Current challenges and recent advances on the path towards continuous biomanufacturing

Drobnjakovic, Milos; Hart, Roger A.; Kulvatunyou, Boonserm; Ivezic, Nenad; Srinivasan, Vijay

doi:10.1002/btpr.3378

Cited by 7 publications

(1 citation statement)

References 222 publications

(548 reference statements)

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“…It is important to note that should these changes be implemented after confirmatory trials or after approval of the drug; then a comparability exercise would be required, including physiochemical and biological in vitro studies, as well as potentially clinical pharmacokinetic and pharmacodynamic comparability studies (European Medicines Agency, 2007;Federal Food and Drug Administration,18, 2018). For implementing process intensification into an already existing commercial product, this may be the biggest hurdle to overcome (Drobnjakovic et al, 2023;Nasr et al, 2017).…”

Section: Levelmentioning

confidence: 99%

Reviewing the process intensification landscape through the introduction of a novel, multitiered classification for downstream processing

Crowley,

Cashen,

Noverraz

et al. 2024

Biotech & Bioengineering

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A demand for process intensification in biomanufacturing has increased over the past decade due to the ever‐expanding market for biopharmaceuticals. This is largely driven by factors such as a surge in biosimilars as patents expire, an aging population, and a rise in chronic diseases. With these market demands, pressure upon biomanufacturers to produce quality products with rapid turnaround escalates proportionally. Process intensification in biomanufacturing has been well received and accepted across industry based on the demonstration of its benefits of improved productivity and efficiency, while also reducing the cost of goods. However, while these benefits have been shown empirically, the challenges of adopting process intensification into industry remain, from smaller independent start‐up to big pharma. Traditionally, moving from batch to a process intensification scheme has been viewed as an “all or nothing” approach involving continuous bioprocessing, in which the factors of complexity and significant capital costs hinder its adoption. In addition, the literature is crowded with a variety of terms used to describe process intensification (continuous, periodic counter‐current, connected, intensified, steady‐state, etc.). Often, these terms are used inappropriately or as synonyms, which generates confusion in the field. Through a detailed review of current state‐of‐the‐art systems, consumables, and process intensification case studies, we herein propose a defined approach in the implementation of downstream process intensification through a standardized nomenclature and viewing it as distinct independent levels. These can function separately as intensified single‐unit operations or be built upon by integration with other process steps allowing for simple, incremental, cost‐effective implementation of process intensification in the manufacturing of biopharmaceuticals.

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Section: Levelmentioning

confidence: 99%

Reviewing the process intensification landscape through the introduction of a novel, multitiered classification for downstream processing

Crowley,

Cashen,

Noverraz

et al. 2024

Biotech & Bioengineering

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Optimizing virus filtration for continuous processing using serial filtration at high area ratio

Giglia,

Cacace,

McCoskey

et al. 2024

Biotech & Bioengineering

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Compared to batch operation, continuous bioprocessing can offer numerous advantages, including increased productivity, improved process control, reduced footprint, and increased flexibility. However, integration of traditional batch operations into a connected process can be challenging. In contrast to batch operations run at constant pressure or high flux, virus filtration in continuous processes may be operated at very low flux. This change in operating conditions may reduce the viral retention performance of the filter which has inhibited adoption of truly continuous virus filtration. To overcome this limitation, a novel approach is described that utilizes serial virus filtration, with a high area ratio between first to second stage filters, to achieve virus retention targets. In this study, virus filters were operated continuously (except for planned process interruptions) for 200 h in a serial configuration at a first to second stage filter area ratio of 13:1 and at a first stage flux of 5 L/m2/h. While the minute virus of mice (MVM) retention performance of the first stage filter was about 4 log reduction value (LRV), there was no virus detected in the second stage filtrate, translating to an MVM LRV across the filtration train of ≥6.7. The second stage filter was the dominant flow resistance at the start of the run but, as it was protected from foulants by the first stage filter, it suffered minimal fouling and the life of the filter train was controlled by the first stage. A theoretical case study projected that continuous virus filtration using serial configuration at high area ratio would have about 30% longer filter changeout time, 14% higher productivity, and virus retention nearly six LRV greater than single stage operation. The findings of this research are expected to provide valuable insights into optimizing virus filtration in continuous bioprocessing.

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Sensitivity Analysis on Policy‐Augmented Graphical Hybrid Models With Shapley Value Estimation

Zhao,

Xie,

Luo

2024

Naval Research Logistics

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Driven by the critical challenges in biomanufacturing, including high complexity and high uncertainty, we propose a comprehensive and computationally efficient sensitivity analysis framework for general nonlinear policy‐augmented knowledge graphical (pKG) hybrid models that characterize the risk‐ and science‐based understandings of underlying stochastic decision process mechanisms. The criticality of each input (i.e., random factors, policy parameters, and model parameters) is measured by applying Shapley value (SV) sensitivity analysis to pKG (called SV‐pKG), accounting for process causal interdependences. To quickly assess the SV for heavily instrumented bioprocesses, we approximate their dynamics with linear Gaussian pKG models and improve the SV estimation efficiency by utilizing the linear Gaussian properties. In addition, we propose an effective permutation sampling method with TFWW transformation and variance reduction techniques, namely the quasi‐Monte Carlo and antithetic sampling methods, to further improve the sampling efficiency and estimation accuracy of SV for both general nonlinear and linear Gaussian pKG models. Our proposed framework can benefit efficient interpretation and support stable optimal process control in biomanufacturing.

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Current challenges and recent advances on the path towards continuous biomanufacturing

Cited by 7 publications

References 222 publications

Reviewing the process intensification landscape through the introduction of a novel, multitiered classification for downstream processing

Reviewing the process intensification landscape through the introduction of a novel, multitiered classification for downstream processing

Optimizing virus filtration for continuous processing using serial filtration at high area ratio

Sensitivity Analysis on Policy‐Augmented Graphical Hybrid Models With Shapley Value Estimation

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