists must continually look for ways to "work smarter, not harder." Within the product development arena, this means reducing the amount of trial and error empiricism in arriving at a formulation and identification of processing conditions which will result in a quality final dosage form. Characterization of the freezing behavior of the intended formulation is necessary for developing processing conditions which will result in the shortest drying time while maintaining all critical quality attributes of the freeze-dried product. Analysis of frozen systems was discussed in detail, particularly with respect to the glass transition as the physical event underlying collapse during freeze-drying, eutectic mixture formation, and crystallization events upon warming of frozen systems. Experiments to determine how freezing and freeze-drying behavior is affected by changes in the composition of the formulation are often useful in establishing the "robustness" of a formulation. It is not uncommon for seemingly subtle changes in composition of the formulation, such as a change in formulation pH, buffer salt, drug concentration, or an additional excipient, to result in striking differences in freezing and freeze-drying behavior. With regard to selecting a formulation, it is wise to keep the formulation as simple as possible. If a buffer is needed, a minimum concentration should be used. The same principle applies to added salts: If used at all, the concentration should be kept to a minimum. For many proteins a combination of an amorphous excipient, such as a disaccharide, and a crystallizing excipient, such as glycine, will result in a suitable combination of chemical stability and physical stability of the freeze-dried solid. Concepts of heat and mass transfer are valuable in rational design of processing conditions. Heat transfer by conduction--the dominant mechanism of heat transfer in freeze-drying--is inefficient at the pressures used in freeze-drying. Steps should be taken to improve the thermal contact between the product and the shelf of the freeze dryer, such as eliminating metal trays from the drying process. Quantitation of the heat transfer coefficient for the geometry used is a useful way of assessing the impact of changes in the system such as elimination of product trays and changes in the vial. Because heat transfer by conduction through the vapor increases with increasing pressure, the commonly held point of view that "the lower the pressure, the better" is not true with respect to process efficiency. The optimum pressure for a given product is a function of the temperature at which freeze-drying is carried out, and lower pressures are needed at low product temperatures. The controlling resistance to mass transfer is almost always the resistance of the partially dried solids above the submination interface. This resistance can be minimized by avoiding fill volumes of more than about half the volume of the container. The development scientist should also recognize that very high concentrations of solute may not be appropriate for optimum freeze-drying, particularly if the resistance of the dried product layer increases sharply with concentration. Although the last 10 years has seen the publication of a significant body of literature of great value in allowing development scientists and engineers to "work smarter," there is still much work needed in both the science and the technology of freeze-drying. Scientific development is needed for improving analytical methodology for characterization of frozen systems and freeze-dried solids. A better understanding of the relationship between molecular mobility and reactivity is needed to allow accurate prediction of product stability at the intended storage temperature based on accelerated stability at higher temperatures. This requires that the temperature dependence of glass transition-associated mobility, particularly at temperatures below the glass transition, be studied in greater depth. The relevance of the concept of strong and fragile glasses to frozen systems and freeze-dried solids has only begun to be explored. The list of pharmaceutically acceptable protective solutes is very short, and more imagination--and work--is needed in order to develop pharmaceutically acceptable alternative stabilizers. There is a need for technology development in process monitoring, particularly in developing a way to measure the status of the product during freezing and freeze-drying without placing temperature measurement probes in individual vials of product. The current practice of placing thermocouples in vials is uncertain with respect to reliability of the data, inconsistent with elimination of personnel in close proximity to open vials of product in an aseptic environment, and incompatible with technology for automatic material handling in freeze-drying. In addition, a method for controlling the degree of supercooling during freezing would allow better control of freezing rate and would, in many cases, result in more consistent product quality.