“This maturation requires robust and flexible manufacturing strategies that fit variable market demand, reduce production costs and support increasingly regionalized supply needs,” according to an article published in Chemical Engineering and Processing: Process Intensification.
That paper focuses on showcasing concrete implementation examples and development tools using intensified processes for monoclonal antibody (mAb) production, but the authors stressed that many of the applications under review can also be applied to other molecule types with appropriate modifications.
"Since many techniques also readily extend to other protein biotherapeutics, intensification can be regarded as key pillar enabling fast, cost-efficient development and production of biopharma products in the coming years."
Technology roadmap
The reviewers, all based at Sartorius, cited the roadmap, published in 2017, by the BioPhorum Operations Group (BPOG) that describes common biomanufacturer needs for different therapeutic application areas with the goal of promoting awareness among suppliers, academics, regulators, and government agencies of industry requirements so that future development directions could be aligned, and collaboration enabled.
That BPOG guide, said the process experts, indicated several areas where changes are needed to achieve this goal, including switching to intensified process variants, developing improved cell lines, shorter seed trains, and robust high-cell density (HCD) harvest technologies for the upstream processing element.
For downstream processing, industry needs to move towards continuous operation, and improved resin usage, with the idea of curbing product purification timelines from several days to one.
“All these improvements target implementation of large-scale processes. In addition, tools are needed [and are available] that facilitate fast and reliable setup of robust intensified processes if these more economic processes are to become the new norm,” said the specialists, which included Dirk Müller, media and process development team lead at the German technology provider.
Significant advances have been made in critical steps like the robust coupling of upstream process and in harvesting technologies for high cell densities, while multi-column chromatography can operate robustly with perfusion processes, supporting improved resin usage and cost reductions, they continued.
Moreover, the widespread use of single-use technologies (SUTs) in bioprocessing in general provides more flexibility in process setups and facility expansion, reduces the risk of batch failures due to contamination, simplifies multi-product operation in the same facility, and reduces required capital spend and environmental impact, added Müller et al.
Outstanding challenges
Still, several challenges remain, outlined the technology specialists.
“More work is needed on demonstrating scalability of new harvest technologies, on concentrated media formulations supporting HCD cultures, or on frozen high cell density bags to further curb seed train duration.
“On the downstream side, more experience with reliable inline dilution solutions, efficient viral clearance and continuous DSP trains is desirable. Plus, major single-use vendors have recently initiated programs to address the topic of SU waste reduction and improving sustainability.”
Different elements of process intensification like optimized clone selection, N-1 perfusion or an intensified N stage can be combined and offer synergistic gains, they explained.
Also, simple intensification steps like high-inoculation fed-batch (HIFB) can be implemented with limited financial and organizational effort in existing facilities, commented the authors.
They also noted that perfusion setups provide higher potential for cost of goods reduction, reduced facility footprints, and capital spend, but that they demand careful planning and come with higher operational cost, for media consumption, for example.
The best intensification approach should thus be chosen for the application scenario at hand, they said.
'Regulatory frameworks must adapt'
They emphasized as well that process intensification not only comes with technical challenges, but also requires adaptations in drug regulatory frameworks, for example, concerning seemingly simple concepts like batch definition for continuous processes.
The regulatory agencies have recognized this need, however, and special task forces like the emerging technologies team at the US Food and Drug Administration (FDA) or the innovation task force at the European Medicines Agency (EMA) have been formed to address this topic and actively support this transition.
“With these changes underway, process intensification provides increased momentum to advance the biopharma industry to the next level of process maturity and economical manufacturing.”