Ali, J; Rafiq, Q; Ratcliffe, E; (2019) A scaled down model for the translation of bacteriophage culture to manufacturing scale. Biotechnology and Bioengineering , 116 (5) pp. 972-984. 10.1002/bit.26911.

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Abstract

Therapeutic bacteriophages are emerging as a potential alternative to antibiotics and synergistic treatment for antimicrobial resistant infections. This is reflected by their use in an increasing number of recent clinical trials. Many more therapeutic bacteriophage are being investigated in pre-clinical research and due to the bespoke nature of these products with respect to their limited infection spectrum, translation to the clinic requires combined understanding of the biology underpinning the bioprocess and how this can be optimised and streamlined for efficient methods of scalable manufacture. Bacteriophage research is currently limited to laboratory scale studies ranging from 1-20mL, emerging therapies include bacteriophage cocktails to increase the spectrum of infectivity and require multiple large scale bioreactors (up to 50L) containing different bacteriophage - bacterial host reactions. Scaling bioprocesses from the millilitre scale to multi litre large scale bioreactors is challenging in itself, but performing this for individual phage-host bioprocesses to facilitate reliable and robust manufacture of phage cocktails increases the complexity. This study used a full factorial Design of Experiments (DoE) approach to explore key process input variables (temperature, time of infection, multiplicity of infection, agitation) for their influence on key process outputs (bacteriophage yield, infection kinetics) for two bacteriophage - bacterial host bioprocesses (T4 - E. coli; Phage K - S. aureus). The research aimed to determine common input variables that positively influence output yield and found that the temperature at the point of infection had the greatest influence on bacteriophage yield for both bioprocesses. The study also aimed to develop a scaled down shake flask model to enable rapid optimisation of bacteriophage batch bioprocessing and translate the bioprocess into a scale up model with a 3L working volume in stirred tank bioreactors. The optimisation performed in the shake flask model achieved 550-fold increase in bacteriophage yield and these improvements successfully translated to the large scale cultures. This article is protected by copyright. All rights reserved.

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