An Advanced Monitoring Platform for Rational Design of Recombinant Processes - Measurement, Monitoring, Modelling, and Control of Bioprocesses - page 67

biopharmaceuticals for human use, additional demanding targets with respect to
product homogeneity, batch-to-batch reproducibility, and process stability must
also be met. Because of this, the pharmaceutical industry sticks to already well-
established process designs, control strategies, and expression systems. Also, the
approval procedure for new strategies, expression systems, or even changes to
existing processes is time and cost intensive.
The state-of-the-art approach in quality assurance is based on comprehensive
testing of final product quality, i.e., the so-called quality-by-testing approach. As a
consequence, the quality and specification of the final product can only be assured
by running the entire process under tight control of a limited number of state
variables and by evaluation of the process performance by extensive testing of the
product quality afterwards. A resulting problem is that systematic ongoing process
optimization and rational process design as practiced in many other industries are
widely ruled out. In comparison with standards established in other production
industries, bioprocess monitoring and control are less well developed.
The recent guidelines for pharmaceutical development by the International
Conference on Harmonisation, e.g., ICH Q8 [ 1 ], strongly emphasize the provision of
comprehensive understanding of product and manufacturing processes for regula-
tory inspections. Greater understanding of pharmaceutical manufacturing creates a
basis for more flexible regulatory approaches. The information gained from phar-
maceutical development studies and manufacturing experience provides scientific
understanding for the establishment of the design space, specifications, and manu-
facturing controls (see also the chapter on QbD and PAT by Rathore et al.).
To realize this flexibility, the applicant should demonstrate enhanced knowl-
edge of product performance over a range of material attributes, manufacturing
process options, and process parameters. Such understanding can be gained by
application of, for example, formal experimental designs, PAT, and/or prior
knowledge. Appropriate use of quality risk management principles can be helpful
in prioritizing additional pharmaceutical development studies to collect such
knowledge.
This chapter describes how improved process understanding can be accom-
plished in recombinant protein production processes with E. coli by M3C tech-
nology. It is shown how iterative process and systems development using an
advanced online and offline process monitoring platform has been achieved, new
concepts for process control have been introduced, and strategies for host cell
design have been successfully put into practice.
1.1 Bioprocess Monitoring
Historically, process monitoring methods employed in bioprocessing were directly
transferred from chemical engineering. Although this approach was very efficient,
upstream bioprocessing is still viewed as a black box and far behind the state of the
art in chemical industry, where real-time measurements of quality properties and