Partnering with CDMOs and the steps of scaling up processes for vaccines and gene therapies
At Cell & Gene Therapy Global 2020, Ellie Hanania, Head of Process Development at Fujifilm Diosynth illustrated the steps towards large scale manufacturing via partnering with a CDMO. Biotech writer Silvia Hnatova revisits the key takeaways.
Dr. Ellie Hanania, Head of Process Development at Fujifilm Diosynth delivered an interesting presentation focused on large-scale manufacturing of vaccines and gene therapy products.
His talk was focused on the offering of contract development and manufacturing companies (CDMOs) and highlighted the importance of flexible large-scale manufacturing.
Dr. Hanania started his talk by explaining that when selecting a contract development and manufacturing company (CDMO), the extent of support is important.
Switching CDMO consumes time and costs – ideally, a CDMO can support all processes from inception to launch, including auxiliary support with testing and regulatory filing.
There are multiple stages of processes supported by CDMO: pre-clinical, Phase I and II, Phase III, and regulatory approval and launch.
Pre-clinical development starts by selecting well-known components for the production process to be developed and optimized.
Later, the process is scaled up to be robust with consistent performance and quality attributes. In later phases of production, key production parameters are characterized and production operation manufacturing ranges are set.
Dr. Hanania added that a few years ago, the majority of gene therapy clinical trials were in Phase I and II, and some of these have gained FDA approvals (e.g. Yescarta by Kite Pharma and Kymriah by Novartis).
Currently, there are only 6 gene therapies approved by either (or both) FDA and EMA.
The advancements in gene therapy resulted in targeting more common disorders, including genetic, oncological, and neurological disorders – as opposed to single-gene disorders.
To satisfy the demand, large-scale manufacturing is key, according to Dr. Hanania. Similarly, the emergence of large-scale epidemics creates such demand, that Dr. Hanania predicts will increase.
Elaborating upon his prediction, Dr. Hanania argued that manufacturing processes must accommodate the option of scaling up, to allow extended applications.
As there are more programs with more patients in late Phase clinical trials, together with the pandemic demand, the overall demand for gene therapies or vaccines will only increase.
Dr. Hanania continued by presenting a high-level overview of manufacturing that incorporates viral vector production and suspension cultures. In general, manufacturing includes 6 phases: inoculum, expansion, production in a bioreactor, two purification phases, and filling.
It was emphasized that manufacturing must be accompanied by testing to characterize the gene therapy products.
The safety of the product must be tested to see whether the product elicits unexpected side effects when used appropriately in a patient.
The product must be characterized to precisely describe the contents on a label. The strength and potency of the product must be tested to deliver the correct dosage over the shelf-life of the product.
The purity of the product is tested to confirm that the product is free from physical, biological, and chemical contamination.
Manufacturing must be conducted adhering to quality measures, to ensure consistency and to meet quality specifications, in all generated batches.
To address the issue of manufacturing, Dr. Hanania focused on the main questions before scaling up that will define the production scale: doses, the process and its productivity, and testing.
Using these three parameters, the production scale can be defined.
It was explained that scaling up can be achieved through linear scaling (switching from smaller to bigger bioreactor) or multiplexing.
Dr. Hanania pointed out that although a linear approach can be simple, it can be time-consuming and will always depend on the products available (e.g. the largest size of a bioreactor on the market).
He instead drew attention to a multiplexing approach that would utilize several largest-size bioreactors, accommodated by the expansion of cells in the expansion phases, shortening the overall time of the production.
Limitations of a multiplexing approach include the availability of equipment and supplies, and the design of the facility to handle the waste.
One of the challenges of scaling up is to have enough clean rooms to accommodate any selected approach, Dr. Hanania explained.
For example, Fujifilm Diosynth offers several standardized rooms, that are flexible and can be scaled up.
The latest edition consists of custom and advanced clean rooms, that can be configured with various ISO configurations.
Multiple cleanrooms can be joined together, and all have high ceilings to accommodate the fitting of large pieces of equipment.
To illustrate scalable manufacturing, an example of a facility configuration to provide high-throughput viral gene therapy product manufacturing was presented.
There were multiple interconnected clean rooms: first to accommodate cell expansion, second to seed the bioreactors, and multiple productions and purification clean rooms, and final clean fill finish.
Scaling up of a process is dependent on having the infrastructure to support this, Dr. Hanania said. The infrastructure to support scaling up includes facility design to support scalability, flexibility, adaptability, robustness, is expandable and durable.
Ideally, there are advanced mobile cleanrooms available in different generations, sizes, and features.
Closed system processing that supports the use of isolators for the different phases, single-use systems, full use of VHP on room scale, and gloveless robotic isolator for aseptic filling with VHP IN and OUT (e.g. Vanrx SA25).
Production processes support scaling up and can be platform or standard. Platform processes can contribute to overall cost reduction to the client.
Dr. Hanania closed his talk by highlighting that to ensure adherence to timelines, early planning and investment are key to ensure adherence to the proposed filing date.
CDMO’s offering can be used to facilitate standardized processes and templated documents. As the field progresses, there will be stable cell lines available, further facilitating the processes.
Regular interactions with the regulators are key to avoid surprises when it comes to enhanced regulations for gene therapy.
