In theory, making biopharmaceuticals 24/7—or close to it—could reduce production costs. Various models suggest switching from batch to continuous mode would cut the cost of producing almost all types of biopharmaceuticals, from monoclonal antibodies to therapeutic proteins.

Yet to date, relatively few companies have opted to switch to continuous mode. Partly this reluctance reflects the industry’s unwillingness to change processes that work, even if they are not optimal.

However, another challenge is that the ecosystem of continuous production methods and technologies is still evolving, says Ohnmar Khanal, PhD, formerly in the department of chemical and biomolecular engineering, University of Delaware, and now a senior scientist at Spark Therapeutics.

“Many of the technologies that are needed for full continuous manufacturing have yet to be fully developed, such as process integration, automation, control, and inline process analytical technologies. Such systems will also play a role in determining the economic feasibility of the continuous integration process,” she points out.

Making sure the processing technologies in a continuous line work together is also key, according to Khanal, who says this can be a particular challenge if bespoke systems are involved.

“The biggest technical challenge in moving to continuous processing is process integration. Integrating all unit operations to form a single train is challenging as some unit operations output the product continuously while others output the product cyclically,” she continues.

“The seamless integration of unit operation will require monetary investment and even specific custom equipment as what is necessary may not be readily available. This level of commitment requires a level of economic risk-taking as there is no precedent, and several technical shortcomings remain.”

Cost complexities

Khanal and colleagues looked at the challenges involved in continuous manufacturing in a recent paper, finding that—in addition to technology related costs—reagents impact the level of savings biopharmaceutical can achieve.

“Specific operational improvements such as inline dilution/preparation of media and buffers need to be implemented to keep the cost and facility footprint low. These efforts will also influence the cost of continuous manufacturing,” says Khanal.

“In general, continuous production reportedly reduces operational cost by ~15–20% and capital cost by 45–50%. However, these numbers will change as the technologies catered for integrated continuous manufacturing mature.”

But despite these challenges, Khanal predicts industry use of continuous mode production will increase in the future, citing recent advances in both up and downstream processing as a positive sign.

“Although it is not a recent technology, the combination of a perfusion cell culture with a continuous cell retention device improves productivity and product quality but requires a large volume of buffer. Current efforts toward media optimization for perfusion processes can reduce the cost associated with perfusion processes,” she says.

“In the downstream purification front, steps towards implementing process analytical technologies and process integration can reduce the operational complexity and risk associated with continuous chromatography approaches.”