Freeze-drying process, different steps

This chapter deals with the different aspects of the freeze-drying process, beginning with the steps involved and the conditions influencing them. The state of the art in freeze-drying technology and equipment is then reviewed, and the aims and major analytical chemical applications of the technique (particularly as regards the pretreatment of solid samples) are discussed. 

Figure 8.7 Overview of the manufacture of Betaferon, a recombinant human IFN-(3 produced in E. coli. The product differs from native human IFN-(3 in that it is unglycosylated and cysteine residue 17 had been replaced by a serine residue. E. coli fermentation is achieved using minimal salts/glucose media and product accumulates intracellularly in inclusion body (IB) form. During downstream processing, the lbs are solubilized in butanol, with subseguent removal of this denaturant to facilitate product refolding. After two consecutive gel-filtration steps, excipients are added, the product is filled into glass vials and freeze-dried. It exhibits a shelf life of 18 months when stored at 2-8 °C...

I have tried to show the interconnection between the property of the product, the goal to make it stable and the necessary processes to achieve this. The problems of the different process steps are discussed with examples and the parameters are described which influence each step. I have avoided following the many theoretical attempts describing one or more of the freeze-drying steps, but have restricted myself to a few equations which permit the calculation of process and product data with sufficient accuracy, or at least, allow an estimate, if some data is mentioned. 

The book describes the up-to-date fundamentals of freezedrying, not just presenting the process in all its seven steps theoretically, but explaining it with many practical examples. Many years of experience in freeze-drying allow the authors to supply valuable criteria for the selection of laboratory, pilot and production plants, discussing the advantages, drawbacks and limitations of different plant designs. 

Plasma-derived therapeutic proteins are parenteral biologies that are purified on an industrial scale. All biologies derived from human sources, such as plasma, carry the risk of viral contamination. Thus, in order to market a medicinal product derived from human plasma, manufacturers must assure the absence of specific viral contamination. Virus validation studies are performed to evaluate the capacity of a manufacturing process to remove viral contaminants. Virus clearance across three different terminal inactivation steps, low pH incubation of immunoglobulins (IgG), pasteurization of albumin, and freeze dry/dry heat treatment of plasma-derived products (Factor VIII and Protein G), is discussed in this article. The data show that, like all other upstream virus reduction steps, the methods used for terminal inactivation are process and product dependent, and that the reduction factors for an individual step may be overestimated or underestimated due to inherent limitations or inadequate designs of viral validation studies. 

Consequently, a common effort should be made to establish and complete the data basis concerning the numerous thermodynamic, thermophysical, transport and rheological properties necessary for modeling and simulating the different steps of this complex mild drying process. Moreover, the methods available for the characterization of most of these end-use properties should be improved and additional characterization methods should be adapted from other research fields (material science, applied biochemistry, physical chemistry, etc.). Improved characterization methods promise a better description and a safer control of numerous end-use properties for existing freeze-dryers as well as for new machines with more possibilities to better comply with more and more severe quality requirements in the future. The use of non-invasive sensors or of rapid non-intrusive methods for on-line and in situ estimation of the main parameters of the process could also help to overcome the difficulties observed, for example, the artifacts resulting from invasive sensors inserted inside vials and presently commonly used. 

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