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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Like QbD, AQbD works on the principle of recognizing and handling variability by understanding its potential impact. By identifying an analytical design space, rather than applying a fixed set of measurement conditions, it enables a responsive approach to the inherent variability encountered in day-to-day analysis throughout the lifecycle of a pharmaceutical product. This delivers an analytical method that is robust in daily use and which also substantially reduces the potential for failure when the method is transferred from, for example, a research laboratory through to QC. The root causes of method transfer failure can usually be traced back to insufficient consideration having been given to the nature of the routine operating environment and a failure to capture and transfer the information needed to ensure robust measurement. Applying AQbD overcomes these issues and has the potential to eliminate costly mistakes.

Addressing a specific analytical challenge helps to clarify what the application of AQbD looks like in practice. Consider the scenario of measuring the particle size distribution of a micronized active pharmaceutical ingredient with the goal of assessing its suitability for downstream processing and bioavailability for a solid oral dose product.

In this situation the ATP is the measurement of particle size distribution at a defined point in the process, in a way that is precise enough to ensure the material will perform to expectations. In practice, the required level of precision may exceed that which is laid down in the US and European Pharmacopoeias [2, 3], but for simplicity we will assume that the USP and Ph. Eur. acceptance criteria are adequate. Many techniques are available for particle size distribution measurement, but laser diffraction is the method of choice for most pharmaceutical applications. So we will base this AQbD example on laser diffraction particle size measurement.

Fast, non-destructive and amenable to automation, particle sizing by laser diffraction is a technique that has been tailored in modern instrumentation for high productivity, routine use. In a laser diffraction particle size analyzer, the particles in a sample are illuminated by a collimated laser beam. The light is scattered by the particles present over a range of angles, with large particles predominantly scattering light with high intensity at narrow angles, and smaller particles producing lower intensity signals over a much wider range of angles. Laser diffraction systems measure the intensity of light scattered by the particles as a function of angle and wavelength. Application of an appropriate light scattering model, such as Mie theory, enables particle size distribution to be calculated directly from the measured scattered light pattern.

Laser diffraction involves relatively little sample preparation, but it is essential to present the sample in a suitably dispersed state to generate data that are relevant. In our example, the need is to measure the primary particle size distribution of the active pharmaceutical ingredient. This means that any agglomerated material present must be dispersed, prior to measurement, to ensure consistent and relevant results. Here then the parameters applied to ensure complete dispersion are CQAs, variables that have a direct impact on the quality of the results. Investigating dispersion in a systematic way is therefore a primary objective when it comes to defining the MODR for a laser diffraction method.

When it comes to dispersing a sample for laser diffraction particle size measurement, there is a choice to be made between dry powder or liquid dispersion. Dry dispersion is the preferred option because it:

• Enables rapid measurement to be made,
• Is well-suited to moisture-sensitive materials,
• Accommodates relatively large sample volumes, enabling reproducible measurement of poly disperse materials, and
• Is environmentally benign, as the use of organic liquid dispersants is avoided.

Although dry dispersion offers these advantages, it is not suitable for all sample types. Dry dispersion involves entraining the sample within a high-velocity air stream. The process of entrainment subjects the particles to substantial shear energy and promotes particle-particle/particle-wall collisions, dispersing any agglomerates.

Friable materials may be damaged by this process. It may also be hazardous to handle highly active ingredients in this way because of the risks associated with aerosolization. Some samples are therefore better suited to liquid-based measurement.