Real time PCR - European Pharmaceutical Review

PAT ISSUE 2009
appear as an inevitable stage for
reaching a competitive manufacture.
However, the design theory is
originally shaped and predominantly
used for “cars and freezers”. The
Hubka-Eder model has, to our
knowledge, never before been
adapted for and applied to sensitive
biological systems in a mechatronic
environment.
It is most likely that a
manufacturing facility for hESC
products needs to be flexible in terms
of different final products, i.e. hESCderived
cell types or undifferentiated
hESC materials of a particular cell line.
The customers will no doubt have
varying demands depending on the
purpose of the cells (for clinical-grade
use, for drug testing etc). The quantity
of the cells required will vary
considerably over time. The
distribution/shipping conditions will be
more or less demanding. A hESC
manufacturer may, of course, specialise
on certain customers and cell types.
However, from a manufacturing
engineering perspective, an interesting
question is how to make a robust
flexible manufacturing system that can
cope with the varying demands in order
to be as competitive as possible on the
market. The demands for robustness
imply that robots should be used
instead of human operators whenever
possible. The variability and risk for
mistakes due to monotonous and
repetitive work are much smaller for
robotic systems than for human
operators.
In Figure 4 (see page 35) the
stem cell production stages are
transformed into the Hubka-Eder
design model on a more detailed
level. The shown example concerns a
manufacture of a differentiated cell
type: from the isolation of embryonic
cells of blastocytes, their
propagations on feeder cells,
Figure 5: Examples of the relationship between the functional and anatomic structures for
the stem cell expansion. The left part shows the functions, i.e. to acquire cells from
supernumerous embryos, isolating the cells from the inner cell mass with the desired
cellular properties, outgrowing these isolates successfully so that the undifferentiated
state is maintained, following by repeated passages to expand the undifferentiated cell
culture and where all these steps are monitored appropriately with characterisation
methods. In the right part of the figure the technical means to accomplish these functions
are added where the physical apparatuses and other equipment/disposables are added.
As illustrated several anatomic units are required to accomplish a particular function. In
reality, many charts of this sort are needed in the HE analysis.
expansion of undifferentiated cells
and further propagation and
differentiation. It should be
understood that the scheme is an
illustration that should be further
detailed to allow a useful analysis of
effects. HE-models should be used for
analysing different levels of detail of
the manufacturing system. You start
with an overall model which is then
further developed into one or several
models that are more detailed. Of
particular interest for the PAT and
QbD issues is how analytical devices
and instruments are utilised and
distributed in order to evolve the
most beneficial effects on the design
solution. The key PAT components are
obviously the tools to characterise the
cells at various stages. The effects of
these analytical procedures, their
precision and just-in-time capacity
could show their most favourable use
for the functional purpose.
The QbD methods, especially the
definition of design space and control
space variables in the procedural
steps of robots, freezing equipment
and time lapses are decisive
parameters for establishing the
optimal manufacturing system. The
number of alternative solutions will,
especially when considering these
aspects, grow significantly which
underscores the need for a systematic
approach when designing the system.
In Figure 5 the HE methodology
for analysing the relationship between
the functional purpose of the
production steps and the anatomy of
operation units in the design is
illustrated. The figure exemplifies a
limited part of a chart of functional
and anatomic steps in stem cell
manufacture – the propagation of
undifferentiated stem cells. The chart
should, in a complete analysis, be
supported by ranking tables that
systematically assess the alternative
design solutions, and their benefits
and capacities. The advantage with
this, if it is done at an early stage of
development, is that there is a good
chance of adapting the design in the
pre-production scaled-down stage.
To include effects of the defined
design space and being supported by
PAT tools is definitely an advantage.
Conclusion
It is not mentioned in the regulators’
guidelines for PAT and QbD that a
bio-mechatronic design tool is one
of the necessary tools for successful
design of pharmaceutical processes.
However, many of the inherent
criteria of such tools are manifested
in the HE design approach. It is an
example of a scientific method and a
tool for knowledge management and
knowledge analysis, albeit not by
using traditional knowledge
management tools.
This short paper has highlighted
some of the specific characteristics
of hESC manufacture which need
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