Disposable bioprocessing, platform expression and purification technologies, and a higher level of bioprocess understanding have made scale-up more robust and predictable, but not quite automatic.
Communication between lab and pilot-scale personnel is critical for successful scale-up, says Klaus Graumann, Ph.D., head of technical development at Sandoz. The company’s Kundl, Austria, production site uses microbial expression systems to produce cytokines, antibody fragments, and peptides. It also performs development for other products and biosimilars.
Lab and pilot groups should work closely, interact, and communicate early in the process to minimize scale-up problems. Co-location of the two competencies can reap huge rewards for understanding and meeting the differences between development and production. “The key to success is to eliminate as many failures and disconnects as possible,” he says.
Dr. Graumann stresses the value of experience and the adoption of platform technologies whenever possible. Processors may still encounter hurdles when utilizing optimized cell lines, media, and unit operations, “but at least they know where to start” to look for problems if issues arise, he notes.
Products introduced into a plant for the first time are particularly prone to scale-up issues, since few production plants are running product for which they were designed. Questions of process–plant fit are common. “Matching process to plant is not much of an issue in early development, but it’s important for laying the foundation for cost-effective process development,” says Dr. Graumann. “Processors prefer not to have to go through too many changes since they introduce comparability questions and regulatory scrutiny.”
The Role of Outsorcing
Contract manufacturing has become a major factor in scale-up work, as it is for manufacturing in general. Virtual companies or firms with minimal production capacity rely on contract manufacturing organizations (CMOs) to perform the heavy lifting of scaling from spinner flasks to the several hundred-liter scale. At this stage in a product’s lifecycle, time is of the essence since preclinical studies cannot begin without sufficient material.
CMOs like Avid Bioservices will often screen for factors that increase production at small scale, then quickly transfer those conditions to small bioreactors. “It comes down to modeling the large process on a small system, showing comparability across scales, and reaching an understanding of variability as the scale increases,” says Thomas Tomzynski, supervisor of upstream process development.
That level of understanding is impossible to achieve in a timely manner without process analytics, real-time measurement of nutrient utilization, and waste product generation, says Tomzynski. “We try to characterize the process as much as possible moving through scale-up, to achieve acceptable product titers and quality.”
Clients normally transfer processes to Avid early, sometimes as soon as cell lines are optimized. After selecting a clone, Avid determines baseline and selects conditions that optimize area under the growth curve, one of the best indicators of productivity. Since speed is highly valued, Avid relies mostly on off-the-shelf media and feeds to optimize the process in the shortest time.
“Off-the-shelf media don’t require a lot of custom tweaking,” observes Tomzynski. “We can try several of them rapidly, and scale them quickly as well.” Avid relies on HyClone disposable bioreactors from Thermo Fisher Scientific for 100 L runs but also uses 5 L and 36 L glass bioreactors and a 1,000 L stainless steel reactor.
The goal is to reach GMP manufacturing rapidly so clients can submit their INDs, and continue supporting clinical and commercial manufacturing.
Tomzynski notes several hurdles to scale-up, notably carbon dioxide build-up at larger scales, pressure on downstream operations due to high titers, and technology transfer. Avid addresses the first with technology to reduce CO2 in both stainless steel and disposable bioreactors.
The downstream issue involves mostly monoclonal antibodies and the capture step, which is conducted with protein A. Tech transfer is another perennial problem as customers often have characterized processes in less-than-ideal fashion. “They don’t always bring in as much information as we would prefer,” says Tomzynski.
Scale-up-based contract relationships are often built around specialized expertise or proprietary technology, for example, formulation, experience with a particular cell line or dosage form, or quality track record, notes Barath Subramanian, senior industry analyst for pharmaceuticals and biotechnology for Frost & Sullivan. “Quality advantages provided by the contract manufacturer are then transferred into the product as part of the outsourcing relationship.”
He mentions Patheon as a CMO offering development and scale-up services for small molecules and Catalent Pharma Solutions for both drugs and biologics.
The economic downturn negatively affected demand for scale-up services from both small and large biopharma, Subramanian adds. Quite a number of small- and mid-sized firms, including discovery-stage companies that outsource most of their development work, have disappeared while others have merged, thus reducing the number of bench-to-development and development-to-pilot scale-up projects.
Even larger companies have scaled back on early-stage molecule development, he says. This slowdown will, five or so years down the road, reduce demand for development and scale-up services from CMOs. Subramanian predicts slower growth for these companies as a result. He does not believe the slowdown will be catastrophic, however, since CMOs can live off the growth from the last decade. “Even with this short-term setback CMOs should be able to maintain growth in the high-single to low-double digits.”