Assessing detergent‐mediated virus inactivation, protein stability and impurity clearance in biologics downstream processes

Assessing detergent-mediated virus inactivation, protein stability and impurity clearance in biologics downstream processes

10.22541/au.163415854.45754951/v1 ◽

2021 ◽

Author(s):

Hasin Feroz ◽

Naresh Chennamsetty ◽

Sara Byers ◽

Melissa Holstein ◽

Sanchayita Ghose

Keyword(s):

Quality Attributes ◽

Valuable Insight ◽

Virus Inactivation ◽

Continuous Manufacturing ◽

Extrinsic Factors ◽

Worst Case ◽

Intrinsic Factors ◽

Modeling Data ◽

Downstream Processes ◽

The Impact

Detergent-mediated virus inactivation (VI) provides a valuable orthogonal strategy for viral clearance particularly for next generation continuous manufacturing. Furthermore, there exists an industry-wide need to replace the conventionally employed detergent, Triton X-100, with eco-friendly alternatives. This study provides a systematic approach to screen detergents as VI agents through the study of VI of three different enveloped viruses for monoclonal antibodies and fusion proteins. We investigated three major aspects of VI namely, the impact of VI agent on the therapeutic quality attributes, clearance of the VI agent and other impurities through subsequent chromatographic steps and lastly the efficacy of VI for the said detergent. Several quality attributes such as charge variance, oxidation, deamidation, glycosylation and aggregation were investigated. Aggregation was a key indicator of stability. Experimental and modeling data was used to decipher the mechanism and kinetics of aggregation for pH sensitive molecules by exploring worst case VI conditions. We found product aggregation and its kinetics to be driven by extrinsic factors such as detergent and protein concentration. Aggregation was also impacted by initial aggregation level as well as intrinsic factors such as the protein sequence and detergent hydrophobicity and critical micelle concentration (CMC). VI efficiency was dependent on the virus tested, duration of incubation as well as detergent CMC and concentration. Dodecyl maltopyranoside (DDM) was found to be a promising candidate for potential application in VI. Knowledge gained here on factors driving product stability and VI provides valuable insight to design, standardize and optimize conditions (concentration, duration of inactivation) for screening of detergent-mediated VI.

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“In vitro” and in Animal Model Studies on a Double Virus- Inactivated Factor VIII Concentrate

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649839 ◽

1995 ◽

Vol 74 (03) ◽

pp. 868-873 ◽

Cited By ~ 9

Author(s):

Silvana Arrighi ◽

Roberta Rossi ◽

Maria Giuseppina Borri ◽

Vladimir Lesnikov ◽

Marina Lesnikov ◽

...

Keyword(s):

Heat Treatment ◽

Animal Model ◽

Factor Viii ◽

Hepatitis A ◽

Hepatitis A Virus ◽

Virus Inactivation ◽

Enveloped Viruses ◽

Model Studies ◽

Heat Treated

SummaryTo improve the safety of plasma derived factor VIII (FVIII) concentrate, we introduced a final super heat treatment (100° C for 30 min) as additional virus inactivation step applied to a lyophilized, highly purified FVIII concentrate (100 IU/mg of proteins) already virus inactivated using the solvent/detergent (SID) method during the manufacturing process.The efficiency of the super heat treatment was demonstrated in inactivating two non-lipid enveloped viruses (Hepatitis A virus and Poliovirus 1). The loss of FVIII procoagulant activity during the super heat treatment was of about 15%, estimated both by clotting and chromogenic assays. No substantial changes were observed in physical, biochemical and immunological characteristics of the heat treated FVIII concentrate in comparison with those of the FVIII before heat treatment.

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Use of vent stack temperature as a feedforward variable for dissolver total titratable alkali (TTA) control

TAPPI Journal ◽

10.32964/tj17.05.261 ◽

2018 ◽

Vol 17 (05) ◽

pp. 261-269

Author(s):

Wei Ren ◽

Brennan Dubord ◽

Jason Johnson ◽

Bruce Allison

Keyword(s):

Feedback Control ◽

Current Practice ◽

Feedforward Control ◽

Control Variable ◽

Indirect Measurement ◽

Tight Control ◽

Transfer Lines ◽

Green Liquor ◽

Process Dynamics ◽

Downstream Processes

Tight control of raw green liquor total titratable alkali (TTA) may be considered an important first step towards improving the overall economic performance of the causticizing process. Dissolving tank control is made difficult by the fact that the unknown smelt flow is highly variable and subject to runoff. High TTA variability negatively impacts operational costs through increased scaling in the dissolver and transfer lines, increased deadload in the liquor cycle, under- and over-liming, increased energy consumption, and increased maintenance. Current practice is to use feedback control to regulate the TTA to a target value through manipulation of weak wash flow while simultaneously keeping dissolver density within acceptable limits. Unfortunately, the amount of variability reduction that can be achieved by feedback control alone is fundamentally limited by the process dynamics. One way to improve upon the situation would be to measure the smelt flow and use it as a feedforward control variable. Direct measurement of smelt flow is not yet possible. The use of an indirect measurement, the dissolver vent stack temperature, is investigated in this paper as a surrogate feedforward variable for dissolving tank TTA control. Mill trials indicate that significant variability reduction in the raw green liquor TTA is possible and that the control improvements carry through to the downstream processes.

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