(344c) Supervisory Control of a Drop-On-Demand Mini-Manufacturing System for the Production of Pharmaceuticals

The support of the FDA in the development of more efficient production technologies creates new possibilities for innovation in pharmaceutical production processes. There is an intention within the pharmaceutical industry to move from traditional batch processing to continuous manufacturing. [1] As a part of the Engineering Research Center for Structured Organic Particulate Systems, a mini-manufacturing process for drug formulation has been built. The process utilizes the drop-on-demand (DoD) printing technology for predictable and highly controllable deposition of active pharmaceutical ingredients (API) onto an edible substrate, using a semi-continuous operation suitable for low volume production of personalized dosage forms.[2] The system consists of a positive displacement pump, xy-staging, camera and temperature controllers.

Here, we present a supervisory control framework for individual dosage forms with precise control of drop size, morphology and formulation composition. Implementing a supervisory control system on the mini-manufacturing process, including automation and closed-loop control, is essential for producing individual dosage forms with the desired properties. The drop volume is monitored using the imaging system, to ensure consistent drop size. The xy-staging allows creating precise drop positioning while printing.

Using this process, different drug formulations including solvent-polymer-API and polymer-API systems, i.e. co-melt systems, can be produced. Polymers are added to the printing material to help control drug morphology, material properties and the formulation composition.[3] In order to produce melt-based dosage forms the complete system must be heated. Therefore we implemented temperature control around the reservoir, around the tubing and within the pump. Since crystallization temperature will have an effect on product quality, influencing the bioavailability of the drug, precise temperature control on the nozzle and substrate is important.[4] After drop deposition, changes in drug morphology can be monitored using Near Infrared spectroscopy and corrected by temperature control action on the substrate. Using the proposed temperature control strategy on the substrate, one can tailor the crystallization behavior to compensate for these variations and achieve consistent drug morphology.

1. K. V. Gernaey, A. E. Cervera-Padrell, and J. M. Woodley, “A perspective on PSE in pharmaceutical process development and innovation,” Computers & Chemical Engineering, vol. 42, pp. 15–29, Jul. 2012.
2. B. Derby, “Inkjet Printing of Functional and Structural Materials: Fluid Property Requirements, Feature Stability, and Resolution,” Annual Review of Materials Research, vol. 40, no. 1, pp. 395–414, Jun. 2010.
3. N. S. Trasi and L. S. Taylor, “Effect of Additives on Crystal Growth and Nucleation of Amorphous Flutamide,” Crystal Growth & Design, vol. 12, no. 6, pp. 3221–3230, Jun. 2012.
4. M. Fujiwara, Z. K. Nagy, J. W. Chew, and R. D. Braatz, “First-principles and direct design approaches for the control of pharmaceutical crystallization,” Journal of Process Control, vol. 15, no. 5, pp. 493–504, Aug. 2005.