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Layout and supply details must be considered when implementing a fully disposable biopharmaceutical manufacturing process.
Single-use systems for biopharmaceutical manufacturing offer advantages such as flexibility, reduced capital cost, and reduced water use. Single-use (i.e., disposable) components are available for the entire process, from storage containers to bioreactors, filtration, and fluid handling systems. Designing a facility and operations for fully disposable systems requires different considerations compared to traditional stainless-steel systems, however. Pharmaceutical Technology spoke with Andrew Bulpin, head of Process Solutions at MilliporeSigma, which provides single-use systems (SUS), and Gene Yoshioka, senior director of manufacturing at Avid Bioservices, a contract development and manufacturing organization (CDMO) that built a fully single-use biomanufacturing suite in California in 2016. Avid Bioservices’ cGMP facility manufactures commercial and clinical biologics, and in 2017, the company added multiple 2000-L Mobius single-use bioreactors. Bulpin and Yoshioka shared some best practices for single-use facility design and operations.
PharmTech: What are the most significant concerns when designing a fully disposable biopharma process?
Yoshioka (Avid Bioservices): With fully disposable processes, detailed thought needs to be put into how process solutions (i.e., media and buffers) are transferred from one point to another. Containers used for single-use solution storage are limited by size and must be placed in relatively close proximity to the process as compared with traditional fixed tank stainless-steel systems. As a result, fluid management-the transport of hundreds to thousands of liters of solutions to a process-becomes a labor-intensive exercise. The payoff is enhanced flexibility, as a single-use plant does not necessitate the extensive equipment infrastructure and plumbing required by a plant with fixed equipment.
Another major difference when dealing with disposable technologies is the shift to relying heavily on raw material procurement and design. In a traditional stainless-steel plant, the focus is on equipment as the driving force for operations. Equipment still plays a big role in disposable plants, but the main systems are the single-use consumables. For example, a stainless-steel bioreactor is the workhorse in traditional plants, with fixed product-contacting surfaces, whereas in disposable plants, the product-contacting bioreactor bag is a material. This difference shifts the focus more toward procurement and acceptance of consumables. In addition, when developing a process, bag and tubing assembly designs need to be thought through to manage a balance between ensuring that assemblies serve their function and minimizing the number of different designs required to complete a process. As a CDMO, managing different assemblies across multiple processes is crucial in reducing consumable costs and warehouse storage requirements. And especially with consumables having a finite shelf-life and long lead times, managing inventories efficiently is a challenge.
Bulpin (MilliporeSigma): The biggest concern when designing a fully disposable biopharma process is ensuring that the fluid contact materials of construction are compatible with the process and will not adversely impact the drug product. When sourcing materials from multiple suppliers, end users must ensure that all materials meet their quality requirements and can be interconnected as needed to run the process.
One of the challenges with operating a fully disposable biopharma process is supply security. With traditional stainless-steel manufacturing, the number of consumables needed to run a process is limited to cell culture media, process chemicals, resins, and filter elements. Additionally, production plans are primarily driven by turnaround time, or the time it takes to clean and sterilize vessels between batches. With single-use, the number of consumables needed to run the process significantly increases, which makes the supply chain, especially procurement and inventory management, much more complex.
PharmTech: What are some of the concerns with testing and validating incoming single-use systems?
Bulpin (MilliporeSigma): While regulations governing single-use processing have yet to be published, industry guidance and best practice recommends users confirm that SUS do not affect the quality, efficacy, or safety of the drug product. One of the biggest challenges end users face is the cost associated with qualifying SUS. Due to the number of different components that make up single-use systems and the variety of different materials of construction of those components, a large amount of testing is required to ensure compatibility with process streams and conditions, and no adverse impact to product quality, efficacy, or patient safety. It benefits users to leverage similar designs where possible and generate a list of preferred components that have been previously validated to minimize additional testing. Users should partner with suppliers that provide robust documentation packages, which will increase the speed and decrease the cost associated with qualification.
Prior to implementing a new SUS, users should confirm that the fluid contact materials of construction are compatible with process streams and conditions and that extractables and leachables levels will not be harmful to patients. Most SUS suppliers provide this type of data and support product-specific testing. It’s also very important to ensure that the SUS performs as intended during processing. This testing is executed by the user as part of a performance qualification.
Once a system is qualified, users perform inspections on incoming lots and may perform leak testing, depending on the criticality of the operation in which the system will be used. The ongoing testing strategy should be determined based on a risk assessment. Evaluation of a new SUS is based on the material of construction and functionality of the system. A risk assessment should be performed to determine if additional testing is required, based on the supplier’s documentation package and historical qualification and use of similar systems by the user.
Yoshioka (Avid Bioservices): Testing and validating hardware of single-use systems is no different from the expectations for stainless-steel systems. There are usually less components to deal with in single-use systems, but the general approach is the same. Where the difference lies is with qualification of the single-use bags and assemblies, which not only includes testing of components, but is also highly dependent on qualification of the vendor itself. Much of the quality of single-use bags and assemblies is determined in the manufacturing and testing process at the vendor site. Users of single-use systems need to ensure that their vendors have appropriate controls in place to ensure quality of product during their manufacturing process and that they hold their component vendors to the same level of scrutiny for quality. Vendors are now working on testing methods that users can implement for testing large-scale bags just prior to use, which will significantly reduce the risk.
PharmTech: What best practices can be used for facility layout?
Yoshioka (Avid Bioservices): Our facility layout is designed such that tanks of buffers, media, and solutions are stored outside of the core production suites. Transfer lines are fed through the walls via transfer panels to reduce the need to move tanks in and out of the processing area. This design also allows for organization of transfer lines, as each port is identified to minimize opportunity for confusion. The segregation of bulk liquids to a supply corridor outside the upstream and downstream process spaces reduces material and personnel traffic into critical areas, reduces equipment congestion in the suites, and facilitates unidirectional process flow, thus improving control and functional operability.
Bulpin (MilliporeSigma): The type of production and manufacturing process should be defined to build the right facility for the right use. For example, will the facility produce small molecules or biologics? Will production be at clinical-scale or commercial-scale? Will the facility be multi-product or product dedicated? Are there plans for future expansion? The facility should have properly sized areas for equipment, people, and storage, and the layout must prevent cross-contamination. As part of the process design, and as a best practice, users should layout the floor plan, using actual equipment dimensions. This layout can be done simply by using tape on the floor. This practice allows operators to provide input to material flows and efficiency, while also providing engineering with the information they need to best design the single-use assemblies that will be used in the process. The next step is to create prototypes of the designs and repeat the exercise, which will help identify the required design changes to the assemblies; identify where supporting brackets, tubing tracks, or organizational systems are needed; and assist with operator training.
One of the biggest concerns with single-use processing is that it is still very manual. Smart design, detailed standard operating procedures, operator training, and clear communication between production planning and procurement are vital to success and staying on schedule. Systems should be designed in such a way that they are effectively ‘plug and play’.
Vol. 42, No. 2
When referring to this article, please cite it as J. Markarian, "Designing a Single-Use Biopharmaceutical Process," Pharmaceutical Technology 42 (2) 2018.