PharmTech: How are quality-by-design (QbD) approaches changing the way that tableting and granulation processes are viewed?

Freeman (Freeman Technology): QbD calls for product quality to be 'designed in' rather than tested for in postproduction. It requires a detailed understanding of all the factors that can impact product quality and clinical efficacy, including those related to the materials employed and the process itself. Traditionally, it has been assumed that raw materials and intermediates can be suitably qualified and the process can be fixed, resulting in a consistent high-quality product. However, this is only achieved by knowing what material properties need to be qualified. While particlesize distribution is important, there are many other particle properties that rarely feature in the specification, but that can be as influential as particle size, such as particle shape and particlesurface roughness. Excluding these properties from the quality specification allows variation in raw materials to go undetected, resulting in variable in-process performance and product quality. Adopting a QbD approach requires an acceptance that raw materials are likely to vary batch to batch, while simultaneously demonstrating a good grasp of how to configure the process settings within the 'control space' to accommodate the unavoidable variation in material properties, and ultimately achieve consistent product with the desired attributes.

Considering a granulation process as an example, this might conventionally be defined in the following terms: process for X minutes at an impeller speed of Y rpm, whilst adding Z% of water at a consistent addition rate. Processing conditions are essentially fixed and applied to each new batch of feed. This means that there is little flexibility to respond to variability arising from any source, such as a new batch of excipient or inadequate control of an upstream operation, for example. Furthermore, problems are usually detected only when granulation is complete.

In the same way, in tableting, a QbD approach would focus on the defining characteristics of the finished product, such as content uniformity and dissolution or disintegration properties. Process development then works back from that point, identifying all the factors that influence these properties.

Levoguer (Malvern Instruments): Successful implementation of QbD relies on understanding both the process and product in detail. The focus is on fully evaluating the impact of all variables that influence product quality, and learning how to control them effectively, rather than just identifying a manufacturing route that works. QbD extends through to control of the commercial process so it serves to highlight areas where real-time monitoring can be beneficially applied to meet processing targets.

One important feature of particlesize analysis is that, unlike many analytical techniques, it is already a proven technology for real-time plant monitoring. In granulation processes, for example, both in-line probes based on spatial particle velocimetry and on-line laser diffraction particle size analysers are regularly used for real-time measurement. Both enable the continuous tracking of particle size growth during the granulation process towards an established endpoint.

Endpoint detection is a notoriously difficult aspect of granulation so this ability to continuously monitor particle size is extremely useful when manufacturing to meet a defined output, as advocated by QbD. In addition, however, real-time measurement is extremely valuable during design space scoping studies because it enables rapid and reliable assessment of the impact of a change in operating conditions. Continuous particle-size measurement can therefore accelerate and improve the process development studies associated with QbD.

PharmTech: What key challenges continue to exist with regards to understanding particle attributes in a tableting and granulation process?

Freeman (Freeman Technology): The bulk properties that define processability depend on a wide array of particle attributes, such as particle size and shape, roughness, surface charge, density and porosity. Learning how to control tableting and granulation processes relies, in part, on understanding the relationships between particle attributes and bulk powder properties.

This is an area of specific interest to Freeman Technology and we have been involved in a number of experimental studies, with industrial partners, to investigate, for example, the influence of particle size and shape, and of surface charge, on powder flowability, shear properties and bulk parameters, such as compressibility and permeability (1, 2).

Levoguer (Malvern Instruments): Because QbD places emphasis on thoroughly understanding the impact of all processing variables, it may call for information that is not easily accessed using conventional testing methods. As a result, the implementation of QbD is encouraging the pharmaceutical industry to adopt new analytical technologies as they become available. One such technology is morphologically directed imaging, which can combine imaging technology with spectroscopy, such as Raman, to provide chemical identification alongside size and shape measurement. It allows different particles in a dispersed sample, often initially screened on the basis of size or shape, to be reliably identified as specific chemical entities.

A conventional way to assay a tablet is to dissolve it and carry out high-performance liquid chromatography analysis. This gives an averaged measure of the concentration of the active that can be used to assess dose consistency, but it provides no information about the size of discrete active particles that are delivered to the body as the tablet disintegrates. In contrast, applying morphologically directed imaging to a disintegrated tablet sample allows differently sized elements of the resulting powder to be precisely identified as active or excipient. This not only generates useful information for engineering sophisticated drug delivery profiles, but also provides evidence to support claims of bioequivalence for a generic product.