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Published on: March 22, 2022
The hidden half of lipid nanoparticle manufacturing: Downstream processing
Peter Sagmeister1, Cedric Devos1, Aniket Udepurkar1
1Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Summary
Downstream processing significantly impacts lipid nanoparticle (LNP) manufacturing, affecting critical quality attributes like size and stability. Integrating upstream and downstream operations is crucial for robust and reproducible LNP production.
Area of Science:
- Biotechnology
- Pharmaceutical Sciences
- Chemical Engineering
Background:
- Lipid nanoparticles (LNPs) are leading nonviral vectors for nucleic acid therapies.
- Current LNP manufacturing faces challenges in complexity and reproducible scalability.
- Downstream processing is vital but understudied compared to particle formation.
Purpose of the Study:
- To highlight the impact of downstream processing on LNP quality attributes.
- To identify knowledge gaps in LNP manufacturing.
- To advocate for a unified approach to upstream and downstream LNP process design.
Main Methods:
- Review of academic literature focusing on LNP downstream operations.
- Analysis of how unit operations affect LNP physicochemical properties.
- Identification of formulation-dependent impacts on biological performance.
Main Results:
- Downstream operations critically alter LNP particle size, morphology, internal structure, payload distribution, and stability.
- Physicochemical changes induced by downstream steps are formulation-dependent and affect biological outcomes.
- Significant gaps exist in analytical methods, mechanistic understanding, and process development for LNP downstream processing.
Conclusions:
- Downstream processing is not merely a finishing step but actively shapes LNP product quality.
- Robust LNP manufacturing necessitates treating upstream and downstream operations as an integrated, coupled process.
- Further research is needed to bridge knowledge gaps in LNP downstream processing for improved therapeutic delivery.
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