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In-line Particle Sizing: A PAT Solution for High Shear Granulation

    In-line Particle Sizing: A PAT Solution for High Shear Granulation

    By Jarvis Jeejing Ng, Malvern Instruments & Stefan Dietrich, Parsum GmbH

    High shear granulation is a widespread unit operation within the pharmaceutical industry. Granulation improves the ease of handling of powder blends and prevents the segregation of fine constituents, improving consistency in subsequent process steps, principally tableting. Compared with fluidized bed processing, high shear granulation produces granules of high bulk density in a relatively fast and efficient manner, and potentially is easier to control. The issue of endpoint detection – deciding when to stop granulating – is the greatest challenge.

    Through the use of appropriate process analytical technology (PAT) the pharmaceutical industry hopes to improve manufacturing efficiency. Real-time monitoring techniques are especially useful in providing information for faster, more efficient process development as well as giving options for improved process control. For high shear granulation, real-time particle sizing has many advantages because the particle size of the final granule is often a defining characteristic. Here we look at the application of an in-line particle measurement probe, a PAT solution for continuous process monitoring that works on the principle of particle velocimetry.

    The PAT Potentia

    Within the pharmaceutical industry there is a heavy reliance on batch manufacture, analysis after each step verifying its success. The FDA PAT initiative invites the industry to fully exploit the potential of available analytical technologies and transition to a more efficient manufacturing model. The continuous monitoring of critical process parameters and real-time product release are long term goals.

    PAT solutions support the implementation of Quality by Design, the practice of reducing risk by building quality into the product and manufacturing process. At the pilot stage, for example, real time analysis instantaneously detects the impact of an experimental change, making it easier to learn about the process. Different operational scenarios can be assessed over a timescale limited solely by the dynamics of the plant, rather than the associated analytical protocols. This accelerates the identification of critical process parameters (those that control product quality) and definition of the design space.

    For manufacture, the automated, continuous real-time analysis of critical parameters brings other benefits, which include:

    • Improved manual control
    • Options for automation
    • A much reduced risk of exposure to toxic substances

    When an operator can always see how the plant is running, manual control becomes smoother and more efficient. Upsets can be detected rapidly and new operating conditions quickly established. Improved control reduces batch-to-batch variability, even if the feed to the process changes, and product quality is enhanced. The automation of control through a simple loop or a more complex multivariate strategy becomes an option. Furthermore, in-line automated analysis largely eliminates the risks associated with loss of containment during process measurement, a major concern when handling pharmaceuticals.

    In summary then, appropriate PAT solutions hold out the promise of faster more successful development and lower risk, more cost efficient production. To deliver on this promise analytical systems need to measure a relevant process variable, in a timeframe appropriate to the process dynamics. Equally importantly they must work reliably under process conditions.

    In-line Particle Size Measurement

    In high shear granulation, particle size is a good indicator of endpoint, making particle size analysis extremely relevant. In-line particle sizing probes such as the Parsum IPP70 (Malvern Instruments, UK) that use spatial particle velocimetry technology fulfill all the requirements of a PAT solution for this application. Measurement rates are sufficiently fast for real-time analysis and such instruments work reliably and accurately in the testing environment of the granulator. Other key benefits include:

    • No moving parts
    • An appropriate measurement range (50 μm – 6 mm)
    • Technology scale up – probes of different lengths are available for measurement at pilot and full scale.

    Figure 1 shows the principle of operation of spatial filter velocimetry. Particles falling through a laser beam cast a shadow, interrupting the flow of light to a linear detector array. The sequential interruption of vertically neighbouring elements of the spatial filter detector triggers a burst signal, the frequency of which is directly proportional to particle velocity. A secondary signal called the pulse signal is also generated. This is a measure of the length of time for which the particle blocks a single detector and in combination with the burst signal gives a measure of particle size.

    Figure 1: The measurement principle of spatial filter velocimetry

    Particle velocimetry is a number-based, chord length, sizing method, data for each measured particle contributing to the development of a size distribution. Dispersion systems may be used to ensure consistent presentation, and/or dilute the process stream, where necessary, for analysis of the dense wet mass typical of high shear granulation, for example. Measuring a large number of particles generates statistically valid results from which various size parameters and volume-based distributions are derived, depending on the needs of the user.

    Monitoring High Shear Granulation

    A plot of changing particle size during high shear granulation is shown in Figure 2. These data were measured in a DIOSNA Pilot Processor System P/VAC 10 – 60 (DIOSNA Dierks and Söhne GmbH, Germany) operating at high moisture content using a standard Parsum IPP 70, 28 cm in length. Air flow across the surface of the optical window prevents material build up to maintain data accuracy. A compressed air driven in-line dispersion unit dilutes the dense granulate mass prior to analysis to ensure the measurement of discrete particles.

    Figure 2: Real-time monitoring of a pilot scale high shear granulator

    While these conditions are clearly arduous (see Figure 3) the probe successfully measures particle size (DV10, Dv50 and Dv90) throughout the process and each stage/transition is visible. Initial mixing of the dry ingredients is followed by the addition of water, which promotes the formation of consistently sized granules with a Dv50 several times larger than that of the feed material. Clearly, if a target granule size is specified this monitoring technique will precisely detect an appropriate process endpoint.

    Figure 3: Image of an in-line particle size probe installed in a pilot scale high shear granulator.

    Figures 4 (a) and (b) show comparable data measured on a larger scale with a longer probe. Together these plots capture in detail evolution of the final granulate size, over a relatively short timeframe. The peaks at lower particle sizes reduce as the fine particles cohere, however, larger particles also break down immediately prior to the endpoint. These are loosely bound aggregates rather than true granules, and are undesirable in the final product. As with the previous example the technology amply demonstrates its suitability for the application.

    Figure 4 (a): Particle size data measured during high shear granulation in a manufacturing scale unit.

    Figure 4 (b): Particle size data measured during high shear granulation in a manufacturing scale unit.

    In Conclusion

    The greater use of PAT is helping the pharmaceutical industry to accelerate development and improve manufacturing efficiency. In many pharmaceutical processes particle size is a critical process parameter, making real-time particle size measurement advantageous. High shear granulation is one such process. Here successful endpoint detection is crucial since over-granulation can negatively impact the properties of the granule. Particle size is a good indicator of endpoint and in-line particle sizing probes a relevant PAT solution.

    Studies show that in-line probes that use spatial velocimetry technology can accurately measure particle size within a granulator in real-time. Although the granulating mass is wet, dense and sticky, measurement is reliable and precise. The data generated accelerate and improve process development and optimisation, and at the manufacturing stage underpin smoother, more efficient operation and timely endpoint detection.

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    4 Responses to “In-line Particle Sizing: A PAT Solution for High Shear Granulation”

    1. J K Nayanar says:

      Dear Sir,
      It is indeed iteresting to read the article.
      Can I have your mail ID to interact

      Regards,
      JKNayanar

      • Hello JKNayanar,
        Please apologize my late reply to your comment. I’m Stefan Dietrich from Parsum. Parsum is the developer and producer of the Parsum-Inline Particle probes that have been described in the article above. I’m located in Germany. For international distribution we work together with Malvern Instruments.
        Could you please let me know where you are located? – so I will try to find out the right partner or specialist from Malvern/Parsum.
        My e-mail is die@parsum.de

        Best regards,
        Stefan

    2. Sudam Kate says:

      Dear Jarvis and Stfean,

      Very good and interesting article. Thanks a lot for this.
      Just wants to know which one is the most accurate and precise technique amongst the all available, as we have so many techniques available to detect end point but no one says which one is the most accurate, robust technique. Because every technique has its own advantages, limitations and so many other equipment, material related factors sometimes makes the technique of limited use.
      So can you please suggest about the most accurate technique and which is widely accepted by pharma companies and regulatory agencies.

      Thanks and Regards
      Sudam

      • Hello Sudam,
        I’ Stefan Dietrich from Parsum. We are the developer and producer of the Parsum-Inline Particle probes that have been described in the article above. I’m located in Germany. For international distribution we work together with Malvern Instruments.
        Could you please let me know where you are located? – so I will try to find out the right partner or specialist from Malvern/Parsum.
        My e-mail is die@parsum.de

        best regards,
        Stefan

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