The Importance of Real-Time Nanoparticle Size Analysis

Original article by Frando van der Pas

Nanoparticle suspensions are increasingly used for a wide variety of applications such as drug delivery in pharmaceutics, catalysts, battery materials, inks,  food ingredients,  cosmetics, coatings, and paints. Many technology and industry sectors including energy, medicines, food, chemicals, etc. are being revolutionized by the design, synthesis, characterization, and application of devices and materials on a nanometer scale. Process Analytical Technology (PAT) instruments include analytical equipment able to measure and monitor physical and chemical properties of nanoparticle suspensions and enable real time monitoring of processes.

The NanoFlowSizer from InProcess-LSP

Nanoparticles and their Applications

Nanoparticles are synthetic and natural particles with a size in the 10-9 m range (1-1000 nm). They have a large surface area in relation to their volume due to their small size, conferring them special properties. Nanoparticles are present in a lot of items in our everyday life, like scratch-proof glasses, medicines, or transparent sunscreens.

Of particular interest to the pharmaceutical industry, nanoparticles are utilized under different formulations, like engineered drug delivery systems targeted to disease cells, reducing damage to healthy ones.

In addition to the major applicability in oncology, a number of vaccine formulations are based on nanoparticle vehicles that contain the active vaccine. Liposomes and other lipid-based nanoparticles (LNP) play an important role as vaccine carriers in the medical industry. Therefore, liposome synthesis is a highly increasing market.


Image credit: InProcess-LSP

The Significance of Particle Size Monitoring

The ability of nanoparticles to perform their function depends on their size. In addition, size distribution is directly related to safety and efficacy (for patients in pharma applications). Nanoparticle size control is paramount to the entire development and manufacturing process of nanoparticle products, as the behavior of particles at the nanoscale is highly dependent on these properties.

The pharma industry must have total control over the production processes of its high-quality products being compliant with stringent demands and regulations. This could cost several € millions/day. So, they need highly efficient and sophisticated Process Analytical Technologies (PAT) which enable continuous insight in process performance in real time.

Yet, something that hinders nanoparticle applications from reaching full potential is a lack of adequate PAT solutions for monitoring particle size and size distribution in the nanoscale regime. It was recognized by health agencies that one of the greatest challenges in bringing new nanomedicines to the market is accurately determining their particle size during manufacturing.


Figure 1. Pat principles

Economic Losses Due to Lack of Solution

The offline analysis approach and associated costs of laboratory usage and personnel were estimated at € 600-700K per drug per year by one of the largest pharmaceutical companies. Additional costs related to lost production capacity, by pausing the production process for offline testing and feedback, were not estimated as a concrete number but are expected to be significantly higher.

Their low-efficiency and effectiveness in quality control brings about a high occurrence of production batches being not compliant or even rejected: creating losses as high as €2 million per event with up to 50% of all cases for complex, less-routine processes.

No Real Solutions Available?

For non-solid products, direct inline (underflow) measurement of nanoparticle size and distribution is crucial to ensure the quality of routine production. Yet, there are no such inline systems currently on the market since the release in 2019 of InProcess-LSP's NanoFlowSizer technology.

Sampling procedures are required for the technologies which are now utilized (mostly Dynamic Light Scattering) and, in most cases, off-site laboratory analysis and sample treatment (quiescent conditions created, diluted, etc.), which presents severe problems: 

  1. Need for laboratory analysis: incurring in laboratory costs (material, equipment, personnel)
  2. Low control over the production process: Due to long feedback time by offline analysis process control options are poor and far from real-time.
  3. Non-representative offline measurement conditions and possible interference with the sterility of the process (invasive process). 
  4. Long time for analysis (10 min - hours): Limiting the number of samples and representativity and increasing the total production time.
  5. Impossibility to measure unstable formulations, since sampling will disrupt the physical and chemical composition immediately.
  6. Sub-optimal process performance: variations in product quality because of the absence of full process control  
  7. Impossibility to carry out continuous manufacturing (24 hours) because of the dependence on laboratory analysis and the requirement to interrupt production flow.


In order to overcome the limitations of conventional DLS for Process Analytical Technologies, InProcess-LSP developed a new innovative technology: Spatially Resolved Dynamic Light Scattering (SRDLS). SR-DLS allows particle size characterization in process flow and is able to measure highly turbid suspensions without dilution. In 2019 InProcess-LSP fully released the NanoFlowSizer as the only TRUE inline particle size measurement technology.

Why can the NanoFlowSizer Perform Inline Analysis? 

The key innovation in the NanoFlowSizer is that it employs Spatially Resolved Dynamic Light Scattering (SR-DLS) based on Fourier Domain Low-Coherence Interferometry (FD-LCI). FD-LCI Light scattering information is gathered from particles at different depths in the sample. The spatially or depth-resolved signal offers new and exciting possibilities of which measurement in flow is one of the most important advantages. 

The unique depth-resolved light scattering information is key and holds information on both particle size and process flow characteristics. The patented algorithms of the XsperGo software can extract the relevant information continuously, supplying size information in less than 10 seconds. (Figure 2) 

Figure 2. Depth-resolved scattering information

NanoFlowSizer System

NanoFlowSizer is made up of three main elements (Figure 3):

  • Probe Unit: Interferometer + Optics
  • The Base Unit: With the spectrometer and light source
  • XsperGo software: Instrument control and particle size characteristics calculations

Figure 3. NanoFlowSizer system, Image Credit: InProcess-LSP

The NanoFlowSizer is a flexible modular system that, depending on the module used, provides different functionalities (Figure 3) for various scales.

  • Offline: At a location not being the production facility, i.e., laboratory (sampling required)
  • At-line: Static measurements carried out in proximity to the production process (sampling required)
  • Online: Connected to the production flow by a sampling loop
  • Inline: In the production flow (continuous real-time measurements, no need for sampling and sample treatment


Image credit: InProcess-LSP

Covering a large scope of customer applications, the modular design enables configuration for all four analysis classifications listed varying from ml scale up to multiple liter scale. The non-invasive measurement process takes 10 seconds for nanoparticle size and particle size distribution.

Real-time process feedback information is enabled by the continuous analysis mode; this is crucial for high-quality control of any production process. The NanoFlowSizer is also applicable to sterile production conditions because measurements are carried out non-invasively without any direct contact with the suspension itself.


As a unique and only inline nanoparticle size analyzer, the NanoFlowSizer is the only system currently on the market that provides all of the advantages associated with inline analysis functionality. It does not require sampling before analysis and decreases risks like contamination and errors related to testing and sampling.

Additionally, continuous monitoring of process performance is possible as inline measurements only takes seconds, giving a complete insight of the production process with real-time performance feedback.

Finally, the NanoFlowSizer provides superior process control, optimizing the state of control and compliance, and decreasing risks for batch-rejections related to particle size.

This information has been sourced, reviewed and adapted from materials provided by InProcess-LSP.

For more information on this source, please visit InProcess-LSP.

This article is written by Frando van der Pas, InProcessLSP.


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