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Pharmaceutical Manufacturing and Packing Sourcer

Seeing in 3D: Crystallisation Validation

Due to the sensitivity of many operations to changes in mixing conditions – whether upon scale-up or when changing vessel design for manufacturing operations – mixing issues are always central to regulatory concerns. All too often, particularly sensitive worries over interactions between mixing and crystallisations are made light of.

Every aspect of a crystallisation operation can potentially be affected, including growth, nucleation and maintenance of a crystal slurry. Crystallisers normally employed in the pharmaceutical industry are multi-purpose vessels with various baffle and impeller configurations designed to help reduce crystal breakage and secondary nucleation, while achieving good circulation and suspension. The shear imparted to the process has a large impact on critical product properties, leading to the development of several impeller styles to achieve good circulation with low shear.

Scales of operation are increasing to 160,000 litres and more in the fermentation industry, but the mechanical and mixing requirements at these capacities are difficult to predict accurately. This can pose a significant problem when working with batches containing extremely valuable amounts of a pharmaceutical product. The perceived sensitivity of animal cells, which lack cell walls to resist hydrodynamic shear stresses, has resulted in low-agitation intensities and less than optimal aeration rates (at large scales, air should be sparged directly into the medium, potentially causing cell rupture). Poor agitation and aeration can lead to inhomogeneities in dissolved O2 and CO2 concentrations and in pH.

Suggested strategies for improving liquid blending include retrofitting the conventional small-diameter, high-powernumber Rushton impeller with a largediameter and a low-power number impeller to disperse gas near the bottom of the fermenter. To improve concentration uniformity, upper impellers may be replaced with up-pumping, axial-flow designs. Most gas-liquid dispersion impeller systems, when gassed, will experience a power drop of 30 per cent, and, in some systems, up to 70 per cent. Manufacturers now have options for impeller systems that will rarely lose more than 15 per cent of power when gassed. Furthermore, most mixers in the biotechnology industry use 10-hp motors, the majority of which are designed with a variable-frequency-drive (VFD) motor. Unless there is a need to adapt the impeller speed for other products, there is no reason to buy a VFD to optimise the newer systems now available.

The deep-tank mixing requirements of fermentation call for long agitator-shaft extensions, as well as slower rotational speeds to avoid mechanical vibration. In the past, to develop the required flow in deep tanks, it was necessary to reduce the impeller speed and increase the impeller diameter. This technique added weight, as well as cost to the impeller, and often pushed impeller-to-tank diameter ratios to over 50 per cent, resulting in efficiency losses.

Innovative new impellers can produce flow characteristics of much larger impellers without the added weight or loss in pumping efficiency. Enhanced designs also produce the same flow characteristics of much larger impellers, but without the added weight, thus facilitating the use of longer shaft extensions. In addition, operating speeds can reach as much as 80 per cent of the first critical speed of the shaft, which allows unrestricted speed turndown.


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Chris Drysdale is a Process Engineer with Pfaudler- Balfour, a provider of glass lined reactors, corrosionresistant equipment and modular process systems to the pharmaceutical, chemical and process industries. An expert at considering the true mixing aspects of a process and specifying or modifying drive and agitator components to suit, Chris has a proven track record with Pfaudler-Balfour. His role also includes analysing the solid, liquid and gas behaviour in the reactor and looking at the energy efficiency of the drive. Email: chris.drysdale@robn.com
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Chris Drysdale
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