Continuous Virus Inactivation: How to Generate a Plug Flow

Jungbauer, Alois

doi:10.1002/biot.201800278

Cited by 13 publications

(13 citation statements)

References 14 publications

(23 reference statements)

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“…For the specific case of continuous VI, the chance of any fluid element leaving the reactor before the target incubation time should be minimized, which highlights the requirement for a narrow RTD (Jungbauer, 2018). To achieve such a goal, three reactors have been patented and published.…”

Section: Introductionmentioning

confidence: 99%

Truly continuous low pH viral inactivation for biopharmaceutical process integration

Martins

Sencar

Hammerschmidt

et al. 2020

Biotech & Bioengineering

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Continuous virus inactivation (VI) has received little attention in the efforts to realize fully continuous biomanufacturing in the future. Implementation of continuous VI must assure a specific minimum incubation time, typically 60 min. To guarantee the minimum incubation time, we implemented a packed bed continuous viral inactivation reactor (CVIR) with narrow residence time distribution (RTD) for low pH incubation. We show that the RTD does not broaden significantly over a wide range of linear flow velocities—which highlights the flexibility and robustness of the design. Prolonged exposure to acidic pH has no impact on bed stability, assuring constant RTD throughout long term operation. The suitability of the packed bed CVIR for low pH inactivation is shown with two industry‐standard model viruses, that is xenotropic murine leukemia virus and pseudorabies virus. Controls at neutral pH showed no system‐induced VI. At low pH, significant VI is observed, even after only 15 min. Based on the low pH inactivation kinetics, the continuous process is equivalent to traditional batch operation. This study establishes a concept for continuous low pH inactivation and, together with previous reports, highlights the versatility of the packed bed reactor for continuous VI, regardless of the inactivation method.

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Section: Introductionmentioning

confidence: 99%

Truly continuous low pH viral inactivation for biopharmaceutical process integration

Martins

Sencar

Hammerschmidt

et al. 2020

Biotech & Bioengineering

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“…The curvature and direction changes induce a secondary flow pattern and momentum shifts, which contribute to narrower RTD. Segregation of fluid parcels inside a tubular reactor, either by immiscible fluid or mechanically, has also been proposed but execution at scale would be challenging . The RTD for any given reactor can be assessed by a pulse of non‐interacting tracer and calculation of the F ‐curve, the cumulative RTD function .…”

Section: Introductionmentioning

confidence: 99%

“…Segregation of fluid parcels inside a tubular reactor, either by immiscible fluid or mechanically, has also been proposed [25] but execution at scale would be challenging. [26] The RTD for any given reactor can be assessed by a pulse of non-interacting tracer and calculation of the F-curve, the cumulative RTD function. [27] The ratio between the time at 50% cumulative RTD curve (F 0.5 ) and the time at 0.5% cumulative RTD curve (F 0.005 ), t[F 0.5 ]/t[F 0.005 ], has been used to measure and compare the RTD narrowness, [20,22] where t[F 0.5 ]/t[F 0.005 ] = 1 for an ideal plug flow.…”

Section: Introductionmentioning

confidence: 99%

Continuous Solvent/Detergent Virus Inactivation Using a Packed‐Bed Reactor

Martins

Sencar

Hammerschmidt

et al. 2019

Biotechnology Journal

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Continuous virus inactivation (VI) remains one of the missing pieces while the biopharma industry moves toward continuous manufacturing. The challenges of adapting VI to the continuous operation are two‐fold: 1) achieving fluid homogeneity and 2) a narrow residence time distribution (RTD) for fluid incubation. To address these challenges, a dynamic active in‐line mixer and a packed‐bed continuous virus inactivation reactor (CVIR) are implemented, which act as a narrow RTD incubation chamber. The developed concept is applied using solvent/detergent (S/D) treatment for inactivation of two commonly used model viruses. The in‐line mixer is characterized and enables mixing of the viscous S/D chemicals to ±1.0% of the target concentration in a small dead volume. The reactor's RTD is characterized and additional control experiments confirm that the VI is due to the S/D action and not induced by system components. The CVIR setup achieves steady state rapidly before two reactor volumes and the logarithmic reduction values of the continuous inactivation process are identical to those obtained by the traditional batch operation. The packed‐bed reactor for continuous VI unites fully continuous processing with very low‐pressure drop and scalability.

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“…On the downstream front, Pall Biotech explore the productivities and cost savings with continuous chromatography setups. There are also two contributions providing insights on continuous virus inactivation from Boehringer Ingelheim and MilliporeSigma with an additional Commentary from BOKU (Austria) …”

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confidence: 99%

“…There are also two contributions providing insights on continuous virus inactivation from Boehringer Ingelheim [7] and MilliporeSigma [8] with an additional Commentary from BOKU (Austria). [9] On the end-to-end front, MedImmune [10] share experiences implementing a fully integrated continuous antibody process with commentary on productivity and cost of goods impacts.…”

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confidence: 99%

Integrated Continuous Biomanufacturing: Industrialization on the Horizon

Farid¹

2019

Biotechnology Journal

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Continuous Virus Inactivation: How to Generate a Plug Flow

Cited by 13 publications

References 14 publications

Truly continuous low pH viral inactivation for biopharmaceutical process integration

Truly continuous low pH viral inactivation for biopharmaceutical process integration

Continuous Solvent/Detergent Virus Inactivation Using a Packed‐Bed Reactor

Integrated Continuous Biomanufacturing: Industrialization on the Horizon

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