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Scenario modeling informs planning for current and future manufacturing needs.
The biopharma industry is changing as it responds to rapidly evolving market conditions and the necessity to produce more treatments and therapies to meet the needs of patients around the world. Accelerated project timeframes have prompted the fill/finish sector to review its approach and consider strategies that support greater agility. Increasingly, modern-day facilities are building flexibility into infrastructures, with an emphasis on the ability to modify capacity and use equipment that can fill multiple drug types in different formats.
This article looks at design considerations required to deliver facilities that offer maximum flexibility and industry best practices in scenario modeling. It also examines the flexible capabilities built into the design of the Mark Cuban Cost Plus Drug Company’s sterile fill/finish facility being built in Dallas, Texas, to provide rapid response to drug shortages and support formulation, filling, and packaging of small batches.
Manufacturers seeking flexibility in their facilities must plan for the long term and consider the various product combinations that could arise over the next five to ten years. Agile processes are critical to react to changes in market demand, for both type of product and volume.
Scenario modeling is used in fill/finish facility design to inform the manufacturing opportunities for ﬁll/ﬁnish facilities. Through simulating different product and production scenarios, manufacturers can make informed decisions about the facility layout and type, capacity, and phasing of equipment required. Phasing involves the installation of equipment capacity as required for production. For instance, manufacturers might require the installation of one or two fill lines during the initial facility construction and have plans for additional fill lines to meet future projections a few years later.
Scenario modeling tests the extremes of facilities, enabling a clear understanding of what opportunities there are for clients to maximize the facility use. Through examining a combination of containers, filler speeds, shifts, doses, and batch-mix percentages, modeling provides clarity on the degree of utilization made possible through different scenarios. Additionally, modeling evaluates the impact of changes in critical parameters on various key performance indicators, such as production cost, cycle times, and plant throughput. These insights enable facility designers to engineer spaces, optimize production lines, and select equipment to provide maximum flexibility. These parameters can then be used to extrapolate sizing for supporting functions and facilities. Ultimately, scenario modeling identifies the bounds of a facility’s capabilities and aligns facility designers with the manufacturer on both their short and longer-term manufacturing goals.
Figure 1 shows an example of scenario modeling that looks at the capacity of a conventional filling line compared to a small batch filling line, recognizing turnaround time as the limiting factor.
This model considers a simple snapshot of filler type, turnaround time, and batch campaigning to evaluate different capacity outputs. During modeling, the design team undertakes interactive simulations utilizing a large number of variables to find the optimized selection of equipment and facility operational efficiency.
Flexibility is particularly important in multi-product facilities, which require additional levels of segregation to optimize the ability to have multiple products in the production process simultaneously. Flexibility can be viewed in a variety of formats, including facility adjacencies, separations, future expansion, and modularization. Facility designers balance adjacency to other processes, maximizing efficiencies of material, product, people, sample, and waste flows, while keeping a focus on expansion plans. Adjacencies are a complex problem, because project priorities and scope vary significantly. For example, a facility designer might consider aspects such as process steps or process time sensitivity and product flow, frequency of sampling and proximity of labs, or location of utilities to critical areas. Scenario modeling feeds into these adjacency discussions, and data from the scenario modeling is critical to design.
To facilitate future process expansion, design teams will need to consider how manufacturing requirements may change over time. Modular construction, such as preassembled cleanrooms, offer manufacturers the flexibility to repurpose spaces to facilitate their evolving manufacturing needs, quickly and cost-effectively. For example, the design team may place low-functioning areas—including collaboration spaces, staging, and storage—in locations adjacent to manufacturing spaces. If an expansion of the manufacturing area is subsequently required, modular systems can easily be removed to enable the low-functioning spaces to be relocated. This requires the design team to be mindful of the lifetime of the facility and foreseeable expansion plans. To accommodate this level of flexible design, facility designers will need to consider door and corridor clearances, ceiling heights, and power and utility requirements to ensure that spaces can accommodate a wide range of equipment sizes, for current and future use. Modular construction is particularly beneficial in cases where repeatability is necessary, as the expanded spaces can be designed once and fabricated multiple times.
Equipment for fill/finish facilities should be selected based on the outputs of scenario modeling, in order to maximize the facility throughput, together with expected growth. A combination of fillers, inspection, assembly, labeling, packaging, and serialization equipment are often selected to enable a balance between speed and capacity. In multi-product facilities, the various unit operations are not directly coupled and do not operate at the same speeds. Flexible fillers maybe used to fill various containers, such as vials and syringes, though often the downstream equipment does not require the same level of flexibility, as syringes and autoinjectors require further assembly but vials do not. Therefore, the assembly equipment may have more availability due to the mix of components and turnaround times and, as a result, does not need to be as fast as the filler .
Adoption of automation technologies into fill/finish processes presents other clear benefits. By making processes consistent and endlessly repeatable, automated equipment eliminates human error and increases a manufacturer’s ability to meet production quotas on tight deadlines. Furthermore, these technologies require less supervision, releasing staff members to work on other processes that are contingent on human intervention, and enabling technicians to work on multiple small batches in the same facility. Automated fill/finish processes can also significantly increase a facility’s capacity, through completing each iteration of a fill/finish step more rapidly than traditional approaches. As enhancements in machine learning improve precision of these systems, their ability to address unexpected deviations and incidents during filling also improves.
Single-use filling systems and ready-to-use components are increasingly being used in flexible, multi-product facilities in place of conventional stainless-steel and bulk component processing. These technologies eliminate the need to sterilize components and address the risk of contamination between batches. Validation and set-up costs also tend to be lower, reducing initial up-front costs.
Typically, a facility is developed with a specific product or products in mind. The facility being built in Dallas for the Mark Cuban Cost Plus Drug Company is unique in that its design must accommodate the production of unknown future product demands. This flexibility will provide a rapid response for drugs that FDA deems to be in short supply and for orphan drugs that are used to treat patients with rare diseases. The 22,000-ft2flexible fill/finish facility is designed to support the formulation, filling, and packaging of up to 250 different medicines in small batches annually.
Scenario modeling during design involves the evaluation of different product mixes to determine batch size and total facility throughput as well as to inform equipment sizing. Scenarios for production of a single product were also evaluated against daily product changes and intermediate product mixes to optimize capacity. Unit operations are split into different rooms using modular systems, allowing up to three different products to be processed simultaneously across formulation, filling, and packaging, without the risk of contamination.
At the heart of this multi-product facility’s design is its ability to produce small batches of products and to keep costs low, with selected equipment supporting these dual objectives. For example, the use of robotics in the fill/finish equipment will facilitate different containers, cartridges, vials, and syringes, with products of varying viscosities. However, in contrast to facilities with high-speed, highly automated filling and packaging equipment, most operations at the facility will be independent of each other, with equipment, such as fillers, standing alone. Stand-alone equipment mitigates the need for retooling and enables the company to continually switch production from one product to another.
Equipment has disposable product path components and minimal changes in parts, further supporting quick changeover between products. Once set up and loaded with ready-to-use components, the fill/finish equipment will operate as a stand-alone work cell, with no operational supervision required. This minimizes operator interventions and enables more repeatable unit operations. The facility also makes use of a combination of portable equipment and single-use components, selected to further limit costs and maximize flexibility. Laboratory services are planned to be outsourced, further limiting onsite footprint and costs.
The future-proofed design of the facility will accommodate growth in the Mark Cuban Cost Plus Drug Company’s demand for filling capacity. This vision is aided through the design of the corridor and utilities, which can be extended to add additional filling capacity.
Looking ahead, flexible facilities will continue to play a central role in supporting biopharma industry requirements, with rapid reconfigurations and new builds underpinning growing demand. The widespread availability of flexible facilities will ultimately ensure that patients worldwide can continue to receive life-saving therapies and treatments.
Jorge Ferreira is fill/finish subject matter expert, email@example.com, and Lora Zeanchock is project manager, both at Jacobs.
Vol. 34, No. 8
Pages: 38–39, 48
When referring to this article, please cite it as J. Ferreira and L. Zeanchock, “Designing Flexible Fill/Finish Facilities,” BioPharm International 34 (8) 38–39, 48 (2021).