Freeze-drying cycle

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 ... 

De Luca, P. P., Klamat, M. S., Koida, C. Acceleration of freeze-drying Cycles of aqueous Solutions of Lactose and Sucrose with tertiary Buthylalcohol (tBA). Congr. Intern. Technol. Pharm. 5th Vol. 1, p. 439-447, 1989... 

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. 

Deactivation due to lyophilization by non-reversible denaturation in freeze/dry cycle... 

The specifications of the plant are given in the caption of Figure 2.58. As can be seen from the tables in the caption, the main drying time depends on the heat transfer and the vapor flow rate. To optimize a freeze-drying cycle it is helpful to calculate a table as shown in Figure 2.58 for mns 1-7, which can be commented upon as follows ... 

The freeze-drying cycle. It is now well established that a freeze-drying operation includes ... 

Figure 1 summarizes the freeze-drying cycle and indicates for each step the different limits that have to be taken into consideration. Figure 2 gives an example of a typical freeze-drying cycle. 

Figure 2 A typical freeze-drying cycle. Note that the pressure is raised to 0.3 mbar to increase the heat transfer during sublimation and then lowered to 0.02 mbar for desorption.

The evolution of electric properties is, thus, at least for us, a major parameter in the design and follow-up of a freeze-drying cycle. It can even be used for an automatic control of the whole operation as we proposed in the past [6]. 

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. 

Although the measurement of product temperature with probes inserted nearly to the bottom of the vials or ampoules is often questioned for many reasons, we use this method routinely to evaluate the duration of primary drying and the maximum primary drying temperature as shown in Figure 1. During prevalidation trials, we have run a series of more or less extreme freeze-drying cycles for sucrose and lactose formulations. The pellets produced were examined for... 

The selection of the process parameters that need to be quantified and validated requires a knowledge of the many variables that may have an effect on the product. There is no universal validation framework, and the critical parameters should be identified based on the profile of the freeze-drying cycle, as well as on the characteristics, requirements, and release specifications of the product. The present section will be restricted to give examples of process parameters that are frequently assessed in validation reports. 

If lyophilizers of different types are used to lyophilize a drug product according to a same freeze-drying cycle, useful information about process robustness can sometimes be gained by comparing the values of the dependent parameters. The analytical properties, in particular the activity and the moisture of product batches manufactured in different lyophilizers, also deserve comparison. 

A poor freeze-drying cycle or an ineffective lyophilizer... 

At the completion of the freeze-dry cycle, the partially inserted rubber closures are fully seated in the vials. The finished product contains a white or off-white sterile dry powder. 

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