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A scaled-down model for the translation of bacteriophage culture to manufacturing scale

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posted on 05.02.2019 by Junaid Ali, Qasim A. Rafiq, Elizabeth Ratcliffe
Therapeutic bacteriophages are emerging as a potential alternative to antibiotics and synergistic treatment of antimicrobial-resistant infections. This is reflected by their use in an increasing number of recent clinical trials. Many more therapeutic bacteriophage is being investigated in preclinical 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 optimized and streamlined for efficient methods of scalable manufacture. Bacteriophage research is currently limited to laboratory scale studies ranging from 1-20 ml, emerging therapies include bacteriophage cocktails to increase the spectrum of infectivity and require multiple large-scale bioreactors (up to 50 L) containing different bacteriophage-bacterial host reactions. Scaling bioprocesses from the milliliter scale to multi-liter 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 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 - Escherichia coli; Phage K - Staphylococcus 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 optimization of bacteriophage batch bioprocessing and translate the bioprocess into a scale-up model with a 3 L working volume in stirred tank bioreactors. The optimization performed in the shake flask model achieved a 550-fold increase in bacteriophage yield and these improvements successfully translated to the large-scale cultures.

History

School

  • Aeronautical, Automotive, Chemical and Materials Engineering

Department

  • Chemical Engineering

Published in

Biotechnology and Bioengineering

Volume

116

Issue

5

Pages

972-984

Citation

ALI, J., RAFIQ, Q.A. and RATCLIFFE, E., 2018. A scaled-down model for the translation of bacteriophage culture to manufacturing scale. Biotechnology and Bioengineering, 116 (5), pp.972-984.

Publisher

© Wiley

Version

AM (Accepted Manuscript)

Publisher statement

This is the peer reviewed version of the following article: ALI, J., RAFIQ, Q.A. and RATCLIFFE, E., 2018. A scaled-down model for the translation of bacteriophage culture to manufacturing scale. Biotechnology and Bioengineering, 116 (5), pp.972-984, which has been published in final form at https://doi.org/10.1002/bit.26911. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

Acceptance date

27/12/2018

Publication date

2018-12-29

Copyright date

2019

ISSN

0006-3592

eISSN

1097-0290

Language

en

Location

United States

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