Physical Sciences Inc. (PSI), in collaboration with the University of Connecticut (UConn), proposes to develop the 2nd generation of an advanced 3D freeze-drying microscopy (FDM) system to advance the understanding of freeze-drying and to enable the development of efficient commercial freeze drying processes. During the Phase I program PSI demonstrated the application of Optical Coherence Tomography (OCT) for imaging the 3D structure of product formulations during freeze drying in commercially relevant pharmaceutical packaging systems, vials. The OCT-FDM system enabled product structure imaging and collapse temperature Tc) determination in a vial, overcoming the limitation of current light transmission (LT) FDM systems which interrogate thin film product samples. The OCT-FDM system eliminates errors in Tc determinations which will lead to shorter processing times and reduced production and drug costs. Biological drugs often require lyophilization to produce stable products that are stored in vials and reconstituted for patient use. The most critical process design parameter is the temperature at which the product undergoes primary drying. Drying above the product Tc results in viscous flow, loss of product structure and elegance, increased residual moisture content, poor storage stability, and long and/or poor reconstitution. LT- FDM, one method currently applied to estimate Tc, uses 1 - 2 ?L liquid product samples frozen between microscope slides, resulting in a frozen product thickness of 50 - 100 ?m. These samples are not representative of samples dried in vials which may have thicknesses of 5 - 50 mm. Thin films have different ice nucleation rates, crystallization tendencies for solutes, frozen product structures and drying rates as compared to vial freeze drying. Thus, LT-FDM does not accurately estimate Tc for freeze drying in a container of practical significance. [Our innovative OCT-FDM technique overcomes all of these shortcomings. The Phase I program demonstrated significantly more accurate determination of Tc using OCT-FDM, especially for a protein formulation. This is an important result as protein drug therapies are the fastest growing segment of the pharmaceutical industry. Laboratory freeze drying of the protein formulation based on the OCT-FDM determination of Tc resulted in an 80% reduction in primary drying time compared to an LT-FDM based process.] During the Phase II program PSI will develop a 2nd generation OCT-FDM system with improved imaging performance, instrument control, data acquisition and image processing software. The OCT-FDM will be used to: investigate ice formation during freezing, monitor 3D structural changes during primary drying, measure Tc in multi-component formulations of varying solid content, and monitor the advancement of the sublimation front. The goal of this R&D is the development and application of a laboratory tool which enables accurate determination of product thermal properties and development of optimal commercial freeze drying processes [for economical drug production].

Public Health Relevance

The purpose of this research is to develop the 2nd generation of an innovative 3D freeze-drying microscopy system to advance the understanding of the freeze-drying process in a product/container format that is the same as typically used during laboratory and manufacturing scale freeze drying and to enable the development of more efficient, economical commercial freeze drying processes.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1)
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Lash, Tiffani Bailey
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Physical Sciences, Inc
United States
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