Enhancing the “right first time” concept in Continuous Manufacturing – Development strategy
The aim of this work is to explore a streamlined development strategy for continuous direct compression. The already reduced time for development of continuous processes (no scale up needed) can be further optimized by an adequate development strategy that enables “right first time”. For the Continuous Direct Compression (CDC) line, digital twin models for the feeding, blending, tableting, and coating, developed using prior experimental data, can greatly reduce experimental work, and consequently API expenditure, and accelerate process development timelines. To that end, appropriate laboratory equipment that is equivalent or mimics unit operations behaviour, such as feeders, tablet presses and coaters is used to facilitate process transferability.
This CDC process development is supported by the thorough laboratory characterization of materials for a data-based benchmark, followed by feeding trials to determine the relative standard deviation (RSD) as a function of flow rate, the feed factor and select the optimal operating conditions and equipment set-up. After assessing the compressibility profile in a laboratory scale tablet press, a coating model is developed to correlate laboratory and industrial scale processes. Following this strategy, the configuration of process parameters and design (e.g., feeder system) can be determined prior to the line integration, improving efficiency, and minimizing the use of the commercial production line.
Furthermore, Process Analytical Technology (PAT) tools are also used in the development phase, to increases process knowledge, such as the determination of the Residence Time Distribution (RTD) of each unit operation, as well as to develop chemometric models, that are then transferred to the commercial line, enabling continuous product quality monitoring.
Trials in the CDC-50 GEA line with a formulation containing a commonly used poorly flowing surrogate (Dv50 = 50 µm, ρbulk = 0.59 mg/mL, HR = 1.31) have demonstrated the ability to attain a low weight variability following this development strategy. At a flowrate of 25 kg/h, 3 formulations between 8% and 13% of API surrogate showed an RSD < 1.3% in tablet weight, without outliers (3SD) in each time point.
These results obtained for a powder surrogate demonstrate the adequacy of this development strategy for robust continuous direct compression process development.