Application of a Quality-by-Design (QbD) approach to a digital twin bioreactor

A. SPRICH, J. BUDZINSKI, T. BASTOGNE1,2,3

1CYBERNANO, 2CRAN UL-CNRS UMR 7039, 2INRIA BIGS

Background. Optimizing the performance of a bioreactor is a multifactorial problem that can take a long time to achieve
the desired objectives. In a competitive context, reducing the time of development becomes a major industrial challenge for
bioproduction. This study presents and compares two different strategies to couple digital twin simulation and
pharmaceutical Quality-by-Design (ICH Q8) to speed up the determination of a Design Space in bioproduction.

Methods
A stirred tank bioreactor simulator proposed was implemented
into the MATLAB/Simulink computational environment (Fig.1). The
EasyQBD platform was used to apply the good practice of
Pharmaceutical Quality by Design, involving the statistical design
of experiments and the identification of the design space. Three
critical process parameters (input factors) were considered :
temperature, pH and concentration of dissolved oxygen. The
critical quality attribute (output variable) is the number of cells in
the bioreactor, with an expected specification on the
production yield of at least 8E+6 cells. This first approach relies on
Fig.1: Simulink model of a bioreactor
a meta-modeling strategy composed of a Doehlert design (13
points, 3 reproductions) and a second-order response surface
model. The alternative approach uses a quasi-Monte-Carlo
design (Sobol sequence based on 1024 points, 100
reproductions) directly applied to the simulator. A 3D probability
map and a design space are computed from the simulated
responses obtained by each design.

Results

The 3D probability maps obtained with the common approach,

is presented in Fig.2. This diagram is a cube whose each axis is
associated with an input factor. It is composed of probability
values to meet the production yield requirement. The green Fig.2 : Probability map and Design Space (green region) built
from the strategy 1 (Doehlert Design + Response Surface Model)
region of this diagram, called Design Space (DS), represents the
set of input values for which this probability is greater than 95%.
Fig.3 presents the design space computed with the second
strategy, i.e. the one based on a space filling design directly
applied to the simulator. The comparison of the two probability
maps shows the size of the design space is clearly overestimated
by the classical approach. This result is probably a consequence
of the meta-modeling approximation.

Conclusion

When a calibrated and validated simulator of a bioreactor is

available, we show how it can be used within an QbD framework
to obtain a first estimate of the Design Space before field trials. Fig.3 : Probability map and Design Space (green dots) built from
Bioreactor simulators are generally computationally time- the strategy 2 (Quasi Monte-Carlo Design applied to the digital
twin without metamodeling)
efficient. For this reason, this study shows that it is preferable to
apply directly space filling designs to digital twins when we wish
to get an initial estimate of a Design Space. The latter can
drastically speed up the Quality by Design study by focusing the
investigation domain on the most promising region.
Congrès France Bioproduction 2023, Tours,
April 5th & 6th 2023