ABSTRACT
INTRODUCTION Critical quality attributes of freeze-dried injectable pharmaceuticals include sterility, freedom from pyrogens, and freedom from extraneous particulate matter. These attributes are achieved by appropriate processing conditions. In addition, these products must completely recover their original activity when reconstituted with water, should be quickly and easily reconstituted, and should retain these attributes over the shelf-life of the product. Stability assessment and shelf-life prediction is usually a major focus of a pharmaceutical scientist’s attention in the development of freeze-dried dosage forms, and stability studies have a critical impact on the time course of product development. Stability of drugs as freeze-dried solids is a concern for both small molecules and large molecule drugs, although there are important differences between these two arenas. For stability assessment of freeze-dried small molecules, the main concern is the infl uence of the physical state of a drug on stability, where the amorphous form may in some cases be at least an order of magnitude less stable than the same drug in its crystalline state ( 36 , 51 ). Acute damage by the freeze-dry process itself is hardly ever a concern. For freeze drying of large molecules, where proteins are the main focus of this discussion, there are two types of stability-short-term stability against loss of protein integrity caused by stresses associated with freezing and freeze drying, and long-term stability, referring to the potential for loss of integrity during storage of the freeze-dried solid ( 3 ). Because of the structural complexity of proteins and the vital role of water in determination of secondary and tertiary structure, freeze drying can, in some cases, result in complete loss of activity. The role of water in maintenance of protein structure may account for another important difference between small molecules and proteins in the context of freeze drying. For small molecules, the conventional wisdom that “dryer is better” in terms of storage stability nearly always applies. For proteins, this is not always the case, since the integrity of some proteins after freeze drying can be adversely affected by over drying.
