Innovations in pharmaceutical manufacturing technology have accelerated in recent years with a range of promising developments, such as continuous manufacturing, modular design as well as additive manufacturing¹. One of the exciting thrusts has been towards developing small-scale integrated manufacturing systems capable of producing pharmaceutical dosages in an End to End Continuous (E2EC) fashion². This involves carrying out all the processing steps, from the reaction step to the drug product formation step, continuously in a single facility. Such manufacturing systems are intended to serve narrower patient populations and offer several advantages, such as, process intensification, distributed manufacturing, robust supply chains, agile manufacturing, and enhanced process efficiency etc³.

There have been many advances in developing upstream unit operations for these small-scale E2EC systems. Specifically, use of miniaturized flow reactors⁴ and continuous crystallizers⁵ have enabled integrated synthesis and purification of the active pharmaceutical ingredient (API) continuously in compact modules. However, design of small-scale downstream operations that can process the API into solid oral dosages remains challenging. A major hindrance is the lack of flexibility afforded by conventional tablet lines in producing small lots of dosages with a wide range of drug loadings. This is necessary for therapies where patient dosing needs can differ widely. Using Additive Manufacturing for drug product manufacture can provide the desired degree of flexibility to vary drug loading. Drop on Demand (DoD) printing is a form of Additive Manufacturing that produces dosages by printing multiple drops of an API containing carrier into substrates (ex. capsule, placebo tablets)⁶. Its advantage over other types of additive manufacturing is that it allows powder-free processing which in turn enables circumventing the multiple challenges associated with powder handling (powder flowability, granulation etc.) at small operating scales⁷.

This study explores development of a processing bridge between the crystal slurry produced in the final crystallization step and a crystal slurry suitable for DoD printing which solidifies at room temperature. The objective is to avoid the need for the traditional intermediate filtration and drying steps while preserving the crystal size distribution and polymorphic form that are achieved in the final crystallization step. In this work we develop and compare several alternative processing routes for achieving these goals, including continuous solvent exchange with settling and evaporative crystallization. These routes require the use of carrier fluids that are immiscible with the solvent used in the continuous crystallizer and are listed in the FDA Inactive ingredients Database. This enables the solvent and carrier to be readily phase separated and the crystals to be transferred between phases by settling or similar operations.

These bridging strategies are validated with a case study involving the manufacture of an anticancer drug Lomustine in an integrated small-scale E2EC facility. Models of these novel routes are developed and used to optimize operating conditions. The performance of these design alternatives are confirmed experimentally and the critical quality attributes of the resulting capsule product compared to those of the commercial product.

References

1. Innovations in Pharmaceutical Manufacturing on the Horizon. National Academies Press; 2021. doi:10.17226/26009
2. Adamo A, Beingessner RL, Behnam M, et al. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science. 2016;352(6281). doi:10.1126/science.aaf1337
3. Srai JS, Kumar M, Graham G, et al. Distributed manufacturing: scope, challenges and opportunities. International Journal of Production Research. 2016;54(23). doi:10.1080/00207543.2016.1192302
4. Jaman Z, Sobreira TJP, Mufti A, Ferreira CR, Cooks RG, Thompson DH. Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions. Organic Process Research and Development. 2019;23(3). doi:10.1021/acs.oprd.8b00387
5. Mackey J, Mufti A, Leec S-L, et al. Process Design and Development of a Small Scale Hybrid Manufacturing System for the Cancer Drug Lomustine. In: ; 2020. Accessed March 29, 2021. https://aiche.confex.com/aiche/2020/meetingapp.cgi/Paper/608189
6. Içten E, Giridhar A, Taylor LS, Nagy ZK, Reklaitis G v. Dropwise additive manufacturing of pharmaceutical products for melt-based dosage forms. Journal of Pharmaceutical Sciences. 2015;104(5). doi:10.1002/jps.24367
7. Radcliffe AJ, Hilden JL, Nagy ZK, Reklaitis G v. Dropwise Additive Manufacturing of Pharmaceutical Products Using Particle Suspensions. Journal of Pharmaceutical Sciences. 2019;108(2). doi:10.1016/j.xphs.2018.09.030