Making Personalized Cancer Vaccines Reality: The Manufacturing Challenge Ahead
By Tony Hitchcock, AGH Bioconsulting, and Philip Probert, director of biologics & RNA Centre for Excellence, CPI
The idea of “vaccinating” the immune system to recognize and destroy cancer cells is not new. What has changed is our ability to identify potential tumor antigen targets. This advancement is making the notion increasingly achievable.
Global initiatives are also accelerating progress. The U.K.’s NHS Cancer Vaccine Launch Pad aims to enroll up to 10,000 patients by 2030, while regulators such as the U.K. MHRA recently published guidance on individualized mRNA immunotherapies.
While peptide vaccines laid early groundwork, DNA and mRNA vaccines dominate today because they can deliver antigens — sometimes more than 20 — in a single formulation. They also support multiple doses over a 12- to 18-month period, often in combination with antibody-based therapies. From a purely manufacturing perspective, mRNA dosing is typically less than 1/100th of what’s required for plasmid therapies, making the mRNA approach more favorable than plasmid DNA. The inherent platform nature of the mRNA production allows the same manufacturing process to be used for multiple types of cancer vaccines. This flexibility disconnects infrastructure investments from any individual product and allows shared process data to accelerate regulatory acceptance.
For these products to be made available to large patient groups at an affordable cost, the question now is how to solve the complex manufacturing challenges ahead.
The Manufacturing Bottleneck
Manufacturing presents three interconnected challenges: time, throughput, and cost.
For products to be effective and overcome issues arising from changes in tumor antigen profiles, they ideally must be delivered to the patient less than two months after the initial tumor characterization. Issues with throughput include current personalized therapies. For example, autologous CAR-T therapies are focused on relatively small patient groups with aggressive blood cancers, while personalized vaccines target more common diseases such as breast and skin cancers, where patient totals are likely to be much higher. Finally, therapies must have a reasonable cost. Current CAR-T therapies have price tags between $400,000 and $500,000, which may be “affordable” for health providers with a small number of patients, but are unsustainable for diseases with larger patient populations.
Manufacturing Processes And Required Scale
To address these challenges, we first need to look at the synthesis process itself. Since the development of the Covid vaccines, a vast amount has been invested in RNA production platforms and LNP formulation; however, significant challenges remain to develop manufacturing processes at the required scale.
While patient doses are small (<1 mg), there is also a need to manufacture sufficient materials for product testing, regulatory retains, and to accommodate potentially meaningful product losses — including losses during fill/finish operations. Batch sizes of 50 mg to 250 mg are common; this to is address the requirements for testing and clinical retains and the system losses, not least during the formulation and filling operations. A critical challenge for equipment suppliers will be minimizing these losses to reduce production scales and costs. Alongside this there is a need to work with regulators to reduce retains and overall amounts required for testing.
A key step in mRNA production is the need to generate a DNA template. Classically, this has been produced through the expansion of a synthetic plasmid using bacterial systems. While there are high-throughput production platforms to produce research grade plasmid, these are unlikely suitable for GMP production. Alternatively, manufacturing from the synthetic plasmid template could save significant time and money, but this option is likely to be dependent on the ability to reduce production scales.
Designing The Facility Of The Future
Two key challenges to producing these products are avoiding cross-contamination and ensuring process consistency.
Single-use systems are the logical choice and common practice to avoid cross-contamination, but they have limitations. One rests with the nature and cost of their sensor technologies, especially if they come in contact with product and need to be integrated into bags or tubing assemblies. The production of these assembles is labor intensive, raising costs and reducing throughput. For example, a tube set for a single chromatography system can cost over $5,000, while each production process may require two or three tube sets per batch.
Logically, process consistency will be achieved through automation. This will increase process control and eliminate human error. In turn, this will link to online data collection and electronic batch records to support QA systems and product release.
Segregation of these products will be a critical requirement; conventionally, this has been achieved through segregated manufacturing areas. This is the approach for cell therapies, with individual products being made in dedicated cleanrooms. However, this process has limitations; cost and throughput may not produce large amounts, while the number of products required could be much higher than those for cell therapies.
An alternative approach, using current technologies, is to produce multiple products within the same cleanroom in fully closed systems. Though this requires rigorous validation of system closure, it enables far higher throughput and cost efficiency.
The Drug Product Frontier
As with drug substance, much of the existing technology around product filling is based on large-scale automated filling systems, with manual fills only being performed for early-phase clinical trial production or “specials.” Once purified, mRNA is formulated into lipid nanoparticles (LNPs) before sterile filtration and filling. The need is for small-scale compliant systems as well as small-scale tangential flow filtration (TFF) systems, which minimize system costs and product losses. This also applies to the filling processes with inherently low throughput and disproportionately high product losses for small-volume fills.
Testing Every Batch — And Rethinking What “Every” Means
Current regulatory guidelines require extensive testing of all batches of pharmaceuticals to demonstrate identity, strength, purity, and safety, and the recent MHRA guidelines reiterate this — including the need for potency testing.
Traditional process validation is based around the production of a single product. Personalized vaccines upend that assumption. But while some assays can be performed on automated, high-throughput platforms, reducing time and cost, others — such as potency assays — pose significant challenges. Additionally, there is a need to adopt new approaches around sterility testing to reduce sample volumes.
Data As The New Validation
A key difference between the production of personalized cancer therapies compared to batch vaccines is the number of sets performed in clinical development. Conventional batch products will be much higher, which means the possibility of licensing over 1,000 products. As a result, a tremendous amount of data will be generated, covering numerous manufacturing processes and product analysis. The question: how can we best exploit this data to address the challenges in producing personalized cancer vaccines?
A key issue with personalized therapies is that each product will be unique and in theory may have different manufacturing outputs. With the collection of such a large amount of data from the production process and analytical testing, it should be possible to gain detailed knowledge of the impact of sequence changes on manufacturing output — in terms of yield and quality. This could allow manufacturers to adjust parameters in real time, minimizing failures while maintaining control.
This raises the question of the need to perform validation studies, as normal guidelines will clearly no longer apply. The key issue will arguably apply to critical quality attributes (CQAs) and critical process parameters (CPPs) and understanding issues about the impact of the process on product functionality.
However, regulators are already recognizing that it should be possible to leverage the data generated from the individual batches and model vaccines to provide sufficient assurance of process control and reproducibility. The challenge: how far can this be done and how quickly within the development process?
This applies to the mRNA product, the formulated LNP particles, and the filling operation, where there is a clear need to not only speed up processes but also reduce product losses.
Over time, data-driven modelling could justify reduced testing regimes, including simplified potency testing, provided the process-product relationship is well understood, documented, and reduces the risk of harm to patients.
Digitizing Quality And Release
Establishing quality systems that meet both the regulatory requirements and the levels of throughput required will be a major challenge for successful vaccine production and will require significant investment and innovation to achieve these goals.
From the outset, production processes will need to lean heavily on electronic systems to manage materials flow and traceability critical to data capture and analytical testing, as well as areas such as environmental monitoring and facility operation.
Regarding the manufacturing process, there is an obvious need for rapid review and product release of multiple batches. To achieve this, there will need to be a high reliance on electronic batch and analytical records. While this will be a significant challenge, there have been substantial technological developments and increased adoption of electronic batch records in the industry recently, but this will still require a considerable amount of investment and development.
The Path Forward
Personalized cancer vaccines have the potential to transform cancer care, but there are important hurdles to overcome if they are to be made available to wide patient populations.
That means:
- building modular, automated, data-driven facilities
- using predictive analytics for process understanding and release
- partnering early with regulators to align on new validation models.
While there is extensive focus on the clinical aspects of these products, suppliers and manufacturers must invest and develop the solutions required to bring these lifesaving advancements to the patient, if we are at all committed to moving along the path forward.
About the Experts
Tony Hitchcock is the principal and owner of AGH Bioconsulting. He has spent his decades-long career in the in the biotechnology field, with over 30 years in the production of complex biologics for clinical trials in the European Union and U.S. He has worked in areas of process development and manufacturing with experience in engineering and process systems. He has worked on the development of more than 30 products for clinical trials, including plasmid DNA, viral and bacteriophage products, and recombinant proteins from microbial, mammalian, and insect cell sources. Contact him at tony@aghbioconsulting.com.
Philip Probert, Ph.D., is a strategic scientific leader with extensive experience in bioprocessing and strategy development. He currently serves as the director of biologics & RNA Centre for Excellence at CPI. Probert is responsible for ensuring safe, compliant, and effective GMP manufacturing of advanced biopharmaceuticals, while driving innovation, capability development, and external partnerships that support the U.K.’s biopharma sector. His expertise spans all biologic modalities, with particular subject expertise in synthetic and cell-free manufacturing processes for nucleic acids and proteins. Probert holds a Ph.D. in hepatic toxicology from Newcastle University and an MBA from the Open University.