As demand grows for increasingly complex biologics, microbial manufacturing is being pushed beyond its traditional limits. Axel Erler, head of commercial development and technical sales, microbial biopharmaceuticals, at Lonza Specialized Modalities, discusses scale-up challenges, regulatory strategy, digitalisation and the technologies shaping the next generation of microbial drug production.

Could you describe the current landscape for microbial manufacturing and why end-to-end capabilities are becoming increasingly important for CDMOs like Lonza?

The microbial manufacturing landscape has come a long way since 1978, when E. coli bacteria were used to manufacture the first genetically engineered synthetic insulin.

Today, amid sustained demand for complex and differentiated biologics, numerous manufacturers are employing microbial fermentation to produce a wide range of biologic drugs, relying on microorganisms such as bacteria, yeast, or fungi. This approach is particularly useful for producing smaller recombinant proteins, including antibody fragments and new types of antibody-like molecules.

However, despite its maturity, microbial manufacturing remains constrained by challenges in scalability, process robustness, sustainability, and yield optimization. In this context, end-to-end capabilities have become a critical differentiator.

CDMOs like Lonza focus on integrating development, scale-up, and commercial manufacturing into a seamless offering, reducing interfaces, accelerating timelines, and de-risking execution for developers.

What strategic investments is Lonza making in expanding its large-scale microbial manufacturing facilities, and how do these investments translate into benefits for your clients?

Lonza has invested strategically in strengthening and optimizing our microbial manufacturing network, most notably at our main site in Visp, Switzerland, where we have teams focusing on innovation in strain engineering, upstream processing (fermentation), and downstream processing (harvesting and purification).

In 2024, we expanded the site to house two 4,000-liter fermenters to accommodate an increasingly diverse biotech pipeline and the emergence of complex next-generation molecules.

The Visp site, with its array of offerings and capabilities, reinforces Lonza’s ability to meet growing market demand, while retaining the operational flexibility needed to support customers with limited in-house development and manufacturing capacity.

Importantly, our focus is not only on capacity expansion, but on maximizing utilization, operational excellence, and flexibility. This ensures that clients benefit from reliable supply, scalable solutions, and a capital-efficient model that seeks to avoid unnecessary risk while maintaining readiness for commercial demand.

Microbial-derived therapies often face complex regulatory environments. What are the main regulatory challenges you see in this space, and how does Lonza help clients navigate them efficiently?

Similar to other complex modalities, microbial-based therapies can present major hurdles for drug developers in terms of ensuring consistency, quality, and stability. Manufacturing these therapies requires a tailored and adaptable CMC strategy with a key emphasis on process validation.

Process validation entails studies that enhance process understanding, identify critical process parameters, and define operating ranges. These studies are specific to each molecule and aligned with current regulatory expectations. The success of these studies — and of the broader CMC strategy — greatly depends on early engagement with regulatory authorities and proactive alignment on regulatory and submission strategies.

Prioritizing robust process validation reduces the risk of delays and is a key enabler of successful IND and BLA submissions.

Can you share examples of how Lonza’s approach to regulatory strategy has helped accelerate time to market for microbial therapies?

As global demand for complex modalities increases, drug developers, especially small and emerging biotechs, face increased pressure to bring therapies to market as quickly as possible.

To accelerate partners’ development timelines, Lonza leverages deep regulatory expertise and historical knowledge of successful filings to build a development roadmap that strategically sequences and parallelizes activities to reduce both time and risk.

For instance, risk assessments are traditionally completed after data from at least three GMP batches at launch-scale are available. However, Lonza leverages its teams’ process expertise and developmental data to complete additional early assessments prior to batch completion.

By advancing these assessments earlier in development and updating them as new data emerges, Lonza mitigates risk while enabling more efficient validation and characterization. This proactive approach ensures that microbial-derived therapies are backed by a scientifically sound, well-documented risk management framework — an essential component for successful IND and BLA submissions.

Tech transfer can be a critical bottleneck in microbial manufacturing. What best practices has Lonza developed to de-risk this process and avoid costly setbacks?

Lonza is continuously advancing technologies that employ organisms such as E. coli and Pichia pastoris as expression hosts. For example, when E. coli is used to express therapeutic proteins, it often makes inclusion bodies and other types of protein aggregates. Purifying the proteins therefore requires recovering the aggregates, breaking them open to release the monomeric proteins from within, and then refolding them. This process is molecule-specific and can be resource-intensive because it usually entails dilution refolding, which requires large vessels and numerous chaotropic buffers.

Consequently, Lonza is exploring advanced approaches of inclusion body folding technology to improve upon traditional methods. One approach is to apply highly pressurized air to protein samples to break the aggregate, solubilize the protein, and facilitate the refolding.

While this method requires specialized equipment, it is more time-efficient and cost-effective. Additionally, it is more environmentally friendly, as it requires fewer chemicals. Pressure-based refolding also enables more concentrated feed streams in downstream processing, allowing processing of smaller volumes while limiting product loss at each step, possibly resulting in higher yields. In a sample we tested, we achieved a higher concentration with protein refolding, as well as a significant reduction in use of chaotropic agents.

We are also investigating automated high-throughput screening platforms to more rapidly and systematically identify optimal refolding conditions. This will allow us to pinpoint a “sweet spot” for each protein in a more comprehensive manner.

How does Lonza leverage its microbial manufacturing expertise to ensure scalability and consistency during tech transfer?

With Lonza’s large-scale production capabilities, scale flexibility, and new-build offerings, we support our partners in managing high product demand as well as demand uncertainty.

Our microbial manufacturing experts design processes with future commercial requirements in mind. These processes increase the likelihood of long-term commercial success by solving hidden inefficiencies, contributing to improved regulatory readiness and yield performance.

This approach enables the development of tailored, robust, and secure manufacturing solutions that then enable seamless transfer, a successful launch, and sustainable market supply.

In your view, what emerging trends or innovations in microbial manufacturing should developers and CDMOs be preparing for in the next three to five years?

We expect growing demand for an increasingly diverse range of molecules including non-Fc modalities like nanobody formats, single-chain variable fragments (scFvs), antigen binding fragments (Fabs), and, possibly, cytokines. Microbial platforms will play a critical role in enabling the efficient and scalable production of these molecules.

Additionally, we anticipate increased adoption of cell-free expression systems, an emerging technology that employs lysates from the organisms of interest for protein production and expression instead of using active cells. Cell-free methods include yeast-moss-, and plant-based systems.

A key challenge will be driving the industrialization and validation of these technologies at scale within the pharmaceutical industry, a sector that remains fairly risk averse. This challenge makes it all the more crucial to demonstrate that these expression systems work correctly at first use.

How do you see the role of digital tools and data analytics evolving to support microbial process development and manufacturing? 

Each microbial-derived therapy’s development process is unique, making digital tools and data analytics increasingly critical.

By integrating advanced analytics and digital platforms, teams can capture and interpret vast datasets across process understanding, characterization, and validation stages. This integrated approach enables a more granular understanding of complex parameter interactions, helping tailor strategies for each molecule rather than applying a one-size-fits-all approach.

Real-time monitoring and predictive analytics further enhance control, allowing early identification of deviations and proactive adjustments to maintain quality and compliance.

Ultimately, digitalization is a key enabler of Lonza’s development and manufacturing strategy because it accelerates decision-making, reduces risk, and ensures that microbial development is optimized for regulatory success and efficient scale-up. 

Could you discuss any particular success stories or case studies where Lonza’s investments and strategies have directly impacted the success of a microbial therapy project?

While specific client programs are confidential, we have multiple examples where our integrated approach has enabled accelerated timelines and improved outcomes.

In several cases, early integration of development and manufacturing teams, combined with proactive regulatory alignment and advanced process optimization, has allowed us to reduce overall development timelines while increasing process robustness.

In particular, our ability to transfer processes efficiently into large-scale commercial facilities, while maintaining yield and quality consistency, has been a key differentiator for clients transitioning from clinical to commercial supply.

Our successes consistently demonstrate that a combination of technical expertise, integrated capabilities, and disciplined execution is critical to delivering reliable outcomes in microbial manufacturing.

What advice would you give to biopharma companies looking to partner with a CDMO for microbial manufacturing to ensure a smooth, efficient development and scale-up process?

When selecting a partner, biopharma companies should prioritize CDMOs with proven microbial expertise, a strong track record in scaling processes, and demonstrated regulatory success. An experienced outsourcing partner is particularly valuable for developers facing challenges in protein expression or process scalability.

Beyond technical capabilities, it is critical to assess a prospective partner’s ability to integrate development and manufacturing, provide transparent communication, and offer flexible capacity solutions.

Choosing the right partner will enable companies to meet growing demand for complex molecules while managing risk, controlling timelines, and ensuring long-term commercial success in an increasingly competitive market.