Risk-Based Bioengineering Strategies for Reliable Bacterial Vaccine Production

• Published in: Trends in biotechnology (Regular ed.) 2019-08, Vol.37 (8), p.805-816
• Main Authors: Kamminga, Tjerko, Slagman, Simen-Jan, Martins dos Santos, Vitor A.P., Bijlsma, Jetta J.E., Schaap, Peter J.
• Format: Article
• Language: English
• Subjects: Antigens; bacterial vaccines; Bioengineering; Biomass; Biosensors; Constraint modelling; constraint-based; Design; Experiments; Fluid dynamics; Gene expression; genome-scale metabolic models; Genomes; Iterative methods; Metabolic networks; Metabolism; Metabolites; Parameter identification; process analytical technology; Process parameters; Risk assessment; risk-based process design; Screening
• ISSN: 0167-7799; 1879-3096
• DOI: 10.1016/j.tibtech.2019.03.005

Design of a reliable process for bacterial antigen production requires understanding of and control over critical process parameters. Current methods for process design use extensive screening experiments for determining ranges of critical process parameters yet fail to give clear insights into how they influence antigen potency. To address this gap, we propose to apply constraint-based, genome-scale metabolic models to reduce the need of experimental screening for strain selection and to optimize strains based on model driven iterative Design–Build–Test–Learn (DBTL) cycles. Application of these systematic methods has not only increased the understanding of how metabolic network properties influence antigen potency, but also allows identification of novel critical process parameters that need to be controlled to achieve high process reliability. Risk-based design, aimed at gaining control over critical process parameters, has become the standard in biopharmaceutical process development; however, application for bacterial vaccines is hampered because structurally complex or undefined antigens are needed. Process analytical technology needs to be applied to actively measure and control novel critical process parameters identified by applying systems metabolic engineering techniques. Standardized systems metabolic engineering techniques have become accessible to generate the knowledge base that is needed to assign critical process parameters in the feasibility phase of vaccine development. To develop reliable production processes for bacterial vaccines, risk-based DBTL cycles should be performed to identify novel critical process parameters using systems metabolic engineering techniques.