Mark A. Sitcoske, Founder & CEO, High Purity New England11.17.20
Single-use technology is changing how biopharmaceuticals are made. Advances in systems mean companies now have a disposable option for almost all unit operations, including buffer mixing.
Understanding which single-use mixing technology is best suited to a particular manufacturing operation is complex. Likewise, knowing how best to integrate the system in a way that makes the most of the advantages provided by single-use technology requires careful assessment.
Mixing things up
Optimal mixing is vital for efficient, high quality biopharmaceutical manufacturing. Ensuring media is mixed appropriately is critical to ensuring cultures achieve the desired productivity and quality.
Traditional stainless-steel mixers have moving parts inside that mix solutions in a controlled manner. Typically, such systems also incorporate a pump to add the fluid, a magnet to rotate the impeller to create mixing, and an outflow pump to remove the media.
While such systems are effective, they represent a significant capex outlay. Furthermore, they are costly to maintain and clean between production runs. Also, these large-scale technologies are less suited to lower volume production that has become increasingly common in the biopharmaceutical industry as drug firms focus on high value products for smaller patient populations.
As a result, in recent years interest in using disposable, single-use mixing technologies has increased.
Single-use savings
Adoption of single-use technologies has increased markedly in recent years, in all unit operations. According to a 2019 BioPlan Associates survey1 over the past 13 years the employment of single-use bioreactors, and mixing systems, grew by 59 and 55 percent, respectively.
Additionally, according to the survey, respondents made the greatest use of single-use mixing technologies during process scale-up, with 58.9% of operations being carried out with such systems.
Some 44.2% of commercial manufacturing operations employ single-use mixing technology, which is a significant increase on the proportion reported in earlier research.2
While the survey is not exhaustive, the results do indicate that adoption of single-use systems is increasing and that the technologies are being used for a wider variety of unit operations, including mixing. So, why is this the case?
Cost advantages
Cost is a major factor driving adoption.3 Firstly, single-use technologies require lower initial capex than stainless steel systems and can accelerate time-to-market—the combined result is a greater overall cost efficiency.
Secondly, additional cost savings can be realized through a reduction in ongoing operating costs such as cleaning chemicals and cleaning processes. While there are disposal and waste management costs associated with single-use systems, such costs are usually relatively low.
Direct costs aside, there are other potential benefits associated with using single-use systems rather than stainless steel technologies. For example, the risk of contamination is an ever present in the stainless-steel facility because the systems are used for multiple production runs.
By contrast, single-use systems are pre-sterilized, often using gamma irradiation. This improves sterility and eliminates the threat of batch-to-batch carry-over contamination.
In addition, single-use technologies have a lower environmental impact than stainless steel systems because they significantly reduce water usage.
Space saving
Another advantage is that single-use systems typically take up much less floor space than equivalent stainless steel technologies. This reduced footprint allows sites to manufacture products in smaller spaces, thereby lowering facility costs.
There are also benefits associated with process scale-up. Because single-use technologies are usually available in a range of sizes, systems used in the discovery or process development laboratory have larger equivalents that can be used for production on the factory floor. The potential to seamlessly scale-up by using single-use equipment and strategies can lead to significant reductions in process rework and inefficiencies that are typically expected in less flexible processes.
Outsourcing
The biopharmaceutical industry’s growing use of outsourcing partners for manufacturing has further increased the adoption of single-use systems of all types.
Contract development and manufacturing organizations (CDMOs) were among the earliest adopters of disposable technologies, primarily because such systems are ideally suited to multiproduct facilities.
The flexibility that single-use systems provide fit with a contractor’s need to be able to adapt to changing supply demands and pivot when client needs’ change. Furthermore, the emergence of so-called virtual biotechnology companies lacking any internal manufacturing capacity has increased demand for CDMOs with flexible manufacturing infrastructure.
Choices
To maximize the potential benefits of switching to a single-use mixing technology it is vital to choose the system that best fits the specific needs of the desired application.
A variety of single-use technologies are available that can be categorized based on the mixing technologies they employ.
There are those systems in which an impellor sits inside the culture bag and is moved using a magnet outside the bag. These technologies typically need a pump to add the fluid and then another to remove the media. While such technologies have obvious advantages over stainless steel systems, they still rely on moving parts.
The same is true for single-use systems that use magnetically driven stir bars4 and motor-driven impellors or wands. There are also technologies that employ bellows systems to force perforated plates through solutions to be mixed.
Other single-use systems eliminate moving parts entirely.
Such technologies use magnetic levitating pumps to spin the entire system, thereby mixing the solution contained. In addition, the most advanced systems of this type feature fluid flow technologies that facilitate faster, better contained transfer of the mixed media.
Another advantage of this second type of single-use mixing system is associated with their smaller footprint. As mentioned above, disposable mixing technologies are smaller than stainless steel counterparts; generally, they are available in the 10L to 500L scale.
These smaller units can be readily integrated into existing processes, either within the laboratory or on the manufacturing floor. As a result, they are ideal for those applications that take place in the lab and then moved into production, including buffer preparation.
Mixing at smaller volumes
Smaller volume single-use mixing technologies have other advantages over larger systems, particularly when it comes to mixture storage.
Many buffer solutions used in biopharmaceutical manufacturing contain hydrophobic components that tend to aggregate to exclude water over time. As a result, after mixing, such solutions will become less homogeneous unless they are continually recirculated.
At large scale the need for constant mixing represents a significant challenge. But users of smaller scale single-use mixing systems have the option of utilizing an ancillary mixer to help maintain solution homogeneity during vial filling operations.
Heterogeneity
Whether a biopharmaceutical company uses a traditional stainless steel mixing technology, or a single-use system ultimately depends on the nature of the manufacturing.
However, as biopharma moves further away from the high-volume blockbuster model towards the high value low volume paradigm, use of single-use systems is likely to increase. The era of personalized medicines and cell and gene therapies will also see more manufacturers recognize the benefits of disposable technologies.
It is also likely that pressure to reduce biopharmaceutical prices will prompt drug companies to employ innovative technologies across the entire value chain to improve efficiency, reduce costs and boost profitability.
Finally, the COVID-19 pandemic has underlined the need for greater flexibility and capacity in biopharmaceutical manufacturing. Indeed, several recent studies5 have suggested that demand for single-use technologies has increased in the past six months as a direct result of the pandemic, reflecting the significant increase in SARS-CoV-2 related R&D.
Conclusion
As the drug development pipeline increasingly focuses on personalized therapies that inherently require more agile, multi-product manufacturing capabilities, more companies are set to adopt single-use technology.
These well-engineered solutions are proven to reduce time, costs and cross-contamination risk across downstream and upstream manufacturing.
References
Mark A. Sitcoske is Founder & CEO of High Purity New England. With over 30 years in the industry, he provides a wealth of experience in bioprocessing. He prides himself on the company’s reputation for providing unique solutions and dedicated customer support, creating a competitive advantage over others.
Understanding which single-use mixing technology is best suited to a particular manufacturing operation is complex. Likewise, knowing how best to integrate the system in a way that makes the most of the advantages provided by single-use technology requires careful assessment.
Mixing things up
Optimal mixing is vital for efficient, high quality biopharmaceutical manufacturing. Ensuring media is mixed appropriately is critical to ensuring cultures achieve the desired productivity and quality.
Traditional stainless-steel mixers have moving parts inside that mix solutions in a controlled manner. Typically, such systems also incorporate a pump to add the fluid, a magnet to rotate the impeller to create mixing, and an outflow pump to remove the media.
While such systems are effective, they represent a significant capex outlay. Furthermore, they are costly to maintain and clean between production runs. Also, these large-scale technologies are less suited to lower volume production that has become increasingly common in the biopharmaceutical industry as drug firms focus on high value products for smaller patient populations.
As a result, in recent years interest in using disposable, single-use mixing technologies has increased.
Single-use savings
Adoption of single-use technologies has increased markedly in recent years, in all unit operations. According to a 2019 BioPlan Associates survey1 over the past 13 years the employment of single-use bioreactors, and mixing systems, grew by 59 and 55 percent, respectively.
Additionally, according to the survey, respondents made the greatest use of single-use mixing technologies during process scale-up, with 58.9% of operations being carried out with such systems.
Some 44.2% of commercial manufacturing operations employ single-use mixing technology, which is a significant increase on the proportion reported in earlier research.2
While the survey is not exhaustive, the results do indicate that adoption of single-use systems is increasing and that the technologies are being used for a wider variety of unit operations, including mixing. So, why is this the case?
Cost advantages
Cost is a major factor driving adoption.3 Firstly, single-use technologies require lower initial capex than stainless steel systems and can accelerate time-to-market—the combined result is a greater overall cost efficiency.
Secondly, additional cost savings can be realized through a reduction in ongoing operating costs such as cleaning chemicals and cleaning processes. While there are disposal and waste management costs associated with single-use systems, such costs are usually relatively low.
Direct costs aside, there are other potential benefits associated with using single-use systems rather than stainless steel technologies. For example, the risk of contamination is an ever present in the stainless-steel facility because the systems are used for multiple production runs.
By contrast, single-use systems are pre-sterilized, often using gamma irradiation. This improves sterility and eliminates the threat of batch-to-batch carry-over contamination.
In addition, single-use technologies have a lower environmental impact than stainless steel systems because they significantly reduce water usage.
Space saving
Another advantage is that single-use systems typically take up much less floor space than equivalent stainless steel technologies. This reduced footprint allows sites to manufacture products in smaller spaces, thereby lowering facility costs.
There are also benefits associated with process scale-up. Because single-use technologies are usually available in a range of sizes, systems used in the discovery or process development laboratory have larger equivalents that can be used for production on the factory floor. The potential to seamlessly scale-up by using single-use equipment and strategies can lead to significant reductions in process rework and inefficiencies that are typically expected in less flexible processes.
Outsourcing
The biopharmaceutical industry’s growing use of outsourcing partners for manufacturing has further increased the adoption of single-use systems of all types.
Contract development and manufacturing organizations (CDMOs) were among the earliest adopters of disposable technologies, primarily because such systems are ideally suited to multiproduct facilities.
The flexibility that single-use systems provide fit with a contractor’s need to be able to adapt to changing supply demands and pivot when client needs’ change. Furthermore, the emergence of so-called virtual biotechnology companies lacking any internal manufacturing capacity has increased demand for CDMOs with flexible manufacturing infrastructure.
Choices
To maximize the potential benefits of switching to a single-use mixing technology it is vital to choose the system that best fits the specific needs of the desired application.
A variety of single-use technologies are available that can be categorized based on the mixing technologies they employ.
There are those systems in which an impellor sits inside the culture bag and is moved using a magnet outside the bag. These technologies typically need a pump to add the fluid and then another to remove the media. While such technologies have obvious advantages over stainless steel systems, they still rely on moving parts.
The same is true for single-use systems that use magnetically driven stir bars4 and motor-driven impellors or wands. There are also technologies that employ bellows systems to force perforated plates through solutions to be mixed.
Other single-use systems eliminate moving parts entirely.
Such technologies use magnetic levitating pumps to spin the entire system, thereby mixing the solution contained. In addition, the most advanced systems of this type feature fluid flow technologies that facilitate faster, better contained transfer of the mixed media.
Another advantage of this second type of single-use mixing system is associated with their smaller footprint. As mentioned above, disposable mixing technologies are smaller than stainless steel counterparts; generally, they are available in the 10L to 500L scale.
These smaller units can be readily integrated into existing processes, either within the laboratory or on the manufacturing floor. As a result, they are ideal for those applications that take place in the lab and then moved into production, including buffer preparation.
Mixing at smaller volumes
Smaller volume single-use mixing technologies have other advantages over larger systems, particularly when it comes to mixture storage.
Many buffer solutions used in biopharmaceutical manufacturing contain hydrophobic components that tend to aggregate to exclude water over time. As a result, after mixing, such solutions will become less homogeneous unless they are continually recirculated.
At large scale the need for constant mixing represents a significant challenge. But users of smaller scale single-use mixing systems have the option of utilizing an ancillary mixer to help maintain solution homogeneity during vial filling operations.
Heterogeneity
Whether a biopharmaceutical company uses a traditional stainless steel mixing technology, or a single-use system ultimately depends on the nature of the manufacturing.
However, as biopharma moves further away from the high-volume blockbuster model towards the high value low volume paradigm, use of single-use systems is likely to increase. The era of personalized medicines and cell and gene therapies will also see more manufacturers recognize the benefits of disposable technologies.
It is also likely that pressure to reduce biopharmaceutical prices will prompt drug companies to employ innovative technologies across the entire value chain to improve efficiency, reduce costs and boost profitability.
Finally, the COVID-19 pandemic has underlined the need for greater flexibility and capacity in biopharmaceutical manufacturing. Indeed, several recent studies5 have suggested that demand for single-use technologies has increased in the past six months as a direct result of the pandemic, reflecting the significant increase in SARS-CoV-2 related R&D.
Conclusion
As the drug development pipeline increasingly focuses on personalized therapies that inherently require more agile, multi-product manufacturing capabilities, more companies are set to adopt single-use technology.
These well-engineered solutions are proven to reduce time, costs and cross-contamination risk across downstream and upstream manufacturing.
References
- https://www.americanpharmaceuticalreview.com/Featured-Articles/561308-Rise-of-Single-Use-Bioprocessing-Technologies-Dominating-Most-R-D-and-Clinical-Manufacture/
- https://www.americanpharmaceuticalreview.com/Featured-Articles/177871-Single-Use-Systems-Not-Helping-Downstream-Bioprocessing-Yet-Alternatives-to-Chromatography-Still-Slow-in-Adoption/
- https://www.researchgate.net/profile/Maik_Jornitz/publication/287842256_Disposable_biopharmaceutical_processes-Myth_or_reality/links/56d842db08aee1aa5f7bb50d.pdf
- https://www.semanticscholar.org/paper/A-Novel-Single-Use-Mixing-System-for-Buffer-Waele-Vandermarliere/0035e9acbbfd95460af253f05f96bfa7be90ebb8?p2df
- https://bioplanassociates.com/wp-content/uploads/2017/02/17th-Annual-2020-Top-Bioprocessing-TRENDS-White-Paper-BioPlan-20200713B.pdf
Mark A. Sitcoske is Founder & CEO of High Purity New England. With over 30 years in the industry, he provides a wealth of experience in bioprocessing. He prides himself on the company’s reputation for providing unique solutions and dedicated customer support, creating a competitive advantage over others.
