The Downstream Column (DsC) is an online publication targeting members of the biologics industry. Our intent is to provide a community to share expertise and best practices as well as discuss topics of interest. The Downstream Column covers areas important to the research, discovery, development, and manufacture of biologic therapeutics. Key industry coverage areas include: purification, formulation, fill/finish and QA/QC for cell and gene therapies, vaccines, biologics, and emerging therapeutic modalities.
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Advancements in Buffer Management and Single Use Inline Buffer Formulation
Friday, February 23, 2024 • Duration 15:46
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.
New online Gene Therapy Academy offers great resources to support scaling up from lab to production scale
Wednesday, October 5, 2022 • Duration 13:59
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 Guide for Navigating the Single Use Technology Supply Chain
Tuesday, September 20, 2022 • Duration 34:17
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,
Manufacturing high concentration mAbs challenges and solutions
Thursday, August 25, 2022 • Duration 15:34
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...
Biomanufacturing Quality Management Systems – A holistic approach
Thursday, August 11, 2022 • Duration
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,
Flexible single-use mixers are key to achieving a next level mixing experience and reducing delivery lead times
Wednesday, July 27, 2022 • Duration 16:22
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,
Optimizing Process Development Early – A critical factor in successful viral vector scale up and large scale manufacture
Tuesday, July 12, 2022 • Duration 13:23
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.
Single-use Mixers – Ensuring the Customization, Scalability and Supply Required for Success
Wednesday, May 25, 2022 • Duration 10:59
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...
Increasing Liquid Chromatography Efficiency with Fully-controlled Binary Blending
Thursday, May 19, 2022 • Duration 07:54
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.
Addressing the increasing demand for single-use technologies and supply chain shortages with future proof systems
Thursday, October 28, 2021 • Duration 16:08
Phil Sanders talks about the increase in demand for single-use equipment and consumables and how this has led to supply chain shortages.
