Cell Culture Dish Podcast

In this podcast, we spoke with Dr. George Wang, Vice President of Discovery and Preclinical Services at WuXi Biologics about the importance of identifying potential manufacturing, stability, and scalability challenges early to mitigate risks, reduce costs, and streamline drug development timelines. By evaluating factors such as solubility, stability, and manufacturability during initial candidate screening, companies can avoid costly setbacks later in the process. Advanced tools like high-throughput assays, computational modeling, and AI-based predictions are now essential for these evaluations.

What Is Developability?

Dr. Wang began by defining developability as the assessment of whether a drug candidate possesses the necessary attributes to be scaled up for production during Chemistry, Manufacturing, and Controls (CMC) development and, ultimately, for clinical trials and commercialization. He explained, “It’s about identifying potential red flags early on—issues like aggregation, degradation, or manufacturing inefficiencies—that could derail a candidate further down the line.”

Why Focus on Developability During Discovery?

Traditionally, discovery efforts have focused on identifying antibodies with the highest efficacy and safety profiles. However, the increasing complexity of biologics, including bispecific antibodies and antibody-drug conjugates, has shifted industry focus. Dr. Wang emphasized the costly consequences of overlooking developability in the discovery phase. “Imagine investing millions into a molecule, only to discover insurmountable stability or manufacturability issues during development,” he said. “Performing these assessments early is like an insurance policy, mitigating risks and saving time and resources.”

The Economic Case for Early Developability Assessments

Dr. Wang highlighted the economic rationale for incorporating developability assessments during the initial discovery phase. “The cost of discovery is less than 1% of the total development cost. Spending a bit more upfront can save millions in reengineering or restarting development,” he noted. He also pointed out that superior developability attributes can provide a competitive edge, enabling faster clinical trial entry or product approval.

Key Challenges and Industry Solutions

Despite its benefits, the integration of developability assessments in discovery labs faces challenges. Labs often lack the tools, materials, and expertise required for systematic evaluations. “Developability attributes must be assessed using a robust combination of computational methods, analytical tools, and high-throughput assays, which many labs are not equipped to handle,” Dr. Wang explained.

Companies like WuXi Biologics have stepped in to bridge this gap. “Our Discovery unit collaborates closely with our CMC team to identify and address developability issues early on,” said Dr. Wang. WuXi’s “WuXiDEEP™,” platform has become a cornerstone of their success, helping fix more than 50 problematic molecules and guiding hundreds of projects through the development pipeline.

A Stepwise Approach to Developability

Dr. Wang outlined a stepwise approach to developability assessments, starting with high-throughput evaluations during the initial screening of hundreds of candidates. “We use computational analysis to identify red flags such as post-translational modification hotspots or aggregation risks,” he explained. Promising candidates then undergo more detailed assessments, requiring larger material quantities and lower-throughput methods.

Even when issues arise, solutions like protein engineering can salvage candidates with strong biological functions. “It’s not about discarding problem molecules outright but addressing and optimizing their developability profiles,” Dr. Wang emphasized.

The Role of AI in Developability Assessments

Artificial intelligence (AI) is playing an increasingly significant role in drug discovery, and Dr.

In this podcast, we spoke with Isha Dey, Senior Scientist, Cell Biology R&D, at Thermo Fisher Scientific about the challenges researchers face in selecting appropriate cell culture conditions due to variability in cell lines, lack of standardized protocols, and inconsistent reagent quality. Thermo Fisher Scientific's new Cell Culture Select Tool was developed to address these challenges by providing specific recommendations for media, FBS, and cultureware for over 150 cell lines, backed by extensive R&D data.

Understanding the Challenges in Cell Culture Selection

Thermo Fisher Scientific's new Cell Culture Select Tool addresses a persistent challenge in laboratory science: identifying the appropriate cell culture conditions and selecting the right media, supplements, and reagents for different cell lines. The process is complicated by factors like cell line variability, lack of standardized protocols, and inconsistent reagent quality. These issues can introduce variability and impact experimental results, posing a challenge for scientists across labs.

“Different cell lines have unique requirements,” explained Isha. “It’s challenging to pinpoint optimal culture conditions due to variability in cell line responses. Additionally, there isn’t always a standardized protocol across labs or comprehensive information on specific culturing needs. This can make it difficult to select the most appropriate media, supplements, and other materials.”

Ensuring a consistent supply of high-quality products is essential for reproducibility in experiments. Thermo Fisher Scientific's trusted brands, such as Gibco, Nunc, and Invitrogen, are known for their quality, which is critical for minimizing variability in experimental readouts.

The Inspiration Behind the Cell Culture Select Tool

The idea for the Cell Culture Select Tool originated from an update to Thermo Fisher Scientific's online technical reference library. Previously, the website listed recommended media types segmented by cell line culture methods—adherent, semi-adherent, or suspension. While helpful, this list was lengthy and lacked interactive functionality.

Isha said, “We realized that we could streamline this information into a user-friendly tool”. “In our R&D labs, we culture over 150 cell lines using various media, supplements, and equipment. By making this data accessible to other researchers through an interactive tool, we hoped to eliminate the guesswork and enable reproducible cell culture success.”

The tool now provides recommendations for specific media, supplements, and cultureware for culturing, passaging, and freezing over 150 cell lines. With in-house data supporting 75% of these lines, researchers gain access to the resources and insights gathered from Thermo Fisher’s extensive R&D experience.

Selecting Cell Lines for the Tool

The team started with cell lines listed in their technical reference webpage and expanded the list based on the lines frequently cultured in their R&D labs. These labs conduct heavy cell culture work for various applications, including media development, fluorescence imaging, Western blotting, flow cytometry, transfection, transduction studies, and more.

“We wanted to make our R&D data available to researchers for convenience,” shared Isha. “This effort involved many scientists across R&D sites who contributed data and images showing how each cell line appears in recommended media.”

Quality and Verification in Thermo Fisher’s Labs

The tool’s data is backed by rigorous testing in Thermo Fisher’s R&D labs. Cells are grown in their respective media, culture plastics, and consumables over multiple passages to ensure accuracy. For cancer cell lines, STR profiling and mycoplasma testing are conducted regularly, while stem cell cultures are assessed for pluripotency and purity using imaging and flow cytometry.

“Representative images of cell lines, captured using our EVOS imaging system,

In this podcast, we spoke with Ryan Bernhardt, CEO of Biosero and Jesse Mulcahy, Director and Head of Automation at Cellino about the importance of utilizing automation in cell therapy research and production and the potential of these technologies to transform the healthcare landscape and improve patient access.

The Challenge of Accessibility in Cellular Therapy

The traditional methods of creating induced pluripotent stem cells (iPSCs) are notoriously laborious and expensive, often costing hundreds of thousands, if not millions, of dollars per patient. This high cost poses a substantial barrier to accessibility for many patients in need of personalized cell therapy treatments. Cellino is leveraging advanced automation, AI, and linear technology to dramatically redefine and improve on traditional production processes.

Advancing Automation in Cell Therapy

Cellino’s approach employs its innovative technology, known as NEBULA. This system utilizes self-contained units, referred to as cassettes, to cultivate personalized cell therapies directly in hospitals.

NEBULA uses AI to monitor cell growth while incorporating laser technology to selectively eliminate unhealthy cells. This level of automation has the potential to reduce the manufacturing costs of personalized stem cell therapies by at least tenfold, making treatments more accessible to a broader range of patients.

Supporting automation for Cellino is Biosero’s Green Button Go software suite, which plays a crucial role in automating the workflows of life science organizations. Ryan explained how their technology empowers life science organizations to automate essential scientific processes, facilitating the scheduling of workflows and direct communication with lab instruments. With the capability to run processes continuously—day or night—labs can maintain and cultivate cells without the constraints of a conventional workweek. This 24/7 operational capacity allows for the rigorous demands of cellular therapeutics to be met more efficiently.

Bridging Gaps with Integrated Automation

Ryan describes how lab automation can no longer be seen as merely robotic arms and conveyor belts; it integrates three key elements: physical, logical, and data. By orchestrating these components, automation streamlines and accelerates research across labs that were traditionally siloed and specialized in specific areas. This approach connects different labs, unifying knowledge, expertise, and data systems, enabling real-time decision-making and data-driven insights. Automation enhances workflows by eliminating delays and optimizing project timelines. It serves as a performance tool for scientists, improving efficiency, consistency, and the ability to address complex challenges, while also incorporating AI and machine learning for smarter, continuous processes.

Jesse Mulcahy, Director and Head of Automation at Cellino emphasized the significance of Biosero’s orchestration software in improving efficiency by optimizing scheduling, reducing downtime, and maximizing throughput in cell therapy production. The Green Button Go orchestrator improves consistency by automating key steps and minimizing human intervention, ensuring reproducible results for quality control. The software is flexible and modular, allowing for easy adaptation of workflows as needs evolve, whether adding new instruments or changing protocols. This scalability is crucial for producing personalized cell therapies more efficiently and at a larger scale.

Addressing Pain Points and Future Trends

Despite the advancements, there are still hurdles to overcome in the biologics’ development landscape. Ryan notes that the field is evolving rapidly, with significant advancements in cell culturing, automation, and decision-making processes. Traditional cell culturing is being automated to assess key factors like cell viability, confluence, and other qualitative aspects, aiding decisions on feeding, splitting, and harvesting.

In this podcast, we spoke with Fran Gregory, Vice President of Emerging Therapies at Cardinal Health about the cell and gene therapy landscape, innovative solutions to reduce cost, the regulatory environment, and reimbursement.

Fran Gregory brings extensive experience in the biologic drug sector. As a pharmacist, she has worked across various areas, including payer PBM, pharmaceutical manufacturing, and now at Cardinal Health. Gregory oversees the advanced therapy solutions and biosimilars business units, which focus on cell and gene therapies and cost-saving biologics, respectively.

Cell and Gene Therapy Landscape

In the cell and gene therapy landscape, there are about 25 FDA-approved products in the U.S., split into 35% cell therapies and 65% gene therapies (at the time of the interview, now 38). This field has rapidly evolved since the approval of the first CAR-T cell therapies in 2017, and the FDA continues to support innovation, with a pipeline of around 1,500 products under development. The agency aims to approve over 100 products by 2030, potentially benefiting more than 100,000 patients. Therapeutic areas include oncology, hematology, neurology, diabetes, and even conditions affecting vision and hearing.

Gregory notes the unique challenges in this field, such as conducting clinical trials with small patient populations, complex manufacturing processes, and stringent cold chain logistics for distribution. The high cost of these therapies also poses a challenge, as some treatments can cost millions. However, opportunities abound as the healthcare system innovates to improve regulatory processes, distribution methods, and patient experiences.

Reducing Cost

She explains that the high cost of cell and gene therapies is due to the intensive research, development, and manufacturing requirements, particularly for treatments targeting rare diseases. Although the upfront cost is high, these therapies can offer long-term savings by reducing ongoing medical expenses for patients. New payment models, such as outcomes-based agreements, annuities, and warranties, are being developed to increase patient access and manage costs.

One innovative approach is the Cell and Gene Therapy Access Model, inspired by President Biden’s 2022 executive order on lowering prescription costs. This model enables CMS to negotiate with manufacturers on behalf of states, enhancing access for patients and encouraging manufacturer participation. The first products under this model, aimed at sickle cell disease, are expected to launch in early 2025. Gregory expresses optimism about the future of these therapies and their potential to drive further healthcare innovation.

Regulatory Environment

The regulatory environment for cell and gene therapies is evolving quickly as the FDA is committed to expediting the market availability of these products. The agency offers pathways like accelerated approval, where manufacturers can bring products to market based on indicative clinical outcomes and continue gathering real-world evidence post-approval. The FDA’s regenerative medicine advanced therapy (RMAT) designation also addresses the small patient populations in cell and gene therapy trials, focusing less on traditional statistical significance. Looking ahead, the FDA will increasingly emphasize outcome measures and closely monitor manufacturing processes to ensure safety and efficiency as technologies evolve.

Reimbursement

Organizations like the Institute for Clinical and Economic Review (ICER) will also play a significant role in evaluating both clinical and economic outcomes, influencing pricing and reimbursement discussions between manufacturers, governments, and insurers. As the landscape grows, these evaluations will guide not only regulatory decisions but also payment models, ensuring that gene therapies offer value and affordability.

Cardinal Health is deeply involved in the commercialization of cell and gene therapies,

In this podcast, we spoke with Luca Alberici, Senior Vice President and General Manager, Milan Facility, AGC Biologics about the road to their recent EC and FDA approval to commercially manufacture Lenmeldy™ and their future plans in cell and gene therapy. 

What is Lenmeldy?

We began the podcast by talking about AGC Biologics’ Milan site and their FDA approval to commercially manufacture Orchard Therapeutics’ Lenmeldy. Luca explained that Lenmeldy is a gene modified cell therapy product for the treatment of Metachromatic leukodystrophy (MLD), an ultra-rare hereditary disease characterized by accumulation of fats that causes neurodegenerative symptoms. It is a pediatric disease, and patients generally die by the age of five.  

With this therapy the patient’s stem cells are collected and modified through the use of a lentiviral vector to add a gene called ARSA that encodes for the right form of the enzyme that these patients are encoding wrong. These modified stem cells are then administered back to the patient so they can immune reconstitute not only the immune system, but the cells will also cross correct through secretion of the right form of the enzyme. After just a single shot of the therapy, there is an improvement in their condition and they develop normally, especially if treated in a pre-symptomatic phase. This is the power of gene therapy at its best.  

The Pathway to FDA Approval for Commercial Manufacture

We then discussed the pathway for receiving approval to commercially manufacture this product and how the AGC Biologics Milan team navigated this process. Luca described that it was quite a long journey. AGC Biologics were manufacturing this product at preclinical and clinical phases dating back roughly 15 years. They worked with a series of different sponsors, it was developed by the San Rafaelle Telethon Institute for Gene Therapy in Milan Italy, then GSK continued the clinical development before it was acquired by Orchard Therapeutics. AGC Biologics remained the manufacturer during this time and in 2020 received approval for commercial manufacture of the product in Europe, but FDA requirements are different so over the last two years, they partnered with Orchard Therapeutics and worked to meet the FDA requirements for approval.  

Luca explained that approval required a great deal of work on the process, the analytics, the quality system, supply chain, and raw materials. One of the most transversal aspects of the validation of a product is getting it ready to be manufactured for the market and it was great to go this last mile with a strong partner like Orchard Therapeutics. He also credits the infrastructure of AGC Biologics, which is a multi-site global organization and provided the Milan site great support in terms of general quality, standards, procedures, and simply by having faced multiple FDA inspections before. The combination of all these factors was what carried them to the finish line, it required extensive teamwork, not only at the Milan site but also the entire organization. 

The Only Site to Receive EC and FDA Commercial Manufacture Approval

I followed up by mentioning how with approval from the European Commission and the FDA, the AGC Biologics Milan facility is the only one in the cell and gene therapy industry to have commercial manufacturing authorization from both the FDA and the EC for LVV and cells. I asked Luca why there are so few CDMO's who have achieved this and what makes the FDA and EMA approval process so challenging? He explained that the Milan site was the first site to receive clinical manufacturing approval for an ex vivo gene therapy in 2003, 21 years ago, when cell and gene therapy was almost nonexistent at the time. They were the first facility to receive approval for commercial manufacturing in Europe for a marketed product in 2015/2016, 10 years ago. Now they are the only site who can do viral vector and cell therapy, both approved from the main authorities,

This panel discussion was originally published in the eBook

“ Monoclonal Antibody Manufacturing Trends, Challenges, and Analytical Solutions to Eliminate Bioprocessing Bottlenecks”

You can download all the articles in the series, by downloading the eBook.

 

Panel discussion members:

Carrie Mason - Associate Director, R&D at Lonza Biologics

Laura Madia - Independent Industry Consultant

Alan Opper – Director of HaLCon Sales at RedShiftBio

David Sloan, PhD – Senior Vice President, Life Sciences at RedShiftBio

Brandy Sargent, Editor in-chief, Cell Culture Dish and Downstream Column (Moderator)

In this panel discussion, we talked with industry experts about antibody process development and manufacturing. Specifically focusing on current antibody titer expectations, analytical challenges and how real time titer measurement is a game changer for bioproduction moving forward.

Where is the industry at today with titer expectations and what are the best practices for measuring titer?

Laura Madia

With respect to expectations regarding titer over the years, what we’ve seen is a need for increased titer

within the upstream development of a drug. As an industry, we have moved from the 80s where titers were closer

to .2 to .5 grams per liter to the early 2000s where concentrations of titer production rose to 3 to 5 grams per

liter. What we see today is a continued increase in titer concentrations, which creates a challenge to make sure

that you have technologies that can accurately measure titer concentration without introducing any errors.

The other thing that we have seen within the industry is the need for more data to not only understand what is

happening in the tank, but also to be able to make decisions about the product as the process is running or

shortly after.

Lastly, it is important to consider people and resources. It has been exacerbated by COVID, but it is difficult

to find people to work within the industry and there are fewer people within a production suite. This has helped

to drive the need for online and remote monitoring and automation to make it easier to get the necessary

measurements.

David Sloan

To follow up on the lack of workers, one of the things that we constantly hear from the customers we are

working with is that training employees can be a real challenge and a very time-intensive process. Technologies

that are easier to use and require less expertise help get people up and running and minimize errors amongst new

users of a technology.

Laura Madia

As for the current best practices for measuring titer, HPLC is the gold standard. But HPLC presents some

challenges including training and HPLC requires a highly skilled person to get accurate results. There is a need

for something that is simple and easy to use when it comes to measuring titer. You will still need HPLC results

for approval and decisions at the end, but to be able to monitor titer throughout the process is important.

What are the challenges associated with the way that titer is measured today and what can we do as an industry

to improve?

Laura Madia

One of the challenges is that most of the assays available today are batch processes, so that lends itself to

providing a retrospective look and means that most people don’t run samples throughout the process. This is

because most people save these tests until the end when they can run a batch and make it more cost effective,

and it is typically a long time to result so running it during the process isn’t helpful. Systems today are more

for batch process and are not set up for at-line measurement, unless you are lucky enough to be able to have an

HPLC that’s dedicated to that tank.

Another challenge is speed and accuracy. Many of the techniques that are offline today are longer assays

because they’re running as a batch. You must wait for the entire batch, which is a long time to first result.

In this podcast, we spoke with Nainesh Shah, Senior Application Engineer at Asahi Kasei Bioprocess about buffer management including the benefits of inline buffer formulation, and single use inline buffer formulation systems.  

Buffer Management 

We started the podcast by talking about how critical buffer management is to bioprocessing. Mr. Shah discussed how buffers are required in large quantities during the biomanufacturing process and that traditionally buffers were made in large tanks, stored, and used as needed. However, now real estate in the bioprocessing industry is at a premium and companies are looking to utilize new technologies that can reduce facility footprint. For buffer management, it makes sense to create buffer on demand to reduce the footprint dedicated to buffer production in the past.  

Inline buffer formulation is a hot topic with companies who require a large quantity of buffer because it provides a way to create buffer on demand in a much smaller footprint. The interesting thing is that it is now also a hot topic among small R&D scale buffer users as well. Inline buffer formulation systems are ideal for users who need 200 to 500 liters of buffer at a time. The system takes the concentrate and adds clean water to provide just the right amount of buffer on demand. Another benefit of inline buffer formulation is that you can achieve a quick process changeover and move on to the next buffer formulation without spending valuable time cleaning the tank, taking samples, and readjusting the critical parameters.  

Recently, any new manufacturer, whether it's a large scale or small scale tends to move into this field of buffer management and operates one or two Inline Buffer Formulation (IBF) systems like the MOTIV™. They then use these systems to make all sorts of buffers needed for their various processes. 

The MOTIV Family of Inline Buffer Formulation Systems

Next, I asked Nainesh if he could talk a bit more about the MOTIV family of inline buffer formulation and fluid management systems that Asahi Kasei Bioprocess America (AKBA) offers. He explained how the award-winning MOTIV family has evolved into a series of inline buffer formulation systems designed to help companies move past downstream bottlenecks by driving buffer productivity. The product family includes 3-pump, 5-pump, and custom IBF configurations that can fit most any space, cost, or performance requirements. The MOTIV is a leader in buffer production with a range of scale from 4,500 liters per hour to 10 liters per minute to fit an entire range of volume requirements. 

He went on to say that they have added a new feature where MOTIV can fill up bags with buffer and monitor the quantity in the bag to make buffer on demand even easier.  

MOTIV SU

Then we talked about the new MOTIV SU, a single use inline buffer formulation system, built to produce complex buffers on-demand effectively and efficiently, all from one pump head, and without the need for CIP/SIP procedures between batches. The innovative design modulates flow through control valves while simultaneously integrating buffer solutions and mixing. As with all the MOTIV systems, OCELOT System Control ensures precise blends every time, controlled by pH and conductivity feedback or flow. 

The MOTIV SU is perfect for a biomanufacturer who does not want to spend time with cleaning and validation. It is great for one time use as it does not require time spent in cleaning, validation, and making sure that it is free of all the contaminants and all the buffers which may be harmful for the next process. Another benefit would be if a biomanufacturer used a buffer which had a chemical or ingredient which would be problematic for other processes, and they wanted to eliminate any risk of contamination.  

Since the MOTIV SU has replaceable parts, which come as a pre-built unit, it is easy to replace the components and then the system is ready to run again.

In this podcast, we spoke with Margherita Neri, Director of Vector Process Development, Milan Site at AGC Biologics, Andrew Laskowski, Global Product Manager Bioreactors at Cytiva and Andreia Pedregal, Upstream Applications Specialist Manager at Cytiva about large-scale viral vector manufacturing. Our conversation included discussions around scalability, AAV (adeno-associated virus) and lentivirus production platforms, adherent culture, and next generation bioreactor improvements.

I began the interview by asking Margherita about her work at AGC Biologics. She explained that as the Director of the Vector Process Development Unit, her team is responsible for process development of large scale viral vector production for gene therapy applications. Her team is also the first point of contact for new clients.

Next, we talked about the types of viral vector platforms that AGC Biologics operates. Margherita described that at their Milan site, they offer AAV (adeno associated virus) and lentiviral vector production platforms in adhesion and in suspension, at 50-to-200-liter scale with expansion planned for up to 1,000 liters.

I then asked her about some of the differences between adherent cell culture and suspension cell culture paths to commercial manufacturing. Margherita said that the first consideration is that most clinical trials in gene therapy have been sustained with vector produced from adherent cells, typically via processes performed using Cell Factory™ or Cell STACK®. Now that those gene therapy products are being commercialized, manufacturers need to increase scale and demonstrate comparability using a minimal comparability exercise. So, systems that allow adherent scale up are very useful in this process.

Suspension processes are appealing from a scalability point of view because historically they were used for traditional protein bioproductions which can be scaled up to 20,000 – 30,000 liters. Of course, this scale still needs to be demonstrated for vector production that is performed mainly using transient transfection at 200-500 liter scale for lentivirus and between 500-to-1,000-liter maximum scale for AAV. Margherita went on to say that another important aspect in comparability between adherent and suspension systems is quality of the vector in terms of impurity profiles. She said that with adherent processes, cells are attached to the growth support, and the levels of host cell protein and cell DNA are lower when compared to suspension processes. This is very important for lentiviral vector production that is used in vivo where the requirements for impurity levels are very challenging, especially considering that for lentiviral vectors there is currently no affinity step for purification.

I followed up by asking her how AGC Biologics can help customers that want to stay in adherent culture to scale up from current processes, for instance, from flatware to larger-scale production. She explained that when customers ask for a scale increase, they usually offer the iCELLis™ platform. First, they demonstrate at small scale the feasibility of the transition from flatware to the iCELLis bioreactor using the iCELLis Nano bioreactor. Using the iCELLis Nano bioreactor, AGC Biologics has developed a full upstream and downstream process that is highly representative of their process using the full-scale iCELLis bioreactor.

AGC Biologics can then propose that customers use the vector produced in the iCELLis scale-down model to perform a comparability study between a clinical vector and the future commercial or large-scale vector. This comparability should be based not only on the comparison of titers, residuals, and all the CQA, but also AGC Biologics suggests performing a test of cell transduction on the target cells (i.e. CD34 or T cells) and evaluation on these cells of transfection efficiency – vector copy number, residuals and functionality.

I followed up by asking Margherita about whether the iCEL...

In this podcast, we talked with Dr. Ma Sha, Head of Bioprocess Applications at Eppendorf SE about advancements and challenges in cell and gene therapy production along with solutions for scale up and transition to stirred-tank bioreactor suspension culture.

We began the interview by talking about the biggest advancements in cell and gene therapy, including CAR T-cell therapy development, clinical results and FDA approvals. Another area of great advancement is induced Pluripotent Stem Cell (iPSC) Culture technique. Dr. Sha explained that it used to be very difficult to culture iPSCs until it was possible to culture iPSC suspension spheres in stirred-tank bioreactors, which was a big breakthrough in the cell and gene therapy area.

I followed up by asking Dr. Sha what he sees as the major challenges in the development and production of cell and gene therapies that still need to be addressed. He said that one of the major breakthroughs has been the autologous therapies that have been approved, particularly CAR T-cell therapies. However, this has also been a major challenge, because the autologous model is not cost effective. As a result, there has been a shift toward developing allogeneic therapies and building this production model will be a major challenge moving forward. Another challenge on the manufacturing side is ensuring to follow Good Manufacturing Practice (GMP), as it has been a common request from cell and gene therapy companies.

Next, I asked him about the move from 2D to 3D culture and his experiences with this transition. Dr. Sha shared that several of the projects that Eppendorf bioprocess works on start as 2D culture in flasks, it is a natural place to start for most of the cell lines since they are attachment cells. They must then be converted into suspension culture to enable 3D culture, since 2D culture significantly limits the yield and productivity. He went on to say that if you look back at the evolution of antibody production, it was important to convert production to suspension cell culture and this is also necessary for the cell and gene therapy field. Moving from 2D to 3D culture and especially utilizing stirred-tank bioreactors enables much higher yields. As it stands, the yield for cellular therapy cell production is fairly low, especially compared to the industry standard of CHO cells used for antibody production, so a lot of improvement needs to happen.

We then discussed stirred-tank bioreactors and their increased use in cell and gene therapy development and production. I asked Dr. Sha what are the key factors that developers should consider when choosing stirred-tank bioreactors. He explained that stirred-tank bioreactors fit the model of allogeneic production. Autologous models are not suitable for stirred-tank bioreactors. Developer companies need to keep in mind that if they want to move to stirred tank bioreactor platform, they need the production model to be allogeneic. In addition, it is important to consider the support available with respect to scaling up and leveraging supplier experience. For example, Eppendorf bioprocess over the years has produced many application notes to help customers scale their manufacturing. They have even built model production systems in Eppendorf stirred-tank bioreactors. The program called “Scale up Assist” allows customers to skip much of the difficult calculations required to achieve reproducible yields when moving from smaller to larger vessels.

Eppendorf has a very long history of working in protein-based therapeutic cell culture production and about ten years ago expanded to include cell and gene therapy. I asked Dr. Sha in his experiences, what are the most important takeaways in terms of areas that still need work and advancements on the horizon. For instance, what can we learn from protein-based therapy cell culture to apply to cell and gene therapy production? He said that he thought that allogeneic production is a great lesson learn...

In this podcast, we talked with Nathalie Dubois-Stringfellow, Senior Vice President of Product Development and Management at Sangamo about Sangamo’s work in gene therapy and the latest data on Sangamo’s gene therapy product candidate for Fabry disease.

I began the interview by asking Nathalie if she could talk about Sangamo and the company’s pipeline. She explained that Sangamo is a genomic medicine company dedicated to translating groundbreaking science into medicine. Their technology includes gene therapy, genome editing, and cell therapy.

Their zinc finger nucleus platform allows them to edit genes either by adding genes, deleting genes, repairing mutation, repressing the expression of the gene, or activating. It is a vast area of technology that they can apply to a variety of diseases.

Using their breakthrough technology, they were the first to edit human genes, treat patients with gene edited T cells, treat patients with in vivo genome editing, and treat patients with engineered T cells.

Our current clinical focus is on Fabry disease, a rare genetic disease and Hemophilia A sickle cell disease.

She then described their recent clinical data on ST-920, a gene therapy product candidate for Fabry disease, that continues to be generally well-tolerated and presents sustained α-Gal A activity based on data from nine patients.

She said that they were extremely excited about the result of this Phase I-II clinical trial. Fabry disease is an inherited disorder that is caused by mutation of the galactosidase alpha (GLA) genes which leads to deficient alpha-galactosidase A (α-Gal A) enzyme activity. This enzyme normally breaks down a fatty substance called globotriaosylceramide and without this enzyme this fatty substance builds up in the cells throughout the body, particularly in the skin, kidneys, heart, and nervous system.

The current standard of care for Fabry disease is an intravenous infusion of the missing enzyme, the treatment being called enzyme replacement therapy or ERT. This provides a high concentration of the missing enzyme for a very short time and the treatment has to be repeated in those patient every two weeks. It's a very cumbersome infusion that can take several hours and typically needs to be done in the hospital, thus negatively impacting patient quality of life.

Sangamo’s approach is a one-time therapy treatment where the gene for the missing enzyme is delivered to the liver cells of the patient, which are then acting as cell factory for producing the missing enzyme.

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