Process transfer and scale-up of an OMV-based vaccine candidate  

Harnessing OMV technology: a new frontier in biopharmaceutical innovation 

Extra cellular vesicles including exosomes and Outer Membrane Vesicles (OMV) are rapidly emerging as a transformative platform in biopharma. OMVs are naturally derived vesicles from Gram-negative bacteria that offer a competitive edge through intrinsic immunogenicity, native antigen presentation, and design flexibility. Unlike traditional platforms, OMVs can carry multiple antigens and adjuvants, enabling multivalent vaccines with broad efficacy. Their ability to activate both innate and adaptive immunity makes them a powerful tool against infectious diseases and beyond. 

OMV therapeutics in the fight against drug-resistant infections 

Drug-resistant bacterial infections are a growing global threat. OMV-based vaccines offer a novel strategy by mimicking natural infection and presenting conserved antigens to trigger strong immune responses. Early studies show OMVs from related species may provide cross-protection, paving the way for targeted vaccines against resistant pathogens. 

Overcoming development and manufacturing hurdles 

Despite their promise, OMV vaccines face significant hurdles in development and manufacturing. One of the most pressing challenges is assuring effective supply and scaling. OMV production requires precise control over bacterial growth conditions, vesicle release, and isolation processes to ensure consistency and potency. Scaling up from laboratory to commercial production while maintaining product quality and yield demands specialized expertise and infrastructure. Additionally, the inherent variability of biological systems adds complexity to process standardization and reproducibility. 

Scientific promise amid regulatory complexity 

OMV-based therapeutics hold strong potential but bringing them to market means navigating complex regulatory terrain. To ensure a safe, effective and regulatory compliant therapeutic product deep characterization of composition, stability, and immune response is essential. For parenteral use, the requirements are even higher: strict controls on microbial contamination, endotoxins, and adventitious agents are non-negotiable. Still, growing clinical data from related OMV platforms is paving the way. With smart regulatory strategy and scientific precision, OMVs are poised to become a next-gen standard in biologics. 

Driving innovation through tech transfer and process development 

To unlock the full potential of OMV vaccines, technical innovation in tech transfer and process development is essential. This includes optimizing upstream fermentation, refining downstream purification, and implementing robust analytical methods. Seamless tech transfer between development and manufacturing organizations ensures that process knowledge is retained and scaled effectively. Collaborative partnerships with experienced CDMOs help accelerate timelines and mitigate risks.  

From bench to clinic: scaling for impact  

Large-scale, GMP compliant manufacturing is key to clinical success. Access to modular platforms, automation, and quality systems enable rapid scale-up and regulatory compliance. With the right infrastructure, OMV-based therapeutics can move from prototype to impactful public health solution. 

NorthX Biologics supports a client with an ambitious target 

This case study showcases one of our GMP campaigns for manufacturing a novel OMV vaccine against a prevalent drug-resistant infection for an international biopharma partner.  

The client was set out to move from process development (PD) to GMP manufacturing in order to begin Phase I/II clinical trials within just one year – an ambitious target for such an emerging technology. 

These constraining timelines were pre-set due to external commitments from the client’s side, including pre-scheduled toxicology (TOX) studies and other binding obligations with relevant regulatory bodies. These challenges added complexity to an already demanding schedule, requiring careful coordination and adaptability throughout the project. 

Effective transfer through accelerated tech transfer 

After establishing a GMP-grade master cell bank for the engineered OMV-producing bacterial strain, technology transfer of the client’s initial lab scale process for the drug substance manufacturing commenced straight away, with two full scaled down development runs focused on both upstream and downstream parameters completed successfully. First, a verification run allowed for data collection, identification of weak points and inefficiencies in the process, followed by a confirmation run where process adjustments were tested further for implementation. 

This comprehensive knowledge transfer and process optimisation at <10 L scale informed critical scale-up decisions for more streamlined and efficient large-scale processes. The tech transfer followed NorthX Biologics’ standard workflow to de-risk the GMP supply by identifying and mitigating constraints and issues early.  

During upstream process (USP) development, excessive foaming was observed inside the single-use 5.7L bioreactor, which posed a risk at scale by potentially causing unstable microbial fermentation in the originally planned 50L fermenter for manufacturing. For OMV manufacturing it is well known that the use of surfactants like common antifoam reagents can affect OMV integrity or interfere with the OMV purification and hence it is desirable to minimize the use of these, and mechanical or other foam control strategies are required. To address this, a 500L stainless-steel bioreactor was selected instead, offering a roomier headspace and a more suitable vessel architecture that mitigates the risks of a foamy culture. 

Agile data-driven optimisation for effective scale-up 

Prior to GMP, an engineering batch was produced with a strong focus on adaptability and rapid response was maintained throughout the technical scale-up, enabling the team to quickly address emerging challenges and evolving requirements. High flexibility and agility were demonstrated in addressing the potential risks identified throughout the technical batch at scale, with immediate implementation of necessary process changes to stay aligned with project needs and timelines. 

Proactive supply chain solutions for navigating logistical complexities  

Material supply issues were managed collaboratively to ensure a consistent resource flow, while pre-emptive procurement strategies enabled effective supply chain forecasting, minimizing potential delays and supporting project momentum. Efficiency was further enhanced through a cross-functional, optimized working approach, allowing multiple project aspects to be addressed in parallel and reducing bottlenecks. 

Leveraging bioprocess expertise and malleable supply chain solutions, together with the versatile repertoire of equipped cleanrooms, provided the scaling flexibility needed to absorb and adapt to late-stage process variations within the two-week window between the engineering and GMP batch. This approach also delivered on the capacity expansion request for increased downstream yield and filling volume. 

Navigating the complex landscape of stringent regulatory framework 

Compressed production timelines and stringent pharmacopeial standards required a robust analytical strategy to ensure drug substance quality. Efficient method validation and transfer enabled rapid, reliable analytics and expanded in-house testing capabilities.  

Reacting to the analytical data of the non-GMP runs, the upstream and downstream processing strategy were reengineered to ensure consistent performance, achieve high yields, and maintain a low total-to-infectious particle ratio in line with regulatory requirements. Additionally, the process was refined to meet stringent residual impurity limits, notably host cell DNA levels below 10 ng per dose, as recommended by global health authorities, while ensuring overall product quality and regulatory compliance. 

Collaborative approach overcame scale-up challenges 

By adopting a collaborative, equal-partner approach with close client engagement, the teams together enabled rapid decision-making, a key for the efficient execution of the process transfer and scale-up for the proprietary OMV vaccine platform. 

This strategy successfully accommodated late-stage process changes and overcame scale-up challenges, from 5.7L to 50L, and ultimately to 500L, while maintaining product quality and meeting regulatory specifications. As a result, GMP-grade drug substance was delivered in time for clinical trials.