A new agitator design has helped optimise the fermentation process at Novozymes Delta, a subsidiary of Novozymes AS. Chemineer engineers explain how it was achieved
By working with Derby-based mixer and agitator specialist Chemineer, Novozymes Delta (formerly Delta Biotechnology) has developed a simple but high-intensity fed-batch fermentation method, using modern impeller technology and a custom-built system to meet the needs of the process.
Novozymes Delta manufactures and distributes Recombumin, a protein drug excipient and the first and only animal-free, recombinant human albumin approved for use in the manufacture of human therapeutics.
Fermentation for its commercial recombinant protein production plant demands high yet energy efficient levels of agitation to provide good oxygen transfer and as close to a homogeneous system as possible.
To consider all aspects of the design prior to manufacture and installation, Chemineer provided 3D/CFD modelling showing how the fermentation process could be optimised. This resulted in successfully mounting a CD6 impeller for gas dispersion, two HE3 impellers for even mixing, and an upper-foam breaker impeller.
Equipment supplied by Chemineer had been a conversion to an existing bottom-entry agitator system that required a steady bearing in the vessel, and had some issues with hygienic design in the areas of seal and impeller fastening. After several years of successful operation, the decision was made to see if the agitation system could be updated.
The objectives of the project were to:
- Retain the existing vessel;
- Improve the hygienic design of the mechanical seal and eliminate potential for puddle formation in the base;
- Remove crevices in the impeller connections;
- Remove the steady bearing; and
- Maintain approved process design.
Through consultation with Novozymes Delta's engineers, the needs of the plant were identified. It was decided that the only practical system would be to retain a bottom-entry agitator. The vessel strength was analysed by finite element analysis.
An innovative design for the fitting of the mechanical seal made it possible to remove the requirement for the steady bearing. It also made it safer and easier to maintain the seal.
The shaft system was designed to be a 100% welded in-situ system, with final polishing after assembly. This minimises crevices that cannot be cleaned by Clean-In-Place (CIP) or sterilised by Steam-in-Place (SIP).
A John Crane 5280 seal was designed to provide improved hygienic features, and used nitrogen gas to act as a barrier. The nitrogen usage is low and is supplied from cylinders and thus is independent of the plant electrical system, maintaining seal integrity during a power failure. This design removed the pressurised condensate system of the original seal and significantly reduced the risk of contamination.
Chemineer created a unit with a vastly improved seal removal for much quicker reinstallation during maintenance. The hygiene of the system was significantly improved.
Roger Freestone, engineering director at Novozymes Delta, said: "From its 3D/CFD modelling, through to the innovative design and installation of the agitator system for the bioreactor, Chemineer has been instrumental in helping us achieve a robust, efficient and highly effective fermentation process, which is essential for the manufacture of recombinant proteins for pharmaceutical use."
He added: "Our process also now benefits from improved hygiene, lower power consumption under non-aerated conditions, and a greatly reduced loss of power output under aeration".
To meet the many challenges of specifying and installing the best mixers for aseptic processes, Aubrey Herbert at Chemineer believes that successful applications require performance on many levels - from the design process, right through to construction, validation and process operation.
Herbert believes validation should be accelerated as standard - not just "an option" that has to be requested throughout a project life cycle.
"Validation should include all product options, assembly and dimensional drawings/data, equipment-tag numbers, surface finish data, material certifications, QA procedures, inspection and test reports, operation and maintenance manuals, as well as electrical data and parts lists.
"This validation procedure, specifically designed for aseptic products, exists to ensure timely execution of projects - and should be provided by a competent and capable mixer manufacturer," he added. "Correct management and accountability for quotations, engineering, approval processes, material handling, manufacturing, inspection and packaging will all help bring about optimum results."