Accelerating Biologics Manufacturing by Upstream Process Modelling

Abstract

Intensified and accelerated development processes are being demanded by the market, as innovative biopharmaceuticals such as virus-like particles, exosomes, cell and gene therapy, as well as recombinant proteins and peptides will possess no available platform approach. Therefore, methods that are able to accelerate this development are preferred. Especially, physicochemical rigorous process models, based on all relevant effects of fluid dynamics, phase equilibrium, and mass transfer, can be predictive, if the model is verified and distinctly quantitatively validated. In this approach, a macroscopic kinetic model based on Monod kinetics for mammalian cell cultivation is developed and verified according to a general valid model validation workflow. The macroscopic model is verified and validated on the basis of four decision criteria (plausibility, sensitivity, accuracy and precision as well as equality). The process model workflow is subjected to a case study, comprising a Chinese hamster ovary fed-batch cultivation for the production of a monoclonal antibody. By performing the workflow, it was found that, based on design of experiments and Monte Carlo simulation, the maximum growth rate µmax exhibited the greatest influence on model variables such as viable cell concentration XV and product concentration. In addition, partial least squares regressions statistically evaluate the correlations between a higher µmax and a higher cell and product concentration, as well as a higher substrate consumption.

Model-Based Design and Process Optimization of Continuous Single Pass Tangential Flow Filtration Focusing on Continuous Bioprocessing

“…Developments of process variables like concentration, flux, or pressure, based on modelling are investigated and by using a model for process optimization, the experimental effort can be drastically reduced, which is especially relevant for multiparameter dependent unit operations. With a systematic approach, modelling can substitute experiments and accelerate the process design [29,44,45]. For this study an experimentally validated physico-chemical model [1] is enhanced and transferred.…”

Accelerating Biomanufacturing by Modeling of Continuous Bioprocessing—Piloting Case Study of Monoclonal Antibody Manufacturing

“…Further emphasis to simplify operation, improve process robustness and reduce handling efforts is; therefore, focused on PAT techniques and process control strategies by advanced process control approaches. This is a logical consequence and straight forward, as those process models are existing and have been experimentally validated [46][47][48]58].…”

“…In terms of process development, a favorable process design space can be established by introducing risk assessments for each unit operation, supported by process modeling and design of experiments (DoE) [1,38,[45][46][47][48]. The development of control strategies for an advanced process control based on the process analytical technology (PAT) initiative is essential for a robust automatization of each unit operation and; therefore, favorable for a global process optimum.…”

Accelerating Biologics Manufacturing by Modeling: Process Integration of Precipitation in mAb Downstream Processing

“…Due to the fact that the use of models is still sparse because of validation, Sixt et al established a workflow that ensures the development of valid physico-chemical models [49]. This has already been described in various papers and the execution was shown using the example of liquid-liquid [55] and solid-liquid extraction [49], chromatography [56], and cultivation [57].…”