Situation
A client is currently developing a liposomal formulation of a hydrophilic small molecule API. During liposome formation, phospholipids and helper lipids are injected into the hydrophilic API solution where the liposomes are formed, and a ~10% API encapsulation is achieved via passive inclusion. The liposomal solution undergoes high pressure removal in order to get the liposomes to the desired particle size. This is followed by Tangential Flow-Filtration (TFF) unit operation to eliminate residual solvent and API, as well as adjusted for final API concentration. In the end, the solution is clarified, diluted to a set API concentration, sterile filtered, and filled in glass vials.
Action
This project has faced multiple challenges requiring significant guidance from Exelead. The first challenge was the large number of extrusion passes that were proposed (>15) due to high solution viscosity. In order to reduce the number of passes and decrease extrusion time, extrusion optimization was performed. This helped to design a scheme that would utilize less than four passes and yet achieve size reduction as well as acceptable API encapsulation.
The process optimization was centered around membrane pore diameter sizes, concentrations and temperatures. Based on the results from that experiment, the extrusion passes were able to be reduced from >15 to ≤4. The particle size was also reduced post-extrusion (Pre-Ext: >5 µm; Post-Ext: 103 nm; PDI <0.1).
The second challenge was the initial lipid to API ratiometric addition to enable liposome formation. In one of the studies of liposome formation, the lipids injected into the API solution produced extremely high viscosity. Subsequently, this led also led to the formation of a curd-like layer clogging up the extrusion membrane. To avoid this issue, in later reviews and optimization cycles, a ratio of 0.24 (lipid:API; w/w) was set as the target while the agitation speeds were re-evaluated and doubled. This reduction in final solution viscosity, as well as optimizing the inconsistent suspension formation, has resulted in improved flux (from 1800 LMH to 4000 LMH) while still achieving the target post-extrusion particle size distribution.
Results
Because of the process performed for this drug product, the extrusion pass flux has more than doubled, lipid to API ratio has remained consistently at 0.24 (w/w), and the liposomal mixing has been maintained consistently at high mixing speeds. Importantly, all optimization has not impacted the further downstream processing via TFF and filtration.
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