Cell Culture Dish Podcast

Surfactants are indispensable in the production of biologics, vaccines, and cell therapies. Yet for years, they’ve posed a persistent challenge: they are notoriously difficult to monitor accurately and in real time. That challenge is now being addressed by Nirrin and its groundbreaking Atlas platform, a real-time spectroscopy solution that is reshaping how biomanufacturers measure and manage surfactants. In this episode of The Cell Culture Dish podcast, Editor Brandy Sargent spoke with Bryan Hassell, Founder and CEO of Nirrin, and Hannah Furrelle, Analytical Scientist at the company, to discuss the science behind Atlas and its implications for bioprocessing. Real-Time Data Without Compromise At the core of Atlas’s innovation is its ability to provide high-quality quantitative data in under a minute—without any sample preparation. “The real breakthrough with Atlas is speed with confidence,” explained Hassell. “Time to market for biopharma is increasingly critical, yet a lot of critical decisions still rely on data from assays that take days or even months. Atlas changes that.” Unlike traditional techniques, which often require significant sample manipulation and suffer from matrix interference, Atlas uses high-precision tunable laser spectroscopy to directly analyze samples in their native form. “What makes Atlas so powerful is that we’re looking at the sample without altering it,” Furrelle explained. “That means the data we get is true to the process—there’s no distortion from prep steps or artifacts introduced by the method.” Moving Beyond PLS: A New Modeling Approach One of the technological breakthroughs enabling this leap in performance is Nirran’s move away from PLS models in favor of an iterative optimization framework. This approach eliminates the need for extensive training data, reducing model complexity while increasing robustness and flexibility. “Where a PLS model might need 20 to 30 bioreactor runs to build a dataset, Atlas delivers data on the fly,” Hassell said. “It’s not only faster, it’s more robust, more compliant, and more versatile—especially for applications like scale-up or tech transfer, where traditional models often break down.” Applications Across the Biomanufacturing Workflow Atlas is already being integrated into real-world bioprocessing environments, including both batch and continuous manufacturing. In batch processes, manufacturers use Atlas to confirm critical parameters—like protein and excipient concentrations—before proceeding to the next unit operation. This enables earlier course corrections and helps prevent downstream failures. “In the past, you either waited days for lab results or moved forward at risk,” said Hassell. “Atlas provides the immediate answers needed to make confident decisions in the moment.” For continuous manufacturing, the value is equally profound. Atlas provides the real-time, quantitative feedback necessary for dynamic process control. “You can’t have continuous processing without real-time data,” he said. “Atlas gives you the insights needed to support real-time decisions at every step.” Eliminating Risk with No-Prep Analysis One of Atlas’s standout features is its ability to deliver no-prep analysis. This eliminates sources of variability that often arise during sample handling and processing. “We’re scanning samples in their native form,” said Furrelle. “That means what we’re measuring reflects what’s actually in the process—without distortion from dilutions or centrifugation.” This no-prep capability also speeds up workflows and eliminates risk by allowing operators to verify component concentrations instantly before committing to the next step in production. Laying the Foundation for Smart Biomanufacturing Nirrin sees Atlas not just as a data tool, but as a stepping stone to smart biomanufacturing. Although full automation isn’t yet widespread, Atlas is helping to lay the groundwork by delivering trustworthy real-time data,

In this podcast, we spoke with Nainesh Shah, Sr. Application Engineer, Asahi Kasei Bioprocess America, about how inline buffer formulation and their MOTIV® system offers a more efficient, scalable, and cost-effective approach to buffer preparation. Traditional methods require large storage spaces, pose risks of leakage, and create inefficiencies that can disrupt production. In contrast, inline buffer formulation enables real-time mixing of concentrated ingredients, eliminating storage constraints and allowing for dynamic adjustments based on demand. With benefits like reduced waste, lower costs, and improved regulatory compliance, this technology is streamlining operations while ensuring precision and adaptability. As the industry shifts toward smarter manufacturing solutions, inline buffer formulation is paving the way for the future of pharmaceutical production. How Inline Buffer Formulation is Changing the Industry Nainesh, who has over 40 years in the pharmaceutical industry and six years at Asahi Kasei, highlights the evolution of buffer preparation. "Traditionally, buffer dilution involved a concentrate formulated in advance, which was then diluted with water to achieve the desired solution.” Modern inline buffer formulation transforms this process by enabling real-time mixing of individual components. "Instead of storing pre-made buffer solutions, MOTIV allows for real-time formulation using individual components. The system precisely combines these ingredients on demand, ensuring accuracy and eliminating storage-related inefficiencies," Shah explains. Enhanced Efficiency, Cost Savings, and Waste Reduction The advantages of MOTIV extend beyond storage and formulation flexibility. "With traditional methods, production can be delayed if pre-made buffers aren’t readily available. If a change in concentration or formulation is required, additional time is needed for sourcing and preparation," Shah notes. "With MOTIV, you can use a single concentrated solution to create multiple buffer variants by adjusting the dilution ratio. This eliminates the need for multiple pre-concentrated stocks, reducing storage space, waste and increasing efficiency." Cost efficiency is another crucial factor. "Return on investment (ROI) depends on whether the facility has an existing buffer preparation setup or is installing a fresh system. For existing setups, ROI typically takes around two years due to transition considerations. However, for new installations, ROI can be achieved within 1.5 years," Shah states. He adds that Asahi Kasei provides an easy-to-use ROI calculator to help companies assess their financial benefits. Additionally, inline buffer formulation improves sustainability by minimizing waste and reducing the environmental impact of excess buffer storage. By eliminating the need for large buffer stockpiles, facilities can lower their material costs and optimize resource utilization. Scalability and Customization for Diverse Production Needs One of the standout advantages of the MOTIV inline buffer formulation system is its scalability. "Our smallest system supports up to 1,200 liters per hour with three inlets—one for water and two for concentrates like acid, base, or salt solutions. On the higher end, we can scale up to 5,000 or even 12,000 liters per hour, completely customizable with multiple inlets based on customer requirements," says Shah. This flexibility is particularly valuable for pharmaceutical manufacturers with varying production demands. Facilities producing multiple types of buffers can benefit from the system’s adaptability, allowing them to switch formulations with minimal downtime. Instead of maintaining separate storage tanks for different buffer types, inline buffer formulation enables dynamic adjustments based on real-time requirements. Addressing Complex Formulations and Space Constraints MOTIV is particularly beneficial for high-volume buffer requirements and complex formulations.

In this podcast, we spoke with Dr. Jorge Escobar Ivirico, Product Manager, Bioprocess Solutions at Eppendorf, about the fascinating world of induced pluripotent stem cells (iPSCs), exploring their groundbreaking potential in regenerative medicine, personalized therapies, and drug development. Our guest explained how iPSCs, created by reprogramming adult somatic cells, can differentiate into virtually any cell type, making them invaluable for research and therapeutic applications. We delved into the importance of consistency, quality control, and reproducibility in iPSC production, alongside the challenges of culturing these cells, such as maintaining pluripotency and scaling production for clinical use. The discussion highlighted exciting advancements, including the development of organoids and universal T cells, as well as the ethical considerations distinguishing iPSCs from embryonic stem cells. Looking to the future, Jorge envisioned iPSCs becoming a cornerstone of standard medical practice, while acknowledging the need to address safety, scalability, and regulatory hurdles to fully realize their potential. What are Induced Pluripotent Stem Cells (iPSCs)? "Induced pluripotent stem cells are a type of stem cell created by reprogramming adult somatic cells, like skin or blood cells, back into an embryonic-like state," explains Jorge. This process involves introducing specific transcription factors, often called Yamanaka factors, to transform these cells into a versatile state. Once reprogrammed, iPSCs can differentiate into almost any cell type, making them invaluable tools for research, drug development, and potentially life-changing therapies. The Growing Importance of iPSCs iPSCs offer a range of advantages, particularly their ability to sidestep ethical concerns tied to embryonic stem cell use. “What makes iPSCs so important today,” Jorge notes, “is their versatility and potential applications. Researchers can create patient-specific cell lines, which are essential for drug screening, disease modeling, and personalized medicine.” This technology is pivotal for regenerative medicine, offering hope for repairing damaged tissues and organs. “From neurodegenerative diseases to heart damage, iPSCs open the door to innovative treatment possibilities,” he adds. Mastering the Production Process Producing iPSCs is a meticulous endeavor. "Consistency is key," emphasizes Jorge. Researchers must ensure that each batch of cells meets strict criteria to avoid unpredictable outcomes, especially when precision is vital in both research and therapeutic applications. Standardized protocols and quality control measures are essential to achieve consistency. These involve monitoring for contamination and verifying the cells' ability to differentiate into various cell types. “Imagine developing a therapy based on a specific batch of cells, only to find that subsequent batches behave differently,” he warns. “Such inconsistencies can jeopardize patient outcomes.” Tackling Challenges in Culturing iPSCs Culturing iPSCs presents its own set of challenges. High cell numbers are often needed for large-scale research or therapeutic applications, but scaling up production without compromising quality is no small feat. Maintaining the cells’ pluripotent state is another hurdle, as they can easily differentiate prematurely under certain culture conditions. "Environmental parameters like temperature, pH, oxygen levels, and nutrient availability must be rigorously controlled," Jorge explains. “Even minor fluctuations can negatively impact cell health and their ability to remain pluripotent.” Innovations Addressing Culturing Hurdles To overcome these challenges, researchers are turning to advanced techniques like 3D culture systems and bioreactors. These provide a more natural growth environment for the cells, enhancing their viability and functionality. “By transitioning from traditional 2D cultures to 3D systems,

In an era where industries are increasingly driven by data and automation, the bioprocessing sector is embracing digital transformation to streamline workflows and improve productivity. However, blending the complex and highly regulated world of bioprocess with digitalization poses unique challenges. In this podcast, we talk to Dr. Simon Wieninger, Head of Portfolio and Applications at Eppendorf SE about how the journey toward digital integration requires well-defined goals, user-centered design, cross-industry learning, and, crucially, trust. Setting Clear Goals: Purpose-Driven Digitalization “Digitalization shouldn’t happen for digitalization’s sake,” Dr. Wieninger advises. While the temptation to adopt cutting-edge technology is high, each digital tool or system must serve a specific purpose. For bioprocessing organizations, establishing these objectives upfront is critical to ensure that digital investments yield meaningful results. Whether the aim is to boost productivity in production facilities, refine R&D processes, or improve operational efficiency in support functions like HR, having clearly defined goals anchors digital efforts in purpose. This intentional approach is especially significant for production and R&D sectors within bioprocessing. Here, digitalization can streamline processes such as real-time data monitoring, automated adjustments to culture environments, and improved reporting and compliance tracking. By aligning digital goals with broader business objectives, organizations can make more effective use of resources and ensure that digitalization contributes positively to organizational growth. Bridging Skill Gaps and Building Trust: Making Digital Tools Accessible A successful digital transformation relies on the people who will use these tools day-to-day. However, not everyone in bioprocessing has a background in software or programming. Simon points out that for digital tools to be effective, they must be intuitive and accessible to all team members, from scientists in the lab to technicians on the production floor. "We need to design solutions that everyone can use," he says, noting the importance of user-friendly interfaces that require minimal technical knowledge to operate. Part of building an accessible digital framework is understanding the varying comfort levels with technology within the workforce. Some employees may be tech-savvy, while others are less familiar with digital tools. Recognizing and accommodating these differences is crucial to creating a smooth transition. Moreover, as Simon explains, trust is fundamental—not only trust in digital tools but also in the partnerships with vendors and technology providers who support this transformation. Organizations should leverage the expertise of these partners, building collaborative relationships to create solutions that meet specific needs and ultimately make bioprocess workflows more efficient. Learning from Other Industries: Adopting Best Practices in Automation and Standards The bioprocess industry has much to learn from sectors like automotive, finance, and telecommunications, which have long relied on automation and standardized processes to boost efficiency. In automotive manufacturing, for instance, high levels of automation allow for the production of thousands of vehicles with minimal human intervention. Bioprocessing, by contrast, has historically been more manual and labor-intensive, particularly in R&D and small-batch production. According to Simon, one of the greatest opportunities for bioprocessing is to adopt industry standards that facilitate automation and improve interoperability across devices. One such example is the OPC (Open Platform Communications) standard, widely used in other sectors for seamless communication between devices. Applying such standards to bioprocessing could simplify data integration across lab instruments and production equipment, allowing researchers to capture and analyze critica...

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. Please listen to our full interview using the player above or download on the player using Apple podcasts, Spotify or More.

In this podcast, we talked with Dennis Hodgson and Phil Sanders from Agilitech about the benefits of single-use mixers, dealing with supply chain concerns, ensuring scalability, and tailoring a mixer to meet specific process needs. Benefits of Single-use Mixers We began the podcast by talking about the overall benefits of single-use technologies for mixing. Dennis explained that single-use mixers are very versatile and can be used to replace stainless steel vessels within the manufacturing area. Single-use mixers all have the same advantages of other single use components, such as coming fully sterile and eliminating the need to steam and clean in place. Dennis went on to say that another big advantage that single-use mixers have over stainless steel is the ability to customize. For example, a 500 L single-use mixer can be used with a virtually unlimited array of customized vessel configurations, which would include the inlet outlet, port configurations, sampling ports, vent filters, and various process analytics that can be added. Next, we talked about adoption of single-use technology for mixing and possible concerns that customers might have. Dennis shared that a big concern recently has been supply chain shortages that have created limited availability and long lead times for single-use consumables. He said that he has heard from some clients that they have had to skip planned production batches because the single use bags that they needed to process the batch were not available. Phil added that supply chain concerns have caused some of their clients to think about moving to stainless steel systems to avoid any production delays. Single-use Technologies Supply Chain Challenges I followed up by asking what could be done to address single use supply chain issues moving forward. Dennis explained that Agilitech has the luxury of not being tied to any one supplier, so they can source from multiple vendors. This allows them the flexibility to move between vendors and load projects based on their capacity and lead times. This also allows them to make sure that they are offering competitive pricing because vendors know that they're not the sole source of a component. Ensuring Flexibility in Single-use Mixing We then talked about mixers presenting unique challenges in that they are used for a variety of applications with many different demands. I asked how Agilitech can ensure that their single-use mixer has the flexibility needed for multiple applications. Dennis explained that because Agilitech isn’t tied to a single design, they are able to have conversations with the client to customize a solution for their needs. Their main goal is to make a product that meets the needs of the individual companies and their process. Additionally, they design their systems purposefully to handle many different capabilities such as sampling, analytical measurements, weight measurements, temperature control, etc. Because they use standard control hardware, their mixing vessels can easily be integrated into existing control systems such as Delta V or Wonderware through the available Ethernet IP connection. This allows users to read and write to certain control parameters. I then asked about which options are available for customization on the single-use mixers. Dennis said that they can customize all the inlet and outlet ports with regards to port size, tubing length, connector type, etc. As far as the mixing units themselves go, they can be jacketed or not, have load cells or not, have probe analytics such as pH, conductivity, temperature, DOE, and optical density, so all those different analytical devices can be incorporated as well. Phil added that if there are specific standards within an organization, for what control systems need to be installed on these systems Agilitech is flexible with Rockwell, Delta V, Siemens, all the major platforms that customers might need. I followed up by asking about how these customizatio...

In this podcast, we spoke with Emanuel Krobath, Biopurification Specialist and Chiara Pacini, Bioprocess Specialist both with Pall Corporation about gene therapy process development including challenges and resources that are available for support. I began the discussion by asking Emanuel and Chiara to tell listeners a little bit more about their jobs and how they support gene therapy developers on the bench. Emanuel started by saying that as a bioprocess product specialist, he performs customer bench case studies at the customer site, specifically for the downstream process including vaccines, recombinant proteins, monoclonal antibodies and gene therapy products. He shared that the customers he works with are usually in preclinical or Phase I studies and he supports them from clarification to the final sterilizing grade filtration. This scale up, optimization, and technical support is offered free of charge to help customers succeed in their process development. He said that he also finds new technologies and ideas for the Pall R&D team during these visits. Chiara shared that she supports customers from bench scale studies through the manufacturing process on downstream starting from clarification to sterile filtration. She spends most of her time traveling to her customers’ laboratories or manufacturing sites to provide general support, conduct optimization studies and technical support training to find the best practice or membrane selection for their process. I then asked if they could share what are the most common questions that they get from their customers. Emanuel said that what size filter do they need for a specific product and what is the best material to use is one of the most common. Chiara said that for her it is how to intensify a process or make it more robust for clarification, TFF, chromatography, and membrane filtration. We also talked about a series of videos on Pall’s website and how these were created to help translational academics who work in gene therapy. Emanuel explained that they wanted to support academia specifically in their scale up and small-scale process development, because often in academia, the user will take the first filter that is available at their site. It is important that they understand and have the support to select the correct filter for their product, so that the process is optimized at manufacturing scale. Chiara agreed that the videos were designed to show we can support the development process not just for manufacturing scale, but also for initial bench scale studies. This and the initial optimization study that Pall performs with the customer ensures scalability to large scale processes and identifies the critical process parameters needed to reach high yield and product productivity. Next, we discussed what they like most about the work that they do. Chiara described how being a bioprocess specialist gives her the opportunity to meet the people in both large and small companies who are working on these therapeutics. She enjoys supporting the development of different molecules and gene therapies and is always updated on the latest techniques used for gene and cell therapy. Emanuel said that he enjoys traveling, which is important because visiting customers in person is a big part of his job. He added that it never gets boring since he is supporting customers as they deal with very diverse processes and challenging problems. His favorite part of the job is that basically they are doing scientific work at the frontline, and he saw this to an even larger extent during the COVID pandemic as they were involved in nearly every vaccine process development. I followed up by asking which projects that they were most proud of. Emanuel said that with the exponential growth of plasmid DNA demand, as it is either used as a template for mRNA vaccines or the molecular function for DNA vaccines, the upstream and downstream processes have not been optimized. Now,

In this podcast, we spoke with Cory Hinz, Engineering Manager at Asahi Kasei Bioprocess about the different methods that are available for liquid chromatography mobile phase solutions and the benefits of inline blending. Cory also describes how to implement binary blending feeding of a liquid chromatography process using inline blending. Liquid Chromatography Mobile Phase Solutions I began the discussion by asking Cory if he could tell listeners about the different methods that are available for liquid chromatography mobile phase solutions. He explained that for chromatography, it's important to remember that the process and the chemistry should drive the method used. Some chromatography processes use prepared mobile phase solutions that don't require inline mixing, while others blend two or more solutions together to formulate. The mobile phase takes these blends and changes their composition over the course of the elution. Each of these methods is driven by the needs of the process. Inline Blending Next, I asked Cory if he could tell us about the benefits of inline blending. He said that inline blending allows solutions to be prepared at their point of use, not just for chromatography processes, but any blending process. This increases the consistency of the blended solution, reduces dependency on the accuracy of raw materials, allows for real time quality assurance, and eliminates the risks and extra resources and space required for traditional tank approaches. Inline blending also adds an element of flexibility, allowing functions such as buffer preparation to become more of a utility than an additional process. Binary Blending Feeding of a Liquid Chromatography Process using Inline Blending Cory then provided details about how to implement a specific solution for binary blending feeding of a liquid chromatography process using inline blending. He explained that binary blending is the most common configuration they see for their chromatography equipment customers, because medium and high-pressure liquid chromatography require a dedicated pump to supply the pressure dictated by the process. It is important to design the binary blending at the suction side of the pump. This is done by employing two modulating control valves, one for each of the two components of the mobile phase, and ensuring sufficient supply pressure to each one. He then told us about the role that each of the valves play in creating the ideal blend. He described how the control valves do most of the heavy lifting for binary blending. The first valve controls the diluent, which will be the purified water or buffer that comprises the majority of the mobile phase blend. The second valve controls the component that is getting diluted. These valves each react to a different process parameter to achieve high accuracy. The second valve is the most intuitive, the component being diluted can have its proportion increase or decrease based on the movement of the control valve. For example, if the concentrate is below target, the valve will open to allow more concentrate through. This can be based on flow connectivity or any critical process parameter that can be measured inline. The first valve is less intuitive. It is controlled by the pressure in the system after the two streams have combined. If the blending pressure is too low, for example, the valve will open to increase that pressure. The result of this configuration is that if the two valves react to one another via the process but are not linked by a system control algorithm. This results in flexibility and accuracy and also provides a way to monitor and mitigate pump cavitation. Next I asked Cory about controlling the incoming process pressures of each of the valves. He said that in order for the binary blending scheme to work optimally, the incoming supply pressures of each stream should be controlled to prevent fluctuation that can disrupt the automatic blending control.

In this podcast, we interviewed Katie Keller, Director of Quality and Safety at Asahi Kasei Bioprocess America, about the importance of quality management and how to achieve the best possible results. Topics included the most critical elements of quality management, how to ensure the purchase of high-quality equipment, and future trends. I started the conversation by asking Katie what she thought were the most critical elements of quality management. Katie replied by saying that a holistic approach to quality is best for any organization. It used to be that the quality unit was considered responsible for product quality, making all the decisions, and driving all the improvements and that's not really the case today. She feels the most successful approach is that since quality is so important, everyone should be responsible for it. She went on to say that when all employees understand how they contribute to product and service quality and therefore customer satisfaction, there is more buy in throughout the organization. People are empowered to take responsibility for the improvement of the processes they manage, and this total quality management is achieved by clearly defining the interaction of each process to another, ensuring employees understand that, and then setting the expectation that quality is achieved from every level of the organization with everyone playing a part. I then asked Katie what should bioprocess equipment customers be looking for to ensure that they are purchasing high quality equipment? She told me that across industries, it's common for customers to search for suppliers with robust quality management systems. As a supplier, Asahi Kasei Bioprocess America (AKBA) can minimally prove this by achieving and advertising certification to ISO 9001. This shows that Asahi Kasei meets the minimum expectations for a manufacturing company to provide those quality products and services, but it really doesn't stop there. If they can show their customers that they have well designed, thorough processes that are continually improving, this naturally leads to better quality products and customers gain confidence in their ability to meet ongoing needs. I continued the discussion by asking if she could talk a bit about ISO certification and why it's an important part of their quality management system. Katie explained that ISO 9001 really is the minimum. Their customers in the pharmaceutical industry might stop and look when they see the ISO certification, but what really brings them confidence and satisfaction are the ways Asahi Kasei goes above and beyond this. For AKBA, ISO certification is not just words on a page, there is a reason why every requirement in that standard exists. Katie shared that she believes it is her job to interpret this in a way that means something to her organization, so they can not only live it but improve upon it and take the next step. She elaborated on her point by saying that it is how you build upon those minimum criteria that truly shows a customer who you are and what is important to you as an organization. This is how a company can start to build that quality culture where the employees believe in the message that customer satisfaction, both internal and external, comes first. I asked her about how these quality management systems affect the design and build of their equipment and how they have an impact beyond the quality management systems. Katie said that having ISO as a guideline is helpful for this, especially if they need to create or revamp a process. Asahi Kasei Bioprocess starts by asking what ISO requires to get a baseline and then looks at what their customers’ expectations for safety, quality, and productivity are. She explained that by keeping both these things in mind, they can create robust processes with controls or checkpoints to ensure they are satisfying all the requirements. However, that example is at the front end of creating a new process,

In this podcast we spoke with Klaus Kienle, Global Product Manager for the Mixing portfolio at Pall Corporation about the latest mixing technologies including single-use solutions, the need for increased flexibility, and a more standard vendor agnostic approach. The Role of Mixing in Biomanufacturing I started the conversation by asking Klaus if he could talk about the role that mixing plays in biomanufacturing and current challenges in this area. Klaus explained that mixing is an omnipresent process. It starts with upstream buffer media and ends in fill and finish. It is an important part of manufacturing across several modalities, including monoclonal antibodies, mRNA based vaccines, gene therapies and various other processes. Across these various applications, flexibility is key, and it is also the primary challenge for the future. He continued by saying that Pall customers have expressed that they want increased flexibility, better lead times, and less supplier dependency in the future. Advancements in Mixing Next, I asked about the latest technological advancements in mixing. Klaus stated that the latest advancements are moving towards tackling the flexibility challenge, which means supplying solutions that are available with shorter lead times and are more vendor agnostic, so they fit with other vendors’ manifolds and full sets. This is consistent with the recent launch of the Allegro™ Ready Standard Solutions from Pall, which is not only limited to mixers, but also includes storage transfer sets and other segments. Pall has launched this new standard set ranging from a 30 liter mixer up to a 3000 liter mixer. I continued the discussion by asking if he could talk a little bit more about some of the additional advantages of this set of new standards. He described how these standards are ready to go, so if a customer is asking for a manifold, there is no time required to generate a drawing or waiting for pricing back, resulting in a short lead time. Pall is working towards having these standards available off the shelf, reducing lead time further with availability in the range of single digit weeks, depending on manufacturing and where the customer is located. He shared that Pall has invested $1.5 billion to increase capacity and reduce lead times. Single Use Mixing I then asked him about some of the remaining challenges that exist with single use technologies. Klaus explained that one of the main challenges that the remains in single use is sustainability, especially since it consists predominantly of plastic components. However, there was a recent publication in New Biotechnology, authored by biopharmaceutical companies, “Streamlined life cycle assessment of single-use technologies in biopharmaceutical manufacture.” It makes the case that single use technology is providing better sustainability in the biopharmaceutical process because single use technology allows customers to use more intensified processes, thereby increasing the efficiency per consumable. Single use technologies also support a closed process and reduced clean room requirements resulting in lower energy requirements. This is in line with the new standard designs from Pall, where the filtered product line is fully closed and processing ready. For instance, now the powder port on these designs ensures a closed and controlled environment. This then allows bioprocessing companies to lower the cleanroom environment requirements, which translates to significant energy savings. Modular Mixing Approach I continued our discussion by asking Klaus about a recent white paper published by Pall and Lonza, that highlighted a modular mixing approach. (need paper link) He described how a modular approach can give customers the flexibility that they are looking for to adapt to new requests, especially in the contract manufacturing organization (CMO) environment. Global CMOs are producing product for developers and as a result,

In this podcast, we spoke to Tom Watson, Group Leader, Product Management – Biotech Division, Gregor Kalinowski, Manager SLS Purification Consultants Europe, and Aude Iwaniec, R&D Bioprocessing Team Leader, all from Pall Corporation, about why high concentration mAbs are an increasingly important part of the biotech landscape, current manufacturing challenges and solutions, and future trends. High concentration drugs offer benefits for patients I began the discussion by asking why high concentration mAbs are an important topic in today’s biotech landscape. Tom explained that high concentration drugs are an important innovation because when a biotech drug can be prepared at high concentration that is administrable, it is usually self-administered in a subcutaneous mode. This method of delivery brings lifestyle benefits to patients and reduces health care costs because it negates the need for an intravenous treatment. Subcutaneous biotech drugs have been available for a while, but recently more companies are developing new drugs or formulating existing ones at high concentration. High concentration mAb manufacturing vs. more traditional mAb production I followed up by asking what some of the differences in terms of manufacturing high concentration mAbs versus more traditional mAb production are. Tom described that a mAb or recombinant protein for subcutaneous delivery is going to be prepared at a high concentration. Starting with the final concentration steps, it is common to have a highly viscous fluid of 10 to 30 centipoise, with a concentration of greater than 100 grams per liter and often higher than 250 grams per liter. He went on to say that the concentration step reduces the volume of the fluid processed across the subsequent unit operations that are typical of a biotech process. What happens then is a reduction in the dosage volume, since you only need 1 to 2 milliliters of a highly concentrated biotech drug for therapeutic effect. So, typically there are small dosage volumes, or in some cases dosage volumes can be several milliliters to permit a slightly longer-term infusion of a subcutaneous drug. However, viscosity makes processing the fluid more challenging across the unit operations including the concentration step itself, but also through filtration, mixing, freeze/thaw, formulation, and dispensing. In addition, the smaller batch volumes that correspond with the increased concentration of the drug raises the cost of the Active Pharmaceutical Ingredient (API) per unit volume and this results in more significant impact with any product loss. Manufacturing challenges with high concentration drugs Next, we discussed some of the main challenges that exist in manufacturing workflows for high concentration mAbs. Tom said that he repeatedly hears from customers about challenges relating to product loss in hold up volume, aggregation of the molecules, limitations with analytical equipment and sampling procedures, and destabilization of filtered fluid due to the stripping out of formulation components. Achieving high product concentrations I then asked Gregor about the specific challenges to achieving high product concentrations. He explained that product viscosity is increasing with increasing product concentration. So, for a given crossflow, the pressures are also increasing with increasing product concentration. He went on to say that the permeate flux is decreasing with increasing product concentrations and therefore the processing times become longer, and the number of pump passes are much higher compared to low concentration processes. This combination of extended recirculation time and the increased concentration carries a significant risk of shear related damage that may impact the product quality. Finally, the high viscosity of the final retentate pools typically results in a poor recovery from TFF systems because of limited drainability. I followed up by asking him which solutions can be app...