title: Application of process analytical technology for monitoring freeze-drying of an amorphous protein formulation: use of complementary tools for real-time product temperature measurements and endpoint detection.
abstract: Process analytical technology (PAT) and quality by design have gained importance in all areas of pharmaceutical development and manufacturing. One important method for monitoring of critical product attributes and process optimization in laboratory scale freeze-drying is manometric temperature measurement (MTM). A drawback of this innovative technology is that problems are encountered when processing high-concentrated amorphous materials, particularly protein formulations. In this study, a model solution of bovine serum albumin and sucrose was lyophilized at both conservative and aggressive primary drying conditions. Different temperature sensors were employed to monitor product temperatures. The residual moisture content at primary drying endpoints as indicated by temperature sensors and batch PAT methods was quantified from extracted sample vials. The data from temperature probes were then used to recalculate critical product parameters, and the results were compared with MTM data. The drying endpoints indicated by the temperature sensors were not suitable for endpoint indication, in contrast to the batch methods endpoints. The accuracy of MTM Pice data was found to be influenced by water reabsorption. Recalculation of Rp and Pice values based on data from temperature sensors and weighed vials was possible. Overall, extensive information about critical product parameters could be obtained using data from complementary PAT tools.
authors.affiliation: Freeze Drying Focus Group, Division of Pharmaceutics, University of Erlangen-Nuremberg, Erlangen, 91058, Germany.
authors.forename: Stefan C
authors.initials: SC
authors.lastname: Schneid
authors.forename: Robert E
authors.initials: RE
authors.lastname: Johnson
authors.forename: Lavinia M
authors.initials: LM
authors.lastname: Lewis
authors.forename: Peter
authors.initials: P
authors.lastname: Stärtzel
authors.forename: Henning
authors.initials: H
authors.lastname: Gieseler
mesh_terms: D000818:Animals; D002417:Cattle; D002626:Chemistry, Pharmaceutical; D003199:Computer Systems; D023381:Endpoint Determination / Q000379:methods*; D005612:Freeze Drying / Q000379:methods*; D012710:Serum Albumin, Bovine / Q000032:analysis / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods*; D013696:Temperature
chemical_list: D012710:Serum Albumin, Bovine
keywords: freeze-drying; lyophilization; manometric temperature measurements; process analytical technology; process optimization; protein formulation; proteins; quality by design; stability; water re-absorption