Freeze-drying cycle, development

X Ma, DQ Wang, R Bouffard, A MacKenzie. Characterization of murine monoclonal anitbody to tumor necrosis factor (TNF-MAb) formulation for freeze-drying cycle development. Pharm Res 18(2) 196-202, 2001. 

The author has used a model and an equation developed by Steinbach [1.511 for many years and for many experiments in a wide field of applications. The model, shown in Fig. 1.60, uses an infinitely expanded plate of the product with the thickness d. Equation (14) describes the time of the main drying part of the freeze drying cycle ... 

Chang, B. S., Fuscher, N. L. The development of an efficient single-step freeze-drying cycle for interleukin-1 receptor antagonist formulation. Pharm. Res. vol. 12, No. 6, p. 831-837, 1995... 

Vries et al. [3.59] described the development of a stable parenteral dosage form of the cytotoxic drug E 09. E 09 dissolves poorly in water and its solution is unstable. With the addition of 200 mg of lactose per vial containing 8 mg of E 09, an optimum formulation was developed with respect to solubility, dosage of E 09 and length of the freeze drying cycle. DSC studies have been used to select the most effective parameters. The freeze dried product remains stable for 1 year when stored at 4 °C in a dark environment. 

Chang and Fischer [24] developed an efficient single-step freeze-drying cycle for protein formulations, namely, human interleukin-1 receptor antagonist (rhIL- Ira) formulations. The process resulted in successful drying of 1 ml of rhlL-Ira formulation to 0.4% moisture content within 6 h. 

At Bayer Biotechnology, we usually develop a freeze-drying cycle in five steps. First, the formulation is characterized. Second, based on the understanding of the formulation, the process is optimized. Third, the range of the critical process parameters is found. Fourth, the process is scaled up and transferred to production. Fifth, the process at the production scale is validated and qualified. Here, we focus only on the formulation characterization. 

In summary, in this chapter we will discuss the freeze-drying formulation characterization, which is the first step and the most important step in developing a freeze-drying cycle. All of the characterization discussion will focus on a crystalline matrix type of formulation. In the discussion, we will follow the order given below ... 

BS Chang, NL Fischer. Development of an efficient single-step freeze-drying cycle for protein formulations. Pharm Res 12 831-837, 1995. 

The final product quality attributes are strongly related to the level of optimization of the composition of the liquid formulation, which is a multidisciplinary and challenging problem usually solved by tedious experimental approaches in the development of freeze-drying cycles. The topics of formulation that involve complex knowledge of physical chemistry, biochemistry and biology are outside the scope of this chapter. However, general concepts that are generally applied are summarized hereafter. 

Gieseler, H., Kramer, T, Pikal, M. J., 2007b. Use of Manometric Temperature Measurement (MTM) and SMART Freeze Dryer technology for development of an optimized freeze-drying cycle. J. Pharm. Sci. 96 3402-3418. 

Sterilization by steam is a standard procedure, but can be replaced by the VHP (Vaporized Hydrogen Peroxides) process, which works at ambient temperature and without pressure. Nakahira [2.11] described the development of applicable sterilization cycles, the necessary changes in the freeze-drying plant and the sterility test necessary to validate the process. Sterilization by VHP requires certain conditions which result from the nature of the H2Oz vapor ... 

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