title: Evaluation of Heat Flux Measurement as a New Process Analytical Technology Monitoring Tool in Freeze Drying.
abstract: This study investigates the suitability of heat flux measurement as a new technique for monitoring product temperature and critical end points during freeze drying. The heat flux sensor is tightly mounted on the shelf and measures non-invasively (no contact with the product) the heat transferred from shelf to vial. Heat flux data were compared to comparative pressure measurement, thermocouple readings, and Karl Fischer titration as current state of the art monitoring techniques. The whole freeze drying process including freezing (both by ramp freezing and controlled nucleation) and primary and secondary drying was considered. We found that direct measurement of the transferred heat enables more insights into thermodynamics of the freezing process. Furthermore, a vial heat transfer coefficient can be calculated from heat flux data, which ultimately provides a non-invasive method to monitor product temperature throughout primary drying. The end point of primary drying determined by heat flux measurements was in accordance with the one defined by thermocouples. During secondary drying, heat flux measurements could not indicate the progress of drying as monitoring the residual moisture content. In conclusion, heat flux measurements are a promising new non-invasive tool for lyophilization process monitoring and development using energy transfer as a control parameter.
authors.affiliation: Coriolis Pharma Research GmbH, Martinsried 82152, Germany; Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-University, Munich 81377, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Vollrath
authors.affiliation: Coriolis Pharma Research GmbH, Martinsried 82152, Germany; Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-University, Munich 81377, Germany.
authors.forename: Victoria
authors.initials: V
authors.lastname: Pauli
authors.affiliation: Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-University, Munich 81377, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Friess
authors.affiliation: Coriolis Pharma Research GmbH, Martinsried 82152, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Freitag
authors.affiliation: Coriolis Pharma Research GmbH, Martinsried 82152, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hawe
authors.affiliation: Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-University, Munich 81377, Germany. Electronic address: gerhard.winter@lrz.uni-muenchen.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Winter
mesh_terms: D003890:Desiccation / Q000379:methods*; D004735:Energy Transfer; D005612:Freeze Drying / Q000379:methods; D006358:Hot Temperature; D012710:Serum Albumin, Bovine / Q000737:chemistry*; D013395:Sucrose / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D012710:Serum Albumin, Bovine; D013395:Sucrose
keywords: freeze drying/lyophilization; lyophilization; process analytical technology; processing; quality by design