Abstract

The biopharmaceutical industry is still running in batch mode, mostly because it is a highly regulated industry sector. In the past, sensors were not readily available and in-process control was mainly executed off-line. The most important product parameters are quantity, purity and potency besides adventitious agents and bioburden. There is increasing economic pressure on time-to-market and also on the environmental sustainability of biopharmaceutical manufacturing. New concepts for manufacturing using disposable single-use technologies and integrated bioprocessing will dominate the future of bioprocessing. In order to ensure the quality of pharmaceuticals initiatives such as Process Analytical Technologies, Quality by Design and Continuous Integrated Manufacturing have been established. The vision must be that these initiatives together with technology development pave the way for process automation and autonomous bioprocessing without any human intervention. Then a real-time release would be realized leading to a highly predictive and robust biomanufacturing system. The steps toward such automated and autonomous bioprocessing are reviewed in context of monitoring and control. Starting from statistical treatment of single and multiple sensors, establishing soft sensors with predictive chemometrics and hybrid models. A scenario is described how to integrate soft sensors and predictive chemometrics into modern process control. This will be exemplified by selective downstream processing steps such as chromatography and membrane filtration, the most common unit operations for separation of biopharmaceuticals.
Keywords: Real-time release, machine learning; process control, continuous integrated biomanufacturing;
Introduction
The biopharmaceutical industry is still running in batch mode, mostly because it is a highly regulated industry sector (Kumar et al., 2020), but there is increasing economic pressure on time-to-market and also on the environmental sustainability of biopharmaceutical manufacturing. New concepts for manufacturing using disposable single-use technologies are being increasingly implemented and manufacturing is turning away from dedicated manufacturing suites to ballroom facilities suited for manufacturing multiple products (Müller et al., 2022). Integrated continuous biomanufacturing will expedite and leverage these developments because it is a way to reduce the footprint of a manufacturing plant and reduce the time required to produce clinical batches(Cataldo et al., 2020; Ding et al., 2022; Farid, 2019; Konstantinov et al., 2015; Patil et al., 2018). The status-quo is still batch processing with quality by testing. After each step samples are taken, tested and then the subsequent step is executed. The PAT initiative (”Guidance for Industry: PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance,” 2004) has encouraged to implement advanced analytical technologies in form of at-line, on-line and off-line analytics to “design, develop and operate processes consistently to ensure a predefined quality at the end of the manufacturing process” (Figure 1). It was obvious from the start that chemometric approaches will allow us to get better process understanding instead of interpreting the analytical results one by one (Lopes et al., 2004; Wasalathanthri et al., 2020).