Microbial fermentation is one of the most versatile and transformative technologies in both the pharmaceutical and food industries.
Within the biopharmaceutical sector, this technology has revolutionized the production of therapeutics, playing a crucial role in manufacturing everything from basic proteins and peptides to sophisticated therapeutic enzymes. The applications extend far beyond traditional pharmaceutical products, reaching into advanced biologics development and providing essential tools for synthetic biology in drug discovery.
In this PharmaSource Masterclass on microbial fermentation, subject matter experts from Olon and GTP Bioways shared their experience from early-stage development to commercial manufacturing:
How Microbial Fermentation is used in biopharma
The technology enables the production of various products including:
- Small Molecules – Antibiotics, amino acids & vitamins
- Biotherapeutics – Therapeutic recombinant proteins and antibodies fragments
- Vaccines – Recombinant proteins and subunit vaccines
- Other large molecules e.g. recombinant enzymes
The sustainability impact is also key. Compared to traditional production methodologies, this technology demonstrates a significantly reduced environmental footprint. The process demands substantially less water consumption, operates with lower energy requirements, and minimizes the use of harmful solvents. This environmental advantage, coupled with its versatility, positions microbial fermentation as a key technology for the future of pharmaceutical manufacturing.
Microbial fermentation vs cell culture
Microbial fermentation offers clear operational advantages to alternatives such as mammalian cell culture.
Lower production costs. Production costs typically fall below alternative methods, particularly compared with mammalian expression systems.
Scalability. The technology demonstrates reliable scalability, with processes showing consistent results from laboratory to industrial volumes.
Efficiency. For suitable proteins, fermentation achieves higher efficiency levels than mammalian cell culture.
Technological advances. Microbial fermentation supports advanced technologies, as integration with CRISPR gene editing and artificial intelligence continues to expand these capabilities.
Microbial Fermentation CDMO Market
The microbial fermentation manufacturing market is in a period of high growth. As of 2023, the market, encompassing both pharmaceutical and food applications, reached a valuation of over USD $34 billion. Industry projections suggest this figure will nearly double within a decade, potentially exceeding $60 billion. This trajectory represents a robust CAGR growth rate of over 5.8% annually, reflecting the technology’s increasing adoption and importance across multiple sectors.
Asia Pacific dominated the microbial fermentation technology market with the largest revenue share of 47% in 2023. This concentration reflects the region’s strong manufacturing base and significant investments in biotechnology infrastructure. However, the market is poised for geographic shifts, with the United States expected to significantly expand its capacity and production capabilities over the next decade.
Contract Development and Manufacturing Organisations (CDMOs) command 44% of revenue share, representing approximately USD $15 Billion in revenue. This proportion demonstrates the sector’s increasing reliance on specialised biotechnology manufacturing partners.
Microbial Fermentation CDMO service growth stems from several market forces.
Rising biologics demand drives immediate expansion, whilst manufacturing complexity necessitates specialist expertise many firms lack internally. The substantial cost of biologics facilities makes outsourcing attractive even for large pharmaceutical companies. Existing CDMO partnerships often create natural expansion opportunities into fermentation projects.
The sector faces distinct challenges. Biologics production operates under stringent regulatory requirements, exceeding traditional pharmaceutical manufacturing standards. Development timelines are longer, creating potential capacity constraints. Quality control demands particular attention, with contamination risks requiring robust management systems.
Early-Stage Development
Early-stage development presents specific challenges. Projects often originate from small biotech companies operating under investor timelines. This creates pressure to reach clinical trials rapidly, sometimes at the expense of process understanding.
Case study 1: Robustness of USP
The study examines challenges with raw material consistency in upstream processing (USP), particularly when using complex media rather than synthetic media. Key findings include:
- Complex media components, especially vegetable peptones and yeast extracts, can introduce significant process variability due to natural variations in their composition
- Raw material supplier selection is critical, focusing on both performance and batch-to-batch consistency, though evaluation is often limited by batch availability
- Different processes require different optimal suppliers – there is no universal “best supplier” that works optimally across all fermentation processes
Case study 2: Robustness of Downstream Processing (DSP) case study in protein purification
The case study details how a biotech company sought help optimising their E. coli protein purification process. While their initial process met specifications (host cell protein/HCP <100 ppm), they wanted greater consistency. Key findings include:
- Original process used three chromatography steps and achieved variable HCP levels (30-95 ppm)
- Process refinement focused on optimising multiple parameters (holding times, buffer conductivity, washing volumes, resin conditions, and elution strategies) while maintaining the same overall DSP flow
- Optimisation achieved more consistent HCP reduction (30-40 ppm), demonstrating that early process characterisation and QbD principles should continue throughout clinical phases to minimise batch failure risks
In summary, successfully scaling microbial fermentation from early development requires focus on three critical elements:
- Strain optimization – selecting and developing strains with proven efficiency, stability and compatibility with both scale-up requirements and CMO capabilities
- Process robustness – ensuring scalable upstream and downstream processes through careful control of raw materials, oxygen transfer rates, and key parameters within acceptable ranges to minimize batch failures
- Analytics and QbD foundation – implementing comprehensive analytical methods and Quality by Design principles early, with more extensive testing and documentation during development versus production phases
New molecule development frequently requires simultaneous creation of analytical methods and production processes. This parallel development demands careful resource management and clear prioritisation.
Commercial Manufacturing
Commercial microbial fermentation spans an extraordinarily wide range of scales and applications:
- Scale: Production volumes range from less than 1 m³ to over 100,000 m³ annually, using fermenters from 100L to 500,000L
- Product diversity: Produces molecules from less than 100 g/mol to over 100,000 g/mol, with market values ranging from under €10/kg to over €1,000,000/kg
- Development timeline: Projects can move from laboratory to commercial production in under 1 year or take more than 10 years, depending on the product and application
Control strategies must adapt for commercial operation as development-stage measurements often prove impractical at scale. Successful commercial processes typically employ time-based control systems, supported by online monitoring tools such as off-gas analysis.
Laboratory processes rarely transfer directly to commercial scale. Simple procedures like sterile filtration become complex engineering challenges at industrial volumes. Medium preparation requires careful consideration of vessel requirements and sterilisation cycles.
Expert Tips
The subject matter experts at Olon and GTP Bioways shared their advice on how to be successful with microbial fermentation
“Continue the development or the characterization… continue to understand your process, even if you have reached the first goal – that is, your first batch can go to clinic. [This] is really key if you want to avoid any trouble, further trouble and loss of time.” said Hervé Ginisty, CSO, GTP Bioways.
“Try to learn as much as possible about your specific product as early as possible. The earlier you understand what are the specific requirements for your product… the more you dive into the specifics, the faster you are going to arrive at commercial manufacturing.” said Gerald Hofmann, Technology Development Manager, Olon
“If you think that you need external capacity, get in touch with the CDMO even if you are making your own development in-house… knowing early what [they] can do later in production for early clinical production or for commercial is better. Don’t hesitate to contact to speak with the CDMO even if you don’t need capacity or short time, it will help you in your process development.” said Andrea Conforto, VP CDMO Biotech, Olon
For more information about microbial process development and GMP manufacturing visit the Olon and GTP Bioways websites.