At the “Biological Production Forum” held recently in Dusseldorf, there were many lessons for those involved in monoclonal antibody manufacturing. In a wide-ranging presentation, Günter Jagschies, Ph.D., senior director R&D, strategic customer relations, GE Healthcare, spoke about future requirements for monoclonal antibodies.
According to a recent PhRMA (Pharmaceutical Research and Manufacturers of America) report, there were over 190 antibodies in clinical development in 2008. Given that the success rate in Phase I is low, it is unlikely that more than 50 new antibodies will actually come onto the market. But how many of these will require large-scale manufacture?
Dr. Jagschies has reviewed the best-selling antibodies and determined that the annual amounts needed range from 1,197 kg (Remicade) to 25 kg (Vectibix). He believes few future monoclonals will need large-scale manufacture, and that the chance of winning market share from the big five (Avastin, Herceptin, Rituxan, Humira, and Remicade) is small. “But there are some monoclonal antibodies in development for other indications, such as osteoporosis and Alzheimer’s disease,” he added. “If these come through, then they may be candidates for large-scale production.”
Titers of monoclonal antibodies have gone up dramatically in recent years and now average 3–5 g/L, while 10 g/L and even greater are possible. This has implications for the economics of large manufacturing facilities. These higher titers spell overcapacity. “We will see people closing down, mothballing, or selling off their facilities. No one is going to build these dinosaurs of capacity,” said Dr. Jagschies.
In the meantime, there are ways of making facilities work despite overcapacity. Smaller reactors, a smaller plant, high-capacity resins, flow-through systems, and two-step purification can all make a contribution. He also suggested reducing hardware, like tanks, by making buffer from concentrate and doing direct transfer between steps to avoid using storage tanks.
Dr. Jagschies’ analysis shows that higher titers do not necessarily lead to decreased cost of goods (COGs), despite popular belief. Beyond 3–5 g/L, the frequently described strong decline of COGs with increasing titer is relevant only if you actually need to manufacture the amount of drug this enables you to make. “The business message is different from the science message,” he said. Nor, he believes, are there any real economic or technical drivers for alternative production systems for monoclonal antibodies.
In the future, process development teams will focus more on understanding the process rather than on economic optimization through increasing the titer. There will, therefore, be more emphasis on quality by design and, it is hoped, less on QA/QC as a consequence, particularly important if one produces a given quantity with smaller batches, which leads to the release of more batches.
GE Healthcare is concentrating on flexible, smart manufacturing with features that include light, mobile units; segregation rather than dedication; and adding and taking away capacity (rather than rebuilding). Straight-through processing, with in-line adjustment, is seen as important. The firm is also looking at periodic counter current continuous processing, which is a way of getting 50% better utilization of resin in purification, according to some experts. High-throughput process development will also play an increasing role in the biopharma industry, concluded Dr. Jagschies.
There is still a great deal of interest in upstream improvement, however. Robert Young, Ph.D., principal scientist, cell culture process development, Lonza Biologics, described some innovative approaches to improving cell-line productivity. These experiments involved the glutamine synthetase expression vector, which is widely used for monoclonal antibody production.
Use of a stronger promoter, alternate arrangement of transcription units (i.e., heavy chain upstream of the light chain instead of the standard arrangement of light chain upstream of the heavy chain), or insertion of a transcription blocking element between the units did not improve cell-line productivity, pointed out Dr. Young.
The researchers then tried GeneArt’s gene sequence optimization service, which involves altering codons without changing the protein sequence to produce the codons that are optimal for host cell expression. This approach did lead to higher productivities.
“Steps downstream of transcription could be the rate-limiting step in productivity,” surmized Dr. Young. Therefore, looking at transcription itself, as well as translation, assembly, secretion, or a combination of these steps are all important aspects of increasing the concentration of monoclonal antibody in the production medium.