(M0930-09-51) Improvements in Liposomal Manufacturing Technology

Purpose: a well-established drug delivery technology in the pharmaceutical industry. Various low- or high-pressure extrusion equipment is available to manufacture liposome formulations. Typically, low or medium pressure liposome extruders provide better particle size control, low temperature variation and pressure control over multiple passes of the formulation. This has a tremendous effect on the stability of the formulation as well as productivity and equipment wear and tear. Some of the early popular low-pressure liposome extruders were introduced to the market in mid 80s’ and these have become a well-established line of equipment for producing liposomal formulations. Since the initial launch of such low-pressure extruders, there have been no major changes or improvements in the design. A major drawback of the existing and early design of extruder was the limited area of the filter that was utilized for extrusion, which causes filter membranes to clog and rapidly foul. This effect is further compounded by a subsequent increase in extrusion pressure that can impact the quality and performance of the final drug product. Frequent and complex filter membrane changes during manufacturing is often required to overcome these challenges. Through 3D computer-aided design (CAD), we have developed a new extruder design, which has an improved membrane support technology to maximize the effective filtration area, significantly reducing back-pressure and filter clogging. This advance in liposomal extrusion technology addresses challenges with process efficiency and product quality, leading to more robust manufacturing processes.

Methods: CAD is a powerful tool used for design and modelling. Computational fluid dynamic (CFD) simulation and finite elemental analysis (FEA) have been used to discover design flaws, create solutions, and allow for further optimization of the design for performance and safety. For this project, prototypes were first tested and optimized by CFD simulation analysis (Figure 1). The prototypes were then manufactured and experimentally tested with two different lipid formulations. Experiments were performed using identical methods, with the only difference being the extruder design.

Results: Figure 2 shows a CFD comparison of the theoretical pressure drop through the range of early and new design of extruders at standard operating flow rate, using different diameters of openings. CFD simulations showed that the new design of extruder could achieve > 50% pressure reduction over the early design. The data in Figure 3 suggests that there are no significant differences between the measured particle size of each pass through either the early or new design of extruders. However, the required pressure to extrude each pass was significantly less for the new design of extruder as compared to old design of extruder. This showed a good correlation with the CFD simulation data.

Conclusion: Through the use of CAD, the increased filter utilization of the new liposome extruder design can increase manufacturing efficiency, resulting in a smoother, safer, cost-optimized process, and improved product quality.

Figure 1 - Computational fluid dynamic analysis of the effect of the new drain cavity on the filter area utilization

Figure 2 - CFD comparison of the theoretical pressure drop through the range of early and new design of extruder at standard operating flow rates

Figure 3 - Comparison of (A) particle size and (B) experimental extrusion pressure required to size down lipid formulation using early and new design extruder