Application of Continuous Crystallization in an Integrated Continuous Pharmaceutical Pilot Plant

Abstract

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. This paper 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%.

CRE for MAGIC (modular, agile, intensified & continuous) processes

“…Integrating multiple process steps: an excellent overview of multistep synthesis [40,41] can be seen in Jamison [42]. Other examples of integrated plants can be seen in [43][44][45].…”

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid–Base Catalyst with Recycle

“…For example reactive crystallization in mixed suspension/mixed product removal (MSMPR) crystallizers is a legitimate option for handling this type of process physically. MSMPRs have been used for antisolvent, 19 cooling, 20 or reactive 21 crystallizations. The intent is to use a continuous reactive crystallization platform for an aza-Henry reaction.…”

Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical

“…The concentration measurement is used to determine the value of this optimal ratio of flow rates. 19 The remaining control loops used for operation of the API crystallizers, combined washing and filtration stage (W12), and buffer tank (D2) are identical to 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 14 the crystallizers, washing and filtration device, and buffer tank used for separation of 4 upstream (Cr1, Cr2, W1, D1, respectively).…”

“…17 Furthermore, detailed discussions about the design and operation of the chemical synthesis including workup steps and of the continuous crystallization of the API are the subjects of separate papers. 18,19 Finally, a short account of our work has been published in conference proceedings. 20 The focus of the current paper is on the interactions between various control loops and the ability of the control system to maintain key intermediate CMAs close to a desired value in the presence of disturbances both on short and long time scales.…”