Biopharm production methods need effective real-time
monitoring and control to guarantee a low-cost, safe
and high quality production. Modern multidisciplinary
concepts are the key to effective manufacturing in
biotechnology, allowing real-time product release.
New production methods and the market demand for faster
development of production processes (shorter time to market) imply a
need for a better understanding of the process. The increased
emphasis on production efficiency (shortening of throughput delays,
up scaling, shift from batch to continuous production methods,
increased capacity and yield) needs real-time process information. On
the other hand, product safety methodologies result in an increased
need for track of product quality throughout the manufacturing
process. Also the FDA (Food and Drug Administration) is encouraging
a more risk-based and science-based approach instead of current
empiric production methods. The FDA’s PAT (Process Analytic
Technologies) initiative is one of the current focus topics.
Process
Modelling
IPD
MES
Figure 2: Bioreactor Process Analytical Technologies (PAT)
Improving the process begins with monitoring the process and
building awareness on the typical behaviour. For the bio-pharm
API production chain, the key process step to monitor is the bioreactor. Process analytic technologies (PAT) act as the “eyes”
inside the bio-reactor. In bioreactor-processes the need for realtime process information is particularly high due to the
complexity and unpredictability of the process.
Recent PAT developments allow instantaneous in-line
measurements (of the liquid and gaseous bio-reactor phase) to
get a whole picture or fingerprint of the process.
Process
Analytics
Process
Automation
Figure 1: Multidisciplinary approach to Bio-reactor optimisation
The use of PAT for both physical and chemical status monitoring and
also for biological or performance monitoring, is a big step forward in
improving process understanding and allowing process optimisation.
Information on individual parameters (physical, chemical and
biological), the so-called absolute values and also relative
measurements, as a measure of change, gives total quality
information on the process. These developments provide a holistic
view on the process and give better insights into what exactly is
happening during the bioreactor process.
These tools speed decisions on the batch endpoint, quality or
efficiency of a certain process stage. New sensor technologies and
also new approaches which can handle a wider range of process
parameters allow strict control of operational conditions throughout the
bio-pharm process. PAT closes the information gap for defining better
control strategies and ultimately optimise the whole process
Start
End
Figure 3: Process fingerprint monitoring of a bio-reactor
However, to improve the control of the bio-reactor, a number of
physical and chemical parameters must be continuously monitored.
Previously, substrate and nutrient contents, metabolite formation
and bio-mass concentration were obtained through off-line
laboratory methods. Results are not obtained until several hours
after sampling and results are fed into the process computer offline. This markedly limits the possibility of controlling and optimising
bioreactor processes.
Figure 4: Methodology for Advanced Process Control (APC) of Bio-reactor processes
The integrated Advanced Process Control solution for bioprocess
control which Siemens has developed as part of the Life Science
Solution consists of APC Tools integrated into the Simatic PCS 7
process control system. These tools are interfaced via an OPC client
channel to the WinCC server, and make use of the SCADA database
(Historian) and data obtained by the used Process Analysers. APC
therefore represents an important link between the planning and
scheduling functions of the execution level and control functions. By
using APC, Simatic PCS7 is expanded by a powerful process
optimisation function and ensures not only a more efficient process
control but also greater transparency in production leading to shorter
batch runs and increased quality consistency.
Consistency in quality is an important condition for Real-time product
release / Parametric release.
Figure 5: Process Control Strategy for Real Time product release
Conclusion
New process monitoring tools (PAT), new control structures and
advanced process control result in an integrated concept for a
“transparent” bioreactor.
These multidisciplinary tools are the key to ...
 ...quickly gain knowledge about the key variables
of their particular process
 ...find out how to minimise by-products (for a simpler
downstream processing) and maximise product yield
 ...have a high process reproducibility (consistent
quality) and early identification of unsuccessful batches
 …control even delicate processes 24 hours a day and
meet future FDA requirements for real-time product
release and a science-based risk approach
Figure 6: Overview of the bio-reactor optimisation and real-time product release concept
For more info, please contact:
Siemens – RHQ Pharma & Fine Chemicals
+32 3 735 0600
e-mail rhq-info@siemens.com
Or visit us at www.siemens.com/pharma