Downstream Process Design, Scale-Up Principles, and Process Modeling

Lacki, K.; Joseph, John R.; Eriksson, Kjell-Ove

doi:10.1016/b978-0-08-100623-8.00032-3

Cited by 9 publications

(9 citation statements)

References 44 publications

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“…The upper pressure limit is the value at which neither polymerization of polyols occur (Liu et al 2010) nor Maillard reactions which are interactions between the carbon source and amino acids at high temperatures and longer heating times (Morioka et al 2000). These reactions produce components that could introduce colour, flavour or aroma to the final product (Labuza et al 1998).…”

Section: Primary Concentrationmentioning

confidence: 99%

From the culture broth to the erythritol crystals: an opportunity for circular economy

Daza-Serna

Serna-Loaiza

Masi

et al. 2021

Appl Microbiol Biotechnol

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The reduction of sugar intake by adults has been stated by the World Health Organization as an important strategy to reduce the risk of non-communicable diseases. Erythritol is a four-carbon sugar alcohol that is considered as a highly suitable substitution for sucrose. This review article covers approaches for the separate stages of the biotechnological production of erythritol from cultivation to the downstream section. The first part focuses on the cultivation stage and compares the yields of erythritol and arising by-products achieved with different types of substrates (commercial versus alternative ones). The reported numbers obtained with the most prominently used microorganisms in different cultivation methods (batch, fed-batch or continuous) are presented. The second part focuses on the downstream section and covers the applied technologies for cell removal, recovery, purification and concentration of erythritol crystals, namely centrifugation, membrane separation, ion and preparative chromatography, crystallization and drying. The final composition of the culture broth and the preparative chromatography separation performance were identified as critical points in the production of a high-purity erythritol fraction with a minimum amount of losses. During the review, the challenges for a biotechnological production of erythritol in a circular economy context are discussed, in particular regarding the usage of sustainable resources and minimizing waste streams. Key points • Substitution of sucrose by erythritol can be a step towards a healthier society • Biotechnological production of erythritol should follow a circular economy concept • Culture broth composition and preparative chromatography are keys for downstreaming • Substrate, mother liquor and nutrients are challenges for circular economy

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Section: Primary Concentrationmentioning

confidence: 99%

From the culture broth to the erythritol crystals: an opportunity for circular economy

Daza-Serna

Serna-Loaiza

Masi

et al. 2021

Appl Microbiol Biotechnol

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“…MF is still broadly used all over the world and has been demonstrated to be a reliable and effective method for filtration of small‐volume samples. Besides MF, depth filtration (DF) relies on the same principles for removing particles from liquid (Lacki et al, 2018). DF is based on a combination of fibres (cellulose; polypropylene), diatomaceous earth (DE) as filter aid, and a resin binder used to make flat sheets of filter medium (Lacki et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Besides MF, depth filtration (DF) relies on the same principles for removing particles from liquid (Lacki et al, 2018). DF is based on a combination of fibres (cellulose; polypropylene), diatomaceous earth (DE) as filter aid, and a resin binder used to make flat sheets of filter medium (Lacki et al, 2018). The porous filtration medium used in depth filters retain a large mass of particles throughout the medium before being clogged (Lacki et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…DF is based on a combination of fibres (cellulose; polypropylene), diatomaceous earth (DE) as filter aid, and a resin binder used to make flat sheets of filter medium (Lacki et al, 2018). The porous filtration medium used in depth filters retain a large mass of particles throughout the medium before being clogged (Lacki et al, 2018). However, DF has some drawbacks including (i) contamination of filtrate during extended filtration processes due to bacterial growth within the filter matrix, (ii) remaining product within the filter matrix after filtration and iii) media migration during filtration due to possible sloughing off the media fragments (Lacki et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…The porous filtration medium used in depth filters retain a large mass of particles throughout the medium before being clogged (Lacki et al, 2018). However, DF has some drawbacks including (i) contamination of filtrate during extended filtration processes due to bacterial growth within the filter matrix, (ii) remaining product within the filter matrix after filtration and iii) media migration during filtration due to possible sloughing off the media fragments (Lacki et al, 2018). Clarification of large‐volume bacterial cultures by MF has considerable drawbacks by being both time‐consuming and labor‐intensive.…”

Section: Introductionmentioning

confidence: 99%

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Clarification of large-volume bacterial cultures using a centrifuge-free protocol

Allahghadry

Bojesen

Whitehead

et al. 2022

Journal of Applied Microbiology

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To provide a reliable, reproducible and centrifuge-free filtration protocol for clarification of large volumes of bacterial cultures. Methods and Results: Four experiments were designed to compare different techniques enabling clarification of Escherichia coli cultures using as a benchmark the concentration and quality of bacterial outer membrane vesicles (OMVs). The experiments were designed to examine the performance of different extraction methods on large volume (≥1 L) filtrations of bacterial culture media. Performance parameters included filtration flow rates, sterility testing and characterization of the filtrates by: (i) SDS-PAGE, (ii) cryogenic transmission electron microscopy, (iii) nanoparticle tracking analysis and (iv) Qubit protein quantification. The experiments revealed that: (i) addition of the filter aid Diatomaceous Earth to the bacterial cultures improved filtration flow rates significantly and eliminated the need for centrifugation prior to filtration; (ii) sterile filtration was successful as no bacterial passage was identified through the membrane filter; (iii) centrifuge-free filtrates contained an increased amount of OMVs compared to centrifuged filtrates. Conclusions:In comparison to conventional centrifuge-based protocols, the clarification method presented has universal applicability for a broad range of microbial extraction procedures, regardless of the volume of culture harvested. Moreover, the decreased amount of OMVs presented in the filtrates following centrifugation step provides an additional argument in favour of a centrifuge-free approach.Significance and Impact of the Study: Sterile filtration is a universal method for the clarification of bacterial cultures. Common challenges related to filtration include filter clogging and long processing times, due to limited centrifugation capacity, which can affect product quality. The proposed protocol is likely to ensure a highly effective filtration process and could be a novel approach in improving the filtrate products without the need of centrifugation.

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Characterization of key manufacturing uncertainties in next generation therapeutics and vaccines across scales

Sarkis

Shah

Papathanasiou

2023

J Adv Manuf & Process

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Viral vectors are advanced therapy products used as genetic information carriers in vaccine and cell therapy development and manufacturing. Despite the first product receiving market authorization in 2012, viral vector manufacturing has still not reached the level of maturity of biologics and is still highly susceptible to process uncertainties, such as viral titers and chromatography yields. This was exacerbated by the COVID-19 pandemic when viral vector manufacturers were challenged to respond to the global demand in a timely manner. A key reason for this was the lack of a systematic framework and approach to support capacity planning under uncertainty. To address this, we present a methodology for: (i) identification of process cost and volume bottlenecks, (ii) quantification of process uncertainties and their impact on target key performance indicators, and (iii) quantitative analysis of scale-dependent uncertainties. We use global sensitivity analysis as the backbone to evaluate three industrially relevant vector platforms: adeno-associated, lentiviral, and adenoviral vectors. For the first time, we quantify how operating parameters can affect process performance and, critically, the trade-offs among them.Results indicate a strong, direct proportional correlation between volumetric scales and propagation of uncertainties, while we identify viral titer as the most critical scale-up bottleneck across the three platforms. The framework can de-risk investment decisions, primarily related to scale-up and provides a basis for proactive decision-making in manufacturing and distribution of advanced therapeutics.

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Downstream Process Design, Scale-Up Principles, and Process Modeling

Cited by 9 publications

References 44 publications

From the culture broth to the erythritol crystals: an opportunity for circular economy

From the culture broth to the erythritol crystals: an opportunity for circular economy

Clarification of large-volume bacterial cultures using a centrifuge-free protocol

Characterization of key manufacturing uncertainties in next generation therapeutics and vaccines across scales

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