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Development of Robust Expanded Bed Adsorption DEVELOPMENT OF ROBUST EXPANDED BED ADSORPTION PROCESSES FOR cGMP MANUFACTURE OF BIOPHARMACEUTICAL PRODUCTS by Stephanie Ewert A thesis submitted to The University of Birmingham for the degree of DOCTOR OF PHILOSOPHY School of Chemical Engineering College of Engineering and Physical Sciences February 2016 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract Abstract Expanded Bed Adsorption (EBA) was deemed to be the next big thing in downstream processing receiving much attention after its introduction in the mid 1990s. Sample clarification appeared to be a ‘thing of the past’ as the increased inter-particle voidage in EBA allowed for direct application of crude feedstocks without blocking the column. Despite acclaimed advantages, such as increased overall yield due to fewer process steps, lower costs and reduced process times, confidence in this technique has waned in recent years, owing to a lack of process robustness and poor understanding of the complexity of the technique as a whole. At the most fundamental level, a persistent lack of detailed knowledge regarding hydrodynamic behaviour within expanded beds impairs optimal operation and prediction of the process. In this work, the technique of Positron Emission Particle Tracking (PEPT) was employed extensively to study solid phase motion and dispersion in expanded beds of commercial media. Comprehensive interrogation of the internal hydrodynamic properties of expanded beds was initially performed using a ‘feedstock-free’, ‘buffer-only’ system for fluidisation. Changes in the position and speed of differently sized positron labelled particle tracers along the length of the bed were identified in response to variations in flow rate, means of fluid distribution and degree of column misalignment. These tracers provided striking evidence of: (i) adsorbent particle classification within the bed; (ii) continuous axial and horizontal motion across surprisingly long distances; and (iii) non-uniform bed expansion with increasing mobile phase velocity. Analysis of PEPT tracking data permitted calculation of solid axial dispersion coefficients for adsorbent particles in EBA for the very first time. The kinetics of bed stabilisation were determined by analysing the time dependent axial positioning of differently sized tracer particles after starting fluidisation, indicating a potential to significantly reduce equilibration times (cf. those commonly i Abstract reported) and concomitant savings in buffer consumption. Destabilisation of the bed as caused by a marginal vertical misalignment of the column was documented by circular motion patterns of the tracer particles and increased solid axial dispersion coefficients. The results were subsequently compared to previous studies conducted with different commercial adsorbent matrices to obtain a comprehensive interpretation. Finally, adsorbent particle motion was investigated under ‘real process’ conditions, i.e. during the application of a porcine serum feedstock. Solid mixing was not significantly increased during feedstock loading. Further, in contrast to previous work using sonicated calf thymus DNA feedstocks, the overall axial position of positron-labelled tracer particles remained relatively constant and stable through the loading phase commensurate with a robust EBA process. ii “Nothing in this world that’s worth having comes easy.” - Robert Kelso iii Acknowledgements Acknowledgements I would like to take this opportunity to thank all those who have contributed to the accomplishment of this dissertation. First and foremost, I would like to sincerely thank Professor Owen R.T. Thomas for his excellent supervision, his guidance and his trust in my abilities. I would also like to say a huge thank you to Dr Eirini Theodossiou for joining hours-long discussions and for giving me the confidence to believe in myself. Special thanks also to Professor Serafim Bakalis for his ideas and for introducing me to PEPT. I would also like to send thanks to my industrial supervisors, Dr Emile van de Sandt and Dr Piet den Boer of DSM and DSM Biologics (now Patheon), for their advice and for funding this work in association with my EPSRC CASE studentship. In addition, thank you to the DSP group at Patheon in Groningen, for their warm welcome and help during my time in Groningen - especially Randal Maarleveld, Diana Mulder-Wesseling and Elham Zolghadr. Furthermore, a huge thank you to Dr Tom Leadbeater and Dr Joseph Gargiuli for all their help and advice regarding the magic that is PEPT. Thank you also to Elaine Mitchell and David French for providing support towards my work in the lab. Special thanks to all the past and present members of the DSP group in BiochemEng, F7 and associates - Christine Müller, Evan Hsu, Ping Cao, Isaac Vizcaino, Johannes Mohr, Neeraj Jumbu, Alfred Fernandez, Ikhlaas Kasli, Asma Nurul, Hong Li, Stephan Joseph, Ursula Simon and Lukas Wenger. Thanks also to the lunch and staff house crew. Last, I am forever grateful to my family, my parents and my siblings, for their unconditional love, support and encouragement. Ohne euch wäre ich nichts. iv Table of Contents Table of Contents Abstract .............................................................................................................................................................................i Acknowledgements ................................................................................................................................................... iv Table of Contents ........................................................................................................................................................ v List of Figures ........................................................................................................................................................... viii List of Tables ............................................................................................................................................................. xiii Abbreviations ............................................................................................................................................................ xiv Latin Symbols ............................................................................................................................................................ xvi Greek Symbols........................................................................................................................................................ xviii 1. INTRODUCTION ................................................................................................................... 1 1.1. Biopharmaceuticals..................................................................................................................... 1 1.2. Downstream processing ............................................................................................................ 3 1.2.1. Liquid chromatography in Downstream Processing ........................................................... 6 1.2.2. Integrated downstream processes ........................................................................................... 11 1.3. Expanded Bed Adsorption (EBA) .......................................................................................... 13 1.3.1. Concept ................................................................................................................................................ 15 1.3.2. Operation ............................................................................................................................................ 17 1.3.3. Equipment .......................................................................................................................................... 19 1.3.4. Adsorbents ......................................................................................................................................... 21 1.3.5. Hydrodynamic principles ............................................................................................................. 23 1.3.6. Biomass-adsorbent interactions ............................................................................................... 29 1.4. Positron Emission Particle Tracking (PEPT) ................................................................... 31 1.4.1. Theory and physics behind PEPT ............................................................................................. 33 1.4.2. Tracer labelling ................................................................................................................................. 37 1.4.3. Data processing and analysis ...................................................................................................... 40 1.5. Aims and outline of the thesis ............................................................................................... 43 1.6. References ...................................................................................................................................
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