Future Downstream Processing
Technologies that will increase overall process efficiency and enable fewer process steps to ultimately reduce cost and project timelines will have the largest impact on the industry. Many agree that the downstream-processing bottleneck will not be overcome by gradual improvement, but via disruptive innovation.
There are many new technologies being explored in the industry, but it is unclear which ones will stand out. “Candidates include optimization of aqueous two-phase systems/crystallization; adoption of alternative chromatographic separations (expanded bed, simulated moving bed, nonaffinity, nonprotein A ligands); and further integration of nonconventional continuous matrix supports (monoliths or membrane absorbers),” Dr. Lias from Eden Biodesign said.
Over the past two years, Cobra has been performing feasibility programs for the integration of disposable technologies into existing in-house platform processes, the cGMP facility, and the quality systems, so that it is ready to meet the ever increasing needs of its customers.
“The introduction of completely disposable flow paths fitted to operational control hardware (i.e., bioreactors, pumping systems, filtration, and chromatography systems) will reduce the requirement for cleaning and validation activities and should, as such, confer an increased safety assurance level to the industry,” Smith said.
“The implementation of new technologies in manufacturing is mainly driven by economic aspects,” according to Dr. Brecht. “Therefore, relevant technologies that make processes more efficient and/or reduce process steps will be implemented in manufacturing, for instance, mixed-mode resins, high-capacity materials for purification, and disposables.”
It is essential that these new technologies have been established in process development, Dr. Brecht noted. “All manufacturing operations have to be established already during process development and be scaled up for production. We are addressing this challenge by having a tight cooperation between our process-development and manufacturing team.”
Disposable membranes may play an increasing role in purification. Laureate Pharma has already made disposable membrane filters for flow-through steps such as ion-exchange, part of its standard process for downstream antibody purification.
“The use of disposable membrane filters avoids the need to pack and qualify columns, speeding turn-around time. The flow properties of the membranes also allow faster processing than columns,” said Dr. Ultee.
“These large disposable membrane columns increase speed, as well as flow rate,” Prof. Wagner added. “To improve downstream performance, many manufacturers are increasingly focusing on improvements to reliability and consistency of their production.
“Many of these changes will be initiated in the process-development area rather than in commercial production. There are a number of Protein A column alternatives in development that promise to perform better, use higher pH, are more durable and cleanable, yet have similar efficiency and better binding capacity. These factors will be critical in the future.”
Financial Market Impact
Despite the economic slowdown, a few CMOs pointed out that their business has increased. “Demand appears to remain robust,” Eden’s Dr. Lias said, “and it can be argued that we are seeing increased interest from multinational pharma and biotech companies as they consolidate and take advantage of the global situation to acquire new projects and products to prop up their pipelines.”
Sandoz has established long-term manufacturing alliances with products that are in late-phase clinical trials or on the market. “With this business model, we see little impact in the current economic situation,” said Dr. Nachtmann.
Some CMOs noted that, although their business has not been impacted, they have seen a slowdown in buying decisions, and U.S. companies, in particular, are taking longer to progress to the clinic and are being more cautious. “This of course has been true of European companies for many years, but is a change in the U.S. market. This has certainly been the situation through 2008 and the first half of 2009. The effect of this is that programs are delayed, a similar situation to that felt by the CMO industry in 2003/2004,” reported Dr. McCudden from SynCo Bio Partners.
It has also been observed that some of the early-stage preclinical or Phase I projects from small biotechnology companies are on hold because of lower funding. The CMOs whose main customers are small biotechnology companies, have seen a reduced number of runs and delays from some of these clients. Boehringer Ingelheim, whose clients are medium-size and big pharmaceutical and biotechnology companies, has not experienced any drawback in business.
“Customers are more cost conscious resulting from the current economic environment,” Julia Knebel, Ph.D., business development, industrial customer business, corporate division biopharmaceuticals at Boehringer, noted. “Even though CMOs might not be strongly impacted by the financial crisis, the awareness for cost savings and the need for competitive technologies that ensure an advantage over other CMOs are absolutely present.”
Regarding the outlook for 2010, Dr. Knebel said that “due to the financial crisis some decisions regarding building up internal manufacturing capacity will be made in favor of future outsourcing, which will lead to new business for CMOs.”
This sentiment of increased outsourcing is echoed by Ridley-Smith who explained, “with the expectation that blockbuster drug products are going to become rarer, the bigger biotechnology and pharmaceutical companies will not be able to justify building new manufacturing facilities and will turn toward contract manufacturing even more. In addition, with the growth of biosimilars, the future for contract manufacturing should be good.”
Despite the current economic environment and the slowdown observed at the early stage of production, CMOs expect outsourcing to continue. The market will no doubt be more competitive, but the use of innovative technologies that add efficiency and flexibility will be a key competitive advantage and a point of differentiation.