Linking laboratory with production
One key factor influencing the choice of technologies for particle size analysis is the desire to correlate lab results with
production information gathered at various stages of the product cycle. However, each stage of product development and manufacture
has a different focus, meaning that the analytical tools employed will vary.
Quality by Design (QbD) encourages the development team to identify and quantify correlations between key product variables
and clinical performance, and to understand how these are controlled by the manufacturing process from the outset. At this
stage, there is an urgent need for detailed knowledge and for instruments that provide a cost-effective route to its acquisition.
As a project moves through pilot plant development and into manufacture, the focus switches to tracking process dynamics and
continuous monitoring, which means the measurement speed of the particle characterisation technology employed becomes critical.
In particular, there is a need for systems that enable real-time process scoping, optimisation, monitoring and control. During
production, effective analysis allows manufacturers to ensure that product quality targets are met consistently, thereby reducing
reliance on pre-release quality control testing.
When it comes to quality control, the demands on particle characterisation systems change again. Here, one may not need to
know the actual size of the particles. It may be enough to have a parameter that can be measured reproducibly and that correlates
with a known performance characteristic of the drug. For example, if the particles are non-spherical, a Laser Light Scattering
method may give a wildly inaccurate value for the true diameter of the crystals, yet give results that are consistent and,
therefore, allow the setting of a specification.
Because the tools employed will vary at each stage, maintaining a consistent specification during transitions from one technique
to another can be complicated. As such, technologies that can be configured for both laboratory and process use, or those
that neatly dovetail, are advantageous. Laser diffraction and automated image analysis are two such techniques.
Laser diffraction is a rapid measurement technique and an established on-line technology that enables real-time, on- or in-line
particle size analysis for both wet and dry systems. Off-line laser diffraction can also be highly automated and robust after
successful method development.
Laser diffraction can be used to develop particle size specifications in the early stages of a project, and then transferred
into production via on-line technology. Many powders have particle size specifications and laser diffraction is often used
as the sizing technique of choice for quality control in this regard. For some applications, however, size data alone will
be insufficient to either fully characterise or define a material.
As imaging technology has become more freely available, the influence of particle shape on performance has become increasingly
well appreciated. Automated imaging overlays size data with statistically relevant information about shape, and can be useful
for detailed development work in troubleshooting and root cause analysis. If two samples behave differently but are classified
as identical by particle size analysis, morphology of the particles may hold the key.
Imaging is much faster than manual microscopy — data for tens of thousands of particles can be obtained in minutes — and,
importantly, it produces more statistically relevant data. Parameters such as circularity, convexity and elongation can be
measured and used to precisely define the shape distributions of a particle population. Each image can be scrutinised by eye
if necessary, whereas size versus shape plots enable the identification of discreet particle populations like APIs and excipients
with overlapping size distribution. The integration of spectroscopy into imaging systems adds a further powerful dimension
to automated image analysis; Raman spectroscopy, for example, can characterise particles by size, shape and chemical composition.
Combining the benefits
Switching between image analysis and laser diffraction needs care — image analysis software is constrained to two dimensions
— but it is entirely feasible and offers many advantages; for example, during method development for laser diffraction, imaging
can identify the presence of any agglomerates. Imaging also adds a layer of detail that cannot be obtained through laser diffraction
particle size analysis alone.
There are also times when manual microscopy proves a valuable addition to the particle characterisation armoury. In particular,
microscopy plays a valuable role in identifying unknown and unwanted particles, i.e., foreign bodies, when linking X-ray diffraction
to the scanning electron microscope to obtain data on chemical composition. In addition, it can be useful for assessing the
mixing quality of two ingredients within a tablet. Similarly, infrared imaging microscopy can be used to analyse the distribution
of organic molecules or particles in complex mixtures, such as tablet formulations and sediments. In both cases, these techniques
can demonstrate whether there is good content uniformity and, by implication, whether there is good distribution of API across
a production run.