Mechanical Characterization of Vial Strain During Freezing and Thawing Operations Using Amorphous Excipients.

The purpose of this study was to investigate the mechanical stresses and strains acting on pharmaceutical glass tubing vials during freezing and thawing of model pharmaceutical formulations. Strain measurements were conducted inside of a laboratory-scale freeze-dryer using a custom wireless sensor. In both sucrose and trehalose formulations at concentrations between 5 % and 20 % w/v, the strain measurements initially increased before peaking in magnitude at temperatures close to the respective glass transition temperatures of the maximally freeze concentrated solutes, Tg'. We attribute this behavior to a shift in the mechanical properties of the frozen system from a purely elastic glass below Tg' to a viscoelastic rubber-like material above Tg'. That is, when the interstitial region becomes mechanically compliant at temperature above Tg'. The outputs were less predictable below 5 % w/v and tended to exhibit two separate peaks in strain output, one near the equilibrium melting temperature of pure ice and the other near Tg'. The peaks merged at concentrations between 4 and 5 % w/v where the largest strain magnitude was observed. The strain on primary packaging has traditionally been applied to evaluate the risk of damage or breakage due to, for example, crystallization of excipients. However, data collected during this study suggest there may be utility in formulation design or as a process analytical technology to minimize potentially destabilizing stresses and strains in the frozen formulation.

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.

Radio Frequency - Assisted Ultrasonic Spray Freeze Drying for Pharmaceutical Protein Solids.

This study examined physical stability of spray freeze dried (SFD) bovine serum albumin (BSA) solids produced using the radio frequency (RF)-assisted drying technique. BSA formulations were prepared with varying concentrations of trehalose and mannitol, using an excipient-free formulation as control. These formulations were produced using either traditional ultrasonic spray freeze drying (SFD) or RF-assisted ultrasonic spray freeze drying (RFSFD). The dried formulations were then characterized using Karl Fischer moisture content measurement, powder X-ray diffraction (PXRD), size exclusion chromatography (SEC), and solid-state hydrogen/deuterium exchange with mass spectrometry (ssHDX-MS). Moisture content did not have a good correlation with the physical stability of the formulations measured by SEC. ssHDX-MS metrics such as deconvoluted peak areas of the deuterated samples showed a satisfactory correlation (R2 = 0.914) with the SEC stability data. RFSFD improved the stability of formulations with 20 mg/ml of trehalose and no mannitol, and had similar stability with all other formulations as compared to SFD. This study demonstrated that RFSFD technique can significantly reduce the duration of primary drying cycle from 48.0 h to 27.5 h while maintaining or improving protein physical stability as compared to traditional lyophilization.

Wireless sensor networks for pharmaceutical lyophilization: Quantification of local gas pressure and temperature in primary drying.

Wireless sensor networks have become prolific in a wide range of industrial processes and offer several key advantages over their wired counterparts in terms of positioning flexibility, modularity, interconnectivity, and data routing. We demonstrate their utility in pharmaceutical lyophilization by developing a series of wireless devices to measure spatial variations in gas pressure and temperature during primary drying. The influence of shelf temperature, chamber pressure, excipient concentration, and dryer configuration are explored for various representative cycles using a laboratory-scale pharmaceutical lyophilizer. Pressure and temperature variations across the shelf for these cases are shown to vary up to 1.2 Pa and 10 °C, respectively. Experimental measurements are supported by computational fluid dynamics simulations to reveal the mechanisms driving the vapor flow. The measurements and simulation data are then combined to estimate the shelf-wise sublimation rate in the inverse sense to within a deviation of 3% based on comparison with gravimetric data. We then apply the sublimation rate profile to obtain the vial heat transfer coefficient and product mass transfer resistance for a 5% w/v mannitol formulation. Finally, these parameters are applied to a one-dimensional quasi-steady heat transfer model to predict the evolution of the product temperature over the course of primary drying. Thermocouple measurements of product temperature are compared directly to the simulated data and demonstrate accuracy comparable to existing published one-dimensional models.

Rapid Depressurization Based Controlled Ice Nucleation in Pharmaceutical Freeze-drying: The Roles of the Ballast Gas and the Vial.

Controlled ice nucleation offers several key benefits to the pharmaceutical lyophilization process, including reducing lyophilization cycle time, control of ice crystal morphology, and increased consistency of lyophilized product quality attributes. The rapid depressurization based controlled ice nucleation technique is one of the several demonstrated controlled ice nucleation technologies and relies on the rapid discharge of an inert pressurized gas to induce ice nucleation. In this work, a series of custom wireless gas pressure and temperature sensors were developed and applied to this process to better understand the mechanism of controlled ice nucleation by depressurization. The devices capture highly transient conditions both in the chamber near the vial and within the vial headspace throughout the entire process. The effects of ballast gas composition, initial charge pressure, and vial size on gas pressure and headspace/chamber temperature are explored individually. We model the depressurization as an isentropic process, allowing the influence of these parameters to be evaluated quantitatively. It is demonstrated that monatomic gases (e.g. argon) with low thermal conductivity produce the most favorable conditions for ice nucleation at the end of depressurization, based on temperature drop in the vial headspace. Experimental data also reveal a correlation between initial charge pressure and vial size with the temperature drop within the vial headspace, during depressurization. These findings ultimately provide deeper insight into the rapid depressurization based controlled ice nucleation process and help lay the foundation for a more robust process development and control.

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.