Effect of Freezing on Lyophilization Process Performance and Drug Product Cake Appearance.
Autor: | Esfandiary R; Department of Formulation Sciences, Biopharmaceutical Development, MedImmune, Gaithersburg, Maryland 20878., Gattu SK; Department of Formulation Sciences, Biopharmaceutical Development, MedImmune, Gaithersburg, Maryland 20878., Stewart JM; Department of Formulation Sciences, Biopharmaceutical Development, MedImmune, Gaithersburg, Maryland 20878., Patel SM; Department of Formulation Sciences, Biopharmaceutical Development, MedImmune, Gaithersburg, Maryland 20878. Electronic address: PatelSaj@medimmune.com. |
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Jazyk: | angličtina |
Zdroj: | Journal of pharmaceutical sciences [J Pharm Sci] 2016 Apr; Vol. 105 (4), pp. 1427-33. |
DOI: | 10.1016/j.xphs.2016.02.003 |
Abstrakt: | 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. (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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