Leonardo Magneschi, vice president of research & technology development, Ingenza looks at building robust and reliable paths for biologics manufacturing.
The biologics landscape is more diverse than ever, with today’s biopharmaceutical pipeline spanning complex antibody-drug conjugates, novel vaccines and recombinant and fusion proteins. Alongside this growth comes mounting pressure to deliver products faster, more sustainably and at lower cost. For many manufacturers, the path from host selection to full-scale manufacturing is shaped by legacy practices, relying on a narrow set of hosts and following fixed processes that are not tailored to the product. These approaches can introduce inefficiencies, increase the likelihood of technical failure during scale-up and lead to inconsistent product quality that triggers regulatory delays, ultimately extending drug development timelines.
This article explores how partnering with a contract research, development and manufacturing organisation (CRDMO) can optimise bioprocesses, and why integration of workflows is the key to success. CRDMOs built around integrated technology platforms provide biomanufacturers with multi-host expertise, high throughput screening and robust downstream processing – all delivered through a single, streamlined solution. Replacing traditional methods with a modern, integrated and data-driven strategy allows manufacturers to achieve scalable, cost-effective and environmentally responsible production of biologics. This positions them for success in a competitive, fast-moving market.
Extending host selection beyond CHO and E. coli
A common legacy practice in biomanufacturing is defaulting to just a few, well-recognised production hosts, such as Chinese hamster ovary (CHO) cells for producing monoclonal antibodies and other complex proteins, or Escherichia coli for simple proteins and enzymes. While these remain the dominant hosts, they are not always the most suitable choice for every molecule. For example, CHO cultures are expensive, grow slowly and are operationally complex, while E. coli lacks glycosylation capabilities, carries a high risk of protein misfolding, and introduces challenges with endotoxin contamination. The unique properties of novel biologics – such as high risk of mis-assembly, inherently low titers and intrinsic toxicity – combined with the increasing demand for faster and more cost-effective development, has highlighted the need for a more targeted approach to host selection, and several alternatives are already gaining attention.
For example, yeast species like Pichia pastoris can combine the ability to perform post-translational modifications and secrete proteins directly into the culture medium with the benefits of high cell density and inexpensive fermentation. Another key advantage of P. pastoris over other hosts is that it does not produce endotoxins, and secretes only small amounts of native proteins, simplifying downstream processing. Saccharomyces cerevisiae also offers several benefits, including suitability for GMP-compliant processes, a well-established genetic toolkit, and a long track record of use for FDA approved therapeutics, particularly for vaccines. Similarly, Gram-positive Bacillus subtilis grows quickly, secretes proteins directly into media, and is inherently free from endotoxins, making it well-suited for producing simple therapeutic proteins or enzymes.
Experience shows that data-driven host selection – based on molecular profiles, process efficiency and scalability – can prevent costly redevelopment later in the pipeline. For example, antimicrobial peptides that are toxic in E. coli have been successfully produced in alternative hosts, achieving higher yields and enabling scale-up for clinical evaluation. In addition, many of these alternative biomanufacturing hosts offer fast, cheap and easily scalable alternatives to E. coli.
Advanced fermentation strategies for scale-up
Once an optimal production host has been chosen, the way the fermentation is run becomes a major factor in how easily and economically the process can be scaled up. Parameters such as feed composition, temperature, pH, oxygen transfer and agitation must be carefully balanced to keep the product quality high while maximising yield.
One common approach is fed-batch fermentation, where fresh nutrients are added over time to extend the exponential growth phase and improve productivity. Another option is continuous fermentation, which – while more complex to manage – keeps the process running non-stop, and can offer higher volumetric productivity from smaller bioreactor footprints, particularly for products in high demand. In some cases, cells can gradually be adapted to specific stressors – a process known as adaptive laboratory evolution (ALE) – in continuous culture. This can help to improve strain resilience and productivity, but is usually more applicable to small molecule production.
These different fermentation strategies can be widely applied in areas such as microbial vaccine antigen production. In such cases, tailored growth media can help to maintain high density cultures, optimised induction processes can trigger protein production at the right stage, and careful control of dissolved oxygen can help to maintain consistency at scale. Together, these measures support high product quality at large volumes, while keeping costs minimised and meeting regulatory standards.
Strengthening process robustness with data-driven strategies
Even after expanding host options and optimising fermentation, manufacturers still face recurring challenges in biologics production. Scaling up from bench to larger development runs can introduce changes in mixing, oxygen transfer and nutrient gradients that affect product yield and quality. Batch-to-batch variability remains a concern – particularly for complex proteins where even small process deviations alter folding and glycosylation, affecting the biological activity. These risks are amplified by analytical limitations at smaller scales, as subtle changes in post-translational modifications or product heterogeneity may go undetected until later stages, when they are more difficult and costly to correct.
Addressing these issues often requires multiple complementary strategies that move beyond traditional trial and error. Design of experiments (DoE) approaches enable systematic exploration of process parameters, revealing how their interactions influence host growth and protein expression. Automation in early-stage strain screening accelerates candidate evaluation while reducing human error, helping to reliably identify promising variants. Integrated workflows help to ensure continuity and avoid process misalignment by linking upstream processes – such as fermentation – with downstream operations, like purification. Equally important is analytical expertise; advanced characterisation methods are needed to detect subtle shifts in glycosylation, folding or product heterogeneity at small scales, before they become costly problems later. These approaches rely on data-rich experimentation, where multiple variables are tested in parallel, rather than sequentially through trial and error. This enables earlier identification of robust operating ranges and lowers the risk of costly failures at later development stages.
Modern CRDMOs are contributing to these solutions by developing multi-host platforms, enzyme-based bioprocesses and fermentation-optimised systems. By embedding these capabilities within integrated platform technologies – where most stages, from strain engineering to downstream processing, are managed in-house – they provide a cohesive framework that improves coordination, accelerates scale-up and minimises technology transfer risks.
The competitive advantage of a specialised biomanufacturing strategy
The ability to coordinate host selection and bioprocess development to the unique demands of each biologic has become a critical differentiator in today’s evolving market. Rather than relying on generic, one-size-fits-all approaches, specialised strategies allow manufacturers to optimise processes around the characteristics of novel modalities, whether that means handling complex folding requirements, improving secretion efficiency or addressing sensitivity to process variability. This targeted focus reduces the risk of inefficiencies, bottlenecks and late-stage failures, while supporting consistent product quality and regulatory compliance.
Specialist CRDMOs can be central to achieving these outcomes, by providing access to multiple host systems, advanced fermentation expertise, integrated analytical and downstream capabilities, and AI-driven process optimisation. This combination forms the framework needed to develop, refine and scale processes efficiently. For companies without extensive in-house infrastructure, or those seeking to accelerate development timelines, partnering with the right CRDMO can unlock the full benefits of an integrated biomanufacturing model.
As biopharmaceutical pipelines continue to diversify, success will favour organisations able to adapt quickly to new product classes and manufacturing challenges. Working within a well-coordinated framework – supported by the right CRDMO partner – offers a clear route to that goal, enabling scalable production and robust, high quality delivery of the next generation of biologics.