Situation
A client is developing a new Lipid Nanoparticle (LNP) formulation encapsulating a short RNA oligonucleotide. The final drug product is composed of a double stranded RNA payload created within an ionizable amino lipid/helper lipid liposomal nanoparticle. The process is primarily a solvent-injection followed by downstream operations such as Tangential Flow Filtration (TFF) and normal filtration. The scope of work included design of the initial mixing as well as scale-up of the complete process before transfer to a full-scale cGMP implementation. Accordingly, Exelead performed multiple experiments at the bench-scale (<100 ml) to design the mixer and characterize the TFF operations for the various operating parameters.
Action
A full-bench-scale DOE was used to define the mixing unit operation and optimize the size distribution (Mean particle size ~ 80-120 nm) and encapsulation yield (>60%) of the LNPs. However, scale-up of the same operations resulted in a minor increase in the particle size that was challenging to control. This issue was resolved by first optimizing the mixer dimensions to increase the cross-flow pressure differential. Secondly, by incorporating an extrusion unit operation to enable the removal of a percentage (<1%) of large debris particles without any significant change to the final Lipid-to-drug ratio (N:P).
The primary lipids involved in the formulation were also highly susceptible to oxidative degradation (>5% loss). To minimize this issue, a nitrogen blanket was adopted into the process. Then multiple temperature hold studies were conducted to define the overnight hold conditions for the in-process batch volumes. Finally, multiple filter screening and flux-throughput experiments were observed to successfully validate a final sterilizing filter along with a change to an alternate MOC for the pre-filter and final filter.
Results
In Exelead’s development laboratories, the process development allowed the 30X scale-up of the original bench-scale process at <100 mL of this finished drug product. Most importantly, further 20X scale-up will be performed in the cGMP manufacturing environment using the same setup and mixer configuration that the development laboratory has designed without requiring any additional component or equipment testing. The primary scale-up factor targeted for this program is the time of mixing (from <1 minute to >3 hours) that allows for significant flexibility on what the final scale of the product could be for clinical and future commercial manufacturing runs.
Case Studies
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Product Development of a Liposomal Antifungal Ophthalmic Formulation – Screening Studies
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Process Optimization for a Liposomal Product – A Potential Metabolic Replacement Therapy Candidate
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Formulation Optimization of a Hydrophilic Small Molecule Liposomal Product
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Process Development of an RNA Oligonucleotide-Based Lipid Nanoparticle Formulation
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