Single-use systems could run perfusion cultures and help biopharma intensify production, but understanding the potential process risks is critical, according to new research.

Perfusion cultures—in which fresh medium is added to growing cells and waste is removed on a continual basis—are not a new idea. Likewise, single-use bioreactors—which are disposed of after use—have been around for decades.

But combining them to support intensified production is novel, according to Merck KGaA scientists, who examined how single-use bioreactors would be likely to perform in perfusion mode in a recently published study.

The idea was to identify risks—issues that would cause a process to fail—using a modeling approach called FEMA, or failure mode and effects analysis, notes lead author Takao Ito, PhD, principal consultant, Global BioPharm Center of Excellence at Merck KGaA.

“We quantified 12 elements, from single-use specification through to operating conditions, that cause potential failures and categorized them into three impact factors: product quality, sterility assurance, and single-use (SU) robustness,” explained Ito. “We also compared the input from subject matter experts, then evaluated them for all upstream operations. This also allowed us to find risk factors that SMEs were unaware of.”

Operator involvement

The key finding is that while single-use technologies do not increase the risk of perfusion culture failure per se, the need for extra manual handling steps compared with multi-use systems is an issue.

“Our results show that a potential risk associated with using single-use is operator involvement. Differences in operator involvement during perfusion create different potential risks compared to fed-batch,” Ito pointed out. “The risk factors that increase with perfusion are long culture duration and the replacement of single-use components during sampling, media change, bleed bag change, etc. From this, the most significant is the increase in sampling for the monitoring of critical process parameters and critical quality attributes.”

However, the analysis also showed that, in other areas, single-use technologies are actually better suited to perfusion cultures than multi-use bioreactor systems.

“The smaller size and easier handling of single-use bioreactors presents less of a risk than the larger fed-batch bioreactors,” said Ito. “Perfusion is also less risky for leachables than fed-batch cultures because of the low residence time.”

Single-use analytics

Ito also stressed the benefits of using FEMA for risk assessment in this way, particularly during process development.

“This work is just an example, but I think it will be helpful for risk analysis of single-use systems. Pharmaceutical companies can improve their processes by regularly reviewing those elements and numerical settings, continually conducting FMEA, and addressing control measures,” suggested Ito. “The good thing about FMEA is that the output can be visualized numerically as a risk priority number. This allows for control measures to be addressed with priority given to those with the highest risk.”

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