»
LYOPHILIZATION
» Step Freezing
Table 2. PAT for Freeze-Drying Process Development Physical Property PAT Tools
ice nucleation temperature
Primary drying
product temperature, drying time sublimation rate gas fl ow velocity product resistance vial heat transfer coeffi cient
Secondary drying
Figure 1. Tg’ and Tc as a Function of Protein Concentration in a Sucrose Containing Formulation Matrix
residual water product temperature drying time
ice fog Controlled Ice Nucleation techniques
MTM Freeze-drying Control Systems Wireless Temperature Monitoring Pirani gauge Spectroscopic techniques RGA
TDLAS
MTM = manometric temperature measurement; PAT = Process Analytical Technology; RGA = residual gas analyzer; TDLAS = tuneable diode laser absorption spectroscopy; TEMPRIS = temperature remote interrogation system
Step 2: Freeze-Drying Cycle Development Technology
The freeze-drying process is based on the fundamental principles of heat and mass transfer. The key objectives during freeze-drying process development are to:
• • •
obtain stable and elegant product with minimal inter- and intra-batch heterogeneity,
develop a process that is scaleable and readily transferable between lyophilizers,
and minimize processing cost.
Defi ning and controlling the critical process parameters is essential to achieve these objectives. Several techniques that are widely used to monitor and control the critical process parameters are listed in Table 2. The application of some of these techniques is described in subsequent sections.
Step 3: Process Characterization and Robustness
Several mathematical models are available to model the freeze-drying process [4, 8, 10-12]. With these models, the number of experiments needed to assess the impact of process variables on product quality can be signifi cantly reduced. However, these theoretical models are only as good as the input parameters. A systematic characterization of the formulation and container closure system is required to obtain the input parameters for these models. Knowledge and experience gained by performing process characterization and robustness can be used to assess the impact on product quality of the temperature and pressure excursions typically encountered in a production scale freeze-dryer. However, the range of process parameters evaluated for each step
80 | | September/October 2013 - 15TH ANNIVERSARY ISSUE
should be based on the equipment capabilities and limitations to control these critical process parameters.
A comprehensive understanding of the formulation, process, equipment (freeze-dryer), and container closure system is essential to address four commonly encountered freeze-drying process development and scale-up challenges: freezing, edge vial effect, determining the end point of primary drying, and the effect of load.
Freezing
Ice nucleation is a random and stochastic process that results in freezing heterogeneity not only from batch-to-batch but also within a batch. Low ice nucleation temperature results in formation of smaller pores and, hence, higher product resistance and longer drying time. Because of the cleaner environment (class 100), the ice nucleation temperature in a production-scale freeze-dryer is typically much lower than that of a lab-scale freeze-dryer, making ice nucleation both a process development and a scale-up issue [16].
Annealing is commonly performed during the freezing step to not only crystallize the crystallizing excipients in the formulation matrix [17], but also to remove freezing heterogeneity and reduce the primary drying time [18, 19]. However, if annealing is applied, selection of the annealing temperature and time is critical. Annealing can potentially lead to product instability due to conformational change in protein structure or amorphous-amorphous phase separation [20, 21]. Hence annealing should be performed with caution.
Alternatively, commercial techniques can be applied to achieve spontaneous ice nucleation at the desired temperature via pressurization and depressurization of the product chamber with an inert gas [22]. This technique has shown potential for application even on a production- scale dryer [23]. Additionally, several other competing techniques [24, 25, 26] can allow controlling the ice nucleation temperature to address this process development and scale-up issue. However, application of many of these techniques on a production-scale dryer is challenging.
Residual water cake appearance reconstitution time physical stability
Potential Product Quality Impact
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