When and Why Hot Melt Extrusion Makes Sense in Pharmaceutical Manufacturing
Author: Brian Anderson, Dir CMC Program Management
Hot Melt Extrusion (HME) is an enabling processing technology that dates back many decades in the plastics, food, and other industries, and has been applied in pharmaceuticals for nearly 30 years now. Pharmaceutical manufacturers choose HME to enable poorly soluble compounds. When executed properly, HME advances poorly soluble compounds in the development pipeline, without adding delays, cost, or significant post-processing activities, and can scale to commercial manufacturing.
HME offers many advantages to pharmaceutical manufacturers who face increasing complexity in the compounds being targeted, as well as pressures to lower costs and get to market ahead of the competition. In addition to increasing the solubility and bioavailability of poorly soluble compounds, HME is an economical and environmentally friendlier processing technology:
- No use of solvents
- Fewer processing steps (no time-consuming drying necessary)
- Continuous operation
- Ease and speed of processing
- Highly reproducible
“When it’s dialed-in in a manufacturing environment, HME can be operated in a continuous fashion, versus other technologies that can only be manufactured in batches,” says Bryan Wiesner, director of external development at AbbVie. “This is particularly valuable for a high-throughput, high-volume product, but equally efficient as a continuous manufacturing technology for smaller, niche products.”
In terms of the finished drug product, HME can improve drug efficacy and drug delivery efficiency. It offers better content uniformity and uniform dispersion of fine particles, and can be used for sustained, modified, and targeted release formulations. It can also be used for abuse-deterrent and taste-masking applications, as well as potents. Finished drugs manufactured with HME can also be stored at room temperature.
How It Works
Hot melt extrusion works by distributing the active pharmaceutical ingredient(s) (API) through a specialized matrix to form a solid uniform dispersion. It processes polymeric materials above (Tg) to effect molecular-level mixing of APIs and thermoplastic binders and/or polymers. Efficient mixing, temperature, and shear energy are imparted throughout the process. Hoppers or feeders are large vessels at the beginning of the HME process that feed pre-blended or individual ingredients into the modular barrels of the extruder. A modular extruder design allows for flexibility in screw configuration to meet a variety of process needs. In the extruder, single, twin, or multiple rotating screws draw the material in, where it is efficiently mixed and kneaded under specific pressure, vacuum, compression, and heating and cooling settings to render the molten matrix — a highly efficient solvent for the API. Now a glassy, viscous, melted ribbon, the material exits the extruder through a die and onto a conveyor belt, either directly shaped by the die or calendar and later milled into appropriately sized particles for tableting and coating (as necessary).
This process increases solubility by disrupting the crystal lattice, reducing particle size, improving wettability, and preventing agglomeration.
Before mixing any ingredients, pharmaceutical companies or their contract manufacturers model the extrusion process. Simulation is one tool that can be used to better understand the internal workings of the proposed process and to reduce experimental burden. Extrusion is a complex processing step composed of several unit operations — involving heat, mass, and momentum transport — and the physics involved must be clearly understood.
Modeling can help develop the control strategies to be put in place to ensure best use of the extruder and ancillary equipment.
The technology and equipment involved include in-process sensors for continuous monitoring; a feeder system to enter the polymer, excipient, and API; the modular extruder, comprised of screws and barrels, wet and dry feeds, and vacuum, that convey, mix, and melt the materials; and shaping tools such as the die, calendar, and cutting system to physically shape the extrudate.
Disadvantages of HME
Because HME is a thermal, high-energy process, it is not suitable for all compounds or excipients and there are limited polymers with the requisite high-flow properties. For the appropriate drug candidates, HME requires demonstrated expertise, thereby ensuring the process results in a safe, efficacious, and compliant drug product.
Unrivaled HME Experience
AbbVie Contract Manufacturing has expertise dating back more than 20 years in HME, as a pioneer in the pharmaceutical application of the proven technology. “Some of our people were the first to take HME into the clinical phase, the first to manufacture a billion dollar product with it, and now we’ve done that multiple times,” says Wiesner. “We’ve proven that HME is a suitable and viable technology for enabling poorly soluble compounds.”
Most customers come to AbbVie knowing their temperamental compound or molecule is a candidate for HME, based on early lab experiments. AbbVie is able to apply its expertise in formulation optimization, scale up, and manufacturing using HME to achieve commercial success.
With pharmaceutical-grade HME equipment ranging from 18 mm to 70 mm twin screws, AbbVie is able to offer a customized approach to hot melt extrusion for regulatory-compliant pharmaceutical applications from pilot scale through commercial supply.
“Customers want a partner with a demonstrated skill set,” Wiesner says. “We have a proven track record of developing formulations that are robust, stable, and reproducible when going from lab scale to GMP at commercial scale. AbbVie has extrusion capabilities — from the smallest lab scale to the largest pharmaceutical extruders in the world — at multiple facilities in both Europe and North America, so customers can contract our customized HME services without compromising speed to market.”
For more information on our HME capabilities, please contact us.