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A matrix of multi-functional cleanrooms can be adapted for launching products.
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.
Figure 1 shows a 23,500-ft2 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 Figure 1 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 Figure 1.
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.
For introducing a new process, equipment is staged in the equipment preparation area located in the lower right of the layout shown in Figure 1 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 via 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.
Using the facility shown in Figure 1 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.
The layout shown in Figure 1 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 Figure 2 will be used.
Figure 2. A single, 2000-L single-use bioreactor (SUB) launch design for a monoclonal antibody process is expanded into a 6x2000-L SUB configuration to support large-scale production.
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.
Figure 3 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 Figure 2. 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 C4â6. The downstream train, if intensified using large multi-cycle chromatography systems, can support three, 2 x 2000-L harvests per week. As shown in Figure 3, 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.
Figure 3. One possible logically operating unit (LOU) arrangement for the large-scale 6x2000-L monoclonal antibody process. Support LOUs are added as needed. SUB is single-use bioreactor.
If operated at capacity, the facility shown in Figure 3 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 Figure 3 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, Emerging Infectious Diseases online, 13(7) 1046. DOI: 10.3201/eid1307.061188.
2. M. F. Witcher and H. Silver, "Multi-Purpose Biopharmaceutical Manufacturing Facilities Part I: Product Pipeline Manufacturing," BioPharmInternational.com, Nov. 29, 2018.
3. FDA, Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics (Procedural) (CDER/CBER, May 2014).
Mark F. Witcher, PhD is a consultant, email@example.com; and Harry Silver is senior process/facility designer at Harry Silver Designs.