Freeze Drying - Lyophilization Books

Freeze drying (4-7) and spray drying (8-10) are drying methodologies in common use in the pharmaceutical industry, and are suitable for the production of glassy solids. Freeze drying is a low-temperature process. In general, a formulation can be dried to 1% water or less, without any of the product exceeding 30?C. Thus, conventional wisdom states that freeze-drying is less likely to cause thermal degradation than a high-temperature process such as spray drying. Historically, freeze-drying is the method of choice for products intended for parenteral administration. Sterility and relative freedom from particulates are critical quality attributes for parenterals. Largely because the solution is sterile filtered immediately before filling into the final container, and further processing is relatively free of exposure to humans, a freeze-drying process maintains sterility and particle-free characteristics of the product much more easily than do processes that must deal with dry powder handling issues, such as dry powder filling of a spray-dried or bulk-crystallized powder. Indeed, with modern robotics automatic loading systems (11), humans can be removed from the sterile processing area entirely, at least in principle. Furthermore, as the vials are sealed in the freeze dryer, moisture control and control of headspace gas can easily be controlled, an important advantage for products whose storage stability is adversely affected by residual moisture and/or oxygen. As the critical heat and mass transfer characteristics for freeze-drying are nearly the same at the laboratory scale as in full production, resolution of scale-up problems tends to be easier for a freeze-drying process than for spray drying, at least in our experience. Also, development of a freeze-dried product requires less material for formulation and process development, a particularly important factor early in a project.
While freeze-drying has a long history in the pharmaceutical industry as a technique for stabilization of labile drugs, including proteins, many proteins suffer irreversible change, or degradation, during the freeze-drying process (12-16). Even when the labile drug survives the freeze-drying process without degradation, the resulting product is rarely found perfectly stable during long-term storage, particularly when analytical techniques with a sensitivity to detect low levels of degradation (0.1%) are employed. Both small molecules (1-3), (17) and proteins (18-21) show degradation during storage of the freeze-dried glass. In some cases, instability is serious enough to require refrigerated storage (18-19), (22).
Stability problems are most often addressed by a combination of formulation optimization and attention to process control. Lyoprotectants are added for stability during the freeze-drying process as well as to provide storage stability, and the level and type of buffer is optimized. Optimization of the freezing process may be critical; control of product temperature during drying is critical for products that tend to suffer cake collapse during primary drying, and control of residual moisture is nearly always critical for storage stability. Formulation and process are interrelated: A bad formulation can be nearly impossible to freeze dry, and even with a well designed formulation, a poorly designed process may require more than a week to produce material of suboptimal quality. Although blind empiricism may, in time, yield an acceptable formulation and process, an appreciation for the materials science of amorphous systems and some understanding of heat and mass transfer relevant to freeze-drying are needed for efficient development of freeze-dried products. Obviously, one also requires at least a phenomenological understanding of the major degradation pathways specific to the drug under consideration.
The objective of this article is to present the scientific and engineering fundamentals most useful in the development of formulations and processes for the manufacture of freeze-dried pharmaceuticals. Generalizations are illustrated with specific examples from the literature, but no attempt is made to survey all published works. Most of the section on the freeze-drying process applies equally well to small molecules and proteins, whereas most of the section on formulation and stability is specific to proteins.