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Scale-Up Challenges in Microbial Fermentation

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A special issue of Fermentation (ISSN 2311-5637). This special issue belongs to the section "Industrial Fermentation".

Deadline for manuscript submissions: closed (15 March 2026) | Viewed by 12324

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Prof. Dr. Tajalli Keshavarz

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Sustainable Biotechnology Research Group, School of Life Sciences, College of Liberal Art and Sciences, University of Westminster, London W1W 6UW, UK
Interests: microbial physiology and microbial communication; fermentation technology and bioreactor design; free and immobilised cell cultures; production and overproduction of antimicrobial agents; enzymes working with bacteria and fungi; microbial fuel cells

Special Issue Information

Dear Colleagues,

Remarkable achievements and progress have been made in all scientific aspects of microbes, from their molecular genetics and metabolic processes to the biosynthesis of industrially important products. However, in most cases, there have been few advancements in the effective and economic translation of these scientific achievements into industrial-scale processes. There are numerous challenges in implementing laboratory experiments in the large-scale production of commercially desirable microbial products.

In this context, this Special Issue is focused on scale-up challenges in microbial fermentation. We invite original research manuscripts and in-depth review articles featuring scale-up and considering the following topics:

Batch, fed-batch, and continuous cultures;

Free- and immobilised-cell cultures;

Pure and mixed microbial cultures;

Scale-down approaches for economic scale-up;

Bioreactor designs (stirred-tank reactors, air-lift reactors, membrane reactors, membrane-linked reactors, and other designs) for successful scale-up;

Microbial fuel cells;

The morphological consideration of cultures;

Hydrodynamics of scale;

Shear stress and biofilm formation and other issues affecting scale-up.

We will consider manuscripts exploring all types of fermentation, including but not limited to those for the production of therapeutics, enzymes, food, vitamins, biofuels, biomass, and fine chemicals.

Prof. Dr. Tajalli Keshavarz
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Fermentation is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2100 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

microbes
free-cell culture
immobilised-cell culture
bioreactor designs
modes of fermentation
scale-up
scale-down

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Published Papers (6 papers)

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Research

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16 pages, 1239 KB

Open AccessArticle

Enhancing Sustainability and Productivity in Komagataella phaffii Fermentation: A Techno-Economic Comparison of Fed-Batch and Continuous Cultivation with Mixed Induction Strategies

by Almir Yamanie, Salomé de Sá Magalhães, Acep Riza Wijayadikusumah, Neni Nurainy and Eli Keshavarz-Moore

Fermentation 2026, 12(2), 97; https://doi.org/10.3390/fermentation12020097 - 9 Feb 2026

Viewed by 1786

Abstract

The increasing demand for recombinant proteins has driven innovation in bioprocessing strategies using Komagataella phaffii as a host organism. Conventional fed-batch cultivation with pure methanol induction remains widely used but presents challenges including high methanol consumption, extended downtime, and elevated operational costs. This study evaluates alternative strategies combining mixed induction (methanol/sorbitol) with continuous cultivation to enhance productivity, sustainability, and improved economic outcome. Using KEX2 protease as a model industrial recombinant protein, we compared four cultivation modes: fed-batch with methanol (benchmark), fed-batch with mixed induction, continuous with methanol, and continuous with mixed induction. Cell growth, volumetric yield, and specific productivity were evaluated at 5L scale and then modelled to simulate industrial scales (40 L and 400 L). Results demonstrate that continuous cultivation with mixed induction significantly improves yield up to 9-fold compared to conventional fed-batch and reduces methanol usage and oxygen demand. Techno-economic simulations reveal that a 40 L continuous process can match or exceed the output of two 400 L fed-batch runs, while lowering capital and operating costs and minimizing environmental footprint. This integrated strategy offers a scalable, low-cost, and safer method for recombinant protein production, supporting compact and sustainable manufacturing solutions. Full article

(This article belongs to the Special Issue Scale-Up Challenges in Microbial Fermentation)

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20 pages, 3013 KB

Open AccessArticle

Exploring Static Biological Aging as a Method for Producing Low-Alcohol ‘Fino’ Type White Wines

by Raquel Muñoz-Castells, Lourdes Vega-Espinar, Juan Carlos García-García, Maria Trinidad Alcalá-Jiménez, Jaime Moreno-García, Cristina Lasanta and Juan Moreno

Fermentation 2025, 11(10), 575; https://doi.org/10.3390/fermentation11100575 - 5 Oct 2025

Cited by 3 | Viewed by 1757

Abstract

Spanish “Fino”-style white wines are traditionally aged by a dynamic process under a flor veil of Saccharomyces cerevisiae, requiring ≥15% (v/v) ethanol, which is typically achieved through fortification. Market demand for lower-alcohol wines and the need to reduce production costs have encouraged the development of alternative approaches. Here, static biological aging was evaluated as a method for producing Fino-type wines with reduced ethanol content. Base wines with ~14% and ~15% (v/v) ethanol were aged for nine months, during which chemical, microbiological, and sensory parameters were analyzed, along with flor veil activity. Lower-ethanol wines showed greater flor activity, with approximately 20 more yeast isolates in the wines with 14% (v/v) ethanol. Higher acetaldehyde levels were detected in these wines, reaching about 377 mg L⁻¹ compared to 230 mg L⁻¹ in the control wines (≥15% v/v ethanol). Significant changes were observed in pH (3.13–3.47 vs. 3.04–3.46), volatile acidity (0.20–0.26 g L⁻¹ vs. 0.31–0.66 g L⁻¹), and several volatile compounds, resulting in chemical and sensory profiles consistent with traditional biologically aged wine. Static biological aging can yield lower-alcohol Fino-style white wines with sensory and chemical attributes comparable to the traditional fortified versions, providing a cost-effective alternative that aligns with evolving consumer preferences. Full article

(This article belongs to the Special Issue Scale-Up Challenges in Microbial Fermentation)

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17 pages, 987 KB

Open AccessArticle

Bioemulsifier Produced by Aspergillus niger UCP 1064 Isolated from Caatinga Soil as a Promising Molecule for Scaled-Up Pharmaceutical Applications

by Uiara Maria de Barros Lira Lins, Rosileide Fontenele da Silva Andrade and Galba Maria de Campos-Takaki

Fermentation 2025, 11(10), 562; https://doi.org/10.3390/fermentation11100562 - 29 Sep 2025

Viewed by 1188

Abstract

This study presents the production, characterization, and potential pharmaceutical application of a bioemulsifier synthesized by Aspergillus niger UCP 1064 by submerged fermentation using agro-industrial residues (cassava wastewater and soluble starch). The compound exhibited a high emulsification index (EI₂₄ > 88%) against hydrophobic substrates, effectively reduced surface tension, and remained stable across a wide range of pH (2–12), temperatures (5–100 °C), and salinity levels (0–20% NaCl). Microscopic analysis confirmed the formation of stable oil-in-water (O/W) emulsions, while biochemical tests identified the compound as a glycolipoprotein. Rheological assays demonstrated a significant reduction in oil viscosity, enhancing fluidity. Through factorial design and response surface methodology, production conditions were optimized, achieving yields of up to 3.18 g/L. A theoretical scale-up indicated technical feasibility for pharmaceutical applications; however, challenges such as process reproducibility, sterility, and regulatory compliance persist. These findings highlight the bioemulsifier’s potential as a sustainable and biocompatible alternative for drug delivery systems. Full article

(This article belongs to the Special Issue Scale-Up Challenges in Microbial Fermentation)

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13 pages, 1712 KB

Open AccessArticle

The Role of Quorum Sensing in Enhancing Lovastatin and Pigment Production in Monascus purpureus C322

by Sirisha Yerramalli, Stephen J. Getting, Godfrey Kyazze and Tajalli Keshavarz

Fermentation 2025, 11(8), 461; https://doi.org/10.3390/fermentation11080461 - 11 Aug 2025

Cited by 1 | Viewed by 1761

Abstract

Monascus purpureus is a filamentous fungus known for producing pharmaceutically valuable secondary metabolites, including azaphilone pigments and lovastatin. Lovastatin is an HMG-CoA reductase inhibitor widely used to manage hypercholesterolaemia, while Monascus pigments serve as natural colourants with antioxidant and antimicrobial properties. This study evaluated the impact of quorum-sensing molecules (QSMs)—tyrosol (0.3 mM), farnesol (0.2 mM) and linoleic acid (0.4 mM)—on pigment and lovastatin yields in shake flasks and 2.5 L stirred-tank bioreactors. QSMs were introduced 48 h post-inoculation in shake flasks and 24 h in bioreactors. All QSMs increased yellow (OD₄₀₀), orange (OD₄₇₀), and red (OD₅₁₀) pigments and lovastatin concentration relative to the control, with scale-up further enhancing yields. Farnesol produced the most pronounced effect: in flasks, OD₄₀₀ 7.10 (1.86-fold), OD₄₇₀ 8.00 (2.12-fold), OD₅₁₀ 7.80 (2.08-fold), and 74.6 mg/L lovastatin (2.05-fold); in bioreactors, OD₄₀₀ 11.9 (2.06-fold), OD₄₇₀ 15.1 (2.71-fold), OD₅₁₀ 13.7 (2.47-fold), and 97.2 mg/L lovastatin (2.48-fold). This was followed by tyrosol treatment and then linoleic acid. These findings demonstrate that QSMs—particularly farnesol—significantly (p < 0.01) stimulate pigment and lovastatin biosynthesis in M. purpureus. Quorum sensing modulation represents a promising, scalable strategy to optimise fungal fermentation for industrial metabolite production. Full article

(This article belongs to the Special Issue Scale-Up Challenges in Microbial Fermentation)

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16 pages, 1392 KB

Open AccessArticle

Bioprospecting for a Wild Strain of Sporisorium scitamineum for the Valorization of Sugarcane Molasses into Mannosylerythritol Lipids and Cellobiose Lipids

by André D. Valkenburg, Breyten van der Merwe, George M. Teke, Eugéne van Rensburg and Robert W. M. Pott

Fermentation 2025, 11(7), 384; https://doi.org/10.3390/fermentation11070384 - 3 Jul 2025

Viewed by 1226

Abstract

Significant wastes such as bagasse, molasses, and vinasses are produced during sugarcane processing. Due to their high sugar content, these wastes are commonly used as low-cost substrates for biofuel production. However, these substrates are also suitable for the microbial synthesis of high-value biochemicals like biosurfactants. Sporisorium scitamineum, a smut fungus capable of growing on sugarcane residues and producing mannosylerythritol lipids (MELs) and cellobiose lipids (CBLs), was identified as a promising candidate for valorizing sugarcane wastes. This study investigated MEL and CBL co-production from pure sugars and sugarcane molasses using an S. scitamineum strain isolated from sugarcane residues originating from KwaZulu-Natal, South Africa. Among the sugars tested, sucrose supported the highest glycolipid production, yielding 0.24 g/L MELs and 2.73 g/L CBLs. Lower titers were achieved with fructose, and no production occurred with glucose. Sugarcane molasses also proved to be an effective substrate, yielding 1.46 g/L CBLs—the highest reported titer from an industrial waste to date. However, all titers remained far below those of other glycolipids, which consistently exceed 50 g/L. Future efforts should focus on enhancing CBL production through process optimization or genetic engineering. Full article

(This article belongs to the Special Issue Scale-Up Challenges in Microbial Fermentation)

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Review

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37 pages, 2650 KB

Open AccessReview

Considerations of Bacterial Robustness and Stability to Improve Bioprocess Design

by Pauline Pijpstra, Stéphane E. Guillouet, Petra Heidinger, Robert Kourist and Nathalie Gorret

Fermentation 2026, 12(1), 54; https://doi.org/10.3390/fermentation12010054 - 16 Jan 2026

Cited by 2 | Viewed by 2612

Abstract

Harnessing nature’s ingenuity with microorganisms for industrial production is an attractive solution to today’s climate concerns. Nature’s innate diversity allows the production of many value-added chemicals and can be expanded on through genetic engineering. Although the use of microbial cell factories (MCFs) has been extremely successful at lab scale, the numbers of successful bioprocesses remain limited. High cell densities and long cultivation times lead to reductions in productivity over the course of the cultivation through the effects of genetic and expression instability of the strain. This instability leads to population diversification. In this review, we explore the roots of genetic instability in microorganisms, focusing on prokaryotic bioprocesses, and how organisms cope with this instability. We spotlight single-cell detection methods capable of monitoring populations within the bioprocess both in- and on-line. We also examine different approaches to minimizing population diversification, both through strain development and bioprocess engineering. With this review, we highlight the fact that population-averaged metrics overlook the single-cell stresses driving genetic and functional instability, leading to an overestimation of microbial bioprocess robustness. High-throughput single-cell monitoring in industry-like conditions remains essential to identify and select truly stable microbial cell factories and bioprocesses. Full article

(This article belongs to the Special Issue Scale-Up Challenges in Microbial Fermentation)

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