Cell and gene therapies (CGTs) are progressing rapidly through development pipelines and advancing through clinical trial phases. Manufacturing capacity will need to be sufficient when such products are approved for commercialization. Thus, biomanufacturers are seeking ways to leverage multimodal facilities. I spoke with Stephen Judd, who is principal process engineer for biologics and cell and gene therapy at DPS Group, an engineering and construction management consultancy. We talked about design considerations for multimodal facilities, how such facilities contribute to overall sustainability efforts, and the advantages brought on by different construction approaches.
What is a multimodal facility? A modality refers to a specific type of manufacturing process or approach. Beyond clinical-sample processing, such approaches in CGT processing include viral and nonviral vector systems, which can be further subdivided into adenoassociated virus (AAV) vectors, lentivirus (LV) vectors, and adenovirus (AdV) vectors for viral vector (VV) systems and exosomes or lipid nanoparticles (LNPs) for nonviral vector systems. Manufacturing processes for AAVs can be based on mammalian or insect cells. Specific modalities support VV processes based on transient transfection. Those include plasmid DNA (pDNA) production through Escherichia coli fermentation. Other modalities support autologous cell therapies such as chimeric antigen receptor T cell (CAR-T) products, for which the transduction step predominantly uses an LV.
Thus, a multimodal facility is one that can support different manufacturing processes, often for different therapies. Ideally, such a facility can operate modes in parallel to provide the maximum level of flexibility.
Commercial-scale CGT manufacturing still is a relatively young field with a limited number of products approved for commercial use. However, a large number of CGTs are in different clinical-trial phases, and the landscape of the field is likely to expand and evolve rapidly over the next few years. Different modalities have different manufacturing, biosafety, and process safety considerations. A key difficulty comes in trying to determine which products will complete the clinical trial phase within a reasonable time frame.
Biomanufacturers need to ensure a robust supply chain across all aspects of their operations required to support a particular CGT product. That includes, for example, ensuring a supply of pDNA materials for manufacturing processes based on transient transfection and LV products for CAR-T manufacturing. Biomanufacturers that rely on other companies to supply those materials could face additional costs and potential risks to their operations.
Thus, a multimodal facility supports either switching easily between distinct manufacturing modalities for different end products or using distinct modalities within a single product‚Äôs complex manufacturing chain. Both options can be accomplished to increasing degrees of ease, economy, efficiency, and regulatory compliance. Given enough time and money, a facility could support either of those possibilities. Premier architectural and engineering companies are working on continually improving multimodal facility designs.
What are main design considerations for a multimodal facility, and how do they compare with those of a single-modality site? Understanding the potential obstacles and risks before you start is key to all effective facility designs. Contract development and manufacturing organizations (CDMOs) face such concerns all the time, but owner manufacturing companies might have less experience. Development companies wanting to commercialize their products have limited experience with facility design in general. Experienced design experts understand the facility, process, personnel, and material-flow requirements as well as the potential problems associated with multiproduct and multimodal manufacturing operations. They work with biomanufacturers from the feasibility stage to ensure that such intricacies are understood. In that way, the optimal approach from both operational and regulatory compliance perspectives is developed to meet the specific needs of a project.
Segregated Suites: Different manufacturing processes such as microbial-cell fermentation and mammalian-cell culture and different manufacturing stages such as drug substance (DS) and drug product (DP) processing require specific segregated areas within an overall facility, with independent personnel gowning access and egress. One principal upfront consideration applies when multimodality operations are to be carried out within the same manufacturing area. In such cases, companies need to define a manufacturing strategy according to whether different modalities will be manufactured in parallel or on a campaign basis. For VV manufacturing, that decision will drive the segregation requirements for the manufacturing operations. Manufacturing different VV modalities in parallel provides the greatest level of flexibility, but regulatory requirements (1) currently stipulate that full segregation of manufacturing systems is required from the viral-particle production step (the N-stage bioreactor step) forward.
The number of up- and downstream process (USP, DSP) trains required then comes down to a facility‚Äôs throughput requirements. Typically, the production bioreactor step is a bottleneck, so high-throughput facilities require multiple USP trains feeding a single (or fewer number of) DSP train(s). For a single-product, single-modality facility, the adjacency between USP and DSP areas is relatively straightforward because multiple USP trains can be operated in the same ballroom suite. The manufacturing suite adjacencies can become more problematic for a multimodal facility that has multiple USP suites feeding into the same DSP suite. The fact that single-use technology (SUT) is used predominantly for such facilities makes this case particularly prominent. Transfer between directly adjacent suites (rather than suites separated by a logistics corridor) is the strong preference of regulatory agencies.
Biosafety level (BSL) requirements also can influence facility design. Modalities require specific BSLs. Thus, a multimodal facility requires consideration of the most stringent requirements to ensure manufacturing flexibility. BSL-2 is the most common requirement for processing blood-product materials, genetically modified cell lines, and virally positive process materials. Several companies classify their operations as ‚ÄúBSL-2+,‚ÄĚ which is a risk-based approach to establishing which BSL-3 enhancements should be implemented over and above baseline BSL-2 requirements. Factors affecting such decisions include manufacturing schedule and time goals, build-expense constraints, manufacturing scale, and type of company (CDMO or owner manufacturer). Whether multiple independent manufacturing areas are located within the same facility also can be a factor.
Flexibility: If multimodal manufacturing operations will be undertaken within the same manufacturing area, then flexibility of the manufacturing suites is a key consideration. Each modality includes a given number of process steps, so a streamlined operation requires a design for straightforward changeover of equipment. Another factor affecting the design of downstream areas relates to differences in VV requirements. For example, because of the size of different viral particles, AAV is the only VV that can undergo a virus-filtration step for the removal of adventitious viruses. Yet the risk of process contamination by adventitious viruses is similar across different modalities. A single-modality AAV manufacturing facility might consider the conservative approach of implementing physical segregation between pre- and postvirus-filtration steps. A practical approach for a multimodal facility might be to establish a single ballroom DSP suite, where comprehensive mitigation of such risks will rely on manufacturing procedures, environments, and equipment design.
What are the main design considerations and operational strategies that affect the flexibility of a multimodal facility? When planning facility layouts to support multiple and different process-train arrangements, the main considerations relate to determining a ‚Äúrationalized equipment list,‚ÄĚ ease of equipment changeover, and the utility panel layout and design. Some equipment can be used for all manufacturing processes, but other equipment (based on type and capacity) is used for dedicated operations.
A rationalized equipment list that identifies the equipment to be purchased should include sufficient units to support all required manufacturing operations. Equipment that is not required for a specific manufacturing process can be moved out of a manufacturing suite and staged in a clean-equipment storage area. The move in‚Äďout process, including deinstallation procedures and transfer routes, needs to be as straightforward as possible to ensure a streamlined process and to minimize downtime.
Utility Panel Design: Implementation of SUTs for manufacturing systems facilitates a plug-and-play approach to equipment installation and optimizes equipment handling requirements. A utility panel design should be standardized to enable different equipment with individual requirements (e.g., temperature-control unit service, number and types of instruments) to be connected to the same panel at different times. An automation design should include utility panels, with the equipment identified to the distributed control system (DCS). That enables the control system to know what services should be provided and which instruments should be monitored for the connected equipment.
Buffer management strategy also can have significant bearing on the ease of a facility‚Äôs operations. Typically, equipment for buffer preparation and hold uses SUTs. Buffer bags are held on mobile totes or carts so that they can be moved to their operational locations. The number of buffer totes that are moved into manufacturing suites should be minimized to control the level of time-consuming and labor-intensive wipe-down and decontamination activities that are required. Although some smaller-volume solutions might need to be brought into manufacturing areas, large totes can be kept out of suites by providing staging space off the logistics corridors adjacent to the applicable suites where through-the-wall transfers can be made. Optimization of a buffer management strategy will help streamline the manufacturing operations in general and mitigate against risks to unforeseen downtime.
SUT Waste: BSL-2 manufacturing operations that use SUTs require waste consumables to be decontaminated before disposal. A common approach is to subject waste consumables to a thermal-decontamination cycle in a waste autoclave. General BSL-2 requirements do not stipulate that a waste autoclave needs to be installed locally to a manufacturing area, but operating a multimodal facility will affect the location for a waste autoclave system. If a manufacturing facility comprises several segregated manufacturing areas, then locating an autoclave at the boundary of BSL-2 manufacturing areas is desirable for mitigating risk of crosscontamination in common spaces.
What are the main considerations relating to environmental sustainability with respect to the design and operation of a multimodal facility? Sustainability is an important part of the design and operation of all new manufacturing facilities. Many aspects of multimodal design reduce the environmental footprint of a facility ‚ÄĒ although that might not be a primary goal of such a facility. Opportunities to reduce the size, number, and/or classification of suites and facilities required to be constructed can reduce the overall manufacturing environmental burden.
Because CGT manufacturing operations predominantly use SUTs, the overall SUT strategy is a key focus area within the sustainability efforts of CGT manufacturers. SUTs facilitate fully closed processing, thus creating certain sustainability opportunities in a facility design. For example, different batches can be manufactured in parallel and in the same seed-train cell-expansion suite in a USP area. That also enables biomanufacturers to reduce a cleanroom grade from grade C to grade D in cell harvest and (potentially) DSP areas. Reducing the cleanroom grade also lowers energy consumption associated with air-handling units (AHUs).
Closed processing also minimizes the risk of spillage and contamination in a manufacturing suite, which streamlines changeover activities. By using SUTs, biomanufacturers remove the need for rigorous cleaning and sterilization associated with product changeover protocols. Depending on the environmental footprint of local power and water sources, that can be a major improvement in the environmental burden of a manufacturing process.Sustainability considerations associated with SUTs strictly involve such science-based analytical approaches as lifecycle analysis (LCA), but biomanufacturers also should consider the immediate burdens associated with alternative materials. For example, facility mangers might compare sustainability burdens from the production and disposal of plastic consumables with those from local power, water, and contaminated-water disposal associated with clean-in-place (CIP) and sterilize-in-place (SIP) requirements of stainless-steel equipment. Buffer-preparation vessels will be turned over frequently and with less exhaustive turnover processing. Potentially, they require only routine rinsing with water for injection (WFI), with a periodic full CIP.
Other factors relate to fuel consumption associated with the delivery and disposal of consumables to and from a facility site. Thus, particularly for high-throughput facilities, use of stainless-steel buffer preparation tanks should be considered to minimize plastic waste. Keeping most media and buffer totes out of BSL-2 and virally positive (V+) manufacturing areas and using through-the-wall transfers also enable such consumables to be treated as nonbiohazardous waste, thus reducing their environmental burden in disposal.
What benefits come with the different construction approaches for building a multimodal facility? One key challenge associated with CGT commercialization is the speed at which such products can be brought to market after they complete all clinical trial phases. Companies might wait until a product is in late-stage clinical trials before planning construction of a commercial manufacturing facility. That would minimize the risk of the facility becoming redundant if that product were to fail clinical trials.
One benefit of constructing a multimodal facility is that it will be capable of manufacturing a wide range of products. If a multimodal facility is constructed by an owner manufacturer as a product launch facility or by a CDMO, then that facility can be ready and waiting as new products are commercialized.
Each approach to constructing a multimodal facility has its own features. The two principal approaches are podular cleanrooms developed offsite and stick-built construction.
Podular cleanrooms have plant services such as the heating, ventilation, and air conditioning (HVAC) systems integrated into the modules and can be tested and qualified largely offsite, which greatly streamlines and reduces site activities. The site‚Äôs requirements also can be minimized with the podular approach. Podular cleanrooms can be installed in a standard warehouse environment with all environmental controls within the units taken care of as part of the modular design. Using that approach, CGT manufacturers can increase speed to market when initially constructing a facility.
However, podular units have certain limitations. The units are expensive, and a podular structure might not have the capability for future expansion that a stick-built construction design would. Podular units also might have layout limitations because they are designed to ensure that individual sections are capable of being transported.
Traditional stick-built constructions have longer project schedules than do podular constructs, but stick-built designs do provide certain advantages. They allow a greater level of flexibility in the sizing and layout of individual manufacturing suites because they offer greater flexibility over where columns can be located. Traditional construction also supports flexibility in the general layout of a facility, which is important when managing the suite adjacencies and aspects of multimodal design described above. The stick-built construction approach also provides greater ease of future expansion or facility modification to support a new production mode. That can be an important factor for CGT products and manufacturing methods.
Thank you to William G. Whitford for his significant contribution to this article.
1 Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products, Section 4.2. EudraLex: The Rules Governing Medicinal Products in the European Union, Volume 4. European Commission: Brussels, Belgium 2011; https://ec.europa.eu/health/medicinal-products/eudralex/eudralex-volume-4_en.