Multimodal manufacturing is about to revolutionize our industry. CMOs, under pressure to stay fast and flexible in the competitive biopharma marketplace, have already introduced product-neutral manufacturing in clinical-phase projects. It’s only a matter of time before this approach reshapes manufacturing at the clinical and commercial scale.
As we deepen our understanding of the science behind it, new equipment, technologies, and environmental designs will emerge to support this shift towards multimodal, and our industry’s comfort level will evolve accordingly. It’s a trajectory that we’ve seen with each historic leap forward, moving us gradually from skepticism to cautious acceptance and finally to industry-wide implementation.
This article will nudge our industry a little further along that trajectory. By holding up the familiar example of a multimodal facility with dedicated manufacturing spaces as our benchmark, we will explore the possibility of campaigning between modalities at the suite level. What are the unique considerations in play? How should operators define the risk profile of these product-neutral spaces in order to ensure their efficient, safe, and reliable operation? What challenges will face us as we move towards this manufacturing approach, and what opportunities await? Let’s find out.
This article will examine two types of manufacturing spaces:
1. Dedicated use
In this environment, manufacturing spaces work in tandem to support concurrent production of multiple products within a shared facility. Each manufacturing space is designed for a unique function and is dedicated to a given product platform for the life of the facility.
2. Campaigned use
The spaces inside this facility operate in the same way as those described above, with this critical difference: they’re specifically designed with the flexibility to campaign between product platforms. The idea is that facility operators will decontaminate each suite and swap out equipment following a product campaign, effectively neutralizing the manufacturing space and readying it for a new product platform. A facility designed with several product-agnostic suites creates unparalleled flexibility; think of it as a Gatling gun for a facility’s complex product pipeline.
Process segregation is necessary both within a given modality and between different modalities across the facility. This means:
- Process closure: Monoclonal antibody production, one of our industry’s most significant innovations, earned industry acceptance because manufacturers proved that they could functionally close their processes, ensuring product segregation in a ballroom operation. But process closure alone won’t be enough for manufacturers of concurrent modalities, whose approach will face intense scrutiny—for now, at least. To earn acceptance, a multimodal facility needs to demonstrate not only proper process closure, but also physical segregation between modalities, an appropriate HVAC strategy, and more.
- Facility segregation: As mentioned above, process closure may be an acceptable way to manufacture two concurrent mAb products in a single ballroom, but the same strategy would be madness in multimodal manufacturing. No facility would rely solely on process closure when manufacturing CHO cells alongside a concurrent bacterial fermentation process, or (even more alarming) human cells alongside a process that manufactures viral components for another product. To ensure the successful operation of a dedicated multimodal manufacturing facility, designers and operators should understand their production risk profiles. From there, an appropriate approach to product segregation—one that goes beyond process closure—will come into focus. It will involve physical segregation of manufacturing spaces and HVAC systems, HEPA filtration, airlocking and pressurization, and much more. Each of these tools and strategies, working together, will prepare these facilities of the future to withstand scrutiny and demonstrate the integrity and safety of their production approach.
- Pathway to QC: Materials moving to and from QC should be transported in closed bins. To prevent product mixups, materials should be easily identifiable through barcodes, color codes, or other robust labeling systems.
- Unidirectional flow: Product-differentiated components (waste, samples, dirty/used equipment, etc.) should move unidirectionally where possible. If bi-directional flow is necessary, components should be contained and the process should be supported by a robust risk assessment.
Although personnel typically move along the same predictable patterns without variation in a dedicated facility, these movements will face increased scrutiny in a facility where more than one modality is manufactured under the same roof. This means:
- The facility’s design (e.g. supply and return corridors) and its SOPs should work together to prevent the risk of cross-contamination. Each dedicated area should have captive or dedicated carts and totes.
- Additional precautions, such as a badge system that blocks personnel from entering more than one product-differentiated space without decontamination, should be in place to reinforce SOPs.
- Support components (e.g. cleaning equipment and solutions) are potential vehicles for cross-contamination; operators should closely scrutinize procedures for storing, transporting, using and decontaminating these components. Where possible, these materials should be dedicated to specific products, or disposed of after a single use.
- Physical segregation is even more critical in the product-agnostic manufacturing suite model. Facility designers should mitigate against additional combinations of potential worst-case scenarios. This requires a detailed understanding of multimodal manufacturing and a thorough risk assessment. System redundancies are especially important in this context, as they will ensure continuous product segregation. This might include exhaust fans, fan arrays for cleanroom HVAC, standby power, and/or a UPS and proper shutdown sequencing. These considerations should inform the suite’s design.
- Robust and validated SOPs, written specifically for the flexible manufacturing environment, are also key to establishing an environment that offers maximum flexibility while minimizing the risk of cross-contamination.
- Process closure, although just one component of the suite’s complex design, plays a crucial role in minimizing interactions within the campaigned space. Closure at the equipment level may not be possible for certain steps in the process, at which point other systems (such as surrounding isolators) should play a key role.
- Uni-directional, segregated material flow is even more important here. For example, these facilities will need a solution for transporting waste (a critical product-differentiated material) without the possibility of contact with other product-specific components. For facilities that utilize single-use technologies, the volume and storage of incoming consumables and resultant waste may be considerable.
- A detailed risk profile should drive the facility’s QC testing process. Operators should conduct tests with high-risk profiles in dedicated testing spaces. If a shared testing lab is part of the facility’s design, it should be backed by a documented risk assessment.
- A facility that operates product-agnostic suites needs a system that tightly controls the flow of personnel. A card access system, for example, will prevent operators from accidentally following an improper path, averting a potential disaster. Each suite—or even each smaller operational area within each suite—should have captive or dedicated carts and totes.
- In a multimodal facility, the flow of personnel and support materials may change as individual suites campaign between modalities. Whether a badge system or another mechanism for controlling access is in place, operators need to be able to reconfigure those access paths as required.
- Signage provides another layer of protection against the risk of cross-contamination in these complex environments. A light indicator system is a good example; different colors could correspond with different modalities, indicating which materials can be placed at the entrance of which manufacturing suite.
These facilities need a robust risk profile of their facility-wide utility systems
WFI: Operators should examine the risk profiles associated with multiple options, including:
- a single-loop system that carries WFI between spaces
- dedicated loops to serve each suite (or grouped by modalities)
- separate WFI tanks
- dedicated WFI generation
In conducting their evaluation, operators should consider the implications of use points, air brakes, and if systems are directly connected.
Gases: Different processes will require different gases, in addition to clean compressed air. As always, project leaders should base their segregation philosophy on a case-by-case assessment, looking at specific scenarios to determine an appropriate risk-based design. For example, does the suite use dedicated gas cylinders or bulk tanks with separate piping systems? If the answer is bulk tanks, where should facility planners place downstream filters in order to provide adequate separation between use points?
The same approach applies when assessing clean compressed air systems, where multiple small compressors are likely to be cost-prohibitive.
Pre-engineered systems to support product changeover and a high level of segregation
- Facilities with product-agnostic manufacturing suites need systems that are pre-engineered to support frequent product changeover while maintaining a high level of segregation. Operators need flexible infrastructure (such as additional gas drops) in order to quickly add utilities as process equipment changes from platform to platform.
- Facing this challenge, operators may fall back on familiar, conservative strategies, perceiving them to be the safest approach. However, a thorough risk assessment, combined with the right design expertise, could yield a leaner and more cost-effective design for certain low-risk utility systems. For example, a leaner approach might mean having fewer WFI drops and dispensing the majority of WFI in a handful of solution prep suites dedicated to compatible modalities. Meanwhile, forward-thinking planners can explore the right balance and future expansion strategy for systems with different risk profiles.
Equipment should be product-dedicated or single-use
- Operators should assess every process component and material to formulate valid and repeatable cleaning SOPs. Cleaning equipment should be product-dedicated or single-use.
- As noted above, cleaning personnel and their equipment and materials should move in and out of performance along segregated facility pathways. Operators should store cleaning components according to validated SOPs to ensure that they’re not vehicles for cross-contamination between product-differentiated areas. In some cases, storing cleaning materials outside of the production core is key to ensuring proper wipe-down.
- The appropriate approach will hinge on the modality in question and whether it is viral or non-viral. Some modalities will require a more invasive approach (e.g. full-room fumigation) while a rotation of benign chemical wipe-downs may suffice for others.
All cleaning and decontamination procedures should be robust, qualified, and specific
- These facilities carry the additional burden of returning the manufacturing space to “product neutral” between campaigns. Cleaning and decontamination procedures should be robust and validated according to that required outcome. As noted throughout this article, processes should be assessed according to their risk profile, and all cleaning procedures and confirmation monitoring should reflect that assessment.
- A simplified decontamination philosophy that tends towards a more thorough and invasive approach is often the best way forward. Between different modalities, a full-room fumigation should be the default. Between different batches of the same product, either a wipedown or fumigation may be appropriate, depending on the established risk profile attached to that modality.
- All cleaning and decontamination procedures should be robust, qualified, and specific to ensure that the space is fully restored to modality-agnostic status.
Install and qualify equipment once
Facilities with dedicated manufacturing areas typically install and qualify their equipment once, and rarely disconnect it to start again. With the possible exception of tech transfers, a total equipment replacement or a tenant changeover is unlikely.
Equipment may be fully disassembled and reassembled on a semi-regular basis
- In production suites that campaign between modalities, the equipment may be fully disassembled and reassembled on a semi-regular basis. This introduces an added layer of complexity in terms of how the space is designed, equipped and operated. Operators should have a strategy in place for returning equipment to a validated and consistent state of performance. They need well-documented procedures for dismantling, storing, reassembling, and calibrating equipment (a challenge that CMOs are accustomed to solving).
- Operators should assess the ergonomics of moving equipment in and out of the suite. This assessment should consider the mobility of the equipment, door sizes, travel pathways, ramps, and turning corner radius. Wherever possible, these barriers should be minimized or eliminated.
- It’s very important to make certain that everything is connected properly and functioning predictably according to robust and streamlined performance re-qualification procedures.
SlateXpace currently includes four distinct product-neutral manufacturing building blocks to suit any product platform. These building blocks are engineered to work together in unique and scalable combinations and are suitable for both clinical-phase projects and—when the need arises—commercial-scale multimodal production. A robust risk assessment drives every unique SlateXpace facility design, ensuring continuous product segregation and operational excellence.
Our industry will come to embrace this revolutionary change in time, which will unlock a new level of quality and versatility in biopharma manufacturing. And when that time comes, SlateXpace will be there.