Membranes, which support a wide swath of upstream and downstream bioprocessing, have evolved along with biopharma’s needs for throughput, timeliness, and quality. A recent paper by Andrew Zydney, PhD, the Bayard D. Kunkle chair and professor of chemical engineering at  Pennsylvania State University, observes that for membranes to continue in this role they must improve further to support paradigm-shifting continuous bioprocessing, single-use flexible manufacturing, purification of genes and cell-based therapies, and “future developments.”

Zydney tells GEN that membrane adsorbers have come a long way, particularly for flow-through applications where impurities (mostly DNA and host cell proteins) bind to an anion exchange ligand.

“Many companies already use membrane adsorbers to produce clinical materials, and I expect to see more applications at manufacturing scale in the future. These are particularly attractive in flexible manufacturing facilities focused on single-use systems,” he notes.

Membrane adsorbers still suffer from limited dynamic binding capacity, which will require significant upgrade for these products to break into large-scale bind-and-elute (capture) applications.

Continuous processing

Continuous processing, like QbD, PAT, and other initiatives, will obviously involve more than having better membranes, however.

“Adoption of continuous processing involves many ‘moving parts.’ Not only do you need separations technology (chromatography, membranes, etc.), but you also require the appropriate PAT, including inline sensors for key quality attributes, plus automation and control strategies to ensure that final drug product retains all the desired CQAs,” explains Zydney.

“For biomanufacturing, this huge advance always entails risk. Slow adoption reflects the challenges involved in effectively de-risking such a large change in manufacturing.  Progress is definitely occurring, but it is very much an ongoing process.”

Membranes are better suited to some applications than others.

“It’s relatively straightforward to develop a skid that can switch between parallel membranes for bioburden reduction whenever a filter reaches a predetermined endpoint (e.g., maximum pressure),” continues Zydney.

“Other applications are more challenging.  In some cases, this may require the development of new membranes or operating strategies with less fouling, for example tangential flow filtration for cell recovery/clarification from continuous perfusion bioreactors.  In others, membrane manufacturers will need to develop completely new processing strategies. For example, current diafiltration systems for final formulation/buffer exchange are inherently batch operations in which the product is recirculated multiple times through the membrane module. Several novel strategies have been proposed for continuous diafiltration, but these have yet to be successfully implemented for large scale manufacturing.”

What about single use, which has likely already been adopted wherever it could be? How will advances in membranes improve single use, or make it more attractive?

Many membrane systems, Zydney says, are already single use and have been for decades, including almost all normal flow filtration systems, e.g., sterile filtration and virus filtration. “Single-use ultrafiltration modules have also been developed, although the costs remain higher than would be desired. This is still an active area of development,” he says.

“Membrane adsorbers have the potential to be an attractive single-use technology as an alternative to large stainless-steel columns, and this is already happening in flowthrough applications. All membrane companies have a wide range of products specifically targeted for single-use facilities.”