Despite new heights of process characterization and knowledge, scaleup still can befuddle the most experienced of bioprocessors.
Wei Chen, Ph.D., chief scientist at Phage Pharmaceuticals, believes that a disconnect between early-stage R&D and manufacturing—a defect that has persisted since biotech’s earliest days—is one culprit.
“Companies have come a long way in streamlining clone selection and expansion, but this activity more closely resembles basic research than manufacturing,” he says. “Cells at this stage have almost no chance of surviving in a large culture in the manufacturing environment.”
The analogous activity in small molecule development, the handoff of an investigatory synthesis route to process development, suffers from far fewer sharp breaks.
Dr. Chen blames both development “silos” and the complexity of biological systems for the discontinuity.
“Particularly as companies grow, the various activities like early clone selection, cell-line engineering, expansion, scaleup, and production become compartmentalized. At larger scale many more variables are operational,” he explains.
While small molecule development teams may re-work a synthetic pathway for lower cost or scalability, scaleup becomes a straightforward chemical engineering problem once the manufacturing process is set. In biotech a cell’s response to media and feed, dissolved gases, waste products, and the myriad stresses of the bioreactor environment are far more complicated than heat and mass transfer in chemical reactors, particularly at significantly different scales.
Dr. Chen suggests an approach involving reverse-engineering the larger process by getting more large-scale parameters into the picture very early in development. “But in most large biopharmaceutical companies this is next to impossible, as cell biologists lack manufacturing expertise and process development and manufacturing specialists know little about cell biology,” he points out.
The other issue Dr. Chen mentions as hampering scaleup is the lack of industrialization and standardization of bioprocesses for therapeutics. While we hear of “platform” processes for certain expression systems and products (e.g., CHO cells and monoclonal antibodies), experts still view many cell culture processes as unique protocols. Hence the intellectually suspect adage, “The process is the product.”
This philosophy seems to repeat in history. Commercial wine-making began with a similar philosophy based on hand-made, empirically individualized recipes. “But today all top wine-makers have standardized their processes, so that the quality of the product can be maintained,” says Dr. Chen. Bioprocess scaleup’s success depends on the integration of biology into engineering.
Introducing new processes into a busy, established facility poses significant logistical and technical challenges, according to Gregory R. Naugle, director of process development at Amgen’s West Greenwich, RI, production facility, the largest in the Amgen manufacturing network. Key issues involve ensuring the new product’s success while not rocking the boat with respect to existing processes.
Tech transfer of multiple products at differing stages of development and scaleup add to the complexity, maintains Naugle. “A high run rate facility runs continuously, and provides very little ‘white space,’ with very little free equipment. There are limited windows of opportunity to modify equipment to accommodate the new product or process.”
The top priority should be maintaining the fidelity of the currently licensed process. “When you modify shared equipment, you want to ensure you’re not altering the process that’s already there,” Naugle adds. “In essence, you want to change something without changing it. If the modification involves hardware, for example piping or the diameter of a transfer panel, you must assure there are no unintended consequences to the existing product.”
Synchronicity is what complicates tech transfers into busy plants. Under circumstances where projects enter sequentially, one is able to conduct a full “lessons learned” and still have time to prepare for the next project.
“When they’re happening simultaneously or nearly so, you don’t have the decompression time to do a lessons learned, implement those learnings, and move forward,” says Naugle. “You need to transmit that knowledge very rapidly.”
Again, the confounding variables concern the fact that cells are living organisms that are significantly affected by environmental factors.
Moreover, with high-run facilities, the operational distinctions between scaleup and tech transfer become more semantic than substantive. Both involve freeing resources for the new process and assuring the integrity of existing processes. “It’s just the nomenclature we choose to use,” Naugle, says. “If we scale up from a pilot facility in a different building we don’t consider that a tech transfer because of the co-location. But if the process were coming in from Amgen headquarters at Thousand Oaks, it would be considered a tech transfer. So yes, scaleup presents many of the same challenges as a full tech transfer, particularly when you’re talking about maintaining the fidelity of the existing process.”