Development of a Triton X‐100 replacement for effective virus inactivation in biotechnology processes

Farcet, Jean‐Baptiste; Kindermann, Johanna; Karbiener, Michael; Kreil, Thomas R.

doi:10.1002/eng2.12078

Cited by 20 publications

(30 citation statements)

References 15 publications

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“…Investigations are underway to analyze and dismantle the exact molecular mechanism of the S/D treatment. Although protein compatibility as well as process compatibility have been verified on a considerable range of products (gene therapy product, recombinant, and plasma‐based biologics), 11 extended studies such as toxicity studies have recently been initiated.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of “Nereid,” a new phenol‐free detergent to replace Triton X‐100 in virus inactivation

Farcet

Kindermann

Karbiener

et al. 2020

Journal of Medical Virology

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In the 1980s, virus inactivation steps were implemented into the manufacturing of biopharmaceuticals in response to earlier unforeseen virus transmissions. The most effective inactivation process for lipid‐enveloped viruses is the treatment by a combination of detergents, often including Triton X‐100 (TX‐100). Based on recent environmental concerns, the use of TX‐100 in Europe will be ultimately banned, which forces the pharmaceutical industry, among others, to switch to an environmentally friendly alternative detergent with fully equivalent virus inactivation performance such as TX‐100. In this study, a structure–activity relationship study was conducted that ultimately led to the synthesis of several new detergents. One of them, named “Nereid,” displayed inactivation activity fully equivalent to TX‐100. The synthesis of this replacement candidate has been optimized to allow for the production of several kg of detergent at lab scale, to enable the required feasibility and comparison virus inactivation studies needed to support a potential future transition. The 3‐step, chromatography‐free synthesis process described herein uses inexpensive starting materials, has a robust and simple work‐up, and allows production in a standard organic laboratory to deliver batches of several hundred grams with >99% purity.

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Section: Discussionmentioning

confidence: 99%

Synthesis of “Nereid,” a new phenol‐free detergent to replace Triton X‐100 in virus inactivation

Farcet

Kindermann

Karbiener

et al. 2020

Journal of Medical Virology

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“…This issue has led biopharmaceutical manufacturers to search for more environmentally friendly detergents that can replace TX-100 while displaying functionally equivalent virus inactivation properties [ 9 , 10 , 11 ]. Accordingly, to test detergent candidates, the major focus has been on treating selected membrane-enveloped viruses with different detergent concentrations under varying environmental conditions and exposure times and measuring the resulting effects on viral infectivity.…”

Section: Introductionmentioning

confidence: 99%

Supported Lipid Bilayer Platform for Characterizing the Membrane-Disruptive Behaviors of Triton X-100 and Potential Detergent Replacements

Gooran

Yoon

Jackman

2022

IJMS

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Triton X-100 (TX-100) is a widely used detergent to prevent viral contamination of manufactured biologicals and biopharmaceuticals, and acts by disrupting membrane-enveloped virus particles. However, environmental concerns about ecotoxic byproducts are leading to TX-100 phase out and there is an outstanding need to identify functionally equivalent detergents that can potentially replace TX-100. To date, a few detergent candidates have been identified based on viral inactivation studies, while direct mechanistic comparison of TX-100 and potential replacements from a biophysical interaction perspective is warranted. Herein, we employed a supported lipid bilayer (SLB) platform to comparatively evaluate the membrane-disruptive properties of TX-100 and a potential replacement, Simulsol SL 11W (SL-11W), and identified key mechanistic differences in terms of how the two detergents interact with phospholipid membranes. Quartz crystal microbalance-dissipation (QCM-D) measurements revealed that TX-100 was more potent and induced rapid, irreversible, and complete membrane solubilization, whereas SL-11W caused more gradual, reversible membrane budding and did not induce extensive membrane solubilization. The results further demonstrated that TX-100 and SL-11W both exhibit concentration-dependent interaction behaviors and were only active at or above their respective critical micelle concentration (CMC) values. Collectively, our findings demonstrate that TX-100 and SL-11W have distinct membrane-disruptive effects in terms of potency, mechanism of action, and interaction kinetics, and the SLB platform approach can support the development of biophysical assays to efficiently test potential TX-100 replacements.

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“…9 Thus, the industry has been searching for suitable replacements for Triton X-100. [10][11][12][13] Compendial monographs are documents maintained by private non-governmental standard setting bodies such as the United States Pharmacopeia (USP) or the European Pharmacopeia (PhEur). These documents contain chemical and testing information for many pharmaceutical inactive and active ingredients.…”

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confidence: 99%

Identification of compendial nonionic detergents for the replacement of Triton X‐100 in bioprocessing

Hunter

Rezvani

Aspelund

et al. 2022

Biotechnology Progress

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We have systematically investigated six compendial nonionic detergents as potential replacements for Triton ×‐100 in bioprocessing applications. Use of compendial raw materials in cGMP bioprocessing is advantageous for a variety of reasons including material specifications developed to meet stringent pharmaceutical product quality requirements, regulatory familiarity and comfort, and availability from vendors experienced supplying the biopharmaceutical industry. We first examine material properties of the detergents themselves including melting point and viscosity. Process performance and product contact in real‐world bioprocess applications are then investigated. Lastly, we test the detergents in virus inactivation (VI) experiments with recombinant proteins and adeno‐associated virus. Two of the detergents tested, PEG 9 Lauryl Ether and PEG 6 Caprylic/Capric Glycerides, showed favorable properties that make them attractive for use as potential Triton X‐100 replacements. Process performance testing indicated negligible impact of the detergents on product yield, purity, and activity compared to a control with no detergent. Importantly, both PEG 9 Lauryl Ether and PEG 6 Caprylic/Capric Glycerides demonstrated very fast VI kinetics with complete inactivation of XMuLV observed in less than 1 min at a target 1% detergent concentration. Potential advantages and disadvantages of both candidate detergents for use in cGMP bioprocessing are summarized and discussed.

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Development of a Triton X‐100 replacement for effective virus inactivation in biotechnology processes

Cited by 20 publications

References 15 publications

Synthesis of “Nereid,” a new phenol‐free detergent to replace Triton X‐100 in virus inactivation

Synthesis of “Nereid,” a new phenol‐free detergent to replace Triton X‐100 in virus inactivation

Supported Lipid Bilayer Platform for Characterizing the Membrane-Disruptive Behaviors of Triton X-100 and Potential Detergent Replacements

Identification of compendial nonionic detergents for the replacement of Triton X‐100 in bioprocessing

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