A PAT Solution for Automated Mill Control - Pharmaceutical Technology

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A PAT Solution for Automated Mill Control
The authors describe the implementation of an on-line particle-size analyzer on an active pharmaceutical ingredient milling operation at a commercial site.

Pharmaceutical Technology
Volume 34, Issue 1

Real-time particle-size measurement

To improve the efficiency of mill operation, and to deliver more consistent milled particle sizes, an Insitec online particle-size analyzer (Insitec, Malvern Instruments, Worcestershire, UK) was identified as a possible solution for continuous milling monitoring and control. This system employs the technique of laser diffraction, a well-established and robust method, and is specifically designed for easy integration into the manufacturing process. Unlike some PAT instruments that are based on modifications from a laboratory unit platform, and which tend to be sensitive to the manufacturing environment, the Insitec was designed to be used on the shop floor. The rugged integrity of the system is well proven across a diverse range of industries. It is being applied increasingly in the pharmaceutical industry as companies implement PAT.

A pilot-plant trial was performed to demonstrate the feasibility of using the Insitec system on an API milling operation. A mobile analyzer was installed on-line at the exit of a comminutor mill. With this on-line setup, material is continuously aspirated from the process stream, through a sample flute, using a venturi eductor, which disperses sample into the measurement zone and is returned to the process line after analysis. The system has no moving parts and operates 24/7 with very little manual intervention. The particle-size distribution is measured continuously and reported with a user-defined frequency (once every 0.25–60 s).

Figure 2: Using the Insitec on-line particle size analyzer to detect changes in particle-size distribution resulting from changes in mill speed, where the blue, red, and black lines show the particle size produced at low, medium, and high mill speeds, respectively.
Figure 2 shows particle-size distributions measured during the pilot-plant trial at low, medium, and high mill speeds. The results of the pilot trial showed the potential of on-line particle-size analysis, demonstrating the ability of the Insitec to track process variation in real time and produce results that can be used in process and quality control.

Figure 3: Spool piece accommodating the sampling probe for the on-line analyzer and directing sample return toward product collection.
Knowledge gained during the pilot-plant trial helped streamline the implementation of on-line particle-size analysis at the commercial manufacturing site. Here, a spool piece was fabricated to accommodate the probe for the analyzer and to interface with the standard product containers used to collect powder exiting the mill (see Figures 1 and 3).

Figure 4: Effect of nitrogen flow through the eductor on measured particle size (flow/size titration) with Dv50 value produced using established off-line measurement technique superimposed (yellow bar). SCFM is standard ft3/min.
Since sampling bias and incorrect dispersion are the main causes of measurement error, both for laboratory and process analysis, experimental work was carried out to optimize the process interface. To ensure sampling was representative, particle size was measured at different points across the diameter of the exit line to detect any segregation and determine a suitable position for the sampling probe. Measuring particle size as a function of gas flow through the eductor generated a particle-size–flow-rate plot that was used to determine suitable conditions for dispersion (see Figure 4).

The results of these investigations showed that a single-holed probe extracting sample from the center of the spool piece produces the most representative sample. The size of the sampling hole was also optimized to ensure an adequate scattering signal was obtained. A dispersion flow rate of 3 standard ft3/min breaks up any agglomerates without causing primary particle attrition and produces a Dv50 (median particle size by volume) that is in close agreement with the established off-line method for particle-size measurement.


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