385349 Hierarchical Control of a Drop-on-Demand Manufacturing System for the Production of Pharmaceuticals

Tuesday, November 18, 2014: 9:42 AM
404 - 405 (Hilton Atlanta)
Elšin Išten, Zoltan K. Nagy and Gintaras V. Reklaitis, School of Chemical Engineering, Purdue University, West Lafayette, IN

The support of the FDA in the development of more efficient production technologies, with frequent use of on-line measurement and process control creates new possibilities for innovation in pharmaceutical production processes. As part of this renewed emphasis on improvement of manufacturing, the pharmaceutical industry has begun the selective transition from traditional batch processing to continuous manufacturing. Continuous production processes offer the potential for reduced production costs, faster product release, reduced variability, increased flexibility and efficiency, and improved product quality [1].

As a part of the research agenda of the 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, using a semi-continuous operation suitable for low volume production of personalized dosage forms [2]. The DoD mini-manufacturing system consists of a precision positive displacement pump, xy-staging, a hot air based heating system, online imaging and sensing, and temperature, pump and stage controllers. While developed for small scale production, the drop on demand concept is readily scalable to intermediate and event large scale production levels.

Here, we present a hierarchical control framework for the formation of individual dosage forms with precise control of formulation composition, dosage size, and deposit morphology. Implementation of a supervisory control system on the mini-manufacturing process, including on-line monitoring, 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 and hence deposit amount. The xy-staging and synchronization logic allows precise drop positioning on the substrate while printing and enables layering of different drugs. The temperature control system allows maintaining printable material rheological properties for the production of melt-based dosage forms, i.e. co-melts of polymer-API systems. Since crystallization temperature has an effect on product morphology, influencing the dissolution properties and hence the bioavailability of the drug, precise control of the drop solidification process once the drop is deposited on the substrate is important [3]. This is achieved indirectly by manipulating the substrate temperature profile using varying temperature gradients. As in the case of bulk crystallization processes, cycling of temperature also can be an effective mechanism for control of crystal size – in this case feature granularity [4].

A polynomial chaos expansion (PCE) based nonlinear surrogate model family has been developed to predict the dissolution profile of the solidified drug deposition given the temperature profile applied on the substrate for several drop sizes. Using the proposed substrate temperature control strategy, the crystallization behavior can be tailored and consistent drug morphology achieved. A hierarchical control system is implemented by monitoring the drop size online and controlling the temperature profile to achieve the desired dissolution profile for the dosage forms created by the deposited drop sizes. The proposed control strategy can eliminate variations in the dissolution profiles due to variable dosage amounts, hence enabling the application of the DoD system for the production of individualized dosage regimens for adaptive clinical trials and personalized treatments.


  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. 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. 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.
  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.

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