Mass spectrometry in freeze-drying: Motivations for using a bespoke PAT for laboratory and production environment

Abstract

Mass Spectrometry has commonly been used in the semi-conductor industry where maintaining a clean environment with minimum contaminants under high vacuum is crucial for successful manufacturing. Since the technology's early usage for pharmaceutical manufacturing in the 1980 s, particularly in the freeze-drying environment, much has changed. The focus of the current work is aimed at asking some key questions regarding the maturity of the technology, its challenges and importance of having an application-specific instrument for quantitative process analyses applied to freeze-drying. Furthermore, we compare the use of mass spectrometers in early installations from the '80s with recent experiences of the technology in the production and laboratory environments comparing data from different MS technologies. In addition, the manuscript covers broad application of the technology towards detection of and sensitivity for analytes including silicone oil and Helium. It also explores the option of using MS in detecting water vapor and nitrogen concentration not just in primary drying, but also in secondary drying. The technology, when purpose built, has the potential for use as a robust, multi-purpose PAT tool in the freeze-drying laboratory and production environments.

Process Analytical Technology Tools for Monitoring Pharmaceutical Unit Operations: A Control Strategy for Continuous Process Verification

“…MS is an extremely useful PAT tool for the qualitative analysis of drug, compound, and related substances. Because it has a high resolution and mass accuracy, it is also used in the qualitative analysis of small molecules and is often selected and used in biological processes, such as in analyzing heterogeneous biomolecules [ 177 , 178 , 179 ]. In addition, it provides quick analysis when high throughput sample preparation and automated data processing are possible [ 8 ].…”

“…The drying process for a solid dosage form is usually done simultaneously with the granulation process or after the granulation process to evaporate the sprayed water. Drying is used to assure the long-term preservation of the product because it provides a dried drug product that quickly and completely rehydrates when added to the solvent [ 178 ]. One of the drying processes, the freeze-drying process, may be performed depending on the needs of the formulation.…”

Recommended Best Practices in Freeze Dryer Equipment Performance Qualification: 2022

“…A systematic discussion involving best practices in preventive maintenance programs will stand to reduce redundancies and lost time. • Silicone oil level detection and characterization: While there is growing interest in the use of mass spectrometry in the detection of trace concentrations of contaminants in the freeze dryer [12], there are currently no industry standards for critical levels of different contaminants in the freeze dryer. • Use of computational fluid dynamics: The community can greatly benefit from systematically and routinely using computational techniques to quantify and characterize equipment limits.…”

In-Line Monitoring of the Freeze-Drying Process by Means of Heat Flux Sensors

“…The pressure in the chamber can be measured by pressure transducers, such as thermal conductivity-type sensors and capacitance manometers. Moreover, the use of comparative pressure measurement is widely adopted as a process-monitoring tool to define the endpoint of both primary and secondary drying. , Recent works have shown similar potential for mass spectroscopy, which might be used to end the cycle at a precise residual moisture level. , Finally, the heat flux exchanged in discrete locations throughout the process can be monitored by heat flux sensors. These are thin-film differential thermopiles that can convert the temperature difference across them into a voltage value as a result of the Seebeck effect and then convert it into the proportional heat flux .…”

“…13,14 Recent works have shown similar potential for mass spectroscopy, which might be used to end the cycle at a precise residual moisture level. 14,15 Finally, the heat flux exchanged in discrete locations throughout the process can be monitored by heat flux sensors. These are thin-film differential thermopiles that can convert the temperature difference across them into a voltage value as a result of the Seebeck effect and then convert it into the proportional heat flux.…”