Characterization of Freezing Processes in Drug Substance Bottles by Ice Core Sampling

Characterization of Freezing Processes in Drug Substance Bottles by Ice Core Sampling

Freezing of biological drug substance (DS) is a critical unit operation that may impact product quality, potentially leading to protein aggregation and sub-visible particle formation. Cryo-concentration has been identified as a critical parameter to impact protein stability during freezing and shoul...

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Bibliographic Details
Published in:AAPS PharmSciTech Vol. 25; no. 5; p. 102
Main Authors: Peláez, Sarah S., Mahler, Hanns-Christian, Vila, Pau Rubirola, Huwyler, Jörg, Allmendinger, Andrea
Format: Journal Article
Language:English
Published: Cham Springer International Publishing 07-05-2024
Subjects:
Biochemistry
Biological Products - chemistry
Biomedical and Life Sciences
Biomedicine
Biotechnology
Drug Packaging - methods
Freezing
Histidine - chemistry
Ice
Osmolar Concentration
Pharmacology/Toxicology
Pharmacy
Polysorbates - chemistry
Research Article
frozen storage
process characterization
drug substance bottles
cryo-concentration
large-scale freezing
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Summary:Freezing of biological drug substance (DS) is a critical unit operation that may impact product quality, potentially leading to protein aggregation and sub-visible particle formation. Cryo-concentration has been identified as a critical parameter to impact protein stability during freezing and should therefore be minimized. The macroscopic cryo-concentration, in the following only referred to as cryo-concentration, is majorly influenced by the freezing rate, which is in turn impacted by product independent process parameters such as the DS container, its size and fill level, and the freezing equipment. (At-scale) process characterization studies are crucial to understand and optimize freezing processes. However, evaluating cryo-concentration requires sampling of the frozen bulk, which is typically performed by cutting the ice block into pieces for subsequent analysis. Also, the large amount of product requirement for these studies is a major limitation. In this study, we report the development of a simple methodology for experimental characterization of frozen DS in bottles at relevant scale using a surrogate solution. The novel ice core sampling technique identifies the axial ice core in the center to be indicative for cryo-concentration, which was measured by osmolality, and concentrations of histidine and polysorbate 80 (PS80), whereas osmolality revealed to be a sensitive read-out. Finally, we exemplify the suitability of the method to study cryo-concentration in DS bottles by comparing cryo-concentrations from different freezing protocols (-80°C vs -40°C). Prolonged stress times during freezing correlated to a higher extent of cryo-concentration quantified by osmolality in the axial center of a 2 L DS bottle. Graphical Abstract
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ISSN:1530-9932
1530-9932
DOI:10.1208/s12249-024-02818-6