(668a) A Drop-on-Demand Manufacturing System for the Production of Melt-Based Pharmaceutical Dosage Forms

In recent years, the FDA has encouraged pharmaceutical companies to place renewed emphasis on the development of more innovative, efficient manufacturing methods with the use of process analytical technologies and the QbD approach. As part of this renewed emphasis on improvement of manufacturing, the pharmaceutical industry has also begun the selective transition from traditional batch processing to continuous manufacturing [1].

As a part of the NSF Engineering Research Center for Structured Organic Particulate Systems, a mini-manufacturing process for drug formation has been under development. 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, such as a polymeric film or placebo tablet, using a semi-continuous operation suitable for low volume production of personalized dosage forms [2].

In this paper, we present a process narrative of the pilot facility and discuss automation and supervisory control of the DoD manufacturing system along with the analysis of the drug forms created which consist of polymer and drug constituents. Implementing a supervisory control system for the manufacturing process, including automation and closed-loop control, is essential for producing individual dosage forms with precise control of dosage amount, morphology and formulation composition. The system consists of a positive displacement pump, xy-staging, imaging system and temperature controllers. The drop volume is monitored using the imaging system, to ensure consistent drop size and thus dosage amount. 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]. Multiple temperature controllers are used to control the temperature of the process elements including material reservoir, pump, tubing and nozzle. Temperature control on the process allows maintaining printable rheological and material properties for the production of melt-based dosage forms. Temperature control on the substrate is crucial, since crystallization temperature has an effect on product quality, influencing the bioavailability of the drug [4]. After drop deposition, changes in drug morphology can be monitored using a spectroscopic technique, such as Raman or NIR, 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. Finally, the drug forms created using co-melt systems will be analyzed.

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2. L. Hirshfield, A. Giridhar, L. S. Taylor, M. T. Harris, G. V. Reklaitis, “Dropwise Additive Manufacturing of Pharmaceutical Products for Solvent-based Dosage Forms,” Journal of Pharmaceutical Sciences, vol. 103, issue 2, pages 496-506, February 2014.
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. E. Icten, Z. K. Nagy, G.V. Reklaitis, “Supervisory Control of a Drop-on-Demand Mini-manufacturing System for the Production of Pharmaceuticals,” Proc. of 24th Eur. Symp. Comput. Aided Process Eng. ESCAPE 24, vol. 24, June 2014.