Manufacturers bristle at the suggestion that their processes harbor upstream/ downstream mismatches. By the time a company registers a process such mismatches are in fact rare, says Erica Shane, Ph.D., director of manufacturing sciences at MedImmune (www.medimmune.com). Glitches do occur, for example in the scaleup of chromatography media or in the event of unexpected surges in upstream productivity. But these events are the exception, not the rule, for well-designed processes. The materials science and physics of chromatography media has evolved to the point where even off-the-shelf resins deliver predictable, if not linear, scalability.
MedImmune says it is eager to tweak processes at any stage, even during clinical trials and post-commercialization. So if an upstream/downstream mismatch were to arise due to some unforeseen event, Dr. Shane and colleagues are ready. “As long as we can show product comparability, we feel it is never too late to improve upstream and downstream processing.”
The use of specialized software for process modeling is growing among bioprocessors. MedImmune, like many biotechs, still uses spreadsheets to model and optimize processes, but the company is looking into dedicated applications for this purpose. (Software vendors often comment that their main competition comes not from dedicated software packages but from generic spreadsheet applications.)
Bayer Technology Services (www.bayertechnology.com) uses several software packages to simulate and model critical processes to avoid mismatches. Sebastian Schmidt, Ph.D., manager for bioprocess technology, mentioned aspenONE® from Aspen Technology (www.aspentech.com), which includes modules for process development and production management. Aspen claims that firms adopting the aspenONE process development module can save $1M within one year of deployment.
Another of Bayer’s preferred simulation packages is Intelligen’s SuperPro Designer®. Among SuperPro’s 140 unique modules are modeling packages for reactors, energy balances, sizing, costing, scheduling, resource/utility management, and economics. SuperPro’s main limitations are its restriction to single-product facilities and narrow scheduling options. Both shortcomings are addressed through Intelligen’s SchedulePro product, which may be used as a standalone modeling package for multiproduct facilities with variable production scheduling.
SuperPro and aspenONE help Bayer to simulate equipment failures and their impact, and especially to calculate costs associated with various scenarios.
One general strategy for harmonizing upstream and downstream operations is to design the process appropriately, to scale, as chemical and polymer processors have done for decades. However, the upstream yields from chemical processes are much more predictable than from cell culture or fermentation. Nevertheless, by drawing on its chemical processing experience, Bayer has achieved process streamlining and eliminated upstream/downstream mismatches.
Dr. Schmit recommends that viewing and designing processes as a whole, rather than as two consecutive but distinct sets of unit operations, provides insights not only into downstream efficiencies, but upstream strategies that may enhance purification as well as “sidestream” operations like waste treatment, utilities, and logistics.
Because of the specialized nature of biopharmaceutical development timelines, harmonizing upstream and downstream operations for many companies means exploiting a narrow time window during development—after proof of principal but before clinical trials.
“The gap where you have enough knowledge to optimize a product, but are not so deeply into clinical and regulatory activities is quite small,” notes Dr. Schmidt, who believes the upstream/downstream mismatch is over-rated as a business or manufacturing issue. The interface between any two steps, he explains, is a possible bottleneck. Upstream and downstream disconnects may be somewhat more pronounced when the respective processes are designed separately, by different teams. But even manufacturers who find themselves “stuck” with a mismatched process can implement work-arounds, for example addition of a hold step.
The real issues, says Dr. Schmidt, are not fermenter size or chromatography column diameters. “Process optimization is about space, people working in it, utilities, waste treatment, and a host of things going on around the actual production. Vessels and columns are easy to dimension. Scaling utilities and facilities are where the real bottlenecks occur.”
The opening of Wyeth Biopharma’s (www.wyeth.com) Grange Castle, Ireland, and Andover, MA facilities in 2005 represented a $2.5 billion infrastructure investment, and a turning point for Wyeth.