Title: How Raw Material Attributes and Process Parameters Affect the Global Residence Time Distribution Behavior in Continuous Direct Compression
Author: Samantha Hurley
The pursuit of drug product continuous manufacturing will revolutionize the pharmaceutical industry by improving product flow in our supply chains, such as leveraging fast cycle times and flexible batch sizes, and by reducing lead times and inventory levels. A successful batch to continuous manufacturing conversion requires a very robust control scheme. One commonly described control scheme involves the use of NIR spectroscopy for blend composition monitoring. This study evaluates the use of an alternate method, a Residence Time Distribution (RTD) based process model for control of the continuous direct compression (CDC) process without direct measurement of blend uniformity. In some cases, this method is preferred over traditional spectroscopic techniques as the primary control across a wide range of throughputs, blender speeds, and material properties.
The CDC system studied consists of two continuous convection blenders in series followed by a tablet press. Each of the blenders and the tablet press are modeled as a Plug Flow Reactor (PFR) in series with two Continuously Stirred Tank Reactors (CSTRs). Since each PFR and CSTR is characterized by a single time constant, tLag and τ respectively, each blending unit can be described by threeparameters. Tracer experiments were conducted by spiking API into either the inlet of blender 1 or blender 2. The effluent API concentration was measured either by blend NIR spectroscopy at the exit of blender 2 or tablet HPLC at the exit of the tablet press. The RTD model parameters were optimized by using a least squares algorithm between the blend NIR/tablet HPLC and the RTD model, previously described. The model parameters were developed across various processing conditions and material properties (e.g., bulk densities and flow indices).
The results from the tracer experiments performed show that a ratio of τ:tLag is constant within each blending unit across all the various conditions. This universal behavior thus allows the development of a simple empirical relationship which describes RTD model parameters across the entirety of the design space. The results indicate that the relationship between the blender 1 and blender 2 model parameters versus throughput (TP) and blender speed (BS) can be described as
where A, B, C, and D are constants. The results also indicate the relationship between the tablet press model parameters versus throughput can be described as
where A, B, and C are constants. Knowledge of this universal behavior allows interpolation of model parameters anywhere within the design space, enables simpler model validation, and significantly simplifies process model development for future products.
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