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Manufacture Technology and Equipment, Analytical Science, Quality & Compliance

Still Sieving...

“Tried and tested” can be a formula for success, but it’s also important to recognize when an analytical technique has drifted into the realm of being tedious and taxing. There are a number of techniques in pharmaceutical production that could fall into this category, but I want to focus on sieving. Sieving has been used to size particles for centuries, but is it fit for the modern pharma manufacturer?

When considering the demands of quality assurance and quality control (QA/QC), queues at the loading bay are unacceptable and costly, so you need a rapid answer to the question, “Can I accept this?” Sieving gets the job done, but there are newer, automated particle sizing techniques available, such as those based on light-scattering measurements.

You may think me biased, but I can say with confidence that laser diffraction is becoming a popular alternative to sieving. I’ll admit that the initial outlay is more expensive, but these costs are easily dwarfed by ongoing savings, especially from productivity gains; laser diffraction requires much less manual attention and is also faster. By using laser diffraction, the time to result is cut to under a minute, compared with a minimum of 10 to 15 minutes with sieving. Furthermore, with a typical stack consisting of just five to eight sieves, sieving offers far lower resolution than laser diffraction, which reports around 100 size classes. Poor resolution can result in a failure to detect subtle differences between samples, thereby obstructing the quest for effective and reliable QC. In contrast, our clients say that laser diffraction pays its way by consistently returning repeatable and reproducible measurements at a speed that eases QA/QC processes.

Resolution is also an important gain when it comes to accelerating formulation development, but here it is the ability of laser diffraction to precisely quantify fines, as well as coarse particles, that is the major benefit. For all pharmaceutical products, from tablets to inhaled formulations, fine particles are important when it comes to controlling dissolution and bioavailability. Controlling fines is crucial from a product quality perspective, and also important when considering processability because excess fines can compromise flow through a tablet press, for example. If you can’t accurately measure fines, then how can you learn about their impact on critical quality attributes?

Advances in laser diffraction technology have extended its range to below 100 nm in size, while sieving remains optimally suited to far coarser particles; below 100 µm, sieves become susceptible to clogging as the forces of attraction between particles start to rise. Switching to wet measurement may address this issue, but can also increase the practical burden of measurement. A laser diffraction system, on the other hand, covers the entire particle size range of interest using a single optical set-up.

Moving from manual to automated techniques cuts the training burden and makes it easier to transfer a measurement and associated specification. Today’s lab technicians are called upon to apply a growing range of techniques, increasing the risk of operator-to-operator variability creeping in, especially when the analytical process is lengthy. “Deskilling” via automation eliminates this risk and safeguards data integrity. Equally important, a locked-down standard operating procedure (SOP) is readily transferred to a different lab, different geography or to an outsourcing company. A laser diffraction method can accompany a product as it exits the lab and transitions to commercial manufacture, no matter how the manufacturing process is ultimately implemented. Real-time particle sizing, with an in- or on-line system is also an option since it’s a proven process analytical technology for automated process control and real-time release.

The pharma industry today is pressured by a number of trends including increased supply chain complexity, concerns over outsourcing, analytical skill shortages and the need for greater manufacturing efficiency. I believe it’s time to re-examine the rationale for using manual techniques when newer options are available. Don’t you?

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About the Author
Paul Kippax

Paul Kippax is Leader – Advanced Materials Group, at Malvern Instruments, Worcester, UK.

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