The pharmaceutical industries have started transitioning toward continuous mode of manufacturing recently. Due to many advantages of the continuous manufacturing over the traditional alternatives, the industries are putting huge effort to efficiently adapt the continuous processing mode. However, even now, the drug product (tablet) manufacturing is separate from the drug substance (active ingredient) manufacturing and no direct connection exists between the two. The physical properties of the active pharmaceutical ingredient (API) crystals (e.g., crystal size, shape, etc.) affect the critical quality attributes (CQAs) of the final solid dosage forms (tablets). In this work a continuous integrated flowsheet model (mathematical representation for in silico simulation) has been developed, which integrates the API purification, separation with a downstream tablet manufacturing unit operation (powder mixing). This flowsheet can be used to study the effect of upstream API properties on the downstream product attributes. The flowsheet model consists of crystallization, filtration (API separation), drying (API purification) followed by a powder-blending operation (to obtain the final formulation). Each unit operation has been developed from first principles and connected in a continuous framework such that the output of one unit operation becomes the input of the next unit operation. These integrated unit operations are highly interactive along with the presence of process delays. A hybrid model predictive control-proportional integral derivative control system has been designed and presented for the continuous flowsheet model as well.

• Rutgers, The State University of New Jersey

• Oral doses
• Modeling

1. continuous processing
2. crystallization
3. Flowsheet simulation
4. modeling
5. MPC
6. Oral doses
7. population balance model
8. powder mixing
9. Research Article