The Downstream Column Podcast

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. The MOTIV SU is on the same platform as the MOTIV and is an ideal solution for companies that don't want to disrupt their regular production lines, but still want to use the same production criteria that in the future could be added to production lines.   Nainesh went on to talk about why single use is such an important option. He said that because there is so much time, energy, and money being spent to clean and provide the proper validation, which then sometimes needs to be reverified or revalidated later. Single use is a good option, and if the process permits, it can be used for a long duration of time provided you have the backup data that you are not contaminating. If you're using the same material repeatedly, yes, it's a single use, it's a replaceable part, but it doesn't mean that it's a one time use and then it is gone. It is just like the bioprocess industry using 50 liter and 100 liter bags for holding their buffers, which are all single use and this goes along that same line for the bioprocessing industry.  Single use versus stainless steel Next he walked through when you would choose a single use option versus a stainless steel option. He explained that a primary consideration would be if you are using anything that would be considered corrosive. If a company is using something in their process and they are not sure whether it is corrosive and they don't have any documentation or any test reports to show whether it is corrosive or whether stainless steel will hold up and they don't want to damage the stainless steel equipment, it would be good to have a single use option as a fail proof. They can start bioprocessing studies in the single use system and at the same time start doing some studies with stainless steel to see if there is any issue with corrosion. In six months time, if they don't find any corrosion issues, they can switch over to a stainless steel option.  Another reason to go with single use is color. Any chemist or bioprocessing person would know whether it's going to impart coloration or affect the stainless steel from the inside, that is again a quick answer to go for a single use option.   Another area where single use is a good option is if you are considering whether to invest and want to prove that your technology works. You could start with the single use and then when you have a more permanent situation you can move into stainless steel.   I followed up by asking if there are any striking differences between the single use and the stainless steel option. He explained that there are a few things that need to be considered when you're using a single use system. First, because it uses only one pump, which is also a mixer and it creates a suction force to take the concentrates in, there are limitations on the maximum or minimum flow that you can get and the concentrations. It is not good to use very concentrated material and then use a small quantity per minute to do the dilution. So that is a limitation that the user should consider.  The MOTIV SU works on the same principle of mixing feedback control loop for the pH and the conductivity, or the flow and it can control in all the three parameters. It has its own tolerance values that the user can put in of what is acceptable or not acceptable. When it is not acceptable, the system will divert buffer out to a waste outlet and then when it gets back into specification it will revert the buffer back into the product outlet or the designated outlet. Collection of the buffer will start and the system will monitor how much is collected. The user can define and set all these parameters in their method, which are very easy to use and intuitive, just a quick 15-20 minute walk through can get a team up and running.  Set up and operation Next, I asked if he could talk specifically about the operating system for this unit and also answer the question of if an end user wants to create a new buffer, do they need to come to AKBA. He said that the operating system is based on a Windows based PC housed inside the electrical enclosure with Allen Bradley controls for all the control mechanisms. The user does not have to contact AKBA or work with AKBA if they want to add any new buffer or modify a new buffer. They can make their own buffers, but we teach the user how to make methods via a drop down menu with fill in blanks. Then they can run the method and the system is ready to go. Customers can always come to AKBA if they're having any issues with making a buffer and we are always there to help guide them through.   Lastly, I asked what the set up is like for end users who are interested in implementing the system. He explained that the regular MOTIV and the MOTIV SU are all skid units which are mounted on wheels that can be easily wheeled in and out of an area as needed. As he said earlier, real estate is very important in the bioprocessing industry and rooms are being utilized for multiple purposes. The mobility of the MOTIV family means that the user can connect to an electrical power supply that can be 110, 220 or 230 volts, in some instances with a higher flow rate it may need the three-phase power supply, but those are all plug ins. Then they connect the air supply for the valves and everything to open. Then connect the concentrate containers, that can be bags, 1 meter cube totes, drums, etc. Lastly, they direct where they want the buffer to go whether it's going to a container sitting right next to the system, or it could go into a port that can transfer the buffer into another room. That’s it, very easy and no special tools required for starting the system up or shutting it down. The floor size requirement is a typical office table space.  It has a small HMI on top of it to see how the process is moving and all the pertinent data is is displayed there. If there are alarms it will show the user right there what is happening and the operator or the user can take care of it right away  For more information,

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, a couple of very eager Pall scientists, including Emanuel, are optimizing the plasmid DNA process map, particularly the clarification, as this seems to be the most challenging. Since Pall and Cytiva are two sister companies under the Danaher umbrella, the goal for this project is to provide a complete process map for the upstream and downstream solely using Pall and Cytiva products. Chiara agreed that they are focused on the plasmid platform due to the COVID pandemic. Last year she worked with an Italian customer to develop a COVID vaccine with plasmid DNA to mRNA in a liposome carrier in the clinical stage. She also worked with Pall colleagues and other companies under the Danaher portfolio, Precision Nanosystems and Cytiva, on a global project. I then asked about what they saw as the most difficult aspects of process development, purification, and downstream processing of viral vectors. Chiara said that she feels the most challenging part is to achieve high virus titer and active particles. For example, she said that they work on the AAV viral vector process and it is very robust and established compared to the lentiviral process which is still very challenging due to stability and therefore you have to manage pressure, temperature and shear stress. Over the last 2-3 years the trend is moving to pDNA and mRNA. I closed the podcast by asking if they had anything else that they would like to add for listeners. Emanuel said that filtration is not something redundant and should be carefully thought through, because perhaps the product becomes a game changer along the line. Studies done during academia studies could save a lot of money and time during the process development. Chiara added that she joined Pall to make a contribution to the development of gene therapies and she has worked on covid vaccines, cancer therapy and personalized medicines. She sees that personalized gene therapies for cancer treatments are a huge target for academia and the emerging cell therapy work. Learn from experts and discover how using scalable manufacturing tools can accelerate your gene therapy developments

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, what could have been done differently, potentially better, and what missteps should be avoided. One thing that we've learned as an industry is that we must be able to react quickly to the market, science had the ability to react quickly to this pandemic and they moved vaccines and treatments to the market in an incredibly short timeline. They took things that historically take several years to accomplish and did it in a matter of months. Suppliers need to be able to respond quickly to increased demand as well. Ultimately, he thinks that customers will need to communicate about what they need in for one to two years in advance instead of in three to nine months. Phil said that he thinks the biggest issues are what we don't know today, what geopolitical event is going to happen that could cause sanctions on a country where we're getting components from and then having to shift those things. What act of God, tsunami, or earthquake, etc. If we can start figuring out what issues that coming, maybe we can maintain a specific inventory on these components. Maybe Chris keeps some of them, Derek keeps some of them, and I keep some of them so that we're working together to provide solution. He thinks over the next three to five years, the things that we're talking about today are going to be a thing of the past and we're going to be talking about a new supply chain shortage. Chris added that as three companies we look at risk and try and share that risk to create a better overall customer experience. We must work together in order to make that a reality, and we have to make sure that we communicate individually and together as a team with the client base that exists along with the client base that we don't even know about yet. All the panelists agreed that there needs to be excellent communication and partnership with customers to fully understand what their needs are and to help them ask the right questions to ensure that they will have the supply they need to move forward. Navigating the Supply Chain Then the panel discussed the things that they recommend customer related to supply chain, not just for purchasing and production, but also for scientists.  Derek started by saying that what they really want to know from their customers is their timeline so they can match it up with what they can deliver. It allows PSG Dover to review all the different options available for the best solution possible and also to make them aware of what is realistic with the current supply chain. Chris added that it is critical to know what the key components for a process are and what are the risk items or items that have volatile lead times. It is critical for customers to be able to rank these items in terms of risk. Because of volatility in the marketplace in terms of getting the product or volatility in terms of price, we're seeing price adjustments 30 days' notice and it's not only for future orders, but also for orders that haven't shipped. New price increases happen because the raw materials that were used to build the product have escalated in price, and this is what's being passed down the supply chain. It is very important to look at the high-risk items and make sure that the product is secure and that there isn’t an issue in a year or two. Phil explained that customers need to understand that assemblies are different components. So, you can't look at an entire assembly and say that that whole thing is at risk. It's the different components and understanding that sensors or pump heads or connectors or any of these things can be a supply chain issue and having that discussion with the team is important. It is important for customers to think about if there is an issue with one of the components, what is plan B? Is there inventory on the shelf or are there other options that can be explored. Phil then gave an example from one of their customers that had a specific design to be able to maintain their TMP control, but the issue was that the team wasn’t sure that the supply chain for that design could be maintained. Instead Agilitech built the unit with interchangeable parts, so if that a component wasn't available, there were others on the market that could be substituted. He reiterated that it is important to be adaptable and flexible and have those conversations, so you have a plan for managing supply chain issues in advance. Chris added that it is very important to have the entire team present when in discovery meetings with the customers. In order to facilitate quick turnaround times, these meetings need to involve not only the scientists, but ideally project managers, people from automation, and people from quality and documentation so that all the expectations can be addressed and met. This post is sponsored by Liquidyne Process Technologies, Inc.. This post is sponsored by Agilitech.

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 applied to overcome these new challenges in the final ultrafiltration/diafiltration (UFD) step? He said that first, an optimization of the TFF cassettes screen type. For example, a coarser screen or suspended screen can be applied, then the resulting cassette pressure drop can be used to process high viscous material. Alternatively, single pass TFF significantly reduces the shear exposure because the entire concentration step is performed in a single pass without a recirculation. This is especially important for sensitive products like sensitive plasma proteins, and plasma derived factors as well as shear sensitive viral particles, as single pass TFF offers a significant reduction in cumulative shear exposure because of the single pass. He went on to say that for high concentrations and high viscosities they have demonstrated concentrations exceeding 250 mg/mL for IgG with single pass TFF technology or even higher concentrations with plasma proteins. The single pass TFF applies a serialized flow path and therefore the feed flow requirement of a single pass TFF system is significantly reduced when compared to a parallel membrane conventional TFF configuration. As a result, the single pass TFF system hold up volume is considerably smaller when compared to a conventional TFF system. The reduced hold up volume of the single pass TFF system also allows for enhanced product recovery, higher step yield, and higher final concentrations. Typical yields at high concentration from single pass TFF systems are equal or greater than 98%, whereas conventional TFF system yields can be as low as 80% or less. High concentration filtration Next, I asked Aude about other types of filtration, including direct flow. She said that higher concentration causes a significant increase in viscosity and that also affects the sterilizing grade filtration after the concentration step for the final formulation and fill. Higher viscosity has a direct impact on the filtration flux and that causes higher processing time. With higher concentration there is a likelihood of having higher aggregate content compared to lower concentration mAbs and this will in turn impacts the sterile filter capacity. It can cause your current filter size to block earlier that you would expect. So again, this means that it will increase your processing time or you might need a larger filter. She then offered her thoughts about solutions. She said that the first approach one might consider in overcoming this challenge would be to use a larger device size for a specific batch size. However, you need to keep in mind that using a larger device size is likely to increase your non-recoverable volume at the end of the sterilizing grade filtration process. She went on to say that that high concentration drugs are highly valuable, so the processing yields in each step is a critical factor to keep in mind. Something else to consider when thinking about larger device size and therefore larger membrane surface area, is that it could impact other product attributes such as excipient concentration. The research shows that polysorbate, which is used as an excipient in mAb formulation, might adsorb to sterilizing grade membrane. Using a larger device, and therefore a larger surface area for the same batch size, might increase the polysorbate adsorption which in turn could decrease your polysorbate concentration; particularly at the beginning of your filtration. High concentration drug production solutions I then asked what else Pall has been working on over the past couple of years to provide solutions suited for high concentration drug production. Tom described a diversity of products well suited to late-stage processing of monoclonals and recombinant proteins, not just direct flow filters or tangential flow filters as discussed. For example, their freeze and go storage and transport solutions, polymeric filling needles, and mixers all have attributes to help sustain critical product quality attributes for a concentrated drug. These products also help minimize costly losses that could be incurred by using technologies that have limited performance with high concentration feeds. In complement to their product offering, Pall also has a validation services team. The team recognizes that generating large sample volumes for process specific validation can be difficult with high concentration feeds, so they offer filter validation studies for fluid volumes in the range of several 100 milliliters rather than a couple of liters that would traditionally be utilized for process specific filter validation. Tom also shared that Pall is proud of their Allegro™ Connect bulk filling system. The recently launched system permits the integration of direct flow filters with high capacity for viscous feeds into a bulk filling manifold. This system automates the critical late stage filtration and dispensing step and has several features designed to maximize recovery of the high value filtered fluid. I then asked how companies can maximize productivity for their high concentration drugs? Tom explained that it is all down to selection, making sure that you've implemented the right equipment in your unit operations. It is important to seek out crossflow tangential flow filtration technologies that reduce shear and permit easy recovery of concentrated fluid. Second generation design, high area sterilizing grade filters with asymmetric PES media can enable smaller footprint filtration systems with less dead volume to occupy non-recoverable/hard to recover hold up. He added that another thing to do is always look towards vendors of single-use systems that are keen to explore your recovery challenge, who when presented with the problem of line loss will try and come up with ideas to minimize them through clever system design, appropriate orientation, or construction of components that help facilitate that fluid recovery and, of course,

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, a robust quality system also ensures you have a mechanism to continue to learn. AKBA uses the data collected from previous equipment builds or customer facing activities to apply lessons learned to future projects. These lessons can come in the form of data compiled from nonconforming product customer feedback at reflection meetings, which are all incredibly important pieces of their quality system. Lessons provide inputs for future process and product improvements. In this way they are always learning, growing, and therefore continually improving their equipment design as well as the customers' experience with it. Next, I asked her what trends she sees in quality management going forward in the industry and what it might look like in five to ten years. Katie responded by saying that right now she can see a digital transformation, because even less than ten years ago, many companies were working on transitioning from paper-based quality management systems to electronic systems and now everything is in the cloud. Moving forward, she feels we can expect full digitization throughout all different kinds of organizations’ quality systems, both large and small companies, and the new norm could be interacting digitally through cloud-based portals instead of emails. Another example could be that communication will be digitally scanned and accepted rather than receiving paper-based packing lists attached to shipments. Additionally, she thinks the implementation of AI is growing at a rapid pace in manufacturing and this will result in the automation of more quality judgments. She went on to say that there has been lots of talk in the quality sphere about quality 4.0 and whether quality professionals will be out of a job soon, but she strongly believes there will still be a need for quality professionals to advise on ways to grow a business using quality tools and concepts. She said that we must make sure we can evolve with the times, but skills like problem solving and process improvement are still innately human skills that will always be needed. By continuing to keep people connected to each other and engaged in the quality system through the total quality management approach, we can continue to build a culture where everyone is responsible and accountable and motivated to keep improving. To sum up her answer she said, “I believe that when you have everyone in an organization living and breathing a unified message for quality, you can really do some great things, and I can't wait to see how far we'll have come in 10 years”. I closed the interview by asking her if she had anything else to add for listeners. She added that with the rapid pace that everything is changing right now, especially in these certain industries like manufacturing and pharmaceuticals, it's an exciting time. She thinks the more that we can embrace the change, the greater things we can do. At Asahi Kasei Bioprocess, they are always innovating and trying to meet customers' needs for tomorrow. She thinks really getting behind that idea with an open mind and  supporting employees internally so they have the empowerment and the mechanisms to be successful will be critical moving forward. To learn more about Asahi Kasei Bioprocess America’s products and services, please visit: https://fluidmgmt.ak-bio.com/

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, they are frequently changing the product they are manufacturing. Their facility needs to be set up with the greatest degree of flexibility to adapt to changing needs as well as short notice production demands. For example, the need to be able to respond under short notice was clearly seen in the push to produce the COVID-19 vaccine. If a CMO gets this request and they’ve built their facility with a modular approach, systems could be interchanged easily. This would allow them to adapt quickly from a monoclonal antibody process to an mRNA process. A modular approach can also save companies on CAPEX as some consumables they will have in stock. The paper illustrates the ease of use of Pall mixer systems and their flexibility, which allowed a fast change over without buying new equipment. What to Consider when Selecting a Mixing System Next Klaus provided advice for listeners about what end users should be considering when selecting a mixing system. He replied that there is a message right now from some suppliers that one size fits all solutions are the best option, but the reality is simply that most processes are so unique and so variable that one size fits all doesn’t work. Pall takes a different approach by offering four different mixers providing a variety of solutions depending on the process. For example, if a customer needs a very powerful mixer, Pall offers the magnetic mixer, but if they need a shear sensitive one, they recommend the LevMixer® system. Because they utilize the same mixing tank, a simple change of the drive unit makes the equipment ready for either the high power demand of the magnetic mixer or the shear sensitive mixing of the LevMixer system. This flexibility allows customers to quickly adapt their entire facility towards a specific process without exchanging the big capital systems. Before we wrapped up the interview, I asked Klaus if he had anything else that he'd like to add for listeners. He told me that the Danaher philosophy is listening to the voice of the customer. Pall embraces this and takes it very seriously. This means that Pall reaches out to customers to ask what their specific needs are and how they can improve. One key slogan within Danaher is continuous improvement and Pall has applied that to their product portfolio by continuing to work on providing flexibility and interchangeability, not just within Pall, but future interchangeability between several technologies in the market. He added that his personal goal is to deliver the next level mixing experience, which in some cases is not the next level technology. It might be the next level of flexibility instead of the technology, but in the end, the bottom line is that the customer is experiencing happy mixing. For more information, please see the white paper Trends in Single-Use Mixing Technologies for Biomanufacturing

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. By doing this they can try to account for any of the differences that they might have, and can identify and define all of the critical process parameters throughout the whole process. Then they test the limits of all of these parameters in their model creation. He shared that working with a group like Pall, they have more consistency and confidence in the platform, so when they scale up, they know that it can work the first time and they don’t spend multiple rounds on large scale experimentation. John continued by saying that to address capacity issues, Andelyn is currently building a new manufacturing facility that will be able to handle additional large scale manufacturing for gene therapies that are coming online. CHOOSING A SCALE UP PLATFORM I then asked them if they could talk a little bit about the key factors that developers should consider in deciding which is the right technology for scale up. Denis replied that where the industry stands today, it is important to realize that there’s currently no one size fits all approach when it comes to production platforms and production systems for gene therapies. There are a multitude of factors that cell and gene therapy developers must consider when deciding what is the right technology and platform for scale up and  it is imperative to evaluate the target patient population size, the overall product demand, and the timelines that are associated with the clinical trial milestone. This work needs to be done in parallel with assessing the risks associated with each development and production platform and evaluating the advantages and challenges associated with each solution. He said that he also believes that it is very important to think about a therapy’s commercial scale needs as early as possible in the development process. Starting this exercise early on, offers an opportunity to think about scalable manufacturing solutions early in the development process, and will likely lead to better process understanding and simplified transfer of the process to a manufacturing scale that meets the program’s needs. John added that it is imperative to have confidence in all the small bench scale studies to be able to translate those results into large scale production. It is helpful to work with a company like Pall to aid in the backlog of experiments and increased manufacturing demands by limiting a lot of the time spent on large scale experiments on your product. SCALING UP AN AAV MANUFACTURING PROCESS TO 500 LITERS Next, we talked about their upcoming webinar on how they scaled up an AAV manufacturing process to 500 liters. I asked them to share some of the highlights. John told me that he will be presenting how Andelyn used design of experiment studies for creation of a model that is robust enough at small flask and bench scale level to translate all of those optimized parameters into a 50 liter pool bioreactor. He will go into detail on their statistical approach and some of the results. He will also touch on some of the issues that they saw after moving from a small flask and benchtop into a 50 liter bioreactor. He will also discuss how they tech transferred that platform to Pall to help scale into a 500 liter bioreactor. Denis spoke next saying that optimizing and successfully scaling a viral vector process to manufacturing scale is not a trivial process. It requires extensive process knowledge and expertise, and one of the major hurdles is scaling the process while maintaining good process control, demonstrating equivalent productivity and maintaining product quality attributes. During the webinar, Denis will discuss how Pall’s Accellerator process development services team can support gene therapy development companies and then he’ll dive deeper into the specific approach that they took during the collaboration with Andelyn Biosciences. He will share some data that demonstrates the successful process scalability from the 50 liter scale to the 500 liter scale using the Pall Allegro™ bioreactor platform. The results demonstrated comparable viral vector production as well as comparable recovery between the two different scales, again using some downstream technologies like Pall’s Stax™ filtration platform. I closed the interview by asking them if there was anything else that they would like to add for listeners. Denis said that we are living in really exciting times, the gene therapy journey through process development as well as industrialization is really a complex one, but the benefits of successful development and robust commercial processes are huge. We are all witness to the extraordinary impact that development and manufacturing of these therapies has on patients. John then said this is a very mission focused project for Andelyn, and their goal is always patient focused and patient oriented – that’s their #1 mission. All of Andelyn’s work has the end goal of improving people’s lives and it’s exciting to be a part of projects that are helping to drive the field forward. To view the webinar, please register at Successful Scale Up of a High Yielding Viral Vector Suspension Platform to 500 L

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 customization options affect the cost of these mixer systems. Phil said that frequently when customers hear the word customization or even tailored, they think that is going to drive the price up or maybe even drive the delivery time out. When Agilitech tailors a solution, it speeds up the delivery time and reduces the cost because everyone is on the same page and has alignment on what will be delivered. Agilitech works through all the issues up front with clients, so customers get exactly what they’ve asked for. Single-use Mixer Scalability We then discussed scalability and about how low volume mixers are difficult to find. I asked how Agilitech has been able to build scalability in their product line. Dennis described that their current sizes that range from 10 L to 650 L. He shared that their 10 L size has a minimum working volume of 1.25 L, which permits a process application such as a highly concentrated TF step to be able to be used with that mixing vessel. Additionally, because Agilitech has a total of seven different sizes, it allows customers to scale up their process for additional capacity using identically designed equipment. Levitronix is working on motors and impeller sizes that would permit Agilitech to offer up to a 3,000 L size in the future. Easy Process Implementation Next, I asked Dennis if he could talk about process implementation. He explained that each vessel comes with its own easy to use touchscreen interface that allows users to locally control the start and stop of the motor, change the setpoint of the speed on the agitator, and read local measurements for the weight, temperature, and other process analytics that are connected. Also, by using standard industrial hardware and standardizing on up-to-date future proof communication protocols such as Ethernet IP these systems can very easily be integrated into existing control systems. Lastly, I closed the interview by asking Dennis and Phil if they had anything else that they wanted to share with listeners. Dennis said that the industry has gotten too used to there being too few options in the market and perhaps have started to shape their processes to align with what is currently available. At Agilitech, the aim is to shift that perception and put the power back with the end user to define their equipment requirements that meet their process instead of vice versa. For example, changing the inlet and outlet size of your single-use mixing bag to better fit your process shouldn't increase the costs and time to receive that bag significantly. End users should remain rigid in their requirements and process. Vendors should be the ones that remain flexible to meet the needs of the user. Phil added that the solution should be plug and play to some extent. It shouldn't be a monumental effort to implement a new solution in an existing process.  A plug and play approach allows companies to get to market faster and to source components quicker. To learn more, please visit Agilitech Single-Use Mixers.

Cory Hinz talks 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.

Phil Sanders talks about the increase in demand for single-use equipment and consumables and how this has led to supply chain shortages.

In this podcast, we spoke with Chris Rombach, Vice President of Sales and Marketing at Asahi Kasei Bioprocess America about buffer prep and delivery systems. We discussed current pain points and how next generation buffer prep solutions can greatly improve upon the status quo, including increasing the use of automation and remote operation, while reducing the overall footprint, labor and cost associated with more traditional approaches.

Claire Jarmey-Swan, Global Product Manager, Pall Corporation talks about the evolution freeze thaw technologies and how these new methods can streamline the process, minimize loss and maintain the highest product quality.

Avril Vermunt, bioprocess hardware specialist at GE healthcare talks about transferring a process from non-GMP to GMP manufacturing, particularly how resource-intensive it is for process development and manufacturing groups. Avril has several years of experience working in the technology transfer group at a large pharmaceutical company. We discussed with her best practices and how being proactive and one step ahead can make the process more seamless.

Dr. Yuyi Shen, Principal Scientist, Grifols, talks about the benefits of modeling downstream disruptive technologies to improve downstream bioprocessing and evaluating the financial impact of implementing these technologies.

Silke Bergheim-Pietza, Global Product Manager Depth Filtration, Pall. discusses challenges faced in the cell harvesting step, in particular, selecting the best cell harvesting method based on the cell density and feed turbidity of the process and meeting the demand of increasing cell densities. Download the cell harvesting technology selection guide and use the guide to compare the latest single-use harvesting technologies.

Dr. Peter Levison, Senior Marketing Director – Downstream Processing, Pall Biotech talks about the evolution and benefits of continuous biomanufacturing, what implementation looks like today and what still needs to be realized for full industry adoption.

Jonathan Royce, Business Leader, Chromatography Resins, GE Healthcare Life Sciences, talks about the biggest challenges in Downstream biomanufacturing including overcoming bottlenecks, changing antibody structures and bioburden control. Jonathan shared how a purification platform can address some of these issues and discusses purification challenges that still need to be resolved.

Jonathan Royce, Business Leader, Chromatography Resins, GE Healthcare Life Sciences, talks about the evolution of Protein A including the latest developments in Protein A chromatography resins. We also discussed what the future holds for this purification mainstay and how it can continue to address the changing needs of biopharma.

Joakim Lundvist, Modality Manager, BioProcess™ Hardware, GE Healthcare talks about large-scale buffer management challenges. Buffer preparation is known to be one of the most resource-intensive activities in biomanufacturing as large volumes of buffers and process liquids are often required. So how can this be done in a more efficient way? How can more capacity be added to buffer preparation without adding major capital investment? Are there ways to reduce the manufacturing footprint and time spent on buffers?

Hillary Kaplan, Director, Bioprocess CMC Development & Operations, Klein Hersh talks about the job outlook for the biomanufacturing industry from a recruiter’s perspective.