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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. -
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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... -
In this podcast we spoke with Derrick Alig, North American Western Regional Sales Manager for PSG Dover Biotech, Chris Couper, President and Founder of Liquidyne Process Technologies, and Phil Sanders Biotech Chief Innovation Officer at Agilitech about current supply chain challenges, possible solutions, what the future holds, and ways to navigate supply chain shortages to ensure manufacturers meet their timelines.
Supply Chain Shortages
I began the discussion by asking our panel members if they could discuss challenges that their customers are currently having with sourcing single use consumables and technologies.
Derek began by discussing the lack of raw materials to make these products, whether it is polymer-based components where lead times have been extended due to lack of raw materials, or other areas such as chips. As a result, customers are having to purchase larger quantities of product in advance, which ultimately leads to even longer lead times.
Chris added that from a distribution perspective and an integrator perspective, many of their primary suppliers have had issues. They have also seen that many manufacturers have been able to ramp up their production with plants that were put in place in 2019-2020. However, it takes one to three years depending upon the complexity and the scope work to create additional manufacturing facilities and production lines. In addition, many manufacturers are using alternate materials. While they may have qualified one product in the past, now they are qualifying additional supply chains, so they have a primary supply chain and also secondary and tertiary chains.
Phil discussed bringing an agnostic approach to managing supply chain shortages to alleviate some of the issues of having a single source. He also pointed out that sometimes the focus is on single use supply chain issues, but there are companies using reusable equipment that are having some of the same supply chain issues, especially when it comes to these things like chips and control systems.
Supply Chain Solutions
Next, I asked the panel how their individual companies are approaching these challenges, specifically how they are working with customers to provide solutions for these challenges.
Derek explained that at PSG Dover they are committed to providing quality products to customers in the biotech market. They focus on delivery times for customers by adding more shifts to keep up with demand and in late 2021, they added a second validated cleanroom to provide additional production capacities. They have also acquired companies to provide additional capacity.
Chris added that the situation could have been much worse if manufacturers had not stepped up and added capacity like PSG Dover and that they have seen improvements in lead times. He added that for Liquidyne they have a minimum of three supply chains for virtually every component that they offer. They let their customers know that they need to qualify the three components so they can be used interchangeably to meet timelines.
Phil added that maintaining flexibility is critical. For example, maybe the entire amount of inventory that is needed isn’t available now, but there is enough to get started while orders are placed for the rest of the material. Instead of trying to provide a customer with inventory for an entire year, provide three months' worth, then another three, and so on.
Supply Chain in the Future
I followed up by asking what they thought the future looks like for the supply chain over the next three to five years. Does this resolve itself or does it shift to another potential supply chain shortage?
Derek said that he thinks that customers will continue to require multiple supply chain solutions and suppliers will also need to continue to add multiple sources for their raw materials and electrical components.
Chris said that he thinks companies that are successful will take the time to study what has occurred, how they reacted, -
This article was originally published in the eBook
“ Future proofing Bioprocessing from Upstream to Downstream”.
You can download all the articles in the series, by downloading the eBook.
Not everyone has the luxury of building from the ground up. How do you create a unified system between upstream and downstream with existing equipment and processes? And if you have the ability to build from the ground up, how can you ensure that your design is future proof? We spoke with Phil Sanders, Biotech Chief Innovation Officer from Agilitech, to develop a set of best practices for creating a holistic process from upstream to downstream.
Create a Growth Plan with Scalability Built in
When companies are developing their process, it is easy to have a more myopic view of focusing on what is needed right now. Unfortunately, from a planning perspective this is very difficult because what is needed now often doesn’t work as companies need to scale up. When Agilitech works with customers, they ask customers to help them envision what their needs will be 3 years from now, 5 years from now, and at full commercialization. These answers are critical for decisions that companies will make right now. Because speed and cost are two driving factors, especially at the beginning of operation, companies often look for what is available now and what is the most cost-effective option. However, later they may learn that the process that they have created can’t scale up or can’t meet other process or quality related requirements. At that point, companies frequently wish they would have made different decisions earlier that took future needs into consideration.
One thing that Agilitech is helping customers with is bringing a holistic view. For instance, even if the project is related to upstream, it is important to think about what is the downstream going to look like. What will it look like in a process development environment, how about a manufacturing environment? Thinking about the scalability earlier in the process allows room to build scalability into the design for the future.
It is common in an industry that is always pushing for speed and efficiency to think about what must be produced now, but later customers often realize that they have wasted a tremendous amount of time creating a process and buying equipment that will ultimately need to be replaced for something that is more scalable or flexible; therefore, off-the-shelf is not always the best solution, even if it serves the purpose in the moment.
Don’t Get Locked into a Proprietary Solution – Remain Brand Agnostic
Agilitech Single-use Multipurpose Filtration Systems are Redefining FlexibilityThe benchtop option (up to 3 LPM) and larger system (up to 90 LPM) both adapt to virtually any external filtration system They can be used for multiple applications including sterile filtration, depth filtration, or virus filtration. Fit-forpurpose options permit reconfiguring the flow path to add more inlets, outlets, and more.
It can be tempting to lock into a single brand or a proprietary solution for your process needs from a convenience or discount standpoint. However, there are several reasons why you may want to remain brand agnostic.
Locking into a single solution may limit the process in the future. Often locking into a platform that works now results in limits on equipment size and volume that require redesigns that are costly and time consuming. A brand-agnostic approach allows companies to create a process that is flexible where all equipment works well together and communicates well across the entire process.
Proprietary software can be extremely limiting in scalability and working with other systems, particularly between upstream and downstream. Companies can find themselves in a situation where they must add another control system to expand their process for a more scalable solution.
Proprietary solutions can also impact support and whether updates and ... -
In this podcast, I spoke with John Ketz and Denis Kole about viral vector production, including current manufacturing challenges, navigating the road to commercialization, and successful scale up strategies.
We began the interview by discussing the strides made in cell and gene therapy. Denis shared information about the several approved therapies and the more than 2,000 ongoing clinical trials. Denis added that while the immense potential of these personalized therapies is becoming more and more clear, the challenges and bottlenecks surrounding their development and manufacturing are also becoming a reality. This is especially true when it comes to producing and delivering sufficient amounts of these complex therapies in a reasonable timeline. He explained that patient demands are increasing and the increase in IND applications for cell and gene therapies is resulting in increased demand as well as competition for resources. Access to qualified labor has become a significant bottleneck and likely will continue to remain so, at least for the foreseeable near future.
He went on to say that the lack of standardized approaches for gene therapy modalities is another challenge that can increase the risk of failure. It can result in increased process complexity due to the need to screen large numbers of variables and can result in extended development times, which in turn affect the time to market for these needed therapeutics.
In addition, the availability of manufacturing capacity is also becoming quite limited with the field currently reporting a significant backlog that can extend as much as 16 to 18 months. John added that he also sees capacity issues and it is something that Andelyn Biosciences® is trying to address.
He also said that they are working on increasing speed and consistency. There are a lot of challenges that need to be addressed when moving from small flask or bench top scale into larger production scales. These may be challenges that you are not aware of or don't encounter at small scale. It is important to be mindful of this during scale up.
Addressing Current Manufacturing Challenges
To continue the discussion, I asked them to share the best way to address these challenges moving forward. Denis began by sharing that the demand for clinical and commercial manufacturing for advanced therapies is expected to continue to increase as more drug development companies entering the space and new therapies continuing their development journey. As a result, the manufacturing backlog currently observed will likely continue to remain present, if not expand. So, while large pharma and a few larger biotech companies may have the resources to internally support their clinical development and manufacturing needs, most of the smaller and medium sized drug development companies will continue to face challenges associated with quick access to qualified labor and access to extensive process expertise and available manufacturing capacity.
He went on to say that this is where groups like Pall’s AcelleratorSM process development services and Andelyn Biosciences can play an important role with support through partnerships and collaborations. These types of collaborations really can provide the necessary resources and support for therapy developers to target shrinking the development timelines, reducing the risks associated with process development, and scaling to commercial scale. In addition, Pall and Danaher's integrated single use bioprocess offerings, provide scalable solutions that can reduce some of the risks associated with the development and manufacturing of therapeutics. These solutions really aim to alleviate some of the bottlenecks and risks associated with the lack of a standardized approach.
John added that at Andelyn Biosciences, they focus on creating a robust small scale model to ensure the consistency of the product when they move into larger scale. -
In this podcast, I spoke with Hanna Lesch Ph.D., Chief Technology Officer at Exothera about viral vector manufacturing. We discussed current industry needs and challenges, scalability, end to end solutions, and key insights to a successful manufacturing and approval process.
I began the discussion by asking Hanna about the viral vector manufacturing that she is working on at Exothera. She explained that Exothera is a Belgium-based CDMO delivering customized process development and GMP manufacturing services for gene therapy and viral vector-based vaccines. In 18 months, they built their new facilities with a GMP qualified manufacturing area of 2100 square meters. They have flexible manufacturing solutions for adherent or suspension scale and can accommodate small to large scale manufacturing up to 2000 L.
Next, I asked if she could share her thoughts on current industry needs in terms of commercial scale production of viral vectors. She said that Exothera was founded to tackle two of the most critical challenges that manufacturers face in bringing advanced therapies to market – lack of production capacity and a shortage of bioprocessing expertise. Another area of focus is on cost of goods, as the cost of manufacturing a gene therapy product is significantly higher compared to conventional products. To reach as many patients as possible these treatments will need to be significantly less expensive.
To succeed in this, Hanna believes that the industry needs to overcome several challenges, including development of standardized processes, consistent product quality, and improving manufacturing yields. She added that today there are also major time constraint risks because of delays in raw materials or consumable supply.
We then discussed scalability and how Exothera manages their scale up needs. Hanna described how Exothera provides access to platforms, technical know-how and facilities to speed clients’ product development time. She said that Exothera has built their capability to serve process development from their parameter screening supported by design of experiments (DOEs), small scale bioreactors for process development, middle scale for process confirmation and large scale systems to meet high yield expectations. All available in both suspension and adherent cell culture. She stated that it is key to be able to provide the full path for the product lifecycle.
Then, I asked her how integrated end-to-end solutions can benefit viral vector manufacturing. She explained that end-to-end solutions can provide a fast track to clinic for their clients. This is supported by a strong technical, analytical and bioprocess know-how. These solutions also minimize the potential risks and surprises during development, providing lower cost and better predictability. She shared an example where they started a collaboration project aiming for quick AAV process scale-up into a 2000 Liter bioreactor in a very short time frame. Working with end-to-end providers, like Pall Corporation, is key to helping Exothera implement new technologies and infrastructure very quickly. She emphasized that time is money.
I then followed up and asked what advice she had for others who need scale up solutions. Hanna shared that making critical decisions about the manufacturing process carefully is important, as this can drastically increase the chances of succeeding the first time. Second, select an easily scalable technology. Last, know your viral construct to avoid any surprises later and ensure regulatory compliance and a solid testing strategy for both your product and your process to achieve a straightforward approval.
I closed the interview by asking Hanna if she had anything else to add for listeners. She said that if you don’t have a manufacturing platform ready, it is important to find the right partner who can support your development and your manufacturing success.
She also told me that she has an upcoming webinar, -
In this podcast, I talked with Dr. Jimmy Li, CEO of WuXi XDC, a WuXi Biologics subsidiary. We discussed the reasons for the formation of WuXi XDC, which was established via a joint venture between WuXi Biologics and WuXi STA, a WuXi AppTec subsidiary, and how one-stop drug development organizations greatly streamline a pathway to the clinic. He also shares new technologies available to make the development of Antibody Drug Conjugates (ADCs) more efficient and effective.
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In this podcast, I talked with Dr. Jimmy Li, CEO of WuXi XDC, a WuXi Biologics subsidiary. We discussed the reasons for the formation of WuXi XDC, which was established via a joint venture between WuXi Biologics and WuXi STA, a WuXi AppTec subsidiary, and how this company provides a true single-source for the discovery, development, and GMP manufacture of antibody drug conjugates and other novel bioconjugates with their highly efficient one-stop drug development platform.
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In this podcast, we talked with Dr. Alison Porter, Head of Expression System Sciences, Lonza, about the use of stable pool expression to reduce drug development timelines. Highlights included the implementation of stable pools in current workflows, expected titers, and cutting-edge applications of the technology.
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