Lake Como 2|4 October 2011 - CHIMICA Oggi/Chemistry Today

On-line NIR spectroscopy to control a seeded API crystallization step
Cédric Schaefer, Clémence Lecomte, David Clicq, Alain Merschaert, Edith Norrant
Biopharma Process Sciences, UCB Pharma S.A., Braine-l’Alleud, Belgium
Process Analytical Technologies (PAT) has emerged as a prominent and powerful tool in the development and manufacture
of pharmaceutical products. Numerous examples have been reported on the use of PAT in recent years but fairly limited
on the use of quantitative on-line NIR methods in chemical processes.
We have recently developed an on-line quantitative NIR method for the seeded crystallization of an API that required a tight
control of solvent composition and concentration. Feasibility of the method was initially demonstrated on laboratory and
technical pilot plant batches with a lab scale spectrometer and probe. In a second phase, the manufacturing equipment
was purchased and implemented in c-GMP environment following ICH qualification requirements.
The presentation will focus on the methodology used for the development of the calibration model which encompasses
experimental design with statistical analysis (DoE), Principal Component Analysis (PCA)
and Partial Least Square (PLS) regression methods.
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Flow-type multi-tubular reactor modeling: the effect of non-uniform radial
E.V. Ovchinnikova, V.A. Chumachenko
Boreskov Institute of Catalysis SB RAS (BIC), pr. Akademika Lavrentieva, 5, Novosibirsk, 630090, Russia
Production of industrial chemicals is infl uenced by fl uctuations in the market demand. At a chemical plant, the production capacity and
consumption of raw materials may change a lot depending on the market situation. For widely used fl ow-type multi-tubular reactors,
variations in raw gas feed can provoke critical regimes, and for highly exothermic processes - even runaways.
In the present work, we study reasons of occurrence of critical reactor regimes on the example of a large-scale process of formaldehyde
production at one of the Russian industrial enterprises and propose possible preventing measures.
The production of formaldehyde in this study is carried out in a multi-tubular fi xed bed reactor by means of oxidizing the methanol to
formaldehyde over metal oxide catalyst. This reaction is exothermic; heat withdrawal is done by the DOWTHERM-type high boiling
organic heat transfer fl uid circulating between the tubes.
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Our QbD approach for model and method validation will also be discussed as well as the
results of the risk analysis performed to define the potentially influential noise as well as
controlled and experimental parameters to include in the calibration. The robustness of
the analysis has thus been constructed into the model development.
Finally, some key learning points from the implementation of an on-line analysis in a
c-GMP environment will be presented.
The performance analysis of the fl ow-type multi-tubular reactor is based on an extended continuous
2D model of heat and mass transfer. The model considers the variation of the gas linear velocity
along the tube’s radius and the dependence of the radial and the axial thermal conductivity on
the gas linear velocity in the tubes and on the parameters of the dispersion medium.
It is established that a decrease in production capacity accompanied with decrease in gas fl ow
feed in the reactor leads to a decrease in the gas linear velocity, which in its turn, decelerates
the heat transfer. The study of the reactor’s mathematical model considering non-uniform radial
heat transfer has exhibited the dependence between the decrease in gas fl ow feed and the
elevation of maximal temperature in the hot spot of the catalyst layer. On a real-world multitubular
reactor, we observe that these changes and irregularities of stream distribution can lead
to critical operating regimes.
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Lake Como
2|4 October 2011