Leveraging Lyophilization Modeling for Reliable Development, Scale-up and Technology Transfer

Abstract

Modeling of the lyophilization process, based on the steady-state heat and mass transfer, is a useful tool in understanding and optimizing of the process, developing an operating design space following the quality-by-design principle, and justifying occasional process deviations during routine manufacturing. The steady-state model relies on two critical parameters, namely, the vial heat transfer coefficient, K v , and the cake resistance, R p . The classical gravimetric method used to measure K v is tedious, time-and resourceconsuming, and can be challenging and costly for commercial scale dryers. This study proposes a new approach to extract both K v and R p directly from an experimental run (e.g., temperature and Pirani profiles). The new methodology is demonstrated using 5% w/v mannitol model system. The values of K v obtained using this method are comparable to those measured using the classic gravimetric method. Application of the proposed approach to process scale-up and technology transfer is illustrated using a case study. The new approach makes the steady-state model a simple and reliable tool for model parameterization, thus maximizes its capability and is particularly beneficial for transfer products from lab/pilot to commercial manufacturing.

Evaluation of Microwave Vacuum Drying as an Alternative to Freeze-Drying of Biologics and Vaccines: the Power of Simple Modeling to Identify a Mechanism for Faster Drying Times Achieved with Microwave

“…First-principle equations for steady-state heat and mass transfer during lyophilization are well-known in the literature (20,21). These equations are used to determine how sublimation rate during primary drying can be optimized by modulation of the vial heat transfer coefficient and the formulation mass transfer resistance term.…”

Advanced Process Analytical Technology in Combination with Process Modeling for Endpoint and Model Parameter Determination in Lyophilization Process Design and Optimization

“…Validated pyhsico-chemical process models deepen process knowledge because they describe the separated physical effects by a coupled mass and energy balance. For Lyophilization, a broad range of models has been developed [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. In combination, PAT and modeling can result in advanced autonomous process control, and real-time release testing can be the final benefit.…”

“…-Gravimetric vial sublimation tests [33,42]; -Tunable Diode Laser Adsorption Spectroscopy (TDLAS) [42][43][44]; -Pressure rise test [45][46][47].…”

“…Therefore, in process development and optimization, both vial classes, edge and center, have to be considered for an optimal process design. The Design Space further depends on the used equipment, and with this approach a technology transfer is possible [33,34].…”

Positioning for a sustainable future—Role of chemical engineers in transforming pharmaceutical process development

“…While complex and highly time‐consuming simulations cannot be performed routinely, it is desirable to develop a simplistic methodology and reduced ordered model to predict the lyophilization process and equipment performance with reasonable fidelity. Some examples include a one‐dimensional model based lyophilization calculator 49 and a lyophilization process equipment capability map developed using an array of CFD simulations of various lyophilizers spanning multiple scales, as shown in Figure 18. Advances in lyophilization modeling at AbbVie were facilitated by collaboration with software vendors and academia 50,51 …”