Industry experts discuss challenges, trends, and innovations in fluid handling.
By Susan Haigney
Contamination prevention in biopharmaceutical manufacturing is crucial, and the proper handling and storage of fluids is essential to limit the possibility of contamination. Facility layout can help determine how companies handle fluid transfer and storage, and increased use of modular facilities and single-use systems (SUS) in the production and transfer of sterile fluids is helping shape the fluid handling landscape.
BioPharm International spoke with Max Blomberg, director of operations at Meissner; Luis Tissone, director of life sciences at Trelleborg Sealing Solutions; Todd Kaap, sales and market development manager, and Nick Hutchinson, global market development manager, at Parker domnick hunter; Thorsten Peuker, vice-president integrated solutions/project execution at Sartorius Stedim Biotech; and Tony Butler, single-use applications engineer at AdvantaPure, to get insight on the challenges and trends in fluid handling for biopharmaceuticals.
Fluid Handling Capabilities
BioPharm: What is the best way to determine which fluid handling capabilities are needed within a facility?
Butler (AdvantaPure): A good start is to overlay your process flow on your facility layout. Any processes not in the same suite will require storage or transfer.
Blomberg (Meissner): This largely depends on the sort of facility that is being contemplated. In the case of a greenfield project (i.e., one that lacks any prior infrastructure or process constraints), early conceptual work, as it pertains to the various process flows that the facility will house, is crucial, as one of the outputs of this exercise is defining the scope of fluid handling requirements. On the other hand, readdressing fluid handling capacity and functionality within an existing facility can yield substantial operational and cost benefits. Here as well, conceptual work pertaining to processes is useful. Often, in the case of an existing facility, this is much more defined predicated on the operational history of a given facility; however, at the same time, one is faced with some additional constraints imposed by the same.
Much has been written in recent years on modular facilities, prefabricated pods, and open-concept floor plans, which are interesting and useful concepts. The common thread that ties all of these concepts together is the implementation of single-use systems, as this is really the enabling technology for many of the new facility layouts.
Tissone (Trelleborg Sealing Solutions): There are several factors that will determine the fluid handling capabilities needed within a facility. In biopharma environments, it is critical to prevent fluid exposure, dangerous spills, and product contamination. The fluid handling process will be defined by regulatory compliance, economics, safety, sterilization, risk management, process control, automation, productivity, cleanliness, and flexibility. For example, flexibility is key in the case of manufacturing facilities that have to deal with multi-products for seasonal vaccines or pandemic response vaccines.
Hutchinson (Parker domnick hunter): Understanding fluid handling capacity should start with an understanding of the flow diagrams for the different processes within the facility. This will show how fluids enter the facility, are modified, and where and when they are used. More challenging is understanding the rate at which batches will be produced and the daily consumption of fluids that will occur. This [consumption of fluids] is often an uncertain factor during the early phases of a project. Careful modeling needs to take place to ensure sufficient water for injection (WFI) is being generated by utilities and sufficient solution storage capacity is available while the process is being run at its maximum rate.
Peuker (Sartorius Stedim Biotech): The customer should be aware of the process he will realize: process volume, process titer, future processes, etc. We made the best experiences with process simulation, which helps the user to determine the right size, mass balances, and potential bottlenecks of the production process.
With this approach, we are able to optimize fluid handling (e.g., transport of bags in palletanks) and facility design in regard to storage.
BioPharm: Which fluids represent the largest volumes within a facility?
Blomberg (Meissner): Typically within a biopharmaceutical manufacturing process that employs single-use systems, buffers and medias account for the largest fluid volumes. This is a departure from manufacturing processes that utilize stainless-steel systems, as in these cases, high-purity water often represents the largest fluid volume in a facility.
Kaap (Parker domnick hunter): WFI and buffer solutions, followed by media feed solutions, are generally the largest volume of use in bioprocessing.
BioPharm: Are single-use systems most often utilized with sterile or nonsterile fluids? Is there a reason for this trend?
Butler (AdvantaPure): In my opinion, single-use systems are used mainly for sterile fluids. I think the cost of SUS must justify the reduction of contamination risk and reduction of facility support/utility requirements, not to mention the shortened start-up time that also includes the training/qualification of employee(s) on the equipment. With nonsterile fluids, typically a sterilizing filter is used and contamination risk is not significant.
Peuker (Sartorius Stedim Biotech): The trend goes to sterile fluids since the benefits of single-use systems are much more valuable for sterile fluids. Particularly, less investments in clean in place and sterilize in place (CIP/SIP) and automation infrastructure are main drivers. For nonsterile fluids, this major point is not important. In addition, there are more and more sterile connections and intelligent systems available, which makes more complex processes and fluid transfers possible.
Kaap (Parker domnick hunter): Besides open-vessel mixing, most single-use applications for bioprocessing steps involve low bioburden fluids being transferred. There is a trend to move to closed systems instead of open systems to help reduce the risk of contamination, as well as reduce the cost of capital expenditures on cleanrooms. With a closed single-use system, the operation can be conducted in a grey space and can open up a lot of opportunities for production and development.
Tissone (Trelleborg Sealing Solutions): Single-use systems will be most often used with fluids that require sterile processing. Disposables could represent a significant benefit in terms of facility design, validation, and investment. This trend will continue to grow as single-use systems increase a product’s speed-to-market and return-on-investment. Due to the nature of the drugs, biopharmaceuticals put special attention on selecting suppliers with the adequate know-how and expertise in single-use products to ensure sterile processing and regulatory compliance.
Fluid Handling Challenges
BioPharm: What special precautions need to be taken into consideration when working with fluids as opposed to powders or other materials?
Tissone (Trelleborg Sealing Solutions): Considerations will revolve around the sealing solutions needed to prevent contamination, maintain a sterile environment, and the use of biocompatible materials that meet FDA standards.
Kaap (Parker domnick hunter): Leak prevention is key when working with fluids. Utilizing tubeset manifolds that have been overmolded instead of mechanically fastened can greatly reduce the risk of leaks occurring. Containers should be designed to avoid the generation of holes or improper seals, which could result in leaks.
Blomberg (Meissner): Insofar as containment, just as with powders, precautionary measures should be based on a sound risk assessment to account for cytotoxicity levels. Beyond the obvious differences in terms of infrastructure used to handle powders versus fluids, one of the primary differentiations associated with fluid handling in a biopharmaceutical process is the sterility of the substance. Whereas powder applications are typically handled in clean and controlled manner, fluids often need to be managed by an aseptic or validated sterile method.
BioPharm: What storage concerns are associated with bulk fluids?
Blomberg (Meissner): Ultimately, this is predicated to some degree on the fluid being stored. However, three common concerns with storage of bulk fluids are: maintaining the sterility of the fluid, the shelf-life of the fluid, and the suitability of the fluid contact materials. These three concerns are typically interrelated, especially when considering single-use systems. For example, the film from which a biocontainer is manufactured-- just one component of a single-use system--needs to serve as a barrier to microbial ingress for the duration of the storage period. At the same time, the film must provide high gas-barrier properties to prevent change (e.g., pH shift or concentration level changes), all while not impacting the contained fluid (e.g., leachable substances).
Butler (AdvantaPure): Concerns include pH shift, evaporative and absorptive losses, loss of bag integrity due to handling, and leachables.
Peuker (Sartorius Stedim Biotech): Bigger volume means higher risk if a bag is damaged. [Bulk fluids] must be filled into smaller containers for transportation or through the wall into the process area, if possible.
Tissone (Trelleborg Sealing Solutions): Storage is a major concern when handling bulk fluids. In the case of biohazard materials, a controlled environment is needed to assure the adequate conditions are met.
Kaap (Parker domnick hunter): [Concerns include] consistent temperature and space to store the items without being affected by the environment.
Hutchinson (Parker domnick hunter): Space constraints are often a key issue. For example, as the productivity of upstream processes has improved, the need to run a greater number of cycles through purification equipment has also increased, which increases buffer consumption. Although buffer requirements have increased, it is not so easy to expand facilities. The use of expensive facility space for storing large volumes of dilute solutions is not particularly efficient. One solution to the problem can be to perform in-line dilution of concentrated buffers at their point-of-use.
BioPharm: How are fluids best transported between process steps?
Peuker (Sartorius Stedim Biotech): [Fluids are best transported] through ports inside the wall or movable containers (palletanks), depending on facility layout.
Blomberg (Meissner): This is fairly process specific, but in broad terms, the simpler the better. Recent advances in continuous processing promise to simplify fluid transport to a degree, while facility design also plays a large role in determining how this is performed. From a practical perspective, 1000 L is generally a good working limit for the quantity of fluid that can be moved around a facility as a unitized load (accounting not just for weight but also for dimensional constraints, e.g., doorway width); however, if [movement of tanks] can be mitigated via the use of fluid paths, it is often preferable.
Butler (AdvantaPure): Using tubing with room pass through from one production vessel to another is the best solution. This eliminates the need for intermediate storage, tank space, and tank traffic.
Hutchinson (Parker domnick hunter): In my opinion, the transportation of process fluids should be minimized wherever possible, especially when operating single-use processes. Achieving a production system where fluids are not transported large distances around a facility implies that manufacturing media and buffers are positioned close to the suite so that they will be used at the time they are required, not before. These process fluids can then be pumped through silicone tubing to the processing step, rather than pushing large volumes of fluids in tanks along corridors, which can be unsafe, can lead to solutions being mixed up, and can increase operating complexity.
Transportation of the intermediate purified product should also be minimized, in my view. The product is extremely valuable and becomes vulnerable when being moved, whether it is moved in mobile tanks or is pumped through single-use tubing. Designing operations with mobile processing equipment can help to minimize these risks, bringing the process to the product rather than transporting the product to the process.
Tissone (Trelleborg Sealing Solutions): In the case of fluid transfer of parenteral drugs within a manufacturing process, it is common to use ultra-pure platinum-cured silicone tubing, which is inert, odorless, withstands autoclaving, and is translucent for flow visibility, just to name a few benefits.
Fluid Handling Innovation
BioPharm: What types of innovation would you like to see in the future of fluid handling systems?
Blomberg (Meissner): Specific to single-use systems, a lot of emphasis has recently been on the development of unit processing operations. Meissner thinks that innovative approaches to fluid handling materials (e.g., next-generation films), as well as leveraging some of the work related to the unit processing operation of basic fluid handling operations--manifested primarily in increased levels of automation—will be well received by end-users.
Kaap (Parker domnick hunter): A single-use closed system that could filter products to be sterile and dispense bulk fluid product [would be a good innovation]. Automating this process into a closed system and out of a laminar flow hood would be of tremendous benefit to the industry.