Beyond SOPs

A decade ago, the introduction of standard operating procedures was groundbreaking, but new understanding now helps bring the rigor of QbD to analytical method development.

By Paul Davies and Paul Kippax, Malvern Instruments

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Figure 3 shows some of the CQAs associated with a dry method for a micronized API powder. In dry dispersion, the air pressure applied during entrainment of the sample is the lever that is used to control the input of energy into the dispersion process. This identifies it as a CQA. Another consideration is the sample feed rate, as this determines the amount of material which passes through the venturi during the dispersion process and therefore the efficiency of dispersion. It also defines the concentration of a sample, which in turn can have an impact on the measurement process itself. If particle number/density is too low, then the signal to noise ratio during measurement may be unreliable. Conversely, a high particle density increases the risk of multiple scattering, where the light interacts with more than one particle prior to detection, a phenomenon that complicates the calculation of particle size. Feed rate, therefore, tends to be the other CQA when using dry dispersion for laser diffraction particle size measurements.

So, working on the basis that dry dispersion is suitable for our model sample, and that the above assessment is realistic in terms of identifying the CQAs for the method, one of the steps needed to scope the MODR is to determine how air pressure influences the results of the analysis. The experiment that delivers the necessary data is commonly referred to as a pressure titration.

Figure 4 shows results from two pressure titrations. These were carried out using the Mastersizer 3000, which has a number of modular dry dispersion units that allow the intensity of dry dispersion to be matched to the sample. The upper of the two plots was measured using a dry dispersion unit fitted with the system’s standard venturi disperser, while the lower plot was generated using a venturi designed to provide high dispersion energies.


The aim with dry dispersion is to completely break up any agglomerates present, without causing damage to the primary particles. The results show that with each venturi increasing pressure decreases particle size. This raises the question of how to determine whether a given pressure is breaking up agglomeratesas required, or is causing damage to primary particles. A comparison with a reference liquid dispersion measurement helps to answer this question since liquid dispersion very rarely results in particle damage.

Results from liquid measurements are shown in blue in Figure 4. These indicate that the standard venturi disperser delivers complete dispersion at a compressed air pressure of around 3 bar, whereas using the high energy venturi disperser an air pressure of around 1 bar is required.

These data suggest that it would be possible to use either of the venturi tested. However, by plotting particle size as a function of air pressure for each venturi (Figure 5) it can be seen that the standard venturi is the better option. This plot shows that the MODR is larger with the standard venturi than with the high energy disperser.

These results show that with the high energy disperser any variation in air pressure will have a significant effect on particle size, compromising the ability of the method to meet the ATP. Using the standard venturi, on the other hand, the particle size results are reasonably consistent across the pressure range 3 to 4 bar. This venturi will therefore deliver an inherently more robust measurement. The MODR associated with its use can be determined, in terms of suitable air pressure, on the basis of these data.


The data shown in Figure 5 enable the selection of a dispersion pressure which would be expected to deliver robust results. To ensure that a proposed method meets the ATP, it is essential to verify that any variability in the way the method is applied does not shift the precision of the results outside the intended limits. This requires the method to be validated, following the guidance outlined in ICH Q2.

Two concepts are central to confirming that a particle sizing method is fit for purpose: repeatability and reproducibility. Assessing repeatability involves duplicate measurements of the same sample. It therefore tests the precision of the instrument, and the consistency of the sampling and dispersion process. Reproducibility is a broader concept that also encompasses multiple operators or even multiple analytical system installations.

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