Topping several lists of the world’s most sustainable enterprises, Novo Nordisk is a Danish pharmaceutical company and one of the largest manufacturers for diabetes medication in the world. For designing the production process, special care is needed as insulin is a peptide that is sensitive to chemical and physical treatment. Today, insulin is produced by means of biotechnology. At their plant in Kalundborg, on Denmark’s largest island, Novo Nordisk uses the cells of yeast strain saccharomyces cerevisiae to produce its diabetes care products.
The production is complex and consists of multiple steps: The yeast cells are cultivated in large-scale fermentation tanks, where they are given the optimal conditions to grow, reproduce and express the desired peptide. Each of the large number of cells functions like a microscopic factory producing the pharmaceutical peptide. The downstream process consists of several different purification steps. Some of the purification steps require solid/liquid separation. Sometimes the liquid component is the value stream, sometimes the solid fraction contains the intermediate product. The production needs to comply with regulatory good manufacturing practice requirements and needs to take place in a controlled, contained production system. The new separation technology to be invested in is required to be a versatile type of solid/liquid separation technology so that the various process tasks can be performed.
The Krauss-Maffei dynamic crossflow filter, with overlapping ceramic membranes was the right solution. The hermetic design is ideal for pharmaceutical applications. Optimum separation and quality is ensured thanks to the single-pass filtration concept and minimum thermal and mechanical impact. The lower impact comes from the reduced feed pressure and the fact that the trans-membrane pressure is homogeneous across the entire surface as there are no inlet or outlet zones in the membranes. Since 2012, Novo Nordisk has purchased several lab-scale test units and pilot equipment to evaluate the technology before accepting delivery of GMP dynamic crossflow filters in 2019 with their respective sensors and actuators. They chose the DCF-technology due to its outstanding process performance, for example filtration speed and solids concentration in multiple test samples. But the control system also played a major role. With one of the most innovative automation solutions on the market today, which is based on the Metris addIQ control system, ANDRITZ also provided the entire control system, incorporating all GMP-relevant software functions and enabling a fully automatic process. The measurements of the calibrated instruments are logged and quality reports are generated so compliance to specification of any batch produced can be verified at any given time. Every operator action is logged with user identification, and every modification of the operation recipes is also logged, and a very strict change control system is implemented.
With the DCF, the efficiency of the separation process and yield of the compound are higher than with any other crossflow technology thanks to the high shear rate that prevents a clogging layer from forming (yield is at least 50% higher than with conventional crossflow technology). The technology is highly reliable as the open filtration area avoids any blockages, while the need for manual intervention is eliminated entirely. The filters work in a way that is completely enclosed and fully automatic – right down to the Cleaning-In-Place (CIP) and Sterilization-In-Place (SIP) features. Safety aside, the high solids concentrations produced allow the process to be intensified at several steps, with favorable results for quality and a reduction in energy consumption of up to 80% compared to traditional crossflow filtration. What’s more, the permeate is absolutely clear, outperforming traditional sedimenting technology or precoat filter technology. And the technology exerts 50% less mechanical force and stress on the product compared to other crossflow filters and disk stack separators. All of the equipment, including the machine itself and peripherals, conform to GMP requirements.
MICHAEL HALLGREN
Senior Vice President of Diabetes API manufacturing, Novo Nordisk
