Many companies are faced with scale-up issues when they design and build new facilities. Peter van der Meijden, Ph.D., section manager process development microbiology at Diosynth Biotechnology, (www.diosynthbiotechnology.com), described the design, construction, and start-up of Diosynth's new large-scale upstream production facility, which is dedicated to microbial and cell culture contract manufacturing.
Diosynth, part of Akzo Nobel, has carried out process development including scale up on over 55 recombinant proteins and clinical cGMP manufacturing on over 35. The new plant, comprising 18,000 liters of mammalian cell culture capacity and 10,000 liters of bacterial fermentation capacity, is located at Oss, The Netherlands, and has been designed as a multipurpose, multiproduct facility. Currently, Puregon, a hormone used in fertility treatment, and recombinant human insulin are manufactured on this site.
When it comes to scale up to large volumes, the ability of a cell line to cope with shear forces arising from mixing can be an issue. Diosynth deals with this using scaled-down 60-L bioreactors.
Computational fluid dynamic modeling is then applied to determine where critical spots for high shear force and low mixing will occur. Mixing characteristics can be predicted in combination with a consideration of aeration strategy. "In this way, we test the cell line for its ability to survive under these conditions," said Dr. van Meijden.
Automation is another important aspect of scale up; it should be used as much as possible in areas such as SIP, CIP, medium preparation, and status checking. However, too much automation results in time-consuming and useless false alarms. It is vital to use only the most foolproof of transmitters and probes to avoid this.
How to run large-scale facilities is also an issue. Currently, the new Diosynth facility is passing through qualification procedures, which has consumed 5,000 man days for the microbial equipment, 3,000 man days for the cell culture equipment, and another 2,000 for qualification of utilities.
Finally, all aspects of scale up are addressed when a company actually turns out commercial quantities of a product. Peter Moestra, Ph.D., divisional vp of biologics manufacturing global pharmaceutical operations at Abbott Laboratories (www.abbott.com), presented some of the financial and technical issues involved in the scale up of Humira.
"Nobody in this industry plans for successbut when the first patient was injected with Humira, the pain went away and there was tremendous pressure on us to produce more," he said. Humira is an anti-TNF antibody licensed for use in rheumatoid arthritis and psoriatic arthritis. It is also under development for ankylosing spondylitis, psoriasis, and Crohn's disease, according to the company.
In 2004, sales of the product reached $1.4 billion. The history of Humira goes back to the initial development of a parental cell bank in 1994 and initial production in a 1,000-liter converted chemical process tank. Since this time, the production of the antibody has gone through a rapid sequence of scale ups and process improvements, culminating in a large-scale (12,000-liter) state-of-the art facility in Worcester, MA, where Humira is made by a robust, high-yield fed batch process.
Dr. Moestra explained that going from 3,000 to 6,000 liters involved some minor changes to the growth medium, but going from 6,000 to 12,000 did not involve much change. For scale up of fermentation the company used computer simulation of mixing to detect any potential problems with shear although, it turns out, Humira cells are shear-insensitive. Cell culture curves showed consistency between 3,000, 6,000, and 12,000 production scales.
"We were able to sail smoothly through the comparison studies," said Dr. Moestra. On lessons learned, he commented, "Success creates demands and you may not find the funding you need in time. For Humira, aggressive investment decisions and process improvements were needed to satisfy demand. Advance planning and experiments can enable process improvement and scale-up to go smoothly."