Optical coherence tomography (OCT) freeze drying microscopy
Inventors
Mujat, Mircea • Kessler, William J.
Assignees
Publication Number
US-8911144-B2
Publication Date
2014-12-16
Expiration Date
2032-04-24
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Abstract
A product critical temperature during freeze drying is determined. The product is imaged using optical coherence tomography (“OCT”). The product is freeze dried while the temperature of the product is measured. The product critical temperature is the temperature at which a product structure event occurs during freeze drying.
Core Innovation
The invention provides a method and system for determining the critical temperature of a product during freeze drying using optical coherence tomography (OCT). The product is imaged with OCT while being freeze dried, and its temperature is concurrently measured. The system acquires both two-dimensional and three-dimensional images of the product, allowing visualization and analysis of events such as structural collapse, eutectic melting, skin formation, and sublimation during the freeze drying process.
The core problem addressed is the inaccuracy of conventional light transmission based freeze drying microscopy (LT-FDM) techniques, which typically use small sample sizes and do not represent the actual freeze drying conditions within product vials. This leads to inaccurate determination of the collapse temperature (Tc), causing suboptimal process control and economic inefficiency in lyophilization of pharmaceutical products. The new system seeks to overcome these issues by enabling accurate measurement of Tc in standard vials of significant thickness, thus providing reliable structural and temperature data relevant to practical manufacturing scenarios.
In the system, a freeze dryer holds the product, a temperature sensor monitors its temperature, and a three-dimensional imager—specifically an OCT system—collects detailed images of structural changes during the primary drying phase. The processor analyzes this combined data to pinpoint the critical temperatures associated with structural events, such as collapse or eutectic melting. This method and system can be applied to a wide range of pharmaceutical formulations and container types, supporting the optimization of freeze drying processes for drug product manufacturing.
Claims Coverage
The patent comprises two independent claims that outline two principal inventive features centered on freeze drying monitoring using three-dimensional imaging and integrated temperature measurement.
System for determining product collapse or eutectic melt temperature during freeze drying
A system comprising: - A freeze dryer with a holder for a product. - A temperature sensor coupled to the product. - A three-dimensional imager (including a source of radiation and a detector) positioned near the holder. - A processor that receives images from the imager and temperature information, and determines the product critical temperature by identifying the temperature at which viscous flow in the product structure occurs during ice sublimation based on the received images and temperature data.
System for measuring onset of viscous flow and consolidation of pores in a dry layer during freeze drying
A system comprising: - A freeze dryer with a holder for the sample. - A three-dimensional imager (with source of radiation and detector) positioned near the holder. - A processor that receives images from the imager and determines a pore structure characteristic within the sample during freeze drying using the images.
The patent's claims focus on integrated systems for precise imaging and temperature-based detection of critical structural events, such as collapse or pore consolidation, during freeze drying, using a combination of three-dimensional imaging and real-time temperature monitoring.
Stated Advantages
The system provides real-time, non-intrusive determination of pharmaceutical product structure and precisely determines critical product temperature during freeze drying in a relevant product container.
It enables accurate determination of collapse temperature (Tc) in conditions representative of actual vial-based manufacturing, thereby optimizing processing efficiency and shortening processing time.
It allows visualization and monitoring of ice crystal formation, pore structure, and other structural events during all phases of freeze drying, supporting robust process design and control.
Documented Applications
Measurement and control of critical process temperatures (collapse temperature, eutectic temperature) in the freeze drying of pharmaceutical products, such as vaccines and anti-cancer therapies.
Visualization and monitoring of structural changes, including ice nucleation, sublimation, collapse, skin formation, and pore structure evolution during the freeze drying process in drug manufacturing.
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