RT-MALS: Real-Time Process Analytics and Control for Vaccine Nanoparticles and Macromolecules

Significance of the Topic

Real-time multi-angle light scattering (RT-MALS) represents a transformative approach in process analytical technology (PAT) for vaccine and biopharmaceutical production. By directly tracking critical product attributes—such as particle size, molar mass, and concentration—RT-MALS enhances the speed, yield, and quality control of complex modalities including mRNA lipid nanoparticles, viral vectors, and protein conjugates.

Objectives and Study Overview

This whitepaper presents RT-MALS as a next-generation PAT tool that extends traditional SEC-MALS and FFF-MALS analyses into continuous, online monitoring. Key goals include:

• Demonstrating inline measurement of vaccine nanoparticles and macromolecules.
• Reducing process development times and scale-up risks.
• Improving end-product consistency and yield.

Methodology and Instrumentation

RT-MALS integrates an ultraDAWN multi-angle light scattering detector with OBSERVER control software. The system connects to upstream units such as reactors, FPLC, or TFF modules. Sample streams are diverted through the detector without external pumps when inline, or with auxiliary pumps for online setups. Digital triggers from OBSERVER enable real-time decisions based on measured radius, molar mass, or particle concentration every 2 seconds.

Main Results and Discussion

Case studies highlight RT-MALS impact:

• Viral vector purification: Inline triggers at 85–120 nm radius allowed real-time collection, distinguishing virus from impurities and calculating virion titer.
• Viral vector concentration by TFF: Triggering at particle concentration >5 × 108 mL⁻¹ validated buffer exchange cycles without process delay (RTD ≈ 12 s).
• Liposome homogenization: Radius triggers of 48–52 nm yielded uniform vesicle populations at zero additional residence time.
• Polysaccharide depolymerization: Online dilution and Mw trigger (<350 kDa) achieved endpoint detection within 3 minutes.

Benefits and Practical Applications

RT-MALS offers:

• Direct monitoring of product attributes versus surrogate process parameters.
• Immediate feedback for process control, reducing development cycles.
• Enhanced productivity and yield across multiple vaccine modalities.

Future Trends and Possibilities

Anticipated developments include integration with continuous manufacturing lines, advanced automation via digital twins, broader deployment in mRNA and viral platform processes, and expanded analytics combining MALS with orthogonal detectors for deeper structural insights.

Conclusion

RT-MALS extends conventional SEC-MALS and FFF-MALS analyses into real-time PAT, enabling precise, rapid control of vaccine nanoparticle and macromolecule production. This paradigm shift promises faster development, higher yields, and superior product quality.

Reference

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