Development & Application of Continuous Crystallization in an Integrated Continuous Pharmaceutical Pilot Plant | AIChE

Development & Application of Continuous Crystallization in an Integrated Continuous Pharmaceutical Pilot Plant


Conference Presentation

Conference Type

AIChE Annual Meeting

Presentation Date

November 10, 2015


30 minutes

Skill Level




Development & Application of Continuous Crystallization in an Integrated Continuous Pharmaceutical Pilot Plant

Haitao Zhang, Richard Lakerveld, Patrick Heider, Justin Quon, James Evans, Allan S. Myerson, Bernhardt Trout

Novartis-MIT Center for Continuous Manufacturing

Department of Chemical Engineering, Massachusetts Institute of Technology, E19-502b, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.


The concept of continuous manufacturing to address key challenges faced by the pharmaceutical industry has gained significant interest. A number of research programs related to this topic have been sponsored by pharmaceutical companies, including Pfizer, Novartis, Merck, and Eli Lilly, etc. The Novartis-MIT Center for Continuous Manufacturing has developed a seamless, end-to-end pilot plant for continuous manufacturing of pharmaceuticals including new pieces of technologies to support integrated continuous manufacturing (ICM). Continuous crystallization plays a critical role within ICM processes in terms of final product quality control. Crystallization processes are designed to obtain active pharmaceutical ingredients (API) crystals with controlled purity, size, shape, and polymorphic form in high yield. Knowledge of the continuous crystallization process conditions required to fabricate crystals with controlled characteristics is critical during process development. Real-time control using process analytical technology (PAT) tools is required for the implementation of continuous crystallization within integrated continuous manufacturing (ICM) of pharmaceuticals. However, appropriate selection of PAT tools is challenging, and the design and operation of automated control loops for continuous crystallization within a continuous pharmaceutical process brings forward important questions.

The aim of this contribution is to investigate the performance of a continuous crystallization step operated for a prolonged period of time within an ICM process. The integration of different unit operations and the steady-state operation of those unit operations are of primary concern. The aim is to keep the critical material attributes (CMAs) for each unit operation including the continuous crystallization units within an accepted range at all times through the control of critical process parameters (CPPs). Consequently, the control strategy should possess the capability to tolerate variations from upstream units and should minimize disturbances that propagate to downstream units. Therefore, the selection and implementation of PAT tools and the design of a control strategy are of vital importance for successful ICM of pharmaceuticals. Such a control strategy would rely on automated feedforward and feedback control loops.

Herein, we discusses the process design and operation of a continuous reactive crystallization of aliskiren hemifumarate as part of an ICM pilot plant. Several PAT tools were used within automated control loops to satisfy specifications on the critical materials attributes of the crystallization process. The operational performance of the process was maintained for periods of time over 100 h. The purity of the targeted product exceeded 99%, and the process yield reached 91.4% with the physical properties in specification.


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