Senthil Ramaswamy (Lonza, Basel, Switzerland) discusses the challenges currently facing the scale up of allogeneic therapies and how he envisions the future of cell and gene therapy.
Can you introduce yourself and tell us about your role?
I am the Head of Cell and Gene Technologies (CGT), R&D, Lonza (Basel, Switzerland) and responsible for our innovation programs in this area. Lonza R&D’s mission is to ensure that we are working to identify and develop the most relevant and innovative technologies in this area, which will translate into enabling CDMO offerings for our clients.
Over the last 10 years at Lonza, I have had a range of technical and operational roles, both in large and small scale biologics and CGT. As R&D Head, my job is to drive innovation while leveraging Lonza’s collective technical, operations and GMP knowledge, as well as its extensive expertise, to achieve our commonly shared goal of industrializing CGT manufacturing. We do this through a deliberate mix of internal and collaborative-external innovation projects since we recognize that there is an incredible amount of technology development happening on many fronts in the industry and we need to leverage this in order to have the best offering available to our clients.
What cell and gene therapy technologies is Lonza working on at the minute?
The clear and present need within the CGT field is to drive industrialization and to meaningfully impact the commercial success of these therapies, via efficient scaling up and maintaining an acceptable cost of goods sold (COGS). CGT R&D at Lonza has a laser-sharp focus on this mission.
Some of our key programs include developing platforms for the suspension-based manufacturing of adeno-associated and lentivirus vectors, via both transient transfection and the design of stably integrated producer cell lines; allogeneic CAR-T manufacturing technologies; and pluripotent stem cell technologies.
There are some excellent examples of how we leverage external innovations too, such as our recent acquisitions of the Cocoonâ„¢ technology for autologous cell therapy and the partnership with Vineti (CA, USA) for vein-to-vein track and trace capability.
From your perspective, what are the major challenges cell and gene therapies face in manufacturing and how Lonza help address them?
Our focus is clearly on commercialization and producing sustainable COGS through well-designed manufacturing processes. In cell therapy manufacturing, the process is the product and therefore, early process design must consider final commercial implementation.
For allogeneic products, if scale up of the process is not considered early on and the appropriate choice of cell culture technologies not made, it is inevitable that the end manufacturing process will carry a high risk and significantly limit scale up. Changing the process at the later stages of clinical development, or even post-commercialization, is very difficult without a clear path to demonstrate product comparability.
For autologous cell therapies, where a product batch is made for every patient, scale out to meet commercialization needs can be quite challenging. A number of treatments in development are reliant on non-optimized, manual and open processes. This is very high risk for manufacturing, in terms of process hygiene and consistency, and consequently batch success, patient safety and product availability. It is absolutely critical that integrated automation and track and trace technologies become the standard for these types of therapies.
There is also a significant challenge in meeting the market demand for the lentivirus vectors utilized in autologous gene-modified cell therapies. We are working on suspension platforms, with both transient transfection and stable producer cell lines, to alleviate this constraint.
Similar to lentiviral vectors, for adeno-associated viruses (AAV), we are working on stable, helper virus-free producer cell lines to support scale up and future process streamlining, as well as downstream platforms for AAV purification where current yields are extremely low.
How early should researchers and manufacturers consider good manufacturing practices (GMP) and why?
For cell therapy, the process is the product, so GMP requirements should be considered very early on via a GMP manufacturability assessment. Once the product has entered clinical trials, it is inevitable that the time pressures of generating clinical data, demonstrating comparability and the urgency of progressing through the clinical stages will set a large barrier to implementing process changes.
An approach we advocate to our CDMO customers is to contemplate a parallel methodology, where products can initiate clinical trials with a phase-appropriate process, whilst keeping the long-term process development ongoing in parallel. As meaningful process evolution occurs, comparability can be included in the clinical trial process, reducing the overall impact to the program and resulting in a fit for purpose manufacturing process that is ready to be commercialized.
Another important aspect for CGTs is the selection of raw materials. We often come across processes that are designed with research use only (RUO) materials, rather than GMP sourced materials. It is critical to carefully source raw materials, select GMP sourced materials where possible and have a comprehensive strategy in those cases where GMP sourced materials are not available very early on in the development process, to avoid challenges down the road.
What do you think the biggest challenge is in scaling up cell and gene therapies for commercial success?
The biggest challenge is that the pace of therapy development and regulatory approval is far ahead of the pace of manufacturing standardization and efficiency. Unlike traditional biologics, where manufacturing platforms are well established and the focus is on drug efficacy, in CGT the urgent focus is on scaling up and reducing COGs since efficacy has been excellent. CDMOs have a central role in this industrialization process: we bring the breadth and depth of experience and technologies to address this challenge for our customers.
What is still required to really allow the expansion of allogeneic therapies?
It is critical that manufacturing for allogeneic therapies moves from partially closed, manual, labor-intensive processes to fully closed and automated processes. The distinction between the two approaches has a major impact on facility design, batch success and, ultimately, COGS.
Any open operations must be carried out in Grade A biological safety cabinet in a Grade B cleanroom, which significantly drives up facility costs. Furthermore, the entire process must be run aseptically and qualified by timed aseptic process qualification runs, which impact plant utilization. Finally, manual processing introduces the risk of process variability, so the need for stringent aseptic training and qualification of manufacturing personnel could become a major bottleneck for getting resources online.
This can greatly impact operational flexibility, especially in a multi-product scenario. Implementing closed, automated processing could allow manufacturing to occur in a Grade C space without the constraints described above and represent a significant step forward towards industrialization of allogeneic therapy manufacturing.
What specific challenges may allogeneic therapies face in their manufacturing over their autologous counterparts?
One clear advantage of allogeneic therapies is better control over starting materials, utilizing healthy donor cells. The significant variability of starting patient material for autologous therapies can translate into process variability and impact batch success. However, autologous therapies may represent a lower safety risk to the patient since the process uses their own cells. In the case of allogeneic therapies, manufacturing and testing controls are critical since any safety or product quality issues will affect a much larger number of patients.
Today, allogeneic therapies that are headed towards Phase III and commercial marketing rely on 2D systems for manufacturing, which severely increases process risk and limits scalability. The material and labor requirements for these processes are exceptionally high and can peak at certain steps of the manufacturing process, such as cell harvest, making planning and control very challenging. Transitioning to closed, 3D automated systems will significantly alleviate these challenges.
Another area to focus on is control of critical raw materials. Many allogeneic therapies are still reliant on fetal bovine serum (FBS) and other naturally sourced materials, which can introduce significant variability and risk. There is tremendous effort going on to replace these materials with chemically defined components and innovators must develop their processes with these new materials from the very start.
What always surprises you about the cell and gene therapy field?
The rapid pace of development can make one’s head spin at times. The strong efficacy demonstrated by this technology has clearly led to manufacturing playing catch up to the clinic. It raises exciting possibilities and the pace of progress in this area is spectacular.
What are your predictions for the next decade in the cell and gene therapy field?
Based on the product approvals that we have seen in the last couple of years, we can expect dozens of new products making it to the market in the next decade. This also means that manufacturing technology and capacity will need to keep up with the rapidly increasing demand in order to ensure industry success and therapy availability.
Consequently, I expect to see rapid progress toward the standardization and automation of cell and gene therapy manufacturing in the next 5—10 years. Autologous therapies will transition to integrated automated manufacturing systems — like the Cocoon — and be supported by automated supply chain frameworks, such as vein-to-vein tracking, since that is critical for sustainable COGS in a one-batch-one-patient system. Specifically, in allogeneic cell therapies, most new processes in development are already transitioning to more scalable and GMP compatible processes, which will achieve the level of standardization that we have for biologics.
How should people contact you if they wish to?
I can be reached at [email protected]. I am always eager to discuss CGT manufacturing technologies and paths to rapid commercial success for these life changing therapies!
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