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).