Quality by Design Process Development Tools for Freeze Drying Co-solvent Pharmaceutical Formulations

Project Summary Abstract Physical Sciences Incin collaboration with the University of Connecticut School of Pharmacy proposes to develop both hardware and software tools that will support Quality by Design based development of freeze drying processes for co solvent product formulationsCo solvent systemswater plus a single organic solventare used in freeze drying particularly when the drug degrades in pure water during upstream processing such as compoundingaseptic fillingloading and freezinge gbendamustinealprostadiland many peptide drugsDegradation may also occur when the drug formulation is not sufficiently soluble in pure watere gprocessing of self assembled nanocarriers with drugUnfortunately there are very few tools that aid process engineers in developing lyophilization cycles for these co solvent formulationsPSI and UConn will develop a Tunable Diode Laser Absorption Spectroscopy based co solvent mass flow rate monitor and a steady state heat and mass transfer model of vial based freeze drying to enable efficient development and verification of co solvent freeze drying cycles based on product temperature requirementsDuring the Phase I effort PSI will focus on the development and testing of an organic solvent mass flow rate monitorThe non contactreal time sensor measurement of the integrated amount of solvent removed will be compared to gravimetric determinations of solvent removedFollowing sensor feasibility testing the Process Analytical Technology tool will be used to measure Key Process Parameters that enable use of the heat and mass transfer model developed by UConn to calculate process knowledge and design spaces to maintain a required product temperatureThe model predicted mass flow rates for solvent sublimation will be compared to sensor measurements to upgrade and verify model performanceDuring subsequent Randamp D efforts the sensor and model products will be matured and further verified by designing and running lyophilization processes which are monitored for product collapse and melt backwhich may occur when operating the process with a product temperature above the collapse temperature or transitioning from primary to secondary drying before all of the vials have completed ice sublimationIn additionwe anticipate creating algorithms that support the automation of co solvent cycle development and testing in both laboratory and pilot scale freeze dryersThe proposed effort supports the US FDA Process Analytical Technology and Regulatory Science initiatives by developing tools that can be directly used to infer information that affects product quality during processingthe product temperatureThe combined use of the proposed sensor and mathematical model will allow end users to predict and verify freeze drying cycle performanceThe proposed effort has support of a well known industry equipment supplier and large pharmaceutical companies Project Narrative This proposed Randamp D will result in products that support the development of efficient co solvent product formulation freeze drying cyclesIt targets some of the novelemerging drug productsThe development of robust and efficient cycles will reduce processing costsresult in lower drug costs and support a reduction in shortages of novel lyophilized drug therapies