Multi-Purpose Biopharmaceutical Manufacturing Facilities Part 1: Product Pipeline Manufacturing

FOTOGENICSTUDIO/SHUTTERSTOCK.COM

The biopharmaceutical industry can no longer afford to design and build manufacturing capacity as a major part of the critical path for launching and supplying products by waiting to define the process and capacity requirements before making the decision to develop or build commercial manufacturing capacity. This two-part article describes how a facility layout composed of multi-functional cleanrooms can be used to both develop and launch new products from a pipeline (Part I) as well as support large-scale commercial manufacturing (Part II) (1). The layout strategy leverages moveable equipment using single-use component technologies to provide agile flexibility. The approach uses large numbers of segregated, multi-functional cleanrooms that can be quickly adapted, configured, integrated, operated, and redeployed as necessary to satisfy a wide variety of complex manufacturing requirements. 

A product’s manufacturing capacity, from clinical testing through early commercial supply, can grow and contract for many reasons that are difficult to predict. Many initiatives have attempted to speed up the creation of manufacturing capacity to satisfy specific production requirements. These efforts, however, have had minimal impact on the overall time required to plan, design, build, start-up, and validate new manufacturing capacity. Without a significant change in the approach, access to manufacturing capacity will remain an expensive, time-consuming obstacle to launching and supplying new products. 

Biopharmaceutical manufacturing’s challenges can be summarized as:

• Market uncertainty: Accurately predicting capacity requirements for biopharmaceuticals, particularly those associated with changing patient requirements and market penetration over the product’s lifecycle from clinical testing to inventory building and long-term market supply, is almost impossible. 

• Process evolution: Continuing process evolution will result in significantly smaller, more efficient processes that will stimulate both internal and competitive biosimilar products for reducing product costs and increasing capacity. These process advances include continuous manufacturing in the form of perfusion and highly concentrated fed batch bioreactors, high cycle rate, and simulated moving bed chromatography, etc. Systems biology and specialized synthetic, purpose-built cell lines may also result in significant process changes in the future that require greater flexibility for running and adapting to new process scales, strategies, and configurations.

• New product development: By using the same facility and dedicated critical personnel, tech transfer can be minimized, if not eliminated, thus increasing the likelihood of consistently high-quality products and lifecycle comparability. Such an approach is especially important for products that must be immediately approved using an Emergency Use Authorization (EUA) to remediate pandemic and bioterrorism threats (2). 

• Expedited product review: The industry’s need for more efficient and flexible manufacturing capacity is significantly impacted by FDA’s guidance, Expedited Programs for Serious Conditions–Drugs & Biologics, which uses surrogate and intermediate therapeutic endpoints to accelerate the approval of breakthrough products (3). The guidance impacts manufacturing in the following ways:

• Places clinical manufacturing capacity on or near the product’s development critical path by significantly increasing the rate products can be developed, clinically tested, approved, and launched.

• Increases the urgency and risks of planning commercial manufacturing capacity by stating: “When sponsor receives an expedited drug development designation, they should be prepared to propose a commercial manufacturing program that will ensure availability of quality product at the time of approval” (3).

• Increases business risks because the products are approved based on intermediate endpoints. If long-term safety or efficacy concerns occur during post-marketing confirmatory monitoring, the product may be withdrawn or sales significantly restricted. 

The next generation of biopharmaceutical facilities must go beyond multiproduct to true multi-purpose capabilities. By facilitating the rapid scale up and, if necessary, scale-out of a process, the multi-purpose facility can be used for clinical testing, product launch, inventory building, and long-term commercial supply. Such flexibility requires facilities designed to be easily adapted to the changing manufacturing needs of a product’s process without facility modifications. These facilities must also be adaptable to many different types of processes as well as able to quickly add or remove support services, such as media and buffer preparation, based on the needs of the processes. 

This article describes a new type of highly flexible, multi-purpose manufacturing facility layout using a matrix of multi-functional operating rooms that can be adapted and used to operate a wide variety of different processes at different scales without changes to the layout. Processes could even include final filling of small-volume or time-sensitive cellular products using movable, self-contained work-cell isolator systems with ready-to-use components. Most importantly, processes can be added, modified, or removed without impacting ongoing operation of other processes currently in the facility. 

Layout concept

Figure 1 shows a basic layout of three arms (A, B, C) divided into six non-dedicated cleanrooms (1 thru 6) per arm. The size of the 18-cleanroom operating core is approximately 23,500 ft². Depending on the projected size of the pipeline and its estimated manufacturing requirements, the facility’s initial capabilities can be increased or decreased by changing the number of arms or the number of cleanrooms per arm during the design. Each process placed into the facility shown in Figure 1 uses only enough cleanrooms to operate the process. The remaining areas are available for other products or process activities. 

Figure 1. Multi-purpose facility. Layout of 18 multi-functional cleanrooms in three arms (A,B,C) with each arm having six operating areas (1-6). All figures are courtesy of the authors.

Figure 1. Multi-purpose facility. Layout of 18 multi-functional cleanrooms in three arms (A,B,C) with each arm having six operating areas (1-6). All figures are courtesy of the authors.

The cleanrooms are connected by interlocking primary and out corridors supporting both bi- and uni-directional flows of equipment, material, and personnel. The layout is a mixture of Grade C and D areas with some adjacent rooms having removable walls to support larger equipment and material space requirements. 

For introducing a new process, equipment is staged in the equipment preparation area located in the lower right of Figure 1 and moved through the primary corridors to the selected operating area. For small-scale processes, raw materials and components are supplied to the operating areas by totes and carts via the primary corridor. Transfer of in-process materials is achieved using totes via the primary corridor. Under normal conditions, personnel movement is controlled using bidirectional flow via the primary corridor. Waste material, used components, and equipment are removed using unidirectional flow via the out corridor. A utility floor above the operating core contains the heating, ventilation, and air-conditioning systems, utility access (including water for injection, air, etc.) as well as closed, stainless-steel piping inter-area connections, if needed. 

The facility’s flexibility comes from each of the 18 multi-functional cleanroom’s ability to accommodate nearly any of the various process or support elements required to operate a process. Because of the separation provided by the many multi-functional areas, the process can be placed within the layout in a wide variety of configurations based on available adjacencies and product priorities. Recent developments in single-use systems (SUS) make it easy to move and setup the process equipment in the assigned cleanrooms, operate them, and then remove or relocate the equipment when the product’s campaign is complete. 

The following example process demonstrates how a variety of manufacturing processes can be organized and controlled for insertion, operation, rearrangement, or removal from the layout. The example process represents a wide variety of possible processes for manufacturing proteins, nucleic acids, cells, or vaccines. 

Example process

The process shown in Figure 2 is a typical monoclonal antibody (mAb) process composed of 11 unit operations (UOs) divided into four logical operating units (LOUs). LOUs are groups of UOs that can or should be operated together for operational convenience or inter-UO connectivity. All process UOs for manufacturing any product can be grouped into LOUs. The LOUs are then appropriately located within the layout depending on available inter-LOU connectivity options and various risk factors associated with each process step, equipment sizes, and various operational considerations such as pre- and post-viral removal steps. 

Figure 2. The 11 unit operations (UOs) of the example monoclonal antibody (mAb) process divided into four logical operating units (LOUs). Process UOs may be redistributed and support LOUs added as needed. SUB is single-use bioreactor.

Figure 2. The 11 unit operations (UOs) of the example monoclonal antibody (mAb) process divided into four logical operating units (LOUs). Process UOs may be redistributed and support LOUs added as needed. SUB is single-use bioreactor.

To demonstrate the facility’s flexibility, the example process is operated at scales ranging from 250 L to 2000 L single-use bioreactors (SUBs). In addition, the facility is adapted to support different operating rates and campaign lengths by adding the necessary support resources. The flexibility and adaptability of the multi-functional areas allows for support resources to be added and removed as necessary to meet product development priorities and optimize the overall facility’s utilization rate. This ability is particularly important for intensified processes that require large amounts of media and buffers. 

A possible portfolio of process scales, which also represents a likely scale-up sequence for developing a new mAb product, is shown in Figure 3. 

Figure 3.Logical operating units (LOUs) for three different scales of the example monoclonal antibody (mAb) process for placement into the multi-functional operating areas. Process sequence shown in Figure 2. Unit operations for Phase III/launch process are redistributed as appropriate. SUB is single-use bioreactor.

Figure 3.Logical operating units (LOUs) for three different scales of the example monoclonal antibody (mAb) process for placement into the multi-functional operating areas. Process sequence shown in Figure 2. Unit operations for Phase III/launch process are redistributed as appropriate. SUB is single-use bioreactor.

A true multi-purpose facility should be able to run many small Phase I processes, several medium-size Phase II processes, and a larger-scale Phase III process when needed. To demonstrate full functionality of the multi-purpose facility concept, a high volume, commercial-scale process is described in Part II of this article (2). 

Operating the multi-purpose facility

One possible process arrangement of the three processes in Figure 3 is shown in Figure 4. The placement of the LOUs within the facility is likely based on the availability of areas as they are cleared by the removal of previous processes. Although the LOUs for the 500-L SUB, Phase II process appears disjointed, raw materials and in-process materials for short clinical manufacturing campaigns can be easily transferred via the B‑C primary corridor. For long or intense campaigns, the process can be rearranged within the facility as operating areas become available to provide more convenient adjacencies for inter-LOU transfer of in-process materials. If the 250-L process in Arm A is removed, the 500-L process can be moved to Arm A to provide more efficient room adjacencies. 

Figure 4: The logical operating units (LOUs) for the three process scales shown in Figure 3, loaded into the layout shown in Figure 1. Support LOUs are added as needed.

Figure 4: The logical operating units (LOUs) for the three process scales shown in Figure 3, loaded into the layout shown in Figure 1. Support LOUs are added as needed.

The 2000-L SUB Phase III/Launch process is shown in Arms B and C along with the 500-L SUB Phase II process. The Phase III/Launch process is initiated in Area B1 and proceeds through upstream operation in Areas C2 and B3, then to the downstream areas in C4 thru C6. In-process materials can be transferred directly through appropriate adjacencies or totes via the B‑C primary corridor. For longer, more intense campaigns, in-process material can be transferred via stainless-steel tubing from Areas B3 (SUB-N) to C4 (Harvest). Other UO/LOU combinations are possible depending on area availability, in‑process volumes, and equipment requirements. In Part II of this article, the same layout will be used to operate a larger-scale process necessary to supply commercial markets. 

Conclusion

The biopharmaceutical industry’s greatest contribution to patients is to rapidly and efficiently develop and quickly supply new, high-quality biopharmaceuticals. Regulatory agencies continue to do much to expedite the approval of important new therapies. The biopharmaceutical industry must complement these regulatory initiatives by creating a new class of manufacturing facilities capable of taking clinical and launch manufacturing off the critical path of bringing new products to patients. Manufacturing these complex products through the development lifecycle requires immediately available and qualified manufacturing facilities that can handle a wide range of processes. These facilities, using modern single-use systems in moveable equipment within appropriately controlled multi-functional cleanrooms, are capable of quickly adapting and accomplishing the required manufacturing challenges. While processes and products will come and go, a flexible multi-purpose facility that can be readily adapted to different processes will essentially remain the same. Only existing, operationally ready facilities flexible enough to manufacture whatever is required with minimal or no modifications can efficiently fulfill the industry’s future product development challenges. 

References

1. M.F. Witcher and H. Silver; “Multi-product Biopharmaceutical Manufacturing Facilities–Part II:  Large-Scale Production,” BioPharmInternational.com, Nov. 29, 2018. 

2. S.L. Nightinggale, J.M. Prasher, and S. Simonson, Emerging Infectious Diseases online, 13(7) 1046. DOI: 10.3201/eid1307.061188. 

3. FDA, Guidance for Industry:  Expedited Programs for Serious Conditions-Drugs and Biologics (Procedural)(CDER/CBER, May 2014). 

About the authors

Mark F. Witcher, PhD is a consultant, witchermf@aol.com; and Harry Silver is senior process/facility designer at Harry Silver Designs.