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The Computational and Experimental Study of the Freeze-Drying Process for a Monoclonal Antibody

Krishnan, Trishanka; (2022) The Computational and Experimental Study of the Freeze-Drying Process for a Monoclonal Antibody. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Freeze-drying for biopharmaceuticals is widely used in industry to fabricate the final therapeutic product intended for administration to patients. Freeze-drying is a highly complex subject area, thus spurring research to make this process more applicable for various products and processes. This thesis first studies the production of a typical mAb therapeutic. A 50L Single-use Bioprocessing run was conducted by small research team (in which the author of this thesis was part of) at UCL to produce a purified mAb substance. The relevant stages detailing the methods and results for the downsteam process have been defined. In particular, this offers a deep dive into three chromatography trains comparing CEX (Cation Exchange Chromatography) methods to SMB (Simulated Bed) Chromatography. These polishing trains are: CEX to AEX (anion exchange chromatography) for main peak eluted mAb, CEX to AEX for shoulder peak eluted mAb) and SMB to AEX for pooled mAb sample. It was seen the Cation exchange to Anion exchange (shoulder peak mAb)) produced the lowest yield of 17.5% whereas the Cation Exchange to Anion Exchange (main peak mAb) produced the highest yield of 57%. The process was successful as it was scaled up from 5L to 50L and purified to a final titre of 0.8 g/L. However, it was concluded that a possible compromise needed to be made between the overall yield and product quality. Next, the freeze-drying of the mAb produced in the bioprocess run is investigated. The mAb substance was formulated and freeze-dried, according to different temperature/time run schemes, vial placement, protein concentrations and two freeze-dryers – SP Scientific LyoStar3 freeze-dryer and a Telstar LyoBeta freeze-dryer. Analyses done on the freeze-dried samples showed interesting results dependent on the specific parameters. It was observed that this mAb product showed little change and degradation in the aggressive freeze-drying run cycles adopted in this research. Finally, the experimental results and the obtained temperature readings to support the development of a novel one-dimensional computational model for the primary drying phase. A novel method to measure the movement of the drying interface was also developed to validate the model simulations. From observing these results, new novel one-dimensional based on heat transfer for the primary drying phase was investigated. This model was adapted from a previous model that studied the solidification of superheated metal.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The Computational and Experimental Study of the Freeze-Drying Process for a Monoclonal Antibody
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
URI: https://discovery.ucl.ac.uk/id/eprint/10161921
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