title: Effect of Freezing on Lyophilization Process Performance and Drug Product Cake Appearance.
abstract: This study highlights the significance of the freezing step and the critical role it can play in modulating process performance and product quality during freeze-drying. For the model protein formulation evaluated, the mechanism of freezing had a significant impact on cake appearance, a potential critical product quality attribute for a lyophilized drug product. Contrary to common knowledge, a freezing step with annealing resulted in 20% increase in primary drying time compared to without annealing. In addition, annealing resulted in poor cake appearance with shrinkage, cracks, and formation of a distinct skin at the top surface of the cake. Finally, higher product resistance (7.5 cm(2).Torr.hr/g) was observed in the case of annealing compared to when annealing was not included (5 cm(2).Torr.hr/g), which explains the longer primary drying time due to reduced sublimation rates. An alternative freezing option using controlled ice nucleation resulted in reduced primary drying time (i.e., 30% reduction compared to annealing) and a more homogenous batch with elegant uniform (i.e., significantly improved) cake appearance. Here, a mechanistic understanding of the distinct differences in cake appearance as a function of freezing mechanism is proposed within the context of ice nucleation temperature, ice crystal growth, and presumed solute distribution within the frozen matrix.
authors.affiliation: Department of Formulation Sciences, Biopharmaceutical Development, MedImmune, Gaithersburg, Maryland 20878.
authors.forename: Reza
authors.initials: R
authors.lastname: Esfandiary
authors.affiliation: Department of Formulation Sciences, Biopharmaceutical Development, MedImmune, Gaithersburg, Maryland 20878.
authors.forename: Shravan K
authors.initials: SK
authors.lastname: Gattu
authors.affiliation: Department of Formulation Sciences, Biopharmaceutical Development, MedImmune, Gaithersburg, Maryland 20878.
authors.forename: John M
authors.initials: JM
authors.lastname: Stewart
authors.affiliation: Department of Formulation Sciences, Biopharmaceutical Development, MedImmune, Gaithersburg, Maryland 20878. Electronic address: PatelSaj@medimmune.com.
authors.forename: Sajal M
authors.initials: SM
authors.lastname: Patel
mesh_terms: D003460:Crystallization; D005612:Freeze Drying / Q000379:methods*; D005615:Freezing; D006023:Glycoproteins / Q000737:chemistry*; D007053:Ice / Q000032:analysis; D044367:Phase Transition; D016062:Porosity
chemical_list: D006023:Glycoproteins; D007053:Ice
keywords: drying; freeze-drying/lyophilization; glass transition; porosity; process analytical technology (PAT); processing; protein formulation; solid-state stability