Adapting viral safety assurance strategies to continuous processing of biological products

Johnson, Sarah; Brown, Matthew R.; Lute, Scott; Brorson, Kurt

doi:10.1002/bit.26060

Cited by 50 publications

(29 citation statements)

References 79 publications

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“…Design of the viral inactivation hold column was a new requirement for continuous application. In short, pH adjustment occurred before and after a flow through “hold” design, similar to other theorized methods . While other flow through viral inactivation approaches were tested, use of a column to achieve required residence time was a compact, inexpensive, scalable, and easily designed solution compared to other technologies or periodic processes found in literature .…”

Section: Resultsmentioning

confidence: 99%

Implementation of Fully Integrated Continuous Antibody Processing: Effects on Productivity and COGm

Arnold¹,

Lee²,

Rucker-Pezzini³

et al. 2018

Biotechnology Journal

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The changing landscape of the biopharmaceutical market is driving a paradigm shift toward continuous manufacturing. To date, integrated continuous bioprocessing has not been realized as enabling technologies are nascent. In this work, a fully integrated continuous process is successfully demonstrated from pilot scale bioreactor to drug substance. Comparable product quality is observed between the continuous process and a 500 L fed-batch conventional process. The continuous process generated material at a rate of 1 kg of purified mAb every 4 days, achieving a 4.6-fold increase in productivity compared to the fed-batch process A plant throughput analysis using BioSolve software shows that a fed-batch facility with 4 × 12 500 L stainless steel bioreactors and purification train of the corresponding scale can be replaced by a continuous facility consisting of 5 × 2000 L single use bioreactors and smaller purification train, with a cost reduction of 15%.

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Section: Resultsmentioning

confidence: 99%

Implementation of Fully Integrated Continuous Antibody Processing: Effects on Productivity and COGm

Arnold¹,

Lee²,

Rucker-Pezzini³

et al. 2018

Biotechnology Journal

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“…Continuous viral inactivation (VI) is a key building block to complete the integrated continuous biomanufacturing process of the future (Johnson, Brown, Lute, & Brorson, 2017; Konstantinov & Cooney, 2015). The biopharmaceutical industry is following other industries in moving from discrete batch operation to integrated continuous manufacturing, especially for high demand products, such as monoclonal antibodies (MAbs; Shukla, Wolfe, Mostafa, & Norman, 2017; Walsh, 2018).…”

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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“…This creates a robust system that greatly reduces the chance of non‐desired infectious agents from entering the final product. Conventionally, non‐enveloped viruses are removed by nanofiltration or chromatographic separation, while enveloped viruses are inactivated by low pH (~3.5), solvent/detergent treatment, or heat treatment . However, conventional processes for enveloped virus inactivation can harm the desired protein product and reduce final yields.…”

Section: Introductionmentioning

confidence: 99%

Arginine‐enveloped virus inactivation and potential mechanisms

Meingast

Heldt

2019

Biotechnology Progress

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Arginine synergistically inactivates enveloped viruses at a pH or temperature that does little harm to proteins, making it a desired process for therapeutic protein manufacturing. However, the mechanisms and optimal conditions for inactivation are not fully understood, and therefore, arginine viral inactivation is not used industrially. Optimal solution conditions for arginine viral inactivation found in the literature are high arginine concentrations (0.7–1 M), a time of 60 min, and a synergistic factor of high temperature (≥40°C), low pH (≤pH 4), or Tris buffer (5 mM). However, at optimal conditions full inactivation does not occur over all enveloped viruses. Enveloped viruses that are resistant to arginine often have increased protein stability or membrane stabilizing matrix proteins. Since arginine can interact with both proteins and lipids, interaction with either entity may be key to understanding the inactivation mechanism. Here, we propose three hypotheses for the mechanisms of arginine induced inactivation. Hypothesis 1 describes arginine‐induced viral inactivation through inhibition of vital protein function. Hypothesis 2 describes how arginine destabilizes the viral membrane. Hypothesis 3 describes arginine forming pores in the virus membrane, accompanied by further viral damage from the synergistic factor. Once the mechanisms of arginine viral inactivation are understood, further enhancement by the addition of functional groups, charges, or additives may allow the inactivation of all enveloped viruses in mild conditions.

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Adapting viral safety assurance strategies to continuous processing of biological products

Cited by 50 publications

References 79 publications

Implementation of Fully Integrated Continuous Antibody Processing: Effects on Productivity and COGm

Implementation of Fully Integrated Continuous Antibody Processing: Effects on Productivity and COGm

Truly continuous low pH viral inactivation for biopharmaceutical process integration

Arginine‐enveloped virus inactivation and potential mechanisms

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