Viral clearance for biopharmaceutical downstream processes

Shukla, Abhinav A.; Aranha, Hazel

doi:10.4155/pbp.14.62

Cited by 45 publications

(28 citation statements)

References 38 publications

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“…To avoid regulatory concerns about the possibility of hanging droplets or fluid inhomogeneities, a “two‐vessel” strategy might be employed. In short, the process intermediate is acidified in a first vessel, transferred to a second vessel and only then the incubation time starts (Shukla & Aranha, 2015). Continuous low pH VI must assure that critical process parameters (CPPs) stay within prevalidated operation limits throughout the whole process.…”

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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show abstract

“…While several technologies have been developed for continuous operation in the upstream and downstream processing, virus clearance operations have been neglected. At the same time, continuous VI has also been highlighted as the missing piece of the continuous processing puzzle …”

Section: Introductionmentioning

confidence: 99%

“…However, additional detergents might be included in some cases, e.g., 0.3% v/v polysorbate 80 (PS80) . In batch operation, the S/D chemicals are homogenized with the process intermediate in a primary vessel and subsequently transferred to a secondary vessel, in which the VI incubation takes place: the “two‐vessel” strategy is preferred by the regulatory authorities and is the industry's current practice . In manufacturing processes, the specified VI incubation ranges from 60 min to 8 h …”

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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“…This material is then transferred to a second large holding tank where the low pH is maintained for 30–60 min. The purpose of the transfer is to reduce the risk associated with any droplets on the wall of the first tank that may not have been exposed to the low pH conditions . As a result, this step requires a large facility footprint from the two holding tanks, and a considerable amount of operator handling and long process times.…”

Section: Introductionmentioning

confidence: 99%

Continuous In‐Line Virus Inactivation for Next Generation Bioprocessing

Gillespie¹,

Holstein²,

Mullin³

et al. 2018

Biotechnology Journal

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Viral inactivation plays a critical role in assuring the safety of monoclonal antibody (mAb) therapeutics. Traditional viral inactivation involves large holding tanks in which product is maintained at a target low pH for a defined hold time, typically 30-60 min. The drive toward continuous processing and improved facility utilization has provided motivation for development of a continuous viral inactivation process. To this end, a lab-scale prototype viral inactivation system was designed, built, and characterized. Multiple incubation chamber designs are evaluated to identify the optimal design that enables narrow residence time distributions in continuous flow systems. Extensive analysis is conducted supporting rapid low pH viral inactivation and included evaluations with multiple viruses, a range of pH levels, buffer compositions, mAb concentrations, and temperatures. Multiple test conditions are evaluated using the in-line system and results compared to traditional batch-mode viral inactivation. Comparability in kinetics of virus inactivation suggests equivalency between the two approaches.

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Viral clearance for biopharmaceutical downstream processes

Cited by 45 publications

References 38 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

Continuous In‐Line Virus Inactivation for Next Generation Bioprocessing

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