Development of an RTD-Based Flowsheet Modeling Framework for the Assessment of In-Process Control Strategies

Abstract

Continuous manufacturing (CM) is an emerging technology which can improve pharmaceutical manufacturing and reduce drug product quality issues. One challenge that needs to be addressed when adopting CM technology is material traceability through the entire continuous process, which constitutes one key aspect of control strategy. Residence time distribution (RTD) play an important role in material traceability as it characterizes the material spreading through the process. The propagation of upstream disturbances could be predictively tracked through the entire process by convolution of the disturbance and the RTD. The present study sets up the RTD-based modeling framework in a commonly used process modeling environment, gPROMS, and integrates it with existing modules and built-in tools (e.g. parameter estimation). Concentration calculations based on the convolution integral requires access to historical stream property information, which is not readily available in flowsheet modeling platforms. Thus, a novel approach is taken whereby a partial differential equation is used to propagate and store historical data as the simulation marches forward in time. Other stream properties not modeled by an RTD are determined in auxiliary modules. To illustrate the application of the framework, an integrated RTD-auxiliary model for a continuous direct compression manufacturing line was developed. An excellent agreement was found between the model predictions and experiments. The validated model was subsequently used to assess in-process control strategies for feeder and material traceability through the process. Our simulation results show the employed modeling approach facilitates risk-based assessment of the continuous line by promoting our understanding on the process.

Residence time distribution of continuous capture of recombinant antibody by precipitation and two stage tangential flow filtration

“…Its determination is particularly useful for understanding process performance during steady-state operation, but also for understanding the effects of transient events such as start-up and shut-down phases, process pauses or disturbances that could lead to product rejection. [2][3][4][5] RTD determination of continuous processes is much more advanced in continuous manufacturing of small molecule pharmaceuticals [5][6][7][8][9] compared to therapeutic proteins. 2,[10][11][12] Commonly, the RTD function is measured experimentally by addition of a tracer pulse or step at the inlet of a unit operation or process and the tracer concentration or another measurable attribute, such as absorbance or fluorescence, is measured at the outlet either on-line or off-line.…”

“…Its determination is particularly useful for understanding process performance during steady‐state operation, but also for understanding the effects of transient events such as start‐up and shut‐down phases, process pauses or disturbances that could lead to product rejection 2‐5 . RTD determination of continuous processes is much more advanced in continuous manufacturing of small molecule pharmaceuticals 5‐9 compared to therapeutic proteins 2,10‐12 …”