Harry Silver is senior process/facility designer at Harry Silver Designs.

Harry Silver

The biopharmaceutical industry must begin designing and building a new generation of highly capable, multi-purpose manufacturing facilities to meet the commercial manufacturing challenges of supplying the next generation of small- and large-volume products, particularly those with short commercial lifespans. Biopharmaceutical manufacturing is challenged by the uncertainty risk of anticipating and establishing the commercial capacity to supply products, including those rapidly approved using an Emergency Use Authorization (EUA) to meet pandemic and bioterrorist threats (1). As described in Part I of this article (2), the manufacturing uncertainty and risk is significantly amplified by therapies following FDA’s guidance on 

Expedited Programs for Serious Conditions

 (3). To support the adequate supply of breakthrough designated therapies, the biopharmaceutical industry can no longer afford to design and build manufacturing capacity based on each product’s process format and scale or in response to changing manufacturing capacity requirements.  

	Dealing with manufacturing’s frequent presence on the critical path has led to many initiatives attempting to speed up the creation of manufacturing capacity. 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, the availability of commercial manufacturing capacity will remain an expensive, time-consuming obstacle to launching and then supplying new products. The industry must have existing, pre-positioned, highly flexible manufacturing resources capable of manufacturing a wide variety of processes at scales necessary to supply products when they are approved. 

	Current trends in designing commercial biopharmaceutical manufacturing facilities are for large operating cleanrooms designed around specific processes where unit operations are commingled for operational convenience.  While optimum for the processes for which they are designed, they are relatively inflexible and inefficient for meeting the challenges described earlier in this article for other process configurations. Once constructed, these facilities do not provide the adaptability required for efficiently changing process scales, unit operation sequences, or segregation strategies without modifications to the facility’s layout that may significantly impact ongoing manufacturing of other products. 

	Rather than commingling many process steps, an approach that distributes the different process unit operations (UOs) into logically operating units (LOUs), as described in Part I, can provide the process and capacity flexibility necessary to quickly adapt an existing layout to the inevitable changes in product demand. Products and processes will come and go, but a multi-purpose facility remains a manufacturing asset capable of manufacturing nearly any future product at the required scale using any process developed in moveable, single-use system (SUS) equipment. 

	Using the example 11-UO, four-LOU monoclonal antibody (mAb) process defined in Part I, this article briefly describes the layout, flows, and operational control systems for commercial-scale, multi-purpose facilities. The approach uses large numbers of segregated, multi-functional cleanrooms that can be rapidly adapted, configured, integrated, operated, and when necessary, redeployed to quickly satisfy a wide variety of complex manufacturing requirements. The multi-functional layout trades some of operating convenience provided by a facility designed around a specific process for the much more important, long-term advantages of a facility that can be configured and reconfigured to a wide variety of different processes and scales necessary for increasing or decreasing operating capacity. 

operating core described in Part I (2) composed of 18 cleanroom operating areas arranged in three arms (A, B, C) with each arm containing six cleanrooms. Depending on the number of potential commercial products and their estimated manufacturing requirements, the facility’s initial capabilities can be increased substantially by increasing the number of arms and possibly increasing the number of cleanrooms per arm in the initial facility design. Additional arms can be added to 

at the top of the layout, either in the original buildout or as a follow-on expansion as Arms D and E, and if needed as Arms F and G, etc. The additional arms are supplied, operated, and controlled using the same systems and facility infrastructure as the initial design in 

	For introducing a new process, equipment is staged in the equipment preparation area located in the lower right of the layout shown in 

and moved through the primary corridors to the designated operating area. Equipment no longer needed is removed to the layout’s right via

the out corridors and then through a de-staging area. Raw materials and components are supplied to the operating areas by totes and carts via

the primary corridor. Transfer of in-process materials in small volumes is achieved using totes via

the primary corridor. For large-scale processes, a variety of options for in-process material movement are available. If the appropriate LOU adjacencies are provided, material can be transferred through walls, particularly in operating room pairs in the center of the arms. For non-adjacent LOUs and large volumes, such as for harvesting 2000-L single-use bioreactors (SUBs) to a non-adjacent area, stainless-steel tubing (with a portable clean-in-place [CIP] system) on the utility floor above the operating areas can be used to transfer the conditioned media from the SUBs to the harvest UOs. Under normal operation, personnel movement is controlled using bidirectional flow 

the primary corridor. Operating problems can be quickly and efficiently remediated using procedural controlled access to the out 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.), and access to operating areas for easily adding inter-room, stainless-steel tubing for transferring large volumes of media, buffers, and in-process materials. 

	The flexibility, high activity level, and complex material and personnel movement of the multi-purpose facility, especially for intensified commercial manufacturing, requires a comprehensive control strategy that assures appropriate control of all aspects of the facility, material, and process unit operations. While the layout provides significant opportunities for physical separation, appropriate procedures supported by a manufacturing execution system (MES) for controlling all people, raw material, waste, product, and in-process material flows in time and space must be fully implemented. Such procedural controls and automated support systems are well within currently available technologies and can be readily developed and implemented. 

and the process LOU strategy described in Part I (2), the capabilities of the multi-purpose layout for large-scale commercial manufacturing can be demonstrated. 

	Phase III: Launch to commercial manufacturing

is identical to the facility described in Part I for running small- and medium-scale processes for supplying product for preclinical (250-L SUB) through product launch (2000-L SUB). To demonstrate the wide variety of options for larger-scale operation, the process LOU distributions in 

	The 2000-L SUB launch process might be used for supplying late-stage Phase III clinical trials, inventory building, and product launch at the time of approval. If product demand is high, the process can be scaled out to multiple 2000-L SUBs or twinned 2000-L SUBs. If the process is properly designed and intensified using a high density and a large-volume seed train, the 2000-L SUBs can be paired and multiple SUB pairs sequentially harvested to a suitably intensified single downstream process. The flexibility of the multi-purpose facility also allows for significant media and buffer resources (support LOUs) to be added for supplying media for many large-scale seed and production SUBs along with intensified downstream processes requiring very large volumes of buffers. 

shows one possible high-capacity, commercial-scale configuration. To show an extreme scenario, the LOU distribution for a high-capacity commercial process is shown as the final process in 

. This process operates three pairs of 2000-L SUBs (located in areas B3, B4, and C3) for an effective bioreactor volume of 12000 L. The pairs are operated on a two-day staggered schedule, such that one pair of SUBs is harvested every other day to a single downstream train located in Areas C4â6. The downstream train, if intensified using large multi-cycle chromatography systems, can support three, 2 x 2000-L harvests per week. As shown in 

, three support LOUs (one media in C2 and two buffer preparation and hold located in B5 and B6) have been added to support the commercial process. Media, buffers, and large volume in-process materials are transferred by CIP-able stainless-steel tubing runs located on the utility floor above the core in addition to the movement of the other in-process materials by totes and inter-area connections via single use tubing between UOs and LOUs in adjacent rooms. Even while running a commercial-scale process, Areas A3 thru A6 are available for operating a small-scale process or a second purification train, if needed.

	If operated at capacity, the facility shown in 

would have a very high utilization rate and an annual capacity of approximately 1.5 Mtons/year (6 grams/L, 42+weeks/year, 50% purification yield). Yet, if the campaign is shortened or the process removed, the same facility without modification can be returned to running small- or medium-sized processes for other products. 

	If Arms B and C are replicated either in the initial design or by an expansion at the top of 

 as Arms D and E, the plant’s capacity can be further increased by an additional 1.5 Mtons/year. Very large-scale production of one or more products can be achieved by building multi-purpose facilities with numerous arms configured like Arms B and C. If sustained long term demand for the product is established, the large-scale process in Arms B and C can be easily transferred to a similarly designed multi-purpose facility for long-term operation and the launch facility returned to developing new processes and products. 

	Regulatory agencies continue to do much to expedite the approval of important new therapies. The biopharmaceutical industry must match these regulatory initiatives by creating a new class of manufacturing facilities capable of taking manufacturing off the critical path of launching and supplying products. Manufacturing these complex products over their entire lifecycle requires immediate access to available and qualified manufacturing facilities that can be adapted to produce a wide variety of products when they are needed using a wide range of processes. These facilities, using modern single-use systems in movable equipment within appropriately controlled multi-functional cleanrooms, are capable of quickly adapting to overcome the industry’s manufacturing challenges. Processes and products will come and go, but the facility that can readily adapt to the different processes remains essentially the same. Only existing, operationally ready facilities flexible enough to manufacture whatever is required with minimal or no modifications can rapidly and efficiently fulfill the industry’s future manufacturing challenges. 

	1. S.L. Nightinggale, J.M. Prasher, and S. Simonson, 

online, 13(7) 1046. DOI: 10.3201/eid1307.061188

Guidance for Industry:  Expedited Programs for Serious Conditions-Drugs and Biologics (Procedural) 


	Vol. 42, No. 11
	November 2018
	Pages: 42–45

	When referring to this article, please cite it as M. Witcher and H. Silver, "Multi-Purpose Biopharmaceutical Manufacturing Facilities Part II:  Large-Scale Production," 

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

Articles

A matrix of multi-functional cleanrooms can be adapted for launching products.

Multi-Purpose Biopharmaceutical Manufacturing Facilities Part II:  Large-Scale Production

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:

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. 

: 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.

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). 

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. 

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 ft

. 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 

uses only enough cleanrooms to operate the process. The remaining areas are available for other products or process activities. 

	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 

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. 

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. 

	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 

	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). 

	One possible process arrangement of the three processes in 

. 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 Bâ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. 

	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 Bâ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, inâ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. 

	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. 

	1. M.F. Witcher and H. Silver; “Multi-product Biopharmaceutical Manufacturing Facilities–Part II:  Large-Scale Production,” PharmTech.com, Sept. 2, 2018. 

	2. S.L. Nightinggale, J.M. Prasher, and S. Simonson, 

Guidance for Industry:  Expedited Programs for Serious Conditions-Drugs and Biologics (Procedural)

	When referring to this article, please cite it as M. Witcher and H. Silver, "Multi-Purpose Biopharmaceutical Manufacturing Facilities Part 1:  Product Pipeline Manufacturing," 

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

A multi-purpose biopharmaceutical manufacturing facility using a matrix of multi-functional cleanrooms can be adapted to efficiently meet the capacity challenges of both supplying clinical trials and launching products.

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

	The biopharmaceutical industry must begin designing and building a new generation of highly capable, multi-purpose manufacturing facilities to meet the commercial manufacturing challenges of supplying the next generation of small- and large-volume products, particularly those with short commercial lifespans. Biopharmaceutical manufacturing is challenged by the uncertainty risk of anticipating and establishing the commercial capacity to supply products, including those rapidly approved using an Emergency Use Authorization (EUA) to meet pandemic and bioterrorist threats (1). As described in Part I of this article (2), the manufacturing uncertainty and risk is significantly amplified by therapies following FDA’s guidance on 

	Rather than commingling many process steps, an approach that distributes the different process unit operations (UOs) into logically operating units (LOUs), as described in Part I, can provide the process and capacity flexibility necessary to quickly adapt an existing layout to the inevitable changes in product demand. Products and processes will come and go, but a multiâpurpose facility remains a manufacturing asset capable of manufacturing nearly any future product at the required scale using any process developed in moveable, single-use system (SUS) equipment. 

	Using the example 11-UO, four-LOU monoclonal antibody (mAb) process defined in Part I, this article briefly describes the layout, flows, and operational control systems for commercial-scale, multiâpurpose facilities. The approach uses large numbers of segregated, multiâfunctional cleanrooms that can be rapidly adapted, configured, integrated, operated, and when necessary, redeployed to quickly satisfy a wide variety of complex manufacturing requirements. The multi-functional layout trades some of operating convenience provided by a facility designed around a specific process for the much more important, long-term advantages of a facility that can be configured and reconfigured to a wide variety of different processes and scales necessary for increasing or decreasing operating capacity. 

the primary corridor. For large-scale processes, a variety of options for in-process material movement are available. If the appropriate LOU adjacencies are provided, material can be transferred through walls, particularly in operating room pairs in the center of the arms. For non-adjacent LOUs and large volumes, such as for harvesting 2000-L single-use bioreactors (SUBs) to a non-adjacent area, stainless-steel tubing (with a portable clean-in-place system) on the utility floor above the operating areas can be used to transfer the conditioned media from the SUBs to the harvest UOs. Under normal operation, personnel movement is controlled using bidirectional flow 

, three support LOUs (one media in C2 and two buffer preparation and hold located in B5 and B6) have been added to support the commercial process. Media, buffers, and large volume in-process materials are transferred by CIP-able stainless-steel tubing runs located on the utility floor above the core in addition to the movement of the other in-process materials by totes and inter-area connections via single use tubing between UOs and LOUs in adjacent rooms. Even while running a commercial scale process, Areas A3 thru A6 are available for operating a smallâscale process or a second purification train, if needed.

	If Arms B & C are replicated either in the initial design or by an expansion at the top of Figure 3 as Arms D & E, the plant’s capacity can be further increased by an additional 1.5 Mtons/year. Very large-scale production of one or more products can be achieved by building multiâpurpose facilities with numerous arms configured like Arms B and C. If sustained long term demand for the product is established, the large-scale process in Arms B and C can be easily transferred to a similarly designed multi-purpose facility for long-term operation and the launch facility returned to developing new processes and products. 

Multi-product Biopharmaceutical Manufacturing Facilities-Part I:  Product Pipeline Manufacturing