LyoPRONTO: an Open-Source Lyophilization Process Optimization Tool.

This work presents a new user-friendly lyophilization simulation and process optimization tool, freely available under the name LyoPRONTO. This tool comprises freezing and primary drying calculators, a design-space generator, and a primary drying optimizer. The freezing calculator performs 0D lumped capacitance modeling to predict the product temperature variation with time which shows reasonably good agreement with experimental measurements. The primary drying calculator performs 1D heat and mass transfer analysis in a vial and predicts the drying time with an average deviation of 3% from experiments. The calculator is also extended to generate a design space over a range of chamber pressures and shelf temperatures to predict the most optimal setpoints for operation. This optimal setpoint varies with time due to the continuously varying product resistance and is taken into account by the optimizer which provides varying chamber pressure and shelf temperature profiles as a function of time to minimize the primary drying time and thereby, the operational cost. The optimization results in 62% faster primary drying for 5% mannitol and 50% faster primary drying for 5% sucrose solutions when compared with typical cycle conditions. This optimization paves the way for the design of the next generation of lyophilizers which when coupled with accurate sensor networks and control systems can result in self-driving freeze dryers.

In-Situ Molecular Vapor Composition Measurements During Lyophilization.

PURPOSE: Monitoring process conditions during lyophilization is essential to ensuring product quality for lyophilized pharmaceutical products. Residual gas analysis has been applied previously in lyophilization applications for leak detection, determination of endpoint in primary and secondary drying, monitoring sterilization processes, and measuring complex solvents. The purpose of this study is to investigate the temporal evolution of the process gas for various formulations during lyophilization to better understand the relative extraction rates of various molecular compounds over the course of primary drying. METHODS: In this study, residual gas analysis is used to monitor molecular composition of gases in the product chamber during lyophilization of aqueous formulations typical for pharmaceuticals. Residual gas analysis is also used in the determination of the primary drying endpoint and compared to the results obtained using the comparative pressure measurement technique. RESULTS: The dynamics of solvent vapors, those species dissolved therein, and the ballast gas (the gas supplied to maintain a set-point pressure in the product chamber) are observed throughout the course of lyophilization. In addition to water vapor and nitrogen, the two most abundant gases for all considered aqueous formulations are oxygen and carbon dioxide. In particular, it is observed that the relative concentrations of carbon dioxide and oxygen vary depending on the formulation, an observation which stems from the varying solubility of these species. This result has implications on product shelf life and stability during the lyophilization process. CONCLUSIONS: Chamber process gas composition during lyophilization is quantified for several representative formulations using residual gas analysis. The advantages of the technique lie in its ability to measure the relative concentration of various species during the lyophilization process. This feature gives residual gas analysis utility in a host of applications from endpoint determination to quality assurance. In contrast to other methods, residual gas analysis is able to determine oxygen and water vapor content in the process gas. These compounds have been shown to directly influence product shelf life. With these results, residual gas analysis technique presents a potential new method for real-time lyophilization process control and improved understanding of formulation and processing effects for lyophilized pharmaceutical products.

In-Process Vapor Composition Monitoring in Application to Lyophilization of Ammonium Salt Formulations.

Quality control is of critical importance in manufacturing of lyophilized drug product, which is accomplished by monitoring the process parameters. The residual gas analyzer has emerged as a useful tool in determination of endpoint for primary and secondary drying in lyophilization process as well as leak detection in vacuum systems. This study presents the application of in situ RGA to quantify outgassing rates of species released from aqueous inorganic and organic ammonium salt formulations throughout the freeze-drying process. The determination of ammonia outgassing conditions aids in ensuring product quality where ammonia release is an indication for loss of co-solvent or degradation of active pharmaceutical ingredients (APIs). Data analysis methods are developed to determine ammonia presence under various process conditions. In-situ real time monitoring of vapor dynamics enables RGA to be used as a tool to characterize counter-ion loss throughout the freeze-drying cycle.

Freeze-Dryer Equipment Capability Limit: Comparison of Computational Modeling With Experiments at Laboratory Scale.

The equipment capability curve is one of the bounding elements of the freeze-drying design space, and understanding it is critical to process design, transfer, and scale-up. The second bounding element of the design space is the product temperature limit beyond which the product collapses. The high cost associated with freeze-drying any product renders it crucial to operate using the most efficient cycle within the limits of the equipment and the product. In this work, we present a computational model to generate the equipment capability curve for 2 laboratory scale freeze-dryers and compare the results to experimentally generated equipment capability curves. The average deviations of the modeling results from the experiments for the 2 lyophilizers modeled are -4.8% and -7.2%. In addition, we investigate the effect of various numerical and geometric parameters on the simulated equipment capability. Among the numerical parameters, the chamber wall thermal boundary conditions exert the largest influence with a maximum value of 12.3%. Among the geometric parameters, the inclusion of the isolation valve reduces the equipment capability by 23.7%. Larger isolation valves, required for controlled nucleation technology, choke the flow in the duct at lower sublimation rates, thereby lowering the equipment capability limit.

Freeze-drying simulation framework coupling product attributes and equipment capability: toward accelerating process by equipment modifications.

A physics-based model for the sublimation-transport-condensation processes occurring in pharmaceutical freeze-drying by coupling product attributes and equipment capabilities into a unified simulation framework is presented. The system-level model is used to determine the effect of operating conditions such as shelf temperature, chamber pressure, and the load size on occurrence of choking for a production-scale dryer. Several data sets corresponding to production-scale runs with a load from 120 to 485 L have been compared with simulations. A subset of data is used for calibration, whereas another data set corresponding to a load of 150 L is used for model validation. The model predictions for both the onset and extent of choking as well as for the measured product temperature agree well with the production-scale measurements. Additionally, we study the effect of resistance to vapor transport presented by the duct with a valve and a baffle in the production-scale freeze-dryer. Computation Fluid Dynamics (CFD) techniques augmented with a system-level unsteady heat and mass transfer model allow to predict dynamic process conditions taking into consideration specific dryer design. CFD modeling of flow structure in the duct presented here for a production-scale freeze-dryer quantifies the benefit of reducing the obstruction to the flow through several design modifications. It is found that the use of a combined valve-baffle system can increase vapor flow rate by a factor of 2.2. Moreover, minor design changes such as moving the baffle downstream by about 10 cm can increase the flow rate by 54%. The proposed design changes can increase drying rates, improve efficiency, and reduce cycle times due to fewer obstructions in the vapor flow path. The comprehensive simulation framework combining the system-level model and the detailed CFD computations can provide a process analytical tool for more efficient and robust freeze-drying of bio-pharmaceuticals.

Quantifying the Knudsen force on heated microbeams: a compact model and direct comparison with measurements.

At the microscale, even moderate temperature differences leading to thermal nonequilibrium can result in significant Knudsen forces generated by the energy exchange between gas molecules and solids immersed in a gas. Experimental measurements of the microscale Knudsen force have been reported by Passian et al., Phys. Rev. Lett. 90, 124503 (2003) using heated microcantilevers of atomic force microscope probes. The present study investigates the mechanism and magnitude of Knudsen forces in detail based on numerical solution of the Boltzmann kinetic equation with the ellipsoidal statistical Bhatnagar-Gross-Krook approximation for the collisional relaxation process. A direct comparison between the numerical simulations and experimental measurements is presented. We show that, assuming a fully diffuse interaction of gas molecules with the surfaces of the heated cantilever, simulations agree with measurements for different operating pressures in argon and nitrogen ambients. For the helium ambient the simulations agree with measurements only when an incomplete accommodation is used. A closed-form model for the nondimensional Knudsen force coefficient on a heated microbeam is obtained that can be used for quantifying such forces in analysis and design of microsystems under a wide range of geometrical, thermal, and pressure conditions.

Computational analysis of fluid dynamics in pharmaceutical freeze-drying.

Analysis of water vapor flows encountered in pharmaceutical freeze-drying systems, laboratory-scale and industrial, is presented based on the computational fluid dynamics (CFD) techniques. The flows under continuum gas conditions are analyzed using the solution of the Navier-Stokes equations whereas the rarefied flow solutions are obtained by the direct simulation Monte Carlo (DSMC) method for the Boltzmann equation. Examples of application of CFD techniques to laboratory-scale and industrial scale freeze-drying processes are discussed with an emphasis on the utility of CFD for improvement of design and experimental characterization of pharmaceutical freeze-drying hardware and processes. The current article presents a two-dimensional simulation of a laboratory scale dryer with an emphasis on the importance of drying conditions and hardware design on process control and a three-dimensional simulation of an industrial dryer containing a comparison of the obtained results with analytical viscous flow solutions. It was found that the presence of clean in place (CIP)/sterilize in place (SIP) piping in the duct lead to significant changes in the flow field characteristics. The simulation results for vapor flow rates in an industrial freeze-dryer have been compared to tunable diode laser absorption spectroscopy (TDLAS) and gravimetric measurements.

Numerical simulation of gas-phonon coupling in thermal transpiration flows.

Thermal transpiration is a rarefied gas flow driven by a wall temperature gradient and is a promising mechanism for gas pumping without moving parts, known as the Knudsen pump. Obtaining temperature measurements along capillary walls in a Knudsen pump is difficult due to extremely small length scales. Meanwhile, simplified analytical models are not applicable under the practical operating conditions of a thermal transpiration device, where the gas flow is in the transitional rarefied regime. Here, we present a coupled gas-phonon heat transfer and flow model to study a closed thermal transpiration system. Discretized Boltzmann equations are solved for molecular transport in the gas phase and phonon transport in the solid. The wall temperature distribution is the direct result of the interfacial coupling based on mass conservation and energy balance at gas-solid interfaces and is not specified a priori unlike in the previous modeling efforts. Capillary length scales of the order of phonon mean free path result in a smaller temperature gradient along the transpiration channel as compared to that predicted by the continuum solid-phase heat transfer. The effects of governing parameters such as thermal gradients, capillary geometry, gas and phonon Knudsen numbers and, gas-surface interaction parameters on the efficiency of thermal transpiration are investigated in light of the coupled model.