Ballroom design is common in pharmaceutical facilities, particularly in biologics. In this design concept, process closure permits upstream and downstream operations to be performed in a shared space.
Consequently, ballroom designs allow for more flexibility than in segregated designs. For example, if business plans change, a larger ballroom offers the flexibility to incorporate different products and equipment (rather than using smaller suites, which can be limiting in nature.)
Although gene therapy manufacturing is primarily closed, utilizing single-use equipment, most gene therapy manufacturers have been reluctant to move away from a segregated layout. Instead, upstream and downstream activities typically are divided between different suites.
Next generation gene therapy facilities, however, are evaluating ballroom design — specifically for the flexibility advantages such design offers. In this article, we will discuss the pros and cons for moving from segregated suites into the ballroom. We’ll also explain why process simulation modelling is essential for organizations considering whether a shift to ballroom design may be right for them.
Gene therapy and single use equipment
The equipment used for gene therapy manufacturing is essentially the same as the equipment used for all biologics manufacturing, just on a smaller scale — single use bioreactors and single use depth filtration are used for upstream processing. Once you get into downstream considerations, single use chromatography and single use Tangential Flow Filtration (TFF) skids are common.
Gene therapy manufacturers have been reluctant to move away from a segregated layout essentially for reasons of throughput. In biologics, three different batches (for example) may be set up in three different bioreactors in the same ballroom. Gene therapy, on the other hand, is more highly segregated. Until batch A leaves the room, you can’t bring in batch B.
The rationale for this difference in design lies in a concern about cross-contamination. With bulk biologics, where proteins are being manufactured, there is less of a risk of contamination from one batch to another. With gene therapy, where the product is viral vectors, it’s harder to eliminate the risk of contamination from the equation.
Increasingly, however, next generation facilities are evaluating ballroom design for future flexibility. Our organization recently concluded a project for a company debating whether or not to employ ballroom design. After some collaborative planning sessions we arrived at two separate layouts — one with individual suites and a second with ballroom design. A process simulation model was developed, and based on their targets, the company concluded they were able to meet their capacity needs with a ballroom layout, while also retaining an option for individual suites, based on their clients’ preferences.
Process simulation modeling is an essential step in determining whether ballroom design is right for your organization. In the sections that follow, we’ll weigh the pros and cons of this design approach.
Pros of ballroom design
There are several advantages to ballroom design for gene therapy, including reduced square footage for facilities, operational efficiency and cost reduction, and the ability to share equipment. Let’s consider each.
Reduced square footage: Here we’re primarily considering reduction in the number of airlocks.
Consider a facility with Grade D corridors and Grade C suites. In that case, there are potentially four airlocks to access each suite: PAL IN, PAL OUT, MAL IN, and MAL OUT. By combining upstream and downstream operations into a single suite, the facility planners can save the square footage of a minimum of four airlocks – perhaps even more, depending on the HVAC strategy being employed.
Operational efficiency/cost reduction: Here we’re particularly focusing on the substantial cost reductions that accrue from reducing gowning expenses. Gowning expenses are surprisingly significant from the perspective of operator costs.
Most gene therapy facilities are “unidirectional,” meaning that operators working in a given suite must return to the locker room before being able to move to a different suite. This means that an operator working in the upstream suite who needs to move to a downstream suite must fully de-gown through the PAL OUT, return to the locker room, then re-gown before entering the downstream suite.
So, every time someone takes a lunch break, every time they use the restroom or any other activity, they have to completely de-gown, go to the locker room, change out of their scrubs, and then come back in and repeat that process. This expense is especially significant when considering maintenance personnel or individuals collecting samples. Operating expenses can mount quickly under those circumstances.
By moving to a ballroom approach, operational efficiency is improved, and gowning costs are reduced. Access for maintenance personnel is also improved with a ballroom design.
Ability to share equipment: In a segregated design, it is difficult and time-consuming to move equipment between upstream and downstream suites. A ballroom approach allows for single use mixers of a similar size, for example, to be shared between upstream and downstream unit operations. This in turn leads to a reduced capital cost investment.
This is not to say, however, that ballroom design is all upsides. There are some distinct disadvantages that companies also must weigh when considering this approach.
Cons of ballroom design
The downsides to ballroom design include potential for higher HVAC classifications, facility throughput issues, and biosafety level considerations. Let’s take each in turn.
Potentially higher HVAC classifications: Many gene therapy manufacturers maintain their upstream suites and downstream suites with different HVAC classifications. It’s common to see upstream suites classified as Grade D, and downstream suites as Grade C.
With a ballroom approach, the higher HVAC classification (Grade C) must apply. This can lead to increased cost for HVAC energy loads, environmental monitoring, and gowning.
Facility throughput: As mentioned earlier, throughput remains the primary reason manufacturers are reluctant to combine upstream and downstream operations into a single ballroom.
Unlike biologics, where multiple batches of products can be manufactured in the same ballroom, gene therapy products are subject to more regulatory scrutiny. According to the EMA GMP Guidelines for ATMPs, “Concurrent production of two different ATMPs/batches in the same area is not acceptable.”
This restriction, by definition, limits manufacturers to one batch per suite. Consequently, a process simulation model is recommended to evaluate the throughput differences between a ballroom approach versus segregated suite design.
As an option to improve efficiency, viral negative cell expansion steps prior to the production bioreactor may be shifted to inoculum prep to improve throughput.
Biosafety level considerations: Some facilities classify their production cleanrooms as Biosafety Level 2 (BSL-2). This ensures maximum flexibility, allowing for retroviral and lentiviral production. On the other hand, however, many manufacturers are dedicated to Adeno-Associated Virus (AAV) production.
With AAV, only the upstream suite needs to be classified as BSL-2 to account for the Human Embryonic Kidney (HEK) host cell line. Downstream suites may be classified as BSL-1.
Shifting to a ballroom design means the entire suite — and therefore all waste, both liquid and solid, from the room — may have to be managed as BSL-2. This can, of course, lead to increased costs. Given the reality that resources are constrained in the case of existing facilities, these concerns can become operationally significant.
Process simulation modeling is key
For readers wrestling over whether the decision of using ballroom design in their facility, process simulation modeling is essential. Understanding the pros and cons described above, when weighed against the organization’s business model, help drive the decision of whether or not ballroom design is appropriate.
This is an especially important part of the decision-making process when an organization is realigning its business goals. In the case of the example cited at the outset of this article, the company is expanding. Their current layout is segregated. They made the decision to add ballroom design, with both configurations in the same facility.
That actually became an internal point of debate: Would there be concerns among prospective clients that half of the facility was upstream/downstream, and half ballroom? From the company’s perspective, that flexibility actually became a benefit. If one of their clients wants segregation, that is possible. If they want a ballroom approach, that option also is available.
It’s important to note that while facility throughput is an essential consideration, so too are the implications of a particular facility design on staffing and equipment sharing.
If all processes will be combined into a ballroom design, will upstream and downstream staffing be shared? Will there no longer be a need to duplicate personnel because of the ballroom approach?
The same consideration applies for equipment. In segregated design, moving equipment between suites may be cumbersome and time-consuming, especially when compared with ballroom design. On the other hand, perhaps given a manufacturer’s particular production requirements, it might be most cost effective to buy additional equipment altogether.
These considerations are particularly relevant for organizations that may be shifting their lines of business — adding some product types, or removing others. And that may be the tipping point when considering ballroom design. If the area of the facility will be expanding, there is greater flexibility in design. A larger piece of equipment may work better in a ballroom, for example, than in an individual suite.
Regardless of where an organization may be in the process of choosing between ballroom design or segregated suites, process simulation modeling is essential in making the choice that will best support its business needs.
