Process developments and critical design attributes in buffer systems for the biopharmaceutical industry

The research presented in this thesis addresses biopharmaceutical buffer management, which has historically received limited attention despite accounting for approximately 20% of the cost of manufacture. Traditional approaches have persisted, resulting in operational bottlenecks, inflexible facility designs, and elevated capital and operating expenditure. This work develops process improvements and identifies critical design attributes to enhance operational efficiency, sustainability, and flexibility. A comprehensive assessment of the current landscape was undertaken, combining literature review, professional design expertise, and a structured industry survey to generate benchmarking data. The results provide unique insights into prevailing practices, challenges, and the barriers to adopting advanced strategies such as inline buffer preparation and buffer concentrates. Economic evaluation of buffer management strategies was performed using multivariate models and BioSolve software, considering variables including bioreactor scale, preparation frequency, stock solution strategy, and product titre. Inline buffer preparation proved transformative, delivering up to 46% cost reduction at industrial scales while also improving operational flexibility. Complementary environmental assessment using Process Mass Intensity (PMI) and embodied and operational energy metrics demonstrated that the economically favourable strategies were also environmentally advantageous, with optimised scenarios reducing PMI and energy metrics by up to 90%. Single-use technology was found to provide environmental benefits in most scenarios, despite the less stringent cleaning requirements associated with buffer systems when compared with product contact systems. To address key barriers to adoption of inline buffer preparation, a cGMP-ready, mass flow-based, NIIMBL-BioPhorum Buffer Stock Blending System was designed, constructed, and validated. The system consistently produced buffers within specification during performance testing and reduces initial capital investment by about 40% while providing open-source design and performance data to support adoption. Bespoke optimisation methodologies were developed to enhance the implementation of inline buffer preparation. These addressed stock solution selection, multi-batch preparation, and operating shift patterns, achieving a mean additional cost reduction of 20% and enabling a transition away from traditional 24/7 buffer preparation. Overall, this research establishes a roadmap for next-generation buffer management, providing designers and decision-makers with tools, quantitative insights, and optimisation methodologies to achieve more efficient, cost-effective, and sustainable biopharmaceutical manufacturing.

Grantor dc:publisher

University College Cork

Year dc:date.issued

2025

Author dc:creator

• Gibson, Kevin

Advisors dc:contributor.advisor

• Ring, Denis
• Oliveira, Jorge C.

• Biopharmaceutical manufacturing
• Buffer management
• Facility design
• Process optimisation

Statement dc:rights

• © 2025, Kevin Gibson.

Licence dc:rights.uri

• https://creativecommons.org/licenses/by/4.0/

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10468/18849

OAI identifier oai:identifier

oai:cora.ucc.ie:10468/18849