Inline Refractive Index for pharmaceutical manufacturing
Continuous, real-time liquid concentration measurement for GMP data integrity
From delayed lab result to active process variable
Modern pharmaceutical manufacturing is increasingly data-driven.
Temperature, pressure, flow, pH – almost all main parameters are measured continuously.
Yet concentration is still often verified through offline laboratory analysis.
Refractive index closes that gap. A fundamental optical property that responds directly to concentration, it can be measured inline and continuously — with no sampling, no reagents and no complex analytical models.
Proven in industrial process control and now validated in pharmaceutical manufacturing, inline refractometry turns concentration into a real-time control variable at every stage — from development and scale-up to routine GMP production.
Development Scale-up Manufacturing Continuous manufacturing
One measurement → every stage of pharmaceutical manufacturing.
What continuous concentration measurement makes possible
Measured continuously and inline, concentration becomes an active process variable rather than a delayed lab result. Continuous concentration measurement lets you:
Accelerate process development and scale-up
Make faster, more confident process decisions
Improve batch-to-batch consistency
Generate reliable data for PAT, digital manufacturing and AI
Enable automation and advanced process control
Improve process understanding and real-time visibility
Why Refractive Index
Refractive index is a fundamental optical property of every liquid that changes with the change of concentration of the measured medium.
Vaisala inline process refractometers measure refractive index continuously to provide real-time concentration data without sampling, reagents or complex analytical models.
Where inline concentration measurement creates most value
Biopharmaceuticals
From monoclonal antibodies and other recombinant proteins to mRNA therapeutics and plasma-derived proteins - inline refractive index provides real-time concentration data across key upstream and downstream process steps. Proteins are particularly well suited to refractive index measurement due to their well-characterized refractive index increment (dn/dc), enabling sensitive and reliable concentration measurement.
Chemical pharmaceuticals
Complex chemistry does not always require complex analytics. Continuous concentration measurement simplifies process control while improving efficiency and reproducibility. Across pharmaceutical chemical synthesis — from small molecules to peptides, oligonucleotides and other complex synthetic APIs — inline refractive index provides real-time visibility into concentration and composition changes, helping identify process transitions and endpoints in synthesis, crystallization, solvent exchange and filter-cake washing — without sampling or added reagents.
Drug product manufacturing
During drug product formulation and compounding, inline refractive index provides real-time concentration monitoring of dissolution, dilution and addition steps. It eliminates sampling bottlenecks, shortens processing time and provides continuous digital data to support process consistency, traceability and Real-Time Release Testing (RTRT) strategies.
Applications
Media and buffer preparation
Inline refractive index continuously monitors media and buffer concentration and homogenization, helping verify preparation and mixing endpoints while reducing offline testing, including for non-ionic components where pH or conductivity provide limited concentration information.
Fermentation
Fermentation is inherently dynamic. Inline refractive index continuously monitors liquid-phase changes, providing real-time insight into process progression, endpoint detection and nutrient-feed control — helping optimize process time and reduce offline sampling.
Chromatography
Inline refractive index continuously monitors feed concentration, enabling accurate control of loading mass, consistent column loading, optimized resin utilization and improved purification efficiency.
UF/DF/SPTFF
Inline refractive index continuously measures protein concentration during UF/DF and SPTFF, including at high concentrations, without dilution, narrow optical path lengths or complex chemometric models. Real-time concentration data enables endpoint control and reliable concentration to target, reducing variability, manual sampling and reprocessing risk.*
Solid-phase peptide and oligonucleotide synthesis
Inline refractive index continuously monitors liquid-phase changes during SPPS and SPOS, providing real-time visibility into deprotection, coupling and wash cycles without sampling, added reagents or complex chemometric models. It enables reliable process-transition and wash-endpoint detection, optimizing cycle times and solvent use while improving consistency.**
API synthesis
Complex chemistry does not always require complex analytics. Continuous concentration measurement simplifies process control across synthesis steps, improving efficiency and reproducibility.
Crystallization
Crystal size, yield, purity and polymorphic form are all governed by supersaturation. Continuous RI monitoring maintains the optimal solute-concentration trajectory for consistent crystal growth and improves downstream separation efficiency. Read more in the blog.
Solvent swap
During solvent swap, inline refractive index tracks liquid composition in real time, enabling endpoint detection and controlled solvent addition to keep the API in solution. This optimizes solvent use and process time while supporting scale-up and technology transfer. Read more in the blog.
Filter cake washing
Inline refractive index continuously monitors changes in the liquid leaving the filter cake, providing real-time visibility into mother-liquor displacement and wash progress. A stable RI signal indicates the wash endpoint, helping minimize solvent use and process time while reducing the risk of API dissolution and product loss. Read more in the blog.
Compounding
Inline refractive index continuously monitors concentration and homogenization in process tanks. A stable RI signal indicates uniform mixing, enabling real-time mixing endpoint detection rather than fixed time — optimizing mixing time, detecting deviations and reducing offline sampling.
Tank & mixing monitoring
Probe-format inline refractometers monitor concentration directly in commercial-scale tanks during mixing — column-pool collection, pH and conductivity adjustment, and TFF rinse. A stable reading confirms complete homogeneity, so mixing can stop on demonstrated uniformity rather than a fixed time, while guarding against undermixing in high-dilution steps.
*Lam, McCann, Loman, Smelko & Brinkmann (Biogen), “Refractive index as a process analytical technology to measure real time protein concentration for monitoring and control of commercial scale tangential flow filtration operations,” Journal of Advanced Manufacturing and Processing. DOI: 10.1002/amp2.10151. Instrument studied: K-Patents PR-23 (Vaisala).
**Lopez (Novartis), “Refractive Index Paves the Way to Greener Peptide and Oligonucleotide Synthesis,” Oxford Global, Sustainable Chemistry 2023; proof-of-concept work with B. G. de la Torre & F. Albericio, University of KwaZulu-Natal.
Why Vaisala?
Trusted by pharmaceutical manufacturers worldwide.
- Trusted by all 50 of the top 50 global pharma, biotech and medical device companies, with 90+ years of measurement experience behind every reading
- Decades of inline process-refractometry expertise — from industrial pioneers to pharmaceutical manufacturing
- Proven at commercial scale and validated in peer-reviewed research, with comprehensive validation and compliance documentation for GMP environments
- Global calibration, service and support network, plus Life Science specialists for method development, scale-up and technology transfer
One measurement partner from development to production — concentration data you can act on in real time, defend in an audit and trust at scale.
The result: concentration data you can act on in real time, defend in an audit and trust at commercial scale.
Customer testimonials
“Inline refractive index measurement complements traditional protein concentration methods, enabling real-time monitoring without sample dilution and supporting process performance from development through manufacturing.”
— Senior Process Development Scientist, Global Biopharmaceutical Company
“With inline RI value during media preparation, we can see when the batch is homogeneous, optimize mixing time and verify the final concentration — reducing the need for pH and offline osmolality checks to a minimum.”
— Manufacturing Engineer, Global biopharmaceutical company
“With inline RI across our UF skids, we can follow concentration throughout the downstream process, compare performance between steps, and quickly identify opportunities to improve process efficiency.”
— Process engineer, Global biotechnology company.
Meet the instrument
Vaisala Polaris inline process refractometers bring the continuous concentration measurement described above to pharmaceutical processes. Robust optical technology — with no moving parts or consumables — delivers maintenance-free operation, while easy system integration makes it ready for GMP process control.
Resources
Protein concentration and filtration
Download the application note to see how inline refractive index (RI) measurement supports tighter control of protein concentration and buffer exchange—without stopping the process to take manual samples.
