Thomas Page, PhD (Fujifilm Diosynth Biotechnologies, LLC) and Parrish Galliher, PhD (Cytiva) reflect on lessons learned from implementing the ballroom and modified ballroom (dance floor) approach for biomanufacturing.
Facility design for biologics manufacturing
The ballroom concept for biomanufacturing facilities was originally defined in the International Society of Pharmaceutical Engineers (ISPE) Baseline Guide: Volume 6 - Biopharmaceutical Manufacturing Facilities (2013) as
A large manufacturing area that has no fixed equipment and minimal segregation due to the use of functionally closed systems.
This manufacturing concept includes placing the bioprocess equipment on wheels instead of fixing them in a permanent place. Advances in single-use systems and bioprocess automation have made system closure more practical, but the gating factor for industry acceptance was the Pharmaceutical Inspection Co-operation Scheme (PIC/S) determination that cleanroom requirements for bioprocessing can be relaxed—or even eliminated—if your process is closed. This signal of acceptance paved the way for industry adoption, which in turn has created new opportunities for risk reduction, cost savings, and facility flexibility.
Early adopters of the ballroom approach have received a lot of attention. Now that their ballroom facilities have been inspected and licensed, their implementations have given much credibility to the operational feasibility and regulatory acceptance of open architecture suites. But the ballroom approach was often perceived as one that was best suited to a large, established biomanufacturer. Questions remained around how practical it is for a contract development and manufacturing organization (CDMO) facility.
What is a modified ballroom (dance floor) concept for biomanufacturing?
As first conceived, the ballroom concept would provide flexibility to deploy equipment to meet the needs of a specific process. Scale up or scale out could be achieved by simply wheeling in and connecting additional operations units, or multiple processes could be run in one space. Another view of flexibility was quickly revealed in relation to facility design—the ballroom does not have to be a single large space. It can be distributed over adjacent smaller spaces and connected with through-the-wall connections to maintain process closure. This modified ballroom approach, which has come to be known by some as the "dance floor" concept, allows the ballroom concept to be applied to existing facilities with minimal modification.
Fujifilm Diosynth Biotechnologies had considered a greenfield implementation for their new CDMO expansion. In the end, they decided to convert an existing but unused facility into a modified ballroom design with single-use equipment. The facility, first planned as a traditional stainless steel manufacturing site, was already divided into rooms. Rather than reconfigure the space with a major construction (or deconstruction) effort, Fujifilm Diosynth made minor changes and through-the-wall connections to implement a modified ballroom in the existing space. While most of the manufacturing area does not follow cleanroom requirements, Fujifilm Diosynth decided to implement cleanroom standards in the final, post-nanofiltration space. Product at this point is most concentrated, therefore most precious, as is cannot be remediated if it is contaminated. By implementing this “dance floor”, Fujifilm Diosynth could easily create a cleanroom in this one area, without the infrastructure and ongoing expense of creating a cleanroom environment for the whole process. This safeguard also instilled confidence for both the Fujifilm Diosynth staff and their multiple contract manufacturing clients.
Maximize flexibility while driving risk out of the system
Fujifilm Diosynth adapted an existing facility with a modified ballroom concept to maximize space utilization while minimizing the capital expense and the ongoing expenses associated with creating and maintaining a cleanroom environment for the whole bioprocess. As a CDMO, they also gained a new level of flexibility to address client needs. But how would clients respond? The response has been very positive, with valuable—and sometimes unexpected—lessons learned. Thomas Page, of Fujifilm Diosynth, sums up:
- Customers like the robustness of the approach, which goes beyond quality to decrease business and schedule risk.
- Deploying a closed system in a facility with a high level of controls will give a high level of quality, and therefore supports the ability to deliver on time.
- The ballroom approach enhances risk control.
Page believes that closed systems will become an expectation from regulatory agencies. Cytiva's Parrish Galliher expects bioprocess manufacturers to adopt a similar modified ballroom model. In that model the seed train and post-filtration operations are in cleanrooms, while the upstream, downstream, and filtration operations are in a shared space. This dance room model would have minimal environmental controls but strong closed-system security.
What to consider before implementing the modified ballroom approach
The closed-system dance floor approach allows biomanufacturers to take full advantage of the flexibility offered by single-use systems. For example, logistics is simpler, gowning is not needed, and the complexity of bringing single-use equipment into a cleanroom environment is avoided. Parallel process trains can be set up for a single product, or for multiple products, with physical separation of closed systems in a shared space. Robust centralized automation provides the controls required to manage each process, and both products and materials are segregated.
After implementing the ballroom and dance floor approach at multiple locations, Galliher has some practical advice for biomanufacturers considering these approaches:
- Meet with regional regulators early on, while you are still in the design phase. Flag any potential regulatory issues to avoid surprises late in the process.
- An engineering firm that understands ballroom bioprocessing, that really "gets it," can help avoid the over-engineering trap and help you realize the full savings of implementing a ballroom for bioprocessing.
- Success is in the details. It's in the details of the connections, the assemblies, and the standards you adhere to. The major unit operations don't really change.
- Connectors, connectors, connectors. When planning a closed bioprocess facility, pay close attention to how your equipment will be connected and how your connections will be validated.
Galliher sees a growing role for the ballroom concept and its key enabler, single-use technology. Single-use technology is well-established and has made its way into commercial licensed facilities, but further innovation in this field will make it more versatile for new markets and technologies.
The next step: standardized single-use connectors
One consistent pain point among biomanufacturers implementing closed bioprocesses is the lack of standards in connectors. At every equipment change-over, the process equipment must be connected. While the methods of making sterile connections are quite reliable and well-known, the lack of standards for connector sizes, materials, and construction often means that custom connectors must be ordered. This adds costs and complexity. Bioprocessors' needs will be better met when equipment manufacturers can agree on standards for sterile connectors. Standardized connectors will also lessen the validation burden.
Galliher envisions that system closures will be expanded and strengthened. Single-use systems that are currently not closed, such as cell harvest depth filters and ultrafiltration/diafiltration (UF/DF) membrane cassette systems, will be replaced with closed processing systems or systems validated to be "functionally closed" after assembly and in situ sanitization. In the end, techniques and methods will be developed to dismantle the single-use production line after use in a closed fashion. This will avoid contamination of the open ballroom facility. It will also result in a production line that is closed not only during bioprocessing, but also during change-over and disposal. As a result, environmental, health and safety (EHS) will improve.
Will the ballroom concept take over the bioprocess world?
There is no denying the appeal of the ballroom approach in emerging markets. Considering only the facility infrastructure, both the initial investment and the ongoing operating expenses are considerably lower than for a traditional cleanroom facility. The facility will require a smaller footprint, less engineering, lower construction costs, and less time to completion. The environmental impact is also much lower when cleanroom standards are limited to the seed train and post-filtration operations. And while it may sound trivial, removing the need for gowning leads to lower labor costs and greater efficiency. These advantages will tip the balance towards ballroom or dance floor implementations in emerging markets, as in Amgen’s Singapore facility.
The ballroom concept is also well-suited for applications that require multiple or rapid change-overs, as well as therapies with small-scale production. With a growing focus on precision healthcare, production environments will need to become more flexible.
There is still a place for large cleanroom facilities with stainless steel bioprocessing for blockbuster drugs. But manufacturers looking to expand capacity or bring a new biopharmaceutical to market are already looking hard and with interest at the ballroom concept. As the existing stainless steel bioprocess facilities come to end-of-life, we will likely see more biomanufacturers implementing the ballroom or modified ballroom approach.
Learn more about how to rapidly create single-use biomanufacturing capacity.