Pharmaceuticals freeze drying process

Fissore, D., Pisano, R., Barresi, A. A., 2011a. Advanced approach to build the design space for the primary drying of a pharmaceutical freeze-drying process./. Pharm. Sci. 100(11) 4922-4933. 

Willemer, H. Water vapour pressure, its influence on the freeze-drying process and its control. 40th Annnual Congress of the International Association for Pharmaceutical Technology, Abstracts 1-67, Medpharm GmbH, Scientific Publishers, Stuttgart, Marz 1994... 

Tang, X.L., Pikal, M.J., and Taylor, L.S., Design of freeze-drying processes for pharmaceuticals practical advice, Pharm. Res., 21, 191, 2004. 

The filling temperature is critical for some pharmaceutical products. It is therefore decisive for the subsequent freeze-drying process that the filled vials pass through a known and reproducible course of temperature and time when the vials are pushed on to the cold shelves, as shown in Figure 2.72. 

Most protein stability studies have focused their interpretation on either a thermodynamic mechanism or a pure kinetic mechanism, and consequently there is some controversy and confusion over which mechanism is correct. Since the direction of a formulation development effort may depend on which theory is being followed, clarification of the roles of thermodynamic stabilization and kinetic stabilization in given stability problems would provide some practical benefit. This chapter is an attempt to provide such clarification. To this end, the major stresses, or destabilizing effects, that operate during the freeze-drying process are discussed, selected empirical observations regarding pharmaceutical stability in protein systems are presented, and the structure and dynamics in amorphous protein formulations are discussed. 

While FTIR spectroscopy may have some limitations as a quantitative predictor of the pharmaceutical stability of a protein [4], it seems clear that protein structure is often altered during the freeze-drying process, and the degree of structural perturbation is specific to the protein and quite specific to the formulation. 

By the development of new galenic systems in the form of freeze-dried Biomatrices, new application possibilities could be developed for the freeze-drying process in the pharmaceutical field as well as in cosmetics. Constant innovations and process optimizations made it possible to produce these products on an industrial scale in constant top quality with a maximum degree of product safety. 

K. Murgatroyd, The freeze-drying process. In Good Pharmaceutical Freeze-Drying Practice (P. Cameron, ed.), Interpharm Press, Buffalo Grove, IL, 1997, pp. 1-58. 

Studies on Development of Manufacturing Processes for Pharmaceutical Freeze-Dried Products... 

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. 

Since we are here concerned mainly with pharmaceutical and, especially, biopharmaceutical freeze-drying, processing costs are of secondary importance. Care must however be taken that limited freeze-drying capacity does not give rise to production problems. Thus, where the total drier capacity threatens to become the limiting factor in the production cycle, the best remedy is to examine whether, and how the cycle length might be reduced, commensurate with the maintenance of an acceptable product quality. This is a problem to which we shall return several times. 

Setting the product composition of a pharmaceutical preparation, so as to effect an efficient and economical drying cycle, will probably always be beyond the remit of the process engineer. However, bearing in mind the complexities of the freeze-drying process, its optimisation should be given due consideration even by those responsible for product development. 

In pharmaceutical freeze-drying, on the other hand, importance is placed not on mass, but on activity/unit mass, and the parameters that govern survival of some biological activity in small volumes are totally different and more subtle than they are for a simple dewatering process. 

The freeze drying process has been a standard approach in making thermally sensitive pharmaceutics. The principles and operation of a freeze dryer are described in Chapter 11 in the handbook. This chapter will focus on two specialized applications of the technique to make nanosized pharmaceutics and protein-based pharmaceutics in particular, the development and important aspects to consider for such applications. 

Readers requiring basic description of the freeze drying process can obtain more information from the preceding chapter on freeze drying in Chapter 11 from the handbook. What follows are some additional considerations on top of the conventional operation of a freeze dryer specific to the freeze drying of protein-based pharmaceutics. 

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