The continuous process of hot-melt extrusion (HME), which is useful for making solid dispersions of poorly-soluble drugs and controlled-release dosage forms, lends itself well to quality-by-design (QbD) principles such as defining a process design space. Design space, by ICH Q8 definition, is the “multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality” (1). Because HME is a well-understood industrial process, it has the sound body of data needed to establish the critical process parameters (CPPs). HME, by nature of being continuous, is run at steady state, which allows multiple, steady-state iterations to be tested while minimizing material use during the process of establishing a design space, notes James DiNunzio, PhD., principal scientist at Hoffman-La Roche. “A structured approach to process design can greatly increase your chances of success,” said Josh Shockey, P.E. and principal at Green Ridge Consulting, in a presentation at last month’s Pharmaceutical Extrusion Seminar organized by Leistritz (2). The TSE incorporates a series of unit operations (e.g., feed, convey, mix, melt, devolatilize). In designing the HME process, one should understand the overall goal, the goals of each of the unit operations, and how these operations interact, Shockey explained.
When producing an amorphous solid dispersion using HME, the overall goals, or critical quality attributes (CQAs), are acceptable levels of degradation and acceptable levels of residual crystallinity. The CPPs in the extruder can be said to be residence time, melt temperature, and an energy component that can be defined as shear rate, shear stress, or specific energy input. These CPPs are not easily defined during extrusion, however, because shear, temperature, and time are distributional in nature, says DiNunzio. “Development scientists need to define these behaviors based on controllable inputs to the process, such as screw speed, screw design, feed rate and process section temperature.” An advantage of a twin-screw extruder is that these inputs have a wide range that can be easily adjusted to get the desired output. Because the extruder is modular, even screw design can be relatively easily modified by changing the segments of the screw.
Since the extruder is operated at steady state, materials that enter the extruder at a given feedport experience a certain residence time distribution and shear distribution within the control volume. Both residence time and shear rate are functions of mass flow, screw speed, and screw design, explained DiNunzio in a presentation (3). Melt temperature is a function of melt pressure, barrel temperature, and viscous heat dissipation. CQAs are affected by a complex interaction of these process parameters. Too low a level of temperature, residence time, or shear will not produce enough mixing to create a stable amorphous dispersion, but too high a level will result in degradation.
The design space becomes further refined as developers move through the development process from early development to optimization. If the process is designed such that the operational space can accommodate normal perturbations, the system parameters can be adjusted to support processing with different material properties (e.g., different API particle size) while remaining in the design space, concludes DiNunzio.